Robert B. Ettenger

Improved cadaveric renal transplant outcome in children

We analyzed the results of 165 pediatric cadaver renal transplants performed at the University of California at Los Angeles to identify the factors which are linked to improved allograft survival. Both univariate life-table analysis and the Cox proportional hazard model were used. The use of a sequential immunosuppressive regimen (P<0.001) and kidneys from of more than 6 years of age (P<0.001) were found to be the factors having the most influence on primary graft survival. The sequential regimen was the only factor favorably influencing retransplants. With sequential therapy 1- and 2-year actuarial graft survival rates were 94% and 91% in primary transplants, and 82% and 70% in retransplants. Medication noncompliance exerted a large negative effect on transplant outcome. Of 70 recipients who had been on cyclosporine for at least 6 months, 50% evidenced noncompliance. Sixty-four percent of adolescents were noncompliant. Thirteen percent of the recipients lost their graft because of noncompliance. We conclude that good results can be obtained with cadaver renal transplants in children with a sequential immunosuppressive regimen and the use of kidneys from adolescent and adult donors. Noncompliance is a great barrier to long-term success in pediatric transplantation.

Medication non-adherence in the adolescent renal transplant recipient: A clinician's viewpoint*

Abstract:  Recent advancements in immunosuppression and surgical techniques have significantly improved the outcome of kidney transplantation in the pediatric population. Adolescents enjoy the best 1‐year graft survival of any age group. However, the long‐term transplant outcome in adolescents is disappointing. Non‐adherence with immunosuppressive medications is one of the most important contributing factors for graft rejection and loss in teenagers. The impact of non‐adherence is perceived to be far more powerful in adolescent transplant recipients than in the transplant population as a whole. To better understand adolescent non‐adherence, the process of transplantation must be placed in the context of adolescent development. Adolescents try to establish their identity and autonomy separately from the parents; however at the same time, adolescents with chronic illness require help, support and guidance from adults, including parents and medical personnel. Adolescents have limited ability to anticipate abstractly the long‐term consequences of their immediate actions. This inconsistency can create frustration in both adolescents and in the supporting systems around them. Despite the significant consequences of adolescent non‐adherence, research in this area is scarce. There are still no established definitions, standardized diagnostic methods and effective interventions to treat and prevent this problem. We propose the recommendations to approach the problems of adolescent transplant non‐adherence from the transplant clinicians viewpoint. With early identification and appropriate interventions, significant improvement in adolescent graft survival is possible.

Therapeutic monitoring of mycophenolic acid: A consensus panel report

Biochem 1998;5:317–22. 4. Oellerich M, Shipkova M, Schütz E, Weber L, Tönshoff B, Armstrong VW, et al. Pharmacokinetic and metabolic investigations of mycophenolic acid in pediatric patients after renal transplantation: implications for therapeutic drug monitoring. Ther Drug Monit 2000;22:20–6. 5. Pescovitz MD, Conti D, Dunn J, Gonwa T, Halloran P, Sollinger H, et al. Intravenous mycophenolate mofetil: safety, tolerability, and pharmacokinetics. Clin Transplant 2000:14;179–88. 6. Tsina I, Kaloostian M, Lee R, Tarnowski T, Wong B. High-performance liquid chromatographic method for the determination of mycophenolate mofetil in human plasma. J Chromatogr B 1996;681:347–53. 7. McBride JH, Kim S, Reyes A, Rodgerson DO. Measurement of plasma mycophenolic acid in pediatric renal transplant recipients. Clin Chem 1998;44(Suppl 6):A93. 8. Shipkova M, Niedmann PD, Armstrong VW, Schütz E, Wieland E, Oellerich M. Simultaneous determination of mycophenolic acid and its glucuronide in human plasma using a simple high-performance liquid chromatographic procedure. Clin Chem 1998;44:1481–8. 9. Shipkova M, Schütz E, Armstrong VW, Niedmann PD, Oellerich M, Wieland, E. Determination of the acyl glucuronide metabolite of mycophenolic acid in human plasma by HPLC and Emit. Clin Chem 2000;46:365–72. 10. Stamm D. A new concept for quality control of clinical laboratory investigations in the light of clinical requirements and based on reference method values. J Clin Chem Clin Biochem 1982;20:817–24. 11. Hyneck ML, Munafo A, Benet LZ. Effect of pH on acyl migration and hydrolysis of tolmetin glucuronide. Drug Metab Dispos 1988;16:322–4.

Gene Transfer-Induced Local Heme Oxygenase-1 Overexpression Protects Rat Kidney Transplants From Ischemia/Reperfusion Injury

Heme oxygenase-1 (HO-1) overexpression using gene transfer protects rat livers against ischemia/reperfusion (I/R) injury. This study evaluates the effects of Ad-HO-1 gene transfer in a rat renal isograft model. Donor LEW kidneys were perfused with Ad-HO-1, Ad-beta-gal, or PBS, stored at 4 degrees C for 24 h, and transplanted orthotopically into LEW recipients, followed by contralateral native nephrectomy. Serum creatinine, urine protein/creatinine ratios, severity of histologic changes, HO-1 mRNA/protein expression, and HO enzymatic activity were analyzed. Ad-HO-1 gene transfer conferred a survival advantage when compared with PBS- and Ad-beta-gal-treated controls, with median survival of 100, 7, and 7 d, respectively (P < 0.01). Serum creatinine levels were elevated at day 7 in all groups (range, 2.2 to 5.8 mg/dl) but recovered to 1.0 mg/dl by day 14 (P < 0.01) in Ad-HO-1 group, which was sustained thereafter. Urine protein/creatinine ratio at day 7 was elevated in both PBS and Ad-beta-gal, as compared with the Ad-HO-1 group (12.0 and 9.8 versus 5.0; P < 0.005); histologically, ATN and glomerulosclerosis was more severe in Ad-beta-gal group at all time points. Reverse transcriptase-PCR-based HO-1 gene expression was significantly increased before reperfusion (P < 0.001) and remained increased in the Ad-HO-1-treated group for 3 d after transplantation. Concomitantly, HO enzymatic activity was increased at transplantation and at 3 d posttransplant in the Ad-HO-1 group, compared with Ad-beta-gal controls (P < 0.05); tubular HO-1 expression was discernible early posttransplant in the Ad-HO-1 group alone. These findings are consistent with protective effects of HO-1 overexpression using a gene transfer approach against severe renal I/R injury, with reduced mortality and attenuation of tissue injury.

Plasma exchange for recurrent nephrotic syndrome following renal transplantation.

Patients with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis (FGS) who develop end-stage renal disease are at risk for recurrence of the disease following renal transplantation. Recurrence of the nephrotic syndrome in renal allografts of two children with primary FGS was successfully controlled by plasma exchange. This report suggests that plasma exchange instituted early in the course of recurrent nephrotic syndrome may be beneficial in some patients with steroid-resistant nephrotic syndrome and FGS.

The pediatric nephrologist's dilemma: growth after renal transplantation and its interaction with age as a possible immunologic variable.

Two important criteria for successful end-stage renal disease therapy in children are achievement of optimal growth and possession of a well-functioning renal transplant. We describe eight children with accelerated post-transplant growth. Accelerated and even catch-up growth was achievable if the transplant occurred at an early age (less than 9 years), the daily dose of prednisone was low (less than or equal to 0.24 mg/kg/d), and renal function was excellent (creatinine clearance greater than or equal to 89 mL/min/1.73 m2). However, the benefit to growth of transplanting a kidney in young children may be offset by reduced cadaver graft survival in children younger than 6 years. To study whether the less favorable graft survival was attributable to an increased immunologic responsiveness in the younger child, we examined three tests of nonspecific immune responsiveness, each of which, when increased, may indicate a propensity toward rejection: total T cell absolute number, T helper/suppressor ratio, and spontaneous blastogenesis. Each measurement was significantly increased in 20 uremic children 5 years old or younger, compared with 81 children 6 to 23 years of age. These data suggest that improved growth may be attained by transplanting a kidney in the young child with end-stage renal disease, but the young child may be at increased risk for rejection. This hypothesis suggests that for optimal rehabilitation, strategies should take into account the unique needs of the young child.

A Peripheral Blood Diagnostic Test for Acute Rejection in Renal Transplantation

Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross‐validated by QPCR in the NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q‐PCR analysis of a five gene‐set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training‐set (n = 47) and validated on independent test‐set (n = 198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non‐AR phenotypes with 91% sensitivity and 90% specificity. The 5‐gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.

The use of mycophenolate mofetil suspension in pediatric renal allograft recipients.

Abstract. Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m2 b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m2 b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC0–12) of 27.2 µg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m2 b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients.

Valganciclovir dosing according to body surface area and renal function in pediatric solid organ transplant recipients.

Oral valganciclovir is effective prophylaxis for cytomegalovirus (CMV) disease in adults receiving solid organ transplantation (SOT). However, data in pediatrics are limited. This study evaluated the pharmacokinetics and safety of valganciclovir oral solution or tablets in 63 pediatric SOT recipients at risk of CMV disease, including 17 recipients ≤2 years old. Patients received up to 100 days’ valganciclovir prophylaxis; dosage was calculated using the algorithm: dose (mg) = 7 × body surface area × creatinine clearance (Schwartz method; CrCLS). Ganciclovir pharmacokinetics were described using a population pharmacokinetic approach. Safety endpoints were measured up to week 26. Mean estimated ganciclovir exposures showed no clear relationship to either body size or renal function, indicating that the dosing algorithm adequately accounted for both these variables. Mean ganciclovir exposures, across age groups and organ recipient groups were: kidney 51.8 ± 11.9 μg * h/mL; liver 61.7 ± 29.5 μg * h/mL; heart 58.0 ± 21.8 μg * h/mL. Treatment was well tolerated, with a safety profile similar to that in adults. Seven serious treatment‐related adverse events (AEs) occurred in five patients. Two patients had CMV viremia during treatment but none experienced CMV disease. In conclusion, a valganciclovir‐dosing algorithm that adjusted for body surface area and renal function provides ganciclovir exposures similar to those established as safe and effective in adults

Recombinant human growth hormone treatment of children following renal transplantation

Nine growth-retarded renal allograft recipients received either thrice weekly or daily subcutaneous recombinant human growth hormone (rhGH) for 6–30 months. The annualized growth velocity for the initial year of rhGH treatment was significantly greater than that of the preceding year (2.5±2.1 vs 5.7±2.7;P<0.0001). There was no advancement in bone age greater than the increase in chronological age, no significant increase in the mean fasting serum glucose or insulin levels, nor significant decrease in the calculated creatinine clearance following rhGH treatment. However, two patients experienced rejection episodes following rhGH treatment indicating the potiental adverse consequences of the treatment on allograft function. This will require further delineation in prospective controlled studies. The serum insulin-like growth factor-1 levels significantly increased at 6 months (P<0.009) and 12 months (P<0.002) following rhGH treatment compared with baseline values. These preliminary data indicate that rhGH treatment may be effective in improving the growth velocity of growth-retarded renal allograft recipients.