High-Risk Genotype Impacts Kidney Disease Trajectory

High-Risk Genotype Impacts Kidney Disease Trajectory 1024 575 Mary Bates, PhD
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Patients with focal segmental glomerulosclerosis that possess two variations in the APOL1 gene experience more rapid progression of kidney disease.

In a new study, researchers from Nationwide Children’s and other institutions quantified the relationship between a high-risk genotype and kidney disease progression in patients with focal segmental glomerulosclerosis (FSGS). The researchers leveraged data from the Cure Glomerulonephropathy consortium to show clinically significant differences in disease trajectory in participants with the high-risk genotype of Apolipoprotein L1 (APOL1) gene.

There are different variations of APOL1 alleles and having one of the high risk alleles provided protective effects against Trypanosoma brucei rhodesiense, the cause of acute African sleeping sickness. However, having 2 high risk alleles increase the risk of kidney disease. High-risk genotype of Apolipoprotein L1 (APOL1) gene are usually found in people of African descent.

In the new study, researchers enrolled patients with FSGS from the Cure Glomerulonephropathy (CureGN) consortium, an ongoing, international cohort study of adults and children with glomerular diseases. The goal was to describe kidney disease progression in patients with FSGS, to evaluate the association between APOL1 genotype and kidney disease progression.

Study included 650 participants with FSGS. Of nearly 500 participants with FSGS who had genetic testing, 13% were high-risk (possessed two high risk alleles), and those patients were more likely to have a more aggressive disease based on their kidney biopsy findings.

“The odds of more rapid progression was 2.76 times higher in the high-risk group compared to other patients with 0-1 risk allele” says Mahmoud Kallash, MD, a pediatric nephrologist at Nationwide Children’s and lead author of the study.

Dr. Kallash and colleagues found that other factors, including uncontrolled proteinuria, uncontrolled hypertension, and the use of multiple immunosuppressive agents (which suggesting a more difficult to control disease), had a higher risk for a rapid loss of kidney function with time. However, these factors had a lesser impact on loss of kidney function than high risk APOL1 genotype.

“If we know that a patient is at high risk of progression to renal failure within a few years, that may impact how we control the disease with medications,” he says. “Intervening early could prove to be beneficial to these patients.”

The research team says their findings suggest that genetic testing should be considered for all patients with FSGS, especially if having a difficult to control disease. Early knowledge of a patient’s APOL1 genotype may help providers optimize patient counseling and provide the most appropriate clinical care, especially that there are currently ongoing clinical trials to treat kidney diseases secondary to APOL1.




Kallash M, Wang Y, Smith A, Trachtman H, Gbadegesin R, Nester C, Canetta P, Wang C, Hunley TE, Sperati CJ, Selewski D, Ayoub I, Srivastava T, Mottl AK, Kopp J, Gillespie B, Robinson B, Chen D, Steinke J, Twombley K, Reidy K, Mucha K, Greenbaum LA, Blazius B, Helmuth M, Yonatan P, Parekh RS, Hogan S, Royal V, D’Agati V, Chishti A, Falk R, Gharavi A, Holzman L, Klein J, Smoyer W, Kretzler M, Gipson D, Kidd JM; CureGN. Rapid Progression of Focal Segmental Glomerulosclerosis in Patients with High-Risk APOL1 Genotypes. Clin J Am Soc Nephrol. 2023 Jan 17. doi: 10.2215/CJN.0000000000000069. Epub ahead of print.


Image credit: Nationwide Children’s

About the author

Mary a freelance science writer and blogger based in Boston. Her favorite topics include biology, psychology, neuroscience, ecology, and animal behavior. She has a BA in Biology-Psychology with a minor in English from Skidmore College in Saratoga Springs, NY, and a PhD from Brown University, where she researched bat echolocation and bullfrog chorusing.