Jacques Lemire

Immunomodulatory actions of 1,25-Dihydroxyvitamin D3

The sterol, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has immunosuppressive activity. The hormone inhibits the production of lymphokines (IL-2, IFN-gamma) and monocyte-derived cytokine (IL-12) leading to inhibition of helper T cell subset type 1 (Th1). When given in vivo, the hormone prevents the development of spontaneous and induced models of autoimmunity. Analogs of 1,25(OH)2D3, with reduced hypercalcemic effects, display an enhanced activity in autoimmunity compared to the sterol and prolong graft survival in experimental transplantation. This paper reviews our understanding of the cellular actions of the hormone and the therapeutic application of 1,25(OH)2D3 and analogs in autoimmunity and transplantation.

1,25-Dihydroxyvitamin D3--a hormone with immunomodulatory properties.

Summary The active vitamin D metabolite, 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], exerts immunosuppressive activity. At a cellular and molecular level, the hormone preferentially targets helper T cell activity (Th1) by inhibiting the secretion of both IL-2 and IFN-γ by Th1 and by suppressing the secretion pro-Th1 cytokine IL-12 by antigen-presenting cells. The active metabolite further inhibits class II antigen expression and enhances suppressor cell activity.In animal models of autoimmunity, 1,25-(OH)2D3 prevents the development of experimental autoimmune encephalomyelitis, reduces the incidence of diabetes, and attenuates murine lupus. The hormone also prolongs graft survival in animal models of transplantation.In humans, non-classical use of 1,25-(OH)2D3 has led to an anti-proliferative effect in psoriasis, anti-neoplastic effect in prostate cancer, and immunomodulatory effect in scleroderma. The development of less hypercalcemic analogs might open a new therapeutic area for vitamin D3.

Everolimus in pediatric de nova renal transplant patients1

Background. The steady-state pharmacokinetics of everolimus were longitudinally assessed in pediatric de novo kidney allograft recipients during a 6-month period. Methods. Nineteen patients received everolimus 0.8 mg/m2 (maximum 1.5 mg) twice daily as a dispersible tablet in water in addition to cyclosporine and corticosteroids. Everolimus and cyclosporine trough concentrations were obtained on days 3, 5, 6, and 7 and at months 1, 2, 3, and 6; an everolimus pharmacokinetic profile was obtained on day 7 and month 3. Results. There were 9 boys and 10 girls with a median age of 9.9 (range, 1–16) years. Steady-state pharmacokinetic parameters were as follows (median, range): Cmin (trough level), 4.7 (2.3- 9.5) ng/mL; peak concentration, 13.5 (5.9–22.2) ng/mL; area under the concentration-time curve (AUC), 77 (53–147) ng·hr/mL; and apparent oral clearance, 10.2 (5.5–15.6) L/hr/m2. Clearance (unadjusted for demographic factors) was positively correlated with age (r =0.66), body surface area (r =0.68), and weight (r =0.67). There were no trends in Cmin or AUC versus patient age when everolimus was dosed on a mg/m2 basis. Everolimus Cmin were stable over time with median values of 3.9, 3.4, and 3.1 ng/mL at months 1, 3, and 6, respectively. Intra- and interpatient variability in AUC was 29% and 35%, similar to that in adults. During the observation period, eight patients maintained stable AUCs and nine patients had increases or decreases, generally between 30% and 50% compared with the AUC at week 1. The concurrent median cyclosporine Cmin were generally at the lower end of conventional target ranges: 156, 83, and 69 ng/mL at months 1, 3, and 6, respectively. There were no graft losses and only three mild or moderate, reversible rejection episodes occurred. Everolimus was generally safe and well tolerated. Conclusions. These data support the use of body surface area-adjusted dosing for everolimus in pediatric patients. Although exposure is generally stable over time with moderate variability in AUC, therapeutic monitoring would be a helpful adjunct for individualizing everolimus exposure, assessing regimen adherence, and adjusting doses as the child matures.

A rational dosing algorithm for basiliximab (Simulect) in pediatric renal transplantation based on pharmacokinetic-dynamic evaluations.

Background. The pharmacokinetics and immunodynamics of basiliximab were assessed in 39 pediatric de novo kidney allograft recipients to rationally chose a dose regimen for this age group. Methods. In study part 1, patients were given 12 mg/m2 of basiliximab by bolus intravenous injection before surgery and on day 4. An interim pharmacokinetic evaluation supported a fixed-dose approach for study part 2 in which infants and children received two 10-mg doses and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for analysis of basiliximab and soluble interleukin-2 receptor concentrations, flow cytometry, and screening for anti-idiotype antibodies. Results. Basiliximab clearance in infants and children (n=25) was reduced by approximately half compared with adults from a previous study and was independent of age (1–11 years), weight (9–37 kg), and body surface area (0.44–1.20 m2). Clearance in adolescents (12–16 years, n=14) approached or reached adult values. CD25-saturating basiliximab concentrations were maintained for 31±12 days in study part 1 with mg/m2 dosing and for 36±14 days in study part 2 based on the fixed-dose regimen (P =0.31). A single patient experienced a rejection episode during CD25 saturation. The duration of CD25 saturation in patients who experienced a rejection episode after desaturation did not differ from those who remained rejection-free for the full 6-month period: 34±6 days (n=6) vs. 35±14 days (n=33 patients);P =0.74. Anti-idiotype antibodies were detected in two patients; however, this did not influence the clearance of basiliximab or the duration of CD25 saturation. Conclusions. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients <35 kg should receive two 10-mg doses and those ≥35 kg should receive two 20-mg doses of basiliximab by intravenous infusion or bolus injection. The first dose is given before surgery and the second on day 4 after transplantation.

A multicenter, open-label, pharmacokinetic/pharmacodynamic safety, and tolerability study of basiliximab (simulect) in pediatric de novo renal transplant recipients

Background. Basiliximab (Simulect) has been shown to be safe and effective in adult renal transplant recipients, when used in combination with cyclosporine (Neoral) and corticosteroids. We report on the safety and preliminary efficacy of basiliximab in pediatric de novo renal transplant recipients. Methods. This was an open-label, 12-month study of basiliximab in 41 patients (2 cohorts: <9 and 9 to <16 years). In phase 1, two intravenous (IV) bolus injections of basiliximab (12 mg/m2) were administered (before and 4 days postsurgery). In phase 2, two injections (<40 kg, 10 mg and ≥40 kg, 20 mg) were administered at the same time points. Most patients (26/41 [63%]) received cadaveric kidneys. Almost half of the patients had three human leukocyte antigen mismatches with the organ donors. Concurrent immunosuppression included Neoral and corticosteroids. Azathioprine was allowed after 28 days. Results. All patients completed the 1-year study. The acute tolerability of basiliximab via IV bolus injection was good, without evidence of cytokine-release syndrome or acute local reactions. All patients experienced adverse events, but most (71%) were mild or asymptomatic. No deaths or malignancies occurred. The incidence and types of serious adverse events (59%) and serious infections (44%) were as expected in this patient population, and few were drug-related (7% and 5%, respectively). Thirty-eight patients (93%) had infections, mostly urinary tract infections, as expected for renal transplant patients. Six patients (15%) had drug-related adverse events. Biopsy-confirmed acute rejection episodes occurred in 6/41 (15%) of patients during the first 6 months posttransplantation and in 9/41 (22%) patients during the first 12 months. Five patients (12%) experienced graft loss, none of which were preceded by acute rejection episodes. Conclusions. Basiliximab is safe and well tolerated when administered by IV bolus injection in de novo pediatric renal transplant recipients. These preliminary data suggest that basiliximab, given in combination with cyclosporine and corticosteroids, is an effective immunosuppressive regimen for the prevention of acute rejection in pediatric renal transplantation.

Single-dose pharmacokinetics and tolerability of everolimus in stable pediatric renal transplant patients

Abstract: Everolimus (Certican; RAD), a novel macrolide with potent immunosuppressive and anti‐proliferative activities, prevents acute rejection in adult recipients of renal transplantation. This phase I trial conducted in stable pediatric renal transplant patients examined the single‐dose pharmacokinetics, safety, and tolerability of everolimus in combination with cyclosporin A (CsA; Neoral®) and corticosteroids, with or without azathioprine. Nineteen pediatric patients were enrolled and received a single 1.2 mg/m2 dose of everolimus. Everolimus was safe and well tolerated, with a low incidence of adverse events reported and none judged to be related to the study medication. Everolimus administration did not increase infection rates or produce clinically significant changes in vital signs or changes in electrocardiograms. Apparent clearance and volume of distribution of everolimus increased with age, weight, and body surface area in a generally linear manner across the pediatric demographic ranges. Compared with adults from a previous study, apparent clearance (L/h) and distribution volume (L) were lower in pediatric patients, whereas the elimination half‐life was similar. Single‐dose everolimus co‐administration did not affect the steady‐state pharmacokinetics of CsA. Based on this information, pediatric patients will need a dose scaled down for body size, but can probably maintain the same twice‐daily dosing schedule used in adults.

Transjugular intrahepatic portosystemic shunt prior to renal transplantation in a child with autosomal‐recessive polycystic kidney disease and portal hypertension: A case report

Abstract: Autosomal‐recessive polycystic kidney disease (ARPKD) can cause renal failure and portal hypertension in children. Portal hypertension may complicate the course of renal transplantation (Tx). We report the successful outcome of a patient with end‐stage renal disease (ESRD) and portal hypertension treated with transjugular intrahepatic portosystemic shunt (TIPS), a minimally invasive endovascular technique of portosystemic shunt, prior to renal Tx.

Neoral pharmacokinetics in Latino and Caucasian pediatric renal transplant recipients

Abstract Interpopulation variability of drug pharmacokinetics (PK) has been described. For example, the systemic clearance of nifedipine is higher in Mexicans than Caucasians. African-Americans have a lower cyclosporine bioavailability than Caucasians. Limited data are available in the Latino population. Under identical conditions, we compared the PK profile of Neoral (cyclosporine for microemulsion) obtained in stable pediatric renal transplant recipients of Latino and Caucasian origin. A slightly lower area under the curve (AUC) when corrected for dose per body surface area or per kilogram of body weight was observed in Caucasians compared with Latinos. This difference was more pronounced in the younger age group (<12 years) with a higher peak-to-trough ratio. However, the Caucasians required a higher dosage of Neoral than the Latinos to achieve that same AUC. There was no difference between the groups in the time (tmax) to reach maximal concentration (Cmax) of Neoral. A higher apparent clearance of the drug was observed in the Caucasians compared with the Latinos, especially in the younger age group. No differences in pre- and post-dose levels were observed between the two groups. These differences might affect dose adjustment between the two subpopulations.

Nonsteroidal anti-inflammatory drug use in adolescence

Nonsteroidal anti-inflammatory drugs (NSAIDs) have been recently released as over-the-counter drugs making them more widely available to the general public. We present five cases of adolescents with complications, including acute and chronic renal failure, related to the use of NSAIDs. Risk factors for NSAID nephrotoxicity include chronic illness, dehydration, ethanol and use of other medications. Adolescents should be educated about the risks and prevention of NSAID toxicity.

Pulmonary hemorrhage in children with glomerulonephritis.

Pulmonary hemorrhage may occur in patients with immune-mediated glomerulonephritis. This association can be seen in a variety of disorders including systemic lupus erythematosus, vasculitis, Wegeners granulomatosis, anaphylactoid purpura and Goodpastures syndrome. Immune mechanisms, such as immune complexes and/or autoantibodies, play a role in the pathogenesis of pulmonary and glomerular injury. Acute pulmonary hemorrhage can lead to respiratory failure and has a high mortality. Therapy with immunosuppressive agents such as pulse methylprednisolone and cyclophosphamide will control the hemorrhage and improve pulmonary function in most cases.