APOL1 Risk Variants and Acute Kidney Injury in Black Americans with COVID-19.

BACKGROUND AND OBJECTIVES: Black Americans have a higher incidence of kidney disease compared with populations that do not have recent African ancestry. Two risk variants in the APOL1 are responsible for a portion of this higher risk. We sought to assess the odds of AKI conferred by APOL1 risk alleles in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Black Americans who tested positive for coronavirus disease 2019 (COVID-19) were genotyped to determine APOL1 risk allele status. We assessed the incidence of AKI, persistent AKI, and AKI requiring KRT within 21 days of the PCR-based diagnosis. Outcomes were adjusted for age, sex, body mass index, hypertension, eGFR, and use of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. RESULTS: In total, 126 cases of SARS-CoV-2 infection were included within a 5-month period, with 16 (13%) and 110 (87%) cases with two and zero/one APOL1 high-risk alleles, respectively. AKI occurred in 11 (69%) patients with two APOL1 high-risk alleles and 39 (35%) patients with zero/one high-risk alleles (adjusted odds ratio, 4.41; 95% confidence interval, 1.11 to 17.52; P=0.04). Persistent AKI occurred in eight (50%) patients with two APOL1 high-risk alleles and 21 (19%) of those with zero/one high-risk alleles (adjusted odds ratio, 3.53; 95% confidence interval, 1.8 to 11.57; P=0.04). AKI KRT occurred in four (25%) of those with two APOL1 high-risk alleles and eight (7%) of those with zero/one high-risk alleles (adjusted odds ratio, 4.99; 95% confidence interval, 1.02 to 24.4, P=0.05). CONCLUSIONS: APOL1 high-risk alleles are associated with greater odds of AKI in Black American patients with COVID-19.

Glomerular Disease in Temporal Association with SARS-CoV-2 Vaccination: A Series of 29 Cases.

Background: Immune responses to vaccination are a known trigger for a new onset of glomerular disease or disease flare in susceptible individuals. Mass immunization against SARS-CoV-2 in the COVID-19 pandemic provides a unique opportunity to study vaccination-associated autoimmune kidney diseases. In the recent literature, there are several patient reports demonstrating a temporal association of SARS-CoV-2 immunization and kidney diseases. Methods: Here, we present a series of 29 cases of biopsy-proven glomerular disease in patients recently vaccinated against SARS-CoV-2 and identified patients who developed a new onset of IgA nephropathy, minimal change disease, membranous nephropathy, ANCA-associated GN, collapsing glomerulopathy, or diffuse lupus nephritis diagnosed on kidney biopsies postimmunization, as well as recurrent ANCA-associated GN. This included 28 cases of de novo GN within native kidney biopsies and one disease flare in an allograft. Results: The patients with collapsing glomerulopathy were of Black descent and had two APOL1 genomic risk alleles. A brief literature review of patient reports and small series is also provided to include all reported cases to date (n=52). The incidence of induction of glomerular disease in response to SARS-CoV-2 immunization is unknown; however, there was no overall increase in incidence of glomerular disease when compared with the 2 years prior to the COVID-19 pandemic diagnosed on kidney biopsies in our practice. Conclusions: Glomerular disease to vaccination is rare, although it should be monitored as a potential adverse event.

Acute Kidney Injury in Severe COVID-19 Has Similarities to Sepsis-Associated Kidney Injury: A Multi-Omics Study.

OBJECTIVE: To compare coronavirus disease 2019 (COVID-19) acute kidney injury (AKI) to sepsis-AKI (S-AKI). The morphology and transcriptomic and proteomic characteristics of autopsy kidneys were analyzed. PATIENTS AND METHODS: Individuals 18 years of age and older who died from COVID-19 and had an autopsy performed at Mayo Clinic between April 2020 to October 2020 were included. Morphological evaluation of the kidneys of 17 individuals with COVID-19 was performed. In a subset of seven COVID-19 cases with postmortem interval of less than or equal to 20 hours, ultrastructural and molecular characteristics (targeted transcriptome and proteomics analyses of tubulointerstitium) were evaluated. Molecular characteristics were compared with archived cases of S-AKI and nonsepsis causes of AKI. RESULTS: The spectrum of COVID-19 renal pathology included macrophage-dominant microvascular inflammation (glomerulitis and peritubular capillaritis), vascular dysfunction (peritubular capillary congestion and endothelial injury), and tubular injury with ultrastructural evidence of mitochondrial damage. Investigation of the spatial architecture using a novel imaging mass cytometry revealed enrichment of CD3+CD4+ T cells in close proximity to antigen-presenting cells, and macrophage-enriched glomerular and interstitial infiltrates, suggesting an innate and adaptive immune tissue response. Coronavirus disease 2019 AKI and S-AKI, as compared to nonseptic AKI, had an enrichment of transcriptional pathways involved in inflammation (apoptosis, autophagy, major histocompatibility complex class I and II, and type 1 T helper cell differentiation). Proteomic pathway analysis showed that COVID-19 AKI and to a lesser extent S-AKI were enriched in necroptosis and sirtuin-signaling pathways, both involved in regulatory response to inflammation. Upregulation of the ceramide-signaling pathway and downregulation of oxidative phosphorylation in COVID-19 AKI were noted. CONCLUSION: This data highlights the similarities between S-AKI and COVID-19 AKI and suggests that mitochondrial dysfunction may play a pivotal role in COVID-19 AKI. This data may allow the development of novel diagnostic and therapeutic targets.

A multi-center retrospective cohort study defines the spectrum of kidney pathology in Coronavirus 2019 Disease (COVID-19).

Kidney failure is common in patients with Coronavirus Disease-19 (COVID-19), resulting in increased morbidity and mortality. In an international collaboration, 284 kidney biopsies were evaluated to improve understanding of kidney disease in COVID-19. Diagnoses were compared to five years of 63,575 native biopsies prior to the pandemic and 13,955 allograft biopsies to identify diseases that have increased in patients with COVID-19. Genotyping for APOL1 G1 and G2 alleles was performed in 107 African American and Hispanic patients. Immunohistochemistry for SARS-CoV-2 was utilized to assess direct viral infection in 273 cases along with clinical information at the time of biopsy. The leading indication for native biopsy was acute kidney injury (45.4%), followed by proteinuria with or without concurrent acute kidney injury (42.6%). There were more African American patients (44.6%) than patients of other ethnicities. The most common diagnosis in native biopsies was collapsing glomerulopathy (25.8%), which was associated with high-risk APOL1 genotypes in 91.7% of cases. Compared to the five-year biopsy database, the frequency of myoglobin cast nephropathy and proliferative glomerulonephritis with monoclonal IgG deposits was also increased in patients with COVID-19 (3.3% and 1.7%, respectively), while there was a reduced frequency of chronic conditions (including diabetes mellitus, IgA nephropathy, and arterionephrosclerosis) as the primary diagnosis. In transplants, the leading indication was acute kidney injury (86.4%), for which rejection was the predominant diagnosis (61.4%). Direct SARS-CoV-2 viral infection was not identified. Thus, our multi-center large case series identified kidney diseases that disproportionately affect patients with COVID-19 and demonstrated a high frequency of APOL1 high-risk genotypes within this group, with no evidence of direct viral infection within the kidney.

Membranous nephropathy in a patient with coronavirus disease 2019 (COVID-19): A case report.

INTRODUCTION: Though respiratory, immune, and coagulation systems are major targets of coronavirus disease 2019 (COVID-19), kidney dysfunction, presenting with acute kidney injury (AKI), is also common. Most AKI cases in COVID-19 manifest as acute tubular injury (ATI) in conjunction with multiorgan failure. While initial renal pathological findings were limited to acute tubular necrosis and collapsing glomerulopathy, a recent case series reported a larger spectrum of findings. CASE REPORT: Here, we report a case of membranous nephropathy (MN) in an 81-year-old Hispanic man with underlying chronic kidney disease (CKD) stage 3 who developed ATI in the setting of COVID-19. The patient was hospitalized for hypoxic respiratory failure in the setting of AKI stage 3 with serum creatinine 7.1 mg/dL 6 days after a positive-SARS-CoV-2 screening. He was found to have nephrotic range proteinuria, glycosuria (with normal serum glucose), anemia, and hypoalbuminemia. Kidney biopsy showed ATI and early MN. Workup for primary and secondary MN was unrevealing, and serum PLA2R antibody was negative. No viral particles were observed in podocytes. CONCLUSION: Although the MN could be incidental, this observation raises the question of whether SARS-CoV-2 infection can trigger or worsen an underlying MN from an exaggerated immune response associated with COVID-19.

Author Correction: COVAN is the new HIVAN: the re-emergence of collapsing glomerulopathy with COVID-19.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

COVID-19-Associated Kidney Injury: A Case Series of Kidney Biopsy Findings.

BACKGROUND: Reports show that AKI is a common complication of severe coronavirus disease 2019 (COVID-19) in hospitalized patients. Studies have also observed proteinuria and microscopic hematuria in such patients. Although a recent autopsy series of patients who died with severe COVID-19 in China found acute tubular necrosis in the kidney, a few patient reports have also described collapsing glomerulopathy in COVID-19. METHODS: We evaluated biopsied kidney samples from ten patients at our institution who had COVID-19 and clinical features of AKI, including proteinuria with or without hematuria. We documented clinical features, pathologic findings, and outcomes. RESULTS: Our analysis included ten patients who underwent kidney biopsy (mean age: 65 years); five patients were black, three were Hispanic, and two were white. All patients had proteinuria. Eight patients had severe AKI, necessitating RRT. All biopsy samples showed varying degrees of acute tubular necrosis, and one patient had associated widespread myoglobin casts. In addition, two patients had findings of thrombotic microangiopathy, one had pauci-immune crescentic GN, and another had global as well as segmental glomerulosclerosis with features of healed collapsing glomerulopathy. Interestingly, although the patients had confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by RT-PCR, immunohistochemical staining of kidney biopsy samples for SARS-CoV-2 was negative in all ten patients. Also, ultrastructural examination by electron microscopy showed no evidence of viral particles in the biopsy samples. CONCLUSIONS: The most common finding in our kidney biopsy samples from ten hospitalized patients with AKI and COVID-19 was acute tubular necrosis. There was no evidence of SARS-CoV-2 in the biopsied kidney tissue.

Detection of SARS-CoV-2 in formalin-fixed paraffin-embedded tissue sections using commercially available reagents.

Coronavirus Disease-19 (COVID-19), caused by the coronavirus SARS-CoV-2, was initially recognized in Wuhan, China and subsequently spread to all continents. The disease primarily affects the lower respiratory system, but may involve other organs and systems. Histopathologic evaluation of tissue from affected patients is crucial for diagnostic purposes, but also for advancing our understanding of the disease. For that reason, we developed immunohistochemical (IHC) and in situ hybridization (ISH) assays for detection of the. virus. A total of eight autopsy lungs, one placenta, and ten kidney biopsies from COVID-19 patients were stained with a panel of commercially available antibodies for IHC and commercially available RNA probes for ISH. Similarly, autopsy lungs, placentas and renal biopsies from non-COVID-19 patients were stained with the same antibodies and probes. All eight lungs and the placenta from COVID-19 patients stained positive by IHC and ISH, while the kidney biopsies stained negative by both methodologies. As expected, all specimens from non-COVID-19 patients were IHC and ISH negative. These two assays represent a sensitive and specific method for detecting the virus in tissue samples. We provide the protocols and the list of commercially available antibodies and probes for these assays, so they can be readily implemented in pathology laboratories and medical examiner offices for diagnostic and research purposes.

AKI and Collapsing Glomerulopathy Associated with COVID-19 and APOL 1 High-Risk Genotype.

BACKGROUND: Kidney involvement is a feature of COVID-19 and it can be severe in Black patients. Previous research linked increased susceptibility to collapsing glomerulopathy, including in patients with HIV-associated nephropathy, to apo L1 (APOL1) variants that are more common in those of African descent. METHODS: To investigate genetic, histopathologic, and molecular features in six Black patients with COVID-19 presenting with AKI and de novo nephrotic-range proteinuria, we obtained biopsied kidney tissue, which was examined by in situ hybridization for viral detection and by NanoString for COVID-19 and acute tubular injury-associated genes. We also collected peripheral blood for APOL1 genotyping. RESULTS: This case series included six Black patients with COVID-19 (four men, two women), mean age 55 years. At biopsy day, mean serum creatinine was 6.5 mg/dl and mean urine protein-creatinine ratio was 11.5 g. Kidney biopsy specimens showed collapsing glomerulopathy, extensive foot process effacement, and focal/diffuse acute tubular injury. Three patients had endothelial reticular aggregates. We found no evidence of viral particles or SARS-CoV-2 RNA. NanoString showed elevated chemokine gene expression and changes in expression of genes associated with acute tubular injury compared with controls. All six patients had an APOL1 high-risk genotype. Five patients needed dialysis (two of whom died); one partially recovered without dialysis. CONCLUSIONS: Collapsing glomerulopathy in Black patients with COVID-19 was associated with high-risk APOL1 variants. We found no direct viral infection in the kidneys, suggesting a possible alternative mechanism: a "two-hit" combination of genetic predisposition and cytokine-mediated host response to SARS-CoV-2 infection. Given this entity's resemblance with HIV-associated nephropathy, we propose the term COVID-19-associated nephropathy to describe it.

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

Collapsing glomerulopathy is an aggressive form of focal segmental glomerulosclerosis with diverse causes. The presence of the apolipoprotein L1 (APOL1) high-risk genotype is a major risk factor for collapsing glomerulopathy in African Americans. Coronavirus disease 2019 (COVID-19) is an emerging pandemic with predominant respiratory manifestations. However, kidney involvement is being frequently noted and is associated with higher mortality. Currently, kidney pathology data for COVID-19 are scant and mostly come from postmortem findings. We report 2 African American patients who developed acute kidney injury and proteinuria in temporal association with COVID-19 infection. Kidney biopsy specimens showed collapsing glomerulopathy, endothelial tubuloreticular inclusions, and acute tubular injury, without evidence by electron microscopy or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in situ hybridization of viral infection of kidney cells. Both patients had the APOL1 high-risk genotype. We propose that collapsing glomerulopathy represents a novel manifestation of COVID-19 infection, especially in people of African descent with APOL1 risk alleles.