Organization and implementation of a diagnostic care model for rare kidney diseases

In this thesis, the accessibility, interpretation, and economic efficiency of Whole-Exome Sequencing (WES) in the diagnosis of genetic kidney disorders are thoroughly evaluated. Building on a univariable analysis of a historical cohort of 392 patients who underwent WES, predictive criteria such as resistance to treatments, familial history of kidney disease, extrarenal involvement, and others were identified. These criteria were prospectively applied to a network of nephrology centers, resulting in a centralized genetic diagnosis through WES, reverse phenotyping, and multidisciplinary board discussions for selected patients. A total of 476 patients across eight clinical categories (podocytopathies, collagenopathies, CKD of unknown origin, tubulopathies, ciliopathies, congenital anomalies of the kidney and urinary tract, syndromic CKD, metabolic kidney disorder) were subjected to this innovative multistep workflow. Remarkably, a genetic diagnosis was attained for 319 patients (67.0%), with a 95% diagnostic rate in patients with disease onset during the fetal period or at birth, 64% in pediatric patients, and 70% in adults. The implementation of this workflow led to the confirmation of the suspected clinical diagnosis in 48% of the total patient population and modification in 19%. One of the standout outcomes of this study was the notable economic efficiency. A modeled cost analysis unveiled that early application of this workflow brought a 20% cost saving per patient at the inception of the diagnostic process. This finding was further corroborated by a real cost analysis conducted on a representative sample of 66 patients, showcasing an actual cost reduction of 41%. This work clearly demonstrates the significant benefits of introducing WES early in the diagnostic process for genetic kidney disorders. It proves to be cost-effective and is applicable in real-world medical settings. The work presented here represent a further step for improving both the diagnosis and management of these complex disorders. The data and insights provided establish a foundation for ongoing and future research in the field of genetic kidney disease diagnostics.