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NDT Advance Access originally published online on August 29, 2006
Nephrology Dialysis Transplantation 2006 21(12):3525-3531; doi:10.1093/ndt/gfl470
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Peripheral arterial disease in patients with stages IV and V chronic renal failure

Angeles Guerrero1, Rafael Montes1, José Muñoz-Terol1, Alberto Gil-Peralta2, Javier Toro1, Macarena Naranjo1, Paloma González-Pérez2, Carmen Martín-Herrera1 and Ana Ruiz-Fernández1

1Department of Nephrology and 2Department of Neurology, University Hospital Virgen del Rocío, Seville, Spain

Correspondence and offprint requests to: Ángeles Guerrero, MD, PhD, C/Garnacha, 54. Urbanización Hacienda El Carmen, Tomares, 41940 Sevilla, Spain. Email: mguerreror{at}yahoo.es



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. Cardiovascular disorders are frequently found among chronic renal failure (CRF) patients due to their higher susceptibility to develop atherosclerosis. However, peripheral arterial disease (PAD), that is associated with a high mortality rate, is not usually assessed in these patients. The aims of this study are to find out the prevalence of PAD affecting lower limbs in a population of CRF patients in stages IV/V, and to assess how much PAD determines the 5-year patient survival.

Methods. The study population (44 males and 29 females) was aged 58 ± 15 years. They suffered from advanced CRF (18.6 ± 6.1 ml/min creatinine clearance), but they were not on dialysis. These patients were sequentially referred initially to the predialysis unit over a period of 14 months. The vascular lesions were assessed by carotid and transcranial ultrasound, as well as by ankle–brachial index test (ABI). Routine 24 h blood and urine laboratory tests were performed for each patient. Cardiovascular morbidity and cardiovascular disease risk factors were evaluated through personal interview.

Results. Fourteen patients had an ABI index of less than 0.91 (PAD indicative), 11 of them also suffered from intermittent claudication. PAD affected significantly more males (P = 0.001) and diabetics (P = 0.001). Also, PAD prevalence was significantly higher in patients with a previous clinical record of coronary heart disease (P = 0.001), increased clinical record of cerebrovascular disease (P = 0.005), a thickness of the left ventricular posterior wall (P = 0.03) and lower cardiac ejection fraction (P = 0.02). PAD patients had a significantly different protein intake (P = 0.003), calcium–phosphorus product (P = 0.001), risk of coronary heart disease based on the Framingham score (P = 0.001) and 5-year survival rate (P = 0.004). There were no significant differences for PAD patients in terms of body mass index, creatinine clearance, lipid profile, Ca and P. Multivariate risk factor analysis revealed that a previous clinical record of coronary heart disease and diabetes increased the risk of developing PAD, as defined by ABI < 0.91. After 5 years, 21 patients (29%) had died: 64% of patients that suffered PAD (9/14) and 20% of the non-PAD population (12/59). The Cox proportional hazards model demonstrated that older age and a lower ABI increased the risk of death.

Conclusions. The present study, conducted on CRF patients in stages IV and V not undergoing dialysis, showed; (a) that a high percentage of these patients developed PAD (19%) or other vascular pathologies; (b) that there was an associated high mortality rate (29%) after 5 years; (c) that the 5-year mortality rate was significantly higher (P = 0.004) in PAD patients (64 vs 20%).

Keywords: ankle–brachial index; cardiovascular risk factors; chronic renal failure; peripheral arterial disease



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Cardiovascular disease is common in chronic renal failure (CRF) patients and is responsible for more than 50% of their deaths [1]. At the same time, renal disease, even at the earliest stages, is a cardiovascular risk factor [2]. Among the different localizations of cardiovascular diseases, peripheral arterial disease (PAD) affecting the lower limbs has a higher morbidity. Nevertheless, despite its importance, there are few reports of this pathology in CRF patients, and most of them, with a few exceptions, have been performed in dialysis patients [3–6]. The study of CRF patients prior to dialysis may help to discard the influence of variables related to dialysis in the development of PAD.

The importance of early PAD diagnosis is supported by studies showing that a high percentage of PAD patients will suffer intermittent claudication which will evolve to pain at rest and risk of tissular necrosis, and even to amputation. Moreover, PAD renal patients showed a higher mortality rate than those not affected by PAD [7]. Consequently, it seems that the prevention of risk factors for the development of PAD may be beneficial and may prevent these adverse outcomes. Likewise, the early diagnosis of PAD makes it possible to act intensively on its risk factors.

In our patient population, PAD had been diagnosed from the clinical records, physical examinations and the ankle–brachial index test (ABI), which is the ratio of the resting systolic pressure in the arteries of the ankle to that of the brachial artery, measured by Doppler ultrasound. ABI is a non-invasive test and has a higher sensitivity than the combination of a detailed clinical record and the careful physical examination of patients aimed at the detection of peripheral vascular disease. A resting ABI of 0.90 or less is 95% sensitive in detecting PAD in patients with positive arteriography and it is almost 100% specific when identifying asymptomatic individuals [8,9].

The primary objective of this study is to find out the prevalence rate of PAD among non-dialyzed CRF patients in IV/V stages, as determined by a pathological ABI. Also, the study will determine the 5-year survival rate for PAD and non-PAD patient groups.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
The study population consisted of 73 patients with CRF who were initially seen in the unit of pre-dialysis from 1 September 1998 to 31 October 1999. The inclusion criteria were as follows: possibility of undergoing a valid ABI test, availability for periodical follow-up visits and written informed consent. During this period, 152 patients were referred for the first visit (mean age 61 ± 15 years); of these patients, 14 were not available for periodical visits, 27 refused to participate in the study, five died before the onset of the study, 10 started dialysis before the onset of the study and 23 did not participate because of unknown reasons. Finally, 73 patients were included in our study. The demographic data of the 73 patients were verified on 31 December 2004 through the Regional Registry of patients and/or personal interviews with the nephrologists in-charge of each patient.

Using the Doppler method (Trans Scan 3D-EME, Uberlinge, Germany), we measured the arterial systolic pressure of patients in the two humeral arteries, two tibial posterior arteries and the pedis arteries (the highest value was used for the ABI test). Measurements were obtained from both arms and legs after 5 min rest in the supine decubitus position. ABI was calculated for each leg in relation to the highest arterial systolic pressure value obtained in both arms, considering as normal those values in the interval 0.91–1.30.

All patients underwent echocardiography, echo-Doppler ultrasound of carotids (resistance index), transcranial Doppler ultrasound (blood velocity in right and left-middle cerebral artery), both under basal conditions and after apnoea. From these data we obtained the pulsatility index, both under basal conditions and after apnoea (this measure is a cerebral resistance index: when the index is higher the capillaries are less adaptable and reactive and the resistance to blood flow is higher). Laboratory measurements included, apart from routine tests (blood, gasometry, hepatic, cardiac and renal profiles), HbA1c, fructosamine, lipidic profile, iPTH, albumin and pre-albumin, proteinuria and 24 h urine albumin. Glomerular filtration rate (GFR) was estimated using urine creatinine clearance and the Cockroft–Gault formula (corrected for body surface area). Protein intake was calculated (assuming equilibrated nitrogen balance) according to Maroni's formula [10]: protein intake normalized to weight (g/kg/day) = 6.25 x {[urea-N excretion urine 24 h (g/day)] + [0.0031 x body weight (kg)]}/body weight (kg).

All patients passed a structured survey on comorbidity and vascular risk factors, which included way of life and toxic habits. A patient was considered a smoker when he/she smoked or had stopped smoking within the last 5 years. A patient was considered to have coronary disease when he/she had been unmistakably diagnosed with angor pectoris, if he/she had suffered from a myocardial infarction or if he/she had undergone coronariography confirming coronary disease. Cerebrovascular disease was considered when the patient had been previously diagnosed with a transient or permanent cerebrovascular accident, confirmed through arteriography, CAT or nuclear magnetic resonance. A patient would be considered as suffering previously from PAD of lower limbs if he/she had undergone any previous amputation due to ischemia, by-pass surgery or angioplasty, or if intermittent claudication was demonstrated according to the Rose questionnaire [11]. A patient was diagnosed with left ventricular hypertrophy whenever the thickness of the septum or the posterior wall of the left ventricle exceeded 12 mm as shown by echocardiography.

Using Framingham's study for men and women, we calculated the absolute coronary risk of our patients for the next 10 years [12].

The statistical analysis was carried out using the SPSS 12.0 package. As some of the variables analyzed in the sample did not have a normal distribution, non-parametric tests were employed such as the Mann–Whitney U-test to compare the groups of patients with and without PAD, and the groups of deceased vs surviving patients. Spearman's coefficient was used to analyze lineal correlations, and the chi-squared test to compare categorical variables. In order to perform the multivariate analysis of those variables with a significant influence on ABI in the bivariate study, we applied the binomial logistic regression model. In order to study those variables affecting survival rate over a 5-year follow-up period, we used Cox proportional hazards model.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Table 1 shows demographical information and other data of interest. Twenty-six patients of the total were diabetics (36%), six of them suffered from diabetes mellitus type I. At the time of the study, 12 were treated with insulin, seven with oral antidiabetics and seven followed a special diet.


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  		Table 1. Patients’ characteristics

 
Fourteen patients had an ABI < 0.91 (19%), and only one patient had an ABI ≥ 1.3 (1.33). In the survey, 59 patients indicated no previous history or ischemic type discomfort affecting the lower limbs; seven mentioned episodes of intermittent claudication when covering a distance over 150 m, and five when covering a distance less than 150 m; two patients had undergone revascularization with by-pass surgery, and one of them had suffered transfemoral amputation. In 11 of these 14 symptomatic patients we found a pathological ABI; of the 14 patients with pathological ABI, 11 referred to intermittent claudication in the survey, and three did not mention any symptom (ABI: 0.90, 0.88 and 0.87, respectively).

The variables under study were compared in the two groups of patients with and without PAD, using the Mann–Whitney U-test. The results are shown in Table 2.


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  		Table 2. Comparison of patients with and without peripheral arterial disease

 
Spearman's coefficient was used to analyse the correlations between the ABI and the variables under analysis. Significant negative correlation coefficients were found for: age (R = –0.310, P = 0.008); pulsatility index in the right-middle cerebral artery after apnoea (R = –0.383, P = 0.001); pulsatility index in the right-middle cerebral artery under basal conditions (R = –0.216, P = 0.06); septum thickness (R = –0.292, P = 0.025); posterior wall thickness (R = –0.307, P = 0.018). Significant positive correlation coefficients were obtained for Ca (R = 0.232, P = 0.04); Ca x P (R = 0.244, P = 0.03); and HDL-cholesterol (R = 0.289, P = 0.013). No correlations were observed regarding total cholesterol, triglycerides, uric acid, platelets, insulin, fibrinogen, glycosylated haemoglobin, creatinine clearance, P, iPTH and wave E/wave A ratio in echocardiography.

Using the binomial logistic regression model we designed a multivariate model, taking into account variables showing significant differences when comparing patients with normal ABI vs a low ABI. Omnibus tests of model coefficients have a significance value of P < 0.001. The Nagelkerke R2 value was 0.535. The equation variables are shown in Table 3.


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  		Table 3. Logistic regression analysis

 
After a follow-up period of 5 years, 21 patients (29%) had died: 12 before onset of dialysis (36 ± 20 months follow-up period, range 1–67 months) and nine on dialysis (30 ± 20 months in dialysis, range 1–70 months). The causes of death were known in 15 of these 21 patients (71%): 8/15 (53%) by cardiovascular events, 4/15 (31%) by neoplasia, 2/15 (14%) by end-stage renal failure not treated by dialysis, and 1/15 (7%) by sepsis of catheter origin. It is to note that five of these six patients with unknown death cause were on pre-dialysis, and died at home, and we can speculate that the cause was sudden death, and then a cardiovascular event. Of the remaining 52 patients still alive: 11 continued in the predialysis unit, 25 received dialysis and 16 had undergone transplantation (15 have working kidneys and the other patient is on dialysis again). Of the 50 patients who began dialysis therapy, 45 received haemodialysis and five peritoneal dialysis. Taking this information into account, we compared several variables between the group of deceased patients and the group of survivors. Table 4 shows the statistically significant variables. No significant differences were observed in the percentage of smokers, diabetics and patients with cerebrovascular disease, levels of haemoglobin, haematocrit, leucocytes, fibrinogen and platelets, calcium, phosphorus, PTH, albumin, pre-albumin, total cholesterol, HDL-cholesterol, triglycerides, glycaemia, insulinaemia, HbAlc, bicarbonate and proteinuria, years of evolution of arterial hypertension and diabetes mellitus, mean arterial pressure, BMI, creatinine clearance rate with 24 h urine samples or glomerular filtration by Cockroft–Gault's formula. None of the patients suffered any amputation in the following 5 years (before 31 December 2004).


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  		Table 4. Comparison of different variables between deceased and survivors after 5 years

 
Survival analysis
Considering the variables that showed significant differences between the group of patients who had died after the 5-year period and those who had survived, we designed a multivariate test based on Cox proportional hazards model. Table 5 shows the equation variables, and Figure 1 shows the survival function according to ABI, adjusted for age.


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  		Table 5. Equation variables

 

Figure 1
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  		Fig. 1. Survival function (Cox proportional hazards model) according to ABI, adjusted for age.

 


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
The study of PAD is important in renal patients, not only as a marker of generalized cardiovascular disease, but also as a prognostic tool for a higher mortality rate. The ABI has shown high sensibility and specificity for the diagnosis of PAD, in comparison with arteriography, the gold standard, and has become an easy and reliable technique for PAD diagnosis [8,9]. However, renal patients have a higher percentage of media layer calcification, and this condition could slightly affect sensitivity, but not specificity, to detect PAD.

The present study reveals the high prevalence (19%) of PAD of lower limbs in our sample of stages IV/V CRF patients attending to the predialysis unit throughout a period of 14 months. This prevalence rate is especially high in comparison with the rate observed in patients without CRF, which is clearly inferior. Thus, in the population aged 50 years, the reported rate of intermittent claudication was 1–2%, and increased from 0.4% to 0.7% every 2 years from this age on [13]. Whenever PAD was diagnosed through ABI, the prevalence rate was found to be higher and it even reached 13% in patients over 65 years of age [14,15]. One study from Spain included 131 patients over 65 years of age, suffering from arterial hypertension and dyslipaemia, but without CRF or any previous cardiovascular event; once they had been divided into two groups, according to low or mild risk for cardiovascular disease, they showed a prevalence rate of 3.4 and 9.9% if there was ABI < 0.9. Considering the total patients the prevalence was 6.9% [16].

Different results have been reported from non-dialyzed CRF patients that were diagnosed with PAD by ABI. One of these studies was recently published from Spain [3]; it included 102 CRF patients in stages III–V, and referred for the first time to a nephrology clinic, and never diagnosed with PAD; but ABI revealed that 32% of the patients suffered from PAD. This prevalence is similar to that observed in dialysed patients [4], but it is much higher than in our study population. Using a subgroup of 2229 patients of NHANES (mean age of 76 years), a 24% PAD prevalence rate was observed in patients with estimated GFR <60 ml/min/1.73 m2 vs a prevalence rate of 3.7% in patients with GFR >60 ml/min/1.73 m2 [5]. These results could differ from the present study because the patient characteristics, such as age, together with sex and diabetes are main factors in determining the reduction of ABI [4]. The average age of the patients was 70 ± 11 years in the first mentioned study [3], and 76 ± 1 years in the second [5], therefore, the patients were older than in our population (57 ± 15 years). Moreover, one other study [6], that included younger patients (55.7 ± 11.4 years), and mean CrCl = 30 ml/min, reported a prevalence rate of 22%, which was closer to our results, and confirms the importance of age in the prevalence of PAD.

When comparing the different variables measured in PAD and non-PAD patients, our results point to the profile for PAD patients: male, smoker or previous smoker, diabetic, in which PAD is a manifestation of a generalized disease and reflecting cardiac problems (left ventricular hypertrophy, lower ejection fraction) and/or cerebrovascular problems (worse parameter of cerebral circulation, more cerebrovascular events) in a context of higher cardiovascular risk, according to Framingham criteria, and with a lower expected survival. Other conventional cardiovascular risks, such as blood pressure, body mass, triglycerides, total cholesterol and its fractions, have not been shown to be determinant factors for our study outcomes. These data agreed with the result of the logistic regression analysis performed to determine independent risk factors associated with PAD. According to this analysis, a clinical record of diabetes mellitus and coronary disease are associated with the development of PAD.

The higher frequency of vascular pathology and its worst evolution in renal patients has been attributed to the coexistence of unconventional risk factors associated with renal failure. One of them was secondary hyperparathyroidism, and the effect of calcium, phosphorus and the calcium–phosphorus product on endothelial dysfunction, and vascular calcification [17]. We have not found significant differences in levels of iPTH, calcium and phosphorus in PAD patients. A higher calcium–phosphorus product is related to a higher ABI, perhaps as a consequence of higher vascular calcification in lower limbs, frequently in the media layer, with higher vascular stiffness and systolic blood pressure.

Microalbuminuria and proteinuria are markers of endothelial lesions [18], systemic and renal and podocyte alterations. We have not found differences between patients with and without PAD.

We have analysed the differences in albumin and pre-albumin, as markers of both nutritional and inflammatory disorders [19] in the group of PAD compared with the group without it, have not seen significant differences between them.

Uric acid has been proposed to have a causal role in renal diseases, hypertension and arteriolosclerosis [20]. In our study the average levels of uric acid were higher in PAD patients (with a lower percentage of them treated with allopurinol), but they were not statistically significant, perhaps due to the sample size. These data were in agreement with the risk attributed to uric acid in vascular and renal damage, as well as the effect of allopurinol as a vascular protector [21].

The use of statins has been proposed to diminish vascular lesions in renal patients, by reducing vascular calcifications [22] and other mechanisms. We found no statistical differences in statin treatment or lipid profiles between PAD and non-PAD groups.

Regarding the 5-year survival among PAD patients, our results revealed an extremely low survival rate in these patients (similar to that observed in left ventricular hypertrophy and previously diagnosed coronary disease patients, according to the results of the survival analysis that are not shown). Thus, only 5 of the 14 PAD patients (36%) were alive after the 5-year period (mortality rate 64%), in comparison with 47 of the 59 non-PAD patients (80%) (mortality rate 20%). The result analysis data (Cox proportional hazards model) also supported these observations, as age and ABI <0.91 turned out to be predictive factors of mortality, increasing 4-fold the risk of death. Moreover, once the results were adjusted for age, a low ABI remained a significant factor.

Our results are similar to those reported in a recent publication [23] that studied mortality 1 year after of the diagnosis (our study was extended to 5 years after diagnosis) of severe PAD (pain at rest, ulcers or gangrene) in 5787 patients with diverse degrees of renal function. In patients with an estimated GFR <30 ml/min the 1-year mortality was 44%. After adjusting for age, diabetes mellitus and previous cardiovascular events, the risk of death in patients with similar degrees of PAD was 2.9 times higher in patients with GFR <60 ml/min vs the group with GFR >60 ml/min. These data confirm the great mortality rate among renal patients that suffer PAD, and the harmful effect of renal insufficiency on the evolution of patients with cardiovascular diseases [24], specifically PAD patients.

In conclusion, our study of stages IV and V CRF patients not undergoing dialysis shows a high percentage of patients suffering from PAD and other vascular pathologies, as well as an association of PAD with a higher 5-year mortality rate. The early diagnosis of PAD by ABI would hasten the onset of therapy and would contribute to detering the development of the disease, and, consequently, it would lower morbidity and mortality rates.



   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors are grateful to Eloisa Guerrero for valuable assistance in the review of this manuscript.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

  1. US Renal Data System. (2003) USRDS 2003 Annual Data Report: Atlas of End-Stage Renal Disease in the United States(National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD).
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  17. Boaz M, Weinstein T, Matas Z, Green MS, Smetana S. (2005) Peripheral vascular disease and serum phosphorus in hemodialysis: a nested case-control study. Clin Nephrol 63:98–105.[Web of Science][Medline]
  18. Stuveling EM, Hillege HL, Bakker SJ, et al. (2004) PREVEND study group. C-reactive protein and microalbuminuria differ in their associations with various domains of vascular disease. Atherosclerosis 172:107–114.[CrossRef][Web of Science][Medline]
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Received for publication: 4. 7.06
Accepted in revised form: 11. 7.06


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