key: cord-0997306-mlcczr8c
authors: Ng, Jia H.; Hirsch, Jamie S.; Wanchoo, Rimda; Sachdeva, Mala; Sakhiya, Vipulbhai; Hong, Susana; Jhaveri, Kenar D.; Fishbane, Steven
title: Outcomes of patients with end-stage kidney disease hospitalized with COVID-19
date: 2020-08-15
journal: Kidney Int
DOI: 10.1016/j.kint.2020.07.030
sha: f9c7e1f0cc2ca6b49a81f977d5d92fb24e4e4c95
doc_id: 997306
cord_uid: mlcczr8c

Given the high risk of infection-related mortality, patients with end-stage kidney disease (ESKD) may be at increased risk with COVID-19. To assess this, we compared outcomes of patients with and without ESKD, hospitalized with COVID-19. This was a retrospective study of patients admitted with COVID-19 from 13 New York. hospitals from March 1, 2020, to April 27, 2020, and followed through May 27, 2020. We measured primary outcome (in-hospital death), and secondary outcomes (mechanical ventilation and length of stay), Of 10,482 patients with COVID-19, 419 had ESKD. Patients with ESKD were older, had a greater percentage self-identified as Black, and more comorbid conditions. Patients with ESKD had a higher rate of in-hospital death than those without (31.7% vs 25.4%, odds ratio 1.38, 95% confidence interval 1.12 - 1.70). This increase rate remained after adjusting for demographic and comorbid conditions (adjusted odds ratio 1.37, 1.09 - 1.73). The odds of length of stay of seven or more days was higher in the group with compared to the group without ESKD in both the crude and adjusted analysis (1.62, 1.27 - 2.06; vs 1.57, 1.22 - 2.02, respectively). There was no difference in the odds of mechanical ventilation between the groups. Independent risk factors for in-hospital death for patients with ESKD were increased age, being on a ventilator, lymphopenia, blood urea nitrogen and serum ferritin. Black race was associated with a lower risk of death. Thus, among patients hospitalized with COVID-19, those with ESKD had a higher rate of in-hospital death compared to those without ESKD.

A novel coronavirus, severe acute respiratory syndrome (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) emerged in late 2019 in Wuhan, China, and rapidly spread throughout the world. 1, 2 The disease has resulted in a large number of hospitalizations and intensive care unit (ICU) admissions, with now well-described pulmonary, cardiac, vascular, and renal complications. [3] [4] [5] [6] [7] To what degree COVID-19 has impacted patients with end-stage kidney disease (ESKD) on dialysis has not been fully elucidated. Understanding the outcomes of COVID-19-infected patients with and without ESKD is important because this information would help risk-stratify patients with ESKD to certain therapies for COVID-19 as they arrive at the hospital.

Patients with ESKD have a dysregulated immune system 8 and carry significant comorbid conditions such as diabetes mellitus (DM), cardiac disease and obesity that are now considered risk factors for severe COVID-19 disease. 9, 10 The ESKD population has higher annual mortality rates compared with the general population, even after adjustment for age, race, and DM. For example, annual mortality secondary to sepsis is 30-45 fold higher in the dialysis population compared to the general population. 11 A recent study found an association between community influenza-like illness activity and seasonal variation in all-cause mortality among patients with ESKD, with an excess mortality of 1100 deaths per year, or 1.5-2% of all deaths per influenza season in the ESKD cohort. 12 Despite recent improvements in mortality among patients with ESKD, with a 28% decline over the last 16 years, the ESKD population has a higher mortality rate compared with the general population even after adjusting for age, race and DM. 13 With COVID-19, either an increased or decreased risk of death related to SARS-CoV-2 infection in ESKD could have been postulated. Severe disease with COVID-19 has been J o u r n a l P r e -p r o o f attributed to direct viral damage as well as the body's exuberant immune response. 14 Thus, the diminished immune response in ESKD could potentially protect against the cytokine storm observed with severe COVID-19 infection. In fact, in a preprint study published by Ma et al, measured levels of inflammatory cytokines in dialysis patients with COVID-19 was found to be lower than in other patients. 15 Another factor to consider is the reduced angiotensin converting enzyme 2 (ACE2) activity seen in dialysis patients. 16, 17 As ACE2 serves as a receptor that allows the novel coronavirus CoV-2 to enter a cell, 18 diminished activity could plausibly mitigate the severity of illness. Alternatively, patients on dialysis may be more susceptible to SARS-CoV-2 infection because of increased transmissibility in dialysis units and diminished ability to fight infection. 19, 20 To date, no large study exists on the outcomes of patients with ESKD hospitalized with COVID-19. Recent studies from China and Europe on patients with ESKD who were infected with COVID-19 have been limited to small numbers and single centers. [21] [22] [23] [24] A single-center study from the United States (US) published recently also showed poor outcomes among 59 patients with ESKD, whereby 18 (31%) had died within the whole cohort and 6 (75%) had died within the subset of patients requiring mechanical ventilation. 25 In the current study, we compared the outcomes of patients with and without ESKD among those hospitalized with COVID-19, and examined the risk factors associated with death in the non-ESKD group and in the ESKD group. From March 1, 2020, to April 27, 2020, there were 11,635 hospital admissions to 13 health system hospitals with a diagnosis of COVID-19 present on admission or made during the hospitalization. Of these, 10,482 were included into the final cohort (Figure 1) We studied various clinical characteristics as potential risk factors of in-hospital death among patients with ESKD and those without ESKD ( Table 3 and 4, Figure 2 ).

For patients without ESKD, the independent risk factors for in-hospital death after adjusting for covariates in Model 1 included increased age, male sex, cardiovascular disease, cancer, requiring mechanical ventilation, requiring vasoactive medications, high blood urea nitrogen (BUN), low albumin, high C-reactive protein (CRP) and high log transformed serum ferritin. The diagnosis of hypertension and use of an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) were associated with a lower risk of inhospital death ( Table 3) . After adjusting for variables in model 2, the independent risk factors J o u r n a l P r e -p r o o f for in-hospital death among patients without ESKD were increased age, male sex, diabetes mellitus, cardiovascular disease, cancer, requiring mechanical ventilation and requiring vasoactive medications ( Table 3) . Hypertension and use of ACE inhibitors or ARB were again associated with lower risk of in-hospital death.

Among patients with ESKD, independent risk factors for in-hospital death after adjustment in model 1 were increased age, requiring mechanical ventilation and lymphopenia, elevated BUN and high log transformed serum ferritin. In model 2, the independent risk factors for in-hospital death were increased age, requiring mechanical ventilation and vasoactive medication use. Black race was associated with a significantly lower risk of death among patients with ESKD in both models (OR 0.47, 95% CI 0.22 -0.98 and OR 0.48, 95% CI 0.24 -0.96, in models 1 and 2, respectively) ( Table 4 and Figure 2 ).

When comparing the odds of in-hospital death in the ESKD group and the non-ESKD group, sensitivity analysis incorporating the assumption that those who were still hospitalized to have either all experienced death or all discharged alive did not significantly alter the results Table S3 ). Similarly, sensitivity analyses examining risk factors for mortality in the ESKD and non-ESKD cohorts separately did not substantially alter the results Table S6 shows the odds ratios of in-hospital death of patients with and without ESKD stratified by mechanical ventilation.

We examined the clinical characteristics, outcomes and risk factors for death in patients with ESKD on chronic dialysis infected with COVID-19. The primary finding was that the risk for in-hospital death was significantly increased among patients with ESKD compared to the non-dialysis population. The increased mortality risk persisted after adjustment for patient demographics and comorbid conditions. Among prespecified secondary outcomes, patients with ESKD had a significantly longer length of hospital stay. In contrast, there was no significant difference between patients with and without ESKD in the need for mechanical ventilation.

Patients on dialysis have long been known to have a greatly increased risk of death compared to the general population. For patients starting hemodialysis, the expected 5-year survival rate is only 42% in the United States, 26 a risk similar to that of various forms of cancer. 27 While the reason for increased risk of death among patients with ESKD has not been fully elucidated, it can be at least partially understood through the greater accumulated comorbidities in this population. The rates of DM, heart disease, vascular disease and other conditions are substantially greater than in the non-dialysis population. 28 Because of this, our finding of a significantly increased risk of in-hospital mortality among ESKD patients with COVID-19 compared to non-dialysis patients would appear to be intuitive. However, adjusting for comorbidities did not meaningfully change the greater risk observed in the ESKD cohort. This suggests that other unmeasured characteristics of the ESKD patients accounted for the increased risk, which may be related to host response to infection.

The increased risk of infections is likely related to a dysregulated immune system, as the uremic milieu has been associated with disturbances in both innate as well as adaptive immunity.

Alterations in the function of neutrophils, Natural Killer cells, macrophages, and T and B J o u r n a l P r e -p r o o f lymphocytes along with inflammation induced by the dialysis procedure itself lead to impaired host immunity. 29, 30 Infections are the second most common cause of death for patients on dialysis, with some studies finding a several hundred fold higher annual mortality rate secondary to sepsis as compared to the general population. 11 The aforementioned susceptibility to both viral and bacterial infections is highly relevant to consider regarding mortality outcomes in patients with ESKD who are infected with SARS-CoV-2.

We found that among the 419 patients with ESKD hospitalized with COVID-19 infection, 133 died (31.7%). Previous studies have examined mortality risk in smaller patient cohorts. 25 Preprint data from Wuhan University, reported 37 COVID-19 positive hemodialysis patients of which 6 (16.2%) died. 15 Another preprint report from Wuhan by Li et al, 31 (30.6%) of whom had died. 23 The Brescia Renal COVID task force in Italy reported 24 (42.1%) deaths among 57 hemodialysis patients. 24 Our results are similar to those from the European centers and recent single center US data. 25 This may be consistent with the findings that patients with COVID-19 infection from China have generally been reported as having better outcomes by a variety of different metrics.

In our study, we found that independent risk factors for death among patients with ESKD were largely similar to those without ESKD. A notable difference that defies obvious explanation was that HTN and the use of ACE inhibitors or ARBs were significant protective factors for death among patients without ESKD. Several articles have proposed the protective effect of Renin-Angiotensin-Aldosterone System (RAAS) inhibitors on lung injury and cardiac injury in J o u r n a l P r e -p r o o f COVID-19 disease, although the subject has remained unsettled. 18, 32 Given that patients with HTN are often prescribed RAAS inhibitors, one could postulate that RAAS inhibitors could be providing a protective effect among those with HTN. Yet after adjusting for use of ACE inhibitors or ARBs, the protective effect of HTN for in-hospital death persisted. In a recent paper from the United Kingdom, Williamson et al had also found the protective effect of HTN. 10 In their post-hoc analysis, the authors found significant interaction between HTN and age, whereby HTN was associated with lower mortality only among those aged 70 and above. The reason for this finding is unclear. The diagnosis of HTN is common in the older population, which may reflect continual access to medical care.

Within the ESKD group, we found that Black race was associated with a significantly reduced risk of death. In contrast, previous studies have found that Black race increases the risk of dying from COVID-19. 33 Our finding of protection associated with Black race among ESKD patients with COVID-19 defies easy explanation. Notably, Black patients with ESKD generally have better survival while on dialysis compared to White patients. This inherent survival advantage may partly explain our finding of improved hospital survival of Black ESKD patients with COVID-19. 34, 35, 36 Dialysis dosing, nutritional factors with higher BMI as a protective mechanism, and racial differences in inflammatory responses are some possible hypotheses that may confer the racial difference in survival improved dialysis survival. 35 Any racial differences in inflammatory or coagulation parameters could be highly relevant in COVID-19 disease. More recently, there is evidence suggesting the role of Apolipoprotein L1 (APOL1) gene allele in the difference in mortality between Black patients with ESKD compared to their White counterparts.

Several studies had found that while APOL1 was strongly associated with the development of ESKD, there was no significant association with cardiovascular diseases. [37] [38] [39] It may be that this J o u r n a l P r e -p r o o f is why among Blacks, the rate of ESKD exceeded the rate of mortality and cardiovascular deaths. [40] [41] [42] This could help to explain the reduced mortality that we observed during COVID-19

infection.

Inflammatory markers, including serum ferritin, have been associated with the severity of COVID-19. 43, 44 In our study, we found that within the ESKD group, serum ferritin levels were higher in patients who expired compared to those who were alive, (3644.0 ng/mL [IQR 1753.0, 7687.0]) vs (2138.0 ng/mL [IQR 1142.0, 3969.0], respectively). Additionally, we found that serum ferritin was and independent risk factor for in-hospital death for both the non-ESKD and ESKD group (Table 3 and 4) . In one study, a serum ferritin increase of >200% was found to be a potentially useful screening marker for dialysis patients infected with COVID-19. 45 Serum ferritin could be potentially used in future research as a screening tool for severity of COVID-19 in ESKD patients.

To date, this is by far the largest cohort of hospitalized patients with COVID-19 comparing mortality between patients with and without ESKD in a diverse patient population. In order to increase the validity of the data, we had prespecified operational definitions for exposures, covariates and outcomes, as well as rigorous adjudication by two independent reviewers for ESKD exposure. Additionally, the findings of the study are further strengthened by various analytical approaches and sensitivity analyses to minimize confounding biases.

The limitations of the study include the retrospective observational design, which leaves open the possibility of missing variables that could potentially be important explanatory factors.

As BMI was a risk factor associated with in-hospital death in other studies, 46,47 our study was limited by 10% of missing BMI data. We had, however, attempted to handle the missing BMI J o u r n a l P r e -p r o o f data through multiple imputation. In addition, despite the larger size of this study compared to other reports, the ESKD sample may still have been relatively underpowered to find other statistically significant risk factors in mortality. Another limitation is the inability to adjust for remdesivir and dexamethasone, the only two drugs associated with improved outcomes for COVID-19. 48, 49 As the evidence for these two drugs came after the surge of COVID-19 cases in our health system, only a small proportion of patients received these two drugs. Only 51 patients (0.5%) in the non-ESKD group received remdesivir and none of the patients in the ESKD group received it. Fewer than 3% of patients in both groups received dexamethasone (Supplementary Table 1 ).

In conclusion, we found that among hospitalized patients with COVID-19, mortality risk was increased in patients with ESKD as compared to the general population. Remarkably, we found that among patients with ESKD who were of Black race, there was a significantly lower risk of death from COVID-19. Taken together, the results suggest both a need for further research and the continued need for careful scrutiny and infection control procedures in the ESKD population at risk for COVID-19.

This was a retrospective observational cohort study of a large New York health system. Data for this study were obtained from the 13 hospitals using the enterprise inpatient electronic health record (EHR) Sunrise Clinical Manager (Allscripts, Chicago, IL). All adult (age ≥18) 

Prior to analysis, we carried out a data cleaning process to screen for duplicate records and missing data, and performed range checks to assess for outliers and erroneous data. We excluded outliers and duplicate records.

Primary exposure was pre-hospitalization diagnosis of ESKD with dialysis dependence.

ESKD diagnosis was defined using International Classification of Diseases, Tenth Revision (ICD-10) code N18.6. Two study investigators (V.S. and J.S.H.) performed independent adjudication of the ESKD diagnosis through manual chart review of hospital admission and nephrology consultation notes for the following key search terms: "ESRD", "ESKD", "end stage renal", and "end stage kidney". We cross-checked ESKD diagnosis by evaluating inpatient hemodialysis and peritoneal dialysis orders. Those identified as ESKD without inpatient dialysis orders underwent further manual chart review.

In order to avoid misclassification of non-dialysis-dependent kidney transplant recipients into the exposed group, we performed additional verification. Kidney transplant was defined using ICD-10 codes T86.1, T86.10, T86.11, T86.12, T86.13, T86.19, and Z94.0 and adjudication J o u r n a l P r e -p r o o f through manual chart review using the following key search terms: "kidney transplant", "renal transplant", "kidney txp", "renal txp", "DDRT" (deceased donor renal transplant), "LRRT" (living related renal transplant), "LURT" (living unrelated renal transplant), and "LDT" (living donor transplant). Adjudication for the kidney transplant diagnosis was carried out by members of the Nephrology COVID-19 Consortium.

The primary outcome was in-hospital death. The secondary outcomes were mechanical ventilation and hospital length of stay.

We collected data on patient demographics, baseline history of comorbid conditions, home medications, dialysis-specific data elements, and details on hospital admissions. Comorbid conditions and home medications were determined from provider-entered past medical history and admission medication reconciliation. Dialysis modality and dialysis vascular access were determined from inpatient dialysis order entry. We collected details of hospital admission such as intensive care unit (ICU) stay, mechanical ventilation, vasopressor support, and baseline laboratory test results within 48 hours of hospital admission. Due to the COVID-19 pandemic, many additional ICUs were created in non-traditional hospital areas and units. Hence, ICU stay was defined as either one of the following: need for invasive mechanical ventilation, need for vasopressor or inotrope support, under the care of an ICU service, or in a known ICU location. To determine if ESKD diagnosis was associated with in-hospital outcomes of death (primary outcome), mechanical ventilation or length of stay of ≥7 days (secondary outcomes), we performed univariate and multivariate logistic regression for each outcome separately. In a stepwise fashion, we adjusted for demographics including age, sex and race/ethnicity, then adjusted for demographics as well as comorbid conditions including diabetes mellitus, hypertension, cardiovascular diseases (coronary artery disease, heart failure and peripheral vascular disease), respiratory diseases (asthma and chronic obstructive pulmonary disease), chronic liver disease and cancer.

For the primary outcome (in-hospital death), we performed several pre-defined sensitivity analyses to determine the robustness of our results. In the primary analysis, we restricted the analysis to patients who died or were discharged alive. In a sensitivity analysis, we included patients still hospitalized in the logistic regression to compare the risk of death of patients with and without ESKD (174 patients [1.7% of cohort]). We repeated the regression model by assuming those who were still hospitalized to have all experienced death, and another model by assuming those still hospitalized to be discharged alive. 

To account for missing data in the regression models, we performed multiple imputation for chained equations using predictive mean matching with 50 imputations and 20 iterations (mice R package, version 3.9.0). 57 Model 1 and 2 estimates and standard errors were calculated using Rubin's rules. 58 The variables used for the multiple imputation procedure are described in the Supplemental Methods. D-dimer had a substantial degree of missingness, with 37% missing J o u r n a l P r e -p r o o f data in the non-ESKD group and 42% missing data in the ESKD group, thus we did not perform multiple imputation for this variable nor included it in any of the models. Other than D-Dimer, we performed multiple imputation for all the missing data including BMI, ACE-inhibitor/ ARB use, basic laboratory tests and inflammatory markers C-reactive protein (CRP) and Ferritin.

All statistical tests were two-sided, and a P value <0.05 was considered statistically significant. All statistical analyses were performed using R version 3. 

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The authors would like to thank the Raggio and Hall Families for their support and making this study possible.J o u r n a l P r e -p r o o f