key: cord-271575-n70rqs8c
authors: Jager, Kitty J.; Kramer, Anneke; Chesnaye, Nicholas C.; Couchoud, Cécile; Sánchez-Álvarez, J. Emilio; Garneata, Liliana; Collart, Fréderic; Hemmelder, Marc H.; Ambühl, Patrice; Kerschbaum, Julia; Legeai, Camille; Dolores del Pino y Pino, María; Mircescu, Gabriel; Mazzoleni, Lionel; Hoekstra, Tiny; Winzeler, Rebecca; Mayer, Gert; Stel, Vianda S.; Wanner, Christoph; Zoccali, Carmine; Massy, Ziad A.
title: Results from the ERA-EDTA Registry indicate a high mortality due to COVID-19 in dialysis patients and kidney transplant recipients across Europe.
date: 2020-10-15
journal: Kidney Int
DOI: 10.1016/j.kint.2020.09.006
sha: 
doc_id: 271575
cord_uid: n70rqs8c

The aim of this study was to investigate 28-day mortality after COVID-19 diagnosis in the European kidney replacement therapy population. In addition, we determined the role of patient characteristics, treatment factors, and country on mortality risk using ERA-EDTA Registry data on patients receiving kidney replacement therapy in Europe between February 1, 2020 and April 30, 2020. Additional data on all patients with a diagnosis of COVID-19 were collected from seven European countries encompassing 4298 patients. COVID-19 attributable mortality was calculated using propensity-score matched historic controls and after 28 days of follow-up was 20.0% (95% confidence interval 18.7%-21.4%) in 3285 patients receiving dialysis, and 19.9% (17.5%-22.5%) in 1013 recipients of a transplant. We identified differences in COVID-19 mortality across countries, and an increased mortality risk in older patients receiving kidney replacement therapy and male patients receiving dialysis. In recipients of kidney transplants older than 75 years of age 44.3% (35.7%-53.9%) did not survive COVID-19. Mortality risk was 1.28 (1.02-1.60) times higher in transplant recipients compared with matched dialysis patients. Thus, the pandemic has had a substantial effect on mortality in patients receiving kidney replacement therapy; a highly vulnerable population due to underlying chronic kidney disease and high prevalence of multimorbidity.

measures, definition of cases, as well as on testing capacity. 1 Mortality due to the SARS-CoV-2 virus is high compared to most other viral infections. Although a case fatality rate of 2.3% was reported from China, 2 the average rate is 11.7 (range 0. 6-18.9 )% in the EU general population. 1 Among hospitalized patients in UK suffering from severe COVID-19 the case fatality rate even reaches 26%. 3 Patients treated with Kidney Replacement Therapy (KRT, either dialysis or kidney transplantation) represent a vulnerable population. Under normal circumstances, age-standardized cardiovascular and non-cardiovascular mortality rates in dialysis patients are already 8.8 and 8.1 times higher than in the general population, respectively, 4 and compared to their age and sex matched counterparts in the general population, kidney transplant recipients experience a 30-50% reduced life expectancy. 5 It may be expected that COVID-19 causes substantial mortality in both the dialysis and kidney transplant populations due to their underlying chronic kidney disease and a high prevalence of comorbid conditions such as diabetes mellitus and cardiovascular disease. In transplant recipients, the potential effect of their long-term use of immunosuppression is a matter of debate. Some argue they may be at greater risk of severe infection because of their impaired immune system, 6 whereas others speculate that immunosuppressive therapy may be protective as it might address the COVID-19

induced cytokine storm. 7 Although no deaths were reported among 5 COVID-19 cases on hemodialysis in a single Chinese centre, 8 several case series from Italy (n=41, n=94), 9, 10 Spain (n=36) 11 and the United States (n=59) 12 with varying follow-up suggest a high mortality in the dialysis population with rates ranging from 29% to 41%. Preliminary reports in transplant recipients seem to suggest a somewhat lower mortality, with estimates ranging from 13% (n=15) in the United States to 25% in Italy (n=20). [13] [14] [15] The largest study to date is from Spain and reports on a group of 868 KRT patients (67% dialysis and 33% transplant patients) with a mortality rate of 23%. 16 J o u r n a l P r e -p r o o f

Risk estimates from studies with small sample sizes are known to suffer from inaccuracy due to random variation. In addition, as some of the above-mentioned samples were derived from in-hospital populations, the estimates reflect risk in a selected group of more severely ill patients and may not be generalizable to the broader KRT patient population. Moreover, most of these studies, including the largest one, used the case fatality rate as a measure of mortality, which is often calculated while the individual outcome (recovery or death) is known only for a proportion of infected patients. 17 To date, large population-based studies on mortality in the KRT population with complete follow-up information are lacking. Therefore, the first aim of this study is to investigate the COVID-19 attributable mortality 28 days after diagnosis in European dialysis patients and kidney transplant recipients using historic cohorts of prevalent dialysis and transplant patients without COVID-19. The second aim is to compare mortality between dialysis and transplant patients with COVID-19. Finally, we aimed to determine the role of patient characteristics, KRT treatment related factors, and country, as risk factors for death in both groups.

Between older. The proportion of males was slightly increased, with 2.0% more men in dialysis patients, and 3.0% more men in transplant recipients (Table S2 ). In both dialysis and transplant patients with COVID-19 there were more patients with diabetes mellitus as PRD (4.7% and 3.9%, respectively).

Twenty-eight days after COVID-19 diagnosis, 628 out of 3160 hemodialysis patients and 30 of 125 patients on peritoneal dialysis had died. Figure 1 shows that in the dialysis group as a whole 21.2% had died 28 days after diagnosis with 0.3% of deaths occurring on the day of diagnosis. In transplant recipients, 191 out of 1013 had died after 28 days. Their crude 28-day probability of death of 20.2% was similar to that in the dialysis cohort ( Figure 1) , with 3.3% of deaths taking place on the day of diagnosis. At 28 days, the survival curves start to level out, reflecting that most of the deaths due to COVID-19 will have occurred within this period.

Compared with the expected 1.2% mortality in the matched control group of dialysis patients without COVID-19, the COVID-19 attributable mortality was 20.0%, and mortality risk was 21.1 (95%CI 18.6 to 23.9) times higher in dialysis patients diagnosed with COVID-19 ( Figure 1 , Table S3 ). In transplant recipients diagnosed with COVID-19, the attributable mortality was 19.9% over the expected 0.2% mortality in the matched control group. As mortality is generally far lower in transplant patients compared with dialysis patients, their mortality risk was multiplied by 92.7 (95%CI 61.0 to 140.7) when compared to their non COVID-19 matched controls ( Figure 1 ).

Supplementary Figure 1 shows that the mortality risk in transplant recipients with COVID-19 was 28% higher (HR 1.28 (95%CI 1.02 to 1.60)) compared with the selected group of dialysis patients that could be matched (Table S4) .

In dialysis patients the analysis of crude mortality by age category revealed substantial differences across age groups, with 28-day mortality in patients older than 75 years of age as high as 31.4% (Table 2, Figure 2 ). The risk of death in men was 22.5% versus 19.0% in women. Dialysis patients with hypertension/RVD as underlying J o u r n a l P r e -p r o o f renal disease had the highest probability of death (24.3%), followed by diabetes mellitus (20.6%), and glomerulonephritis (16.7%). The 28-day probability of death in those treated with peritoneal dialysis was 25.0%

and 23.8% in hemodialysis patients. There were substantial differences in mortality across the seven participating countries, which was highest in the Netherlands (29.7%) and lowest in Romania (8.5%) ( Figure 3 ).

Multivariable analyses identified higher age and male sex as risk factors for 28-day mortality in COVID-19 dialysis patients (Table 2) . After adjustment for all available confounders, dialysis patients in Romania and

France had a lower mortality risk than those in Switzerland. The probability of death by age group, sex, and PRD, is provided in Figures S2, S3 , S4, and the COVID-19 attributable mortality in Table S5 .

In kidney transplant recipients, the analysis of crude mortality by age group showed a high 44.3% probability of death in those older than 75 years of age -comprising almost half of the patients ( (Figure 3 ). In multivariable analyses only higher age was identified as a risk factor for 28-day mortality ( Table 3 ). The probability of death by age group, sex, and PRD, is provided in Figures S2, S3 , S4, and the COVID-19

attributable mortality in Table S5 .

In the current paper, we present complete population-based data on more than 4000 KRT patients affected by COVID-19 collected through national and regional renal registries in Europe. We report the probability of death 

The data suggest that the incidence of diagnosed COVID-19 in the KRT population was low. Nevertheless, as 2.9% of the prevalent dialysis population and 1.4% of those living on a functioning graft were affected by COVID-19, this disease seems to have had a greater impact on the KRT population compared to the general population, 1 which may be due to their older age, or perhaps the consequence of more frequent testing.

Even though our COVID-19 patients were sourced from population-based registries, they may not represent all KRT patients with COVID-19. The majority of infections are asymptomatic or mild and do not require hospitalization, and perhaps not even consultation of a general practitioner or a nephrologist. Those patients may not have been tested and may therefore have remained undiagnosed. As testing in dialysis centres became more common, sometimes even standard, during the unfolding of the pandemic this is less likely the case for hemodialysis patients who visit their dialysis centre a few times a week. The proportions of patients with COVID-19 were considerably lower in patients on peritoneal dialysis and in transplant recipients. We speculate that in these groups testing may have been restricted to the symptomatic and more severe cases, and therefore our data for these populations likely represent a sicker group of patients. This is supported by the relatively high number of transplant recipients who died on the day of diagnosis (3.3%). This sampling bias may explain our finding that transplant patients are at higher risk of death than dialysis patients of similar propensity score. On the other hand, being immunocompromised may still have been more of a disadvantage while countering the infection than an advantage through reducing the cytokine storm. 6, 7 Although the absolute risk of contracting COVID-19 was low in KRT patients, 28-day mortality in COVID-19

patients far exceeded the mortality that -based on the historic controls -may be expected for KRT patients of similar propensity score. Information on the 28-day probability of death due to COVID-19 by age category in the general population is lacking. However, data on the case-fatality rate in the Italian general population amounted to 3.5% in 60-69-year old's and to 12.8% for those 70-79 year of age. 18 Similar data from Spain indicate slightly higher percentages, 5.2% and 14.6% respectively. 19 This may suggest that mortality from COVID-19 in the dialysis population (median age 71.7 years) is around 2 times higher and that in transplant patients (median age 60.9 years) mortality is multiplied by at least 6, compared to non-KRT patients with COVID-19 of similar age.

Undoubtedly, multimorbidity in the dialysis and transplant patients will have played an important role in explaining this substantial mortality, but unfortunately our data did not permit further investigation on this topic.

We should, however, keep in mind that in both the dialysis and transplant group almost 80% of patients survived COVID-19 at least up to 28 days after diagnosis, despite the fact that a substantial number of them may not have been admitted to ICU due to their supposedly high risk of death.

Both in dialysis and transplant patients with COVID-19, higher age remained the most important risk factor for mortality in our multivariable analysis. The finding that male sex was a risk factor in dialysis patients with COVID-19 is of interest. It confirms previous findings in the general population and also the slightly increased cardiovascular mortality found in elderly men compared with women on dialysis without COVID-19. 20 Previous studies found pre-existing heart disease to be a risk factor in dialysis patients. 10 We did not have access to comorbidity data, but PRD can be considered as a proxy for comorbidity. In our study the point estimates of the additional risk induced by diabetes mellitus and hypertension/RVD did suggest a rise in mortality. However, an additional independent effect of PRD on top of age could not be detected, possibly as a consequence of insufficient statistical power. In dialysis patients with COVID-19, we found that the probability of death varied across countries. Although interesting, we do not wish to draw any conclusions from this finding, as much of this variation may be attributed to dissimilarities in the identification of COVID-19 cases (as a result of varying testing strategies), differences in the severity of infections, and to the inability to adjust for unmeasured countryand patient-level confounders.

This study reports data from renal registries who aim to include complete data with full national coverage, eliminating the sampling bias found in smaller and non-population-based studies. Notwithstanding this unique strength, when it comes to reporting on patient populations with COVID-19, renal registries too cannot avoid the effects of impaired testing strategies resulting from test kit shortages. Underreporting of cases -irrespective of the reason (no symptoms, lack of care seeking behavior, lack of testing or reporting to the KRT treatment centre) -will have led to an overestimation of mortality. This overestimation is likely to be small for hemodialysis patients, but may be more important for peritoneal dialysis patients and transplant recipients where possibly more severe cases were included. The extent of this sampling bias, induced by varying testing strategies, may have differed across countries and centres. Furthermore, using registry data as a source, we had no access to additional information on patient and treatment characteristics that could potentially be important to the outcome of COVID-19 patients on KRT. Finally, even if this study includes the highest number of COVID-19 patients on KRT to date, it may still suffer from problems of statistical power resulting in an inability to identify truly existing associations.

The COVID-19 pandemic has had a substantial effect on mortality in all subgroups of KRT patients affected by the disease, culminating in elderly KRT patients and in transplant recipients. It is conceivable that, early in the pandemic, hemodialysis centres may have served as important foci of infection. It is of vital importance that in future pandemics the nephrology community will have crisis management and control protocols in place and will be able to act swiftly to increase the safety of their patients and mitigate the damage to their health as much as possible. Recommendations in this direction have been published, and many studies on prevention of COVID-19

in KRT patients are still underway.

The sex, year of start RRT, primary renal disease, and country). Results from this analysis did not differ meaningfully from the main results.

In dialysis and transplant patients with COVID-19 crude and adjusted probabilities of death were studied for age categories (<65 years, 65-74 years and ≥75 years), for men and women, by PRD category, by treatment modality (dialysis versus transplantation) and by country. We used Cox regression analysis to investigate the association of COVID-19 with the probability of death. In COVID-19 patients, we applied Cox regression to adjust for age, sex, PRD, year of start KRT or year of transplant, treatment modality, and country, where appropriate.

All analyses were performed using SAS software version 9.4.

No conflicts of interest were reported Tables   Table 1. Characteristics of KRT patients diagnosed with COVID-19, by treatment modality and country Table 2 . Probability of death in subgroups and risk factors in dialysis patients with COVID-19 Table 3 . 

KJ Jager, A Kramer, NC Chesnaye, and VS Stel contributed to the study design, data collection, data analysis, interpretation, and writing of the paper. All other authors contributed to study design, data collection, interpretation, and writing of the paper. 

Dr Carol Davila

Dutch Renal Registry, Nefrovisie foundation

Austrian Dialysis and Transplant Registry, Department of Internal Medicine IV -Nephrology and Hypertension

Direction Prélèvement Greffe Organes-Tissus

Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension

Unit 1018 team5, Research Centre in Epidemiology and Population Health (CESP)

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Situación de COVID-19 en España a 21 de mayo de 2020

Situación de COVID-19 en España a 21 de mayo de 2020

Cardiovascular and noncardiovascular mortality among men and women starting dialysis

75+, n (%) 1340 (40.8) 1297 n (%)

Other, n (%) 1370 (41.7) 1313 start KRT, median (IQR) 2017

Belgium (French-speaking part)

Probability of death (95% CI)

We would like to thank the patients and the staff of the dialysis and transplant units for contributing the data via their national and regional renal registries. Furthermore, we gratefully acknowledge the following registries and