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We report the management of a patient with the late onset of chronic graft-versus-host disease (GVHD) after orthotopic liver transplantation. GVHD is a rare complication of solid organ transplants that usually presents early after transplantation and is fatal in the majority of cases. Our patient differs from the typical patient with GVHD in that the onset of her disease was very late. Although most treatment to date consisted of an increase in immunosuppressive therapy, our patient showed an excellent response to a reduction. This resulted in the abatement of the symptoms of GVHD and the preservation of her allograft function.

Background: The major immunosuppressive effect of cyclosporine is through the inhibition of calcineurin, an enzyme important in the activation of T lymphocytes. In children, neither calcineurin activity nor its inhibition by cyclosporine (CsA) has been investigated., Methods: Calcineurin activity, was measured in stable pediatric renal transplant patients, with healthy children used as controls. Whole blood CsA concentrations were measured by monoclonal radioimmunoassay. Simultaneous calcineurin and CsA levels were measured before and 1, 2, 3.5, 5, and 12 hr after their routine morning CsA dose., Results: Calcineurin activity was approximately 50% inhibited at trough blood concentrations (148 microg/L); moreover, inhibition increased as CsA concentrations rose and declined as concentrations fell. Maximum calcineurin inhibition was about 70% at concentrations of about 431 microg/L. Linear regression analysis revealed a significant correlation between mean CsA blood concentration and the mean degree of inhibition of calcineurin activity (P=0.005, one-tailed)., Conclusion: We conclude that inhibition of calcineurin activity by CsA in pediatric renal transplant recipients correlates with CsA blood concentrations.

Background: A comparison of the oral bioavailability of cyclosporine from the original formulation (CsA) and from the new formulation, cyclosporine for microemulsion (CsA-ME), was made in pediatric maintenance liver transplant patients within two age groups (group 1, ages 1-5 years; group 2, ages 6-17 years) in an open-label, multicenter, randomized crossover trial. All patients were at least 6 months past transplantation and were receiving CsA maintenance therapy., Methods: In study period 1 (days 1 through 14), patients were administered either CsA or CsA-ME at the same b.i.d. dosage as their maintenance therapy. Upon entry into period 2 (days 15 through 28), patients were converted to the alternate formulation at a 1:1 mg dose ratio. On day 29, all patients returned to the CsA treatment administered at study entry, with follow-up on day 35. Dosage adjustments were not allowed with either CsA or CsA-ME. Twelve-hour pharmacokinetic profiling was performed at the end of periods 1 and 2., Results: Both the mean area under the concentration-versus-time curve and the mean maximum blood concentration of cyclosporine-both normalized for dose-were significantly increased: by 66% and 109%, respectively, in patients receiving CsA-ME compared with those receiving CsA in group 1 and by 39% and 75%, respectively, in group 2. During this study, liver function remained stable, and serum creatinine and blood pressure did not differ significantly between treatment groups., Conclusions: This study shows increased bioavailability in all patients converted to CsA-ME, with the greatest increase seen in patients with the lowest initial cyclosporine bioavailability. The tolerability was similar between the two formulations during this study.

Veno-occlusive disease (VOD) is the third leading cause of mortality after bone marrow transplant. Management consists of supportive care, with restricted fluids and diuretics. Most patients will recover, but approximately 25% may develop severe life threatening VOD with subsequent respiratory compromise and multiorgan failure. Orthotopic liver transplant has been attempted for a few patients with intractable VOD, but this approach is limited by availability of a cadaveric organ. We report a child who underwent a T-depleted unrelated donor bone marrow transplant for severe aplastic anemia as a manifestation of Schwachman-Diamond syndrome who developed severe VOD. She had evidence of engraftment when liver transplant was considered, and had no evidence of major organ dysfunction. The left lateral segment of her mother's liver was transplanted at day +33 following bone marrow transplantation. The child remains well ten months post-BMT and nine months after liver transplant. A related donor liver transplant may be a justifiable approach in a patient with severe VOD post-BMT.

In pediatric liver transplant recipients, oral cyclosporine (CsA) therapy may be complicated by impaired or delayed absorption during the initial weeks posttransplant. Neoral (NL) is a microemulsion preconcentrate formulation of CsA expected to increase the rate and extent of absorption of CsA and have less pharmacokinetic variability. The absolute bioavailability (F) of CsA from NL was compared with that of the currently marketed Sandimmune (SM) formulation in a double-blind, crossover study conducted in 9 pediatric liver transplant recipients (age 6 months to 11 years) between 8 and 20 days posttransplant. After determination of CsA pharmacokinetics for a steady-state intravenous dose, patients were randomized to receive a single oral dose of NL or SM in period I and the alternative formulation in period II. Clearance (Clt) and volume of distribution (Vss) values (mean +/- s.d.) calculated from the i.v. dose were similar to that previously reported for pediatric patients (Clt = 12.0 +/- 1.3 ml/min/kg; Vss = 2.2 +/- 0.2 L/kg). Mean F (+/- SD) for NL was significantly higher than SM (NL = 37.6 +/- 14.6%; SM = 24.7 +/- 8.0%; P = 0.05). Although not reaching statistical significance, the observed maximum blood concentration (Cmax) was higher, and the time to Cmax (Tmax) was shorter for NL in 8 or 9 patients. There were no significant correlations between age and any pharmacokinetic parameter for the group as a whole--however, there were statistically significant correlations between age and F for NL (r = 0.87; P = 0.02), and for age and Vss (r = 0.91; P = 0.01) for the 6 patients aged 2 years or less. In this pediatric liver transplant population, Neoral demonstrated improved absorption (% increase in F) compared to Sandimmune. In liver transplant recipients aged 2 years or less, absorption of Neoral may be a function of age and/or bowel length.

Children who survive liver transplantation (LT) suffer the adverse effects of life-long immunosuppression. In an attempt to minimize these effects, we have instituted a program of tapering immunosuppression, resulting in chronic monotherapy for children after LT. Seventy-three children ages 4 months to 19 years received LT between January 1987 and December 1992. Patient survival was 85% (62/73), with graft survival of 73%, at one year. Triple therapy with prednisone, cyclosporine, and azathioprine begun at transplant was tapered as follows: 1-2 mg/kg prednisone at discharge was reduced by .2 mg/kg every 2 months until a .2 mg/kg total was reached. Alternate-day steroids (.2 mg/kg) were begun at 1 year and discontinued at 1.5 years. AZA (1 mg/kg) was begun posttransplant and discontinued after any serious viral illness or by 1 year. Currently 37 survivors are > 18 months post-LT and were considered candidates for monotherapy. Monotherapy was attempted in 28 (76%), and 25 of these remain on monotherapy an average of 2 years later. All have normal liver function. After monotherapy and alternate-day steroids were achieved, 66% of children < 5th percentile for height at the time of transplant improved to greater than the 5th percentile. There were 3 (11%) patients who rejected while on monotherapy an average of 1.15 years after it was started. These patients had the following predisposing factors that decreased cyclosporine levels and led to rejection: common bile duct stricture, chronic and intermittent antibiotic administration for urinary tract infection, and noncompliance. In the 9 potential candidates not tapered to monotherapy, 6 have had recurrent acute or chronic rejection; 2 of these now receive FK506. We conclude that the majority of stable pediatric LT recipients may be safely tapered to chronic cyclosporine monotherapy. Increased growth is a major benefit of decreased steroid dosing in these children. Cyclosporine absorption and adequate levels are crucial for success of this approach.

Hilar drainage fluid of dog kidneys was analyzed as an approximation to renal extracellular fluid after preservation by flushing with chilled high K-low Na solution (Collins C4) followed by ice-cold storage for 24 and 48 hr in a bath of flushing medium. Compared with the medium, Na and Cl were increased to 30 mM/liter and K decreased slightly to 93 mM/liter. Glucose decreased, whereas lactate, lactic dehydrogenase, and creatine phosphokinase increased by significant amounts in both the drainage fluid and bath. The inulin space of the undrained kidney average 37% of wet weight. Calculated intracellular Na and Cl concentrations averaged 50 and 37 mM/kg cell water while K remained within normal limits. A significant fraction of red blood cells retained during initial flushing entered the effluent during storage. Bath and effluent composition of a human cadaver kidney approximated those of a dog.