Benefit-risk assessment of ciclosporin withdrawal in renal transplant recipients.

Ciclosporin is associated with significant toxicity, including nephrotoxicity, and with an increased risk of cardiovascular events. Many attempts have been made to wean patients from ciclosporin. Before the availability of new immunosuppressive drugs, the acute rejection rate observed after ciclosporin withdrawal did not permit the widespread use of withdrawal regimens even though meta-analysis did not show that they adversely affected patient or graft survival. Nevertheless, maintenance therapy with azathioprine and corticosteroids has not become routine practice. The introduction of mycophenolate mofetil and subsequently sirolimus has increased the number of clinical studies of the effects of ciclosporin withdrawal. In stable patients, this withdrawal is associated with a small but significant increase in the incidence of acute rejection episodes. Declining renal function and other forms of ciclosporin-related toxicity have improved. However, this improvement was also observed when ciclosporin was only reduced (and not withdrawn), which did not increase the risk of acute rejection. More precise definition of the patients who could benefit from ciclosporin-withdrawal may help to optimise the immunosuppressive regimen in this setting. In patients with chronic allograft deterioration, ciclosporin withdrawal together with mycophenolate mofetil introduction has been shown to improve renal function significantly in many small studies, and a large prospective randomised study. For the time being, ciclosporin withdrawal is a good therapeutic option for patients with declining renal function and signs of chronic ciclosporin nephrotoxicity on renal biopsy. Finally, recent preliminary studies have reported the results of complete avoidance of calcineurin inhibitors after renal transplantation. These results are promising as regards the incidence of acute rejection, renal function and safety, but need confirmation in larger trials with a longer follow-up. Nevertheless, it has become clear that the concept of an immunosuppressive regimen with little or no nephrotoxicity after renal transplantation is more and more important and plays a crucial part in tailoring immunosuppression to the needs of specific patient populations.     

羟苯磺酸钙在肾移植后蛋白尿治疗中的应用

目的探讨羟苯磺酸钙辅助治疗肾移植后蛋白尿的有效性和安全性。方法 60例肾移植后蛋白尿患者随机分为两组,每组30例,均常规应用免疫抑制剂治疗,观察组加用羟苯磺酸钙0.5 g,po,tid。分别于治疗前和治疗1、3、6个月后检测24 h尿蛋白定量(Urp)、尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、血β2微球蛋白(β2-MG)、肌酐清除率(Ccr)、肝及肾功能,并记录不良反应的发生情况。结果治疗前两组各项指标均相近(P>0.05)。观察组临床总有效率、完全缓解率分别为83%、27%,均高于对照组(33%、7%,P<0.05),两组疗效差异显著(P<0.05)。对照组治疗后各项指标均无显著变化(P>0.05),观察组治疗1个月后,Urp、尿NAG酶、血β2-MG均开始下降,Ccr开始升高(P<0.05),且各观察时点Urp、尿NAG酶、血β2-MG低于对照组,Ccr高于对照组,差异均有显著意义(P<0.05)。治疗期间两组均未见严重不良反应。结论羟苯磺酸钙辅助治疗肾移植后蛋白尿安全有效。     

Patient factors associated with adherence to immunosuppressant therapy in renal transplant recipients.

PURPOSE: Factors associated with adherence to immunosuppressant therapy (IST) in renal transplant recipients were studied. METHODS: The Immunosuppressant Therapy Adherence Scale (ITAS) was completed by adult renal transplant recipients in Georgia. Those completing the ITAS were classified as adherent to IST if their ITAS score were 12 and nonadherent if their score was less than 12. The relationship between the dichotomized ITAS scores and patient variables that are readily available to clinicians, such as sex, age, kidney donor type, income, marital status, race or ethnicity, and time since transplantation, was assessed. The relationship of ITAS scores to patients' clinical and pharmacy data (e.g., graft rejection, serum IST concentrations, serum creatinine [SCr] concentrations, and pharmacy refill-based adherence rates) was also assessed. RESULTS: One hundred thirty-seven patients completed the ITAS. Eighty-nine patients (65%) were adherent to IST, and the remaining 48 (35%) were nonadherent. Patient sex was unrelated to adherence. Compared with nonadherent patients, adherent patients tended to be younger, to take cyclosporine, to have lower incomes, to have received their transplant more recently, to have targeted immunosuppressant concentrations, to have greater refill-based adherence rates, and to be less likely to exhibit an increase in SCr concentration (p < 0.05). There was no significant difference in the number of rejections between adherent and nonadherent patients. CONCLUSION: Patient age, income, time since transplantation, and the immunosuppressant agent prescribed were associated with IST adherence.     

他克莫司在肾移植术后肝功能异常中的应用

目的 :观察他克莫司 (tacrolimus)在肾移植术后肝功能异常病人中应用的有效性及安全性。方法 :将 47例病人分成环孢素组 ,给予环孢素 1 .5～3 .5mg·kg-1,po,bid ,作对照 ;他克莫司治疗组 ,给予他克莫司 0 .0 5～ 0 .1 5mg·kg-1,po,bid。 2组均同时给予霉酚酸酯、泼尼松及保肝药物治疗 ,观察 3mo。结果 :治疗后 90d,他克莫司组的ALT ,SCr,BUN指标分别下降 (1 0 0±s 45 )IU·L-1,(5 8± 3 9)μmol·L-1和 (7± 4)mmol·L-1,(P <0 .0 1 ) ;环孢素组的ALT下降 (4 6± 2 5 )IU·L-1,(P <0 .0 1 ) ,SCr及BUN分别升高 (4 3± 69) μmol·L-1(P <0 .0 1 )和(3± 6)mmol·L-1(P <0 .0 5 )。 2组间比较P <0 .0 5或P <0 .0 1。不良反应环孢素组出现 1 3例 ,他克莫司组出现 1例。结论 :他克莫司在肾移植术后肝功能异常病人中应用有利于肝功能的恢复 ,是安全有效的免疫抑制药     

Daclizumab induction therapy in liver transplant recipients with renal insufficiency

Background The role of interleukin 2 (IL‐2) receptor antibodies to avoid the nephrotoxic effects of calcineurin inhibitors in the early post‐liver transplant (LT) period is not well defined. Aim To examine the use of daclizumab induction in LT recipients with renal insufficiency. Methods Between 2002 and 2005, 62 patients (median pre‐LT creatinine 2.4 mg/dL, IQR 1.9–3.7) received daclizumab induction with tacrolimus being administered when serum creatinine was <2.0 mg/dL. A concurrent comparison group (n = 221, 2002–2005) received tacrolimus‐based immunosuppression without daclizumab (median pre‐LT creatinine 1.1 mg/dL, IQR 0.9–1.4). A second historical comparison group (n = 103, 1995–2005) not receiving daclizumab was matched to the daclizumab patients by pre‐LT serum creatinine (2.2 mg/dL, IQR 1.8–3.1). All patients received mycophenolate mofetil and steroids. Results Serum creatinine improved in the daclizumab group (?1.0 mg/dL, IQR ?2.2 to ?0.4) and worsened in the concurrent comparison group (+0.2 mg/dL, IQR 0–0.5) from pre‐LT to 4 months. However, there was no difference when daclizumab group was compared with the historical comparison group matched on pre‐LT creatinine (median change: ?0.8 mg/dL vs. ?0.7 mg/dL). Daclizumab induction was not associated with improvement in renal function at 4 months (P = 0.34) after adjusting for pre‐LT creatinine, age, gender, hepatitis C status and simultaneous liver kidney transplantation. Conclusion The incremental benefit offered by induction therapy with IL‐2 receptor antibodies to preserve renal function is questionable.     

Relationships between sirolimus dosing, concentration and outcomes in renal transplant recipients

AIM: To explore relationships between sirolimus dosing, concentration and clinical outcomes. METHODS: Data were collected from 25 kidney transplant recipients (14 M/11 F), median 278 days after transplantation. Outcomes of interest were white blood cell (WBC) count, platelet (PLT) count, and haematocrit (HCT). A naive pooled data analysis was performed with outcomes dichotomized (Mann-Whitney U-tests). RESULTS: Several patients experienced at least one episode when WBC (n = 9), PLT (n = 12), or HCT (n = 21) fell below the lower limits of the normal range. WBC and HCT were significantly lower (P < 0.05) when sirolimus dose was greater than 10 mg day(-1), and sirolimus concentration greater than 12 microg l(-1). No relationship was shown for PLT and dichotomized sirolimus dose or concentration. CONCLUSIONS: Given this relationship between sirolimus concentration and effect, linked population pharmacokinetic-pharmacodynamic modelling using data from more renal transplant recipients should now be used to quantify the time course of these relationships to optimize dosing and minimize risk of these adverse outcomes.     

Complication of renal neoplasms with cystic disease: an indication for nephrectomy in potential transplant recipients

Thirty-five (1.1%) out of a total of 3,133 autopsied cases of renal tumors were complicated by renal malignant tumors and cystic renal disease. They accounted for 1.4% of 2,417 cases of renal malignant tumors and for 4.7% of 751 cases of cystic renal disease. Among the 35 complicated cases, 10 cases or 28.6% were free of metastasis. The incidence of complicated cases and those without metastasis aged over 60 years or over was 12.2% and 29.2% respectively, while the 10-59 year-old age group displayed a lower incidence of 3.6% and the same incidence of 27.3% respectively. In 26 out of 35 cases the malignant tumors was renal adenocarcinoma with no evidence of metastasis in nine cases (34.6%). Although it is unknown whether cystic renal disease undergoes malignant changes, not all of the patients undergoing chronic hemodialysis should be indicated for nephrectomies since such patients with renal malignancies are mostly elderly and are frequently free from metastases.     

Plasma protein binding of valproic acid in healthy subjects and in patients with renal disease.

1 Based on the Scatchard plot of the binding data of valproic acid (VPA) it is concluded that the drug is bound by two groups of binding sites with the association constants K1=40.0 X 10(-3) and K2=0.39 X 10(3), and the number of binding sites n1=1.5 and n2=6.8. 2 The binding is dependent on dialysis time, on temperature, on the drug concentration, and on the protein concentration in plasma. 3 At therapeutic plasma concentrations unbound VPA is 8.4 +/- 2.5%, but is increased to 20.3 +/- 4.7% in patients with significant impairment of renal function (P less than 0.001). 4 In patients with renal disease a good correlation is found between unbound VPA and serum creatinine, creatinine clearance, blood nitrogen and uric acid, respectively. A poor correlation is seen between unbound VPA and total protein or albumin concentration in plasma.     

Cyclosporin-erythromycin interaction in renal transplant patients.

1. The interaction between cyclosporin (CyA) and erythromycin was studied in renal transplant patients following oral and intravenous administration of CyA. 2. Blood and plasma CyA concentrations and blood concentrations of metabolite 17 were measured by h.p.l.c. 3. Erythromycin produced almost a two-fold increase in bioavailability, from 36% to 60%; with a small (13%) decrease in clearance of CyA. 4. The metabolite 17 data further support the postulate that erythromycin increases the absorption of CyA rather than inhibits its metabolism, as generally believed.     

Free mycophenolic acid should be monitored in renal transplant recipients with hypoalbuminemia

The current approach for therapeutic drug monitoring in renal transplant recipients receiving mycophenolate mofetil (MMF) is measurement of total mycophenolic acid (MPA) concentration. Because MPA is highly bound, during hypoalbuminemia the total concentration no longer reflects the free (pharmacologically active) concentration. The authors investigated what degree of hypoalbuminemia causes a significant change in protein binding and thus percentage free MPA. Forty-two renal transplant recipients were recruited for the study. Free and total concentrations of MPA (predose, and 1, 3, and 6 hours post-MMF dose samples) and plasma albumin concentrations were determined on day 5 posttransplantation. Six-hour area under the concentration-time curve (AUC(0-6)) values were calculated for free and total MPA, and percentage free MPA was determined for each patient. The authors found a significant relationship between low albumin concentrations and increased percentage free MPA (Spearman correlation = -0.54, P < 0.0001). Receiver operating characteristic (ROC) curve analysis was performed on the albumin versus percentage free MPA data. The cutoff value of albumin determined from the ROC analysis that differentiated normal from elevated percentage free MPA (defined as > or = 3%) in this patient population was 31 g/L. At this cutoff value albumin was found to be a good predictor of altered free MPA percentage, with a sensitivity and specificity of 0.75 and 0.80, respectively, and an area under the ROC curve of 0.79. To rationalize MMF dosing regimens in hypoalbuminemic patients (plasma albumin < or = 31 g/L), clinicians should consider monitoring the free MPA concentration.     

肾移植术后吗替麦考酚酯替换硫唑嘌呤的临床分析

目的 :观察肾移植后吗替麦考酚酯 (MMF)替换硫唑嘌呤 (Aza)的安全性及其临床效果。方法 :回顾分析16例由Aza转换为MMF患者的临床资料。4例因肝功能损害而改用MMF,7例肾功能损害 ,5例应患者要求而换用MMF。结果 :4例肝功能损害者肝功能均恢复正常 ,7例肾功能损害者2例逆转 ,4例肌酐 (SCr)下降但未能恢复正常 ,1例继续恶化恢复血液透析。2例不良反应包括原有贫血明显加重 ,1例腹泻。结论 :Aza可以安全替换为MMF。因环孢素 (CsA)加Aza引起肝功能损害者 ,换用MMF ,减少CsA用量 ,肝功能可望恢复。MMF对部分慢性排斥反应可能有效     

Variation in plasma prednisolone concentrations in renal transplant recipients given enteric-coated prednisolone.

Renal transplant recipients receiving intermittent haemodialysis and kept under normal ward conditions showed appreciable differences in plasma prednisolone concentrations after therapeutic doses of enteric-coated prednisolone tablets. This gross day-to-day variation occurred irrespective of the dosage used. Breakfast given before prednisolone tended to reduce the rate of absorption of the drug, the effect being quantitatively most pronounced with large doses. Haemodialysis had no apparent effect on the elimination of prednisolone from plasma. Such erratic blood concentrations of prednisolone as observed in these patients, possibly resulting from variable absorption, may be potentially hazardous. Hence use of enteric-coated tablets in renal transplant recipients should be viewed with caution.     

Pharmacokinetics and pharmacodynamic response of methylprednisolone in premenopausal renal transplant recipients

Chronic glucocorticoid therapy is prescribed in renal transplant recipients according to empiric dose-tapering schedules, which assume a similar pharmacologic response in men and women. The study objectives were (a) to compare the pharmacokinetics of methylprednisolone in premenopausal renal transplant recipients with previously studied male counterparts and (b) to describe the pharmacodynamic response of the hypothalamic-pituitary-adrenal axis during chronic steroid therapy. Thirteen stable premenopausal subjects (ages 30 to 相似文献   

Strategies to reduce toxicities and improve outcomes in renal transplant recipients

Ongoing improvements in immunosuppression and posttransplantation care have dramatically improved patient and graft outcomes after transplantation. The frequency of graft loss due to acute rejection has declined considerably as a result of the availability of a variety of more potent immunosuppressive agents and probably also because of refined clinical care and follow-up. Complications of long-term administration of corticosteroids (steroids) and calcineurin inhibitors, however, have become increasingly apparent as patients live longer with their transplant, and attention is shifting to long-term issues. Use of both steroids and calcineurin inhibitors is associated with metabolic toxicities such as hypertension, hyperlipidemia, diabetes, bone loss, and cataracts. These contribute to posttransplantation morbidity and may negatively affect patient and allograft survival. A variety of troublesome cosmetic side effects, such as hirsutism, gingival hyperplasia, alopecia, obesity, and cushingoid appearance, also are associated with these drugs. These effects can detract from patient self-esteem and compliance with the immunosuppressive regimen. In the past 2 decades, the introduction of second-generation immunosuppressive drugs, such as tacrolimus, mycophenolate mofetil, sirolimus, and anti-interleukin-2 receptor monoclonal antibodies, has provided some alternatives to classic immunosuppressant choices. Patients experiencing undesirable adverse events now can be converted to another immunosuppressive regimen that ultimately will improve graft and patient survival rates and improve quality of life after transplantation.     

Digoxin-like immunoreactive substance in renal transplant patients.

Digoxin-like immunoreactive substance (DLIS) has been detected in several patient populations that were not receiving digoxin, including those patients with end-stage renal disease. The structure and physiologic significance of this compound are unknown, and the fate of DLIS after renal transplantation has not been studied. The authors prospectively evaluated 163 patients (not receiving digoxin) before and after transplantation for the presence of DLIS. Three different assays were used: radioimmunoassay (RIA), affinity mediated immunoassay (ACA), and fluorescence polarization immunoassay (TDX I). Depending on the assay method used, 11% (RIA), 6% (ACA), and 9% (TDX) of patients had detectable DLIS pretransplant. Using all 3 assays, a total of 34 patients (21%) were found to have DLIS. The mean serum digoxin concentration was 0.41 +/- 0.13 ng/mL (range: 0.2-1.2 ng/mL) and DLIS was detectable by greater than 1 assay method in seven patients. DLIS persisted longer in patients who had delayed allograft function (13.7 +/- 7 days) than in those who did not (3 +/- 1.9 days), P less than .05. In summary, detection of DLIS in renal transplant recipients appears to be an infrequent occurrence when using a single digoxin assay method. When detected, the concentration of DLIS is often below the usual therapeutic range for digoxin and disappears once allograft function is established. The authors conclude that the presence of DLIS is unlikely to be clinically significant in the renal transplant population.     

Entry-into-human study with the novel immunosuppressant SDZ RAD in stable renal transplant recipients

AIMS: To evaluate the tolerability of single oral SDZ RAD doses in stable renal transplant recipients and the pharmacokinetics of ascending SDZ RAD doses when coadministered with steady-state cyclosporin A microemulsion (Neoral). METHODS: This randomized, double-blind, placebo-controlled, sequential study involved 54 patients in six treatment groups; a different SDZ RAD dose (0.25, 0. 75, 2.5, 7.5, 15, 25 mg) was assessed in each group. Patients received a single oral dose of SDZ RAD (n=6) or placebo (n=3) with their usual Neoral dose. SDZ RAD and cyclosporin A pharmacokinetic parameters were determined. RESULTS: All SDZ RAD doses were well tolerated, with no discontinuations due to adverse events, serious adverse events, or deaths. Similar proportions of patients receiving SDZ RAD and placebo had at least one adverse event (44% and 50%, respectively). Mean changes in laboratory variables (baseline to endpoint) showed no clinically meaningful differences between SDZ RAD and placebo groups. SDZ RAD was absorbed rapidly and showed dose-proportional pharmacokinetics (dose: 2.5-25 mg), based on systemic exposure. Multiple postabsorptive phases in the pharmacokinetic profile indicate tissue distribution. The elimination half-life ranged from 24 to 35 h across the five highest dose groups. Pharmacokinetics were similar in men and women. Co-administration of escalating single oral SDZ RAD doses did not affect steady-state cyclosporin A pharmacokinetics. CONCLUSIONS: SDZ RAD was well tolerated; safety profiles of SDZ RAD and placebo were similar. SDZ RAD pharmacokinetics were dose-proportional across the range 2.5-25 mg in conjunction with cyclosporin A-based therapy, according to systemic exposure. Cyclosporin A pharmacokinetics were not affected by coadministration of single oral doses of 0.25-25 mg SDZ RAD.     

Unintentional and intentional non-adherence to immunosuppressive medications in renal transplant recipients

Background Non-adherence to immunosuppressive medications following renal transplantation is a risk factor for rejection and graft loss. Despite the dire consequences, adherence lapses, both unintentional and intentional, are common and poorly understood. Objective The present study sets to compare the rates and determinants of unintentional, intentional and overall self-reported non-adherence. Setting Outpatient clinic at the National University Centre for Organ Transplantation, Singapore. Method This was a cross-sectional survey administered to N?=?152 renal transplant recipients. Main outcome measure They completed the Transplant Effects Questionnaire, Beliefs about Medications Questionnaire, Multidimensional Scale of Perceived Social Support, the Depression, Anxiety and Stress Scale, and the Medication Adherence Report Scale. Clinical and laboratory information were also assessed. Results The prevalence rates for overall, unintentional, and intentional self-reported non-adherence were 19.7, 47.4, and 15.1% respectively. Unintentional non-adherence was predicted by engagement in formal work, a primary diagnosis of autoimmune nephritis, and being a recipient of a living-donor renal transplant (i.e. stable characteristics). In contrast, intentional non-adherence was predicted by co-morbid burden and patients’ evaluation of the side effects of their medications. Overall non-adherence was predicted by a deliberate decision-making process involving the weighing of the costs of using immunosuppressive drugs against their perceived benefits. Conclusion The survey highlighted the importance of making a distinction between unintentional and intentional non-adherence in renal transplant recipients, and suggested that modifiable factors may be targeted in different ways in interventions to increase adherence.

     

Prednisolone protein binding in renal transplant patients.

Prednisolone pharmacokinetics and protein binding characteristics were studied in 10 renal transplant patients with various degrees of renal function (serum creatinine: 80-380 mumol/l) who received their usual oral maintenance dose of prednisolone (0.18 +/- 0.04 mg/kg). Plasma was assayed for prednisolone and hydrocortisone by h.p.l.c. and free prednisolone concentrations were determined in each sample by a rapid ultrafiltration technique. Free prednisolone area under curve (AUCu) ranged from 101 to 436 ng ml-1 h and was 6.3 to 15.0% of total prednisolone AUC. The fraction AUCu/AUC was closely related to serum albumin and creatinine concentrations determined at the time of study (multilinear regression correlation coefficient r2 = 0.830, P less than 0.0001); elevated serum creatinine and low albumin concentrations were associated with a higher % free. These results suggest that much of the variability in prednisolone protein binding could be attributed to inter-patient variability in serum albumin and creatinine concentrations. Total prednisolone concentrations would be potentially misleading in any comparisons made between patient groups with different renal function.