Acute kidney injury in hospitalized patients with COVID-19

Joana Gameiro (  joana.estrelagameiro@gmail.com ) Centro Hospitalar Lisboa Norte, EPE José Agapito Fonseca Centro Hospitalar Lisboa Norte, EPE João Oliveira Centro Hospitalar Lisboa Norte, EPE Filipe Marques Centro Hospitalar Lisboa Norte, EPE João Bernardo Centro Hospitalar Lisboa Norte, EPE Claudia Costa Centro Hospitalar Lisboa Norte, EPE Carolina Carreiro Centro Hospitalar Lisboa Norte, EPE Sandra Braz Centro Hospitalar Lisboa Norte, EPE Lourdes Alvoeiro Centro Hospitalar Lisboa Norte, EPE José António Lopes Centro Hospitalar Lisboa Norte, EPE


Introduction
Since late 2019, the coronavirus disease 2019 (COVID-19) outbreak has resulted in over 4.5 million cases worldwide as of May 2020. 1,2The World Health Organization (WHO) classi ed COVID-19 as a pandemic which has been associated with signi cant morbidity and caused over 300.000 deaths. 3e majority of patients present with mild symptoms including fever, dyspnea, cough, headache and diarrhea or are even asymptomatic. 4,5More severe cases of pneumonia can lead to acute respiratory distress syndrome (ARDS), septic shock, multiple organ failure and death. 6,7rrent literature reports that the incidence of acute kidney injury (AKI) in COVID-19 patients ranges widely from 0.5 to 35% and has been associated with worse prognosis.9][10][11][12][13] AKI is characterized by a rapid decrease in renal function de ned as an increase in serum creatinine (SCr) and/or a decline in urine output (UO). 14AKI is a common in hospitalized patients, with an incidence which can reach 60% in critically ill patients and is associated with increased in-hospital mortality. 15AKI is a frequent complication in ARDS patients, namely in older patients and patients with signi cant comorbidities. 16 COVID-19 patients, kidney impairment appears to be multifactorial resulting from systemic in ammatory response to sepsis, local disruption in renin angiotensin aldosterone system (RAAS) homeostasis and direct cytopathic effect of the virus.17   The present study retrospectively analyzed data to study the incidence, severity, duration, risk factors and prognosis of AKI in hospitalized patients with COVID-19.

Materials And Methods
This study is a retrospective analysis of hospitalized patients admitted to a Dedicated Unit for COVID-19 patients (UICIVE) at the Department of Medicine of the Centro Hospitalar Universitário Lisboa Norte (CHULN), in Lisbon, Portugal, between March 2020 and May 2020.The Ethical Committee approved of this study, in agreement with institutional guidelines and informed consent was waived, given its retrospective and non-interventional nature.
We selected as eligible all adult patients (≥18 years of age) who tested positive by polymerase chain reaction testing of a nasopharyngeal sample for COVID-19 and were admitted at the UICIVE from March 1 st to May 31 st of 2020.For patients who had multiple qualifying hospital admissions, we included only the rst hospitalization.Exclusion criteria comprised (a) chronic kidney disease (CKD) patients on renal replacement therapy, (b) patients who underwent renal replacement therapy one week prior to admission, (c) patients who had less than 2 determinations of SCr and (d) patients who were discharged or died less than two days after admission.
Diagnosis of COVID-19 was based on the WHO interim guidelines. 19I was de ned according to the Kidney Disease Improving Global Outcomes (KDIGO) classi cation, using the serum creatinine (SCr) criteria, as follows: Stage 1: increase in SCr by 0.3 mg/dL within 48 hours or a 1.5-1.9times increase in SCr from baseline within 7 days; Stage 2: 2.9 times increase in SCr within 7 days; Stage 3: 3 times or more increase in SCr within 7 days or initiation of renal replacement therapy (RRT). 20Patients were strati ed according to the highest AKI stage attained during their hospital stay.Persistent AKI was de ned as continuance of AKI according to KDIGO criteria beyond 48 h according to the consensus report of the ADQI 16 Workgroup. 22Transient AKI was de ned as AKI of less than 48 h duration.22   Pre-admission SCr (SCr within the previous three months) was considered as baseline value.The estimated glomerular ltration rate (eGFR) for patients with previous baseline SCr was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation. 21When unavailable, baseline SCr was estimated from the MDRD equation, accepting the lower limit of a normal baseline GFR of 75 mL/min/1.73m2,as previously proposed. 20abetes mellitus was diagnosed according to the American Diabetes Association criteria.23 Hypertension diagnosed according to the 2018 European Society of Cardiology (ESC) and European Society of Hypertension Guidelines.24 COPD comprised emphysema and chronic bronchitis. CV was considered whenever a history of cerebrovascular disease, chronic heart failure of any cause, cardiac ischemic disease and/or peripheral arterial disease was documented.N/L ratio at admission was calculated as: Neutrophil count / Lymphocyte count.
The analyzed outcomes were the development of AKI and in-hospital mortality.
Categorical variables were described as the total number and percentage for each category, whereas continuous variables were described as the mean ± standard deviation.Continuous variables were compared with the Student's t-test and categorical variables were compared with the Chi-square test.All variables underwent univariate analysis to determine statistically signi cant factors which may have contributed to AKI development and in-hospital mortality.Subsequently, variables with a signi cant statistical difference were included in the multivariate analysis using the Cox logistic regression method.Data were expressed as odds ratios (ORs) with 95% con dence intervals (CIs).Statistical signi cance was de ned as a P-value <0.05.Statistical analysis was performed with the statistical software package SPSS for windows (version 21.0).

Participants
From March 1 st to May 31 st , 236 patients were admitted to UICIVE with a diagnosis of COVID-19 on admission.We focused on 192 patients after excluding 44 patients as depicted in Figure 1.
Mean length of hospital stay was 22.3±23.9days.Baseline characteristics of this cohort are described in Table 1.

AKI
In this cohort of COVID-19 patients, 55.2% developed AKI (n=106).Of these, 64.2% of patients (n=68) presented AKI at admission and the remaining developed AKI within the rst week of hospitalization.Mean time to AKI development was 2.2±0.9 days.Patient characteristics according to AKI development are described in Table 1.
Transient versus Persistent AKI There were no statistically signi cant differences between transient versus persistent AKI concerning demographic and clinical characteristics, nor laboratory values at admission.

Discussion
In this retrospective cohort we report a high incidence of AKI associated with COVID-19.More than 50% of infected patients developed AKI and the majority of these were transient and had lower severity changes in renal function.Remarkably, only persistent AKI and higher severity AKI were associated with mortality in these patients.
AKI is a frequent diagnosis in hospitalized patients. 14Recent studies have suggested the association of AKI and COVID-19, despite an initial report by Wang et al which described there was no AKI in 116 patients in Wuhan. 25This study included a majority of mild pneumonia patients had no patients had previous CKD which may explain the absence of AKI.In fact, in our cohort previous CKD and baseline SCr were important risk predictors of AKI development.
One of the studies which reports the lower rate of AKI is a retrospective study of 1099 hospitalized patients and outpatients in China, in which AKI was only present in 6 patients (0.5%). 5 In a retrospective cohort of 52 critically ill COVID-19 patients, Yang et al reported a 29% incidence of AKI and a mortality of 61.5% which was associated with the severity of the pneumonia. 11In another study, the incidence of AKI ranged from 3.5% in moderate disease patients to 42.9% in critically ill patients. 26urthermore, AKI patients had a higher mortality rate. 27Indeed, AKI was most often present in more severe cases of COVID-19. 28 our cohort of hospitalized COVID-19 patients, AKI was present in 55%.The more frequent use of hydroxycloroquine and corticosteroids in AKI patients in our cohort re ects the presence of moderate to severe disease in these patients.This severity of COVID-19 in our cohort explains the large incidence of AKI.The fact that 30% of AKI patients required ICU admission within the rst week of admission, also points out the contribution of AKI to disease severity.
The largest multicenter cohort included 5449 hospitalized COVID-19 patients in which 36.6% developed AKI.Hirsch et al reported a majority of patients with lower severity of AKI, in this study 46.5% of patients were KDIGO stage 1, and also reported that most AKI cases developed early in the course of COVID-19. 29This is in accordance with our results as we reported a prevalence of 60% of KDIGO stage 1, and most patients presented with AKI at admission or within the rst two days.
The etiology of AKI in patients with COVID-19 appears to be multifactorial, including ischemic injury, cytokine storm, and direct cytopathic effects on the kidney. 30[33] AKI has been associated with an increased risk of in-hospital mortality in multiple settings. 15,34[37] Cheng et al demonstrated that renal dysfunction de ned as either elevated baseline SCr, hematuria, proteinuria and AKI, was associated with mortality in a prospective cohort of 701 hospitalized patients with COVID-19. 38Despite reporting an incidence of AKI of only 5.1%, this study reported a higher risk of mortality according to AKI severity. 39Lim et al studied 164 hospitalized patients with an AKI incidence of 18% and demonstrated that AKI KDIGO stage 3 was independently associated with mortality. 40This is also consistent with the results of our cohort, as we reported an increased risk of mortality with the severity of AKI (adjusted OR 2.30 per increase in KDIGO stage (95% CI 1.10-4.82),p=0.027).Consistent with previous data we reported an increased risk of mortality associated with older age, lower hemoglobin and acidemia.
Our cohort is the rst to study the impact of AKI duration in COVID-19 patients and its association with outcomes.2][43] The impact of AKI duration on prognosis led to the development of a standardized de nition of transient and persistent AKI, based on recovery of kidney function within 48 hours, by the ADQI Workgroup. 22bin et al analyzed AKI in 77 critically ill patients with COVID-19 and demonstrated that persistent AKI was present in the majority of patients (93%). 44In their study, clinical and laboratory characteristics were similar between patients with persistent and transient AKI. 44These ndings were also present in our cohort.
We demonstrated that persistent AKI was present in 60% of patients and was associated with a signi cant increase in mortality risk (adjusted OR 7.91 (95% CI 2.39-26.21),p=0.001).In our study, transient AKI did not carry an increased risk for inhospital mortality.
Our study has some important virtues.Firstly, we de ned AKI according to the KDIGO classi cation using SCr criteria.Additionally, we applied the standardized de nitions of transient and persistent AKI as de ned by the ADQI workgroup to evaluate its impact on prognosis.Also, despite its retrospective design, the studied variables were routinely recorded in daily practice which allowed for the analysis of important covariates with impact on AKI development and outcome.
This study has important virtues to be noted.This is the rst study demonstrating an association between duration of AKI and mortality in patients with COVID-19.This is the largest single center cohort of AKI patients with COVID-19.Also, we used the current KDIGO de nition of AKI and the AKIN de nitions of transient and persistent AKI.
Nevertheless, this study has certain limitations.Firstly, the single-center and retrospective nature of our study limits generalizability.Secondly, 15.6% of patients did not have baseline SCr and baseline renal function had to be estimated with the MDRD equation, which might have led to overestimation of AKI.Finally, we could not determine the exact mechanisms contributing to AKI and mortality in these patients.
To conclude, we demonstrated that AKI was frequent in hospitalized patients with COVID-19 and that persistent and higher severity of AKI were predictors of in-hospital mortality.Although we could not nd predictors of persistent AKI in this modest cohort size, further studies should focus on this matter to allow for the early recognition of high-risk patients.

Table 1 -
Patients' baseline characteristics and according to AKI development

Table 2 -
Characteristics of patients according to in-hospital mortality

Table 3 -
Univariate and multivariate analysis of factors predictive of AKI and mortality in COVID-19 patients Figures Figure 1 Flow-chart of patient selection