THE LIBRARY OF THE UNIVERSITY OF CALIFORNIA LOS ANGELES GIFT OF SAN FRANCISCO COUNTY MEDICAL SOCIETY >>^^ WORKS OF DR. MARTIN H. FISCHER PUBLISHED BY JOHN WILEY & SONS The Physiology of Alimentation. Large i2mo, viii + 348 pages, 30 figures, cloth, $2.00 net. (Edema. A Study of the Physiology and the Pathology of Water Absorption by the Living Organism. 8vo, 209 pages, 51 figures, including full-page plates, cloth, $2.00 net. Nephritis. An Experimental and Critical Study of its Nature, Cause, and the Principles q,f its Relief. Large i2mo, ix + 203 pages, 31 figiires, including a colored plate, cloth, $2.50 net. TRANSLATION Physical Chemistry in the Service of Medicine. Seven addresses by Dr. Wolfgang Pauli, Professor in the University of Vienna. Authorized translation by Dr. Martin H. Fischer. i2mo, k + 156 pages, cloth, $1.25 net. NEPHRITIS AN EXPERIMENTAL AND CRITICAL STUDY OF ITS NATURE, CAUSE AND THE PRINCIPLES OF ITS RELIEF BY DR. MARTIN H. FISCHER Bichberg Professor of Physiology in the University of Cincinnati ^> THE 191 1 CARTWRIGHT PRIZE ESSAY OF THE ASSOCIATION OF THE ALUMNI OF THE COLLEGE OF PHYSICIANS AND SURGEONS, MEDICAL DEPART- MENT OF COLUMBIA UNIVERSITY, NEW YORK FIRST EDITION- FIRST THOUSAND NEW YORK JOHN WILEY & SONS London: CHAPMAN & HALL, Limited 1912 Copyright, 191 i, BY MARTIN H. FISCHER Stanbopc Press H.CILSON COMPANY BOSTON. U.S.A. biomedical Library TO C. R. F. OUSiC'\-)' secretor>' system. We need not especially empha- size the fact that taken strictly this is not correct; there really exist several phases within the blood itself. Under the urinary membrane we will include all the structures that lie between the blood on the one side and the urine on the other. The urinary membrane as we will use the term is made up of all the different cells that are found between the blood on the one side and the urine on the other, together with their various intercellular sub- stances. The whole constitutes a fairly firm structure to which we may again apply the term " jellylike." In the terms of physical chemistr}^ this membrane consists of a mixture of various emulsion colloids in the solid or gel state. We find present here also, as in all the body tis- sues, various electrolytes and nonelectrolytes. This mem- brane has not the same composition ever}'where. Not only does histological evidence show a striking difference in the character of the cells that make up the different parts of the urinajy^ membrane (different cell structure in the glomeruH, convoluted and straight tubules, etc.) but so does physiological evidence (absorption of dyes). So this membrane also is itself composed of several phases, but un- less specially noted we will simply refer to the whole as the second phase of our secretor}^ system. The third phase of our secretory system, is formed by the urine. As is well known this is, under normal conditions, an aqueous solution of various cr}'stalloids, — electrolytes, and nonelectrolytes. Colloidal material is present in only ver>' small amount and consists of that trace of albumin al- ready referred to that is found in normal urine, together with some mucin, etc., derived from the urinary^ tract. When the urine becomes albuminous, as in nephritis, this colloid content rises. As we have said, this is because in albuminuria tJte albumin of the urinary membrane goes into NEPHRITIS 7 " solution " in the urine; the solid colloidal urinary mem- brane (a gel) becomes a sol. To indicate what is meant by this and to show what are the conditions that make certain soHd colloids of the type that we know compose the urinary membrane go into " solution " we will detail some obser- vations on the subject. 3. Introductory Remarks on Colloids and the Colloidal State. As is familiar to everyone since the classical studies of Thomas Graham on diffusion, different chemical substances differ greatly in the rate with which they diffuse through solvents of various kinds. While such crystalHne bodies as the sugars, the salts, and urea diffuse rapidly, the amor- phous bodies represented by glue, starches, and various albumins do so only very slowly. While no absolutely sharp dividing line may be drawn between these two groups, the behavior of the t}^ical members of the former is so decidedly different from the behavior of the second that there is ample justice in calling the first crystalloids and the second colloids. Of the various substances that may be found classed under the heading colloids it is again possible to distinguish between two great groups. One of these consists of those colloids that are viscous, gelatinizing bodies which cannot be readily precipitated by salts, while another is made up of the nonviscous, nongelatinizing ones that are easily precipitated by salts {A. A. Noyes^). Typical examples of the former class are found in gelatine and various albumins, of the latter in the colloidal solutions of various metals and certain dyes. The essential difference between the two resides in the relation which the colloid bears to the solvent in which it finds itself. When these two classes of colloids * A. A. iVo;yej; Journal of the American Chemical Society, 27, 85 (ipc^). 8 NEPHRITIS arc obtained in a solid form it is found that the former con- tains much of the solvent while the latter holds little or none. For this reason the former are also known as lyophilic or, if water is the solvent, hydrophilic, the latter as lyophobic or hydrophobic colloids (/. Perrin^ and H. Freundlich-). But the terms most employed take cognizance of the fact that the separation of the solvent from the colloid is diffi- cult to obtain in the one case because the colloid present in it is itself a Hquid while this separation is easier when the colloid is a solid. For this reason the lyophilic colloids are identical with the emulsion colloids (or emulsoids), the lyophobic with the suspension colloids (or suspensoids) of Wolfgang Ostwald} Of these two groups of colloids our immediate problem is most concerned with the emulsion colloids, for it is of a mixture of these that the urinary membrane is composed. The emulsion colloids are capable of existing in two fairly well defined states : in a solid or gel state and in a liquid or sol state. A familiar example of this fact is found in ordi- nary gelatine. Under certain conditions this appears in the form of a stiff jelly, under others as a " solution." In the same way fibrin represents the gel form of the sol fibrinogen, paracasein (casein) the gel of casein (caseinogen) , ordinary soft rubber the gel of a " dissolved " rubber, etc. It is generally recognized that in the case of the emulsion colloids a rather close relationship exists between the gel state in which the colloid is '' swelled " and the sol state of this same colloid in which it is "dissolved," and yet the tran- sition from the one state into the other is not a perfectly smooth affair. We need only call attention to the fact that * /. Pcrrin: Journal de Chimie Physique, 3, 84 (1905). *//. Freundlich: Kolloid Zeitschr., 3, 80 (1908). Kapillarchemie, 309, Leipzig, 1909. ^ Wolfgang Ostwald: Kolloid Zeitschr., 1, 291 and 331 (1907). Grundriss der KoUoidchemie. Zweite Aufl. Dresden, 191 1. NEPHRITIS 9 ordinary gelatine, for example, when thrown into cold water merely swells up — it enters the gel state. But in this state it remains, one might almost say indefinitely; to mere ap- pearance it does not seem to go into solution at all as would, for example, the crystals of any salt that had thus been thrown into the solvent. But if the temperature of the water is raised then the gelatine goes into solution rapidly — it passes over into the sol state. A change in temperature in this case is necessary to accomplish its " solution." As to our mind albuminuria represents just such a passage of a colloid in the gel state (the proteins of the urinary mem- brane) over into a colloid in the sol state (the proteins con- tained in the urine of the albuminuric individual), let us study the conditions favoring such a transition in a little more detail, paying especial attention to a consideration of the influence of such changes in surroundings as we might imagine could come into play in the cells of the living ani- mal. I studied fibrin and gelatine in this regard. The fol- lowing facts regarding their behavior are of importance in the further development of our subject. 4. Observations on the " Solution " of Colloidal (Protein) Gels. {a) Fibrin. — When well- washed fibrin that has been thoroughly dried and then powdered in a mortar is thrown into water it swells up somewhat. Even though the vessel is thoroughly shaken none of the protein goes into solution in the water. The matter is easily tested by filtering the water off the fibrin and then treating the filtrate in any of the accepted ways for albumin. One must only be careful in this simple experiment to use a fine filter or else not powder the fibrin so thoroughly that gross particles of it can pass through the pores of an ordinary paper filter. By similar means it can be shown that the fibrin will not dis- 10 NEPHRITIS solve in any solution of the ordinary neutral salts. On the other hand, if the fibrin is placed in a solution of any acid {or alkali) it not only swells up more than in water hut it goes into solution. Within certain limits more and more fibrin goes into '' solution " with ever}- increase in the concentra- tion of the acid (or the alkali). But in this matter there seems to exist an optimum above which the progressive increase in ** solution " stops and gives way to a fall in this regard. The optimum point for the " solution " of the fibrin seems, so far as my present experiments indicate, to coincide with the optimum found for the " swelling " of this same substance. There is, moreover, an upper limit to the total amount of the fibrin that goes into solution in a given volume of the solvent. Under given conditions one has quite as much albumin in '^ solution " after shaking a mixture for two or three hours as after two or three days. In a given acid or alkali mixture the amount of fibrin that will '^ dissolve '' is fnarkedly decreased through the addition of any neutral salt. With a progressive increase in the con- centration of the salt there is a progressive decrease in the amount of the fibrin that ^' dissolves." But the character of the salt is not immaterial. When equimolecular solu- tions of different salts are compared it is found that some act more powerfully than others, but on the basis of my experiments as thus far carried out it is as yet unsafe to state definitely the order in which the various ions affect the " solution " of the solid gel. The order seems, however, to be identical with the order in which the ions affect the swelling of fibrin. Monovalent ions are, as a group, less powerful in decreasing the " solution " of fibrin in an acid or an alkali than are bivalent ions, and these than trivalent ions. What has been said will be rendered clearer by intro- ducing the results of a few typical experiments. Figure i in- NEPHRITIS II dicates the general way in which these experiments were performed. Weighed amounts of powdered fibrin were placed in measured volumes of various solutions contained in Erlenmeyer flasks which were then placed in a shaking Fig. I. machine and shaken for various periods of time. At the expiration of this time the fibrin was allowed to settle, and the supernatant liquid was decanted off into a filter-lined funnel and received into a second flask. After stirring the filtrate, a measured volume was taken and the amount of albumin contained in it determined quantitatively through precipitation with phosphotungstic acid^ and measurement of the heights of the precipitate either in the graduated EshacJi albuminometer tubes or ordinary test tubes of uni- form diameter. As the experiments are purely compara- tive in character I have contented myself in this paper with simply photographing the results of a few of such ex- periments as have a direct bearing upon our subject. ^ The phosphotungstic acid reagent had the following composition: Phosphotungstic acid, loo grams. Sulphuric acid (sp. gr, 1.84), 100 grams. Water enough to make 1000 c.c. 12 NEPHRITIS Experiment i. — 0.5 gram of powdered fibrin was shaken up for 5 hours in each of the following solutions: I. 50 c.c. 0.008 normal HCl 2. 50 c.c. 0.012 normal HCl 3- 50 c.c. 0.02 normal HCl 4- 50 c.c. 0.04 normal HCl 5- 50 c.c. 0.1 normal HCl 6. 50 c.c. H2O. The appearance of the fibrin in each of .the flasks at the end of this time is shown in Fig. i. In the first three flasks (i, 2, 3) there is a progressive increase in the swelling of the fibrin with the progressive increase in the concentration of the acid. Beyond this point (flasks Fig. 2. 4 and 5) there is a decrease in the swelling in spite of the further increase in the concentration of the aci^. The least amount of swelling is noted in flask 6 which contains water only. The solu- tion of the fibrin is indicated in Fig. 2. From left to right these tubes correspond with the flasks of Fig. i. No precipitate of albumin is seen in the tube on the extreme right, indicating that the fibrin did NEPHRITIS 13 not go into solution in the water (neutral reaction). All the remain- ing tubes show a precipitate of albumin. Experiment 2. — 0.5 gram of powdered fibrin is put into each of the following solutions and shaken for 5 hours : 1. 10 c.c. To normal HCl + 40 c.c. H2O. 2. 10 c.c. TO- normal HCl + 40 c.c. \ molecular NaCl. 3. 10 c.c. tV normal HCl + 40 c.c. \ molecular NaCl. 4. 10 c.c. To normal HCl + 40 c.c. \ molecular NaCl. 5. 50 c.c. H2O. The amount of albumin that went into solution is indicated in Fig. 3. No precipitate is seen in the tube on the extreme right Fig. 3. (water). Most albumin is found in the first tube (pure acid solution;. It is evident that the presence of the sodium chloride reduces the amount of the albumin that goes into solution. The amount of this reduction is the greater the higher the concentration of the salt. Experiment 3. — 0.5 gram of powdered fibrin was placed in each of four flasks containing the following solutions and shaken for 5 hours: 14 XEPHRITIS 1. lo c.c. i\t normal HCl + 40 c.c. HjO. 2. 10 c.c. 15 normal HCl + 40 c.c. | molecular Xa2S04. 3. 10 c.c. Jo normal HCl -i- 40 c.c. | molecular MgSO*. 4. 10 c.c. A normal HCl -|- 40 c.c. | molecular CuSO^. After filtering, the amount of albumin dissolved in the supernatant liquid found above the fibrin in each of the flasks was determined by mixing 20 c.c. of filtrate with 14 c.c. phosphotungstic acid. The re- FiG. 4. suit is shown in Fig. 4. As is readily apparent, each of the salts markedly reduced the amount of albumin that was dissolved. Experiment 4. — 0.5 gram of powdered fibrin was introduced into each of five flasks containing the following solutions and shaken for 5 hours: 1. 10 c.c. ^6 normal HCl -f- 40 c.c. | molecular sodium acetate. 2. 10 c.c. 15 normal HCl -j- 40 c.c. i molecular sodium nitrate. 3. 10 c.c. tV normal HCl + 40 c.c. | molecular sodium sulphate. 4. 10 c.c. ^6 normal HCl + 40 c.c. i molecular sodium citrate. 5. 10 c.c. 1^0 normal HCl + 40 c.c. H2O. NEPHRITIS 15 The relative amounts of albumin found dissolved in each of these mixtures at the end of this time are indicated in Fig. 5. As is again Fig. 5. evident, most albumin was dissolved by the pure acid solution. Each of the salts decreased through its presence the amount thus dissolved. {h) Gelatine. — What has been said under paragraph (a) regarding tlte "solution'' of fibrin holds almost word for word for the " solution " of gelatine. The best commercial gela- tine shows some solubility in water. The commercial product, as is well known, has a decidedly acid reaction. WTien, instead of being placed in water, gelatine is dropped into solutions of acids (or alkalies) this solubiHty of the (commercial) gelatine is greatly increased. The presence of neutral salts in the acid (or alkah) solution decreases the amount of the gelatine that will go into solution. As in the case of fibrin we note here again a progressive decrease i6 NEPHRITIS in the amount that " dissolves " with every increase in the concentration of the added salt. With a given concentra- tion, the amount of such a decrease varies with the salt em- ployed, and here again it seems that monovalent ions do not as a group decrease the " solubility " of the gelatine as much as bivalent ions, or these as much as trivalent ions. The following experiments will serve in illustration of what has been said. Experiment 5. — - The fol lowing solutions we I. 100 c.c. H,0. 2. 100 c.c. o.ooi normal HCl. 3- 100 c.c. 0.002 normal HCl. 4- 100 c.c. 0.005 normal HCl. 5- 100 c.c. o.oi normal HCl. 6. 100 c.c. 0.015 normal HCl. 7- 100 c.c. 0.02 normal HCl. 8. 100 c.c. 0.025 normal HCl. 9- 100 c.c. 0.035 normal HCl. Five leaves of dry gelatine, each measuring 3I by i^ cm., weigh- ing altogether 0.5 gram, and obtained by cutting them out of the central portions of the large gelatine leaves that are obtained com- mercially, were dropped into each of these solutions. From time to time the dishes containing the solutions with their gelatine leaves were agitated so as to keep the gelatine from adhering to the sides, and aid the solution of the gelatine. All the vessels were treated exactly alike. The degree of solution of the gelatine after 28 hours in these various solutions is indicated in Fig. 6. As the photograph shows, least gelatine is dissolved in the pure water. With the in- crease in the concentration of the acid there is a progressive increase in the amount of dissolved gelatine, but only up to a certain point, after which it falls in spite of the continued further increase in the concentration of the acid. Experiment 6. — In the manner just described, 5 leaves of dry gelatine, weighing in toto 0.5 gram, and of the same surface were placed in each of the following solutions: NEPHRITIS 17 100 c.c. HoO. 15 c.c. To normal HCl + 85 c.c. H2O. 15 c.c. tV normal HCl + 2| c.c. f mol. NaCl + 82^ c.c. H2O. 15 c.c. tV normal HCl + 5 c.c. f mol. NaCl + 80 c.c. H2O. tV normal HCl + 10 c.c. i mol. NaCl + 75 c.c. HoO. 15 c.c 15 c.c. tV normal HCl + 15 c.c. f mol. NaCl + c.c H2O. 1 ■T ^H 1 ^H j ^H i ]Hff rl^^^l 1 ^Hj 11 ^H 1 mm ■hj Q Fig. 6. The relative degree of solution of the gelatine after a residence in these mixtures of 18 hours is indicated in Fig. 7. The addition of the salt has decreased the amount of the gelatine that goes into solution in the hydrochloric acid, and this the more the higher the concentra- tion of the added salt. Experiment 7. — Five leaves of dr>' gelatine weighing altogether 0.4 gram and having the same surface were placed in each of the fol- lowing solutions: 1. iscciVn. HCl +85 c.c. HoO. 2. 15 c.c. \Q n. HCl + 10 c.c. \ mol. sodium acetate -f- 75 c.c. HoO. 3. 15 c.c. T(y n. HCl -f 10 c.c. \ mol. sodium chloride + 75 c.c. HoO. 4. 15 c.c. tV n. HCl -f 10 c.c. \ mol. sodium nitrate + 75 c.c. HoO. 5. 15 c.c. tV n. HCl -f 40 c.c. \ mol. disodium hydrogen phosphate + 45 c.c. H2O. NEPHRITIS . Fig. 7. 1 1 1' 11 ' l«llll« Fig. NEPHRITIS 19 6. 15 c.c. tV n. HCl + 40 c.c. \ mol. sodium sulphate + 45 c.c. H2O. 7.15 c.c. tV n. HCl + 10 c.c. T mol. sodium citrate + 75 c.c. H2O. The relative amounts of gelatine dissolved in these various solu- tions after the gelatine leaves had with occasional agitation remained in them for 19^ hours are indicated in Fig. 8. As is readily evident, each of the salts decreases by its presence the amount of gelatine dissolved in the acid solution. The divalent and trivalent anions are more powerful in this respect than the monovalent ions, with the ex- ception of the acetate. The intermediate position taken by this ion, in this matter of the solution of the gelatine, corresponds with the intermediate position occupied by this same ion in the swelling of the colloid under similar circumstances. It is clearly apparent from what has been said that the " solution " of two typical emulsion colloids (protein gels) is intimately connected with the character of the medium in which these gels find themselves. Acids (and alkalies) favor their solution while various other substances (notably salts) either do not affect the solubility of the gel at all, or if present in conjunction with an acid (or alkali) depress the amount that would have been '' dissolved " if the acid (or alkali) had been present alone. We will now adduce the evidence which is intended to show that the colloidal gel that constitutes the urinary mem- brane goes into ^^ solution " in the urine {albuminuria results) under the same conditions under which fibrin or gelatine gels go into " solution " in water. 5. Albuminuria as a Phenomenon Identical with the " Solution " of a Protein Gel. No special argument is necessary to prove that what lies between the urine on the one hand and the blood on the other {the kidney) represents physicochemically a colloidal gel. The general physical properties of the kidney as a whole betray this fact, and from chemical analysis we know that the albumins, globulins, higher carbohydrates, fats, and 20 NEPHRITIS " lipoids " which constitute, exclusive of water, the bulk of this organ, are all to be counted in the group of our most tj-pical emulsion colloids. What we need to show is that under normal circumstances, in " health," the con- ditions are such as to keep these colloids (as we are dis- cussing albuminuria this means the proteins) in the gel state, while under other circumstances (for example in nephritis) conditions are offered which permit these col- loids to pass over into the sol state and so escape with the urine. As we found changes in the reaction of the medium to play a most important role in the '^ solution " of such emulsion colloid gels (fibrin and gelatine), we will direct our chief inquiry into the question of whether such changes occur in the kidney in every condition characterized by an albuminuria. An ahnormal production or accumulation of acid ijt the kidney lies at the bottom of every albuminuria and is responsible for it. Our support for such a \dew will come from three directions. 1. Evidence of an abnormal production or accumulation of acid in the kidney, or conditions predisposing thereto, exist in every case of albuminuria, and conversely; 2. Any means which leads to an increased production or favors the accumulation of acid in the kidney results in albuminuria. 3. Any means by which we can decrease the '' solu- bility " of various protein gels (fibrin and gelatine) in an acid medium constitutes a means by which we can decrease albuminuria. The first two of these we will consider at once. The third we will take up separately later in this paper when we discuss the subject of the treatment of nephritis. NEPHRITIS 21 § I. I. If albuminuria is to be regarded as a process of " solution " of the urinary membrane in consequence of the presence of acids in it, then evidently the maintenance of the gel state of the normal membrane must be intimately associated with a maintenance of neutrality in it. We are therefore first of all interested in the fact that (exclusive of the gastric juice, the urine, and less positively, the sweat, vaginal secretion, and alimentary contents when fat is fed) the fluids and tissues composing the living mammal are to all intents and purposes neutral in reaction and are capable of maintaining this neutrality against the introduction of con- siderable acid into them. In the terms of our modern physical chemistry, an acid reaction is due to the presence of free hydrogen ions, an alkaline reaction to the presence of free hydroxyl ions. A neutral reaction means, therefore, one of two things: either neither of these ions are present, or else just as many of the one as of the other, so that they balance each other (the latter is the case in the body). The neutral reaction of the blood (and from this it has been generally assumed that the tissues themselves are also neutral in reaction) seems at first sight a rather surprising fact when considered in the light of our older teachings that the body fluids and the cells are all " alkaline." But these older teachings are erroneous for they are based upon an improper interpreta- tion of the results obtained with titration methods. The blood, for example, has generally been held to be " alkaline " because it is capable of neutralizing acid. But as we know now, the power of a solution to neutralize an acid is no index of its content of free, that is to say, active, hydroxyl ions which is the true measure of its alkalinity. For a proper measure of this hydroxyl ion concentration in the blood (or 22 NEPHRITIS in the tissues) all the determinations are valueless that antedate the fundamental measurements of P. Fraenkel,^ G. Farkas,^ and Rudolf Hober ^ who first used proper physico- chemical methods (so-called gas chains) in the biological study of this problem. The observations of all these authors agree in pronouncing the normal blood neutral in reaction ; as neutral as pure distilled water. Of further interest is the fact that this state of neutrality of the blood {and of the tissues) is maintained against the in- troduction of considerable acid or alkali into them. When ex- posed to the action of an acid, it is found that the normal hydrox>'l ion concentration of the blood drops with the progressive introduction of acid into it in the form of a curve, which falls only very slowly at first, and then more rapidly. Just why and how the state of neutrality is thus maintained for a period does not at this particular moment interest us, but it may not be amiss to point out that two factors are involved in the process. The first lies in the fact that such salts as sodium carbonate and disodium hydrogen phosphate are capable of uniting with acids (carbonic and phosphoric acids) to form salts having a higher hydrogen content (sodium bicarbonate and sodium dihydrogen phosphate), but which in their dissociation yield few more hydrogen ions than the salts from which they were originally formed and which were present in the blood to start with. In other words, there is for a time only a slight increase in the concentration of the hydrogen ions (increase in acidity) in spite of the considerable intro- duction of free acid into the system. (Z. /. Eenderson.y ^ P. Fraenkel: Pfluger's Archiv, 96, 6oi (1903). 2G. Parkas: Pfluger's Archiv, 98, 551 (1903); Archiv f. (Anat. und) Physiol., Supplement, 517 (1903). 3 Rudolf Hobcr: Pfluger's Archiv, 81, 522 (1900); 99, 572 (1903). *L. J. Henderson: American Journal of Physiology, 16, 257 (1906); 21, 169 (1908); 21, 427 (1908); Ergebnisse d. Physiologic, 8, 257 (1909), where extensive references to the literature will be found- 1 NEPHRITIS 23 The other and lesser element for the maintenance of neu- trality resides in the amphoteric character (that is to say their power of combining either with acids or alkalies) of the colloids found in the blood or the tissues. The albu- mins, for example, can unite with considerable quantities of acid (or alkali) without any decided change in their be- havior toward indicators. The presence of certain colloids in any system will therefore serve to delay the increase in the concentration of the hydrogen ions when an acid is added to this system.^ But let not the impression be gained from these remarks that the blood or the tissues are not sensitive to even very minute additions of acid (or alkali) to them. Such an increase in the concentration of the carbonic acid as occurs when normal arterial blood be- comes venous is already sufficient to reduce the hydroxy! ion concentration in the latter to one half that existing in normal arterial blood. How profoundly even such a change affects the state of the colloids we will have occasion to discuss later. For the present we are content with mak- ing the point that the blood and (presumably) the tissues are neutral in reaction, that they are capable of maintaining this neutrality within rather wide limits, even when subjected to the action of an acid, and that in consequence, under normal circumstances, conditions are such in the cells of the kidney as to inaintain the colloids here in their gel state. 2. As modern physicochemical studies have reduced what we formerly regarded as the " alkalinity " of the blood to a point where we may call it neutral, so also have they reduced the normal " acidity " of the urine from what we used to assume this to be. Just as the neutralizing power ^ J. Sjoqiiist: Skand. Arch. f. Physiol., 5, 277 (1895); Otto Cohnheim: Zeitschr. f. Biol., 33, 489 (1896); K. Spiro and W. Pemsel: Zeitschr. f. Physiol. Chem., 26, 233 (1898), 5. Bugarszky and L. Liehermann: Pfliiger's Arch., 72, 51 (1898); r. B. Robertson: Jour, of Physical Chem., 11, 542 (1907); 12, 473 (1908). 24 NEPHRITIS of the blood for acids is no indication of its true reaction, so also is the amount of alkali with which a given speci- men of urine will combine no measure of its true, that is to say, active, acidity. To gauge this properly the concen- tration of the hydrogen ions in it must be determined and this was not done until von Rhorer ^ and Rudolf E'dher ^ ap- plied the principle of the gas chain to the physicochemical analysis of the urine. The following Table I, taken from Hoher,^ indicates what is the concentration of the hydrogen ions in a series of normal morning urines. This gives a measure of their true acidity. TABLE I. — NORMAL URINE. 4 Hydrogen ion acidity (IO-5 . Ch). Titration acidity. 0.58 0.52 0.50 0.46 0.31 0.046 0.034 0.042 0.069 0.075 It would support our idea of the cause of albuminuria if it could be shown that this acidity of the urine increases in conditions associated with an albuminuria. How strikingly true this is, is clearly evident from the following analyses of nephritic urines also taken from E'dher and made of course without thought of using them for such purposes as we do here. As is clearly evident on comparing these two tables the active acidity of the urine of nephritics may be more than four times that of the normal urine. But Table II already suffices to betray another fact. The highest acidities occur 1 L. von Rhorer: Pfliiger's Archiv, 86, 586 (1901), 2 Rudolf Ilobcr: Hofmeister's Beitrage, 3, 525 (1903). 3 Rudolf Ilobcr: Physikalische Chemie d. Zelle u. d. Gewebe. Zweite Aufl. 158. Leipzig, 1906. NEPHRITIS 25 in the acute jorms of nephritis, in other words, in the same forms in which we find most albumin. The lowest values are found in the chronic interstitial forms, in other words, in the very types in which albumin is very likely to be found only in traces or at times not at all. The degree of the albuminuria therefore follows very closely the degree of acidity. We shall have occasion to return to this question later. TABLE 11. — ABNORMAL URINE. Hydrogen ion acidity (10-5 -Ch), Titration acidity. Remarks. 2.34 1.50 0.84 1. 10 2.20 2.10 0.56 0.67 0.019"] 0.018 ! 0.027 f 0.020J 0.022 ) 0.020 ) 0.014 1 0.050 ( Interstitial nephritis. Acute nephritis. Chronic interstitial nephritis. Let us now look at the columns in these tables that record the titration acidities. It is such values — erro- neously interpreted as measures of the true acidity of the urine — that we find recorded in all the studies of nephritis. When the individual titration acidities in the above tables are compared with their corresponding active acidities as determined by measuring the hydrogen ion concentrations in the urine, it is readily apparent that the two values do not even approximately parallel each other. What is learned when the titration acidity of the urine is determined is its capacity to neutralize alkali. Under otherwise con- stant conditions it is clear that this titration acidity of the urine must grow with every increase in the amount of acid in the urine. The uniformly higher titration acidity of the urine in nephritis, as is shown not only in the above tables I and II but by the scores that may be found in any of the 26 NEPHRITIS larger works that deal with this question of nephritis, be- comes further evidence therefore in favor of our contention that an abnormal production or an abnormal accumulation of acid occurs in the kidney in every albuminuria. 3. In the same way that we use the increased alkah ca- pacity of the urine as e\idence for the presence of abnor- mally large amounts of acid in it (and so in the kidney cells from which this comes), so also may w^e use the decreased acid capacity of the blood as evidence in the same direction. The titration values of the blood, w^hich the older clinical observers looked upon as indices of its " alkalinity," may be drawn upon for evidence to show that in the albumi- nurias there exists a decreased power of the blood to neutral- ize acids. As studied particularly by Rudolf von Jaksch,^ W. H. Rionpf,^ E. Peiper ^ and F. Kraus ^ a decrease in the acid capacity of the blood is noted in no conditions more strikingly than in nephritis and its oft associated urcEmia. 4. Our argument thus far has shown that in nephritis there is a great increase in the true acidity of the urine, and that in both the urine and the blood there occur changes in the titration values which clearly indicate that both are holding a more than normal amount of acid. Our knowl- edge of physical chemistry (the laws of chemical equilibrium) permits us to utilize these facts as e\adence indicating that the tissues of the kidney which He between the urine on the one hand and the blood on the other (all that we in our definition sum up as the urinar^^ membrane) must, under such circumstances, also show a rise in acid con- centration. But it would further strengthen this view if we could bring a more direct proof in support of this de- 1 R. V. laksch: Zeitschr. f. klin. Medicin, 13, 350 (1887). 2 W. n. Rumpf: Centralbl. f. klin. Medicin, 12, 441 (1881). »£. Peiper: Virchow's Arch., 116, 337 (1889). *F. Kraus: Zeitschr. f. Heilkunde, 10, 106 (1889); Archivf. exp. Path. u. Pharm., 26, 181 (1889). NEPHRITIS 27 duction. It would be well of course if wx could obtain a direct measure of the hydrogen ion concentration in the kidney. Gas-chain methods are naturally not applicable to solid organs, and to apply them to the expressed juice of the kidney would be to introduce so many errors into the whole problem as to render the conclusions valueless. We can, however, obtain material help by using indicators. Proof of an increase in the amount of acid held by the kidney cells in conditions associated with an albuminuria is furnished by the following facts : In 1885, E. Dreser ^ described a series of experiments on the excretion of dyes by the kidney which differed from the preceding studies of this subject as first made by R. Heid- enhain ^ and M. Nussbaum,^ in that he utilized the results of his experiments in an attempt to get an answer to the question as to where in the kidney the acid of the urine is secreted. Dreser made chief use of acid fuchsin which he injected in 5 to 10 per cent solutions (amounts not stated) into the dorsal lymph sacs of frogs. This dye has the property of being red in aqueous solution only in the pres- ence of an acid; in an alkaline solution it becomes practi- cally colorless (yellow). Dreser therefore reasoned that the presence of a red color in any tissue after the injection of this dye into the circulation of an animal was evidence for an acid reaction in that tissue. The first fact noted by Dreser that is of interest to us is that after a single dose of acid fuchsin the urine is found shortly thereafter to be- come brilHantly red. If the kidney from such an animal is examined no stained cells are noted anywhere in the kidney. To interpret this fact we would have to say that normally the urine is acid in reaction hut the cells of tJie 1 H. Dreser: Zeitschr. f. Biol., 21, 41 (1885); ibid, 22, 56 (1886). 2 R. Heidenhain: Pfliiger's Archiv, 9, i (1875). ^ M. Nussbaum: Pfliiger's Archiv, 16, 141 (1878). 28 NEPHRITIS normal kidney have not an acid reaction. The following may serve to corroborate this finding of Dreser. Experiment 8. — Three frogs, weighing 35 grams each, are in- jected, respectively, with 0.25, 0.5, and i.o c.c. of an aqueous i per cent acid fuchsin solution, into the dorsal lymph sac. All are seen to secrete a red colored urine before being killed. They are killed re- spectively after i, i^ and 4^ hours. On autopsy, red urine is found in the bladder of each anitnal. The kidneys are not stained. They are rapidly removed from the freshly killed animals, frozen with liquid carbon dioxide gas (on a Bardeen freezing microtome where the gas does not come in contact with the tissue) and sectioned. The sections are immediately transferred to a slide (without being brought in contact with water or any other medium except air), covered with a cover slip, and examined under the microscope. None of the kidney tissues are seen to he stained. To be sure that the freezing plays no part in the findings, a parallel series of free-hand sections, and crush preparations of the kidneys are made. No stained cells are found. When the uncolored sections are touched with very dilute acetic acid they are seen gradually to assume a pink color. Acid fuchsin is therefore present in the kidney tissues, but as cut from the body the reaction of this organ is not such as to allow its red color to appear. The pink tinge visible in the kidney after being touched with acid in- cludes the glomeruli. ExPERniEXT 9. — To show that what was said for the frog holds also for the mammal, two young rabbits, weighing, respectively, 184 and 189 grams, received into the ear veins 2.0 and 4.0 c.c, respectively, of a I per cent aqueous acid fuchsin solution. At the end of 30 and 35 minutes, respectively, they were killed by a blow on the head and immediately autopsied. Light red urine was found in the bladder of the first, deep red urine in that of the second. The appearance of the kidneys in both animals was entirely normal, and no dye was visible in the kidneys either macroscopically or microscopically. When a little very dilute acetic acid was permitted to flow under the cover slips, the sections" turned uniformly pink. Drcscr noted no staining of the frog's kidney until he had repeated his acid fuchsin injections several times. Then he found that the cells of the convoluted and of the NEPHRITIS 29 straight tubules began to stain red. He interpreted this finding by saying that from the long-continued effort on the part of these cells to excrete the dye, they become fatigued and so some of the dye remains behind to be dis- covered on subsequent section of the kidney. From all these facts Dreser concluded that the acid constituents of the normal urine are " secreted " by the convoluted tubules, and that since the glomeruli and their capsules remain un- stained, the '' urine " coming from these must be '* alkaline " in reaction, to change to an acid reaction after passing by the convoluted tubules. Whether such conclusions are really justified we shall have occasion to discuss later. No one can quarrel with the simple experimental finding that acid fuchsin does not stain the normal kidney, and does do this after repeated and long-continued injections. Such staining of the kidney Dreser still regards as '^ physi- ological." Strictly speaking, and for reasons that will be apparent as we go on, I should myself be more inclined to regard it as "pathological." What Dreser calls the ^^ fatigue " of the cells of those portions of the kidney which stain after repeated infections of the acid fuchsin, we are per- fectly safe in regarding as the first evidences of an abnormal acid content in these cells, and we may hold that the repeated infection of this dye is itself responsible for such a condition. Acid fuchsin is a weak acid, and must produce the same effects upon the kidney that we know are produced by the injection of any other acid.^ After the injection of acids we note regularly all the signs of a nephritis, and that these were not absent in Dreser's experiments is clearly evidenced by the " anuria " which this author so often noted in his frogs. Eut Dreser ^ describes yet another experiment which ^ See the succeeding § 2 on page 35. ^H. Dreser, Zeitschr. f. Biol., 21, 53 (1885). 30 NEPHRITIS shows that an abnormal production or storage of acid occurs in the kidney in nephritis. The kidney of the frog receives a blood supply, it will be remembered, from two sources — through the renal artery, as in mammals, and through a sort of portal system analogous to that existing in the liver. The blood from both these sources mixes to leave the kidney by way of the renal vein. Dreser noted that if acid Jiichsin is injected into the abdominal vein an hour after the renal artery has been tied, the co7ivoliited tubides stain red. As already pointed out, no such red staining of the cells is noted if the dye is so injected without ligature of the renal artery. Dreser interprets his finding in terms of physiolog}', but that we deal here with a pathological con- dition of the kidney — a nephritis — is evidenced not only by the fact noted by Dreser, that kidneys so treated secrete no urine, but by the evidence furnished below, ^ that after occlusion of the arterial blood supply to the kidney, acid develops in this organ, the kidney swells, the water secre- tion falls, and casts and albumin appear in the urine. Further tinctorial evidence of an abnormal production or accumulation of acid in the kidney in nephritis is furnished by certain experiments of R. Hetdenhain, M. Nnssbatim, and P. Grutzner with sodium indigosulphonate. This dye behaves in a way entirely similar to that of acid fuchsin. It is deep blue or indigo in an acid solution and yellow in an alkaline solution. The somewhat contradictory conclu- sions of these authors, based on their studies with this dye, are easily put in order if we try to separate those of their findings which are pathological from those which are physiological. In my own experiments on rabbits and frogs, I have, first of all, never been able to confirm any but the conclusion of Niissbanm ^ that no part of the normal * See pages 50, 123 and 151. *if. Ntissbaum: Pfliiger's Archiv, 16, 141 (1878). NEPHRITIS 31 kidney stains with sodium indigosulphonate. This corrobo- rates the finding obtained with acid f uchsin — the normal kidney is not acid in reaction. Experiment 10. — Four frogs, weighing 30 grams each, are in- jected, respectively, with 0.25, 0.5, i.o, and 0.25 c.c. of a i per cent aqueous sodium indigosulphonate solution into the dorsal lymph sac. Blue urine is voided by each of the animals before being killed. After, respectively, 40 minutes, 50 minutes, 70 minutes, and 3I hours, their heads are cut off and they are autopsied. Blue urine is found in the bladders of the last three. ^Macroscopic examination shows no color anywhere in the kidneys of these animals, and microscopic exami- nation of frozen sections only confirms this fact. Experiment ii . — Three rabbits from the same litter, and weigh- ing 497, 575, and 447 grams, respectively, receive, respectively, through the ear vein, i, 2, and 5 c.c. of a i per cent aqueous sodium indigosulphonate solution. They are killed by a blow on the head one hour after being injected. Blue urine is found in the bladder of each. This is also present in the ureter of the third. The kidneys are entirely unstained in the first two, and no color is found anywhere in the frozen sections prepared from these kidneys. The kidney of the third animal has a mottled blue appearance superficially, and one section shows some blue streaks radiating toward the pelvis of the kidney. Frozen sections show no dye anywhere in the kidney substance proper. The blue streaks are due to dye found in the lumina of a few of the collecting tubules. In apparent contradiction to this simple conclusion that the normal kidney does not stain with sodium indigo- sulphonate, stand the classical experiments of Heidenhain,^ who found certain portions of the kidney, notably, again, the convoluted tubules, to stain when the "secretion of the urine was sufficiently depressed." Heidenhain brought about the desired reduction in the secretion of urine by such procedures as transverse section of the spinal cord in the neck. But as he himself has noted, this produces an ^ R. Heidenhain: Pfliiger's Archiv, 9, i (1875); Hermann's Handbuch d. Physiol., 5, 346. Leipzig, 1883. 32 NEPHRITIS enormous fall in blood pressure. Such a fall in blood pressure does not, however, leave the kidney in a normal condition — it spells not alone an anuria but an albumi- nuria, and casts, in other words, a "nephritis." The staining of the kidney under these circumstances is again evidence of an abnormal production or accumulation of acid in this organ, a conclusion that we shall shortly be able to corroborate by entirely different methods. Both Heidenhain and Dreser have laid special stress on the fact that the convoluted tubules stain under the con- ditions offered in their experiments, while the glomeruli re- main unstained, because it is upon this fact chiefly that they (and their followers) have based their conclusion that the different parts of the uriniferous tubule in its course from the glomerulus to the pelvis of the kidney have differ- ent functions. As generally held, these dift'erent parts are supposed to secrete into (or, according to Carl Ludwig, absorb from) the mother urine, — the liquor postulated by IF. Boivman to be separated from the blood in its passage through the glomeruli, — as this flows down the uriniferous tubules, the different substances which serve to character- ize the urine. Now, I do not myself question the proba- bility that the different portions of the uriniferous tubules have different functions, but strictly speaking, this is not proved by these particular experiments. The findings of Dreser and Heidenhain show only that, under the conditions of their experiments, the neutrality mechanism existing in the convoluted tubules is broken down more easily than that exist- ing, for example, in the glo7neruli. That this approximates more nearly a correct interpretation of the observed phe- nomena is, as a matter of fact, indicated by the following: By simply continuing the conditions which were men- tiofied as effective in leading to a staining of the convoluted tubules, we get a staining of the glomeruli. Evidence for the NEPHRITIS 33 correctness of this conclusion can be adduced even from some cursory experiments mentioned by Heidenhain and Griitzner. As pointed out above, the conditions which lead to a staining of certain portions of the kidney with acid fuchsin or sodium indigosulphonate (excessive acid in- jection, ligature of renal artery, gross falls in blood pres- sure) are conditions which we can show by other means to be such as are associated with an abnormal production or accumulation of acid in the kidney. No matter how we interfere with a proper blood supply to the kidney we get such a production of acid. It does not therefore surprise us to note that when P. Griitzner ^ produced circulatory disturbances in the kidney by injecting gum arable, he noted not only the development of anuria and albumi- nuria, but he found at the same time that the glomeruli and their capsules now stained with sodium indigosulphonate. Quite as simply can we interpret Heidenhain^ s^ finding that the glomerular tufts stain with sodium indigosulphonate when the ureters are ligated. When this is done the urine is dammed back and accumulates in the space between the glomerular tuft and the parietal layer of the capsule, in con- sequence of which the capillaries composing the tuft are compressed, so that the normal circulation of blood cannot now occur through them. Under these circumstances an abnormal production or accumulation of acid in the cells of the glomerulus and the capsule is rendered possible and so the tissues making up these structures now stain. One can further test the soundness of the reasoning de- tailed here, namely, that a staining of the kidney as a whole or in part marks the presence of an acid, by working with excised kidney. Slices of fresh kidney kept in dilute solu- tions of sodium indigosulphonate or acid fuchsin stain only ip. Grutzner: Pfliiger's Archiv, 24, 461, 1882. ' R. Heidenhain: Hermann's Handbuch d. Physiol., 5, 372 . Leipzig, 1883. 34 NEPHRITIS very slowly and very slightly. Hours elapse before even a faint tinging of the tissues of the kidneys results. But let a trace of acid be added and all parts of the section may be made to stain a deep blue in a few minutes. In the same way a section of tissue from a kidney that has been dead some time (and so contains post mortem acids) stains readily, and, let it be noted, in all its parts. It will be recalled by anyone familiar with such studies as those of Heidenhain, Dreser, or the numerous investi- gators who since their day have adopted similar experi- mental methods, that these studies are intended to throw light on the problem of secretion by the kidney cells. This process of secretion is, of course, made up of two parts, the one concerned with the taking up from the blood of the substance to be secreted, the other with the giving off of this same substance in the urine. The problems in- volved here are discussed in detail later, but it may not be amiss to point out even now that what is so often done, namely, the regarding of a mere staining of some or all of the cells of an organ as dependable evidence indicating that the dye is '' secreted " by these cells, is entirely wrong. The presence of a dye in a cell does not mean this; nor when cells stain unequally does it mean that those most deeply stained are most involved in this process. It may mean just the reverse. The staining of the excised kidneys described above shows this very clearly. A kidney touched with a little acid, or one showing post mortem change, stains better than a normal kidney, and this without any hope of subsequently " secreting " the absorbed dye. Again, a kidney rendered " nephritic " by ligation of its arterial blood supply stains better than a normal one, and yet no one would maintain that a nephritic kidney " secretes " all dissolved substances better than a healthy one. NEPHRITIS 35 What really happens in the excised kidneys, or in the ^' nephritic " kidneys contained in the still Uving animal, represents but an isolated expression of the general laws that we to-day know to underlie all that is comprised in the physical chemistry of the dyestuffs. The kidney cells in the experiments that have been detailed are stained for the same reason, and their staining reactions mean the same thing, as when any ordinary lyophilic colloid such as fibrin or gela- tine takes up acid fuchsin or sodium indigosulphonate. If these colloids are seen to be stained red or blue it means, first of all, that they have, under the conditions of our ex- periment, an acid reaction. But with a given concentra- tion of the dye the depth of the staining becomes a measure of the degree of such an acid reaction, for a given colloid will absorb the more of any so-called " acid stain " the higher the concentration of the acid in which it finds itself. Other things being equal, the kidney cells must stain the more intensely with acid fuchsin or sodium indigosulpho- nate, the higher the acid concentration developed in them. To this whole question we shall have to return later. §2- We are now ready to discuss the converse of what has gone before, and so try to show that any means by which we can bring about an abnormal production or accumulation of acid in the kidney constitutes a method of producing an albuminuria. I. The simplest way to upset the normal conditions of neutrality as existing in the kidney lies, of course, in the in- troduction into this organ of an acid of some kind. This is done most easily by injecting the acid, either in solution in water or in a "physiological" salt solution, directly into the general circulation of an animal. For this purpose I used, in my own experiments, a large-sized aspirating syringe 36 NEPHRITIS with a two-way valve, rubber tubing, and a hypodermic needle, as illustrated in Fig. 9. The acid solution wanned to 37° C. is sucked into the syringe through the tube a. After turn- ing the valve v it can be ejected on lowering the plunger through the tube b, which ends in the hypodermic needle n. The needle is inserted into the ear vein of a rabbit and is held in place by a couple of small artery forceps. As the acid is injected intravenously, one observes the normally alkaline urine of the rabbit to turn acid, and as this acidity rises, albumin appears in the urine. The following ex- periments dealing with the ef- fects of such intravenous acid injections will serve to illustrate this point. Let it be noted that in addition to the appear- ance of albumin in the urine, this comes to contain various casts, epithehal cells, blood cor- puscles, and haemoglobin. By comparing the urinary output in these animals with that shown by normal animals, as detailed further on, it is evident that this is decreased. Evi- dences of an oedema are also not wanting; animals injected with an acid do not excrete the water that is injected with Fig. NEPHRITIS 37 this acid as does a normal animal that is given'^water only. The water when injected with an acid is retained in the body, but to this phase of the problem of nephritis we shall need to return later. For the present it is clear that there develop all the most typical signs of an acute nephritis when acid in sufficient amount is injected into an animal. Experiment 12. — Belgian hare; weight 1870 grams. Has been fed corn, oats, hay, and cabbage. Urine obtained by gentle man- ual pressure over the bladder.^ In the time of the experiment there are injected, at 37.0° C. and at a uniform rate, with the excep- tions noted, 291 c.c. of the following mixture: 300 c.c. 2V normal HCl + 20 c.c f molecular NaCl. Amount of Time. urine in cubic centimeters. Remarks. 1.20 — Tied to animal board. No anaesthetic. 1-45 2.00 4.0 ) 6. of Turbid, yellow, no albumin, no casts. Injection into ear vein begun. 2.15 Fe w drops Turbid, yellow, no albumin, no casts. 2.30 1.9 Clear, yellow, faint trace albumin, no casts. 2.45 •'\ Clear, brownish tinge, albumin present, few 3.00 red blood corpuscles, isolated kidney cells, no casts. 3-15 1.6 1 1-3 1 Smoky urine, albumin, isolated granular and 3-30 epithelial casts. ( Smoky urine, albumin, isolated granular and 3-45 - \ epithelial casts. Injection interrupted for 2^ min. Smoky urine, albumin, isolated granular and 4.00 1 4.8 \ epithelial casts. Injection interrupted for 5 min. Smoky urine, albumin, isolated granular and 415 I ) epithelial casts. Hasmoglobinuria. Injec- 4-45 1 21.0 i tion interrupted for 10 minutes. 5-00 J Animal dies. Total urine secreted since beginning injection 34.3 c.c. Autopsy. — Weight of animal 2135 grams! No free fluid in peri- toneal, pericardial, or pleural cavities. Kidneys slightly bluish, and bleed freely on section. Nothing about them is strikingly abnormal. ^ In these experiments on albuminuria the greatest care is necessary not to injure the lower urinary passages and so get a bleeding that might, 38 NEPHRITIS Experiment 13. — Belgian hare; weight 2008 grams. Has been fed a mixed diet of corn, oats, hay, and cabbage. Urine obtained by gentle pressure over bladder. During the course of the experiment there are injected at 37.0° C, and at a uniform rate with the ex- ception noted, 90 c.c. of the following mixture: 90 c.c. to normal HCl plus 6 c.c. I molecular NaCl. Amount of Time. urine in cubic centimeters. Remarks. 3-35 Tied down. No anaesthetic. 3 40 Injection into ear vein begun. 6.0 1 Turbid, yellow, alkaline to litmus. No al- 3-55 buminuria, no casts. 4.05 1-7 Clearer, trace of albumin present. Urine smoky, albumin increasing. Injection 4.20 0.8 I stopped for 15 minutes as animal threatens to die. 4.40 ( Injection recommenced. Bloody, much albumin, red blood corpuscles 4-45 Few drops < are present, filled with granular casts of various sizes. 4.47 Animal dies. Total urine secreted since commencing injection 8.5 c.c. (+) .4 utopsy. — Weight 2087.5. No free fluid in the peritoneal, pleural, or pericardial cavities. Kidneys sHghtly swelled. Under the cap- sule appear tiny haemorrhagic points. through the presence of albumin and blood in the urine, lead to the erroneous conclusion that a nephritis is at hand when only some bleeding is occurring into the bladder or urethra. ^Manual pressure over the bladder must be made with gentleness, and care must be taken not to so crowd the bladder into the pelns as to kink the urethra. Only thesmallest soft rubber catheter, well vaselined, must be introduced. If these precautions are not followed, fallacious, if not worthless, results are obtained. When an animal dies or is killed, the lower urinary passages must be examined for haemorrhagic points. NEPHRITIS 39 Experiment 14. — Belgian hare; weight 2259 grams. Diet un- known, as he has just been received in the laboratory. Urine obtained with a catheter. In the course of the experiment 75 c.c. of the following solution are injected at a uniform rate, with the exception noted: 75 c.c. h normal HCl plus 5 c.c. f molecular NaCl. Time. Amount of urine in cubic centimeters. Remarks. 11.30 11-45 12.00 12.15 12.30 12 .40 12.45 1-45 7.0 19.4 0.4 1.6 3.7 \ II-5 Tied to animal board. Urine thick, chrome yellow, no albumin. Thick, chrome yellow, no albumin, alkaline to litmus paper. Injection into vein of ear begun. Thick, chrome yellow, no albumin, alkaline to litmus. Clearer, pinkish tinge, albumin present. Injection stopped entirely. Urine distinctly red, much albumin, many casts. Urine turbid, red, shows spectrum of oxyhae- moglobin,. filled with albumin, casts, (epi- thelial, granular, and mixed) epithelial cells, and red blood corpuscles. Animal released in good condition, returned to hutch. Total urine secreted since beginning injection 19.2 c.c. 530 Next morning 50 per cathe- ter. 370 per cathe--< ter. Clear, yellow, acid. Casts and albumin still present. Dark amber, thick, faintly acid, clear. Mi- croscopic examination shows many squa- mous epithelial cells and isolated casts. Carefully filtered urine shows a trace of albumin. It SO happens that the sum total of the chemical changes that go on in the living animal organism are of such a character as to threaten the normally neutral reaction ex- isting in the tissues chiefly from the acid side. Even under normal conditions, the tissues have to guard themselves against becoming acid in reaction. Do we not have to count carbonic acid among the chief end products of the oxidation of our foodstuffs? This normal tendency of the 40 NEPHRITIS tissues to become acid in reaction is enormously increased under various pathological conditions, and as we shall find these conditions to be just such as are likely to lead to a nephritis, the discussion of this subject will naturally tend to center about a discussion of the conditions which favor such an abnormal production or accumulation of acids in •the tissues. An abnormally high alkali content in the cells under normal circumstances is scarcely possible, and when it is induced artificially it is difficult to maintain, for the normal acid production (CO2 production) in the living cell tends quickly to neutralize it. The question of an abnormally high alkali content of the cells is therefore scarcely to be considered in our further discussion of the problem of nephritis. And yet from a theoretical stand- point it is quite as important as that upon which we shall lay the greater stress. As we pointed out in our discussion of the " solution " of colloidal protein gels (such as fibrin or gelatine) these colloids go into " solution " quite as readily in alkalies as in acids. Therefore, even though an abnormally high alkali content is scarcely to be considered as a cause of "nephritis" in living animals (except in cases of poisoning with alkalies) we should, on the basis of our colloidal conceptions of nephritis, be able to induce this condition experimentally almost as easily through alkalies as through acids. As the following experiments show, this is actually the case. NEPHRITIS 41 Experiment 15. — Belgian hare; weight 2085 grams. Has been fed hay, oats, corn, and cabbage. In the course of the experiment there are injected intravenously at a uniform rate 125 c.c. of the fol- lowing mixture: 150 c.c. NaCl. :V normal NaOH plus 10 c.c. f molecular Time. Amount of urine in cubic centimeters. Remarks. 2.35 3-15 330 3-45 4.00 415 4-30 4-45 4.58 31- 0.7 1.2 .8.4 6.0 1.2 0.7 0.4 0.4+ 0.6 con- tained in cathe- ter. Catheterized. Dark amber, acid to litmus paper. No albumin. No casts. Catheterized. Weighed. Placed in animal board. Injection into ear begun. No al- bumin. No casts. Acid in reaction. Urine clearer. Acid in reaction (?). Trace of albumin (?). Milky, alkaline to litmus. Faint trace of albumin. Milky, alkaline to litmus. Also isolated casts. Faint trace of albumin. Milky, alkaline to litmus. More albumin. Many long hyaline casts with coarsely granular material sticking to them. Milky, alkaline to litmus. Much albumin. Filled with casts. Bloody tinge to urine. Milky, alkaline to litmus. Much albumin. Filled with casts. Bloody tinge to urine. Animal dies. i.o gram of faeces lost. It is noted that the albumin reactions as obtained with cold nitric acid applied to the filtered acidified urine are not as intense as in the albuminu- rias induced by acid injections. (Less al- bumin ?). Total urine since beginning injection 18.9 c.c. Autopsy. — Weight 2187 grams! No fluid in the cavities. In- testinal contents seem somewhat more fluid than usual. Kidneys are firm, apparently somewhat swelled, and do not bleed easily. 42 NEPHRITIS Experiment i6. — White rabbit; weight 1911 grams. Fed hay, oats, corn, and greens. In the course of the experiment there are injected at a uniform rate 185 c.c. of the following mixture: 225 c.c. T^j normal NaOH plus 15 c.c. f molecular NaCL Time, 215 2.30 430 Amount of urine in cubic centi- meters. 85. 0.7 I 2-45 0.7 300 0. 2 315 1 .0 330 6.4 3-45 15-5 4.C50 22.0 4-15 24-5 4.2s 23 o \ Remarks. Catheterized. Turbid, dark amber, acid. No albumin, no casts. Turbid, dark amber, acid. No albumin, no casts. Weighed. Injection into ear vein begun. Urine as before. Neutral to litmus. Clearer. Small amount of albumin. Many hyaline casts. Some have coarse granules in them. Urine clear as water. Many hyaline casts. Some have coarse granules in them. Urine clear as water. Only a few casts can be found. Albumin present. Weakly alkaline. Albumin present. Isolated casts only can be found. Albumin present. No casts can be found. The urine has a pink tinge (haemoglobinuria). No red blood corpuscles microscopically. Injection stopped. Faintly alkaline. Clear, pink, no casts, no red blood corpuscles. Albumin present. Animal released. Seems entirely normal, and eats at once. Weight 2000 grams! NEPHRITIS 43 Experiment 1 7. — White rabbit; weight 2177 grams. Fed hay, oats, corn, and cabbage. In the course of the experiment there are injected at a uniform rate 240 c.c. of the following mixture: 225 c.c. 2V normal NaOH plus 15 c.c. | molecular NaCl. Injection made into ear vein. Amount of urine in cubic cen- timeters. I drop 0.5 drops •IS 13.0 •30 12.0 ■45 16.0 .00 19.0 •IS 23.0 Remarks. Catheterized. Turbid, yellow urine. No al- bumin. No casts. Weighed. No albumin. Injection begun. Albumin present. Filled with casts, mainly hyaline in character, but some are finely granular. Much squamous epithelium and cell detritus. Alkaline to litmas. Albumin and casts as before, but all the casts are hyaline except for coarse, granular material contained in or attached to some. Strongly alkaline. Albumin and casts as before. Strongly alkaline. Albumin and casts as before. The urine has a pinkish tinge (haemoglobi- nuria). Strongly alkaline. Albumin and casts as before. Urine pinkish (haemoglobinuria). Red blood corpuscles are found and two microscopic blood coagula. This bleeding is attributed to traumatism (animal struggled and whipped catheter about). Urine strongly alkaline. The animal has begun to shiver (acid production!) during the last 15 minutes. The previously warm ears are pale and cold. The urine becomes faintly alkaline, then scarcely affects either red or blue litmus. The urine is clear like water except for a clouding due to (traumatic) blood. Careful search of the sed- imented urine reveals only an occasional cast. The animal is shivering constantly. It is killed. Total urine since beginning injection, 87.7 c.c. Autopsy. — Weight 2326 grams! The peritoneal, pleural, and pericardial cavities are dry. The kidneys are soft and bleed a normal amount. A few pinpoint haemorrhagic spots are found in the bladder. 44 NEPHRITIS 2. We need not, however, go outside of the body in order to get a sufficient amount of acid to so upset our neutrality mechanism in the kidney as to lead to an albumi- nuria. As is well known, large amounts of acid (especially lactic acid) are produced in the muscles when these con- tract. If the muscle works under physiological conditions and not too fast, the acid as formed may be largely oxidized in situ. But if the muscle works more rapidly then more acid is produced than can be oxidized in the muscles and so in the higher animals some passes unchanged into the blood, with this to the kidneys, and then out in the urine. ^ It is evident that the opportunities for such an accumula- tion of acid in the body become the greater the more rapidly and the harder the musculature of the body works, and we should add, the more defective the oxygen supply to the working muscles, for this element is necessary for the proper oxidation of the acid in the body. Now such a combination of hard work with a (temporarily) defective ox>^gen supply to the active muscles is furnished whenever the organism engages in exercise that calls for more than usual effort. We are therefore not surprised to find that soldiers after prolonged marches, women in labor, Marathon runners, etc., give evidences of an albuminuria when ex- amined after such exertions. ^ The amount of exercise needed to bring about such albuminurias is really sur- prisingly low, as is indicated by the following: Experiment i8. — Seven trained athletes just before entering upon a game of basket ball were asked to void their urine into a series of flasks. At the end of the game which lasted one and a half 1 Trasahuro Araki: Zeitschr. f. physiol. Chemie, 19, 422 (1894), where ref- erences to his eadier papers may be found; Hoppc-Seylcr, ibid 19, 476 (1894)- Fletcher and Hopkins, Journal of Physiology, 35, 247 (1907). 2 ir. Leube: Virchow's Arch., 72, 145 (1878); G. Edlefsen: Centralbt. f. d. med. Wissensch., 762 (1879); C. von Noorden: Arch. f. klin. Med., 38, 205 (1886). NEPHRITIS 45 hours they voided their urine a second time into a second series of flasks. Heller's test was then applied to the various specimens of urine. While none of the players showed any trace of albumin in his urine before the play, all gave strikingly marked reactions after the game. The results of the tests applied to the urines voided after the game are shown in Figs. lo and ii. The first four tubes are photographed Fig. io. Fig. II. against a white background, the three of Fig. 1 1 against a black. The faint albumin ring present in the tube on the extreme right of Fig. ii scarcely shows in the photograph. Interestingly enough, this specimen of urine came from a player who was in the game but five minutes. Experiment 19. — Five trained athletes shortly before engaging in a match game of basket ball void their urine into a series of flasks. All the urine voided during the succeeding 1 1 hours during which the game is played is collected in a parallel series of flasks. In none of the control urines with the exception of that of Player IV are there found albumin or casts. This player had found it necessary before coming to the game to rush about town making train and street-car connections and had moreover had a " cold " for three days previ- ously. After the game all the players showed an albuminuria and a great many granular, hyaline, and mixed casts. The albumin and the casts in the previously affected individual were markedly increased. The findings are illustrated in Fig. 12 and in the appended Table III. 46 NEPHRITIS The five tubes on the right show the results of applying the cold nitric acid test to the urine after the game. The tube on the extreme left shows the albuminuria existing in Player IV even before entering the game. The quantitative estimations in the Eshach tubes were Fig. 12. carried out in the ordinary way using Tsuchiya's^ phosphotungstic acid reagent. The photograph was made after the tubes had stood for only 6 hours. The readings in the table were made after 24 hours. TABLE III. Before the Game. Player Amount of urine in cubic centimeters. Nitric acid test. Casts. I II III IV V 60 ) 158 5 ) 47 134 Negative Positive < Negative None Occasional granular and hyaline None * Tsuchiya: Centralbl. f. inn. Med., 29, 105 (1908). Phosphotungstic acid, 1.5 grams. Concentrated hydrochloric acid, 5.0 c.c. Alcohol to make, loo.o c.c. NEPHRITIS After the Game (i| Hour Period). 47 Player. Amount of urine in cubic centi- meters. Nitric acid test. Casts. Esbach reading with phospho- tungstic acid. Albumin excreted in grams. I II III IV V i68 69 35 30 94 Positive -| Many hyaline, granular, and mixed casts present in all. 0.6 325 2.3 50 2.75 O.III 0.224 0.080 0.150 0.258 Av. 0.163 A remarkably short period of hard athletic work suffices to produce a great albuminuria, as the following taken from many such observations shows : Experiment 20. — B , a well-trained and expert Uni- versity runner ran a quarter- mile race. Before starting he voided 54 c.c. of urine which on examination showed no albumin. After his race (time: 58 seconds!) he voided 59 c.c. of urine in which much albumin was found. In Fig. 13 are shown the results of the albumin tests as applied to the two samples of urine. In the two tubes on the right the cold nitric acid test has been applied to the urines; in the tube on the left a quantitative estimation has been carried out in an Esbach tube with Tsuchiya^s phospho- tungstic acid reagent. 3. A condition in the body entirely analogous to that produced voluntarily by the athlete in his athletic activi- ties is created through any uncompensated heart lesion or any disease of the lung of such a character as to materially inter- fere with the proper aeration of the blood. Either of these Fig. 13. 48 NEPHRITIS conditions interferes with the proper escape of carbon dioxide from the blood (and so from the cells in which this is produced).^ But they do more than this, they place the organism as a whole in a state of lack of ox}^gen, and as a necessary consequence of this we know from the studies of Trasahuro Araki,- Hermann Zillessen,^ and P. von Terray^ that we get an abnormal production and accumulation of other acids, notably lactic and oxalic acids, in the tis- sues. Heart or lung lesions therefore are potent to lead to that same abnormally high acid content of the cells of the kidney that we previously found created through the direct injection of acids, or the hard work of the athlete, and so we are prepared to find in these pathological states of the heart and lung that albuminuria is again a common consequence. As a matter of fact the association of ^' nephritis " or ^'Bright' s disease " with heart lesions of the most varied kinds, or pathological conditions in the lung (manual compression of the thorax, pleurisy with effusion) that reduce its ventilation area sufficiently, is so constantly observed that it is taken for granted clinically. 4. It requires no special comment to recognize that a whole series of pathological states such as the severer anaemias, carbon monoxide poisoning,^ and epileptic seiz- ures, which at first sight seem to have nothing in common with each other, contain within themselves all the elements necessary for the development of an albuminuria. The severe anaemias (leukaemia or pernicious anaemia) merely constitute further ways of interfering with a proper oxygen 1 Slrassburg: Pfluger's Arch., 6, 94 (1873); yl. Ewald: Arch. f. (Anat. und) Physiol., 663 (1873); 123 (1876). 2 T. Araki: Zeitschr. f. physiol. Chemie, 15, 335 and 546 (1891); 16, 453 (1892); 17, 311 (1893); 19, 422 (1894). 3 //. Zillessen: Zeitschr. f. physiol. Chemie, 15, 387 (1891). * P. von Terray: Pfluger's Arch., 65, 393 (1896). 5 G. Thompson: Trans. Assoc. Am. Physicians, 1902; William Ravine: Per- sonal Communication. NEPHRITIS 49 supply to the tissues. Both are accompanied by an abnormal storage and production of acid in the tissues as evidenced by Felix Hoppe-Seyler's ^ and T. Irasawa's ^ chemical analysis of the urine, and R. von JakscKs ^ titrations of the blood in cases of severe anaemia. An abnormal acid production in carbon monoxide poisoning has been proved by T. Araki,^ E. Munzer and P. P alma ;^ in epilepsy (severe muscular exertion with defective breathing) by Araki and E. Mendel. As cHnicians well know, the existence of an albuminuria in any of these pathological states is usual. 5. The aetiological importance of " cold " (in the strict sense of the word as a lowering of the body temperature and unaccompanied by an infection) in the production of an acute nephritis, or in the lighting up of a chronic one that has slumbered for a time, has always been insisted upon by the older observers. This view finds a rigid scientific support in our present knowledge of the physiological effects of low temperature upon the warm-blooded animals. Of these none is more characteristic than the rise in the acid content of the cells of an animal so exposed.^ In this ^ F. Hoppe-Seyler: Zeitschr. f. physiol. Chemie, 19, 473 (1894). 2 T. Irasawa: Zeitschr. f. physiol. Chemie, 15, 380 (1891). 3 R. von Jaksch: Klinische Diagnostik, Fiinfte Aufl. 2. Berlin, 1901. * T. Araki: Zeitschr. f. physiol. Chemie, 15, 335 (1891). ^ E. Miinzer and P. Palma: Prager Zeitschr. f. Heilk, 15, (1894). 6 See Araki: Zeitschr. f. physiol. Chemie, 16, 453 (1892). On the basis of this same acid production we can with the greatest ease explain the pre- cipitation of an attack of haemoglobinuria in the cases of so-called paroxys- mal hoemoglobinuria when these patients take a cold bath, are exposed to cold, etc. The acid produced under these circumstances rises to the point where it leads to a haemolysis of the patient's red blood corpuscles. This view is supported by the fact that it is possible to precipitate an attack of haemoglobinuria for diagnostic purposes quite as easily through temporary obstruction of the circulation in the arm by applying a band about it (ac- cumulation of carbon dioxide and production of other acids due to a lack of oxygen), as through the customary immersion of the extremities in cold water. The essential nature of the paroxysmal haemoglobinurias would seem to reside in the lesser resistance which the red blood corpuscles of such 50 NEPHRITIS way do we find a ready explanation of why such trivial ex- posure to cold as is produced by a cold bath leads, in not a few individuals, to the appearance of albumin in the urine. 6. Thus far we have discussed only general conditions — conditions affecting the whole animal — that are capable of inducing an abnormal storage or production of acid in the body, and so of inducing an albuminuria. We will now consider a series of more local conditions that bring about the same result. Instead of interfering with the normal action of the heart or lungs an effective state of lack of oxygen in the kidney can, of course, be induced by direct interference with the normal blood flow through this organ (see Experiment 33). Experimentally such a condition is easily established by total or partial ligation of either the arterial or the venous blood supply of this organ, a state that has its clinical parallel in such affections as partial or complete occlusion of the renal vessels through arteriosclerosis, thrombosis, embolism, or the pressure of tumors, etc., upon these vessels. But as the experiments of T. Araki and H. Zillessen have shown such an interference with the normal blood supply (oxygen supply) to any of the parenchymatous organs is followed immediately by the accumulation of acids in the affected tissues. Do we now find that in such local circulatory disturbances of the kidney we get an albuminuria? That we do is, of course, known to everyone — it constitutes, since Max Herrmann^ s ^ experimental studies, one of the patients have to such a haemolytic agent as an acid. The resistance to such a hemolytic agent is enormously increased by the addition of various salts to the blood, as Oscar Berghausen has sho\\Ti. This fact is not only of theoretical interest, as I have tried to show in discussing the nature of haemolysis [Fischer: KoUoid Zeitschr. 5, 146 (1909) or (Edema, 166 (New York, 19 10)], but of direct therapeutic use in the treatment of these cases of haemoglobinuria (diet rich in alkahes, administration of calcium salts, etc.). ^ Max Herrmann: Sitzungsber. d. \\^iener Acad. Math.-phys. Klasse, 65, (1861). NEPHRITIS 51 classical facts of pathological physiology; it is attested to by the experience of any medical diagnostician ; it is the bug- bear of surgeons who operate on the kidney and find a tem- porary closure of the renal vessels expedient or necessary. ^ 7. Instead of interfering directly with the oxygen supply to the kidney by procedures which interfere with the blood supply to this organ, we can bring about the same result in a more subtle way by giving the kidney parenchyma its normal oxygen supply, but by so interfering with the chemistry (enzymatic processes) of the cells themselves that make up the kidney as to render these incapable of utilizing in proper form the oxygen that is freely supplied them. So far as the end result is concerned, it matters little, of course, whether we interfere with the normal oxida- tion, for example, of the carbohydrates of the living cell into carbon dioxide and water by shutting off the oxygen supply to the cell and so halting the decomposition of the carbohydrates when these have been changed to lactic, oxalic, formic, and other acids (saccharinic acids) ; ^ or whether we do nothing about the oxygen supply but intro- duce something into the cell which prevents the oxidation of the lactic acid as formed to carbon dioxide and water (or more probably the mother substance of the lactic acid glycerine aldehyde).^ The cells of the living body in the ^ For a discussion of the methods to be employed in combating the evil consequences of such temporary closure see Part IV dealing with the treat- ment of nephritis. 2 The chemical aspects of this problem of the formation of acids from carbohydrates in the absence of oxygen are discussed by Felix Hoppe-Seyler: Berichte d. deut. chem. Gesellsch. 4, 346 (1871); H. Kiliani: ibid, 15, 701 (1882); Diiclaux: Compt. rend., 94, 169; Schiitzenherger: ibid, 76, 470; Buchner, Meisenheimer, and Schade : Berichte d. deut. chem. Gesellsch., 39, 4217 (1906); /. U. Nef: Liebig's Annalen, 357, 214 (1907)- The biochem- ical aspects of this same problem are discussed in the papers on lack of oxygen already referred to on pages 48 and 49. 3 In this connection see the interesting work of R. T. Woodyait: Journal of the American Medical Association, 65, 2109 (1910). 52 NEPHRITIS end get into the same state whether they have their oxygen supply cut off, or whether this is not interfered with, but they are '' poisoned " in such a way as to be unable to utilize this oxygen as normally. As has been shown particularly well by T. Araki, a large number of poisons lead to the same state of lack of oxygen, with its associated abnormal production and accumulation of acids in the tissues, as do the grosser interferences with the oxygen supply to the various organs or the body as a whole, that have already been described. And so it can- not surprise us to discover that ArakVs list of poisons — poisons utilized to show that an abnonnal acid production is the constant accompaniment of a state of lack of oxygen in the tissues no matter how produced — is identical with the list of poisons familiar to any laboratory or clinical worker who has busied himself with the problem of the toxic nephritides: metallic salts, such as those of arsenic, uranium, chromium, and lead; alkaloids, such as morphine, cocaine, and strych- nine; anaesthetics, such as alcohol, ether, and chloroform; unclassified poisons, such as amyl nitrite, the cyanides, and phosphorus. 8. In concluding this section we need to discuss the albuminurias encountered in three conditions which not only are readily interpretable on the basis of our conten- tion that albuminuria results whenever abnormally great amounts of acid accumulate in the kidney but give this contention valuable support. Since Rudolph Virchow^s description of the condition fifty years ago, the albuminuria of the newborn constitutes a matter of common knowledge to every pasdiatrist. It occurs in perfectly healthy infants as a transitory phenome- non, is regarded as ''physiological," and to it ordinarily no clinical importance is attached. Whence comes it? The condition is most commonly found in " hard '* labors, when NEPHRITIS 53 the cord prolapses, in breech presentations, etc., all of them conditions which mean a state of more than the normal lack of oxygen in the organism of the child during the process of its birth. Even normal labor means of course a decided interference with the circulation of the infant, — is it not in this fact and the associated accumu- lation of carbon dioxide and other acids in the blood that the cause of the first respiration is to be sought, as Zuntz has shown? Difficult labors mean in to to only a more than usual interference with the circulation of the child. It is entirely a matter of definition as to just how much of this we will accept as '^ physiological." But when we have thus connected the development of the albuminuria with a dis- turbance in the general circulation of the child then we have made it, at the same time, a mere subheading of the albuminurias discussed in paragraph 3 of this section (page 47), and the albuminuria is '' physiological " only as we will accept little or great interference with the circulation in the infant during its birth as " physiological." Albuminuria is the constant accompaniment of salt starva- tion, be this a complete salt starvation or only such a par- tial one as is induced by ehminating completely the sodium chloride from the food. Under this same heading is to be classed the albuminuria consequent upon the excessive con- sumption of water low in salts. The latter washes the salts out of the body (see Section 4 of Part III) and so leads indirectly to the same state as that induced by a lack of salts in the diet. The effect of a salt-free diet is twofold. In the first place it leads to the accumulation of acids in the tissues.^ Other things being equal, we have on this basis alone therefore a reason for the albumin going into solution (and so an albuminuria) when salts are withheld from the ^G. Bunge: Zeitschr. f. Biol., 10, iii (1874); see also /. Forster: ibid, 9, 297, 369 (1873); N. Lunin: Zeitschr. f. physiol. Chemie, 5, 31 (1881). 54 NEPHRITIS diet. But the salts act in yet another way. We found, in detailing the experiments on the ^' solution " of fibrin and of gelatine in acids, that this tendency of the colloidal gels to go into solution in a given concentration of acid is greatly inhibited through the presence of all salts, even neutral salts incapable of an effect that might be construed as due to a mere neutralization of the acid. Through the withdrawal of salts from the tissues, whether by salt starvation or through leaching these out with water, we favor therefore the tendency of the proteins to go into solution in two ways: not only do we render possible an abnormal production or accumulation of acids in the tissues, but we take away at the same time the effect of the salts in reducing the tend- ency of the colloids to go into solution in such acids as may be abnormally present, or those which, like carbon dioxide, are normally produced in the tissues. 9. If now albuminuria represents merely that simple ** solution" of the albumin of the kidney substance itself in the urine, or if, in other words, it does not come from the blood (except in that indirect way in which the pro- teins of any cell come originally from the blood), then albuminuria cannot be that strange and specific thing which as clinicians we are likely to make it. Any cell must, under conditions similar to those existing in the cells of the kidney when this is nephritic, be capable of serving as a source of albumin to a surrounding liquid medium, a7id so be capable of being responsible for a state which in the kidney goes by the name of ^'albuminuria.'' A little thought will show that such actually is the case. Any worker in the biological sciences is familiar with the ancient fact that ''dead" organisms, be these unicellular or multicellular, allow the escape of albumin from them. A frog or fish living in his aquarium does not impart an albumin reaction to the water in which he lives. But let NEPHRITIS 55 him die and in a few hours the previously clear water gives a positive result when tested for albumin, and this reaction becomes the more intense as time goes on. What happens is, of course, that after death the tissues become acid in reaction, and so some of the protein now goes into "solu- tion" in the surrounding medium. But we need not wander so far away from the mammals, or in fact the living animal itself, in order to show that ''albuminuria" is not the specific thing we think it. As surgeons well know, the normal intestinal juices scarcely yield an albumin test, yet the fluid contained in a strangu- lated hernia or a volvulus is rich in albumin. Here the interference with the circulation to the gut, produced through the strangulation or the twist, has placed a section of the bowel in a state of lack of oxygen; it develops in consequence an abnormally high acid content, and so some of the proteins of the gut wall go into "solution" — in other words, we get in the bowel what in the kidney is called albuminuria. Analogous conditions exist for any of the parenchym- atous organs. When any organ is placed under conditions which lead to an increase in its acid content, a state analo- gous to the albuminuria of the kidney results. The lymph coming from a muscle that is made to work hard has a higher albumin content than that coming from this same muscle when at rest, and when the circulation through the liver is impeded (I should say oxygen supply through the hepatic artery is interfered with), either through ligation of the inferior vena cava or obturation of the thoracic aorta, the albumin content of the lymph coming from this organ begins to rise as E. H. Starling'^ has clearly shown. *£. H. Starling: Jour, of Physiology, 16, 224 (1894); 17, 30 (1895); see also Bayliss and Starling: ibid, 16, 159 (1894). 56 NEPHRITIS 11. THE ^MORPHOLOGICAL CHANGES IN THE KIDNEY. I. Introduction. Anyone who has on the one hand busied himself with the clinical, or as we might better say, the biochemical, aspects of nephritis, on the other wdth the morphological aspects of this same problem, as this has been developed for us during the last two or three decades, must be struck not alone by the fact that the two have grown up practi- cally independently of each other, but that they have made but slight effort to find common ground. As a matter of fact, w^hen we attempt to fiind a con- nection between the comparatively simple biochemical characteristics of nephritis and the elaborate morphological analyses of the organs from patients who have clinically shown the biochemical marks of a nephritis, this is at first sight not easy. Even if we ignore the fact that much of that which is supposed to characterize nephritis morpho- logically has nothing to do with the albuminuria, the changes in the secretion of water, the changes in the secre- tion of dissolved substances, etc., which are the distinguish- ing marks of a nephritis biochemically, there still remains an apparent lack of connection between the facts, to which any clinician or pathologist will testify, namely, that indi- viduals may die of an acute Brighfs disease and show sur- prisingly little macroscopic or microscopic change in the kidney, while others, never affected with any symptoms referable to the urinary system, may show on autopsy the infant-sized kidneys of chronic interstitial nephritis. And yet if we will but free our minds from the erroneous con- clusions to which the temptations of elaborate fixing and staining methods and high power microscopes have led us, NEPHRITIS 57 it is an easy matter to see that all the morphological changes that occur in a kidney, the seat of an acute or chronic nephritis, are fundamentally simple in character, and that they are easily brought into connection with the clinical manifestations of the disease. We will discover at the same time that the essential morphological changes of acute and chronic nephritis were recognized and a satis- factory classification of the nephritides on morphological grounds was made decades ago, more especially by Weigert,^ and that a classification of the nephritides on the basis of pathological physiology brings us in 'these modern days back to yet older teachings, to those of Frerichs^ for example, who regarded all the nephritides to be in essence the same. The morphological changes that occur in the kidney, which any pathologist will accept as characteristic of the acute forms of nephritis, and for the recognition of which no elaborate histological technique is at all necessary, are : 1. An increase in the size of the kidney, traceable on the examination of fresh, unfixed, and unstained cells, back to an increase in the size of the individual cells and tissues composing the kidney. 2 . A loss of the normal color of parts or all of the kidney which assume a less gHstening, drier, and more opaque (boiled) look. On microscopic examination this change is found to be associated with the appearance of granular substances in the cells of the affected portions of the kidney. This change in color, taken in conjunction with the increase in the size of the kidney, constitutes the *' cloudy swelling" of the pathologists. 3. The appearance of blood corpuscles extra vascularly. 1 The most accessible of Weigert's papers on nephritis appear in Virchow's Archiv during the years i860 to 1875. * Frerichs: Die Bright'sche Nierenkrankheit. Braunschweig, 185 1. 58 NEPHRITIS They may be found in the tissues of the kidney itself, or in the spaces about the glomerular tufts and in the urinifer- ous tubules. 4. Evidences of a falling apart of the kidney as a whole and of a disintegration of the indi\idual cells of the kidney. Under this heading are grouped not only the gross destruc- tive lesions observed in the kidney, such as the rupture of capillary tufts, but the separation of individual and groups of cells from their attachments in the glomeruli, Bowman^s capsule and the uriniferous tubules (formation of casts). This catalogue of morphological changes as given for acute nephritis, or as we might better call it acute parenchym- atous nephritis, holds with but small modification for the chronic parenchymatous forms also. The chronic forms show all the changes of the acute with certain others added to them, notably a ''fatty degeneration," and the develop- ment of a certain amount of scar tissue. But where are we to put the chronic interstitial type of nephritis? 2. The Relation Morphologically of the So-called Chronic Interstitial Nephritis to the Parenchymatous Tjrpes. The most apparent difference between the parenchyma- tous forms of nephritis and the chronic interstitial resides in the difference in the comparative sizes of the organs as a whole in the two conditions. While the former is larger than normal, the latter is smaller. And yet this does not constitute the most characteristic difference between the two. This is rather to be sought in the way in which the two pathological states are brought about. In the frankly parenchymatous forms of nephritis the whole kidney is usually affected at once and, on the whole, equally. If the kidney cells are sufficiently damaged, and the patient dies, we find on autopsy the familiar large kidney. NEPHRITIS 59 In chronic interstitial nephritis the ultimate picture is pro- duced through a gradual but complete destruction of one piece after another of the kidney parenchyma, with re- placement of the defect with connective tissue. The por- tions of kidney involved in this localized destruction of kidney parenchyma show all the signs characteristic of parenchym- atous nephritis. Between these localized areas of paren- chymatous nephritis the kidney tissue is healthy. When, now, we remember that less than one-third of the total kidney substance is necessary for the maintenance of life, it is easy to see why a patient with chronic interstitial nephritis runs along in a fairly normal way. The de- struction of the kidney occurs so very slowly that little albumin appears in the urine, and casts only in small num- bers. So the patient may die without his kidney state ever having been recognized, or the symptoms of intoxi- cation characteristic of removal of kidney substance down to the physiological minimum may be the first to draw our attention to the pathological state, clinically. We shall have occasion to return to all this later. For the present it is sufficient to merely emphasize the fact that a chronic interstitial nephritis is in essence also a paren- chymatous nephritis, — a slow-going hut progressive localized parenchymatous nephritis resulting in death and loss of the involved portions of the kidney, and resulting ultimately in a picture which is best described by calling it an atrophy of the kidney. The patient with chronic interstitial nephritis is, therefore, in the same position as an animal that has had its kidney substance progressively diminished in amount by successive operations and ablations of kidney paren- chyma. The man who has gone through Kfe without signs or symptoms of kidney disease, who dies of other causes than kidney disease and shows on the autopsy table what, as morpholo gists, we call chronic inters titi?l nephritis, is 6o NEPHRITIS simply like the animal that has suffered a great reduction in total kidney substance, but has not yet reached the physiological minimum compatible with life for that animal under the conditions under which it has to live. What is left of kidney parenchyma to man or animal is still physi- ologically active and physiologically adequate. Such a biological contention finds its morphological support in the fact that the parench}Tna of such (morphologically) chronic interstitial t}^es of nephritis shows little or no change either macroscopically or microscopically (''small red kidney"). The presence of the connective tissue in the kidney is an accident, it is scar tissue, and whatever importance we may care to attach to it morphologically, this is no more any indication of the physiological state of the kidney parench}Tna that is left than the scar which re- pairs and serves to reunite the ruptured ends of a muscle is any index of the physiological efficiency of that muscle. With this we have disposed of the apparent difference be- tween parenchymatous nephritis and what is called chronic interstitial nephritis so far as differences in the sizes of the kidney as a whole are concerned. At the same time we ha\'e indicated why what parenchyma is left in the (morphologically) chronic interstitial nephritis may look fairly normal both macroscopically and microscopically. Not until larger portions of the kidney, or maybe all that is left of the organ, shows the changes characteristic of the paren- chymatous types of nephritis {^^ small gray kidney ^^), do we have added to the morphological picture of chronic interstitial nephritis, as already described, the increase in the size and changes in the color of the individual cells of the kidney, and franker evidence of albumin, blood, and casts in the urine, as listed above, vn discussing the parenchymatous types of nephritis. In thus getting the chronic interstitial forms of nephritis NEPHRITIS 6l back into a group with the frankly parenchymatous forms, one point remains undiscussed, and that is the association of an oedema and a diminished secretion of urine with the one form, while a lack of oedema and an (so-called) increased urinary output go with the other. But these physiological phenomena can also be easily explained, as will be done later. Let us now discuss the morphological changes observed in the nephritic kidney as listed above, seriatim. 3. The Changes in the Size and in the Color of the Kidney in Nephritis (Cloudy Swelling).^ §1. While we shall later find ourselves compelled to discuss these two changes in the kidney separately, we will first take them up together because it is in this form, under the caption of cloudy swelling, that they have been chiefly discussed by the pathologists. As is familiarly known, we are indebted to Rudolph Virchow not alone for a first clean-cut description of this cloudy swelling as it occurs in the kidney (and other parenchymatous organs) , but for a first attempt to analyze its nature. Virchow held cloudy swelling to be '' a kind of acute hypertrophy with tendency to degeneration," a phrase which has found its way into even our most mxodern textbooks of pathology. But while such a phrase still serves many as a satisfactory characterization of the condition from a biological standpoint, it means nothing, of course, from the standpoint of its physicochemical analysis. Toward the physicochemical analysis of cloudy sweUing Virchow contributed the important suggestion that the cause of the granule formation in the cells is due ^Martin H. Fischer: Kolloid Zeitschr., 8, 159 (191 1). 62 NEPHRITIS to a change in their albun^inous constitution. He based this conchision upon the fact that the granules are soluble in acids and alkalies, and not in ether, thereby distin- guishing them from fat deposits in the cells (fatty degenera- tion) which at times mimic in general appearance cells affected with cloudy sweUing. For the increase in the size of the cells Virchow gave only the biological explanation of an ''increased irritation " of the affected cells, caused for example by the products of an infectious disease, in conse- quence of which they were made to take up '' excessive amounts of nutrient material." That cloudy swelhng represents a change in the albumi- nous constitution of the cell seems never to have been questioned. Eduard Rindfleisch ^ accepted this belief and, m.oreover, expressed himself of the opinion that cloudy swelling was '' passive " in its nature and due to '' a kind of corrosive action in consequence of which the albuminous matters, held in solution by the protoplasm, undergo coagulation and become visible as minute granules." In 1882, Julius Cohnheim ^ subjected Virchow^ s teachings to a rigorous critique. That the process of cloudy swelHng in- volved the albuminous constituents of the cell he did not question, but he perpetuated a conclusion (erroneous as we shall see) of Virchow^ when he wrote, "Of course we must deal here with a protein that is different from that which is normally present in the cell protoplasm ... as we could not otherwise account for the optical difference." But Cohnheim, too, expressed the possibility of cloudy swelling representing '' a spontaneous precipitation in solid form, or the coagulation of a previously fluid protein." ^ Eduard Rindfleisch: Pathological Histology. Translated by Baxter, 30. London, 1872. 2 Julius Cohnheim: Allgemeine Pathologic, Zweite Auflage 1, 662; 2, 570. Berlin, 1882. NEPHRITIS 63 What underlies such a change in the albuminous consti- tution of the cell, he did not attempt to say, but he showed very conclusively that the causes proposed by older writers were questionable if not entirely inadequate. Thus he showed that the fever accompanying the various infections liable to be accompanied by a cloudy swelling could not by itself be the cause of the change, by calHng attention to the well-known fact that cloudy swelling may be absent in cases that have run a high fever, or present in conditions not associated with an abnormal rise in temperature. In such a half-hypothetical state did the subject of cloudy swelling remain until 1901, for in spite of various discussions of the subject, no clear-cut advajice was made either toward defining more precisely what cloudy swelling is, nor yet in discovering a something common to all con- ditions associated with cloudy swelling, which might justly be regarded as its fundamental '' cause." At this time H. J. Hamburger ^ reported a series of observations on iso- lated liver, kidney, and spleen cells which served to establish more firmly what can justly be regarded as little more than lucky speculation on the part of the older writers. Ham- burger applied to these cells some earlier observations made on red and white blood corpuscles. In a study of the latter he had found that various acids, including carbon dioxide, bring about an exchange of substances, including water, between the red and white blood corpuscles and the serum in which they are contained. Under the influence of acids all these cells take up water from their surround- ings. He paralleled this with the findings of previous ob- servers that, in fevers of the most varied origins, acids are produced and the '^ alkalinity" of the blood is reduced, and ^H. J. Hamburger: Osmotischer Druck und lonenlehre, 3, 49 (Wies- baden, 1904), where references to his earher articles may be found. See also Karl Landsteiner: Ziegler's Beitrage, 33, 237 (1903). 64 NEPHRITIS so concluded that in this acid production resided the cause for the enlargement of the cells in cloudy swelling. Just why acids bring about any enlargement he does not state defi- nitely, though changes leading in the aggregate to an in- crease in the osmotic pressure of the cell contents are held mainly responsible. Hamburger then points out that the white opaque appearance of isolated kidney, liver, and spleen cells exposed to dilute acids is identical with that of cells affected with cloudy swelling and discovered post mortem. Cells treated with an acid are studded with granules, as are the cells showing a cloudy swelling that are found post mortem, and to prove that the granules are similar in character in both, and represent albumin precipitates, he calls attention to the fact that the granules which he has made appear through a weak acid dissolve again as the acid concentration is increased. An analogue of the pro- duction of the granules in the isolated parenchyma cells Hamburger found in the precipitation of albumin from a diluted blood serum when an acid is added to this. The first great value of Hamburger^ s studies resides in the fact that he has detailed experiments which show that all the necessary elements for cloudy swelling reside in the parenchyma cells themselves, and that he has pointed out that what is added through an infectious disease (or as we might say in order to make our contention more pointed, any condition which is capable of inducing a nephritis) may be nothing more than a Uttle acid. This simple reason- ing of Hafuburger does away with the biological terminol- ogy that has so long been appHed to the subject of cloudy swelling, and renders possible an attack upon the problem in the Hght of the simpler concepts of physics and chemistry. Since Hamburger^s work I know of no contributions to the subject of cloudy swelling which have either ques- tioned the correctness of his view, that the increased ab- NEPHRITIS 65 sorption of water by the cell affected with cloudy swelling represents an osmotic phenomenon, nor yet any which have adduced further evidence in support of the protein precipi- tation idea of the granule formation in this condition. As the subject is intimately connected with our problem of the morphological changes occurring in nephritis, I felt that it could to advantage be restudied at this time, es- pecially since the acquisitions of colloid chemistry — the chemistry of the very substances of which the kidney is composed — have furnished us with data and theoretical deductions that are of immediate applicability in the analysis of this problem. By utilizing these we shall find ourselves in a position to give a simpler physicochemical explanation for the increased water absorption by the tissues in cloudy swelling than is contained in the unsatis- factory osmotic explanation of this part of the phenomenon, and at the same time we shall learn how the clouding of the parenchymatous organs follows the same laws as the pre- cipitation of such a simple colloid as casein. In this way we shall find a ready explanation of the first two of the morphological changes in the kidney catalogued above and characteristic of nephritis, namely, the increase in the size of the parenchymatous elements, and their change in color. At the same time we shall find that both arise from the same abnormal production and accumulation of acid in the kidney, — the same condition therefore that we have previously held responsible for the albuminuria. § 2. We shall first describe a series of observations on the artificial production in excised kidneys of the changes characteristic of nephritis (production of cloudy swelling) which will prove themselves of service in the further analysis of our problem. The methods employed in these 66 NEPHRITIS experiments were the same throughout. The kidneys of healthy, freshly-killed rabbits and guinea pigs were used, which after being sliced were distributed into bowls each containing loo ex. of the necessary solutions. As it is im- possible to give absolute values to the various grades of grayness and opacity observed in the different solutions, one can, in the description of the findings, only compare the appearance of a tissue in one solution with that of a similar piece in a different solution at the same time. The general conclusions from a long series of experiments may be sum- marized as follows: (a) When slices of fresh kidney are dropped into dis- tilled water they slowly swell and at the same time become gray. A tone of gray that is readily distinguishable from the color of the normal organ appears over the cut surface some three or four hours after being dropped into the water. This gradually increases in intensity until, twenty- four hours after the beginning of the experiment, the tissues look decidedly gray. For a day or two longer this may continue to increase in intensity, but the change from the first twenty-four hours is not very marked. As the tissue becomes gray it shows an acid reaction to litmus, and this acid production in even a small piece of tissue may be sufficiently great to impart an acid reaction to the sur- rounding fluid. {h) The pieces of tissue swell much more rapidly if they are placed in any dilute acid instead of in distilled water. This is shown in Fig. 14. A has sunply been protected against evaporation. B has lain for an hour and a half in a 0.003 normal hydrochloric acid solution. The two pictures represent opposite faces of the same cut through the kidney. The tissues also become gray sooner in an acid solution than in distilled water. In 0.005 normal solutions of lactic, formic, acetic, tartaric, hydrochloric, NEPHRITIS 67 sulphuric, or nitric acids a decided cloudiness is visible in ten minutes after immersion. This cloudiness becomes gradually more marked. After three hours, when the con- trol in distilled water is just showing a grayness, the sHces of tissue in the dilute acids are grayer than the controls appear the following day. The various acids show some difference in the intensity of the cloudiness that they pro- duce, but this is so much a function of their concentration Fig. 14. and the time that a table of their relative effectiveness cannot be given to advantage. After another two hours the tissues in all the acid solutions are intensely gray. The control in pure water is about as gray as the tissues placed in the dilute acids were after ten minutes of immer- sion. On the following day an ultimate degree of grayness (a typical "boiled" appearance) is shown by all the organs in the dilute acids. Speaking generally, it may be said that when the effects of different concentrations of the same acid are compared, the cloudiness develops the more rapidly the greater the concentration of the acid. So far as intensity is concerned 68 NEPHRITIS there is, however, Httle difference. In the end every acid gives the tissues a boiled appearance. With different concentrations of nitric acid I found the boiled appear- ance after a ten -minute immersion in o.i normal acid. In 0.05 normal acid the same appearance was attained in an hour; in 0.025, o.oi, and 0.002 normal in two to three hours. What has been said of nitric acid holds true in general for all acids, though there are more or less specific differ- ences with the different acids both so far as rapidity of de- velopment and intensity of the cloudy sweUing is concerned. Acetic acid is particularly interesting. With increasing concentrations of the acid there is first an increase in the rate and (in units of tim.e) in the intensity of the cloudiness produced. If we observe closely, this is seen to be followed with increasing concentrations of acid (above o.i normal acetic acid) by a stage in which the cloudiness is less than in lower concentrations. To see these successive changes one must observe especially the superficial portions of the tissues. A second clouding can now^ be obtained by chang- ing to one of the ''strong" acids (nitric, sulphuric, or hydrochloric) of the same or of a higher normality than that of the acetic acid which has brought about the dis- appearance of the first clouding. This change from cloud- iness to clearness and back again to cloudiness, with progressive increase in the concentration of an acid, can be followed particularly well under the rricroscope [see {g) below]. But even in the sections of tissue kept in the " stronger " acids can two such regions of cloudiness sep- arated by one of clearness be discerned. I found, for ex- ample, that the marked cloudiness of slices of kidney, which had been kept for one and one-half hours in concen- trations of nitric acid up to 0.005 normal, disappeared when the surface of the organ was touched with the ordinary NEPHRITIS 69 weak acetic acid of our laboratory reagents, to reappear when dilute nitric acid was substituted for it. The cloudiness of the tissues obtained in any of the acids listed above, if developed in not too high concentrations (below 0.005 normal), can also be made to disappear if the tissues are placed in equinormal alkali solutions, or in alkali solutions of a higher concentration. {c) Through the addition of various salts the develop- ment of a cloudiness in any acid solution can be either re- tarded or hastened. So far as the absorption of water is concerned, all the salts have but one effect — they decrease the amount of the swelling in the acid solution. When to a 0.005 normal hydrochloric acid solution enough of various potassium salts is added to make their final concentration 0.05 molecular, the following is noted. After ten minutes immersion it is plainly evident that some of the salts are accelerating the effect of the acid in producing the devel- opment of the cloudiness, while others are inhibiting it. In an hour the differences are very marked. The sul- phocyanate, iodide, bromide, and nitrate all increase the cloudiness, the first named being the most powerful in this respect. Then comes the pure acid. Following this comes the chloride, the acetate, the tartrate, and the citrate. After three to six hours of immersion the differences are still more striking. In the solutions containing the first- mentioned salts the tissues are ^'boiled" in appearance. In the pure acid the grayness is well marked. The tissues in the solutions containing the chloride and the acetate lag somewhat behind the pure acid. In the tartrate a faint film is only just visible over the surfaces of the organs. The sections in the solutions containing the citrate look perfectly normal. In fact, in the two last-named solutions the organs retain an almost normal appearance for two to three days. 70 NEPHRITIS Similar results are obtainable by using sodium or ammo- nium salts in place of the potassium salts, or lactic, formic, or m'tric acid in place of the hydrochloric, except that in the latter case the absolute rates at which any degree of cloudiness is obtained is not quite the same as in hydro- chloric acid. {d) Various salts accelerate or retard the development of a cloudiness in sections of kidney placed in their pure solutions, in just the same way as they accelerate or re- tard the development of a cloudiness if an acid is added at the same time, only the rate of development and the absolute intensity of the cloudiness attained is less in the pure salt solutions than in mixtures of these with any acid. In all salt solutions the kidney slices swell less than in pure water. These findings are to be interpreted by noting that the excised tissues become acid, so that the tissues placed in the pure salt solutions are really in the same state as the tissues described in the preceding para- graph — the tissues are really in an acid solution plus cer- tain salts — only the concentration of acid is lower in this case than in the previously described experiments. {e) Alkalies do not produce a cloudiness of kidney parenchyma in any concentration. Sodium, potassium, ammonium, and calcium hydroxides were employed in con- centrations up to 0.03 normal. The superficial layers of the tissue slices ''dissolve" in the hydroxides, covering the tissues with a clear gluey mass. After two or three days the tissues lose their bright normal color, but the gra>Tiess assumed is only slight. The sHces of kidney swell just as they do in acid solutions. (/) The addition of any salt to the solution of an alkali does not lead to any cloudiness of the tissues, though it markedly reduces the tendency of the superficial layers of the tissues to go into ''solution," and the swelHng of the NEPHRITIS 71 tissue fragments as a whole. I have tried the chlorides, bromides, iodides, nitrates, sulphates, sulphocyanates, ace- tates, tartrates, and citrates of sodium, potassium, and ammonium in conjunction with the hydroxides of sodium, potassium, and ammonium without effect. I have also tried a few strontium and barium salts with these hydroxides and calcium hydroxide, employing all in such low concentrations as to prevent the formation of precipitates, but I got no cloudiness of the immersed tissues. {g) The macroscopic changes observed in the kidney when this is immersed in water, various acids, or alkalies, in salt solutions or these in combination, show a series of interesting parallels microscopically. A perfectly fresh scraping from the kidney shows the cells to possess a fairly clear protoplasm in which lie but few granules. Even after the kidney cells have been kept for twenty-four hours (simply in their own moisture, and pro- tected against evaporation by being covered) they show no change from this appearance. But as soon as water touches the cells, especially if the organ has been kept for twenty-four hours, or if they are placed in any very dilute acid, a grayish film is seen to develop macroscopically, and microscopically the cells are now found thickly studded with granules. This is the typical histological picture of the cloudy swelling described in our textbooks of pathology. If now, while such cells are being observed, a little caustic soda is allowed to run under the cover slip, the cells as a whole are seen to swell, the granules to become fainter, then fewer, and finally to disappear entirely, and if enough alkali is added the whole goes into homogeneous ''solution." The granules can also be made to disappear by the ad- dition of more acid ; they form, for example, in very dilute 72 NEPHRITIS acid, and disappear again if the concentration of this same acid is raised. ]\Iost interesting is the fact that this granu- lar appearance can be made to come a second time by still further increasing the concentration of the acid. Acetic acid will not do this, but nitric acid will do it promptly. If strong nitric acid is used this second appearance of the granules is only a temporary affair, for they again dis- appear as the whole tissue goes into ''solution." With the second appearance of the granules the cells undergo a marked shrinkage from the more swollen state attained pre- viously, but this shrinkage, like the second appearance of the granules, is also only temporary, and the cell undergoes a final enormous swelling before being ''dissolved." §3- How now are we to interpret these various findings, and what light do they bring us regarding the cause and the essential nature of those changes of like character, which we observe in the kidney in nephritis and which lead to the increase in its size and to the change in its color? Our first attention must be dedicated to the matter of the increase in the size of the cells. H. J. Hamburger recognized very clearly that the funda- mental cause for the increase in the size of the cells affected with cloudy swelling lies in the production of acid in them. As we have already learned, evidences of an abnormal pro- duction and accumulation of acid in the kidney occurs in every case of nephritis, and so we may make this condition, which we have already made responsible for the albuminuria, responsible for this increase in the size of the kidney also. But how does an abnormal acid content manage to bring about the increased water absorption which leads to the increase in the size of the cells (and so of the kidney as a whole) in nephritis? Hamburger answered this question by NEPHRITIS 73 attributing an indirect effect to the acid, whereby this was assumed to increase the osmotic concentration within the cells. The enlargement of the cells in "cloudy swelling" represents an oedema of the affected cells, and this is most easily accounted for on the basis of the colloidal constitu- tion of living matter. 1 The serious objections that can be lodged against the widely-accepted belief that cells repre- sent osmotic systems cannot be raised against the view that the (lyophihc or emulsion) colloids of the tissues and their state determine the quantity of water absorbed by a cell. As is well known, the amount of water that such colloids (as represented by gelatine, fibrin, and serum albu- min, for example) will absorb is enormously increased if any acid is present. This fact receives incidental illustration in Fig. I. On this basis, it is easy to parallel the absorption of water, and so the enlargement of the cells and the kidney as a whole, when affected with nephritis, with the increased amount of water absorbed, say by a gelatine cube or some fibrin particles, when instead of being placed in water they are placed in a dilute acid of some kind. In the case of gelatine and fibrin, and similarly in the case of the experiments on excised kidneys, the source of the water for the increased swelling is to be found in the solutions surrounding these colloidal structures; in the case of the nephritic kidney, in the blood and lymph streams passing through the organ. There is, within certain limits, an increase in the amount of the swelKng of such emulsion colloids as gelatine or fibrin with every increase in the concentration of the acid surrounding them. On this basis we can understand the increase in the swelling of the kidney cells with every increase in concentration of the acid up to a certain point. When a certain optimal concentration of the acid is 1 See Mariin H, Fischer: (Edema, 85, New York, 19 10. 74 NEPHRITIS exceeded, the colloid swells less than in weaker solutions (see Fig. i). This furnishes a ready interpretation of the finding detailed above, that on substituting nitric acid for a weaker solution of acetic acid, kidney and liver cells are seen to shrink. Incidentally, it is worth while to empha- size that in the great rapidity with which such cells will give up and take up water, in changing from a medium of one concentration to another having a lower or a higher one, lies a powerful argument against the osmotic pressure idea of water absorption in cells. I have seen these cells pass from the swollen state, in a weak acetic acid solution, to the greatly shrunken state induced by nitric acid, and through a second swollen state into '' solution " in less than two seconds. Equalizations of osmotic differences either through a movement of solvent, or of dissolved sub- stance, do not occur with such velocity. We may now turn to a consideration of the changes in tJte color of the kidney in nephritis, and see how^ these be- come interpretable on the basis of the fact that in this condition an abnormal amount of acid is present in the kidney. The statements made above regarding the means by which a cloudiness can be produced in the parenchymatous cells of the kidney, or the rate of development, or the in- tensity of such a cloudiness be increased or decreased, have all of them parallels in the ways and means by which protein may be precipitated from one of its '* solutions," or such a precipitation be hastened or retarded. TJie development of a cloudiness in the kidney cells follows most closely tlie solution and precipitation of such a colloid as casein.^ Casein ^ is insoluble in water. It is soluble in dilute ^ This term is used in Hammarsten^s sense and corresponds therefore with the caseinogen of Halliburton. 2 For a discussion of the general properties of casein see 0. Hammarsten: Physiological Chemistry, Translated by Mandel, New York; E. Laqueur NEPHRITIS 75 hydroxides, in which state it is electro-negative. It is in this state that we find the body proteins normally, as Wolf- gang Pauli 1 has shown. When a dilute acid is added to such an electro-negative protein, let us say to a solution of casein in any hydroxide, a precipitate of the casein is thrown down. A similar precipitation of an electro- negative colloid occurs when our sections of kidney are immersed in any dilute acid. The development of a cloud- iness in tissues immersed in water is also to be regarded as a precipitation through a dilute acid, only in this case the tissues themselves produce the acid. Similar conditions hold in nephritis, when, in consequence of the abnormal acid content of the kidney, some of the protein constituents of the cells composing this organ are precipitated. As we have already found this same acid to be responsible for an increased affinity of the tissue colloids for water, it is easy to see how from the two there results, when water is avail- able, the picture we designate '' cloudy swelling." But our analogy goes further than this. If we continue to add acid to the reaction mixture in which our casein was last precipitated, we find that with an increase in the con- centration of the acid the casein goes back into solution. This is what we observe in the kidney cells when we note the cloudiness produced in a weak solution of any acid, or that found in the nephritic kidney on autopsy, to dis- appear on applying a stronger solution of the acid (say acetic acid) to the kidney. This macroscopic change has its parallel in the microscopic disappearance of existing granules in a cell, the seat of a cloudy swelHng (found either post mortem or induced artificially) , when acetic acid is run under the cover slip. But the casein thus redissolved in and 0. Sackiir: Hofmeister's Beitrage, 3, 193 (1903); W. A. Osborne: Jour. Physiol. 27, 398 (1901); T. B. Robertson: Jour. Biol. Chem., 2, 317 (1907); L. L. van Slyke and E. B. Hart: Am. Chem. Jour., 33, 461 (1905). ^ Wolfgang Pauli: Naturwissensch. Rundschau, 21, 3 (1906). 76 NEPHRITIS such an acid as acetic acid can be precipitated a second time if strong nitric (or hydrochloric or sulphuric) acid is allowed to flow into the test tube. If the protein is not present in excessive amounts, this second precipitate also disappears: we say it goes into solution in the excess of the nitric acid. It is not difficult to see that this is entirely analogous to the reappearance of granules in the kidney cells, with subsequent total solution of the affected cells, on the addition of nitric acid for example, to cells in which a previous set of granules has been made to disappear by the addition of acetic acid. Equinormal solutions of different acids are not equally effective in producing a precipitation of casein, neither are they equally effective in producing the cloudiness of cloudy swelling. In low concentrations certain salts favor the precipitation of casein in dilute acids while others hinder this. The sulphocyanates and iodides quickly pre- cipitate casein from an acid solution in heavy curds. Equimolecular solutions of the bromides, nitrates, and chlo- rides produce only an opalescence, while in citrates the casein remains in solution. When arranged according to the in- tensity with w^hich these anions favor the development of a cloudiness in the kidney the order is the same. Various kations, in the dilute solutions in which they have to be used to prevent their precipitation as hydroxides, do not influence the precipitation of casein. Neither do they^affect the development of cell cloudiness. Kidney cells also follow the behavior of casein tow^ard alkahes. All the alkahes make casein go into solution and, similarly, the alkalies do not produce any clouding in kidney cells. ^ Casein is not precipitated in alkaHne solu- ^ The slight grayness developed by slices of kidney, kept for several days in a dilute alkali, has its parallel in the turbidness which we find developed in alkaline solutions of casein, when these are kept for longer periods of time. NEPHRITIS 77 tion by the addition of any of the ordinary salts. Neither is a cloudiness produced when any salts are added to slices of liver or kidney immersed in a dilute alkali. Point for point the analogy between the precipitation of casein and the artificial development of a cloudiness in kidney cells seems therefore to be complete, and since there exists no discoverable difference between the changes thus artificially induced in excised kidneys and those which nature produces for us in this same organ in nephritis, nor yet in the conditions leading to these changes in either case, we would seem to be justified in considering all these changes as in essence the same, and as caused funda- mentally by the same circumstances. As this process of cloudy swelling represents a series of changes in the state of the cell colloids, it is clear that the employment of any methods in its study — such as fixing agents and various stains — which in themselves are capa- ble of producing changes in the state of cell colloids, should be excluded. Nevertheless, to meet the possible objection that what has been described in these pages as cloudy swelling might really not be identical with this change as observed on the autopsy table, our pathologist, Paul G. Woolley, generously offered to examine by approved his- tological methods the tissues in which I had produced cloudy swelling artificially. He reports that the pictures obtained are identical with the most extreme grades of cloudy swelling that are encountered pathologically. In concluding these paragraphs we have to answer the final question of the relation of the swelling of the kidney cells to the clouding in them. On the basis of the fundamental work of Wolfgang Pauli ^ and his coworkers, Hans Han- ^ Wo. Pauli: Kolloid Zeitschr., 7, 241 (1910); Pauli and H. Handovsky: Biochem. Zeitschr., 18, 340 (1909) 24, 239 (1910); H. Handovsky: Kolloid Zeitschr., 7, 183, 267 (1910); Fortschritte in der Kolloidchemie der Eiweisskorper, Dresden, 191 1; Karl Schorr: Cited by Pauli and Handovsky. 78 NEPHRITIS dovsky and Karl Schorr, this is easily done. As these in- vestigators have shown, the sweUing and solution of a protein colloid (its hydration) and the loss of water and precipitation of this same colloid (its dehydration) repre- sent antagonistic processes and are therefore mutually exclu- sive. It follows from this that the swelling of the cells in a parenchymatous nephritis, and the development of a cloudiness in them, can impossibly involve the same colloid, — in other words, at least two must be involved. The conditions w^hich permit the one of these to imbibe w^ater and so lead to an increase in the size of the cell are of such a character as to lead to the precipitation of another, and so to the cloudiness. Wolfgang Paidi kindly advised me to test out this idea in a model made by pouring a solution of casein (prepared by saturating sodium hydroxide with casein) into a concentrated, carefully-washed gelatine (20 per cent) and allowing the whole to stiffen. When plates are cut from such a mixture they swell (absorption of water by the gelatine) and become cloudy (precipitation of casein) under the same conditions (presence of acids and various salts) as were found above to lead to a ''cloudy swelling " in slices of kidney. 4. The Bleeding into and from the Kidney in Nephritis (Haemorrhage by Diapedesis). The blood that appears in the urine in some cases of nephritis may have a purely traumatic origin; in larger part, however, pathologists hold that it gets from the capillaries into the urine by diapedesis. Through diapede- sis are also explained the haemorrhages into the kidney substance itself. As such bleeding does not occur from the normal kidney, we become interested in its mechanism, and it becomes a part of our problem to discover why in NEPHRITIS 79 nephritis such a process of diapedesis, which occurs also in other pathological states, should be especially prone to appear. We still lack a satisfactory explanation of the mechanism of diapedesis. Our present teachings continue to partake of the views of von Recklinghausen and Julius Arnold, who held that holes (so-called stomata) exist in the capillaries, and that through these the red blood corpuscles escape in conditions associated with a bleeding by diapedesis. But such a condition, as Julius Cohnheim pointed out years ago, is grossly incorrect, for what escapes from the blood in haemorrhage by diapedesis is not the whole blood, but only the red blood corpuscles, and it is inconceivable how holes which would permit the passage of the cellular ele- ments of the blood through them should hold back the liquid portion of the blood, Cohnheim believed diapedesis to be dependent upon changes in the blood vessel walls whereby these became abnormally permeable, after which he held the blood pressure to be able to force the red blood corpuscles through them. How such an abnormal per- meability was brought about he declared himself unable to explain. Haemorrhage by diapedesis, while discussed by us be- cause present in some forms of nephritis, is really, of course, a widely distributed pathological phenomenon. As is famil- iarly known, it occurs in any well-marked passive con- gestion, produced, for example, by ligation of the veins of any of the parenchymatous organs, of the mesenteric veins, or of those coming from the leg or the ear of a rabbit or dog. But it occurs also after ligation of the arterial blood supply to a part, and I have observed it in the entire absence of any circulation in the legs of frogs so ligated as to close both arteries and veins, and kept in a little water. Haemorrhage by diapedesis occurs also in 8o NEPHRITIS conjunction with the acuter forms of inflammation no matter how induced. It is clear from these few remarks that blood pressure, which might at first sight be thought to be of some impor- tance in squeezing the red blood corpuscles out of the blood vessels into the surrounding tissues, cannot be of great im- portance in this regard, for diapedesis occurs in conditions associated Tvith a decrease in the blood pressure, or, as just pointed out, even in its entire absence. What is present in all the conditions noted is such a disturbance in the circulation as to lead to a state of lack of ox}'gen in the tissues, and, we have to repeat, an abnormal production and accumulation of acids in the affected regions. .\nd this is what we have in the kidney in nephritis. But how does this now lead to the diapedesis? The answer is not hard to find. We have already called attention to the well-known fact that the cells of the living organism represent in the main a mixture of several so-called lyophilic or emulsion colloids. Under normal circumstances in the body these are in a swollen state that is similar to that assumed by fibrin or gelatine when placed in water. If a little acid is introduced into such a colloid the absorption of water by it is enor- mously increased, and as we have already pointed out be- fore, this is what happens when acid is introduced into the kidney (or into the tissues of the other parenchymatous organs, the intestine, the leg, or the ear), in other words, an " oedema " develops. But this increased absorption of water makes the tissue softer (or to put it more technical!}^, its internal friction is decreased and its surface tension is changed) and now the red blood corpuscle which lies in contact with its surface is no longer held out by the surface layer of the tissue colloids (the blood vessel wall) but pene- trates this — is really "swallowed" by the tissue. The NEPHRITIS 8i increased fluidity of the kidney tissues, after these have been treated with a little acid in the presence of water, is readily observable under the microscope. The cells can be pushed about and molded on slight pressure in a most striking way. What makes the red blood corpuscle move through the tissues are inequalities in the stresses present in the tissue colloids. By a process, the reverse of that described, the tissue which has once swallowed a red blood corpuscle may again get rid of it, though in practice such a result is hardly to be expected, for after a softened tissue that has swallowed some red blood corpuscles has a more normal circulation once more restored to it, it is likely to lose its excess of acid, and so its water, so rapidly that the red blood cor- puscles remain behind entangled in the tissues. As a matter of fact we know that the red blood corpuscles that have escaped into the tissues are usually absorbed indirectly, after they have disintegrated. What we have said here regarding the red blood cor- puscles holds of course also for the white blood corpuscles only these possess in addition independent powers of move- ment which are lacking to the red blood corpuscles.^ More strictly in the class with the red blood corpuscles belong the bacteria which we know may reach the kidney from any part of the body and pass through the kidney substance out into the urine. Briefly formulated, the problem of how the red blood cor- puscles in nephritis pass into the tissues of the kidney or ^ In the discussion of the migration of white blood corpuscles in inflamma- tion (chemotaxis) most emphasis is always laid upon the changes that the white blood corpuscles themselves are believed to suffer (for example, changes in surface tension), which result in their movement toward the in- flammatory center. This is only half the problem. The changes in the tissues themselves (changes in viscosity, for example), produced through the action of the excitant of the inflammation, also play a role. 82 NEPHRITIS through these out into the urine, or the problem of how white blood corpuscles or bacteria do this comes to be the problem of how one colloidal body may pass through another, and of the laws that govern such a passage. No holes are necessary in order that one colloid may pass through another, and such a passage is accomplished without one colloid losing its identity in the other or leaving behind it any evidence of its passage. The matter can be prettily illustrated by letting a mer- cury drop or solid metals (iron fragments or shot, or these covered with colloidal material as agar-agar or collodion), under the influence of gravity, move in all directions through a soHdified gelatine. The mercury is particularly suitable, for, while not a colloid, it has the " Hquid " character pos- sessed by the red and white corpuscles. In the body the mi- gration of the blood corpuscles (or metal fragments, etc.) does not of course occur under the influence of gravity, but in consequence of inequalities in the pressure exerted upon the surface of these elements, occasioned through inequalities in the stresses present in the tissues (brought about in turn through local changes in the water content of the lyophilic colloids comprising the tissues). And as the question of whether a mercury drop will enter a solidified gelatine, and the rate at which it will move about in this are matters that have to do with the surface tension relationships that exist between the mercury and the gelatine, and the viscosity of the gelatine (in its turn, affected by concentra- tion, temperature, acids, bases, and salts), so these same factors play a role in diapedesis as observed in the hving organism. In Fig. 15 is shown how a mercury drop is unable to penetrate a stiffened gelatine (3 per cent) at room tem- perature. It may be rolled about on the surface of the gelatine without entering it. If now this experiment is NEPHRITIS 83 repeated at the same temperature, with a stiffened gela- tine of a somewhat lower concentration, the mercury drop enters it and falls slowly to the bottom (Fig. 16, a, h, c). By turning the tube about (Fig. 17), the mercury drop will move in all directions through the stiff gelatine in which of course no holes exist, and in which none remain after the mercury has passed.^ The essential change in the gelatine, which makes such pen- etrability possible in this exper- iment, was induced through regulation of the concentration. A similar change can be induced by raising the temperature some- what (not to the point of melt- ing the gelatine, of course) or, in the presence of water, by adding a little acid. This approximates most closely the change that occurs in the body when in pas- sive congestion, for example, a diapedesis into the cedematous tissues is noted. What happens under such circumstances can also be mimicked with some gelatine cubes and a few mercury drops. If two gelatine cubes are placed, the one in water, the other in a dilute acid, the one in acid ^ It is this property of colloids which explains easily why small wounds made in the hving animal close immediately. The property of colloids, which gives them such great interest biologically, is the fact that they com- bine in one the properties of liquids (surface tension, viscosity, diffusion of dissolved particles) with the properties of solids (maintenance of form). Fig. 15. 84 NEPHRITIS undergoes a swelling, which after a time reaches a stage at which it will readily admit of the passage of a mercury drop, while the control in water will not do so. b Fig. 1 6. 5. On the Origin and the Different Types of Tube Casts. In this section we will discuss how the abnormal acid content of the kidney in nephritis leads to the formation of casts. At the same time we will learn how the various types of casts that are discovered in the urine in nephritis NEPHRITIS 85 bear a simple relationship to each other ; how, in fact, it is possible to convert one type of cast into another, and back again if we so choose, under the con- ditions found in the kidney and in the urine in nephritis. What must be the effect of the ab- normal production or accumulation of acid in the kidney, so far as this prob- lem of casts is concerned, may be de- termined in any one or all of several ways. We may simply leave the nor- mal kidney, freshly removed from the body, to itself, protect it against evapo- ration, and study the effects of the post mortem development of acid in it. Or, we may slice the kidney into several pieces and place them in water, or, finally, we may place such slices directly into slightly acidified water. The kid- neys of guinea pigs and rabbits furnish excellent material and it is on these that the following observations were made. When we take a fresh kidney that has been cut across and squeeze it gently, we only see a little blood ooze from the blood vessels. If we scrape the surface and put a little of the scrapings on a sUde, we find little more than some red blood corpuscles mixed in with a little granular material. We find that it is difficult to obtain any kidney parenchyma cells, — they do not separate easily from their attachments. The same kidney, preserved for several days, presents a somewhat different appearance. The surface may not be quite so glistening when cut, and on squeezing the Fig. 17. 86 NEPHRITIS organ turbid points arise over the surface of the kidney which, when examined microscopically, are seen to be made up of epithelial cells which have loosened from the kidney tubules. These may be single, or joined together in groups, and with them are again found the red blood cells and the granular detritus that was observed in a scraping from the perfectly fresh kidney. A somewhat different picture is presented by the sections of kidney that are placed in water. These tissues become gray more quickly than the tissues that do not come in con- tact with water, and develop an opaque appearance. The normal kidney markings become gradually more and more obscured, and the tissues as a w^hole are seen to swell some- what. The whole makes up the typical picture of that which the pathologists call cloudy swelHng, and the nature of which we discussed in a foregoing section. A scraping from the surface of such a gray kidney shows a large num- ber of free epithelial cells, w^hich one has no difficulty in recognizing as coming from glomerular tufts and from the uriniferous tubules. In making the scraping one notices, moreover, that while vigorous scraping yielded little or nothing when appHed to the healthy kidney, it is no trick at all to get an abundant amount of material from the surface of a kidney that has lain in water for a day or two. One notices, moreover, that the numerous epithelial cells are swollen and studded with granules. But beside the individual epithelial cells one notices groups of these, and then casts with rounded ends of whole tubes. One has no difficulty in recognizing these as duplicates of the epithelial casts found in the urine in certain t}^es of nephritis. But the most striking picture is that presented by the sections of kidney that we have thrown into a very weak acid of some kind. In this the cloudy swelHng of the sHces of kidneys already described occurs very rapidly. A gentle NEPHRITIS 87 b Fig. 18. 88 NEPHRITIS scraping jrom the surface of a kidney slice, treated with such a dilute acid (0.002 normal lactic, for example), shows in several hours after immersion a granular detritus, separate epithelial cells, groups of epithelial cells, and casts of various kinds (Fig. 18, a and h). When the kidney is simply gently squeezed and its surface touched to a slide, and this is then ex- amined 7?ticroscopically, one cannot escape the impression that he is examining a centrifuged urinary specimen from a case of acute nephritis. The epithelial cells, the epithelial casts, the granular casts are all there. One misses only tJte hyaline cast, hut this can he promptly ohtained by simply adding a little stronger acid to our specimen under the micro- scope, when our granular casts are seen to lose their gran- ules, swell somewhat more decidedly, and become difficultly visible. Scattered nuclei may stick to the casts, but if enough acid is added, these too go, so that only the greatly swollen, entirely hyaline '' cylindroids " of some authors remain. Or, we can assure ourselves of a generous yield of hyaline casts and cyhndroids from the start if we simply increase the acid concentration into which we drop our kidney slices, or prolong their residence in the solution. We can convert the granular casts into hyaline ones quite as easily through the addition of an alkali as through the addition of an acid, and if the kidney slices are from the first dropped into a dilute alkali, only hyaline casts are obtained. The hyahne casts produced through the acids can be converted back into granular casts, if we wish, by simply running a little salt under the cover slip. A sul- phocyanate is particularly good for this purpose, but if we wish to use a salt that is more " physiological " in nature, sodium nitrate or sodium chloride will do. The hyaline casts produced through alkalies can also be converted into granular ones, though to accomplish this they must be treated with an equinormal acid. Why all these I NEPHRITIS 89 transformations are possible is, of course, readily intel- ligible when the experiments on cloudy swelling as detailed in the previous sections are recalled to mind. In Fig. 19 is shown the appearance of a gentle scraping taken from a sHce of kidney that had lain in water for several hours. A granular cell detritus and isolated casts characterize such a specimen. Nuclear fragments are Fig. 19. prominent, and the epithehal cells may in places still be made out. The cells are granular. In Fig. 20, a, is shown a scraping similarly prepared from a sHce of kidney that had lain in a 0.005 normal acetic acid for three hours. The cast formation (falHng apart of the kidney) is a far more prominent feature. In the cast occupying the central point in the photomicrograph remnants of an epithehal structure are still present. In the casts lying above this all evidences of nuclear structure have disappeared. They are filled 90 NEPHRITIS with fine granules. When these casts were treated with a stronger solution of acetic acid they became hyaline, as shown in Fig. 20, b. It is clear therefore that under the influence of a little acid the kidney drops apart into its morphological elements. While these are firmly cemented together in the healthy kidney (as witness the attempt to obtain them by scraping Fig. 2q. the surface of the kidney with a knife), they are separated with the greatest ease after the kidney has lain in acid for a while. The answer as to why the kidney falls apart as it does under the influence of acid it is needless to discuss, but the \'iew that some of the (colloidal) '' cement sub- stance " is easily " soluble " or is easily '' digested " in weak acids at once suggests itself. Such a view finds support in our previous considerations of albuminuria and the fact, easily observed in these experiments, that the solutions in NEPHRITIS 91 which the kidney slices lie come to contain with time pro- gressively larger amounts of albumin. That some con- stituents of the kidney (or of any other organ) are more readily soluble in an acid than are others, is clearly enough evident under the microscope. The nuclei of the cells still retain their outlines, for example, in concentrations of acid in which the protoplasm generally has become entirely hyaline. The action of the acid could be aided and abetted, of course, by various enzymes. What is important to us, from the standpoint of the theory of nephritis, is the way in which the kidney falls apart. The epithelial cells tend to stick together while they separate in mass from their supporting membrane. This marks the origin of the urinary cast which, in clinical cases, is washed down into the bladder by the force of the secreted urine. These simple facts regarding the origin of casts, and the conditions under which the one type may be converted into another, are not without some cHnical significance. In treatises on medicine and in works on cHnical diagnosis much has been said, not only regarding the significance of the appearance of casts in the urine, but of the significance of the different kinds of casts. It seems to me that the experiments that have just been detailed urge upon one the necessity of caution in drawing too sweeping conclu- sions from such data. So far as mere numbers of casts are concerned it requires no special emphasis to reah'ze that great numbers of casts present in the urine at one time, while indicative of a more extensive involvement of the kidney parenchyma, may not be as significant as a lesser number present over longer periods of time. The aggre- gate destruction may in the latter case, of course, be much greater than in the former (a condition further modified in the living organism by the rate and quantity of the re- generation occurring in the kidney). 92 NEPHRITIS In judging of the meaning of the character of the cast, whether epithehal, granular, or hyahne, one must be ex- ceedingly careful. We have seen, first of all, that the epithelial cast is readily convertible into either the gran- ular or the hyaline, depending only upon how much acid is present and the length of time that it is allowed to act ; and the hyaline, we have seen, can be reconverted into the granular. The thought might suggest itself that we use the nature of the cast as an index of the degree of the acid concentration in the kidney and so as a measure of the in- tensity of the nephritis. But this may not be done, for we know from autopsy findings that a nephritis need not affect all the parts of a kidney equally, or at the same time, and the urine represents a mixed product of the whole kidney. Moreover, the urine itself varies so in composition under different (physiological) circumstances that it may alter the character of the cast in its passage through the ureter and bladder, no matter what its nature when it left the kidney. A highly acid urine would on the whole tend to yield granular or, if sufficiently high, hyaline casts. An alkaline urine would tend to yield only hyaline casts. On the other hand, the salts of the urine would tend to counteract the acid and make the casts not only smaller (loss of water by the colloid) but more granular (precipitation of the colloid). One can easily satisfy himself of these facts by providing himself with casts from a clinical case of acute nephritis, or from such kidneys as I have described, and examining them under the microscope, while a little acid, or this in conjunction with various salts, is allowed to run under the cover slips of the preparations. In concluding this section it is well to revert for a moment to the question of albuminuria. It is possible to test the idea that albuminuria results from a " solution " of the proteins of the kidney under the influence of an acid in NEPHRITIS 93 conjunction with these experiments on the formation of casts. If we take a perfectly fresh kidney from either a rabbit or a guinea pig, cut it into several slices, and then wash the pieces a few times in water or a '' physiological "0.9 per cent NaCl solution, so as to get rid of the blood in the kidney, we find thereafter that the wash water gives little or no reaction for albumin. But if we permit the pieces of kidney to lie in the wash water until next day, we have no difficulty in getting the albumin reaction. Still more rapidly do we get this reaction if we immerse the washed slices of kidney from the start in a weak acid solution. Then we get the reaction for albumin promptly. If we pipette off the sediment found about the kidney pieces and examine this under the microscope, we find at the same time various kinds of casts. But the albumin is not simply due to these, for we get a marked albumin reaction after carefully filtering the solution about the kidney pieces. III. THE DISTURBANCES IN SECRETION IN NEPHRITIS. I. General Considerations. The changes observed in the secretion of urine in any case of nephritis fall into two groups: the changes in the amount secreted in any unit of time, and the changes in the quantitative composition of the urine. In all except the so-called chronic interstitial types of nephritis the secre- tion of water is diminished. In the chronic interstitial types it is said to be increased. So far as the secretion of dissolved substances in nephritis is concerned, it is gener- ally accepted that (diet duly considered !) there exists not only a diminution in the total amount of dissolved sub- stances ehminated, but variations in the proportion of the dissolved substances ehminated when compared with each 94 NEPHRITIS other and regarded in the hght of the way in which these same substances are eliminated during health. What happens here is very interesting. We find that certain sub- stances may be eUminated as well by the diseased kidney as by the normal. Certain other substances are ehminated in much smaller amounts than is normal, so small, in fact, that it is often said not at all. Experiments and observa- tions to indicate that a nephritic kidney may secrete yet other substances even better than a normal kidney are not on record so far as I know. Quantity of urine duly con- sidered, such a thing is theoretically not impossible. Before we can to advantage consider the secretion of water and of dissolved substances by the kidney, we shall first have to return to a further consideration of the posi- tion occupied by chronic interstitial nephritis in our gen- eral classification of the nephritides. As is generally known, the secretion of water by the patient with chronic intersti- tial nephritis is not diminished as in all the parenchyma- tous forms, it is normal in amount, or, as the majority of cHnicians and pathologists are wont to say, it is increased in amount. In discussing this problem of why in chronic interstitial nephritis wx do not have the diminution in out- put of water observed in the parench^miatous forms, we shall at the same time touch upon the questions of the in- creased blood pressure and the heart hypertrophy observed in the chronic interstitial forms and absent from the paren- ch}/Tnatous forms. 2. Further Remarks on the Relation of Chronic Intersti- tial Nephritis to the Parenchymatous Types. I. To the claim that in chronic interstitial nephritis the amount of urine secreted is increased, serious objection must be made. It is better to simply say that the out- put is normal. Urinary secretion is normal if (with due NEPHRITIS 95 regard to loss of water through skin, lungs, and intestinal tract) all the water consumed by an individual is excreted again, as urine, — that is to say, none is retained (oedema) and not more than has been consumed is excreted (abnormal loss). If a man consumes only a Hter of water a day and secretes a liter of urine (skin, etc., being ignored) his uri- nary secretion is normal, and if he consumes twenty liters and secretes twenty it is normal. We may differ as to which of these amounts, if either, we consider as normal (better optimal) from the standpoint of consumption, but so far as secretion is concerned, both are normal. And for this reason I would insist that the patient with chronic in- terstitial nephritis, who happens to consume in response to his tastes three Hters of water and so secretes three liters of urine (skin, etc., again ignored) has not an increased urinary output, but a normal one. So far as water output is concerned the patient with chronic interstitial nephritis is simply not nephritic. But he is not a nephritic from other standpoints either. He has not the oedema of the parenchymatous types. He has not the evidence of excessive acidity in his urine, as already pointed out in discussing R. Hober^s analy- ses of the urine in nephritis. Neither has he the albumin, the casts, or the blood that are found in parenchymatous nephritis. We can carry this still further. If a patient without these signs and symptoms dies, and on the autopsy table we find the small kidneys {" small red kidneys ") that we diagnose anatomically as chronic interstitial nephritis, then the parenchyma cells of the kidney — the only parts of the kidney that are concerned with its physiological function — are also found looking normal. The small, red kidneys are, except for size, normal kidneys. So far, chronic interstitial nephritis is not nephritis at all, it is an atrophy of the kidney. This is the typical picture of the 96 NEPHRITIS man who lives for months or years without symptoms of kidney disease, and in whom we diagnose chronic inter- stitial nephritis post mortem. Let us now consider the man who has been less fortu- nate in this regard, the patient in whom we have before death diagnosed a chronic interstitial nephritis because we have found a few casts, occasional traces of albumin, and let us add, an arteriosclerosis, a hypertrophy of the left ventricle, and a high blood pressure. To drag in a symptom often referred to in these cases let us suppose that he tells us that he has to rise one or more times nightly to urinate. The more pronounced the albuminuria, and the more steady the appearance of casts, the more certain are we of finding, on autopsy, not the small, red kidney, but the swelled (small) gray kidney! In other words we get the (physiological) characteristics of parenchymatous nephri- tis added to what (morphologically) we call chronic inter- stitial nephritis. And when we study these cases carefully we find that, as the albuminuria and the formation of casts increase, the (''increased") urinary output also falls, and along with it we are Hkely to note the first evidences of an oedema. Symptomless and signless, interstitial nephritis is therefore essentially an atrophy of the kidney, and the in- dividual so affected behaves and dies like the animal that has had its kidney substance removed by successive opera- tions down to the physiological minimum. Chronic inter- stitial nephritis with casts, albumin, etc., is the mixed picture resulting from a (morphologically) chronic intersti- tial nephritis plus a parenchymatous nephritis. All that now remains unexplained in this picture of chronic interstitial nephritis is the arteriosclerosis, the hypertrophy of the heart, the increased blood pressure, and the incident that the urinary secretion is of such a charac- ter that the patient is disturbed at night. Let us take NEPHRITIS 97 these up seriatim, and in our discussion let us not be misled into that pitfall which would make of a sick animal a some- thing for which the established laws of physiology are no longer valid. 2. The bearing of arteriosclerosis upon kidney disease has to be considered from two viewpoints. Is the arterio- sclerosis responsible for the kidney disease, or vice versa? The kidney associated with arteriosclerosis is the con- tracted kidney, the chronic interstitial type. Such a kidney shows as a rule the greatest variety of morpho- logical changes. While certain regions are entirely normal in appearance, other patches show characteristic '' degener- ative " changes, as evidenced by the presence of cells that are swollen and granular, or perhaps have lost their nuclei and are disintegrated {localized parenchymatous nephritis). To take the place of the dead cells we may find new paren- chyma cells forming, or there may be found evidences of connective tissue proliferation indicating the ultimate for- mation of a scar.^ This patchy appearance, resulting from a mixture of nor- mal, degenerating and regenerating cellular elements in the kidney, stands in marked contrast to the uniformity of ap- pearance presented by a kidney that has been poisoned, say, with the toxines of an acute infectious disease. Here, in a certain sense, all parts of the kidney are affected and to about the same degree. The appearances correspond with the fact that in the first case small patches of the kidneys are successively affected by local disturbances in the circulation in the kidney, in the second all the cells are ^ The morphological changes that characterize chronic interstitial nephri- tis are in no sense specific. They represent the consequences of a progres- sive destruction of piece after piece of kidney parenchyma and replacement of this by scar tissue. Entirely similar pictures are obtainable in any gland in which the blood supply is cut down directly, or indirectly through ligation of the secretory duct, as Dudley Tail has shown. 98 NEPHRITIS at once subjected to the same destructive agent. All this suggests that arteriosclerosis is under such circumstances the primary cause of the nephritis, and not a result of the same. Whether nephritis may in its turn lead to a reten- tion of toxic substances, these to an arteriosclerosis, and so to the establishment of a vicious circle is another question. While satisfactory experiments and cHnical observations proving that nephritis is followed by an arteriosclerosis can hardly be said to exist, an enormous number show clearly enough that nephritis does follow arteriosclerosis. From all of which it is clear that the treatment of chronic interstitial nephritis (secondary to arteriosclerosis) calls not so much for a treatment of nephritis as for a treatment of arteriosclerosis, — and the more liberal rules laid down for the guidance of the patient with chronic interstitial ne- phritis than for him who suffers from any of the paren- ch3niiatous forms constitutes the tacit acceptance of this belief on the part of the therapist.^ 3. Just as the arteriosclerosis associated with kidney disease is not to be discussed as the consequence, but rather as the cause of the kidney disease, so the hypertrophy of the heart observed in such cases is more the consequence of the arterial disease than of the kidney disease. This is clearly enough evidenced by the fact that the (physiologi- cally) worst types of nephritis are those least liable to be ^ In spite of years of experimental work, the numerous observ^ers who have tried to reproduce experimentally the picture of chronic interstitial nephritis in animals can scarcely be said to have been successful. Their failure resides in their methods, and it may safely be predicted that their present methods never can be successful. As must appear from the re- marks made here, the picture of chronic interstitial nephritis will be pro- duced only if a method is devised (analogous to the arteriosclerosis observed in the vessels of the kidney parenchyma) which will little by little destroy one fragment of kidney after the other. Injections of lead, arsenic, chro- mium, etc., do not attack the kidney in any such locahzed ways — they attack, generally speaking, all portions of the kidney equally and at once. J NEPHRITIS 99 associated with any hypertrophy of the heart. That, on the other hand, enormous hypertrophies of the heart may be associated with no kidney symptoms whatsoever is famihar to everyone. In discussing this subject of heart hypertrophy and chronic interstitial nephritis we seem, as cHnicians, all too often to lose sight of the fact that the hypertrophy of the heart results in this case, as in any case, from the increased demands for work made upon the heart. In the hyper- trophy associated with arteriosclerosis these increased de- mands result from at least two changes in the circulation: the reduction in the calibre of the blood vessels, and the loss of the elasticity of the blood-vessel walls. It should be clearly borne in mind that the mere roughen- ing of the blood-vessel walls has nothing to do with in- creasing the work of the heart. The friction encountered in driving the blood through the vessels is not that of blood against blood vessel wall. Since the blood '' wets " the blood vessel walls the friction is that of one layer of liquid over another. With a given kind of blood, the blood vessels determine how much energy is required to force the blood through them, only so far as their length (constant in body), diame- ter, and elasticity are concerned. So far as the effect of changes in diameter is concerned (and in arteriosclerosis the diameter of the blood vessels is diminished) , it must be borne in mind that the force required to drive a given vol- ume of liquid through a tube increases about as the cube when the cross section is diminished one-half. The loss of elasticity becomes a factor because, under physiological conditions, in the time of a single contraction of the ven- tricle an amount of blood, the equivalent of that ejected from the heart, is not at once pushed along the entire arterial and capillary bed out into the veins. Under normal loo NEPHRITIS circumstances it is simply thrown into the elastic arterial system which dilates somewhat, and then, during the period that follows the systole of the heart, the elastic forces resi- dent in the arteries slowly recoil and squeeze the blood on out into the veins. When this elasticity is markedly diminished, the heart must in that proportion force its quota of blood during the time of each systole at once through the whole arterial and capillary system, and this demands an enormously greater outlay of energy. A third factor for the hypertrophy of the heart might re- side in the blood itself. A Hquid moves through a tube with greater and greater difficulty the more viscid it is. Anything that would increase the viscosity of the blood would therefore increase the amount of work demanded of the heart to push the blood ahead. The viscosity of such colloidal solutions as the blood is enormously increased by sHght traces of acid (P. vo7i Schroeder,^ W. B, Hardy, '^ and especially Wolfgang Pauli and Hans Handovsky ^) and so this factor which comes into play not only in nephritis but in hard work of any kind (laborers, athletes) needs to be considered. While certain clinical studies of the viscosity of the blood have not as yet brought any proof to show that this undergoes any material change in nephritis, that such changes might well be expected is indicated by certain experiments of R. Burton-Opitz,^ who found venous blood to have a higher viscosity than arterial, due to the CO2 in it, and the blood of dogs after the feeding of proteins (acid production) to have a higher viscosity than before such feeding. 4. From what has been said it is clear that we cannot 1 P. von Schroeder: Zeitschr. f. physik. Chem., 45, 106 (1903). 2 W. B. Hardy: Journal of Physiology, 33, 251 (1905); Proceedings of the Royal Society, 79, 413 (1907). 2 Wo. Pauli and H. Handovsky: Biochem. Zeitschr., 18, 340 (1909). ^R, Burton-Opiiz: Pfliiger's Archiv, 119, 359 (1907). NEPHRITIS loi regard the heart hypertrophy as something primary, but as something secondary — as an example of the wide range of adaptation to changed conditions of which the cells and organs of our body are capable. The high blood pressure, far from being in itself an evil thing, is decidedly good — only through the increased pressure are the various tissues of the body guaranteed a blood supply sufficient to satisfy their physiological demands. This holds for the kidney as for any other organ in the body. Only the increased blood pressure renders it possible that the normal parts remain- ing in an arteriosclerotic kidney maintain what I have called the normal secretion of water from such a kidney. While conditions may exist or arise in the body which make the high blood pressure in itself dangerous (weaken- ing of blood vessel walls and rupture), a high blood pressure must with this exception not be regarded as something evil, but as an attempt on the part of the body to keep our various organs working at their physiological optimum. Measures that merely reduce blood pressure can therefore hardly be looked upon with favor. We must treat the underlying cause of the increased blood pressure, not the blood pressure itself. To apply this to the kidney, with which we happen to be dealing here, I can recall several cases of chronic interstitial nephritis with high blood pressure and cardiac hypertrophy in which a too enthusiastic desire to reduce the blood pressure led to the use of the nitrites, and with serious con- sequences. While the blood pressure fell, the urinary out- put also decreased, the albumin rose, and casts became numerous. In other words, the general fall in blood pres- sure made for a decreased circulation of blood through the kidney, and so for an aggravation of the kidney state. Only when we think that such a bad result will not follow the use of nitrites are we justified in using them. One case developed immediately after a single dose of amyl I02 NEPHRITIS nitrite a complete anuria which some eight days later killed the patient. 5. It remains for us to discuss the question of why the patient \\ith chronic interstitial nephritis must rise to uri- nate at night. Such is the case even when there exist no pathological conditions in the lower parts of the urinary tract that might be considered responsible. But on the basis of our analysis, which makes chronic interstitial ne- phritis more an atrophy of the kidney than a nephritis (except in the small patches which are Httle by little cut out from the kidney), the matter is easily understood. As the studies of Bradford have shown, we can spare some two-thirds or even more of our total kidney substance without serious inconvenience. It is in about such a state that the man with chronic interstitial nephritis finds him- self. What must be the conditions for urinary secretion in such an individual? The normal man with all his kidney substance intact will secrete the five hundred, or say a thousand, cubic centimeters of water consumed with a meal in the two or three hours that follow this meal. The patient with only a third the normal kidney substance must take, other things being equal, three times as long to secrete this same amount of water, in other words, six to nine hours. While the normal man will be largely rid of the water he has drunk with his supper when he urinates for the last time before going to bed, the man with the chronic interstitial nephritis will continue to secrete urine into his bladder for hours afterward, and as this organ fills he must rise during the night to empty it. 3. The Secretion of Water by the Nephritic Kidney. In support of the thesis that an abnormal accumulation or production of acid in the kidney constitutes the basic cause of every nephritis, it would be sufficient in this NEPHRITIS 103 section merely to show that such a condition always leads to a decrease in the secretion of water by the kidney. We shall, however, not stop with this but try to indicate in a little more detail where lies the point of attack for the acid that is responsible for such a change in secretion. It is an easy matter to show that the direct introduction of acid into the kidney, or any method capable of leading to an abnormal acid content in the kidney, is followed by a decrease in urinary secretion which may go to the point of absolute stoppage. This is clearly evident in the accompanying drawings which have been constructed from the experi- ments detailed in various parts of this paper. Figure 22 on page 142 has been introduced to show the normal secretion of urine in three rabbits, kept on a mixed diet, when these are brought into the laboratory and are loosely tied into an animal holder. When the animals are snugly tied into a holder, the urinary secretion is decreased in amount. This is clear from Fig. 23, in which are shown the curves for the urinary secretions obtained in the animals that were rendered albuminuric by this means (Experiments 22, 23, 24, and 25). If instead of such a general state of lack of oxygen in the body we interfere locally with the blood supply to the kidney, as through clamping of the renal blood vessels, the same great fall in urinary output is observed, as is evidenced in the lowermost curve of Fig. 28. But to show that it is really the acid developed in the body as a whole, or in the kidney specifically, that under these circumstances is responsible for such a fall in secre- tion, it is best to inject the acid directly. The effect of such a proceeding is shown in Fig. 24 based on Experiments 12, 13, and 14. It would be purposeless to multiply these ex- periments to further support the contention that an abnor- mal acid content in the kidney leads to a decrease in the secretion of water. As a matter of fact, this finds daily I04 NEPHRITIS corroboration in the decreased urinary output observed in all those clinical cases, such as heart disease, respiratory disease, etc., which we know to be associated with an ab- normal accumulation and production of acids in the body. But how may we imagine the acid to be effective in this regard? A proper answer to this question demands a criti- cal review of all the various theories that have been pro- posed from time to time to explain the mechanism of normal urinary secretion, and this would lead us too far afield.^ We can, however, help toward a more circum- scribed formulation of the whole problem. Defined physicochemically, the problem of water secre- tion by the kidney is essentially the problem of how water contained in the blood is made to pass through a solid (hydrophylic) colloidal membrane, this being represented, in the case of the kidney, by the various cells and their inter- cellular substances that lie between the blood on the one hand and the urine on the other. Two possible sources for the forces necessary to get the water through this mem- brane are available. The membrane may be perfectly passive and the blood itself suffer changes which result in driving the water through the membrane ; or the membrane itself may be concerned in the process, in that it first ab- sorbs water from the blood to give it up again later into the uriniferous tubules; or, finally, both may 'act together. Two theories of urinary secretion that have considered changes in the blood as primarily responsible for the giving 1 See R. Heidenhain: Hermann's Handbuch d. Physiologic, 5, Leipzig, 1883; jE. Waymouth Reid: Schaefer's Textbook of Physiology, 1, 261, Lon- don and Edinburgh, 1898; E. H. Starling: ibid 1, 285; Oppenheimer's Hand- buch d. Biochemie, 3, 206, Jena, 1909; H. J. Hamburger: Osmotischer Druck und lonenlehre, 2, 93, Wiesbaden, 1904; E. Overton: Nagel's Handbuch der Physiologic, 2, 774, Braunschweig, 1907; 0. Cohnhcim: ibid, 2, 607; R. Hober: Kordnyi-Richter, Physikalische Chemie und Medi- zin, 1, 295, Leipzig, 1907; Martin H. Fischer: (Edema, 186, New York, 1910; KoUoidchemische Beihefte, 2, 304 (191 1). NEPHRITIS 105 off of water by the kidney have attained special distinc- tion. The older of these is that of Bowman and Ludwig which, briefly put, holds changes in blood pressure respon- sible for the changes in the amount of urine secreted. An increase in blood pressure is held to yield a freer secre- tion of urine, a decrease the reverse. In spite of Heiden- hain's clear-cut criticism of this theory it still finds wide acceptance and, since it is the chief one that is discussed by pathologists and cUnicians, a few words regarding it may not be amiss. Pathologists and cHnicians are inclined to adopt the mechanical pressure theory of urinary secretion and to apply it to the problem of nephritis, because it has been generally observed that in the acute types of (parenchyma- tous) nephritis, which are associated with a decrease in uri- nary secretion, no appreciable changes in blood pressure are to be noted, while in the chronic interstitial types, which are generally held to show an increase in urinary secretion, there is often a marked increase in general blood pressure. And yet that the blood pressure per se can have nothing to do with this matter of water secretion is clearly evidenced by the experiments of Ponfick ^ and Magnus 2 who found that when the blood pressure is artificially increased in the normal animal, through injection of blood or blood plasma, no increase in urinary output results. In the light of what we know to-day regarding the filtra- tion under pressure of any Kquid through a colloidal mem- brane — and that is the problem involved when we hold that under the influence of blood pressure water is squeezed through the colloidal urinary membrane to make the urine — this filtration hypothesis must be abandoned entirely. On the pressure basis, the urinary secretion problem ^Ponfick: Virchow's Archiv, 62, 277 (1875). 2 Magnus: Arch. f. exp. Path. u. Pharm., 45, 210 (1901). io6 NEPHRITIS would be analogous to the filtration of water, for example, through a thin gelatine membrane, and the amount of pressure required to do this is out of all proportion to that available in the li\'ing animal. The maximal filtration pressure available in the body is the maximal blood pres- sure, and one equal to 250 millimeters of mercury easily covers even pathological states of high blood pressure. Yet we need no such pressures to get a urinary secretion. A normal blood pressure suffices to enable our kidneys to get rid of all the water we may be pleased to consume and Gottlieb and Magnus ^ have shown that under certain cir- cumstances a secretion of urine can still be obtained when a blood pressure of only 9 to 12 millimeters of mercury is available. But even if one were disincKned to regard such a state as '' physiological," and so insisted on 125 millimeters of pressure, or to cover the pathological states, 250 milHmeters, we could still get no filtration of water through a colloidal membrane of the t}'pe that character- izes the kidney. As the studies of H. Bechhold - have shoTVTi, five to ten atmospheres, in other words, five to ten times 760 milHmeters of mercury are necessary before water can be squeezed through a thin layer of gelatine. By treating the gelatine with various chemicals it is possible to increase its permeabiHty to water. But the chemicals most effective in this regard still leave the gelatine mem- brane in a state where it demands half an atmosphere pressure, in other words, 380 milHmeters of mercury. The chemical substances that thus alter the permeabiHty of the gelatine filtration membranes are all such as either precipi- tate or change (denature) the character of the gelatine. We might therefore recaU the precipitations (cloudy sweH- ing) observed in kidney ceUs in cHnical cases of nephritis, ^ Gottluh and Magmis: Archiv. f. exp. Path. u. Pharm., 45, 223 (1901). 2 H. Bechliold: Kolloid Zeitschr. 3, 3, 33 (1907). NEPHRITIS 107 or in those of our kidney sections put into this state by artificial means, and so think to help ourselves over some difficulties, by saying that under these circumstances the urinary membrane becomes more '' permeable." Actually, we only get ourselves more involved, for the very con- ditions (acute parenchymatous nephritis) , which in the liv- ing animal show these membrane changes, are those in which urinary secretion is most definitely diminished} Very evidently, therefore, if we note changes in urinary secretion with changes in blood pressure, the secretory changes are not to be attributed to the changes in blood pressure per se, but to some of the accompaniments of such changes in blood pressure. Heidenhain expressed this thought by saying that it was not the pressure which de- termined the secretion, but the amount of blood passing through the kidney. But this also does not adequately ex- press the problem. It is not alone the amount of blood but the kind of blood. Only when blood rich in oxygen and low in carbon dioxide goes through the kidney do we have secretion. No amount of venous blood going through the organ will yield a drop of urine. Since the blood does not carry its great oxygen content for its own benefit, and since the arterial blood which enters the kidney leaves this organ as venous blood, it is clear that the cells here use it up, and since the kidney actively secreting water uses up more oxygen and yields more carbon dioxide ^ than a rest- ^ The recent experiments of Alfred Schoep, Kolloid Zeitschr., 8, 80 (191 1), can also not be called upon for help. That Schoep got a filtration of water through collodion membranes with only a few millimeters of mercury pressure constitutes an experimental fact that cannot immediately be used for biological purposes. Collodion is a lyophilic colloid in such solvents as ether, alcohol, etc. It is a lyophobic one in water and therefore does not represent a membrane at all of the nature of those existing in the living animal (which are lyophilic in water). 2 See Barcroft and T. G. Brodie: Journal of Physiology, 32, 18 (1904); 33, 52 (1905)- io8 NEPHRITIS ing kidney, it follows that this secretion demands work on the part of the kidney structures — the secreting colloidal 7nemhrane. Further evidence that the kidney does such work is furnished by the higher temperature that prevails in the urine over that prevailing in the blood from which it is derived. A second theory of urinary secretion that regards changes in the composition of the blood as of primary importance in determining the secretion of water from the kidney is that proposed by Isador Trauhe} According to this author, changes in the surface tension of the blood are re- sponsible for a squeezing of fluid through the capillary structures composing the kidney (the cells and intercellular substances) that he between the blood on the one hand and the urine on the other. The ingenious ideas of Trauhe have scarcely received the attention from physiologists and pathologists that they deserve. In connection with our problem I should only Hke to point out that should they ultimately prove adequate to account for the phenomena of secretion — a subject of doubt to my mind, chiefly be- cause during secretion the secretory membrane does work and in proportion to the amount of secretion, while Trauhe' s ideas do not demand this — the introduction of acid into the blood or into the kidney would be associated with such changes in the surface tension of the blood and in the capillarity of the kidney as to render the changes in secre- tion observed in nephritis readily intelligible. The theories of urinary secretion which lay the main stress upon the kidney cells themselves, as the sources for the energy required to separate water from the blood, may be briefly considered under three heads — the "physiologi- cal" or "secretory" theory, the osmotic theory, and the colloidal theory. ^Isador Trauhe: Pfluger's Archiv, 105, 541 (1904); 123, 419 (1908); 133, 511 (1910); Biochem. Zeitschr., 10, 371 (1908); 16, 182 (1909). NEPHRITIS 109 The "physiological" or "secretory" theory of urinary secretion suffers from the defects of every such "physio- logical" theory — it explains nothing. The osmotic theory suffers through its inadequacy. In spite of all one's re- luctance to give it up, when one considers its tempting simplicity and the wealth of biological fact that its dis- cussion and experimental study have yielded, it seems now as though it would scarcely be able to maintain even a par- tial role in the phenomena of water absorption and secre- tion as observed in plant or animal cells. ^ If the osmotic theory of absorption and secretion has to be reHnquished in working with individual cells, it will have to go all the more certainly in the special problem of absorption and secretion as presented to us in the kidney. 1 have suggested that the explanation of urinary secre- tion be sought in the colloidal constitution of the kidney and in the physicochemical changes that this suffers under the various conditions which we know to influence the secretion of water from this organ.- The separation of water from the blood by the urinary membrane) that is, all the structures that He between the blood on the one hand and the urine on the other) involves two processes — an absorption of water from the blood, and a subsequent giv- ing off of this same water out into the uriniferous tubules. How is this accomplished? As already pointed out, the urinary membrane is built up of a series of (hydrophilic) emulsion colloids. That half of the process of urinary secretion which consists of an ab- sorption of water from the blood by the urinary membrane is entirely analogous to the absorption of water by fibrin, gelatine, or serum albumin, — technically put, it consists of ^See Wolfgang Pauli: Sitzungsberich. d. Wiener Akad. Math-naturw. Klasse, 113, 38 (1904); Martin H. Fischer: Physiology of .Alimentation, 182-187, 267-269. New York, 1907; CEdema, 85. New York, 1910. 2 Martin H. Fischer: (Edema, 180. New York, 19 10. no AEPHRITIS a hydration of some or all of the (hydrophilic) emulsion col- loids composing the kidney. The other half of the process of urinary secretion consists in a giving up of this absorbed water; it is analogous to the loss of water by fibrin, gela- tine, or serum albumin, in other words, to the dehydration of a (hydrophiKc) emulsion colloid. To accompKsh the secre- tion of urine a cycle of changes must therefore occur in the kidney, which leads first to the absorption of water and then to its secretion. Let us ask of what such a cycle of changes might consist, and though in the case of the kidney we ven- ture here upon treacherous ground, a few experimentally well-estabhshed facts point out a road rather clearly. In discussing the problem of absorption^ which appar- ently is to be regarded in every sense as the mirror image of secretion, I pointed out how the carbonic acid produc- tion in cells may be one — or under physiological conditions the chief — factor in determining the absorption of water from the peritoneal cavity or the intestinal tract. Experi- mental observations seem to indicate that the following happens: the cells of the peritoneum or of the intestinal tract produce carbonic acid. This increases the hydration capacity of the colloids constituting the peritoneum or in- testinal tract for water, and so if any is present in either location it is absorbed. But the arterial blood entering the peritoneum or the mucous membrane of the intestine has a lower carbon dioxide tension than that found in the cells here, and so this diffuses over into the blood. As this enters the blood the capacity of the blood colloids for hold- ing water is increased (as is evidenced microscopically by a swelHng of the blood corpuscles in a venous blood, and physicochemically by an increase in the viscosity of the blood). Between the increased capacity of the blood to carry water, and the now diminished capacity of the cells ^Martin H. Fischer: KoUoidchemische Beihefte, 2, 304 (191 1). NEPHRITIS III of the peritoneum and intestinal tract to hold on to it, the water previously absorbed from the peritoneal cavity or the intestinal lumen is now dragged over into the blood. As long as the circulation is maintained water must there- fore be absorbed from the peritoneum or the lumen of the intestine, and as steadily be lost on the opposite side of the absorbing membrane into the blood. In the case of the kidney, a reverse series of changes brings about a secretion of water. To render secretion possible we must first of all supply the kidney with oxygen. In the process of water secretion by the kidney this oxygen is not only used up but carbon dioxide is produced, and the loss of one and the production of the other run the higher the greater the amount of water secreted by the kidney.^ In the carbon dioxide production in the cells of the urinary membrane we have, therefore, the estabhshment of conditions which increase the capacity of the colloids here for absorbing water. In the loss of this same carbon dioxide to the blood we have subsequently the cause for the loss of the previously absorbed water out into the space of Bowman's capsule or the uriniferous tubules. The only part of water secretion by the kidney that this simple in- terpretation does not explain is why the water is lost toward the lumen, and not back into the blood with the carbon dioxide. But for this a simple explanation (based on certain anatomical relationships existing in the kidney and on differences in rates of diffusion) can also be given, as I hope to show at another time in discussing some col- loidal models of secretion. As I have previously pointed out,^ the kidney is not alone involved in this matter of urinary secretion, but the 1 Barcroft and T. G. Brodie: Journal of Physiology, 32, i8 (1904); 33, 52 (1905)- 2 Martin H. Fischer: (Edema, 184. New York, 1910. 112 NEPHRITIS blood as well, and, somewhat more remotely, all the tissues of the body. We have already touched upon the fact that only arterial blood will yield a secretion, and that no amount of venous blood will do so. But aside from this important fact it must always be borne in mind that the mere coursing of blood through the kidney does not repre- sent the existence of an inexhaustible fountain of water out of which urine can be manufactured as is so frequently done by physiological and clinical workers. The water found in the blood is ordinarily to be regarded as bound to the colloids of the blood. Only as these suffer a change which makes them incapable of holding as much water as they once did, or the colloids of the urinary membrane develop an avidity for water that overtops that of the blood col- loids for this same water, does water from the blood be- come available for absorption (preparatory for secretion) by the kidney. The body tissues generally play a role in the whole problem as they give up or take water away from the blood. Other things being equal, it is evident that the kidney ^\dll secrete water the more easily, the less firmly it is bound to the colloids of the blood. These remarks have all been necessary in order to show w^hy it is that the abnormal production or accumulation of acid in the kidney, as occurs in nephritis, must be followed by a decrease in the secretion of water (urine) from the kidney. The acid must interfere, first of all, with the chemical (enz}Tnatic) changes in the kidney cells them- selves, which are responsible for the normal oxidation proc- esses that occur here (such as the production of caibon dioxide). While such an increase in the amount of acid held in the kidney as occurs in nephritis, does not inter- fere with the absorption of water from the blood, favors it, rather (as evidenced by the swelling of the kidney), it in- terferes decidedly with the subsequent loss of the absorbed NEPHRITIS 113 water which constitutes the palpable external evidence of secretion. The loss of the acid to the blood must be ren- dered the more difficult the higher the amount of acid already present here, — wherefore the question of the amount of acid contained in the body as a whole becomes an important factor in the problem of nephritis. As a final word let us point out the fact that the nephritic kidney in swelling (as it possesses a firm capsule) compresses its vascu- lar supply. In consequence of this it not only decreases, through the decrease in the absolute amount of blood going through the kidney, its opportunities for losing such acid as it has already accumulated, but places its com- ponent cells in a position where an abnormal acid produc- tion is immensely favored (lack of oxygen) . All these facts must be borne in mind, and point the way to be followed when we come to discuss the matter of treatment. 4. The Changes in the Secretion of Dissolved Substances by the Nephritic Kidney. As already noted, the nephritic kidney shows devia- tions from the normal secretion of dissolved substances by it in two directions. There is, first of all, a decrease (other conditions remaining the same) in the absolute amounts of the various substances secreted, and second, in the relative proportion that these bear to each other when compared with the secretion of these same substances as observed in health. The nephritic kidney secretes some substances as well as does the healthy kidney, others de- cidedly less well. It is our problem to say how such a con- dition as an acid production in the kidney brings such a state of affairs to pass. In order to do this we must recall some of the facts of normal secretion by the kidney. As is famiUar to everyone, a secretion of some sub- stances proportionately more easily than others, in other 114 NEPHRITIS words, a ''selective" secretion by the kidney, such as we have just outlined, is not characteristic of the diseased kidney, but of the healthy kidney as well. This is really the rock on which most of the mechanical, or to use a broader and better term, nonvitaHstic or physicochemical conceptions of urinary secretion have foundered, — and these founderings have given momentary comfort to those who believe that kidney secretion, as many another physio- logical phenomenon, is "vital" in character. But such a pessimism would seem to be premature, for we are already famiHar in physical chemistry with not a few sys- tems in which differences in the concentration of any sub- stance are easily maintained over indefinitely long periods of time, and, of course, without the assistance of those "pecuHar" forces believed by some to inhabit the Hving cell. Reference is here made to the differences in the dis- tribution {distribution coefficient) of any substance between two phases. Through the work of Hans Meyer and E. Overton the differences in the solubility of such substances as alcohol, ether, chloroform, morphine, cocaine, etc., in water and in fats and fathke bodies (lipoids) — their distribution co- efficients between two solvents — have been shown to ex- plain very satisfactorily why these substances not only diffuse with greater speed into and through cells, especially rich in the fatlike bodies (the fat cells and the cells of the central nervous system), than into and through such as con- tain these in smaller amounts (yellow elastic tissue, white fibrous tissue) , but why in the end they are found in larger absolute amounts in some tissues than in others. A second property of protoplasm which permits one cell or tissue to take up more of any given substance, and this more speedily than is the case with another cell, is the character of the colloids contained in the cells and the NEPHRITIS 115 state in which these find themselves. This is one of the reasons why certain stains when injected intravenously are not taken up with the same speed, or to the same extent, by all the tissues of the body. A third property of protoplasm, which makes for in- equalities in the distribution of a substance, resides in the chemical differences existing between different kinds of protoplasm. Certain of the '' vital " and " specific " pro- toplasmic stains are examples of this class. In these a chemical combination results between the dye and the chemical compounds found in some cells. What use can we make of these facts in the explanation of the alterations observed in the secretion of dissolved substances by the nephritic kidney? In proposing a col- loidal theory of urinary secretion,^ I have tried to show how the ^' selective " character of secretion may be explained in the following way : All secretion of dissolved material by the kidney is de- pendent, first of all, upon a secretion of water by the kidney. After the water is secreted I hold that all the con- stituents which characterize it as urine come to be added to it, in its course through the uriniferous tubules, by a process of leaching out of the dissolved substances present in the kidney cells. But in this process of leaching out not all the constituents present in the protoplasm leave the cells in which they are originally present with the same ease. Depending upon the character of the dissolved sub- stance, and the state of the protoplasm as to lipoid content, colloidal state, and chemical composition, the water pres- ent in the uriniferous tubule may come to take up the dis- solved substance to an extent which allows it ultimately to be found here in a lower concentration than in the kidney cells, in the same concentration, or in a greater one. It is 1 Martin H. Fischer: (Edema, 180. New York, 1910. ii6 NEPHRITIS all a matter of equilibrium. But the equilibrium points with different substances are different, and so the relative amounts of these different substances that appear in the urine are also different. In other words, the (normal) leach- ing out is '' selective," or, to put it biologically, the '' secre- tion " of the dissolved substances is selective. But this leaching out of dissolved substances from the kidney is only one-half of the process of urinary secretion. The other half is the process of the absorption of dissolved substances from the blood by the kidney cells preparatory to their secretion into the lumen of the uriniferous tubules. This is also a selective process, and here the same laws of lipoid solubility, colloidal adsorption, and chemical combi- nation, which have already been discussed in the leaching out process, again come into play. All these various processes of absorption and secretion of dissolved substances by the kidney cells are most markedly in- fltcenced by the reaction existing in them, and it is for this reason that the observed variations from the normal in the secretion of dissolved substances by the nephritic kidney occur. It is easily appreciated w^hy there must be a decrease in the absolute amount of dissolved substance secreted by the nephritic kidney. If the secretion of water through the kidney is diminished, then clearly not as much dissolved substance can be leached out of the kidney parenchyma as when more is secreted. Into this, however, enters the ele- ment of time. When much water is being secreted by a kidney its discharge into the pelvis of the kidney is also hastened. The time that a given portion of the urine (secreted as water initially) is in contact with the kidney cells is thereby diminished, and so not all that this water is capable of absorbing is taken up. When the water is secreted more slowly, the ultimate equihbrium point for the distribution of dissolved substances between the kidney 1 NEPHRITIS 119 and the urine is more nearly approximated. We find daily expression of this fact in the clinical observation that after the consumption of much water the concentration of the urine falls, while with a diminished intake of water, or when the kidney cannot secrete it (as in nephritis), the con- centration of the urine becomes progressively higher. Yet, other things being equal, the absolute amount of any dis- solved substance secreted by the kidney must be the greater, the larger the absolute amount of water secreted by the kidney in any unit of time. To illustrate how the increased acid content in the kidney in nephritis leads to variations in the secretion of the dissolved substances, I would like to introduce a few simple test-tube experiments and experiments on rabbits, which concern themselves particularly with that part of the selective secretion which deals with the colloidal state of the kidney cells. This constitutes by far the most im- portant part of the whole problem of selective absorption and secretion, for the state of a colloid in the body is more easily affected by external conditions than is the solvent property of a lipoid, or the chemical character of any part of living protoplasm. As the various dyes betray them- selves not only qualitatively, but, in a sense, also quanti- tatively, to the naked eye, illustrations of the " absorption " and the " secretion " of these, under conditions that interest us in our discussion of nephritis, seemed to me best suited to our needs. I chose, moreover, dyes that have been used physiologically in the study of the kidney. The results of a few experiments on the staining of fibrin, which are familiar to any worker who has at all touched upon the problem of dyeing, and which might be multiplied indefi- nitely by using other dyes and different colloids, are shown in Fig. 21. Tube I contains an aqueous solution of toluidin blue. 120 NEPHRITIS If into another tube (2), containing the dye in the same concentration, some powdered fibrin is dropped, this soon absorbs most of the dye and stains intensely blue. The supernatant Hquid retains only a faint tinge of the blue but this remains indefinitely. If the supernatant solution is carefully pipetted off, and distilled water is placed over the dyed fibrin, the water now slowly turns blue. In this way, through successive washings, we can again get considerable of the blue out of the fibrin. In other words, the fibrin absorbs the dye until an equilibrium is reached between the concentration of the dye in the fibrin and the concentration of the dye dissolved in the supernatant liquid. If now wt disturb this equilibrium by removing the blue solution above the fibrin and substituting water for it, some of the dye comes out of the fibrin until equiHb- rium is once more established. If we will now write kidney coUoids for fibrin we have what happens in this organ when it secretes any dye. The absorption of the dye by the kidney cells from the blood is analogous to the first series of changes that we describe, the leaching out of the dye by the urine to the second series. We can also see at once why the quantity of urine secreted and the time that this remains in contact with the kidney cells are of such importance. This cor- responds with the renewal of the distilled water above the dyed fibrin and the time this is allowed to remain there before being pipetted off. What happens if we introduce into this w^hole system a trace of acid? The result is shown in tube 3. The fibrin swells somewhat, but the toluidin blue is now scarcely taken up. The supernatant liquid remains practically as blue as the control tube i. What would this mean when applied to the kidney affected with nephritis, for which we have maintained that an abnormal acid content is respon- NEPHRITIS 121 sible? That the kidney would swell as does the fibrin, with this we are already familiar. But such a kidney would now not absorb the toluidin blue preparatory for secretion as does the healthy kidney. On the other hand, we must not hastily conclude herefrom that under such circumstances the kidney would necessarily also secrete this dye badly. Once any dye was in the kidney colloids this would rapidly diffuse into the urine, not only because the kidney colloids are not holding on to the dye particularly firmly, but because the acid Hable to be in such urine as is secreted from the nephritic kidney would further favor the passage of the dye into it. In tubes 4, 5, and 6 are shown a parallel series of experi- ments carried out with sodium indigosulphonate. It is clear that with this dye conditions are exactly the reverse of those obtaining in the case of toluidin blue. The very circumstances which favored absorption before, hinder it here, and those which hindered it before now favor it. In tubes 7, 8, and 9 are shown the results obtainable with neutral red, which, it will be observed, behaves like toluidin blue. But the kidney is not thus offered one substance at a time to secrete into the urine. The blood that passes through this organ brings it many at once. What must be the behavior of the tissue colloids under such circumstances? As tubes 10, II, and 12, and tubes 13, 14, and 15 clearly show, a colloid under such circumstances behaves toward each of the substances offered it as though the others were not present. In tube 10 is shown the effect of mixing so- dium indigosulphonate and neutral red. If some fibrin is introduced into this mixture it absorbs the red (chiefly) and leaves behind (almost) all the blue. This would correspond with the kidney function in health. If now an abnormal amount of acid were present in the kidney (nephritis) 122 NEPHRITIS just the reverse would result — the red would now be left behind in the blood, while the blue would be absorbed. In tubes 13, 14, and 15 are shown the results on "the staining of fibrin when toluidin blue and neutral red are mixed. The resulting color is shown in tube 13. In the presence of fibrin both of the dyes are absorbed as shown in tube 14, but if a Httle acid is present, or is subsequently added, the fibrin fails to stain. Figure 21 was painted from the results obtained in the following Experiment 21, after the tubes had stood some eighteen hours. Marked differ- ences in the degree of staining are readily visible, however, after ten minutes. Experiment 21. 1. 15 c.c. .01 per cent toluidin blue plus 15 c.c. water. 2. 15 c.c. .01 per cent toluidin blue plus 15 c.c. water plus 0.4 gram fibrin. 3. 15 c.c. .01 per cent toluidin blue plus 15 c.c. ^V normal acetic acid plus 0.4 gram fibrin. 4. 15 c.c. .02 per cent sodium indigosulphonate plus 15 c.c. water. 5. 15 c.c. .02 per cent sodium indigosulphonate plus 15 c.c. water plus 0.4 gram fibrin. 6. 15 c.c. .02 per cent sodium indigosulphonate plus 15 c.c. ^tf normal acetic acid plus 0.4 gram fibrin. 7. 15 c.c. .02 per cent neutral red plus 15 c.c. w^ater. 8. 15 c.c. .02 per cent neutral red plus 15 c.c. water plus 0.4 gram fibrin. 9. 15 c.c. .02 per cent neutral red plus 15 c.c. 2V normal acetic acid plus 0.4 gram fibrin. 10. 15 c.c. .02 per cent sodium indigosulphonate plus 15 c.c. .02 per cent neutral red. 11. 15 c.c. .02 per cent sodium indigosulphonate plus 15 c.c. .02 per cent neutral red plus 0.4 gram fibrin. 12. 7I c.c. .04 per cent sodium indigosulphonate plus 7! c.c. .04 per cent neutral red plus 15 c.c. 2V normal acetic acid plus 0.4 gram fibrin. 13. 15 c.c. .01 per cent toluidin blue plus 15 c.c. .02 per cent neutral red. NEPHRITIS 123 14. 15 c.c. .01 per cent toluidin blue plus 15 c.c. .02 per cent neutral red plus 0.4 gram fibrin. 15. 7I c.c. .02 per cent toluidin blue plus ^7^ c.c. .04 per cent neutral red plus 15 c.c. ^V normal acetic acid plus 0.4 gram fibrin. The details of this experiment have already been discussed in the text. It follows from all this that the presence of a little acid in such a colloidal material as that which we know to com- pose the kidney must be followed by profound changes in the character of the secretion of dissolved substances by this organ as compared with the normal secretion of these same substances. But depending upon the way in which the acid displaces the equilibrium point it is clear that, with otherwise constant conditions, the secretion of any substance may not only be decreased or simply remain unaffected, but it may actually be increased. With illus- trations of the first two of these possibilities we are familiar from the analyses of the urine in nephritis. Examples of the third have not yet been sought for. Before closing this chapter it is well to refer to a few animal experiments which show that what has been said above regarding the staining of fibrin actually holds in the case of the living animal. As pointed out in our discussion of the experiments of Heidenhain, Dreser, and Nussbaum, these authors found the kidneys of their ex- perimental animals stained most deeply, and most generally with sodium indigosulphonate or acid fuchsin (which stains fibrin just as does sodium indigosulphonate) when con- ditions favoring the accumulation of acid in the kidney were most clearly at hand. This corresponds with the im- proved tendency of fibrin to stain with these dyes when an acid is present. When in a rabbit under morphine an- esthesia the artery to one kidney is clamped for an hour or two, and then sodium indigosulphonate or acid fuchsin is 124 NEPHRITIS injected intravenously, while the clamp is removed from the artery, it is found that tJie clamped kidney not only stains sooner than the undamped one, hut more intensely. Wrhen now frozen sections are made of the two kidneys the dye in the healthy kidney is found only in the lumina of the uriniferous tubules, while in the Hgated kidney it is found in the cells themselves. And yet a kidney so clamped for an hour or two will not yield any urine for hours after- wards, if ever again. The staining of the kidney^ as already once noted above, is therefore not an index of secretion, but in this case rather of its lack. The reverse of this experiment can be done with neutral red. Here the normal kidney stains well and rapidly, while the clamped one remains without color, owing to the acid developed in it in the absence of a circulation. Clearly, therefore, mere staining of a cell can by itself tell us Uttle regarding the secretion of such a stain by that cell. After what has been said it must be self-evident that too many factors enter into the picture of the secretion of any dissolved substances by the kidney — too many factors at which we can to-day but guess in a clinical case — to make any conclusions regarding the functional activity of the kidney, as derived from a study of the ehmination of some one compound swallowed by the patient and sought for in his urine, of any material value. Even though we ignore all other elements of error, the state of the blood, the state of the kidney colloids, and the state of the urine all in- fluence the rapidity and perfection of the elimination of the substance in so marked and (for us) uncontrollable a way, that trustworthy conclusions are impossible, and when we take the Hberty, as is so often done, of applying what we may have learned from the elimination of one substance without modification to some other or all other constitu- ents found in the urine, then we are on dangerous ground NEPHRITIS 125 indeed. Until we have learned far more regarding the laws that govern the secretion of dissolved substances by the kidney than we know to-day, we had best accept as the most reliable test for the Junctional activity of this organ its ability to eliminate water. IV. ON THE TREATMENT OF NEPHRITIS. For the treatment of nephritis everything has been sug- gested; a discussion of the subject can scarcely, therefore, hope to bring the mention of anything new that might be tried. It can hope to be of interest or importance only as on the basis of the views entertained by an author regard- ing the nature and the cause of nephritis he will assign to certain practices grades of importance different from those assigned to these same practices by another — a difference of opinion that may perhaps be carried to the point where the one will find virtue in procedures that another regards only as evil, and vice versa. It is not our purpose in these pages to discuss the whole question of the therapeutics of nephritis, but on the basis of what has been written we may advantageously take up a few points in this field. In so doing we will discover further support for the concep- tion of nephritis that has been advanced in the preceding pages. I. Some General Considerations. Were we to formulate a general rule for the prophylaxis and for the treatment of nephritis we would evidently have to say that this lies in an avoidance, as far as possible, of every condition that favors the abnormal production or ac- cumulation of acid in the kidney. What such a rule would mean in the language of every day is easily seen. We have long paid attention to the diet in this matter of nephritis. Clearly, the direct consumption of acid by the nephritic individual is contraindicated. The mineral acids 126 NEPHRITIS which would be worst in this regard do not enter into our foods to any appreciable extent, though in the forms of fruits, sour wines, etc., not inconsiderable amounts of organic acids are swallowed. Most of these undergo oxi- dation in the body rather easily and are converted into car- bonic acid which, imder ordinary circumstances, is readily excreted. The organic acids are therefore less poisonous than might at first appear, but from this is not to be con- cluded that they are of no importance at all in the con- sideration of this subject of nephritis. Not only are certain " weak " organic acids (notably tartaric, acetic, and lactic) quite as active physiologically as the " stronger " acids, but consumed in excessive amounts they are not without effect, as witness the oedema observed in children that are fed buttermilk,^ the urticarias following the consumption of excessive amounts of grapes, ^ etc. In the metabolism of proteins not inconsiderable amounts of acid are produced.^ Herein is to be sought at least part of the explanation of why a restriction of the proteins in nephritis is of use. The fats also yield acids when digested and so may the carbohydrates under certain circumstances. But before one proceeds to a too drastic rex-ision of the dietary, a process in which we are particularly Kable to elimi- nate the proteins too vigorously, the absolute amounts of acid formed by the various constituents of the food should be considered. When this is done it will be found that the "^ Ernst Scldoss: Deut. med. Wochenschr., No. 22. (1910). Schloss does not, however, consider this an oedema due to feeding acid, but as " idio- pathic." He found it to disappear on administering calcium salts. 2 Personal observation. The urticaria disappears as soon as calcium salts are given, or fails to appear entirely if such are consumed with the grapes. 3 G. von Bunge: Zeitschr. f. Biol., 10, iii (1874); N. Liinin: Zeitschr. f. physiol. Chem., 5, 31 (1881); Emil Ahdcrhalden: Biochem. Zentralbl., 2, 257 (1904). See also the important studies on the balance of acid-forming and base-forming elements in food by H. C. Sherman and A. 0. GeUler: Proc. Soc. Exp. Biol, and Med. 8. 119 (1911). NEPHRITIS 127 evil consequences expressed in terms of a direct acid yield from the proteins of our food, for example, are small com- pared with those that may be calculated from a bottle of dry wine. Consideration of the acid content of alcoholic beverages helps us moreover to understand why some of these exercise a worse effect in nephritis than others. We have long recognized that the alcohol content is not alone responsible for the effects of alcoholic beverages in kidney disease, for while it is true that in large doses alcohol alKes itself with the general anaesthetics, small doses do not in- terfere with the oxidative reactions in the living cells, but rather favor these (and so kidney function). But what- ever is fed, it is clear that all the acid effects of the food need not appear if we will take the precaution of seeing that the diet contains sufficient alkali to neutrahze the acid. The role of hard work as a factor in inducing nephritis, or aggravating an already existing one has been too long recognized to demand any special comment. Muscular work and, less obviously, mental work lead to an enormous acid production in the body. Sufficiently hard work makes any man show all the symptoms and signs of a nephritis. Under normal circumstances the acids produced in muscu- lar or mental endeavor are quickly oxidized and leave the body in the form of carbon dioxide. But for this a plenti- ful oxygen supply is demanded, and when this is not fur- nished, as in close rooms and factories, then such conditions become factors in our problem of nephritis. Let now an anaemia^ be added and we have built out of a few circum- ^ A satisfactory explanation of why an anaemia is so often associated with nephritis has not yet been given. The anaemia is a prominent sign only in the parenchymatous types of nephritis — those that have an oedema. This, it seems to me, is not an accidental combination. May we not regard the acid which yields the kidney changes and which is to be held responsible for the oedema of the tissues generally also responsible for the anaemia, in that it behaves like a " haemolytic " agent? See my remarks on the nature of haemolysis [Kolloid Zeitschr. 5, 146 (1909) or (Edema, 166 (New York, 1910)]. 128 NEPHRITIS stances, each simple enough in itself, a vicious circle that has in it all the possibilities of speedy death. How a heart lesion, or an ansesthetic, or a drinking bout, or exposure to cold may push the acid content of the kidney up to the point where it can care for it no longer is self apparent. Just as we have seen how certain circumstances favor the development of a nephritis so also can we see how others counteract this. Most notable here are the long observed beneficent effects that follow the use of alkalies and the substitution of a more strictly vegetarian diet for our ordi- nary mixed diet. The alkaline mineral waters are of course capable of pushing the equihbrium existing in the kidney between the hydrogen ions and the hydroxyl ions toward the hydroxyl side, and so of counteracting that rise in acidity here which we consider Kes at the bottom of nephritis. A diet rich in vegetables helps our nephritic in part in the same way as though he consumed alkalies directly. The bases present in vegetables are combined with weak organic acids; in other words, the vegetables contain salts which when dissolved in water are alkaline in reaction. In the body these organic acids are largely oxidized to car- bonates and so the tendency of the body tissues to become alkahne in reaction is still further developed. How suc- cessfully a diet rich in fruits and vegetables counteracts even the normal tendency of the body to become acid is a matter of common knowledge to any physician who has watched the urine of any patient turn from its normal acidity to an alkalinity, when ordered from an ordinary mixed diet upon one richer in the vegetables and fruits. But I would like to insist that this neutraHzation capacity of the vegetable diet for acids is not the only factor to be considered in accounting for its beneficent effect in ne- phritis. We learned earHer in this paper that the solubiUty of protein in any acid is markedly reduced by salts. Not NEPHRITIS 129 only are the vegetables rich in salts but they are rich in the very ones which act most powerfully in reducing the solu- bihty of the protein. So we may find in this fact, along with what has already been said regarding the capacity of the vegetable diet to neutraHze acids, a satisfactory scientific foundation for the reduction of the albuminuria in Bright' s disease, when a diet rich in vegetables follows one in which these were not so abundant. Such salts also serve to reduce the size (swelHng) of the kidney, and as we have seen, they practically prevent those precipitation effects in the kidney cells (granule formation) that are characteristic of the early changes of nephritis from a mor- phological point of view. Speaking generally, a diet high in vegetables also means that the individual is consuming more water. The effect of this will next be discussed, and later we shall return once more to the question of salts in the diet. 2. Water Consumption in Nephritis. The question of water consumption resolves itself into two parts, on the one hand, into the use of water in cases where a nephritis is likely to arise, on the other, to its use in an established case. From all that has been said it must be clear that the intake of water should never be re- stricted. To this rule there exists to my mind only one possible exception, and that is the advisabihty of stopping water temporarily — say for an hour or two for reasons that will appear later — in cases of complete suppression of the urine. Neither does this statement mean that pure water is necessarily the best form in which to take this, but with this matter we will deal immediately. The reasons why water should be given without restriction are obvious. No matter with what condition we are dealing that we may consider liable to lead to a nephritis, what produces that I30 NEPHRITIS pathological state in the end is an intoxication. This is strikingly true of course in the infectious diseases or in an eclampsia case. Here the whole organism is suffering from the effects of a poison. The effect of that poison depends not alone upon the length of time that it acts upon the organism as a whole or any individual part of it, but upon the concentration of the poison present at any one time. If now our interest centers upon a toxic effect that such a poison may have upon the kidney, and we are anxious to protect this organ, it is clear that the concentration of the poison must be kept as low as possible in this organ. To do this we have only two possibiHties open to us and when we cannot control the factor of poison production, we can hope to cut dow^n the eft'ect of the poison only by keeping what is produced as dilute as possible, which means the giving of water. In this connection the practical point should be remembered that in ordinary practice an ever so patient administration of water through the day is Hkely to be neglected in the night. As toxine production does not cease wdth nightfall, it is clear that water administration also should not, otherwise we are likely to lose in a few hours at night what we cannot subsequently regain in days, if at all. At this point we are likely to be met by the argument that while such a water therapy is accepted as advisable in the toxic nephri tides, those associated with heart lesions, etc., are not to be similarly treated. Let us first point out the fact that these too are toxic nephritides — the patient with a broken heart compensation, or a compressed lung due to a carcinomatous pleurisy, and albumin in his urine shows this (according to our views), because the acid con- tent in his kidneys is abnormally high. The more the con- centration of this can be reduced the less will be its effect on the kidneys. Thus far, therefore, he needs water quite NEPHRITIS 131 as much as the nephritic who is such in consequence of an infectious disease. But it will be argued that the giving of water increases the work of the heart in these cases, and so is bad. Let us consider this problem dispassionately. The beHef that the giving of water increases the work of the heart is based upon the notions of urinary secretion, which imagine that water is pushed through the kidney cells by gross mechani- cal means. And so it is reasoned that the more water that is given, the more push is required, that is to say, the more blood pressure, and so the more work from the heart. Actu- ally such a belief lacks every experimental support. If one fact regarding urinary secretion stands out as well estab- lished, it is that the forces active in producing the urinary secretion lie within the kidney itself. The only thing there- fore that we might call upon as responsible for increasing the work of the heart would be some product of the work of the kidney in separating urine from the blood. We have a right to consider here the effect on the heart of the extra carbon dioxide^ produced whenever the kidney functions. But the effect of this cannot be greater than that of an equal amount produced normally, or in a given case of kidney disease than an equal amount produced in some other organ. And when compared with the total amount of carbon dioxide produced from all other sources, the amount of carbon dioxide produced in the kidney because of the consumption of a few extra hters of water is small indeed. Even were we to admit that the effect of such an increased carbon dioxide production by the kidney did markedly in- crease the work of the heart — a view for which we have not a single unequivocal clinical observation — it would still have to be proved that such an effect is worse than that 1 Barcroft and T. G. Brodie: Journal of Physiology, 32, 18 (1904); 33, 52 (1905)- 132 NEPHRITIS resulting from an accumulation of acid in the kidney (and in the body generally) because of an insufficient eKmination of water through the kidney. As a matter of fact, we know this reasoning to be sound from the fact that the parenchymatous t^'pes of nephritis, in which water elimi- nation is most decidedly insufficient, and in which it would be expected in consequence that the heart would be work- ing hardest in order to rid the body of any consumed water, are the very types in which heart complications (hyper- trophy) are most conspicuously absent. Let us now ask if in the chronic interstitial types of ne- phritis this rule of no water restriction also holds good. We have sufiiciently dilated upon the fact that chronic in- terstitial nephritis without urinary findings is not physio- logically a nephritis. When albumin, casts, and oedema appear, that which we have just said for parenchymatous nephritis holds for it. But what is to be our position when the urinary findings are absent? As we have already pointed out, the work done by the heart in pumping blood through the blood vessels depends upon the length, diameter, and elasticity of the blood vessels, and upon the viscosity of the blood. The giving of water certainly does not affect the first three factors. So far as viscosity is concerned, it can only decrease this and so dimin- ish the work of the heart, as diluting a syrup with water makes it easier to draw it through a straw. If we are will- ing to admit that in consequence of the general circulatory disturbances in our patient with chronic interstitial ne- phritis the increased work thrown upon his heart is in part due to an increase in the viscosity of his blood occasioned by the presence of abnormal amounts of acid in it, then the giving of water must again be of help, for this aids in decreasing the concentration of the acid. The only objections that may be raised against a too NEPHRITIS 133 vigorous administration of water, it seems to me, are two. The first is associated with the fact that in the parenchyma- tous types of kidney disease the kidney swells; the second with the effect of the water in washing out salts. We have already said why the swelling occurs in nephritis — the abnormal acid content of the kidney cells increases the capacity of their colloids for water, and consequently if this is offered them they swell. And so it might be reasoned that to give water in the acuter forms of nephritis would be to aid this swelhng. Such swelling of the cells, so far as the cells themselves are concerned, can hardly be considered serious, any more than a moderate oedema of any tissue is in itself particularly destructive to the tissue. But in the case of the kidney a complicating circumstance arises which does make such a swelHng dangerous. This resides in the fact that the capsule of the kidney is not as expansible as the rest of the kidney substance. As the kidney substance swells this tends, therefore, to press upon the blood vessels and retard the circulation of the blood through the kidney. This condition actually comes to pass in the acuter forms of nephritis. The kidney already nephritic, say from the tox- ine of an infectious disease or an anaesthetic, tends to make itself worse by thus hampering its blood flow. The washing out of salts from the kidney acts in the same general direction, for, as already noted, the presence of salts tends to counteract the effects of acids in producing swell- ing of the (hydrophiHc) emulsion colloids of the kidney. Our problem might, therefore, seem to become that of bal- ancing the good effects of water against certain bad ones. Actually the problem is much simpler. A kidney that is killing itself clearly needs water to rid itself of the poisons that are killing it and so, from this point of view, water is indicated. We can give the kidney the benefit of these virtues of the water, while we protect it at the same time from the 134 NEPHRITIS dangers associated with the water by giving along with the water certain salts. To a consideration of this subject we will now turn. 3. The Role of Salts in the Relief of Nephritis. We have labored thus far to show how a parallelism ex- ists between the changes that various colloids undergo in the presence of any acid and the changes that are observed in the kidney when this becomes the seat of a nephritis. We have noted how the swelHng of the kidney in nephritis is like the sweUing of fibrin or gelatine in water when a little acid is added to this; how under the same circum- stances some of the colloids go into solution, and so the development of an albuminuria is simulated; how when a colloid of the nature of casein is mixed with these, this is precipitated under conditions which make the others swell, thus behaving Hke certain granules observed to arise in the cells of the kidney under conditions associated with a nephritis. In studying the behavior of the pure colloids we learned more than this. We learned, first of all, that the swelling of the colloids could be reduced, not only by neutralizing the acid, but by adding to the acid any neutral salt. So far as the precipitation of casein was concerned the salts divided themselves into two groups — the one added itself to the effect of the acid and favored precipitation, the other counteracted such an effect. If now our contention is correct that the series of changes observed in these simple colloids and in the kidney are identical in character, then it was to be expected that the administration of properly selected salts should relieve the various signs characteristic of a fiephritis. That such is in fact the case is shown by the experiments that follow. The choice of salts for these experiments was not an NEPHRITIS 135 arbitrary one, and what would constitute an ideal salt for the relief of nephritis could well be told in advance. Clearly, no salt which, when employed in the concentrations and amounts necessary to get the desired effects, had any "specific" poisonous action upon the experimental animal or human being was of any use. Beyond this it was necessary to find one which combined a maximum of those effects which tended on the whole to help the nephritis (reduction of protein solubihty and swelling of the kidney) with a minimum of those which aggravated such a condition (aug- mentation of protein precipitation in the cells). As part of the relief of a nephritis centers in the neutralization of acid, a salt capable of combining with such clearly possesses certain advantages. For this reason such salts as are the combination of a weak acid with a strong base, as the phosphates, citrates, tartrates, and malates of sodium at once suggest themselves. But neutral salts are also effec- tive in reducing the solution and the swelling of such emul- sion colloids as fibrin, gelatine, and serum albumin and so the use of the chlorides and sulphates of sodium, potassium, and magnesium suggests itself. But which of these salts may, or can in the end, be employed depends upon how urgently we wish to use them to get our effects, or how much of them we wish to give at one time, and the mode of administration employed. The citrates which, on theo- retical grounds, one is tempted to use cannot be given in- travenously in sufficient amounts to prove useful, though administration through the alimentary tract renders them safe. And this explains why when we come to use these salts clinically our hst becomes comparatively short, and, for intravenous injection, very short indeed. As our argument thus far has seemed to indicate to us that all the signs of a nephritis are referable to a single underlying cause, so of course we would expect that did we 136 NEPHRITIS succeed in discovering any means of combating this cause all the signs of the nephritis would disappear en masse. Such is as a matter of fact the case, though to show the salutary action of the various procedures employed their effect on the various signs has been studied separately. §1. In order to show that salts inhibit the development of the signs of a nephritis it was necessary, first of all, to decide upon satisfactory methods of producing a nephritis experi- mentally in animals, upon which might then be tried the action of various salts. Three different methods of pro- ducing the nephritis were employed: interference with the respiration of the animal, the intravenous injection of acid, and direct clamping of the renal blood vessels. Of all these the last named is probably grossest in its effects upon the kidney. For the sake of comparison the pro- tocols of the experiments on the animals which served as controls have been inserted in each case. Let us turn first to a consideration of the nephritis that develops in rabbits, when these are tied into the animal holder sufficiently tight to interfere with their respiration. One always gets an albuminuria after such a procedure as the following protocols show: NEPHRITIS 137 Experiment 22. — White rabbit; weight 898 grams. Fed wheat and grass. Snugly tied into holder. Urine obtained with a soft rubber catheter. Time. Urine in c.c. Remarks. 3-00 Bound into holder. 3-30 3-7 Alkaline to litmus paper. No albumin. 3-45 5.0 { Clearer urine. Neutral to litmus paper. Trace of albumin. 4.00 3.0 1 Clear urine. Neutral to litmus. Albumin present. 41S 1.8 ^ 0.9 I.I J> 1-5 1.8 J 4.30 4.45 5 00 Clear. Neutral to litmus. Albumin present in every sample, and increasing in amount. 515 S.16 Animal seems entirely well. Returned to hutch. Experiment 2^. — Belgian hare; weight 1226 grams. Fed wheat and grass. Snugly tied into holder. Urine obtained with a soft rubber catheter. Time. Urine in c.c. Remarks. 2.45 Few drops' 1 .0 0.5 ' Few drops J 3 3 00 15 Alkaline, thick, chrome yellow. No albumin. 3 30 3 4=; Few drops Neutral and clearer. Trace of albumin. 4 00 Few drops"! 4 I"? Few drops 4 4'> 2.0 ^ Neutral and clearer. Albumin present. 5 00 Few drops 5 IS Few drops ^ 5 16 Animal released and returned to hutch. 138 NEPHRITIS Experiment 24. — Belgian hare; weight 1020 grams. Fed wheat and grass. Snugly tied into animal holder. Urine obtained with a soft rubber catheter. Time. Urine inc.c. Remarks. 3-30 30 1 3-45 0.7 1 Tied down. Turbid, dark yellow. Alkaline 4.00 05 r to litmus. No albumin. 4-15 Few drops J 1 Turbid, dark yellow, alkaline to litmus. No 4-30 2.4 albumin. A A- 8.5 \ Clearer, pale yellow. Acid to phenolphthal- 4-4o ein. Albumin present. 5.00 4.0 1 5-15 2.0 1 Few drops Y Clear, acid to phenolphthalein. Albumin present. 5-45 Few drops | 6.00 3-0 J Experiment 25. — Belgian hare; weight iioo grams. Fed wheat and grass. Snugly tied into holder. Urine obtained with a soft rubber catheter. Time. Urine in c.c. Remarks. 4 00 1 .0 "1 4 15 2.0 ^ Tied down. Alkaline, turbid, thick. No 4 30 Few drops [ albumin. 4 45 1-5 J 5 00 2.0 1 5 5 15 30 ^■5 i> Urine clear, acid to litmus. Albumin present. 2o 1 S 45 3-0 J 5 46 Liberated. Returned to cage. When, now, rabbits fed the same food are treated from an experimental standpoint in an identical way but have in addition a concentrated salt solution injected intrave- nously, the albuminuria does not develop. NEPHRITIS 139 Experiment 26. — Black rabbit; weight 917 grams. Fed wheat and grass. Snugly tied into animal holder. Urine obtained with a soft rubber catheter. 105 c.c. | molecular NaCl solution^ are given intravenously in the course of the experiment at the rate of 5 c.c. every five minutes. Remarks. Thick, chrome yellow, alkaline. No albumin. Injection begun. Thick, chrome yellow, alkaline. No albumin. Clearer. No albumin. Time. Urine, in c.c. 4 00 7.5 1 4 15 2.5 4 30 7-5 4 45 22. o(?)- 5 00 23.0 5 15 36.5 y 5 30 32.0 1 5 45 27.5 J 5 46 — 1 Clear as water. Neutral to litmus. No albumin. Animal well. Released and killed by blow on head. Nothing abnormal noted on autopsy. Experiment 27. — Belgian hare; weight 919 grams. Fed wheat and grass. Snugly tied into holder. Urine obtained with a soft rubber catheter. 105 c.c. ^ molecular NaCl solution are injected intravenously in the course of the experiment at the rate of 5 c.c. every five minutes. Time. Urine in c.c. Remarks. 4.0 1 2.5 Alkaline to litmus, thick, yellow. No albumin. 3 3 ^6 30 Injection begun. Somewhat clearer. No albumin. 3 45 20.0 .4 00 57-5 4 4 15 30 40.0 . 390 1 Clear, colorless. Neutral to litmus. No albumin. 4 45 29.0 37-0 J 5.00 As there is much reason to believe that a mixture of different salts when injected intravenously is less poison- ous than any pure salt solution, I made the following experiments with Ringer solution. * That is a 2.925 per cent solution of sodium chloride. I40 NEPHRITIS Experiment 28, — Belgian hare; weight 901 grams. Fed wheat and grass. Snugly tied into holder. Urine obtained'.with a soft rubber catheter- In the course of the experiment there are injected intravenously 135 c.c. of a Ringer solution X 4/ at the rate of 5 c.c. every five minutes. Time. Urine in c.c. Remarks. 1.40 4.0 Turbid, alkaline to litmus. No albumin. 1-45 2.00 4.0 Injection into ear begun. Turbid, alkaline to litmus. No albumin. 2.15 16.0 ^ 2.30 2.45 38.0 47-0 r Clear, alkaline. No albumin. 3.00 40.5 32.0 J 315 330 3-45 I3-0 ) 7.0 \ Clear, neutral. No albumin. 4.00 6.0 ) 4-05 No urine Animal well. Returned to cage. Experiment 29. — Belgian hare; weight 823 grams. Fed wheat and grass. Tied tightly into holder. Urine obtained with a soft rubber catheter. In the course of the experiment there are injected 125 c.c. of a Ringer solution X 4, at the rate of 5 c.c. every five minutes. Time. Urine in c.c. Remarks. I -50 Tied down. 1-55 Injection into ear begim. 2.10 2.25 30 Turbid, alkaline. No albumin. 2.40 18.0 Clear, alkaline. No albumin. 2.55 130^ 3.10 17.0 3-25 20.0 y Clear, neutral to litmus. No albumin. 3 40 8.0 3-55 4-o^ 4.00 Dies. Nothing abnormal noted on autopsy. ^ The sodium, potassium, calcium chloride mixtures that are known as Ringer solutions have a different composition with different authors. I used the following: NaCl 0.7, CaCl2 0.0026, KCl 0.035, and H2O enough to make 100 c.c. Ringer solution X 4 means four times this amount of salts in each 100 c.c, a solution which has then about the same osmotic concen- tration as a ^ molecular NaCl solution, as used in the previous experiments. NEPHRITIS 141 Experiment 30. — Belgian hare; weight 855 grams. Fed wheat and grass. Tied tightly into holder. Urine obtained with a soft rubber catheter. In the course of the experiment there are injected 150 c.c. o£ a Ringer solution X 4, at the rate of 5 c.c. every five minutes. Time. Urine in c.c. Remarks. I.O Turbid, alkaline. No albumin. Tied down and 2 ""^ 6^ intravenous injection into ear begun. 2 45 1-7 3 00 3-6 3 15 II. 12.5 > 21.0 Urine clears until it looks like water. No albu- 3 3 30 45 min at any time. 4 00 25.0 4 15 23.0 J 4 30 25-o(?)1 9.5 I 12.5 f 10. J 4 5 45 00 Clear, acid. No albumin at any time. 5 15 r Killed. On autopsy nothing abnormal except 5 20 ... j that 25 c.c. fluid are obtained from the peri- toneal cavity! Our interest in these experiments has thus far centered in the development and the nondevelopment of an albu- minuria. Let us now retrace our steps and see what has happened so far as urinary secretion is concerned, for we were rather particular to emphasize the fact that the ability of the kidney to secrete water was perhaps the best index of its functional activity. What we are inter- ested in knowing is concerned with a problem of immediate practical worth. Can the secretion of urine from a nephritic kidney, or one threatened with a nephritis, he maintained at a normal level or he increased hy the giving of various salts? The experiments detailed above already suffice to answer this in the affirmative, and let it be noted that this holds true even in the case of sodium chloride which in recent years has been particularly warmly criticised, it having even been maintained by not a few authors that this particular 142 NEPHRITIS salt is responsible for the water retention in nephritis (and in certain other diseases associated with oedema). That such a beUef is unwarranted is proved as soon as we com- pare with each other Figs. 23, 24, and 25, and Experi- ments 22, 23, 24, 25, 26, 27, 28, 29, and 30, upon which these are based. All the figures are drawn to the same scale (though they have not been reproduced on the same scale) . The rate of urinary secretion is indicated in number of cubic centimeters obtained in each 15 minutes. Figure 22 shows normal urinary secretion in three rabbits that were loosely tied into an animal holder. The curves Houi-s Fig. 22. 10 ' 8 - / \ 6 4 - / \ / \ / 2 CC. '/^ ^ Hours Fig. 23. a, h, c, and d of Fig. 23 (based respectively on Experiments 25, 22, 24, and 23) show, when compared with the curves of Fig. 22, how the secretion of urine is diminished when, in- stead of being loosely tied into the animal holder, the rabbits NEPHRITIS 143 are so snugly tied down as to embarrass their respiration. The diminished secretion gives way to an enormously height- ened one if animals similarly treated are injected with a con- centrated sodium chloride solution. Figure 24, drawn to the same scale as Fig. 23, shows this very well. The curve a is taken from Experiment 27, curve h from Experiment 26. These experiments (as others to be described directly) show very well that sodium chloride does not lead to a retention of water by the living animal. Let us now look at Fig. 25 which shows the curves obtained by injecting concentrated Ringer solution. Evi- dently all salts (that have not specific poisonous effects) if injected in sufficient concentrations increase the output of urine. The curves a, b, and c are constructed respectively from Experiments 28, 29, and 30. As noted in the proto- cols the rabbits were again snugly tied into animal holders, but not only did none of them develop an albuminuria but, in consequence of the injection of the concentrated Ringer solution, the urinary output was enormously increased in all. §2- We will now consider a second method of inducing a nephritis, namely, through the injection of acid into an animal, and see if our concentrated sodium chloride is again able to prevent or relieve the signs of a nephritis as thus induced. As the following experiment shows, sodium chloride when injected intravenously, in concentrated solution, simultaneously with a hydrochloric acid solution of a con- centration which we found in Experiments 13 and 14 (pages 38 and 39) to lead to the symptoms of a most intense acute nephritis, practically suppresses this entirely. The albumi- nuria scarcely appears, and there are no casts, no red blood corpuscles, no hcemoglobinuria, no decrease in the amount of urinary secretion, and no general oedema. 144 NEPHRITIS Hours Fig. 24. NEPHRITIS HS 146 NEPHRITIS Experiment 31. — Belgian hare; weight 2136 grams. Has been fed hay, oats, corn, and greens. In the course of the experiment there are injected intravenously at a uniform rate 140 c.c. of the following mixture: 150 c.c. xV normal HCl plus 4.666 grams sodium chloride and enough water to make the whole up to 160 c.c. This yields a final solution that is | molecular so far as the sodium chloride is con- cerned. Urine obtained with a catheter. Time. Urine in c.c. Remarks. 1 Catheterized. Weighed and fastened to animal 3 30 board. 3-45 Injection into ear begun. 1 Slightly turbid, neutral to litmus paper. No al- 4.00 03 bumin. No casts. 1 Clear as water, barely reddens blue litmus paper. 4-15 17.0 No albumin. No casts. 61.0 \ Clear, barely affects blue litmus paper. Faint 4 -30 shimmer of albumin! No casts! 64.5 58.0 38.0 r Urine clear, barely affects blue litmus paper. 4-45 1 < Faint trace of albumin. No casts. No 5-00 haemoglobinuria at any time. No red blood 5-15 I corpuscles in the urine. 5.18 I .0 Dies. Total amount of urine secreted since beginning injection 239.8 c.c. Autopsy. Weight 2035 grams! Nothing abnormal is noted. The body cavities contain no fluid. The blood seems to coagulate abnormally rapidly. It might be insisted in criticism of this experiment, that while sodium chloride is thus able to counteract the effects of an acid in producing a nephritis, it cannot relieve such after once being established. This criticism is met in the following Experiment 32, in which a nephritis is first in- duced by injecting (practically) pure acid, after which its relief is brought about by injecting ^ molecular sodium chloride. Experiment 32. — Belgian hare; weight 2343 grams. Fed hay, oats, corn and greens. Urine obtained with a soft rubber catheter. In the course of the first i \ hours of the experiment there are injected at a uniform rate 125 c.c. of the following mixture: 120 c.c. to normal NEPHRITIS 147 HCl plus 8 c.c. f molecular NaCl, in consequence of which all the signs of a nephritis develop. For the acid mixture is then substituted a pure | molecular NaCl solution of which, up to the end of the experiment, there are injected 125 c.c. Coincident with this change in the character of the injection fluid all the signs of the nephritis are seen to disappear. Time. Urine in cubic centi- meters. Remarks. 2.45 3.00 3-15 3-30 3-45 4.00 4.15 30 50 1-5 0.7 7.0 ^ I 20.0 < 42.0 j 60.0 < 53-0 I 32.0 j ii.o(?)| Catheterized. Turbid, light yellow, faintly al- kaline to litmus paper. No albumin. No casts. Weighed. Tied to animal holder. Intravenous injection of acid mixture into ear begun. Urine turbid, light yellow, faintly alkaline to litmus paper. No albumin. No casts. Urine neutral to litmus paper. No albumin. No casts. Urine neutral to litmus paper. No albumin. No casts. Urine faintly acid. Albumin. Isolated casts. Epithelial cells and red blood corpuscles. Urine has a pink tinge. More albumin. Nu- merous casts and a larger number of red blood corpuscles. Injection of acid mixture stopped. Injection of \ molecular NaCl begun. Urine decidedly red (haemoglobinuria). Albu- min content still rising. Fewer casts and red blood corpuscles. Pink color to urine. Albumin decreasing. No casts can be found after long search of sedi- mented urine. Pale pink. Albumin decreasing. No casts or red blood corpuscles. Like water. Barely visible trace of albumin. No casts or blood corpuscles. Like water and neutral to litmus paper. No albumin. No casts. No blood cells. Injection stopped, as animal has embarrassed respiration. Some urine accidentally lost as animal dies. No albumin. No casts. No blood cells. Autopsy. — Weight 2342 grams. Nothing abnormal in any of the organs. The peritoneal cavity is wetter than normal. The pericar- dial and pleural cavities are empty. A number of interesting facts come to light in the two experiments just detailed. Let us first ask about the out- 148 NEPHRITIS put of urine. In Fig. 26 we find in the curves a and b (Experiments 13 and 14) a graphic representation of the amount of urine secreted when a to normal hydrochloric acid solution (in | molecular, that is 0.733 P^^ cent sodium chloride, added to reduce somewhat the haemolytic action of the acid) is injected intravenously. When w^e compare these curves with those of Fig. 22 (normal secretion in rabbits), we notice that in spite of the great injection of water, the urinary output lies below the normal. The 10 8 6 / V 6 / " c 2 CC. s^,..-- ...y • 3 Hours 1 2 3 Fig. 26. presence of the acid along with the water brings it to pass that the water is retained in the body; in other words, an oedema develops. The same factor, therefore, which we are holding responsible for certain of the kidney changes in nephritis, is responsible for one of the most prominent symptoms of such kidney disease, namely, the oedema. How enormously the urinary output is increased if a con- centrated sodium chloride solution is injected along with the hydrochloric acid is apparent when Fig. 27, drawn to the same scale, is compared with Fig. 26. And when we look through the protocols we find that this increased uri- nary output is associated with a loss of weight by the animal, in other words, a failure to develop an oedema, or the re- duction or total disappearance of such as may be existing. NEPHRITIS 149 ISO NEPHRITIS Clearly, therefore, salts, including sodium chloride, all tend to reduce oedema, as I have previously insisted. Another point of interest in these two experiments is the fact that when enough sodium chloride is injected along with the acid, the haemoglobinuria fails to develop. As is well knowTi a pure acid solution when injected intrave- nously leads to a rapid and extensive destruction of the red blood corpuscles (haemolysis) and the escape of haemoglobin in the urine. The only reason why some sodium chloride was given along with the acid injections in the various ex- periments described in this volume, in which the effects of the pure acid on the kidney were particularly sought, was to escape in part this so great dissolution of the red blood corpuscles. When enough sodium chloride is added the haemolytic action of the acid is avoided altogether, as Experiment 31 shows. This fact is of interest and im- portance not only because it teaches us that by increasing the salts in the diet we can relieve the signs and symptoms of parox>^smal haemoglobinuria, ^ but because it was a result to be expected if a theory of haemolysis which I have pre- viously advanced^ should be correct. Incidentally, these last two experiments in conjunction with Experiments 12,13 ^^^ ^4 (p^-ges 37 to 39) serve to meet a criticism that might have been raised against our experi- ments on asphyxia nephritis, in which it might have been said that the great urinary secretion obtained after injecting salt solutions was due merely to the injection of so much water. §3- As Max Herrmann first showed, direct interference with the blood supply to the kidney leads to very destructive changes in this organ in an incredibly short space of time 1 Oscar Berghausen: Unpublished paper. 2 Martin H. Fischer: Kolloid Zeitschr. 6, 146 (1909) and (Edema, 166, New York, 1910. NEPHRITIS 151 — the output of urine falls or may be stopped entirely and albumin, casts, and blood are found in such as is secreted. If the kidneys are examined these are found to be swollen, maybe grayish, and to present varying degrees of haemor- rhage into the kidney substance. The following experi- ment illustrates this. Experiment 33. — Belgian hare; weight 2335 grams. Fed hay, oats, corn, and greens. Urine obtained with a catheter. The right renal artery and vein, and the left renal artery are clamped for one- half hour. Time. Urine in c.c. Remarks. 2.05 -1 0.008 gram morphine hydrochloride given sub- cutaneously. C Clear, brownish yellow, faintly acid to litmus. 2-15 150 \ No albumin. No casts. After catheterizing the animal is weighed. 2.50 Tied into holder. 3.00 0.5 1 Right renal artery and vein and left renal artery are clamped. 3.15 3-30 Clamps removed. 3-45 4.00 .o| Much albumin. Hyaline casts and red blood 415 corpuscles. 4-30 4-45 0.5 \ 0.8 ] Thick, turbid, acid to litmus. Full of albumin 5.00 and casts. 5-15 0.8 1 Thick, turbid, acid to litmus. Full of albumin 5-30 and casts. 5-31 Animal appears well, is killed. Autopsy. — Kidneys are swollen and deep red, but otherwise show nothing strikingly abnormal to the naked eye. The urinary output in this experiment is illustrated in curve c of Fig. 28. Let us now see how an animal similarly treated fares if it receives an intravenous injection of a " physiological," \ molecular (0.733 per cent) sodium chlo- 152 NEPHRITIS CC. Hours 1 Fig. 28. NEPHRITIS 153 ride solution. Such an experiment serves to answer two very important questions. First, is the giving of water to a case of " acute nephritis " dangerous because it " throws work on the kidney " and we need to " protect " this organ against doing any work; and second, does the administra- tion of sodium chloride aggravate such a nephritis because, Experiment 34. — Belgian hare; weight 2184 grams. Fed hay, oats, corn, and greens. Urine obtained with a catheter. The right renal artery and vein, and the left renal artery are clamped for one-half hour. Thereafter, 215 c.c. of a | molecular NaCl solution are injected at a uniform rate intravenously. Time. 11.20 11.40 12.10 12.25 12.40 12.50 I 05 1 .20 1-35 Urine in c.c. 2.0 4.7 12.0 I 50 12.5 2.05 150 2.20 18.5 2-35 2.50 30s 3.06 19.0 20.0 21 .0 Remarks. 0.016 gram morphine hydrochloride given sub- cutaneously. Thick, yellow, turbid, acid to rosolic acid. No albumin. No casts. Catheterized and weighed. Same. R.ight renal artery and vein and left renal artery clamped. Clamps removed. Injection of \ molecular NaCl into ear begun. Accident to needle interrupts injection for 10 minutes. Full of albumin, epithelial, finely granular, and hyaline casts. Acid to rosolic acid. Full of albumin, epithelial, finely granular, and hyaline casts. Clear as water. Albumin going down. It is noted that there is decidedly more albumin in this experiment than when \ molecular NaCl is used, volume of urine duly considered. Decided drop in albumin. Still some casts. Clear as water. Albumin present in traces only. Occasional cast only. Same. Trace of albumin visible after standing. No albumin. No casts. Killed. Autopsy. Weight 2269 grams. Pleural and pericardial cavities dry. organ. 6.0 c.c. fluid in peritoneum. Nothing abnormal noted in any 154 NEPHRITIS as some say, it '' further increases the work of the kidney " or because it '' irritates " this organ? A no inconsiderable portion of the therapeutic world to-day insists on both restriction of water and of sodium chloride in cases of acute nephritis. That both should be given and that the sodium chloride, far from adding itself as a factor of evil to the water, really counteracts the only bad effects this might have (through favoring the swelling of the kidney and washing out salts) is shown by the results of the Experi- ment 34. The increased urinary output, in consequence of the in- jection of the I molecular sodium chloride solution, is clearly evident when curve h of Fig. 28, based on this experiment, is compared with the curve c as obtained in the previously described Experiment 33. We note, more- over, that with the concentration of sodium chloride em- ployed in Experiment 34 a not inconsiderable amount of the injected water is retained, in other words, the animal develops an oedema. In the terms of the osmotic theory of water absorption (which we do not accept) this would be explained by saying that a 0.733 P^^ cent sodium chloride solution has a lower osmotic concentration than the body fluids of the rabbit. Many clinicians who believe that so- dium chloride " leads to oedema " might be inclined to say that this experiment supports their contention. That it does not is shown by the following Experiment 35 in which an animal, again rendered nephritic by clamping the renal vessels, is again injected with the same amount of water at the same rate, but the concentration of the sodium chloride is further increased (to | molecular NaCl, that is 2.918 per cent). As the protocol and curve a of Fig. 28 show, the urinary output under such circumstances is still further, really enormously increased, and also not only does no oedema develop, but the animal actually loses in weight. NEPHRITIS 155 To the interpretation of these various findings, which it was entirely possible to predict, we shall come immediately. Experiment 35. — Black rabbit; weight 2778 grams. Fed hay, oats, corn, and greens. Urine obtained with a catheter. The right renal artery and vein, and the left renal artery were clamped for one-half hour. Thereafter, the animal received at a uniform rate an intravenous injection of 170 c.c. I molecular sodium chloride solution. Time. Urine in c.c. Remarks. 1-55 1 0.016 gram morphine hydrochloride are given subcutaneously. r Yellow, turbid, alkaline to litmus. No albumin. 2.20 14.0 \ No casts. After catheterizing the animal is I weighed. r Yellow, clear, alkaline. No albumin. No casts. 2.45 2-3 < Right renal artery and vein, and left renal ar- 3.00 3-iS I tery are clamped. Clamps removed. 3-25 Intravenous injection of | molecular NaCl begun. 1 Filled with casts and red blood corpuscles. 3 40 3 i Fairly sets with albumin. 3-55 32 5 Last portions clear as water. 4.10 68 1 4-25 73 Clear as water. Acid to phenolphthalein, alka- 4.40 59 line to rosolic acid. Faintest trace of albumin 4-55 46 5 r only. No casts. Occasional red blood cor- 5-IO 2,7 puscles. 5-25 39 5 \\ Animal killed. Approximately 10 c.c. urine lost 5-26 ? \ in interval between stopping injection and making autopsy. Autopsy. — Weight 2554 grams! 19.0 c.c. fluid found in perito- neal cavity. Pleural and pericardial cavities are dry. Kidneys are slightly grayish. The following Experiment 36 shows for what a long period the blood supply to the kidney may be cut off and yet the dangers ordinarily incident to such a procedure (partial to complete suppression of urine) be reduced by giving a concentrated salt solution. The experiment was really undertaken to indicate how the so-feared conse- 156 NEPHRITIS quences of temporary occlusion of the blood vessels in oper- ations on the kidney may be largely avoided — a discussion to which we shall return immediately. ExPERQiENT 36. — White and blue rabbit; weight 2344 grams. Fed hay, oats, corn, and greens. Urine obtained with a catheter. The right renal artery and vein and the left renal artery and vein are clamped for i\ hours. After an interval, 90 c.c. ^ molecular NaCl solution are injected at a uniform rate intravenously. Time. Urine in c.c. Remarks. 9.20 1 0.016 gram morphine hydrochloride are given subcutaneously. 9 50 Tied down. 10.05 1-3 Deep brownish-yellow. No albumin. No casts. Renal blood vessels are clamped. 10.20 10.35 10.50 11.05 11.20 11-35 Clamps removed. 11.50 12.05 12.20 12.35 12.50 I -05 1.20 1-35 1-55 Injection of | molecular NaCl into ear begun. 2. 10 2.25 0.3 ' 2.40 0.4 Filled with albumin and hyaline casts (exclu- 2.55 0.4 sively). 3.10 0.8 ..' Injection stopped. 3 25 2.6 1 Urine clearer. Filled with hyaline and granular casts. 3 -40 2.8 Casts fewer. 3-55 i-S No casts. 3-55to 5-25 ^.3 i No casts. Red blood corpuscles found (trau- matic). 5 40 1-5 No casts. 541 Killed. Autopsy. — Weight 2300 grams. 10 c.c. fluid in peritoneal cavity. 1,2 c.c. in right pleural cavity. Left unusually moist. Kidneys soft and somewhat gray. NEPHRITIS The secretion of urine in this experi- ment is represented graphically in Fig. 29. The first arrow indicates the point in the experiment when the clamps were removed. Up to point of the second arrow no urine was obtained. At this time the sodium chloride injection was started. The secretion of urine began less than half an hour afterwards. § 4- It behooves us now to pause for a moment and to study the just described experiments in order to discover the principles that underlie the results ob- tained, for only by knowing these can we hope to put them to any intelligent therapeutic use. In the light of the ideas developed in this volume, and my remarks on urinary secretion^ the follow- ing seems to me safe ground. The living organism represents in the resting state a series of colloids which are saturated with water. The blood and lymph constitute an integral part of this system. No water can be absorbed by the living organism, and none be given off except as conditions are first offered in the body as a whole or locally (individual organs or cells), which in- crease or decrease this normal relation- 1 Martin H. Fischer: (Edema, 180. New York, 1910. See also Kolloidchemische Beiheftc, 2, 304 (1911). 157 158 NEPHRITIS ship between the colloids and the water bound to them. As in our discussion of the kidney we are dealing with the prob- lem of secretion, we can at once recall to mind experimental and clinical evidence to support such a view by remember- ing that in absolute starvation urinary secretion ceases (prac- tically) entirely. And so we are not surprised to find that the urinary output of a normal rabbit shortly after we stop feeding it shows signs of diminution and soon thereafter signs of complete cessation (Fig. 22). From this we can immedi- ately learn a practical point that is ignored medically all too often, and that is that the only way to increase the uri- nary output is to give water, and (if we ignore the skin and respiration) we can say that we increase this in proportion to the amount of water given. Many if not all of the diu- retics act in the same way. They are diuretics only because they make for conditions in the body which decrease the avidity with which the colloids of the body are holding on to their water. Let us see now what happens when we tie our otherwise normal rabbit so snugly into an animal holder that we in- terfere with its easy respiration. That the urinary output falls under such circumstances is shown in Fig. 23. What happens here is this: we favor under these circumstances the accumulation of carbon dioxide and other acids in his body. This raises the avidity with which the colloids of all the tissues of the body hold on to their water, and so none is left over to be secreted as urine. The animal is, in other words, at once put into a condition similar to that attained after several hours by the animal simply kept off of food and water. In addition to any local acid effect we may have in the kidney (swelling of the kidney, etc.), we have also in this case an acid effect upon all the tissues of the body. Not only therefore is the kidney placed in a position in which it cannot secrete as well as normally, but the material necessary for this secretion (water) is also NEPHRITIS 159 withheld. Parenthetically we may add that a state similar to that induced here by tying the animal down is obtained when we give a dose of morphine, cocaine, atropine, arsenic, an anaesthetic like chloroform or ether, an excessi-ve dose of alcohol, or a nitrite. Essentially the same state of affairs is produced if we inject an acid solution intravenously. The acid acts upon the tissue colloids, increases their affinity for water, and these therefore absorb and hold on to all that is given them in these experiments along with the acid. And so we have again none left over to be secreted by the kidney. The animal retains the water, increases in weight; it develops an " oedema." This general effect of the acid on the body as a whole, adds itself therefore to the acid changes that occur in the kidney itself under such circumstances. The acid circulating in the kidney makes the cells here swell. This compresses the blood vessels of the kidney, and so the state of the kidney becomes still more precarious. To its already serious acid state the kidney adds further danger by reducing its own blood supply (which means a further formation and accumulation of acid in the kidney), and so a vicious circle is estabhshed. Let us consider, first of all, what must happen if we give pure water to such an animal. Its effects are in part good, in part bad. Very evidently only by giving water can we hope to get the body colloids generally once more saturated with water and so get some left over for a urinary secretion, and only as we get a urinary secretion can we hope to wash out the acids (and other toxic substances) that are killing the kidney cells. And this holds, as we shall see, even when we deal with a case of generalized oedema. The only bad effects of giving water reside in favoring the swelling of the kidney. But this feature we can avoid, as we have said before, by giving salts. i6o NEPHRITIS To the relief of all the conditions that characterize our picture of nephritis comes the administration of salt (along with the water). The salts — including sodium chloride — reduce the amount of water that can be held by the body colloids generally, and so this freed water now becomes available for urine. The kidney itself shares in this process and by shrinking admits a better circulation to be once more estabhshed through it. In this way ever\'thing tends to be reestabhshed in a normal way once more. The body now loses water, and so the animal weight, in other words the oedema disappears again. Under the same cir- cumstances the kidney proteins become less soluble and so the albuminuria goes. The disappearance of the casts is pecuHarly interesting. Immediately follo\^dng a salt in- jection the number of casts seems increased. We note, moreover, that they are smaller, and while hyaline casts may have predominated before, granular ones now nil the field. The sudden apparent increase in the number of casts is due to the shrinkage under the influence of the in- creased salt concentration of the casts as they lie in the kidney tubules, and so their easier and sudden washing out from these tubules by the increased urinary flow obtained under the same circumstances. The granular casts repre- sent the reconversions of the hyaline casts back into the granular under the influence of the salt. § 5- We come now to the highly important matter of apply- ing what has been found to hold in animals to human cases. The credit of having been the first to adapt the principles outhned in this volume to chnical cases belongs to James J. Hogan. An abstract of his first two cases follows. Since then others of my friends and colleagues have used alkalies, salts, and water for the relief particularly of the acuter ne- NEPHRITIS i6i phri tides, and with favorable results. My thanks are due all these for permitting me to use the facts that are con- tained in the following brief outlines of their cases. The entire purpose of our therapy must be to get alkali into our patient in order to neutralize the acids present; to get salt into him to aid in the reduction of the oedema of the kidney (and other organs) ; and finally, to give him water in large doses at regular intervals in order to have ''free" water available for urine. How we may accom- phsh our ends by administering these by mouth, or in the acuter cases by giving properly concentrated solutions of sodium carbonate and sodium chloride by rectum or in- travenously is indicated in the abstracts. Case i. — {Dr. James /. Hogan, Vallejo, California.) Mrs. R., pregnant and practically at term, entered the hospital March 7, at 5.30 p.m., complaining of continuous uterine pain. The patient had a general oedema. Signs and symp- toms indicating that a nephritis had existed for at least some days past were evident, but no proper examination of the urine had been made. The os on examination was found rigid. Because of the intense pain 0.015 gram mor- phine was given h}^odemiically at 9.00 p.m. She went to sleep but awoke at 11.00 in a severe convulsion. The patient w^as catheterized and 60 c.c. of bloody urine of a s>Tupy consistency were obtained. On testing this for albu- min it fairly set. Casts, cellular detritus, red blood cells, etc., were found microscopically. 600 c.c. of an 0.85 per cent sodium chloride solution were given by rectum and immediate emptying of the uterus was deemed necessary. This was done under ether anaesthesia and as the os was very rigid required a half hour. A second convulsion oc- curred on the operating table. Immediately after the oper- ation another 500 c.c. of an 0.85 per cent sodium chloride solution were given by rectum. Between this time (11.30 P.M., March 7) and 4.50 p.m., March 11, in other words, for practically four days, no urine could be obtained by cath- eter. During this"^ time no con\nalsions occurred and the 1 62 NEPHRITIS patient's mind remained clear. A continuous salt drip was used in the rectum and water and magnesium sulphate were given by mouth, but no evidence of a return of urinary function was obtainable. It was now decided to use a more concentrated sodium chloride solution and alkali. The following mixture was therefore prepared. Sodium carbonate (crystallized) ^ . . 20 grams Sodium chloride 14 grams Water enough to make 1000 c.c. This was injected into the rectum at body temperature by a continuous drip method. In an hour and ten min- utes 30 c.c. of bloody urine were obtained, and an hour later 80 c.c. more. From now on the urine fairly streamed out. The secretion continued and the albumin and casts entirely disappeared from the urine by the fourth day. The patient made an uninterrupted recovery. Case 2. — {Dr. James J. Hogan, Vallejo, California.) Mrs. W., 22 years old. Dr. Hogan was called in consultation on the evening of March 11, and found the patient uncon- scious with practically complete suppression of the urine that had lasted for twenty-four hours. The unconscious- ness had lasted for twelve hours. The nephritis in this case was secondary to scarlet fever. The formula used in Case I was given by the continuous drip method per rectum. The urinary flow recommenced after four hours ; on the fol- lowing day her mind had cleared, and the patient made a subsequent uneventful recovery. Case 3. — {Dr. H. Kennon Dunham, Cincinnati.) Master M., 7 years old, was seen on April 30, 191 1, by Dr. Wm. C. Schmidter in a rather mild attack of scarlet fever. The temperature at no time ran above 101° F. In spite of the apparent mildness of the attack, the child devel- oped urinary symptoms. On May 7, when Dr. Dunham 1 When the crystallized sodium carbonate is not at hand, and only the ordinary dried preparation is available, only about one third of this must he employed, for approximately two thirds of the crystalUzed substance is water of crystallization. NEPHRITIS 163 was first summoned in consultation, a complete suppres- sion of urine had lasted for fifty-one hours, the child was conscious, but very stupid, presenting a grave picture of intoxication. The eyehds and ankles were swollen, the pulse 105, respiration 24. At 4.00 A.M. the following mixture was prepared and its injection into the rectum begun: Sodium chloride 30 grams Sodium carbonate (crystallized) ... 20 grams Water 1000 c.c. The injection required one and a half hours. About 180 c.c. were rejected, the remainder of the above solu- tion was retained. Three and a half hours after the in- jection was completed the patient passed involuntarily a large watery stool. Ten hours after the completion of the injection he passed a small amount of highly colored urine. Following this at short intervals came large voidings of urine which were lost into the bed as the child could not control himself sufficiently to use a bedpan. Not until this secretion had lasted for four hours could the urine be collected. Not counting that which was lost there were collected 2272 c.c. of urine in the first twenty-four hours after urinary secretion commenced. The first specimens of urine obtained were so filled with albumin as to set into a solid mass on boiling. The amount of albumin rapidly de- creased in amount, so that during the second day after the injection only a moderate reaction for albumin was obtained, and on the ninth day it disappeared entirely. The intense stupor left the child within the first twenty-four hours after injection, and on the third day he was actively inter- ested in his surroundings and free from oedema. His urinary secretion after being started was readily main- tained by the milk diet on which he had been from the first and to which alkaline mineral water was added ad libitum. Case 4. — {Dr. Lemuel P. Adams, Oakland, California.) Mrs. E., 26 years old and a primipara, began to feel below par, became pale, and developed a generalized oedema when 1 64 NEPHRITIS pregnant seven and a half months. The secretion of urine was low, and this contained much albumin and various casts. Her condition gradually grew worse, so that it was deemed wise to put her to bed in the hospital. For ten days, here on a milk diet, and cared for in the approved ways, she showed no improvement, passing between 240 and 360 c.c. of urine per twenty-four hours, filled with albumin, casts, and red and white blood corpuscles. As she now began to develop twitchings, was extremely oedema- tous and nearly blind, and as the onset of convulsions was feared, premature labor (at 8 months) was induced through gradual dilatation of the uterine os by means of water bags. Complete suppression of urine followed dehvery. After this had lasted for thirty-one hours and no urine had come consequent upon hot packs, cupping, digitalis, etc., a slow in- jection of the following mixture into the rectum was begun : Sodium chloride 14 grams Sodium carbonate (crystallized) ... 20 grams Water 1000 c.c. Urine began to come four hours after the injection was commenced and amounted to 1536 c.c. in the first twenty- four hours. Two injections daily of 500 c.c. each of the above formula were continued for three days, together with water, milk, and cereals by mouth. On the second day 2176 c.c. of urine were obtained, on the third 2140, on the fourth 2180, and on the fifth 1856. On the fifth day casts and blood cells had entirely disappeared from the urine and only the faintest trace of albumin remained. The oedema had diminished greatly, eyesight was returning, and the patient was actively interested in her surroundings. On the following day the last of the albumin was gone and the patient went on to an uneventful recovery. Case 5. — {Drs. Otto P. Geier and J. L. Tuechter, Cin- cinnati.) G. L., a 34-year-old attorney, developed a severe tonsilHtis involving both tonsils on May 17, 191 1. His temperature was 103.5° F., pulse 120. The urine was very scanty, high colored, and contained albumin and casts. The next day the patient had intense headache, and in the NEPHRITIS 165 evening became delirious. During these second twenty- four hours of his illness he passed but 90 c.c. of urine, very smoky in color and filled with albumin, red and white cor- puscles and casts of all sorts. On the third day of his illness he passed no urine at all. His dehrium continued and his temperature remained at 103° F., his pulse at 124. Late at night he was given the following mixture per rectum: Sodium chloride 14 grams Sodium carbonate (crystallized). . . 20 grams Water 1000 c.c. In his delirium most of this first injection was rejected. At 3.00 A.M., May 20, the injection was therefore repeated. About. 500 c.c. of the formula were retained. At 6.00 a.m. 150 c.c. of dark, thick urine were obtained, which on heat- ing fairly set into a jelly. The urinary secretion became more profuse as the day wore on, and in the first twenty- four hours after the successful injection 1184 c.c. of urine were obtained. As the urinary secretion increased, the drowsy delirium passed away, the headache disappeared, and the patient volunteered that he felt well. The tem- perature fell to 101° F., the pulse rate to 100. The later specimens of urine voided in these twenty-four hours after the successful injection were clear and amber in color and contained only a little albumin, and few casts and blood cells. The rectal injections of 500 c.c. of the above formula were repeated May 21 (temperature 99.5° F., pulse 90) and May 22 (temperature normal, pulse 70), and the patient was urged to take as much Vichy water by mouth as he could. The urine secreted May 21 measured 1376 c.c, that secreted May 22, 1408 c.c. Some albumin and casts were found in the former, only a trace together with some red blood corpuscles but no casts in the latter. On May 23 all urinary signs had disappeared, and the patient made an uneventful recovery. Case 6. — {Dr. Dudley Smith, Oakland, Cahfornia.) Mrs. W., aged 30, and seven months pregnant, presented herself for examination in May, 191 1, with a history of nephritis and threatened eclampsia in her first pregnancy, 1 66 NEPHRITIS ten years before. The second pregnancy three years be- fore had been uneventful. Urinary examination when the patient first presented herself was negative. On June 7, she began to show albumin in her urine and marked signs of general intoxication. (Edema of the face and feet de- veloped. She was put to bed and placed on a milk diet, and salhie cathartics were administered. Under this treat- ment she got no better. About the first of July, active administration of alkalies was begun in the form of one to one and a half grams of sodium carbonate dissolved in a glass of plain water, or Vichy water, every two hours. Marked and positive improvement occurred in all her general symptoms and the oedema disappeared entirely. She was permitted to get out of bed again, but the alkali therapy was continued. On this regime she was carried to full term with no further general symptoms of consequence. Her urinary output lay between 1800 and 2800 c.c. daily and some albumin and casts continued in the urine. On July 24 she complained of severe continuous uterine pain, and with this came a marked reduction in the urinary out- put, extreme nervousness, and severe headache with nausea and vomiting. On the morning of July 25 the urinary secre- tion had stopped entirely. She was sent to the hospital at noon and the following formula was slowly injected into the rectum: Sodium chloride 14 grams Sodium carbonate (crystallized) . . 15 grams Water 1000 c.c. At 3.00 P.M. the uterine pain, the headache, and the nau- sea had disappeared and the patient went to sleep. At 4.00 P.M. the rectal infusion was given a second time and almost a liter was absorbed. At 11.00 p.m., 258 c.c. of urine were voided and the patient passed a good night, sleeping soundly. The following morning 500 c.c. of urine, very high in albumin, casts, and blood were passed. At three o'clock of this day, she again developed severe headache, nausea, and vomiting, and was unable to retain the rectal infusions or anything by mouth. At 10.00 p.m. all the symptoms had so increased in severity, that 300 c.c. of the NEPHRITIS 167 above solution were given intravenously. In fifteen min- utes the patient volunteered the information that her head- ache and nausea were gone. She was comfortable until the next afternoon when periodic uterine pains developed, and the headache and vomiting returned. The patient was taken to the operating room, and the cervix was dilated slowly by hand. Delivery of the hving child was ac- complished in an hour and a half. This was followed by another intravenous injection of 645 c.c. of a solution containing 7I grams crystallized sodium carbonate and 14 grams sodium chloride to the liter. In the following twenty-four hours 2200 c.c. of urine were voided, and as the nausea, vomiting, etc., had disappeared it was an easy matter to maintain such a urinary output by giving water and alkalies by mouth. Albumin and casts disappeared from the urine on the fourth day and the patient had an uneventful convalescence. Case 7. — (Dr. W. A. Clark, San Leandro, California.) Mrs. C. H., aged 35, and pregnant for the second time, presented herself for examination in March, 191 1. She had menstruated slightly, and for the last time, January 22. A year previously she had given birth to a healthy child at term, though in the later months of her pregnancy her limbs and face had swelled, she had much headache, and her eyes had troubled her. At the time of her first visit, and repeatedly afterward, physical examination and ex- amination of the urine showed nothing abnormal. On August II, she showed a well-marked generalized oedema, and complained of headache, extreme restlessness, sleep- lessness, dimness of vision, and constant nausea. Her uri- nary secretion had fallen to 500 c.c. per twenty-four hours, was highly acid, and high in albumin and casts. She was immediately sent to the hospital and kept in bed on a diet rich in water, alkalies, vegetables, and milk. Epsom salts were administered by mouth, and 0.85 per cent^ sodium chloride solution was repeatedly injected slowly into the rectum. On this regime all of her symptoms and signs in- cluding the albumin and casts disappeared, and the urinary output rose so that 2200 to 2674 c.c. were voided every i68 NEPHRITIS twenty-four hours. August 26 the patient felt so well that she insisted on getting out of bed and busied herself about her room. On the second day following this renewed activity, her headaches again showed themselves, and her nervousness and sleeplessness returned. On August 29 her nausea and vomiting became severe, and her vision very dim. The oedema of the legs and face returned, and her urinary output fell sHghtly, to 1984 c.c. WQien the heat test w^as applied to the urine, the w^hole became solid. This condition continued until 11.30 p.m. of August 30, when the headache, nausea, vomiting, etc., were so severe that it was decided to give alkali and salt intravenously. The following formula was given: Sodium carbonate (crystallized) . . 10 grams Sodium chloride 14 grams Water 1000 c.c. In an hour the patient volunteered the information that her headache and nausea were better, and that she felt brighter. She slept well, and passed the next morning comfortably. Examination of the urine passed in the night and early morning showed a decided drop in the amount of albumin excreted. Even though the subjective S}TTiptoms of the patient continued well, the albumxin con- tent of the urine again rose so that on the morning of September i this was sufficient to make the contents of the test tube again set in a soKd mass when boiled. The amount of urine obtained continued good, being 1984 and 2048 c.c. respectively, for the last two twenty-four-hour periods. It was deemed best to empty the uterus, and at 10.00 A.M. of September i, dilatation of the uterine os by means of rubber bags was begun. Rhythmic pains began two hours later and as these increased in number and severity, the patient's headache and nausea increased, and the urinary secretion fell. At 4.00 p.m. the patient vomited and developed a twitching of the face and arms. This continued at intervals until 11.00 p.m. when two liters of the alkali-salt mixture of the composition previously used in this case were injected intravenously. Shortly after this, the subjective symptoms of the patient became NEPHRITIS 169 better, and she fell asleep, passing a fairly good night, and examination of the urine again showed a decided drop in the amount of albumin present. The general condition of the patient continued good, and on the evening of Sep- tember 2, she was delivered under chloroform anaesthesia of a 1750-gram, living, female child (left shoulder pre- sentation with version). On the operating table the patient received 1000 c.c. of 0.85 per cent sodium chloride solution under the skin, and for subsequent treatment the patient was given this same salt solution by rectum and alkahne water (a gram of sodium carbonate in a glass of water every hour) by mouth. The urinary secretion on this regime never fell below 2200 c.c. On September 4 the albumin in the urhie had dwindled to a trace, and on the next day it had disappeared entirely. Examination of the urine twice daily from this time on invariably showed an alkaline reaction to litmus paper and no albumin. The general oedema disappeared on the third day after delivery. On September 17 the patient was fully convalescent. Case 8. — {Dr. N. A, Hamilton, FrankHn, Ohio.) Mrs. C, 27 years old, and a primipara in the seventh month, showed nothing abnormal on examination, September 8. On September 20 some albumin was found in the urine, and on September 27 it was present in abundance. Her general condition was good. At 10.00 P.M., October 2, she was seized with sudden nausea and vomiting which continued through the night. At 3.30 A.M., October 3, she had short lapses of conscious- ness. Headache was severe; there was some oedema of the face and legs; the pulse was 100 and hard. Veratrum was given by hypodermic injection. At 8.30 a.m. her pulse had fallen to 52; her temperature was normal. No urine had been passed through the night, but at this time she passed 30 c.c. The patient was dizzy, still vomiting, had pain in her neck, and her sight was blurred. She w^as now given 800 c.c. of a strong (hypertonic) sodium chloride solution (1.5 per cent) by rectum. This was all retained. At 11.30 a.m. 90 c.c. of dark-colored urine filled with casts and con- taining so much albumin that on boiling it fairly set was lyo NEPHRITIS passed. Another 800 c.c. of the sodium chloride solution were now given and at 2.00 p.m. an unknown amount of urine was lost with a stool. Twenty minutes later a con- \ailsion lasting a minute occurred, and this was repeated a half hour later. The patient was vomiting, and could not distinguish colors. There was a general twitching of the muscles. A general anaesthetic was given at 3.30 and an attempt made to dilate the very rigid uterine os instru- men tally. At 5.00 p.m. the membranes ruptured, and at the same time 30 c.c. of dark brown urine were obtained by catheter. At 6.00 p.m. the temperature of the patient was 100.2° F. by axilla. Another injection of 800 c.c. of the strong saline solution was given by rectum at this time and repeated at 8.00 p.m. but neither was retained well. At 10.00 p.m. a little urine (estimated as 30 c.c.) was passed with a stool. At midnight the patient's temperature was 100.2° F., she was dizzy, could not distinguish between'men and women, and was unable to differentiate white from black. At this time she was given the following formula intravenously : Sodium carbonate (crystallized) . . 20 grams Sodium chloride 28 grams Water 2000 c.c. The injection required an hour. While giving the in- jection the patient volunteered the information that her nausea had left her, and that her headache was disappear- ing. At 2.30 A.M., October 4, she passed 75 c.c. of dark brown urine filled with casts and fairly solid with albumin on boiling. At 4.00 a.m. she passed another 75 c.c. and at 6.45 A.M. 95 c.c. During these hours she slept at inter- vals. When she awakened her headache and nausea were gone, and she could distinguish between gross objects, and recognize colors. From now on and through the day she was plied with water by mouth and five injections of 400 c.c. each of the above sodium carbonate-sodium chloride mixture were given by rectum. These were well retained. Urine was voided about every three hours, and in increas- ing quantity. By midnight, that is to say in the first twenty-four hours after the intravenous injection, she had NEPHRITIS 171 voided 572 c.c. not counting two ''large" voidings that were lost. The later portions of this urine were clearer in color and contained much less albumin than the specimens already described. In the night of October 5, the patient went into labor, and at 8.00 a.m. forceps were introduced and she was de- livered of a macerated foetus. In spite of the exertions of labor she passed 320 c.c. urine, between midnight and the time of the delivery of the placenta. Through the night the alkali-salt enemas could not be retained, but through the day she took and retained four enemas of 400 c.c. each. In this second period of twenty-four hours she passed 734 c.c. of urine. After delivery, her temperature, which on the night before had risen to 103.6° F. (by mouth), fell to normal. In the twenty-four hours of October 6, she received and retained four enemas of 500 c.c. each of the alkali-salt mixture, and drank freely of water (a glass every hour). She passed in this period 1840 c.c. of urine, not counting two voidings that were lost with the stools. The later por- tions of this urine contained only a little albumin. The patient was sleeping well, and relishing her toast, gruel, eggs, milk, and broth. In the next two days the alkali-salt enemas were re- duced to two daily, one night and morning, and then stopped entirely. She was given a liberal diet, and water was insistently given by mouth. Lemonade and orange- ade were urged. When the alkali was no longer given by rectum, sodium carbonate (0.5 gram) was given in a glass of water as often as the patient would take it both day and night, and she was asked to salt her food hberally. Her urinary output on this regime was as follows: October 7 . October 8. October 9 . October 10 October 11 October 12 October 13 3616 c.c. October 14. .24ooH- c.c. 3264 c.c. October 15. .4096+ c.c. 3520 c.c. October 16. .3808 c.c. 2528 c.c. October 17. .3200 c.c. 2108 c.c. October 18. .1920 c.c. 2396-f c.c. October 19 . . 1915 c.c. 2432 -f c.c. 172 NEPHRITIS The great rise in urinary output on October 15 followed an increase in the amount of alkali and salt given by mouth; the fall on October 18 a reduction of this. The oedema had disappeared and the albumin dwindled to a trace by October 7. This trace persisted up to October 19. The patient developed a slight temperature (100.8° F.) on the fourth day after delivery, but following intrauterine douches with bichloride of mercury and iodine this fell so that only a temperature of 99.0° or 99.2° was registered in the afternoons up to October 17. From October 16 she was given an unrestricted diet, and on October 17 she sat up for the first time. On October 24 she "is downstairs, voiding an abundance of urine and happy." Case 9. — {Dr. E. A. Majors, Oakland, California.) Mrs. A. B., pregnant for the second time and at term was found in labor and delivered of a healthy living child, in an entirely normal way at i.oo a.m. No previous history was obtainable. Following labor she fell into a deep sleep and at 5.00 a.m. it was impossible to arouse her. As there was no evidence of urinary secretion, she was cathe- terized at 6.00 a.m. No urine was obtained. At 7.00 a.m. she had two severe convulsions. Following this she lay in a deep stupor with rapid breathing. At 10.00 she was again catheterized but no urine was obtained. She now received by slow injection into the rectum the following: Sodium carbonate (crystallized) . . 15 grams Sodium chloride 14 grams Water 1000 c.c. Sixty c.c. of urine were obtained an hour after the beginning of the injection, and half an hour later another 130 c.c. filled with albumin and casts were obtained. At the same time the patient began to clear mentally. Three hours after beginning the injection she would respond to questions. She was plied with water by mouth. Later in the afternoon 500 c.c. of the above formula were again given by rectum and this was repeated next day. In the first twenty-four hours 1525 c.c. of urine were obtained, NEPHRITIS 173 and 2240 c.c. in the second. At the same time the albu- min and casts diminished and on the third day the urine cleared entirely. Uneventful convalescence followed.-^ Case 10. — {Dr. William E. Kiely, Cincinnati.) Three weeks before entering the hospital S. C. W., 38 years old, and a moderate beer drinker, became short of breath, suffered from headaches, and noticed a swelling of his legs and abdomen. Physical examination showed no disease of the heart or lungs, but fluid in the pleural and peritoneal cavities, with a general oedema of the subcutaneous tissues. The urine was low in amount, of high specific gravity, and contained much albumin, some blood cells, and hyaline casts. On this a diagnosis of (chronic) parenchymatous ne- phritis was made. After twenty-five days of rest in bed, a milk diet, a daily hot bath, saline cathartics, and digitalis, no improvement in his general condition was noted. There was now added to his diet a liter of water daily containing 25 grams of sodium chloride. Improvement in his general signs and symptoms began immediately, the urinary out- put rose, the blood disappeared, and the casts and albumin progressively diminished in amount. After ten days of this treatment he had improved most markedly, and at the end 1 The methods of treatment as applied in this volume to nephritis can naturally be used in a whole series of clinical conditions in which a gen- eralized or localized oedema as an expression of a generalized or a localized abnormal production or accumulation of acid is responsible for the signs or symptoms observed. A detailed discussion of this problem is out of order here, but it may not be out of place to catalogue some of the con- ditions in which excellent results have been obtained. Administration of water, alkali, and salt by mouth, by rectum, or intravenously, works ex- cellently in the brain oedemas following injury, arsenic injections, etc.; in glaucoma; in the oedemas of heart disease; in the labored breathing of arteriosclerosis; in the delirium, twitchings, and convulsions seen in the acute infectious diseases; in the marasmus of infants and children; in bronchial asthma. C. C. Fihe has obtained excellent results by using salt, alkali, and water in hay fever and mucous colitis. In the latter condition W . S. Kuder has also reported good results. James J. Hogan uses salt and alkali injections with excellent effect in the pernicious vomiting of pregnancy even when no signs of nephritis or a generalized cedema are present. 174 NEPHRITIS of twenty-five days all signs of his oedema and the effusions into his serous cavities had disappeared. At his own request he got out of bed and began to work about the ward, and shortly thereafter left the hospital free of all signs and s}Tnptoms, except for the faintest trace of albumin in his urine. In this state he has continued up to the present time (that is, for two months since leaving the hospital). Case ii. — {Dr. Julius H. Eichberg, Cincinnati.) A. B., a 40-year-old lawyer, entered the hospital in April, 191 1, with a history of kidney disease of eight years' standing. At various times during these years he had had a diagnosis of chronic parenchymatous nephritis made upon him. He had no enlargement of the heart and no increased blood pressure. The original cause of the nephritis could not be made out. When first seen the patient was passing about 400 c.c. of urine per twenty-four hours, containing 4 grams of albumin per liter and filled with all varieties of casts. On a milk and vegetable diet, sweat baths, and saline cathartics his urinary secretion increased somewhat, but his general condition did not improve, the number of grams of albumin lost each twenty-four hours did not decrease, and his oedema, ascites, etc., increased. After two weeks in the hospital he had a well-marked oedema of his legs, back, chest- wall, scalp, and face. The fluid in his abdomen extended to the umbilicus when sitting up. While his general hospital regime and diet were kept as before, he now had added to his drinking water and con- sumed each twenty-four hours 7 grams of dried sodium car- bonate. After ten days of the carbonate administration his oedema and ascites disappeared completely, his urine increased to approximately 800 c.c. per twenty-four hours, though the quantity of albumin lost per twenty-four hours did not change perceptibly. The patient at this point refused to continue taking the carbonate. In five days his weight went up 2^ kilos. Dr. Eichberg persuaded the patient to resume the carbonate, and at the end of another seven days his original weight had again been attained, and the visible signs of oedema NEPHRITIS 175 which had developed when the carbonate was discontinued had once more disappeared. The urinary output amounted at this time to 800 c.c. daily, and the albumin dropped to 2.5 grams per liter. At this point the patient refused a second time to take the sodium carbonate, and again the sweUing of his legs and back developed, while his weight rose as before, 2| kilos in less than a week. Following this period he re- turned a third time to the carbonate, and in six days had again lost his 2J kilos and the obvious signs of an oedema. This is his state at the present writing when for four months he has been passing 1280 c.c. or more of urine daily, con- taining some casts and 0.75 gram of albumin per Hter. He has left the hospital in fair condition, has a good appetite, sleeps well, and has resumed the practice of his profession. The following case will serve to illustrate how the oppor- tunities of relieving the acute manifestations of nephritis are decreased pari passu with the decrease in the absolute amount of kidney substance present. Case 12. — {Drs. Jo. Hamilton, Fruitvale, and W. S. Kuder, Oakland, Cahfornia.) A. D. P., a 16-year-old high- school boy, first showed albumin and casts in his urine three years ago. During the past year, no analysis of his urine had been made. The boy's general health had been good. On September 4 he had been very active, and that night he slept badly. At six in the morning of September 5, he was found unconscious and in a convulsion. The convulsions were general, very severe, and practically continuous. Between the more severe paroxysms there was a constant twitching of the body and extremities. No urine had been voided, and none was found in the bladder when brought into the hospital at i.oo p.m. and catheterized. Two Uters of the following formula were at once injected in- travenously : Sodium carbonate (crystallized). . . 10 grams Sodium chloride 14 grams Water 1000 c.c. 176 NEPHRITIS At 2.30 P.M., 64 c.c. of highly albuminous urine contain- ing large numbers of granular and hyaline casts were obtained by catheter. Half an hour later a good amount of urine was voided into the bed. The patient seemed de- cidedly more relaxed and the convulsions gave way to less severe twitchings in the legs, arms, and trunk. The pulse which pre\'iously could not be counted dropped to no and the panting respiration fell to 24. At 5.00 p.m. 256 c.c. of urine were obtained by catheter. At this time the pa- tient was perspiring profusely. At 6.00 p.m. two convul- sions of moderate severity occurred. Permission to give another intravenous injection was denied, and so 400 c.c. of the formula given above were injected into the rectum. No more convulsions occurred at this time and the twitch- ing stopped entirely. At 8.40 p.m. 96 c.c. of urine were obtained. At 11.00 p.m. permission to give another two liters, intravenously, of the sodium carbonate-sodium chlo- ride-water mixture was obtained, and this was done. By 1. 00 a.m. 352 c.c. of urine were collected by catheter, and at 2.00 a.m. 192 c.c. At 3.00 a.m. the patient had a slight convulsion, and at 4.00 he had a severe one and died. A hasty physical examination of this boy immediately after being brought into the hospital showed no signs of oedema anywhere, readily palpable arteries everywhere, and an enlargement of the area of heart dullness toward the left and downwards, with no heart murmurs. On these find- ings a diagnosis of chronic interstitial nephritis secondary to an arteriosclerosis was made, and an unfavorable prog- nosis was given. It was felt (on the theory that uraemia represents an oedema of the brain) that the convulsions could be ameliorated, and that the secretion of urine could again be started, but more than this could not be promised as the degree of kidney atrophy, upon which the question of the ultimate recovery of the patient depended, could only be guessed at. An autopsy made a few hours after death confirmed the clinical diagnosis of generalized arteriosclerosis with hypertrophy of the heart. The kidneys together weighed 112 grams, the surfaces were rough; the capsule was inti- NEPHRITIS 177 mately adherent to the kidney parench3rma. On section the kidneys were a mottled gray, and so hard that they could not be broken by pinching with the finger nails. The cortex was reduced to a mere line. The results outlined in the cases that have been briefly abstracted here seem to indicate very clearly that we have, in the administration of alkalies, sodium chloride, and water, a means by which we can rapidly combat those kidney symptoms that we are particularly liable to en- counter in eclampsia, the acute toxic nephritides, the acute suppressions of urine that follow anaesthetics, surgical oper- ations of various sorts, including those on the kidney in which the blood supply to this organ has been temporarily occluded, alcoholic debauches, too enthusiastic use of the nitrites, 1 etc. While for the most part the alkali-salt-water mixtures were in these cases given by slow injection into the rectum, there is no danger, if a case is deemed sufficiently acute, in giving the mixture intravenously. To do this the elabo- rate surgical procedures usually adopted to make an in- travenous injection (excepting the asepsis) can be largely dispensed with. In the way of apparatus we need only to insert an ordinary hypodermic needle into the rubber tube ^ I have several times seen alarming falls in the urinary output and once a complete suppression of urine with death of the patient eight days later after the administration of nitrites to reduce blood pressure in cases of arteriosclerosis in association with chronic interstitial nephritis. As I have pointed out, mere reduction of blood pressure (except in cases of haem- orrhage) is scarcely to be looked upon as a therapeutic gain. Suppression of urine is bound to follow the lack of blood supply to kidneys which are barely getting enough with a high blood pressure. There is no justification for giving nitrites in chronic interstitial nephritis, imless we can show that while reducing general blood pressure we are not at the same time reducing the blood supply to the kidney down to a dangerous point. If an arteriosclerosis is killing a kidney, we can hope to help the situation only by treating the arteriosclerosis. 178 NEPHRITIS coming from the irrigation vessel which is filled with the solution to be injected. The irrigation vessel is raised to a proper height and, after all air has been driven out of the outflow tube, the h}^odermic needle may be inserted through the skin or, after a small cut has been made into this, directly into one of the numerous veins in the forearm or at the bend of the elbow. It is best to simply hold the needle in position, but if so desired it may be fastened down with an adhesive strap. The solution must be injected slowly so as to allow ample time for mixing with the blood. In the preparation of the solutions for intravenous injec- tion it must be remembered that a carbonate cannot be boiled without driving of its CO2 and so converting it into the more alkaline hydroxide. To get a sterile solution the sodium car- bonate is dissolved in as little cold distilled and sterilized water as possible. The sodium chloride is then dissolved in an appropriate amount of distilled water and sterilized by heat. After this solution has cooled sufficiently the carbonate solution is added to it. When dried sodium carbonate is used instead of the crystallized only one-third as much is to be employed, for crystallized sodium carbonate is approximately two-thirds water of crystallization, j.7 grams dried sodium carbonate is equal to 10 grams of the crystallized. Some surgeons have advised and operated on acutely nephritic kidneys and stripped the capsule. In at least some instances good has followed such a procedure, but this can be expected only if the deciding element between the recovery of the affected kidney and death is thought to be measurable in the increased circulation obtainable through the kidney by stripping the capsule. Even after the answer to this is given in the affirmative, then before operating, the effects of an anaesthetic and the shock of an operation must be considered, and not unless these are taken to be negligible should the operation be done, es- NEPHRITIS 179 pecially since it appears from the experiments and clinical reports detailed in these pages that all that can be gained through an operation can be gotten by the simpler means of injecting the proper alkali-salt-water solutions. These alkaH-salt-water injections must also prove of ser- vice in surgical operations on the kidney, in which it is at times deemed necessary to occlude temporarily the blood supply to the kidney. The consequences of such a pro- cedure are those of the experiments already detailed in which the blood vessels to the kidney were clamped. It has been shown by C. C. Guthrie ^ that perfusion with a phy- siological salt solution or a Ringer solution ^ of kidneys so treated affects them more deleteriously than if they are left alone. This is because such salt solutions are not sufficiently concentrated to prevent the swelling, etc., of the kidney cells. Most perfusion mixtures lack moreover the necessary colloids — the water in them is free, which is not the case in blood and lymph. ^ It is self-evident that that which will relieve a nephritis when once established should, when properly used, prevent such a nephritis from developing, and so we must consider how useful in the prophylaxis of nephritis must be the giving of water, alkalies, and salts. Especially serviceable must these prove themselves when preparing for an opera- tion, in a threatened nephritis during pregnancy, when we deal with the acute infectious diseases, etc. There exist as a matter of fact any number of clinical facts to prove this. The milk diet has, not without reason, enjoyed for decades the popularity that it has attained. By giving milk we give a patient a very useful balanced ration of fat, carbohy- drate, and protein. But we do more than this — we give water and salts. The water helps to wash out poisons and 1 C C. GiUkrie: Arch. Int. Med. 5, 232 (1910). 2 See page 193. i8o NEPHRITIS the salts contained in the milk have a concentration which just sufi&ces to do away with the effects of giving an equal amount of water pure. Similar reasoning explains the beneficent effects of giv- ing " physiological " salt solution in large amounts by rec- tum, intravenously or subcutaneously, in various acute in- fections. It is again the combined effects of much water to wash out poisons and enough salt to counteract that acci- dentally lost ^ by the same procedure that washes out the poison. When in spite of such procedures the signs of a nephritis develop we need to press alkalies (alkaline drinks) and to give more salt. We will conclude this section by giving a concrete illus- tration of the fact that, by increasing the alkali-salt content of the body, the opportunities for the development of the signs of a nephritis are greatly reduced. For such a test the albuminuria that develops in athletes after hard work was used, and with the following results: In Experiment 19 on page 45 we detailed the quantita- tive findings regarding the excretion of albumin during an ordinary match basket-ball game, as determined by collect- ing the urine over the period of an hour and a half, in which time the game was played. In the following two experiments the urine was similarly collected, every pre- caution being taken to have the conditions for collection, regarding time, etc., as nearly the same as in the control experiment. The athletes were under no restrictions re- garding diet, the only difference being that in the two ex- periments now to be detailed, the players took in addition 1 We have become all too inclined to consider everything that comes out in the urine as something that the intelligence of the kidney has found harmful to the body. It is scarcely as wise as this. It is rather hard to see, for example, why in a salt-starved animal that is being given water, the ani- mal continues to eliminate some salt in the urine up to the moment of death, when it is this very elimination that is killing the animal. NEPHRITIS 181 to their ordinary food the juice of six sweet oranges in the first, and twelve in the second. The six oranges were con- sumed in the course of three hours preceding the game; the twelve in the twelve hours preceding the game. Oranges were chosen not alone because they are palatable, and so offer no difficulty in having the men take them, but be- cause the salts contained in them have not only a decided capacity of combining with stronger acids, but the citrates, malates, etc., are the very salts which act most powerfully in reducing the solution of proteins in acids (as well as the swelling of organs under these circumstances, etc.). The game played in Experiment 37 was decidedly harder than that detailed for control purposes in Experiment 19, that of Experiment 38 fully as hard. The first five players were the same in all these three games, though the order in which they are numbered is not the same. l82 NEPHRITIS Experiment 37. — Juice of six oranges fed the players. Urine collected for period of i| hours, during which time the play occurred. Phosphotungstic-hydrochloric acid-alcohol reagent used mth&Eshach albuminometer. Before the Game. Player. Urine, in cubic centimeters. Nitric acid test. Heat test. I 2 3 4 5 232 72 30 85 280 > Negative -^ Negative After the Game. Urine, in Albumin Player. cubic centi- meters. HNO3 test. Heat test. Esbach reading. excreted, in grams. I 62 >| r 1-25 .078 2 17 1-5 • 025 3 152 y Positive Positive < 0.75 .114 4 42 0.75 .132 5 228 ^ - less than 0.2 .046 Av. .079 Experiment 38. — Juice of twelve oranges fed each of the players. Urine collected for period of i| hours, during which time the play occurred. Phosphotungstic-hydrochloric acid-alcohol reagent used in Esbach albuminometer. Before the Game. Player. Urine, in cubic centimeters. Nitric acid test. Heat test. I 2 3 4 5 6 73 170 187 6 62 > Negative Negative NEPHRITIS 183 After the Game • Player. Urine, in cubic centi- meters. HNOatest. Heat test. Esbach reading. Total albumin excreted, in grams. I 97 1 Positive -l 0.7S •073 2 3 56 II ^ Positive 1 1-25 1.6 .070 .018 4 44 J I 1-3 •057 Av. .054 5 6 44 45 1 Positive Positive \ 0.6 0.2s .028 .011 Player number 5 played first half only; number 6, second half only. Even when we count out the player in the control game who started with an albuminuria, and those in the succeed- ing games who did not play through, we still find that the albumin secretion, both so Jar as average concentration and average absolute amount is concerned, is decidedly lower after feeding citrus fruit than without such feeding. 4. On the Treatment of (Edema. A generalized oedema constitutes so prominent a feature of certain cases of nephritis that it of itself becomes at times an object of treatment. Of the various methods that have been suggested for the control of this condition we will take up only one for discussion here, that of the question of salt restriction. When we discussed in the earlier sections of this paper the enlargement of the kidney in the parenchymatous types of nephritis, we noted that this enlargement of the organ, which is in essence an oedema, can be reduced through the presence of salts, and as, for reasons already set forth, such oedematous swelling (just what occurs in the acute forms of nephritis) is a serious menace to the kidney, because it tends to shut off its blood supply, it was recommended to combat this condition by increasing the salt concentration 1 84 NEPHRITIS in the nephritic individual. The thought, of course, at once suggests itself that this scheme of treatment might be ex- tended to the treatment of the general oedema occurring in nephritis.^ While such a course has for decades been ap- 1 F. G. Goodridge and William I. Gies [Proc. Soc. Exp. Biol, and Med. 8, io6 (191 1)], while apparently accepting the teaching that the colloids of the tissues are responsible for the amount of water held by them, have taken exception to my assertion that an abnormal production or accumulation of acid in the tissues of the body plays an important if not the chief role in the production of oedema, in that these increase the power of certain of the tissue colloids to absorb water. While it would not at all surprise me to have it shown that some other or some series of other changes in the body tissues than an abnormal production or accumulation of acid is responsible for the increased hydration of the colloids here, which is the characteristic feature of oedema, the experiments of Goodridge and Gies do not do this. These authors base their criticism on the fact that fibrin threads sus- pended in such colloidal solutions as gelatine, peptone solution, egg white, blood, milk, and meat juice, do not swell visibly on the addition of acid to these solutions until this is added up to the point where it is " free " in the solution. When these authors add acid to the colloidal solutions in which they immerse their fibrin threads they increase the hydration by this means, not of the fibrin threads, but of the colloidal solution (they give this the "oedema"), as they would find if they measured its viscosity. Up to a certain point (maximum hydration under the influence of the acid) the ad- dition of the acid would therefore tend to prevent the fibrin from absorbing water. Only if acid got into it and free water were available could we expect the fibrin thread to swell. The question has also been asked if the views expressed in this book and in my volume on " CEdema " are correct, why in the "acidosis" of diabetes we do not have symptoms of nephritis and oedema. In answering this several facts must be remembered. First, the presence of some abnormal acid in the urine does not yet prove that the actual acidity of the body as a whole has risen. As a matter of fact Yandell Henderson and Frank P. Underhill [American Journal of Physiology, 28, 275 (191 1)] have recently shown that m the "acidosis" of diabetes just the reverse is probably the case, the body acidity is diminished. Secondly, in cases of diabetes in which the acid intoxication is great enough we do have casts and albumin in the urine. Furthermore, moderate degrees of oedema are difficult to discover by our ordinary rough clinical tests, and the high concentration of sugar present in the cells and fluids of the body also tends to reduce this oedema, for while the non-electrolytes do not reduce appreciably the swell- ing of certain hydrophilic colloids in low concentrations they do this in the higher concentrations. NEPHRITIS 185 proved of empirically, as evidenced by the use of saline pur- gatives, saline diuretics, etc., in the treatment of oedema, a marked reaction against the giving of salts in oedematous states has more recently set in. Of the scores of salts that might have been attacked in this way, sodium chloride has been especially marked out, and to-day it is a widely ac- cepted behef that the presence of this particular salt in the body is responsible for the retention of water and so the oedema of nephritis, of certain cases of heart disease, etc. Evidence for the support of such a view has been entirely clinical. It has been noted that nephritic individuals with oedema and on a constant diet increase in weight when sodium chloride is added to their food, lose again when this is taken away, etc. From our knowledge of the general physicochemical activities of the salts it is absolutely impossible to understand why, first of all, sodium chloride should, of all the common salts that are found in the liv- ing organism, act in this specific way, and second, how it accomplishes the results that are claimed for it. In order to satisfy myself as to whether sodium chloride (or any of the other common salts found in our tissues) really has any such specific action in the production of oedema, I decided to test the matter out in a way that had not yet been done, and which was freer from objection than the experiments to determine this point that have been made on mammals. For experimental purposes I used frogs which had been rendered nephritic by being injected with uranium nitrate — a poison which is generally ac- knowledged as one of the best for the production of ne- phritis experimentally. By placing these animals in water they absorb all they need to saturate their oedematous tissues through the skin. Normal frogs (practically) do not change in weight when kept in water. Let it be added that these frogs were really nephritic — albumin and casts i86 , NEPHRITIS were plentiful in th-e urine, and the tables and photographs illustrate the cedema'. Parenthetically it is well to point out in this connection that we are in the habit of considering the generahzed cedema noted in nephritis as secondary to the nephritis — in other words it is imagined that a condition capable of producing a nephritis first reduces the function of the kid- neys, and because of this an oedema of the body tissues generally results. This is not correct. If the cedema were secondary to the loss of kidney function then we should be able to produce a generalized oedema experimentally most rapidly by complete removal of the kidneys. As a matter of fact, nephrectomized animals either develop no oedema at all or only a very sKght one when compared with the oedema developed, say after the injection of uranium nitrate. This shows clearly that the oedema of tJie tissues and the cede?na of the kidney (nephritis) arise simultaneously, and from the same cause — the uranium nitrate interferes with the oxi- dation chemistry in all the tissues of the body at once and leads to an abnormal accumulation of acid in them. In the kidney we call this condition nephritis; in the body tissues generally, oedema; in the eye, glaucoma. As the following experiments show very clearly, salts decrease the cedema of nephritis, and sodium chloride is no exception to this rule. Experiment 39. — Twelve frogs that have been kept in jars of tap water for several days have the urine squeezed from their blad- ders, are weighed, and divided into two sets of six each in such a way that the weight of any one frog in the first series is about that of a corresponding one in the second series. They are then all injected with 0.2 gram uranium nitrate into the dorsal lymph sac and placed in separate finger bowls each containing 100 c.c. distilled water in the first series and 100 c.c. Ringer solution in the second. The fluid in the bowls is changed once in 24 hours. The changes in the weights of the frogs are indicated in the following tables: NEPHRITIS 187 » H ^ H 0^ 0» On '^ 04 04 M CO '^ CO CO JvO 00 OnOO 0^ H M 04 CO + + + + to M t^ CO NO NO t^ t^CO \r> 49 % 53.5 (+ 9.1) 57 (+16.3) 62 (+26.5) 69 (+40.8) dead •^ 00 b? 6 t+t to 04 M NO Tt to to CO t^ 04 to vOCO 6 M t-> to^ OI Tt T:f t;1-_^ + + + + I to ^ '^ M On "^ to to to 10 c< ±±2 to to O) tJ- CO ^ '^ H CO On vO CO CO CO 0^ CO ^ Ttr^ to 1 to 10 C CO M M (W •:> 00 ^CC M rJ-NO OC ^ If l>.NO t^- O^00 CO M 04 fO > to 04 CO >^ 00 M On CO 0^ 01 01 ro + + + + to l~-» 0\ ':t r^ NO t^CO 00 > 00 .jO ^ CO oo t/-> 0^ H 04 04 rrt ±+±±s 'a to <^ -^ On Tt- to to to too > 1— 1 o'^o't^ «^ 04 OJr^ to C4 M 00 T}- t1- to 10 - On vo "sho to t)\ M oo CO ++++ 04 T}- ON to t^ rf -^ "^ to to K On to CO CO jsOOO CO CO . 04 01 TO ■^ ■* to to - •^ -"^ CO CO IsP 00 04 M O^ M 04 CO ^rrt ttttt to COOO H Th J>. CO CO Tj- Tl- '^l- 1 to to _ CO MM CO 00 Tl- 00 H '^O CO i88 NEPHRITIS Experiment 40. — Six frogs are weighed, each injected with 0.05 gram uranium nitrate into the dorsal lymph sac, and divided into two sets of three each. Those of the first are kept in separate finger bowls, each containing 100 c.c. water; those of the second in bowls containing 100 c.c. | molecular sodium chloride solution. The changes in weight observed are as follows: Series in Water. Hours. I 2 3 18 26 42 68 92 30 % 33 (+10.0) ' 36 (+20.0) 37 (+23.3) 38 (+26.6) 39 (+30.0) 27 % . ? ' 30.5 (+12.9) 35 (+29-6) 41 (+51.8) dead 24 % 28 (+16.6) 29 (+20.8) 29.5 (+22.9) ? 30 (+25.0) Series in \ Molecular NaCl (0.975%). Hours. I. II. III. 18 26 42 68 92' 34 % 32 (- 5-8) 33 (- 2.9) 33 (- 2.9) 38 (+11. 7) 39 (+14.7) 29 % 29 (+ 0) 30 (+ 3-4) 31 (4- 6.8) 33 (+13-8) 35 (+20.7) 26 % 26 (+ 0) 27 (+ 3-8) 28 (+ 7.7) 30 (+15-3) dead The effect of the sodium chloride in reducing the oedema is evident to mere inspection. In Fig. 30, a and h, is shown frog 3 of Experiment 40, photographed at the time of in- jection and 42 hours later. Figure 31, a and 6, shows frog III similarly photographed. Are we now to conclude that the observations are wrong of those who have, by careful methods, noted an increase in weight (increase in oedema) after the feeding of salts, par- ticularly sodium chloride, to patients afflicted with oedema? Not necessarily, though it must be said that grave objec- tions may be raised against many of the clinical studies of this subject. NEPHRITIS 189 1 90 L NEPHRITIS c NEPHRITIS 191 When one studies carefully the cases in the literature in which salts have been found to increase oedema, one notes the fact that these are for the most part such as have been afHicted with ascites, hydrothorax, etc. When now any salt is given such an individual his tissues may very well give up water as do the frogs that have just been de- scribed. But where does the water go? The body weight as a whole can diminish only if this water is lost from the body through the urine (skin, gastro-intestinal tract, or lungs). But in nephritis the kidney does not so readily rid the body of water as in health, and so this water must go somewhere else. If it does not come out through some other emunctory (as in the diarrhoeal stools at times observed in nephritis), this water can only escape into the cavities. What happens here is identical with the development of ascites, etc., in our experimental ani- mals when we make these (especially after first render- ing them oedematous by any means we choose) very rapidly give up their water by injecting a concentrated salt solution. I saw a good clinical illustration of this in a patient of W. S, Kuder. A woman who for several weeks had been in bed, suffering from an extensive generalized oedema, with collections of fluid in the pleural cavities and abdomen, secondary to a heart muscle insufficiency of several years duration, had the abdominal effusion removed by para- centesis. In order to keep up the drainage some strands of silk were left in the opening made by the trocar. Seep- age stopped at the end of twenty-four hours, but the silk was left in place. On the third day a liter of water containing 14 grams of sodium chloride and 10 grams of crystallized sodium carbonate, was given intravenously to combat the tissue oedema. This went down enormously, and as it disappeared the abdominal wound began to seep 192 NEPHRITIS once more, so that pad after pad had to be applied to the abdomen to absorb the liquid. It is clear therefore that while the oedema of the tissues is reduced, when salts or alkali are given an cedematous in- di\ddual, the collection of fluid in the cavities is increased. When now we deal with a clinical case, the thirst ^ (from which the animals also suffer) leads the patient to drink water and so his total body weight (which in turn is taken as a measure of his oedema) increases. But such a secretion of. fluid into the peritoneal or other cavity would not by itself be a particularly serious thing, nor does this alone explain what happens in a persistent ascites. As we have long known, alike from experiment and from clinical observation, water and various salt solu- tions are readily absorbed from the peritoneal (and other serous) cavities. And yet the ascitic fluid is not absorbed. Why not? E\^dently, after water or a salt solution has been secreted into the peritoneal or other cavity something must happen to this fluid which prevents its reabsorption. What this something is, is that albumin is added to it. Why this renders the ascitic fluid unabsorbable is appar- ent when the following considerations are borne in mind. With the origin of the albumin we are not immediately concerned, though it is of interest to recall, after what was said regarding the origin of albumin in the urine, that the ascitic fluid may be looked upon as an albumin- containing secretion from the peritoneal tissues which, in its general composition and mode of origin, finds an analogue in the highly albuminous urine secreted by the kidney in acute nephritis. 1 Living animals and plants do not behave passively toward an abstrac- tion of water. As soon as this occurs conditions develop in the cells which increase their avidity for water. Certain plants, for example, begin to de- velop acid as soon as we try to abstract water from them by any means. Animals behave similarly when they are robbed of their water. NEPHRITIS 193 As outlined in the discussion of our experiments on urinary secretion, special emphasis must be laid upon the fact that only '^ free " water is secreted by the kidney. The water of the blood is not '' free " but is combined with the colloids of the blood. This water is not available for urine until it is freed from the colloids of the blood. The water of the blood becomes available for absorption (and subsequent secretion) by any tissue only as this tissue is first able to set the water free from the colloids of the blood and lymph or as the blood and lymph themselves suffer changes which make them yield up some of their water. Only such " free " water can be available for urine and conversely it is only because the water in the blood is held in combination by the colloids here that not all the blood and lymph are absorbed from their respective vessels by the tissues.^ The colloids of the blood keep the water in the blood and prevent its total absorption by the tissues. When now we recall the fact that except for the presence of the red blood corpuscles, blood and lymph are practically identical in composition, and that the so-called transudates in ascites, hydrothorax, etc., are identical with lymph, then we have no difficulty in understanding why these too may persist for days, weeks, or months in the body cavities without being absorbed. They are colloidal solutions in which the solvent is bound to the colloid, and not until the solvent is rendered ^^ free " can it be absorbed."^ 1 It is because no adequate (hydrophilic) colloidal solution has as yet been prepared that we are still far from possessing a perfusion liquid that will act better than our present "physiological " salt solutions in haemorrhage, certain poisonings, and shock. James J. Hogan and I will shortly discuss the theoretical and experimental foundations for the preparation of such solutions in another place. See for a discussion of the factors involved in shock Yandell Heftderson's excellent papers, especially Am. Jour. Physiol. 27, 167 (1910). 2 Certain experiments of R. Heidenhain, E. W. Reid, and 0. Cohnheim might lead one to think that animals do absorb their own blood and lymph 194 NEPHRITIS In order to show that such colloidal solutions can, as a matter of fact, not be absorbed we need but recall how blood extravasations and lymph introduced into the perito- neal ca\ity, even in entirely healthy animals, may remain here unchanged and undiminished in amount for periods of time in w^hich other aqueous solutions not containing such colloidal material (which in other words contain '' free " water) are readily absorbed. The following experiments prove this very clearly. Experiment 41. — A black and white rabbit is taken from his hutch, catheterized, and then weighed. His weight is found to be 1493 grams. A shght opening is made in the abdominal wall and traction made on this so as to make the entrance of fluid into the peritoneal cavity easy. A second rabbit has the carotid laid bare for as great a distance as possible in the neck. It is ligated high up, an artery forceps is attached to the coat of the vessel, a Langeiiheck forceps is placed below this, and the carotid is severed. This second animal is now placed in such a position that the blood will flov: directly from his carotid into the abdominal cavity of the first animal when the Langenheck forceps is removed. The blood passes in a stream directly from the cut artery of the second animal into the peritoneal cavity of the first. This procedure is carried out at 2.40 p.m. The abdominal wound is closed immediately and the animal is weighed a second time to see how much blood has flowed in. The second weighing registers 1504 grams, which means that 11 grams of blood have flowed in. At the end of an hour the animal is killed by a blow on the head and immediately autopsied. The blood is found unco- agulated in the folds of the intestine. It is carefully aspirated into a tared flask and weighed. 11 grams of blood are recovered. Experiment 42. — In an entirely similar way a guinea pig, weighing 520 grams, has a small opening made in its abdomen, and the blood from the carotid of a rabbit is made to flow directly into it. An increase in the weight of the guinea pig of 2.2, grams is thereby brought about. At the end of ij hours the pig is killed by as such. This is not the case. For a discussion of this problem and a crit- icism of the experinrents of Heidenhain, Reid and Cohnheim see my paper on absorption and secretion. Kolloidchemische Beihefte, 2, 304 (1911). t NEPHRITIS 195 a blow on the head and the unabsorbed blood is aspirated into a tared flask. 2.1 grams are recovered. Experiment 43, — A black and white rabbit, weighing 1630.5 grams, receives intraperitoneally in the already described way enough blood from the carotid of a second rabbit to raise the weight of the former 26.0 grams. At the end of an hour the rabbit is killed, and the unabsorbed blood is carefully recovered by aspiration into a tared flask. 26.0 grams of blood are recovered. Experiment 44. — A white rabbit, weighing 767 grams, receives intraperitoneally 45 grams of blood from the carotid of a Belgian hare. At the end of 70 minutes the animal is killed by a blow on the head and the blood found in the peritoneal cavity is aspirated into a tared flask. 42.2 grams are recovered. As the impression might be obtained that the failure of an animal to absorb its own blood is connected in some way with the nature of blood itself, and not merely with the fact that this is a solution in which all the water is held in combination with a colloid and, therefore, simply cannot be absorbed until first separated from the colloid, it was necessary to repeat this experiment with a colloidal solution other than blood. The result obtained with natural white- of-egg follows. In a similar way it can be shown that cubes of agar-agar do not lose in weight, and that gelatine solu- tions are absorbed only very slowly (not until the gelatine is '' digested " and so loses its colloid character). Experiment 45. — Into the peritoneal cavities of two guinea pigs, weighing respectively 537 and 563 grams, are injected by means of a large aspirating syringe respectively 20.8 c.c. and 31.2 c.c. white-of- egg (natural). At the end of an hour they are killed by a blow on the head and the unabsorbed peritoneal contents are aspirated into tared flasks. 18.4 c.c. are recovered from the first, 27.7 c.c. from the second. In concluding this argument it is only necessary to show what is a familiar fact in physiology, that under identical conditions, water and salt solutions are readily absorbed (because they contain ''free" water). 196 NEPHRITIS Experiment 46. — Three guinea pigs, weighing respectively 417, 397, and 419 grams, are each injected intraperitoneally with 20.8 c.c. respectively of water, 1^2 and \ molecular NaCl solution. At the end of an hour the unabsorbed fluid is recovered and found to measure respectively 5.4, 11.8, and 13.0 c.c. From what has been said it must be clear that little justification exists for the exclusion of sodium chloride, as for the exclusion of any other of the ordinary salts found in the body tissues, from the diet with the thought of thereby relieving the oedema of nephritis. Such a procedure does just the reverse. We have seen how the only untoward action of giving salts might reside in an increase of ascites, hydrothorax, etc. When such accumulations of fluid in the cavities become sufficiently great to demand attention on their own account, then we have to bear in mind that their composition is of such a character as to render their ab- sorption without antecedent change (digestion of the protein colloids, reduction of their affinity for water) impossible. Clearly, the thing to do then is to tap. Nor is there anything strange in the fact that the re- moval of a comparatively small amount, say of an ascitic accumulation, may be followed by a rapid absorption of the rest. As the amount of fluid in a serous cavity in- creases, the circulation through the surrounding tissues be- comes more and more embarrassed, and so the possibilities for absorption progressively poorer. To relieve this pressure even somewhat wiU improve the circulation, not alone as to quantity but as to quahty of blood passing through the part (a blood more nearly arterial in character replacing one highly venous in character), and so by favoring the removal of CO2 and other acids always found in such serous accumu- lations^ decrease the power of the colloids here for holding 1 G. Slrasshurg: Pfliiger's Arch., 6, 65 (1872); A. Ewald: Arch. f. (Anat. u.) Physiol., 1873,663; Felix Iloppe-Seyler: Physiologische Chemie, 1, 601. Berlin, 1877. NEPHRITIS 197 water, and so bring about further opportunity for the ab- straction of water ^from the transudates found in these cavities. What holds for the ''transudates" and their ab- sorption holds also, of course, for the absorption of inflam- matory ''exudates." From what has been written in this volume, it is clear that we have held the evidence to indicate that nephritis results from any condition or combination of conditions which lead to the abnormal production or accumulation of acid in the kidney, and the action of this acid upon a series of such colloidal structures as characterize those found in the kidney. From these considerations we have then tried to obtain an "explanation" of the various phenomena which serve to characterize nephritis from a physiological and a morpho- logical standpoint. The question now arises whether the acid factor is the only one concerned in producing the picture. This does not, of course, follow. Any condition present in the kidney and capable of exerting an action like that of an acid could add itself to the acid factor. What all such are or may be it would be purposeless to count up, — they are the factors which we know now, or may discover, to be effective in influencing the physical state of the body colloids, — but as a striking illustration we might mention the ferments. Not only do the proteolytic ferments, for example, bring about a splitting of the protein molecule which is similar or identical with the splitting produced by acids, but certain antecedent physical changes produced in the colloids by the action of the two are also identical, a point which Wolfgang Pauli ^ has recently emphasized from a physicochemical point of view in a way that gives it a special interest biologicaUy. ^ Wolfgang Pauli: Pfliiger's Archiv, 136, 495 (1910). 198 NEPHRITIS . . With this we will end for "the present our discussion of nephritis, and our attempt to find a unifying interpretation for the myriad facts bearing upon its nature and cause, that fourscore years and a thousand workers have left us as a lavish heritage. AUTHOR INDEX. Abderhalden, Emil, 126. Adams, L. P., 163. Araki, Trasaburo, 44, 48, 49, 50, Barcroft, 107, III, 131. Bechhold, H., 106. Berghausen, Oscar, 50, 150. Bowman, W., 32, 58. Bradford, 102. Brodie, T. G., 107, iii, 131. Buchner, 51. Bugarszky, S., 23. Bunge, G. von, 126. Burton-Opitz, 100. Clark, W. A., 167. Cohnheim, Julius, 62, 193, 194. Cohnheim, Otto, 104. Dreser, H., 27, 28, 29, 30, 32, 123. Duclaux, 51. Dunham, H. K., 162, 163. Edlefson, G., 44. Eichberg, J. H., 174. Ewald, A., 48, 196. Farkas, G., 22. Fihe, C. C, 173. Fischer, M. H., 50, 61, 73, 104, no. III, 115, 150, 157. Fletcher, 44. Fraenkel, 22. Frerichs, 57. FreundHch, H., 8. Geier, O. p., 164. Gettler, A. O., 126. Gies, W. J., 184. Goodridge, F. G 184. Gottheb, 106. Graham, Thomas, 3, 7. Griitzner, 30, 33. Guthrie, C. C, 179. Halliburton, 75. ' Hamburger, H. J., 63, 72, 73, 104. 52. Hamilton, Jo., 175. Hamilton, N. A., 169. Hammarsten, O,, 75. Handovsky, H., 78, 100. Hardy, W. B., 100. Hart, E. B., 75. Heidenhain, R., 3, 27, 30, 31, 32, 33, 34, 104, 105, 107, 123, 193, 194. Henderson, L. J., 22. Henderson, Yandell, 184, 193. Herrmann, Max, 50, 150. Hober, R., 22, 24, 104. Hogan, James J., 160, 161, 162, 173, 193; Hopkins, 44. Hoppe-Seyler, F., 49, 51, 196. 34, Irasawa, T., 49. Jaksch, R. von, 26, 49. Kiely, W. E., 173. Kiliani, H., 51. Kraus, F., 26. Kuder, W. S., 173, 175, 191. Landsteiner, 63. Laqueur, E., 75. Leube, W., 44. Liebermann, 23. Ludwig, Carl, 32. Magnus, 105, 106. Majors, E. A., 172. Mandel, J. A., 75. Meisenheimer, 51. Mendel, E., 49. Meyer, Hans, 114. Miinzer, E., 49. Nef, J. U., SI. Noorden, C. von, 44. Noyes, A. A., 7. Nussbaum, 27, 30, 123. 109, 199 200 AUTHOR INDEX OSBORXE, W. A., 75. Ostwald, Wolfgang, 8. Overton, E., 104, 114. Palma, p., 49. Pauli, Wolfgang, 75, 78, 100, 109, 197. Peiper, E., 26. Pemsel, W., 23. Perrin, J., 8. Ponfick, 105. Reid, E. Waymouth, 104, 193, 194. Rhorer, Ludwig von, 24. Rindfleisch, E., 62. Robertson, T. B., 23, 75. Rumpf, W. H., 26. Sackur, O., 75. Schade, 51. Schloss, Ernst, 126. Schmidter, W. C, 162. Schoep, Alfred, 107. Schorr, Karl, 78. Schroeder, P. von, 100. Schiitzenberger, 51. Sherman, H. C, 126. Sjoquist, 23. Slyke, L. L. van, 75. Smith, Dudley, 165. Spiro, K., 23. Starling, E. H., 104. Strassburg, G., 48, 196. Tait, Dudley, 97. Terray, P. von, 48. Thompson, G., 48. Traube, Isador, 108. Tuechter, J. L., 164. Underhill, F. p., 184. ViRCHow, R., 52, 61, 62. Weigert, 57. Woodyatt, R. T., 51. WooUey, Paul G., 77. Zillessen, Hermann, 48, 50. Zuntz, 53. SUBJECT INDEX. Acid, 2, 125; as cause of albuminuria, 20; effect of, on kidney, 35, 125; in nephritis, 125; in oedema, 184. Acidity, of normal urine, 24; of nephritic urine, 25. Acidfuchsin, 27, 123. Acidosis, 184. Albumin, in effusions, 192; absorp- tion of solutions containing, 193, Alhumimma, definition of, i; cause of, 2; after injection of acid, 35; after injection of alkali, 40; after hard work, 44, 45, 18°; in heart disease, 47; in lung disease, 47; in anaemia, 48; in epilepsy, 48; after exposure to cold, 49; after interference with blood supply, 50; after intoxication, 51; of the newborn, 52; after salt restriction, 53; after excessive consumprion of water, 53; hypertrophy of heart and, 98; treatment of, 125. Anamia, albuminuria in, 48; due to nephritis, 127. Arsenic oedema, 173. Arteriosclerosis, 97, 173, 176. Ascites, 191. Asthma, 173. .re Athletes, albuminuria in, 44; rehef of albuminuria in, 180. Basket-hall, 45, i8o> 181, 182. Blood, physicochemical characteris- tics of, 5; reaction of, 21; in nephrids, 26; absorption of, 193. Blood corpuscles, diapedesis of red, 78; migration of white, 81. Blood pressure, 100. Brain oedema, 173. Bronchial asthma, 173. Case reports, of nephritis, 161. Casein, 75. Casts, origin of, 84; types of, 88; significance of, 92. Cavities, collection of fluid in, 191, 193- Chronic interstitial jiephritis, 58, 94, 176, 177; water output, in, 95; and nitrites, 177. Classification of colloids, 7. Cloudy swelling, 61. Coefficient of distribution, 114. Colitis, mucous, 173. Colloids, 7, 83; classification of, 7, 8; absorption of dyes by, 119; in perfusion liquids, 193; absorption of solutions containing, 194. Crystalloids, 7. Diabetes, 184. Diapedesis, 78. Diet, in nephritis, 125. Distribution coefficient, 114. Diuretics, 158. Dyes, absorption of, by colloids, 119. Eclampsia, 161, 163, 165, 167, 168, 169, 172, 177. Emulsion colloids, 8. Epilepsy, albuminuria in, 48. Exercise, albuminuria after, 44. Exudates, 191, 193, 196. Ferments, 197. Fibrin, solution.of, 9; swelling of, 12, 184. Filtration, 105. Food, in treatment of nephritis, 125. Free water, 193. Gel, 8. Gelatine, solution of, 15. Glaucoma, 173. Hcemoglobinuria, 49, 127. Hemolysis, 49, 127. Hemorrhage, by diapedesis, 78; per- fusion in, 193. Hay fever, 173. Heart, albuminuria in diseases of, 47; oedema in diseases of, 173, 191. 202 SUBJECT INDEX Hydrothorax, 191, 193. Hypertrophy of heart in nephritis, 98. Injections of alkali and salt, 161; by- rectum, 162, 163, 164, 165, 166, 169, 172, 173, 175; intravenously, 168, 170, 173, 175, 178. Kidney, physicochemical structure of, 5; staining of, 27, 123; mor- phological changes in, 56; small red, 60; small gray, 60; cloudy swelling of, 61; secretion of water by, 102; secretion of dissolved sub- stances by, 113. LeukcBmia, albuminuria in, 48. Ligation, of kidney vessels, 50, 124. Lipoids, 115. Lung, albuminuria in diseases of, 47. Lymph, absorption of, 193. Marasmus, 173. Milk, 179. Membrane, urinary, 6, 109. Mucous colitis, 173. Nephritis, definition of, i; cause of, 2; after injection of acid, 35; after injection of alkali, 40; after hard work, 44; in heart disease, 47; in lung disease, 47; in anaemia, 48; in epilepsy, 48; after exposure to cold, 49; after interference with blood supply, 50; after intoxica- tion, 51; of the newborn, 52; after salt restriction, 53; parenchyma- tous, 57, 173, 174; chronic inter- stitial, 58, 94, 176; water secretion in, 95; arteriosclerosis and, 97, 173,176; hypertrophy of the heart and, 98; blood pressure in, 100; night urination in, loi; treatment of, 125; water in, 127; salts in, 134, 161, 180; clinical reports of, 160; of pregnancy, 161, 163, 165, 167, 168, 169, 172; sodium carbonate in, 161; stripping of capsule for, 178; milk in, 179; prevention of, 179; citrus fruit in, 180; in frogs, 185. Neutral red, 121. Neutrality, maintenance of, in tis- sues, 22. Nitrites, 177, (Edema, of brain, 173; after arsenic injections, 173; treatment of, 183; and salt restriction, 183; criticism of theory of, 184. Partition coefficient, 114. Paroxysmal hcemoglohinuria, 49, 127. Perfusion mixtures, 178, 179, 193. Pernicious ancemia, albuminuria in, 48. Plants, reaction of, to loss of water, 192. Pregnancy nephritis, 161, 163, 165, 167, 168, 169, 172. Protein gels, solution of, 9. Proteins, 9, 126. Reaction^ of blood, 21, 26; of tissues, 21, 26; of normal urine, 24; of nephritic urine, 25, 27. Red blood corpuscles, diapedesis of, 78. Salts, in treatment of nephritis, 134; in treatment of oedema, 183. Salt restriction, albuminuria of, 53; in nephritis, 134; and salt elimi- nation, 180; and oedema, 183. Scarlet fever, 162. Shock, 193. Selective absorption and secretion, 115- Secretion, 34; disturbances in, 93; of dissolved substances, 113. Serous cavities, 191, 193, 196. Serous elusions, 191, 193, 196; acids in, 196. Stnall red kidney, 60. Small gray kidney, 60. Sodium carbonate, in nephritis, 161; preparation of solutions of, 178; dried, 178; cr>'stallized, 178; in oedema, 191. Sodium chloride, in nephritis, 134, 161; in oedema, 185, 191. Sodium indigosulphonate, 30, 121. Sol, 83. Stains, absorprion of, by colloids, 119. Staining of kidne}^ 27, 123; with acid fuchsin, 27; with sodium indigosulphonate, 30. State, colloidal and crj'^stalloidal, 7. Suppression of urine, 161, 162, 163, 164, 165, 166, 172. Suspension colloids, 8. SUBJECT INDEX 203 Tapping, iq6. Therapy, see Treatment. Tissues, neutral reaction of, 21. Toluidin blue, 119. Tonsillitis, 164. Transudates, 197. Treatment, of paroxysmal haemo- globinuria, 49; of nephritis, 125; of oedema, 183. Urcemia, 26, 176. Urinary secretion, theories of, 104; selective character of, 115. Urinary membrane, 6, 109. Urine, physical chemistry of, 6; re- action of, 23; acidity of normal, 24; acidity of nephritic, 25; sup- pression of, 161, 162, 163, 164, 165, 166, 172. 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