Acute Kidney Injury in COVID-19: Clinical Profile and Outcome

Introduction

Acute kidney injury (AKI) has been commonly described among coronavirus disease 2019 (COVID-19) patients. The initial studies, mainly from China, showed a much lower incidence rate of around 3.6%[1] to 5.1%.[2] However, later reports, especially from the West have shown higher AKI incidence rates. A study of 5,700 patients from New York[3] has shown AKI in COVID-19 patients to be around 22% among discharged and 67% among deceased patients.

The pathogenesis of AKI in COVID-19 is multifactorial with profoundly interconnected pathways of cytokine storm, organ cross-talk, systemic effects, and various mechanisms of renal involvement that include[45] prerenal azotemia, cytokine release (acute tubular necrosis [ATN], myoglobin cast nephropathy, collapsing glomerulopathy, and thrombotic microangiopathy), direct viral invasion, medication-induced effects (acute interstitial nephritis [AIN] with antiviral agents, oxalate nephropathy with vitamin C, and various antibiotics causing AIN/ATN). COVID-19 patients with AKI have high mortality ranging from 35% to 71%, and mortality is even higher in Stage 3 AKI ranging from 52% to 88% regardless of RRT usage.[6] AKI secondary to other causes is associated with an eightfold increased risk of developing the end-stage renal disease (ESRD).[7] It is, therefore, conceivable that survivors of COVID-19 AKI will be at increased risk of progression to CKD.

Mumbai was one of the initial hotspots of COVID-19 infection in India, and ours was the first fully COVID-19 dedicated tertiary government hospital in Mumbai. Information regarding incidence rate, the clinical course of AKI, and mortality among our population is extremely limited, and no long-term data regarding their follow-up and CKD progression are available till now. This study was undertaken to address the above points.

Methodology

This was a prospective, observational single-center study to assess the clinical profile and outcome of AKI in patients with COVID-19 disease admitted in a tertiary care hospital, from June 1, 2020, to August 25, 2020, after obtaining permission from the Institutional Ethics Committee. They were followed up telephonically 3 months later to determine if renal functions had returned to baseline or if they had progressed to CKD with available previous serum creatinine levels; the latest serum creatinine before admission was noted as the baseline serum creatinine. In patients with unknown previous renal function, imputation of baseline creatinine was done by entering back-calculated values using the MDRD (Modification of Diet in Renal Disease) formula with a target glomerular filtration rate of 75 mL/minute/1.73 m². However, if the nadir creatinine during hospital admission or at 3 months follow-up was lesser than the imputed value, the baseline creatinine was corrected to the nadir creatinine value.

Results

A total of 4,613 patients with SARS-CoV-2 infection were admitted to the hospital from June 1, 2020, to August 25, 2020, of which 146 (3.16%) patients had AKI [Table 1]. The outcomes were available for 111 patients at the end of the study period; 35 patients were without outcome (discharge/mortality) and hence not included in the data set. Limited manpower availability during the pandemic made it difficult to collect their data retrospectively.

While most of these patients had severe COVID-19 disease, 18.9% of patients developed AKI despite having mild COVID symptoms, without any features of ARDS. Our patient set was from the early phase of the pandemic, wherein 4,613 COVID-19 patients were admitted in 86 days, with resources limited comparatively; thus kidney biopsy was logistically not possible. Baseline details of subjects are shown in Table 2. At admission, the patients had been symptomatic for a mean of 6.29 ± 3.09 days. Most patients were nonoliguric (57.7%) at diagnosis of AKI. About 37% of patients had hypotension and needed inotropes.

Overall, out of 111 patients, 20 (18%) patients were Stage 1 AKI, 16 (14%) were Stage 2 AKI, and 75 (68%) were Stage 3 AKI. Out of 111 patients, 45 (40.54%) patients needed RRT [Table 1]. The patients were dialyzed for clinical and biochemical indications such as uremia, fluid overload, hyperkalemia, or metabolic acidosis. The increasing stage of AKI was not associated with increased mortality. However, hemodialysis initiation was a poor prognostic marker (P = 0.022) with two-thirds of patients eventually dying, and the majority (70%) of them dying within 4 days of initiation (P < 0.001) of hemodialysis. Dialysis in all our patients was provided as SLED/HD. Acute peritoneal dialysis was not done in any patients.

At the time of discharge, AKI recovered completely in 31 of 53 (58%) patients and partially in 20 of 53 (38%) patients. AKI did not recover in two of 53 (4%) patients [Figure 1]. Patients with underlying CKD fared like AKI patients in terms of recovery of renal functions at discharge (66% vs. 56%). Investigations are mentioned in detail in Table 3. Urine abnormalities [Table 4] were seen in most patients.

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Figure 1

Of 111 patients, 58 patients died in the hospital. A total of 53 patients of COVID-19 with acute kidney injury were discharged, of whom 31 (28%) patients had complete remission, 20 (18%) patients had partial remission, and two (2%) patients had no remission of acute kidney injury

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Over the 3 months, treatment protocols changed with gathering evidence [Table 5]. Steroids were given as methylprednisolone 80 mg/day for 7 to 14 days or dexamethasone 6 mg tablet once daily. All patients received antibiotics. Patients of AKI were switched to unfractionated heparin (81.1%) from low-molecular-weight heparin. Three months follow-up outcome is shown in Table 6. The mortality of AKI patients with COVID-19 at 3 months was found to be 55.85%. Similarly, eight out of 20 (40%) patients who had partial recovery of renal functions at discharge progressed to CKD at 3 months [Figure 2].

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Figure 2

A total of 53 out of 111 COVID-19 patients who had AKI were discharged. Thirty-one had complete recovery, 20 had partial and, two out of 53 had no recovery. After 3 months follow-up, among patients with complete recovery (n = 31), 16 progressed to CKD, 14 recovered renal functions, and one died. Among patients with partial renal recovery at discharge (n = 20), eight progressed to CKD, nine recovered renal functions, and three expired. Both patients with no renal recovery at discharge progressed to CKD AKI: Acute kidney Injury; CKD: chronic kidney disease

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Discussion

AKI incidence rate (3.16%) in our hospitalized study population of COVID-19 patients was comparable with other eastern countries such as China[10] even though the Western countries have much higher incidence rates of around 22% to 40%.[311] AKI incidence of 8.6% has been noted by a South Asian country in intensive care unit COVID-19 admissions.[12] Greater age; comorbidities, mainly diabetes; and need for mechanical ventilation are some of the important factors associated with increased AKI incidence. The wide variation in incidence is probably related to population demographics, variable inclusion criteria, and AKI risk factors.[13] Comorbidities were present in around two-thirds of our patients. Diabetes was present in 64% of our population and was associated with high in-hospital mortality. These patients often were found to have DKA on admission and secondary infections such as cellulitis. Control of blood sugar levels was especially challenging considering all of them were given steroids for 14 days and most patients requiring continuous insulin infusions. In a Spanish study of 11,312 patients with COVID-19 disease, regardless of the previous history of diabetes, admission hyperglycemia was found to be an independent risk factor for mortality.[14]

AKI is more common in severe COVID-19 disease. Patients of AKI who died in our cohort had a statistically significantly higher incidence of dyspnea (95%), encephalopathy (83%), fluid overload (20.7%), and hypotension needing inotrope support (68.9%) and oxygen support (100%) when compared with survivors. Patients needing mechanical ventilation had the worst prognosis with no patients surviving in our study. Although most patients of AKI (80%) had underlying ARDS, up to 20% of patients developed AKI despite having a milder disease and no ARDS suggesting different mechanisms from organ cross-talk, sepsis, cytokine storm, and maybe direct viral nephrotoxicity.

The mortality rate of AKI in our cohort was high with 52.25% of patients dying in the hospital and an additional 3.6% of patients at home after discharge, amounting to a total mortality rate of 55.85%. This is much higher than the COVID-19 mortality rate in the general population, which is estimated to be around 2% to 9% the world over.[15] AKI is an independent risk factor for mortality in COVID patients. COVID-19 patients with AKI have high mortality ranging from 35% to 71%, and mortality is even higher in Stage 3 AKI patients ranging from 52% to 88%, regardless of RRT usage.[6]

Of all the COVID-19 AKI patients in our study, less than one-third of patients (28%) were discharged to home with complete recovery of renal functions, and at 3 months only 21% were alive with fully recovered AKI. Among patients who survived post-COVID-19 AKI, almost half (49%) progressed to CKD. A similar study of follow-up of COVID-19 AKI patients from New York[16] studied 1,835 patients of COVID-19 AKI and followed them up for a median of 21 days post-discharge. A total of 832 patients were discharged, of which 65% had complete recovery of renal functions, and 35% had acute kidney disease (AKD). Follow-up creatinine values were available for 212 patients. Around 18% of patients with complete recovery and 64% of AKD patients on follow-up had persistent renal dysfunction. The SARS-CoV-2 virus enters the host cell via membrane-bound ACE2, which is also present on podocytes and renal tubular cells. Autopsy studies and renal biopsy series have found most patients to have diffuse acute tubular injury along with other findings such as collapsing glomerulopathy, thrombotic microangiopathy, and myoglobin cast nephropathy. Electron microscopy in some, but not all, studies has shown the presence of SARS-CoV-2 viral particles in the kidney.[171819] Direct viral effects with collapsing glomerulopathy, endothelial damage, coagulopathy, and complement activation may be responsible for incomplete recovery. Given that COVID-19 is a pandemic that has already affected millions of people worldwide with a high incidence of AKI and potentially higher incomplete recovery, as seen in our study, close surveillance after discharge in this group is essential.

In some studies, CKD was found to be an independent risk factor for mortality.[2] Although AKI was associated with high mortality overall, patients with underlying CKD were similarly distributed among the survivor and mortality groups in our cohort.

In our study, proteinuria was seen in 66%, leukocyturia in 38%, and hematuria in 42% as per urine dipstick findings. Of these, hematuria and leukocyturia were seen in significantly higher numbers in the mortality group. A study by Cheng et al.[2] revealed hematuria and proteinuria in 43.9% and 26.7% COVID-19 AKI patients, respectively, and the presence of these both was associated with a higher risk of mortality. Another study by Hirsch et al.[20] from New York noted proteinuria, hematuria, and WBC in urine in 64%, 74%, and 36.5% of AKI patients, respectively. Inflammatory markers including ESR, ferritin, IL-6, and LDH were all raised in our whole cohort, and the difference between the survivors and deceased was statistically significant. As with other studies, lymphopenia with a high NLR ratio (P = 0.004) was also seen in a higher proportion of patients who died.[21]

Rhabdomyolysis has been associated with AKI in some studies.[2223] In our study, higher CPK levels were associated with increased risk of mortality, but they were not quantitatively as high as seen in diagnosed cases of rhabdomyolysis, which are typically >1,000 units/L.