key: cord-0924151-hi6adbch
authors: Fishbane, Steven; Hirsch, Jamie S.
title: Erythropoiesis-Stimulating Agent Treatment in Patients With COVID-19
date: 2020-05-29
journal: Am J Kidney Dis
DOI: 10.1053/j.ajkd.2020.05.002
sha: 8794034343ba64dc01991df84d403e3e7e555628
doc_id: 924151
cord_uid: hi6adbch

nan

The severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), and the resulting illness, COVID-19, developed in Wuhan, China in late 2019 (1) . Within months, COVID-19 became a worldwide pandemic, with millions cases reported (2). Nephrologists have been front-and-center, caring for infected dialysis patients while also treating hospitalized COVID-19 patients with acute kidney injury (AKI). A controversial aspect of therapy in both settings has been the use of erythropoiesis-stimulating agents (ESA) to treat anemia experienced by patients with COVID-19.

Both COVID-19 patients with AKI and maintenance dialysis patients infected with the virus have a high rate of anemia, often severe. The worst anemia in COVID-19 occurs in temporal relation with a burst of severe systemic inflammation that may occur during the course of the disease. We have witnessed this relationship in recent months, caring for patients hospitalized with COVID-19 in Northwell Health hospitals. Among 11,265 patients across 13 hospitals admitted between March 1 and April 27, 2020, we found that elevated concentrations of D-dimer were associated with lesser hemoglobin and greater serum ferritin concentrations ( Figure 1 ).

The association of anemia and inflammation has long been recognized as the syndrome of anemia of chronic disease or the anemia of inflammation. The hepatic-derived protein, hepcidin, modulates the ferrokinetic response to inflammation (3). In the presence of inflammation, hepcidin restricts iron absorption from the intestines and iron release from storage tissues in the spleen and liver. The net effect is to limit iron entering circulation and tissues (3).

As many microbes are highly dependent on iron as a key nutrient, the teleology may be thought of as a protective action defending against infection by hepcidin-driven diminution in available iron supply. Simultaneously, however, this lessens iron availability for host erythropoiesis, resulting in development or worsening of anemia. In maintenance dialysis patients, inflammation-induced hepcidin production even without infection may be maladaptive, making anemia more difficult to treat. Clinical signs of hepcidin induction include reduced hemoglobin and elevated serum ferritin due to iron trapped in storage tissues, even with low circulating iron (low transferrin saturation [TSAT]).

In COVID-19, not much is known regarding the so-called "cytokine surge" and coincident hepcidin levels and iron kinetics. Severe anemia often seen in these patients may in part be due to hepcidin effects and dysregulated iron kinetics, though this has not yet been established. But clearly, patients with severe COVID-19 usually have an intense inflammatory phase. In similar states of inflammation, ESAs have greatly limited efficacy (4) . Thus, in COVID-19, patients with or without kidney disease but with anemia are unlikely to mount an effective response to ESAs due to the inflammation. Interestingly, the new class of hypoxia inducible factor (HIF) stabilizers are oral drugs that cause erythropoietin production and enhanced iron availability. Early study results hint at the fact that these drugs may be able to treat anemia more effectively in an inflammatory milieu than ESAs (4).

Treatment with ESAs in COVID-19 would not only have limited effectiveness but could also be potentially harmful. This is due to a remarkably prothrombotic state seen with severe COVID-19 (6), and the tendency of ESAs to induce thromboses. Blood clots in COVID-19 have been found frequently in both venous and arterial systems. Hemodialysis filters clot more frequently, particularly those used for continuous renal replacement therapies. Pulmonary embolism is an important problem as well, and in one study of 106 pulmonary CT angiograms in COVID-19 patients, 32 patients (30%) had acute pulmonary emboli (7) . Typically, in critically ill patients the rate is much lower (8) . The cause of the prothrombotic state in COVID-19 is unclear. However, the intimate interplay of the inflammatory / immune system with coagulation is remarkable in these patients. As a result, a more aggressive thromboprophylaxis policy is in order for many patients hospitalized with COVID-19.

While ESA treatment has been remarkably successful for treating anemia, reducing blood transfusions and possibly improving quality of life, thrombotic episodes have been frequently noted in treatment studies (9) . This has been most clearly observed in studies in which ESAs have been used to raise the hemoglobin concentration to higher than usual targets, particularly into the normal range (10) . The prothrombotic effect of ESAs in concert with the prothrombotic milieu of COVID-19 could have an additive adverse effect.

When considering the probable reduced efficacy of ESAs in patients with COVID-19 inflammation and the potential for increasing thrombotic risk, the role for these agents should be significantly limited in these patients. Our recommendations are:

ESAs in this setting. Hemoglobin concentrations will often be quite low and may require blood transfusion to maintain adequate systemic oxygen delivery. The risks of ESA treatment generally outweigh potential benefits.

in that endogenous erythropoietin production is substantially reduced. As a result patients have little ability to withstand the anemic effects of COVID-19. If the patient enters the hospital already receiving an ESA dose as an outpatient, we continue the dose in the hospital. However, we lower the hemoglobin target to attempt to mitigate thrombotic risk to the greatest extent possible. We only attempt to raise the hemoglobin to 8-9 g/dL in these patients, and do not escalate ESA doses if the goal cannot be achieved.

In conclusion, the anemia experienced by hospitalized COVID-19 patients can be severe. While the idea of using ESA treatment may be enticing, in most cases the expected limited efficacy due to inflammation in this setting and potential risks limit the role of these agents.

Support: None. Financial Disclosure: Dr Fishbane reports receipt of fees for research consulting from Astra Zeneca, Fibrogen, Akebia, Megapro. Dr Hirsch declares that he has no relevant financial interests.

Peer Review: Received May 13, 2020 in response to an invitation from the journal. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form May 20, 2020. Figure 1 . Median hemoglobin and serum ferritin levels by ranges of D-dimer for patients treated in Northwell Health hospitals in New York. There were 11,265 patients across 13 hospitals, admitted between March 1 and April 27, 2020. Of these, 8,232 had at least 1 D-dimer and hemoglobin measurement, and 7,994 had a D-dimer and ferritin measurement. Elevation in Ddimer level above normal in the 1-4x and >4x the upper limit of normal (ULN, 229 ng/mL) groups was associated with a stepwise lesser median hemoglobin and a corresponding stepwise greater serum ferritin.

Anemia of inflammation

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Roxadustat Treatment for Anemia in Patients Undergoing Long-Term Dialysis

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

Acute Pulmonary Embolism in COVID-19

Patients on CT Angiography and Relationship to D-Dimer Levels

Failure of anticoagulant thromboprophylaxis: risk factors in medical-surgical critically ill patients*

R; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease

Meta-analysis: erythropoiesis-stimulating agents in patients with chronic kidney disease