COVID 19 and Acute Kidney Injury

Introduction

Coronavirus disease-19 (COVID-19) is caused by a beta-coronavirus, which has been named as severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) on February 11, 2020, by the International Committee on Taxonomy of viruses by the World Health Organisation (WHO).[1] It has been called SARS-Cov2 because the primary manifestations of the disease are severe respiratory tract involvement, similar to severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).[2]

AKI and SARS-CoV-2:Clinical Manifestations

Though COVID-19 manifests primarily as diffuse alveolar damage, interstitial pneumonia, and acute respiratory failure, the involvement of other organs such as the kidney, heart, digestive tract, blood, and nervous system is potentially possible.[8910] It has been reported that SARS-CoV and MERS-Co-V had infected more than 10,000 people in the past 2 decades, with mortality rates of 10% and 37%, respectively.[1112] In the previous reports of SARS and MERS-CoV infections, acute kidney injury (AKI) developed in 5% to 15% cases and carried a high (60%–90%) mortality rate.[13] A study reported that although AKI was uncommon in SARS but accounted for the fiercely high mortality of 91.7%, notably 33 out of 36 cases died.[14] Kidney involvement was a strong and independent predictor of mortality during the SARS and MERS outbreak, suggesting the similar situation for the kidney involvement with COVID-19 infection as well.

The incidence of AKI with COVID-19 has been reported varying from 3%–9%.[15161718] A large prospective study has reported the overall incidence of 5.1%.[7] In a study of 59 COVID-19 patients with 28 severe cases and 3 deaths, Li et al.[19] found that 34% of patients had proteinuria on the first day of admission, and 63% developed proteinuria during the hospital stay. Nineteen percent of people showed an elevated level of serum creatinine. Blood urea nitrogen (BUN) was elevated in 27% patients andin two-thirds of patients who died. Each one of those (27/27) who had computerized tomography (CT) abdominal scan showed radiographic abnormalities of the kidneys with reduced density suggesting inflammation and edema. The study also emphasized that renal impairment may be an independent factor of mortality.

In another larger prospective study, Cheng Y et al.[7] reported 701 patients (median age 63 years with interquartile range, 50–71 years, and 367 males) admitted in a tertiary teaching hospital following the outbreak of COVID-19 in Wuhan city of China. A total of 113 (16.1%) died in the hospital, and the median time to death was 6 days (IQR 3–12) days. On admission, 43.9% of patients had proteinuria, and 26.7% had hematuria. The prevalence of elevated serum creatinine, elevated BUN, and estimated glomerular filtration (eGFR) under 60 ml/min/1.73m² were 14.4%, 13.1% and 13.1%, respectively. Overall, AKI was reported in 5.1% of patients. Patients with kidney disease had a significantly higher risk of in-hospital death. Cox proportional hazard regression confirmed that elevated baseline BUN (3.97, 2.57–6.14), and elevated baseline serum creatinine (hazard ratio: 2.10, 95% CI: 1.36–3.26) was an independent predictor of mortality. It has also been observed that the hazard ratio for mortality also increases with the staging of AKI from 1.9 in stage 1, 3.51 in stage 2, and 4.38 in stage 3 AKI. The hazard ratio of mortality also increased with the degree of proteinuria and hematuria. These factors remain significant factors for in-hospital death after adjusting for age, sex, disease severity, comorbidity, and leukocyte count. The incidence of in-hospital mortality in patients with elevated baseline serum creatinine was 33.7%, significantly higher than patients with normal baseline serum creatinine (13.2%). However, the major limitation of the study was that base line coexisting chronic kidney disease (CKD) could not be assessed.

Mechanism of AKI with COVID-19

The mechanism of kidney involvement is at present speculative and appears multifactorial. The susceptible host, particularly elderly and people with underlying diseases like hypertension, cardiac diseases, bronchial asthma, diabetes, etc., are at a risk of severe disease. Like any other viral infection causing kidney injury, the direct viral cytopathic effect on kidney is a postulated mechanism. The virus does not show any evidence of renal tropism. The viral nucleic acid material of CoV in blood and urine in SARS-CoV infection as well as in COVID-19 patients, supports this hypothesis.[2021] Recently, SARS-CoV-2 from the urine sample of an infected patient has been isolated, suggesting the kidney as the target of this novel coronavirus.[22]

The molecular study showed SARS CoV-2 uses angiotensin-converting enzyme 2 (ACE2) receptor for cell entry like SARS-CoV. ACE2 and dipeptidyl peptidase-4 (DPP4), both expressed on renal tubular cells, were identified as binding partners for SARS-CoV and MERS-CoV, respectively.[2324] ACE2 expression is 100-fold higher in kidney tissues than the lung.[19] However, still clinical observation is different that there is more severe lung injury than kidneys in SARS and SARS-CoV-2 as well.

The normal glomerular pathology on microscopy and the absence of electron-dense deposit on ultrastructure microscopy in SARS-CoV patients, do not support the hypothesis of the immune complex-mediated glomerular injury though direct effector T cell-mediated injury could be another postulated mechanism.[14] Another important mechanism appears to be virus-induced sepsis and the release of cytokines in circulation leading to severe inflammatory response, hypotension, hypoxia, shock, and the aggrevation of target organ injuries, including kidneys as well. The clinical pictures of patients with COVID-19 with sepsis supports this hypothesis.

Most of the patients had mild symptoms with fever, sneezing, cough, sputum, and dyspnea, which indicate severe lower respiratory tract injury. The manifestations with severe COVID-19 are multi organ involvement, which includes respiratory events such as severe dyspnea and hypoxemia, renal impairment with reduced urine output, tachycardia, altered mental status, and functional alterations of other organs. The functional changes were expressed as the laboratory data of hyperbilirubinemia, acidosis, high lactate, coagulopathy, and thrombocytopenia. These patients may require intensive care unit treatment. Huang et al.[21] revealed that all of their 41 patients in the study had pneumonia with bilateral lobular and sub segmental consolidation on CT, and 32% of them required intensive care. The patients requiring intensive care had higher plasma cytokine levels of (interleukin [IL]-2, IL-7, IL-10, granulocyte-colony stimulating factor, interferon-inducing protein-10, monocyte chemoattractant protein 1, macrophage inflammatory protein-1a, and tumor necrosis factor α) on admission. These findings suggest that some of them may benefit from the removal of cytokines during continuous renal replacement therapy (CRRT).

Treatment

At present, the management strategies of COVID-19 with AKI is primarily conservative in the form of good hydration, nutritional support, paracetamol for fever, headaches and body aches, and antibiotics in the case of secondary bacterial infection only, with aiming for the self-recovery. Along with patient treatment, spread to others also should be given importance. The patient with respiratory distress may require oxygen therapy and intensive care with ventilatory support in the case of acute respiratory distress syndrome. All confirmed COVID-19 patients need to be isolated. An N95 fit-tested respirator and protective clothing and equipment are essential for patients, and the caregivers should also use appropriate approved personal protective equipments (PPEs).

There is no evidence-based effective antiviral therapy available. In a prospective study of AKI with COVID-19, the three most used medicines were antivirals (73.0%), antibiotics (71.0%), and glucocorticoid (36.9%). Antivirals showed mortality benefit, and the glucocorticoids did not, which is possible because clinicians have used steroids mainly in the terminally sick patients. The varieties of anti virals were used, including arbidolhydrochloride, ganciclovir, interferon, lopinavir and ritonavir, oseltamivir, and ribavirin. However, there was no significant difference on AKI with these therapies.[7]

The most recent New England Journal of Medicine (NEJM) study of a randomized controlled trial[29] showed no mortality benefit of treatment with lopinavir-ritonavir combination (19.2%) as compared to the standard of care arm (25%). The median time of clinical improvement was only one day shorter in the treatment arm. Lopinavir-ritonavir treatment was stopped early in 13.8% because of adverse events. With some success story with remdesivir in COVID-19 treatment, a clinical trial is currently going on.[30] Chloroquine phosphate showed some efficacy against COVID-19 associated pneumonia in a multicentre clinical trial conducted in China.[31] The National Taskforce for COVID-19 by the ICMR recommended the use of hydroxy-chloroquine for prophylaxis of SARS-CoV-2 infection for healthcare workers involved in the care of suspected or confirmed cases of COVID-19 in a dose of 400 mg twice a day on Day 1, followed by 400 mg once weekly for next seven weeks; and for household contacts of laboratory-confirmed cases in the dose of 400 mg twice a day on Day 1, followed by 400 mg once weekly for next three weeks; to be taken with meals. The warning with this advisory also mentioned that the health care workers should not have a false sense of security with this chemoprophylaxis and other preventive measures should remain continued.[3233]

Few retrospective analyses showed benefit with the use of glucocorticoids in SARS-CoV infection.[3435] Metanalysis on the use of glucocorticoids in previous SARS-CoV infection do not support the use of glucocorticoids in COVID-19 as well. In a meta-analysis of corticosteroid use in patients with SARS, four studies showed harm with higher psychosis, diabetes, avascular necrosis, and delayed viral clearance.[36] WHO does not recommend the use of steroid expecting potential inhibition of viral clearance and prolongation of the duration of viremia.[37]