FC030: Diagnostic Yield of Exome Sequencing in Hypertensive Nephropathy

Abstract

Abstract BACKGROUND AND AIMS Hypertensive nephrosclerosis ranks as one of the most frequent causes of chronic kidney disease (CKD) worldwide and is deemed to be especially prevalent among patients of African ancestry [1]. The very existence of hypertensive nephropathy has been called into question, especially in young adults. Its diagnostic framework is based on non-specific clinical criteria, and its histopathological features are in fact unspecific. Genetic testing with exome sequencing (ES) has emerged as a comprehensive tool to detect Mendelian diseases in nephrology with a significant number of post-hoc re-established diagnoses [2]. Nevertheless, ES has yet to be incorporated into the diagnostic workup of patients with hypertensive nephropathy consistently. This study aimed to investigate the diagnostic yield of ES in patients with a clinical diagnosis of hypertensive nephropathy. METHOD Since September 2018, ES is readily available as part of the routine diagnostic workup in our institution. The indication of ES includes hypertensive nephropathy of early onset (i.e. <45 years old). We retrospectively collected the ES performed in the context of hypertensive nephropathy [3] in our institution between September 2018 and February 2021. RESULTS A total of 128 patients were sequenced in the context of hypertensive nephropathy with early-onset. Women were 29 (22.7%), the mean age was 43 (35; 51) years and 60% of them were patients of African ancestry. The main indications of ES was an early onset of CKD (47%), a family history of kidney disease (8%) or both (18%). We detected diagnostic variants (ACM class 4/5) in 22 of the 128 patients (17.2%) encompassing a total of 16 different monogenic disorders. Two diseases accounted for more than half of the genetic diagnoses: nephronophthisis (n = 7, 32%) and Alport syndrome (n = 5, 23%). Complement variation did not account for a significant part of the diagnosis. The diagnostic yield of ES was lower in patients of African ancestry (diagnostic yield of 10.4% versus 27.4% in the non-African ancestry patients; P = 0.01). Co-segregation data was lacking in patients of African ancestry, with significantly more ES performed in singleton (96% compared with 76% in non-African ancestry patients; P < 0.001). In addition to disease reclassification, genetic diagnosis enabled guidance for family counseling (n = 11, 50% of positive patients) and thus helped for potential related donor selection for transplantation. In the whole cohort, ES results modified the therapeutic in 6 patients (5%) and ruled out potential recurrence in the graft in 10 patients (8%). CONCLUSION Physicians should be wary of tentative diagnosis of nephrosclerosis, especially in patients of non-African ethnic background. Instead, it should prompt genetic investigations, which overturned the initial diagnosis in 17% of the cases. The lower diagnostic yield of ES in patients of African ancestry in our cohort might partly be due to the lack of available co-segregation data, as well as the underrepresentation of subjects of African ancestry in the reference genome.