Assessment of mycophenolic acid-induced immunosuppression: a new approach

BACKGROUND: Mycophenolic acid (MPA), a metabolite of mycophenolate mofetil (MMF), is an immunosuppressive agent that inhibits inosine monophosphate dehydrogenase (IMPDH), a key enzyme in the ex novo synthesis of GTP. We measured IMPDH activity in peripheral blood mononuclear cells (PBMCs) from MMF-treated patients to evaluate the efficacy of MMF in individual patients. METHODS: IMPDH activity was measured by (3)H released from [2,8-(3)H]IMP that had been formed in the cells from added [2,8-(3)H]hypoxanthine in PBMCs of 35 renal transplant recipients treated with cyclosporin A and corticoids plus MMF: 2 g (n = 10), 1.5 g (n = 7), 1 g (n = 10), or 0 g (n = 8) per day. An alternative method, based on the capacity of the patients' sera to inhibit spontaneous proliferation of the CEM cell line, was also analyzed. RESULTS: The IMPDH activity of PBMCs in transplanted patients was highly variable. For the method based on CEM cell line proliferation: (a) cell proliferation was inhibited only in MMF-treated patients; (b) there was a clear postdose increase in inhibition; (c) inhibition was not affected by other immunosuppressants in vitro or in vivo; (d) inhibition from predose to predose sample was correlated; and (e) when the MMF dosage was <20 mg. kg(-1). day(-1), two groups of patients were identified, one that maintained a high inhibitory capacity in all dose intervals, and one with periods of low inhibitory capacity. CONCLUSIONS: Measurement of the inhibition of CEM cell line proliferation by sera from MMF-treated patients may be useful for evaluating the relative efficacy of MMF treatment in individual patients, especially those receiving low doses of MMF.     

他克莫司替代环孢素A为基础方案治疗不同病理类型慢性移植肾肾病:有效性和安全性

背景:研究证实以他可莫司代替环孢索A的免疫抑制方案能够改善移植肾的功能,提高移植肾的牛存率,但国内外尚未报道这种以他可莫司联合霉酚酸酯为主的免疫抑制方案是否对所有病理类型的慢性移植肾肾病(chronic allograft nephropathy,CAN)都有相同或相似临床有效性.目的:观察以他可莫司联合霉酚酸酯为基础的免疫抑制方案对不同病理类型CAN的有效性和安全性.方法:59例接受尸体供肾移植患者,移植后均接受以环孢素A为主的免疫抑制方案;经病理证实和分型后分为2组:CAN伴慢性排斥组(n=31)和CAN不伴慢性排斥组(n=28).所有患者在被病理证实为CAN时,立即停止环孢素A,转换为他可莫司联合霉酚酸酯为主的免疫抑制方案,他可莫司的起始剂量为0.08 mg/(kg·d),其目标血药质量浓度为5～8 μg/L.,霉酚酸酯按固定剂量1.0 g/d,2次/d.根据患者的自身情况和药物的副作用调整药物剂量.随访期间,所有患者血肌酐、总胆固醇、三酰甘油和低密度脂蛋白、24 h蛋白尿和肾小球滤过率及并发症发生情况.结果与结论:59例患者均进入结果分析.随访6个月后,CAN伴慢性排斥组和CAN不伴慢性排斥组患者血肌酐、总胆同醇、三酰甘油和低密度脂蛋白和24 h蛋白尿均较转换前明显降低(P<0.05),CAN伴慢性排斥组更明显(P<0.05),两组肾小球滤过率均明显升高(P<0.05).CAN伴慢性排斥组中20例患者好转,7例患者稳定,4例患者无效;CAN不伴慢性排斥组中9例患者好转,15例患者稳定,4例患者无效.两组有效率分别为64.5%,32.1%,差异有显著性意义(P<0.05).与转换前相比较,患者高血压的发病率和高脂血症的发病率有显著性下降(P<0.05),而糖尿病、机会性感染和恶性肿瘤的发病率无统计学意义.提示以他可莫司联合霉酚酸酯为基础的免疫抑制方案可以显著性的改善CAN患者移植肾肾功能,尤其是对CAN伴慢性排斥反应患者.     

Ethnic disparities in outcome from posttransplant infections

Black transplant recipients have decreased graft survival and increased rejection rates compared with whites. Because increased rejection rates may lead to more immunosuppression in black recipients, ethnic differences may exist for outcomes of posttransplant infectious complications. All episodes of infection between December 1996 and October 1998 on the transplant services at the University of Virginia Health Sciences Center were prospectively evaluated. Parameters recorded included self-designated ethnicity, demographics, APACHE II scores, laboratory and microbiologic data, immunosuppression, episodes of rejection, and outcome measures. Evaluation of 303 episodes of infection demonstrated an increased mortality rate for white compared with black recipients (19% vs. 3%, P = 0.0006) despite having a similar severity of illness (APACHE II score). Among renal transplant recipients, episodes of infection occurring in black recipients (n = 46) were also associated with a decreased mortality rate versus whites (n = 89) (0% vs. 15%, P = 0.006) and shorter mean length of stay (12 +/- 2 vs. 25 +/- 4 days, P = 0.002) despite similar severity of illness and rejection rates. For posttransplant infections in liver transplant recipients, blacks (n = 23) demonstrated a trend toward decreased mortality (9% vs. 26%, P = 0.07) but equal lengths of stay despite similar APACHE II scores, rejection rates, and age. White liver transplant recipients had an increased incidence of viral infections (15% vs. 0%, P = 0.03). All other infecting organisms were similar. The unexpected finding of a significantly decreased rate of mortality associated with posttransplant infections in black recipients remains largely unexplained but may be related to subtle differences in immune response between racial or ethnic groups.     

Tacrolimus pharmacokinetic drug interactions: effect of prednisone, mycophenolic acid or sirolimus

This study was conducted to evaluate time-dependent pharmacokinetic changes and drug interactions over the first 6 months after transplantation in kidney transplant recipients receiving tacrolimus (TAC), prednisone (PRED) and mycophenolate mofetil (MMF) or sirolimus (SRL). Pharmacokinetic assessments were carried out at day 7 and months 1, 3, and 6 in kidney transplant recipients receiving TAC plus PRED with either MMF (2 g/day, n  = 13) or SRL (15 mg loading dose, 5 mg for 7 days followed by 2 mg/day, n  = 12). There were no differences in the main demographic characteristics or in mean PRED doses during the first 6 months after transplant. From day 7 to month 6, there was a 65% increase in TAC dose corrected exposure (dose corrected area under the curve; AUC) in patients receiving MMF ( P  = 0.005) and a 59% increase in TAC dose corrected exposure in patients receiving SRL ( P  = 0.008). From day 7 to month 6, there was a 72% increase in mycophenolate dose corrected exposure ( P  = 0.001) and a 65% increase in SRL dose corrected exposure ( P  = 0.008). TAC dose corrected exposure was 23% lower in patients receiving SRL compared with MMF ( P  = 0.012) on average over the study period. PRED dose reduction was associated with increase in TAC (in patients receiving SRL, P  = 0.040) and mycophenolic acid (MPA) ( P  = 0.070) drug exposures. Tercile distribution of TAC drug exposure showed a positive correlation with mean SRL exposures ( P  = 0.016). Conversely, tercile distribution of SRL drug exposure showed a positive correlation with mean TAC exposures ( P  = 0.004). Time-dependent increases in TAC, MPA and SRL drug exposures occur up to 6 months after transplantation. Drug-to-drug interactions indicate that intense therapeutic drug monitoring is required to avoid under- or over-immunosuppression.     

Mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase, causes a paradoxical elevation of GTP in erythrocytes of renal transplant patients

The immunosuppressant MMF (mycophenolate mofetil) has increasingly replaced AZA (azathioprine) in renal transplantation. MMF is a prodrug of MPA (mycophenolic acid), which inhibits lymphocyte IMPDH (inosine monophosphate dehydrogenase), thereby drastically decreasing GTP concentrations essential to lymphocyte proliferation in vitro and in vivo. Erythrocyte GTP concentrations are commonly elevated in severe renal disease, but normalize following successful engraftment. Consequently, elevated GTP in renal transplant recipients might signal impending loss of immunosuppression and graft failure. In the present study, we compared erythrocyte nucleotides and plasma metabolites in two groups of 25 patients after renal transplantation, both receiving prednisolone and cyclosporin A, but one group receiving MMF and the other AZA. No patients had recent allograft biopsy evidence of rejection. Erythrocyte GTP concentrations at MMF commencement were 50.4+/-23.4 micromol/l. An increase occurred during the first 3 months after transplant when MMF was used de novo, stabilizing at 146.7+/-62.9 micromol/l after 4 months. This was significantly higher (P=2.5 x 10(-6)) than erythrocyte GTP (40.4+/-15.9 micromol/l) in the AZA group, which was essentially unchanged from values immediately after successful transplantation. The effect of MMF on erythrocyte GTP levels was reversible, since GTP levels fell when MMF therapy was terminated. The results demonstrate paradoxically high GTP concentrations in erythrocytes of renal transplant patients receiving MMF. MPA may stabilize reticulocyte IMPDH, allowing the protein to persist during erythropoiesis. This behaviour is in marked contrast with the decrease in GTP levels seen in white blood cells of patients on chronic MMF therapy.     

肾移植术后应用骁悉与硫唑嘌呤的安全性评价

目的 系统评价肾移植术后免疫抑制剂骁悉(mycophenolate mofetil,MMF)与硫唑嘌呤(azathioprine,AZA)导致的不良反应发生情况.方法 计算机检索MEDLINE(1966～2004.6)、EMBASE(1984～2004.6)、Cochrane图书馆(2004第2期)及中国生物医学文献数据库(1979～2004.6),纳入涉及肾移植术后使用MMF与AZA出现不良反应的随机对照试验(RCT),对其方法 学质量进行评价后,采用RevMan 4.11软件进行统计分析.结果 共纳入24个RCT,涉及不同剂量MMF与AZA治疗肾移植术后的排斥反应.MMF的胃肠道不良反应发生率明显高于AZA,特别是MMF3 g/d组的呕吐、腹痛、腹泻发生率与AZA组比较有明显差异(P<0.05).MMF3 g/d组的巨细胞病毒感染发生率在6个月、1年及3年观察期内明显高于AZA组,其差异有统计学意义;MMF2 g/d组在1年随访期内感染发生率也高于AZA组.MMF3 g/d组的白细胞减少发生率明显高于AZA组,其差异有统计学意义;而MMF2 g/d组的白细胞减少发生率与AZA组相比差异不具统计学意义.MMF的血小板减少发生率低于AZA组,MMF3 g/d组与AZA组相比差异有统计学意义.MMF各组及AZA组皮肤肿瘤的发生率无明显差异.结论 MMF与AZA相比,其不良反应发生主要表现为较高的胃肠道不良反应、白细胞减少发生率和机会感染发生率,较低的血小板减少发生率.而且不良反应的发生呈现一定的剂量效应关系.     

Mycophenolate mofetil treatment following renal transplantation decreases GTP concentrations in mononuclear leucocytes

MMF (mycophenolate mofetil) has been proven to provide an effective immunosuppression by non-competitive selective reversible inhibition of IMPDH (inosine monophosphate dehydrogenase), the enzyme playing a crucial role in GTP biosynthesis. However, the exact metabolic changes induced by inhibition of IMPDH in target cells of the immune system have been the subject of recent debate. The aim of the present study was to evaluate whether MMF treatment produced sustained changes in the guanosine nucleotide pool of MNLs (mononuclear leucocytes) in vivo. Sixty-two renal failure patients were divided into three groups: chronic renal failure patients undergoing haemodialysis (CRF-HD; n=20) and two groups of patients after renal transplantation, the first on AZA (azathioprine; TN-AZA; n=23) and the second treated with MMF (TN-MMF; n=19). In addition, MNLs from 25 healthy subjects were analysed as controls. Anion-exchange HPLC was used to quantify purine and pyrimidine nucleotides in MNLs. We report a significant decrease in GTP and the total MNL guanine nucleotide pool in the TN-MMF group (P<0.05) compared with control, CRF-HD and TN-AZA groups, although no significant differences were found between any of the other groups. Adenine nucleotide concentrations in MNLs were decreased in the TN-AZA group, but not in the TN-MMF group compared with the CRF-HD group and controls. There were no differences in CTP concentrations, but UTP concentrations were decreased in the CRF-HD, TN-AZA and TN-MMF groups compared with controls. MMF caused a significant and sustained decrease in the guanine nucleotide pool in MNLs from renal transplant recipients. This decrease contrasts with the elevation in GTP reported in erythrocytes of MMF-treated patients.     

Pharmacodynamic approach to immunosuppressive therapies using calcineurin inhibitors and mycophenolate mofetil

BACKGROUND: Graft survival depends on adequate immunosuppression. To evaluate the effect on the immune system of immunosuppressive therapies using calcineurin inhibitors (CNIs), several pharmacodynamic indices have been proposed to complement pharmacokinetic data. In this preliminary study we compared some of these parameters during combined immunosuppressant therapies. METHODS: We treated 65 stable renal transplant recipients with cyclosporin A (CsA; n = 16), tacrolimus (TRL; n = 10); CsA + mycophenolate mofetil (MMF; n = 14); TRL + MMF (n = 13), and MMF (n = 12). Twelve nontreated healthy controls were also included. Calcineurin activity (CNA) in peripheral blood mononuclear cells was measured using (32)P-labeled peptide. Interleukin-2 (IL-2) and interferon-gamma production in phytohemagglutinin-activated whole blood were measured at 0 and 2 h postdose. The areas under the curves, c(min), c(max), and concentration at 2 h (c(2 h)) were also measured. RESULTS: We found no differences in CNA between groups receiving CNIs alone or combined with MMF [median (25th-75th percentiles)]: CsA(2 h), 3.87 (3.00-6.85)% alkaline phosphatase (AP); CsA+MMF(2 h), 3.90 (1.78-5.19)% AP; TRL(2 h), 5.68 (3.02-16.00)% AP; TRL+MMF(2 h), 11.80 (4.05-14.63)% AP. In vitro IL-2 production was significantly lower in the groups receiving combined therapy than in groups receiving CNIs alone [median (25th-75th percentiles)]: CsA(2 h), 276.52 (190.41-385.25) ng/L; CsA+MMF(2 h), 166.48 (81.06-377.01) ng/L (P <0.001); TRL(2 h), 249.34 (127.48-363.50) ng/L; TRL+ MMF(2 h), 122.13 (51.02-180.00) ng/L (P <0.001). The correlations (r) between c(2 h) and CNA 2 h postdose were as follows: CsA, r = -0.74; CsA+MMF, r = -0.84; TRL, r = -0.70; TRL+ MMF, r = -0.70 (P <0.001 in all cases). CONCLUSIONS: The measurement of CNA may be of help in following the effect on the immune system of CNI treatments, even in combined therapies, but does not reflect the additional effect of MMF. In contrast, IL-2 in vitro production reflects the effect of both MMF and CNIs.     

Randomized trial of the addition of gram-positive prophylaxis to standard antimicrobial prophylaxis for patients undergoing autologous bone marrow transplantation.

The purpose of the study reported here was to investigate the impact of prophylaxis against gram-positive infections in patients undergoing high-dose chemotherapy and autologous bone marrow transplantation in a randomized trial. Forty-three patients undergoing high-dose chemotherapy with autologous bone marrow transplant were enrolled in a nonblinded randomized trial to receive or not to receive prophylaxis for gram-positive infections with 10(6) U of penicillin intravenously (i.v.) every 6 h (q6h) (if penicillin allergic, 750 mg of vancomycin i.v. q12h) in addition to standard antimicrobial prophylaxis with 400 mg of norfloxacin orally three times a day, 200 mg of fluconazole orally once a day, and 5 mg of acyclovir per kg of body weight i.v. q12h. The patients were being treated for germ cell cancer (n = 15), breast cancer (n = 16), Hodgkin's disease (n = 3), non-Hodgkin's lymphoma (n = 4), acute myeloid leukemia (n = 1), acute lymphoblastic leukemia (n = 1), and ovarian cancer (n = 3). The trial was stopped because of excess morbidity in the form of streptococcal septic shock in the group not receiving gram-positive prophylaxis. There were significantly fewer overall infections (10 versus 3; P = 0.016) and streptococcal infections (9 versus 1; P = 0.0078) in the group receiving gram-positive prophylaxis. There were no significant differences in the numbers of deaths, duration of broad-spectrum antibiotics, or incidence of neutropenic fever between the two groups. Prophylaxis for gram-positive infections with penicillin or vancomycin is effective in reducing the incidence of streptococcal infections in patients undergoing high-dose chemotherapy and autologous bone marrow transplant. However, this approach may carry a risk of fostering resistance among streptococci to penicillin or vancomycin.     

3种免疫抑制方案对肾移植患者不良反应的观察与护理

目的 分析肾移植术后常用的3种免疫抑制方案的不良反应及并发症,提出相关护理对策。方法 对采用环孢素A(CsA)+硫唑嘌呤(Aza)+泼尼松(Pred)(A组)、骁悉(MMF)+CsA+Pred(B组)、普乐可复(FK506)+MMF+Pred(C组)治疗的1 196例肾移植患者进行回顾性研究,统计肾移植术后3组患者的药物不良反应及并发症情况。结果 B组或C组的肝功能损害(肝损)、肾毒性和高血压的发生率明显低于A组(P<0.05);但感染的发生率3组均高达21.0％以上。结论 肾移植术后应加强感染的预防,使用A组免疫方案的患者比B、C组更应注意肝损伤、高血压的监护。     

群体反应性抗体与慢性移植肾肾病的关系

目的:探讨群体反应性抗体(pannelreactive antibody,PRA)与慢性移植肾肾病(chronic allograft nephopathy,CAN)的关系及其临床意义。方法:对36例CAN患者(CAN组)和106例移植肾功能稳定受者(对照组)术前PRA、术后PRA及其特异性进行比较。结果:(1)CAN组术后PRA阳性率明显高于对照组(58.3%vs20.8%,P<0.05),术前PRA阴性而术后转为阳性者比率也明显高于对照组(51.7%vs16.3%,P<0.05);两组术前PRA阳性率无统计学差异。(2)CAN组术后抗HLAⅠ类抗体阳性2例,抗HLAⅡ类抗体阳性16例,抗HLAⅠ、Ⅱ类抗体均阳性3例,对照组术后抗HLAⅠ类抗体阳性8例,抗HLAⅡ类抗体阳性8例,抗HLAI、Ⅱ类抗体均阳性6例。CAN组抗HLAⅡ类抗体阳性率明显高于对照组(76%vs36%,P<0.05)。结论:术后PRA与CAN的发生有关,抗HLAⅡ类抗体介导的慢性体液性排斥在CAN的发生发展中起着主要作用。动态监测肾移植受者术后PRA变化,对寻找及区别引发CAN的主要病因,选择最佳的防治方案和治疗措施具有重要意义。     

Association of methylenetetrahydrofolate reductase T677 allele with early development of chronic allograft nephropathy

OBJECTIVES: The aim of this study was to evaluate the role of genetic polymorphisms on the development of chronic allograft nephropathy (CAN). DESIGN AND METHODS: Using the polymerase chain reaction (PCR), polymorphisms of methylenetetrahydrofolate reductase (MTHFR C677T), interleukin-6 (IL-6 G-174C) and CD14 (C-260T) were evaluated in 92 kidney transplant recipients with stable renal graft function and no signs of acute rejection in a protocol that included graft biopsy at 12 months after kidney transplantation. A normal population sample (n = 365) was also included. Multivariate analysis was used to evaluate the effect of different variables on the CAN appearance. RESULTS: There were no differences in alleles and genotypes distribution between transplant group and normal population sample. The CAN+ group (n = 69) significantly differed from CAN- (n = 23) in both MTHFR (P < 0.05) and IL-6 (P < 0.01) genotype distribution. Using logistic regression multivariate analysis, MTHFR T677 allele (OR: 3.91, CI: 1.11-13.8; P < 0.05), patient age (OR: 0.94, CI: 0.88-0.98; P < 0.01) and proteinuria (OR: 3.63, CI: 1.25-10.6; P < 0.05) were associated with CAN. Although the IL-6 G-174 allele was shown to be associated with CAN development in univariate analysis (P < 0.01), the multivariate analysis did not show an association. There was no relation between CD14 gene polymorphism and CAN. CONCLUSION: The MTHFR T677 allele is associated with the presence of CAN in kidney graft biopsies 12 months after transplantation.     

Similar reduction of cytomegalovirus DNA load by oral valganciclovir and intravenous ganciclovir on pre-emptive therapy after renal and renal-pancreas transplantation

BACKGROUND: Pre-emptive treatment of CMV infection in transplant recipients aims at prevention of clinical disease by early detection. However, current treatment requires the intravenous (iv) administration of ganciclovir for 2 weeks, which is a considerable burden for the patient. In this observational study, the efficacy of the new oral prodrug valganciclovir was compared with iv ganciclovir. METHODS: To facilitate the introduction of valganciclovir, a therapeutic guideline was developed to use this drug under controlled conditions with regard to safety in renal/renal-pancreas transplant recipients requiring CMV therapy. Subsequently, a group of 57 consecutive transplant recipients was evaluated. Onset and treatment of CMV infections were followed by frequent monitoring of CMV DNA in plasma by quantitative real-time PCR. Details of antiviral therapy were documented. RESULTS: In 15 out of 57 transplant recipients, a total of 27 anti-CMV treatment episodes were recorded: 18 with valganciclovir (900 mg twice daily) and nine with iv ganciclovir (5 mg/kg twice daily) as initial treatment. Median CMV DNA load reduction during treatment was 0.12 log10/day in the valganciclovir group and 0.09 log10/day in the ganciclovir group. There were no haematological side effects in any group and no patient developed signs of clinical CMV disease. CONCLUSION: Similar reduction of CMV DNA load was observed during pre-emptive treatment with oral valganciclovir and iv ganciclovir in transplant recipients. Oral valganciclovir would provide an attractive and safe alternative for pre-emptive CMV treatment in renal/renal-pancreas transplant patients, however, confirmation in larger randomized studies would be desirable.     

Cyclosporine versus azathioprine therapy in high-risk idiopathic membranous nephropathy patients: A 3-year prospective study

There is no consensus regarding the modality of therapy for idiopathic membranous nephropathy (IMN), especially for patients who did not react to treatment with cytotoxic drugs. This study followed prospectively for 3-year IMN patients who did not react to Ponticelli protocol comparing effects of 2-year course of cyclosporine (CsA) with azathioprine (Aza) treatment both with small doses of prednisolone. Twenty-three patients were randomly assigned to receive either cyclosporine at 3 mg/kg per day (10 patients) or azathioprine at 1.5 to 2 mg/kg (13 patients). Both groups were comparable regarding age, sex and renal function, except for proteinuria, which was significantly greater in CsA group (P = 0.003). Similar rate of remission of nephrotic syndrome (NS) have been noted at the end of treatment (80% CsA versus 93% Aza). During last year, follow-up relapses of NS were more frequent in Aza group (5 versus 1). A fall in proteinuria was recorded in both groups during treatment, but it rose significantly in Aza group (1.5 g/day versus 3.1 g/day, P = 0.04) and remained unchanged in CsA group (3.9 g/day versus 4.1 g/day) after treatment cessation. Renal function deteriorated in Aza group (sCr 120.5 versus 269.8 μmol/L; P < 0.01) and was stable in CsA group. In conclusion, CsA and steroids may be a very important option in the management of high-risk IMN patients. Long-term treatment is necessary for achievement of full therapeutic effect. Treatment with Aza did not have long-term benefits particularly regarding renal function preservation.     

Homocysteine and B-group vitamins in renal transplant patients.

Increased plasma homocysteine is an independent risk factor for cardiovascular disease. We have investigated homocysteine and B-group vitamin levels in renal transplant patients. Fasting blood was collected from 55 renal transplant recipients with good renal function and 32 age/sex matched control subjects. Total homocysteine was increased in transplant recipients in comparison to controls (10.9+/-1.5 vs. 6.7+/-1.3 micromol/l, P < 0.001). There was no difference in homocysteine between patients receiving cyclosporin (n = 39, homocysteine 11.0+/-1.5 micromol/l) and patients receiving prednisolone + azathioprine (n = 16, 10.8+/-1.6 micromol/l, mean+/-S.D.), although there was a significant correlation between homocysteine and serum cyclosporin concentration in the sub-group of patients receiving that immunosuppressive regimen (r = 0.42, P < 0.05). Levels of B-group vitamins were similar in patients and controls. Plasma homocysteine is increased in renal transplant recipients even in the presence of minor degrees of renal impairment and normal levels of B-group vitamins.     

A comparison of measured trough levels and abbreviated AUC estimation by limited sampling strategies for monitoring mycophenolic acid exposure in stable heart transplant patients receiving cyclosporin A-containing and cyclosporin A-free immunosuppressive regimens

BACKGROUND: Mycophenolate mofetil (NIMF) pharmacokinetics vary widely, and enterohepatic recirculation of the drug and its metabolites may be altered by concurrently administered immunosuppressants, including the widely used agent cyclosporin A (CsA). A reliable method of achieving effective and well-tolerated levels of NIMF-based immunosuppression would be of eminent interest. OBJECTIVE: This study compared the use of measured mycophenolic acid (MPA) trough levels (C0) and abbreviated AUC estimation by limited-sampling strategies for monitoring MPA exposure in stable heart transplant recipients (>1 year after transplantation) receiving a CsA-containing or CsA-free immunosuppressive regimen. METHODS: The treatment groups were receiving chronic maintenance immunosuppressive regimens consisting of either CsA/MMF or rapamycin (RAPA)/MMF. An additional subgroup of patients was switched from the CsA-containing regimen to the RAPA-containing regimen. Fasting venous blood samples were obtained before dosing and at 40, 75, 120, and 240 minutes after administration of the morning dose of MME The validated Emit assay was used to measure MPA plasma concentrations. Dose adjustment of AUCs was performed by dividing the AUC by the morning NIMF dose in grams. Cmax after administration of the morning dose was determined from available MPA data points using curve-fitting analysis. The increase to Cmax (Cmax-C0) was calculated, and dose adjustment was performed as before. Abbreviated 12-hour MPA AUCs were estimated using a limited-sampling strategy (before dosing and 30 and 120 minutes after dosing) based on high-performance liquid chromatography data. Adverse events were monitored during routine follow-up visits. RESULTS: The study included 47 patients receiving CsA/MMF, 15 receiving RAPA/MMF, and 9 who were switched from CsA/MMF to RAPA/MME The population included 55 men and 7 women, with a mean age of 58.94 years and a mean weight of 81.85 kg. The only significant differences in baseline clinical characteristics between groups were the mean number of years since heart transplantation (3.62 CsA/MMF vs 8.53 RAPA/MMF; P<0.01) and the proportions of patients still receiving corticosteroids (44.7% vs 13.3%, respectively; P<0.01). Reported adverse events were generally mild, including leukopenia (8.1%), diarrhea (6.5%), and abdominal pain (4.8%), and did not require drug discontinuation. In patients receiving CsA/MMF, MPA AUCs ranged from 19.67 to 81.80 mg/h.L (mean [SD], 41.92 [14.14] mg/h.L). MPA Co levels were poorly correlated with total AUC (r2=0.36). MPA Co levels of 0.5 and 1.6 mg/L were correlated with AUCs of <30 and <40 mg/h.L, respectively. In patients receiving RAPA/MMF, MPA AUCs ranged from 34.40 to 87.60 mg/h.L (mean, 51.07 [15.80] mg/h.L). The correlation between Co and total AUC was better than in the CsA/MMF group (r2=0.61). MPA C0 levels of 1.0 and 2.3 mg/L were correlated with AUCs of 30 and 40 mg/h.L, respectively. Statistically significant differences between RAPA/MMF and CsA/MMF were noted in the mean MMF dosage (1.90 [0.71] vs 2.87 [0.78] g/d, respectively; P<0.001), the mean dose-adjusted MPA AUC (60.95 [27.42] vs 31.92 [16.12] mg/h.L.g MMF; P<0.001), and mean dose-adjusted MPA C0 levels (5.10 [3.41] vs 1.41 [0.95] mg/L.g; P<0.001). The dose-adjusted increase to Cmax after morning dosing was comparable between groups, and there was no difference in the frequency distribution of Cmax. In the group switched from the CsA-containing regimen to the RAPA-containing regimen, the changes in MMF dose, dose-adjusted AUC, and MPA C0 levels were similar to those in the CsA/MMF and RAPA/MMF groups. CONCLUSIONS: In this comparison of measured MPA C0 levels and 12-hour MPA AUCs estimated by a limited-sampling strategy in stable heart transplant patients receiving chronic maintenance immunosuppressive therapy with CsA/MMF or RAPA/MMF, abbreviated AUC estimation predicted drug exposure more accurately than did measured C0 levels. Thus, MPA AUCs obtained by limited sampling may be useful in guiding clinical management and dosing. However, further study is required, including validation of these findings in clinical outcome studies.     

霉酚酸酯等新三联在肾移植术后的近期疗效

目的：观察霉酚酸酯（MMF）在预防肾移植术后急性排斥及肺部感染的情况。方法：89例肾移植后应用皮质激素（Perd），环孢素（CsA），MMF（或）硫唑嘌呤（Aza）三联免疫抑制剂治疗，其中分成MMF组52例，Aza组37例，MMF组中适当减少CsA用量。结果：临床观察3个月中，急性排斥（AR）发生率MMF组7．7％（4／52），Aza组16．2％（6／37），肺部感染率MMF组13．5％（7／52），Aza组21．6％（8／37），两者之间存在明显差异（P＜0．05）。结论：MMF组方案对减少AR发生率与并发肺部感染率有一定作用。     

康复期肾移植病人护理干预的效果分析

目的　分析护理干预对康复期肾移植病人的影响。方法　将 2 0 0例康复期肾移植病人随机分为 2组 ,干预组(10 0例 )进行生理、心理、社会行为等护理干预 ,对照组 (10 0例 )未实施干预 ,运用日常生活能力量表 (ADL)、社会功能评定量表 (SDSS)、抑郁自评量表 (SDS)及护理依赖性评估对干预前后的效果进行分析、比较 ;同时比较 2组并发症发生情况。结果　干预组病人的心理功能、社会功能及日常生活能力较干预前显著改善 ,差异有显著性或极显著性意义 (P <0 .0 1) ;2组并发症发生率比较 ,差异有极显著意义 (P <0 .0 1)。结论　护理干预可提高肾移植病人的生活质量 ,减少术后并发症的发生率。     

Pharmacokinetic basis for the efficient and safe use of low-dose mycophenolate mofetil in combination with tacrolimus in kidney transplantation.

BACKGROUND: Mycophenolate mofetil (MMF) is an effective posttransplantation immunosuppressive agent used in combination with cyclosporin A (CsA) or tacrolimus (Tc). An increase in plasma mycophenolic acid (MPA) has been shown in patients receiving Tc-MMF combination therapy compared with CsA-MMF combination therapy at the same dose of MMF. The aim of this prospective study was to assess the pharmacokinetic/pharmacodynamic (PK/PD) relationship for MPA in kidney transplant patients receiving low-dose MMF (500 mg twice a day) in combination with Tc. METHODS: Adult kidney transplant recipients (n = 51) were included. MPA-PK profiles (blood sampling at 0, 0.5, 1, 2, 4, 6, and 12 h after MMF oral dose) were obtained within the first 2 weeks after transplantation, 3 months after grafting, and at every adverse clinical event [side effect or acute rejection (AR)]. All patients received Tc, MMF (500 mg twice a day), and steroids. RESULTS: Thirty patients (59%) had uneventful outcomes, and 21 patients had 33 episodes of MPA-related side effects; only 3 patients had AR. A total of 78 MPA-PK profiles were obtained. The following PK parameters were increased in the side-effects group compared with the non-side effects group: mean MPA c(min), 2.63 +/- 1.58 vs 1.75 +/- 0.82 mg/L (P = 0.016); mean c(30), 10.47 +/- 6.27 vs 7.66 +/- 8.95 mg/L (P = 0.009); mean c(60), 9.67 +/- 5.42 vs 5.83 +/- 2.6 mg/L (P = 0.0002); mean area under the MPA time-concentration curve from 0 to 12 h [MPA-AUC((0-12))], 48.38 +/- 18.5 vs 36.04 +/- 10.82 mg. h/L (P = 0.0006); mean dose-normalized MPA-AUC, 0.16 +/- 0.05 vs 0.12 +/- 0.04 (mg. h/L)/(mg/m(2)) (P = 0.0015). For the three AR patients, MPA concentrations obtained at the time of AR revealed MPA c(min) values of 1.86, 1.76, and 3.83 mg/L, respectively, and MPA-AUC((0-12)) values of 37.7, 24.9, and 104.9 mg. h/L. The threshold of toxicity was 3 mg/L (sensitivity, 38.7%; specificity, 91.5%) for c(min), 8.09 mg/L for maximum MPA concentration during the first hour (sensitivity, 77.8%; specificity, 67.4%), and 37.6 mg. h/L for MPA-AUC((0-12)) (sensitivity, 83.3%; specificity, 59.6%). CONCLUSIONS: These results demonstrate the relationship between plasma MPA concentrations and toxicity. High c(min), c(30), and c(60) values as well as AUC((0-12)) are associated with increased risk for side effects. These values may have an importance in a routine monitoring program.     

夫妻间活体供肾肾移植的疗效分析

目的：总结夫妻间活体供肾肾移植的临床经验。方法：回顾分析2004—2008年实施夫妻间肾移植14例的临床资料,妻子作为供体9例,丈夫作为供体5例。收集供受体基本信息及手术方式、术后免疫抑制剂方案和随访结果,分析受体的临床疗效。结果：8例（57.1%）采用手助腹腔镜方式取肾,6例（42.9%）采用小切口开放方式取肾。12例（85.7%）以左肾作为供肾,2例（14.3%）以右肾作为供肾。受体全部应用激素＋CNI类免疫抑制剂＋抗代谢类免疫抑制方案,8例患者接受免疫诱导（57.1%）。随访1~4年,因肺部重症感染死亡1例,转为血液透析1例,1年受体/移植肾存活率分别为92.9%和85.7%。介入B超穿刺移植肾6例,病理结果示3例正常,3例（21.4%）出现不同程度细胞排斥反应。结论：亲属移植成为治疗终末期肾病的主要手段,夫妻间肾移植效果良好。