ABSTRACT Aim Diabetic nephropathy (DN) progression involves pyroptosis. Interferon regulatory factor 7 (IRF7) can regulate pyroptosis, but its role in DN is unknown. The RNA modifier N ‐acetyltransferase 10 (NAT10) catalyses N4‐acetylcytidine (ac4C) and is linked to diabetic complications. This study tested whether NAT10‐mediated ac4C modification of IRF7 mRNA exacerbates DN by promoting pyroptosis. Methods The NAT10 expression levels in renal tissues from DN mice and in high‐glucose (HG)‐treated HK‐2 cells were assessed by RT‐qPCR and western blot. Cell viability, pyroptosis rate, levels of inflammatory cytokines (IL‐1β, IL‐18) and expression of pyroptosis‐related proteins (NLRP3, cleaved caspase‐1, GSDMD‐N) were evaluated by CCK‐8 assay, flow cytometry, ELISA and western blot, respectively. The interaction between NAT10 and IRF7 mRNA was investigated through bioinformatics prediction, RIP, acRIP‐qPCR and actinomycin D chase assays. In vivo, an AAV‐mediated shRNA targeting NAT10 was delivered to DN mice. Renal function, histopathology, tissue inflammation and protein expression were analysed using biochemical assays, HE staining, ELISA, immunohistochemistry and western blot. Results NAT10 was upregulated in DN mice and HG‐exposed HK‐2 cells. Depletion of NAT10 inhibited HG‐induced pyroptosis in HK‐2 cells. Notably, NAT10 stabilized IRF7 through ac4C modification. Moreover, knockdown of NAT10 was found to alleviate HG‐induced HK‐2 cells' pyroptosis and DN in mice by downregulating IRF7 expression. Conclusion NAT10 upregulation promotes DN progression by enhancing IRF7 mRNA stability through ac4C modification, which provides new therapeutic targets for DN treatment.
ABSTRACT COQ8B (formerly ADCK4)‐associated glomerulopathy is an autosomal recessive primary coenzyme Q10 deficiency that typically presents with proteinuria, focal segmental glomerulosclerosis and progressive kidney dysfunction during childhood or adolescence. We report extended longitudinal follow‐up of a family carrying the homozygous COQ8B c.1339dupG, p.(Glu447Glyfs*10) variant, demonstrating marked intrafamilial phenotypic heterogeneity despite an identical genotype. Two homozygous siblings developed kidney failure in childhood or adolescence and underwent living‐related kidney transplantation, with prolonged allograft survival and no clinical recurrence of the native disease. In contrast, a third homozygous sibling was identified through cascade testing at age 24 with preserved kidney function and non‐nephrotic proteinuria and has remained free of kidney failure for more than 10 years. The fourth sibling, who was heterozygous, remained clinically unaffected and both heterozygous parental donors maintained normal kidney function without proteinuria during long‐term follow‐up. This family illustrates the broad clinical spectrum of COQ8B‐associated glomerulopathy and shows that identical homozygous variants may be associated with markedly divergent long‐term kidney trajectories. Cascade testing may identify mildly affected adults before advanced kidney impairment and should be considered an integral component of familial evaluation in genetically defined glomerular disease.
ABSTRACT Autoinflammatory‐pancytopenia syndrome (AIPCS) is a rare autosomal recessive disease caused by a mutation in the deoxyribonuclease II (DNASE2) gene. It has mainly haematological manifestations and recurrent fevers. The kidney could be involved in the form of proteinuria, membranoproliferative glomerulonephritis (MPGN) or immune complex deposition rather than acute kidney injury (AKI) or C3 glomerulopathy (C3G). A six‐year‐old male child presented with high‐grade fever, AKI, generalized edema and hypertension. He had a history of recurrent hospital admission with fever, arthritis, skin rash and recurrent infections in the form of diarrhoea and chest infection. He had stunted growth, pallor, hepatosplenomegaly (HSM) and skin hyperpigmentation at the sites of the healed vasculitic skin rash. He was diagnosed with hemophagocytic lymphohistiocytosis and received its protocol of treatment with improvement of fever. However, pancytopenia and HSM were still progressive. Laboratory investigations revealed pancytopenia, impaired kidney function tests and heavy‐range proteinuria with persistent low C3 level. Kidney biopsy revealed C3 deposition suggestive of C3G, with 20% global glomerulosclerosis, mild interstitial fibrosis and tubular atrophy (10%). Kidney function tests normalized after receiving intravenous methylprednisolone, but proteinuria is still persistent, which indicates that AKI was on top of chronic kidney disease in the presence of C3G. Whole exome sequencing revealed a homozygous (missense) variant of uncertain significance with pathogenic evidence in exon‐6 of the DNASE2 gene causing AIPCS. In conclusion, C3G is a new form of kidney involvement associated with AIPCS. Kidney histopathology should be combined with phenotypic‐genotypic aspects of AIPCS.
ABSTRACT Aim Hypoxia‐inducible factor prolyl hydroxylase (HIF‐PH) inhibitors constitute novel oral pharmacotherapy for anaemia in chronic kidney disease (CKD). Although a possible HIF‐PH inhibitor‐induced increase in vascular endothelial growth factor could exacerbate retinal diseases, real‐world evidence is limited, particularly among Japanese non‐dialysis patients. Methods We conducted a retrospective cohort study using the DeSC administrative claims database (DeSC Healthcare Inc., Tokyo, Japan; December 2019 to June 2023). We identified patients with CKD who newly used HIF‐PH inhibitors or long‐acting erythropoiesis‐stimulating agents (ESAs). The primary outcome was the first treatment‐requiring retinal disease. We employed the matching weight method using high‐dimensional propensity scores to adjust for confounding and inverse probability of censoring weights (IPCW) to account for informative censoring. Results The study included 74 530 treatment‐naïve patients (mean age: 84.7 years; 49 928 ESA users; 24 602 HIF‐PH inhibitor users). The risk of retinal diseases did not differ significantly between the HIF‐PH inhibitor and ESA groups. The adjusted hazard ratio (HR) with matching weights was 0.65 [95% confidence interval (CI): 0.37–1.12]. The HR with matching weights and IPCW was 0.55 (95% CI: 0.22–1.38). Sensitivity analyses supported these findings. Negative control analysis using cataracts yielded an adjusted HR of 0.85 (95% CI: 0.67–1.07). Subgroup analyses showed no increased risk across categories. Conclusions HIF‐PH inhibitors were not associated with an increased risk of treatment‐requiring retinal disease. These real‐world data suggest the retinal safety of HIF‐PH inhibitors in non‐dialysis patients with CKD. Retinal concerns may not necessarily be a limiting factor while selecting HIF‐PH inhibitors for non‐dialysis patients with CKD.
ABSTRACT Aim Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited causes of kidney failure. We performed a whole‐exome sequencing study that aimed to characterize the spectrum of PKD1 and PKD2 variants in a Vietnamese ADPKD cohort and to evaluate the clinical utility of family‐based cascade genetic testing. Methods This cross‐sectional descriptive study included 40 unrelated patients with clinically diagnosed polycystic kidney disease. Variants were identified in probands using whole‐exome sequencing. Family‐based genetic testing was subsequently performed using Sanger sequencing in 104 relatives. Cascade screening was restricted to families with pathogenic or likely pathogenic variants, whereas variant of uncertain significance families were evaluated separately through segregation analysis to support variant interpretation and potential reclassification. Clinical and genetic characteristics were described and exploratory genotype–phenotype analyses were performed. Results Genetic testing identified PKD1 variants in 77.5% of patients, PKD2 variants in 17.5% and no ADPKD‐related variants in 5.0%. A total of 37 potentially relevant variants were detected, including 31 in PKD1 (83.8%) and six in PKD2 (16.2%). Nine novel variants were identified. PKD1 carriers were younger than PKD2 carriers ( p = 0.029) at the time of evaluation. Apart from this age difference, no other clinical characteristics differed significantly according to gene type or variant class. Cascade screening of 89 relatives from families with pathogenic or likely pathogenic variants revealed that 53 (59.6%) carried the familial variant, whereas 36 (40.4%) did not. Among 53 variant‐positive relatives, 34 (64.2%) were symptomatic and 19 (35.8%) were asymptomatic at the time of evaluation. In contrast, no variant‐negative relatives showed clinical evidence of ADPKD ( p < 0.001). These findings are consistent with autosomal dominant segregation of the familial variant and support the clinical utility of cascade screening. Conclusion This study expands the known genetic spectrum of ADPKD in Vietnamese families and demonstrates the predominance of PKD1 variants in this cohort. Family‐based cascade screening was useful for identifying variant‐positive relatives before overt clinical manifestation, thereby supporting earlier surveillance and genetic counselling.
