This article is more than 5 years old. Information may no longer be current.
Two key CKD biomarkers predict risk for future peripheral artery disease
Among patients without symptomatic peripheral artery disease at baseline, a lower estimated glomerular filtration rate and higher urinary albumin to creatinine ratio — even when not rising to the level of albuminuria — significantly increase the risk for developing future vascular disease, according to findings from a large meta-analysis of international prospective cohorts.
“Even mild to moderate chronic kidney disease conferred 1.5 to four times increased risk of peripheral artery disease beyond traditional risk factors,” Kunihiro Matsushita, MD, associate professor of epidemiology at the Johns Hopkins Bloomberg School of Public Health, and colleagues wrote. “For [albumin to creatinine ratio], we identified a risk gradient even within the range currently regarded as normal or mildly raised (ie, < 30 mg/g). The associations were largely consistent across different cohorts and across key demographic and clinical subgroups, such as participants with vs. without diabetes or hypertension.”
Matsushita and colleagues analyzed data from 817,084 adults without a history of peripheral artery disease (PAD) at baseline from 21 cohorts in the Chronic Kidney Disease Prognosis Consortium, an international consortium including more than 70 prospective cohorts from 40 countries (mean age, 54 years). Included cohorts had at least 1,000 participants with baseline measurements of eGFR and urinary albumin to creatinine ratio and at least 50 PAD events. Participants were followed for a median of 7.4 years.
Researchers used Cox proportional hazards models to quantify associations of creatinine-based eGFR, urine albumin to creatinine ratio and dipstick proteinuria with the incidence of PAD, including hospitalization with a diagnosis of PAD, intermittent claudication, leg revascularization and leg amputation. Discrimination improvement was assessed through C-statistics.
Across the cohorts, 268,385 adults had diabetes, and 72,183 adults had a history of cardiovascular disease. Among general population cohorts, 17% of adults had an eGFR of 60 mL/min/1.73 m² or less vs. 14% in the high CV risk cohorts and 66% in the CKD cohorts.
During follow-up, 18,261 incident cases of PAD were reported based on study-specific definitions across all cohorts, in addition to 8,014 cases of PAD-related hospital admissions from eight cohorts, 2,549 cases of leg revascularization from 10 cohorts, and 1,754 cases of leg amputation from seven cohorts, according to researchers.
Researchers found that eGFR and urinary albumin to creatinine ratio were independently associated with the incidence of PAD. Compared with an eGFR of 95 mL/min/1.73 m², the adjusted HR for incident, study-specific PAD was 1.22 (95% CI, 1.14-1.3) at an eGFR of 45 mL/min/1.73 m² and 2.06 (95% CI, 1.7-2.48) at an eGFR of 15 mL/min/1.73 m².
Associations between urinary albumin to creatinine ratio and PAD were generally linear, according to researchers. Compared with a urinary albumin to creatinine ratio of 5 mg/g, the adjusted HR for incident, study-specific PAD was 1.5 (95% CI, 1.41-1.59) at a urinary albumin to creatinine ratio of 30 mg/g and 2.28 (95% CI, 2.12-2.44) at a urinary albumin to creatinine ratio of 300 mg/g.
The HR for leg amputation was 3.68 (95% CI, 3-4.52) for adults with a urinary albumin to creatinine ratio of 300 mg/g when compared with 5 mg/g.
Through modeling cross-categories in general and high CV risk cohorts, the researchers also confirmed multiplicative contributions of eGFR and albuminuria to the increased risk for PAD. Researchers found that, irrespective of PAD definition, the highest risk for PAD was observed in the setting of a severely reduced eGFR (< 30 mL/min/1.73 m²) plus severely raised urinary albumin to creatinine ratio ( 300 mg/g) or dipstick proteinuria ( 2); adjusted HR for PAD was 5.76 (95% CI, 4.9-6.77) when compared with those with an eGFR of 90 mL/min/1.73 m² plus a urinary albumin to creatinine ratio of 10 mg/g or less. Patterns were consistent across clinical subgroups.
“Overall, our results suggest important pathophysiological contributions of chronic kidney disease to the development of peripheral artery disease above and beyond traditional risk factors, although the present study is not designed to elucidate mechanisms,” the researchers wrote. “Nonetheless, it is worth emphasizing that both chronic kidney disease measures contributed to peripheral artery disease risk, even among participants without diabetes or hypertension, suggesting that eGFR and albuminuria are not merely end-organ damage markers of these traditional atherosclerotic risk factors.”
In commentary accompanying the study, Austin G. Stack, MBBCh, MD, MSc, foundation chair of medicine at the Graduate Entry Medical School and consultant nephrologist at University Hospital Limerick, Ireland, wrote that the analysis sheds new light on the importance of two simple measures of kidney function in predicting vascular disease risk.
“A striking feature of this study was the large amplification of risk associated with the combination of chronic kidney disease measures compared with each measure individually,” Stack wrote. “An important take-home message from this study is that the omission of either eGFR or [albumin to creatine ratio] from the risk prediction model would lead to significant underestimation of the future risk for peripheral arterial disease.” – by Regina Schaffer
Disclosure s : Matsushita reports receiving grants and personal fees from Fukuda Denshi and Kyowa Hakko Kirin. Please see the study for all other authors’ relevant financial disclosures. Stack reports receiving personal fees and nonfinancial support from AstraZeneca, Gruenenthal, Menarini and Vifor Pharma.