Nephrol Dial Transplant (2001) 16: 302-306
© 2001 European Renal Association-European Dialysis and Transplant Association
Impaired endothelium-dependent vasodilatation in renal failure in humans
Department of Medical Sciences, University Hospital, Uppsala, Sweden
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Abstract |
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Background. The main causes of death in patients with chronic renal failure (CRF) are cardiovascular complications. The aim of the present study was to compare endothelium-dependent vasodilatation (EDV) in patients with chronic renal failure with a control population controlling for hypertension, diabetes mellitus and hypercholesterolaemia.
Methods. Fifty-six patients with moderate CRF (mean creatinine clearance 29.4 ml/min/1.73 m2) underwent evaluation of EDV and endothelium-independent vasodilatation (EIDV) by means of forearm blood flow (FBF) measurements with venous occlusion plethysmography during local intra-arterial infusions of methacholine (Mch, 2 and 4 µg/min evaluating EDV) and sodium nitroprusside (SNP, 5 and 10 µg/min evaluating EIDV). Fifty-six control subjects without renal impairment underwent the same investigation.
Results. Infusion of Mch increased FBF significantly less in patients with renal failure than in controls (198 vs 374%, P<0.001), whereas no significant difference was seen regarding the vasodilatation induced by SNP (278 vs 269%). The differences in EDV between the groups were still significant after controlling for hypertension, blood glucose, and serum cholesterol in multiple regression analysis (P<0.001). EDV was related to serum creatinine (r=-0.37, P<0.01), creatinine clearance (r=0.45, P<0.005) and to serum triglyceride levels (r=-0.29, P<0.005) in the CRF group.
Conclusions. Patients with moderate CRF have an impaired EDV even after correction for traditional cardiovascular risk factors and this impairment is related to the degree of renal failure.
Keywords: chronic renal failure; endothelium; renal function; triglycerides; vasodilatation
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Introduction |
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TopAbstractIntroductionSubjects and methodsResultsDiscussionReferences |
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In spite of different kinds of renal replacement therapy the mortality among patients with chronic renal failure (CRF) is high. The major cause of death in patients with CRF is cardiovascular disease (CVD). Cardiovascular causes of death in renal replacement therapy patients are 10–20 times higher than in general population [1].
Uraemia is associated with increased incidence of cardiovascular risk factors such as hypertension, dyslipidaemia, impaired glucose tolerance and diabetes mellitus. However, based upon conventional risk factor analysis, these factors would not fully explain the extraordinary increase in morbidity and mortality in cardiovascular disease among uraemic patients [1].
In recent years, the role of endothelial dysfunction for development of coronary heart disease and congestive heart failure has been highlighted [2]. Apart from being regarded to be of major importance for the development of CVD, associations between endothelial dysfunction and hypertension, dyslipidaemia and diabetes mellitus have been demonstrated [3,4]. This prompted us to further investigate endothelial vasodilatory function in patients with CRF. Previous studies of endothelial function in patients with renal failure have been performed using ultrasound-based methods in children with CRF [5], by a vessel wall movement detector [6], circulating levels of vascular cell markers [7], daily urinary nitric oxide (NO) excretion [8], and the muscle bath technique [9], indicating impaired endothelial function in patients with renal failure.
The primary aim of the present study was to use intra-arterial infusion of vasodilator agents and to measure changes in forearm blood flow (FBF) by venous occlusion plethysmography in order to characterize endothelium-dependent and endothelium-independent vasodilatation in patients with renal insufficiency compared with control subjects, controlling for traditional cardiovascular risk factors, such as hypertension, hyperlipidaemia and glucose levels. A second aim was to study the relationship between the degree of renal function and the endothelial function within patients with renal impairment.
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Subjects and methods |
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The study population consisted of 56 patients (36 men and 20 women) with renal impairment. All were out-patients recruited from the Renal Unit of the Department of Medical Sciences, University Hospital, Uppsala, Sweden. The patients are characterized in Table 1
. The diagnoses of renal patients were as follows: glomerulonephritis (23), diabetes (10) polycystic kidneys (5), pyelonephritis (5), nephrosclerosis (4), hypoplastic kidneys (2), nephrolithiasis (2), lithium nephropathy (2) and unknown diagnoses (3). The majority of patients had moderate CRF and no patient was considered to be in need of renal replacement therapy in the near future. Fifty-one of the patients were on antihypertensive therapy, 10 were on anti-diabetic therapy and 18 were on lipid-lowering therapy (Hmg CoA reductase).
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A control population (n=56, Table 1
) was recruited with high prevalence of hypertension from the general population in Uppsala. All controls were without history of renal disorders.
Measurement of forearm blood flow
Endothelium-dependent vasodilatation (EDV) was measured using venous occlusion plethysmography [10,11]. During the blood flow measurements the subjects were supine in a quiet room maintained at a temperature 21–22°C. An arterial cannula was inserted into the brachial artery of one arm for regional infusions of methacholine (Mch) and sodium nitroprusside (SNP). A mercury-in-silastic strain gauge, connected to a calibrated plethysmograph, was placed at the upper third of the forearm, which rested comfortably slightly above the level of the heart.
Venous occlusion was achieved by blood pressure cuff applied proximal to the elbow and inflated to 40 mmHg by a rapid cuff inflator. Approximately four inflations/min for about 7 s each were performed. After a measurement of resting forearm blood flow (FBF) with venous occlusion plethysmography, local infusion of Mch (2 µg/min and 4 µg/min) was performed. This muscarinergic agonist has been shown to increase the forearm release of nitrite and nitrate, the breakdown products of NO, more than eightfold in healthy volunteers in a recent study [12].
To control the mechanical properties of the vascular bed in the skeletal muscle the exogenous NO-donor SNP (5 µg/min and 10 µg/min) was infused. The vasoactive drug infusions were given during 5 min for each dose, with a 20-min wash-out period between the drugs. The order of the vasodilatations was randomized. The relative increase in FBF after Mch or SNP infusion was taken as a measure of EDV or EIDV respectively.
We have previously shown the short-term (2 h) and long-term (3 weeks) variability of FBF during vasodilatation with Mch and SNP with this method to be less than 5% [13].
Laboratory variables
Measurements of serum creatinine and urea were performed by routine methods of the Clinical Chemistry Laboratory. Twenty-four-hour urine collections were sampled, then acidified to a pH <2 before laboratory measurements. Excretion of albumin was measured on a free diet by routine methods. Triglyceride and cholesterol concentrations in serum were measured after an overnight fast by enzymatic methods, using IL Test Cholesterol Trinder's Method 181618–80 and IL Test Enzymatic-Colorimetric Method 181709–00 for use in a Monarch apparatus (Instrumentation Laboratories, Lexington, MA, USA). These laboratory variables were only measured in the patients with CRF.
The study protocol was approved by the local Ethical Committee and informed consent was obtained from all participants.
Statistical analysis
Numerical data are presented as mean values±SD. Differences between groups were calculated by factorial ANOVA. The relationships between studied variables were evaluated by univariate regression analysis. Interactions between several independent variables were then examined with multiple regression analysis. P<0.05 was regarded significant.
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Results |
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TopAbstractIntroductionSubjects and methodsResultsDiscussionReferences |
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Clinical and laboratory characteristics of the patients and controls are given in Table 1
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Infusion of Mch increased forearm blood flow in both groups: In patients with renal failure from 5.6±1.9 (SD) to 15.3±4.2 ml/min/100 ml tissue at the highest dose and in controls from 4.4±1.4 to 19.6±6.3 ml/min/100 ml tissue (Figure 1). As compared with controls, FBF was significantly lower during Mch infusion in patients with renal failure (P<0.0001). A significant difference between the groups was seen also when EDV was calculated as the percentile increase in FBF from baseline during Mch infusion (P<0.001).
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Infusion of SNP caused an increase in the forearm blood flow in renal patients from 5.6±1.9 to 16.0±4.6 ml/min/100 ml tissue at the highest dose and from 4.4±1.4 to 16.5±5.3 ml/min/100 ml tissue in control subjects (no significant difference between the groups) (Figure 1
). Also when the vasodilatory action was expressed as the endothelial function index (the Mch to SNP FBF ratio at the highest doses) a highly significant (P<0.001) difference between the groups was seen (Figure 2).
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As significant differences in age, frequency of hypertension treatment, blood pressure and fasting blood glucose levels were seen between CRF patients and controls, multiple regression analyses were performed in order to assess if the differences in EDV and endothelial function index still persisted after the differences in these cardiovascular risk factors had been adjusted for. Without including the risk factors, the independent variable uraemia/control (uraemia=1) yielded an R2 of 0.21 and a regression coefficient of -176 (95% CI (-242, -110), t=5.34, P<0.0001) for EDV and an R2 of 0.14 and a regression of -0.26 (95% CI (-0.39, -0.13), t=4.13, P<0.0001) of EFI as dependent variables. The multivariate models are given in Table 2
. In these models it could be seen that uraemia was the major, significant, independent variable explaining the variation in EDV and EFI. The classical risk factors did not contribute in a significant way in this aspect.
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There was a negative correlation between the index of endothelial function (EFI) and serum creatinine (r=-0.34; P=0.01) in patients with renal failure (Figure 3
), while EDV was related to serum creatinine (r=-0.37; P<0.001), creatinine clearence (r=0.45; P<0.005) and to serum triglyceride levels (r=-0.29; P<0.005) (Figure 4). EIDV was not related to the degree of renal function, but was inversely related to serum triglyceride levels (r=-0.26; P<0.05) (Figure 4).
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Discussion |
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TopAbstractIntroductionSubjects and methodsResultsDiscussionReferences |
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The present study showed that EDV was impaired in adult patients with moderate CRF and that EDV was related to degree of renal failure. Furthermore, the impairment in EDV found in CRF was not due to hypertension, hypercholesterolaemia or diabetes mellitus. There is increasing recognition about the endothelium acting as a first-line defence mechanism against the development of vascular injury. It exerts a protective action through modulation of vascular tone, vascular structure and interaction of blood components with the vessel wall [14,15]. To achieve optimal control of these aspects of vascular function, the endothelium synthesizes vasoconstrictive, proliferative and thrombotic factors, as well as vasodilatory, antiproliferative and antithrombotic moieties. A disturbance in the balance between these factors as part of ‘endothelial dysfunction’ has been associated with processes that promote cardiovascular injury, such as vasoconstriction, enhanced platelet-vessel wall interaction and recruitment of inflammatory cells [14].
Since vasomotor tone can be assessed in vivo, clinical studies have mostly focused on endothelium-dependent vasoconstriction and vasodilatation. In this respect, the vasoconstrictor and proliferation-stimulating peptide endothelin-1 and the vasodilating and antiproliferative NO molecule appear to be the most potent endothelium-derived mediators. Endothelial dysfunction, assessed by impairment of endothelium-dependent vasodilatation, has been demonstrated in patients with classical risk factors for atherosclerosis, such as hyperlipidaemia, hypertension, and diabetes [4,5,16,17].
Early and rapidly developing atherosclerosis is a major cause of morbidity in patients with CRF, and is responsible for a mortality rate in myocardial infarction, which is 10 times greater than in the normal population, and occurs more rapidly [18]. The clinical sequelae of atherosclerosis, coronary heart disease and cerebrovascular disease, are the leading causes of morbidity and mortality in renal replacement therapy patients [1].
Risk factors for coronary heart disease in uraemic patients, which have been identified, include dyslipidaemia, hypertension and diabetes mellitus. They could not alone explain the extremely high morbidity in patients with renal failure, however [1].
This prompted us to investigate EDV and its correlations with laboratory variables in patients with CRF. Our findings demonstrated that patients with renal failure showed a significantly less pronounced vasodilatation during Mch infusion, when compared to the controls. However, there was no significant difference between the renal patients and controls regarding SNP-induced vasodilatation, which indicates that there is no difference in blood vessel smooth-muscle function in patients with renal failure. Thus the vasodilatory dysfunction in CRF patients seems to be limited to the bioavailability of NO.
To exclude the possibility that differences in the occurrence of hypertension, hypercholesterolaemia, and diabetes mellitus could explain the impairment in EDV in CRF patients, we performed multiple regression analysis to evaluate the role of these cardiovascular risk factors on EDV. The multiple regression analysis revealed that EDV was impaired in CRF patients irrespective of these cardiovascular risk factors. Another finding in this study was that EDV was correlated with serum creatinine level and creatinine clearance. These findings allow us to conclude that the renal impairment in itself is related to impaired EDV.
It is well known that uraemia is associated with dyslipidaemia [19]. Previous studies in animals and humans have demonstrated that hypercholesterolaemia may lead to an impaired delivery of nitrovasodilators to the vascular media and that elevated circulating free fatty acid levels could induce an impaired EDV [3,5,12]. De Gruijter et al. [20] found that an increased level of plasma triglycerides leads to an increased adhesion of monocytes to the endothelium of the vessel wall. In the present study, total serum cholesterol and serum triglyceride levels were mainly in the normal range in patients with renal failure. Notwithstanding a significant correlation between serum triglycerides and EDV, but not serum cholesterol and EDV was found in the patients with renal failure, indicating that triglyceride metabolism may have an important influence on EDV in this patient group.
It should also kept in mind that different drugs (anti-hypertensive or lipid-lowering drugs) might affect EDV in patients with chronic renal failure.
In conclusion, patients with moderate renal disease have an impaired EDV compared to controls, which indicates that endothelial dysfunction may contribute to the increased cardiovascular morbidity and mortality seen in patients with renal failure.
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Acknowledgments |
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This study was supported by grants from CUWX Counties Renal Patients' Foundation, Swedish Physicians' Society Foundation, and Medical Research Council.
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Notes |
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Correspondence and offprint requests to: Margus Annuk MD, Department of Medical Sciences, Renal Unit, University Hospital, entr 40, SE-751 85 Uppsala, Sweden.
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Revision received 14. 9.00.
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