Risk Of Acute Rejection Episodes Research Articles

Suspicious of Acute Kidney Graft Rejection: Tacrolimus Pharmacokinetics Under Methylprednisolone Therapy.

Acute rejection remains one of the main complications in the first months after transplantation and may influence long-term outcomes. Tacrolimus has proven its usefulness in solid organ transplants and its monitoring through the application of pharmacokinetic concepts to optimize individual drug therapy. This research proposes to evaluate the tacrolimus pharmacokinetic parameters in patients suspected of acute kidney graft rejection under methylprednisolone pulse therapy. Eleven adult tacrolimus-treated renal recipients were selected from a prospective, single-arm, single-center cohort study, with suspicion of acute rejection although in use of methylprednisolone pulses therapy. They were followed up for three months posttransplantation, being tacrolimus trough serum concentrations determined using a chemiluminescent magnetic immunoassay, and pharmacokinetic parameters were estimated by using a nonlinear mixed-effects model implemented by Monolix 2020R1. A tacrolimus trough serum concentration range of 8 to 12 ng.mL-1 was considered therapeutic. Six patients showed acute cellular rejection, and two of them in addition had an antibody- mediated rejection. Tacrolimus trough serum concentration was below the reference range in eight patients. Most patients showed a high tacrolimus concentration intrapatient and pharmacokinetic parameters variability. The obtained pharmacokinetics parameters helped in understanding the kidney recipient patients' tacrolimus behavior, assisting in the improvement of individual drug therapy and reducing the risk of acute rejection episodes.

The weekend effect in kidney transplantation outcomes: a French cohort-based study.

Numerous studies have reported a weekend effect on outcomes for diseases treated at hospitals. No study has been conducted in France for kidney transplantation. We therefore performed a cohort-based study to evaluate whether outcomes of kidney transplant recipients display a weekend effect. Data were extracted from the French DIVAT cohort. Patients aged 18years and older, transplanted with a single kidney from deceased donors between 2005 and 2017 were studied. Linear regression, logistic regression, and cause-specific Cox model were used. Among the 6652 studied patients, 4653 patients were transplanted during weekdays (69.9%) versus 1999 during weekends (30.1%). The only statistically significant difference was the percentage of patients with vascular surgical complication(s) at 30days: 13.3% in the weekend group versus 16.2% in the weekday group 0.79 (95% CI: 0.68; 0.92). We did not observe other significant differences for the other outcomes: patient or graft survival, the risk of acute rejection episodes, the 30-day percentage of urological complications, and the 1-year estimated glomerular filtration rate. Our study highlights a small protective weekend effect with less post-surgery vascular complications compared to weekdays. This paradox might be explained by a different handling of weekend transplantations.

P1619OUTCOME OF HIGH DONOR-RECIPIENT AGE GAP IN LIVE-DONOR RENAL TRANSPLANTS IN TACROLIMUS ERA

Abstract Background and Aims High donor-recipient age gap among deceased-donor renal transplant patients leads to worse outcomes. However, the impact of this gap among live-donor renal transplants is unclear. The aim of this study is to assess the effect of this age gap on graft survival and acute rejection rates among renal transplants in tacrolimus era. Method 14390 live-donor renal transplant patients who received a single organ transplant, had no previous renal transplants, discharged on tacrolimus-based immunotherapy and were registered in the Organ Procurement Transplantation Network from January 2000 till June 2017 were included in the study. Donor–recipient age difference was divided into 5 groups; group A (difference <−10,n=4375), group B (difference from -10 to 10,n=7229), group C (difference between 10-20, n=861), group D ( difference between 20–29, n=1406) and group E (difference ≥30 years, n=519). Poisson regression analysis was used to assess effect of age gap on acute rejection rates. Kaplan-Meier survival curves and Cox hazard regression analysis were used to assess this effect on graft survival. Results Regarding graft survival, groups with age difference ≥30 years and between 20-29 years showed a significantly higher risk of graft loss when compared to group with age difference <−10 (HR equals 4.6 and 3.8 respectively). Groups with age difference between 10 to 20 years and between -10 to 10 years showed no significant difference in graft survival when compared to same group (HR equals 1.03 and 0.95 respectively). Groups B,C,D,E were not associated with increased risk of acute rejection episodes when compared to group A (IRR=1.001, 1.001, 1.022, 1.027 respectively). Conclusion Donor-recipient age difference up to 20 years has similar renal transplant outcomes to those receiving kidneys from younger donors and therefore, should not be precluded from paired kidney donation programs. The donor-recipient age difference above 20 years is associated with worse outcomes in terms of graft survival.

The Frequency and Risk Factors of Delayed Graft Function in living Donor Kidney Transplantation and Its Clinical Impact on Graft and Patient Survival in Part of Middle East.

Delayed graft function (DGF) is a form of acute renal failure which results in increased post-transplantation allograft immunogenicity and risk of acute rejection episodes in addition to decreased long-term survival. Its incidence and risk factors have been extensively studied, especially after deceased donation. Until now, only few data has beenpublished on DGF in living donor kidney transplant recipients. The present study was performed to investigate the frequency and risk factors of DGF among living- kidney transplant recipients. In this retrospective study, data had been collected from existing local hospital registries in three countries (Iran, Kingdom of Saudi Arabia (KSA) , and Kuwait ).

CYP3A genotypes of donors but not those of the patients increase the risk of acute rejection in renal transplant recipients on calcineurin inhibitors: a pilot study.

We aimed to determine whether polymorphisms in CYP3A genes may affect the risk of acute rejection episodes (ARE) in renal transplant recipients treated with calcineurin inhibitors (CNIs). One hundred and thirty seven patients and their respective donors were screened, by RT-PCR techniques, for three polymorphisms previously related with CNI pharmacokinetics and pharmacodynamics (CYP3A4*1B, CYP3A4*22 and CYP3A5*3). Genotypes of donors and recipients were associated by logistic regression models with ARE risk and exposure to CNIs. Clinical and pharmacokinetic parameters were recorded at four time-points after transplant (1week and 1, 5 and 12months). Nineteen patients (13.86%) experienced ARE. Patients who received a kidney from a donor carrying the CYP3A4*1B or CYP3A5*1 variant experienced ARE more frequently than those whose donor carried wild-type genotypes [OR=6.29 (1.62-24.39), p=0.008 and OR=3.42 (1.06-11.01), p=0.039, respectively]. The combined analysis of the CYP3A4*1B/3A5*1 alleles also revealed an increased risk in patients whose donors carried both variants [OR=6.24 (1.60-24.33), p=0.007]. The CYP3A genotype of the recipient did not affect ARE risk, although it did determine the degree of exposure to CNI throughout the first year after transplant. Patients with one or two variant alleles displayed lower concentration-to-dose ratios (CDRs) than non-carriers, with differences increasing with time after transplant (p values=0.039, 0.004, 6.0 e-04 and 2.7 e-07 in the four time-points). Our preliminary findings suggest that the determination of the CYP3A genotype of the donor, but not that of the recipient, may be useful to predict the incidence of acute rejection in renal transplantation.

Should belatacept be the centrepiece of renal transplantation?

Belatacept was developed to minimize cardiovascular risk and nephrotoxicity associated with calcineurin inhibitor (CNI)-based immunosuppression. Recently, 7-year data from the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial (BENEFIT), a phase III study comparing belatacept with cyclosporine, have been published. While during the first year of belatacept the risk of acute rejection episodes was elevated, this seemingly had marginal consequences for long-term graft survival and function as well as patient survival.For patients at a low-immunological risk, this drug seems to be a safe and effective alternative to CNI-based immunosuppression. Whether the higher rates of acute rejection episodes in the first year outweigh the gain in long-term graft function is still debated. In particular, the lower incidence of donor-specific antibodies indicates that belatacept should not be considered as lower intensity immunosuppression over the long term.Therefore, should belatacept be the centrepiece of immunosuppression for renal patients?All randomized trials so far have focussed on patients at a low immunological risk. Furthermore, cyclosporine A (CsA), the comparator of belatacept in BENEFIT and the Belatacept Evaluation of Nephroprotection and Efficacy as First-line Immunosuppression Trial-EXTended criteria donors (BENEFIT-EXT), is not the CNI of choice in modern transplantation. Furthermore, while at Year 7 the rate of cancer and infections was comparable with the CsA group, long-term data are missing on safety issues for a large number of patients. Thus, currently belatacept may be the drug of choice for a select group of patients, but not for everyone.This review highlights the benefits and uncertainties of the use of belatacept in kidney transplantation.

Association of Endothelial Nitric Oxide Synthase Gene Polymorphisms With Acute Rejection in Liver Transplant Recipients.

Polymorphisms of the endothelial nitric oxide synthase gene have been associated with altered endothelial nitric oxide synthase activity. The purpose of this study was to investigate the relation between endothelial nitric oxide synthase -786T/C and 894G/T polymorphism and their haplotypes on the occurrence of acute rejection episodes in liver transplant recipients. We conducted a case control study in which 100 liver transplant recipients and 100 healthy controls were recruited from Shiraz Transplant Center. The patients used triple therapy including tacrolimus, mycophenolate mofetil, and prednisolone for immunosuppression maintenance. DNA was extracted from peripheral blood and endothelial nitric oxide synthase polymorphisms were determined by polymerase chain reaction and restriction fragment length polymorphism. Patients included 60 men and 40 women (mean age, 32.35 ± 10.2 y). There was a significant association of endothelial nitric oxide synthase 894G/T and acute rejection episode. The GT* gen-otype and acute rejection episodes had a significant association (odds ratio, 2.42; 95% confidence interval, 0.97-6.15; P = .03). The GG and GT* genotype and T* allele frequency were significantly different between patients and control subjects (P = .001). Haplotype TT* was higher in recipients than control subjects (odds ratio, 2.17; 95% confidence interval, 1.12-4.25; P = .01). Haplotype TG was higher in the control group (odds ratio, 0.62; 95% confidence interval, 0.40-0.96; P = .02). Our results suggest a relation between different endothelial nitric oxide synthase geno-types and risk of acute rejection episodes. However, further study is necessary to determine genetic susceptibility for transplant patients.

Early Proteinuria After Renal Transplantation and Allograft Outcomes

BackgroundProteinuria is among the major and nonspecific sign of the renal disease. It is well known that late-onset proteinuria after renal transplantation has been associated with poor allograft outcomes and with mortality. Knowledge about the impact of early proteinuria on the various outcomes is limited. We have evaluated the utility of measuring early proteinuria in the management of pediatric renal transplant recipients. MethodsWe analyzed the effect of proteinuria at 3 months of posttransplantation on allograft rejection, graft loss, and estimated glomerular filtration rate (GFR) at 3 years. Proteinuria was assessed using 24-hour urine protein excretion. Renal biopsy was performed when elevated creatinine levels were elevated during routine follow-up and an acute rejection episode was proven with biopsy. ResultsSixty-seven pediatric renal transplant recipients were included to the study. Mean follow-up time after transplantation was 48.8 ± 12.1 months. Thirty-nine recipients (58%) have proteinuria >500 mg/d. The relationship could not be shown between proteinuria at posttransplant month 3 and other outcomes parameters, such as graft loss and lower estimated GFR. A significant positive correlation between acute rejection and the proteinuria at posttransplant month 3 was shown. ConclusionWe demonstrated that early proteinuria is a common finding in children after transplantation. Posttransplant early proteinuria cannot be used as a long-term prognostic marker of poor renal outcome. However, early proteinuria is associated with an high risk of acute rejection episodes. This would permit an opportunity for early intervention.

Value of Early Diethylentriamine Penta-acetic Acid Renograms in Predicting Late Allograft Outcomes

BackgroundTc-99m-diethylentriamine penta-acetic acid (DTPA) renal scintigraphy is useful, noninvasive diagnostic tool for the management and follow-up of the transplanted kidney. There have not been any studies of the predictive value of DTPA renal scintigraphy for short- and long-term allograft functions. Our aim was to reveal the significance of different perfusion–uptake patterns observed on Tc-99m-DTPA renal scintigraphy for long-term graft outcomes. MethodsWe retrospectively analyzed 59 renal transplanted children (30 male and 29 female). All patients were underwent DTPA on posttransplant day 7. Perfusion- and function-related parameters of DTPA (the ratio of peak perfusion counts to plateau counts [P:PL], the ratio of counts at peak perfusion to counts at peak uptake [P:U], and glomerular filtration rate [GFR] calculated using commercially available software) were studied. The mean P:PL and P:U calculated using the half-moon–shaped background region of interest. A renal time activity curve was generated for evaluate perfusion- and function-related parameters. The patterns were classified and the value of these early DTPA parameters in predicting long-term graft function was analyzed. ResultsThe mean age of patients was 16.69 ± 4.77 years. The mean posttransplant follow-up time was 3.5 ± 0.4 years. Thirty-nine patients received living-related donor allografts and the remaining 20 were from deceased donors. Thirteen children suffered ≥1 acute rejection episode. Eight patients lost their grafts during follow-up. Mean GFR value at year 3 was 80.61 ± 39.03 mL/1.73 m2 BSA/min. There was a significant difference for mean creatinine values at year 3 between recipients with normal perfusion and function and normal P:PL with decreased P:U patterns in early DTPA (P < .05). The normal P:PL with decreased P:U pattern is associated with lowest GFR value at posttransplant year 3. There was also a significant difference for mean GFR values at year 3 between recipients with normal perfusion and function and acute tubular necrosis (P < .05). Acute rejection episodes and graft loss were mostly seen in recipient with a decreased P:PL with or without decreased P:U pattern in early DTPA. The decreased P:PL with or without decreased P:U pattern may be associated with high risk of acute rejection episodes and graft loss. ConclusionPosttransplant early perfusion uptake patterns observed on Tc-99m-DTPA renal scintigraphy can be used as a long-term prognostic marker of poor renal outcomes. This would permit an opportunity for early intervention.

Does Lymphocyte Cross-Matching Predict Acute Rejection and Graft Survival in Liver Transplantation?

IntroductionThe role of lymphocyte cross-matches (LCM) remains controversial in the liver transplant field. The aim of this study was to correlate the risk for acute rejection episodes and graft survival in liver transplantation with pretransplant LCM results. Patients and MethodsWe enrolled 184 adult liver transplantation patients, excluding pediatric and second grafts. The 129 living donor and 55 deceased donor liver transplantations were divided into 2 groups: LCM (+); (n = 20) and LCM (−); (n = 164). ResultsThere were no differences in the demographic features, such as gender and recipient age, original disease, Model for End-Stage Liver Disease score, donor type, number of human leukocyte antigen mismatches, and cold ischemia times. There were no hyperacute rejection episodes in the LCM (+) group. Also, posttransplant complications such as acute rejection episode, biliary complication, or hepatic artery thrombosis were not different. Acute rejection episodes occurred in 5.0% of the LCM (+) group and 15.2% of the LCM (−) group (P = .317). Bile duct complications after transplantation arose in 20.0% of the LCM (+) group and in 32.9% of the LCM (−) group (P = .312). The 2 groups showed no difference in graft survival rate analyzed by the Kaplan–Meier method according to LCM results. ConclusionPretransplant LCM results were not associated with overall graft survival or acute rejection episodes in this study.

Impact of IL2 and IL2RB Genetic Polymorphisms in Kidney Transplantation

Patient genetic make-up may contribute to a higher risk for acute rejection episodes (AREs). Because interleukin-2 (IL2) and IL2 receptor β (IL2RB) play key roles in immune modulation, we investigated the effect of single-nucleotide polymorphisms (SNPs) in the IL2 gene (rs2069762; T>G, promoter; and rs2069763; G>T, exon 1, Leu38Leu) and IL2RB gene (rs228942: C>A, exon 1, Asp391Glu; and rs228953: C>T, exon 8, Gly250Gly) on renal ARE risk in 61 ARE patients and 276 control renal allograft recipients in Korea.The genotype frequencies of the IL2 and IL2RB SNPs showed Hardy-Weinberg equilibrium in both ARE and control groups. No significant difference in the genotype frequencies of the 2 IL2 SNPs was detected between non-ARE and ARE subjects (P > .05). The occurrence of AREs was significantly associated with genetic variants of the IL2RB gene (rs228942: odds ratio [OR] 2.11, 95% confidence interval [CI] 1.19–3.74; P = .0096, dominant model; rs228953: OR 1.58, 95% CI 1.04–2.38; P = .029, codominant model). In the haplotype-based analysis, the AC haplotype of IL2RB (χ2 = 4.738; P = .0295) showed associations with ARE. Our results demonstrate that genetic variants of IL2RB may be associated with the development of AREs and may help predict ARE risk in kidney transplantation patients.

“Immuknow” to Measurement of Cell-Mediated Immunity in Renal Transplant Recipients Undergoing Short-Term Evaluation

The aim of this preliminary, observational study was to evaluate the value of ImmuKnow (IK), a new tool to measure the net state of immunefunction among renal transplant recipients, in correlation with clinical and laboratory data among unselected renal transplant recipients. Forty-nine recipients of mean age of 51 years were enrolled and followed for 1 year after transplantation. All subjects received the same immunosuppressive strategy with basiliximab induction and tacrolimus, mycophenolate mofetil and steroid maintenance therapy. Samples for IK were collected before transplantation as well as at 7, 14, 21 and 42 days and after 3, 6, and 12 months. There were 54 samples with IK <225 ng/mL, 201 samples with normal IK values, and 135 samples with >525 ng/mL. We divided recipients into 3 groups with respect to their basal IK values: Group 1 (Gr1; IK <225 ng/mL); Group 2 (Gr2; normal values of IK between 226 and 524 ng/mL); and Group 3 (Gr3; IK >525 ng/mL). At 1 year, we observed a significant difference among IK values at the start and the end of the study: Gr1 vs Gr2, P < .0001; Gr2 vs Gr3, P < .06 and Gr 1 vs Gr 3, P < .01). We observed reduced IK values to predict an increased risk of infection, particularly with cytomegalovirus (CMV) replication while higher IK value did not correlate with an increased risk of acute rejection episodes. Reduction of serum creatine levels occurred within 1 year in all groups ( P < .005), but there was a significant difference between Gr 2 versus Grs 1 and 3 ( P < .0001 and P < .0005, respectively). There findings suggested that more stable IK values were associated with clinical quiescence and laboratory stability. In conclusion, our preliminary analysis showed a beneficial capacity of this assay to represent the global depression of the immune system. We noted that reduced IK values, as a sign of excessive immunosuppressive therapy, were associated with an increased risk of infection. We did not confirm the predictive value of higher IK values for an increased risk of an acute rejection episode.

Calcineurin Inhibitor-Free Immunosuppression in Pediatric Renal Transplantation

The introduction, in the mid-1980s, of calcineurin inhibitors - namely ciclosporin (cyclosporine) and later tacrolimus - has significantly improved short-term renal graft survival by lowering acute rejection rates in both adult and pediatric kidney transplantation. Nonetheless, long-term transplant survival is still not satisfactory, with calcineurin inhibitor-induced chronic nephrotoxicity being one of the main causes of progressive nephron loss and declining renal transplant function. Hence, different immunosuppressant regimens have been proposed to avoid or ameliorate calcineurin inhibitor-induced nephrotoxicity. These comprise the use of non-depleting or depleting antibodies for calcineurin inhibitor minimization, calcineurin inhibitor avoidance, or calcineurin inhibitor withdrawal from mycophenolate mofetil-based immunosuppressant protocols. De novo use of a mammalian target of rapamycin (mTOR) inhibitor (sirolimus or everolimus) or conversion from a calcineurin inhibitor to an mTOR inhibitor may constitute another therapeutic option to avoid or reduce calcineurin inhibitor-induced nephrotoxicity. To date, complete calcineurin inhibitor avoidance seems to be inappropriate because other relatively potent immunosuppressant agents such as lymphocyte-depleting antibodies are needed for rejection prophylaxis, which are frequently accompanied by a higher incidence of infections and an unacceptably high acute rejection rate under calcineurin inhibitor avoidance. In some studies, calcineurin inhibitor withdrawal in adult and pediatric kidney allograft recipients with stable or declining transplant function has been associated with an amelioration of renal function; however, this is attained at the cost of a higher acute rejection rate in 10-20% of patients. It has been frequently stressed that conversion from a calcineurin inhibitor-based regimen to an mTOR inhibitor-based immunosuppressant regimen should be performed early (e.g. 3 or 6 months post-transplant) in patients with well-preserved renal transplant function without significant proteinuria in order to prevent, or at least limit, calcineurin inhibitor-induced tissue damage and provide long-term benefit. It should be borne in mind though that the use of an mTOR inhibitor carries the risk of potential adverse events such as aggravation of proteinuria, hyperlipidemia, myelosuppression, and hypergonadotropic hypogonadism. Even though everolimus may be better tolerated than sirolimus, studies on everolimus for calcineurin inhibitor-free immunosuppression in the pediatric kidney transplant patient population are lacking. At present, the safest therapeutic strategy for pediatric renal allograft recipients with chronic calcineurin inhibitor-induced nephrotoxicity appears to be a mycophenolate mofetil-based regimen with low-dose calcineurin inhibitor therapy and corticosteroids; available published data show that dual immunosuppression with mycophenolate mofetil and corticosteroids, as well as an mTOR inhibitor plus mycophenolate mofetil plus corticosteroid-based regimens, are associated with an increased risk of acute rejection episodes. In individual patients with evidenced chronic allograft dysfunction and over-immunosuppression leading to recurrent infections, dual maintenance immunosuppression with mycophenolate mofetil and corticosteroids may be appropriate. As stated in the annual report issued by the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) Registry, currently the most popular immunosuppressant protocol consists of a calcineurin inhibitor combined with mycophenolate mofetil and corticosteroids: 59.1% and 53.2% of patients with a functioning graft receive a calcineurin inhibitor plus mycophenolate mofetil plus corticosteroid-based immunosuppression at 1 and 5 years post-transplant, respectively. 91.4% and 87.8% of patients are administered a calcineurin inhibitor-containing regimen 1 and/or 5 years after transplantation, respectively. Undoubtedly, the use of calcineurin inhibitor-free immunosuppressant regimens with or without antibody induction, plus an mTOR inhibitor and mycophenolate mofetil, requires more comprehensive long-term investigations to determine whether acceptable rejection rates and conservation of renal function can be achieved.

Clinical Implications of Initial Renal Function After Deceased Donor Transplant

The aim of this study was to investigate whether slow graft function (SGF) after transplantation of deceased-donor kidneys affected the prevalence of anemia or the glomerular filtration rate (GFR). We retrospectively evaluated the records of 534 kidney transplant patients who were classified based on their initial renal function, namely, immediate graft function (IGF), slow graft function (SGF), or delayed graft function (DGF). Among the 534 kidney transplant patients studied, the occurrences of each condition were IGF 104, SGF 133, and DGF 297. Six months after transplantation, a greater percentage of DGF patients were anemic compared with the others ( P = .028). However, at 12 months after transplantation, SGF patients showed more anemia than the IGF group. DGF and SGF patients displayed similar GFR values at 18 and 24 months after transplantation. However, IGF patients displayed higher GFRs, even when subjects who experienced acute rejection episodes were censored ( P = .004). The incidence of acute rejection episodes was similar among SGF and DGF patients. Patients displaying SGF after deceased-donor transplantation showed a greater tendency to be anemic than those displaying IGF. This study also suggested that SGF patients were at risk for acute rejection episodes and/or significantly reduced kidney function as measured by GFR.

Superior Efficacy of Enteric-coated Mycophenolate vs Mycophenolate Mofetil in De Novo Transplant Recipients: Pooled Analysis

Dose reduction and discontinuation of mycophenolate mofetil (MMF) therapy because of gastrointestinal complications has been associated with increased risk of acute rejection episodes and graft loss. Enteric-coated mycophenolate sodium (EC-MPS) delays release of mycophenolic acid (MPA), and was designed to reduce MPA-related gastrointestinal adverse events. Data comparing the efficacy of EC-MPS vs MMF in de novo renal transplant (RTx) recipients from large prospective studies are limited. Therefore, a pooled data analysis was performed based on 1891 de novo RTx recipients receiving EC-MPS (n = 1289) or MMF (n = 602) plus cyclosporine and steroid therapy in 4 prospective multicenter studies with similar entry criteria. In all trials, the initial dose of EC-MPS was 1440 mg/d, and of MMF was 2000 mg/d; both dosages deliver equimolar amounts of MPA. Induction therapy was permitted in 2 studies per center practice. Multivariate logistic regression analysis was performed, adjusting other potential explanatory variables including recipient age, sex, and race/ethnicity; induction therapy; and diabetes mellitus at baseline. In addition, propensity scores were used to explain potential bias. Mean (SD) MPA dose (EC-MPS dosage was converted to MMF equivalent) during months 0 to 12 was similar: EC-MPS, 1820 (370) mg/d, vs MMF, 1860 (290) mg/d. However, at univariate and multivariate analyses, the rates of treatment failure, biopsy-proved acute rejection episodes, and graft loss were significantly lower with EC-MPS compared with MMF at month 12. In conclusion, this pooled analysis documents a substantial improvement in efficacy in de novo RTx recipients receiving EC-MPS vs MMF with concomitant cyclosporine and steroid therapy.

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.

A limited sampling strategy for estimating mycophenolic acid area under the curve in adult heart transplant patients treated with concomitant cyclosporine

Heart transplantation studies have shown a relationship between the mycophenolic acid area under the curve (AUC) 0-12 h (MPA AUC(0-12h)) values and risk of acute rejection episodes and fewer side-effects in patient receiving cyclosporine during the first year post-transplant. However, measurement of full AUC is costly and time consuming and in this case it is an impractical approach to drug monitoring. Therefore, the authors describe a limited sampling strategy to estimate the MPA AUC(0-12h) value in adult heart transplant recipients. Ninety MPA pharmacokinetic (PK) profiles were studied. The samples were collected immediately before and 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 9, 12 h after the morning dose of mycophenolate mofetil (MMF) following an overnight fast. PK profiles were determined at 6-8 weeks, 6, 12 months and more than 1 year after transplantation. Using stepwise multiple linear regression analysis a sampling strategy from 60 of PK profiles was obtained and next the bias and precision of the model were evaluated in another 30 PK profiles. The three-point model using C(0.5h), C(1h), C(2h) was found to be superior to all other models tested (r(2) = 0.841). The regression equation for AUC estimation which gave the best fit to this model is: 9.69 + 0.63C(0.5) + 0.61C(1) + 2.20C(2). Using that model 63 of the 90 (70%) full AUC values were estimated within 15% of their actual value. For the best-fit model, the mean prediction error was 3.2%, with 95% confidence intervals for prediction error to range from -42.2% to 40.3%. All other models which use one, two or three time-points over the first 2 h are poorer predictors of the full AUC than the model above. The proposed three time-point equation to estimate AUC will be helpful in optimizing immunosuppressive therapy in heart transplantation.

Influence of CYP3A5 Genetic Polymorphism on Tacrolimus Daily Dose Requirements and Acute Rejection in Renal Graft Recipients

Tacrolimus is a widely used immunosuppressive drug in organ transplantation. Its oral bioavailability varies greatly between individuals, and it is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein. Our objective was to determine the influence of CYP3A5 and ABCB1 genetic polymorphisms on tacrolimus daily requirements and on transplantation outcome. One hundred and thirty-six renal graft recipients treated with tacrolimus were genotyped for CYP3A5 (6986A>G), ABCB1 exon26 (3435C>T) and exon21 (2677G>T/A) single nucleotide polymorphisms. Genotypes were correlated to tacrolimus daily dose at 1-week, 1-, 6- and 12-month post-transplantation and with transplantation outcome. At 1-month post-transplantation, tacrolimus daily dose was higher for patients with CYP3A5*1/*1 genotype compared to CYP3A5*3/*3 genotype (0.26 +/- 0.03 versus 0.16 +/- 0.01 mg/kg/day, respectively, P < 0.0001). Similar results were obtained at 6- and 12-month post-transplantation. Furthermore, CYP3A5*1 homozygotes were associated with increased risk of acute rejection episodes compared to patients with CYP3A5*1/*3 and CYP3A5*3/*3 genotypes (38% versus 10% and 9%, respectively, P = 0.01). CYP3A5 genetic polymorphism was not associated with tacrolimus-related nephrotoxicity. ABCB1 polymorphisms were not related with transplantation outcome. CYP3A5 genetic polymorphism appeared in our study to affect tacrolimus daily dose requirements and transplantation outcome. Screening for this single nucleotide polymorphism before the transplantation might be helpful for the selection of adequate initial daily dose and to achieve the desired immunosuppression.

Evaluation of Pretransplant Serum Cytokine Levels in Renal Transplant Recipients

Aim Cytokines are early predictors of graft dysfunction. In this study we evaluated pretransplant cytokine levels and graft outcomes among renal transplant recipients. Patients and methods Donor selection was based on results of blood group matching and negative crossmatches. A panel of 35 human serum samples from patients (female/male = 0.4) awaiting renal transplantation and 15 healty control sera were analyzed for interleukin (IL) 1α, IL-2, IL-6, IL-10, tumor necrosis factor-α, interferon-γ, transforming growth factor-β concentrations by enzyme-linked immunosorbent assay. The average age of the patients was 34.5 ± 10.1 years (range 15 to 60). The average duration of renal replacement therapy before renal transplantation was 42.1 ± 57.9 months (range 0 to 288). The types of renal replacement therapy were; hemodialysis ( n = 27) and CAPD ( n = 8). Results Pretransplant IL-6 levels were higher among recipients who displayed acute rejection episodes compared with those fact of this complications ( P < .05) or control sera ( P < .05). Pretransplant IL-6 levels were higher among recipients with graft failure than those with a functioning graft ( P < .05). Pretransplant IL-10 levels were higher among recipients with acute rejection episodes and graft failure than those without acute rejection or control subjects, but the difference did not reach significance. There was no correlation between pretransplant cytokine levels and age, gender, type, or duration of renal replacement therapy ( P > .05). Conclusion High pretransplant serum IL-6 levels are associated with an increased risk of acute rejection episodes and graft failure. IL-10 might contribute an anti-inflammatory action to patients with high serum IL-6 levels.

Acute rejection episodes in pediatric renal transplant recipients with cytomegalovirus infection

CMV infection is the most important opportunistic virus infection after renal transplantation leading to increased patient mortality, graft loss, risk for acute rejection episodes and impaired renal function. The potential impact of prophylactic anti-viral therapy on long-term graft outcome is relevant. The aim of this study was to evaluate the incidence of CMV infection, its risk factors and long-term outcome in children after renal transplantation. 103 children (mean age 10.6 +/- 5.3, range 1.6-22.0 yr) were monitored weekly for pp65 for the first 6-8 wk after renal transplantation, followed by a monthly monitoring for the first year. CMV infection occurred in 23/103 children (21.1%) with 10 patients (9.7%) developing CMV disease characterized by positive pp65 in the presence of organ involvement. The CMV R-/D+ and R+/D+ serostatus was significantly associated with an increased risk of CMV infection (p < 0.0001 and p = 0.009). 14/28 R-/D+ patients developed CMV infection despite prophylactic treatment with CMV hyperimmune globulin. The incidence of acute rejection episodes after or during CMV infection was significantly increased (p = 0.003) and the D+ serostatus was significantly associated with acute rejection episodes within the first year after transplantation (p = 0.006). In summary the overall incidence of CMV infection in this single center experience is 21.1%. The D+ serostatus represents a serious risk factor for both CMV infection and acute rejection episodes. In future the potential impact of different modalities of prophylactic anti-viral therapy on the prevention of acute rejection should be considered.