Genotype-phenotype correlations and clinical outcomes of genetic TRPC6 podocytopathies.
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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
Аннотация
METHODS: 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 (KF)]. Logistic regression, Cox proportional hazards model and Kaplan-Meier analyses investigated the associations between genetic variants and disease progression.
RESULTS: 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 KF. Sporadic TRPC6-AP demonstrated an earlier progression to KF than familial cases (P = .001) and were more likely to present with nephrotic syndrome [odds ratio 4.34 (1.85-10.15); P = .001]. Gain-of-function TRPC6 variants were more frequent in familial than sporadic TRPC6-AP (70.8% vs 44.4%; P = .004). Compared with patients with other TRPC6 variants, patients with TRPC6 p.R175W and p.R895C variants progressed to KF earlier [median kidney survival of 21 years, hazard ratio 2.985 (95% confidence interval 1.40-5.79); and 38 years, hazard ratio 1.65 (95% confidence interval 1.01-2.81), respectively, log-rank P = .005].
CONCLUSION: Our study shows unique clinical and genetic correlations of TRPC6-AP, which may enable personalized care and promising novel therapies.