Targeted Next-Generation Sequencing Identifies Pathogenic Variants in Diabetic Kidney Disease.

INTRODUCTION: Diabetes is the most common cause of chronic kidney disease (CKD). For patients with diabetes and CKD, the underlying cause of their kidney disease is often assumed to be a consequence of their diabetes. Without histopathological confirmation, however, the underlying cause of their disease is unclear. Recent studies have shown that next-generation sequencing (NGS) provides a promising avenue toward uncovering and establishing precise genetic diagnoses in various forms of kidney disease. METHODS: Here, we set out to investigate the genetic basis of disease in nondiabetic kidney disease (NDKD) and diabetic kidney disease (DKD) patients by performing targeted NGS using a custom panel comprising 345 kidney disease-related genes. RESULTS: Our analysis identified rare diagnostic variants based on ACMG-AMP guidelines that were consistent with the clinical diagnosis of 19% of the NDKD patients included in this study. Similarly, 22% of DKD patients were found to carry rare pathogenic/likely pathogenic variants in kidney disease-related genes included on our panel. Genetic variants suggestive of NDKD were detected in 3% of the diabetic patients included in this study. DISCUSSION/CONCLUSION: Our findings suggest that rare variants in kidney disease-related genes in a diabetic background may play a role in the pathogenesis of DKD and NDKD in patients with diabetes.

The Familiality of Rapid Renal Decline in Diabetes.

Sustained and rapid loss of glomerular filtration rate (GFR) is the predominant clinical feature of diabetic kidney disease and a requisite for the development of end-stage renal disease. Although GFR trajectories have been studied in several cohorts with diabetes and without diabetes, whether rapid renal decline clusters in families with diabetes has not been examined. To determine this, we estimated GFR (eGFR) from serum creatinine measurements obtained from 15,612 patients with diabetes at the University of Utah Health Sciences Center and established their renal function trajectories. Patients with rapid renal decline (eGFR slope < -5 mL/min/1.73 m2/year) were then mapped to pedigrees using extensive genealogical records from the Utah Population Database to identify high-risk rapid renal decline pedigrees. We identified 2,127 (13.6%) rapid decliners with a median eGFR slope of -8.0 mL/min/1.73 m2/year and 51 high-risk pedigrees (ranging in size from 1,450 to 24,501 members) with excess clustering of rapid renal decline. Familial analysis showed that rapid renal decline aggregates in these families and is associated with its increased risk among first-degree relatives. Further study of these families is necessary to understand the magnitude of the influence of shared familial factors, including environmental and genetic factors, on rapid renal decline in diabetes.