Podocytopathies represent a group of glomerular disorders associated with minimal changes (MC) or focal segmental glomerulosclerosis (FSGS) lesion patterns at biopsy and heterogeneous responses to steroids. Anti-nephrin antibodies were previously found in such patients, suggesting an autoimmune form of podocytopathy. High resolution confocal microscopy on kidney biopsies of a cohort of 128 pediatric patients revealed localization of IgG along the slit diaphragm in 30% of patients with MC and 25% of those with FSGS, but not in other lesion patterns. Anti-nephrin IgG ELISA assay in the serum and stimulated emission depletion microscopy of kidney biopsies showed IgG-nephrin co-localization only in 77.8% of cases. Similar observations were obtained in a cohort of 48 adult patients with MC or FSGS at kidney biopsy, where IgG-nephrin colocalization was only 44.4%, suggesting the existence of autoantibodies binding to other slit proteins. Patients with anti-slit antibodies showed nephrotic syndrome at onset in 94.4% of cases. Patients with primary steroid-resistance had anti-slit antibodies in 27%, while those with secondary steroid-resistance in 87.5% of cases, irrespective of the histopathological lesion pattern. Steroid-resistant patients with anti-slit antibodies responded to second-line immunosuppressants in 92.3% vs. only 20% of patients that were anti-slit negative. No patient with anti-slit antibodies developed kidney failure vs. 51.7% of those negative for antibodies (66.7% with a genetic cause and 41.2% with a non-genetic cause). Thus, the detection of anti-slit antibodies can identify patients with an autoimmune podocytopathy responsive to treatment with second-line immunosuppressants, irrespective of the histopathological lesion pattern at biopsy.

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Bartter (BS) and Gitelman (GS) syndrome are autosomal recessive inherited tubulopathies, whose clinical diagnosis can be challenging, due to rarity and phenotypic overlap. Genotype–phenotype correlations have important implications in defining kidney and global outcomes. The aim of our study was to assess the diagnostic rate of whole-exome sequencing (WES) coupled with a bioinformatic analysis of copy number variations in a population of 63 patients with BS and GS from a single institution, and to explore genotype-phenotype correlations. We obtained a diagnostic yield of 86% (54/63 patients), allowing disease reclassification in about 14% of patients. Although some clinical and laboratory features were more commonly reported in patients with BS or GS, a significant overlap does exist, and age at onset, preterm birth, gestational age and nephro-calcinosis are frequently misleading. Finally, chronic kidney disease (CKD) occurs in about 30% of patients with BS or GS, suggesting that the long-term prognosis can be unfavorable. In our cohort the features associated with CKD were lower gestational age at birth and a molecular diagnosis of BS, especially BS type 1. The results of our study demonstrate that WES is useful in dealing with the phenotypic heterogeneity of these disorders, improving differential diagnosis and genotype-phenotype correlation.

Acute kidney injury (AKI) is a life-threatening condition characterized by a rapid and transient decrease in kidney function. AKI is part of an array of conditions collectively defined as acute kidney diseases (AKD). In AKD, persistent kidney damage and dysfunction lead to chronic kidney disease (CKD) over time. A variety of insults can trigger AKI; however, chemotherapy-associated nephrotoxicity is increasingly recognized as a significant side effect of chemotherapy. New biomarkers are urgently needed to identify patients at high risk of developing chemotherapy-associated nephrotoxicity and subsequent AKI. However, a lack of understanding of cellular mechanisms that trigger chemotherapy-related nephrotoxicity has hindered the identification of effective biomarkers to date. In this review, we aim to (1) describe the known and potential mechanisms related to chemotherapy-induced AKI; (2) summarize the available biomarkers for early AKI detection, and (3) raise awareness of chemotherapy-induced AKI.

Key Points: Piezo1 regulates perinuclear actin remodeling, and its loss induces nuclear envelope defects and accumulation of DNA damage. Piezo1 loss in podocytes leads to mitotic catastrophe. Podocyte-specific and podocyte progenitor–specific knockout of Piezo1 in mice result in severe albuminuria after adriamycin nephropathy. Background: Podocytes and podocyte progenitors are interdependent components of the kidney's glomerular structure, with podocytes forming the glomerular filtration barrier and progenitors being key players in podocyte regeneration during pathophysiologic processes. Both cell types are subjected to constant mechanical forces, whose alterations can initiate podocytopathy and worsen glomerular injury. Despite this, the specific mechanosensors and mechanotransduction pathways involved in their response to mechanical cues remain only partially explored. Methods: We used transcriptomics, immunofluorescence, and silencing experiments on human primary podocyte progenitor cell cultures to demonstrate the expression and function of Piezo1 channels. We generated inducible podocyte-specific and podocyte progenitor–specific Piezo1 knockout (KO) mice to evaluate the effects of Piezo1 loss in the context of adriamycin nephropathy and over 10 months of aging. Results: Silencing of Piezo1 in progenitors triggered F-actin remodeling, which induced cell shape modification and nuclear envelope defects with accumulation of DNA damage that led to mitotic catastrophe in differentiated podocytes. Podocyte-specific KO of Piezo1 induced higher susceptibility to podocyte injury in adriamycin nephropathy and led to accumulation of DNA damage and mild albuminuria starting from adult age. Podocyte progenitor–specific KO of Piezo1 in mouse resulted in severe albuminuria during adriamycin nephropathy, leading to the generation of defective podocytes. Conclusions: These results demonstrated that Piezo1, thanks to its role in F-actin cytoskeleton maintenance, is essential for the survival of podocytes exposed to mechanical stress conditions and for their correct regeneration.

The global burden of kidney disease displays marked sexual dimorphism. Lineage tracing and single-cell RNA-sequencing revealed that starting from puberty, estrogen signaling in female mice supports self-renewal and differentiation of renal progenitors to increase filtration capacity, reducing sensitivity to glomerular injury compared with that of males. This phenomenon accelerated as female kidneys adapted to the workload of pregnancy. Deletion of estrogen receptor α in renal progenitors disrupted this adaptation, leading to preeclampsia, fetal growth restriction, and increased maternal risk of hypertension and chronic kidney disease. Offspring from affected mothers had fewer nephrons, resulting in early-life hypertension and greater susceptibility to kidney disease. These results highlight the fundamental role of kidney fitness and renal progenitors for pregnancy and preeclampsia and as a determinant of sexual dimorphism in kidney disease.