Higher Tacrolimus Dose Research Articles

Interaction Between Everolimus and Tacrolimus in Renal Transplant Recipients: A Pharmacokinetic Controlled Trial

Clinical data are lacking concerning therapeutic action and systemic exposure of tacrolimus (TAC) and everolimus (EVL) in a combined regimen in renal transplantation. A prospective randomized phase II pharmacokinetic study was conducted comparing two fixed EVL dosages (0.75 mg two times per day (BID), group A, or 1.5 mg BID, group B) in combination with standard TAC dose. Complete 12-hr pharmacokinetic curves of both drugs were performed at days 4, 14, and 42 posttransplant. A higher TAC Cmin was observed with EVL dose of 0.75 mg BID (TAC 11.1+/-6.4 group A vs. 9.4+/-5.0 ng/mL group B, P=0.03), with equivalent TAC area under the curves (162+/-61 vs. 171+/-75). The exposure to TAC was lower in group B despite higher TAC doses were required to maintain target concentrations (day 14: 9.5 vs. 12.5 mg and day 42: 6 vs. 9 mg, P<0.05). Cmin-TAC/dose and area under the curve-TAC/dose ratios were significantly lower, from day 4 to day 42, in group B. Both groups achieved good graft function and acute rejection rate was similar (20% and 15%, respectively). We conclude that in adult renal transplant recipients, EVL significantly decreases TAC oral bioavailability in a dose-dependent manner. Doses higher than 1.5 mg BID would be probably needed for TAC-minimization strategies because 3 mg/day is not enough to achieve levels more than 3 ng/mL during the first 2 weeks. Therapeutic drug monitoring is mandatory to adjust the dose and prevent low TAC exposure. This regimen of low EVL exposure plus standard TAC exposure avoids wound healing problems with good efficacy.

Post-transplant lymphoproliferative disorder in pediatric heart transplant recipients

Post-transplantation lymphoproliferative disorder (PTLD) is a major cause of morbidity and mortality after pediatric heart transplantation. Heart transplant recipients at The Hospital for Sick Children, Toronto, from 1990 to May 2008, were reviewed. Competing risk hazard analysis was used to model the natural history of the disease. Patients were matched for gender and duration of follow-up to identify potential covariates associated with increased risk of PTLD. A total of 173 heart transplant recipients (42% <1 year old) were reviewed. Twenty-three developed PTLD at a median of 4 years post-transplantation. After transplantation, PTLD affected 9%, 15% and 28% at 3, 5 and 10 years, respectively. Freedom from death or PTLD recurrence was 72%, 58% and 50% at 1, 3 and 5 years, respectively, after PTLD diagnosis. Higher maximum Epstein-Barr viral (EBV) load (hazard ratio [HR]: 2.6, p = 0.004) and longer duration of induction therapy (HR: 1.7, p = 0.02) were associated with increased risks of PTLD. Higher cumulative cyclosporine doses over the first year post-transplantation were associated with increased risks of PTLD (HR: 1.2 per 1 mg/kg/day equivalent, p = 0.03), but higher tacrolimus doses were not (p = 0.38). Patients on cyclosporine at 6 months post-transplantation were at higher risk of PTLD than those on tacrolimus (HR: 5.2, p = 0.003). The use of anti-viral prophylaxis in patients with high EBV load may provide some protection (HR: 7.6 vs 15.4 with no anti-viral, p = 0.02). PTLD is a major concern in pediatric heart transplant recipients and is associated with high morbidity/mortality. Exposure to EBV and higher intensity of immunosuppression seems to be associated with increased risk.

Factors affecting the long-term response to tacrolimus in renal transplant patients: Pharmacokinetic and pharmacogenetic approach

The aim of our study was to determine the impact of CYP3A5*1 and CYP3A5*3 on the kinetics of tacrolimus in renal transplant recipients. Forty kidney recipients were selected to participate. Maintenance scheme consisted of tacrolimus, a purine inhibitor and a steroid. CYP3A5 genotyping was performed with PCR and RFLP. Pharmacokinetic model was developed with Linear Regression and General Linear Model repeated measures approach. The impact of sex, CYP3A5*1 allele, age at transplantation, hepatic and renal function on tacrolimus kinetics was examined. The frequency of CYP3A5*3/*3 and CYP3A5*1/*3 genotype was 35/40 and 5/40, respectively. No CYP3A5*1/*1 was detected. CYP3A5*1 variant was associated with significant lower TAC dose adjusted concentration at 3, 6, 12 and 36 months after transplantation. Hepatic and renal function showed a significant effect on tacrolimus dose adjusted concentration 3 months after transplantation (p=0.000 and 0.028, respectively). Sex did not show a significant impact on tacrolimus kinetics. Carriers of CYP3A5*1 allele had lower predicted measures for tacrolimus dose adjusted concentration and higher predicted measures for volume of distribution. We proved that CYP3A5*1 carriers need higher tacrolimus dose than CYP3A5*3 homozygotes to achieve the target blood concentration.

Post-transplant diabetes mellitus

In recent decades, Diabetes Mellitus has become a severe and growing global public healthcare problem due to the increase of its prevalence, morbidity and mortality. Post-transplant diabetes mellitus (PTDM) is a complication which takes place after a solid organ transplant, and its incidence is widely variable, ranging from 2 to 53%. Some factors increase the risk of PTDM, such as age, ethnicity, cadaver-donor kidney presence of the hepatitis C virus and cytomegalovirus, overweight and obesity and the Immunosuppression scheme established in the immediate post-transplant period. High doses of tacrolimus and corticosteroid represent the highest risk for developing PTDM.Considering that the development of PTDM is associated with a higher risk of complications, such as infections and cardiovascular disease - thus representing a higher life threatening risk and a higher cost for the Health System - the relevance of identifying the risk factors and of the early diagnosis combined with appropriate therapy will be high for the follow up, and eventually resulting in the success of the procedure as far as patient survival and transplantation durability.

Renal Transplantation in Emigrants From Africa in Spain: Similar Results but Different Infectious Profile Compared With Spanish People

The number of renal transplantation of emigrants from Africa in Europe is increasing. However, there is little information about the results. The aim of this study was to compare the results of renal transplantation among this African emigrant population compared with a matched group of Spanish patients. From 1996-2006, 27 African emigrants (from Morocco, Guinea, and Nigeria) received renal transplants in Madrid. We compared their results with a matched cohort, including 69% who received a kidney from the same donors to 49 Caucasian Spanish patients. Demographic data were similar except that retransplantation was more frequent (32% vs 0%; P = .02) among Spanish patients and hepatitis B was more frequent among the African group (22% vs 2%; P = .004). For both groups the most frequent regimen was steroids, tacrolimus, and mycophenolate mofetil. Acute rejection incidence was similar (Africans 26% vs Spanish 22%), but rejection as a cause of graft loss was numerically more frequent in Africans (4 of 6). Patient and graft survival rates were identical in both groups (96% and 80%, respectively) at a mean follow-up of 76 months in Africans versus 68 months in Spanish people. Characteristically African patients required higher dose of tacrolimus to maintain the same levels; and notably, they suffered rare opportunistic infections, such as Phonopsis longicolla and visceral Leishmania. In summary, renal transplantation in African emigrant patients in Spain showed excellent results similar to those obtained with a Spanish population. However, these patients needed higher doses of Tacrolimus and experienced more rare opportunistic infections.

A Therapeutic Dose of FK506 Does Not Affect Collagen Turnover Pathways in Healthy Human Gingival Fibroblasts

We previously demonstrated that a high dose of tacrolimus (1 μmol/L) induced expression of matrix metalloproteinase (MMP) proteins in human cultured gingival fibroblasts, suggesting a molecular mechanism maintaining gingival collagen homeostasis in tacrolimus-treated patients. Herein we have analyzed whether the effect on collagen turnover might be influenced by a therapeutic tacrolimus dose. Human gingival fibroblasts were incubated for 72 hours with 10 nmol/L, 100 nmol/L, and 1 μmol/L tacrolimus, or left untreated (CT). Collagen type I and III (COL-I, COL-III), lysyl hydroxylase 2b (LH2b), MMP-1 and -2, tissue inhibitor of MMP-1 and transforming growth factor-β1 (TGF-β1) mRNA levels were assayed by reverse-transcriptase polymerase chain reaction, collagen protein levels by dot blot, and MMP activity by sodium dodecyl sulfate zymography. Tacrolimus did not affect COL-I, COL-III, or MMP gene expression, while LH2b and TGF-β1 tended to be down-regulated after 1 μmol/L FK506. Conversely, protein levels of MMP-1 ( P = NS) and MMP-2 ( P < .05 vs CT, 10 nmol/L, 100 nmol/L) were up-regulated after 1 μmol/L tacrolimus. Our findings confirmed that a high dose of tacrolimus does not induce interstitial collagen overexpression by gingival fibroblasts and induces up-regulation of MMPs protein levels. Interestingly, at doses corresponding to whole blood trough levels, tacrolimus did not exert any evident effect on collagen turnover pathways, suggesting that tacrolimus is likely to not affect collagen homeostasis in the gingival connective tissue compartment of FK506-immunosuppressed subjects. This effect did not seem to be dose-dependent.

Pharmacokinetics of mycophenolic acid, tacrolimus and sirolimus after gastric bypass surgery in end‐stage renal disease and transplant patients: a pilot study

Promising data regarding the safety and efficacy of gastric bypass surgery (GBS) as an option to address obesity in the transplant population are emerging. The data lack on how GBS may alter the pharmacokinetics (PK) of modern immunosuppression. The objective of this study was to describe the alterations in the PK of modern immunosuppressants and the GBS population. Data are presented on six subjects who participated in this trial--four were on dialysis and two were renal transplant recipients. Dialysis-dependent bypass subjects received a single dose of 6 mg of sirolimus, two 4-mg doses of tacrolimus and two 1000-mg doses of mycophenolate mofetil (MMF) over the 24-h study period. Transplant recipients continued their current regimen. Maximum plasma concentration (C(max)), time to reach the maximum plasma concentration (T(max)) and the area under the plasma concentration vs. time curve (AUC(0-12) and AUC(0-infinity) where appropriate) were calculated for tacrolimus, sirolimus, mycophenolic acid (MPA) and mycophenolic acid glucuronide (MPAG). Significant inter-patient variability in the C(max), T(max) and AUC of tacrolimus, sirolimus MPA and MPAG was observed. A notable difference in the AUC:dose ratio for tacrolimus was seen when comparing data with published data in the non-bypass population. Similar differences in PK were seen with sirolimus, MPA and MPAG. When comparing the PK of sirolimus, tacrolimus, MPA and MPAG to published PK data in the non-bypass population, significant differences are observed. It is likely that transplant recipients with GBS would need higher doses of tacrolimus, sirolimus and MMF to provide similar exposure to a non-bypass patient.

Tacrolimus Dose in Black Renal Transplant Recipients

Black patients require higher doses of tacrolimus to achieve target blood concentrations than do individuals from other ethnic groups (1, 2) leading to concern that they are under-immunosuppressed in the critical early posttransplant period (3). Our cohort of black patients, treated with an initial daily tacrolimus dose of 0.2 mg/kg, had twofold lower dose-normalized blood concentrations (median (IQR) 4.08 (3.6–7.7) ng/mL per 0.1 mg/kg) than white patients (8.51 (5.7–12) ng/mL per 0.1 mg/kg) on day 7 posttransplant (P<0.001). These data led to the adoption of a twofold higher initial tacrolimus dose for black patients than our standard regimen. All black renal transplant recipients transplanted in our center between 1995 and 2005 were studied (Table 1). Twenty-two were of African Caribbean origin, 16 from West Africa, and 1 from East Africa. One patient in the 0.4 mg/kg cohort was switched to sirolimus on day 8 posttransplant. We are reporting a change in standard clinical protocol that did not require ethical approval.TABLE 1: DemographicsBefore July 2002 an initial oral loading dose of 0.2 mg/kg was given preoperatively followed by a maintenance dose of 0.1 mg/kg twice daily (0.2 mg/kg daily). Subsequently, the loading dose was 0.4 mg/kg, followed by 0.2 mg/kg twice daily (0.4 mg/kg daily). Subsequent dosing was directed by thrice weekly measurement aiming for 12 hr postdose whole blood concentration of 15–20 ng/mL for days 0–7 and then 10–15 ng/mL. The dose was adjusted by 20% for results outside the target range except for high concentrations when fewer than 3 doses had been given. The Tacrolimus II immunoassay (Abbott diagnostics, Abbott Park, IL performed on an IMx clinical analyser) was used throughout the study. The laboratory was a member of the International Tacrolimus Proficiency Testing Scheme. Methyl prednisolone (500 mg) was given intravenously perioperatively, then 20 mg of oral prednisolone daily. On day 7, 21/26 patients (80.8%) in the 0.2 mg/kg group had concentrations below the target of 15 ng/mL compared to 3/13 (23.1%) in the 0.4 mg/kg group (P=0.03, Figure 1). All patients in the 0.4 mg/kg group achieved the lower target of 10 ng/mL, that would now be regarded as conventional, on day 7 compared with 16/26 (61.5%) in the 0.2 mg/kg group (P<0.03). On day 7, 3/26 (11.5%) of the 0.2 mg/kg group had values greater than 20 ng/mL compared with 7/13 (53.8%) in the 0.4 mg/kg group (P<0.02). The blood tacrolimus concentration exceeded 15 ng/mL on day 7 in 5/26 patients (19.2%) in the 0.2 mg/kg group and 10/13 (76.9%) with the higher dose (P<0.007).FIGURE 1.: Blood tacrolimus concentrations. The 12-hr postdose tacrolimus concentration on days 7 (±1 day) and day 14 (±1 day) after transplantation are shown for individual patients. The dashed lines represent the minimum target blood tacrolimus concentrations at which we were aiming: 15 ng/mL during week 1 and 10 ng/ml during week 2. The area between these lines represents what would now be regarded as an appropriate therapeutic range. Values for the 0.4 mg/kg group were significantly higher than for the 0.2 mg/kg group on day 7 (Mann–Whitney P=0.001), but not on day 14.An increase in the initial daily tacrolimus dose from 0.2 mg/kg to 0.4 mg/kg allowed most patients to achieve minimum target blood concentrations during the first week posttransplant, but at the expense of potentially toxic blood concentrations. The degree to which the patients in the 0.4 mg/kg group exceeded the target range was surprising. Tacrolimus exposure increases linearly with increasing doses up to 10 mg (4) but there are no published data for higher doses. A possible explanation would be a saturable barrier to drug absorption with greater oral bioavailability at higher tacrolimus doses. An initial daily dose of 0.4 mg/kg is probably excessive and provides the basis for testing an initial starting dose of tacrolimus at 0.3 mg/kg. Nidyanandh Vadivel Ashwani Garg Renal Medicine and Transplantation St. George’s Hospital London, United Kingdom David W. Holt Cardiac and Vascular Sciences: Analytical Unit St. George’s, University of London London, United Kingdom Rene W. S. Chang Renal Medicine and Transplantation St. George’s Hospital London, United Kingdom Iain A. M. MacPhee Cellular and Molecular Medicine: Renal Medicine St. George’s, University of London London, United Kingdom

Multiglycosidorum tripterygii versus Tacrolimus for rat tracheal allografts

Several other immunosuppressive agents still need to be found for rejection as alternatives to Tacrolimus in lung transplantation. We tried to elucidate the treatment effect of Multiglycosidorum tripterygii on tracheal allografts in comparison to that of Tacrolimus. Treatment effect of agents on tracheal allografts, undergoing incomplete immunosuppression for 12 weeks after transplantation, was investigated using a heterotopic rat tracheal transplantation model. Treatments with Tacrolimus (1.0 or 1.5mg/kg per day), Multiglycosidorum tripterygii (150 or 225mg/kg per day) and a combination of Tacrolimus (1.0mg/kg per day) and Multiglycosidorum tripterygii (150mg/kg per day) were applied as a therapy for allografts. Four weeks after administering this therapy, the effect of each treatment was investigated by the morphologic assessment of transplants. Treatment group with high doses of Multiglycosidorum tripterygii demonstrated a significantly better graft patency and lower cartilage dislocation than that without any treatment and tended to show better morphological findings than the other treatment groups, in addition to being safe. Some of allografts with high doses of Tacrolimus or Multiglycosidorum tripterygii therapy had a viable epithelium and viable tracheal glands in part, whereas the allografts with other treatments showed almost a completely denuded epithelium. High doses of Multiglycosidorum tripterygii therapy demonstrated less infiltration of mononuclear cells into the allografts, whereas other therapies showed a higher infiltration of such cells. We conclude that high doses of Multiglycosidorum tripterygii may be a useful alternative to Tacrolimus as an immunosuppressant for rat tracheal allografts.

Successful treatment of Diamond‐Blackfan anemia with metoclopramide

Diamond-Blackfan anemia (DBA) is a congenital anemia characterized by a low reticulocyte count, the absence or severe reduction of hemoglobin-containing cells in the bone marrow, and normal megakaryocytic and granulocytic differentiation. Although the anemia may initially respond to corticosteroid therapy, many patients require lifelong red blood cell (RBC) transfusion, leading to infectious complications and iron overload. Metoclopramide has recently been used to treat DBA. Treatment with metoclopramide induces the release of prolactin from the pituitary and stimulates erythropoiesis. For these reasons, we used metoclopramide to treat a 20-year-old man with DBA refractory to low and high doses of corticosteroids, cyclosporin A, and tacrolimus (FK506). The hemoglobin and hematocrit slowly increased, and he has remained asymptomatic and transfusion-independent for 8 months. Metoclopramide therapy should be considered in patients with refractory DBA before treatment-related complications develop.

THE EFFECT OF A NOVEL INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITOR IN PREVENTION OF CHRONIC AORTIC REJECTION IN RATS

P1219 Background: Cytotoxic nitric oxide (NO) is produced during ischemia/reperfusion (I/R) injury, acute and chronic rejection in the allograft by expression of inducible NO synthase (iNOS). Therefore, continuous inhibition of iNOS may prevent early graft disfunction and immune injury (rejection), and consequently improve graft survival. FR260330 is a potent and selective inhibitor of iNOS activity by preventing iNOS monomers from dimerization. In this study, the authors evaluated the effect of FR260330 in prevention of chronic rejection in a model of rat aortic allografts. Methods: Male Lewis (LEW, RT1l) rats received male ACI (RT1a) aorta allografts or LEW aorta isografts. Fourteen groups (n ≥ 6) were involved in this study. FR260330 and/or tacrolimus were administered orally for 14 or 90 days according to protocol. The degree of intimal proliferation of graft aorta was determined by a computerized image system. Results: Both low and high doses of FR260330 or tacrolimus treated grafts showed significantly decreased intimal/(intimal + media) ratios at days 90 compared to placebo controls. Combination therapy of low-dose of FR260330 with low-dose of tacrolimus produced significant decrease of intimal/(intimal + media) ratios with intact endothelium to compare with placebo controls. Anti-α-actin immunohistochemical staining demonstrated that one of the mechanisms of intimal proliferation is related to migration of vascular smooth muscle cells. Conclusion: A selective inhibitor of nitric oxide synthase, FR260330 plays a protective role in chronic aortic allograft rejection in the rat. Combination therapy of low-dose of FR260330 with tacrolimus produces significant protection of immnue injury and may serve to improve long-term graft survival and function.

CYP3A5*1-carrying graft liver reduces the concentration/oral dose ratio of tacrolimus in recipients of living-donor liver transplantation.

Tacrolimus is widely used for immunosuppressive therapy after organ transplantation, but its pharmacokinetics shows such great interindividual variation that control of its blood concentration is difficult. We have previously reported that an intestinal P-glycoprotein (MDR1) contributes to this variation as an absorptive barrier, but the role of hepatic metabolism is not clear. In this study, we have evaluated the genotypes of MDR1 and cytochrome P450 (CYP) 3A in donor and recipient, and the influence of polymorphisms on mRNA expression and the tacrolimus concentration/dose (C/D) ratio in recipients of living-donor liver transplantation (LDLT). The expression level of MDR1 and tacrolimus C/D ratio were not affected by either MDR1 C3435T or G2677T/A. The CYP3A4*1B genotype was not detected, but the CYP3A5*3 genotype had an allelic frequency of 76.3%. The mRNA level of CYP3A5 was significantly reduced by the *3/*3 genotype, and the tacrolimus C/D ratio was decreased in recipients engrafted with partial liver carrying CYP3A5*1/*1 genotype. An analysis of the combination of intestinal MDR1 level and liver CYP3A5 genotype revealed that the tacrolimus C/D ratio was lower in the group with higher MDR1 levels regardless of CYP3A5 genotype during postoperative week 1. These results indicate that in recipients of LDLT, the pharmacokinetics of tacrolimus is influenced by flux via P-glycoprotein in the intestine during the first week; after that, it is mostly the hepatic metabolism that contributes to the excretion of tacrolimus, and carriers of the CYP3A5*1/*1 genotype require a high dose of tacrolimus to achieve the target concentration.

Short- and long-term effects of T-cell modulating agents in experimental autoimmunity.

Due to the easy and reliable induction of a disease condition with many of the features present in human autoimmunity, mercury-induced autoimmunity (mHgAI) in rodents is a favourable autoimmune model. Genetically susceptible (H-2(s)) mice develop in response to mercury (Hg) a systemic autoimmune condition with antinucleolar antibodies (ANoA) targeting the protein fibrillarin, transient polyclonal B-cell activation, hyperimmunoglobulinemia, and systemic immune-complex (IC) deposits. In order to study the short- and long-term effects of treatment with immunomodulating agents on the disease parameters in HgAI, groups of B10.S (H-2(s)) mice were given 6 mg HgCl(2)/l drinking water for 22 weeks. Three weeks initial treatment with cyclosporin A (CyA), a high dose of tacrolimus (HD tacrolimus), or anti-CD4 monoclonal antibody (a-CD4) inhibited induction of ANoA and IC deposit by Hg. This effect persisted for the subsequent 19 weeks when the mice were only treated with Hg. Initial treatment with anti-IL-4 monoclonal antibody (a-IL-4) for 3 weeks inhibited induction of IgE and IC deposits by Hg, but not ANoA. However, subsequent treatment with Hg without a-IL-4 for 19 weeks induced IC deposits. The T-cell modulating agents aggravated some of the HgAI disease parameters: a-CD4 stimulated the polyclonal B-cell activation, a-IL-4 increased the IgG antichromatin antibody response, and a low dose of tacrolimus (LD tacrolimus) enhanced the ANoA, the polyclonal B-cell activation, and the IC deposits. We conclude that a short initial treatment with a-CD4 or CyA efficiently protects against induction of systemic autoimmunity for an extended period of time. However, some of the T-cell modulating agents, especially a low dose of tacrolimus, aggravate autoimmune manifestations not only during ongoing treatment, but also after treatment with these agents has ceased.

Cytochrome P-450 3A4, 3A5, and MDR-1 as pharmacogenomic predictors of tacrolimus pharmacokinetics and clinical outcomes in liver transplant recipients

Tacrolimus is a macrolide immunosuppressant used to prevent allograft rejection in organ transplantation. CYP3A4, CYP3A5, and P-glycoprotein (MDR1) may play significant roles in drug disposition of xenobiotics including tacrolimus. Single nucleotide polymorphisms (SNPs) in CYP3A4 (A-290G), CYP3A5 (A22893G), and MDR1 (C3435T) may result in altered in vivo catalytic activity. This study explored the pharmacogenomic impact of CYP3A4, CYP3A5, and MDR1 on tacrolimus dosing and clinical outcomes in liver transplant recipients. In 45 patients, phenotypic data were collected for the first 10 days post-transplant and at Month 4. Genomic DNA was isolated from human liver tissue with genotypic determination done via PCR-based detection methods. Unpaired T-tests compared two genotype groups with P<0.05 considered significant. Significantly, CYP3A4 AA genotype had higher mean tacrolimus trough concentrations than AG/GG (11.8±2.7 vs 9.7±2.9 mcg/dL, p=0.027), and individuals with CYP3A5*3/*3 required higher tacrolimus doses than those with a CYP3A5*1 allele (0.054±0.02 vs 0.040±0.02 mg/kg/d, p=0.040). Renal clearance significantly declined from transplant to Month 4 in all groups (p<0.0001), but no genotype interactions were identified. Thus, genetic variants of CYP3A4 and CYP3A5 may be useful predictors of tacrolimus requirements and outcomes in liver transplant patients and may contribute to the construction of clinically relevant pharmacogenomic models in transplantation. Clinical Pharmacology & Therapeutics (2004) 75, P39–P39; doi: 10.1016/j.clpt.2003.11.149

Pharmacokinetic interaction between corticosteroids and tacrolimus after renal transplantation.

Tacrolimus is an immunosuppressive drug that is a substrate of cytochrome P450 3A (CYP3A) enzymes and P-glycoprotein (P-gp). After transplantation, many pharmacological interactions have been described. Corticosteroids induce both CYP3A and P-gp activity. This study was designed to investigate the presence of a clinically significant interaction between steroids and tacrolimus after renal transplantation. We studied 83 renal transplant recipients receiving tacrolimus after transplantation. Patients were divided into three groups, according to steroid dose (low: 0-0.15 mg/kg/day; intermediate: 0.16-0.25 mg/kg/day; and high: >0.25 mg/kg/day). All other medications, including those known to interact with CYP3A and/or P-gp, were recorded. Steroid dosage, tacrolimus dosage, tacrolimus trough concentration (C0) and tacrolimus concentration/dose ratio [C0 divided by the 24 h dosage (mg/kg)] were assessed for each dosage group after 1 and 3 months of tacrolimus treatment. The three groups were not different as regards the use of non-immunosuppressive treatments or clinical events. At 1 and 3 months, the tacrolimus doses and concentration/dose ratios differed significantly in the three steroid dosage groups. With the higher doses, higher tacrolimus doses were needed to achieve the blood tacrolimus targeted trough level. We demonstrated that pharmacokinetic interaction occurs between steroids and tacrolimus in renal transplant patients. The higher the steroid dosage, the higher the dosage of tacrolimus needed to achieve target trough levels in these patients. The most likely interaction mechanism is specific enzymatic induction of CYP3A and/or P-gp. Interaction is present, even when the steroid dosage is low. The clinical events liable to occur during steroid sparing or tapering must be taken into account because it may be associated with episodes of tacrolimus-related nephrotoxicity.

Outcomes of African American kidney transplant recipients treated with sirolimus, tacrolimus, and corticosteroids.

African American kidney transplant recipients generally exhibit poor long-term graft survival compared with other ethnic groups. The combination of sirolimus, tacrolimus, and corticosteroids has proven to be effective in reducing rejection episodes in high-risk organ and islet cell transplant recipients but has not yet been tested in a large number of African American patients. The outcomes of 56 African American adult, primary kidney transplant recipients treated with corticosteroids, sirolimus, and tacrolimus targeted to relatively low trough blood levels were compared with those of a concurrent group of 65 white patients treated with steroids, mycophenolate mofetil, and tacrolimus targeted to relatively high blood levels. Induction antibody therapy was not routinely used in either group. The incidence of acute rejection in the first 3 posttransplantation months was 7.1% in African Americans and 16.9% in whites (P=NS). Actuarial 2-year patient, graft, and rejection-free graft survival rates were equivalent in the two groups. Posttransplantation diabetes mellitus occurred in 36% of the African American patients, despite similar doses of corticosteroids and lower trough levels of tacrolimus, compared with 15% of white patients (P=0.024). The combination of corticosteroids, sirolimus, and relatively low doses of tacrolimus results in acute rejection, graft survival, and patient survival rates equivalent to those achieved in white patients receiving steroids, mycophenolate mofetil, and relatively high doses of tacrolimus, even without the routine use of induction antibody therapy. Posttransplantation diabetes mellitus remains a problem for African Americans receiving this combination of immunosuppressants, despite relatively low tacrolimus blood levels.

Lymphoproliferation in children after liver transplantation.

Lymphoproliferation in children after liver transplantation.

Heart Transplantation in Neonates: Achievements, Controversies, and Challenges for the Future

After completing this article, readers should be able to: 1. Compare the results of pediatric heart transplantation with those of transplantation in adults, including the survival rates. 2. Compare and contrast the indications for pediatric heart transplant among those younger and older than 1 year of age. 3. List the common complications after pediatric heart transplantation. 4. Compare and contrast new immunosuppressive agents (tacrolimus, mycophenolate, humanized anti-Tac antibodies) and standard therapies (cyclosporine, azathioprine, prednisone, antithymocyte globulin). 5. Describe the controversy surrounding the proper management of infants who have hypoplastic left heart syndrome. Not long after the first successful human heart transplant was performed, the first neonatal heart transplant was attempted. In December of 1967, Kantrowitz and colleagues at Maimonides Hospital in New York transplanted the heart of an anencephalic infant into a 3-week-old who had tricuspid atresia. Although the recipient survived only 6.5 hours, the technical feasibility of cardiac transplantation in the pediatric patients was proven. Thirty-three years later, heart transplantation has gained widespread acceptance as a standard treatment modality for end-stage cardiomyopathy or noncorrectable congenital heart disease in infants and children. The 2 years following Barnard’s pioneering first transplant saw explosive growth in the field of adult heart transplantation, but poor 1-year survival dampened much of the initial enthusiasm and with it, any hope for bringing heart transplantation to the pediatric population. Most centers eventually abandoned the procedure, and many physicians denounced the concept. However, a few centers persisted, most notably Dr Norman Shumway and colleagues at Stanford, gradually improving survival through strong collaborations with basic immunologists and cardiac pathologists. By the mid-1970s, heart transplantation had been extended successfully to teenagers. The introduction of the “wonder drug” cyclosporine in 1980 so dramatically improved survival in adult cardiac transplant recipients that the extension of transplantation to even younger patients became feasible. Almost as important as …