An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) that began in Wuhan, China, has spread rapidly and has already taken on pandemic proportions. After China, Italy is the country with the highest number of cases so far (41,035 confirmed cases according to Dipartimento della Protezione Civile as of March 19, and 3,405 deaths). In Northern Italy, where the current prevalence of confirmed cases has surpassed in some areas 2 per 1,000 people, kidney transplant patients are getting infected and starting to develop coronavirus disease 2019 (COVID‐19).

Acute kidney injury (AKI) is a common finding in kidney donors and recipients. AKI in kidney donor, which increases the risk of delayed graft function (DGF), may not by itself jeopardize the short- and long-term outcome of transplantation. However, some forms of AKI may induce graft rejection, fibrosis, and eventually graft dysfunction. Therefore, various strategies have been proposed to identify conditions at highest risk of AKI-induced DGF, that can be treated by targeting the donor, the recipient, or even the graft itself with the use of perfusion machines. AKI that occurs early post-transplant after a period of initial recovery of graft function may reflect serious and often occult systemic complications that may require prompt intervention to prevent graft loss. AKI that develops long after transplantation is often related to nephrotoxic drug reactions. In symptomatic patients, AKI is usually associated with various systemic medical complications and could represent a risk of mortality. Electronic systems have been developed to alert transplant physicians that AKI has occurred in a transplant recipient during long-term outpatient follow-up. Herein, we will review most recent understandings of pathophysiology, diagnosis, therapeutic approach, and short- and long-term consequences of AKI occurring in both the donor and in the kidney transplant recipient.

Retinitis pigmentosa (RP) is the most common inherited retinal disease (IRD) and is characterized by photoreceptor degeneration and progressive vision loss. We report 4 patients presenting with RP from 3 unrelated families with variants in TBC1D32 , which to date has never been associated with an IRD. To validate TBC1D32 as a putative RP causative gene, we combined Xenopus in vivo approaches and human induced pluripotent stem cell–derived (iPSC-derived) retinal models. Our data showed that TBC1D32 was expressed during retinal development and that it played an important role in retinal pigment epithelium (RPE) differentiation. Furthermore, we identified a role for TBC1D32 in ciliogenesis of the RPE. We demonstrated elongated ciliary defects that resulted in disrupted apical tight junctions, loss of functionality (delayed retinoid cycling and altered secretion balance), and the onset of an epithelial-mesenchymal transition–like phenotype. Last, our results suggested photoreceptor differentiation defects, including connecting cilium anomalies, that resulted in impaired trafficking to the outer segment in cones and rods in TBC1D32 iPSC-derived retinal organoids. Overall, our data highlight a critical role for TBC1D32 in the retina and demonstrate that TBC1D32 mutations lead to RP. We thus identify TBC1D32 as an IRD-causative gene.

Aberrant O -glycosylation of the IgA1 hinge region is a characteristic finding in patients with IgA nephropathy (IgAN) and is thought to contribute to immune-complex formation and kidney injury. Other studies have suggested that abnormalities in mucosal immunity and lymphocyte homing are major contributors to disease. We identified a family with IgAN segregating a heterozygous predicted loss-of-function (LOF) variant in GALNT14 , the gene encoding N -acetylgalactosaminyltransferase 14, one of the enzymes involved in mucin-type protein O -glycosylation. While GALNT14 is expressed in IgA1-producing cells, carriers of the LOF variant did not have altered levels of poorly glycosylated IgA1, suggesting other disease mechanisms. Investigation of Galnt14 -null mice revealed elevated serum IgA levels and ex vivo IgA production by B cells. These mice developed glomerular IgA deposition with aging and after induction of sterile colitis. Galnt14 -null mice also displayed an attenuated mucin layer in the colon and redistribution of IgA-producing cells from mucosal to systemic sites. Adoptive-transfer experiments indicated impaired homing of spleen-derived Galnt14 -deficient B lymphocytes, resulting in increased retention in peripheral blood. These findings suggest that abnormalities in O -glycosylation alter mucosal immunity and B lymphocyte homing, pointing to an expanded role of aberrant O -glycosylation in the pathogenesis of IgAN.

Key Points: We conducted a clinical, genetic, and pathological analysis on 64 cases from 39 families with TRPC6-associated podocytopathy (TRPC6-AP). Analysis of 37,542 individuals excluded a major contribution of loss-of-function variants to TRPC6-AP, legitimating current drug discovery approaches. This study identifies key features of disease that can help intervention studies design and suggests similarities between TRPC6-AP and primary FSGS. Background: Understanding the genetic basis of human diseases has become integral to drug development and precision medicine. Recent advancements have enabled the identification of molecular pathways driving diseases, leading to targeted treatment strategies. The increasing investment in rare diseases by the biotech industry underscores the importance of genetic evidence in drug discovery and approval processes. Here we studied a monogenic Mendelian kidney disease, TRPC6-associated podocytopathy (TRPC6-AP), to present its natural history, genetic spectrum, and clinicopathological associations in a large cohort of patients with causal variants in TRPC6 to help define the specific features of disease and further facilitate drug development and clinical trials design. Methods: The study involved 64 individuals from 39 families with TRPC6 causal missense variants. Clinical data, including age of onset, laboratory results, response to treatment, kidney biopsy findings, and genetic information, were collected from multiple centers nationally and internationally. Exome or targeted sequencing was performed, and variant classification was based on strict criteria. Structural and functional analyses of TRPC6 variants were conducted to understand their effect on protein function. In-depth reanalysis of light and electron microscopy specimens for nine available kidney biopsies was conducted to identify pathological features and correlates of TRPC6-AP. Results: Large-scale sequencing data did not support causality for TRPC6 protein-truncating variants. We identified 21 unique TRPC6 missense variants, clustering in three distinct regions of the protein, and with different effects on TRPC6 3D protein structure. Kidney biopsy analysis revealed FSGS patterns of injury in most cases, along with distinctive podocyte features including diffuse foot process effacement and swollen cell bodies. Most patients presented in adolescence or early adulthood but with ample variation (average 22, SD ±14 years), with frequent progression to kidney failure but with variability in time between presentation and kidney failure. Conclusions: This study provides insights into the genetic spectrum, clinicopathological associations, and natural history of TRPC6-AP. Clinical Trial registry name and registration number: A Study to Test BI 764198 in People With a Type of Kidney Disease Called Focal Segmental Glomerulosclerosis, NCT05213624.