Saudi Journal of Kidney Diseases and Transplantation

: 2021  |  Volume : 32  |  Issue : 6  |  Page : 1543--1551

Acute Kidney Injury Associated with Coronavirus Disease 2019 – One Year Later, What Do We Know So Far?

Ankita Gharge1, Shobhana Nayak-Rao2,  
1 Department of General Medicine, Jawaharlal Nehru Medical College, Belgaum, Karnataka, India
2 Nephrology Unit, GNRC Institute of Medical Sciences, Silagrant, Amingaon, Guwahati, India

Correspondence Address:
Shobhana Nayak-Rao
Nephrology Unit, GNRC Institute of Medical Sciences, Silagrant, Amingaon Guwahati, India.


Initial reports early on in the pandemic in 2020 indicate a high incidence of acute kidney injury (AKI) in coronavirus disease 2019 (COVID-19). There is a need to better understand risk factors for AKI in patients with COVID-19. It is also unclear if AKI in patients with COVID-19 differs from AKI due to other causes. More data are required to clarify if COVID-19 is an independent risk factor for AKI and how COVID-19-associated AKI may differ from AKI due to other causes. We, therefore, sought to review the published evidence about the reported relationship between COVID-19, AKI, and outcomes. We performed a systematic search via PubMed and EMBASE using key words “COVID-19” and “AKI” to identify relevant observational studies, case series, and cohort studies published between March 2020 and April 2021. We also manually examined the reference lists of included studies and reviewed the AKI reports published in general medicine journals such as BMJ, Lancet, NEJM, and JAMA. The prevalence of AKI in hospitalized patients with COVID-19 differed across various regions of the world. Initial reports from China where cases of COVID-19 began initially have shown a much lower prevalence compared to those from Europe and North America, especially in critically ill patients in the intensive care unit with acute respiratory distress syndrome. The various components of severe acute respiratory syndrome-associated AKI appear in large parts to be similar to sepsis-induced AKI. However, affinity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specifically to the angiotensin-converting enzyme 2 receptors located on podocytes and endothelial cells of the kidney also points toward the direct cytotoxic effects of the virus on the kidney. Numerous mechanisms likely occur simultaneously and hence more treatment approaches need to be streamlined based on pathophysiology. Although data from published literature regarding previous SARS coronaviruses can give some useful insights, we will know more going forward about the nature of kidney injury associated with COVID-19 virus as well as optimum-specific therapeutic management.

How to cite this article:
Gharge A, Nayak-Rao S. Acute Kidney Injury Associated with Coronavirus Disease 2019 – One Year Later, What Do We Know So Far?.Saudi J Kidney Dis Transpl 2021;32:1543-1551

How to cite this URL:
Gharge A, Nayak-Rao S. Acute Kidney Injury Associated with Coronavirus Disease 2019 – One Year Later, What Do We Know So Far?. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Aug 7 ];32:1543-1551
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Full Text


In late 2019, an emerging epidemic was identified in the Wuhan region of China. The virus responsible was termed as the novel coronavirus and led to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the resultant disease named coronavirus disease 2019 (COVID-19). The rapid progression of the global pandemic caused by the then-novel coronavirus, SARS-CoV-2, has resulted in an urgent need to understand the pathogenesis and variable clinical features of COVID-19. Lung involvement in the form of viral pneumonia, inflammatory infiltrates, and endothelial damage resulting in respiratory failure has been well documented and has been the focus of attention, but other organs including the kidneys have also been early on affected in COVID-19.[1],[2] In the previous SARS epidemic, the reported incidence of acute kidney injury (AKI) was 6.7% with a high mortality of over 90%.[3] However, SARS-CoV-2 is a novel betacoronavirus belonging to the Sarbecovirus subgenus of Coronaviridae family, and its effect on the kidneys has not yet been fully understood. There have been reports of nephrology services being overwhelmed with new consults and the need for renal replacement therapy (RRT), which increased 18-fold during the COVID-19 pandemic.[4] In initial reports, AKI incidence in people with COVID-19 has ranged from 5% to 29% with substantial variation between centers, possibly due to differences in population demographics and preexisting risk factors for AKI.[1],[2],[5],[6],[7],[8],[9] Some reports on a small number of patients suggest that SARS-CoV-2 may have a specific effect on the kidneys, but it is not yet clear to what extent COVID-19 increases the risk of AKI or how AKI associated with COVID-19 may differ from AKI due to sepsis-induced AKI.[10],[11]


Direct pathogenic mechanisms are implicated in occurrence of COVID-19 associated AKI (as shown in [Figure 1]: SARS-CoV-2 spike protein (S) binds to the angiotensin-converting enzyme 2 (ACE2) receptor employing cellular transmembrane serine proteases (TMPRSSs) for priming. Binding of the virus to the ACE2 receptor activates the S protein allowing endocytosis of the SARS-CoV-2. A study of normal kidney samples has found expression of ACE2 receptor and TMPRSSs in the podocyte and the proximal tubules. Histopathological data are limited, but a wide range of pathological findings have been described in patients with COVID-19, in keeping with the idea that multiple causes of AKI exist, including those associated with sepsis in critically ill patients. Some of those mechanisms include:

1 SARS-CoV-2 might display viral tropism and directly affect the kidney

2 Endothelial dysfunction, coagulopathy, and complement activation are likely important mechanisms for AKI in a subset of patients with COVID-19

3 The role of systemic inflammation and immune dysfunction in the development of COVID-19 AKI is still uncertain.{Figure 1}

Indirect pathogenic mechanisms implicated in COVID-19 AKI.

1. Systemic effects of COVID-19 and critical care interventions may contribute to AKI

2. Organ crosstalk is likely an important mechanism for AKI in patients with COVID-19

3. Baseline patient characteristics contribute to AKI, acting as modifiers of direct pathogenic mechanisms.

The most commonly reported reasons for intensive care unit admission for patients with severe COVID-19 are either hypoxemic respiratory failure leading to mechanical ventilation or multi-organ failure with sepsis and hypotension requiring vasopressor support. Data on AKI report incidence on the basis of case series and retrospective studies [Table 1]. In this perspective, we emphasize that AKI can be a severe complication of COVID-19 and highlight the importance of assessing, defining, and reporting the course of AKI.[5],[12]{Table 1}

The incidence and reported severity were lesser in the region of Wuhan where the epicenter of this global pandemic has been described. The rates of severe AKI and those requiring intensive care and RRT were also higher during the first wave of the pandemic in March-April 2020 when compared to later data toward the end of the year. Relevant information that normally would be part of clinical descriptions and research publications had not been collected initially because of the magnitude and accelerated pace of the COVID-19 pandemic, and this is reflected in some of the initial publications pertaining to AKI in COVID-19 that did not have complete demographic data or risk factors elucidated. One study reported a 23% AKI incidence among 85 patients (over 60% in high-risk patients). The authors analyzed kidney histology from autopsies of six patients who had AKI showing severe acute tubular necrosis with lymphocyte and macrophage infiltration, but it is not clear from this report if these patients had actually developed cortical necrosis.[13] An important report on autopsy findings from deceased patients with COVID- 19 again demonstrated prominent acute proximal tubular injury but also peritubular erythrocyte aggregation and glomerular fibrin thrombi with ischemic collapse. This paper also reported endothelial damage, hemosiderin deposition, pigment casts related to rhabdo-myolysis, and inflammation. Notably, some of these patients lacked evidence of AKI as detected by routine measures (creatinine and/or BUN), highlighting the possibility of substantial subclinical kidney injury.

Recent clinical and autopsy reports of COVID-19 from China and the United States confirm increased clotting and disseminated intravascular coagulation with small vessel thrombosis and pulmonary infarction.[9] Further, elevated D-dimer and low platelet levels correlated with worse outcomes.[9] Some patients with COVID-19 manifest evidence of microangiopathy in other organ systems, such as splenic infarction or presenting symptoms of loin pain and hematuria suggesting renal infarction. Numerous observations by treating physicians attest that there is increased occurrence of circuit clotting in patients with COVID-19 undergoing dialysis. COVID-19 is also associated with increased myocardial injury that mimics myocardial infarction, possibly from myocarditis and microangiopathy.[14] Thus, it is conceivable that the hypercoagulable state that appears to be a characteristic complication of severe COVID-19 could, in some cases, foster the evolution of acute cortical necrosis and, therefore, irreversible kidney failure. The risk of long-term CKD and irreversible kidney failure will know over the next few years during follow-up of patients who had developed AKI during hospitalization.

Innate immunity and coagulation pathways are intricately linked.[15] COVID-19-associated macrophage activation, hyperferritinemia, cytokine storm, and release of pathogen-associated molecular patterns and damage-associated molecular proteins can result in release of tissue factor and activation of coagulation factors creating a predisposition to hypercoagulability.[15] SARS-CoV-2 may also target lymphocytes since they express ACE2, leading to lymphocyte activation and, consequently, activation-induced cell death than can result in lymphopenia of both CD4+ and CD8+ T-cells.[16] Further, procoagulation pathways and complement systems can activate each other. In support of this - interaction in COVID-19, Diao et al[13] observed strong complement C5b-9 (membrane attack complex) deposition in renal tubules of six patients with SARS-CoV-2 infection, suggesting activation of the complement pathway. An interaction between angiotensin II (AngII) overactivity, innate/adaptive immune and complement pathways, and the coagulation system could influence AKI severity and outcomes. Inflammation-induced erythrocyte aggregation (reflected as elevated erythrocyte sedimentation rate) and heme-mediated pathology may worsen oxidative stress, inflammation, and complement activation, to aggravate microvascular injury.[17] Further, organ crosstalk between the injured lung, the heart, and the kidney can worsen pathology. Detailed studies to decipher the nature of coagulation dysfunction, microangiopathy, and potential role for innate immune and complement pathways are required to gain further insights regarding kidney pathology in COVID-19.

Also of interest is the finding that SARS-CoV-2 nucleocapsid protein was observed in tubular structures in the kidneys from the six patients examined, and nucleocapsid proteinpositive inclusion bodies were also observed in the cytoplasm.[13] Su et al[11] similarly observed the presence of virus-like particles in podocytes and renal tubular epithelial cells by electron microscopy, and SARS-CoV-2 nucleoprotein antibody stained renal tubular epithelia positive, but the specificity of the antibody used needs to be established. Although, as far as we know, SARS-CoV-2 RNA has not been detected in the kidney, these results indicate that SARS-CoV-2 could directly infect human kidney tubules and induce cytoplasmic renal tubular inclusions, a feature observed in other virus-associated nephropathies. Although AKI may be attributable to hypotension and decreased kidney perfusion secondary to hemodynamic or hemostatic factors or associated sepsis, viral infection of the kidneys with viral replication directly in kidney parenchyma may also play a role [Figure 2]. The main binding site for SARS-CoV-2, like SARS-CoV, is the ACE2 protein, which is expressed in the kidney much more than the lungs.[18],[19] ACE2 is expressed on the brush border apical membrane of the proximal tubule, where it co-localizes with ACE, and is also present at lower levels in podocytes.[19] It is conceivable that the virus could enter the kidney by invading podocytes first, and thus gain access to the tubular fluid and subsequently bind to ACE2 in the proximal tubule. In primary human airway epithelia, ACE2 is expressed apically, and SARS-CoV-2 infection predominantly occurs on the apical surface, but infection can occur on the basolateral surface at low efficiency.[20] Coronavirus entry into host target cells also requires fusion of the viral envelope with cellular membranes. Fusion-activated SARS-CoV peptides are created by specific proteolytic cleavage of the S proteins in a step called “priming.”[21] As a consequence, cell infectivity not only depends on ACE2 expression but also is governed by types of proteases found in a given cell type. In the kidney, transmembrane protease, serine 2 (TMPRSS2) which primes the SARS-CoV-2 S protein, is robustly expressed in the distal nephron rather than the proximal tubule. It remains to be determined if other TMPRSSs in the proximal tubule can mediate the priming step, such as TMPRSS 4, 5, or 9. Alternatively, tropism of SARS-CoV-2 might be expanded by the unique furin cleavage site in the Spike protein that is processed during biogenesis.{Figure 2}

Any effect of proteinuria, hyperinflammation, or tubular injury on proximal tubular ACE2 expression or SARS-CoV-2 viral entry is currently unknown. Viral replication in podocytes and the ensuing damage could in theory account for the proteinuria that has been reported in patients with COVID-19. Further, COVID-19-associated hemophagocytic macrophage activation and microangiopathy could also cause AKI and podocyte damage. Of interest, cases of COVID-19-associated collapsing glomerulopathy have been described largely in Black patients who have expressed the APO-L 1 genotype.[22]

Regardless of direct viral infection of the kidney, AngII is likely increased in the context of acute lung injury and there is evidence that ACE2 is downregulated in AKI. This may lead to type 1 angiotensin receptor activation as well as decreased angiotensin (1−7) formation and subsequent worsening of AKI. This is particularly important in subpopulations of patients who have CKD, especially those with diabetic kidney disease (DKD). ACE2 and ACE mRNA and protein expression are altered in mouse models of DKD and in patients with DKD.[19],[23],[24] Thus, patients with CKD, especially those with DKD, who develop COVID-19 may be at higher risk of AKI because of baseline upregulation of the ACE and down-regulation of ACE2, a combination that primes a pro-inflammatory (including complement activation) and profibrotic state in the kidneys.

Interestingly, a recent study described singlecell transcriptome analysis in 15 normal human kidney samples.[20] In this study, the proportions of kidney cells expressing ACE2, the SARS-CoV-2 binding site, and proteases of the TMPRSS family were compared between occidental and Asian individuals.[25] Interestingly, the expression of ACE2 and kidney disease-related genes was higher in occidental donors relative to Asian donors. This would suggest that the susceptibility to kidney injury from coronavirus infection might be higher in individuals of occidental rather than Asian descent. We are not aware, however, of data supporting this possibility.

Despite the very limited information on kidney involvement in COVID-19, AKI appears to involve a complex process driven by virusmediated injury, cytokine storm, AngII pathway activation, dysregulation of complement, hypercoagulation, and microangiopathy interacting with common and known risk factors for AKI[26] [Figure 2]. Risk factors that increase the risk of developing AKI have been elucidated, and these are mentioned in [Table 2].{Table 2}

Studies describing and analyzing the clinical course of patients with COVID-19 include appropriate indices of kidney function and diagnosis of AKI in their analyses, including kidney injury markers, urine microscopy, quantified urine protein, urine output, and urine electrolytes. Markers of macrophage activation, coagulation, microangiopathy, and complement activation, as well as kidney imaging and need for KRT (with relevant details), are important data needed to further our understanding of AKI pathophysiology associated with COVID-19. Rates of reversibility or partial improvement in, kidney function and any kidney biopsy results (including immunofluorescence and electron microscopy) should be reported. In the rush to report medical complications of COVID-19, we are missing valuable clinical information. Speculation about specific interventions would not be appropriate until we obtain further information. We advocate for a complete and standardized appraisal of the clinical and laboratory picture so that preventative and therapeutic strategies for AKI can be appropriately designed and implemented.

 Future Research Recommendations

1. Future studies should consider the impact of geographical variation in incidence of AKI and its severity, differences in healthcare systems, the influence of hospital capacity, the preparedness of health-care systems, and social determinants on the epidemiology of COVID-19 AKI, including analysis of how these factors influence risk factors, management of disease, and outcomes

2. Incorporation of information about the proportion of different comorbidities in patients with and without AKI, including potential risk factors for the development of COVID-19 AKI before and after hospital admission

3. Determination of different phenotypes of COVID-19 AKI based on clinical presentation at diagnosis, patterns of injury, duration and course of AKI, and progression to CKD

4. The severity of COVID-19 disease at AKI diagnosis and the interventions that have been used for the management of the individual should be reported when describing COVID-19 AKI

5. The relationship between markers of systemic disease (for example, ferritin, D-dimers, and nonrespiratory organ failure) and the severity of pulmonary disease to the development, course, and outcomes of COVID-19 AKI warrants further study. Risk factors for developing severe AKI (stage 3 AKI or requiring RRT initiation) need to be explored to identify approaches to prevent AKI

6. The mechanism, timing, and clinical implications of traditional markers of AKI (proteinuria and hematuria) as well as novel biomarkers for the diagnosis and prognosis of AKI need to be studied and correlated with markers of systemic disease

7. Kidney recovery and mortality should be assessed at ICU and hospital discharge. Posthospitalization outcomes and longterm renal recovery data should be evaluated across different countries.

Conflict of interest: None declared.


1Guan WJ, Ni ZY, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020;382:1708-20.
2Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020;395:507-13.
3Chu KH, Tsang WK, Tang CS, et al. Acute renal impairment in coronavirus-associated severe acute respiratory syndrome. Kidney Int 2005;67:698-705.
4Fisher M, Prudhvi K, Brogan M, Golestaneh L. Providing care to patients with acute kidney injury and COVID-19 infection: Experience of front line nephrologists in New York. Kidney 360 2020;1:544-8.
5Cheng Y, Luo R, Wang K, et al. Kidney disease is associated with in-hospital death of patients with COVID-19. Kidney Int 2020;97: 829-38.
6Mohamed MM, Lukitsch I, Torres-Ortiz AE, et al. Acute kidney injury associated with coronavirus disease 2019 in urban New Orleans. Kidney 360 2020;1:614-22.
7Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-9.
8Chen T, Wu D, Chen H, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: Retrospective study. BMJ 2020;368:m1091.
9Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet 2020;395: 1054-62.
10Kissling S, Rotman S, Gerber C, et al. Collapsing glomerulopathy in a COVID-19 patient. Kidney Int 2020;98:228-31.
11Su H, Yang M, Wan C, et al. Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China. Kidney Int 2020;98:219-27.
12Bhatraju PK, Ghassemieh BJ, Nichols M, et al. COVID-19 in critically ill patients in the seattle region - Case series. N Engl J Med 2020;382:2012-22.
13Diao B, Wang C, Wang R, et al. Human kidney is a target for novel severe acute respiratory syndrome coronavirus 2 infection. Nat Commun 2021;12:2506.
14Delvaeye M, Conway EM. Coagulation and innate immune responses: Can we view them separately? Blood 2009;114:2367-74.
15Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest 2020;130:2620-9.
16Frimat M, Tabarin F, Dimitrov JD, et al. Complement activation by heme as a secondary hit for atypical hemolytic uremic syndrome. Blood 2013;122:282-92.
17Serfozo P, Wysocki J, Gulua G, et al. Ang II (Angiotensin II) conversion to angiotensin-(1- 7) in the circulation is POP (Prolyloligopeptidase)-dependent and ACE2 (Angiotensin-Converting Enzyme 2)- independent. Hypertension 2020;75:173-82.
18Ye M, Wysocki J, William J, Soler MJ, Cokic I, Batlle D. Glomerular localization and expression of Angiotensin-converting enzyme 2 and Angiotensin-converting enzyme: Implications for albuminuria in diabetes. J Am Soc Nephrol 2006;17:3067-75.
19Jia HP, Look DC, Shi L, et al. ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia. J Virol 2005;79:14614-21.
20Wu H, Uchimura K, Donnelly EL, Kirita Y, Morris SA, Humphreys BD. Comparative analysis and refinement of human PSC-derived kidney organoid differentiation with single-cell transcriptomics. Cell Stem Cell 2018;23:869- 81.e8.
21Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020;181:281-92.e6.
22Larsen CP, Bourne TD, Wilson JD, Saqqa O, Sharshir MA. Collapsing glomerulopathy in a patient with COVID-19. Kidney Int Rep 2020; 5:935-9.
23Reddy R, Asante I, Liu S, et al. Circulating angiotensin peptides levels in Acute Respiratory Distress Syndrome correlate with clinical outcomes: A pilot study. PLoS One 2019;14:e0213096.
24Mizuiri S, Hemmi H, Arita M, et al. Expression of ACE and ACE2 in individuals with diabetic kidney disease and healthy controls. Am J Kidney Dis 2008;51:613-23.
25Wilson PC, Wu H, Kirita Y, et al. The singlecell transcriptomic landscape of early human diabetic nephropathy. Proc Natl Acad Sci U S A 2019;116:19619-25.
26Pan XW, Xu D, Zhang H, Zhou W, Wang LH, Cui XG. Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: A study based on singlecell transcriptome analysis. Intensive Care Med 2020;46:1114-6.