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Lower extremity peripheral artery disease in patients with chronic kidney disease

Lower extremity peripheral artery disease in patients with chronic kidney disease
Author:
Jeffrey S Berger, MD, MS, FAHA, FACC
Section Editors:
Joseph L Mills, Sr, MD
John F Eidt, MD
Deputy Editor:
Kathryn A Collins, MD, PhD, FACS
Literature review current through: Nov 2022. | This topic last updated: Mar 23, 2021.

INTRODUCTION — Chronic kidney disease (CKD), which refers to individuals with decreased kidney function for three or more months, is an independent risk factor for the development of generalized atherosclerosis and peripheral artery disease (PAD).

Most patients with CKD have only moderate reductions in estimated glomerular filtration rate (eGFR). These patients generally have a higher risk of morbidity and death related to cardiovascular disease than of eventually requiring renal replacement therapy. In patients with PAD, CKD is associated with a worse prognosis compared with patients without CKD [1-4]. Outcomes for such events are even worse for CKD patients who have progressed to requiring dialysis [5-16].

The epidemiology and outcomes of treatment of PAD relevant to individuals with CKD will be reviewed. More detailed management recommendations for PAD in the general population are presented separately. (See "Overview of lower extremity peripheral artery disease" and "Management of claudication due to peripheral artery disease" and "Management of chronic limb-threatening ischemia".)

EPIDEMIOLOGY AND RISK FACTORS — Many guidelines do not specifically identify CKD as a risk factor for PAD [17-20]. Older epidemiologic studies of cardiovascular disease did not report subgroup analyses among patients with CKD [21-30]. However, an association between PAD and CKD is being recognized and reported with increasing frequency. While an increased risk has generally been recognized for patients with severely reduced renal function (table 1), a growing number of studies have suggested an increased risk for even mild to moderately reduced renal function. CKD is considered a coronary heart disease risk equivalent. (See "Overview of established risk factors for cardiovascular disease", section on 'Chronic kidney disease' and "Chronic kidney disease and coronary heart disease".)

PAD appears to be more prevalent among patients with CKD than in the general population. To some extent, this may reflect older age and higher prevalence of known risk factors for PAD among those with CKD. (See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease".)

However, even after adjustment for potential confounders, CKD is independently associated with an increased prevalence of PAD, and with the future risk for developing clinically significant PAD [31-33]. There is a higher prevalence of abnormal ankle-brachial index (ABI; ≤0.9, >1.3) among patients with a low estimated glomerular filtration rate (eGFR) and in those with albuminuria [34-41]. The highest prevalence of PAD is among those with both a low eGFR and albuminuria [34-41]. However, it is unclear from the existing literature to what extent these associations differ in patients with and without coexistent diabetes.

The prevalence of PAD among patients on dialysis ranges from 15 to 25 percent [42-46]. Estimates vary in part according to the specific population studied. The diagnosis of PAD in many of the studies is made by chart review or patient questionnaire rather than by diagnostic testing. Therefore, these data probably underestimate the true prevalence of PAD in dialysis patients. A few small studies have measured prevalence in patients using the ABI. The prevalence of abnormal ABI measurements ranged from 4 to 38 percent depending upon the population studied [13,31,34,35,47-51]. Higher estimates are obtained when measures of toe (rather than lower leg) perfusion are used [48]. The prevalence of PAD appears to be particularly high in older dialysis populations. As an example, the North Thames Dialysis study of patients over the age of 70 reported PAD prevalences of 28 and 46 percent among chronic dialysis patients and incident patients, respectively [52].

Even mild-to-moderate chronic kidney disease increases the risk of incident PAD, with a strong association between albuminuria and amputation. In a large review of over 800,000 individuals in the Chronic Kidney Disease Prognosis Consortium without a known history of PAD, 18,261/817,084 cases of incident PAD were recorded during a median follow-up of 7.4 years [53].

Using a baseline eGFR of 95 mL/min per 1.73 m2, the risk of incident PAD was:

●For eGFR of 45 mL/min per 1.73 m2, hazard ratio (HR) 1.22 (95% CI 1.14-1.30)

●For eGFR of 15 mL/min per 1.73 m2, HR 2.06 (95% CI 1.70-2.48)

Using a baseline albumin-to-creatinine ratio (ACR) of 5 mg/g, the risk of incident PAD was:

●For ACR of 30 mg/g, HR 1.50 (95% CI 1.41-1.59)

●For ACR of 300 mg/g, HR 2.28 (95% CI 2.12-2.44)

Patients with ESRD are at increased risk for vascular calcification, which independently increases the risk of cardiovascular morbidity and mortality [54,55]. Calcification is an active cell-mediated process involving key regulatory proteins typically involved in bone formation and structure that become expressed in arterial tissue and lead to ossification of the vasculature. (See "Vascular calcification in chronic kidney disease".)

Symptomatic PAD — Patients with CKD have an increased risk of developing symptomatic PAD even after adjustment for other known risk factors, such as older age and diabetes. Furthermore, PAD and CKD appear to have a synergistic effect on mortality [56].

In the general adult population, the reported prevalence of intermittent claudication is 1 to 5 percent [27,28,57-63]. In the Cardiovascular Health Study, compared with normal kidney function, individuals with CKD at baseline had a higher incidence of intermittent claudication after a median follow-up of 7.3 years (10.6/1000 versus 3.5/1000 patient-years) [21]. In a study from Finland, the prevalences of PAD among predialysis and dialysis patients based upon ABI measurements were 22 and 31 percent, respectively [34].

CKD may also be a risk factor for the development of chronic limb-threatening ischemia. In the Heart and Estrogen/Progestin Replacement Study (HERS), incident lower extremity PAD event rates (revascularization, amputation, or lower extremity sympathectomy) among women with creatinine clearances 30 to 59 and <30 mL/min per 1.73 m2 were higher at 0.9 and 2.7 percent per year, respectively, compared with 0.6 percent per year among women with normal kidney function [32].

Risk factors — Risk factors for PAD among those with CKD are similar to the general population and include smoking, hypertension, and diabetes [45,46,64-68]. (See "Epidemiology, risk factors, and natural history of lower extremity peripheral artery disease".)

Among dialysis patients, some traditional risk factors do not appear to be as important. In the HEMO study, hypercholesterolemia, male sex, and hypertension did not correlate with PAD in chronic hemodialysis patients [68]. Similarly, in the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS), high serum cholesterol and triglycerides were also not significantly associated [45].

Some studies have reported associations supporting a role for nontraditional risk factors (eg, hyperphosphatemia, hyperparathyroidism) in the development of PAD in dialysis patients [45,69,70]. Soft tissue and vascular calcification is reportedly associated with hyperphosphatemia, use of calcium-containing binders, hypervitaminosis D, and dialysis vintage. However, the nature of the relationship between PAD and such vascular calcification has not been clearly established.

Patients receiving peritoneal dialysis may have a lower risk of developing PAD compared with those receiving hemodialysis (12.4 versus 20.7 per 1000 person-years) in one Taiwanese study [71].

CLINICAL PRESENTATION AND DIAGNOSIS — The clinical manifestations of PAD are largely similar in patients with and without CKD. (See "Clinical features and diagnosis of lower extremity peripheral artery disease".)

However, CKD patients are more likely to present with chronic limb-threatening ischemia due to more diffuse and distal disease compared with those who have normal renal function, possibly reflecting the high prevalence of coexistent diabetes in this population [72]. In a study of 5787 male veterans with chronic limb-threatening ischemia, patients with CKD had more severe disease at presentation [73]. Among those with an estimated glomerular filtration rate (eGFR) 30 to 59 and <30 mL/min per 1.73 m2, more patients presented with ischemic ulceration or gangrene rather than rest pain compared with those with eGFR ≥60 mL/min per 1.73 m2 (77 and 87 percent, respectively, versus 70 percent).

One clinical presentation of PAD that is unique to dialysis patients is the interaction between PAD and the hemodialysis access. While lower extremity dialysis access is overall uncommon, clinical manifestations of preexisting PAD may worsen after creation of permanent hemodialysis access in the lower extremity [74,75]. (See "Hemodialysis access-induced distal ischemia".)

Diagnosis — Although ankle-brachial index (ABI) is a relatively simple and inexpensive method to confirm the clinical suspicion of arterial occlusive disease, reduced ABI may be less reliable in identifying PAD among patients with CKD. Many of these patients have falsely elevated ABIs due to arterial incompressibility from medial arterial calcification, which may contribute to underestimation of PAD prevalence in CKD patients. In one Finnish study, the prevalence of medial arterial calcification was 24 and 42 percent for patients with predialysis and hemodialysis patients, respectively [34]. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'High ABI'.)

If the ABI is elevated (>1.3), the toe systolic pressure and waveform and the toe-brachial index (TBI) can be used instead to assess the level and severity of PAD and potential for wound healing in those with chronic limb-threatening ischemia. (See "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Pulse volume recordings' and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Toe-brachial index'.)

Vascular imaging is generally necessary for patients with indications for lower extremity revascularization. The risk of nephrotoxicity related to iodinated radiocontrast administration (computed tomographic [CT] angiography, catheter-based digital subtraction angiography) must be carefully weighed against the benefits of this procedure among patients with CKD. A duplex ultrasound study may be a helpful preliminary study to identify potential arterial lesions. If revascularization is indicated, imaging and intervention can be planned simultaneously to minimize the dose of radiocontrast to be administered. In addition, selective arteriography or carbon dioxide arteriography can help to minimize the dose of contrast and lower the risk of nephrotoxicity. For patients with distal disease, an antegrade study from the groin selectively imaging the tibial and more distal arteries may provide the necessary information while minimizing contrast exposure. Measures to limit contrast nephropathy when it is necessary to administer it are reviewed separately. (See "Prevention of contrast-associated acute kidney injury related to angiography".)

Magnetic resonance (MR) angiography is also accurate for imaging the lower extremity vasculature and can be performed without contrast or with a gadolinium-based contrast agent [76]. For patients with only modest reductions in eGFR, MR angiography with gadolinium will often provide high-quality digital images that can be used to plan revascularization procedures. However, among patients with eGFR <30 mL/min or who are dialysis dependent, administration of gadolinium has been associated with the potentially severe syndrome of nephrogenic systemic fibrosis. In such patients, gadolinium-based imaging should be avoided if possible. There is no consensus among experts concerning the decision to administer gadolinium among patients with an eGFR between 30 and 60 mL/min. These issues are discussed separately. (See "Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy in advanced kidney disease".)

MEDICAL RISK AND MANAGEMENT — The general medical management of symptomatic PAD primarily consists of risk factor reduction and exercise rehabilitation, with a possible role for medical therapy aimed at diminishing claudication symptoms. Although traditional risk factors for cardiovascular disease are highly prevalent in individuals with CKD, these patients were often excluded from studies targeting modification of these risks. Few studies have specifically evaluated the impact of medical treatment on PAD outcomes in those with CKD, such as symptom relief or the subsequent need for procedures such as revascularization and amputation [2]. In the absence of better data, recommendations for medical management of PAD are extrapolated from the general population. A full discussion of accepted and investigational therapies for symptomatic PAD is presented elsewhere. (See "Overview of lower extremity peripheral artery disease" and "Management of claudication due to peripheral artery disease" and "Investigational therapies for treating symptoms of lower extremity peripheral artery disease".)

Impact of CKD on outcomes — Patients with peripheral artery disease (PAD) are at increased risk for adverse cardiovascular events (eg, myocardial infarction, stroke).

Among patients with PAD, the prognosis is worse for patients with CKD compared to those without CKD [1-4]. Outcomes are even worse for CKD patients who have progressed to requiring dialysis [5-16]. In a post hoc analysis of the EUCLID trial, the incidence of cardiovascular and limb events in patients with PAD and CKD (eGFR <60 mL/min/1.73 m2) were compared to those without CKD [77]. In a cohort of 13,483 PAD patients, 3332 (25 percent) had CKD. After a median follow-up of 30 months, patients with CKD had a higher rate of cardiovascular death, myocardial infarction, and ischemic stroke, but the incidence of acute limb ischemia and major amputation was similar for those with and without CKD.

Risk factor reduction — PAD is a marker for more generalized atherosclerosis and is considered a coronary heart disease risk equivalent. CKD is also a coronary heart disease risk equivalent. As a result, aggressive risk factor reduction is recommended for secondary prevention [78]. (See "Chronic kidney disease and coronary heart disease".)

The effects of risk reduction strategies in patients with PAD and CKD, where available, are summarized below.

Smoking cessation — Smoking is associated with an increased risk of death and worse vascular outcomes. Thus, smoking cessation should be strongly encouraged in patients with CKD and PAD given their high risk for PAD events and for other cardiovascular events [2,79-83]. (See "Management of claudication due to peripheral artery disease", section on 'Smoking cessation' and "Overview of smoking cessation management in adults".)

In a systematic review and meta-analysis, the pooled risk for all-cause mortality in dialysis patients who were smokers compared with nonsmokers was significantly increased (hazard ratio [HR] 1.65, 95% CI 1.26-2.14) [83]. The risk for cardiovascular events was also increased (HR 1.01, 95% CI 0.98-1.05).

In a subgroup analysis of the Study of Heart Protection (SHARP) trial, 9270 participants with CKD were enrolled [82]. Vascular event rates were 36 percent higher for current compared with never smokers (relative risk [RR] 1.36, 95% CI 1.19-1.55). All-cause mortality was 48 percent higher among current smokers (RR 1.48, 95% CI 1.30-1.70), with significant increases in vascular (RR 1.35, 95% CI 1.07-1.69) and nonvascular (cancer, respiratory disease) (RR 1.60, 95% CI 1.34-1.91) causes of death.

Antiplatelet therapy — Large clinical trials in the general population have demonstrated that antiplatelet therapy (such as aspirin or clopidogrel) reduces the risk of cardiovascular events [18,84-88]. Based upon these data, antiplatelet therapy is recommended for patients with PAD to reduce the risk of overall cardiovascular events and death, unless contraindications exist.

The balance of benefit and harm associated with antiplatelet therapy is less certain in this population, given that the risk for bleeding is overall increased with antithrombotic therapies in patients with CKD, particularly dialysis patients. The Hypertension Optimal Treatment (HOT) study randomly assigned over 18,000 participants with diastolic hypertension, 3619 of whom had an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, to aspirin (75 mg) or placebo [88]. Major cardiovascular events were significantly reduced by 66 percent for patients with baseline eGFR <45 mL/min/1.73 m2 (HR 0.34, 95% CI 0.17-0.67), and overall mortality in this group was reduced by 49 percent (HR 0.51, 95% CI 0.027-0.94). However, the risk of bleeding was overall increased (HR 1.61, 95% CI 1.21-2.14), but nonsignificantly greater among those with a lower eGFR.

There is little information regarding the impact of antiplatelet agents on symptoms and other PAD outcomes such as lower extremity revascularization or amputation in patients with CKD.

Blood pressure control — Hypertension is a major risk factor for PAD. However, there are no data evaluating whether antihypertensive therapy alters the progression of PAD in patients with CKD. Nevertheless, hypertension should be controlled to reduce morbidity from cardiovascular, renovascular, and cerebrovascular disease and also to delay progression of CKD [89-92]. (See "Overview of hypertension in acute and chronic kidney disease" and "Antihypertensive therapy and progression of nondiabetic chronic kidney disease in adults".)

Lipid lowering — Cholesterol lowering with statins appears to reduce the overall frequency of cardiovascular events among high-risk individuals in the general population [93]. Thus, statin therapy is recommended for patients with CKD based on their elevated risk for cardiovascular related events and mortality [94]. (See "Chronic kidney disease and coronary heart disease", section on 'Statin therapy' and "Lipid management in patients with nondialysis chronic kidney disease".)

The Study of Heart Protection (SHARP) trial supports the efficacy of lipid-lowering therapy for reducing cardiovascular mortality and cardiovascular events in patients with CKD [95]. This trial randomly assigned 9270 patients with CKD aged 40 years and older to receive ezetimibe 10 mg plus simvastatin 20 mg, or placebo. The risk of major atherosclerotic events was significantly reduced in the treatment group (risk ratio [RR] 0.83, 95% CI 0.74-0.94) compared with placebo. The need for coronary revascularization was lower in the treatment compared with placebo group. While these data suggest that low-dose statin therapy and ezetimibe are effective in lowering the risk of atherosclerotic vascular events in patients with CKD, specific data for concomitant PAD and CKD are lacking.

Preventive care — Patients with CKD are at risk for impaired wound healing. (See "Risk factors for impaired wound healing and wound complications".)

Efforts should be made to improve access to effective preventive foot care and to identify those at greatest risk for limb loss who might benefit the most from these preventive efforts. In at least one study, a comprehensive program for diabetes care delivered in the dialysis unit that included preventive foot care and education was effective at lowering the incidence of PAD and amputation-related admissions in the treatment group [96].

TREATING CLAUDICATION

Exercise therapy — Exercise therapy, preferably a supervised walking program, is considered first-line therapy for improving intermittent claudication. The safety and efficacy of exercise therapy for PAD among patients with CKD has not been specifically investigated; however, exercise as a component of a healthy lifestyle is advocated [97]. (See "Management of claudication due to peripheral artery disease", section on 'Exercise therapy'.)

Cilostazol — Cilostazol, a phosphodiesterase inhibitor that has both antiplatelet and vasodilating properties, may be indicated for improving intermittent claudication. Cilostazol increases pain-free and maximal walking distance among persons with claudication [98-100]. Patients with CKD were not explicitly excluded from these trials, but no subgroup analyses have been reported. (See "Management of claudication due to peripheral artery disease", section on 'Cilostazol'.)

No dosing adjustment is necessary for adults with renal impairment, though metabolite concentrations may be increased. Cilostazol is not appreciably removed by dialysis, and while there is no dosage adjustment for those on dialysis provided for by the manufacturer, a lower trial dose (eg, 50 mg twice daily) may be prudent [4]. The dose can then be adjusted upward as tolerated.

Indications for revascularization — The indications for revascularization (percutaneous, surgical) for intermittent claudication are no different for patients with CKD than for the general population. (See "Approach to revascularization for claudication due to peripheral artery disease", section on 'Clinical criteria for revascularization'.)

Revascularization is only considered for patients with severe lifestyle-limiting symptoms that are refractory to conservative management. The same considerations apply to patients with PAD and CKD [3]. Disease in CKD is likely to be more advanced, more distal in location, and associated with more calcified vessels, which reduces durability and may increase complication rates. Thus, intervention should only be used for severe symptoms with disease patterns that are likely to achieve reasonably successful outcomes.

Management decisions related to PAD should be individualized to reflect patient preferences and expected prognosis. An explicit discussion of goals of care and treatment priorities in these patients may help shape management decisions. However, endovascular revascularization is more likely to be selected in patients with CKD [1].

TREATING CHRONIC LIMB-THREATENING ISCHEMIA — As with any other patient with PAD, those with CKD who develop chronic limb-threatening ischemia (as manifested by rest pain, foot ulceration, or gangrene) should receive immediate evaluation and referral to a specialist (typically a vascular surgeon). (See "Management of chronic limb-threatening ischemia".)

It is valuable to identify patients who are not good candidates for limb salvage and who might be better served by conservative treatment options for ischemic ulceration or with primary amputation. The Society for Vascular Surgery Wound, Ischemia, foot Infection classification system (ie, WIfI) can be used to help identify such patients. Stage IV WIfI predicts a poor outcome for revascularization among those on hemodialysis [101,102]. (See 'Conservative management' below and 'Amputation' below and "Classification of acute and chronic lower extremity ischemia", section on 'WIfI (Wound, Ischemia, foot Infection)'.)

Compared with medical therapy alone, revascularization improves amputation-free survival in patients with CKD and chronic limb-threatening ischemia for all levels of renal impairment [37,103]. In the Veterans study, compared with revascularization, the risk for death was significantly increased for conservative management (odds ratio [OR] 1.6, 95% CI 1.3-1.9) and for amputation (OR 1.7, 95% CI 1.4-1.0) [37]. However, determining the best approach to the treatment of chronic limb-threatening ischemia remains problematic because some patients with CKD do poorly regardless of which treatment is selected, particularly those who are on hemodialysis [73,101,102,104-108]. In addition, both dialysis-dependent patients and those with milder forms of CKD are at greatly increased risk for postoperative cardiovascular complications after revascularization (open or endovascular) [109]. As examples:

●In a cohort of 1041 new dialysis patients followed over three years after dialysis initiation, those who underwent a procedure for PAD (including revascularization or amputation) were far more likely to experience a cardiovascular event (68 versus 30 percent), be hospitalized for infection (85 versus 66 percent), or die (81 versus 59 percent) [106]. Most deaths were not PAD related.

●In a retrospective review of 572 patients with CKD undergoing percutaneous peripheral intervention, cumulative mortality was 21 percent (mean follow-up 1135 days) and increased with increasing CKD stage (stage 2: 16 percent, stage 3: 29 percent, and stage 4 and 5: 47 percent (table 1)) [110].

●Among patients receiving dialysis, a large retrospective study of 9932 patients undergoing initial surgical revascularization reported an increased risk of limb loss during the year after revascularization, but not among other patients with CKD [107].

●In a review from the 2014 Nationwide Readmissions Database, the risk of clinical adverse events was greater in patients with CKD compared to those without including: cardiovascular events (5.2 versus 2.5 percent); lower extremity amputation (26.1 versus 12.2 percent); and bleeding (25.7 versus 14.8 percent) [1]. A significantly greater proportion of patients with CKD were rehospitalized within six months after revascularization (61.0 versus 43.6 percent), and patients with CKD were significantly more likely to be rehospitalized with major adverse limb events compared with those without CKD (21.1 versus 13.5 percent).

Thus, intervention is generally recommended only when the expected benefits exceed the risk. It is very important that management decisions related to PAD are individualized to reflect patient preferences and expected prognosis given the very limited life expectancy of many dialysis patients with PAD, particularly those with severe symptoms, and the absence of evidence to support any particular treatment strategy. An explicit discussion of goals of care in these patients can be very helpful in shaping management decisions.

Unfortunately, only about one half of patients with chronic limb-threatening ischemia are offered an opportunity for revascularization. In a study of veterans, men with chronic critical limb ischemia and CKD were even less likely to be offered revascularization compared to those without CKD [37]. However, this may be related to the severity of disease at presentation. In a large cohort study of 41,882 individuals admitted with PAD, the 8470 with CKD were more likely to have Rutherford categories 5 and 6 (table 2) [111]. Revascularization was attempted in significantly fewer individuals, and those with CKD had a nearly twofold higher amputation rate compared with non-CKD patients. CKD patients were also more likely to develop an infection, sepsis, myocardial infarction, or acute kidney injury during admission for PAD.

Conservative management — Some patients with CKD and nonhealing wounds or ulcers can be successfully treated with medical management and aggressive wound care rather than revascularization [112]. (See "Management of chronic limb-threatening ischemia", section on 'Counseling the high-risk patient'.)

An observational study reported outcomes of 49 patients assigned to receive conservative management, including 6 dialysis-dependent patients [112]. All patients had a nonhealing wound (ie, ulcer, gangrene, or a stagnant surgical wound) for at least six weeks, low ankle-brachial index, and a transcutaneous oxygen measurement ≥30 mmHg. Two thirds of the wounds healed with conservative management alone. Predictors of healing included mean ABI (0.62 versus 0.42) and ankle pressures >70 mmHg.

Other conservative therapies, as yet unproven, that are under study for patients with lower extremity PAD are reviewed elsewhere. (See "Investigational therapies for treating symptoms of lower extremity peripheral artery disease".)

Limb salvage — Revascularization (open surgical bypass or percutaneous angioplasty/stenting) is the treatment of choice for chronic limb-threatening ischemia. However, the management of chronic limb-threatening ischemia in patients with CKD, particularly those who are dialysis dependent, can be challenging. Most surgeons will offer revascularization to CKD patients with chronic limb-threatening ischemia when revascularization is technically feasible and the patient is reasonably medically fit to withstand the procedure and sufficiently active to benefit from revascularization. (See "Management of chronic limb-threatening ischemia".)

For most patients with CKD and PAD who have chronic limb-threatening ischemia, there are insufficient data to recommend one revascularization approach over another. Nonetheless, we prefer an angioplasty-first approach, particularly for severe renal disease, given the limited life expectancy and comorbidities. The use of endovascular techniques has increased overall and also among those with CKD. In a study using data from the Nationwide Inpatient Sample (NIS), among hemodialysis patients, the use of endovascular techniques nearly doubled over the study period [113]. Outcomes of revascularization are improved for endovascular compared with open surgical bypass, at least in the short term.

Patients with non-dialysis-dependent CKD have an increased risk for perioperative mortality after lower extremity revascularization, but limb salvage rates are not substantially different from the general population [107,109,114].

●In a cohort study of 9932 patients undergoing an initial surgical revascularization procedure, the rate of major amputation within one year of open surgical revascularization correlated with estimated glomerular filtration rate (eGFR), occurring in 10 percent of those with normal renal function, 11 percent of those with moderate CKD (eGFR 30 to 59 mL/min per 1.73 m2), 12 percent of those with severe CKD (eGFR <30 mL/min per 1.73 m2), and 29 percent of dialysis patients, respectively [107].

●In a study of 56 patients with serum creatinine concentration >2 mg/dL (177 micromol/L) who underwent 70 open surgical bypass procedures, the five-year cumulative limb salvage rate was 80 percent [114]. This was similar to expected outcomes among patients with normal kidney function at that institution.

Limb salvage and survival are all lower for those on dialysis [1,107,115-123]. The possibility of amputation in the presence of a patent bypass graft is a problem almost exclusively confined to patients with severe renal dysfunction or who are dialysis dependent, occurring in 10 percent of patients in one review [116]. Complication rates (infection, graft loss) are also generally higher for lower extremity bypass in those on dialysis.

●In a retrospective study using the United States Renal Data system database, the need for amputation was lower among dialysis patients who underwent angioplasty compared with bypass surgery (5.7/100 versus 22.6/100 person years), as was mortality [115].

●In a review of 1244 patients undergoing 1414 endovascular interventions for chronic limb-threatening ischemia, the risk of amputation at one year for dialysis compared with nondialysis patients was nearly threefold (hazard ratio 2.7; 95% CI 1.6-4.5) [117].

●In a meta-analysis of 28 studies involving dialysis-dependent patients undergoing infrainguinal bypass surgery, the pooled estimate for primary patency was 50 percent, which is lower compared with the general population [116]. Limb salvage and mortality at five years were 66 and 23 percent, respectively.

Amputation — Amputation is generally undertaken as a last resort when revascularization has failed, and in those who are not candidates for revascularization. Some authors have advocated primary amputation over revascularization in some patients with CKD, while others have argued that chronic limb-threatening ischemia should be managed no differently in this population compared with those with normal renal function [118,124]. (See "Lower extremity amputation".)

Dialysis patients have an extremely high rate of nontraumatic lower extremity amputation compared with the general population. One study reported crude amputation rates of 4.3/100 persons per year for all Medicare ESRD patients, with rates as high as 13.8/100 persons per year for diabetic ESRD patients [7]. The risk of amputation was increased for Black or Native Americans compared with White Americans, older patients, diabetes as the cause of renal failure (versus glomerulonephritis), male sex, and dialysis (versus transplant) status. Similar findings concerning risk factors for amputation were found in a second study [125]. Kidney transplantation has been associated with a significant reduction in mortality (56 percent reduction in one retrospective review [126]). (See "Kidney transplantation in adults: Patient survival after kidney transplantation".)

Those with CKD have an increased risk of death following amputation compared with the general population [15,109,127]. This was illustrated in a study of 17,000 patients undergoing their first amputation, in which postoperative (30 day) mortality was 9, 15, and 16 percent in patients with moderate CKD, severe CKD, and on dialysis, respectively [15]. By comparison, postoperative mortality was 6 percent in those with eGFR ≥60 mL/min per 1.73 m2. These postoperative mortality rates most likely reflect the greater severity of PAD (and perhaps other comorbidities) among patients undergoing an amputation.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".)

SUMMARY AND RECOMMENDATIONS

●Peripheral artery disease (PAD) is common among patients with chronic kidney disease (CKD). Risk factors for PAD include advanced age, hypertension, hyperlipidemia, smoking, diabetes mellitus, male sex, and coronary heart disease. Increased time on dialysis may also confer increased risk. (See 'Introduction' above and 'Epidemiology and risk factors' above.)

●The clinical manifestations of PAD are largely similar in patients with CKD as in those without CKD, though patients with CKD are likely to have more severe disease at initial presentation and are at increased risk for limb loss. One clinical presentation unique to dialysis patients is the exacerbation of symptoms after the creation of permanent hemodialysis access in the lower extremity. However, lower extremity arteriovenous access is overall uncommon. (See 'Clinical presentation and diagnosis' above.)

●The diagnosis of PAD in patients with CKD using reduced ankle-brachial index (ABI) is less reliable due to the high prevalence of medial arterial calcification. The toe systolic pressure and waveform and the toe-brachial index (TBI) can be used instead in situations where the ABI is incompressible (>1.3) to assess the level and severity of PAD. (See 'Clinical presentation and diagnosis' above and "Noninvasive diagnosis of upper and lower extremity arterial disease".)

●PAD is managed with risk factor reduction with exercise therapy and possibly medical therapy aimed at improving symptoms of claudication. The indications for revascularization are no different compared with the general population, but decision making in patients with CKD must take into account their greater risk of perioperative morbidity and mortality regardless of the type of intervention (open, endovascular). (See "Management of claudication due to peripheral artery disease" and "Management of chronic limb-threatening ischemia" and "Lower extremity surgical bypass techniques" and "Endovascular techniques for lower extremity revascularization".)

●For chronic limb-threatening ischemia (nonhealing wound, ulcers, gangrene), a limb salvage procedure is preferred over primary amputation whenever possible. We prefer an angioplasty-first approach, particularly for severe renal disease, given the comorbidities and limited life expectancy. Some patients with ischemic ulceration can be treated with conservative management and aggressive wound care rather than revascularization or amputation. (See 'Medical risk and management' above and 'Treating chronic limb-threatening ischemia' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Kirsten Johansen, MD, and Ann M O'Hare, MD, who contributed to an earlier version of this topic review.

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Topic 1928 Version 25.0

References

1 : Chronic kidney disease and outcomes of lower extremity revascularization for peripheral artery disease.

2 : Management of Traditional Cardiovascular Risk Factors in CKD: What Are the Data?

3 : Peripheral artery disease and chronic kidney disease: clinical synergy to improve outcomes.

4 : Peripheral artery disease and CKD: a focus on peripheral artery disease as a critical component of CKD care.

5 : Lower-extremity peripheral arterial disease among patients with end-stage renal disease.

6 : Cardiovascular morbidity and risk factors in renal transplant patients.

7 : Nontraumatic lower extremity amputations in the Medicare end-stage renal disease population.

8 : Survival after acute myocardial infarction in patients with end-stage renal disease: results from the cooperative cardiovascular project.

9 : Impact of new variables reported to the UNOS registry.

10 : Major role for arterial disease in morbidity and mortality after kidney transplantation in diabetic recipients.

11 : Risk factors for prolonged hospitalization after kidney transplants.

12 : Risk factors for hospital utilization in chronic dialysis patients. Southeastern Kidney Council (Network 6).

13 : Ankle-arm blood pressure index as a predictor of mortality in hemodialysis patients.

14 : Peripheral vascular disease in end-stage renal disease patients.

15 : Postoperative mortality after nontraumatic lower extremity amputation in patients with renal insufficiency.

16 : Critical limb ischaemia as a main cause of death in patients with end-stage renal disease: a single-centre study.

17 : 2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

18 : ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation.

19 : Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II).

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21 : Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals.

22 : Moderate renal insufficiency and the risk of cardiovascular mortality: results from the NHANES I.

23 : Level of kidney function as a risk factor for cardiovascular outcomes in the elderly.

24 : Renal insufficiency and subsequent death resulting from cardiovascular disease in the United States.

25 : Renal insufficiency and cardiovascular events in postmenopausal women with coronary heart disease.

26 : Mortality over a period of 10 years in patients with peripheral arterial disease.

27 : Edinburgh Artery Study: prevalence of asymptomatic and symptomatic peripheral arterial disease in the general population.

28 : Intermittent claudication. A risk profile from The Framingham Heart Study.

29 : Prevalence and clinical correlates of peripheral arterial disease in the Framingham Offspring Study.

30 : Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease.

31 : High prevalence of peripheral arterial disease in persons with renal insufficiency: results from the National Health and Nutrition Examination Survey 1999-2000.

32 : Renal insufficiency and the risk of lower extremity peripheral arterial disease: results from the Heart and Estrogen/Progestin Replacement Study (HERS).

33 : Kidney function and risk of peripheral arterial disease: results from the Atherosclerosis Risk in Communities (ARIC) Study.

34 : The prevalence of peripheral arterial disease and medial arterial calcification in patients with chronic renal failure: requirements for diagnostics.

35 : Cardiovascular disease risk status in elderly persons with renal insufficiency.

36 : Albuminuria and peripheral arterial disease: results from the multi-ethnic study of atherosclerosis (MESA).

37 : Renal insufficiency and use of revascularization among a national cohort of men with advanced lower extremity peripheral arterial disease.

38 : Peripheral arterial disease: a guide for nephrologists.

39 : Association of low glomerular filtration rate and albuminuria with peripheral arterial disease: the National Health and Nutrition Examination Survey, 1999-2004.

40 : Relationship between ankle-brachial index and chronic kidney disease in hypertensive patients with no known cardiovascular disease.

41 : Combined role of reduced estimated glomerular filtration rate and microalbuminuria on the prevalence of peripheral arterial disease.

42 : Combined role of reduced estimated glomerular filtration rate and microalbuminuria on the prevalence of peripheral arterial disease.

43 : Changing risk factor demographics in end-stage renal disease patients entering hemodialysis and the impact on long-term mortality.

44 : Atherosclerotic cardiovascular disease risks in chronic hemodialysis patients.

45 : Peripheral vascular disease risk factors among patients undergoing hemodialysis.

46 : Peripheral arterial disease in patients with end-stage renal disease: observations from the Dialysis Outcomes and Practice Patterns Study (DOPPS).

47 : Peripheral arterial disease, prevalence and cumulative risk factor profile analysis.

48 : Peripheral arterial disease as a predictor of outcome after renal transplantation.

49 : The distribution of peripheral arterial disease in a defined population of elderly high-risk Saudi patients.

50 : [Ankle-arm blood pressure index (AABPI) in hemodialysis patients].

51 : Ankle-brachial blood pressure index predicts all-cause and cardiovascular mortality in hemodialysis patients.

52 : Clinical outcomes, quality of life, and costs in the North Thames Dialysis Study of elderly people on dialysis: a prospective cohort study.

53 : Measures of chronic kidney disease and risk of incident peripheral artery disease: a collaborative meta-analysis of individual participant data.

54 : Vascular calcification in end-stage renal disease.

55 : Pathogenesis and Management of Vascular Calcification in Patients with End-Stage Renal Disease.

56 : Combined effect of chronic kidney disease and peripheral arterial disease on all-cause mortality in a high-risk population.

57 : Critical issues in peripheral arterial disease detection and management: a call to action.

58 : The prevalence of peripheral arterial disease in a racially diverse population.

59 : High prevalence of peripheral arterial disease and co-morbidity in 6880 primary care patients: cross-sectional study.

60 : The role of comorbidity in the assessment of intermittent claudication in older adults.

61 : Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) Study.

62 : Intermittent claudication. Incidence in the Framingham Study.

63 : Update on some epidemiologic features of intermittent claudication: the Framingham Study.

64 : Progression of aortic arch calcification and all-cause and cardiovascular mortality in chronic hemodialysis patients.

65 : Novel and traditional cardiovascular risk factors for peripheral arterial disease in incident-dialysis patients.

66 : Hyperhomocyst(e)inemia and the prevalence of atherosclerotic vascular disease in patients with end-stage renal disease.

67 : Fasting total plasma homocysteine and atherosclerotic peripheral vascular disease.

68 : Cross-sectional and longitudinal predictors of serum albumin in hemodialysis patients.

69 : Improvement in lower-extremity peripheral arterial disease by nocturnal hemodialysis.

70 : Peripheral vascular disease and serum phosphorus in hemodialysis: a nested case-control study.

71 : Hemodialysis Is Associated With Increased Peripheral Artery Occlusive Disease Risk Among Patients With End-Stage Renal Disease: A Nationwide Population-Based Cohort Study.

72 : Hemodialysis Is Associated With Increased Peripheral Artery Occlusive Disease Risk Among Patients With End-Stage Renal Disease: A Nationwide Population-Based Cohort Study.

73 : Impact of renal insufficiency on mortality in advanced lower extremity peripheral arterial disease.

74 : Arteriovenous fistula construction in the thigh with transposed superficial femoral vein: our initial experience.

75 : Results and complications of arteriovenous access dialysis grafts in the lower extremity: a five year review.

76 : Magnetic resonance angiography for the evaluation of lower extremity arterial disease: a meta-analysis.

77 : Chronic kidney disease and risk for cardiovascular and limb outcomes in patients with symptomatic peripheral artery disease: The EUCLID trial.

78 : K/DOQI clinical practice guidelines for cardiovascular disease in dialysis patients.

79 : Association of Smoking Status With Mortality and Hospitalization in Hemodialysis Patients.

80 : Smoking cessation in patients with chronic kidney disease.

81 : Helping Patients With ESRD and Earlier Stages of CKD to Quit Smoking.

82 : Smoking and Adverse Outcomes in Patients With CKD: The Study of Heart and Renal Protection (SHARP).

83 : Smoking in dialysis patients: a systematic review and meta-analysis of mortality and cardiovascular morbidity.

84 : A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.

85 : Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

86 : 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease (updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society for Vascular Medicine, and Society for Vascular Surgery.

87 : Antithrombotic therapy in peripheral arterial occlusive disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

88 : Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial.

89 : Blood pressure lowering and major cardiovascular events in people with and without chronic kidney disease: meta-analysis of randomised controlled trials.

90 : Hypertension in hemodialysis patients treated with atenolol or lisinopril: a randomized controlled trial.

91 : Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial.

92 : Lower progression rate of end-stage renal disease in patients with peripheral arterial disease using statins or Angiotensin-converting enzyme inhibitors.

93 : AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation.

94 : KDOQI US commentary on the 2013 KDIGO Clinical Practice Guideline for Lipid Management in CKD.

95 : The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial.

96 : Diabetes education and care management significantly improve patient outcomes in the dialysis unit.

97 : Healthy lifestyle and risk of kidney disease progression, atherosclerotic events, and death in CKD: findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

98 : A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial.

99 : Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease.

100 : Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial.

101 : Use of the Wound, Ischemia, foot Infection classification system in hemodialysis patients after endovascular treatment for critical limb ischemia.

102 : Outcomes of Critical Limb Ischemia in Hemodialysis Patients After Distal Bypass Surgery　- Poor Limb Prognosis With Stage 4 Wound, Ischemia, and Foot Infection (WIfI).

103 : Survival benefits of revascularization in patients with critical limb ischemia and renal insufficiency.

104 : Interventional management of critical limb ischemia in renal patients.

105 : Long-term outcomes of revascularization for peripheral vascular disease in end-stage renal disease patients.

106 : Peripheral vascular disease-related procedures in dialysis patients: predictors and prognosis.

107 : Influence of renal insufficiency on limb loss and mortality after initial lower extremity surgical revascularization.

108 : Refinement of survival prediction in patients undergoing lower extremity bypass surgery: stratification by chronic kidney disease classification.

109 : Impact of renal insufficiency on short-term morbidity and mortality after lower extremity revascularization: data from the Department of Veterans Affairs' National Surgical Quality Improvement Program.

110 : Long-Term Mortality After Invasive Angiography and Endovascular Revascularization in Patients With PAD Having Chronic Kidney Disease.

111 : CKD and Acute and Long-Term Outcome of Patients with Peripheral Artery Disease and Critical Limb Ischemia.

112 : Management of lower extremity wounds in patients with peripheral arterial disease: a stratified conservative approach.

113 : Nationwide Trends in Hospital Outcomes and Utilization After Lower Limb Revascularization in Patients on Hemodialysis.

114 : Infrainguinal reconstruction for patients with chronic renal insufficiency.

115 : Predictors of amputation and survival following lower extremity revascularization in hemodialysis patients.

116 : An updated meta-analysis of infrainguinal arterial reconstruction in patients with end-stage renal disease.

117 : Determinants of survival and major amputation after peripheral endovascular intervention for critical limb ischemia.

118 : End-stage renal disease--is infrainguinal limb revascularization justified?

119 : Failure of foot salvage in patients with end-stage renal disease after surgical revascularization.

120 : Is lower extremity revascularization worthwhile in patients with end-stage renal disease?

121 : Infrainguinal bypass grafting in patients with end-stage renal disease: improving outcomes?

122 : Infrainguinal revascularization in end-stage renal disease.

123 : Infrainguinal revascularization for limb salvage in patients with end-stage renal disease.

124 : Limb salvage in end-stage renal disease (ESRD). Comparison of modern results in patients with and without ESRD.

125 : Factors associated with future amputation among patients undergoing hemodialysis: results from the Dialysis Morbidity and Mortality Study Waves 3 and 4.

126 : The survival benefit of kidney transplantation in the setting of combined peripheral arterial disease and end-stage renal failure.

127 : Results of lower extremity amputations in patients with end-stage renal disease.