key: cord-1027274-ofynl2ro
authors: Gameiro, Joana; Agapito Fonseca, José; Oliveira, João; Marques, Filipe; Bernardo, João; Costa, Claudia; Carreiro, Carolina; Braz, Sandra; António Lopes, José
title: Acute kidney injury in hospitalized patients with COVID-19: a Portuguese cohort
date: 2021-05-14
journal: Nefrologia
DOI: 10.1016/j.nefro.2021.04.002
sha: 319b6e96ee6a1870c2c52cb14159b8752ae068bc
doc_id: 1027274
cord_uid: ofynl2ro

Introduction: The incidence of AKI in coronavirus disease 2019 (COVID-19) patients ranges from 0.5 to 35% and has been associated with worse prognosis. The purpose of this study was to evaluate the incidence, severity, duration, risk factors and prognosis of AKI in hospitalized patients with COVID-19. Methods: We conducted a retrospective single-center analysis of 192 hospitalized COVID-19 patients from March to May of 2020. AKI was diagnosed using the Kidney Disease Improving Global Outcome (KDIGO) classification based on serum creatinine (SCr) criteria. Persistent and Transient AKI were defined according to the Acute Disease Quality Initiative (ADQI) workgroup definitions. Results: In this cohort of COVID-19 patients, 55.2% developed AKI (n=106). The majority of AKI patients had persistent AKI (n=64, 60.4%). Overall, in-hospital mortality was 18.2% (n=35) and was higher in AKI patients (28.3% vs 5.9%, p<0.001, unadjusted OR 6.03 (2.22-16.37), p<0.001). In this multivariate analysis, older age (adjusted OR 1.07 (95% CI 1.02-1.11), p=0.004), lower Hb level (adjusted OR 0.78 (95% CI 0.60-0.98), p=0.035), duration of AKI (adjusted OR 7.34 for persistent AKI (95% CI 2.37-22.72), p=0.001) and severity of AKI (adjusted OR 2.65 per increase in KDIGO stage (95% CI 1.32-5.33), p=0.006) were independent predictors of mortality. Conclusion: AKI was frequent in hospitalized patients with COVID-19. Persistent AKI and higher severity of AKI were independent predictors of in-hospital mortality.

Since late 2019, the coronavirus disease 2019 (COVID-19) outbreak has resulted in over 130 million cases worldwide as of april 2021. (1, 2) The World Health Organization (WHO) classified COVID-19 as a pandemic which has been associated with significant morbidity and caused over 2.8 million deaths. (3) The majority of patients present with mild symptoms including fever, dyspnea, cough, headache and diarrhea or are even asymptomatic. (4, 5) More severe cases of pneumonia can lead to acute respiratory distress syndrome (ARDS), septic shock, multiple organ failure and death. (6, 7) Current literature reports that the incidence of acute kidney injury (AKI) in COVID-19 patients ranges widely from 0.5 to 45% and has been associated with worse prognosis.

The disparities in incidence reports may result from different definitions to classify AKI, different populations studied, different admission criteria and different resources in countries studied. (7) (8) (9) (10) (11) (12) (13) (14) AKI is characterized by a rapid decrease in renal function defined as an increase in serum creatinine (SCr) and/or a decline in urine output (UO). (15) AKI 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. (16) AKI is a frequent complication in ARDS patients, namely in older patients and patients with significant comorbidities. (17) In COVID-19 patients, kidney impairment appears to be multifactorial resulting from systemic inflammatory response to volume loss, sepsis, local disruption in renin angiotensin aldosterone system (RAAS) homeostasis, rhabdomyolysis, and it is also suggested that the virus might have direct cytopathic effects. (14, 18, 19) The present study retrospectively analyzed data to study the incidence, severity, duration, risk factors and prognosis of AKI in hospitalized patients with COVID-19.

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 noninterventional nature.

We selected as eligible all adult patients (≥18 years of age) who tested positive by polymerase chain reaction (PCR) testing of a nasopharyngeal sample for COVID-19 and were admitted at the UICIVE from March 1st to May 31st of 2020. For patients who had multiple qualifying hospital admissions, we included only the first 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. 

The analyzed outcomes were the development of AKI during the first week of admission and in-hospital mortality. The Shapiro-Wilk test was used to assess the normal distribution of variables. Categorical variables were described as the total number and percentage for each category, whereas continuous variables were described as the mean ± standard deviation or median and range. 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 significant factors which may have contributed to AKI development and in-hospital mortality.

Subsequently, only variables with a significant statistical difference in the univariate analysis were included in the multivariate analysis using the logistic regression method.

Data were expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Statistical significance was defined as a P-value <0.05. Statistical analysis was performed with the statistical software package SPSS for windows (version 21.0).

From March 1st to May 31st, 217 patients were admitted to UICIVE with a diagnosis of COVID-19 on admission. We focused on 192 patients after excluding 25 patients as depicted in Figure 1 .

A majority of Caucasian (n=174, 90.6%) males (n=100, 52.1%) were hospitalized with a mean age of 72.2±16.4 years. There was a large prevalence of hypertensive (n=131, 68.2%), CVD (n=68, 35.4%), diabetic (n=54, 28.1%) and CKD (n=38, 19.8%) patients.

Baseline creatinine was estimated in 5.7% of patients (n=11). Forty-two percent of patients were medicated with RAAS inhibitors. Almost 20% of hospitalized patients (n=38) required admission to an intensive care unit (ICU) mostly due to respiratory failure, 15.1% of patients fulfilled ARDS criteria and 16.7% of patients required mechanical ventilation. Most patients had a SOFA score of at least 2 (57.8%), and 12.5% of patients had a SOFA score of at least 4. Almost 30% of patients had a BCRSS score of at least 2.

At admission, median SCr was 1.00 (0.37-19.10) mg/dL, mean hemoglobin was 13.0±2.1 and almost 40% of patients were anemic, mean NL ratio was 6.49±5.71, mean serum albumin was 3.37±0.59 g/dL and more than 70% of patients had hypoalbuminemia, median serum ferritin was 707.0 (66.0-7884.0) ug/L, mean CRP was 9.71±8.72mg/dL, mean lactate level was 15.65±10.60 mg/dL and 27% of patients were acidemic.

During the first week of admission, 20.8% of patients were exposed to nephrotoxins, namely NSAIDS, radiocontrast, vancomycin or aminoglycosides. Concerning treatment, a vast majority of patients were medicated with hydroxychloroquine (n=140, 72.9%) and lopinavir/ritonavir (n=128, 66.7%). Only 3 patients were treated with tocilizumab and 10.9% of patients required corticosteroids. Mean time to ICU admission was 3.2±1.8 days.

Median length of hospital stay was 15 (0-136) days. Baseline characteristics of this cohort are described in Table 1 . J o u r n a l P r e -p r o o f

In this retrospective cohort of hospitalized patients, 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 persistent and had lower severity changes in renal function.

Remarkably, only persistent AKI and higher severity AKI were associated with mortality in these patients.

Recent 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. (30) This 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. (11) In another study, the incidence of AKI ranged from 3.5% in moderate disease patients to 42.9% in critically ill patients. (31) Furthermore, AKI patients had a higher mortality rate. (32) Indeed, AKI was most often present in more severe cases of COVID-19. (33) In our cohort of hospitalized COVID-19 patients, AKI was present in 55%. The more frequent use of hydroxychloroquine and corticosteroids in AKI patients in our cohort reflects the presence of moderate to severe disease in these patients, in the first months of the pandemic when this was common practice. This severity of COVID-19 in our cohort explains the large incidence of AKI. Indeed, patients with AKI had higher BCRSS scores.

The fact that 30% of AKI patients required ICU admission within the first week of admission, also points out the contribution of AKI to disease severity. The etiology of AKI in patients with COVID-19 appears to be multifactorial, due to direct cytopathic effects and indirect lesion. The mechanisms include ischemic injury due to fluid loss and heart failure, cytokine release syndrome, exposure to nephrotoxins, rhabdomyolysis, microcirculatory thrombi, hypercoagulability, direct podocyte and epithelial lesion, RAAS activation and renal vasoconstriction. (19, 35, 36) Consistent with this, in our cohort AKI was more frequent in patients with higher disease severity, higher inflammatory markers and also in patients exposed to nephrotoxins, namely contrast, nonsteroidal anti-inflammatory drugs, vancomycin and aminoglycosides.

Despite the considerable focus on the use of RAAS inhibitors and severity of COVID-19, as it is theorized that the intake of these drugs might enable virus entry and replication, which relies on bonding to the angiotensin converting enzyme 2 (ACE-2), in both Hirsch's study and in our cohort the use of RAAS inhibitors was not associated with AKI development or mortality. (37) (38) (39) AKI has been associated with an increased risk of in-hospital mortality in multiple settings. (16, 40) The mortality rate of COVID-19 is estimated to be around 6% worldwide, still 81% of COVID-19 cases are mild. (1) The rate of mortality in hospitalized patients ranges from 10-30% and is much higher in critically ill patients. (9, 41, 42) Cheng et al demonstrated that renal dysfunction defined as either elevated baseline SCr, hematuria, proteinuria and AKI, was associated with mortality in a prospective cohort of 701 hospitalized patients with COVID-19. (43) Despite reporting an incidence of AKI of only 5.1%, this study reported a higher risk of mortality according to AKI severity. (44) Lim et al studied 164 hospitalized patients with an AKI incidence of 18% and demonstrated that AKI KDIGO stage 3 was independently associated with mortality. (45) AKI was also an independent risk factor for hospital mortality in a prospective study by Portolés et al. (46) This is also consistent with the results of our cohort, as we reported an increased risk of mortality with the severity of AKI (adjusted OR 2.65 per increase in KDIGO stage (95% CI 1.32-5.33), p=0.006)).

Our cohort is the first to study the impact of AKI duration in COVID-19 patients and its association with outcomes. Indeed, the association of rapid kidney function recovery and better short-term survival has been previously reported in other settings. ( to nephrotoxins or hemodynamic changes and persistent AKI is more likely a result of conditions less easily reversed and these patients may consequently require more RRT. 50, 51 Rubin 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%). ( 52 ) In their study, clinical and laboratory characteristics were similar between patients with persistent and transient AKI. ( 52 ) These findings were also present in our cohort. Interestingly, a prospective study of 52 critically ill COVID-19 patients reported that 50% of patients with AKI stage 2 progressed to stage 3, and 28% required RRT. 53 We demonstrated that persistent AKI was present in 60% of patients and was associated with a significant increase in mortality risk (adjusted OR 7.34 for persistent AKI (95% CI 2.37-22.72), p=0.001). In our study, transient AKI did not carry an increased risk for in-hospital mortality. This highlights the importance of assessing the severity and duration of AKI as both influences prognosis.

Our study has some important virtues. This is the first study demonstrating an association between duration of AKI and mortality in patients with COVID-19. We defined AKI according to the KDIGO classification using SCr criteria. Additionally, we applied the standardized definitions of transient and persistent AKI as defined 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.

Nevertheless, this study has certain limitations. Firstly, the single-center and retrospective nature of our study limits generalizability. Secondly, the small size of our cohort may have compromised, at least in part, the results. Thirdly, 5.7% 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 find predictors of persistent AKI in this modest cohort J o u r n a l P r e -p r o o f size, further studies should focus on this matter to allow for the early recognition of highrisk patients.

 AKI is a frequent diagnosis in hospitalized patients with COVID-19  In this cohort, more than 50% of patients had AKI  Most AKI episodes were persistent (longer than 48 hours) and of lower severity  Persistent and higher severity of AKI were predictors of in-hospital mortality 

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Page 26 of 29 J o u r n a l P r e -p r o o f AKI acute kidney injury, ARDS acute respiratory distress syndrome, CRP c reactive protein, CKD chronic kidney disease, CVD cardiovascular disease, COPD chronic obstructive pulmonary disease, ICU intensive care unit, GFR glomerular filtration rate, LOS length of stay, NL neutrophil and lymphocyte, RRT renal replacement therapy, RAAS renin angiotensin aldosterone system, SCR serum creatinine, SOFA sequential organ failure assessment ICU admissionn (%) 38