key: cord-0837320-nb4od9cp
authors: Carriazo, Sol; Mas-Fontao, Sebastian; Seghers, Clara; Cano, Jaime; Goma, Elena; Avello, Alejandro; Ortiz, Alberto; Gonzalez-Parra, Emilio
title: Increased one-year mortality in hemodialysis patients with COVID-19: a prospective, observational study
date: 2021-12-20
journal: Clin Kidney J
DOI: 10.1093/ckj/sfab248
sha: 673a4f944b012ef110b858f04ecf0f0472ec8983
doc_id: 837320
cord_uid: nb4od9cp

BACKGROUND: Dialysis confers the highest risk of COVID-19 death among comorbidities predisposing to severe COVID-19. However, reports of COVID-19-associated mortality frequently refer to mortality during the initial hospitalization or first month after diagnosis. METHODS: In a prospective, observational study, we have analyzed the long-term (one year follow-up) serological and clinical outcomes of 56 hemodialysis patients that were infected by SARS-CoV-2 during the first pandemic wave. COVID-19 was diagnosed by a positive PCR test (n = 37) or by the development of anti-SARS-CoV-2 antibodies (n = 19). RESULTS: After over one year of follow-up, 35.7% of hemodialysis patients infected by SARS-COV-2 during the first pandemic wave had died, 6 (11%) during the initial admission, and 14 (25%) died in the following months, mainly within the first 3 months after diagnosis. Overall, 30% of patients died from vascular causes, and 40% from respiratory causes. In adjusted analysis, positive SARS-CoV-2 PCR test for diagnosis (HR 5.18 [1.30–20.65] p = 0.020), higher baseline C reactive protein levels (HR 1.10 [1.03–1.16] p = 0.002) and lower hemoglobin levels (HR 0.62 [0.45–0.86] p = 0.005) were associated with higher one-year mortality. Mortality in the 144 patients that did not have COVID-19 was 21 (14.6%) over 12 months [hazard ratio for death for COVID-19 patients 3.00 (1.62–5.53), log-rank p = 0.00023]. Over the first year, the percentage of patients having anti-SARS-CoV-2 IgG decreased from 36/49 (73.4%) initially to 27/44 (61.3%) at 6 months, and 14/36 (38.8%) at 12 months. CONCLUSIONS: The high mortality of hemodialysis patients with COVID-19 is not limited to the initial hospitalization. Defining COVID-19 deaths as those occurring within 3 months of a COVID-19 diagnosis may better represent the burden of COVID-19. In hemodialysis patients, the anti-SARS-CoV-2 IgG response was suboptimal and short-lived.

. A meta-analysis that included 3,867,367 patients from 12 studies, reported that the mortality rate was higher among CKD patients with COVID-19 infection than among CKD patients without COVID-19 infection: OR 5.81 (95% CI 3.78-8.94, P < 0.00001, I2 = 30%) (5) . Reasons associated to this increased risk are not completely elucidated. Kidney failure is considered a immunosuppressed state characterized by altered innate and adaptative immunity (6, 7) . The combination of a systemic pro-inflammatory state (8) , impaired immune response and high cardiovascular risk (9) , might contribute to this increased risk of severe COVID-19.

Reports of COVID-19-associated mortality frequently refer to mortality during the initial hospitalization or 28 days after diagnosis (10) (11) (12) . We previously reported an

overall mortality rate of 10% in hemodialysis patients with COVID-19 during hospitalization in the first pandemic wave starting in March 2020 (13) . We further reported that 17% of SARS-CoV-2 PCR+ hemodialysis patients failed to develop detectable antibodies against SARS-CoV-2 by 3 months of infection (14) .

We have now analyzed the long-term (one year of follow-up) serological and clinical outcomes of hemodialysis patients that were infected by SARS-CoV-2 during the first pandemic wave and survived hospitalization or the initial COVID-19 episode and present data on overall 12-month mortality from the diagnosis of COVID-19.

In a previous retrospective observational study (13) Additional laboratory tests at baseline included hemoglobin (Hb), interleukin-6 (IL-6), ferritin, C reactive protein (CRP) and D-dimer levels, and lymphocyte count.

Furthermore, the weekly-doses of erythropoiesis-stimulating agents (ESA) and erythropoietin resistance index (ERI) were also included in the analysis. ERI was calculated by dividing the weekly body-weight-adjusted epoetin dose by the hemoglobin concentration. 

A total of 56 hemodialysis patients with a COVID-19 diagnosis during the first wave (March-May 2020) were prospectively followed and anti-SARS-CoV-2 IgG

antibodies were evaluated at 3, 6, 9 and 12 months. The primary clinical endpoint was all-cause death. Deaths were separated into those occurring during the first hospitalization and those occurring later. As a sensitivity analysis, early deaths were defined as those occurred within the first 30 days after diagnosis of COVID-19. The secondary endpoint was a composite of hospitalization from any cause and events requiring therapeutic intervention even if there was not hospitalization. During the follow-up period, Spain suffered successive COVID-19 waves (Suppl Figure 1) . Thus, re-infection was theoretically possible.

At the end of follow-up, 9/36 survivors had been vaccinated from January of 2021 onwards, starting by the elderly. Hemodialysis patients not yet vaccinated because of age were vaccinated between April and May 2021. The type of vaccine administered was decided by health authorities according to Spanish health authorities' guidelines (mRNA vaccine) and to availability by regional health authorities: all 9 patients received BNT162b2 (Pfizer-Biontech).

Data are presented as medians and interquartile ranges (IQR) except when otherwise specified. Normality of the data was assessed using the Kolmogorov-Smirnov Table 3) .

Over the first year, the percentage of patients who had anti-SARS-CoV-2 IgG 

experienced re-infection, the second patient had been vaccinated before the end of the follow-up period and the third had not been vaccinated, whether this patient had experienced re-infection is unclear). In total, 9/32 patients were vaccinated before the end of the follow-up period: the 2 just described, 4 who were positive throughout the follow-up, and 3 that never showed positive antibodies, even after vaccination.

The present study has several main findings that may impact on care of comorbidities or other factors (17, 18) . In Madrid, mortality rates during the acute episode (defined as during hospitalization or within 28 days after diagnosis) in hemodialysis patients were 16.2% (19) to 30.5% (20) . In our unit, mortality during the initial admission was 11%. However, an unexpectedly high number of deaths was observed over 1 year of follow up, as 36% of COVID-19 hemodialysis patients died.

This was higher than the historical annual mortality at our center of 9.2% per year (21) , and higher than mortality of hemodialysis patients in Spain which has been relatively stable (range 14.1 to 16.8%) from 2007 to 2019(15). Above all, the overall 12-month mortality in COVID-19 patients was higher than the mortality of hemodialysis patients not diagnosed of COVID-19 in our unit. This population represents the most appropriate controls, as they were exposed to the same pandemic-associated restrictions and potential limitations in access to healthcare. Although a higher mortality would be expected for a potentially lethal condition, the higher mortality was observed for up to 3 months after diagnosis, illustrating a persistently high mortality risk. Only after this point the mortality in COVID-19 patients ran in parallel to that in non-COVID-19

patients.

COVID-19 can have long-term consequences (22, 23) . The most visible manifestations are symptoms such as asthenia or brain fog. However, in hemodialysis patients, this may also include an increased mortality rate. The most frequent non-lethal and lethal episodes were related to ischemia or bleeding. In this regard, persistently dysregulated hemostasis has been observed following acute COVID- 19 of anti-SARS-CoV-2 antibodies is a cause of concern regarding the intensity and duration of the response to vaccination. Multiple studies are currently ongoing to define the immune response to SARS-CoV-2 vaccine in hemodialysis and the optimal vaccination schedule. Patients with kidney failure have significantly weaker antibody response than controls (33, 34) .

Factors associated with 3-month and one-year mortality included low Hb and high CRP levels. Anemia has been also associated with mortality in non-hemodialysis patients with COVID-19 (35) (36) (37) (38) . In a prospective study, the presence of Hb <13 g/dl in hospitalized males and <12 g/dl in females with COVID-19 was association with mortality (35) . The association between anemia and inflammation is well recognized (39) . In anemic patients, low Hb levels may impair further impair tissue oxygenation (37) , especially in patients with respiratory compromise (36) .

Hemodialysis patients have a high prevalence of anemia, related to both erythropoietin deficiency and erythropoietin resistance caused by inflammation, iron deficiency and others (40) Resistance to erythropoiesis stimulating agents (ESA) and the associated requirement for higher ESA doses have been associated to mortality in hemodialysis patients (41, 42) . Although we did not find an association between ERI and mortality, the study size was small to draw definite conclusions.

Some limitations should be acknowledged. This was a single center study with a 

All data from the study is available upon request 

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ADPKD: autosomal dominant polycystic kidney disease. Hb: hemoglobin, IL-6: interlukin-6, CRP: C reactive protein, EPO: erythropoietin, ERI: erythropoietin resistance index