Association between insulin resistance and endothelial dysfunction in renal transplant recipients

BACKGROUND: Endothelial dysfunction is a common finding in renal transplant recipients (RTR) and is related to impaired local regulation of vasodilative and vasoconstrictive substances, such as nitric monoxide (NO) and endothelin-1 (ET-1). In non-transplanted patients, an association between impaired endothelial function and insulin resistance has been shown. Whether such an association also exists in RTR is unknown. OBJECTIVE: The aim of the present study was to examine whether insulin resistance is associated with endothelial dysfunction in RTR. MATERIAL AND METHODS: A total of 47 RTR in a stable phase six yr post-transplant were included in the statistical analysis. The immunosuppressive therapy was based on cyclosporine and prednisolone. Non-invasive assessment of endothelial function was performed with laser Doppler flowmetry of the forearm skin vasculature after local acetylcholine stimulation. Oral glucose tolerance tests comprising both glucose and insulin measurements were used to calculate insulin sensitivity (IS) indices. NO, ET-1 and von Willebrand factor were measured in fasting plasma samples. RESULTS: Normal glucose tolerance was found in 31 RTR. In these subjects, both IS (r(2) = 0.164, p = 0.044) and plasma NO (r(2) = 0.326, p = 0.002) were significantly correlated with endothelial function. Patients with glucose intolerance (n = 16) had higher plasma ET-1 and lower NO levels, but the association between IS and endothelial function was not significant in these subjects. In the total patient cohort, IS and endothelial function tended to be correlated (p = 0.127). CONCLUSIONS: Endothelial dysfunction is significantly associated with insulin resistance in normoglycemic RTR but explains a rather small part of the variation. In glucose-intolerant recipients, IS appears to be more critically dependent on other factors not revealed in the present study.     

Regular physical exercise improves endothelial function in heart transplant recipients

BACKGROUND: Impaired endothelial function is detectable in heart transplant (HTX) recipients and regarded as risk factor for coronary artery disease. We have studied whether endothelial function can be improved in HTX patients participating in a regular physical training program as demonstrated in patients with chronic heart failure, hypertension and coronary artery disease. METHODS: Male HTX patients and healthy, age-matched controls were studied. Seven HTX patients (age: 60 +/- 6 yr; 6 +/- 2 yr of HTX) participated in an outpatient training program, six HTX patients (age: 63 +/- 8 yr; 7 +/- 1 yr of HTX) maintained a sedentary lifestyle without regular physical exercise since transplantation. A healthy control group comprised six subjects (age: 62 +/- 6 yr). Vascular function was assessed by flow-mediated dilation of the brachial artery (FMD). Systemic haemodynamic responses to intravenous infusion of the endothelium independent vasodilator sodium nitroprusside (SNP) and to NG-monomethyl-L-arginine (L-NMMA), an inhibitor of constitutive nitric oxide synthase, were also measured. RESULTS: Resting heart rate was significantly lower (p < 0.05) in healthy controls (66 +/- 13) than in the HTX training group (83 +/- 11) and in non-training HTX patients (91 +/- 9), baseline blood pressure also tended to be lower in healthy subjects and in the training HTX patients. FMD was significantly higher (p < 0.05) in the control group (8.4 +/- 2.2%) and in the training group (7.1 +/- 2.4%), compared with non-training HTX patients (1.4 +/- 0.8%). The response of systolic blood pressure (p = 0.08) and heart rate (p < 0.05) to L-NMMA was reduced in sedentary HTX patients compared with healthy controls and heart rate response to SNP was also impaired in sedentary HTX patients. DISCUSSION: Regular aerobic physical training restores vascular function in HTX patients, who are at considerable risk for developing vascular complications. This effect is demonstrable in conduit and systemic resistance arteries.     

Peripheral vascular disease in heart transplant recipients.

The improved longevity of heart transplant recipients demands heightened awareness of the long-term complications of the procedure. Between 1979 and 1990, 232 patients received 241 heart transplants at our institution. Accelerated coronary atherosclerosis occurred in 45 (19%) of the 232 patients, typically appearing within 2 years of transplantation, whereas peripheral vascular disease (PVD) appeared in 23 (10%) of the 232 patients, usually within 3 years of transplantation. In the patients with PVD, 13 had occlusive disease, nine had aneurysms, and one patient suffered a vertebral artery dissection. Accelerated coronary atherosclerosis afflicted 12 (52%) of the 23 patients affected by PVD (p < 0.05) and preceded the development of PVD in all 12. Logistic regression analysis revealed risk factors predictive of the development of PVD after transplantation to be a pretransplant history of ischemic cardiomyopathy and posttransplant hypertension and hypertriglyceridemia (p < 0.05), with the presence of more than one risk factor increasing the probability of development of PVD. Those patients thus identified as at risk should be closely monitored for the development of PVD. Aggressive medical management of hypertension and hyperlipidemia in this subpopulation may forestall or prevent the development of peripheral vascular disease after heart transplantation.     

Hepatic dysfunction in kidney transplant recipients: prevalence and impact on graft and patient survival

Background Liver disease has emerged as an important cause of morbidity and mortality in renal transplant recipients. Liver insufficiency is the cause of death in up to 28% of long-term survivors after renal transplantation. The aim of this work was to evaluate the prevalence and causes of hepatic dysfunction in renal transplant recipients in Egypt, and its impact on both renal graft function and patient survival. Methods This study comprised 447 kidney transplant recipients who received their grafts between January 1999 and December 2003 at Mansoura Urology and Nephrology Center. Among these recipients, 104 patients showed persistent hepatic dysfunction, while the remaining 343 had normal liver function or transient hepatic dysfunction of less than 6 months’ duration. Results We found that the prevalence of persistent hepatic dysfunction in our recipients was 23.3%. Infections such as hepatitis C virus (HCV;, with longer dialysis duration and blood transfusion as risk factors), HBV, and cytomegalovirus (CMV), were the main causes of persistent hepatic dysfunction. Drugs (e.g., the sirolimus and tacrolimus; cyclosporine; and azathioprine) were also associated with hepatic dysfunction. We did not find a significant impact of hepatic dysfunction on either patient or graft survival. Conclusions Viral infections–especially HCV and CMV–were more prevalent in the group of patients with persistent hepatic dysfunction, with duration of dialysis as an important risk factor for HCV infection. Dose-dependent cyclosporine-induced hepatic dysfunction was observed early post-transplant. Neither tacrolimus- nor sirolimus-associated hepatic dysfunction was dose-dependent. Hepatic dysfunction had no significant impact on either patient or graft survival; however, this finding may be due to the relatively short duration of follow up.     

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.     

Microalbuminuria: a marker of systemic endothelial dysfunction during burn excision

INTRODUCTION: Systemic endothelial dysfunction characterises both burn injury and surgery and can be monitored by serial immunoassay of urine albumin (microalbuminuria). The aim of this study was to assess microalbuminuria before and during burn excision and identify factors that may influence it. METHODS: Serial half-hourly urine albumin/creatinine ratio (ACR, normal <2.3mg/mmol) was measured in 25 adult patients during 44 burn-excision procedures, at a median of 5 days post-injury. Median total body surface area (TBSA) excised was 12%. RESULTS: Pre-operative median ACR was normal rising to 3.25mg/mmol at 1.5h of surgery (p<0.05). Per-operative ACR at 0.5, 1, 2 and 2.5h were all associated with % TBSA burn excised (p<0.04). Median intraoperative ACR at 1h was 2.3mg/mmol for surgery within 48h post-injury, 1.6 for surgery at 2-7 days and 25.5 during excisions later than 1 month after injury (p<0.05). ACR at 1h was associated with CRP at 48h post-surgery (p=0.04). Per-operative ACR was also significantly correlated with post-operative complications. CONCLUSION: Systemic endothelial dysfunction of acute thermal injury assessed by microalbuminuria recurs with surgery, is minimal at 2-7 days post-burn and affected by % TBSA burn excised and post-operative complications.     

Endothelial function is more impaired in hemodialysis patients than renal transplant recipients

BACKGROUND: Endothelial dysfunction (ED) is a common precursor and denominator of cardiovascular events including development of atherosclerosis. In this cross-sectional, controlled study, we aimed to investigate ED measured by ischemia-induced forearm vasodilatation in chronic hemodialysis (HD) patients and renal transplant recipients (rTX). PATIENTS AND METHODS: Thirty-nine HD patients, 39 rTX and 38 normotensive healthy controls were included. There was no difference in age and gender distribution among the study groups. The mean time spent on dialysis and transplantation were 74 +/- 46 and 68 +/- 39 months. Serum high sensitive C-reactive protein (hs-CRP) and plasma fibrinogen levels were measured. Endothelium dependent post-ischemic vasodilatation of brachial artery was used to evaluate ED. RESULTS: The hs-CRP and plasma fibrinogen levels were significantly increased in HD patients when compared with rTX. On high resolution ultrasonographic examination, post-ischemic vasodilatation values in HD patients (9.55 +/- 6.47%) were significantly lower than rTX (14.39 +/- 8.06%, p = 0.007) and controls (20.42 +/- 6.10%, p < 0.001). Renal transplant recipients also had significantly lower post-ischemic vasodilatation values than controls (p = 0.001). The hs-CRP levels were negatively correlated with endothelium-dependent dilatations in TX (r = -0.59, p = 0.001), however, this correlation was not detected in HDp. CONCLUSION: Patients with end-stage renal disease have ED. Endothelial function is more impaired in HD patients than rTX. Different mechanisms might be responsible for ED in HD patients and rTX.     

Peripheral neuropathy: an underdiagnosed cause of erectile dysfunction

OBJECTIVES

? To assess the prevalence of peripheral neuropathy in patients with erectile dysfunction (ED). ? To evaluate the reliability of clinical tests such as the five‐item version of the International Index of Erectile Function (IIEF‐5) and the Neuropathy Symptom Score (NSS) classification system in predicting the concurrence of peripheral neuropathy.

PATIENTS AND METHODS

? We studied 90 patients who were consecutively recruited from the Department of Andrology of the Central Hospital of Asturias. ? Anamnesis included questions about risk factors related to ED. ? The severity of ED was classified according to IIEF‐5 scores and symptoms of peripheral neuropathy were assessed using the NSS. ? Neurophysiological tests included electromyography, nerve conduction studies, evoked potentials from pudendal and tibial nerves as well as bulbocavernosus reflex. ? Small fibre function was assessed using quantitative sensory tests and sympathetic skin response. Statistical analysis was performed using the SPSS‐11 program.

RESULTS

? Patients with more severe symptoms of peripheral neuropathy showed lower (worse) IIEF‐5 scores (P= 0.015) and required more aggressive therapies (P < 0.001). ? Neurophysiological exploration confirmed neurological pathology in 68.9% of patients, of whom 7.8% had myelopathy and 61.1% peripheral neuropathy. ? Polyneuropathy was found in 37.8% of the patients, of whom 8.9% had pure small fibre polyneuropathy, and pudendal neuropathy was diagnosed in 14.4%. ? No association between neurophysiological diagnosis and IIEF‐5 score was detected, but a statistical association was found between neuropathy and NSS scores.

CONCLUSIONS

? Up to now, the impact of peripheral neuropathy in the pathogenesis of ED has been underestimated. The combination of anamnesis and an ad hoc neurophysiological protocol showed its high prevalence and provided a more accurate prognosis. ? In future, clinical practice should optimize the assessment of pelvic small fibre function.     

The effect of calcineurin inhibitors on endothelial function in renal transplant recipients

Endothelial dysfunction is of vital importance, as it may cause ischemia and dysfunction in various organs. Despite, this problem has been well documented in patients with end-stage renal disease (ESRD), there is not enough data considering this issue following renal transplantation. One of the potential causes of endothelial dysfunction in renal transplant recipients may be administration of calcineurin inhibitors. The aim of this study is to evaluate the effects of two different calcineurin inhibitors [cyclosporin A (CsA) and tacrolimus (FK506)] on endothelial function in renal transplant patients. Forty-four renal transplant recipients [22 on FK506 (group I) and 22 on CsA (group II)] were studied. Endothelial functions of the brachial artery were evaluated by using high resolution vascular ultrasound. Endothelium-dependent and -independent vasodilations were assessed by establishing reactive hyperemia and using sublingual nitroglycerine (NTG), respectively. Results are presented as percentage change from baseline values. Significant endothelial dysfunction was noted in renal transplant patients treated with CsA. While endothelium-dependent vasodilation was 12.1 +/- 5.1% in group I and it was 6.5 +/- 3.7% in group II (p < 0.001). The increase in brachial artery diameter after sublingual NTG was 20.1 +/- 6.3 and 12.7 +/- 5.6% in groups I and II, respectively. This indicates that the endothelium-dependent and -independent vasodilation of the patients on FK506 is better preserved than the patients on CsA therapy. Besides, blood flow volume (BFV) increase was 51.2 +/- 39.4 and 43.9 +/- 24.3%, in groups I and II, respectively, in reactive hyperemia period (p > 0.05). Post-transplant course of renal transplant recipients is complicated by endothelial dysfunction. This problem is more prominent in patients on CsA therapy, which can predispose these patients to more frequent cardiac complications.     

Anti-intercellular adhesion molecule-1 antibodies in sera of heart transplant recipients: a role in endothelial cell activation

BACKGROUND: Antiendothelial antibodies to non-human leukocyte antigens are made by a subset of heart transplant recipients, but the specificity of such antibodies is undefined. Intercellular adhesion molecule (ICAM)-1 is an abundantly expressed adhesion molecule with polymorphic residues, expressed on the surface of endothelial cells. The hypothesis that ICAM-1 acts as a minor histocompatibility antigen and that anti-ICAM-1 antibodies, directed against polymorphic residues, could be one component of the antiendothelial antibodies found after heart transplantation has been tested. METHODS: Chinese hamster ovary cells were transfected with full-length polymorphic variants of human ICAM-1. The binding of antibodies (immunoglobulin [Ig] G or IgM) to these cells was measured using sera from 50 heart transplant recipients (pretransplant and 1 and 2 years posttransplant) and sera from 20 normal volunteers by flow cytometry. The recipients and donors were genotyped for ICAM-1 polymorphisms. RESULTS: Sixty-eight percent (n=34) of patients made IgM antibodies that bound to ICAM-1. However, it seems unlikely that ICAM-1 is a minor transplantation antigen, because there were no differences in antibody production from recipients matched or mismatched for ICAM-1 alleles. The antibodies bound to mouse endothelial cells that were engineered to overexpress human ICAM-1, and induced a robust activation of the Erk-2 mitogen-activated protein kinase pathway. CONCLUSIONS: Anti-ICAM-1 antibodies are produced after cardiac transplantation, but not to polymorphic residues. Such antibodies may contribute to the endothelial activation by binding to the endothelium, causing activation of proinflammatory signaling pathways.     

BALF cytokines in different phenotypes of chronic lung allograft dysfunction in lung transplant patients

The long‐term success of lung transplantation (LT) is limited by chronic lung allograft dysfunction (CLAD). Different phenotypes of CLAD have been described, such as bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). The purpose of this study was to investigate the levels of cytokines and chemokines in bronchoalveolar lavage fluid (BALF) as markers of these CLAD phenotypes. BALF was collected from 51 recipients who underwent (bilateral and unilateral) LT. The study population was divided into three groups: stable (ST), BOS, and RAS. Levels of interleukin (IL)‐4, IL‐5, IL‐6, IL‐10, IL‐13, tumor necrosis factor alpha (TNF‐α), interferon‐gamma (IFN‐γ), and granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) were measured using the multiplex technology. BALF neutrophilia medians were higher in BOS (38%) and RAS (30%) than in ST (8%) (P=.008; P=.012). Regarding BALF cytokines, BOS and RAS patients showed higher levels of INF ‐ γ than ST (P=.02; P=.008). Only IL‐5 presented significant differences between BOS and RAS (P=.001). BALF neutrophilia is as a marker for both CLAD phenotypes, BOS and RAS, and IL‐5 seems to be a potential biomarker for the RAS phenotype.     

Mobilisation of endothelial progenitor cells: one of the possible mechanisms involved in the chronic administration of melatonin preventing erectile dysfunction in diabetic rats

Diabetes-induced oxidative stress plays a critical role in the mobilisation of endothelial progenitor cells (EPCs) from the bone marrow to the circulation. This study was designed to explore the effects of chronic melatonin administration on the promotion of the mobilisation of EPCs and on the preservation of erectile function in type I diabetic rats. Melatonin was administered to streptozotocin-induced type I diabetic rats. EPCs levels were determined using flow cytometry. Oxidative stress in the bone marrow was indicated by the levels of superoxide dismutase and malondialdehyde. Erectile function was evaluated by measuring the intracavernous pressure during an electrostimulation of the cavernous nerve. The density of the endothelium and the proportions of smooth muscle and collagen in the corpus cavernosum were determined by immunohistochemistry. The administration of melatonin increased the superoxide dismutase level and decreased the malondialdehyde level in the bone marrow. This effect was accompanied by an increased level of circulating EPCs in the diabetic rats. The intracavernous pressure to mean arterial pressure ratio of the rats in the treatment group was significantly greater, compared with diabetic control rats. The histological analysis demonstrated an increase in the endothelial density of the corpus cavernosum after the administration of melatonin. However, melatonin treatment did not change the proportions of smooth muscle and collagen in the corpus cavernosum of diabetic rats. Chronic administration of melatonin has a beneficial effect on preventing erectile dysfunction (ED) in type I diabetic rats. Promoting the mobilisation of EPCs is one of the possible mechanisms involved in the improvement of ED.     

肾移植术后肝功能异常患者用他克莫司替换环孢素A疗效的初步观察

目的　观察他克莫司 (FK5 0 6 )替换环孢素A(CsA)并联合应用霉酚酸酯 (MMF)及泼尼松 (Pred)防治肾移植术后肝功能异常患者的有效性及安全性。方法　肾移植术后 8例肝功能异常患者 (男性 5例 ,女性 3例 ,平均 38.2 3岁 ) ,用FK5 0 6替换CsA治疗 ,停用CsA 2 4h后 ,开始给予FK5 0 6。FK5 0 6初始剂量根据患者体重、肝功能损害程度及术后时间确定 ,服药 1周后 ,根据全血FK5 0 6谷值浓度调整剂量 ,使其谷值浓度维持于 5～ 15 μg/L。结果　用FK5 0 6替换CsA ,1个月后患者血中直接胆红素从替换前的 (2 2 .6 6± 17.19) μmol/L下降至 (7.0 5± 2 .32 ) μmol/L ,P <0 .0 5 ;间接胆红素从替换前的 (4 2 .15± 34.15 ) μmol/L下降至 (14.5 4± 2 .5 9) μmol/L ,P <0 .0 5 ;血清丙氨酸转氨酶从替换前的 (83 .0 0± 93 .14)IU/L下降至 1个月后的 (2 9.5 0± 15 .41)IU/L ,P >0 .0 5 ;血清肌酐从 (177.91±86 .41) μmol/L下降至 (135 .92± 34.0 5 ) μmol/L ,P >0 .0 5。 3例腹水的患者均于药物替换 1个月后完全消失。仅有 1例患者出现便秘、食欲下降伴上肢颤抖。结论　用FK5 0 6替换CsA并联合应用MMF及Pred对防治肾移植术后肝功能异常是安全和有效的措施     

The association between high‐grade varicocele and endothelial dysfunction

Varicocele is determined as dilatation of veins in the pampiniform plexus of the spermatic cord. Although various factors have been implicated in the pathophysiology of varicocele, the underlying aetiological cause is not fully understood. Endothelial dysfunction is a precursor of vascular pathologies that may develop gradually and a substantial inducer in atherosclerosis aetiology. Brachial artery flow‐mediated dilatation (FMD) measurement with sensitive brachial artery ultrasonography for assessing endothelial function is the most common noninvasive method. Similarly, carotid intima–media thickness (CIMT), measured using noninvasive ultrasonographic methods, is a tool for evaluating subclinical atherosclerosis and gives information on early changes in the vessel wall structure. Totally, 128 patients met the criteria were evaluated in this study. FMD was significantly lower in the varicocele group compared with the control group (9.16 ± 3.34 vs.7.96 ± 1.88, p = .013). CIMT measurements were similar between the groups (p = .091). Multivariate logistic regression revealed that FMD was independently associated with varicocele [odds ratio (OR): 0.814; 95% confidence interval (CI): 0.697–0.950; p = .009]. We suggest that endothelial dysfunction may have a role in the varicocele. Therefore, we recommend that every patient with symptomatic varicocele should be evaluated and followed up regularly for cardiovascular pathologies.     

肾移植受者血清抗血管内皮细胞特异性抗体的提取和纯化

目的  探讨肾移植术后出现排斥反应的受者血清中抗血管内皮细胞特异性抗体的提取和纯化方法。方法  首先分离培养人脐静脉血管内皮细胞(HUVEC)。收集肾移植术后肾功能不良受者的血清样本, 应用流式细胞术进行抗血管内皮细胞特异性抗体的筛选; 用Luminex抗体检测平台检测血清中抗人类白细胞抗原(HLA)和主要组织相容性复合体Ⅰ类相关链A (MICA)的抗体。在确定血清标本中存在有抗血管内皮细胞特异性抗体后, 用HUVEC将其吸附。洗涤细胞后再将吸附的抗体从细胞膜上洗脱下来, 再用Protein-A/G磁珠再次纯化和浓缩洗脱液中的抗体IgG。采用流式细胞术检测洗脱液中抗体活性, 用SDS-聚丙烯酰胺凝胶(SDS-PAGE)凝胶和免疫印迹法鉴定纯化的抗血管内皮细胞特异性抗体(IgG)。结果  在386例肾移植受者的血清中, 选取血清肌酐(Scr)>400 μmoI/L、抗HLA抗体阴性、抗MICA抗体阴性和荧光反应强度(MFI)>16的5例受者的血清样本, 纯化后的抗血管内皮细胞特异性抗体IgG在SDS-PAGE凝胶显示免疫球蛋白重链(纯度>95%)。流式细胞术结果显示纯化的抗体具有重新结合血管内皮细胞表面抗原的特性。结论  采用人脐静脉血管内皮细胞吸附肾移植受者血清中抗血管内皮细胞特异性抗体的提纯方法可取得较好效果。