Renal Histopathological Changes in Coronavirus Disease 2019 Patients: A Systematic Review and Meta-analysis of Individual Patient Data.

The major targets of coronavirus disease 2019 (COVID-19) are the respiratory and immune systems. However, a significant proportion of hospitalized patients had kidney dysfunction. The histopathological surveys have principally focused on respiratory, hematopoietic, and immune systems, whereas histopathologic data of kidney injury are lacking. Our study aimed to summarize the renal histopathological findings in COVID-19 from the published case report and case series. We conducted a systematic searching of databases such as MEDLINE, EMBASE, and Cochrane Library for published reports of COVID-19 patients with renal histopathological changes from autopsy studies and from "for cause" indication biopsies. Included in our study are case reports and case series with extractable quantitative data on patient demographics such as age, sex, ethnicity, as well as data on renal function tests, their comorbidities, and biopsy to study the histopathological changes. Data were analyzed with Microsoft Excel. To evaluate the methodological quality, we chose the framework for appraisal, synthesis, and application of evidence suggested by Murad et al. Systematic searches of literature found 31 studies that fulfilled the eligibility criteria. These studies included a total of 139 cases, where individual case details including clinical and histopathological findings were available. The median age of the cases was 62 years with a male:female ratio of 2.5:1. Associated comorbidities were noted in 78.4% of cases. The majority of the cases had renal dysfunction with proteinuria which was documented in more than two-thirds of the cases. The histopathological findings observed the frequent tubular involvement manifested by acute tubular injury. Regarding glomerular pathology, collapsing glomerulopathy emerged as a distinct lesion in these patients and was noted among 46.8% of cases with glomerular lesions. A small subset of cases (4.3%) had thrombotic microangiopathy. Collapsing glomerulopathy emerged as a hallmark of glomerular changes among COVID-19 patients. Tubular damage is common and is linked to multiple factors including ischemia, sepsis among others. In the form of thrombotic microangiopathy seen in a subset of patients, vascular damage hints toward the hyper-coagulable state associated with the infection. The demonstration of viral particles in renal tissue remains debatable and requires further study.

COVID-19-associated Nephropathy Includes Tubular Necrosis and Capillary Congestion, with Evidence of SARS-CoV-2 in the Nephron.

Background: Kidney damage has been reported in patients with COVID-19. Despite numerous reports about COVID-19-associated nephropathy, the factual presence of the SARS-CoV-2 in the renal parenchyma remains controversial. Methods: We consecutively performed 16 immediate (≤3 hours) postmortem renal biopsies in patients diagnosed with COVID-19. Kidney samples from five patients who died from sepsis not related to COVID-19 were used as controls. Samples were methodically evaluated by three pathologists. Virus detection in the renal parenchyma was performed in all samples by bulk RNA RT-PCR (E and N1/N2 genes), immunostaining (2019-nCOV N-Protein), fluorescence in situ hybridization (nCoV2019-S), and electron microscopy. Results: The mean age of our COVID-19 cohort was 68.2±12.8 years, most of whom were male (69%). Proteinuria was observed in 53% of patients, whereas AKI occurred in 60% of patients. Acute tubular necrosis of variable severity was found in all patients, with no tubular or interstitial inflammation. There was no difference in acute tubular necrosis severity between the patients with COVID-19 versus controls. Congestion in glomerular and peritubular capillaries was respectively observed in 56% and 88% of patients with COVID-19, compared with 20% of controls, with no evidence of thrombi. The 2019-nCOV N-Protein was detected in proximal tubules and at the basolateral pole of scattered cells of the distal tubules in nine out of 16 patients. In situ hybridization confirmed these findings in six out of 16 patients. RT-PCR of kidney total RNA detected SARS-CoV-2 E and N1/N2 genes in one patient. Electron microscopy did not show typical viral inclusions. Conclusions: Our immediate postmortem kidney samples from patients with COVID-19 highlight a congestive pattern of AKI, with no significant glomerular or interstitial inflammation. Immunostaining and in situ hybridization suggest SARS-CoV-2 is present in various segments of the nephron.

Digital spatial profiling of collapsing glomerulopathy.

Collapsing glomerulopathy is a histologically distinct variant of focal and segmental glomerulosclerosis that presents with heavy proteinuria and portends a poor prognosis. Collapsing glomerulopathy can be triggered by viral infections such as HIV or SARS-CoV-2. Transcriptional profiling of collapsing glomerulopathy lesions is difficult since only a few glomeruli may exhibit this histology within a kidney biopsy and the mechanisms driving this heterogeneity are unknown. Therefore, we used recently developed digital spatial profiling (DSP) technology which permits quantification of mRNA at the level of individual glomeruli. Using DSP, we profiled 1,852 transcripts in glomeruli isolated from formalin fixed paraffin embedded sections from HIV or SARS-CoV-2-infected patients with biopsy-confirmed collapsing glomerulopathy and used normal biopsy sections as controls. Even though glomeruli with collapsing features appeared histologically similar across both groups of patients by light microscopy, the increased resolution of DSP uncovered intra- and inter-patient heterogeneity in glomerular transcriptional profiles that were missed in early laser capture microdissection studies of pooled glomeruli. Focused validation using immunohistochemistry and RNA in situ hybridization showed good concordance with DSP results. Thus, DSP represents a powerful method to dissect transcriptional programs of pathologically discernible kidney lesions.

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.

COVID-19 Survival and its impact on chronic kidney disease.

Up to 87% of patients hospitalized with coronavirus disease 2019 (COVID-19) experience chronic sequelae following infection. The long-term impact of COVID-19 infection on kidney function is largely unknown at this point in the COVID-19 pandemic. In this review, we highlight the current understanding of the pathophysiology of COVID-19-associated kidney injury and the impact COVID-19 may have on long-term kidney function. COVID-19-induced acute kidney injury may lead to tubular injury, endothelial injury, and glomerular injury. We highlight histopathologic correlates from large kidney biopsy and autopsy series. By conducting a comprehensive review of published literature to date, we summarize the rates of recovery from COVID-19-associated-AKI. Finally, we discuss how certain genetic differences, including APOL1 risk alleles (a risk factor for collapsing glomerulopathy), coupled with systemic healthcare disparities, may lead to a disproportionate burden of post-COVID-19-kidney function decline among racial and ethnic minority groups. We highlight the need for prospective studies to determine the true incidence of chronic kidney disease burden after COVID-19.

Glomerular filtration barrier dysfunction in a self-limiting, RNA virus-induced glomerulopathy resembles findings in idiopathic nephrotic syndromes.

Podocyte injury has recently been described as unifying feature in idiopathic nephrotic syndromes (INS). Puumala hantavirus (PUUV) infection represents a unique RNA virus-induced renal disease with significant proteinuria. The underlying pathomechanism is unclear. We hypothesized that PUUV infection results in podocyte injury, similar to findings in INS. We therefore analyzed standard markers of glomerular proteinuria (e.g. immunoglobulin G [IgG]), urinary nephrin excretion (podocyte injury) and serum levels of the soluble urokinase plasminogen activator receptor (suPAR), a proposed pathomechanically involved molecule in INS, in PUUV-infected patients. Hantavirus patients showed significantly increased urinary nephrin, IgG and serum suPAR concentrations compared to healthy controls. Nephrin and IgG levels were significantly higher in patients with severe proteinuria than with mild proteinuria, and nephrin correlated strongly with biomarkers of glomerular proteinuria over time. Congruently, electron microcopy analyses showed a focal podocyte foot process effacement. suPAR correlated significantly with urinary nephrin, IgG and albumin levels, suggesting suPAR as a pathophysiological mediator in podocyte dysfunction. In contrast to INS, proteinuria recovered autonomously in hantavirus patients. This study reveals podocyte injury as main cause of proteinuria in hantavirus patients. A better understanding of the regenerative nature of hantavirus-induced glomerulopathy may generate new therapeutic approaches for INS.

Acute necrotizing glomerulonephritis associated with COVID-19 infection: report of two pediatric cases.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is thought to cause kidney injury via a variety of mechanisms. The most common reported kidney injury following COVID-19 infection is acute tubular injury (ATI); however, the procoagulant state induced by the virus may also damage the kidneys. CASE-DIAGNOSIS/TREATMENT: Herein, we report two cases of acute necrotizing glomerulonephritis (GN) with fibrinoid necrosis in the context of COVID-19 infection. The one with more chronic features in the kidney biopsy progressed to permanent kidney failure but the second one had an excellent response to glucocorticoid pulse therapy with subsequent normal kidney function at 2-month follow-up. CONCLUSIONS: Both reported cases had an acute presentation of kidney injury with positive nasopharyngeal PCR test for COVID-19. Based on the data review by the researchers, this is the first report of acute necrotizing GN associated with COVID-19 infection.

COVID-19-Associated Glomerular Disease.

BACKGROUND: Studies have documented AKI with high-grade proteinuria in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In some patients, biopsies have revealed collapsing glomerulopathy, a distinct form of glomerular injury that has been associated with other viruses, including HIV. Previous patient reports have described patients of African ancestry who developed nephrotic-range proteinuria and AKI early in the course of disease. METHODS: In this patient series, we identified six patients with coronavirus disease 2019 (COVID-19), AKI, and nephrotic-range proteinuria. COVID-19 was diagnosed by a positive nasopharyngeal swab RT-PCR for SARS-CoV-2 infection. We examined biopsy specimens from one transplanted kidney and five native kidneys. Three of the six patients underwent genetic analysis of APOL1, the gene encoding the APOL1 protein, from DNA extracted from peripheral blood. In addition, we purified genomic DNA from paraffin-embedded tissue and performed APOL1 genotype analysis of one of the native biopsies and the donor kidney graft. RESULTS: All six patients were of recent African ancestry. They developed COVID-19-associated AKI with podocytopathy, collapsing glomerulopathy, or both. Patients exhibited generally mild respiratory symptoms, and no patient required ventilator support. Genetic testing performed in three patients confirmed high-risk APOL1 genotypes. One APOL1 high-risk patient developed collapsing glomerulopathy in the engrafted kidney, which was transplanted from a donor who carried a low-risk APOL1 genotype; this contradicts current models of APOL1-mediated kidney injury, and suggests that intrinsic renal expression of APOL1 may not be the driver of nephrotoxicity and specifically, of podocyte injury. CONCLUSIONS: Glomerular disease presenting as proteinuria with or without AKI is an important presentation of COVID-19 infection and may be associated with a high-risk APOL1 genotype.

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.

Lessons for the clinical nephrologist: recurrence of nephrotic syndrome induced by SARS-CoV-2.

SARS-CoV-2 is characterized by a multiorgan tropism including the kidneys. Recent autopsy series indicated that SARS-CoV-2 can infect both tubular and glomerular cells. Whereas tubular cell infiltration may contribute to acute kidney injury, data on a potential clinical correlative to glomerular affection is rare. We describe the first case of nephrotic syndrome in the context of COVID-19 in a renal transplant recipient. A 35 year old male patient received a kidney allograft for primary focal segmental glomerulosclerosis (FSGS). Three months posttransplant a recurrence of podocytopathy was successfully managed by plasma exchange, ivIG, and a conversion from tacrolimus to belatacept (initial proteinuria > 6 g/l decreased to 169 mg/l). Six weeks later he was tested positive for SARS-CoV-2 and developed a second increase of proteinuria (5.6 g/l). Renal allograft biopsy revealed diffuse podocyte effacement and was positive for SARS-CoV-2 in RNA in-situ hybridation indicating a SARS-CoV-2 associated recurrence of podocytopathy. Noteworthy, nephrotic proteinuria resolved spontaneously after recovering from COVID-19. The present case expands the spectrum of renal involvement in COVID-19 from acute tubular injury to podocytopathy in renal transplant recipients. Thus, it may be wise to test for SARS-CoV-2 prior to initiation of immunosuppression in new onset glomerulopathy during the pandemic.

Spectrum of podocytopathies in new-onset nephrotic syndrome following COVID-19 disease: a report of 2 cases.

BACKGROUND: Coronavirus disease-2019 (COVID-19) is an ongoing pandemic which has affected over 12 million people across the globe. Manifestations in different organs systems are being reported regularly. Renal biopsy findings in hospitalized COVID-19 patients presenting solely with acute kidney injury (AKI) have recently been described in published literature in few case reports. The findings include diffuse acute tubular injury (ATI) along with the glomerular lesion of collapsing glomerulopathy (CG). However, nephrotic syndrome as the presenting complaint of COVID-19 has not been reported widely, neither has any other glomerular lesion other than CG. CASE PRESENTATION: We describe the kidney biopsy findings of two patients who had recent diagnoses of COVID-19 and presented with new-onset nephrotic syndrome. Renal biopsy in both patients showed ATI (as in previous reports) and distinct glomerular findings on light microscopy - that of minimal change disease (MCD) initially in one patient followed by CG in a subsequent biopsy and CG at the outset in the other patient. The electron microscopic findings in both patients were that of severe podocytopathy (diffuse and severe podocyte foot process effacement). CONCLUSION: Our cases highlight a novel clinical presentation of COVID-19 renal disease, not described before, that of new-onset nephrotic syndrome. While all published case reports describe CG as the glomerular pathology, we describe a non-CG pathology (MCD) in one of our cases, thereby adding to the repertoire of renal pathology described in association with COVID-19 patients. However, the exact mechanism by which podocyte injury or podocytopathy occurs in all such cases is still unknown. Optimal treatment options for these patients also remains unknown at this time.

Single-cell RNA sequencing analysis of human kidney reveals the presence of ACE2 receptor: A potential pathway of COVID-19 infection.

BACKGROUND: A novel coronavirus called SARS-Cov-2, which shared 82% similarity of genome sequence with SARS-CoV, was found in Wuhan in late December of 2019, causing an epidemic outbreak of novel coronavirus-induced pneumonia with dramatically increasing number of cases. Several organs are vulnerable to COVID-19 infection. Acute kidney injury (AKI) was reported in parts of case-studies reporting characteristics of COVID-19 patients. This study aimed at analyzing the potential route of SARS-Cov-2 entry and mechanism at cellular level. METHOD: Single-cell RNA sequencing (scRNA-seq) technology was used to obtain evidence of potential route and ACE2 expressing cell in renal system for underlying pathogenesis of kidney injury caused by COVID-19. The whole process was performed under R with Seurat packages. Canonical marker genes were used to annotate different types of cells. RESULTS: Ten different clusters were identified and ACE2 was mainly expressed in proximal tubule and glomerular parietal epithelial cells. From Gene Ontology (GO) & KEGG enrichment analysis, imbalance of ACE2 expression, renin-angiotensin system (RAS) activation, and neutrophil-related processes were the main issue of COVID-19 leading kidney injury. CONCLUSION: Our study provided the cellular evidence that SARS-Cov-2 invaded human kidney tissue via proximal convoluted tubule, proximal tubule, proximal straight tubule cells, and glomerular parietal cells by means of ACE2-related pathway and used their cellular protease TMPRSS2 for priming.