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Patients with Chronic Kidney Disease (CKD) are at an increased risk of Cardiovascular Diseases (CVDs) and associated causes of mortality. Amongst them is also Peripheral Artery Disease (PAD), which is not only often asymptomatic, but may prove difficult to accurately diagnose using standard diagnostic methods in patients with comorbid CKD.

In 2015 there were 236.62 million individuals with PAD (also known as Lower Extremity Artery Disease or LEAD for short) and that number is likely to continue rising in the near future, primarily to the general ageing of the population and an increase in other relevant risk factors [1]. In the same year there were an estimated 415 million diabetics worldwide [2], but why even mention diabetes mellitus in the same breath as PAD? The reasons are numerous.

Firstly, diabetes is a significant risk factor for PAD and has serious effects on the course of the disease, its severity and the risk of adverse outcomes and complications. Secondly is the ‘masking’ effect of one of the complications of diabetes when it comes to diagnosing PAD using standard the Ankle-Brachial (Pressure) Index (ABPI or ABI) assessment. Lastly, diabetes is the most prominent common dominator for both CKD and PAD (in addition to hypertension) [3].

The Framingham Heart Study revealed that at least 20 % of patients with diabetes also have PAD – there are doubts about the accuracy of such a low prevalence [4]. The main reason for this is the fact that the number derived in the study represented only symptomatic patients and did not take into account the often-asymptomatic nature of the disease (in both diabetic and non-diabetic individuals). Only about 10 % of all patients with PAD experience typical symptoms (intermittent claudication), 40 % are entirely asymptomatic and the rest have atypical symptoms that could be attributed to other medical conditions [5, 6]. Intermittent claudication is on the other hand far more prevalent in diabetics: males are 3.5-times more at risk, while females are 8.6-times more at risk than non-diabetics of their respective genders [7].

Additionally, at least 50 % (some estimates go as high as 76 %) of those with Critical Limb Ischaemia (CLI), the most serious advanced stage form of PAD, also have diabetes and suffer worse outcomes in relation to lower-extremity amputations and mortality than non-diabetics [8, 9, 10]. More specifically, the amputation rates are between 5 and 15-times higher in those individuals with both diseases than those with only PAD [11]. On the other hand diabetics who are candidates for vascular surgery or endovascular intervention deal with more complications and suffer more severe outcomes, particularly if they have poor glycaemic control [12].

(Diabetic) neuropathy and incompressible arteries are amongst the many other deleterious effects of diabetes on the cardiovascular system and (directly or indirectly) PAD. Lifetime prevalence of diabetic (poly)neuropathy is in the area of 50 % and associated pain and discomfort can easily be mistaken for intermittent claudication caused by peripheral neuropathy, which is also common in patients with PAD [4, 13-15].

Diabetic neuropathy is likewise associated with medial arterial calcification (incompressible arteries), which is also a predictor of total, cardiovascular, coronary artery disease (CAD) mortality and future CAD events, amputation and strokes [16, 17]. From the perspective of PAD incompressible arteries preclude the use of an ABI assessment, which returns abnormally high scores (generally in the ≥1.30 range) and renders this diagnostic method unusable for diagnosing PAD (though, it has certain limited diagnostic value) [18, 19]. The only other (cost and otherwise comparable) option is the use of Toe-Brachial Index (TBI) assessment since the toe arteries are rarely affected by calcification [20].

Incompressible arteries can likewise be found in those with CKD (in addition to those with rheumatoid arthritis) [21]. This brings us to the last reason for an in-depth overview of the interaction between diabetes, CKD and PAD: the contribution of diabetes to the development of CKD and End-Stage Renal Disease (ESRD)/End-Stage Kidney Disease (ESKD). Diabetic Kidney Disease (DKD) develops in about 40 % of patients and is the leading cause of CKD worldwide and a significant contributor to a higher risk of all-cause and cardiovascular mortality in diabetics [22, 23]. More specifically those with PAD and renal insufficiency are more likely to require distal procedures and present with limb-threatening infections than those without renal issues [24, 25]. On top of this patients with renal insufficiency and PAD (an estimated 24 % of them) have far higher mortality rates than those with either or no disease [26, 27].

What should a nephrologist ask every patient?

Screening of patients with CKD for PAD is mandatory, or at least should be given the overwhelming prevalence of various comorbidities, many of which have been recognised as risk factors for the development of PAD. This is most easily done through an ABI assessment, in particular if performed using an oscillometric-plethysmographic diagnostic device, which is a superior method (faster procedure and user-error free) in comparison to the Doppler probe/sphygmomanometer combination [28-30]. But, as previously mentioned, this may not be suitable for those with incompressible arteries, requiring the substitution of ABI for the TBI assessment, which is particularly suitable for patients with excruciating pain in the lower-extremities due to ulcers or other causes (CKD is a risk factor for development of foot ulcers in diabetics) [31-33].

Despite the low cost of acquisition and use (in comparison with for example angiography) and the clinically proven usefulness of their utilisation, these modern diagnostic tools are often absent in places where they are needed most. Physical examination is one alternative, but this is notoriously unreliable, even if performed by a skilled examiner [34]. A more valuable tool is a comprehensive questionnaire that touches upon known risk factors for PAD with addition of those specific to patients with CKD. One such questionnaire is presented below.

List of questions for assessing the relative risk of PAD in patients with CKD:

1. Age. How old is the patient in question?

Older patients (generally over 50 years of age) are at an increased risk of PAD, which might be asymptomatic [35].

2. Ethnicity. In most cases self-evident.

There are statistically significant discrepancies in PAD prevalence and morbidity in individuals from different ethnic groups. Studies have shown that blacks (specifically African Americans) are at a higher risk of developing PAD than whites [36].

3. Gender. Self-evident as well.

Some studies have indicated a greater prevalence of PAD (particularly more severe forms) in women rather than men [37].

4. Tobacco smoking. Does the patient smoke (current smoker) and how much or did s/he ever smoke (is a former smoker)?

Current smokers have a far greater risk of developing PAD [38]. Association between tobacco smoking and PAD is especially strong in female smokers who are at an up to 20-times greater risk for the disease than females who have never smoked [39]. Information about past smoking (former smokers) is also important: the health benefits of smoking cessation don’t translate well to PAD as even former smokers are at an increased risk with up to 2.6-times greater prevalence of PAD (in comparison with non-smokers) [40].

5. Diabetes. Does the patient have type 1 or 2 diabetes mellitus?

Diabetes-induced hyperglycaemia greatly increases the incidence and prevalence of PAD [4].

6. Previous diagnosis of Coronary Artery Disease (CAD). Does the patient have CAD?

Already present (diagnosed) CAD is indicative of possible atherosclerosis in other vascular beds – prevalence rates of PAD in CAD patients range from 22 % to 42 % [41-43].

7. History of Myocardial Infarction (MI), strokes or Transient Ischemic Attacks (TIA). Was the patient diagnosed with MI, a stroke or TIA?

History of MI and cerebrovascular events is associated with higher prevalence rates of PAD, often in its asymptomatic form (diagnosis on basis of the ABI score) [44-46].

8. Diagnosis of Chronic Kidney Disease (CKD). Was the patient diagnosed with CKD or renal insufficiency in general (self-evident if the nephrologist is already treating such a patient)?

Individuals with renal insufficiency are 9-times more likely to have an abnormal (defined as ABI <0.9) ABI score (indication of PAD) [47].

9. Diagnosis of rheumatoid arthritis. Was the patient diagnosed with rheumatoid arthritis?

Patients with rheumatoid arthritis are more likely to have incompressible arteries, precluding the use of some diagnostic methods for PAD [21].

10. Diagnosis of incompressible arteries. Does the patient have incompressible arteries (this is not really a question for the patient, as incompressible arteries are rarely diagnosed on their own and it is unlikely s/he would have this information, but up to the physician (nephrologist) to determine)?

Incompressible arteries are quite likely in those who have answered the 5th, 8th and 9th question with YES – a warning sign for the examiner that diagnostic methods other than ABI (i.e. TBI) will have to be used.

11. Diagnosis of chronic obstructive pulmonary disease (COPD). Was the patient diagnosed with COPD?

Patients with COPD are at double the risk of developing PAD [48].

12. Hyperlipidaemia. Does the patient suffer from abnormally elevated levels of lipids (lipoproteins)?

Abnormal levels of blood lipids and lipoproteins is associated with mild risk for development of large-vessel PAD [49].

13. Hypertension. Is the patient hypertensive or is receiving treatment for hypertension?

Hypertension is a known risk factor for PAD (and other CVDs) [50].

14. Weight. Is the patient over or underweight for her/his height and sex?

Weight is a risk factor for PAD (and many other medical conditions) as studies have shown that older individuals with greater BMI (body mass index) have a higher incidence of PAD [51].

15. Intermittent claudication. Does the patient report pain during any sort of physical exercise, even walking? Does the pain subside when s/he takes a rest? Where (part of the leg) is the pain located?

Accurately diagnosing intermittent claudication on the basis of physical sensations the patient feels during physical exertion and when still/resting is best done using the Edinburgh Claudication Questionnaire [52].

16. Cold feet/legs. Does the patient report cold feeling in his leg(s) or feet despite feeling otherwise (in other parts of the body) warm or otherwise comfortable at the current ambient temperature?

Reduced blood flow leads to disruption of normal thermoregulation.

17. Scaly skin/of pale or blueish hue/deformed toenails. Does the patient have abnormal skin texture and colour and/or suffers from deformed toenails?

Occlusion in the arteries of lower extremities reduces flow of nutrients to skin and toenails, leading to stunted growth and deformations. Possible pallor in the affected leg when it is in an elevated position [53].

18. Open wounds and sores. Does the patient have any types of wounds or other tissue damage on her/his legs/feet that heals very slowly or doesn’t appear to heal at all or had ulcers that already healed?

Another tell-tale sign of PAD, but one that is typical for advanced form of the disease are open sores/wounds – arterial insufficiency ulcers (ischemic ulcers), usually on patient’s feet. They can be similar to venous ulcers, which have significantly different underlying pathophysiology and treatment regime, necessitating the use of modern diagnostic methods to differentiate between them (ABI or TBI) [54].

19. Erectile dysfunction (men). Does the patient suffer from erectile dysfunction?

Diagnosis of erectile dysfunction carries a two-fold increase in the likelihood of PAD [55].

20. Family history. Does the patient have any relatives that have or have had PAD?

Patients with a family history of PAD are at twice the risk of the disease than those without such familial medical history [56].

A comprehensive questionnaire tailored for a nephrologist for the preventive screening of patients with CKD for PAD is a valuable tool, but should not be used in lieu of modern diagnostic methods. Any suspicion of possible PAD derived from a patient’s answers to the questionnaire should be followed-up by an ABI or TBI assessment.


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