Presence of peripheral artery disease in renal transplant outcomes – Don’t throw the baby out with the bath water

Guidelines for the evaluation of renal transplant candidates are well established and comprehensive, including assessment of an individual’s cardiovascular function and co-morbidities. ¹ Regarding the evaluation, treatment, and follow-up of peripheral artery disease (PAD) in renal transplant candidates, the American Society of Transplantation recommends that angioplasty or surgical intervention for PAD be reserved for patients with symptomatic disease. ¹ However, these guidelines do not specify which patients should or should not be considered for renal transplant in the presence of PAD.

Given the high prevalence of PAD in this population, an understanding of its impact on outcomes, including graft failure and mortality, is important.

In order to examine this relationship, Patel and colleagues performed a retrospective analysis investigating the ability of pre-transplant ankle–brachial index (ABI) measurements to predict graft failure and mortality in kidney transplant recipients. ² The authors analyzed the medical records of all kidney transplant recipients from 1994 to 2014 at three Mayo Clinic campuses and included 819 patients with ABI measurements within 5 years of the renal transplant. ABI measurements were ultimately grouped into normal ABI (0.90–1.39), low ABI (≤ 0.89), and high ABI (≥ 1.40). A predictive model of graft failure and mortality after adjustment for known cardiovascular risk factors (age, sex, smoking history, hypertension, diabetes, stroke, known coronary artery disease or heart failure, and years of dialysis) was then performed. Using multivariate logistic regression and Cox proportional hazard models, the authors report that low ABI was a significant predictor of graft failure (odds ratio (OR) 2.77, 95% confidence interval (CI) 1.68–4.58, p < 0.001) and secondary endpoints, including myocardial infarction, cerebrovascular accident and limb ischemia/gangrene/amputation (hazard ratio (HR) 1.39, 95% CI 0.97–1.99, p < 0.076), and death (HR 1.84, 95% CI 1.26–2.68, p = 0.002).

We commend the authors for their important work in bringing to attention the prognostic importance of pre-transplant ABI to potentially predict graft failure and mortality in these high-risk patients. ² Their results, if reproducible when performed prospectively, could potentially lead to routine screening for PAD with an ABI in all patients undergoing renal transplant evaluation. However, the study has a number of limitations that merit further consideration. The population included patients from three Mayo Clinic sites: Florida (606 patients, 74%), Arizona (73 patients, 9%), and Rochester, Minnesota (140 patients, 17%). The authors explain that patients at the Arizona and Rochester sites were selected for ABI measurements based upon clinicians’ suspicion of significant PAD, while the patients in Florida underwent routine ABI testing as part of pre-transplant evaluation. Over one-quarter (26%) of patients in this study had a clinical presentation that warranted ABI measurement, such as limb ischemia, gangrene, or ulcer. As a result, this could have introduced inherent selection bias in favor of ABI as a strong predictor of outcomes and may not support routine screening ABI measurement. Patients in the cohort had a high prevalence of diabetes (70%), which itself has been associated with higher graft failure and decreased survival; however, this was not adjusted for in the current study. The presence of PAD in kidney transplant candidates creates issues related to the suitability of the lower aorta and common and external iliac arteries for allograft placement. Since graft failure was greater among those with PAD, and technical issues (usually surgical) did not appear to be accounted for in the models, this may have also contributed to the worse outcomes in the PAD cohort. In their analysis, Patel and colleagues separated their analysis into low ABI (< 0.9) and elevated ABI (> 1.4) groups; however, it is well known that elevated ABI is associated with poor prognosis, as many of these patients likely have PAD despite a non-compressible ABI.^3–5 Since the authors did not use other reliable diagnostic methods such as toe pressures or the toe–brachial index (TBI), it is likely that many patients with PAD were included in the high ABI group. Hence, their finding that a high ABI did not predict transplant outcomes is not a true reflection on the presence or absence of PAD in this group.^3–5 The 5-year window for pre-transplant ABI is relatively long, especially among patients with end stage renal disease (ESRD), diabetes, and many other risk factors that are known to accelerate PAD. ⁶ This may have actually led to an underestimation of the association between low ABI and outcomes.

PAD can affect renal transplant patients in a number of ways (Figure 1). First, it can impact acute allograft placement when there is disease of the aorta and common and external iliac arteries. Such issues can lead to acute graft failure due to poor anastomoses, cholesterol emboli, or hypoperfusion. Careful surgical considerations and/or upstream vascular interventions may mitigate some of these concerns. Second, PAD may lead to transplant renal artery stenosis and resultant hypertension and progressive renal failure. ⁷ While rare, this association can lead to graft failure but can easily be mitigated with endovascular therapy. ⁷ Third, PAD can result in claudication but more importantly can progress to critical limb ischemia (CLI). The latter, when present with tissue loss and gangrene, can have significant implications in patients who have undergone renal transplant and are maintained on immunosuppressive therapy. These patients typically present with non-compressible arteries and have isolated infragenicular tibial disease. In approximately 30% of these patients, ABI is inaccurate and may be normal or falsely elevated.^3,4 Therefore, the presence of any ulcer or tissue loss in a kidney transplant patient should render an early referral to a vascular and wound specialist with a low threshold for early intervention. These procedures should be performed carefully to prevent damage to the transplanted kidney and also to minimize iodinated contrast dye usage in these patients. Importantly, the presence of abnormal ABI and PAD, especially among patients with ESRD with diabetes mellitus, should prompt routine foot and nail evaluation including assessment for appropriate orthotics. Fourth, PAD has a well-established association with cardiovascular outcomes. It is even more pronounced among those with diabetes and ESRD. Therefore, these individuals will require aggressive risk factor modification with smoking cessation and guideline-directed medical therapy including tight blood pressure control, statin therapy (with careful dosing of statins in those on particular immunosuppressive drugs), diabetes control, and anti-platelet therapy. Ultimately, all patients with a renal transplant should undergo a thorough cardiovascular history and physical exam at every visit and should be promptly referred to appropriate specialists in the presence of cardiac or vascular symptoms or signs. Fifth, beyond ABI, atherosclerosis is a systemic disease that can affect the carotids, mesenteric, aorta, and other vascular beds. ⁸ Therefore, an abnormal ABI/TBI should heighten concerns about disease in other vascular beds, some of which could have significant morbidity and mortality (e.g. carotid artery disease, abdominal aortic aneurysm).

Figure 1.

Impact of PAD on renal transplant patients. (PAD, peripheral artery disease; TIA, transient ischemic attack; AAA, abdominal aortic aneurysm.)

In conclusion, ABI and TBI are simple, non-invasive, and cost-sensitive tools that could provide important information about the presence of PAD among renal transplant patients. Knowledge of PAD status can have a potentially significant impact on mortality, morbidity, and graft longevity in this high-risk patient population; however, this will need to be proven in more rigorous prospective studies. Until then, the presence of PAD alone should rarely discourage renal transplantation, as long as all the potential aspects of the impact of PAD have been evaluated and are continuously monitored after transplantation (Figure 1).