key: cord-0979232-r3ifwgya
authors: Liu, Ye-Mao; Xie, Jing; Chen, Ming-Ming; Zhang, Xiao; Cheng, Xu; Li, Haomiao; Zhou, Feng; Qin, Juan-Juan; Lei, Fang; Chen, Ze; Lin, Lijin; Yang, Chengzhang; Mao, Weiming; Chen, Guohua; Lu, Haofeng; Xia, Xigang; Wang, Daihong; Liao, Xiaofeng; Yang, Jun; Huang, Xiaodong; Zhang, Bing-Hong; Yuan, Yufeng; Cai, Jingjing; Zhang, Xiao-Jing; Wang, Yibin; Zhang, Xin; She, Zhi-Gang; Li, Hongliang
title: Kidney function indicators predict adverse outcomes of COVID-19
date: 2020-10-02
journal: Med (N Y)
DOI: 10.1016/j.medj.2020.09.001
sha: 5db9dc14fe19de90ff7b96c97253e51e6d433b52
doc_id: 979232
cord_uid: r3ifwgya

Background The coronavirus disease 2019 (COVID-19) is an emerged respiratory infectious disease with kidney injury as a part of the clinical complications. However, the dynamic change of kidney function and its association with COVID-19 prognosis are largely unknown. Methods In this multicenter retrospective cohort study, we analyzed clinical characteristics, medical history, laboratory tests, and treatment data of 12,413 COVID-19 patients. The patient cohort was stratified according to the severity of the outcome into three groups: non-severe, severe, and death. Findings. The prevalence of elevated blood urea nitrogen (BUN), elevated serum creatinine (Scr), and decreased blood uric acid (BUA) at admission was 6.29%, 5.22%, 11.66%, respectively. The trajectories showed elevation of BUN level and Scr level, as well as a reduction of BUA level during 28 days after admission in death cases. Increased all-cause mortality risk was associated with elevated baseline levels of BUN and Scr, and decreased level of BUA. Conclusion The dynamic changes of the three kidney function markers were associated with different severity and poor prognosis of COVID-19 patients. BUN showed close association and high potential for predicting adverse outcomes in COVID-19 patients for severity stratification and triage.

The coronavirus disease (COVID-19) is a recently emerged disease with unprecedented scale and high infectivity (Huang C et al., 2020; Lu H et al., 2020; Zhu et al., 2020) . There is accumulating evidence indicating that the respiratory system is not the only organ damaged by the virus. Indeed, kidney impairment has been reported to be a frequent complication resulted from this infection, especially among the patients with severe symptoms (Deng et al., 2020; Naicker S et al., 2020) . The latest data showed that acute kidney injury (AKI) occurred in about 37% of COVID-19 patients in New York (Hirsch et al., 2020) , and pre-existing history of kidney diseases and AKI during hospitalization were linked to an increased risk of mortality (Cheng et al., 2020) . However, the dynamic changes of kidney function after SARS-Cov-2 infection and its predictive value for poor prognosis of COVID- 19 have not yet been reported. To answer these fundamental questions, here, we conducted a large scale analysis based on 12,413 COVID-19 cases from multicenter in Hubei

Province, China. We demonstrated the dynamic trajectories of kidney injury indicators in patients stratified based on disease severity and outcome, and uncovered that these kidney injury indicators, in particular the blood urea nitrogen (BUN), were significantly associated with and had significant predictive property to poor outcomes of COVID-19.

We enrolled a total of 15,512 patients with COVID-19, of whom 12,413 (80.02%) met the eligibility criteria (Figure 1) , including 8,441 non-severe cases, 3,202 severe (non-death) cases, and 770 deaths (Figure 1) . The clinical, biochemical characteristics and pre-existing complications of the study cohort at baseline, as well as treatment information during hospitalization were described in Table 1 .

The median age of the entire study cohort was 58 (interquartile range, 46 -67 years), and 48.22% were males. The median duration from the first symptom to hospitalization was 11 days for all patients. At admission, 764 (6.29%) had an elevated level of blood urea nitrogen (BUN), 633 (5.22%) patients had an elevated level of serum creatinine (Scr), and 1422 (11.66%) had a decreased level of blood uric acid (BUA). Coexisting chronic diseases, including diabetes, hypertension, coronary heart disease, chronic obstructive pulmonary disease, cerebrovascular disease, and chronic liver disease J o u r n a l P r e -p r o o f had higher frequencies in the death group than in other groups. Of note, compared to the other groups, the patients from the death group had higher proportions of elevated BUN (37.86%), elevated Scr (18.64%), and decreased BUA (25.49%). During hospitalization, the highest incidence of AKI was observed in the patients who died from COVID-19 (death group: 29.22%, severe group:

1.59%, non-severe group: 0.49%). There are 62 patients and 81 patients received renal replacement therapy (RRT) and continuous renal replacement therapy (CRRT), respectively. And patients in death group had significantly higher ratio to receive RRT and CRRT relative to other groups. There were still 73 patients who met indications but didn't receive RRT or CRRT (death group: 9.09%, severe group: 0.03%, non-severe group: 0.02%).

As depicted in Figure 2 , locally weighted scatterplot smoothing (Loess) was used to determine the distribution and trajectory of the three renal parameters in the three different severity groups. At admission, baseline levels of kidney markers in non-survivors were the highest among all patients.

Within 28 days after admission, there was a modest fluctuation of the three renal indicators over time in the non-severe-case and severe-case groups. In sharp contrast, however, the temporal specific pattern of the kidney parameters in the death-group was markedly different. Plot linear fitting curve revealed a marked elevation of BUN level and Scr level, while a sustained downtrend followed by a plateau of BUA level was observed. A subgroup analysis demonstrated that males and females had comparable temporal dependent profiles; however, the trends in the males were more significant than those in the females ( Figure S1 ). The dynamic trends suggested a potential association between levels of kidney function markers and the mortality of patients with COVID-19.

Mixed-effect Cox regression analyses (Table 2) and Kaplan-Meier survival curves (Figure 3 ) were used to demonstrate the associations of BUN, Scr and BUA with the mortality risk within the study cohort. Increased all-cause mortality risk was detected to be associated with elevated levels of BUN (aHR: 6.27, 95%CI: 5.29 -7.42) and Scr (aHR: 2.65, 95%CI: 2.17 -3.23) or decreased level of BUA (aHR: 2.10, 95%CI: 1.75 -2.51) at admission, by applying a mixed-effect Cox model treating hospital site as a random effect and adjusting for age, gender, and comorbidities. Among the three J o u r n a l P r e -p r o o f biomarkers, an elevated baseline BUN was associated with the highest risk of mortality. Figure 3 presented that patients with elevated baseline BUN, elevated baseline Scr, or decreased BUA had markedly lower survival rate than those with normal levels of the three kidney indicators.

We further analyzed the associations between baseline levels of BUN, Scr, BUA and secondary outcomes in COVID-19 patients. Mixed-effect Cox models demonstrated that the increased BUN level and Scr level, as well as decreased BUA level at admission were also significantly associated with poor secondary outcomes in patients with COVID-19 (Table 3) . Again, among the three markers, an elevated baseline BUN was associated with the highest risk of poor prognosis.

Logistic regression analyses were used to investigate the effects of baseline characteristics and laboratory indexes on the baseline levels of kidney indicators in the study cohort ( Table 4 ). The results showed that male gender, age, neutrophil count increase, lymphocyte count decrease, oxyhemoglobin saturation (SpO 2 ) < 95, and diabetes were all positively correlated with elevated BUN, elevated Scr, and decreased BUA. Among them, neutrophil count increase and lymphocyte count decrease were the most significant factors, indicating the potential association of inflammation with kidney markers after SARS-CoV-2 infection.

To our knowledge, this is one of the largest cohort to verify the relation between kidney indicators and adverse outcomes in COVID-19 patients. From 12,413 cases, we found a remarkable increase of BUN, Scr and reduction of BUA in patients who died during hospitalization, but only modest fluctuation within normal ranges of the three kidney markers in the survivors with COVID-19.

Furthermore, elevated baseline levels of BUN and Scr, as well as decreased baseline BUA were associated with increased risks of adverse outcomes. This is the first report demonstrating that BUA is dramatically lower in COVID-19 patients with more severe symptoms and is significantly associated with a higher risk of COVID-19 death. Among the three indicators, an elevated baseline BUN was most significantly associated with the highest risk of adverse outcomes. These findings suggested that three kidney indicators could reliably predict the risk of COVID-19 patients, among J o u r n a l P r e -p r o o f 7 which BUN was the most impactful indicator.

Our study illustrated the important role of kidney markers on admission in predicting the adverse outcomes of hospitalized patients with COVID-19. The results suggest that patients with elevated BUN, Scr, or decreased BUA on admission should be monitored more carefully for early intervention, which may improve the survival rate of patients with COVID-19. These results are further corroborated by a recent study by Cheng et al. which also reported that elevated BUN and elevated Scr increased the mortality risk in COVID-19 patients based on a relatively small cohort of 701 cases (Cheng et al., 2020) . In addition, our findings linked a decrease in BUA with higher all-cause mortality, which is consistent with an observational study on SARS patients (Wu VC et al., 2005) .

Our results indicate that patients with an elevated baseline of BUN level are at higher risk of all-cause death and poor outcomes than those with normal range of BUN level. Thus, it is critically important that the BUN levels should be closely monitored. When the medical resources are limited, the BUN level on admission can provide a simple tool for early risk stratification among COVID-19 patients, and guide physicians to reserve more medical resources to patients at higher risk in order to reduce the death rate. While an optimized management strategy is not the focus of this study, aggressive treatment with proper medication to reduce BUN level and the related organ injury might contribute to mitigating the death risk and adverse outcome for COVID-19. However, due to the inherent limitation of retrospective study, this study cannot directly address whether increased BUN is a causal factor of poor prognosis and whether reducing BUN would benefit the COVID-19 patients. These questions need to be addressed in future prospective studies and clinical trials.

The mechanism involved in the increase of BUN level after SARS-CoV-2 infection has not been fully elucidated. Given that angiotensin-converting enzyme 2 (ACE2) is the primary cellular receptor of SARS-CoV-2 and highly expressed in the renal epithelial cells, it is possible that the viral infection might directly lead to an interaction of SARS-CoV-2 with its receptor in the kidney to reduce ACE2 expression, leading to abnormal activation of the renin-angiotensin-aldosterone system (RAAS) (Soleimani, 2020; Wang et al., 2020) . The activated RAAS can significantly increase absorption of water by kidney tubules while enhancing resorption of urea, leading to elevated BUN levels (Macedo, 2011) . Elevation of BUN level is not only a kidney dysfunction indicator but can J o u r n a l P r e -p r o o f also reflect inflammatory status, catabolism, nitrogen equilibrium, and renal hypoperfusion from hypovolemia, sepsis, or reduced cardiac output, many of which have been reported to be closely associated with the adverse outcomes in COVID-19 patients (Cauthen et al., 2008; Li et al., 2020; Macedo, 2011; Oudit and Pfeffer, 2020; Ren et al., 2020; Ronco et al., 2020; Thum, 2020; . And the coagulation status might progress and exacerbate along with the systematic inflammatory response and multiple organ injury. This is perhaps the reason why we observed a strong correlation between abnormal BUN with a broad spectrum of symptoms during pneumonia progression and why high BUN level showed a more significant association with the adverse outcomes than Scr since the latter of which mainly represents a status of kidney injury and metabolic disturbance (Wyss and Kaddurah-Daouk, 2000) . Finally, the elevated BUN might also be caused by cortisone therapy or an abnormal catabolic state. Nevertheless, findings from this retrospective study cannot provide a direct causal effect of BUN increase on all-cause mortality of COVID-19. Thus, the predictive value of BUN on the prognosis of COVID-19 still needs to be further validated by prospective studies and clinical trials, and more basic research is required in order to elucidate the underlying mechanisms.

In the present study, the level of BUA was much lower in the severe group than the non-severe group and was associated with increased risks of adverse outcomes in COVID-19 patients. Since uric acid is mainly dissolved in the blood, filtered through the kidneys, and expelled in the urine, it was commonly recognized as a kidney function marker (Maiuolo et al., 2016) . Under normal conditions, the reabsorption and excretion by kidney tubules of blood uric acid are maintained in a balanced state.

In the setting of SARS, decreased levels of blood uric acid might as a result of defective tubular handling of uric acid and may be associated with cytokine storm. (Wu VC et al., 2005) . Since the dysfunction of kidney tubules was also observed after SARS-COV-2 infection (Werion et al., 2020) , the declined uric acid level might be correlated with cytokine storm in the setting of COVID-19.

Also, the decreased uric acid level might be a marker of kidney involvement severity, e.g., proximal tubular damage, in patients infected by SARS-COV-2. Except for kidney dysfunction, the reduced blood uric acid might be related to the increase of decomposition by the intestinal tract, but the mechanism is unclear. It has been reported that the gut microbiome was disturbed in patients with COVID-19 (Zuo et al., 2020a; Zuo et al., 2020b) , which may lead to reduced uric acid in those patients (Chiaro et al., 2017; Guo et al., 2016; Pan et al., 2020) . Thus, the decreased blood uric acid J o u r n a l P r e -p r o o f level during SARS-CoV-2 infection might be due to an abnormal increase in BUA excretion by abnormal renal handling due to inflammatory injury or hypoxemia, or an intensive uricolysis due to enteric dysbacteriosis. However, these postulated mechanisms will still need to be further investigated.

Remarkably, not only the baseline renal parameters can predict adverse outcomes of COVID-19, the dynamic changes of these renal parameters may serve as warning signs for mortality in COVID-19 patients. In our study, we found that the dynamic changes of these kidney indicators were associated with different severity and outcome of COVID-19. Importantly, the sharp differences in the dynamic changes of the three markers for kidney function in the non-survivors vs. the relatively stable patterns observed in the survivors implied a significant association between the aggravation of kidney injury and the deterioration of the disease and death in the pathogenesis of COVID-19.

Similar results were observed in male and female subgroups, with more significant trends in males than those in females. It is known that estrogen affects ACE2 expression in the kidney, which could be one of the reasons for gender-related differences in the dynamic patterns of kidney parameters during hospitalization observed in our study (Cagnacci and Xholli, 2020; Garovic and August, 2016; Gebhard et al., 2020) .

Several limitations of this study should be noted in interpreting the results. First, it was a retrospective study on a limited number of available kidney markers, and other biomarkers of kidney function, such as urine protein level and hematuria were not investigated due to data availability.

Second, smoking status and medical history of chronic kidney diseases might not be collected sufficiently, especially from severely ill patients under urgent circumstances of COVID-19 surge.

Third, we cannot determine the causal relationships between kidney indicators and the severity as well as the mortality of COVID-19. Fourth, due to limited medical resources, an increase of Scr within 48 hours was the only criterion for the diagnosis of AKI; thus, this may result in an under-diagnosis of AKI in our population. A combination with a 7-day Scr and urine output criterion may increase the accuracy of AKI diagnosis. We noticed there were geographical differences in the incidence of AKI in patients with COVID-19. For instance, the AKI incidence in US was reported about 37% (Hirsch et al., 2020) , which is much higher than 2.55% in our study and 0.5% in another J o u r n a l P r e -p r o o f multicentered study in China (Guan et al., 2020) . This discrepancy might be related to the difference in the occurrence of comorbidities, the severity of symptoms, and the exclusion of patients with chronic kidney diseases in our study. Therefore, the conclusions in this study require validation by prospective studies and RCTs in cohorts from extensive geographical regions. Fifth, the levels of kidney function indicators might be influenced by other factors. For example, the increased BUN might be also due to cortisone therapy or catabolic state, while the Scr level might be influenced by persistent muscle wasting in critical ill patients. Sixth, in our study cohort, the relatively small number and percentage of patients received RRT might be related to the shortage of medical resources during the COVID-19 pandemic and the varied criteria of RRT initiation in different hospitals. And not all patients with the indications of RRT received that therapy during hospitalization, which might induce potential confounding into the conclusion.

The dynamic changes of three markers for kidney function, including elevated BUN, elevated Scr, and decreased BUA, were associated with different severity and mortality of patients with COVID-19. Among the three markers, an elevated baseline BUN was associated with the highest risk of adverse outcomes. BUN level at admission might represent a sensitive factor for predicting death and adverse outcomes in COVID-19 patients and can be valuable for patient stratification and triage. data. YW, Xin Zhang, ZGS, and H.L. contributed equally, designed the project, edited the manuscript, and supervised the study. All authors have approved the final version of this paper.

The authors declare that there are no competing interests associated with the manuscript.

Further information and requests for resources and reagents should be directed to the Lead Contact, Hongliang Li (lihl@whu.edu.cn).

The study did not generate any new reagents or materials.

Data and codes involved in this research are available from the corresponding author upon reasonable request. The research team will provide an email address for communication once the information sharing are approved. The proposal should include detailed aims, statistical plan, and other information/materials to guarantee the rationality of requirement and the security of the data.

The related patient data will be shared after review and approval of the submitted proposal and any Figure 1 . 820 cases transferred to other hospitals, 404 patients aged > 85 or < 18 years, 165 cases with pregnancy, 10 cases with the acute fatal disease, 681 cases with a medical history of kidney diseases (599 with chronic kidney diseases of unknown causes, 16 with chronic glomerulonephritis, 3 with chronic pyelonephritis, 5 with diabetic nephropathy, 1 with hypertensive nephropathy, 4 with nephrotic syndrome, and 53 with kidney stones or cysts that might affect kidney function, kidney malformation, tumor, or transplant), and 1,019 patients without any test of three kidney markers during 28-day hospitalization were excluded. Patients with kidney stones or cysts but without renal dysfunction were not excluded. At last, 12,413 cases met the eligibility criteria and were enrolled in further analysis.

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Heart rate, median(IQR)

Respiratory rate, median(IQR)

Days from symptom onset to hospitalization, median(IQR)

Symptoms upon admission Fever, n(%)

Co-existing chronic diseases Diabetes, n(%)

BUA decrease

Male sex 2.25(1.89-2.67)

This work was supported by grants from the National Key R&D Program of China