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

Abstract

<b>Background</b> Metabolite levels reflect physiologic homeostasis and may serve as biomarkers of disease progression. Identifying metabolites associated with <i>APOL1</i> 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.<b>Methods</b> We evaluated associations between the number of <i>APOL1</i> risk alleles and 760 serum metabolites identified <i>via</i> untargeted profiling in participants of the African American Study of Kidney Disease and Hypertension (AASK) (<i>n</i>=588; Bonferroni significance threshold <i>P</i><6.5×10^-5) and replicated findings in 678 black participants with CKD in Bio<i>Me</i>, an electronic medical record-linked biobank. We tested the metabolite association with CKD progression in AASK, Bio<i>Me</i>, and the Modification of Diet in Renal Disease (MDRD) Study.<b>Results</b> One metabolite, 6-bromotryptophan, was significant in AASK (<i>P</i>=4.7×10^-5) and replicated in Bio<i>Me</i> (<i>P</i>=5.7×10^-3) participants, with lower levels associated with more <i>APOL1</i> risk alleles. Lower levels of 6-bromotryptophan were associated with CKD progression in AASK and Bio<i>Me</i> 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; Bio<i>Me</i>, 0.61; 95% CI, 0.43 to 0.85; MDRD, 0.52; 95% CI, 0.34 to 0.79). The interaction between the <i>APOL1</i> 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.<b>Conclusions</b> Serum 6-bromotryptophan is a consistent and novel risk factor for CKD progression.