An Overview of PAD Guidelines for Nephrology

There are many risk factors for the development of Peripheral Artery Disease (PAD) and quite a few medical conditions that contribute to greater morbidity and higher rates of complications. Smoking is the most prominent modifiable risk factor, while diabetes takes the first place as both a risk factor and detrimental comorbid condition. There are however contenders which, although less known, are as serious or, in certain aspects, even more so, such as Chronic Kidney Disease (CKD).

Peripheral Artery Disease (PAD), or Lower Extremity Artery Disease (LEAD) as it is also known, could very well be called a modern-day disease, although this is technically not true as we now have archaeological evidence that it was already present in ancient times [1]. We are talking of course from the perspective of rise in modifiable risk factors, which contribute to the greater prevalence and severity of symptoms. Smoking, hyperlipidaemia, hypertension, a lack of regular physical activity and an unhealthy weight are prime examples [2-7]. These, along with diabetes mellitus and the general ageing of the population, are the main culprits for 236.62 million patients in 2015 (up from 202 million in 2010) and the continuing projected rise in the prevalence of PAD [8, 9].

Increasing numbers of patients naturally translate to a greater workload for physicians and financial expenses for the healthcare systems. Additionally, comprehensive treatment of PAD often requires synergetic approach, not only on the part of general practitioners (patient’s personal physician) and cardiologists, but also other healthcare professionals like diabetologists (endocrinologists), wound care providers and nephrologists. The latter are usually well acquainted with the harmful effects of renal insufficiency on the cardiovascular system and, in particular, its association with Coronary Artery Disease (CAD), but may be less aware of dangers of other conditions like PAD.

Are patients with CKD at greater risk for PAD?

Cardiovascular Diseases (CVDs), especially those of an atherosclerotic type, are in general far more common in those with CKD than in individuals without renal issues [10]. There’s more: patients with CKD are more likely to die from CVD complications than they are to progress to End-Stage Renal Disease (ESRD) [11, 12]. A fair share of those complications is connected with PAD and patients with CKD are at more than two time the risk of developing this insidious disease than those with normal renal function [13]. Those who already have both diseases are at a markedly increased short-term risk of myocardial infarction and stroke, have greater mortality rates than those with either disease and suffer worse and more frequent complications post revascularisation procedures [14, 15].

Other notable complications at the intersection of CKD and PAD are incompressible arteries. Patients with CKD are more likely to suffer from arterial media calcification (the most common causative mechanism for incompressible arteries), as those with diabetes and rheumatoid arthritis [16, 17, 18]. Accordingly diagnosis of incompressible arteries is associated with greater overall and cardiovascular mortality in haemodialysis patients, while from the perspective of PAD the significance lies in an increased likelihood of misdiagnosis if the Ankle-Brachial (Pressure) Index (ABPI or ABI) assessment method is used [18, 19].

Regardless of which method for measuring PAD is used, be it a Doppler probe/sphygmomanometer combination or the more easy to use and reliable oscillometric-plethysmographic diagnostic device, an abnormally high ABI (generally in the ≥1.30 to 1.40 range) is of little diagnostic value for PAD, but may be an indicator of an increased risk for myocardial infarction [19-22]. A Toe-Brachial Index (TBI) assessment can be used instead as toe arteries are rarely affected by calcification [23].

Despite such overwhelming evidence of disastrous collusion of CKD and PAD, many large PAD epidemiological studies have not included CKD as a risk a risk factor and consequently have not reported information about level of renal function, hindering accurate estimates of prevalence of PAD in patients with CKD [24, 25, 26]. Some studies put that number in between 23 % and 25 %, while others, through the use of the ABI as diagnostic criteria, report much a higher prevalence of up to 35 % [27, 28, 29]. Moreover randomised clinical trials of PAD therapies have often excluded patients with severe renal insufficiency, although they are at highest risk [29].

Patients with CKD or already receiving dialysis should therefore be given comprehensive screening on the basis of inclusion in risk groups (a comprehensive questionnaire tailored especially for nephrologists is invaluable in such instances) and ABI or TBI assessments [30]. The latter is recognised as more sensitive in ESRD patients than the ABI and has additional diagnostic value as a predictor of mortality in dialysis patients [31, 32]. A positive diagnosis on the basis of PAD and TBI is often followed by magnetic resonance angiography to better assess the extent of atherosclerotic lesions and occlusions, although this diagnostic procedure is not without risk. There is evidence that the use of contrast medium in these tests, specifically gadolinium, is associated with development of Nephrogenic Systemic Fibrosis (NSF) in those with severe renal dysfunction [33, 34].

On the other hand there is a marked lack of high-quality evidence when it comes to a proper therapeutic approach for treating PAD in patients with renal insufficiency, or more specifically those on dialysis. In general the joint goals are treatment of PAD and a reduction in cardiovascular risk factors. These may be achieved by secondary risk reduction (lifestyle modification), such as smoking cessation, which improves functional capacity for those with PAD, but there is no evidence that the effect is the same in those with comorbid CKD [35]. The benefits of statin therapy are likewise (currently) unclear [36].

The consequences of a lack of proper and/or timely treatment of PAD are well-known, as are the higher rates of complications in those with comorbid CKD. Untreated PAD may manifest as arterial insufficiency ulcers (ischaemic ulcers/wounds), which can quickly progress into gangrene and Critical Limb Ischaemia (CLI). This end stage of PAD is associated with high amputation rates, from 10 % to 40 % for a 6-month period after diagnosis, and mortality in the ballpark of 20 % in the 6-month period to 50 % in 5 years after diagnosis [37-41].

Revascularisation is usually the only option to save the patient’s limb. Outcomes of such procedures are mixed: in patients with moderate renal insufficiency rates of both successful outcomes and complications are acceptable, while for those undergoing dialysis they were much worse, particularly amputation rates (three times greater than in the first group) [42]. Nevertheless, one thing is certain: there is still much to be done in regards to optimal treatment of PAD in individuals with renal insufficiency.

Patients with CKD are especially at risk for development of PAD and they suffer higher rates of more severe complications and adverse outcomes. Preventive screening is therefore strongly recommended no later than at the commencement of dialysis.