Serum 6-Bromotryptophan Levels Identified as a Risk Factor for CKD Progression

Background Metabolite levels reflect physiologic homeostasis and may serve as biomarkers of disease progression. Identifying metabolites associated with APOL1 risk alleles-genetic variants associated with CKD risk commonly present in persons of African descent-may reveal novel markers of CKD progression relevant to other populations.Methods We evaluated associations between the number of APOL1 risk alleles and 760 serum metabolites identified via untargeted profiling in participants of the African American Study of Kidney Disease and Hypertension (AASK) (n=588; Bonferroni significance threshold P<6.5×10^-5) and replicated findings in 678 black participants with CKD in BioMe, an electronic medical record-linked biobank. We tested the metabolite association with CKD progression in AASK, BioMe, and the Modification of Diet in Renal Disease (MDRD) Study.Results One metabolite, 6-bromotryptophan, was significant in AASK (P=4.7×10^-5) and replicated in BioMe (P=5.7×10^-3) participants, with lower levels associated with more APOL1 risk alleles. Lower levels of 6-bromotryptophan were associated with CKD progression in AASK and BioMe participants and in white participants in the MDRD Study, independent of demographics and clinical characteristics, including baseline GFR (adjusted hazard ratio per two-fold higher 6-bromotryptophan level, AASK, 0.76; 95% confidence interval [95% CI], 0.64 to 0.91; BioMe, 0.61; 95% CI, 0.43 to 0.85; MDRD, 0.52; 95% CI, 0.34 to 0.79). The interaction between the APOL1 risk alleles and 6-bromotryptophan was not significant. The identity of 6-bromotryptophan was confirmed in experiments comparing its molecular signature with that of authentic standards of other bromotryptophan isomers.Conclusions Serum 6-bromotryptophan is a consistent and novel risk factor for CKD progression.