ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: SA-PO543

Genetic Glomerular Disorders Are Associated With Worse Outcomes in CureGN

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Elliott, Mark, Columbia University Irving Medical Center, New York, New York, United States
  • Vena, Natalie, Columbia University Irving Medical Center, New York, New York, United States
  • Cocchi, Enrico, Columbia University Irving Medical Center, New York, United States
  • Marasa, Maddalena, Columbia University Irving Medical Center, New York, New York, United States
  • Milo Rasouly, Hila, Columbia University Irving Medical Center, New York, New York, United States
  • Kretzler, Matthias, University of Michigan, Ann Arbor, Michigan, United States
  • Kiryluk, Krzysztof, Columbia University Irving Medical Center, New York, New York, United States
  • Gharavi, Ali G., Columbia University Irving Medical Center, New York, New York, United States

Group or Team Name

  • CureGN Consortium
Background

The true pevalence of monogenic glomerular disease is not known. Prognosis and treatment response may differ between genetic and sporadic forms of disease thus identifying a genetic etiology can have clinical significance in this patient population.

Methods

2018 individuals enrolled in the international, multicenter Cure Glomerulonephropathy Network (CureGN) underwent genome sequencing. 513 with focal segmental glomerulosclerosis (FSGS), 465 with minimal change disease (MCD), 476 with membranous nephropathy (MN), and 564 with IgA nephropathy. Cases with a strong suspicion of a genetic diagnosis and those with kidney failure were excluded prior to enrolment. Variants in 180 genes with glomerular phenotypes were classified per ACMG/AMP guidelines. Pathogenic and likely pathogenic variants consistent with the inheritance pattern and patient phenotype were considered diagnostic. APOL1 high risk genotypes were evaluated. The risk of immunosuppression resistance and kidney failure, defined by chronic dialysis or transplantation, was determined over a median of 4.3 years of follow-up, adjusted for demographic, clinical and biopsy characteristics.

Results

14 different monogenic glomerular disorders were detected in 42 individuals (2% diagnostic rate): 28 with FSGS (5.4% diagnostic rate), 8 with MCD (1.7% diagnostic rate), 6 with IgAN (1.1% diagnostic rate), and 0 in MN. Over half were due to variants in NPHS2 (16 variants in 10 individuals) and Alport spectrum disorder genes (18 variants in 18 individuals). 124 individuals have high-risk APOL1 genotypes, including 3 with Mendelian diagnostic variants. On logistic regression, individuals with monogenic glomerular disease and those with high-risk APOL1 genotypes were more likely to have immunosuppression resistant disease (OR=4.46, P=7x10-4; OR=1.83, P=0.02, respectively), particularly resistance to two or more therapies (OR=3.40, P=0.002; OR=2.19, P=0.003, respectively), and were also at increased risk of kidney failure (Cox proportional hazards OR=2.03, P=0.02; OR=1.88, P=0.002, respectively).

Conclusion

Monogenic glomerular diseases were identified in 42 subjects, with the highest diagnostic rate among FSGS cases. Individuals with monogenic disorders and those with high risk APOL1 genotypes had an increased risk of multidrug resistant disease and kidney failure.

Funding

  • NIDDK Support