The P450 oxidoreductase *28 SNP is associated with low initial tacrolimus exposure and increased dose requirements in CYP3A5-expressing renal recipients.

Aim: Recently a SNP of the gene encoding P450 oxidoreductase (POR*28; rs1057868C>T) has been associated with increased in vivo CYP3A activity using midazolam as a drug probe. Because tacrolimus is metabolized by CYP3A isoenzymes, this SNP might affect tacrolimus pharmacokinetics.

Materials & Methods: To test this hypothesis we performed a study in a cohort of 298 de novo renal allograft recipients stratified according to CYP3A5 genotype, which has a known impact on tacrolimus pharmacokinetics.

Expression of CYP3A5 and P-glycoprotein in renal allografts with histological signs of calcineurin inhibitor nephrotoxicity.

Background: Susceptibility to calcineurin inhibitor nephrotoxicity (CNIT) after solid organ transplantation could be related to an interindividual variability in renal expression and function of the metabolizing cytochrome P450 3A5 (CYP3A5) isoenzyme and of the multidrug efflux transporter P-glycoprotein (P-gp, ABCB1).

Methods: We compared renal expression of CYP3A5 and P-gp, measured by immunohistochemistry, in 32 renal allograft biopsies with de novo arteriolar hyalinosis as a sign of CNIT with a control group, consisting of normal protocol allograft biopsies (n=50) and protocol biopsies demonstrating alloimmune injury (n=21). In addition, we studied the association between renal expression and donor and recipient single-nucleotide polymorphisms CYP3A5 A6986G (rs776746), ABCB1 C3435T (rs1045642), and G2677T (rs2032582).

Replicative senescence in kidney aging, renal disease, and renal transplantation.

Cellular or replicative senescence is classically seen as the key element of aging. In renal disease and after kidney transplantation, there is increasing evidence that replicative senescence pathways (p53 and p16) play a central role in disease progression and graft outcome, independent of chronological age. In this review, we summarize the current concepts in the molecular mechanisms of cellular senescence, and correlate these theories with the available literature on aging of native kidneys, kidney diseases, and outcome of renal allografts.

A prospective, open-label, observational clinical cohort study of the association between delayed renal allograft function, tacrolimus exposure, and CYP3A5 genotype in adult recipients.

Background: Tacrolimus, a calcineurin inhibitor with a macrolide lactone structure, is currently used as a cornerstone immunosuppressive drug in solid organ transplantation. It is metabolized by hepatic and intestinal cytochrome P450 (CYP) 3A4/3A5 enzymes and is a substrate for P-glycoprotein (ABCB1). The disposition of tacrolimus might be influenced by severe renal allograft dysfunction (eg, in cases of delayed graft function [DGF]).

Harnessing the diversity of the human T-cell repertoire: a monitoring tool for transplantation tolerance?

There is significant diversity in the TCR repertoire in heterologous and allogeneic immunity. A paper in this issue of the European Journal of Immunology shows that changes in the TCR repertoire can be correlated with outcomes of renal transplantation. This indicates that the diversity of the TCR repertoire could be utilized to monitor clinical phenotypes, such as chronic humoral rejection and operational tolerance in organ transplantation.

Molecular diagnostics in transplantation.

The past few decades are characterized by an explosive evolution of genetics and molecular cell biology. Advances in chemistry and engineering have enabled increased data throughput, permitting the study of complete sets of molecules with increasing speed and accuracy using techniques such as genomics, transcriptomics, proteomics, and metabolomics. Prediction of long-term outcomes in transplantation is hampered by the absence of sufficiently robust biomarkers and a lack of adequate insight into the mechanisms of acute and chronic alloimmune injury and the adaptive mechanisms of immunological quiescence that may support transplantation tolerance.

Tacrolimus dose requirements and CYP3A5 genotype and the development of calcineurin inhibitor-associated nephrotoxicity in renal allograft recipients.

Objectives: Prolonged calcineurin inhibitor maintenance therapy in kidney allograft recipients is complicated by the development of chronic irreversible drug-induced nephrotoxicity (CNIT).

Methods: In 304 de novo renal graft recipients, the association among tacrolimus exposure indices (dose, C(0), AUC(0-12h)), CYP3A5, CYP3A4 and ABCB1 polymorphisms, clinical covariables and de novo arteriolar hyalinization as a histologic sign of CNIT was examined.

Results: Tacrolimus C(0) and AUC(0-12h) at 3 and 12 months posttransplantation did not differ between patients with and without CNIT.

Balancing efficacy and toxicity of kidney transplant immunosuppression.

Late renal allograft loss is mainly the result of progressive histological damage. Both underimmunosuppression (rejection phenomena) and overimmunosuppression (calcineurin inhibitor nephrotoxicity) contribute to the progression of chronic histological damage. The current study was performed to elucidate the complementary impact of immune and nonimmune phenomena on renal allograft histology and function.

Donor age and renal P-glycoprotein expression associate with chronic histological damage in renal allografts.

The contributions of donor kidney quality (partially determined by donor age), allograft rejection, and calcineurin inhibitor nephrotoxicity on the progression of histologic damage of renal allografts are not completely defined. Moreover, the determinants of individual susceptibility to calcineurin inhibitor nephrotoxicity are not known but may include variability in drug transport and metabolism. In a prospective cohort of 252 adult renal allograft recipients treated with a combination of tacrolimus, mycophenolate mofetil, and corticosteroids, we studied 744 renal allograft biopsies obtained regularly from time of transplantation for 3 yr.

Localization, etiology and impact of calcium phosphate deposits in renal allografts.

Hypercalcemia, hypophosphatemia and renal phosphate wasting are common after kidney transplantation. Animal data suggest that these alterations in mineral metabolism may contribute to calcium phosphate (CaPhos) deposition in the kidney and renal dysfunction. We tested the hypothesis that CaPhos deposition is highly prevalent in the early posttransplant period and is related to a disturbed mineral metabolism.

New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation.

Although therapeutic drug monitoring (TDM) of immunosuppressive drugs has been an integral part of routine clinical practice in solid organ transplantation for many years, ongoing research in the field of immunosuppressive drug metabolism, pharmacokinetics, pharmacogenetics, pharmacodynamics, and clinical TDM keeps yielding new insights that might have future clinical implications. In this review, the authors will highlight some of these new insights for the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus and the antimetabolite mycophenolic acid (MPA) and will discuss the possible consequences. For CNIs, important relevant lessons for TDM can be learned from the results of 2 recently published large CNI minimization trials.

Steroid-free immunosuppression since 1999: 129 pediatric renal transplants with sustained graft and patient benefits.

Despite early promising patient and graft outcomes with steroid-free (SF) immunosuppression in pediatric kidney transplant recipients, data on long-term safety and efficacy results are lacking. We present our single-center experience with 129 consecutive pediatric kidney transplant recipients on SF immunosuppression, with a mean follow-up of 5 years. Outcomes are compared against a matched cohort of 57 concurrent recipients treated with steroid-based (SB) immunosuppression.

Expression of complement components differs between kidney allografts from living and deceased donors.

A disparity remains between graft survival of renal allografts from deceased donors and from living donors. A better understanding of the molecular mechanisms that underlie this disparity may allow the development of targeted therapies to enhance graft survival. Here, we used microarrays to examine whole genome expression profiles using tissue from 53 human renal allograft protocol biopsies obtained both at implantation and after transplantation.

Standardizing resistive indices in healthy pediatric transplant recipients of adult-sized kidneys.

Small pediatric recipients of an adult-sized kidney have insufficient renal blood flow early after transplantation, with secondary chronic hypoperfusion and irreversible histological damage of the tubulo-interstitial compartment. It is unknown whether this is reflected by renal resistive indices. We measured renal graft resistive indices and volumes of 47 healthy pediatric kidney transplant recipients of an adult-sized kidney in a prospective study for six months post-transplant.

Calcium metabolism in the early posttransplantation period.

Background And Objectives: Information on the time course of serum calcium levels after renal transplantation is scanty, especially in the early posttransplantation period. Both the abrupt cessation of calcium-containing phosphorus binders and vitamin D (analogs) at the time of surgery and the recovery of renal function may be hypothesized to affect serum calcium levels in this period.

Design, Setting, Participants, & Measurements: In this prospective observational study, biointact parathyroid hormone, calcidiol, calcitriol, calcium, and phosphorus levels were monitored in 201 renal transplant recipients at the time of transplantation and 3 mo thereafter.

Identifying compartment-specific non-HLA targets after renal transplantation by integrating transcriptome and "antibodyome" measures.

We have conducted an integrative genomics analysis of serological responses to non-HLA targets after renal transplantation, with the aim of identifying the tissue specificity and types of immunogenic non-HLA antigenic targets after transplantation. Posttransplant antibody responses were measured by paired comparative analysis of pretransplant and posttransplant serum samples from 18 pediatric renal transplant recipients, measured against 5,056 unique protein targets on the ProtoArray platform. The specificity of antibody responses were measured against gene expression levels specific to the kidney, and 2 other randomly selected organs (heart and pancreas), by integrated genomics, employing the mapping of transcription and ProtoArray platform measures, using AILUN.

Calcineurin inhibitor nephrotoxicity.

The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis.

Recovery of hyperphosphatoninism and renal phosphorus wasting one year after successful renal transplantation.

Background And Objectives: In the first months after successful kidney transplantation, hypophosphatemia and renal phosphorus wasting are common and related to inappropriately high parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) levels. Little is known about the long-term natural history of renal phosphorus homeostasis in renal transplant recipients.

Design, Setting, Participants: We prospectively followed parameters of mineral metabolism (including full-length PTH and FGF-23) in 50 renal transplant recipients at the time of transplantation (Tx), at month 3 (M3) and at month 12 (M12).

Effects of CYP3A5 and MDR1 single nucleotide polymorphisms on drug interactions between tacrolimus and fluconazole in renal allograft recipients.

Objective: Drug interactions between tacrolimus and azole antifungals are characterized by a large clinical variability. The aim of this study was to examine the influence of the CYP3A4, CYP3A5, and MDR1 single nucleotide polymorphisms on changes in tacrolimus exposure and dosing in renal allograft recipients treated with fluconazole.

Methods: Twenty-nine patients who had received documented fluconazole treatment were identified out of a total of 753 renal recipients on maintenance tacrolimus therapy.

Current target ranges of mycophenolic acid exposure and drug-related adverse events: a 5-year, open-label, prospective, clinical follow-up study in renal allograft recipients.

Background: Two recent randomized clinical trials--Fixed Dose Versus Concentration Controlled and the Apomygre--evaluating the benefit of therapeutic drug monitoring of mycophenolate mofetil (MMF) in renal allograft recipients reported conflicting results. In both studies, target mycophenolic acid (MPA) AUC(0-12 h) ranges (ie, values used to guide MMF dosing) were derived from a previous study establishing target MPA AUC(0-12 h) ranges in cyclosporine-treated patients between 30 and 60 mg/L x h(-1). Both studies found an association between MPA exposure and acute rejection.

Maturation of dose-corrected tacrolimus predose trough levels in pediatric kidney allograft recipients.

Background: In contrast to adult kidney recipients, in whom the long-term evolution and clinical determinants of tacrolimus pharmacokinetics are well studied, less is known about the long-term evolution of tacrolimus pharmacokinetics in pediatric kidney transplant recipients.

Methods: One-hundred and five pediatric recipients of a kidney allograft, all treated with a corticosteroid-free immunosuppressive protocol, were included. The evolution of tacrolimus doses and predose trough (C0) levels was recorded at 3, 6, 9, 12, 18, and 24 months after transplantation, as well as all C0 levels obtained in the first 2 years after transplantation.