Background Alport syndrome (AS) is an inherited type IV collagen-related disorder with an irreversible tendency to progress to end-stage renal disease (ESRD). X-linked AS (XLAS) is caused by mutations in the COL4A5 gene. The aim of this study was to investigate the effects of underlying mutations on clinical manifestations and the response to therapy in XLAS. Methods We conducted a retrospective cohort study of 187 Chinese male patients with XLAS confirmed by pathological examination and genetic analysis. The Kaplan-Meier method and Cox proportional hazards model were used to assess the age and risk of progression to ESRD under different genotypes and treatment conditions. Results A strong relationship between transcript type and renal outcome was observed, with the median age of ESRD onset being 22 years for truncating mutations and 39 years for nontruncating mutations. The response of affected patients to renin-angiotensin-aldosterone system (RAAS) blockers was genotype-associated. This therapy delayed the onset of ESRD by 16 years in patients with nontruncating mutations and 3 years in patients with truncating mutations. The efficacy of RAAS blockers functioned in a time-dependent manner, with a 7% reduction in the risk of progression to ESRD per each 6-month increase in treatment duration (HR 0.93; 95% CI 0.89–0.96) (P < 0.001). Conclusions Clinical features and response to RAAS blockers were observed to be strongly correlated with the genotypes of male XLAS patients. Genotyping of COL4A5 gene mutations is essential and is a useful tool to assess the prognosis of AS patients.
Background Though renin-angiotensin-aldosterone system (RAAS) blockers have been considered the primary treatment for patients with Alport syndrome (AS) for a decade, there is no comprehensive review with evidence-based analysis evaluating the effectiveness of RAAS blockers in AS. Methods A systematic review and meta-analysis was performed of published studies that compared outcomes related to disease progression between patients with AS receiving RAAS blockers with those taking non-RAAS treatment. Outcomes were meta-analyzed using the random effects models. Cochrane risk-of-bias, Newcastle-Ottawa Scale and GRADE assessment determined the certainty of evidence. Results A total of eight studies (1182 patients) were included in the analysis. Overall, the risk of bias was low to moderate. Compared with non-RAAS treatment, RAAS blockers could reduce the rate of progression to end-stage kidney disease (ESKD) (four studies; HR: 0.33; 95% CI: 0.24–0.45; moderate certainty evidence). After stratified by genetic types, a similar benefit was detected: male X-linked Alport syndrome (XLAS) (HR: 0.32; 95% CI: 0.22–0.48), autosomal recessive Alport syndrome (HR: 0.25; 95% CI: 0.10–0.62), female XLAS and autosomal dominant Alport syndrome (HR: 0.40; 95% CI: 0.21–0.75). In addition, RAAS blockers showed a clear gradient of benefit depending on the stage of disease at the initiation of treatment. Conclusion This meta-analysis suggested that RAAS blockers could be considered as a specific therapy to delay of ESKD for AS with any genetic type, especially at the early stage of the disease, and every further more-effective-therapy would be advised to be applied on top of this standard of care.
BackgroundX-linked Alport syndrome (XLAS) caused byCOL4A5pathogenic variants usually has heterogeneous phenotypes in female patients. The genetic characteristics and glomerular basement membrane (GBM) morphological changes in women with XLAS need to been further investigated.MethodsA total of 83 women and 187 men with causativeCOL4A5variants were enrolled for comparative analysis.ResultsWomen were more frequently carrying de novoCOL4A5variants compared with men (47% vs 8%, p=0.001). The clinical manifestations in women were variable, and no genotype–phenotype correlation was observed. Coinherited podocyte-related genes, includingTRPC6,TBC1D8B,INF2andMYH9, were identified in two women and five men, and the modifying effects of coinherited genes contributed to the heterogeneous phenotypes in these patients. X-chromosome inactivation (XCI) analysis of 16 women showed that 25% were skewed XCI. One patient preferentially expressing the mutantCOL4A5gene developed moderate proteinuria, and two patients preferentially expressing the wild-typeCOL4A5gene presented with haematuria only. GBM ultrastructural evaluation demonstrated that the degree of GBM lesions was associated with the decline in kidney function for both genders, but more severe GBM changes were found in men compared with women.ConclusionsThe high frequency of de novo variants carried by women indicates that the lack of family history tends to make them susceptible to be underdiagnosed. Coinherited podocyte-related genes are potential contributors to the heterogeneous phenotype of some women. Furthermore, the association between the degree of GBM lesions and decline in kidney function is valuable in evaluating the prognosis for patients with XLAS.
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