Value of renal gene panel diagnostics in adults waiting for kidney transplantation due to undetermined end-stage renal disease

Abstract

End-stage renal disease (ESRD) of undetermined etiology is highly prevalent and constitutes a significant clinical challenge, particularly in the context of kidney transplantation (KT). Despite the identification of numerous rare hereditary nephropathies over the last few decades, patients with undetermined ESRD are not being systematically investigated for rare genetic causes in clinical practice. To address this, we utilized mutation analysis in patients on the kidney transplant waitlist and scrutinized underlying renal diagnoses of 142 patients in a single center KT-waitlist. This cohort was stratified into 85 cases of determined and 57 cases of undetermined ESRD. The latter patients were analyzed by a renal gene panel for mutations in 209 genes associated with ESRD. The most likely genetic diagnoses in 12% of the tested individuals with undetermined ESRD were established. All of these patients showed mutations in genes encoding components of the glomerular filtration barrier. Taken together, hereditary nephropathies, including autosomal dominant polycystic kidney disease, were identified in 35 of the 142 patients of the waitlist cohort. By significantly increasing the proportion of hereditary diagnoses from 29 to 35 patients, the rate of undetermined ESRD significantly decreased from 57 to 51 patients. This study demonstrates the beneficial use of genetic diagnostics in significantly unraveling undetermined ESRD cases prior to KT. Thus, in the absence of renal histology or the presence of unspecific histological conditions, such as hypertensive nephrosclerosis, focal segmental glomerulosclerosis or thrombotic microangiopathy, genetic analysis may provide a robust and specific renal diagnosis and allow for optimizing pre-and post-KT management.

Diagnostic Yield of Next-Generation Sequencing in Patients With Chronic Kidney Disease of Unknown Etiology

“…The diagnostic value of gene panels in patients with undetermined ESRD is demonstrated by Ottlewksi et al, who tested 50 patients on the kidney transplantation waiting list with undetermined CKD (Ottlewski et al, 2019). The renal gene panel, consisting of 209 genes associated with ESRD, identified a causative variant in 6 of 50 (12%) these patients.…”

“…The genetic diagnosis consisted of X-linked and autosomal dominant forms of Alport syndrome and familial FSGS. The identification of a genetic diagnosis in six patients significantly reduced the proportion of patients with unexplained ESRD on the kidney transplant waiting list (Ottlewski et al, 2019) ( Table 3).…”

“…The study by Ottlewski et al also has a limited sample size, but it is not clear what the proportion of patients with familial CKD or extra-renal features is. However, five of six patients in which a genetic diagnosis was identified had a positive family history (Ottlewski et al, 2019). In addition, it is the only study using gene panels instead of targeted WES.…”

Novel nephronophthisis-associated variants reveal functional importance of MAPKBP1 dimerization for centriolar recruitment

“…2 Similarly, pathogenic MAPKBP1 variants have to be considered in young adults with otherwise unexplained ESRD, a phenomenon that was shown to pertain to 20% to 40% of the patients on renal replacement therapy waiting for kidney transplantation. 14,15 Detection of pathogenic MAPKBP1 variants should prompt screening for skeletal abnormalities, as those were present in 8 of 10 reported cases to date. 1 Notably scoliosis (as in patient 1) was already observed previously in 3 affected family members with an adjacent homozygous truncating mutation (p.Gln943*).…”

Genetic testing for kidney disease of unknown etiology

“…Recent studies indicate that genetic testing can identify the cause in approximately 10% to 40% of cases of KDUE. [13][14][15][16][17][18] In the following review, we discuss the role of genetic testing for KDUE. We review the epidemiology of KDUE, focusing on Mendelian etiologies.…”