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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2021  |  Volume : 32  |  Issue : 2  |  Page : 468-480
Severe acute respiratory syndrome coronavirus 2 and risk of inhospital mortality among end-stage renal disease patients with rheumatoid arthritis: A scientific perspective


1 Morbidity and Mortality Review Unit, King Saud University Medical City; Department of Public Health, Research Chair of Evidence-Based Healthcare and Knowledge Translation, College of Medicine, King Saud University, Riyadh, Saudi Arabia
2 Department of Medicine, Faculty of Medicine, Tabuk University, Tabuk, Saudi Arabia

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Date of Web Publication11-Jan-2022
 

   Abstract 


According to the elevated infection mortality risks, the incidence of coronavirus disease 2019 (COVID-19) could be raised in rheumatoid arthritis patients with end-stage renal disease (ESRD). Our objectives are to describe the impact of COVID-19 infection on rheumatoid arthritis patients with end-stage renal disease and to identify the risk of in-hospital mortality, comorbid conditions. and the proper way to deal with this category. It was a retrospective analysis of COVID-19 patients in Saudi Arabia from March 1, 2020 to April 27, 2020 and from May 27, 2020 to August 20, 2020. Of 10,482 patients with COVID-19, 419 had ESRD. We assessed main (in-hospital death) outcomes and secondary (mechanical breathing and residence) outcomes. Patients with ESRD were aged and more comorbid disorders. Rheumatoid arthritis patients with ESRD were aged. ESRD rheumatoid arthritis patients have a higher hospital mortality risk relative to rheumatoid arthritis patients not getting complicated with ESRD (31.7% vs. 25.4%, chances 1.38, and 95% trust range 1.12–1.70). After population and comorbid conditions had changed, the rate of rise stayed the same (changed chances: 1.37, 1.09–1.73). In both the crude and modified study (1.62, 1.26–2.07; vs. 1.57, 1.22–2.02), chances for the period of stay of seven or more days have been higher inside a group than in the non-ESRD group. Old age, respiratory support, lymphopenia, and elevated blood urea nitrogen and low serum ferritin were the independent contributing factors for the in-hospital mortality of ESRD rheumatoid arthritis patients infected with severe acute respiratory syndrome coronavirus 2.

How to cite this article:
El-Malky AM, S. Albalawi YA, Alanazi SM, Saed Albalawi MA, Althobaiti AN, A. Kassarah ZA, I. Alzahrani HA, A. Al-Balawi AS. Severe acute respiratory syndrome coronavirus 2 and risk of inhospital mortality among end-stage renal disease patients with rheumatoid arthritis: A scientific perspective. Saudi J Kidney Dis Transpl 2021;32:468-80

How to cite this URL:
El-Malky AM, S. Albalawi YA, Alanazi SM, Saed Albalawi MA, Althobaiti AN, A. Kassarah ZA, I. Alzahrani HA, A. Al-Balawi AS. Severe acute respiratory syndrome coronavirus 2 and risk of inhospital mortality among end-stage renal disease patients with rheumatoid arthritis: A scientific perspective. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jan 28];32:468-80. Available from: https://www.sjkdt.org/text.asp?2021/32/2/468/335459



   Introduction Top


The disease has been quickly spreading in late 2019 and in Wuhan, China, triggering new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggering the coronavirus disease 2019 (COVID-19).[1],[2] The disease contributed to significant numbers of hospitalization and intensive care unit (ICU) (including well-described pulmonary, neurological, and vascular and renal complications).[3],[4],[5],[6],[7] Understanding the effects of COVID-19-affected rheumatoid patients with and without end-stage renal disease (ESRD) is important because it will help to risk-stratify ESRD patients with such COVID-19 therapies as hospital patients arrive.

The ESRD rheumatoid patients have a dysregulated immune system with severe comorbid disorders such as diabetes mellitus (DM), cardiovascular disorder, and obesity that are already recognized as serious risk factors for COVID-19 disease.[8],[9],[10] ESRD group, also after adaptation for age, ethnicity, and DM, has a rise in annual mortality rates compared with the overall group. The reduced immune response in ESRD is therefore likely to defend against cytokine storm found in the case of extreme COVID-19 infections. In particular, the calculated concentration of inflammatory cytokines has been documented to be lower in the preprinted research published by Ma et al in dialysis patients with COVID-19 than that in other patients.[11] A further aspect that requires consideration is the decreased activity of angiotensin-converting enzyme (ACE) 2, seen in dialysis patients.[12],[13] Alternatively, dialysis patients could be more resistant to SARS-CoV-2 infection as dialysis units are more transmissible and infections have decreased.

To date, there is no systematic report on the effects of ESRD COVID-19 rheumatoid patients. A research from the United States (US) has recently been published and revealed weak outcomes for 59 ESRD patients. Eighteen (31%) had died in the cohort, while six (75%) had died in the subset of patients needing COVID-19. Recent reports by China or Europe on ESRD rheumatoid patients who had obtained COVID-19 have been confined to smaller numbers and single centers.


   Methods Top


Study design and cohort

This was a retrospective observational analysis by the cohort of 1800 beds in Riyadh, Saudi Arabia, a big university medical city. Data from the three leading hospitals utilizing the electronic health record (EHR) service for this analysis were collected. Both adult patients (age of >18 years) who were positive for COVID-19 and hospitalized from March 1, 2020 to April 27, 2020 through checking for polymerase chain reaction were eligible for a nasopharyngeal examination. Patients have been tracked by May 27, 2020. We only included the first hospitalization for patients who had several qualifying hospital admissions. Patients were removed whether they were moved from their treatment system or committed to hospitalization. Before the beginning of the study, the institutional review board of King Saud University Medical City accepted the analysis procedure.

Data cleaning and preparation process

In order to scan for redundant information and incomplete documents, we carried out a document purification protocol before study and undertook scope tests to evaluate outliers and incorrect data. Duplicate documents and outliers were removed.

End-stage renal disease

Diagnosis of ESRD with dialysis dependency was key exposure. The international classification of diseases, 10th revision (ICD-10) code N18.6 was used to describe the ESRD diagnosis. A manual analysis of the patient admission map and consulting observations in nephrology for the main words of the search were done independent ESRD diagnosis by two research investigators (A. M. and A. E.): “ESRD” and “ESKD,” “end-stage renal,” and “end-level kidney.” We confirmed the diagnosis of ESKD by examination of stationary hemodialysis (HD) and peritoneal dialysis (PD) instructions. Further manual charts were checked for those classified as ESRD without inpatient dialysis orders.

We conducted an additional verification to discourage misclassification into the exposed community of nondialysis-dependent kidney transplant recipients. The concept of kidney transplant was described in the following main terms: “kidney transplant,” “renal-treated” [“renal” “renal”, “DDRT” (deceased renal donor)], “LRRT” (living renal transplant), “LURT” (living nonrelated renal transplant), and “LDT,” using ICD-10 code T86.1, T86.11, T86.13, T86.19, and Z94.0 and manually charged adjudication by means of a chart review. Nephrology COVID-19 consortium has been awarded for the diagnosis of kidney transplantation.

Inclusion and exclusion criteria

We included all hospital admissions for patients with COVID-19 having rheumatoid arthritis together with renal disease. Comorbidities derived from the patients were abstracted from physician documentation on the EHRs. Patients were classified into two categories based on the presence or absence of ESRD: (i) absent and (ii) present. Outcomes were analyzed in patients with chronic kidney disease (ESRD) versus those without kidney disease. Body mass index (BMI) ≥30 kg/m2 was used to identify obesity. Race/ethnicity was classified into one of the four categories: Caucasian, African American, Hispanic ethnicity regardless of race, and others.

Severe disease was defined as clinical pneumonia with a respiratory rate >30 breaths/min or oxygen saturation <90% on room air, per the World Health Organization guidelines. Acute respiratory distress syndrome was defined as the ratio of arterial oxygen partial pressure to fractional inspired oxygen of ≤300 on a positive end-expiratory pressure ≥5 cm of water, as per the Berlin guidelines. Mortality was defined as in-hospital death. Need for aggressive oxygen supplementation with high-flow nasal cannula, noninvasive positive pressure ventilation, or mechanical ventilation was defined as high oxygen support.

Rheumatoid arthritis was defined as pain and stiffness in multiple joints, clinically apparent joint swelling, fatigue, weight loss, and low-grade fever. Serological tests, positive RF, positive ACPA, and positive acute phase reactants.

Almost all patients had stable functional status measured accordingly by DALYs, the scale used to measure health state is inverted to a “severity scale,” whereby “0” equates perfect health and “1” equates death. The weight factors are age adjusted to reflect social preference toward life years of a young adult (over an older adult or young child). Furthermore, they are discounted with time, thus favoring immediate over future health benefits.

We excluded any patient had a score of DALYs beyond 0.06–0.6. We excluded multiple admissions for one patient: only the first hospital episode was included (n = 373). Age <18 years (n=106). Admitted to inpatient obstetric service (n = 287). Hospital transfers out of the health system (n = 384). We exclude also patients with other comorbidities; diabetics (n = 171), cardiac patients (n = 123), and patients diagnosed with different neoplasms (n = 117) [Figure 1].
Figure 1: Flow chart of the study.
COVID-19: Coronavirus disease 2019, RA: Rheumatoid arthritis, ESRD: End-stage renal disease.


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Outcomes

In-hospital mortality was the main outcome. Mechanical ventilation and hospital stay were the secondary outcomes.

Variables assessed

Data have been gathered on patient group, comorbidity base history, home prescriptions, dialysis-specific data elements, and hospital admission records. Due to the personal records and admission reunion of providers joined the past, the comorbid disorders and home prescriptions were known. The system of dialysis and vascular access to dialysis was developed from the entry order of the hospital dialysis. Within 48 h of hospital admission, we gathered information on hospital admission such as ICU stay, mechanical ventilation, and vasopressor assistance and baseline laboratory test results. In non-traditional clinics and units, several new ICUs were installed owing to the COVID-19 pandemic. The need of intrusive mechanical ventilation, the need of vasopressor or inotropic assistance, the maintenance of an ICU service, or in a known ICU position was thus described as one of the following stays.


   Statistical Analysis Top


For naturally distributed continuous measurements, intermediates and interquartile ranges of distorted constant measures, and proportions of categorical measures, we conducted descriptive statistics. Fisher’s reliable experiments were used to evaluate categorical variables and Kruskal–Wallis nonparametric experiments with continuous variables. We conducted a uniform and multivariate logistical analysis independently for each outcome to assess whether ESRD diagnosis was correlated with hospital outcomes of death (primary outcome), mechanical ventilation, and/or stay period of €7 days (secondary outcomes). We have increasingly been adapted to demographics such as age, sex, and race/ethnicity, accompanied by demographic change as well as comorbid conditions such as DM, hypertension (HTN), coronary disease, heart problems and peripheral vascular disease, and breathing disorders (asthma and obstructive chronic pulmonary disease).

We conducted many predefined sensitivity analyses to assess the strength of our findings for the principal outcome (in-hospital death). We limited our study to patients who died or were released alive in the primary analysis. The sensitivity study involved patients who had yet hospitalized to compare the mortal danger of ESKD patients [174 patients (1.7% of the cohort)] with and without ESRD. We replicated the formula for regression by assuming that those remaining in hospital were all deceased and another by assuming that those remaining hospitalized were released alive.

We performed stratified research to independently examine the risk factors for death in ESRD and non-ESRD subgroups and hypothesize the discrepancy between the risk factors for death and the level of risk factors. Low hemoglobin levels, low serum albumin, and high blood urea nitrogen (BUN) were shown to be mortality risk factors for those without EBLDs but not a standard mortality risk for those without ESRD in the absence of the COVID-19 disease. Two related logistic regression models have been conducted in each ESRD and non-ESRD subgroup. In Model 1, we used the following variables: age, race/ethnicity, BMI, DM, HTN, usage of ACE inhibitors or angiotensin receptor II blockers (ARBs), and cardiovascular disease (coronary artery sickness, heart failure or peripheral vascular diseases, and cancan disease). The variables selected were calculated a priority based on established mortality risk factors in the general population and for patients with ESRD. The categorical component comprised BMI of three subweight categories (BMI <18.5 kg/m2), average weight (BMIs of 18.5–29.9 kg/m2), and obesity (BMI = 30 kg/m2) as well.

In order to normalize the distribution, the serum ferritin amounts were transformed log and log transformed values in the models were used. Model 2 had variables identical to Model 1, but laboratory test values were omitted. Model 2, which contains clinic properties and characteristic of disease seriousness (mechanical breathing and vasoactive medicines), is accepted as significant risk factors for inhospital mortality.

Missing data

In order to take account of missing data in regression models, a multiple imputation of the chained equations was rendered using the predictive mean of 50 imputations and 20 iterations (Mice R kit, 3.9.0 version Contributed @Mingyang-Cai, @gerkovink (#408)). The estimation and standard error models 1 and 2 were estimated by the Rubin rules. We did not pertain to a multiple imputation for this variable nor did we include it in any one of the models, with D-dimer had considerable messiness with 37% missing data in the non-ESRD community and 42% missing in the ESRD community. Other than D-Dimer for all the missing results including BMI, ACE-inhibitor/ARB use, simple laboratory tests and C-reactive protein (CRP), and ferritin inflammatory markers have been multilevelly impetrated.

Both the statistical analyses were double-sided and statistically important was the P-<0.05. All analyses were done with R version 3.6.3. (R Mathematical Computation Foundation, Wien, Austria). This research preceded “Recording experiments conducted using the observational regular health data obtained (RECORD)” in the EQUATOR monitoring guidelines.


   Results Top


Six hundred and thirty-five hospital admissions to health system hospitals with a diagnosis of COVID-19 present on admission or made during the hospitalization. Of these, 482 patients were diagnosed as rheumatoid arthritis and included into the final cohort and were followed through May 27, 2020. Of the included cohort, 450 were discharged home, 11 died, and 174 were still admitted. Within the cohort, 246 patients were discharged home in the non-ESRD group and 236 in the ESRD group. Rheumatoid arthritis patients with ESRD were treated in the hospital for COVID- 19, of whom 225 were on HD and 11 were on PD [Table 1]. 82.1% of individuals have permanent vascular connection to either arteriovenous (AV) graft or AV fistula, and 17.9% have a catheter of HD. [Table 1] offers the baseline functionality contrasting patients with and without ESRD at admission to hospital. In the two classes, ESRD patients were aged, black, lower BMI, and Medicare were more likely to be the principal assurance organization. In comparison, ESRD patients had more home medicines and had a higher percentage of antihypertensive, antiplatelet, anticoagulant, and antistatin patients.
Table 1: Demographic and clinical characteristics of patients with and without end-stage kidney disease.

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The proportion of comorbid DM, HTN diagnoses, coronary artery disease, peripheral vascular disease, and cardiac failure was also higher in patients obtained from ESRD. In both classes, the seriousness of the disease in terms of stay with ICU and vasopressor usage was comparable during the hospital course. In comparison, [Table 1] indicates in the hospital drugs used for the care of COVID-19 of the two classes.

In ESRD patients, mortality in hospitals was greater than that of ESRD patients (31.7% vs. 25.4%; chances 1.38, 95% CI: 1.12–1.70%). The odds of hospital mortality stayed higher for the ESRD community relative to that for the non-ESRD [adjusted odds ratio (OR): 1.37, 95% confidence interval (CI): 1.09–1.73] [Table 2] after modification of baseline populations and comorbid conditions. The key results at patient level are seen in [Table 2] (expired or live).
Table 2: Odds ratios for in-hospital outcomes among patients with and without end-stage kidney disease (the group without end-stage kidney disease is the reference).

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Mechanical ventilation ratios were comparable in ESRD patients to those without ESRD [89 (21.2%) vs. 2076 (20.6%)]. The ESRD category did not have substantially higher mechanical ventilation chances in all crude analysis as well as adjusted analysis than non-ESRD groups (OR 1.07, 95% CI: 0.84–1.36) versus (adjusted 0.97 OR: 0.75–1.25, 95%). The median stay time was higher for the ESRD community compared with the non-ESRD community for patients released alive [7.7 days (IQR 4.8–13.4) versus 6.1 days (IQR 3.4–10.8), respectively]. The chances of stays of ~7 days is better in the category of the ESRD relative to the group of non-ESRD (OR 1.62, 95% of the CI: 1.27–2.06) in the crude study. The modified OR was 1.57, 95% CI: 1.22–2.02 after the adaptation for baseline groups and comorbid conditions.

In ESRD patients and others without ESRD, we have reviewed different clinical aspects as probable risk factors for in-hospital mortality [Table 3], [Table 4] and [Figure 2]. The independent risk factors for mortality at in-hospital after covariate adjustment in model 1 for patients with ESRD were elevated age, male sex, cardiovascular disease, cancer, mechanical ventilation, high blood urea (BUN), low-albumin (CRP) and high-log transformed serum ferritin. The risk factors were elevated age and lower BUN. A reduced probability of mortality in the hospital was correlated with the diagnoses of hypertension and the use of ACE or ARB [Table 3]. The independent risk factors for death in a hospital in patients without ESRD were strengthened in age, men’s sex, and mellitus, as well as cardiovascular disease, cancer that involved mechanical ventilation and vasoactive treatment after adapting to the variables in model 2 [Table 3]. Again, a decreased chance of in hospital mortality was linked with the hypertension and the usage of ACE-inhibitors or ARB.
Figure 2: The risk factors of in-hospital death, by ESKD status.
ACE-i: Angiotensin converting enzyme inhibitor, ARB: Angiotensin receptor blocker, BMI: Body mass index, ESKD: End-stage kidney disease.


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Table 3: Univariate and multivariate logistic regression analyses of risk factors associated with in-hospital death in patients without end-stage kidney disease.

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Table 4: Univariate and multivariate logistic regression analyses of risk factors associated with death among patients with end-stage kidney disease.

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Increased age, mechanical ventilation, and lymphopenia required by elevated BUN and high-log transformed serum ferritin were independent risk factors of death in hospital among patients with ESRD. Model 2 raised old age, involving artificial breathing and vasoactive drug usage, with independent risk factors for mortality in the hospital. In the two models (OR: 0.47, 95% CI: 0.22–0.98 and OR 0.48, 95% CI: 0.24–0.96, respectively) ([Table 4] and [Figure 2], the probability of mortality for ESRD was slightly lower in patients) (Model 4 and [Figure 2], respectively).

By compared in-patient mortality rates in the ESRD community with those of non-ESRD, the sensitivity evaluation includes the presumption that the findings did not greatly impact all remaining in patient who either sustained mortality or all had been discharged alive. These susceptibility analyses, independently, have not dramatically modified the outcomes of risk factors for mortality in ESRD and non-ESRD cohorts. Additional [Table 4] displays the odds ratios of in-hospital mortality of the manually ventilated patients with or without ESRD.


   Discussion Top


Among COVID-19 patients, we analyzed the physiological features, effects and risk factors for death in ESRD. In contrast with the nondialysis group, the main result was that the probability of mortality in hospital is substantially increased for ESRD patients. In comparison, the criterion for mechanical ventilation did not vary greatly between patients with or without ESRD.

Dialysis patients are considered to have a much greater mortality rate relative to the general population for a long period. In hemodialytic patients, the predicted five-year survival rate is only 42.0% in the US[14] and a risk comparable to different categories of cancer.[15] As a consequence of this, it would be intuitive for patients with COVID-19 to find a substantially elevated chance of in-hospital death in comparison to patients with non-dialysis. The greater danger found in the ESRD cohort, however, was not changed by the modification of comorbidities. This means that the host reaction to infection can be associated with other un-scanned features of ESRD patients.

The risk of infection and infection-related death is increased in patients with ESRD. The higher risk of infections is presumably due to a dysregulated immune system because the uremic environment is correlated with both inborn and adaptive immunity disruptions. Changes in neutrophils, the natural killer cells, macrophages, T and B lymphocytes, and inflammation from the dialysis phase caused by the host immunity itself are contributing to a decline.[16],[17] An host immunity infection is the second most frequent cause of death for dialysis patients.

Of the 419 ESRD-infected patients, 133 (31.7%) were considered to be dead with COVID-19. Previous research also investigated the mortality incidence in smaller patient units.[18] Wuhan University pre-print findings,[19] COVID-19 positive HD patients, of whom six (16.2%) died.[20] A further Wuhan pre-print study from Alberici et al. The percentage of mortality of patients was 13.3% (12 of 90 patients with infection reported or suspected). The Brescia Renal COVID Task Force in Italy recorded 24 deaths (42.1%) of 57 HD patients.[21] Our results are comparable to those of the European Centers and the latest one-center US data[18] which may be associated with the reports from patients who obtained COVID-19 infects from the Brescia Renal COVID Taskforce.[18] This is a comparable analysis with outcomes from the European Center and the latest single case US data.[18]

In our research, we observed that independent mortality risk factors were largely identical in those without ESRD among ESRD patients. A notable distinction in the usage of HTN or ACE inhibitors or ARBs was that HTN and patients without ESRD were major death-protective variables. Several articles recommend a preventive impact on lungs and heart damage from COVID-19, but the issue has remained unsettled.[22],[23] Provided the frequently administered HTN inhibitors, RAAS inhibitors could be postulated to have a safety effect for those with HTN. RAAD-19 patients are often administered as a RAAS inhibitor and a RAAS inhibitor.[22],[23]

Inflammatory markers, including serum ferritin, were correlated with magnitude of COVID-19.[24],[25] Moreover, for both non-ESRD and ESRD categories, we have observed that serum ferritin is a contributing factor in patient mortality [Table 3] and [Table 4]. In a trial, an improvement of >200% in serum ferritin was shown to be a potentially valuable screening method for COVID-19 contaminated dialysis patients, as a method of extreme screening for COVID-19 in ESRD patients could potentially be used in further testing.

To date, it has by far been the largest cohort of hospitalized COVID-19 patients, contrasting losses in a varied patient group of patients with and without ESRD. To enhance the validity of this data, two independent reviewers for ESRD exposures have defined operational meanings for exposures, covariates, and effects and have a comprehensive assessment. In addition, different methodological methods and sensitivity analysis improve the conclusions of the research more, in order to reduce uncertainty. The research drawbacks involve the retrospective empirical nature, which makes the probability of missing variables which could be significant factors in understanding them. Since in other experiments, BMI was linked to the risk factor of in-hospital mortality of the lack of BMI evidence was reduced to 10%. However, through multiple imputation, we tried to manage the lack of BMI info. Furthermore, the ESRD sample could also be reasonably weak in order to identify other statistically relevant mortality risk factors considering the greater scale of the analysis compared to other studies. The only two medications linked to better ODS results for COVID-19,[26],[27] As proof was identified for these two medicines after the rise in COVID-19 cases in our health-care system, a limited proportion got the two medicines. In the non-ESRD group, remdesivir was obtained by only 51 patients (0.5%) and none of the patients in the ESRD group. Dexamethasone was received in fewer than 3% of patients in both categories [Table 1].


   Conclusion Top


We found that mortality rate was higher among elderly patients on respiratory support. Infected patients with rheumatoid arthritis and ESRD who had; lymphopenia, elevated BUN, and low serum ferritin were more prone for the higher in-hospital mortality. The probability of mortality was lower for; young age, good respiratory function, and regulated laboratory results. The findings indicate that more study is required as well as maintaining diligent inspection and infection management procedures in the COVID-19 risked community in the ESRD.

Conflict of interest: None declared.



 
   References Top

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Correspondence Address:
Ahmed M El-Malky
Morbidity and Mortality Review Unit, King Saud University Medical City, Riyadh
Saudi Arabia
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DOI: 10.4103/1319-2442.335459

PMID: 35017341

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