Effects of cyclosporine on glucose metabolism

Cyclosporine may have deleterious effects on glucose metabolism. This study was designed to characterize more precisely cyclosporine-induced alterations in glucose homeostasis in a large animal model with hyperglycemic and euglycemic clamp studies in addition to simple bolus glucose (IVGTT) and insulin (IVITT) tolerance tests. In experiment 1, IVGTTs and hyperglycemic clamp studies were performed in eight ewes before and after 4 weeks of cyclosporine treatment. Studies were repeated 4 weeks after cessation of therapy. In experiment 2, IVITTs and euglycemic clamp studies were performed in seven ewes before and after 4 weeks of cyclosporine treatment. Fasting glucose and insulin levels were not affected by cyclosporine treatment. In experiment 1 cyclosporine did not alter IVGTTs; however, during sustained hyperglycemia, cyclosporine caused a 37% decrease in net glucose disposal (p less than 0.001) and a 39% decrease in plateau plasma insulin levels (p less than 0.05). In experiment 2 cyclosporine had no effect on IVITTs. Plateau insulin values in euglycemic clamp studies were lowered by 27% (p less than 0.05) after cyclosporine treatment. In addition, the metabolic clearance rate of insulin was increased by 25% (p less than 0.05), and the steady-state insulin clearance rate was increased by 16% (p less than 0.003). Measurements of insulin sensitivity were unchanged by cyclosporine. These experiments suggest that cyclosporine treatment results in impairment of sustained synthesis and secretion of insulin, increased insulin clearance, and unaltered insulin sensitivity.     

Glucose metabolism after pancreas transplantation: cyclosporine versus tacrolimus

BACKGROUND: The results of the new immunosuppressants in simultaneous pancreas-kidney transplantation (SPK) concerning organ survival and rejection rates are excellent. Tacrolimus as well as cyclosporine are assumed to be diabetogenic; however, there are no comparative studies investigating their effects on glucose metabolism. METHODS: One hundred thirty-six type 1 diabetic patients who had undergone successful SPK were investigated. Glucose and insulin levels during an oral glucose tolerance test as well as hemoglobin (Hb) A1c were analyzed. Investigations were performed early (3 months, n = 136) and late (3 years, n = 83) after transplantation. Graft recipients were grouped according to the first-line immunosuppression: group 1, cyclosporine; group 2, tacrolimus. There were no differences concerning age, gender, body mass index, and renal function between the groups. RESULTS: Early after transplantation, there was no difference between the groups concerning fasting glucose, HbA1c levels, basal and stimulated insulin secretion, and incidence of normal glucose tolerance. Late after transplantation, the incidence of a normal glucose tolerance tended to be lower (70% vs. 78%), whereas HbA1c (5.3% vs. 5.0%) and fasting glucose (81 vs. 78 mg/dL) levels tended to be higher in tacrolimus-treated patients. However, these differences were not significant. Insulin secretion was not reduced in the tacrolimus group. CONCLUSIONS: Concerning glucose metabolism and secretory capacity of the pancreas graft, no significant differences were found comparing tacrolimus- versus cyclosporine-treated graft recipients.     

Pharmacokinetic studies of cyclosporine in Oriental kidney transplantation patients

SUMMARY: Pharmacokinetic studies were performed in 10 stable kidney transplantation patients who received microemulsion formulation (Neoral^®) of cyclosporine A (CsA) twice daily. No agents having pharmacokinetic effects on CsA had been used in these patients. The values of various basic pharmacokinetic parameters were similar to those reported in Western literature. The complete area under the blood concentration–time curve (AUC) of CsA for the duration of 12 h (12‐h AUC) was determined using the linear trapezoidal rule from seven concentrations at 0, 1, 2, 4, 6, 8, and 12 h after CsA administration. The mean values of 12‐h AUC were 4603.63 ± 344.61 ng h/mL. CsA concentrations at 2 h after dosing (not the trough levels) showed the best correlation with the complete AUC (r² = 0.9322). The abbreviated AUC of CsA was calculated either by stepwise multiple linear regression analysis or by the linear trapezoidal rule from a few sampling time points. Using stepwise multiple linear regression analysis, which was used in calculating abbreviated AUC in all previous studies, the model equation that had the highest correlation and the lowest prediction error with the complete AUC was derived by using CsA concentrations at 2 and 8 h after dosing (12‐h AUC = 4.262C₂ + 8.390C₈? 669.417; r² = 0.9808, absolute prediction error = 3.97 ± 0.96). Two model equations derived using the linear trapezoidal rule provided the best correlation with the complete AUC: (1) The two time points selected model equation 12‐h AUC = 4C₂ + 5C₈; r² = 0.9780, absolute prediction error = 6.41 ± 1.22). (2) The three time points selected model equation 12‐h AUC = 4C₀ + 3C₂ + 5C₆; r² = 0.9475, absolute prediction error = 5.00 ± 1.41). When different pharmacokinetic data sets were applied to the model equations derived using regression analysis, the values of coefficients and the constant of the regression equation had changed from the initial equation. Thus, new model equations will emerge every time the new data are applied. In contrast, the values of coefficients in the model equation calculated using trapezoidal rule were unaltered when tested by the new pharmacokinetic data set. Thus, the abbreviated AUC derived using the linear trapezoidal rule would be simpler than and superior to that obtained using stepwise multiple linear regression analysis in prediction of the complete AUC.     

Demographics of glucose metabolism in cystic fibrosis

We investigated the prevalence of cystic fibrosis-related diabetes (CFRD) and its association with various demographic and clinical conditions in a Dutch child and adult cystic fibrosis (CF) population.Patients were classified as having either normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or CFRD. Associations with the following parameters were studied: age, gender, BMI, mutations, pulmonary function, infection status, and hospitalization.In our patient population the prevalence of IGT and CFRD was 16% and 31% respectively. After excluding pancreatic sufficient patients, the prevalence of CFRD was 40% and in patients over 40 years 52%. Compared with patients with NGT, CFRD patients were older, had more in-hospital days and had worse pulmonary function. Women developed CFRD at a significantly younger age than men.CFRD is a frequently occurring co-morbidity in patients with CF. The prevalence of CFRD is increasing in ageing CF populations and deserves rising attention in CF management.     

Risk factors for glucose metabolism disorders after kidney transplantation with uneventful course

A wide range of glucose metabolic disorders (GMDs) often arise after renal transplantation that predispose to graft dysfunction, infections, and cardiovascular disease. This study evaluated the risk factors for GMDs among 50 patients including 30 males and overall mean age 44.9 +/- 12.1 years. All 50 subjects displayed normal glucose tolerance tests pretransplantation and no family history of diabetes. They were selected from the 99 consecutive patients transplanted from April 2005 to January 2006 based upon uneventful posttransplantation course, without rejection episodes or hepatitis C virus (HCV) infections. The study concentrated on risk factors originating during the dialysis period. Even in this selected group, the risk of posttransplant GMD development was high (28%). Patients with GMDs showed significantly worse renal function at 1 month after transplantation (serum creatinine concentration: 1.70 +/- 1.67 mg/dL in the GMD group vs. 1.44 +/- 0.96 mg/dL in the group without GMDs [P = .027] and eGFR, 56.68 +/- 22.70 mL/min/1.73 m(2) versus 71.29 +/- 27.37 mL/min/1.73 m(2), respectively, [(P = .099)]. In a logistic regression model, a statistically significant difference between the groups was shown only for cold ischemia time (P = .037). In the logistic regression model with two independent variables, statistical significance was observed (P = .038) for body mass index at the time of transplantation. In this model, a lower pretransplant serum insulin concentration showed an influence that bordered on significance (P = .074). This study confirmed that the etiology of GMD after kidney transplantation is multifactorial, and at least in part connected with the pre-transplantation period.     

Effects of glucose homeostasis on protein metabolism in patients with advanced chronic kidney disease.

Insulin deficiency is known to be associated with a state of increased muscle protein breakdown; this process is mediated by the ubiquitin-proteasome pathway. Convincing in vitro data are further supported by extensive studies in humans with insulin deprivation and are further substantiated by reversal of muscle protein breakdown with insulin treatment. In patients with end-stage renal disease (ESRD) and diabetes mellitus (DM), muscle protein breakdown is enhanced in both acute and chronic conditions. Recent data also point to the potential protein catabolic effects of insulin resistance combined with insulin deficiency. Because ESRD is associated with a state of insulin resistance, uremic muscle wasting may also be mediated by this pathway.     

The impact of azathioprine and cyclosporine on long-term function in kidney transplantation

To assess the impact of cyclosporine on long-term kidney function in transplant patients, we retrospectively analyzed 273 patients on azathioprine and 308 on CsA with graft functioning at 1 year. To balance the length of follow-ups, the observation of patients was cut at 5 years. Actual graft survival rate at 5 years was similar in Aza and CsA (88% vs. 90%). Multivariate analysis in Aza pts showed that proteinuria (P = 0.006) and hypertension at 1 year (P = 0.002) increased the probability of irreversible graft failure by 2.47 and 2.85, respectively. In CsA patients, proteinuria (P = 0.007) and plasma creatinine higher than 2.5 mg/dl (P = 0.006) increased the probability of graft failure by 5.12 and 6.48, respectively. In both Aza and CsA patients with a follow-up of at least 5 years, plasma creatinine levels were significantly worse at 5 years vs. 1 year (P = 0.004). The slopes of plasma creatinine values plotted vs time were not different between the two groups. Chronic graft dysfunction (CGD) was defined as a stable increase of plasma creatinine of at least 50% above stable values at 1 year. The probability of remaining without CGD at 5 years was 75% for CsA and 80% for Aza patients (P = N.S.). Multivariate analysis of factors influencing the development of CGD showed that hypertension (P = 0.003) and proteinuria at 1 year (P = 0.081) increased the probability of developing CGD by 2.19 and 1.76, respectively, in Aza, while in CsA patients proteinuria only (P = 0.063) increased the probability of developing CGD by 2.29. Graft survival at 5 years after development of CGD was 34% in Aza and 53% in CsA-treated patients. These data confirm that in the long-term CsA does not cause a higher prevalence of CGD and show that, in the presence of CGD, CsA has a superior protective effect than Aza.     

他克莫司与环孢素A在高致敏肾移植受者中的应用比较

目的 观察和比较高致敏肾移植受者应用他克莫司(FK506)与环孢素A(CsA)的有效性和安全性.方法 根据术后免疫抑制方案的不同,将147例高致敏肾移植受者(其中术前群体反应性抗体＞50%的首次肾移植受者59例,2次肾移植受者88例)分为FK506组(53例)和CsA组(94例),两组的免疫抑制方案分别为FK506(或CsA)+霉酚酸酯+泼尼松.观察并分析两组受者术后移植肾存活率、血肌酐水平以及并发症的发生率.结果 FK506组术后1、3和5年的移植肾存活率(86.8%、82.3%和75.3%)略高于CsA组(81.9%、75.4%和66.9%),但差异无统计学意义(P＞0.05);FK506组术后1年时血肌酐水平为(100.72±15.88)μmol/L,CsA组为(117.29±11.77)μmol/L,两组比较,差异有统计学意义(P＜0.01);FK506组与CsA组相比,术后急性排斥反应、慢性排斥反应、肝功能损害、高血压和高血脂的发生率显著降低(P＜0.05),而高血糖的发生率明显升高(P＜0.01),两组移植肾功能延迟恢复和感染的发生率无明显差异(P＞0.05).结论 FK506与CsA相比,能有效降低高致敏受者肾移植术后急、慢性排斥反应的发生率,减少术后并发症的发生,提高移植肾的长期存活率,对高致敏肾移植受者是非常有效和安全的.     

Lipid metabolism in chronic kidney disease: the role of statins in cardiovascular risk.

In the general population, the relation between lipids and cardiovascular disease is clearcut, whereas it is highly controversial in chronic kidney disease (CKD) patients. This is primarily due to diverging results of retrospective observational trials. This study design often encounters confounding, especially in renal disease patients. Even if analyses are corrected for multiple influences, there might be unknown confounders changing the results. Prospective randomized trials assure that groups are comparable except for the intervention used. Confounding is eliminated by randomization. Nevertheless, the lipid discussion was restarted when two randomized, placebo-controlled, interventional trials on lipid-lowering therapy in renal patients have been published (Assessment of Lescol in Renal Transplantation and 4D Study [Atorvastatin in patients with type 2 diabetes on hemodialysis]). Surprisingly, both showed no significant reduction of the primary endpoint by statin therapy. In addition to other factors, this might be due to an altered pathogenesis of atherosclerosis in renal patients where multiple nontraditional cardiovascular risk factors are to be mentioned and different characteristics of cardiovascular disease with a high proportion of sudden cardiac death are present. This review will focus on dyslipidemia in renal failure and its treatment. The data published so far is summarized and grouped according to the different stages of CKD.     

Renal function following kidney transplantation in children treated with cyclosporine

The study was performed to evaluate the longterm renal function of children treated with cyclosporine after kidney transplantation. Renal function was determined with clearances of inulin and aminohippurate sodium for evaluating glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Thirty-six children aged 0.4–16.2 (median 6.9) years at transplantation were examined within 5 months of transplantation and then yearly over 0.3–7.1 years. Twenty-five children and young adults, 1.5–20 (median 7.7) years of age, with solitary kidneys because of renal agenesis or nephrectomy, served as controls. The GFR and ERPF within 1 year of transplantation were significantly lower than those of controls (65±19 and 345±88 vs 96±12 and 474±91 ml/min per 1.73 m², respectively). GFR remained constant 4 years after transplantation, but ERPF decreased significantly. Significant inverse correlations were found between GFR within 5 months of transplantation and the mean cyclosporine concentration and the number of rejection episodes. The frequency of hypertension decreased from 82% within 5 months of transplantation to 0% after 4 years. The absolute GFR increased during follow-up. In conclusion, kidney transplantation results in a reduced renal function compared with that of solitary native kidneys. The reduction in renal function correlated with the number of rejection episodes and the cyclosporine load. The increase in absolute GFR during follow-up suggests a remaining capacity for growth and/or compensatory hypertrophy.     

罗格列酮对慢性环孢素肾病大鼠肾间质纤维化的保护作用

目的 探讨罗格列酮(RGZ)对环孢素A(CsA)所致慢性环孢素肾病(CCN)大鼠肾间质纤维化的保护作用.方法 28只健康雄性SD大鼠被随机分成4组:(1)对照组(n=6):低盐饮食(LSD); (2)RGZ组(n=6):LSD+RGZ(5 mg·kg-1·d-1);(3)CsA组(n=8):LSD+CsA(15 mg·kg-1·d-1),(4)RGZ+CsA组(n=8):LSD +CsA(15 mg·kg-1·d-1)+RGZ(5 mg·kg-1 ·d-1).实时荧光定量PCR观察骨调素(OPN)及RANTES表达量;RT-PCR法检测MMP-9和TIMP-1的表达量;常规染色观察肾脏病理改变.结果 RGZ可改善CsA所致大鼠肌酐清除率的降低[(0.253±0.027)比(0.133±0.018) ml/min,P＜0.05];降低CCN大鼠肾间质单个核细胞浸润[(22.50±2.71)比(30.38±3.11),P＜0.05];减轻肾间质纤维化程度[(1.707±0.019)比(2.335±0.022),P＜0.05].与CsA组比较,RGZ+CsA组大鼠肾组织中OPN和RANTES mRNA表达量和MMP-9、TIMP-1 mRNA表达量降低(均P＜0.05).结论 RGZ可能通过下调趋化因子OPN、RANTES及MMP-9、TIMP-1的表达,改善CCN大鼠肾间质纤维化.     

The influence of kidney transplantation on carnitine metabolism

In this study, we examined all three plasma carnitine fractions, free carnitine (FC), short-chain acyl- (SCC), and long-chain acylcarnitine (LCC), as well as the urinary excretion of FC and SCC in 62 patients with functioning renal allografts 1-70 months following the kidney transplantation (KT). Patients were classified into three groups according to their transplant function, as characterized by the serum creatinine concentration (CR). A comparison with normal subjects (n = 20) and with patients on chronic hemodialysis (HD, n = 46) revealed a complete normalization of all carnitine plasma fractions for group I patients (Cr less than 120 mumol/l). In contrast, significant elevations of plasma free and esterified carnitine were found in group II (Cr greater than 120, less than 200 mumol/l; with FC + 27%, SCC + 82%, and LCC + 49% and group III patients (Cr greater than 200 mumol/l; with FC + 39%, SCC + 122%, and LCC + 106%), as compared to healthy subjects (p less than 0.001). The elevations in concentrations of SCC were more pronounced than those of FC; consequently, we found a higher ratio of acylcarnitine (AC) to FC in group III than in group I patients (+ 41%, p less than 0.001). Yet even in the former group, this ratio was found to be markedly reduced when compared to HD patients (-41%, p less than 0.001). We found no significant differences in the urinary excretion of FC and SCC between the 3 groups of KT patients. It is thus to conclude that in patients with a well-functioning transplant, the pattern of carnitine fractions in plasma is fully normalized. The decrease in the ratio of AC to FC following a successful KT might suggest a better availability of FC and thereby be associated with an enhanced fatty acid oxidation.     

Approaching the therapeutic window for cyclosporine in kidney transplantation: a prospective study

Neoral dosing is traditionally based on cyclosporine (CyA) trough levels (C(0)). Four-h area under the curve (AUC(0-4)) for Neoral in the early posttransplantation period was shown previously to have a better correlation to acute rejection (AR) and CyA nephrotoxicity (CyANT), compared with C(0). An AUC(0-4) range of 4400 to 5500 microg/h per L during the first week was associated with the lowest AR and CyANT. This article describes a prospective study to assess the feasibility, safety, and efficacy of dosing Neoral solely by AUC(0-4) monitoring, regardless of C(0), in the first 3 mo after kidney transplantation. Fifty-nine kidney transplant recipients received Neoral-based triple immunosuppression. AUC(0-4) was measured on days 3, 5, 7, 10, and 14 and weeks 3, 4, 6, and 8, then monthly. Target AUC(0-4) was 4400 to 5500 microg/h per L. Dose was adjusted by percentage difference from target AUC(0-4). Ninety-four percent of AUC were performed on the scheduled day or close to it. No patients had CyANT while AUC(0-4) was in target range. Four patients had reversible CyANT with AUC(0-4) > 5500. Only 1 of 33 patients (3%) who achieved and maintained AUC(0-4) > 4400 by day 3 posttransplantation had AR, whereas 10 of 22 (45%) of those with day 3 to 5 AUC(0-4) < 4400 had AR (P: = 0.0002). In logistic regression analysis, higher early AUC(0-4) was the only significant variable associated with lower serum creatinine at 3 mo. Neoral dose monitoring by AUC(0-4) is a potentially valuable tool for optimizing Neoral immunosuppression. Attainment of a target range of 4400 to 5500 microg/h per L for AUC(0-4) early after transplantation has been demonstrated to reduce significantly the risk of AR and CyANT.     

Outcome of microemulsion cyclosporine C2 concentration monitoring in kidney transplantation

Profiling of absorption of cyclosporine (CsA) microemulsion is a concept in therapeutic drug monitoring (TDM) designed to optimize the clinical benefits of the drug in transplant recipients. A single blood concentration at 2 h (C(2)) after CsA microemulsion administration in kidney transplant recipients accurately predicts graft outcome. An international guidelines has recommended the target C(2) over time-course post-transplantation. We determined whether this recommendation is appropriate for our patients who are Asian ethnic. The clinical data of these C(2) monitoring kidney transplant recipients were compared with the historical cohort of microemulsion CsA trough (C(0)) level monitoring during the first 24-month post-transplantation. The inclusion and exclusion criteria were applied for both C(2) and C(0) cohorts. The mean target C(2) concentrations at 1, 3, 6, and 12-month post-transplantation were achieved in the C(2) cohort as the international guildlines. At 3-month post-transplantation, patients who had C(2) concentrations over 1500 ng/mL had higher serum creatinine as compared with those who had C(2) levels <1300 ng/mL (2.23 +/- 0.8 vs. 1.44 +/- 0.38 mg/dL: p = 0.01). Also, at 6-month post-transplantation, patients who had C(2) concentrations over 1300 ng/mL had higher serum creatinine (1.96 +/- 0.29 vs. 1.37 +/- 0.34 mg/dL: p < 0.01) as compared with those who had C(2) levels <1100 ng/mL. There was no statistical difference of acute rejection episodes between the two cohorts. The international consensus for C(2) concentraion may be too high for Asian ethnic kidney transplant recipients. The data from this study indicated lower than recommended C(2) concentraion as an appropriate C(2) target concentraion.