Genetic Diagnosis of Adult Hemodialysis Patients With Unknown Etiology

Abstract

Introduction: Kidney disease of unknown etiology accounts for 1 in 10 adult end-stage renal disease (ESRD) cases worldwide. The aim of this study is to clarify the genetic background of patients with chronic kidney disease (CKD) of unknown etiology who initiated renal replacement therapy (RRT) in adulthood.

Methods: This is a multicenter cross-sectional cohort study. Of the 1164 patients who attended 4 dialysis clinics in Japan, we first selected patients who started RRT between the ages of 20 and 49 years. After excluding patients with apparent causes of CKD (e.g., diabetic nephropathy, polycystic kidney disease (PKD) with family history, patients who underwent renal biopsy), 90 patients with CKD of unknown cause were included. The 298 genes associated with CKD were analyzed using capture-based targeted next-generation sequencing.

Results: Of the 90 patients, 10 (11.1%) had pathogenic variants in CKD-causing genes and 17 (18.9%) had variant of unknown significance (VUS). Three patients had PKD1 pathogenic variants, and 1 patient had PKD1 and COL4A4 pathogenic variants. In addition, 2 patients were diagnosed with atypical hemolytic uremic syndrome (aHUS) due to C3 or CFHR5. One patient each was diagnosed with Alport syndrome due to COL4A4 and COL4A3 variants, nephronophthisis due to NPHP1 variants, Fabry disease due to GLA variants, and autosomal-dominant tubulointerstitial kidney disease due to UMOD variants. Genetic diagnoses were not concordant with clinical diagnoses, except for patients with PKD1 variant.

Conclusion: This largest study on genetic analysis in hemodialysis-dependent adults revealed the presence of undiagnosed inherited kidney diseases.

Keywords: chronic kidney disease; genetic analysis; hemodialysis; inherited kidney disease.

Graphical abstract

Figure 1

Flow chart of patient selection. Of the 1164 patients treated in 4 dialysis clinics, 283 started hemodialysis between the ages of 20 and 49 years. Of the 283 patients, 114 patients met the inclusion criteria, and 93 underwent genetic analysis. After genetic analysis and reevaluation of the medical history, 3 patients with a genetic diagnosis of autosomal dominant polycystic kidney were found to have a family history of polycystic kidney disease and were excluded from the final cohort. PKD, polycystic kidney disease.

Figure 2

Variants in patients who started hemodialysis between the ages of 20 and 49 years. Of the 90 patients, 10 (11.1%) had disease-causing variants and 17 (18.9%) had variants of unknown significance in genes linked to chronic kidney disease. Four patients (4.4%) had truncation variants in genes with autosomal-recessive inheritance.

Figure 3

Breakdown of genetically confirmed diagnosis rates and responsible genes for each clinical diagnosis. ADPKD, autosomal -dominant polycystic kidney disease; ADTKD, autosomal-dominant tubulointerstitial kidney disease; aHUS, atypical hemolytic uremic syndrome; C3GN, C3 glomerulopathy; CGN, chronic glomerulonephritis; HNS, hypertensive nephrosclerosis; PKD, polycystic kidney disease;

Figure 4

Proportions of hereditary disorders within each age group at RRT initiation. Age at RRT initiation is presented in 5-year intervals. There was no discernible correlation between the age at RRT initiation and the prevalence of genetic diseases. ADPKD, autosomal -dominant polycystic kidney disease; ADTKD, autosomal-dominant tubulointerstitial kidney disease; aHUS, atypical hemolytic uremic syndrome; C3GN, C3 glomerulopathy; CGN, chronic glomerulonephritis; PKD, polycystic kidney disease; RRT, renal replacement therapy