Establishing A New Diagnostic Paradigm for Peripheral Artery Disease among Patients with Chronic Kidney Disease

PROJECT SUMMARY
Peripheral artery disease (PAD) is highly prevalent in patients with chronic kidney disease (CKD). In addition,
the adverse consequences of PAD are more severe in patients with CKD compared to those without. The
pathophysiology and clinical manifestations of PAD might be unique among CKD patients. Vascular
calcification and arterial stiffness are common in CKD patients and cause non-compressible arteries and an
artificial elevation of ankle brachial index (ABI). Our previous study reported that both reduced ABI (<1.0) and
elevated ABI (≥1.4) were associated with a higher risk of PAD-related revascularization and amputation, as
well as a higher risk of myocardial infarction, compared to those with an ABI between 1.0 to <1.4 in CKD
patients. In addition, our pilot study suggested that the current diagnostic criteria of ABI ≤0.9 and toe-brachial
index (TBI) ≤0.7 had poor sensitivity in detecting PAD defined as ≥50% artery stenosis in the lower extremities
by Doppler ultrasound among CKD patients. PAD risk classification models including multiple cardiovascular
disease (CVD) risk factors in addition to ABI or TBI significantly improved discrimination of those with and
without PAD. Furthermore, the diagnostic value of TBI, a measurement of perfusion of the foot, especially in
patients with incompressible vessels, has not been well evaluated in CKD patients. The overall objective of the
proposed study is to identify more accurate cut-points of ABI and TBI for PAD screening and diagnosis and to
develop a novel approach for PAD screening and diagnosis among CKD patients. The specific aims are: (1) to
assess the accuracy of current ABI and TBI diagnostic criteria and to identify more accurate cut-points of ABI
and TBI for PAD defined as ≥50% artery stenosis in the lower extremities by Doppler ultrasound; (2) to assess
whether the inclusion of multiple CVD risk factors in addition to ABI or TBI will improve discrimination and to
develop novel risk classification models for PAD screening and diagnosis; and (3) to compare the new cut-
points of ABI for PAD vs. the conventional cut-point (ABI ≤0.9), as well as risk classification models vs. ABI
alone, in predicting risk of clinical PAD, CVD, and all-cause mortality in CKD patients. We will recruit 420 pre-
dialysis CKD patients from three Chronic Renal Insufficiency Cohort (CRIC) study centers and conduct ABI,
TBI, and Doppler ultrasound tests. Color Doppler ultrasound, which will employ multiple features including
reduction in luminal diameter, monophasic waveform, peak systolic velocity ratio >2.0, and presence of special
broadcasting, will be used as the reference standard. The CRIC study recruited about 5,500 CKD patients with
ABI measurements and followed clinical outcomes for up to 17 years. The proposed study has 99% statistical
power to detect an area under the curve (AUC) of 0.70, with the null hypothesis AUC value of 0.50 and a 2-
sided significance level of 0.05 (Aim 1), and over 90% power to detect the difference of comparing AUC of 0.85
vs. AUC of 0.75 (Aim 2). The proposed study may change clinical practice regarding the screening and
diagnosis of PAD in CKD patients, with the aim of reducing PAD-related morbidity and mortality.

Grant Number: 7R01HL157903-04
NIH Institute/Center: NIH
Principal Investigator: JING CHEN