Abstract: SA-OR053

Metabolomic Profiling of APOL1 Risk Alleles

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 301 CKD: Risk Factors for Incidence and Progression

Authors

  • Tin, Adrienne, Johns Hopkins University, Baltimore, Maryland, United States
  • Coresh, Josef, Welch Center for Prevention, Epidemiology & Clinical Research, Baltimore, Maryland, United States
  • Grams, Morgan, Johns Hopkins University, Baltimore, Maryland, United States
  • Nadkarni, Girish N., Ichan School of Medicine, New York, New York, United States
  • Winkler, Cheryl Ann, NCI, NIH, Frederick National Laboratory, Frederick, Maryland, United States
  • Bottinger, Erwin P., Berlin Institute of Health, Berlin, Germany
  • Inker, Lesley, Tufts Medical Center, Boston, Massachusetts, United States
  • Levey, Andrew S., Tufts Medical Center, Boston, Massachusetts, United States
  • Lipkowitz, Michael S., Georgetown University Medical Center, Washington, District of Columbia, United States
  • Appel, Lawrence J., Johns Hopkins Medical Institutions, Baltimore, Maryland, United States
  • Arking, Dan, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
Background

Apoliprotein L1 (APOL1) risk alleles have been associated with chronic kidney disease (CKD) progression. Metabolomic profiling by APOL1 risk allele status may inform our understanding of the pathogenesis of APOL1-associated kidney disease.

Methods

We evaluated the association between 1,133 serum metabolites identified via an untargeted approach at Metabolon and the number of APOL1 high risk alleles (0,1, or 2) in the African American Study of Kidney Disease (AASK) (N=609). The significance threshold was set at 2.4e-4 based on principal component analysis. Significantly associated metabolites were then tested in a second cohort of African American patients with CKD (BioMe; N=680). Metabolites that replicated were evaluated as risk factors for CKD progression, defined as ESRD or at least doubling of serum creatinine.

Results

Of the six metabolites significantly associated with APOL1 in AASK, one, 5-bromotryptophan, was also significant in BioMe, with lower levels associated with higher number of risk alleles (beta per APOL1 risk allele, AASK: -0.23, p=2.5e-5; BioMe: -0.14, p=4.1e-3). In further analysis in AASK, lower levels of 5-bromotryptophan, a product of tryptophan metabolism, were associated with CKD progression adjusting for demographics, study assignments, baseline GFR, proteinuria, and APOL1 high-risk status (adjusted HR by tertile [T]: T2 vs T1 (lowest): 0.86 (95% CI: 0.64, 1.16); T3 (highest) vs T1: 0.63, 95% CI: 0.45, 0.88, p for trend: 0.008, figure).

Conclusion

Metabolomic profiling identified an association of APOL1 high risk alleles with lower 5-bromotryptophan levels, which was also associated with CKD progression, a finding which was consistent in two cohorts.

Kaplan-Meier estimates of proportion free of CKD progression by tertile of 5-bromotryptophan

Funding

  • NIDDK Support