Declined eGFR Associated with Poor Prognosis in COVID-19 Patients in Wuhan, China: A Retrospective Cohort Study

Background: Increasing evidence revealed that kidney was one of the targets of SARS-CoV-2. However, the incidences of kidney abnormalities were signi�cantly different, from 0.5 to 75.4% in coronavirus disease 2019 (COVID-19) patients. The association of kidney injury with prognosis remain controversial. Methods: In this retrospective cohort study, laboratory conrmedCOVID-19inpatients with severe type were enrolled. Demographic, clinicaland laboratory data were collected. Association of estimated glomerular ��ltration rate (eGFR)with 28-days mortality was analyzed. Results: The total 28-days mortality of hospitalizationwas 22.3% (79/354). Non-survivors had a signi�cantly declined eGFR levels than survivors (75.95 [IQR: 47.22,92.84] ml/min/1.73m 2 vs. 96.43 [IQR: 84.11,108.47] ml/min/1.73m 2 , P<0.001). The 28-days mortality in declined eGFR group (<90 ml/min/1.73m 2 ) was signi�cantly higher than that in normal eGFR group (38.5% vs. 10.7%, P <0.001). Multivariate logistic regression revealed that the independent risk factors of 28-days outcome included lower eGFR (OR: 3.97, 95%CI: 1.42-11.11), elevated WBC (OR: 7.08, 95%CI: 3.15-15.90), lymphopenia (OR: 2.58, 95%CI: 1.21-5.49)andIL-6 (OR: 7.90, 95%CI: 2.19-28.49). Kaplan-Meier analysis indicated the survival disadvantage in patients with declined eGFR. ROC curve showed the eGFR cut-off value for predicting 28-days death was 82.2 μmol/L, with the sensitivity of 76.7% and speciality of 66.3%. Conclusion: Declined eGFR was associated with poor prognosis and could be used an independent risk factor of 28-days mortality in COVID-19 patients. Early detection


Background
Coronavirus disease 2019 (COVID-19) has resulted in considerable morbidity and mortality worldwide since December 2019, with at least 20% of COVID-19 patients have severe disease.Recent reports showed the mortality of COVID-19 patients with severe form or critical illness as high as 28.3% [1].Although lungs were the main targets of SARS-CoV-2, increasing evidence revealed that SARS-CoV-2 infection could also be found out of lung, such as digestive system, cardiovascular system and kidney [2].Disorder of coagulation and injury of cardiovascular system have been proved associated with inhospital mortality in COVID-19 patients.
However, the association of kidney injury with prognosis remain controversial.The incidences of kidney abnormalities were signi cantly different.Some studies revealed acute kidney injury (AKI) occurred in 2.9-23% of ICU patients [3][4][5].A recent report indicated 75.4% patients had abnormal urine dipstick tests or AKI [6].A recent study showed that kidney diseases was associated with in-hospital death of patients with COVID-19 [3].However, another report indicated that COVID-19 did not result in acute kidney injury (AKI) [6].This might be due to the different methods of kidney injury evaluation and de nition.Although serum creatinine remains the most widely used biomarker to evaluate renal function, it is a delayed renal functional marker when it is generally increased after sever kidney damage [8].
The estimated glomerular ltration rate (eGFR) is widely accepted as the total index to evaluate renal function for acute or chronic kidney disease [9][10][11][12].However, the relationship of eGFR and prognosis of COVID-19 patients was unclear.So, aim of this study was to estimate the potential association of kidney function (using eGFR) with 28-days mortality of COVID-19 patients, which would help for the early identi cation of patients with progression risk.

Subjects and methods
In this retrospective single-centre cohort study, we enrolled 354 laboratory con rmed COVID-19 inpatients who were admitted to Wuhan Tongji Hospital from February 10 to March 29, 2020.Diagnosis and disease severity of all patients were determined according to the Chinese management guideline for COVID-19 (version 7.0).This study was approved by the institutional review boards at the First A liated Hospital of Soochow University and Wuhan Tongji Hospital.As COVID-19 is an emerging infectious disease, the written informed consent was exempted.
Baseline demographic data and clinical features were recorded.The eGFR was estimated using the Modi cation of Diet in Renal Disease Study equation [12].Patients were followed-up to 28 days after admission.The primary outcome was 28-days mortality in hospital.The criteria for discharge were de ned as all of the following: absence of fever for at least 3 days; clinical remission of respiratory symptoms; substantial improvement in both lungs in chest CT; and two throat-swab samples with SARS-CoV-2 RNA negative obtained at least 24 hours apart.

Statistical analysis
Continuous data with normal distribution were presented as mean ± standard deviation.Continuous data with skewed distribution were presented as median [interquartile range (IQR)].Frequency data were expressed as proportions.Comparisons of continuous variables were made with Student's t test or the Mann-Whitney U test when appropriate.Categorical variables were assessed using the x 2 test or Fisher's exact test as appropriate.Multivariate logistic regression models were used to determine the independent risk factors for 28-days mortality after hospitalization.Kaplan-Meier analysis was used for survival curves by the log-rank test.Data were analyzed using SPSS 19.0.A two-tailed P value < 0.05 was considered statistically signi cant.

Decline Egfr Associated With Short-term Prognosis In Covid-19 Patients
As shown in Table 2, the 28-days mortality in decline eGFR group was signi cantly higher than that in normal eGFR group (38.5% vs. 10.7%,P < 0.001).Multivariate logistic regression analysis (Table 3) revealed that the independent risk factors of 28-days outcome included lower eGFR (OR: 3.97, 95%CI: Kaplan-Meier analysis (Fig. 1A) indicated that patients with declined eGFR levels had a signi cant survival disadvantage (log-rank P < 0.01) as compared to patients with normal eGFR levels.The ROC curve (Fig. 1B) showed that the area under curve (AUC) was 0.772.The cut-off value of eGFR for prognosis prediction was 82.2 µmol/L, with the sensitivity of 76.7% and speciality of 66.3%.

Discussion
In this retrospective study, we identi ed the association of lower eGFR with 28-days mortality in COVID-19 patients.The cut-off value of eGFR for predicting the 28-days mortality was 82.2 µmol/L, with the sensitivity of 76.7% and speciality of 66.3%.This cut-off value was slightly lower than the normal range (at least 90 ml/min/1.73m 2 ), which suggesting that potential kidney injury might represented a higher risk of diseases progression.It is essential of early detection and precaution to improve the prognosis of COVID-19.
Although the respiratory and immune systems are the major targets of COVID-19, kidney injury is a major complication.Some patients with COVID-19 also present with kidney injury, and autopsy ndings of patients who died from the illness sometimes show renal damage.AKI occurred in 2.9-23% of ICU patients [3][4][5].But another report indicated that 68.5% patients experienced remission of proteinuria, 45.7% experienced complete recovery of kidney function [6].Update, it is remain controversial how to evaluated renal function or AKI precisely in COVID-19.SCr remains widely used as biomarker for renal function evaluation, but it is a delayed marker when it is generally increased after sever kidney damage.
Although it is inconvenient to measure GFR directly, eGFR is widely accepted as the total index to evaluate renal function for acute or chronic kidney disease [9][10][11].So, we used eGFR for the assessment of kidney injury in COVID-19 patients in this study.The median eGFR levels of total patients was 92.82 ml/min/1.73m 2 .The median eGFR levels of non-survivors was signi cantly lower than survivor.In a recent study, eGFR < 60 ml/min per 1.73 m 2 was reported in 13.1% of COVID-19 patients [3].In our study, the ratio was 16% (46/275), which was similar to previous report.
In declined eGFR group, the median serum creatinine level was 87.00 (IQR: 73,108) µmol/L, which remained in normal range.A recent study demonstrated that among patients with baseline SCr ≥ 0.7 mg/dl (61.9µmol/l) those who experienced a 0.3mg/dl increase in SCr within 48 h had clinically meaningful differences in outcomes (including length of hospital stay and mortality) when comparing with those who experienced a 50% increase in SCr from baseline within 7 days [8].It indicated the advantage of eGFR in sensitivity for early-stage kidney injury evaluation as compared with SCr.Moreover, the cut-off value of eGFR for predicting the 28-days mortality was 82.2µmol/L, which was slightly lower than the normal range (at least 90 ml/min/1.73m 2 ).It reveals that potential kidney impairment might occur before eGFR decreased signi cantly in early stage of SARS-CoV-2 infection.It is important of early detection and precaution to improve the prognosis of COVID-19.
A recent study showed that kidney diseases was associated with early in-hospital death of patients with COVID-19 [6].However, another report indicated that COVID-19 did not result in acute kidney injury [7].In previous study of patients with H1N1 virus infection, only those cases in the AKI III category were independently associated with mortality [13].In this study, we identi ed that declined eGFR associated with poor short-term prognosis in COVID-19 patients.Previous studies have demonstrated that lower eGFR was risk factor for all-cause and cardiovascular mortality in high-risk populations, independent of each other and of cardiovascular risk factors [9][10][11].In this study, we showed lower eGFR as an independent risk factor of 28-days mortality.This was in consistent with previous study.Previous reports have identi ed the direct cytopathic effects of SARS-CoV-2 on kidney tissue, the up-regulation of ACE2 in patients with COVID-19 and the SARS-CoV nucleoprotein antibody in tubules [14][15].These provide direct evidence of the invasion of SARSCoV-2 into kidney tissue.About 5-10% of hospitalized patients and up to 60% of patients admitted to the intensive care unit had experienced acute kidney injure [16].
Early improvement in kidney injure may lead to a signi cant survival in severe sepsis [17].This study and previous reports demonstrated the association of kidney impairment with short-term mortality, which indicated the necessity of early detection and early interference of kidney injury in COVID-19 patients.However, there was no evidence for the impact of early kidney improvement on survival in COVID-19 patients.A prospective randomized controlled clinical trial could provide convincing evidence.
There are some limitations.First of all, this study only represented a part of COVID-19 patients in Wuhan as it is a single-center retrospective study.A large scale and multiple-center study might be more persuasive.Secondly, the role of different treatments might result in bias, including antiretrovirals and immunologic antibody therapy.We do not have statistical power to determine if these antiviral treatments had an effect on mortality, because of the lack of standardized antiviral therapies for the COVID-19 patients.

Conclusion
Lower eGFR was associated with poor prognosis and could be used an independent risk factor of 28days mortality in COVID-19 patients.The eGFR cut-off value for predicting the 28-days mortality was 82.2µmol/L, with the sensitivity of 76.7% and speciality of 66.3%.Early detection and surveillance for eGFR may bene t to identify patients with high-risk of progression.
The authors declare that they have no competing interests.

Figures
Figure 1

Table 1
Baseline characteristics of 354 COVID-19 patients with different outcomes.

Table 2
Characteristics of 354 COVID-19 patients with different eGFR levels.Includes congestive heart disease and coronary atherosclerotic heart disease.
OutcomeContinuous variables are expressed as median values (interquartile ranges), and categorical variables are presented as number of patients (percentages).WBC, white blood cell; hs-CRP, high-sensitive C-reactive protein; IL-6, interleukin-6.IMV: invasive mechanical ventilation; NIPPV: nonivasive positive pressure ventilation.aIncludes congestive heart disease and coronary atherosclerotic heart disease.a

Table 3
Multivariate logistic regression analysis of risk factors for 28-days mortality in severe COVID-19 patients.