Kidney function, bone-mineral metabolism markers, and future risk of peripheral artery disease

Abstract

Background and aims: Reduced kidney function is a risk factor for lower-extremity peripheral artery disease (PAD). However, the associations of novel filtration markers with PAD are yet to be quantified. Moreover, little is known on whether bone-mineral metabolism (BMM) markers are related to incident PAD beyond kidney function.

Methods: Using data from 12,472 participants at baseline (1990-1992) of the Atherosclerosis Risk in Communities (ARIC) study, we comprehensively quantified the associations of kidney related markers with incident PAD (defined as hospitalizations with diagnosis of lower-extremity atherosclerosis, revascularization, or amputation). Kidney related markers of interest included estimated glomerular filtration rate (eGFR) (based on creatinine, cystatin C, and both), cystatin C, beta-2 microglobulin (B2M), and BMM markers (serum fibroblast growth factor 23, parathyroid hormone, calcium, and phosphorus).

Results: During a median follow-up of 21 years, 471 participants developed incident PAD. Low eGFR was significantly associated with future PAD risk, with slightly stronger relationship when cystatin C was used (adjusted hazard ratio [HR] 6.3-8.3 for eGFR <30 and 2.4-3.5 for eGFR 30-59 vs. eGFR ≥90 mL/min/1.73 m²). Among all filtration markers, B2M had the strongest association with incident PAD (HR for top vs. bottom quartile 2.60 [95% CI: 1.91-3.54] for B2M vs. 1.20 [0.91-1.58] for creatinine-based eGFR). Among BMM markers, only phosphorus remained significant for PAD risk beyond potential confounders, including kidney function (HR 1.47 [1.11-1.94] in top quartile).

Conclusions: Kidney dysfunction was independently associated with future PAD risk, particularly when assessed with cystatin C and B2M. Among the BMM markers tested, phosphorus was most robustly associated with incident PAD beyond kidney function. Our results suggest the potential usefulness of novel filtration markers for PAD risk assessment and the possible role of phosphorus in the pathophysiology of PAD.

Keywords: Bone-mineral metabolism markers; Kidney markers; Peripheral artery disease; Prospective cohort study.