Reduction of estimated glomerular filtration rate after COVID-19-associated acute kidney injury

ABSTRACT Introduction: Acute Kidney Injury (AKI), a frequent manifestation in COVID-19, can compromise kidney function in the long term. We evaluated renal function after hospital discharge of patients who developed AKI associated with COVID-19. Methods: This is an ambidirectional cohort. eGFR and microalbuminuria were reassessed after hospital discharge (T1) in patients who developed AKI due to COVID-19, comparing the values with hospitalization data (T0). P < 0.05 was considered statistically significant. Results: After an average of 16.3 ± 3.5 months, 20 patients were reassessed. There was a median reduction of 11.5 (IQR: –21; –2.1) mL/min/1.73m2 per year in eGFR. Forty-five percent of patients had CKD at T1, were older, and had been hospitalized longer; this correlated negatively with eGFR at T1. Microalbuminuria was positively correlated with CRP at T0 and with a drop in eGFR, as well as eGFR at admission with eGFR at T1. Conclusion: There was a significant reduction in eGFR after AKI due to COVID-19, being associated with age, length of hospital stay, CRP, and need for hemodialysis.

Introduction: Acute Kidney Injury (AKI), a frequent manifestation in COVID-19, can compromise kidney function in the long term.We evaluated renal function after hospital discharge of patients who developed AKI associated with COVID-19.Methods: This is an ambidirectional cohort.eGFR and microalbuminuria were reassessed after hospital discharge (T1) in patients who developed AKI due to COVID-19, comparing the values with hospitalization data (T0).P < 0.05 was considered statistically significant.Results: After an average of 16.3 ± 3.5 months, 20 patients were reassessed.There was a median reduction of 11.5 (IQR: -21; -2.1) mL/ min/1.73m 2 per year in eGFR.Fortyfive percent of patients had CKD at T1, were older, and had been hospitalized longer; this correlated negatively with eGFR at T1. Microalbuminuria was positively correlated with CRP at T0 and with a drop in eGFR, as well as eGFR at admission with eGFR at T1. Conclusion: There was a significant reduction in eGFR after AKI due to COVID-19, being associated with age, length of hospital stay, CRP, and need for hemodialysis.

IntRoductIon
In addition to the respiratory system, COVID-19 affects other systems, such as the kidney, leading to Acute Kidney Injury (AKI).The pathogenesis of COVID-19-associated AKI involves direct virus injury to the kidney and indirect injury by cytokine storm, hypoxia, and hypoperfusion 1,2 .
The incidence of AKI due to COVID-19 can range from 4.7% to 55.9%, and AKI is associated with a higher mortality compared to patients without AKI [3][4][5] .About 32% of individuals with AKI associated with COVID-19 may not fully recover their kidney function after hospital discharge 6 .
Progression to CKD after AKI may be due to failure to recover from AKI, development of CKD after recovery from AKI, or progression of pre-existing CKD 7 .A longitudinal cohort found that 35% of patients who develop AKI associated with COVID-19 had reduced glomerular filtration rate (GFR) six months after hospital discharge 8 .
To date, there are no Brazilian data on the evolution of renal function in patients with AKI associated with COVID-19.Therefore, the objective of this study was to evaluate renal function after hospital discharge in patients who developed AKI associated with COVID-19.

methods
This was an ambidirectional cohort.The following data were collected from the medical records of patients hospitalized at Hospital Santa Casa de Misericórdia de Maceió (HSCMM) with COVID-19 who had AKI between March 2020 and May 2021 (T0): age, gender, length of hospital stay, comorbidities such as systemic arterial hypertension (SAH) and diabetes mellitus (DM), use of iACE or ARB, AKI stages according to AKIN, need for hemodialysis (HD), laboratory dosages (creatinine, urea, C-reactive protein -CRP, ferritin, lymphocyte count), pulmonary involvement of COVID-19 on chest computed tomography (CT)), need for invasive mechanical ventilation (IMV), and use of vasoactive amines.In a second moment (T1), the patients were reassessed and submitted to anamnesis, measurement of blood pressure (BP), and dosage of creatinine, microalbuminuria and urine summary.Creatinine values were used to estimate GFR using the CKD-EPI (2021) equation (eGFR).Sarcopenia was an exclusion criterion.Data were analyzed using IBM SPSS Statistics software for Macintosh (Version 23.0.Armonk, NY: IBM Corp).Categorical variables are presented as absolute count and relative frequency in percentages.To assess the association between categorical variables, the chi-square or Fisher's exact tests were used.Continuous variables were evaluated for normality using the Shapiro-Wilk test, and Q-Q plots, histograms, and dispersion measures.Variables with normal distribution are presented as mean ± standard deviation and those with non-normal distribution as median and interquartile range (IQR).Student's t-test and Mann-Whitney test were used for independent comparisons of normal and non-normal data, respectively.To compare two dependent groups, the paired t-test was used.Correlation analyses between continuous variables were performed using Spearman's non-parametric correlation with rho coefficient.P values < 0.05 were considered significant.The study was approved by the National Research Ethics Committee (CAAE 51031521.3.0000.5641)and patients gave their consent to participate in the study.
Mean T1 eGFR levels were lower compared to mean baseline eGFR (65.9 ± 21.7 vs 95.9 ± 16.7 mL/ min/1.73m 2 p < 0.001), which is a reduction rate of -11.5 (IQR: -21; -2.1) ml/min/1.73m 2 per year.Comparing clinical and laboratory characteristics on T0 and T1 between patients with eGFR < 60 and eGFR > 60 on T1 (Table 2), mean age and length of hospital stay were higher in the group of patients with eGFR < 60 (p = 0.023 and p = 0.003, respectively).Furthermore, patients with eGFR < 60 at T1 had lower levels of eGFR on admission (p = 0.041).In addition, the group with eGFR < 60 at T1 showed higher levels of albuminuria and the presence of microalbuminuria (albuminuria > 30 mg/g-Cr) more frequently than the group with eGFR > 60 (p = 0.041).There was no difference when comparing hematuria variables at T1, and most hospitalization parameters, including DM, SAH, use of IMV, use of vasoactive amines, pulmonary involvement of COVID-19 on chest CT, need for HD, ferritin, and lymphocyte count between eGFR groups at T1 (Table 2).

dIscussIon
There are few data on long-term progression to CKD in hospitalized patients who survived COVID-19associated AKI.This is the first Brazilian study on the subject, and it showed a significant reduction in eGFR after about 16 months of hospitalization, on average by 32.2% compared to baseline eGFR.A Chinese study that evaluated AKI associated with COVID-19 found a 19.8% reduction in eGFR 9 .In AKI due to other causes, the reduction in eGFR is around 17% 10 .
In the present study, the length of hospital stay was negatively correlated with eGFR at T1 and the average number of days in hospital was higher in patients who evolved with eGFR < 60 mL/min.In contrast, a Swedish study with methodology similar to ours did not find differences in hospitalization time between those who evolved to CKD and those who did not 11 .
Older age is associated with a greater chance of failure to recover to baseline renal function after an AKI episode and consequent progression to CKD 12 .In this study, patients who evolved to CKD were older than patients who did not.
eGFR on admission was correlated with a better renal outcome at T1, in line with a study that compared the renal function of patients with AKI of various causes with the degree of impairment of eGFR on admission, determining the decline in eGFR in the long term 13 .
CRP is a risk factor for AKI associated with COVID-19 14,15 and is also considered a predictor of worse clinical outcomes, such as severe AKI and slow renal recovery 14 .On the other hand, microalbuminuria is a well-established biomarker of progression to CKD 16 .In our study, there was a positive correlation between CRP levels at hospitalization and microalbuminuria eGFR ≥ 60 mL/min/1.73m 2 (n = 11) eGFR < 60 mL/min/1.73mcompariSon of characteriSticS between patientS with egfr < 60 and egfr > 60 at t1 levels at T1, reinforcing the inflammatory role in the progression to CKD.Furthermore, albuminuria levels also correlated positively with the drop in eGFR between T0 and T1.
There was no difference in the comparison between the other hospitalization variables in relation to the renal function assessment variables at T1.A similar study also found no association between these variables and progression to CKD, except for the need for HD and AKIN 3 11 .
A limitation of this study is the small sample size, which may have influenced the analysis of some variables and results.In addition, we recognize that the single measurement of eGFR can introduce bias during patient follow-up.
Patients with AKI associated with COVID-19 evolved with a significant reduction in eGFR after hospital discharge.Age, length of hospitalization, and need for HD were associated with a greater reduction in eGFR.Such results point to the need for routine nephrological evaluation in these patients.

Figure 1 .
Figure 1.Selection of patients and reasons for exclusion from the study.AKI: acute kidney injury.

Figure 2 .
Figure 2. Correlations between eGFR at T1 and T0, eGFR reduction, hospitalization time, CRP, and microalbuminuria.A: Positive correlation between hospitalization time and percent eGFR reduction between T0 and T1.B: Negative correlation between hospitalization time and eGFR values at T1. C: Positive correlation between microalbuminuria values at T1 and CRP values at T0. D: Positive correlation between microalbuminuria values at T1 and reduction in eGFR between T0 and T1.E: Positive correlation between eGFR values at T0 and eGFR values at T1. F: Negative correlation between eGFR values at T0 and reduction in eGFR between T0 and T1.

tAble 1
Summary of clinical and laboratory data of patientS in t0 and t1 and according to the need for hemodialySiS during hoSpitalization