2023年 · 第103卷第18期

Chronic kidney disease and type 2 diabetes are independently associated with heart failure (heart failure). Finerenone is a new generation mineralocorticoid receptor antagonist. Results from the FIDELIO-DKD study (a study in which Finerenone slows down kidney failure and disease progression in diabetic nephropathy) and FIGARO-DKD study (a study in which Finerenone reduces the incidence and mortality of cardiovascular events in diabetic nephropathy) show that Finerenone improves cardiovascular outcomes in patients with chronic kidney disease and type 2 diabetes. The primary objective of this study was to evaluate the effect of feneridone on clinical heart failure outcomes. A total of 7 532 patients with type 2 diabetes mellitus combined with proteinuric chronic kidney disease were enrolled and randomly divided into fenelidone and placebo groups with a median follow-up time of 3.4 years, of which 571 (7.8%) had a history of heart failure. Endpoint events included: new heart failure [first hospitalization for heart failure (HHF) in a patient with no history of heart failure at baseline], composite endpoint of cardiovascular death and first HHF, composite endpoint of heart failure-related death and first HHF, composite endpoint of first HHF, composite endpoint of cardiovascular death or HHF (first or non-first), composite endpoint of heart failure-related death and HHF, HHF. Compared with the placebo group, the risk of new heart failure was significantly lower in the feneridone group (1.9% vs. 2.8%,HR=0.68，95%CI：0.50~0.93，P=0.016）； In the overall population, the risk of heart failure-related outcomes, including cardiovascular death or an 18% reduction in first-time HHF, was reduced in the fenelidone group compared with the placebo group (HR=0.82，95%CI：0.70~0.95，P=0.011), with a 29% reduction in the risk of first HHF (HR=0.71，95%CI：0.56~0.90，P=0.004) and a 30% reduction in total HHF risk (RR=0.70，95%CI：0.52~0.94）。 It is therefore concluded that fenelidone reduces new onset heart failure and improves other heart failure outcomes in patients with chronic kidney disease and type 2 diabetes, with or without a history of heart failure.

C3 glomerulopathy is a heterogeneous chronic kidney disease that is mainly characterized by glomerular C3 deposition and complement dysregulation. Mutations in the H factor-associated protein (FHR) gene leading to repeated dimerization domains are typical of C3 glomerulopathy, but the underlying pathogenic mechanism is unclear. This study provides an in-depth analysis of the characteristics of FHR-1 mutants with repeated dimerization domains. To assess the association of FHR-1 mutants with disease susceptibility and renal prognosis, the researchers also analyzed FHR-1 gene copy number variants and plasma FHR-1 levels in two Spanish C3 glomerulopathy cohorts and control populations. Duplication of the dimerization domain increases the ability of FHR-1 to regulate surface interactions with C3, leading to overactivation of the complement bypass pathway. Meanwhile, FHR-1 promotes complement bypass pathway activation without involving competition with H factor for binding to C3b, mutated FHR-1 binds to C3-activated fragments and recruits native C3 and C3b, leading to the formation of alternative pathway C3 convertase, increasing the deposition of C3b molecules, suggesting that a balanced FHR-1/H factor ratio is crucial for controlling surface complement amplification. Furthermore, the results of the study's analysis in the clinical cohort of C3 glomerulopathy showed that genetic defects in FHR-1 or a decrease in FHR-1 in plasma are protective factors for progression of C3 glomerulopathy and are associated with better renal prognosis. The study's findings explain how FHR-1 mutants with repeating dimerization domains contribute to susceptibility to C3 glomerulopathy, while also suggesting a pathogenic mechanism that may be shared with other diseases, such as IgA nephropathy or age-related macular degeneration, and identifying FHR-1 as a potential novel therapeutic target for C3 glomerulopathy.