Kidney Week

Abstract: FR-PO644

Kidney Outcomes in APOL1 High-Risk and Mendelian Variant in Patients with Adult Nephrotic Syndrome in Mass General Brigham Biobank

Session Information

• Genetic Kidney Diseases: Cohort Studies - Genetic Associations and Diagnoses
  October 25, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1202 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Wongboonsin, Janewit, Mahidol University Faculty of Medicine Siriraj Hospital, Bangkok, Thailand

Janewit Wongboonsin, MD, MS

• Greenberg, Anya, Boston Children's Hospital, Boston, Massachusetts, United States

Anya Greenberg

• Mcnulty, Michelle, Boston Children's Hospital, Boston, Massachusetts, United States

Michelle Mcnulty, MS

• Onuchic-Whitford, Ana C., Brigham and Women's Hospital, Boston, Massachusetts, United States

Ana C. Onuchic-Whitford, MD

• Lee, Dongwon, Boston Children's Hospital, Boston, Massachusetts, United States

Dongwon Lee, PhD

• Nigwekar, Sagar U., Massachusetts General Hospital, Boston, Massachusetts, United States

Sagar U. Nigwekar, MD

• Sampson, Matt G., Boston Children's Hospital, Boston, Massachusetts, United States

Matt G. Sampson, MD

Background

Published studies demonstrating the value of genetic stratification in nephrotic syndrome (NS) have often focused on children or research cohorts with specific characteristics. The prevalence and clinical correlates of known genetic forms of NS in adults are less well understood but may have important implications. The EHR-linked Biobank provides a unique opportunity to identify patients with NS for subsequent genomic discovery

Methods

Patients with NS were identified via ICD-10 diagnosis codes, reviews of renal pathology, and manual chart review. Exome data of NS patients were analyzed using VarSeq, with variants assessment using published guidelines. 192 genes associated with proteinuric kidney disease were evaluated. Clinical data were extracted from the Research Patient Data Registry. Adjudication of End-Stage Kidney Disease (ESKD) status was combined with data from the United States Renal Data System. ESKD status was evaluated by both logistic regression and time-to-event survival analysis. Longitudinal trends in laboratory data were analyzed using a linear mixed model

Results

693 patients had NS, 358 of these have exome data. Diagnoses included FSGS (299 cases), MCD (29 cases), and MN (45 cases), with some patients having multiple diagnoses. 37 patients (11%) had pathogenic Mendelian variants (MV) considered causative of disease and 25 (7%) carried high-risk APOL1 genotype (APOL1-HR). 213 (59%) progressed to ESKD. Upon adjusting for age, sex, race, presence of hypertension, and diabetes mellitus, patients with MV had a 3.0 (1.3–7.3) increased odds for developing ESKD. Those with APOL1-HR had an OR of 7.6 (1.5–37.8). There was a higher hazards for ESKD in both genetic groups: 1.7 (1.2–2.6) for MV and 3.1 (1.8–5.3) for APOL1-HR. Genetic variants were significantly associated with increased monthly creatinine elevation compared to patients without variants (MV: 0.02 ml/min/month; APOL1-HR: 0.04 ml/min/month)

Conclusion

The Biobank presents an opportunity for assessment of genetic variant impact in rare kidney diseases like NS. In this population cohort of adults, both MV and APOL1-HR have a negative impact on kidney health. These findings emphasize the critical role of genetic characterization in predicting renal prognosis among nephrotic syndrome patients

Funding

• Private Foundation Support