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Ferraresso M, Turolo S, Belinghieri M, Tirelli AS, Grillo P, Groppali E, Edefonti A, Ghio L. The potential of steroids and xenobiotic receptor polymorphisms in forecasting cyclosporine pharmacokinetic variability in young kidney transplant recipients. Abstract: The steroids and xenobiotics receptor (SXR) up-regulates the expression and the synthesis of key enzymes in CyA metabolism. In this study, we examined the possible interactions between CyA exposure and SXR polymorphisms during the first year after renal transplantation. The study involved 66 pediatric renal transplant recipients (25 women and 41 men, mean age 13.9 ± 7.4 yr). All patients were genotyped for two sequence variations in the NR1I2 gene: g.-205_-200delGAGAAG and 7635 A>G. CyA trough levels and CyA weight-adjusted daily dose were recorded at 30, 90, 180, and 360 days after transplantation and compared between the different genotypes. A third newly discovered SXR polymorphism was characterized and also included in the study. CyA trough levels and CyA weight-adjusted daily dose were comparable on four time points throughout the first year post-transplant in all three groups. GEE showed a significant reduction in weight-adjusted CyA daily dose in patients carrying the deletion of 6 bp in SXR with a significant group-by-time effect that persisted also when analysis was corrected for age, prednisone dose, and acute rejection episodes. In our group of patients, only the g.-205_-200delGAGAAG SXR polymorphism was able to influence the metabolism of CyA continuously, during the first year after transplantation.

Belingheri M, Comoli P, Locatelli F, Baldanti F, Martina V, Giani M, Ferraresso M, Cro L, Edefonti A, Ghio L. Successful medical treatment of EBV smooth muscle tumor in a renal transplant recipient. Pediatr Transplantation 2010: 14:E101–E104. © 2009 John Wiley & Sons A/S. Abstract: EBV is associated with various malignancies in patients with acquired or induced immune impairment. EBV-SMT is very uncommon in immunocompromised patients, and a kidney localization has been described only anecdotally. We report the case of a 17-yr-old kidney transplant recipient diagnosed as having an EBV-SMT inside the renal graft, which was successfully managed by minimizing isolated immunosuppression.

CYP3A enzyme plays a pivotal role in TAC metabolism. The aim of this study was to analyze retrospectively the influence of CYP3A5 gene polymorphism on TAC pharmacokinetics and pharmacodynamics in 30 teenage kidney transplant recipients. TAC dose, trough blood levels, apparent volume of distribution, as well as blood pressure and antihypertensive therapy obtained at different post-transplant periods, were correlated with the corresponding genotype. Despite a therapeutic monitoring strategy, heterozygotes (CYP3A5*1/*3) displayed a lower TAC blood concentration compared with homozygotes (CYP3A5*3/*3). Therefore, a two-fold increase of the daily TAC dose was required in the heterozygotes to reach the desired therapeutic target level. A significant group by time interaction effect was present for both variables (repeated measures ANOVA: p = 0.002) meaning a significant different pharmacokinetic response in these two cohorts. Mean blood pressure was also elevated in CYP3A5*1/*3 recipients despite similar antihypertensive treatment. This was parallel with an elevated apparent volume of distribution of TAC in this group. Thus, the allele-effect was correlated with one of the most common TAC side-effects suggesting a possible influence of CYP3A5 polymorphism on TAC pharmacodynamics. The authors concluded that a pre-emptive CYP3A5 pharmacogenetic screening could contribute to better individualization of TAC therapy.

The steroids and xenobiotics receptor (SXR) up-regulates the expression and the synthesis of key enzymes in CyA metabolism. In this study, we examined the possible interactions between CyA exposure and SXR polymorphisms during the first year after renal transplantation. The study involved 66 pediatric renal transplant recipients (25 women and 41 men, mean age 13.9 ± 7.4 yr). All patients were genotyped for two sequence variations in the NR1I2 gene: g.-205_-200delGAGAAG and 7635 AG. CyA trough levels and CyA weight-adjusted daily dose were recorded at 30, 90, 180, and 360 days after transplantation and compared between the different genotypes. A third newly discovered SXR polymorphism was characterized and also included in the study. CyA trough levels and CyA weight-adjusted daily dose were comparable on four time points throughout the first year post-transplant in all three groups. GEE showed a significant reduction in weight-adjusted CyA daily dose in patients carrying the deletion of 6 bp in SXR with a significant group-by-time effect that persisted also when analysis was corrected for age, prednisone dose, and acute rejection episodes. In our group of patients, only the g.-205_-200delGAGAAG SXR polymorphism was able to influence the metabolism of CyA continuously, during the first year after transplantation.

EBV is associated with various malignancies in patients with acquired or induced immune impairment. EBV-SMT is very uncommon in immunocompromised patients, and a kidney localization has been described only anecdotally. We report the case of a 17-yr-old kidney transplant recipient diagnosed as having an EBV-SMT inside the renal graft, which was successfully managed by minimizing isolated immunosuppression.

The clinical management of cyclosporine has evolved greatly during the last decade thanks to the use of pharmacokinetic (PK) studies which confirmed the dose relationship between drug exposure and its biological effects. Therefore, cyclosporine PK monitoring during the early phase of the post-transplant period became essential to avoid over or underexposure to the drug thus preventing the risk of nephrotoxicity or acute rejection episodes. More recently, a simple PK determination based on cyclosporine blood concentration measured 2 h after the morning dose, has proven to be very effective for monitoring cyclosporine exposure in the early postoperative period. In this paper, the authors present a set of PK profiles obtained from a stable, long-term pediatric kidney transplant population and correlate these parameters with the risk of chronic rejection development. The study shows how cyclosporine monitoring based on the sole trough level determination misled a correct therapeutic behavior, as revealed by the PK parameters that were constantly below the therapeutic threshold in a small patient cohort who eventually developed chronic rejection. The C2 determination should be considered as the gold standard for cyclosporine monitoring in long-term pediatric recipients.

To evaluate the effect of recombinant human growth hormone (rhGH) treatment on the lipid profile of pediatric renal transplant patients, we studied nine children treated with rhGH for 1 yr and a control group of 12 untreated patients matched in terms of age, renal transplant function and post-transplant follow-up. The levels of lipoprotein (a [Lp(a)], cholesterol, triglycerides, apolipoprotein A (APO A) and apolipoprotein B (APO B), and the APO B/APO A ratio, were determined at baseline and after 6 and 12 months of follow-up. RhGH therapy had no effect on cholesterol, triglycerides or apolipoproteins. Mean serum Lp(a) levels increased from 6.7 +/- 5.7 mg/dL at baseline to 11.8 +/- 10.7 after 6 months (p = 0.018) and 13.6 +/- 15.1 after 12 months of rhGH treatment (p = 0.04), but did not change in the control group. Lp(a) is a risk factor for cardiovascular morbidity, and increased Lp(a) levels may be a side-effect of rhGH treatment in renal transplant patients. Although long-term follow-up of a large number of patients is needed to establish the duration and extent of the effects of rhGH treatment on Lp(a) levels in transplanted children, serum Lp(a) levels should be carefully monitored in those receiving rhGH therapy.

A considerable proportion of patients with renal transplant, evaluated many years after transplant, lack protective diphtheria antibody levels, despite primary immunization, but maintain immunity to tetanus. These patients respond to a diphtheria and tetanus booster but the duration of the response is uncertain. This study was undertaken to assess if protective antibodies evoked by primary immunization are lost quickly after transplantation, and whether the extent of the immune response to a booster influences the persistence of protective antibodies. We studied 15 patients (group 1) immediately after renal transplant and 35 patients with renal transplant for 6 +/- 4 yr who received a diphtheria and tetanus booster (group 2). Six patients (40%) of group 1 lost protective diphtheria antibodies a median time of 6.5 months after transplant. Thirty-three patients of group 2 responded to the booster with normal diphtheria antibody titers (> 1 IU/mL) in 22 cases and with low titers in 11. Four of the latter lacked immunity to diphtheria at 12 months follow-up. All patients with normal immunity maintained protective levels of diphtheria antibodies. The low responders had a creatinine clearance of 50 +/- 20 mL/min/1.73 m2. Tetanus immunity was maintained in almost all patients of both groups. In conclusion, renal transplant patients had an accelerated loss of diphtheria antibodies in the early post-transplant period. Response to a diphtheria booster identified a group at particular risk, namely the low responders, who may require frequent booster doses. This group had significantly poorer renal function than the normal responders.