COVID-19 and acute kidney injury – A new medical condition

Natália Silva¹, Catarina Isabel Ribeiro²

Both authors contributed equally to this work

Correspondence to:

ABSTRACT

Thus the authors consider the development of acute kidney injury in patients with COVID-19 an important issue, worthy of clinical attention, and they present this point in the current review.

Keywords:Coronavirus Disease 19 Infection; Severe Acute Respiratory Syndrome-CoV-2; Acute Kidney Failure

INTRODUCTION

COVID-19 is an abbreviated name for coronavirus disease 2019, suggested by the World Health Organization¹. In December of 2019, this new coronavirus infection ravaged the city of Wuhan, sweeping not only through China, but also spreading to many countries around the world^2-6.

COVID-19 is highly contagious and person-to-person transmission routes include droplet inhalation transmission (through coughing or sneezing), and direct contact with oral, nasal and eye mucous membranes^7,8.

The estimated incubation period is 1 to 14 days. The common clinical manifestations include fever, unproductive cough, dyspnea, myalgia, and fatigue, with accompanying leucopenia and lymphopenia^5,7.

It is well documented that the lungs are the main target organ of the new coronavirus, and the incidence of acute respiratory distress syndrome in patients with COVID-19 is reported to be up to 30% of cases. However, recent reports have also revealed involvement of other organs, including kidneys, especially in severe patients^9-11.

Identifying and eliminating factors predicting a negative outcome is key to improving survival from COVID-1912; thus the authors consider the development of acute kidney injury in patients with COVID-19 an important issue worthy of clinical attention. In this manuscript they review the most recent findings of the effects of SARS-CoV-2 infection on the kidney and examined the potential factors with impact on the outcomes of these patients.

A search was performed for clinical guidance standards, review articles, systematic reviews, meta-analyses and randomized controlled clinical trials on Medline, evidence-based medicine sites, index of Portuguese medical journals and bibliographic references of selected articles published in 2020, in Portuguese, English and Spanish, using the keywords (MeSH terms) “coronavirus infection”, “severe acute respiratory syndrome-CoV-2” and “acute kidney failure”.

CLINICAL REVIEW

Epidemiology

Acute kidney injury (AKI) is one of the most important complications of the 2019 novel coronavirus disease, occurring in 0.5 to 28% of cases^1,5,10,11. Different studies report a highly variable prevalence of AKI in COVID-19 hospitalized patients.

Luwen Wang et al. reported the clinical characteristics of 116 hospitalized COVID-19 patients and none met the diagnostic criteria of AKI during a 1 month follow-up¹³. On the other hand, a recent study of 193 hospitalized COVID-19 patients with follow-up of 1.5-2 months demonstrated that kidney dysfunctions, although they might not be readily diagnosed as AKI at admission, gradually worsened during hospitalization and were later diagnosed as AKI, especially in severe patients¹¹.

In a prospective cohort study of 710 COVID-19 cases, more than 40% had evidence of abnormal kidney function on admission and 5.1% had AKI during their hospital stay. The incidence of AKI was significantly higher in patients with elevated baseline Scr (9.1%) than in patients with normal baseline Scr (2.0%)¹².

Pathophysiologic mechanisms

The genomic characterization of SARS-CoV-2 revealed a significant phylogenetic distance from previously identified coronavirus that caused human diseases, sharing only 79% and 50% identity with SARSCoV and MERS-CoV, respectively^14,15.

Regardless of these differences, several studies reported that SARSCoV-2 uses the same membrane-bound angiotensin-converting enzyme 2 (ACE2) as SARS-CoV to gain access to its target cells¹⁶, although it has greater binding affinity¹⁷.

Recent studies have reported that the human kidney is a specific target for SARS-CoV-2 infection^19-21. The authors examined the viral nucleocapsid protein in situ in the kidney post-mortem and found that SARS-CoV-2 antigens accumulated in renal tubular epithelium and podocytes, suggesting that it infects the human kidney directly, inducing mitochondrial dysfunction, acute tubular necrosis, the formation of protein reabsorption vacuoles, collapsing glomerulopathy, and protein leakage in Bowman’s capsule.

The greater renal tropism of SARS-CoV-2 versus SARS-CoV could be explained by the increased affinity for ACE222. Recently, Zhong’s lab in Guangzhou successfully isolated SARS-CoV-2 from the urine sample of an infected patient, suggesting the kidney as the target of this novel coronavirus23. Varga et al. also reported that virus particles were present in renal endothelial cells, indicating viremia as a possible cause of endothelial damage in the kidney and a probable contributor to AKI²⁴.

Some authors report that AKI could be a result of cytokine release syndrome, rather than active viral replication in the kidney²⁵. These cytokines or mediators might exert indirect effects on renal tissue, such as hypoxia, shock, and rhabdomyolysis. What has been described so far is that a specific inhibitor of interleukin 6 (IL-6) appears to be helpful in severe cases of COVID-1926. This drug, tocilizumab, is currently being investigated in a controlled trial in China (ChiCTR2000029765)²⁶.

Other potential mechanisms for AKI associated to SARS COV2 have been suggested: cardiorenal syndrome either due to right cardiac failure or left cardiac failure with low output, rhabdomyolysis, sepsis, alveolar damage/acute respiratory distress syndrome, and development of microemboli and microthromi in the context of hypercoagulability and endothelitis^20,27.

Risk factors

A recent study investigated the differences in ACE2 gene expression between individuals in relation to race, age, sex and smoking status, in order to identify possible disparities between patients that would result in increased COVID-19 susceptibility²⁸. Five large-scale bulk transcriptomic datasets of normal lung tissue and two single-cell transcriptomic datasets were investigated and showed that race (Asian vs. Caucasian), age (>60 vs. < 60) and sex did not correlate with significant disparities in ACE2 gene expression²⁸.

Two thirds of patients who died from COVID-19 had diabetes or cardiovascular disease, and most of these patients were treated with angiotensin-receptor blockers (ARBs)29. Some studies have demonstrated that ARBs could significantly increase ACE2 expression in the kidney and heart^30,31. Could these drugs be a risk factor? An experimental study showed that the pharmacological inhibition of the angiotensin type< 1 receptor with losartan attenuated severe lung injury in mice infected with SARS-CoV-2³². Other experimental studies have supported this finding^33,34.

Patients infected with SARS-CoV-2 are at higher risk of AKI than those infected with SARS-CoV22. Additionally, several studies revealed that proteinuria and hematuria are common features of patients on hospital admission^11,12.

Zhen Li et al. have reported an elevation of plasma creatinine (SCr) and blood urea nitrogen (BUN) in 22% and 31% of 193 COVID-19 cases, respectively¹¹. The duration from the onset of admission to the presence of the SCr increase was in the range of 0 to 20 days (median 5 days). The prevalence of proteinuria was 60% and hematuria 48%¹¹.

Serum creatinine and BUN were elevated in 14% and 13%, respectively. During hospitalization, peak serum creatinine was 5.3 ±3 mg/dL¹².

Although classical assessment of AKI is still based on serum creatinine and urine output, they represent only indicators of established kidney damage. Novel biomarkers of acute tubular damage/stress such as TIMP-2 (tissue inhibitor of metalloproteinase 2) and IGFBP⁷ (insulin-like growth factor binding protein 7) identified using the Nephrocheck Test can improve physicians’ ability to predict the risk of impending AKI in critically ill patients³⁵.

According to existing data, the proportion of COVID-19 patients who needed renal replacement therapy ranged from 1.5% to 17%, mainly critically ill patients^1,36.

Treatment

There is currently no definitive treatment for COVID-19, and the prescribed treatment regimens are the ones that have previously been effective in SARS-CoV and MERS-CoV. Currently prescribed drugs include oseltamivir, lopinavir/ritonavir, ribavirin, chloroquine phosphate and corticosteroid therapy. In a recent prospective study of 199 hospitalized adult patients with severe Covid-19, no benefit was observed with lopinavir–ritonavir treatment beyond standard care37. Chloroquine phosphate has been shown to have some efficacy against COVID-19-associated pneumonia in a multicenter clinical trial conducted in China³⁸.

Recently, two double-blind placebo-controlled randomized clinical trials (RCT) also showed remdesivir’s efficacy in shortening the time to recovery in adults hospitalized with severe Covid-19^39,40. In June 2020, the European Medicines Agency’s (EMA) committee responsible for human medicines (CHMP) recommended granting a conditional marketing authorization to remdesivir for the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen.

The safety and efficacy of tociluzumab, a monoclonal antibody against the IL-6 receptor, is also undergoing evaluation by a multicenter randomized-controlled trial²⁶.

By combining the information of different meta-analyses which included RCT, the World Health Organization (WHO) has made two recommendations for the use of corticosteroid therapy in COVID-19: a strong recommendation for systemic (i.e. intravenous or oral) therapy for 7 to 10 days in patients with severe and critical COVID-19, and a conditional recommendation not to use corticosteroid therapy in patients with nonsevere COVID-1941. The RECOVERY study, one of the largest RCT analyzed, showed the effects of dexamethasone 6 mg given once daily (oral or intravenous) for up to 10 days in 6425 hospitalized patients with COVID-19. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%), but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%)⁴².

Based on these findings, CHMP approved dexamethasone as a treatment option for patients who require oxygen therapy (from supplemental oxygen to mechanical ventilation) in September 2020.

The treatment of these patients with AKI includes general and supportive management and kidney replacement therapy. Supportive care, namely bed rest, nutritional and fluid support, and maintenance blood pressure and oxygenation are important measures.

Continuous renal replacement therapy (CRRT) has been successfully applied in the treatment of SARS, MERS and sepsis^44,45. In patients with COVID-19 and AKI, early initiation of renal replacement therapy (RRT) and extracorporeal organ support (ECOS) seem to provide adequate organ support and prevent progression of disease severity.

Ronco et al. published a recent review describing the potential role of extracorporeal therapies as a blood purification treatment for severe COVID-19 patients with a systemic inflammatory syndrome and multiorgan dysfunction⁴⁶.

CRRT not only corrects hyperkalemia, volume overload and metabolic acidosis but can also adsorb cytokines and endotoxins⁴⁵. Heart-kidney and lung-kidney crosstalk, as described above, can also contribute to AKI. Extracorporeal membrane oxygenation (ECMO) provides support to both heart and lungs and can be used in conjunction with CRRT⁴⁷.

However, more research is needed to fully understand the benefits of these therapies in the novel coronavirus disease.

Outcomes

Recent studies revealed an association between elevated levels of proteinuria, BUN, SCr and hematuria with higher probability of death^11,12. Mortality risk for COVID-19 patients with AKI was 5 times higher than patients without AKI¹¹.

Cheng et al. also reported a significantly higher mortality rate of COVID-19 patients with AKI (33% vs 16%)¹².

In a retrospective study of 2003 SARS-CoV outbreak, , AKI while described as a relatively uncommon feature of the disease, was also identified as a fatal complication of SARS, given that almost 92% of SARS patients with AKI died⁴¹.

CONCLUSION

AKI is uncommon in COVID-192. However, it can lead to potentially significant morbidity and mortality3. The pathophysiologic mechanisms of acute kidney injury could be multifactorial, including direct infection with the SARS-CoV-2, immune and inflammatory response induced by viral infection, and systemic toxic reaction resulting from respiratory failure⁶.

In COVID-19 patients, kidney injury is an independent risk factor for poor prognosis9. Therefore, kidney function monitoring must be emphasized even in patients with mild respiratory symptoms, and particular attention must be given to altered kidney function after admission in clinical practice¹². To reduce the mortality risk for severely ill COVID-19 patients worldwide, the authors recommend early supportive interventions. The data is still preliminary and there is a need for continued research into different aspects of viral injury to the kidney.

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Correspondence to:

Natalia Silva, MD

Nephrology Department, Trás-Os-Montes e Alto Douro Hospital Center

Av. Noruega, Lordelo, 5000-508 Vila Real, Portugal

Author’s statement:This paper reviews an area of knowledge in permanent update. The information presented here is up-to-date at the date of submission.

Disclosure of potential conflicts of interest: none declared

Received for publication: May 30, 2020

Accepted in revised form: Sep 30, 2020