The impact of body weight on cyclosporine pharmacokinetics in renal transplant recipients

In order to assess the effect of body weight on cyclosporine disposition, 45 adult uremic candidates for renal transplantation underwent detailed nutritional assessment and pharmacokinetic analysis. There were 10 obese and 35 nonobese patients defined as actual body weight (ABW) greater than 125 Per cent of ideal body weight (IBW), and arm fat area greater than 90th percentile. There was no significant difference in demographic variables such as age, sex, number of diabetics, IBW, serum lipids, or liver function tests between the 2 groups. Although there was a significant difference in ABW, pharmacokinetic analyses failed to demonstrate significant differences in bioavailability, elimination half-life, clearance, or apparent steady state volume of distribution when these calculations were normalized by IBW, body surface area, or as absolute values. Multiple stepwise linear regression failed to demonstrate a significant correlation between serum lipids or body size measurements and these parameters. When dosed according to ABW, obese recipients of renal allografts had a mean serum RIA trough level of 227 ng/ml as compared to 121 ng/ml in nonobese recipients on day 7. Therefore in order to achieve comparable drug concentrations in the early transplant period, CsA should be given to obese patients based on their IBW.     

The effect of ethanol on serum cyclosporine A levels in renal transplant recipients

Following an alcohol binge, cyclosporine A (CyA) levels rose by 100% in a 51-year-old transplant recipient treated with CyA. As CyA and ethanol are both metabolized by the cytochrome P-450 enzyme system, ethanol could theoretically interfere with CyA metabolism. Therefore, eight male renal transplant recipients were assessed in a crossover study to determine the effects of acute ethanol ingestion on CyA serum concentrations. CyA serum concentrations did not rise following 50 mL of 100% alcohol. We conclude that heavy alcohol intake may increase CyA levels but that acute moderate intake does not.     

Correlation of serum cyclosporine concentration with renal dysfunction in marrow transplant recipients

We retrospectively analyzed the relationship of serum cyclosporine concentration to renal dysfunction in 63 marrow transplant recipients who received cyclosporine for prophylaxis of acute graft-versus-host disease. Patients were divided into three groups according to their mean trough cyclosporine concentration for the first 28 days of therapy: less than 150, 150-250, and greater than 250 ng/ml. Baseline renal function and exposure to nephrotoxic antibiotics was comparable in the three groups. Renal dysfunction was defined as doubling of baseline serum creatinine. The likelihood of developing renal dysfunction was analyzed with Kaplan-Meier product limit estimates. The log-rank test was used to compare the three groups. Fifty-four (86%) of the patients developed renal dysfunction. The incidence of renal dysfunction was 73%, 95%, and 100%, and it developed at a median of 46, 29, and 20 days in patients with a mean trough concentration of less than 150, 150-250, and greater than 250 ng/ml, respectively (P less than 0.001). Eight of the nine patients who did not develop renal dysfunction had a mean trough concentration of less than 150 ng/ml. These data indicate that the incidence and the rate of development of renal dysfunction are related to serum cyclosporine concentration.     

Endothelial dysfunction in renal transplant recipients maintained on cyclosporine

BACKGROUND: Hypertension is almost universal following renal transplantation and may contribute to the already poor cardiovascular prognosis of this group. Cyclosporine-induced hypertension is a particular problem and has variously been attributed to increased sympathetic nerve activity, salt and water retention, and increased circulating endothelin levels. However, the effects of cyclosporine on the L-arginine/nitric oxide (NO) system in vivo in humans are unknown. In this present study, we examined basal and stimulated NO production from the vascular endothelium in cyclosporine-treated renal transplant recipients using the technique of forearm venous plethysmography. METHODS: In study 1, stimulated NO production was assessed in 9 cyclosporine-treated renal transplant recipients (CsA), 7 azathioprine-treated renal transplant recipients (AZA), and 12 controls, using carbachol (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). In study 2, basal NO production was assessed in 9 cyclosporine-treated patients and 11 controls using L-NMMA (inhibits NO synthase), with norepinephrine as a control vasoconstrictor. Drugs were infused into the nondominant forearm through a sterile 27-gauge needle, and changes in forearm blood flow (FBF) were measured using venous occlusion plethysmography. RESULTS: In study 1, sodium nitroprusside caused a similar dose-dependent increase in FBF in all groups. However, the median (range) percentage increase FBF to carbachol (3 micrograms/min) was markedly reduced in the CsA patients (188.8; 72.5 to 385.1) compared with AZA patients (378.1; 124.0 to 548.9; P = 0.042) and to controls (303.8; 124.8 to 813.3; P = 0.028). In study 2, the maximum percentage reduction in FBF to L-NMMA (4 mumol/min) was less pronounced in CsA patients (-19.5; -4.7 to -63.1) compared with controls (-39.5; -15.7 to -52.8; P = 0.056), and while controls vasoconstricted to the maximum dose of norepinephrine (240 pmol/min) as expected (-26.9; -1.4 to -38.6), CsA patients as a group tended to vasodilate (7.9; -36.8 to 92.6; P = 0.02). CONCLUSION: These data demonstrate impaired stimulated and basal NO production in CsA patients, indicating endothelial dysfunction. This may predispose patients to atherosclerosis and may be involved in the etiology of post-transplant hypertension.     

Subclinical inflammation in renal transplant recipients: impact of cyclosporine microemulsion versus tacrolimus

BACKGROUND: Renal insufficiency and renal transplant (RT) provoke a microinflammatory state that leads to increased atherosclerosis. It is not fully known whether calcineurin inhibitors (CNIs) play a role in the inflammation observed in these patients or whether any differences exist between CNIs. OBJECTIVES: The study aimed to establish differences in the inflammatory state of two groups treated with cyclosporine microemulsion (CyA) or tacrolimus (TC). PATIENTS AND METHODS: This prospective study included 81 RT patients divided into two groups according to the CNI: CyA group, n = 35 versus TC group, n = 46. The markers of inflammation (MIF) were determined preRT and at 3 and 12 months' postRT: C-reactive protein (CRP), serum amyloid protein A (SAA), interleukin-6 (IL-6), soluble interleukin-2 receptor (sIL-2R), tumor necrosis factor-alpha (TNF-alpha), and pregnancy-associated plasma protein A (PAPP-A). Samples were collected in stable patients in the absence of rejection, active infection, or inflammatory processes. RESULTS: No significant differences existed between the markers of inflammation in the two treatment groups prior to transplantation. At 3 months' posttransplant, patients treated with CyA showed significantly higher levels of IL-6 (P = .05), SAA (P = .03), and sIL-2R (P = .008) compared with patients treated with TC. These differences were maintained for IL-6 (P = .03) and sIL-2R (P = .027) at 12 months' posttransplant. A multivariate analysis at 3 months showed that only age [OR 10.1; CI (95% 2.6-38.4); P = .001], SAA [OR 4.8; IC (95% 1.4-16.5); P = .015], and sIL-2R [OR 4.9; IC (95% 1.5-16.2); P = .009] were independent predictors of the CNI used. At 12 months, age [OR 3.7; IC (95% 0.9-14.2] and sIL-2R [OR 6.04; IC (95% 1.5-23); P = .006] continued to be independent predictors. CONCLUSIONS: Patients treated with CyA displayed significantly higher levels of inflammatory markers (IL-6, SAA, sIL-2R) at 3 and 12 months' posttransplantation, independent of age, gender, time on dialysis, diabetes mellitus (preRT and de novo postRT), and renal function measured by serum creatinine.     

Compliance with cyclosporine in adolescent renal transplant recipients

  Inadequate compliance with prescribed medication regimens in children is complex and poorly understood. We measured the extent and pattern of noncompliance with cyclosporine in our adolescent renal transplant population and attempted to determine factors associated with poor compliance. After informed consent, each patient was provided cyclosporine capsules in a medication bottle equipped with an electronic monitoring device (MEMS-4) in the lid. Of the 24 patients eligible, 19 patients (8 female, 11 male) completed the study. Four (21%) patients took less than 80% of the prescribed cyclosporine doses. Five (26%) patients took drug holidays involving ≥3 consecutive doses. There was a trend towards improved compliance with the evening dose (88.5% vs. 93.4%, P = 0.09) and a downward trend in compliance over the course of the study (P = 0.17). None of the variables tested were found to be associated with noncompliance. Experienced physicians and nurses were able to identify 2 of the 4 individuals who were identified by MEMS as noncompliant. Additionally, 2 of the 4 noncompliant patients demonstrated low cyclosporine trough levels (<50 ng/ml). Noncompliance with cyclosporine regimens occurs commonly in adolescent renal transplant recipients. Unexpectedly low cyclosporine levels are strongly suggestive of noncompliance, whereas other variables, including prediction by physicians and nurses intimately involved in the care, were not reflective of noncompliance. Received October 19, 1996; received in revised form February 18, 1997; accepted March 18, 1997     

Pharmacokinetics and nephrotoxicity of cyclosporine in renal transplant recipients

Pharmacokinetics of Cyclosporine (CsA) were studied in 14 renal transplant patients during a three-month period of treatment. At 3 and 15 days after transplantation 12-hr blood level studies of the drug were performed to calculate the elimination half-life, area under the curve (AUC), and total blood clearance; trough levels were measured twice weekly. In 9 patients terminal half-lives could be calculated after discontinuation of CsA treatment. In the course of CsA treatment, prolongation of half-life was found in most cases, with a significant decrease in clearance (46 +/- 17 L/hr on day 3 versus 28 +/- 10 L/hr on day 15). This resulted in a continuous increase in the CsA blood level. The terminal half-life varied considerably among the patients (24-93 hr) and did not correlate with other pharmacokinetic parameters. A good correlation (r = 0.9589) was observed between CsA trough levels before discontinuation of CsA and the increment in renal function two weeks after conversion to azathioprine. This indicates that short-term CsA treatment induces a dose-dependent reversible nephrotoxic effect in renal transplant recipients.     

Epithelial-to-mesenchymal transition predicts cyclosporine nephrotoxicity in renal transplant recipients

Maintenance immunosuppression with cyclosporine A (CsA) can cause nephrotoxicity in renal transplant recipients. Identifying patients at increased risk for CsA nephrotoxicity may allow interventions to prolong graft survival. Here, we studied the effect of early CsA withdrawal or maintenance among 96 kidney recipients at risk for interstitial fibrosis and tubular atrophy (IF/TA) on the basis of tubular expression of vimentin and β-catenin in a protocol biopsy performed 3 months after transplant. In this retrospective analysis of biopsies collected during a randomized trial of early withdrawal of CsA or mycophenolate mofetil, the semiquantitative score of early phenotypic changes suggestive of epithelial-to-mesenchymal transition (EMT) progressed with time among those maintained on a CsA-containing regimen. EMT-positive grafts displayed a significantly higher IF/TA score and greater progression of the IF/TA score at 12 months (P=0.001 and 0.008, respectively). EMT-positive grafts exposed to CsA also had a greater decrease in estimated GFR compared with EMT-negative grafts exposed to CsA and EMT-positive grafts withdrawn from CsA exposure. Multivariable analysis revealed that the presence of EMT was an independent risk factor for a 10% decline in graft function up to 4 years posttransplant (odds ratio 4.49; 95% confidence interval 1.02 to 19.9). Collectively, these data demonstrate that changes consistent with EMT are strong prognostic biomarkers in renal transplant recipients exposed to CsA.     

Significant impact of gene polymorphisms on tacrolimus but not cyclosporine dosing in Asian renal transplant recipients

Calcineurin inhibitors (CNI) are metabolized by cytochrome-P4503A (CYP3A) enzymes and extruded into the intestinal lumen by the drug efflux pump, P-glycoprotein (P-gp). The impact of single nucleotide polymorphisms (SNPs) of genes encoding CYP3A5 and P-gp on CNI dosing was examined among Asian renal transplant recipients. Frequencies of CYP3A5*1 versus *3 and MDR1-C3435T were correlated with tacrolimus (TAC) and cyclosporine (CSA) concentration-to-dose (C/D) ratios. Among 82 recipients (49% male; 88% Chinese), the majority were CYP3A5 expressors (*1*1 and *1*3, 11% and 40%, respectively) and 49% were nonexpressors (*3/*3). The prevalence of MDR-1-C3435T variants was 3435CC (41%), 3435CT (46%), and 3435TT (13%). Among 18 TAC-treated recipients, all receiving Diltiazem (DTZ), the median C/D ratio was lower for CYP3A5 *1/*1 versus *1/*3 versus *3/*3 (1.9, 4.6, and 13.5 ng/mL per 0.1 mg/kg/d, respectively; P = .001). The median C/D ratio was higher for TAC-treated patients with MDR-1-3435CC (14.1, 7.3, and 2.2 ng/mL per 0.1 mg/kg/d for CC, CT, and TT, respectively; P = .023). Neither CYP3A5 nor MDR-1-C3435T variants had an impact on CSA C/D ratios. Thus, CYP3A5 SNP has a significant impact on TAC dosing in Asian renal transplant recipients, which was likely to facilitate TAC metabolism. Although MDR-1-3435CC with higher P-gp expression should experience more TAC efflux and, therefore, lower TAC C/D ratios, all MDR-1-3435CC carriers were CYP3A5 nonexpressors; the latter ultimately contributed to the observed higher TAC C/D ratios in this population. This study advocates starting with a higher TAC dose for CYP3A5 expressors. Coadministration of DTZ may further optimize the TAC level through preferential P-gp binding and CYP3A4 inhibition.     

大黄制剂对肾移植受者环孢素血药浓度的影响分析

目的研究肾移植受者服用大黄制剂对环孢素血药浓度的影响。方法 2008年1月至2012年12月,湖州市第一人民医院10例肾移植受者术后采用环孢素＋吗替麦考酚酯/硫唑嘌呤＋泼尼松三联免疫抑制方案,环孢素用量为5~7 mg·kg-1·d-1,受者术后2~5年因便秘同时服用大黄苏打片（每片含大黄0.15 g,碳酸氢钠0.15 g）,3片/次,3次/d。服用当天及15 d监测受者环孢素血药浓度谷值（C0）、2h后血药浓度峰值（C2）以及肝肾功能,停药15d复查环孢素C0和C2。结果服用大黄苏打片15 d受者环孢素C0、C2均高于服用当天检测值,差异均有统计学意义（t=11.754和12.822,P均〈0.05）。停用大黄苏打片15 d复查环孢素C0、C2均低于服用15 d时检测值,差异均有统计学意义（t=10.020和13.596,P均〈0.05）;与服用当天检测值比较,差异均无统计学差异（t=1.375和0.251,P均〉0.05）。服用大黄苏打片15 d,受者肝肾功能指标与服用当天比较差异均无统计学差异（P均〉0.05）。结论肾移植术后服用环孢素的受者在长期使用含有大黄制剂的药物时,应注意监测环孢素血药浓度,必要时适当调整环孢素用量。     

Impact of long-term immunosuppression with cyclosporin A on serum lipids in stable renal transplant recipients

To determine the impact of long-term immunosuppression on serum lipids in stable renal graft recipients we measured serum lipids and apolipoprotein B concentrations in 20 patients receiving therapy with cyclosporin (CsA) and low-dose prednisolone (CsA/P) and in 18 patients on therapy with azathioprine and maintenance steroids (Aza/P). The patients were matched for age, body mass index, primary renal disease and dose of prednisolone, but not for the duration in transplantation and serum creatinine concentration. Triglyceride concentrations were significantly higher in the CsA/P group than in Aza/P-treated patients: 2.62±0.35 vs 1.62±0.23 mmol/l (P<0.05). Similarly, total cholesterol (C) levels were significantly more elevated in the CsA/P recipients than in the other group: 7.44±0.32 vs 5.84±0.25 (P<0.02). CsA/P patients had higher serum levels of LDL-C (4.79±0.20 vs 3.43±0.19 mmol/l P<0.001) and apolipoprotein B concentrations (191±13 vs 128±9 mg/dl; P<0.001). CsA/P and Aza/P recipients had similar concentrations of HDL-C (1.73±0.13 vs 1.52±0.09 mmol/l; NS). We conclude that in stable renal graft recipients with good transplant function long-term immunosuppression with CsA/P is associated with a more atherogenic lipid status than therapy with Aza/P.     

Long-term effects of cyclosporine on renal function in liver transplant recipients

The long-term effects of cyclosporine on renal function were evaluated in eleven liver transplant recipients over a 6-26-month follow-up period. Renal hemodynamic function (glomerular filtration rate [GFR], effective renal plasma flow [ERPF]) fell 60% postoperatively, subsequently improved, and stabilized at 45-60% of normal despite continued drug administration. Tubular sodium transport studies during water diuresis suggested that the proximal tubule is a major site of cyclosporine nephrotoxicity. In contrast to the acute effects of cyclosporine on renal function, the fraction of glomerular filtrate reabsorbed in the proximal tubule was less in the patient group while the fractional excretion of sodium, potassium, and phosphate was increased. When the fraction of filtered sodium reabsorbed in the diluting segment was examined as a function of sodium delivery, functional impairment occurred in the diluting segment as well. Eight renal biopsies performed in six patients 4-29 months posttransplantation showed only mild to moderate changes, predominantly vascular, which correlated poorly with corresponding renal function. These data showed that long-term cyclosporine administration produced early and persistent depression of both hemodynamic and tubular function. A functional rather than structural mechanism appears to be more significant during this period of observation.     

Impact of long-term immunosuppression with cyclosporin A on serum lipids in stable renal transplant recipients

Abstract. To determine the impact of long-term immunosuppression on serum lipids in stable renal graft recipients we measured serum lipids and apolipoprotein B concentrations in 20 patients receiving therapy with cyclosporin (CsA) and low-dose prednisolone (CsA/P) and in 18 patients on therapy with azathioprine and maintenance steroids (Aza/P). The patients were matched for age, body mass index, primary renal disease and dose of prednisolone, but not for the duration in transplantation and serum creatinine concentration. Triglyceride concentrations were significantly higher in the CsA/P group than in Aza/P-treated patients: 2.62 ± 0.35 vs 1.62 ± 0.23 mmol/l ( P < 0.05). Similarly, total cholesterol (C) levels were significantly more elevated in the CsA/P recipients than in the other group: 7.4410.32 vs 5.84 ± 0.25 (F<0.02). CsA/P patients had higher serum levels of LDL-C (4.79 ± 0.20 vs 3.43 ± 0.19 mmol/l ( P < 0.001) and apolipoprotein B concentrations (191 ± 13 vs 128 ± 9 mg/dl; P < 0.001). CsA/P and Aza/P recipients had similar concentrations of HDL-C (1.73 ± 0.13 vs 1.52 ± 0.09 mmol/l; NS). We conclude that in stable renal graft recipients with good transplant function long-term immunosuppression with CsA/P is associated with a more atherogenic lipid status than therapy with Aza/P.     

肾移植术后撤除环孢素A的观察和体会

目的 总结肾移植术后因某些原因而撤除环孢素Ａ（ＣｓＡ）的经验教训,并对其可行性及安全性进行评价。方法 总结２０例术后撤除ＣｓＡ的肾移植患者的有关资料。结果 ２０例患者在撤除ＣｓＡ并同时调整其它免疫抑制剂剂量后,其肾功能、肝功能及白细胞计数等与撤药前比较,差异均无显著性;与周期常规治疗者比较,两组肾功能的差异也无显著性。结论 在调整其它免疫抑制剂剂量的前提下,逐步减少ＣｓＡ的用量并最终撤除ＣｓＡ,可