Summary We report a comprehensive molecular characterization of pheochromocytomas and paragangliomas (PCC/PGLs), a rare tumor type. Multi-platform integration revealed that PCC/PGLs are driven by diverse alterations affecting multiple genes and pathways. Pathogenic germline mutations occurred in eight PCC/PGL susceptibility genes. We identified CSDE1 as a somatically-mutated driver gene, complementing four known drivers (HRAS, RET, EPAS1, NF1). We also discovered fusion genes in PCC/PGL, involving MAML3, BRAF, NGFR and NF1. Integrated analysis classified PCC/PGLs into four molecularly-defined groups: a kinase signaling subtype, a pseudohypoxia subtype, a Wnt-altered subtype, driven by MAML3 and CSDE1, and a cortical admixture subtype. Correlates of metastatic PCC/PGL included the MAML3 fusion gene. This integrated molecular characterization provides a comprehensive foundation for developing PCC/PGL precision medicine.

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 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 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, demonstrated a high frequency of APOL1 high-risk genotypes within this group, with no evidence of direct viral infection within the kidney.

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Introduction Novel anticancer therapies include anti–programmed cell death protein-1 (PD-1) and anti–programmed death ligand-1 (PD-L1) drugs. These novel medications have side effects in different organs, including the kidney. The most common adverse effect in the kidney is acute interstitial nephritis (AIN). No diagnostic criteria are available to distinguish AIN associated with anti–PD-1 therapy from other AINs. Methods Kidney biopsy specimens from patients on anti–PD-1 therapy were stained with antibodies to PD-1 and PD-L1. Herein we report morphologic and immunohistochemical findings in 15 patients who received anti–PD-1 therapy and developed acute kidney injury requiring a kidney biopsy. Results Among these patients, 9 had AIN and 6 had no AIN but showed acute tubular necrosis (ATN). Immunohistochemistry with antibodies to PD-1 and PD-L1 was performed on all of these biopsy specimens and on 9 randomly selected biopsy specimens with AIN from patients who did not receive anti–PD-1 medications, as well as 9 patients with lupus nephritis and active-appearing interstitial inflammation. There was weak staining for PD-1 in T cells in all patients with AIN and lupus; however, tubular epithelial cell membrane staining for PD-L1 was seen only in patients with anti–PD-1 therapy−associated AIN, and not in patients with anti–PD-1 therapy−associated ATN, and not in those with AIN secondary to other medications, or patients with lupus nephritis. Conclusion We propose that immunohistochemistry with PD-L1 could be a useful tool to differentiate AIN associated with anti–PD-1 therapy from other AINs.

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 case 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 glomerulonephritis, collapsing glomerulopathy, and diffuse lupus nephritis diagnosed on kidney biopsies post-immunization, as well as recurrent ANCA-associated glomerulonephritis. This included 28 cases of de novo glomerulonephritis within native kidney biopsies and one disease flare in an allograft. Results: The patients with collapsing glomerulopathy were of African American descent and had two APOL1 genomic risk alleles. A brief literature review of case 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 to the two years prior to the COVID-19 pandemic diagnosed on kidney biopsies in our practice. Conclusions: This suggests that glomerulonephritis in response to vaccination is rare, although should be monitored as a potential adverse event.