Renal Genetics Program: The Beginning and the Future

A young patient with focal segmental glomerulosclerosis (FSGS), a condition that can cause kidney failure, was being treated with a standard regimen of steroid and other immunosuppressive drugs. His mother had died from kidney failure after being on dialysis for years.

After a few months with no improvement, the patient came for an evaluation at Cleveland Clinic’s renal genetics clinic, a new collaboration of Glickman Urological & Kidney Institute and Cleveland Clinic’s Center for Personalized Genetic Healthcare. Genetic testing revealed that the patient’s FSGS was inherited, due to a mutation in one gene.

This diagnosis led to a markedly different approach to therapy. Steroids and other immunosuppressive drugs were discontinued as they would not work for inherited FSGS. Instead the patient was recruited into a clinical trial targeting the genetic form of FSGS with a novel small-molecule drug.

This patient is among 30% to have changes in the management of their kidney disease since the start of Cleveland Clinic’s Renal Genetics Program in October 2019. In addition, 58% of patients in the program have learned the genetic cause of their disease could also affect their family members.

“Nearly 400 genes — plus other chromosome anomalies — are associated with kidney disease,” says Xiangling Wang, MD, PhD, Director of Renal Genetics at Cleveland Clinic. “Today genetic testing is more affordable and is better directing kidney disease diagnosis and treatment.”

The most common conditions evaluated in the program include:

• Cystic kidney diseases.
• Glomerular diseases, such as FSGS, and systemic genetic disorders involving glomeruli (e.g., Alport syndrome, atypical hemolytic uremic syndrome, Fabry disease).
• Electrolyte disturbance, such as Gitelman syndrome, Bartter syndrome, Gordon syndrome, Liddle syndrome, renal tubular acidosis, familial hypocalciuric hypercalcemia and hypophosphatemic rickets.
• Early onset kidney stones and nephrocalcinosis.
• Congenital anomalies of the kidneys and urinary tract (CAKUT).

A growing program

Although the demand is growing, there are still very few renal genetics programs in the U.S. Cleveland Clinic’s program, now with more than 140 patients, grew sevenfold in less than a year.

In addition to Dr. Wang, a double-trained medical geneticist and nephrologist, the program includes a team of experienced medical geneticists, nephrologists and genetic counselors. They see patients referred across the nation for:

• Diagnosis. Evaluations often involve a thorough review of family history, physical exam and genetic testing (e.g., chromosome karyotype, chromosome microarray, single-gene test, multiple-gene panel, whole exome sequencing).
• Genetic counseling. After genetic testing, counselors educate patients about their genetic diagnosis as well as their family members’ risk of having the same disease.
• Management. Patients can receive ongoing care from a nephrologist in the program or return to their primary nephrologist.

“Genetic kidney disease centers are changing the practice of nephrology, making genetic testing and service more accessible to patients, as well as inspiring research,” says Dr. Wang.

The nascent program at Cleveland Clinic has been collaborating with national researchers to conduct clinical and basic studies to advance the understanding of mechanisms of genetic kidney disorders and develop targeted therapies.

“The ultimate aim of renal genetics is to deliver care tailored to individual patients,” says Dr. Wang. “With the rapid progress in research, I’m optimistic that genetically targeted therapy for inherited kidney disease will be a reality in the near future.”

That’s promising news to the growing number of patients diagnosed with genetic kidney disease, which Dr. Wang estimates affects 1% of the world population.

“Referral to a renal genetics clinic should be considered for all patients with chronic kidney disease of uncertain cause and a positive family history or early-onset kidney disease,” she says. “About 70% of children with chronic kidney disease have some genetic involvement.”

For more about the Renal Genetics Program, see my.clevelandclinic.org/renalgenetics.