key: cord-311129-5p9mf37g
authors: Yang, Dong; Xiao, Yushuo; Chen, Jian; Chen, Yuchen; Luo, Pengcheng; Liu, Qiaomei; Yang, Chen; Xiong, Mingrui; Zhang, Yu; Liu, Xinran; Chen, Hong; Deng, Aiping; Huang, Kun; Cheng, Biao; Peng, Anlin
title: COVID-19 & Chronic Renal Disease: Clinical characteristics & prognosis
date: 2020-08-25
journal: QJM
DOI: 10.1093/qjmed/hcaa258
sha: 
doc_id: 311129
cord_uid: 5p9mf37g

BACKGROUND: Patients on dialysis were susceptible to COVID-19 and were prone to severe clinical characteristics after infection; acute kidney injury was related to mortality in COVID-19 cases. Limited is known about the characteristics of COVID-19 patients with end-stage renal disease not requiring renal replacement therapy (RRT). AIM: Evaluate clinical characteristics, course and outcomes of COVID-19 patients with chronic kidney disease (CKD) who did not require RRT and those on dialysis. DESIGN: A two-center retrospective study. METHODS: 836 adult patients with COVID-19 (24 CKD not on dialysis; 15 dialysis-dependent CKD) were included. The study includes no patients with renal transplantation. Risk factors were explored. RESULTS: CKD not requiring RRT is an independent risk factor for in-hospital death [adjusted OR (aOR) 7.35 (95%CI 2.41-22.44)] and poor prognosis [aOR 3.01 (95%CI 1.23-7.33)]. Compared to COVID-19 cases without CKD, those with CKD not requiring RRT showed similar percentage of initial moderate cases (75.00% vs. 73.65%) but higher incidence of in-hospital neutrophilia (50.00% vs. 27.30%) or death (50.00% vs. 9.03%). The odds ratio of dialysis associated to mortality in CKD patients was 2.00 (95%CI 0.52-7.63), suggesting COVID-19 patients with dialysis-dependent CKD were at greater risk of in-hospital death. For COVID-19 patients with CKD not requiring RRT, statins reduced the risk of neutrophilia [OR 0.10 (95%CI 0.01-0.69)] while diuretics increased the risk of neutrophilia [OR 15.4 (95%CI 1.47-160.97)], although both showed no association to mortality. CONCLUSION: COVID-19 patients with CKD presented high incidence of neutrophilia, poor prognosis and in-hospital death, with dialysis patients being more vulnerable.

Coronavirus disease 2019 (COVID- 19) , which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 1 primarily manifests as an acute respiratory illness, but it can affect multiple organs including kidney; 2 in cases COVID-19 may also be presented asymptomatically without organ manifestations. 3 Kidney was reported with high expression of ACE2, an important target of SARS-CoV-2; 4,5 moreover, SARS-CoV-2 has been identified in urine and kidney of COVID-19 patients, suggesting kidney as a target of this coronavirus. 6, 7 Amounting evidence has indicated correlation between kidney abnormalities and COVID-19.

Acute kidney injury (AKI) occurred in 5.1% of 701 COVID-19 patients, and the risk of mortality increased 4-fold among patients with stage 3 AKI. 8 COVID-19 patients with renal involvement showed higher overall mortality than those without (11.2% vs.1.2%). 9 Patients receiving dialysis therapy were more vulnerable to SARS-CoV-2, and those who infected may present worse clinical characteristics than general COVID-19-infected population. 3, 10, 11 The morbidity of COVID-19 in 7154 patients undergoing hemodialysis was 4 times higher than that of the general population during the same period. 3 Of 36 hospitalized maintenance hemodialysis patients from Spain who were diagnosed with COVID-19, 50% underwent radiological worsening during the first week after admission and 30.5% died, 10 and high mortality (41%) was also reported in another cohort from Italy. 11 CKD was among common comorbidities in COVID-19 patients. [12] [13] [14] However, when it comes to the specific clinical characteristics of COVID-19 patients with underlying CKD not requiring renal replacement therapy (RRT), much remains unclear. 7 G3-G5 and were on dialysis. Patients not requiring RRT at admission did not receive RRT during hospitalization.

All clinical investigations were conducted in accordance with the guidelines of the Declaration of Helsinki. The Research Ethics Commissions of both hospitals approved this study [ -76 (April 29, 2020 ) and KY2020-20 (March 8, 2020)] and granted waiver of informed consent from study participants due to the study's retrospective design.

The demographics, baseline characteristics, laboratory findings, treatment, and outcome data were extracted from electronic medical records and reviewed by co-author Dr. Luo and two other physicians (Drs. B. Shu and G. Li). Estimated glomerular filtration rate (eGFR) was calculated by the CKD-EPI equation. 18 COVID-19 were defined as 4 grades, 16 this cohort includes moderate, severe and critical cases. Fever was defined as axillary temperature of at least 37.3°C.

Poor prognosis included progress to severe or critical illness, and in-hospital death.

Lymphopenia was defined as number of lymphocytes <1.0 ×10 9 /L, neutrophilia was defined as neutrophil counts ≥7.5 ×10 9 /L.

Categorical and continuous variables were respectively described as number (%) and median [ COVID-19 cases on admission (75.00% vs. 73.65%, P = 1.000), which were much higher than the percentage of initial moderate cases (40.00%) in COVID-19 patients with dialysis-dependent CKD. However, in-hospital mortality (50.00% vs. 66.67%, P = 0.343) and poor prognosis rate https://mc.manuscriptcentral.com/qjm 9 (83.33% vs. 80.00%, P = 1.000) of CKD cases not on dialysis vs. dialysis cases were similar, and were all significantly higher than those of COVID-19 patients without CKD (in-hospital mortality, 9.03%; poor prognosis rate, 39.40%; Table 1 ).

Compared to COVID-19 patients without CKD, the values of D-dimer and neutrophils of COVID-19 patients with CKD not on dialysis were higher, and lymphocytes and hemoglobin were lower ( Table 2 ). Dialysis patients with COVID-19, comparing to the CKD cases not requiring RRT, suffered from even severe kidney abnormalities, anemia, and infection, and showed abnormally increased creatine kinase and lactate dehydrogenase (LDH) on admission (Table 2) .

The percentages of initial critical cases (33.33% vs. 3.14%, P = 0.016) were higher in COVID-19 patients with CKD not on dialysis than those without CKD in <65 group (Supplementary Table   S1 ). In ≥65 group, COVID-19 patients with CKD not on dialysis showed higher prevalence of poor prognosis than those without CKD (Supplementary Table S1 ).

Men accounts for the majority of COVID-19 cases with CKD not requiring RRT (75%) and of those on dialysis (66.67%). Within male but not female COVID-19 patients, CKD cases not on dialysis vs. cases without CKD had significantly higher poor prognosis rate, larger percentage of hypertension and diabetes, and lower albumin (Supplementary Table S2 ). In addition, the https://mc.manuscriptcentral.com/qjm 10 differences of laboratory findings between COVID-19 patients with CKD that on and not on dialysis were overall age-and gender-independent.

CKD is an independent risk factor for either in-hospital death or poor prognosis (Supplementary (95%CI 1.23-7.33), P = 0.016]. Besides, patients ≥65 years old and men were prone to higher mortality, while higher initial neutrophils and CRP were associated to increased odds of in-hospital death and poor prognosis among the study population (Table 3) . Lineal models showed similar results when adjusting for study center (Supplementary Table S4 ).

Univarible analyses suggested that low initial lymphocytes [OR 0.11 (95%CI 0.02-0.73), ×10 9 /L, P = 0.022] was significantly associated to higher odds of in-hospital death within COVID-19 patients with CKD (Supplementary Table S5 ). We further analyzed the incidence of in-hospital lymphopenia or neutrophilia that associated with cytokine storm and COVID-19 severity. 2, 19 Patients with CKD are prone to be lymphopenic. At admission, the proportion of patients presenting lymphopenia was 43.77% amongst those without CKD, and 71.79% amongst those with CKD (62.50% of CKD cases not requiring RRT and 86.67% of dialysis cases). During hospitalizaition, 51.57% of COVID-19 patients without CKD, and over 90% of those with CKD https://mc.manuscriptcentral.com/qjm 11 (95.83% of CKD cases not requiring RRT and 93.33% of dialysis cases) underwent lymphopenia.

Moreover, the prevalence of in-hospital neutrophilia was smaller in COVID-19 patients without CKD (27.30%) than in CKD cases not requiring RRT (50.00%) and dialysis cases (46.67%) (Supplementary Table S6 ).

Univariable regression among COVID-19 patients with CKD showed the odds ratio of dialysis associated to mortality was 2.00 (95%CI 0.52-7.63, P = 0.310; Supplementary Table S5), suggesting COVID-19 patients with dialysis-dependent CKD were at greater risk of in-hospital death than those with CKD not on dialysis. Notably, one week after admission, worsening changes in neutrophils and LDH were observed in COVID-19 patients with dialysis-dependent CKD, but not in those with CKD not requiring RRT (Supplementary Figure S1 ). For both groups, no significant differences were observed between initial and one-week-after-admission test results in other laboratory indices (Supplementary Figure S2 ). On day 7 after admission, non-survivors vs. survivors with CKD not requiring RRT showed significantly lower concentration of platelets and elevated level of creatine kinase (Table 4 ). For dialysis patients with COVID-19, lymphocytes level on admission were significantly lower in non-survival group than in survival group (Table 4 ). Other one-week-after-admission laboratory findings were provided in Supplementary Table S7 .

Medications https://mc.manuscriptcentral.com/qjm Among COVID-19 patients with CKD not on dialysis, usages of glucocorticoid, antibiotics, blood glucose-lowering drugs, statins, diuretics and calcium antagonists showed no significant difference between survivors and non-survivors (Table 4 ). Univariable regression suggested that most of the analyzed medications had no association with in-hospital mortality, except for usage of beta blocker which was a risk factor, however, whether this was due to effect of beta blocker or to characteristics of the patients for whom it was prescribed is unclear (Supplementary Table   S8 ). None of the 3 patients with CKD not requiring RRT who were taking angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker, which may increase the level of ACE2, 20 underwent in-hospital neutrophilia or death (Table 4 ). In addition, among Table S9 ].

Information about patients with CKD not requiring RRT who infected with COVID-19 is limited.

This two-center retrospective study identified that CKD not requiring RRT is an independent risk factor for in-hospital death and poor prognosis of patients with COVID-19 (Table 3) , which is consistent to previous meta-analyses revealing the association of CKD and severe COVID-19 illness. 14, 21 Besides, age ≥65 years old, higher neutrophils, CRP and men were associated to https://mc.manuscriptcentral.com/qjm 13 higher mortality, echoing to previous reports regarding COVID-19. 22, 23 The incidence of fever on admission were lower in COVID-19 patients with either CKD not requiring RRT or dialysis-dependent CKD than in those without CKD (Table 1) , and similar findings were observed in dialysis population, which may be related to their reduced immune function. 3,10,24 COVID-19 patients with CKD not requiring RRT vs. those with dialysis-dependent CKD presented overall less severe clinical features, however, no significant difference in poor prognosis rate or in-hospital mortality was identified between these two groups, which may be partly attributed to the older age of the CKD population who were not on dialysis (Table 1) .

Although patients with CKD not requiring RRT, compared to patients without CKD, had similar proportions of moderate cases on admission, they showed significantly higher incidence of in-hospital death and poor prognosis (Table 1 ). This may be explained by our findings that lymphopenia and neutrophilia, which were associated to cytokine storm as well as worse clinical progress in COVID-19 cases, 19,23 occurred more commonly in patients with CKD not requiring RRT than in those without CKD (Supplementary Table S6 ). Notably, among CKD cases not requiring RRT, non-survivors comparing to the survivors presented significantly increased creatine kinase after one-week hospitalization (Table 3) , suggesting worse multi-organ damage which also relate to inflammation. 25, 26 These findings together indicated that the disease tend to progress to more severe illness in COVID-19 patients with CKD not requiring RRT, and in clinical management of this kind of patients, attention needs to be paid to laboratory parameters relating to inflammation, such as lymphocytes, neutrophils and creatine kinase.

https://mc.manuscriptcentral.com/qjm 14 After 7-day hospitalization, patients on dialysis, but not those with CKD requiring no RRT, presented significant increases in LDH and neutrophils, indicating they were prone to more severe status. In addition, lymphopenia was common in dialysis patients, and non-survivors in CKD patients on dialysis presented significantly lower lymphocytes on admission than survivors, echoing to another study on dialysis patients which suggested lymphopenia and high LDH at 7 days after clinical onset as predictors of mortality. 10 Interestingly, although showing no association with mortality, usage of diuretics increased the risk of in-hospital neutrophilia for patients with CKD and COVID-19 who were not on dialysis;

whereas statins reduced the risk of in-hospital neutrophilia, which may due to its anti-inflammatory and immunomodulatory activities, 27 echoing to a recent finding that statin use is associated with lower risk of mortality in COVID-19 patients. 28 However, investigations on larger population are still necessary to confirm these effects. Moreover, consistent to recent consensuses, 29,30 our data suggest no evidence for the need of discontinuing the chronic drugs that patients took before admission due to chronic diseases.

Strengths of our study include a cohort of CKD patients with COVID-19 from two study centers, and a detailed presentation focusing on clinical characters, course and outcomes of COVID-19 patients with underlying CKD who were not on dialysis. There are also limitations. Our results only presented short-term outcomes in this cohort, and it was not a randomized, controlled trial, the analyses were based on clinically available data, rather than protocol-driven timed measurements.

In conclusion, CKD not requiring RRT as an independent risk factor for in-hospital death and https://mc.manuscriptcentral.com/qjm 15 poor prognosis in COVID-19 patients. COVID-19 patients with CKD not requiring RRT compared to those without CKD were prone to neutrophilia during hospitalization and worse clinical outcomes. Among patients with CKD and COVID-19, dialysis-dependent cases vs. CKD cases that not on dialysis presented higher risk of in-hospital death, more malignant laboratory findings on admission, and worsen changes of neutrophilia and LDH within first week after admission. For patients with CKD and COVID-19, neutrophils, creatine kinase and lymphocytes were noteworthy laboratory indices when treating those who were not on dialysis.

None. 

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We thank Tongji-Rongcheng Center for Biomedicine, Huazhong University of Science and Technology for support. We also appreciate Dr. B. Shu and Dr. G. Li (Department of Urological Surgery, The Central Hospital of Wuhan) for their help in extracting and reviewing electronic medical records.

The authors declare that they have no conflicts of interest.

https://mc.manuscriptcentral.com/qjm 16 A.P. and C.B. designed the study; D.Y., Y.X., J.C., P.L., Q.L., A.D., C.B., and A.P. extracted the data; D.Y., Y.X., J.C., Y.C., B.C., A.P., C.Y., M.X., Y.Z., X.L., and H.C. analyzed the data; D.Y., Y.X., Y.C., K.H., C.B., and A.P. drafted the paper; all authors revised the paper and approved the final version of the manuscript