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

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Summary

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.

Introduction

Lower-extremity peripheral artery disease affects 8–10 million adults in the USA1 and more than 200 million adults around the world.2 Its prevalence increased by 24% globally in the past decade.2 Peripheral artery disease increases the risk of adverse clinical outcomes3, 4 and impairs lower-extremity function.5 It is especially important for people on haemodialysis and its incidence (about 400 per 1000 patient-years) is much higher than the incidence of coronary heart disease and stroke (about 100–150 per 1000 patient-years each) in this clinical population.6

Several previous studies have been done to investigate the association of mild and moderate stages of chronic kidney disease with peripheral artery disease.7, 8, 9, 10, 11, 12, 13, 14 However, most of these studies were cross-sectional7, 8, 9, 10 or investigated either, but not both, of the two kidney measures (estimated glomerular filtration rate [eGFR] or albuminuria) used to define and stage chronic kidney disease.9, 10, 11, 12 This limited evidence might have contributed to chronic kidney disease not being included among the risk factors for peripheral artery disease in the 2016 guidelines on peripheral artery disease from the American Heart Association (AHA) and the American College of Cardiology (ACC).15

Research in context

Evidence before this study

Lower-extremity peripheral artery disease is an important complication for patients on haemodialysis, and its incidence is much higher than that for coronary heart disease and stroke in this clinical population. No formal systematic review was undertaken; KM searched PubMed for papers published to June 30, 2016, and co-authors provided feedback on relevant articles. For low-severity stages of chronic kidney disease, several previous studies have investigated the risk for peripheral artery disease, but most of them were cross-sectional or investigated either (but not both) of the two kidney measures used to define and stage chronic kidney disease: estimated glomerular filtration rate (eGFR) or albuminuria. This limited evidence might have contributed to 2016 guidelines on peripheral artery disease from the American Heart Association and the American College of Cardiology not including chronic kidney disease among the risk factors for peripheral artery disease.

Added value of this study

In this individual-level data meta-analysis, with 18 261 incident peripheral artery disease cases from 0·8 million participants from 21 cohorts, we examined the prospective and independent associations of eGFR and albuminuria with future risk of peripheral artery disease. Our results showed that both albuminuria and reduced eGFR were independently associated with future risk of peripheral artery disease. Even mild-to-moderate chronic kidney disease (when either of eGFR 30–59 mL/min per 1·73 m2 or urine albumin-to-creatinine ratio 30–299 mg/g is present) conferred 1·5–4-times higher risk of peripheral artery disease beyond traditional risk factors. Accordingly, both kidney measures improved the prediction of peripheral artery disease risk beyond traditional risk factors, with more evident improvements with albuminuria than with eGFR. Albuminuria was particularly strongly associated with the risk of leg amputation and substantially improved its risk prediction.

Implications of all the available evidence

Our results suggest that individuals with chronic kidney disease, even at mild-to-moderate stages, might warrant clinical attention to leg signs and symptoms of peripheral artery disease. Annual foot care is currently recommended in patients with diabetes, but adherence to this recommendation is low. Thus, as the first step to improve this low adherence, people with both diabetes and chronic kidney disease (particularly when albuminuria is present) might be a reasonable target for strong encouragement of regular foot care. Assessment of kidney function and albuminuria is already recommended in patients with diabetes or hypertension. As such, in these clinical populations, the chronic kidney disease measures should be readily available to classify the risk of peripheral artery disease.

We aimed to quantify the independent and joint associations of eGFR and albuminuria with future risk of peripheral artery disease using data from eligible cohorts in the Chronic Kidney Disease Prognosis Consortium (CKD-PC).16 These rich data also allowed us to assess improvement of prediction of peripheral artery disease with these measures of chronic kidney disease and to investigate several different definitions of peripheral artery disease such as leg amputation and revascularisation.

Section snippets

Study design and data sources

Details of the CKD-PC are described elsewhere.16, 17 Briefly, the CKD-PC is an international consortium established to provide evidence that can improve prevention and management of chronic kidney disease and currently consists of more than 70 prospective cohorts, including participants from 40 countries or regions with data for eGFR, albuminuria, and clinical outcomes. The present study is a collaborative meta-analysis including data from nine general population cohorts, eight cohorts of

Results

A total of 817 084 individuals without a history of peripheral artery disease from 21 cohorts in the CKD-PC, with a mean age of 54 years (SD 12), were followed up for a median of 7·4 years (IQR 5·7–8·9, table). Overall, 268 385 (33%) had diabetes and 72 183 (9%) had a history of cardiovascular disease. The prevalence of an eGFR of less than 60 mL/min per 1·73 m2 was 17% (64 926 of 385 764 patients) in the general population cohorts, 14% (57 366 of 421 840) in high cardiovascular risk cohorts,

Discussion

This international collaborative meta-analysis of individual-level data in about 0·8 million individuals without peripheral artery disease at baseline shows that both eGFR and ACR were independently associated with future risk of peripheral artery disease. Even mild-to-moderate chronic kidney disease conferred 1·5–4-times increased risk of peripheral artery disease beyond traditional risk factors. For ACR, we identified a risk gradient even within the range currently regarded as normal or

References (45)

  • CS Fox et al.

    Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis

    Lancet

    (2012)
  • VN Varu et al.

    Critical limb ischemia

    J Vasc Surg

    (2010)
  • E Ratto et al.

    Microalbuminuria and cardiovascular risk assessment in primary hypertension: should threshold levels be revised?

    Am J Hypertens

    (2006)
  • M Tonelli et al.

    Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study

    Lancet

    (2012)
  • D Mozaffarian et al.

    Executive summary: heart disease and stroke statistics—2016 update: a report from the American Heart Association

    Circulation

    (2016)
  • Ankle brachial index combined with Framingham risk score to predict cardiovascular events and mortality: a meta-analysis

    JAMA

    (2008)
  • MR Nehler et al.

    Epidemiology of peripheral arterial disease and critical limb ischemia in an insured national population

    J Vasc Surg

    (2014)
  • MM McDermott et al.

    Ankle brachial index values, leg symptoms, and functional performance among community-dwelling older men and women in the lifestyle interventions and independence for elders study

    J Am Heart Assoc

    (2013)
  • 2013 Atlas of CKD & ESRD

  • E Selvin et al.

    Kidney function estimated from serum creatinine and cystatin C and peripheral arterial disease in NHANES 1999–2002

    Eur Heart J

    (2009)
  • K Wattanakit et al.

    Kidney function and risk of peripheral arterial disease: results from the Atherosclerosis Risk in Communities (ARIC) Study

    J Am Soc Nephrol

    (2007)
  • AK Bello et al.

    Associations among estimated glomerular filtration rate, proteinuria, and adverse cardiovascular outcomes

    Clin J Am Soc Nephrol

    (2011)
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