McAnallen Susan M, Elhassan Elhussein A E, Stoneman Sinead, Pinto E Vairo Filippo, Hogan Marie C, Hoefele Julia, Clince Michelle, Mekraksakit Poemlarp, Titan Silvia M, Jorge Sofia, Calado Joaquim, Decramer Stéphane, Colliou Eloïse, Tellier Stéphanie, Francisco Telma, Servais Aude, Cornet Joséphine, de Fallois Jonathan, Dossier Claire, Fenoglio Roberta, Renieri Alessandra, Pinto Anna Maria, Daga Sergio, Loberti Lorenzo, Fila Marc, Quintana Luis F, Becherucci Francesca, Nathalie Godefroid, Astrid Dubrasquet, ToryDolan KálmánNiamh, Alawi Bushra Al, Sweeney Clodagh, Riordan Michael, Stack Maria, Awan Atif, Hui Ng Kar, McCarthy Hugh, Biros Erik, Harris Trudie, Kidd Kendrah, Haeberle Stefanie, Bleyer Anthony J, Mallett Andrew J, Sayer John A, Schafer Franz, Benson Katherine A, McCann Emma, Conlon Peter J
Department of Nephrology and Transplantation, Beaumont Hospital, Dublin, Ireland.
Nephrology Department, St. James's Hospital, Dublin, Ireland.
Nephrol Dial Transplant. 2025 May 19. doi: 10.1093/ndt/gfaf086.
Podocytopathy associated with likely pathogenic/pathogenic variants of TRPC6 (TRPC6-AP) has been recognised for about 20 years. As a result of its rarity however, the spectrum of clinical phenotypes and genotype-phenotype correlation of TRPC6-AP remains poorly understood. Here, we characterised clinical, histological, and genetic correlates of familial and sporadic patients with TRPC6-AP.
In this multicentre observational study, an online questionnaire followed by a systematic literature review was performed to create a cohort with comprehensive data on genetic and clinical outcomes (age of onset, clinical presentation, treatment response, kidney biopsy findings, and progression to kidney failure). Logistic regression, Cox proportional hazards model and Kaplan-Meier analyses investigated the associations between genetic variants and disease progression.
Among 87 families (96 familial and 45 sporadic cases), 31 distinct missense TRPC6 variants (including 2 novel) were identified, with c.2683C > T p.(Arg895Cys) and c.523C > T p.(Arg175Trp) the commonest variants. Proteinuric kidney disease/nephrotic syndrome was the most common clinical presentation (83.7%), while focal segmental glomerulosclerosis was the most common histological finding (89.4%). By 33 (interquartile range: 17-40) years, 48.9% (69/141) of patients had progressed to kidney failure. Sporadic TRPC6-AP demonstrated an earlier progression to kidney failure than familial cases (P = 0.001) and were more likely to present with nephrotic syndrome (odds ratio: 4.34 (1.85-10.15); P = 0.001). Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs. 44.4%; P = 0.004). Compared to patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to kidney failure earlier (median kidney survival of 21 years; Hazard ratios (HR): 2.985 [95% CI: 1.40-5.79] and 38 years; HR: 1.65 [95% CI: 1.01-2.81], respectively, log-rank P = 0.005).
Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalised care and promising novel therapies.
与瞬时受体电位通道蛋白6（TRPC6）可能的致病/致病变异相关的足细胞病（TRPC6-AP）已被认识约20年。然而，由于其罕见性，TRPC6-AP的临床表型谱以及基因型-表型相关性仍知之甚少。在此，我们对家族性和散发性TRPC6-AP患者的临床、组织学和遗传学相关性进行了特征分析。
在这项多中心观察性研究中，我们先进行了一项在线问卷调查，随后进行了系统的文献综述，以创建一个包含遗传和临床结局（发病年龄、临床表现、治疗反应、肾活检结果以及进展至肾衰竭情况）全面数据的队列。采用逻辑回归、Cox比例风险模型和Kaplan-Meier分析来研究基因变异与疾病进展之间的关联。
在87个家族（96例家族性和45例散发性病例）中，共鉴定出31种不同的错义TRPC6变异（包括2种新变异），其中c.2683C>T p.(Arg895Cys)和c.523C>T p.(Arg175Trp)是最常见的变异。蛋白尿性肾病/肾病综合征是最常见的临床表现（83.7%），而局灶节段性肾小球硬化是最常见的组织学表现（89.4%）。到33岁（四分位间距：17 - 40岁）时，48.9%（69/141）的患者进展至肾衰竭。散发性TRPC6-AP比家族性病例更早进展至肾衰竭（P = 0.001），且更易出现肾病综合征（优势比：4.34（1.85 - 10.15）；P = 0.001）。功能获得性TRPC6变异在家族性TRPC6-AP中比散发性TRPC6-AP更常见（70.8%对44.4%；P = 0.004）。与其他TRPC6变异的患者相比，携带TRPC6 p.R175W和p.R895C变异的患者更早进展至肾衰竭（中位肾脏生存期分别为21年；风险比（HR）：2.985 [95%置信区间：1.40 - 5.79]和38年；HR：1.65 [95%置信区间：1.01 - 2.81]，对数秩检验P = 0.005）。
我们的研究显示了TRPC6-AP独特的临床和遗传相关性，这可能有助于实现个性化医疗并推动有前景的新疗法的发展。
