A Prospective Study of Incidence, Risk Factors, and Outcomes of Acute Kidney Injury in Coronavirus Disease 2019

Introduction

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), leading to coronavirus 2 (COVID-19), was detected 1^st time in Wuhan, China, in December 2019 and declared a pandemic by the World Health Organization (WHO) on March 11, 2020.¹ In India, the first wave of COVID-19 occurred between October to December 2020, and the second, more deadly wave due to a delta variant between April to June 2021.² Most of the patients infected with COVID-19 develop a variety of symptoms ranging from cough, sore throat, fever, diarrhea, and headache; however, a small proportion advance to severe lung disease characterized by acute hypoxic respiratory failure requiring oxygen supplementation to non-invasive ventilatory support to the requirement of mechanical ventilation.^3,4 COVID-19 primarily manifest as a respiratory tract infection, the data indicate that it should be regarded as a systemic disease involving multiple systems, including cardiovascular, respiratory, gastrointestinal, neurological, hematopoietic, immune, and kidneys.^3-5 The kidneys are the second most frequently affected organ by COVID-19 after the lungs.^6,7

Acute kidney injury (AKI) is one of the most frequently encountered complications of COVID-19 infection.^6-8 The reported incidence of AKI varies worldwide due to geographical differences in the incidence of COVID, level of care provided and the need for hospitalization.^6-8 In a meta-analysis of 20 cohorts worldwide, the incidence of AKI during admission ranged from 0.5% to 80.3%.⁸

AKI in COVID-19 can lead to a variety of consequences including prolonged hospitalization, higher morbidity and higher in-hospital mortality.^7-9 Studies have reported a mortality rate of 35–52% in severe COVID-19 with AKI needing kidney replacement therapy (KRT).^7,8

Although there are numerous studies on the incidence of AKI in COVID-19 from many countries, most of the studies are retrospective in nature, and secondly, there is little data from the Indian subcontinent. The data from India are important as there might be differences in geographical conditions, susceptibility, risk factors, and outcomes in the Indian population. We conducted a prospective observational study of incidence, risk factors, and outcomes of AKI in COVID-19 disease from a large tertiary care center in North India.

Materials and Methods

The study was conducted in a large tertiary care multi-super specialty hospital in the national capital region of Delhi between September 1, 2020, and December 31, 2020. During this period, 921 patients were admitted to the hospital. After excluding 65 patients [<18 years of age, known chronic kidney disease [CKD] on maintenance hemodialysis (MHD) or continuous ambulatory peritoneal dialysis, or those who were discharged/died within 24 h of admission], 856 patients were enrolled in the study. This study was duly approved by the Ethics Committee of our institute (Ref-MICR-1142/2020). We prospectively analyzed these 856 patients to know the incidence, risk factors, and outcome of AKI and followed up for 3 months to see how many of these developed CKD. The data were collected for baseline characteristics, functional parameters, comorbidities, treatment regimen, and outcomes.

Out of these 856 patients, 207 developed AKI and these were compared with 649 patients who did not develop AKI. AKI was diagnosed based on the KDIGO-2012 criteria.¹⁰ KRT was performed for standard indications such as stage 3 AKI with uremic symptoms, refractory fluid overload, metabolic acidosis, or hyperkalemia. Sustained low-efficiency dialysis and continuous renal replacement therapy were performed in those who developed hemodynamic instability.

Statistical analysis

The data were analyzed using the Statistical Package for the Social Sciences (SPSS) Statistics version 21. All the variables were tested for normality using Kolmogorov–Smirnov test. Categorical variables were summarized as frequencies and proportions, while continuous variables as mean, medians, and range interquartile range (IQR). Univariate analysis was first carried out to assess the relationship between variables and AKI incidence. Chi-square was used to test the difference between two proportions and Mann–Whitney U-test was used to test the difference between two medians. The variables significant in univariate analysis were considered for multivariable regression analysis. A binary logistic regression technique with enter method was done to predict the independent variable (AKI incidence). Fitness, if the model was determined by Hosmer–Lemeshow goodness-of-fit statistic and Nagelkerke R². Survival analysis was done using Kaplan Meier’s Survival Analysis [Figure 1]. Significance was considered at P < 0.05.

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Figure 1:

Kaplan Meier’s survival analysis between acute kidney injury (AKI) and non-AKI (320 × 320 pixel).

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Results

The demographics of AKI and non-AKI groups are listed in Table 1. Patients who developed AKI were older as compared to the non-AKI group (58.19 vs. 51.07, P < 0.001). Diabetes, coronary heart disease (Coronary artery disease [CAD] [18%]), chronic liver disease (CLD), chronic obstructive pulmonary disease (COPD), and CKD were common in AKI group. The baseline hemoglobin, total and absolute lymphocyte count, and estimated glomerular filtration rate (eGFR) were lower in the AKI group, whereas CRP, LDH, D-dimer, and ferritin were significantly higher in those with AKI [Table 1]. Those with AKI had significant lung involvement on admission as compared to those without AKI (CTSS 26 vs. 15, P ≤ 0.001) [Table 2].

Discussion

In this single-center prospective study of COVID-19-associated AKI, we analyzed the incidence, risk factors, and outcomes in hospitalized patients with AKI. We also followed those with AKI for up to 90 days for renal recovery or conversion to CKD, which was lacking in many earlier studies.^6,7,9

In our study, we found that 24.18% of patients hospitalized with COVID-19 developed AKI. The rate of AKI reported to date has ranged from 0.5% to 29% in various studies, which might be due to the adoption of different definitions, the severity of AKI and the population studied.^6-8,15-18

In our study, the incidence of AKI in ICU patients was 88%, which is higher than in the previous studies in which incidence ranged from 8% to 62%.^6,7,16-18 This difference could be explained by the fact that most of our patients admitted to ICU had severe disease and, 36% of all patients required mechanical ventilatory support. Patients admitted with mild-to-moderate disease were managed in wards during hospitalization and received oxygen support as required. In our study, 70% of patients had moderate to severe COVID-19 diseases at admission. In our study, patients who developed AKI were older as compared to the non-AKI group (58.19 vs. 51.07, P = 0.0001). This was similar to seen in many previous studies.^6-8

Risk factors such as diabetes mellitus (DM), CAD, COPD, CKD, and CLD were significantly associated with the development of AKI in our study. Patients with DM were twice more likely to develop AKI as compared to non-diabetics in our study. This finding was in line with previously published studies in which similar risk factor were associated with the development of AKI.^6-8 CKD was found to be a significant risk factor for AKI in our study.

Patients who developed AKI also had significant increases in inflammatory markers, on admission which include CRP, ferritin, D-dimer, and LDH. Several studies have shown increased proinflammatory cytokines in the serum of COVID-19 patients.^16,18,19 The RECOVERY trial has shown the beneficial effects of corticosteroids for the treatment of moderate to severe disease in those requiring oxygen support, accordingly, most of our patients’ received steroids in doses of 40–80 mg/day. Remdesivir has been shown to fasten recovery and reduce hospitalization in some previous studies; however, it is usually not recommended in patients with eGFR <30 mL/min until an Indian study used remdesivir in patients with End stage kidney disease (ESKD) on MHD, and it was well tolerated.²⁰ Remdesivir was used in 45% of patients in our study and we did not encounter any serious side effects. Some studies have also used other anti-inflammatory agents, particularly IL-6 inhibitor-tocilizumab in patients with cytokine storm; however, the results are mixed.²¹ We used tocilizumab in 12% of our patients, however as the numbers were small, it is difficult to make any conclusion about its efficacy in severe disease from this study.

In our analysis, the risk factors for the development of AKI were indicators of severe COVID-19, specifically the need for ventilator support (88%, P < 0.001) or vasopressor drug treatment (64%, P < 0.001). Studies have shown that the use of invasive mechanical ventilation was associated with an increased risk of AKI by about fourfold.^18,22

In our study, 180 patients died, with a mortality rate of 21.02%. The mortality was significantly higher in patients with AKI as compared to those without AKI (153/207 vs. 27/649, P = 0.0004) and more so in those requiring KRT (153/173). A similar higher mortality ranging from 35% to 52% has been reported in patients with COVID-19 and AKI, and mortality is higher in patients who require KRT and mechanical ventilation as in our study.^7,23,24

In our study, renal recovery was seen in 21/54 (39%) patients with AKI who were discharged. The rest 33 (61%) patients developed AKD. In a study by Chan et al., renal recovery was 65 % at discharge.¹⁶ This lower rate of renal recovery could be explained by the severity of diseases on admission.

We also followed those with AKD on discharge for 90 days. Out of the 54 AKI survivors, 10 (18.5%) patients were converted into CKD, which was similar to a study by Lumlertgul et al. who showed that 16% of all AKI survivors developed CKD at 3 months.¹⁸

This study has many strengths: It was a prospective study in which the patients were meticulously followed up and have follow-up data about CKD conversion.

The limitation of this study is that it was a single-center study.

Conclusion

AKI is common in patients with COVID-19. Patients with severe COVID-19 disease were more likely to require mechanical ventillation, inotropic support and kidney replacement therapy and had high mortality. Approximately one fifth of surviving patients developed CKD on three months follow up.