1. Lower extremity peripheral arterial disease in end-stage renal disease
Seo Mi Seon

2. Introduction common associated with substantial morbidity & mortality
Survival in 322 ESRD patients
with no risk, diabetes, CAD and CLI
during 5 years of observation
74%
73%
Patients with CLI carry the highest mortality risk.
According to life-table analyses, the 5 year survival rate in patients with no risk was 74%, in diabetics without CAD or CLI 73%, in CAD 50% and in CLI 10% (Figure 1).
50%
10%
Nephrol Dial Transplant 2004; 19:2547.

3. Epidemiology estimates of the prevalence vary
in part according to the specific population studied
J Am Soc Nephrol 12: 2838–2847, 2001

4. A few small studies have measured prevalence using the ABI
The prevalence of low ABI measurements ranged from 4 to 38 percent
Higher estimates are obtained when measures of toe (rather than lower leg) perfusion are used
Estimates reported in these studies range from 16 to 48%, depending on the specific populations studied and the diagnostic
techniques used.
In general, estimates of the prevalence of PAOD among dialysis patients that are based on diagnostic testing results are almost double those that are based on history and physical findings alone.
J Am Soc Nephrol 12: 2838–2847, 2001

5. Numbers of patients with incident ERRD and peripheral arterial occlusive disease, 1995 to 1998
Figure 1 presents the trend in PAOD prevalence among incident ESRD patients from 1995 to 1998.
Although the percent prevalence of PAOD has remained fairly stable with time, there has been an increase in the absolute number of incident ESRD patients and PAOD, which reflects expansion in ESRD program enrollment during this period.
J Am Soc Nephrol 12: 2838–2847, 2001

6. Risk factors In the general population,
advanced age, hypertension, hyperlipidemia, smoking, diabetes mellitus, male gender, coronary artery disease
→ similar among dialysis patients
In the HEMO study, diabetes and smoking were associated with PAD in chronic hemodialysis patients [24] . Age was significantly associated with PAD in non-diabetics but not in diabetics. Hypercholesterolemia, male gender, and hypertension did not correlate with PAD.
Kidney International, Vol. 58 (2000), pp. 353–362
936 HD pt.

7. the USRDS Dialysis Morbidity and Mortality Study (DMMS)
Among patients enrolled in the USRDS Dialysis Morbidity and Mortality Study (DMMS) waves 1, 3 and 4, PAD was associated with increased age, male gender, white race, diabetes, smoking (past or present), ECG evidence of left ventricular hypertrophy, and longer time on dialysis (vintage) in adjusted analysis [16] . As with the HEMO study, high serum cholesterol and triglycerides were not significantly associated with the disorder.
the USRDS Dialysis Morbidity and Mortality Study (DMMS)
J Am Soc Nephrol 13: 497–503, 2002

8. Clinical manifestations
most patients do not exhibit symptoms
the earliest symptom : intermittent claudication
asymptomatic PAOD & intermittent claudication
→ “noncritical ischemia”
more advanced disease
: onset of rest pain, ischemic ulceration, eventually gangrene
(in increasing order of severity)
→ “critical ischemia”
history and physical examinations
: insensitive indicators of the presence of PAOD

9. largely similar in patients with and without ESRD
no systematic reports of differences in the clinical presentation
among patients with and without renal failure
1. dialysis patients → more diffuse and distal disease
(high prevalence of diabetes)
2. interaction between PAD and the hemodialysis access
preexisting lower extremity ischemia may worsen
after creation of permanent hemodialysis access in the lower extremity
common among those undergoing the procedure
25 pt. single center review
superficial femoral artery arteriovenous fistula creation
→ 8 patients (32%) : symptomatic distal leg ischemia in (3D-3M)
J Vasc Surg 2001; 33:968.

10. Diagnosis noninvasive examinations : ankle-brachial index
toe-brachial index
exercise treadmill test
segmental limb pressures
segmental volume plethysmography
ultrasonography

11. Measurement of the ankle-brachial index
> 1.30
: noncompressible O
: normal
: Mild to moderate PAD
: severe PAD
< 0.9
: 95% sensitivity
100% specificity
for detecting angiogram-positive PAD
≥ 50 % stenosis
in one or more major vessels
In order to calculate the ankle-brachial index (ABI), systolic blood pressure is measured by Doppler ultrasonography in each arm and in the dorsalis pedis (DP) and posterior tibial (PT) arteries in each ankle. The higher of the two arm and ankle pressures is selected. The right and left ABI values are determined by dividing the higher ankle pressure in each leg by the higher arm pressure. A ratio greater than 1.30 suggests a noncompressible, calicified vessel; in this situation, the true pressure at that location cannot be obtained, and additional tests are required to diagnose peripheral arterial disease. Patients with claudication typically have ankle-brachial index values ranging from 0.41 to 0.90, and those with critical leg ischemia have values of 0.40 or less. Reproduced with permission from: Hiatt, WR. N Engl J Med 2001; 344:1608. Copyright © 2001 Massachusetts Medical Society.
N Engl J Med 2001; 344:1608

12. Algorithm for evaluation of patients with suspected PAD
Patients should be evaluated for peripheral arterial disease if they are at increased risk because of their age or the presence of artherosclerotic risk factors, have leg pain on exertion, or have distal limb ulceration for which the history and examination do not provide an obvious explanation. Reproduced with permission from: Hiatt, WR. Medical treatment of peripheral arterial disease and claudication. N Engl J Med 2001; 344:1608. Copyright © 2001 Massachusetts Medical Society.
N Engl J Med 2001; 344:1608.

13. N Engl J Med 2001; 344:1608.

14. * ABI
: less useful in patients with ESRD
d/t high prevalence of medial arterial calcification
falsely elevated lower extremity blood pressure readings
d/t arterial incompressibility

15. The prevalence of PAD and MAC in the study groups
Am J Kidney Dis 2002; 40:472.
The prevalence of PAD and MAC in the study groups
22%
1.7%
23.7%
3.4%
30.6%
23.1%
41.7%
14.6%
prospective cross-sectional study
Finnish population
59 : CRF
36 : Dialysis
: renal transplant
59 : control
Prevalences of PAD on this study were 22.0% in patients with predialysis CRF, 30.6% in patients on dialysis therapy, 14.6% in renal transplant recipients, and 1.7% in control subjects
MAC was observed in 23.7% of patients with predialysis CRF, 41.7% of patients on dialysis therapy, 23.1% of renal transplant recipients, and 3.4% of control subjects (P ; Fig 1).
P < 0.001

16. Both asymptomatic PAD and MAC are common in patients with CRF
Am J Kidney Dis 2002; 40:472.
Prevalences of findings according to different diagnostic methods for subgroups of patients withCRF are listed in Table 2.
Only 9 patients had claudication, and 6 of those patient had PAD.
Conclusion: Both asymptomatic PAD and MAC are common in patients with CRF.
Therefore, we recommend the use of both ABI and TBI measurements in the evaluation of PAD in patients with CRF.
these authors advocate first using the ankle-brachial index and (when the ankle-brachial index is elevated) the toe-brachial index (which is less likely to be affected by medial arterial calcification) for screening for PAD in patients with renal insufficiency.
Both asymptomatic PAD and MAC are common in patients with CRF
we recommend the use of both ABI and TBI measurements in the evaluation of PAD in patients with CRF
(TBI : less likely to be affected by medial arterial calcification)

17. iodinated contrast arteriography : the gold standard
Magnetic resonance angiography (MRA)
: also accurate
nephrogenic systemic fibrosis

18. Treatment N Engl J Med 2001; 344:1608.
All patients with peripheral arterial disease, regardless of the severity of symptoms, should undergo risk-factor modification to achieve the listed treatment goals and should receive antiplatelet therapy with aspirin or clopidogrel. Angiotensin-converting-enzyme inhibitors may be considered because of the potential for prevention of ischemic events that is independent of blood pressure lowering.
N Engl J Med 2001; 344:1608.

19. Treatment of early disease
Early PAD
: asymptomatic disease or intermittent claudication
without severe symptoms and/or complications of ischemia
(eg, rest pain, ischemic ulcers, gangrene)
Risk factor reduction 
Exercise 
: the impact of exercise in ESRD patients
has not been specifically investigated
3. Medications
: Cilostazol
phosphodiesterase inhibitor
substantially improves physical function
in patients with claudication and normal renal function
4. Preventive foot care
There have been few studies of the efficacy of preventive foot care
among ESRD patients

20. Kaplan-Meier curves for the primary endpoint
Clin J Am Soc Nephrol 2008; 3:1034.
Kaplan-Meier curves for the primary endpoint
: The 5-yr event-free rate from restenosis
372 consecutive lesions
in 193 HD pt
successfully undergoing PTA
100 mg cilostazol twice daily
(130 lesions in 71 patients)
no cilostazol
(242 lesions in 122 patients)
52.4% vs 32.9%, HR 0.55
Kaplan-Meier analysis demonstrated the 5-yr patency rate was significantly higher in the cilostazol group than in
the control group [52.4 versus 32.9%, hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.39 to 0.77, P ].
this agent may improve long-term patency after lower extremity percutaneous transluminal angioplasty in hemodialysis patients

21. Am J Kidney Dis 2002; 40:566. . amputation 5 P < 0.05
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
There were no amputations in the study group versus five amputations in the control group (P < 0.05). Ten
patients in the control group were hospitalized with diabetes- or vascular-related admissions versus one patient in
the study group (P < 0.002).
amputation 5
P < 0.05
diabetes- or vascular-related admissions 10 1
P < 0.002

22. 5. Revascularization Revascularization has rarely been performed for early disease among ESRD patients since there is concern about a high mortality rate the benefits of revascularization for non-limb-threatening claudication are unknown in this setting

23. Treatment of limb-threatening ischemia : Limb-sparing procedures
Surgical revascularization
: the management of limb-threatening ischemia can be difficult
comorbid conditions, tend to heal slowly,
high rate of infection, high operative risk,
high prevalence of vascular calcification
the management of limb-threatening ischemia in ESRD patients can be difficult.

24. study populations, surgical procedures, indications for surgery
Table 3 presents the results of surgical revascularization studies among patients with ESRD and demonstrates that there was considerable variation in outcomes among those studies.
For example, 1-yr graft patency rates ranged from 53 to 90%, 1-yr limb salvage rates ranged from 56 to 91%, 2-yr patient survival rates ranged from 32 to 67%, and 30-d operative mortality rates ranged from 0 to 13%.
Amputation in the presence of a patent bypass graft seems to be more common among patients with ESRD (65–68)
and among patients with chronic renal failure (69).
Graft failure is most common in the setting of frank gangrene.
Differences in individual study outcomes may reflect differences in the study populations (i.e., percentages of diabetic
patients, smokers, and transplant recipients), in the surgical procedures performed (i.e., percentage of revascularization
procedures with distal anastomosis below the popliteal artery), and in the indications for surgery (i.e., the percentage of
patients for whom the indication for surgery was gangrene).
J Am Soc Nephrol 2001; 12:2838.
study populations, surgical procedures, indications for surgery

25. J Am Soc Nephrol 2001; 12:2838.
Table 4 presents outcome data for the non-ESRD control groups included in six of the aforementioned case series.
Comparisons of outcomes weighted according to the number of patients and procedures demonstrated that patients with ESRD
exhibited significantly higher 30-d operative mortality rates and lower graft patency, limb salvage, and patient survival
rates, compared with control subjects without ESRD.

26. J Am Soc Nephrol 2003; 14:1287. J Am Soc Nephrol 2003; 14:1287.
Even moderate renal insufficiency (estimated GFR 30-59cc/min/1.73m2) was associated with an increased incidence
of postoperative death (adjusted odds ratio (OR) 1.44, 95% confidence interval (CI), 1.17 to 1.77, P ), cardiac
arrest (OR 1.43, CI 1.09 to 1.88, P ), myocardial infarction (OR 1.68, 1.39 to 2.16, P ), unplanned intubation (OR 1.69, CI 1.39 to 2.07, P ) and prolonged intubation (OR 1.57, CI 1.28 to 1.94, P ) within 30 d of lower extremity revascularization.
J Am Soc Nephrol 2003; 14:1287.
prospectively collected Data, 30 d of lower extremity surgical revascularization (n = 18,217)

27. Am J Kidney Dis 2001; 38:57. Patient survival Limb survival
Graft survival
Median patient survival was 1.72 years in the ESRD group compared with 5.17 years in the control group (P ) after surgery. Time to
50% limb loss was 1.24 years in the ESRD group and longer than 5.65 years in the control group (P0.001). Time to 50% graft patency was 0.70 years in the ESRD group and longer than 5.5 years in the control group (P 0.05). Kaplan-Meier survival curves for patient survival (Fig1), limb survival (Fig 2), and graft patency (Fig3) are shown for patients with and without ESRD after lower-extremity revascularization. Statistically significant differences existed between patients with and without ESRD with respect to each of these outcomes.
P < 0.001
P < 0.001
P < 0.039
retrospective case-control analysis
ESRD :31 procedures (20 pts)
w/o ESRD : 64 procedures (57 pts)

28. Angioplasty Limited data exists
discrete proximal lesions are most amenable to angioplasty
→ dialysis patients are poor candidates for this procedure
d/t the frequent presence of diffuse disease and distal lesions

29. PTA was successful in 97% of cases Cumulative limb salvage rates
at 12, 24, 36, 48 months
: 86, 84, 84, 62%
107 dialysis patients
(mean age 67±10, 75 males) 132 ischemic limbs
Median f/u : 22M
Kaplan–Meier survival curve of amputation-free time for limbs
As shown in Figure 2, upper panel, major amputation tended to occur more commonly in the case of diabetes
mellitus (P¼0.06 by log-rank test). Presence at baseline of ulcer and/or gangrene of the foot was significantly associated (P¼0.04, by log-rank test)with major amputation (Figure 2, lower panel).
Kaplan–Meier survival curve of amputation-free time for
limbs, divided according to the presence or not of diabetes mellitus
(upper panel) and foot lesions (lower panel).

30. Kidney Int 2004; 65:613.
All-cause cumulative mortality
Cardiac cumulative mortality
Infectious cumulative mortality
Fig. 1. Mortality of patients after undergoing initial peripheral vascular
disease procedure (PVD) by surgical bypass or percutaneous transluminal
angioplasty. (A) All-cause cumulative mortality. (B) Cardiac cumulative mortality. (C) Infectious cumulative mortality.
retrospective study using the United States Renal Data system database found that the risk of amputation and all-cause mortality was higher among dialysis patients who underwent bypass surgery compared with angioplasty
longitudinal cohort study, retrospective study
United States Renal Data System

31. Amputation undertaken as a last resort
Dialysis patients have an extremely high rate of nontraumatic lower extrem ity amputation compared to the general population
: crude amputation rates
4.3/100 persons per year for all Medicare ESRD patients
13.8/100 persons per year for diabetic ESRD patients
harbinger for future morbidity and mortality in patients with ESRD
Kidney Int 1999; 56:1524.
Amputation is undertaken as a last resort in patients for whom more conservative measures and/or revascularization have failed and who are not candidates for revascularization.

32. Am J Kidney Dis 2003; 41:162.
US Renal Data System Dialysis Morbidity and Mortality Study Waves 3and 4 in combination with Medicare discharge data to
identify factors associated with lower-extremity amputation (excluding toe amputations) in hemodialysis patients.
Increased age, African American and Native American (versus white) race, diabetes as the cause of renal failure (versus glomerulonephritis), male gender and dialysis (versus transplant) status placed patients at increased risk for amputation over a one-year period. Similar findings concerning risk factors for amputation were found in a second study
Male sex, diabetes, previous diagnosis of peripheral
vascular disease (PVD), mean systolic blood pressure, and elevated serum phosphorus level were associated with
the outcome of amputation within 2 years of the study start date. Among patients without diabetes, a previous
diagnosis of cardiac disease, longer time from initiation of dialysis therapy (vintage), and previous hospitalization
for limb ischemia were associated with increased risk for future amputation.
US Renal Data System Dialysis Morbidity and Mortality Study Waves 3and 4
factors associated with lower-extremity amputation (excluding toe amputations)
in hemodialysis patients
the outcome of amputation within 2 years of the study start date