Effects of lactational cyclosporine A use on rat pups

Abstract:  We aimed to evaluate the structural and functional changes in the thymus and kidneys of rat pups whose mothers were given cyclosporine A (CsA) during lactational period. Six adult nursing Wistar rats and their 30 pups were studied. Rat pups were divided into four groups as follows: 21-day treated group and 21-day placebo group, each including 10 breastfeeding pups sacrificed on the 21st day, whose mothers were given CsA or placebo, respectively ( infancy groups ) and, 60-day treated group and 60-day placebo group, each including five breastfeeding pups sacrificed on the 60th day, whose mothers were given CsA or placebo, respectively ( puberty groups ). While CsA levels of mother rats were very high, CsA levels of 21-day treated group pups were zero. There were no renal histomorphometric differences between study and control pups in both age groups. Renal function parameters showed significant differences between study and control pups in the infancy group: the 21-day treated group pups had significantly lower urine volume, proteinuria, FE_Na and urinary NAG/creatinine ratio. GFR was also lower in the 21-day treated group, but the difference was not significant, and serum creatinine levels were also not different. Renal function differences were not present among the pubertal pups. Thymic corticomedullary ratio of the 21-day treated group was significantly higher than the 21-day placebo group, while there was no difference between the 60-day treated group and 60-day placebo group. There were no significant changes in the number and distribution of CD3+, CD4+, and CD8+ thymocytes between study and control pups in both age groups. In conclusion, breastfeeding by CsA-treated mother rats induced structural alterations in the thymus and functional changes in the kidneys of the rat pups during infancy. Disturbances in the kidneys and thymus mostly improved after CsA exposure was over.     

环孢素A在小儿肾病综合征中的应用

环孢素A(cyclosporine A,CsA)自1986年开始用于治疗儿童肾病综合征(NS),是目前激素依赖或耐药型NS的选择性治疗药物之一,特别是在细胞毒性药物不耐受或出现不良反应的患儿,长期应用安全性和耐受性均较好。但在应用期间必须监测CsA的血药浓度和肾功能,对接受长期持续CsA治疗的儿童每2～3年进行1次肾活检,以发现肾毒性的组织学证据。     

环孢素A治疗儿童难治性肾病综合征疗效观察

目的观察环孢素A(CsA)治疗儿童难治性肾病综合征(RNS)的临床疗效。方法回顾性分析CsA联合泼尼松治疗儿童RNS的疗效,监测CsA治疗前后相关生化指标,并观察药物不良反应。27例患儿中激素抵抗14例,激素依赖6例,频复发7例;其中25例行肾活检,微小病变型肾病15例,局灶性节段性硬化性肾小球肾炎4例,系膜增生性肾小球肾炎4例,膜增殖性肾小球肾炎2例。CsA剂量2～5mg/(kg·d),疗程6～24个月(平均11.6±6.6个月)。结果完全缓解15例,部分缓解9例,无效3例,总有效率88.9%。激素抵抗组、激素依赖组及频复发组的疗效差异无统计学意义。激素抵抗组完全缓解者起效时间较激素依赖组及频复发组长。不同病理类型的RNS患儿对CsA的治疗反应差异无统计学意义。血胆固醇≤9.0mmol/L组的完全缓解率较血胆固醇>9.0mmol/L组高。CsA的主要不良反应依次为多毛、轻度肝损、血肌酐升高等,均不影响CsA继续使用。结论CsA联合泼尼松治疗难治性肾病综合征安全有效。     

Mycophenolate mofetil introduction stabilizes and subsequent cyclosporine A reduction slightly improves kidney function in pediatric renal transplant patients: a retrospective analysis

Chronic allograft nephropathy (CAN) is the major cause of late graft loss. Among others, chronic calcineurin inhibitor toxicity (CNI) contributes to the development of CAN. Therefore, reduction in CNI dosage may delay the development of CAN, leading to longer graft survival. It was the aim of the present retrospective analysis to investigate the effect of mycophenolate mofetil (MMF) addition with subsequent cyclosporine A (CSA) reduction on renal function in pediatric kidney allograft recipients. Seventeen patients (aged 8.3-17.6 yr) with monotherapy with CSA and progressive loss of renal function at a median of 3.4 yr after kidney transplantation were enrolled. After at least three months of MMF treatment, CSA dosage was stepwise reduced to trough levels of 100, 80, and 60 ng/mL. In all patients, introduction of MMF prevented a further decrease of glomerular filtration rate (GFR). The mean GFR 12 months before study enrollment was 96.1+/-24.5 and 71.0+/-21.0 mL/min/1.73 m2 at start of MMF. After introduction of MMF and unchanged CSA dosage GFR was stabilized to 71.1+/-23.8 mL/min/1.73 m2. After CSA reduction to trough levels of 60 ng/mL, GFR was slightly ameliorated up to 76.3+/-24.1 mL/min/1.73 m2. Within the follow-up period, one borderline rejection occurred in a patient in whom the CSA trough level was 60 ng/mL since seven months. In pediatric kidney allograft recipients with progressive loss of renal function reduction of CSA after introduction of MMF may stabilize and even slightly ameliorate renal function.     

环孢素A治疗126例儿童非重型再生障碍性贫血疗效分析

目的 评价环孢素A(CSA)治疗儿童非重型再生障碍性贫血(NSAA)疗效.方法 回顾性分析2005年1月至2014年6月径CSA口服治疗的126例NSAA患儿的临床资料.结果 126例患儿中男76例、女50例,中位年龄7岁11月(1岁11个月~14岁),中位随访时间14.5个月(3~79个月);非输注依赖型NSAA78例(61.9%),输注依赖型NSAA48例(38.1%).总有效率55.6%;CSA治疗输注依赖型NSAA有效率77.1%,非输注依赖型NSAA有效率42.3%,差异有统计学意义(χ2=15.83,P=0.000).CSA治疗后,14.1%非输注依赖型NSAA病例完全缓解,80.8%维持非输注依赖NSAA,5.2%进展为输注依赖NSAA或重型/极重型再生障碍性贫血(SAA/VSAA);16.7%输注依赖型NSAA患儿完全缓解,60.4%好转为非输注依赖,23.0%维持输注依赖型NSAA或进展为SAA/VSAA.结论 CSA治疗可以延缓NSAA患儿的疾病进展,但CSA治疗完全缓解率低,尚需更多临床试验建立更有效的NSAA治疗方案.     

环孢霉素A治疗以肾病综合征为表现的局灶节段性肾小球硬化的疗效观察

为了观察环孢霉素A(CyA)对以肾病综合征为表现的局灶节段性肾小球硬化 (FSGS)的疗效。对11例病儿进行治疗 ,年龄2岁～11岁。CyA开始治疗剂量3mg/ (kg·d) ,1周后加至5mg/ (kg·d) ,以后根据CyA血浓度调整剂量 ,维持CyA血浓度在100μg/L～200μg/L。用药6个月～9个月后逐渐减量 ,总疗程12个月。结果显示完全缓解7例 (63.6% ) ,部分缓解3例 (27.3 % ) ,无效1例 (9.1% ) ,CyA治疗激素耐药FSGS ,总有效率高达91 % ;5例治疗后尿视黄醇结合蛋白 (RBP)升高。提示CyA治疗以肾病综合征为表现的FSGS在临床上具有良好疗效 ,RBP则可作为CyA副作用的监测指标     

Serum cyclosporine level and orange juice in pediatric renal-transplanted patients

Abstract:  Organ transplant survival has been improved with CsA, but the PK of CsA may be affected by many drugs and foods. This study was performed to investigate the impact of orange juice on PK of CsA in children who had received a renal transplant. This cross-over placebo-controlled study was performed on 10 pediatric kidney-transplanted patients. All children received orange juice (Thomson novel) or water. After morning dose of CsA, patients were given 250 mL orange juice or water and investigation of the PK was performed in 12 h. Co-administration of orange juice with CsA compared with water did not significantly increase the area under the curve from 0–12 h (AUC_0–12) of CsA (orange juice 2833 ± 553, water 3053 ± 1532, p > 0.05). Also, there were not significant effects on peak concentration ( C _max) or time to C _max ( t _max). Orange juice can be used with CsA and there was no interaction between the juice and CsA in pediatric renal transplants.     

Independent risk factors for chronic cyclosporine induced nephropathy in children with nephrotic syndrome

Background

Cyclosporine A (CsA) has been widely used in children with steroid dependent and steroid resistant nephrotic syndrome (NS) because of its efficacy in relieving these patients from systemic side effects of steroids. However, its long term use is controversial, since chronic CsA induced nephropathy (CsAN) may develop in a considerable number of patients.

Aims and Methods

In order to clarify the risk factors for the development of CsAN, the clinical characteristics of children with steroid dependent or steroid resistant NS taking CsA (target blood trough levels 50–150 ng/ml) for more than six months, managed at a single centre, were retrospectively analysed.

Results

Thirteen of 30 children (24 boys and 6 girls) taking CsA (mean duration 43 months, range 6–144) had CsAN defined as the presence of CsA associated arteriopathy with or without striped tubulointerstitial lesions. The multivariate analysis revealed that CsA treatment for more than 36 months and an age younger than 5 years at the start of CsA treatment were independent risk factors for the development of CsAN. The univariate analysis also showed that patients with CsAN had more frequent relapses during CsA treatment than those without CsAN.

Conclusion

An alternative treatment should be seriously considered after a 36 month administration of CsA in order to prevent CsAN. Data also suggest that CsA treatment in children younger than 5 years should be avoided if possible.     

Pharmacodynamic monitoring of cyclosporine A by NFAT‐regulated gene expression and the relationship with infectious complications in pediatric renal transplant recipients

Billing H, Giese T, Sommerer C, Zeier M, Feneberg R, Meuer S, Tönshoff B. Pharmacodynamic monitoring of cyclosporine A by NFAT‐regulated gene expression and the relationship with infectious complications in pediatric renal transplant recipients.
Pediatr Transplantation 2010: 14:844–851. © 2010 John Wiley & Sons A/S. Abstract: Pharmacokinetic monitoring of CsA is unsatisfactory, because at comparable CsA blood concentrations, the frequency and severity of adverse effects vary considerably among patients. We have therefore recently developed a precise, reliable, and robust whole‐blood pharmacodynamic assay that measures the suppression of CsA‐target genes in T lymphocytes. Because of the different characteristics of CsA pharmacokinetics in children and the higher propensity for infectious complications, this assay requires validation in the pediatric patient population. We therefore quantified in a prospective study of 45 pediatric renal transplant recipients the residual expression of NFAT‐regulated genes in lymphocytes by RT‐PCR and correlated these findings with the frequency of recurrent infections in the maintenance period post‐transplant. Patients with recurrent infections showed a significantly stronger inhibition of NFAT‐regulated gene expression (18.2%) than patients without recurrent infections (31.7%; p = 0.012). This difference was specific, because various PK parameters of CsA and the concomitant immunosuppressive therapy were comparable between patients. Multivariate regression analysis showed that patient age and residual NFAT‐regulated gene expression were the only independent determinants of recurrent infections. By ROC curve analysis, a cutoff value of 23% residual NFAT‐regulated gene expression had the highest sensitivity (71.1%) and specificity (65.4%) for the discrimination of patients with and without recurrent infections. Pharmacodynamic monitoring of CsA by measurement of residual NFAT‐regulated gene expression in T lymphocytes has the potential to identify over‐immunosuppressed pediatric renal transplant recipients and is therefore a useful tool for the optimization of CsA therapy.     

Pharmacokinetic monitoring of intravenous cyclosporine A in pediatric stem-cell transplant recipients. The trough level is not enough

Abstract:  In order to monitor CsA serum levels after SCT, trough levels (C0) are widely used. The aim of this study was to estimate the population and individual PK parameters for patients receiving intravenous CsA after SCT. In 27 pediatric patients after SCT receiving CsA (3 mg/kg/day) every 12 h, a total of 289 CsA concentrations was obtained. To describe the PK parameters of CsA, a two-compartment model with first order elimination was used. Covariate analysis identified body weight, age, and the co-administration with itraconazole and tobramycine as factors influencing the Cl. The statistical comparison of AUC, trough level, and C2 indicates a correlation between AUC and C2, but no correlation between the AUC and C0, r = 0.24 (p = 0.146) vs. r = 0.526 (p = 0.000692), respectively. Our results underscore the fact that CsA trough levels do not reflect the drug exposure in patients receiving intravenous CsA after SCT. By contrast, CsA blood levels measured 2–6 h after CsA infusion showed a better correlation with the AUC. Our data provide new information to optimize the balancing act between GvHD-prophylaxis, graft vs. leukemia effect, and CsA side-effects after SCT.     

Adjunct cyclosporine therapy for refractory Kawasaki disease in a very young infant

Herein we describe the case of a 6‐week‐old boy who developed complete Kawasaki disease (KD). The cytokine profile and activation of monocytes and subsequent T cells matched the typical feature of refractory KD. The patient received a total of three courses of i.v. immunoglobulin (IVIG), but did not achieve clinical relief. Adjunctive therapy with oral cyclosporine A (CsA) led to prompt defervescence. This was continued for 7 days without serious adverse events. Coronary artery dilatations regressed within 3 months of follow up. KD infants <3 months of age are at higher risk of coronary artery aneurysm than the older ones. To our knowledge, oral CsA treatment has not been reported in such young infants with KD. The diagnosis and treatment of very young infants with KD are challenging. Adjunctive use of CsA in IVIG treatment could be effective for refractory KD in infants <3 months of age.     

Efficacy of 1.25% and 1% topical cyclosporine in the treatment of severe vernal keratoconjunctivitis in childhood

Cyclosporine eyedrops 2% have been used for treatment of corticosteroid-resistant vernal keratoconjunctivitis (VKC) cases. The purpose of our study was to verify the efficacy of 1.25% vs. 1% topical cyclosporine in improving severe form of VKC in childhood. Twenty children with severe VKC, were enrolled in a double-blind, placebo-controlled study and received cyclosporine 1.25% in one eye for 2 wk. Then an open trial was conducted during the next 3 months and 2 wk. Thirty-two more patients were recruited the next year into a new open trial and they received cyclosporine 1% for 4 months. Ocular subjective symptoms and objective signs were scored in all children at entry, 2 wk and 4 months. Skin prick tests and conjunctival scraping tests were also performed; serum immunological and biochemical markers were assessed. The mean score values for severity of subjective symptoms and objective signs were significantly decreased after 2 wk, and 4 months, compared with those at entry (p < 0.001), in both groups of children who received cyclosporine eyedrops 1.25% and 1%, respectively. Serum markers did not differ from the beginning to the end of treatment. Conjunctival eosinophils and cyclosporine serum levels were not detectable at the end of therapy, nor were endothelial corneal cells damaged. Our findings suggest that 1% cyclosporine concentration might be the minimal effective treatment regimen to control symptoms and local inflammation in severe forms of VKC.     

Effects of exchange transfusion on cytokine profiles in necrotizing enterocolitis

To study the effect of exchange transfusion on cytokine profiles in a patient with necrotizing enterocolitis, the levels of 12 cytokines and serum calprotectin were measured among exchange transfusion. A male extremely low birth weight infant was in non‐compensated shock and diagnosed stage 3 necrotizing enterocolitis. Exchange transfusion was performed for critical condition, refractory hypotension and disseminated intravascular coagulation. After exchange transfusion, the patient's blood pressure increased and stabilized. Then an enterostomy was performed and revealed necrosis of the ascending colon. Of the cytokines examined, interleukin‐8 and serum calprotectin were high before exchange transfusion and decreased after exchange transfusion.     

Anorexia nervosa in a pediatric renal transplant recipient and its reversal with cyclosporine

We report a 16‐yr‐old female who developed AN within a month after renal transplantation and its resolution after switching from tacrolimus to cyclosporine. Her initial maintenance immunosuppressive regimen after renal transplantation consisted of tacrolimus, mycophenolate, and steroid. She had 7 kg weight loss within the first month of transplant with subsequent 10, 12, 17, and 19 kg loss after three, five, seven, and nine months of transplant, respectively. Besides weight loss and disturbances in body image, the patient developed alopecia, bradycardia, and persistent secondary amenorrhea. Upon switching to cyclosporine from tacrolimus nine months after transplant, she started regaining weight with 5 kg gain within two months and 10 kg after four months. She restarted her menstrual cycle, alopecia and bradycardia resolved, and her body image disturbance improved. Here, we describe a very unusual neuropsychiatric side effect of tacrolimus and its resolution with another calcineurin inhibitor, cyclosporine, in an adolescent renal transplant recipient.