Alterations of CYP3A4 and P-glycoprotein activity in vivo with time in renal graft recipients

BACKGROUND: Catabolism by intestinal and hepatic cytochrome P450 3A4 (CYP3A4), and excretion by P-glycoprotein (PGP), has a major influence on oral bioavailability of calcineurin inhibitors. In this study, the activity of intestinal and hepatic CYP3A4 and PGP in vivo was assessed in renal transplant recipients during the first year after transplantation (Tx). METHODS: Stable Caucasian renal transplant patients were tested at 1 week, 3 months, and 1 year after Tx, and compared with the results obtained in drug-free healthy volunteers. Intestinal and hepatic CYP3A4 and PGP activity were determined by measurement of (14)C-excretion dynamics in breath and urine after oral and intravenous administration of [N-methyl-(14)C]-erythromycin. RESULTS: Compared with 1 week after Tx, intestinal and hepatic CYP3A4 activity significantly decreased at 3 months and 1 year after Tx (-33% and -45%; -7% and -33%, respectively). Compared with the healthy volunteers, intestinal and hepatic CYP3A4 activity of the patients was significantly increased at 1 week after Tx, but normalized at 1 year after Tx. A similar pattern, though not significant, was seen for intestinal PGP activity. CONCLUSION: Phenotypic expression of hepatic and intestinal CYP3A4 was increased immediately after Tx, but gradually decreased to basal levels toward the end of the first year after Tx. The most plausible explanation for this evolution was the tapering of corticosteroid (CS) doses. These findings may also explain the increasing bioavailability of tacrolimus with time after Tx.     

Impact of gastric acid suppressants on cytochrome P450 3A4 and P-glycoprotein: consequences for FK506 assimilation

BACKGROUND: Cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (PGP) are important determinants of the oral bioavailability and clearance of tacrolimus. Cimetidine and omeprazole are known modulators of several CYPs in vitro. In the present study, the impact of cimetidine and omeprazole on tacrolimus exposure and on CYP3A4/PGP activity in vivo was examined. METHODS: In a cohort of 48 renal transplant recipients who switched standard ulcer prophylaxis with 400 mg of cimetidine daily to 20 mg of omeprazole, dose/weight normalized trough levels of tacrolimus during a 5-day interval before and after switch were compared and further studied using multivariate analysis. In a cohort of 6 healthy volunteers, the effect of a 5-day course of ranitidine, cimetidine, and omeprazole on overall CYP, CYP3A4, and PGP activity in vivo was assessed with the (13)C-aminopyrin breath test and the combined per oral and intravenous (14)C-erythromycin breath and urine test. RESULTS: Dose/weight normalized trough levels of tacrolimus decreased significantly (-15%) after switch from cimetidine to omeprazole. In healthy volunteers, a significant increase of intestinal CYP3A4 activity was observed after omeprazole, whereas no change was noted after cimetidine/ranitidine. Overall CYP activity was significantly decreased after cimetidine and remained unchanged after omeprazole/ranitidine. No effects on PGP or hepatic CYP3A4 were seen. CONCLUSION: Switching treatment with cimetidine to omeprazole in renal transplant recipients is associated with a decrease of dose/weight normalized trough levels of tacrolimus. Studies in healthy volunteers suggest that this may be explained by an increase of intestinal CYP3A4 activity.     

Combined Therapy with Atorvastatin and Calcineurin Inhibitors: No Interactions with Tacrolimus

Increased systemic exposure to statins and consequent risk for complications has been reported in patients concomitantly treated with cyclosporin A (CsA). This has been ascribed to inhibition of drug catabolism by cytochrome P450 3A4 (CYP3A4) or drug transport by P-glycoprotein (PGP) and organic anion transporting polypeptide (OATP1B1). It is not known whether the combination of statins and tacrolimus (Tac) also suffers from this drawback.
Therefore, a pharmacokinetic study of atorvastatin and its metabolites was performed in 13 healthy volunteers after 4 days' treatment, and after short (12 h) concomitant exposure to CsA and Tac. A complementary assessment of overall CYP, and hepatic and intestinal CYP3A4 + PGP activity was performed after each treatment episode and compared to baseline (no drugs). Systemic exposure to atorvastatin acid and its metabolites was significantly increased when administered with CsA. In contrast, intake of Tac did not have any impact on atorvastatin pharmacokinetics. Concomitantly, a profound decrease of hepatic and intestinal PGP and an increase of intestinal CYP3A4 were noted with CsA, whereas no effect was seen after atorvastatin therapy with or without Tac. Based on these findings treatment with Tac appears a safer option for patients needing a combination of statins and calcineurin inhibitors.     

Enhanced expression of enterocyte P-glycoprotein depresses cyclosporine bioavailability in a recipient of living donor liver transplantation

We evaluated levels of intestinal expression of absorptive-barrier P-glycoprotein (PGP) and cytochrome P-450 IIIA4 (CYP3A4) and immunosuppressant therapy in a patient who underwent living donor liver transplantation (LDLT) and received a second living donor liver transplant after chronic rejection of the first. PGP and CYP3A4 expression were measured using part of a Roux-en-Y limb. After the first LDLT, the concentration-dose ratio of orally administered tacrolimus was 159.8 ± 125.3 (average ± SD of 32 different days), similar to the average for 46 recipients of living donor liver transplants in our hospital (161.3 ± 88.1). However, the recipient required very large oral doses of cyclosporine (703.9 ± 385.4 mg/d, average ± SD of 13 different days) after the second LDLT. Although intestinal PGP level was increased markedly at the second LDLT, CYP3A4 level was decreased. In addition, levels of messenger RNA expression of several gene products related to the local inflammation, such as cyclooxygenase 2, interleukin-1β (IL-1β), IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-α, were increased. These results suggest that hepatic failure after LDLT, including chronic rejection and/or cholangitis, was accompanied by upregulation of intestinal PGP expression, which could depress the bioavailability of the immunosuppressant. (Liver Transpl 2003;9:1108-1113.)     

Effects of Elevated Tacrolimus Trough Levels in Association With Infectious Enteritis on Graft Function in Renal Transplant Recipients

Background

The bioavailability of oral tacrolimus is influenced by enterocyte metabolism, which involves CYP3A and P-glycoprotein. Viral infection–induced intestinal inflammation damages the enterocytes and causes unfavorable elevations in blood tacrolimus levels in transplant recipients, which may lead to nephrotoxicity.

Methods

From May 2000 to May 2011, 56 renal transplant recipients receiving tacrolimus at our hospital suffered from infectious enteritis with diarrhea. We investigated the tacrolimus trough levels before and after the onset of enteritis and evaluated the influence of elevated tacrolimus trough levels on the rate of changes in serum creatinine levels.

Results

Elevated tacrolimus trough levels were observed in 52 recipients (93%) after the onset of diarrhea, and the mean value was 2.3 times higher than that before the onset of enteritis (P = .0175). Tacrolimus trough levels returned to their previous levels 2 weeks after the onset of enteritis, even in recipients with >2-fold increase, following dose adjustments. Serum creatinine levels did not significantly differ between recipients with >2-fold increase in tacrolimus trough levels and those with <2-fold increase in trough levels during a 6-month period after the onset of enteritis.

Conclusions

Elevations in the tacrolimus trough levels due to infectious enteritis with diarrhea can improve in ∼2 weeks by adjusting the tacrolimus dosage. Such temporary elevations in the tacrolimus trough levels may not produce serious nephrotoxicity even in recipients with remarkably elevated trough levels.     

CYP3A4 and P-Glycoprotein Activity in Healthy Controls and Transplant Patients on Cyclosporin vs. Tacrolimus vs. Sirolimus

This study aimed to determine the impact of maintenance immunosuppressive therapy with cyclosporin A (CsA), tacrolimus (FK506) and sirolimus (Rapa) on the in vivo activity of both intestinal and hepatic cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (PGP) in renal transplant patients. The activity of these four elimination pathways was measured by the recently validated intravenous (iv) and per oral (po)14C erythromycin breath and urine test. In addition, overall hepatic P450 activity was measured by the (13)C aminopyrin breath test. Three groups of stable renal transplant patients on maintenance therapy with corticosteroids (CS) and mycophenolate mofetil (MMF) plus either CsA or FK506 or Rapa were examined. A significant increase in intestinal CYP3A4 activity and a significant decrease in hepatic and intestinal PGP activity was seen in patients on CsA in comparison with those on FK506 or Rapa (p < 0.01). A similar analysis in six healthy volunteers at baseline and after intake of CsA, FK506 and Rapa confirmed the results seen in the patients. There was no difference in CYP3A4 and PGP activity in the patients taking either FK506 or Rapa and healthy controls. These data suggest that a different pattern of drug interactions might be expected in patients treated with CsA vs. FK506/Rapa.     

Increased tacrolimus trough levels in association with severe diarrhea, a case report

It is well known that during diarrhea episodes decreased cyclosporine and tacrolimus levels are often observed, usually requiring an increase in dose. An increase in tacrolimus trough levels is infrequently recognized as a potential cause of the adverse effect of severe diarrhea. Herein, we report the case of a renal transplant patient who displayed increased tacrolimus trough levels during an episode of gastroenteritis with severe diarrhea. The patient is 32-year-old male who received a renal transplant from his mother. Immunosuppression was initiated with tacrolimus in combination with mycophenolate mofetil and prednisone. The postoperative course was uneventful. The function of the transplanted kidney was normal. Eight months after transplantation he presented to our hospital with a history of high fever, abdominal pain, nausea and severe diarrhea. He was admitted with a diagnosis of enterocolitis of unknown etiology. The blood trough level of tacrolimus had increased from 6.7 ng/mL to 28.7 ng/mL after the onset of diarrhea. A therapeutic trough level of tacrolimus was reached 6 weeks after complete relief of diarrhea. Tacrolimus shows large variability in bioavailability after oral administration, both due to intestinal metabolism by cytochrome P450 (CYP3A4) and active secretion from enterocyte into intestinal lumen by P-glycoprotein. The epithelial cells of the intestine, may be destroyed abrogating P-glycoproteins during the course of enterocolitis, thereby increasing the levels of tacrolimus. It is recommended to monitor trough levels of tacrolimus during severe diarrhea of any nature to prevent tacrolimus-related complications.     

Different evolution of trough and dose levels during the first year after transplantation for tacrolimus versus cyclosporine

At present, the two calcineurin inhibitors-cyclosporine (CsA) and tacrolimus (FK506)-are among the most frequently used immunosuppressants in clinical transplantation. Both drugs share variable oral bioavailability, which necessitates intense drug monitoring. This variability is attributed to large interindividual differences in drug catabolism by cytochrome P450 3A4/5 (CYP3A4/5) and drug efflux by P-glycoprotein (PGP). In addition, the activity of both CYP3A4 and PGP can vary substantially within the same individual due to environmental factors such as concomitant intake of inducing/inhibiting medications (eg, rifampicin/sporanox) or food substances (eg, grapefruit juice). More recently, an inducing effect of methylprednisolone on intestinal and hepatic CYP3A4 has been shown. Also, an influence of gender on CYP3A4 activity (being higher in women) has been reported. Once CsA and FK506 are absorbed and reach the bloodstream, both drugs are avidly bound to erythrocytes (up to 95% for FK506 and 50% for CsA) and plasma proteins, leaving only a small fraction of circulating active drug. This phenomenon also limits further hepatic catabolism and hence clearance of drug, which is influenced by hematocrit and levels of plasma proteins such as albumin. The aim of the present study was to compare the influence of changing steroid doses, hematocrit, and albumin on trough and dose levels of FK506 versus CsA during the first year after transplantation. In addition, the evolution of trough and dose levels of FK506 versus CsA was stratified according to gender.     

CYP3A5 and ABCB1 Polymorphisms and Tacrolimus Pharmacokinetics in Renal Transplant Candidates: Guidelines from an Experimental Study

Genetic polymorphisms in biotransformation enzyme CYP3A5 (6986G > A, CYP3A5*3; 14690A > G, CYP3A5*6) and drug transporter ABCB1 (1236C > T; 2677G > T/A; 3435C > T) are known to influence tacrolimus (Tac) dose requirements and trough blood levels in stable transplant patients. In a group of 19 volunteers selected with relevant genotypes among a list of 221 adult renal transplant candidates, we evaluated whether consideration of CYP3A5 and ABCB1 genetic polymorphisms could explain the interindividual variability in Tac pharmacokinetics after the first administration of a standard dose (0.1 mg/kg body weight twice a day). Lower area under the time versus blood concentration curves (AUC) or lower trough concentrations were observed among CYP3A5 expressors (n = 9) than among nonexpressors (n = 10) using two different analytical methods for Tac determination (liquid chromatography with tandem mass spectrometry (LC-MS/MS) and immunoassay). The median AUC(0-infinity) was 2.6- and 2.1-fold higher in nonexpressors for LC-MS/MS and immunologic methods, respectively. No difference was observed in Tac pharmacokinetic parameters in relation to ABCB1 polymorphisms. In conclusion, our study confirms the very significant effect of CYP3A5 polymorphism early after the first administration of Tac. It also provides a strong argument for a doubling of the loading dose in patients early identified a priori on the transplantation list as possessing at least one CYP3A5*1 allele.     

Conversion of stable kidney transplant recipients from a twice-daily prograf to a once-daily tacrolimus formulation: a short-term study on its effects on glucose metabolism

Background

The adverse effects of tacrolimus are known to play major roles in posttransplantation diabetes mellitus (PTDM). In the present study, we investigated the effects of conversion from a twice-daily (Tac BID) to a once-daily prolonged release of tacrolimus formulation (Tac OD) on glucose metabolism in stable kidney transplant recipients.

Patients and Methods

In this prospective study, 26 patients converted from Tac BID to the same milligram-milligram daily dose of Tac OD were examined for the effects on renal function, drug trough levels, and glucose metabolism over a 4-week period.

Results

Conversion from Tac BID to Tac OD on a 1:1 mg basis resulted in a significant decrease in tacrolimus trough levels, but no significant changes in renal function. At 4 weeks after conversion, a homeostasis model assessment of β-cell function, and hemoglobin A1c (HbA1c) decreased significantly.

Conclusions

This study demonstrated a significant reduction in tacrolimus trough levels after switching from Tac BID to Tac OD, which increased insulin secretion and decreased HbA1c, suggesting that it may decrease the frequency of PTDM among stable renal transplant recipients.     

稳定期肾移植受者将他克莫司普通剂型转换为缓释剂型对移植肾功能的影响

目的观察稳定期肾移植受者由普通剂型他克莫司(Tac)转换为缓释剂型Tac后对移植肾功能的影响。方法回顾性分析山西省第二人民医院2011年12月至2019年6月由普通剂型Tac转换为缓释剂型Tac的83例稳定期肾移植受者,随访12~36个月,同时匹配83例继续服用普通剂型Tac的稳定期肾移植受者作为对照组。观察稳定期肾移植受者由普通剂型Tac转换为缓释剂型Tac后肾功能、谷值浓度个体内变异度(IPV)及依从性的变化、排斥反应的发生率及移植肾和移植受者的存活率。结果普通剂型Tac转换为缓释剂型Tac时间为移植后(42.76±30.50)个月,转换后24个月血清肌酐(SCr)明显低于转换前(P=0.013),估算肾小球滤过率(eGFR)明显高于转换前(P=0.005)。试验组较对照组在转换后36个月SCr明显降低(P=0.017),eGFR明显增高(P=0.038)。试验组转换前免疫抑制剂治疗障碍量表(ITBS)得分为(20.23±2.89)分,转换后为(17.63±3.08)分(P=0.000);Tac每日剂量转换前是(2.09±0.84)mg,转换后为(2.10±0.83)mg;Tac谷值浓度转换前为(7.22±2.84)ng/mL,转换后显著降低,人/肾均健康存活。结论稳定期肾移植受者由普通剂型Tac转换为缓释剂型Tac肾功能保持稳定且较普通剂型Tac相对更好,依从性明显改善,谷值浓度个体内变异度明显降低,长期服用的临床疗效和安全性良好。     

Altered first-pass effects in a liver transplant recipient explained intraindividual variation in calcineurin inhibitor concentrations: a case report

BACKGROUND: The significant interindividual and intraindividual variability in the blood concentrations of the most commonly used calcineurin inhibitors such as tacrolimus and cyclosporine makes the exact dosing of these agents in transplant recipients very challenging. As both of these drugs have narrow therapeutic index and are metabolized by hepatic and intestinal cytochrome P450 3A, we tested the hypothesis that these variations are secondary to varying first-pass effects in the gut and the liver over a period of time. CASE REPORT: A liver transplant recipient, who had previously presented with tacrolimus toxicity on his usual dosing regimen and intolerant to standard doses of cyclosporine, was selected to undergo the study. Oral and intravenous midazolam was used as the probe to measure hepatic and intestinal CYP3A4 activities at two different time points (phases one and two). Small intestinal biopsies were also obtained for measuring CYP3A4 activity for in vitro studies. On serially determining the patient's hepatic and intestinal CYP3A activities, we concluded that the variability in the dosing requirements is due to altered first-pass effects in the intestine. DISCUSSION: Transplant recipients receive multiple medications that may inhibit or induce these metabolizing enzymes, which eventually determine the concentrations of these narrow therapeutic agents. If no obvious etiology of intolerance to calcineurin inhibitors in a transplant recipient is identified, one should consider altered first-pass effects in the gut and the liver contributing to intraindividual variations in the blood concentrations.     

Erosive enterocolitis in mycophenolate mofetil-treated renal-transplant recipients with persistent afebrile diarrhea

BACKGROUND: Diarrhea is the most frequently reported adverse event in mycophenolate mofetil (MMF)-treated transplant patients. The aim of this study was to explore the gastrointestinal tract in MMF-treated renal transplant recipients with persistent afebrile diarrhea to characterize its nature and etiology. METHODS: Renal transplant recipients with persistent afebrile diarrhea (daily fecal output >200 g) were prospectively investigated for infections, morphologic, and functional (gastrointestinal motility and intestinal absorptive capacity) integrity of the gastrointestinal tract; 26 patients met the inclusion criteria. RESULTS: All but one patient had an erosive enterocolitis. Seventy percent of the patients had malabsorption of nutrients, contributing to the diarrhea. In +/-60%, an infectious origin was demonstrated and successfully treated with antimicrobial agents without changes in immunosuppressive regimen. In +/-40%, no infection occurred, but a Crohn's disease-like pattern of inflammation was noted. These patients also had a less pronounced bile-acid malabsorption but a significant faster colonic transit time, correlating with the trough level of mycophenolic acid (MPA). Cessation of MMF, however, was associated with allograft rejection in one third of these patients. CONCLUSIONS: Persistent afebrile diarrhea in renal transplant recipients is characterized by erosive enterocolitis, which is of infectious origin in +/-60%. In +/-40%, a Crohn's disease-like (entero-)colitis was present. Because reduction or cessation of MMF was the only effective therapy, MPA or one of its metabolites may be suggested as a possible cause. However, reduction or cessation of MMF was associated with an increased risk for rejection.     

Bioavailability and costs of once‐daily and twice‐daily tacrolimus formulations in de novo kidney transplantation

The use of once‐daily tacrolimus in de novo kidney transplantation is increasingly common. Therefore, we were interested in bioavailability aspects of novel once‐daily tacrolimus (LCPT, Envarsus) and once‐daily tacrolimus extended‐release formulation (ER‐Tac, Advagraf) compared with twice‐daily immediate‐release tacrolimus (IR‐Tac, Prograf). Furthermore, we calculated the costs. Kidney allograft recipients on tacrolimus‐based immunosuppression within 2 clinical trials were included in a single‐center analysis. The tacrolimus formulations were compared with respect to daily doses, doses per body weight, trough levels, and concentration‐dose (C/D) ratio over 12 months. Intrapatient variability in trough levels and C/D ratios after 3 months was calculated. For the calculation of tacrolimus costs, German list prices were used. Eighty patients (21 with LCPT, 23 with IR‐Tac, and 36 with ER‐Tac) were analyzed. Pharmacokinetic comparisons revealed significantly higher bioavailability of LCPT at all visits. The variability of trough levels and C/D ratios in general was high and highest in LCPT patients. Different dose requirements translated into different costs. Median treatment costs during the first year were 7.825€ (IQR 6.195‐8.892€) for LCPT, 9.813€ (IQR 7.630‐16.832€) for IR‐Tac, and 9.838€ (IQR 7.503‐ 13.541€) for ER‐Tac (Kruskal‐Wallis test, P = .003). The 3 tacrolimus formulations exhibit different dose requirements, exposure, and costs in favor of LCPT.     

Interleukin-2 profiles shortly after tacrolimus conversion from a twice-daily to once-daily regimen

A number of studies have indicated that kidney recipients can be safely converted from the twice-daily formulation (Tac-T) to the same dose of a once-daily tacrolimus (TAC) regimen (Tac-O) based upon monitoring of renal function. Conversion from Tac-T to Tac-O is commonly followed by a reduction in Tac trough levels, estimated by some authors to be about 20%. These alterations seem to not be associated with a modification of graft function, but study of inflammatory cytokines would be useful. The aims of our study were to monitor Tac, C-reactive protein (CRP), and interleukin (IL)-2 levels as well as to evaluate renal function among stable renal transplant patients converted from a Tac-T to a Tac-O regimen. We enrolled 10 consecutive stable kidney transplanted patients. Tac trough levels, serum creatinine concentrations, glomerular filtration rates using the Modification of Diet in Renal Disease formula (MDRD), CRP, and clinical assessment were performed monthly for 6 months before and 3 months after the conversion. After conversion we observed a slight but not significant reduction in Tac trough level. Renal function evaluated by serum creatinine and MDRD as well as CRP were not significantly different after conversion. IL-2 levels remained stable after conversion. We identified a group of patients showing reduced Tac trough levels below the therapeutic range and a group with stable Tac levels. No significant differences were observed among the two groups before versus after the conversion. Our results did not show a modification of IL-2, CRP and renal function levels, at 3 months after conversion despite the lower Tac trough concentrations. The clinical meaning of Tac trough alterations is not clear. They might reflect inter- and intraindividual differences in the clearance of Tac as recently described. They did not seem to be associated with activation of an inflammatory pathway.     

肝移植受者CYP3A5基因多态性对他克莫司血药浓度与剂量比值的影响

目的 研究CYP3A5基因多态性对肝移植受者术后他克莫司血药浓度与剂量比值（C/D比值）的影响.方法 选取2011年1月至2012年12月在上海交通大学医学院附属仁济医院肝脏外科接受原位肝移植术的86例受者,记录其术后1,2周和1,2,3,6个月他克莫司剂量,并测定相应时间点的他克莫司血药谷浓度,计算他克莫司C/D比值.检测肝移植受者CYP3A5基因多态性,观察不同基因型对他克莫司C/D比值的影响.结果 86例受者中,5例为CYP3A5＊1/＊1型（5.8%）,38例为CYP3A5＊1/＊3型（44.2%）,43例为CYP3A5＊3/＊3型（50%）.受者术后1,2周和1,2,3个月他克莫司C/D比值与CYP3A5基因型明显相关,携带CYP3A5＊1等位基因受者的C/D比值低于CYP3A5＊3/＊3型受者,差异有统计学意义（P〈0.05）.结论 CYP3A5基因多态性是影响肝移植受者术后他克莫司血药浓度的重要遗传因素.CYP3A5＊1/＊1型和CYP3A5＊1/＊3型受者需要比CYP3A5＊3/＊3型受者服用更高剂量的他克莫司才能达到相似的血药浓度.用药前检测受者基因型可以更有效地对他克莫司进行剂量调整.     

肾移植受者将环孢素A转换为他克莫司治疗的三年疗效分析

目的 评价肾移植受者将环孢素A(CsA)转换为他克莫司(Tac)治疗的有效性和安全性。方法 回顾将CsA转换为Tac治疗的97例肾移植受者的资料,转换治疗的原因分别为慢性移植肾肾病62例,难治性排斥反应21例,肝功能异常8例,齿龈增生、多毛6例。观察转换治疗后3年内的肾功能、肝功能、血脂、血压、血糖、急性排斥发生率、人/肾存活率以及药物不良反应等指标。结果 与转换前相比较,慢性移植肾肾病及难治性排斥反应患者转换治疗1年后肾功能明显好转(P＜0.01),患者第2、3年肾功能稳定。转换治疗后,肝功能异常者的肝功能明显改善,齿龈增生和多毛患者的症状也明显改善。97例转换治疗后第1年的人/肾存活率分别为100％和97.9％,第3年为100％和92.8％,患者血浆胆固醇、低密度脂蛋白、甘油三酯和血压均下降(P＜0.05)。转换治疗后,13例需用药物控制血糖(13.4％),另发生腹泻和食欲不振2例(2.1％),震颤5例(5.2％)。观察期内患者均未发生严重肺部感染和肿瘤。结论 使用CsA行免疫抑制治疗的肾移植受者发生相关并发症后转换为Tac治疗是安全和有效的。     

Posterior Reversible Encephalopathy Syndrome Independently Associated With Tacrolimus and Sirolimus After Multivisceral Transplantation

Posterior reversible encephalopathy syndrome (PRES) is a small vessel microangiopathy of the cerebral vasculature that occurs in 0.5–5% of solid organ transplant recipients, most commonly associated with tacrolimus (Tac). Clinical manifestations include hypertension and neurologic symptoms. We report an adult multivisceral transplant recipient who experienced recurrent PRES initially associated with Tac and subsequently with sirolimus. A 49‐year‐old woman with short bowel syndrome underwent multivisceral transplantation due to total parenteral nutrition–related liver disease. She was initially maintained on Tac, mycophenalate mofetil (MMF) and prednisone. Three months after transplantation, she developed renal dysfunction, leading to a reduction in Tac and the addition of sirolimus. Eight months after transplantation, she developed PRES. Tac was discontinued and PRES resolved. Sirolimus was increased to maintain trough levels of 12–15 ng/mL. Fourteen months after transplant, she experienced recurrent PRES which resolved after discontinuing sirolimus. Currently 3 years posttransplant, she is maintained on cyclosporine, MMF and prednisone with no PRES recurrence. In addition to calcineurin inhibitors, sirolimus may also be associated with PRES after solid organ transplantation. Ours is the first report of sirolimus‐associated PRES in the setting of multivisceral transplantation. Identifying a safe alternative immunosuppression regimen was challenging but ultimately successful.     

Late,Severe, Noninfectious Diarrhea After Renal Transplantation: High-Risk Factors,Therapy, and Prognosis

Objective

Late severe noninfectious diarrhea in renal transplant recipients can lead to malnutrition and even graft loss. The purpose of this study was to evaluate risk factors associated with this condition and summarize therapy for these patients.

Methods

For more than 36 months we observed a cohort of 541 recipients who underwent kidney transplantation from January 2001 to June 2007. They were provided a calcineurin inhibitor (CNI) combined with mycophenolate mofetil (MMF). The four group includes a continuous cyclosporine (CsA); a preconversion to tacrolimus and a postconversion group as well as a continuous tacrolimus group. The rate of severe late noninfectious diarrhea was compared among the four groups. Risk factors were analyzed between the diarrhea and nondiarrhea cohorts. Clinical characteristics, efficacy, and safety were observed after modifying the immunosuppressive protocol for late severe noninfectious diarrhea recipients.

Results

Twenty-eight recipients presented with late sever noninfectious diarrhea. No patients displayed chronic diarrhea in the CsA (n = 145) or preconversion group (n = 95). The rate of diarrhea was 7.31% in the postconversion and 7.35% in the tacrolimus group. Using multivariate Cox proportional hazards analysis, factors associated with an increased risk of noninfectious diarrhea were cytochrome P450(CYP)3A5 *3/*3 type, chronic renal allograft dysfunction, and patient ingestion of Tripterygium wilfordii Hook F. All diarrheal recipients experienced weight loss, hypoalbuminia, and an increased serum creatinine. All affected patients underwent adjustment of the immunosuppressive regimen to achieve remission. Renal allograft survival in recipients with diarrhea was worse than that in nondiarrheal recipients receiving tacrolimus combined with MMF.

Conclusion

Tacrolimus with MMF increased the risk of late severe noninfectious diarrhea among renal transplant recipients compared with hosts treats with CsA plus MMF. The CYP3A5 *3/*3 type, chronic renal allograft dysfunction, and T wilfordii supplementation were high-risk factors for late diarrhea. Prompt adjustment of immunosuppression was an effective, feasible therapy for these patients.     

Long-term renal transplant function in recipient of simultaneous kidney and pancreas transplant maintained with two prednisone-free maintenance immunosuppressive combinations: tacrolimus/mycophenolate mofetil versus tacrolimus/sirolimus

BACKGROUND: It is not known how different steroid-free immunosuppressive combinations affect long-term kidney transplant function in recipients of simultaneous kidney and pancreas transplant (SPK). Here, we sought to evaluate, in SPK recipients, the impact on long-term renal allograft function of two Tac-based prednisone-free maintenance immunosuppressive protocols: tacrolimus (Tac)/mycophonelate mofetil (MMF) versus Tac/ sirolimus (SRL). METHODS: In this single-center, retrospective, sequential study, we analyzed 59 SPK transplant patients with at median follow up of 5 years. All patients received induction therapy with thymoglobulin and maintenance immunosuppression with Tac/MMF (n=22) or Tac/SRL (n=37). There were no differences between the two groups in regards to age, gender, race, panel reactive antibodies, degree of mismatch, donor age, incidence of delay graft function, and Tac trough levels at different time points after transplantation. RESULTS: Kaplan-Meier patient survival at 6 years after transplantation was not statistically different between the two groups. Rate of ACR was similar. Kidney survival, even if not statistically significant, was better in the Tac/MMF group than in the Tac/SRL (90.7% vs. 70.7%, P=0.09). The slope of glomerular filtration rate decline per month at 5 years after transplantation was not statistically different between the two groups. Both groups had the same decline over time in glomerular filtration rate of 0.40+/-0.06 mL/min/1.73/month. Pancreas survival at 6 years after transplantation was 100% in both treatment groups. CONCLUSIONS: Our data suggest that, in SPK recipients, long-term kidney allograft survival and function are not statistically different. A trend toward an increased rate of renal allograft loss was found in the Tac/SRL-treated group.