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     

Risk factors for allograft failure in United kingdom renal transplant recipients treated with cyclosporine A

BACKGROUND: After the introduction of cyclosporine A (CsA), 2-year graft survival of transplanted kidneys improved from less than 60% to more than 80%, but long-term graft survival and graft half-life have shown less change. This study investigates the impact of a range of demographic and treatment factors on long-term graft survival in renal recipients treated with CsA from all renal transplant centers in the United Kingdom. METHODS: Data were obtained from the Long-Term Efficacy and Safety Surveillance study of renal transplant recipients receiving CsA (Neoral; Novartis, Basel, Switzerland). A total of 1,757 de novo patients with a functioning graft at 1 year were evaluated. The endpoints considered were the need for regular dialysis or death. A stepwise stratified Cox model was used to identify the factors associated with outcome. RESULTS: Seven independent risk factors for allograft failure were identified: older recipient (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.2-2.6), male recipient (HR 1.8, 95% CI 1.2-2.7), younger donor (HR 1.7, 95% CI 1.2-2.5), above average creatinine (HR 1.9, 95% CI 1.3-2.8), chronic allograft nephropathy (HR 7.0, 95% CI 4.7-10.4), diabetic recipient (HR 2.2, 95% CI 1.2-4.1), and neoplasm after transplant (HR 1.7, 95% CI 1.2-2.6). CONCLUSION: Seven independent risk factors were found to influence graft survival. Only two of these can be modified by clinical intervention, elevated serum creatinine at 1 year and the occurrence of chronic allograft nephropathy. To influence these two factors, the optimization of immunosuppressive therapy is essential.     

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     

Gastric emptying time in renal transplant recipients treated with cyclosporine

Gastric emptying time (GET) appears to be a rate-limiting factor in the absorption of cyclosporine-A (CsA) and may be responsible for intra- and interpatient variability of CsA bioavailability. Few studies have assessed gastric motility after renal transplantation. The purpose of this study was to evaluate gastric emptying of semi-solid material in stable renal transplant patients with reference to blood CsA levels. The GET of semi-solids (GET t(1/2), half emptying time) was measured in 16 transplant recipients who were taking CsA (Neoral), prednisolone and azathioprine (or mycophenolate mofetil). The GET (t(1/2)) measured by radionuclide methods, was analyzed with reference to the daily CsA doses, levels of CsA (C(0)), and serum creatinine concentrations. The mean GET (t(1/2)) was 89.1 +/- 26.4 minutes. Twelve patients exhibited delayed gastric emptying with a mean CsA level of 171.8 +/- 56 ng/mL and a mean dose of 4.1 +/- 1.1 mg/kg/d. The GET (t(1/2)) was not significantly correlated with the serum creatinine levels, the time since transplantation, or the CsA concentration. In addition, the correlation between the mean daily CsA dose and the GET (t(1/2)) was only weakly positive, (r =.33, P =.2) and therefore, statistically insignificant. In conclusion, it could not be ascertained whether a higher dose of CsA delays gastric emptying or whether patients with delayed emptying require higher doses of CsA. However, it is believed that determining the GET after transplantation helps in the adjustment of immunosuppressant doses.     

De novo use of everolimus with elimination or minimization of cyclosporine in renal transplant recipients

Background

The purpose of two similarly designed multicenter, prospective, parallel-group, open-label studies was to evaluate early cyclosporine (CsA) elimination versus minimization from an everolimus-CsA-steroid regimen in de novo renal transplant patients.

Methods

Within 24 hours after transplantation, 170 renal transplant patients received everolimus (trough levels 3-8 ng/mL), CsA, and steroids. Those eligible (n = 114) were randomized (1:1) at 3 months to have CsA elimination by month 4 to 6 (±1 week) with everolimus trough levels maintained at 6 to 12 ng/mL or CsA minimization, until 12 months. The randomized population excluded those who discontinued the study prior to randomization due to adverse events, acute rejection episodes of Banff grade IIb/III, or worsening renal function during the month prior to randomization.

Results

At 12 months, the estimated glomerular filtration rate (Nankivell) with CsA elimination was noninferior versus CsA minimization (P < .0001, α-level 0.05; 90% confidence interval 0.6-8.5) by 7 mL/min/1.73 m² (noninferiority margin). Composite efficacy failure was comparable with CsA elimination and CsA minimization (18.9% and 17.5%, respectively, P = 1.000) and no graft loss or death was reported after randomization. Cytomegalovirus infections were rare under everolimus treatment, and no pneumonitis episode was reported.

Conclusion

In our selected randomized study population, immediate initiation of everolimus allowed CsA elimination. Renal function was stable on everolimus-based, CsA-free maintenance regimen without compromising efficacy.     

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.     

Benign breast diseases associated with cyclosporine therapy in renal transplant recipients

PURPOSE: Our aim was to correlate the radiologic characteristics of cyclosporine-induced benign breast diseases with clinical and pathologic findings. MATERIALS AND METHODS: The clinical, mammographic, and ultrasonographic records of 33 female renal transplant recipients who received cyclosporine were retrospectively reviewed. Eleven patients had 46 breast masses on ultrasonography. We performed core needle biopsies on 20 masses and reviewed the pathologic findings. RESULTS: Among 33 female renal transplant recipients, 11 (33%) had 46 benign breast lesions detected on ultrasonography. We performed core needle biopsies on 20 of the 46 masses. On pathologic examination, 12 were fibroadenomas, 6 showed fibrocystic changes, and 2 revealed dense fibrosis. Regardless of the final pathologic diagnosis, more than half of the lesions revealed severe lymphatic and venular swellings. Among 11 patients with breast lesions on ultrasonography, 10/11 (91%) showed multiplicity, and 7/11 (64%) bilaterality. Mammographically, patients with breast lesions revealed heterogeneous or extremely dense breast patterns, and 8 of 11 patients, circumscribed masses. Twenty-two patients without breast lesions showed scattered fibroglandular densities (n = 7), or heterogeneously dense (n = 11) or extremely dense (n = 4) breast patterns, and 3 of 22 patients showed vague or asymmetric densities that needed further evaluation. CONCLUSION: The development of new breast lesions in patients after renal transplantation should suggest a diagnosis of cyclosporine-induced benign breast disease including fibroadenoma, fibrocystic changes, and dense fibrosis.     

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.     

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.     

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.     

Role of postdose cyclosporine monitoring in living renal transplant recipients

Achieving optimal cyclosporine (Neoral) absorption is critical for successful graft outcome. Recently there have been studies on postdose monitoring of cyclosporine. Two- and 3-hour postdose cyclosporine levels measured by radioimmunoassay were correlated with occurrence of rejection and cyclosporine nephrotoxicity in 30 patients; C₂ and C₃ levels were significantly lower than the desired therapeutic levels in patients with acute rejection. Based on our study and those of others we suggest C₃ levels should be adopted in clinical practice.