Chronic kidney disease measures and incident peripheral artery disease: A collaborative meta-analysis from the Chronic Kidney Disease Prognosis Consortium

Background Few studies evaluated associations of key measures of chronic kidney disease (CKD), estimated glomerular filtration rate (eGFR) and albuminuria, with incident lower-extremity peripheral artery disease (PAD). Thus, we aimed to quantify the independent and joint associations of these two CKD measures with incident PAD. Methods In 21 cohorts (801,731 participants) free of PAD at baseline, we quantified associations of creatinine-based eGFR, urine albumin-to-creatinine ratio [ACR], and dipstick proteinuria with incident PAD (including PAD hospitalization, intermittent claudication, leg revascularization, and leg amputation). Discrimination improvement was assessed through c-statistics. Findings There were 17,852 PAD cases across cohorts (a median follow-up ranging from 2.0-15.8 years across cohorts). Both CKD measures were independently associated with incident PAD. Adjusted hazard ratios (HRs) at eGFR 45 and 15 (versus 95) ml/min/1.73m2 were 1.22 (95%CI, 1.14-1.30) and 2.06 (1.70-2.48), respectively. Adjusted HRs at ACR 30 and 300 (versus 5) mg/g were 1.50 (1.41-1.59) and 2.28 (2.12-2.44), respectively. ACR-amputation association was particularly strong (HR at ACR 300 mg/g 3.68 [3.00-4.52]). eGFR and ACR contributed multiplicatively (e.g., adjusted HR 5.76 [4.90-6.77] mg/g for incident PAD and 10.61 [5.70-19.77] for amputation in eGFR <30 ml/min/1.73m2 plus ACR ≥300 mg/g vs. eGFR ≥90 plus ACR <10). Both eGFR and ACR significantly improved PAD risk discrimination beyond traditional predictors, with a considerable improvement for amputation with ACR (Δc-statistic: 0.058 [0.045-0.070]). Patterns were consistent across clinical subgroups and with dipstick proteinuria. Interpretation Even mild to moderate CKD conferred increased risk of incident PAD, with remarkable albuminuria-amputation relationship. Clinical attention should be paid to the development of PAD symptoms and signs in persons with any stages of CKD.