Nephrotic Syndrome in Adult Patients With COVID-19 Infection or Post COVID-19 Vaccine: A Systematic Review.

Nephrotic syndrome is a condition characterized by damage to podocytes that results in significant proteinuria, edema, hyperlipidemia, and hypercoagulability. Infections and malignancies are frequently associated with nephrotic syndrome. The COVID-19 virus has been associated with several atypical presentations of upper respiratory infections and acute kidney injury. Considering that COVID-19 causes systemic inflammatory changes, it seems plausible that it may also lead to nephrotic syndrome. This study aimed to investigate if an association between COVID-19 and the different types of nephrotic syndromes exists. Data were extracted into a spreadsheet. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS, IBM Corp., Armonk, NY, USA). We performed a systematic search of PubMed/Medline and Embase databases using both medical subject headings (MeSH) and regular keywords associated with COVID-19 and nephrotic syndrome, including different types of nephrotic syndromes. The search was performed on 17th December 2021. We included case reports and case series about adult patients who developed findings suggestive of nephrotic syndrome shortly after infection or vaccination. We excluded cases involving children, pregnant women, articles written in languages other than English, and those that were not retrievable. The relevance and quality of identified articles were assessed. We included 32 articles in the study, primarily case reports and case series. In our study, COVID-19 and the COVID-19 vaccine have been associated with the development of nephrotic syndrome, primarily a collapsing form of focal segmental glomerulosclerosis, although other forms have been observed as well. There was little consistency in patient histories, clinical presentations, clinical courses, or treatment regimens, although it appeared that most cases eventually resolved. More cases need to be reported and analyzed before more definitive conclusions can be reached. In conclusion, nephrotic syndrome is a possible complication of both COVID-19 infection and the COVD-19 vaccine and should be considered in patients exhibiting sudden onset edemas or deterioration in kidney function. While the majority of cases respond to standard treatment, clearer guidelines will need to be developed once more data is available.

Similarities and Differences between COVID-19-Associated Nephropathy and HIV-Associated Nephropathy.

Kidney disease is a major complication of viral infection, which can cause both acute and chronic kidney diseases via different mechanisms such as immune-mediated injury, kidney cell injury from a direct viral infection, systemic effects, and antiviral drug-induced nephrotoxicity. HIV-associated nephropathy (HIVAN), characterized by collapsing focal segmental glomerulosclerosis (cFSGS), has been described 2 decades ago as a major complication of acquired-immunodeficiency syndrome. The pathogenesis of HIVAN has been well studied, including viral entry, host response, and genetic factors. The incidence of this disease has been dramatically dropped with current antiretroviral therapy. In the recent severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic, acute kidney injury was also found to be a major complication in patients with (coronavirus disease) COVID-19. These patients also developed glomerular disease such as cFSGS in African Americans with apolipoprotein L1 risk alleles, similar to HIVAN. Whether SARS-CoV-2 can infect kidney cells locally remains controversial, but both local infection and systemic effects are likely involved in the pathogenesis of this disease. In this review, we present a comparison of the clinical presentations, pathological findings, disease mechanisms, and potential treatments between HIVAN and COVID-19. Leveraging the knowledge in HIVAN and experimental approaches used to study HIVAN will facilitate the exploration in the pathogenesis of COVID-19-associated kidney disease and improve our management of COVID-19 patients.

Longitudinal Outcomes of COVID-19-Associated Collapsing Glomerulopathy and Other Podocytopathies.

BACKGROUND: The long-term outcome of COVID-19-associated collapsing glomerulopathy is unknown. METHODS: We retrospectively identified 76 native kidney biopsies from patients with history of COVID-19 between March 2020 and April 2021. Presenting and outcome data were obtained for all 23 patients with collapsing glomerulopathy and for seven patients with noncollapsing podocytopathies. We performed APOL1 genotyping by Sanger sequencing, immunostaining for spike and nucleocapsid proteins, and in situ hybridization for SARS-CoV-2. RESULTS: The 23 patients with COVID-19-associated collapsing glomerulopathy were median age 57 years (range, 35-72), included 16 men, and were predominantly (91%) Black. Severity of COVID-19 was mild or moderate in most (77%) patients. All but one patient presented with AKI, 17 had nephrotic-range proteinuria, and six had nephrotic syndrome. Fourteen (61%) patients required dialysis at presentation. Among 17 patients genotyped, 16 (94%) were high-risk APOL1. Among 22 (96%) patients with median follow-up at 155 days (range, 30-412), 11 (50%) received treatment for COVID-19, and eight (36%) received glucocorticoid therapy for podocytopathy. At follow-up, 19 (86%) patients were alive, and 15 (68%) were dialysis free, including seven of 14 who initially required dialysis. The dialysis-free patients included 64% (seven of 11) of those treated for COVID-19 and 75% (six of eight) of those treated with glucocorticoids for podocytopathy. Overall, 36% achieved partial remission of proteinuria, 32% had no remission, and 32% reached combined end points of ESKD or death. Viral infection of the kidney was not detected. CONCLUSIONS: Half of 14 patients with COVID-19-associated collapsing glomerulopathy requiring dialysis achieved dialysis independence, but the long-term prognosis of residual proteinuric CKD remains guarded, indicating a need for more effective therapy.

Molecular Analysis of the Kidney From a Patient With COVID-19-Associated Collapsing Glomerulopathy.

Recent case reports suggest that coronavirus disease 2019 (COVID-19) is associated with collapsing glomerulopathy in African Americans with apolipoprotein L1 gene (APOL1) risk alleles; however, it is unclear whether disease pathogenesis is similar to HIV-associated nephropathy. RNA sequencing analysis of a kidney biopsy specimen from a patient with COVID-19-associated collapsing glomerulopathy and APOL1 risk alleles (G1/G1) revealed similar levels of APOL1 and angiotensin-converting enzyme 2 (ACE2) messenger RNA transcripts as compared with 12 control kidney samples downloaded from the GTEx (Genotype-Tissue Expression) Portal. Whole-genome sequencing of the COVID-19-associated collapsing glomerulopathy kidney sample identified 4 indel gene variants, 3 of which are of unknown significance with respect to chronic kidney disease and/or focal segmental glomerulosclerosis. Molecular profiling of the kidney demonstrated activation of COVID-19-associated cell injury pathways such as inflammation and coagulation. Evidence for direct severe acute respiratory syndrome coronavirus 2 infection of kidney cells was lacking, which is consistent with the findings of several recent studies. Interestingly, immunostaining of kidney biopsy sections revealed increased expression of phospho-STAT3 (signal transducer and activator of transcription 3) in both COVID-19-associated collapsing glomerulopathy and HIV-associated nephropathy as compared with control kidney tissue. Importantly, interleukin 6-induced activation of STAT3 may be a targetable mechanism driving COVID-19-associated acute kidney injury.

Severe Acute Respiratory Syndrome Coronavirus 2 Induced Focal Segmental Glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a common cause of nephrotic syndrome affecting adults and children. Collapsing focal segmental glomerulosclerosis (FSGS), one of five histologic variants of FSGS is described as segmental or global collapse and sclerosis of the glomerular tufts and has been frequently associated with human immunodeficiency virus-associated nephropathy (HIVAN). Its association with other viral and non-viral causes, medications and other disease states has since been established. Due to its resistance to therapy, rapid progression to end-stage renal disease (ESRD) and overall poorer prognosis, identification with electron microscopy examination of the kidney biopsy sample is required during evaluation.

Collapsing Focal Segmental Glomerulosclerosis and Acute Oxalate Nephropathy in a Patient With COVID-19: A Double Whammy.

As COVID-19 (coronavirus disease 2019) spreads across the world multiple therapeutic interventions have been tried to reduce morbidity and mortality. We describe a case of collapsing focal sclerosing glomerulosclerosis (FSGS) and acute oxalate nephropathy in a patient treated with high-dose intravenous vitamin C for severe COVID-19 infection. Collapsing FSGS has been described in patients with COVID-19 infection associated with APOL-1; however, this case had collapsing FSGS developing in low-risk heterozygous APOL-1 variant, and we postulate that the intensity of the COVID-19 cytokine storm overwhelmed the protective state of APOL-1 heterozygosity. This case illustrates the importance of assessing the risk and benefit of planned therapeutic interventions on a case-by-case basis especially when there are still so many unknowns in the management of COVID-19 infection. Strong consideration should be given for performing a renal biopsy in patients who develop multifactorial acute kidney injury.

COVID-19-Related Glomerulopathy: A Report of 2 Cases of Collapsing Focal Segmental Glomerulosclerosis.

Coronavirus disease 19 (COVID-19), an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with acute kidney injury, presumably due to acute tubular injury. However, this does not explain proteinuria, sometimes severe, and hematuria often observed. We present 2 African American patients with glomerulopathy demonstrated by kidney biopsy in the setting of acute kidney injury and COVID-19 infection. Kidney biopsy specimens showed a collapsing variant of focal segmental glomerulosclerosis in addition to acute tubular injury. Both patients were homozygous for apolipoprotein L1 (APOL1). COVID-19 infection likely caused the interferon surge as a second hit causing podocyte injury leading to collapsing focal segmental glomerulosclerosis. APOL1 testing should be strongly considered in African American patients with nephrotic-range proteinuria. More data from future kidney biopsies will further elucidate the pathology of kidney injury and glomerular involvement from COVID-19 infections.