Patrick Vosters
Medical Student, Medical College of Wisconsin – Green Bay
The coronavirus disease 2019 (COVID-19) pandemic constitutes one of the most disruptive events in recent history. Amidst the pathological, political, and social turmoil, the kidney was not spared. Incidence of acute kidney injury (AKI) in COVID-19 has been marked at 23% and rises to over 60% in high-risk patients. Studies to date have identified multiple pathophysiological patterns of how severe acute respiratory virus coronavirus 2 (SARS-CoV-2) and COVID-19 lead to kidney injury. Still, questions remain—particularly regarding the phenomenon and role of direct viral infection by SARS-CoV-2 in kidney parenchyma versus secondary effects of systemic immune activation. Moreover, researchers have sought to investigate if these mechanisms differentiate COVID-19 from other etiologies of AKI. As such, this post aims to summarize and discuss what is currently known about the pathophysiology of SARS-CoV-2 infection and COVID-19 in the kidney.
Pathophysiological mechanisms associated with COVID-19-related acute kidney injury Ng, et al
While studies have identified a range of pathologic findings associated with SARS-CoV-2 infection and COVID-19, three emerge as most prominent: acute tubular injury (ATI), collapsing glomerulopathy (CG), and thrombotic microangiopathy (TMA). Other recurrent findings include crescentic glomerulonephritis and podocytopathies such as membranous nephropathy and minimal change disease. ATI stands as the most common finding as shown in all 16 immediate post-mortem biopsies of patients diagnosed with COVID-19 disease in one study. Proposed contributors to the development of ATI include regional factors such as inflammation, hypoxia, or rhabdomyolysis and local factors such as direct viral infection or nephrotoxic injury from antibiotics or antivirals. CG is the most common COVID-19-linked glomerular disease and appears similar to HIV-associated and other viral-associated nephropathies. It has demonstrated close links to high-risk APOL1 genotypes and those of recent African American ancestry who have two high risk alleles. As such, CG may share a pathophysiological mechanism with HIV-associated nephropathy (HIVAN) involving disrupted autophagy and mitochondrial homeostasis. Alternatively, evidence exists suggesting that upregulation of interferons produced in response to viral infection may be responsible for the glomerular damage. Lastly, TMA is thought to result from inflammation-induced, pro-thrombotic conditions and complement activation. However, one large cohort study identified no cases of TMA, and some investigators hypothesize that hydroxychloroquine stands as a confounding variable between COVID-19 and TMA.
Global collapse of the glomerular capillary loops accompanied by hyperplasia of overlying glomerular epithelial cells, many of which contain abundant eosinophilic intracytoplasmic protein droplets; Peleg, et al
Glomerulus with multiple microthrombi and extensive coagulative necrosis of proximal tubules with ghost cells and nonviable nuclei;Jhaveri, et al
The findings described above help distinguish COVID-19-related AKI from other etiologies of AKI. This is also achieved in a study that found vascular alterations including glomerular and peritubular congestion exclusively in postmortem kidney biopsies with COVID-19-linked AKI. Further distinction is generated by evidence of potential direct viral infection of kidney epithelial cells by SARS-CoV-2.
Yet, uncertainty remains concerning direct viral infection of SARS-CoV-2 in the kidney. Supporting evidence includes positive immunostaining for viral nucleoprotein, positive in situ hybridization for viral RNA, demonstration of ability of virus to infect kidney cells in vitro, identification of viral components via electron microscopy, identification via microdissection in renal compartments, and observation of COVID-19 particles in urine samples. However, these findings have been rare overall and largely limited to post-mortem analyses, results for in-situ hybridization and RT-PCR have been mixed, and positive identification of viral particles via electron microscopy is prone to oversensitivity. Further, while the angiotensin-converting enzyme 2 (ACE2) protein constitutes the site of entry for SARS-CoV-2 and is expressed highly in the kidney, other proteases necessary for viral entry fail to co-localize with ACE2. This renders direct viral infection unlikely from a molecular perspective. As such, the existing body of evidence suggests that, while direct viral infection of kidney cells is possible, it is more often the exception than the rule. Furthermore, the link between direct viral infection of kidney tissue and pathogenesis is not well-delineated.
In conclusion, SARS-CoV-2 infection and consequent COVID-19 commonly results in kidney injury. Infection with COVID-19 has been linked to a spectrum of histologic findings including acute tubular injury, collapsing glomerulopathy, and thrombotic microangiopathy. A large body of epidemiologic and immunologic associations exist which have prompted investigation of mechanisms. Nevertheless, much remains unclear about the pathophysiology of COVID-19 in the kidney and how we can use our existing understanding to optimize future outcomes.
Reviewed by Matthew A. Sparks, MD
