Peripheral arterial disease is common among diabetic patients with renal insufficiency, and most of the diabetic patients with end-stage renal disease (ESRD) have peripheral arterial disease. Ischaemia is probably overrepresented as an etiological factor for a diabetic foot ulcer in this group of patients compared with other diabetic patients. ESRD is a strong risk factor for both ulceration and amputation in diabetic patients. It increases the risk of nonhealing of ulcers and major amputation with an OR of 2.5–3.
Diabetes and renal disease are independent risk factors for peripheral arterial disease (PAD) . In particular, the prevalence of PAD among patients with end-stage renal disease (ESRD) has been reported in up to 77% of patients . Although the definition of ESRD is not consistent throughout different studies, it is mostly regarded as the dependency on dialysis or previous kidney transplantation. In turn, ESRD is, per se, a strong risk factor for both foot ulceration and amputation in patients with diabetes [3-5].
Renal failure has been reported to independently predict nonhealing of ischaemic and neuroischaemic foot lesions and major amputations [6, 7]. Indeed, there is a clear temporal association between the incidence of foot ulceration as well as of major amputation and the worsening of kidney function to a level necessitating dialysis . Primary amputation rates of 22% to 44% have been reported for ischaemic foot lesions in ESRD patients .
These patients are difficult to treat, and long-term mortality is high and might negatively affect the decision to perform a revascularization procedure. The aim of this review was to evaluate how the combination of PAD and renal insufficiency affects vascular assessment, treatment, and the outcome of diabetic patients with ulcerated foot.
The outcome data on individuals with diabetic foot ulcers and critical leg ischaemia (CLI) or impaired perfusion are scarce, and even more so, in the presence of renal insufficiency. In a study by Gershater et al.  on 1007 diabetic patients with ischaemic or neuroischaemic foot ulcers, 36% of these ulcers healed primarily. These authors observed that uraemia had a negative effect on ulcer healing because nonuraemic patients had an OR of 2.45 (95% CI, 1.35–4.46) for primary healing of the ulcer . ESRD has been observed to worsen the healing of ischaemic or neuroischaemic ulcers (OR, 3.04; 95% CI, 1.38–6.7, p = 0.006) . Accordingly, ESRD seems to have a stronger negative effect in diabetic patients with PAD than in those without  likely because of the severity of PAD with accompanying diffuse arterial medial calcification in patients with ESRD.
The healing of minor amputations is not always predictable. Transmetatarsal amputation is often a durable solution when tissue loss or infection involves more than one digit and extends onto the dorsum of the foot, but plantar tissue is spared. The influence of ESRD is illustrated in a small study by Toursarkissian et al. , including 44 ischaemic feet, 33 of which were revascularized. Three of four dialysis patients but only 11 of 40 nondialysis patients needed subsequent major amputations because of nonhealing of the metatarsal stump.
Major amputations and limb salvage
The severity of ischaemia, peripheral oedema, rest pain, and proteinuria were found to be the most important risk factors for amputation in diabetic patients with ulcerated ischaemic foot . Recently, the role of kidney disease has been emphasized with special attention to its severity [11, 12]. Indeed, in patients with uraemia and ischaemic or neuroischaemic diabetic foot ulcers, the OR for major amputation was 2.43 (95% CI, 1.33–4.45) in all surviving patients when nonuraemia was used as the reference . The role of revascularizations was not analysed in this context, although vascular intervention was reported to be performed at the discretion of a vascular surgeon according to a jointly accepted programme . Primary major amputations of legs of diabetic patients with ESRD are connected to 17–20% perioperative death rate [13, 14].
Revascularization of ulcerated foot in diabetic patients with renal insufficiency
Lower extremity revascularization in this patient group is challenging because of susceptibility to infection, poor wound healing, and high risk of amputation. High perioperative mortality rates (3–17%) and low 3-year leg salvage (40–76%) and survival (0–45%) have been reported as well [15-17]. Apparently, patient selection is crucial because choosing the right treatment for the right patient in this multimorbid group of patients is problematic.
Imaging for CLI in diabetic patients with renal insufficiency
Anatomic imaging is mostly strategic, not diagnostic, because it is primarily performed once a clinical decision to intervene has been made . Imaging is of key importance in the decision of how to treat the arterial lesions. It may be carried out by colour Duplex ultrasound, contrast-enhanced magnetic resonance angiography, multidetector-row computed tomography, or intra-arterial digital subtraction angiography (DSA).
In diabetic patients, the aortoiliac arteries, common femoral artery, or even superficial femoral artery may be unaffected, and occlusive lesions are concentrated to the distal parts of lower limb arterial tree [19, 20]. Extensive calcification of infrapopliteal arterial tree may prevent proper duplex diagnostics and computed tomography angiography (CTA), although the use of multisliced devices decreases interpretation difficulties caused by arterial wall calcifications [21-24]. The problem with CTA is that it requires the highest volume of contrast media. Magnetic resonance angiography may have limited spatial resolution, and its images may be distorted by previous stents, implants, and flow disturbances. Yet, any of these techniques are useful for mere imaging because the accuracy of different techniques in diagnosing stenosis of >50% in the infrapopliteal segment is acceptable and similar to DSA .
Chronic renal insufficiency is increasingly common in diabetic patients with foot ulcers. This may influence the choice of imaging method, because iodinated contrast media are nephrotoxic agents and may be associated with an increased risk of contrast-induced nephropathy. Diabetic patients with baseline renal insufficiency are at highest risk. In the case of mild chronic renal failure, regular DSA and CTA can be performed, but intravenous hydration of the patient is recommended before and after the examination [18, 25]. Otherwise, contrast media should be avoided or at least diluted with saline, and half-and-half concentration, for instance, gives images of acceptable quality. If traditional DSA is contraindicated, arterial tree can be evaluated by duplex ultrasound imaging alone or as an adjunct to contrast angiography, which can be limited to the stenosed arterial segments identified by duplex. The endovascular procedure, if further needed, can be implemented using CO2 angiography, with or without a small amount of diluted nonionic iso-osmolar contrast media, focused on the target lesion .
The use of paramagnetic contrast agent gadolinium has been reported to cause nephrogenic systemic fibrosis in patients with renal disease [26-28]. Patients at greatest risk of developing nephrogenic systemic fibrosis after receiving gadolium-based contrast agents are those with impaired elimination of the drug, including patients with acute kidney injury or severe chronic kidney disease corresponding to the chronic kidney disease (CKD) class 4–5 (estimated glomerular filtration rate <30 mL/min per 1.73 m2). Three of the products, including gadopentetate dimeglumine, gadodiamide, or gadoversetamide, are contraindicated in these patients . Some suggest almost total abandonment of gadolinium as contrast agents for vascular imaging . Others are willing to compare benefits against risks and consider the use of FDA-accepted products even in patients with severe kidney disease if the need for diagnostic information is essential and not available by alternative imaging modalities . Intravenous single dose is recommended and repeat administration forbidden during a single imaging session  to minimize the risk.
Metformin has been considered to increase the risk of lactic acidosis and deterioration of the kidney function. Approximately 90% of metformin is eliminated via the kidneys in 24 h. Therefore, metformin has traditionally been stopped 48 h before angiography or general anaesthesia. Renal insufficiency (estimated glomerular filtration rate <70 mL/min per 1.73 m2 or serum creatinine >140 µmol/L) results in tissue retention of biguanides with potential for development of fatal lactic acidosis. Therefore, metformin is contraindicated in patients with chronic renal failure . The use of contrast media in patients receiving metformin should be carried out with care. Contrast media can induce a reduction in renal function, which occurs after the contrast medium has reached the kidney, leading to retention of metformin that may induce acidosis, typically in non-insulin-dependent diabetic patients with abnormal kidney function. If serum creatinine is normal, the radiological examination can be performed and intake of metformin stopped from the time of the study. Metformin should not be resumed for 48 h and should only be restarted if renal function/serum creatinine is normal . If renal function is abnormal and alternative imaging techniques are not feasible, metformin should be stopped and contrast study delayed for 48 h, and it should be restarted 48 h after the procedure if renal function is unchanged. In emergency situations, when urgent examination is necessary, metformin can be stopped at the time of study. Patients with abnormal renal function should be hydrated before and after angiography [25, 30].
Perioperative outcome after vascular intervention
High incidence of perioperative complications is a characteristic of vascular interventions for these patients, the majority of them being cardiac, septic, or local infections. The reported perioperative mortality rates range from 2.4% to 13% after bypass surgery. Myocardial infarction is the most important cause of death [12-14, 31-34]. As to the severity of renal insufficiency, CKD classes 4 and 5, that is, with estimated glomerular filtration rate <30 mL/min per 1.73 m2, had a significantly higher perioperative (30-day) risk of myocardial infarction or death than those in CKD classes 1 to 3 (16.4% versus 5.4%; OR, 2.72; 95% CI, 1.27–5.83, p = 0.01) in a mixed group of patients .
Ulcer healing after revascularization
Despite acceptable patency, diabetic foot ulcers heal poorly because of a number of conditions often connected to ESRD, such as anaemia, malnutrition, depressed immune defence, and a deficient collagen content in granulation tissue . Data on ulcer healing in ESRD patients with ulcerated ischaemic diabetic foot are scarce.
Leg salvage after revascularization
Pooled estimates of outcome of infrainguinal revascularizations for CLI in patients with ESRD have been summarized in a meta-analysis of eight studies (1987–2000), including 288 patients, 73% of whom having diabetes and 80% presenting with a foot ulcer . Pooled leg salvage was 77% (95% CI, 69–84%) at 1 year and 73% (95% CI, 64–81%) at 2 years, with corresponding pooled graft patency of 79% (95% CI, 70–87%) at 1 year and 74% (95% CI, 63–85%) . Acceptable limb salvage was reported to be achievable also by endovascular revascularization in diabetic patients with CLI and ESRD, although no cumulative leg salvage was reported . Recently, in a large systematic review on revascularizations for ulcerated diabetic foot in patients with ESRD, six acceptable studies (1995–2009) were identified . All 391 openly revascularized patients had ESRD, whereas only 45% had ESRD and 75% had renal insufficiency in the only endovascular series included . All in all, 89% had diabetes and 87% had ulcers, and most of the patients were treated with infrainguinal revascularization [12, 31-34, 36]. One-year limb salvage rates were 70% (interquartile range, 65–75%) among the operative survivors. Remarkably, 26–59% of the major amputations were performed with open graft [12, 31-33]. Persistent ischaemia, extension of gangrene, uncontrolled infection, and, particularly, involvement of the heel or forefoot were major causes of limb loss [31, 32]. Low ejection fraction, gangrene, and poor run-off were associated with increased risk of major amputation .
Another way to try to look at the predictors of amputation after revascularization was to count the overall incidence of subsequent amputations per 100 person years, which was performed in a longitudinal cohort study of hemodialysis patients enrolled in special studies of the United States Renal Data System, identifying 800 patients undergoing their first lower extremity revascularization . Patients with diabetes had higher risk of amputation than patients without diabetes after revascularization, and bypass surgery carried higher risk of amputation than endovascular approach, which was interpreted to probably reflect the underlying severity of PAD . In the large study by Faglia et al. , patients in dialysis had an HR of 4.7 (95% CI, 1.9–11.7) for major amputation. This mixed series included 564 consecutive diabetic patients with foot ulcers, 539 having been revascularized and all analysed together as to the role of dialysis. Of note is that unsuitability for revascularization, per se, carried an HR of 3.06 (95% CI, 1.4–6.7) for major amputation .
In a recent study, we aimed to stratify the risk of diabetic patients with an ischaemic ulcerated diabetic foot undergoing infrainguinal revascularization for limb salvage . The study cohort included 732 revascularization procedures performed in 597 diabetic patients. Logistic regression and classification and regression tree analysis were used for identification of predictors of 1-year outcome. CKD classes were independent predictors of 1-year leg salvage (OR, 1.38; 95% CI, 1.16–1.65) and 1-year amputation-free survival (OR, 1.43; 95% CI, 1.24–1.65) (Figures 1 and 2). Indeed, the initial risk stratification by classification and regression tree analysis identified high CKD classes (classes 4–5 for 1-year leg salvage and classes 3–5 for 1-year amputation-free survival) as the most powerful predictor of poor intermediate outcome. Accordingly, in the study by Owens et al. , CKD staging adequately differentiated the survival and risk of major amputation among patients with renal insufficiency who were undergoing bypass surgery, although these data came from a mixed series, in which only patients in the CKD 4 and 5 categories predominantly had diabetes and had foot ulcers.
Poor longevity is a characteristic of patients with ischaemic diabetic ulcers in ESRD patients, despite the acceptable 30-day mortality of 4.6% after revascularization . One-year mortality was 38% according to the systematic review by Hinchliffe et al. . Long-term outcomes were also poor because the reported mortalities at 2 years were 48–72% [31, 32]; at 3 years, 56% ; and at 5 years, 91% .
In a series of 564 diabetic patients with foot ulcers, Faglia et al.  observed that ESRD was an important risk factor for mortality (HR, 3.00; 95% CI, 1.63–5.53). Similarly, Abularrage et al.  showed, in a large study of 533 diabetic patients undergoing infrainguinal endovascular intervention for mixed indications, that CLI (HR, 2.99; 95% CI, 2.01–4.44) and dialysis (HR, 4.24; 95% CI, 2.8–6.45) were associated with poorer long-term survival.
Composite end points
Taylor et al.  studied the risk of not achieving clinical success, defined as reconstruction patency until wound healing, limb salvage for 1 year, maintenance of ambulation for 1 year, and survival for 6 months. They found that impaired ambulation status, gangrene, and ESRD, together with prior vascular surgery, were connected to 93% (OR, 23.7) probability of failure. It is clear that the more risk factors there are for a poor outcome, the more likely primary amputation becomes the treatment option of choice.
ESRD is a strong risk factor for both foot ulceration and amputation in diabetic patients. Lower limb revascularization in these high-risk patients can be difficult and frustrated by poor immediate and intermediate results. However, revascularization may be beneficial in selected patients. Extensive infection, forefoot and especially heel ulcers, poor run-off, and poor ejection fraction are risk factors for major amputation. Indeed, almost half of these amputations are made with open bypass graft, which emphasize the special requirements for perfusion as well as control of infection and tissue damage. Early referral of patients with a diabetic foot ulcer and ESRD to vascular consultation is necessary to decrease amputations. Although there is no evidence to support endovascular treatment instead of open bypass in these high-risk patients, the endovascular revascularizations appears attractive as a first-line treatment approach provided that proper flow to the ulcer area can be achieved.