Beyond the kidney biopsy: genomic approach to undetermined kidney diseases

Abstract

Background: According to data from large national registries, almost 20%-25% of patients with end-stage kidney disease have an undetermined kidney disease (UKD). Recent data have shown that monogenic disease-causing variants are under-diagnosed. We performed exome sequencing (ES) on UKD patients in our center to improve the diagnosis rate.

Methods: ES was proposed in routine practice for patients with UKD including kidney biopsy from January 2019 to December 2021. Mutations were detected using a targeted bioinformatic customized kidney gene panel (675 genes). The pathogenicity was assessed using American College of Medical Genetics guidelines.

Results: We included 230 adult patients, median age 47.5 years. Consanguinity was reported by 25 patients. A family history of kidney disease was documented in 115 patients (50%). Kidney biopsies were either inconclusive in 69 patients (30.1%) or impossible in 71 (30.9%). We detected 28 monogenic renal disorders in 75 (32.6%) patients. Collagenopathies was the most common genetic kidney diagnosis (46.7%), with COL4A3 and COL4A4 accounting for 80% of these diagnoses. Tubulopathies (16%) and ciliopathies (14.7%) yielded, respectively, the second and third genetic kidney diagnosis category and UMOD-associated nephropathy as the main genetic findings for tubulopathies (7/11). Ten of the 22 patients having ES "first" eventually received a positive diagnosis, thereby avoiding 11 biopsies. Among the 44 patients with glomerular, tubulo-interstitial or vascular nephropathy, 13 (29.5%) were phenocopies. The diagnostic yield of ES was higher in female patients (P = .02) and in patients with a family history of kidney disease (P < .0001), reaching 56.8% when the patient had both first- and second-degree family history of renal disease.

Conclusion: Genetic diagnosis has provided new clinical insights by clarifying or reclassifying kidney disease etiology in over a third of UKD patients. Exome "first" may have a significant positive diagnostic yield, thus avoiding invasive kidney biopsy; moreover, the diagnostic yield remains elevated even when biopsy is impossible or inconclusive. ES provides a clinical benefit for routine nephrological healthcare in patients with UKD.

Keywords: chronic kidney disease; exome sequencing; undetermined nephropathy.

Graphical Abstract

Figure 1:

Diagnostic workflow for undetermined kidney diseases selection.

Figure 2:

Gene-associated kidney disease according to the category of genetic kidney disease. The inner circle represents the categories of genetic kidney disease and in the outer circle, gene reported with a pathogenic variant in patients; numbers in brackets represent the number of patient's carrier. Genes have been clustered according to their associated categories of genetic kidney disease.

Figure 3:

Genetic findings according to nephropathy category. (A) The diagnostic yielded according to the clinical nephropathy category. (B) The distribution of the genetic kidney disease category according to the clinical nephropathy category.

Figure 4:

Distribution of genetic kidney disease categories based on kidney biopsy findings.

Figure 5:

ES yielded according family history of kidney disease. (A) Comparison of the prevalence of kidney disease in relatives of positive and negative ES patients; panel (B) shows in positive ES patients the proportion of familial history of kidney disease by degree in the relatives.