Long-term follow-up of co-administration of diltiazem and cyclosporine in Chinese kidney transplant recipients

Background: Co-administration of diltiazem and cyclosporine A (CsA) in kidney transplant recipients shows improvement of renal transplantation outcomes. Methods: We respectively analyzed 1531 kidney transplant recipients treated by different immunosuppressive therapy schemes from 1986 to 2003. They were divided into three groups depending on their immunosuppressive therapy schemes: control group with a standard triple therapy without use of diltiazem; study group I with the combination of diltiazem and the standard triple therapy but slightly low CsA; study group II with combination of diltiazem and a modified standard triple therapy but lower CsA. The CsA blood concentrations, posttransplant complications, and long-term survival in the three groups were compared. Results: The results showed that the patient and allograft survival in the study group II was 69.9 and 65.1%, respectively, significantly higher than that in the control group (50.7 and 47.6%). Occurrence of hepatotoxicity and nephrotoxicity episodes was higher in the control group than those in the study group I and the study group II. The incidence of acute rejection in the control group was 30.3% (23/76), similar to 28.0% (184/657) in study group I, but statistically significantly higher than 7.6% (61/798) in the study group II. Conclusion: Combination of diltiazem and CsA in the kidney allograft recipients tends to reduce the CsA oral dosage, improve patient survival, and decrease the occurrence of hepatotoxicity and nephrotoxicity.     

Tacrolimus plus mycophenolate mofetil vs. cyclosporine plus everolimus in deceased donor kidney transplant recipients: three‐yr results of a single‐center prospective clinical trial

We compared in kidney transplantation two immunosuppressive regimens: tacrolimus plus mycophenolate mofetil (MMF) (TAC) and everolimus plus low‐dose cyclosporine (EVE). Sixty consecutive patients received TAC (30 patients) or EVE (30 patients) as immunosuppressive regimen; all subjects also received induction with basiliximab and corticosteroids. After three‐yr follow‐up, no difference was found in patient and graft survival (PTS: TAC: 97% vs. EVE: 100%; GS: TAC: 93% vs. EVE: 93%). The incidence of acute rejection was higher in the EVE group but the difference was not statistically significant (17% vs. 23%, p = ns). Patients in EVE showed higher serum cholesterol (205 ± 41 vs. 235 ± 41 mg/dL, p = 0.0012) and lower hemoglobin concentration (13.6 ± 1.4 vs. 12.4 ± 1.9, p = 0.01). Renal function was not significantly different in the two groups (3 Y creatinine: TAC 1.4 ± 0.8 vs. EVE 1.6 ± 0.8 mg/dL, p = ns). Treatment discontinuation was higher in the EVE group (TAC 17 vs. EVE 36%, p = ns). Our data show that in the middle‐term follow‐up, an immunosuppressive regimen with tacrolimus plus MMF has a similar efficacy and safety profile in comparison with the combination of low‐exposure cyclosporine plus everolimus. Further follow up could evidence the benefits related to the anti‐proliferative effects of everolimus.     

Long‐Term Belatacept Exposure Maintains Efficacy and Safety at 5 Years: Results From the Long‐Term Extension of the BENEFIT Study

The Belatacept Evaluation of Nephroprotection and Efficacy as First‐line Immunosuppression Trial randomized patients receiving a living or standard criteria deceased donor kidney transplant to a more (MI) or less intensive (LI) regimen of belatacept or cyclosporine A (CsA). The 5‐year results of the long‐term extension (LTE) cohort are reported. A total of 456 (68.5% of intent‐to‐treat) patients entered the LTE at 36 months; 406 patients (89%) completed 60 months. Between Months 36 and 60, death occurred in 2%, 1% and 5% of belatacept MI, belatacept LI and CsA patients, respectively; graft loss occurred in 0% belatacept and 2% of CsA patients. Acute rejection between Months 36 and 60 was rare: zero belatacept MI, one belatacept LI and one CsA. Rates for infections and malignancies for Months 36–60 were generally similar across belatacept groups and CsA, respectively: fungal infections (14%, 15%, 12%), viral infections (21%, 18%, 16%) and malignancies (6%, 6%, 9%). No new posttransplant lymphoproliferative disorder cases occurred after 36 months. Mean calculated GFR (MDRD, mL/min/1.73 m²) at Month 60 was 74 for belatacept MI, 76 for belatacept LI and 53 for CsA. These results show that the renal function benefit and safety profile observed in belatacept‐treated patients in the early posttransplant period was sustained through 5 years.     

Amelioration of cyclosporine-induced testicular toxicity by carvedilol and/or alpha-lipoic acid: Role of TGF-β1, the proinflammatory cytokines,Nrf2/HO-1 pathway and apoptosis

Cyclosporine is an immunosuppressive agent that is used to prevent organ rejection after organ transplantation. Due to the widespread use of this type of surgery, the effect of cyclosporine on reproduction and fertility should have a specific interest. Our aim was to assess the effect of carvedilol and/or alpha-lipoic acid on cyclosporine-induced testicular toxicity in rats. Sixty male Wistar rats were divided into six equal groups: Control; cyclosporine; cyclosporine + carvedilol; cyclosporine + alpha-lipoic acid; cyclosporine + carboxymethyl cellulose; and cyclosporine + carvedilol +alpha-lipoic acid. Food intake, testis weight, testicular functions, serum testosterone, luteinizing hormone and follicle-stimulating hormone were measured. Also, testicular tissue 3 β-hydroxysteroid dehydrogenase, 17 β- hydroxysteroid dehydrogenase, paroxonase-1, proinflammatory cytokines, transforming growth factor beta-1, nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Heme oxygenase-1 (HO-1) content and sperm characteristics were determined. Parts of the testes were subjected to histopathological and electron microscopic examination. The carvedilol/alpha-lipoic acid combination restored the food intake, testicular weight and functions, sperm characteristics, hormonal profile and the antioxidant defences compared to the use of each of these drugs alone. Also, this combination significantly ameliorated inflammation (P < .05) and induced significant increase in tissue Nrf2/HO-1 content (P < .05) and significant improvement of the histopathological and electron microscopic picture (P < .05) compared to the use of each of these drugs alone. So, carvedilol/alpha-lipoic acid combination might represent a novel therapeutic strategy to ameliorate testicular damage induced by cyclosporine.     

Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10‐year postrandomization follow‐up study

Long‐term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post‐transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients’ survival was 100%, 94.2%, and 95.8% (P = 0.25), and death‐censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m², respectively (P = 0.16). The incidence of biopsy‐proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus‐associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody‐mediated rejection (n = 6). De novo donor‐specific antibodies were detected in 13% of AZA‐, 21% of MMF‐, and 14% of CsA‐treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well‐selected renal transplant recipient ( ClinicalTrials.gov number: 980654).     

Calcineurin inhibitors and male fertility after renal transplantation – a review

Renal transplantation and restoration of renal function are associated with significant favourable changes regarding the reproductive capacity of male patients with previous end‐stage renal disease. However, there is evidence that some of the immunosuppressive agents may impair male fertility after all. Calcineurin inhibitors (CNIs), cyclosporine A and tacrolimus (FK506), which constitute the cornerstone of immunosuppression regimen following renal transplantation, have been implicated in causing an overall decline in the fertilisation capacity of male renal transplant recipients (RTRs). In this review, data from human clinical studies are collectively presented in an effort to estimate the potential adverse effects of CNIs on the masculine reproductive organs, the hormonal axis of males, the process of spermatogenesis and generally the male RTRs capacity to fertilise.     

Altitude and arteriolar hyalinosis after kidney transplantation

The kidney is very susceptible to hypoxic injury. Calcineurin inhibitors (CNIs) induce vasoconstriction and might reduce renal tissue oxygenation. We aimed to investigate if the synergistic deleterious effects of CNI‐treatment and hypoxia of high altitude living might accelerate the development of arteriolar hyalinosis in kidney allografts. We stratified all patients who received a kidney graft from 2000 to 2010 in our centre (n = 477) in three groups according to the residential elevation (below 400, between 400 to 600 and above 600 m above sea level) and we retrospectively re‐evaluated all transplant biopsies performed during follow‐up, specifically looking at the degree of arteriolar hyalinosis, the hallmark of chronic CNI nephrotoxicity. Living at high altitude was markedly associated with a higher degree of arteriolar hyalinosis (P < 0.001). Haemoglobin levels confirmed the functional relevance of different arterial oxygenation among the groups (P = 0.01). Thus, patients living at high altitude seem to be more susceptible to the development of arteriolar hyalinosis after kidney transplantation.     

应用非线性混合效应模型法考察儿童疾病因素对环孢素药动学的影响

目的:考察疾病因素对于环孢素A(CsA)在儿童体内药动学的影响,促进个体化用药。方法:收集150例包括再生障碍性贫血(AA)、嗜血细胞综合征(HPS)和难治性肾病综合征(RNS)不同病种患儿的CsA血药浓度数据和临床资料。采用非线性混合效应模型法考察疾病种类因素对于CsA药动学的影响。采用Bayesian最大后验概率法获取并比较CsA在不同病种患者中药动学参数的差异。用拟合优度(goodness-of-fit)、自举法(bootstrap)、直观预测检验法(VPC)、正态化预测分布误差(NPDE)对最终模型的预测性能进行验证。结果:最终模型药动学参数的群体典型值分别为:吸收速率常数(k_a)1.22 h^-1,吸收时滞时间(T_lag)0.45 h,表观分布容积(V_d)218.18 L,口服清除率(CL)14.45 L·h^-1。拟合优度、自举验证、VPC和NPDE结果表明最终模型稳定,预测结果可靠。模型结构显示只有患者的体质量和AST值是影响CsA清除率的显著性因素。CsA在AA、HPS和RNS患者中的药动学参数差异无显著性(P>0.05)。结论:本研究成功获取了CsA在儿童AA、HPS和RNS患者中的药动学参数,上述疾病因素不会显著影响CsA在儿童体内的药动学过程。     

细胞色素P4503A5~*3基因多态性与环孢素所致肝损伤相关性的评价

目的系统评价细胞色素P450 3A5*3(CYP3A5*3)基因多态性与环孢素所致的肝损伤的相关性。方法系统检索Pub Med、MedLine、EMbase、Cochrane图书馆、维普数据库、中国知网和万方数据库,查找CYP3A5*3基因多态性与环孢素致患者肝损伤相关性的研究,检索时间自各数据库建库至2016年3月。试验组为环孢素致肝损伤患者,对照组为无肝损伤患者或其他原因致肝损伤患者。用Rev Man 5. 2. 0软件进行Meta分析。结果共纳入病例对照研究3篇(包括英文1篇和中文2篇),患者807名。患者的基因型分布均符合Hardy-Weinberg平衡定律。试验组和对照组CYP3A5*3AA型的分布率分别为21. 70%(87例/401例)和22. 36%(91例/407例),差异有统计学意义(P <0. 01)。试验组和对照组中携带等位基因A的分布率分别为21. 20%和32. 89%,携带等位基因G的分布率分别为78. 80%和67. 11%,差异均无统计学意义(均P> 0. 05)。结论 CYP3A5*3基因多态性与环孢素致患者肝损伤相关,其中携带CYP3A5*3AA基因型的患者服用环孢素所致肝损伤的发生率较低,而此发生率与等位基因A和G的分布无关。     

环孢霉素滴眼液联合人工泪液治疗角结膜干燥症患者的临床研究

目的观察环孢霉素滴眼液联合人工泪液治疗角结膜干燥症患者的临床研究及对泪液乳铁蛋白的影响。方法将80例角结膜干燥症患者随机分为对照组和试验组,每组40例。对照组给予聚乙烯醇滴眼液治疗,tid,每次1滴。试验组在对照组的基础上,用环孢霉素滴眼液治疗,tid,每次1滴。2组均持续治疗8周。比较2组患者的乳铁蛋白、泪液分泌试验(SIT)、泪膜破裂时间(BUT)、角膜荧光素染色(FS)评分及药物不良反应发生情况。结果治疗后,试验组和对照组乳铁蛋白分别为(1.72±0.22)和(1.57±0.18)g·L^-1,SIT分别为(13.60±1.90)mm/5 min和(11.65±1.18)mm/5 min,BUT分别为(8.86±1.22)和(7.59±1.11)s,FS评分分别为(0.87±0.10)和(1.43±0.21)分,差异均有统计学意义(均P<0.05)。试验组出现结膜轻度充血3例,眼部刺激2例,药物不良反应发生率为12.50%(5例/40例);对照组出现短暂性视力模糊3例,药物不良反应发生率为7.50%(3例/40例),差异无统计学意义(P>0.05)。结论环孢霉素滴眼液联合人工泪液治疗角结膜干燥症的效果较好,能够增加泪液乳铁蛋白水平,改善泪液环境。