Sequencing Shows Promise in Care of Common Kidney Disease

Exome sequencing can yield a genetic diagnosis in almost 10 percent of patients with chronic kidney disease (CKD), according to a study published Jan. 10 in the New England Journal of Medicine. This yield, the authors say, is similar to what is seen for other conditions for which genomic diagnostics are used and establishes CKD as the most common adult disease, aside from cancer, for which sequencing has clinical utility.

"Our study shows that genetic testing can be used to personalize the diagnosis and management of kidney disease, and that nephrologists should consider incorporating it into the diagnostic workup for these patients," says coauthor Ali Gharavi, M.D., from Columbia University in New York.

Despite how common it is, the underlying mechanism of CKD remains poorly understood. Estimates show that more than 10 percent of adult cases of newly diagnosed end-stage renal disease may have an unknown diagnosis. This "diagnostic ambiguity" can negatively impact clinical management, the authors say.

The researchers conducted exome sequencing and diagnostic analysis in two cohorts totaling 3,315 patients with CKD (91.6 percent were over 21 years of age and 35.6 percent were self-identified as of non-European ancestry). The sequencing examined a manually curated list of 625 nephropathy-associated genes plus variants in other Mendelian disease–associated genes on Illumina platforms using in-house pipeline. In the cohort from the Columbia University Medical Center Genetic Studies of Chronic Kidney Disease biobank, 59 medically actionable genes recommended by the American College of Medical Genetics and Genomics (ACMG) were also assessed.

Overall, nephropathy of unknown origin was seen in 8.5 percent of the patient population. The researchers identified diagnostic variants across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients) and nephropathy of unknown origin (48 of 281 patients). Additionally, 1.6 percent of the Columbia cohort had genetic findings for ACMG medically actionable disorders that, although unrelated to their nephropathy, the authors say the secondary findings had implications for nephrologic care in all cases.

More than one-fourth (28.3 percent) of the Columbia cohort had a family history of kidney disease. Diagnostic variants were found in 94 of these 619 patients (15.2 percent of patient with a family history of kidney disease versus findings in 4.8 percent without a family history).

Further, the researchers say that among the patients with a genetic diagnosis, it gave new clinical insights in nearly three-fourths of the cases, including estimation of the risk of nephropathy progression, guidance for family counseling, and donor selection for transplantation. The genetic information could inform therapy for half of patients receiving a genetic diagnosis (e.g., tailored therapies, clinical trial recommendation, or immunosuppression decision making). For just over one-third of patients, the genetic findings reclassified disease or provided a cause for undiagnosed nephropathy, emphasizing "the usefulness of the 'agnostic' approach" of exome sequencing, the authors say.

"We noted diagnostic variants in 48 of the 281 patients (17.1 percent) with nephropathy of unknown origin, a population that may comprise up to 15 percent of patients with newly diagnosed end-stage renal disease and for whom traditional diagnostic methods are often unrevealing or contraindicated," write the authors.

Takeaway: Sequencing shows promise for informing diagnosis and clinical management of CKD, particularly in patients with a family disease history and patients with unknown nephropathy.