Rate Of Acute Rejection Episodes Research Articles

Steroid Elimination—Who, When, How?

Steroids have numerous side effects, many occurring early posttransplantation with relatively low prednisone doses. Consequently, investigators have attempted steroid minimization or withdrawal. The first attempts at steroid minimization used early low-dose steroids and were associated with an increased rate of acute rejection episodes, late graft dysfunction, and graft loss. Subsequent studies, with cyclosporine-based immunosuppression, attempted steroid withdrawal late posttransplantation (>3 months) in highly selected, clinically well, and immunologically low-risk recipients. Again, steroid withdrawal was associated with an increased risk of acute rejection episodes and these episodes were associated with graft dysfunction and increased graft loss. The development of new powerful immunosuppressive agents has led to renewed attempts at late prednisone withdrawal. These also have been associated with increased late rejection risk. A more exciting innovation has been the attempts at rapid discontinuation (≤7 days posttransplantation) of prednisone with the following results: (1) Randomized studies have shown no significantly increased risk of acute rejection; (2) Randomized and nonrandomized studies have shown no increase in late graft loss; (3) Successful use in living and deceased donor recipients, primary and re–transplant recipients, adult and child recipients, white and black recipients, and low-risk and highly sensitized recipients; (4) About 80% of recipients remain prednisone-free long term. Recent nonrandomized data suggest that recipients who have an acute rejection episode while prednisone free are more likely to have a second rejection episode if they are returned to prednisone-free immunosuppression. In these cases the acute rejection episode should be treated and long-term prednisone continued at 5 mg/d.

Rationale and criteria of eligibility for calcineurin inhibitor interruption following kidney transplantation

To summarize predictive low-risk parameters of renal allograft recipients for purposes of improving the initiation of calcineurin inhibitor withdrawal protocols. Clinical trials have demonstrated the potential global benefit of calcineurin inhibitor interruption protocols on graft survival despite being associated with an increased rate of acute rejection episodes, thus underlying a number of risk factors. Recent identification or confirmation of variables updating the list of parameters and molecular markers that can be used to predict graft outcome are described. The effect of calcineurin inhibitor withdrawal on long-term graft and recipient survival patterns is assessed in relation to the large number of calcineurin inhibitor-related side-effects. However, current protocols are based on empirical observations and there is a clear requirement for reliable parameters to define patient eligibility for calcineurin inhibitor weaning procedures. Here, we review biological, clinical and genetic parameters that can be used as predictive markers of long-term graft outcome and could serve as criteria for patient selection in calcineurin inhibitor weaning protocols.

Outcome after renal transplantation in children from native and immigrant families in Austria

Renal transplantation is the therapy of choice for children with end-stage renal disease (ESRD). Ethnicity affects the transplant survival rates substantially, but there has been no European academic evaluation of the effects of immigration on the pediatric renal transplantation outcome. The aim of this study was to compare the outcomes of renal transplantation between the children of immigrant families and the children of native families at the pediatric nephrology unit of the Medical University of Vienna, Austria. We conducted a retrospective study on all children who underwent renal transplantation at our center between January 1997 and June 2005. The patients were separated into two groups according to their immigration backgrounds. During the time frame of our study, 59 children underwent a total of 63 transplantations. Of these children, 42 were from native Austrian and 17 were from first-generation immigrant families. We analyzed the demographic data and outcome parameters for each of the 59 patients. We found no difference in patient and graft survival rates or long-term function between native and immigrant children. The two groups were also comparable in the rates of acute rejection episodes, 24-h blood pressure, and growth velocity. Living donor source had a positive influence on graft function (p=0.06), 24-h blood pressure (p=0.05), and growth velocity (p=0.02) only in the immigrant group. Our retrospective analysis shows no influence of the migration status on the patient or graft outcome, but we did find that immigrant children benefitted more than native children from living donation as opposed to deceased donation. To explain this fact, biological, heath-economical, psychosocial, and cultural background aspects must be investigated.

Donor age intensifies the early immune response after transplantation

Increasing donor age is associated with reduced graft function. We wondered if donor age may not only affect intrinsic function but also alter the immune response of the recipient. Kidneys from young and old F-344 rats (3 vs 18 months) were transplanted into bilaterally nephrectomized young Lewis recipients and compared with age-matched controls (follow-up: 6 months). Renal function and structural changes were assessed serially in both native kidneys and allografts. Host alloreactivity, graft-infiltrating cells, and their inflammatory products were determined at intervals to examine the correlation of immune response and donor age. Functional and structural deterioration had advanced significantly in older allografts compared with age-matched native controls, whereas differences between young allografts and native controls of similar age were only minor. Changes in grafts from elderly rats were associated with a more intense host immune response early post-transplant (up to 1 month) reflected by significantly higher numbers of peripheral T and B cells, increased T-cell alloreactivity and modified cytokine patterns associated with elevated frequencies of intragraft dendritic cells, B cells, and CD31+ cells. By 6 months, recipients of young donor grafts produced comparable or more intense alloantigen-specific immune responses. Older donor grafts elicit a stronger immune response in the early period after transplantation.

Economic Evaluations of Calcineurin Inhibitors in Renal Transplantation

People receiving a renal transplant require long-term treatment with immunosuppressant drugs. Contemporary regimens usually include a calcineurin inhibitor (CI), either ciclosporin or tacrolimus, in conjunction with at least one other drug. The aim of this study was to review the economic literature relating to the choice of CIs in patients following renal transplantation, with the specific intention of highlighting the challenges in estimating their cost effectiveness.A systematic literature search and narrative analysis was carried out, and 12 studies of varying quality and complexity were reviewed. All of the studies compared ciclosporin, azathioprine and a corticosteroid (CAS) with tacrolimus, azathioprine and a corticosteroid (TAS) but only three also evaluated the costs and effects of other possible treatment regimens. A variety of different evaluative frameworks were employed, from single randomised controlled trial-based studies over relatively short-time periods (6 months) to more complex Bayesian modelling techniques.The studies were broadly consistent in concluding that TAS was more effective than CAS in terms of reducing the rate of acute rejection episodes. Of the studies that undertook decision modelling, all but one estimated that TAS was associated with better graft-related outcomes such as rejection-free life-years, patient-survival and QALYs. Six of the studies concluded that the healthcare costs associated with TAS were lower than those for CAS. A seventh study suggested that TAS was the least costly option if costs were considered over a relatively long time period (14 years). Only one study clearly concluded that CAS was more cost effective than TAS.Clinical evidence clearly shows that TAS is more effective than CAS in terms of reducing the incidence of acute rejection following renal transplantation. The majority of published economic evaluations suggest that TAS is also the more cost-effective option. However, the economic evaluations contained a number of methodological limitations, undermining the confidence that can be attached to their results. Future economic evaluations of the CIs, and immunosuppressants in general, should address these issues in order to produce more robust cost-effectiveness estimates. Most importantly, they should evaluate a wider range of potential treatment options.

The role and value of sirolimus administration in kidney and liver transplantation

Enormous advancements in visceral transplantation have led to significant improvements in the quality of life of patients. However, despite these developments, the average graft half-life after transplantation has remained almost unchanged and chronic rejection is still considered a major problem. In this regard, more concerns have shifted to factors influencing long-term graft survival, patient survival, and quality of life. To achieve this goal, detrimental effects of immunosuppressive (IS) agents, which have deleterious influence on the quality of life and/or patient survival, should be reduced. In the course of recent years, the transplant community has worked on reducing these side effects by developing new ISs, employing new combination regimens, or finding and adjusting optimal dosages and blood level concentrations. Among the IS agents, the antifungal, antitumoral and IS activity of mammalian target of rapamycin (mTOR) inhibitors without nephrotoxicity, have received special attention regarding this new class of IS. Sirolimus (SRL), as the first member of mTOR inhibitors, has been utilized in many clinical trials with respect to its benefit-risk assessment. In our review, the clinical evolution of SRL, as well as the evidence-based clinical benefits of SRL in kidney and liver transplantation (KTx, LTx), are summarized. Various studies of SRL in KTx and LTx have shown that combination therapy with SRL will enrich the variety of IS modalities. It also can be regarded as a safe base therapy to which other necessary drugs can be added. In addition to the enhanced acute rejection prophylaxis, and in contrast to the calcineurin inhibitors (CNI) and steroids, this drug solely does not have common side effects such as nephrotoxicity, neurotoxicity, diabetes mellitus and hypertension. Moreover, this agent might diminish vasculopathic processes that mediate chronic allograft nephropathy (CAN). Therefore, by reducing the likelihood of CAN it can decrease the rate of long-term organ failure. One possibly desirable characteristic of SRL is its antiproliferative effect, which could provoke antitumoral or antiatherogenic activity following transplantation. Despite all promising impacts of SRL in organ transplantation, there are some concerns regarding the adverse effects of this drug, for instance dyslipidemia, pneumonitis and wound healing problems. However, the majority of these side effects can be reduced or ceased by careful dose adjustments and correct timing of use. In conclusion, after a decade of both in vivo and in vitro studies on SRL, it can be advocated that SRL is a promising, potent and effective IS agent as it reduces the rate of acute rejection episodes in de novo transplants. It could improve the quality of life, graft and patient survival rate, and achieve excellent outcomes with few adverse effects when wisely used in combination with other immunosuppressants.

The advantage of allocating kidneys from old cadaveric donors to old recipients: a single‐center experience

In January 1999 a new kidney allocation program was launched by the Eurotransplant Foundation, the 'Eurotransplant Senior Program' (ESP). Cadaveric donors above the age of 65 yr are allocated to kidney transplant recipients of the same age group. Using a single-center database, 91 patients who underwent first renal transplantation at the age of 65 yr and older in the years 1999-2002 were identified. Fifty-six patients were transplanted through ESP allocation (study group) and 35 patients (control group) via normal Eurotransplant Kidney Allocation System (ETKAS) procedure. Age, sex and comorbid conditions did not differ by group. The rate of acute rejection episodes, primary non-function, delayed graft function, perioperative mortality did not differ by group. Serum creatinine was significantly lower in the ETKAS group (1.3 vs. 1.9 mg/dL; p=0.015) from six months after the transplantation on. Overall graft survival at six yr was 56% in the ETKAS group and 52% in the ESP group. With 73% in the ETKAS group and 71% in the ESP group, cumulative patient survival according to the Kaplan-Meier estimation was not statistically different at five yr. We did not find a relevant difference in the outcome between young and old kidney transplants in old recipients after this long observation period.

Long-Term Patient and Graft Survival in the Eurotransplant Senior Program: A Single-Center Experience

BACKGROUND The Eurotransplant Senior Program (ESP) was launched in 1999, targeted to increase the supply of donor kidneys to the elderly. This program requires local allocation of kidneys from cadaveric donors >>65 years to recipients >>65 years. METHODS Of all patients >>65 years who received a kidney transplant in 1999-2002 at our center, 59 patients were transplanted through the ESP protocol (ESP group), and 44 patients received a transplant from a younger donor (EuroTransplant Kidney Allocation System, ETKAS group). Recipients were followed for up to 5.3 years using the Austrian Dialysis and Transplant Registry. Outcomes studied included all-cause mortality and allograft loss. RESULTS Age, sex, and comorbid conditions did not differ by group. Donor age was higher (69 vs. 36 years; P < 0.001) and cold ischemia time shorter in the ESP group (10 vs. 15 hr; P < 0.001). Number of HLA mismatches was greater in the ESP group (3.8 vs. 3.0; P = 0.003). ESP patients were more likely to receive induction therapy and less likely to receive cyclosporine A. Primary nonfunction, delayed graft function, operative mortality, rate of acute rejection episodes, and length of stay did not differ by group. Although serum creatinine at discharge was higher in ESP patients (1.7 vs. 1.4 mg/dL; P < 0.001), 4-year mortality (hazard ratio [HR] = 0.68; 95% CI: 0.31-1.49) and graft loss (HR = 0.61; 95% CI: 0.29-1.28) tended to be less. CONCLUSIONS Long-term patient and graft survival were comparable between elderly patients who received their organ via the ESP and the regular ETKAS algorithm.

Outcome after kidney transplantation in children with thrombotic risk factors

According to the data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), vascular thrombosis accounts for 11.6% of graft losses in pediatric renal transplantation. In adults, inherited and acquired thrombophilic risk factors, e.g. factor V Leiden mutation, have been associated with early graft loss and increased rejection episodes. Data on the impact of these factors on the outcome of children after renal transplantation are rare. Sixty-six pediatric patients awaiting renal transplantation (mean age 10.1 yr) were screened for inherited and acquired risk factors for hypercoagulable disorders (protein C, S, and antithrombin III deficiency, antiphospholipid antibodies, factor V Leiden, prothrombin, and MTHFR mutation) in order to intensify anticoagulation in those with an increased risk for thrombophilia: intravenous heparin was administered with a partial prothrombin time (PTT) prolongation of 50 s for 14 days and switched to low-molecular-weight heparin for another 8 wk before aspirin was introduced for the first year. Patients without hypercoagulable risk factors were treated with heparin without PTT prolongation for 14 days and switched to aspirin immediately afterwards. The results on graft survival, incidence of acute rejection episodes, and long-term renal graft function were analyzed between recipients with and without hypercoagulable risk factors. Thrombophilic risk factors were identified in 27.3% of our patients. No thrombosis occurred. One serious bleeding complication led to a second surgical intervention. The rate of acute rejection episodes was not increased in patients with and without thrombotic risk factors after 90 days (16.7 vs. 25%), 1 yr (22.2 vs. 33.3%), and 3 yr (38.9 vs. 41.7%) of follow-up, respectively (p = n.s.). After a mean follow-up of 3 yr the kidney function was comparable in both groups, with 63.1 in recipients with and 69.8 mL/min/1.73 m(2) in recipients without hypercoagulable risk (p = n.s.). At latest follow-up, three graft losses were found not to be attributed to thrombotic risk factors. Children with thrombophilic risk factors were identified and treated with an intensified anticoagulation regimen after renal transplantation. An increased risk for graft failure, acute rejection episodes, or impaired renal function for pediatric renal transplant recipients with hypercoagulable status was not found.

Long-Term Trends in Allograft Survival

Kidney transplantation has changed dramatically over the past decade. Many advances have occurred that result in shorter hospital stays, decreased acute rejection, less infectious morbidity, and improved long-term allograft survival. Many factors are responsible for the improvement in kidney transplantation, and these factors are discussed in this review. These successes have led to a paradox in the care of the kidney-transplant recipient, however. As the short-term complications are prevented or successfully managed, more patients will develop chronic problems with the function of the allograft.

Individualization of Immunosuppressive therapy: I. Sirolimus Improves Outcomes in African-American Renal Transplant Recipients

Introduction African-American renal transplant recipients are prone to acute rejection episodes and graft loss owing to genetic, pharmacokinetic, cultural, and socioeconomic factors. While more intense exposures to antirejection agents can mitigate this propensity, heightened immunosuppressive regimens are accompanied by an array of toxicities. Our study sought to examine the impact of a combination of sirolimus (SRL) and cyclosporine (CsA) on the outcomes of African-Americans vs Caucasians. Materials and Methods The outcomes of African-Americans treated with either CsA-prednisone (Pred, n = 90) or SRL-CsA-Pred (n = 86) were compared with 148 SRL-CsA-Pred-treated Caucasians. Results The addition of SRL to a CsA-Pred regimen reduced the rate of acute rejection episodes within 2 years in African-Americans from 43.3% to 17% ( P = .004), a value similar to that observed in Caucasian patients (18%). At 2 years, the graft survival rate of 79% among African-American patients treated with SRL-CsA-Pred was similar to that in the Caucasian cohort (80%). The respective patient survival rates also were similar: 93% and 90%, respectively. Multivariate analysis of 5-year outcomes among patients treated with SRL-CsA-Pred revealed the hazard ratios of African-Americans vs Caucasians to actually be reduced for acute rejection (.22; P = .01) and for death (.15; P = .01), but similar for chronic rejection (.77; P = NS) and graft loss (1.03; P = NS). Conclusion The use of SRL-based regimens mitigated the otherwise enhanced risk for acute rejection episodes or graft loss otherwise experienced by CsA-treated African-American renal transplant recipients.

Long-Term Patient and Graft Survival in the Eurotransplant Senior Program: A Single-Center Experience

The Eurotransplant Senior Program (ESP) was launched in 1999, targeted to increase the supply of donor kidneys to the elderly. This program requires local allocation of kidneys from cadaveric donors >>65 years to recipients >>65 years. Of all patients >>65 years who received a kidney transplant in 1999-2002 at our center, 59 patients were transplanted through the ESP protocol (ESP group), and 44 patients received a transplant from a younger donor (EuroTransplant Kidney Allocation System, ETKAS group). Recipients were followed for up to 5.3 years using the Austrian Dialysis and Transplant Registry. Outcomes studied included all-cause mortality and allograft loss. Age, sex, and comorbid conditions did not differ by group. Donor age was higher (69 vs. 36 years; P < 0.001) and cold ischemia time shorter in the ESP group (10 vs. 15 hr; P < 0.001). Number of HLA mismatches was greater in the ESP group (3.8 vs. 3.0; P = 0.003). ESP patients were more likely to receive induction therapy and less likely to receive cyclosporine A. Primary nonfunction, delayed graft function, operative mortality, rate of acute rejection episodes, and length of stay did not differ by group. Although serum creatinine at discharge was higher in ESP patients (1.7 vs. 1.4 mg/dL; P < 0.001), 4-year mortality (hazard ratio [HR] = 0.68; 95% CI: 0.31-1.49) and graft loss (HR = 0.61; 95% CI: 0.29-1.28) tended to be less. Long-term patient and graft survival were comparable between elderly patients who received their organ via the ESP and the regular ETKAS algorithm.

Steroid Maintenance Therapy after Transplantation-Quo Vadis?: Long-Term Prospective Study of Steroid Withdrawal in Kidney and Heart Transplant Recipients. Am J Transplant 5: 720-728, 2005.

Steroid Maintenance Therapy after Transplantation-Quo Vadis?: Long-Term Prospective Study of Steroid Withdrawal in Kidney and Heart Transplant Recipients. Am J Transplant 5: 720-728, 2005.

C 2 Monitoring of Cyclosporine in Stable Renal Transplant Patients Results in Lower Costs and Improved Renal Function

Introduction C 2 (2-hour post–absorption levels) monitoring of cyclosporine (CsA) seems to reduce the rate of acute rejection episodes (ARE) without increasing nephrotoxicity during the first months after transplant. There are a few reports on the impact of adopting this strategy in patients with stable renal transplants. We herein report a prospective trial in long-term renal transplant patients (>6 months) monitored by C 0 or C 3 who were switched to C 2 monitoring. Methods Seventy-six (mean age = 43 ± 11 years) kidney transplant patients (mean = 37 ± 21 months after transplant) receiving CsA, steroids, and azathioprine were switched to C 2 monitoring, seeking to achieve a target range of 800 ± 100 ng/mL. The patients were followed for at least 6 months. Results At conversion the C 2 values of 61% of the patients were above and 17% below the therapeutic range. Six months after conversion there was a significant reduction in BUN (29 ± 11 vs 27 ± 10, P < .01), Creatinine (Cr), cholesterol, and triglyceride levels were unchanged. Mean CsA dose was decreased 10% from 244 ± 63 to 220 ± 52 ( P < .01), implying a net savings of US$390 per patient per year. Among the group of patients who showed a high C 2 level, there was also a reduction in BUN (30 ± 12 vs 27 ± 10, P < .01) and a nonsignificant decrease in Cr (1.53 ± 0.6 vs 1.50 ± 0.6). Conclusions C 2 monitoring in stable kidney transplant recipients is feasible and safe. The strategy results in reduced drug costs and improved renal function.

Living Donor Kidney Transplantation: Impact of Differentiated Immunosuppressive Regimen

Introduction Recipients of related (R) and unrelated (NR) living donor kidney transplantations (LDKTX) receive immunosuppressive (IS) therapy 5 days in advance in order to achieve low rates of acute rejection episodes. We herein report the different IS regimens for R and NR transplants as well as acute rejection and primary function rates. Methods Ninety-five LDKTX (69% R, 31% NR) were performed with mean cold ischemia time (CIT) of 145 ± 32 minutes. In R-LDKTX mean age of recipients was 31 ± 12.5 years. This cohort included 41 men and 25 women whose mean age was 50 ± 11.1 years. The therapeutic regimen for R-LDKTX included CyA/MMF/prednisone; for NR-LDKTX, FK/MMF/prednisone. Among the recipients of NR grafts the mean recipient age was 51 ± 8.5 years. This cohort included 23 men and 6 women whose donor mean age was 50 ± 8.8 years. The mean HLA mismatch among R-LDKTX (2.3) was significantly less than that in the NR-LDKTX cohort (3.51). Results At a mean follow-up of 35 months, 94.7% of grafts were functioning. DGF was seen in only one recipient (1%). Three grafts were lost due to acute (R) or chronic (NR) rejection or to multiorgan failures. Two recipients died with functioning grafts. Biopsy-proven rejection episodes were observed in 17.2% of NR-LDKTX and 9% of R-LDKTX. In R-LDKTX 50% of rejection episodes were corticoid-sensitive, while 33% needed ATG, and 16% were treated by a switch to FK. In NR-LDKTX 20% of rejections were corticoid-sensitive, 40% needed ATG, and 40% were treated with rapamycin rescue therapy. Conclusion Although HLA mismatching is significantly different between R- and NR-LDKTX, no difference in outcome was observed, which may be due to the specific therapeutic regimen and short CIT.

Steroid withdrawal in pediatric and adult renal transplant recipients

Corticosteroids are still a cornerstone in the immunosuppressive regimen in pediatric renal transplant recipients despite their numerous side effects, such as inhibition of longitudinal growth, body disfigurement, arterial hypertension, cardiovascular complications, osteopathy, and others. Previous attempts to spare steroids in cyclosporine (CsA)-based protocols have been associated with an increased risk for acute rejection episodes. The recent introduction of more-potent immunosuppressive medications, such as mycophenolate mofetil (MMF), have, however, renewed interest in steroid-sparing protocols to avoid or ameliorate steroid-associated side effects. Recent studies in Caucasian adult renal transplant recipients receiving CsA and MMF have shown a beneficial effect of late (>/=6 months post transplant) steroid withdrawal on steroid-associated side effects without the burden of an increased rate of acute rejection episodes. These favorable results compared with previous reports in patients on CsA and azathioprine (AZA) can be ascribed to the higher immunosuppressive potency of MMF compared with AZA. We have shown in a retrospective case control study in 40 pediatric renal transplant recipients that late steroid withdrawal is safe and successful in stable patients under an immunosuppressive maintenance therapy with CsA and MMF. The Mid-European Study Group on Pediatric Renal Transplantation and the Arbeitsgemeinschaft fur Padiatrische Nephrologie are currently performing a prospective randomized trial to validate these observations.

Open versus laparoscopic donor nephrectomy in live related renal transplantation

Background This analysis sought to evaluate the efficiency and safety of laparoscopic nephrectomy (LDN) for the donor, the recipient, and the graft. LDN seems to have advantages over the open donor nephrectomy (ODN) in length of hospital stay, postoperative comfort, and pain control. Methods The results of 40 patients who underwent LDN between October 2000 and September 2003 were compared to those of 40 ODN patients just preceding the LDN patients. Eight laparoscopy patients required conversion to an open procedure due to bleeding (4; two major and two minor), technical problems with the instrument ( n = 1) and difficulty in the dissection ( n = 3). Results The demographic data, percentages of right and left nephrectomy, number of vessels, rates of acute rejection episodes, as well as the rates of urologic and vascular complications were similar between the two groups. The time of hospital stay was shorter, and the duration of the operation and of the warm ischemia time were significantly longer for the LDN group. The postoperative decline in serum creatinine levels were similar for the two groups. Graft survival rates were 91.7% at both the first and third years in the LDN group; 92.5% and 87.0% for the ODN group, a difference that was not statistically significant. Conclusion LDN is as efficient and safe as ODN for donors, recipients, and grafts.

The pharmacokinetics of mycophenolate mofetil in Thai kidney transplant recipients

Mycophenolate mofetil, in addition to cyclosporine and prednisolone significantly reduces the rate of acute rejection. The original recommended dose of MMF is fixed at 2 g/day. However, Thai patients cannot tolerate this dose due to gastrointestinal adverse effects. So the majority of patients are maintained on MMF at doses ranging from 0.5 to 2 g/day, according to their tolerability with an acceptable rate of acute rejection episodes. This study sought to determine the steady state pharmacokinetics of MMF in Thai kidney transplant recipients on stable doses of MMF. Forty-six kidney transplant patients more than 3 months on a stable MMF dose of 0.5, 1, 1.5, and 2 g/day together with cyclosporine and prednisolone underwent a single pharmacokinetic blood sampling for 12 hours following the morning dose of MMF. The analysis of plasma concentrations of mycophenolic acid (MPA), the sole pharmacologically active metabolite of MMF, was performed by using an high performance liquid chromatography method. Sparse efficient sampling strategies were employed to optimize the blood sampling schedule. Hence, blood samples were collected at 0, 0.5, 2, 12 hours after the MMF dose. The sampling time was designed to best estimate AUC 0–tau at steady state. The initial MPA-Bayesian estimator were used for MPA concentrations that would allow the best estimation of Vc, CLt, and Ka. In this study, there is a high interindividual variability in the AUC. The median MPA AUC was 34.3 ug.h/mL (range 14.1–65.4). Thirty-one of 45 (68.9%) patients had a MPA AUC within 20 to 40 ug.h/mL, which is the most reasonable risk: benefit ratio in terms of preventing acute rejection episodes. Forty-one of 45 (91.1%) patients had MPA AUC within 20 to 60 ug.h/mL, which is the MPA therapeutic range. The highest Pearson correlation coefficient of determination between MPA AUC and a single concentration was observed with MPA 2 hours ( r = 0.622) Without a fixed dosing regimen, most Thai kidney transplant recipients who receive MMF as part of a maintenance immunosuppressive regimen have the MPA AUC within the therapeutic window. The single drug concentration that correlates well with the AUC is MPA at 2 hours postdose.

Survival and complication rates in liver transplant patients showing primary dysfunction versus normofunction

Aims To determine rates of vascular and biliary duct complications, acute rejection, and graft and patient survival according to function status following liver transplantation. Methods We classified 248 consecutive liver transplants performed at the Hospital Ramón y Cajal, Madrid, over a 79-month period according to initial function as primary function (NP) versus dysfunction (PD). The latter group was subdivided into grafts showing primary failure (PF) or inadequate function (IPF). The classes NP and IPF were distinguished according to whether transaminase (GOT or GPT) levels and prothrombin activity were above or below 2000 IU and 50%, respectively. Results There were 23 (9.3%) patients with PD, of whom 12 (4.8%) showed PF. The incidence of vascular and biliary duct complications was similar in both groups, although acute rejection showed a significant difference (PD 3/23 versus NP 98/225; odds ratio = .18). In contrast, the mean survival rates of the grafts (NP 60.37 versus IPF 39.90 months) or patients (NP 63.02 versus PD 47.10 months) were not significantly different. Only 1- and 3-month graft survival rates significantly differed between the NP and IPF groups (NP 95% versus IPF 63%; P = .03 and NP 89% versus IPF 58%; P = .02, respectively). Conclusions Recipients with PD or NP after liver transplant showed no differences in the incidence of vascular or biliary duct complications. These groups did vary, however, in terms of rates of acute rejection episodes. No differences in graft and patient survival rates were observed except a significantly lower graft survival at 1 and 3 months, among patients with inadequate primary function.

Effect of sirolimus on the metabolism of apoB100- containing lipoproteins in renal transplant patients.

Sirolimus (Rapamune, rapamycin, RAPA) is a potent immunosuppressive drug that has reduced the rate of acute rejection episodes by more than 40% in phase III trials when added to an immunosuppression regimen of cyclosporine (CsA) and prednisone. However, RAPA treatment tends to increase lipid levels, particularly among patients with pre-existing hyperlipidemia. To identify the metabolic pathway(s) leading to RAPA-mediated hyperlipidemia, five patients with renal transplants maintained on CsA+/-prednisone+/- azathioprine (AZA) were studied before and after 6 weeks of treatment with RAPA (off RAPA and on RAPA, respectively). Each study patient was infused with a single bolus of [2H4]-lysine to derive metabolic parameters for apoB100-containing lipoproteins by using kinetic analysis based upon quantitation of isotopic enrichment by gas chromatography-mass spectrometry. Serial lipid measurements revealed that four patients displayed increased plasma triglyceride levels after RAPA treatment, which coincided with significantly higher plasma VLDL-apoB100 concentrations (21.7+/-12.1 mg/dl off RAPA vs. 38.7+/-14.8 mg/dl on RAPA, mean+/-SD, P<0.05). Kinetic analysis showed that the RAPA-induced increase in VLDL-apoB100 concentrations was due to a significant reduction in the fractional catabolic rate (FCR) of very low-density lipoprotein (VLDL) apoB100 (0.83+/-0.65 off RAPA vs. 0.24+/-0.10 on RAPA, mean+/-SD, P<0.05), rather than an enhanced VLDL-apoB100 synthesis. In one patient, RAPA treatment induced hypercholesterolemia but not hypertriglyceridemia. This hypercholesterolemia was due to elevated low-density lipoprotein (LDL) cholesterol levels, which coincided with a decreased FCR of LDL-apoB100. Heparin-induced lipoprotein lipase activity was significantly lower in the immunosuppressed hyperlipidemic patients than in normolipidemic controls. However, RAPA treatment did not significantly alter basal lipoprotein lipase activity in renal transplant patients in this study. This study indicates that for renal transplant patients in whom RAPA treatment induces hyperlipidemia, this effect is the result of reduced catabolism of apoB100-containing lipoproteins.