Genotype–phenotype correlations and clinical outcomes of genetic TRPC6 podocytopathies

• Published in: Nephrology, dialysis, transplantation
• Main Authors: 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, Godefroid, Nathalie, Dubrasquet, Astrid, Kálmán, Tory, Dolan, Niamh, Alawi, Bushra Al, Sweeney, Clodagh, Riordan, Michael, Stack, Maria, Awan, Atif, Hui, Ng Kar, McCarthy, Hugh J, 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
• Format: Journal Article
• Language: English
• Published: England 19.05.2025
• Subjects: FSGS; podocytopathy; TRPC6; steroid-resistant nephrotic syndrome; CKD
• ISSN: 0931-0509; 1460-2385; 1460-2385
• 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.