Measures of chronic kidney disease and risk of incident peripheral artery disease: a collaborative meta-analysis of individual participant data

Abstract

Background: Some evidence suggests that chronic kidney disease is a risk factor for lower-extremity peripheral artery disease. We aimed to quantify the independent and joint associations of two measures of chronic kidney disease (estimated glomerular filtration rate [eGFR] and albuminuria) with the incidence of peripheral artery disease.

Methods: In this collaborative meta-analysis of international cohorts included in the Chronic Kidney Disease Prognosis Consortium (baseline measurements obtained between 1972 and 2014) with baseline measurements of eGFR and albuminuria, at least 1000 participants (this criterion not applied to cohorts exclusively enrolling patients with chronic kidney disease), and at least 50 peripheral artery disease events, we analysed adult participants without peripheral artery disease at baseline at the individual patient level with Cox proportional hazards models to quantify associations of creatinine-based eGFR, urine albumin-to-creatinine ratio (ACR), and dipstick proteinuria with the incidence of peripheral artery disease (including hospitalisation with a diagnosis of peripheral artery disease, intermittent claudication, leg revascularisation, and leg amputation). We assessed discrimination improvement through c-statistics.

Findings: We analysed 817 084 individuals without a history of peripheral artery disease at baseline from 21 cohorts. 18 261 cases of peripheral artery disease were recorded during follow-up across cohorts (median follow-up was 7·4 years [IQR 5·7-8·9], range 2·0-15·8 years across cohorts). Both chronic kidney disease measures were independently associated with the incidence of peripheral artery disease. Compared with an eGFR of 95 mL/min per 1·73 m², adjusted hazard ratios (HRs) for incident study-specific peripheral artery disease was 1·22 (95% CI 1·14-1·30) at an eGFR of 45 mL/min per 1·73 m² and 2·06 (1·70-2·48) at an eGFR of 15 mL/min per 1·73 m². Compared with an ACR of 5 mg/g, the adjusted HR for incident study-specific peripheral artery disease was 1·50 (1·41-1·59) at an ACR of 30 mg/g and 2·28 (2·12-2·44) at an ACR of 300 mg/g. The adjusted HR at an ACR of 300 mg/g versus 5 mg/g was 3·68 (95% CI 3·00-4·52) for leg amputation. eGFR and albuminuria contributed multiplicatively (eg, adjusted HR 5·76 [4·90-6·77] for incident peripheral artery disease and 10·61 [5·70-19·77] for amputation in eGFR <30 mL/min per 1·73 m² plus ACR ≥300 mg/g or dipstick proteinuria 2+ or higher vs eGFR ≥90 mL/min per 1·73 m² plus ACR <10 mg/g or dipstick proteinuria negative). Both eGFR and ACR significantly improved peripheral artery disease risk discrimination beyond traditional predictors, with a substantial improvement prediction of amputation with ACR (difference in c-statistic 0·058, 95% CI 0·045-0·070). Patterns were consistent across clinical subgroups.

Interpretation: Even mild-to-moderate chronic kidney disease conferred increased risk of incident peripheral artery disease, with a strong association between albuminuria and amputation. Clinical attention should be paid to the development of peripheral artery disease symptoms and signs in people with any stage of chronic kidney disease.

Funding: American Heart Association, US National Kidney Foundation, and US National Institute of Diabetes and Digestive and Kidney Diseases.

Figure 1

Adjusted hazard ratios and 95% confidence intervals (shaded areas) for each definition of peripheral artery disease according to eGFR (panels A-D) and ACR (panels E-H). The reference value is eGFR 95 mL/min/1.73m² and ACR 5 mg/g (diamonds). Adjusted for age, sex, race or ethnic origin, smoking, systolic blood pressure, antihypertensive drugs, diabetes, total and HDL cholesterol concentrations, and albuminuria (ACR or dipstick) or eGFR, as appropriate. Panels A-D included cohorts with dipstick proteinuria, and panels E-H were based on cohorts with ACR data.

Figure 2

Categorical analysis of peripheral artery disease outcome definitions with eGFR and ACR in the combined general population and high-risk cohorts. Panels show adjusted hazard ratios derived from categorical analysis of the general population and high-risk cohorts. Dipstick −, ±, 1+, and ≥2+ were combined with ACR categories, as appropriate. Color coding is based on following cutoffs: green indicating <1.5; yellow 1.5 − <2; orange 2−<4; and red ≥4. Bold indicates statistical significance.

Figure 3

Difference in C statistics and 95% CIs for each definition of peripheral artery disease after addition of kidney measures to traditional models (age, sex, race, smoking status, systolic blood pressure, antihypertensive drug use, and diabetes, levels of total and high-density lipoprotein cholesterols, and history of cardiovascular disease) in the combined general population and high-risk cohorts.

Figure 4

Difference in C statistics and 95% CIs for each definition of peripheral artery disease after addition of kidney measures and traditional risk factors to the demographic model (age, sex, and race) in the combined general population and high-risk cohorts.