Studies on effects of calcineurin inhibitor withdrawal on arterial distensibility and endothelial function in renal transplant recipients

Whether withdrawal of calcineurin inhibitors has a beneficial effect on disturbed endothelial function and large artery distensibility in renal transplant recipients is not clear. We studied the effects of cyclosporine A (CsA) withdrawal on arterial compliance and endothelium-dependent flow-mediated vasodilatation (FMD) in a prospective, randomized trial; 24 renal transplant recipients receiving mycophenolate mofetil were randomized to withdrawal (n=12) or continuation of CsA (n=12). At baseline and after 6 months, carotid and brachial artery distensibility coefficients and brachial FMD were measured. Brachial distensibility coefficients increased in both groups (withdrawal: 11.1+/-1-14.9+/-2 10(-3)/kPa, continuation: 10.7+/-1-15.2+/-3 10(-3)/kPa, P<0.05, respectively). However, there was no significant effect of treatment on carotid artery distensibility coefficients, FMD, or graft function. Withdrawal of CsA failed to improve carotid artery distensibility or brachial FMD in patients after renal transplantation. Our data indicate that CsA treatment does not contribute significantly to endothelial dysfunction observed in renal transplant recipients.     

Flow-mediated vasodilation and distensibility of the brachial artery in renal allograft recipients

BACKGROUND: Alterations of large artery function and structure are frequently observed in renal allograft recipients. However, endothelial function has not yet been assessed in this population. METHODS: Flow-mediated vasodilation is a useful index of endothelial function. We measured the diameter and distensibility of the brachial artery at rest using high-resolution ultrasound and Doppler frequency analysis of vessel wall movements in the M mode. Thereafter, changes in brachial artery diameter were measured during reactive hyperemia (after 4 min of forearm occlusion) in 16 cyclosporine-treated renal allograft recipients and 16 normal controls of similar age and sex ratio. Nitroglycerin-mediated vasodilation was measured to assess endothelium-independent vasodilation. Brachial artery blood pressure was measured using an automatic sphygmomanometer, and brachial artery flow was estimated using pulsed Doppler. RESULTS: Distensibility was reduced in renal allograft recipients (5.31 +/- 0. 74 vs. 9.10 +/- 0.94 x 10-3/kPa, P = 0.003, mean +/- sem), while the brachial artery diameter at rest was higher (4.13 +/- 0.14 vs. 3.25 +/- 0.14 mm, P < 0.001). Flow-mediated vasodilation was significantly reduced in renal allograft recipients (0.13 +/- 0.08 vs. 0.60 +/- 0.08 mm or 3 +/- 2 vs. 19 +/- 3%, both P < 0.001). However, nitroglycerin-mediated vasodilation was similar in renal allograft recipients and controls (0.76 +/- 0.10 vs. 0.77 +/- 0.09 mm, NS, or 19 +/- 3 vs. 22 +/- 2%, NS). There were no significant differences in brachial artery flow at rest and during reactive hyperemia between both groups. The impairments of flow-mediated vasodilation and distensibility in renal allograft recipients remained significant after correction for serum cholesterol, creatinine, parathyroid hormone concentrations, end-diastolic diameter, as well as blood pressure levels, and were also present in eight renal allograft recipients not treated with cyclosporine. Flow-mediated vasodilation was not related to distensibility in either group. CONCLUSIONS: The results show impaired endothelial function and reduced brachial artery distensibility in renal allograft recipients. The impairments of flow-mediated vasodilation and distensibility are not attributable to a diminished brachial artery vasodilator capacity, because endothelium-independent vasodilation was preserved in renal allograft recipients.     

Statin therapy improves brachial artery endothelial function in nephrotic syndrome

BACKGROUND: Patients with nephrotic syndrome have impaired endothelial function probably related to dyslipidemia. This study evaluated the effects of statin therapy on dyslipidemia and endothelial function in patients with nephrotic syndrome. METHODS: A sequential, open-label study of the effects of statins on endothelial dysfunction in 10 nephrotic patients treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II (Ang II) receptor antagonist. Endothelial function was assessed at baseline, after 12 weeks of treatment with statins, and after an 8-week washout. Brachial artery endothelial function was measured as post-ischemic flow-mediated dilation (FMD) using ultrasonography. Endothelium-independent, glyceryl trinitrate-mediated vasodilation (GTNMD) also was measured. RESULTS: Serum lipids were significantly lower following statin: total cholesterol mean 8.2 +/- 0.4 (standard error) mmol/L versus 5.2 +/- 0.3 mmol/L, triglycerides 2.6 +/- 0.4 mmol/L versus 1.6 +/- 0.2 mmol/L, non-HDL-cholesterol 6.7 +/- 0.4 mmol/L versus 3.7 +/- 0.2 mmol/L (all P < 0.001). There was a trend to an increase in serum albumin (31.0 +/- 1.3 g/L vs. 33.8 +/- 1.5 g/L; P = 0.078) and FMD improved significantly following treatment (3.7 +/- 1.1% vs. 7.0 +/- 0.8%, P < 0.01). After washout, FMD deteriorated significantly to 3.5 +/- 1.4% (P < 0.05) versus week 12 FMD. GTNMD was unchanged. In multivariate regression, reduction in non-high-density lipoprotein (HDL)-cholesterol (beta - 0.736, P = 0.027) and increase in serum albumin (beta 0.723, P = 0.028), but not the on-treatment level of non-HDL-cholesterol, were significant independent predictors of improvement in FMD after adjusting for change in resting brachial artery diameter. Changes in serum lipoprotein and albumin concentrations off treatment were not associated with deterioration in FMD. CONCLUSION: Statin therapy significantly improves dyslipidemia and brachial artery endothelial function in patients with nephrotic syndrome. Improvement in brachial artery endothelial function may be in part related to a non-lipid effect of statins. The findings also suggest a role for dyslipidemia in endothelial dysfunction and the risk for cardiovascular disease in nephrotic syndrome.     

Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk

OBJECTIVE: Erectile dysfunction (ED) is often associated with a cluster of risk factors for coronary artery disease and reduced endothelial function. Acute and chronic administration of oral sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, improves endothelial function in patients with ED. Tadalafil (TAD) is a new PDE5 inhibitor with a long half life that allows alternate day administration. Aim of the study was to evaluate whether chronic therapy (4 weeks) with TAD improves endothelial function in patients with increased cardiovascular risk and whether this effect is sustained after discontinuation of therapy. METHODS: We randomized 32 patients with increased cardiovascular risk to receive either TAD 20 mg on alternate days or matching placebo (PLB) for 4 weeks. Patients underwent evaluation of brachial artery flow-mediated dilation (FMD), nitrite/nitrate and endothelin-1 plasma levels at baseline, at the end of treatment period and after two-weeks follow-up. RESULTS: At 4 weeks, FMD was significantly improved by TAD (from 4.2+/-3.2 to 9.3+/-3.7%, p<0.01 vs. baseline), but was not modified by PLB (from 4.1+/-2.8 to 4.0+/-3.4%, p=NS). At 6 weeks the benefit in FMD was sustained in patients that received TAD (9.1+/-3.9% vs. 4.2+/-3.2%, p=0.01 vs. baseline; 9.1+/-3.9% vs. 9.3+/-3.7%, vs. 4 weeks, p=NS) while no changes in FMD were observed in patients randomized to PLB. Also, compared to baseline, a net increase in nitrite/nitrate levels (38.2+/-12.3 vs. 52.6+/-11.7 and 51.1+/-3.1, p<0.05) and a decrease in endothelin-1 levels (3.3+/-0.9 vs. 2.9.+/-0.7 and 2.9+/-0.9, p<0.05) was found both at four and six-weeks after TAD; these changes were inversely correlated as shown by regression analysis (adjusted R2=0.81, p<0.0001). CONCLUSIONS: Chronic therapy with TAD improves endothelial function in patients with increased cardiovascular risk regardless their degree of ED. The benefit of this therapy is sustained for at least two weeks after the discontinuation of therapy. Larger studies are needed in order to assess the possible clinical implications of chronic therapy with TAD.     

Arterial distensibility and pulse wave velocity in patients with primary hyperparathyroidism before and after parathyroidectomy

AIMS: There is evidence that secondary hyperparathyroidism alters arterial vessel wall properties. However, it is unclear whether effects of parathyroid hormone (PTH) on the vascular wall are direct or permissive and related to hypertension and renal failure. To assess early direct effects of PTH on large artery wall properties isobaric distensibility (DC), pulse wave velocity (PWV) and intima-media thickness (IMT) were studied before and after parathyroidectomy (Ptx) in patients with primary hyperparathyroidism (pHPT). METHODS: DC and IMT of the brachial and carotid artery were measured by echo-tracking and tonometry, PWV by the automatic Complior-device at baseline and 6 months after Ptx in 20 patients with pHPT (data mean +/- SEM, age 45+/-5 years, PTH 240+/-61 ng/l). Cardiovascular risk factors like diabetes, hypertension, renal insufficiency and hypercholesterolemia were excluded. Twenty healthy volunteers matched for age, sex and blood pressure served as controls. RESULTS: Six months after Ptx, PTH decreased to normal; however, blood pressure levels and vessel wall parameter remained unchanged. At baseline, there were no significant differences in brachial and carotid IMT (0.48+/-0.04 and 0.62+/-0.04 mm vs. 0.47+/-0.06 and 0.61+/-0.06 mm), radial and aortic PWV (9.1+/-0.4 and 9.9+/-0.7 m/s vs. 9.2+/-0.5 and 10.0+/-0.6 m/s), brachial and isobaric carotid DC (10.1+/-1.4 and 19.5+/-3.4 10(-3)/kPa vs. 9.1+/-0.9 and 20.4+/-3.2 10(-3)/kPa) or artery diameter between patients and controls. CONCLUSIONS: Structural and viscoelastic properties of large arteries are not disturbed and not influenced by parathyroidectomy in patients with early pHPT devoid of hypertension and renal disease. We conclude that increased PTH levels per se are not associated with alterations of mechanical arteriall wall properties; permissive factors like renal insufficiency may be necessary to mediate vessel wall alterations in patients with hyperparathyroidism.     

Vascular defect beyond the endothelium in type II diabetic patients with overt nephropathy and moderate renal insufficiency

There is a paucity of data on the effects of overt nephropathy and moderate renal impairment on endothelial function in diabetic patients. A total of 26 type II diabetic (DM) patients with nephropathy (DMN+) (mean +/- s.d. age: 63.7 +/- 6.3 years), 32 diabetic patients without nephropathy (DMN-) (59.4 +/- 10.1 years), and 52 non-diabetic subjects (54.9 +/- 8.2 years) were recruited. High-resolution ultrasound scan was used to measure carotid intima media thickness (IMT) and flow-mediated dilation (FMD) of the brachial artery. Endothelium-independent dilation was determined by maximal vascular dilation after sublingual nitroglycerine (glyceryl trinitrate (GTN)-induced dilation). The mean carotid IMT increased progressively from non-DM to DMN- to DMN+ groups (0.74 +/- 0.23 vs 0.80 +/- 0.25 vs 1.03 +/- 0.38 mm; P=0.001 for trend) whereas FMD- (4.3 +/- 2.5 vs 3.9 +/- 1.7 vs 1.9 +/- 2.0%, P<0.001 for trend) and GTN-induced dilation (14.7 +/- 4.0 vs 14.5 +/- 3.9 vs 10.3 +/- 3.2%; P<0.001 for trend) declined in an opposite manner. On multivariate analysis, age (beta=0.257, P=0.009), glomerular filtration rate (beta=-0.364, P<0.001), and smoking (beta=0.25, P=0.013) were independently associated with carotid IMT (F=15.76, R(2)=0.340, P<0.001). After adjustment for baseline brachial arterial diameter, history of smoking (beta=-0.039, P<0.001), fasting plasma glucose (beta=-0.033, P=0.002), and total cholesterol (beta=-0.023, P=0.024) were independently associated with vessel diameter after FMD (F=2446.5, R(2)=0.992, P<0.001); whereas age (beta=-0.069, P=0.001) and urinary albumin excretion (beta=-0.048, P=0.018) were independently associated with vessel diameter after GTN (F=851.6, R(2)=0.967, P<0.001). Type II diabetic patients with overt nephropathy and moderate renal impairment had both structural and functional vascular abnormalities beyond the endothelium.     

Angioplasty does not affect subsequent operative renal artery revascularization

BACKGROUND: Although increased application of percutaneous renal artery angioplasty and stenting has facilitated nonoperative renal revascularization, patient outcomes after failed angioplasty are not established. METHODS: Renal artery revascularization was performed in 31 patients (38 arteries) from 1993 to 1999. Twenty patients underwent primary surgical repair, and 11 patients underwent secondary reconstruction after angioplasty (n = 7) or angioplasty and stenting (n = 4). Before operation, all patients had severe hypertension (blood pressure 166+/-5.2/92 +/- 2.7 mm Hg) that required an average of 3.0 +/- 0.2 medications for control. In addition, 12 patients (primary 45% vs secondary 27%; P = NS) had evidence of renal insufficiency (creatinine > or =1.7 mg/dL). RESULTS: There was no difference between primary and secondary procedures in the length of hospital stay (12+/- 1.4 vs. 12+/-3.2 days; P = NS), major morbidity (10% vs. 18%; P = NS) or perioperative mortality (overall mortality 2 of 31; primary 5% vs secondary 9%; P = NS). The majority of patients demonstrated improvement or cure of hypertension (primary 94% vs secondary 90%; P = NS) and stable or decreased creatinine (primary 74% vs secondary 82%; P = not significant). Overall survival (mean follow-up 22+/-3.5 months) was 89%+/-5.7%. CONCLUSIONS: Although this surgical series does not address the true outcomes of renal artery angioplasty, the results suggest that renal artery angioplasty does not prejudice subsequent surgical outcomes in patients who are carefully followed after angioplasty.     

Acute effects of haemodialysis on endothelial function and large artery elasticity.

BACKGROUND: Disturbances of functional properties of large arteries contribute to increased cardiovascular morbidity and mortality in patients with end-stage renal disease. However, it is not clear whether haemodialysis per se acutely affects mechanical vessel wall properties or endothelial function. METHODS: Twenty-five chronic haemodialysis patients (mean+/-standard error of the mean (SEM): age 52+/-5 years; time on dialysis 63+/-7 months; blood pressure 132+/-4/72+/-2 mmHg) were studied before and immediately after a haemodialysis (HD) session using a polysulphone dialyser (ultrafiltration 1460+/-54 ml), as well as on the following day. Blood pressure was measured with an automatic sphygmomanometer and applanation tonometry. End-diastolic diameter and distension of the brachial and carotid arteries were measured by Doppler frequency analysis of vessel wall movements in M-mode using a multigate pulsed Doppler system and aortic pulse wave velocity (PWV) by an automatic device (Complior). Endothelial function was determined as brachial artery flow-mediated dilation (FMD) and compared with endothelium-independent nitroglycerine-induced dilation (NMD). RESULTS: FMD was 7.9+/-1.8% in patients before HD and did not change significantly after HD or in the dialysis-free intervall (6.7+/-2.1 and 7.1+/-2.0%, respectively; NS). The same was true for NMD and PWV (12.6+/-0.8 m/s before HD, 12.8+/-0.8 m/s after HD, and 11.9+/-0.7 m/s on the HD-free day). Carotid distensibility coefficients decreased significantly during HD (from 18.1+/-1.9 x 10(-3)/kPa to 16.7+/-2.2 x 10(-3)/kPa, P<0.05) and increased again on the HD-free day (19.8+/-2.4 x 10(-3)/kPa). However, when corrected for blood pressure by tonometry, isobaric carotid distensibility did not change significantly. Brachial artery distensibility also did not show significant acute changes. CONCLUSIONS: Haemodialysis per se did not have a significant effect on endothelial function or large artery mechanical vessel wall properties in patients on maintenance dialysis therapy.     

Forearm vascular tone and reactivity during lumbar epidural anesthesia

Forearm vascular tone and sympathetic reactivity were investigated in ten unpremedicated patients during two levels of epidural sensory blockade, neither of which levels was high enough to block cardiac sympathetic pathways. An 8-MHz pulsed Doppler blood flowmeter was used to determine brachial artery diameter and flow characteristics. Measurements were made before and during sympathetic stimulation induced by a contralateral isometric handgrip. The lower level of sensory blockade (T11) in the absence of sympathetic stimulation was associated with decreases in right atrial pressure, brachial artery diameter (3.9 +/- 0.2 vs 4.2 +/- 0.2 mm, P less than 0.05) and brachial blood flow (42 +/- 5 vs 66 +/- 7 ml.min-1, p less than 0.001), whereas forearm vascular resistance increased significantly (2.2 +/- 0.3 vs 1.5 +/- 0.2 mm Hg.ml-1.min-1, P less than 0.01). Neither heart rate nor mean arterial pressure changed. At the higher level of blockade (T7), right atrial pressure and systemic arterial pressure decreased further without change in heart rate. Brachial artery diameter (3.8 +/- 0.2 mm) remained unchanged while brachial blood flow additionally decreased (30 +/- 3 ml.min, P less than 0.05), and forearm vascular resistances further increased (3.0 +/- 0.2 mm Hg.ml-1.min-1, P less than 0.01). Changes in heart rate and in mean arterial pressure associated with isometric exercise were similar before and during epidural anesthesia at both levels of epidural blockade.(ABSTRACT TRUNCATED AT 250 WORDS)     

Insulin resistance, dyslipidaemia, inflammation and endothelial function in nephrotic syndrome.

BACKGROUND: Nephrotic syndrome (NS) is associated with an increased risk of cardiovascular disease (CVD). We have shown previously that endothelial function, measured by post-ischaemic flow-mediated dilatation (FMD) of the brachial artery, is impaired in NS. In this study our aim was to assess the potential roles of insulin resistance, plasma non-esterified fatty acids (NEFAs) and inflammation in endothelial dysfunction in NS patients. METHODS: FMD was compared between NS patients (n=19) and controls (CS, n=19). Plasma glucose, insulin and NEFAs were measured. Insulin resistance was calculated using the Homeostasis Model Assessment (HOMA) score. C-reactive protein (CRP), interleukin-6 (IL-6), tumour necrosis factor alpha (TNFalpha) and fibrinogen were measured as markers of inflammation. RESULTS: FMD was significantly lower in the NS group (mean+/-standard error, NS 5.1+/-0.7%, CS 7.3+/-0.7%, P=0.02). Fasting insulin (NS 12.5+/-1.5 mU/l, CS 6.8+/-0.7 mU/l, P<0.01), fasting glucose (NS 5.3+/-0.2, CS 4.8+/-0.1, P=0.02) and the HOMA score (NS 3.0+/-0.4, CS 1.5+/-0.2, P=0.001) were significantly higher in NS. These differences persisted after adjusting for waist circumference. Of the inflammatory markers, only fibrinogen (P<0.01) and IL-6 (P=0.01) were significantly increased in NS. Despite significantly lower plasma NEFAs in NS, the NEFA:albumin ratio showed a non-significant trend to higher levels in NS (NS 10.7+/-0.1 micro mol/g, CS 8.7+/-0.1 micro mol/g, P=0.06). Within the NS group, multivariate backward regression analysis showed that NEFAs (P<0.01) and low-density lipoprotein (LDL) cholesterol (P=0.05) were significant negative independent predictors of FMD. CONCLUSION: Endothelial function in NS is inversely correlated with plasma concentrations of NEFAs and LDL cholesterol. Dyslipoproteinaemia and NEFAs probably contribute to the increased risk of CVD seen in NS. We also postulate that in NS, hypoalbuminaemia increases the delivery of NEFAs to endothelial cells thereby impairing the synthesis and release of nitric oxide.     

Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle

We have previously shown that skeletal muscle capillaries are rapidly recruited by physiological doses of insulin in both humans and animals. This facilitates glucose and insulin delivery to muscle, thus augmenting glucose uptake. In obese rats, both insulin-mediated microvascular recruitment and glucose uptake are diminished; however, this action of insulin has not been studied in obese humans. Here we used contrast ultrasound to measure microvascular blood volume (MBV) (an index of microvascular recruitment) in the forearm flexor muscles of lean and obese adults before and after a 120-min euglycemic-hyperinsulinemic (1 mU . min(-1) . kg(-1)) clamp. We also measured brachial artery flow, fasting lipid profile, and anthropomorphic variables. Fasting plasma glucose (5.4 +/- 0.1 vs. 5.1 +/- 0.1 mmol/l, P = 0.05), insulin (79 +/- 11 vs. 38 +/- 6 pmol/l, P = 0.003), and percent body fat (44 +/- 2 vs. 25 +/- 2%, P = 0.001) were higher in the obese than the lean adults. After 2 h of insulin infusion, whole-body glucose infusion rate was significantly lower in the obese versus lean group (19.3 +/- 3.2 and 37.4 +/- 2.6 mumol . min(-1) . kg(-1) respectively, P < 0.001). Compared with baseline, insulin increased MBV in the lean (18.7 +/- 3.3 to 25.0 +/- 4.1, P = 0.019) but not in the obese group (20.4 +/- 3.6 to 18.8 +/- 3.8, NS). Insulin increased brachial artery diameter and flow in the lean but not in the obese group. We observed a significant, negative correlation between DeltaMBV and BMI (R = -0.482, P = 0.027) in response to insulin. In conclusion, obesity eliminated the insulin-stimulated muscle microvascular recruitment and increased brachial artery blood flow seen in lean individuals.     

Dialysis filter type determines the acute effect of haemodialysis on endothelial function and oxidative stress.

BACKGROUND: Endothelial function of large arteries is impaired in chronic haemodialysis patients and oxidative stress due to the dialysis procedure has been suggested as a causal factor. However, it is not clear whether different types of dialysis membranes affect endothelial function differently. Therefore we determined endothelium-dependent, flow-mediated dilatation (FMD) of the brachial artery as well as markers of oxidative stress immediately before and after haemodialysis (HD) with either a cellulosic cuprophane or a synthetic polysulphone dialyser in a blinded, randomized, cross-over study. METHODS: Twelve haemodialysis patients (age 55+/-3 years, time on dialysis 20+/-2 months, mean fluid change -1782+/-21 ml, systolic/diastolic blood pressure 139/75 mmHg) were included. Using a multi-gate-pulsed Doppler system (echo-tracking device) brachial artery FMD and nitroglycerine-induced, endothelium-independent vasodilatation (NMD) were measured. Patients were randomized to HD with either a polysulphone or a cuprophane membrane and were crossed over to the other filter. Investigators were blinded to the type of membrane used. Serum concentrations of oxidized LDL (oxLDL) and alpha-tocopherol as markers of oxidative stress were measured before and after each dialysis session. RESULTS: Data are given as mean+/-SEM. Treatment with polysulphone filter HD did not significantly affect FMD (baseline 9.3+/-2.0% vs after HD 9.6+/-1.8%). After dialysis with a cuprophane membrane FMD decreased from 9.4+/-2.1 to 7.4+/-1.8% (P<0.05). NMD was not significantly affected by HD irrespective of the membrane material used. Serum levels of oxLDL were not changed by either treatment; however, alpha-tocopherol concentrations fell significantly after dialysis with the cuprophane filter (baseline 18.0+/-2.3 after HD 16.6+/-1.3 micro g/ml, P<0.05), while alpha-tocopherol levels remained unchanged when the polysulphone membrane was used. CONCLUSIONS: The type of dialysis filter membrane determines the acute effect of haemodialysis on arterial endothelial function. Differences in biocompatibility and oxidative stress may account for the observed differential effects, since the decrease of FMD after dialysis with a cellulosic cuprophane membrane-but not with a synthetic polysulphone membrane-was associated with a reduction in serum vitamin E.     

The effect of occult diabetic status and oral glucose intake on brachial artery vasoactivity in patients with peripheral vascular disease.

Brachial artery vasoactivity is a well known non-invasive method of assessing arterial endothelial function in vivo. Brachial artery vasoactivity has been found to be impaired in overt diabetes and in patients with coronary artery disease. Impaired brachial artery vasoactivity is felt to be an early indicator of atherosclerosis. The authors identified a group of patients with lower extremity peripheral vascular disease, who had normal fasting glucose level and were not known to be diabetics. An oral glucose tolerance test was performed in this group of patients. Brachial artery vasoactivity was assessed at each step of the oral glucose tolerance test to examine their occult diabetic status and correlate brachial artery vasoactivity to that status. The authors studied 23 randomly selected patients from the vascular surgery clinic between the ages of 50 and 79 years. Serum glucose level was assessed after a 10-h fast and at 30, 60 and 120 min after a 75-g oral glucose challenge. Any patient with two serum glucose values > 140 mg/dl was considered to have a positive oral glucose tolerance test. Using duplex ultrasound, the brachial artery diameter (cm) and blood volume (ml/min) were assessed before and after tourniquet occlusion at each step of the oral glucose tolerance test. Paired and unpaired t-tests were used to evaluate the results, P < 0.05 was considered significant. Nine patients had abnormal oral glucose tolerance test for a prevalence of 39%. There was no significant difference in fasting glucose levels between positive and negative oral glucose tolerance test patients (97.4+/-16.7 versus 88.5+/-5.8, P = 0.23). Patients with a positive oral glucose tolerance test had impaired vasoactivity at fasting and at each step of the test with no significant changes in brachial artery diameter or blood flow in response to brachial artery occlusion. Patients with a negative oral glucose tolerance test exhibited increased brachial artery diameter at fasting in response to brachial artery occlusion (0.43+/-0.02 versus 0.46+/-0.02, P = 0.03), but not after oral glucose challenge. In patients with a negative oral glucose tolerance test, brachial artery flow volume increased significantly in response to hyperemia at fasting (240+/-61 versus 578+/-262, P = 0.001) and at 30 min after glucose intake (260+/-53 versus 358+/-72, P = 0.01). At 60 and 120 min after glucose intake, brachial artery flow volume did not significantly increase in response to brachial artery occlusion. These results indicate that individuals with PVD and normal fasting glucose levels have a high prevalence of positive oral glucose tolerance test (39%). Patients with normal fasting glucose levels and abnormal oral glucose tolerance test have impaired brachial artery vasoactivity at fasting and after oral glucose challenge, this is in contrast to patients with normal oral glucose tolerance test who have normal fasting hyperemic response to brachial artery occlusion. However, this normal brachial artery vasoactivity is lost in the negative oral glucose tolerance test group in response to oral glucose load. These results suggest that endothelial function in diabetics is impaired in the early stages of the disease even before overt hyperglycemia occurs. Tight control of blood glucose level in glucose-intolerant patients prior to occurrence of overt fasting hyperglycemia may prove protective.     

Endothelial dysfunction and oxidative stress in chronic renal failure

Uremic patients have an increased incidence of cardiovascular disease (CVD), endothelial dysfunction and oxidative stress that can contribute to cardiovascular (CV) events. To assess the relationship between endothelial dysfunction, oxidative stress and renal failure severity, we studied 40 patients (age 57 +/- 7 yrs, 24 males) affected by chronic kidney disease (CKD) K/DOQI stage 3-5 (serum creatinine (Cr) 5.6 +/- 2.2 mg/dL) on conservative treatment, 20 uremic patients (age 57 +/- 12 yrs, 13 males) on hemodialysis (HD) and 30 healthy controls (56 +/- 12 yrs, 20 males). Before and 2 hr after oral vitamin C (2 g) administration, we measured brachial artery endothelium-dependent vasodilation (flow mediated dilation (FMD)) to reactive hyperemia following 5 min of forearm ischemia and the response to sublingual glyceril trinitrate (GTN). Measurements were made by high-resolution ultrasound and computerized analysis. FMD was lower in CKD patients than in controls (5.3 +/- 2.2 vs. 6.9 +/- 2.8%; p<0.01) and was further reduced in HD patients (3.6 +/- 2.7; p<0.01 vs. CKD patients). Response to GTN was similar in all groups. FMD was related to Cr clearance (r=0.42; p<0.01) in CKD patients, while it related inversely to Kt/V(urea) (r=-0.52; p<0.05) in HD patients. After vitamin C administration, FMD was significantly enhanced in HD (4.7 +/- 2.4%; p<0.01 vs. baseline), but not in CKD patients. Response to GTN was unaffected. However, vitamin C load reduced oxidative stress markers, and increased plasma antioxidant capability in both groups. In conclusion, the reduced endothelium-dependent dilation in the brachial artery of CKD patients is related to renal failure severity. HD patients showed a more marked alteration, which seems to be related, at least in part, to increased oxidative stress.     

Effect of renal transplantation on endothelial function in haemodialysis patients.

BACKGROUND: Haemodialysis patients (HD) have been characterized by a high incidence and prevalence of atherosclerotic cardiovascular disease. Based on the traditional cardiovascular risk factors in this population, we cannot explain this high incidence and prevalence. One of the mechanisms contributing to cardiovascular risk in HD patients may be to uraemic toxins. Cardiovascular risk factors and uraemic toxins themselves may cause endothelial dysfunction, which may play a pivotal role in the development and progression of atherosclerosis in this population. We hypothesized that elimination of uraemic toxins in response to renal transplantation (RTx) can improve endothelial function as assessed by flow-mediated dilatation of brachial artery in haemodialysis (HD) patients. METHODS: Endothelial function measured by flow-mediated dilatation of the brachial artery (FMD) and glyceryltrinitrate-induced dilatation of the brachial artery (NMD) were assessed twice, during haemodialysis treatment and after RTx in 30 chronic haemodialysis patients. All patients were characterized by absence of known atherosclerotic disease and traditional cardiovascular risk factors. We also studied age- and gender-matched 20 normotensive healthy controls. RESULTS: FMD values significantly improved after RTx (6.69+/-3.1% vs 10.50+/-3.0%, P<0.001) in HD patients. FMD of patients both during haemodialysis and after RTx was lower than in healthy controls (6.69+/-3.1%, 10.50+/-3.0% vs 14.02+/-2.3%, P<0.001 and P<0.01, respectively). There was no change in NMD values after RTx in HD patients (16.27+/-1.9% vs 16.30+/-1.8%, P>0.05). Also, NMD values in all patients were similar to healthy control values. CONCLUSIONS: There is an improvement of endothelial function as assessed by FMD of the brachial artery after RTx in HD patients. This may be attributed to the elimination of uraemic toxins by successful RTx.     

Soy protein diet improves endothelial dysfunction in renal transplant patients.

BACKGROUND: Since it has been demonstrated that soy diet can improve endothelial function, in the present study we evaluated the effect of dietary substitution of 25 g of animal proteins with soy proteins on endothelial dysfunction in renal transplant patients. METHODS: In 20 renal transplant patients (55 +/- 11 years, serum creatinine 1.7 +/- 0.6 mg/dl), brachial artery flow mediated dilation (FMD) and endothelium-independent vasodilation (sublingual nitroglycerine, 25 microg) were measured at baseline, after 5 weeks of a soy diet and finally after 5 weeks of soy wash-out. Changes in plasma lipids, markers of oxidative stress (lipid peroxides, LOOH) and inflammation (C-reactive protein), isoflavones (genistein and daidzein), asymmetric dimethyl arginine (ADMA) and L-arginine were also evaluated. RESULTS: At baseline, patients showed a significantly lower FMD as compared with age-matched healthy subjects (3.2 +/- 1.8 vs 6.3 +/- 1.9, respectively; P < 0.001), while response to nitroglycerine was similar. After soy diet, actual protein intake was not changed, cholesterol and lipid peroxides were significantly reduced, and isoflavones were detectable in plasma. Soy diet was associated with a significant improvement in FMD (4.4 +/- 2.0; P = 0.003 vs baseline), while response to nitroglycerine was unchanged. Improvement in FMD was related to L-arginine/ADMA ratio changes, but no significant relation was found to changes in cholesterol, lipid peroxides or genistein and daidzein plasma concentrations. After 5 weeks of soy diet discontinuation, FMD (3.3 +/- 1.7%) returned to baseline values and isoflavones were no longer detectable in plasma. CONCLUSIONS: A soy protein diet for 5 weeks improves endothelial function in renal transplant patients. This effect seems to be strictly dependent on soy intake as it disappears after soy withdrawal and is mediated by an increase in the L-arginine/ADMA ratio, independently of change in lipid profile, oxidative stress or isoflavones.     

Surgery after failed percutaneous renal artery angioplasty.

PURPOSE: This retrospective review describes the surgical management of 51 patients after failed percutaneous renal artery angioplasty (F-PTRA). METHODS: From January 1987 through June 1998, 51 consecutive patients underwent surgical repair of either atherosclerotic (32 patients) or fibromuscular dysplastic (FMD; 19 patients) renovascular vascular disease after F-PTRA. These patients form the basis of this report. Surgical repair was performed for hypertension (29 patients with atherosclerosis: mean blood pressure, 205 +/- 34/110 +/- 23 mm Hg; 18 patients with FMD: mean blood pressure, 194 +/- 24/118 +/- 18 mm Hg) or ischemic nephropathy (20 patients with atherosclerosis: mean serum creatinine level, 2.0 +/- 0.8 mg/dL; three patients with FMD: mean serum creatinine level, 2.0 +/- 1.1 mg/dL). Emergency operation was required in four patients for acute renal artery thrombosis (one patient with atherosclerosis, one patient with FMD), renal artery rupture (one patient with atherosclerosis), or infected pseudoaneurysm (one patient with atherosclerosis). Operative management, blood pressure and renal function response to operation, and dialysis-free survival rate were examined and compared with 487 patients (441 patients with atherosclerosis, 46 patients with FMD) treated by operation alone. RESULTS: Among the patients with atherosclerotic renovascular disease, there were three postoperative deaths (9.4%) after repair for F-PTRA. Secondary operative repair was associated with emergent repair or nephrectomy in 16% of cases, while more extensive renal artery exposure and more complex operative management was required in 50% of patients with atherosclerosis and 65% of patients with FMD repaired electively. Among the 28 operative survivors with hypertension and atherosclerotic renovascular disease, blood pressure benefit after F-PTRA was significantly lower when compared with patients with atherosclerosis who underwent treatment with operation only (57% vs 89%; P <.001). However, blood pressure benefit in the 19 patients with FMD did not differ (89% vs 96%). Among the 28 patients with atherosclerosis, preoperative estimated glomerular filtration rate (EGFR) as compared with postoperative EGFR was significantly increased (47.4 +/- 4.2 mL/min/1.73m(2) vs 56. 6 +/- 5.1 mL/min/1.73m(2); P =.002). However, EGFR prior to PTRA was not significantly different from postoperative EGFR (51.6 +/- 3.4 mL/min/1.73m(2) vs 56.6 +/- 4.9 mL/min/1.73m(2); P =.121). As compared with patients with atherosclerosis who underwent treatment with operation alone, there was no difference in the dialysis-free survival rate. CONCLUSION: Operative repair after F-PTRA was altered in 59% of the patients with atherosclerosis and in 68% of patients with FMD. Blood pressure benefit for patients with FMD was unchanged after F-PTRA. However, the blood pressure benefit was significantly decreased among patients with atherosclerosis. Decreased EGFR after F-PTRA was recovered with operative renal artery repair. However, postoperative EGFR as compared with EGFR prior to PTRA was unchanged. Blood pressure and renal function response after F-PTRA for atherosclerotic renovascular disease warrants further study.     

Effect of atorvastatin therapy and conversion to tacrolimus on hypercholesterolemia and endothelial dysfunction after renal transplantation

BACKGROUND: Hypercholesterolemia is a frequent complication in renal transplant patients treated with cyclosporine A (CsA). Whether it is preferable to treat hypercholesterolemia with statins or to switch patients from CsA to tacrolimus (TRL) has not been investigated. METHODS: Twelve CsA-treated kidney transplant recipients with hypercholesterolemia were successively crossed over from CsA alone to: CsA plus atorvastatin; TRL alone; and TRL plus atorvastatin. Total cholesterol (C), Low density lipoprotein (LDL)-C, high density lipoprotein (HDL)-C, LDL and HDL alpha-tocopherol content, lag-time of LDL oxidation, plasma levels of oxidized LDL and the percentage of small dense LDL were assayed at the end of each treatment period. Endothelial function was assessed by high resolution ultrasound measurement of flow-mediated brachial artery vasodilatation (FMD). RESULTS: Atorvastatin therapy was more efficient in reducing total cholesterol and LDL-C levels than conversion from CsA to TRL. Combining TRL with atorvastatin further reduced LDL-C levels as compared to TRL alone, but was no more efficient than the CsA-statin combination. Neither atorvastatin therapy nor conversion to TRL significantly changed the proportion of dense LDL, lipoprotein alpha-tocopherol contents or the lag time of LDL oxidation. Addition of atorvastatin to CsA increased FMD from 4.0+/-1.8% to 6.5+/-4.0% (P<0.05 vs. CsA). Conversion from CsA to TRL caused a slight improvement in FMD (5.1+/-2.1%, P<0.05 vs. CsA). Adding atorvastatin to TRL had no detectable effect on FMD (5.5+/-2.3%, P=NS vs. TRL). CONCLUSIONS: Atorvastatin was more efficient in reducing total and LDL cholesterol levels of CsA-treated renal transplant patients than conversion to TRL and significantly improved endothelial dysfunction.     

Endothelial dysfunction in renal transplant patients is closely related to serum cyclosporine levels

BACKGROUND: Cyclosporine (CsA), one of the standard agents used in renal transplant recipients, has been considered to cause endothelial dysfunction and to contribute to arterial complications posttransplant. Since concentration-dependent effects of CsA on endothelial functions in humans have not been examined, this study was performed to investigate this relationship. METHODS: Fifteen renal transplant patient and 20 healthy subjects (controls) were evaluated for brachial artery endothelial function using high-resolution vascular ultrasound just before the CsA dosage (baseline) and at the second hour after the administration. Endothelium-dependent and -independent vasodilatations (EDD and EID, respectively) were assessed by establishing of the responses to reactive hyperemia and by using sublingual nitroglycerine, respectively. CsA levels were assessed at baseline and at second hour, times when performing brachial artery measurements. RESULTS: There were no significant differences between recipients and controls with respect to atherosclerosis risk factors. Mean EDD of recipients at baseline times were significantly less than those in controls (9.1% +/- 5.5% vs 15.2% +/- 7.2%, respectively; P < .001). CsA levels at trough and at second hour were 153.9 +/- 74.8 ng/mL and 646.8 +/- 163.2 ng/mL, respectively (P < .0001). Recipient, EDD at second hour was significantly reduced compared to baseline values (5.3% +/- 3.6% vs 9.1% +/- 5.5% respectively; P = .014) while changes in EID and in the diameter of the brachial artery between baseline and second hour were insignificant. CONCLUSION: Endothelial dysfunction evaluated by brachial ultrasound in renal transplant recipients is closely related to CsA levels. It is more pronounced at 2 hours after CsA dosage, at the time of peak drug levels.     

Regression of sclerosis in aging by an angiotensin inhibition-induced decrease in PAI-1

BACKGROUND: Glomerular and vascular sclerosis increase with aging, and angiotensin inhibitors ameliorate progression of this injury. We investigated the potential for achieving regression of existing age-related sclerosis, and the mechanisms by which angiotensin type 1 receptor antagonist (AIIRA) may affect remodeling of this sclerosis. We focused on plasminogen activator inhibitor-1 (PAI-1) because it is directly induced by angiotensin, inhibits matrix degradation, and may thus be pivotal in remodeling. METHODS: Eighteen-month-old male Sprague-Dawley rats were treated with the AIIRA losartan (N = 8, 80 mg/L, dry weight), sacrificed at age 21 and 24 months, and compared with age-matched untreated controls (N = 15). Blood pressure and renal function were monitored, and morphological, biochemical, and molecular analyses were done on aorta and kidney. RESULTS: Body weight increased in both groups. Mean arterial pressure (MAP) and serum creatinine remained normal (24-month MAP 115 +/- 8 vs. 113 +/- 6 mm Hg, controls vs. AIIRA, P = NS). Aorta wall thickness ratio was reduced by AIIRA at 21 and 24 months vs. age-matched controls (21 months 0. 12 +/- 0.01 vs. 0.15 +/- 0.01, P = 0.006; 24 months 0.10 +/- 0.005 vs. 0.14 +/- 0.003, AIIRA vs. controls, respectively, P = 0.0027). The aorta wall thickness ratio after treatment with AIIRA for six months was even lower than that of 18-month control rats (P = 0.018). AIIRA reduced proteinuria versus age-matched control at 24 months (253 +/- 62 vs. 390 +/- 51 mg/24 h, P = 0.0017). AIIRA at 24 months decreased glomerulosclerosis versus age-matched control (sclerosis index, 0 to 4+ scale: 0.06 +/- 0.02 vs. 0.49 +/- 0.12, P = 0.0082) to levels even lower than the 18-month baseline (0.37 +/- 0.14, P = 0.014). Renal collagen content increased with aging and was decreased by AIIRA at 24 months (5.0 +/- 0.7 vs. 3.1 +/- 0.5% collagen, P < 0.05). Apoptosis, assessed by TUNEL, was increased in tubular and interstitial cells in aging and was reduced by AIIRA versus control and baseline, respectively (TUNEL scoring, AIIRA 24 months 0.33 +/- 0.16 vs. 1.06 +/- 0.23 and 0.80 +/- 0.05, P < 0.05). PAI-1 mRNA in kidney was decreased at 24 months in AIIRA versus age-matched controls (PAI-1/GAPDH density ratio: AIIRA 24 months 0. 34 +/- 0.05 vs. 24-month controls 0.99 +/- 0.05, P < 0.05). Increased glomerular PAI-1 immunostaining with aging was decreased by AIIRA at 24 months versus age-matched controls, even below baseline (staining score 0 to 4+, 0.57 +/- 0.15 vs. control 0.90 +/- 0.07, P < 0.05; baseline 1.05 +/- 0.02, P < 0.01). CONCLUSION: We conclude that AIIRA not only slows the progression of glomerular and vascular sclerosis in aging, but can also induce regression of these processes. The mechanisms appear to involve modulation of cortical cell turnover and inhibition of PAI-1 expression.