Discussion
In this large prospective cohort study conducted in a tertiary teaching hospital with 3 branches in Wuhan, China, we observed a high prevalence of kidney disease in hospitalized patients with COVID-19. More than 40% of them had evidence of kidney disease, with elevated serum creatinine and BUN values in over 13% of them. Strikingly, the presence of kidney disease was associated with greater in-hospital mortality.
Multiple organ involvement including the liver, gastrointestinal tract, and kidney have been reported during the course of SARS in 20036 and very recently in patients with COVID-19.7 One possible explanation of the high prevalence of kidney involvement at hospital admission is that some the patients with COVID-19 had a past history of chronic kidney disease. Such patients have a proinflammatory state with functional defects in innate and adaptive immune cell populations8 and are known to have a higher risk for upper respiratory tract infection9 and pneumonia.10 Of note, the median time period between the first symptoms and signs of COVID-19 and hospital admission was slightly more than a week in our study. An alternative explanation is that many patients with COVID-19 could not be admitted in the very early stage of disease outbreak because of the acutely increasing, large number of patients and limited availability of hospital beds in Wuhan. Earlier admission to hospital might have helped to prevent disease spread and deterioration.
This is the first study showing an association between kidney involvement and poor outcome in patients with COVID-19. We found that patients with elevated baseline serum creatinine were more likely to be admitted to the intensive care unit and to undergo mechanical ventilation, suggesting that kidney disease on admission represented a higher risk of deterioration. It has been reported previously that kidney injury was associated with an increased risk of death in patients with influenza A virus subtype H1N1 and SARS.5 , 11 In our study, indicators of kidney involvement at admission were associated with a higher risk of in-hospital death even after adjustment for potential confounders. This observation indicated poor prognosis regardless of initial COVID-19 severity and general physical condition. Monitoring kidney function must therefore be emphasized even in patients with mild respiratory symptoms, and altered kidney function should be given particular attention after admission in clinical practice. Early detection and treatment of renal abnormalities, including adequate hemodynamic support and avoidance of nephrotoxic drugs, may help to improve the vital prognosis of COVID-19.
AKI results from an abrupt loss of kidney function and is strongly associated with increased mortality and morbidity.12 We found that patients with elevated serum creatinine were more likely to develop AKI during hospitalization, which is consistent with study in SARS.5 It is therefore important to increase the awareness of AKI in those who entered the hospital with an elevated serum creatinine. In our cohort, the detection rate of AKI in patients with COVID-19 was 5.1%, which is in keeping with recent reports of small sample size1 , 4 , 7 , 13 and much higher than the 0.5% of a large observational study.14 This may be explained by an extremely high proportion of severely sick patients in a previous case series and only 15.7% in the large observational study. In our cohort study, 42.7% of patients were severely ill, and this may explain the higher detection rate of AKI in clinic practice in Wuhan. Importantly, the present method of detecting AKI is mainly based on acute changes in serum creatinine and the frequency of serum creatinine tests has a substantial impact on detection rate.15 In a nationwide cross-sectional survey of hospitalize adult patients in China, the detection rate of AKI was only 0.99% by Kidney Disease: Improving Global Outcomes (KDIGO) criteria.16 After adjusting for the frequency of serum creatinine, determinations of the incidence of AKI in Chinese hospitalized adults rose to 11.6%.17 Thus, to improve early detection of kidney injury, more frequent serum creatinine measurements should be performed in patients with COVID-19.
The etiology of kidney disease involvement in patients with COVID-19 is likely to be multifactorial. First, the novel coronavirus may exert direct cytopathic effects on kidney tissue. This is supported by the detection of polymerase chain reaction fragments of coronavirus in blood and urine in both the patients with the 2003 SARS virus18 and those with COVID-19.4 Recently, it has been shown that the novel coronavirus uses angiotensin converting enzyme 2 (ACE2) as a cell entry receptor, which is identical to that of the SARS-CoV as reported in 2003.19 Recent human tissue RNA-sequencing data demonstrated thatACE2 expression in urinary organs (kidney) was nearly 100-fold higher than in respiratory organs (lung).20 Therefore, the kidney disease may be caused by coronavirus entering kidney cells through an ACE2-dependent pathway. Second, deposition of immune complexes of viral antigen or virus-induced specific immunological effector mechanisms (specific T-cell lymphocyte or antibody) may damage the kidney. However, kidney microscopy specimens from patients with SARS were reported to show a normal glomerular aspect and absence of electron-dense deposits.5 This is not in support of an active immune-mediated glomerulonephritis. Clearly, potential pathological kidney changes in patients with COVID-19 require further study. Third, virus-induced cytokines or mediators might exert indirect effects on renal tissue, such as hypoxia, shock, and rhabdomyolysis. In fact, some of the patients with the 2009 H1N1 virus had mild to moderate elevations of serum creatine kinase.21 In keeping with this observation, 138 patients with COVID-19, who were admitted to an intensive care unit, showed a tendency toward increased creatine kinase levels,13 and the patients with kidney involvement in our study tended to have increased creatine kinase levels as well.
We compared the medications on the first day of admission and during the hospitalization in patients with AKI and non-AKI. We found that patients with AKI were more likely to have higher proportion of glucocorticoid and lower proportion of antiviral drugs and renin-angiotensin-aldosterone system inhibitors treatment on admission. The difference in the use of glucocorticoids may be explained by the condition of patients with AKI that was more severe, thus physicians tended to use glucocorticoids in the most critically ill patients, even if there is a controversy on the use of glucocorticoids in patients with COVID-19.22 , 23 However, the oral antiviral drugs, including umifenovir, oseltamivir, and lopinavir with ritonavir, were preferred in moderate patients on admission. Given that ACE2 is a functional receptor for SARS-CoV-2, the safety and potential effects of renin-angiotensin-aldosterone system inhibitors in patients with COVID-19 should be carefully considered.24 These potentially harmful effects may account for the low proportion of renin-angiotensin-aldosterone system inhibitors used by physicians in our cohort, especially in patients with AKI who had higher level of creatinine on admission. Due to the small number of patients with AKI and the bias in different therapy of patients with COVID-19, causal relationship between drug and AKI in patients with COVID-19 remains undetermined.
Even though this study included a large number of patients from a tertiary teaching hospital in Wuhan, it has several limitations. First, an accurate baseline serum creatinine was not available, which may have led to an underestimation of AKI or erroneous associations. Second, although we attempted to adjust for many confounders, other unmeasured or unknown confounders might have played a role. Third, clinical data of patients after discharge were lacking, so we could not assess COVID-19 effects on long-term outcomes. The precise impact of COVID-19 on kidney structure and function and the incidence of chronic kidney disease in these patients require further investigation.
In conclusion, the prevalence of kidney disease in patients with COVID-19 hospitalized in Wuhan, China, was high. After adjustment for confounders, kidney disease on admission and AKI during hospitalization were associated with an increased risk of in-hospital death. Clinicians should increase their awareness of kidney disease in hospitalized patients with COVID-19. Early detection and effective intervention of kidney involvement may help to reduce deaths of patients with COVID-19.