Sharon M. Bartosh

Adolescent Transition to Adult Care in Solid Organ Transplantation: A consensus conference report

Transition of care from pediatric to adult‐oriented health care providers is difficult for children with special health care needs. Children who have received solid organ transplants and their providers experience the same difficulties and frustrations as children with other major illnesses. A consensus conference was organized by several transplant organizations to identify major issues in this area and recommend possible approaches to easing the process of transition for solid organ transplant recipients. This report summarizes the discussions and recommendations.

Changing trends in pediatric transplantation: 2001 Annual Report of the North American Pediatric Renal Transplant Cooperative Study

Abstract:  The North American Pediatric Renal Transplant Cooperative Study has collected clinical information on children undergoing a renal transplantation since 1987. This cooperative group now includes over 150 participating medical centers in the United States, Canada, Mexico, and Costa Rica. This report covers the years from 1987 through 2001 and includes data on 7545 renal transplants in 6878 patients. This report demonstrates changing trends in many areas of pediatric transplantation including increasing numbers of African American and Hispanic children receiving transplantation, remarkable improvements in the rate of acute rejection, rejection reversal, and short‐ and long‐term allograft survival. In the most recent cohorts of patients, we now see that 1‐yr allograft survival is no different in cadaver donor compared to living donor recipients and in infants compared to all other age groups. However, this analysis also reveals areas of continued challenges including inferior outcomes in African American and adolescent populations, chronic rejection, and the adverse effects of immunosuppression.

Recurrence of Membranoproliferative Glomerulonephritis Type II in Renal Allografts: The North American Pediatric Renal Transplant Cooperative Study Experience

Membranoproliferative glomerulonephritis type II (MPGN II) is an uncommon form of complement-dependent acquired renal disease. Although it has been recognized since the 1970s that MPGN II recurs almost universally in renal transplants, data regarding the long-term consequences of disease recurrence are limited. Therefore, a retrospective comparative analysis of 75 patients with MPGN II contained in the North American Pediatric Renal Transplant Cooperative Study transplantation database was performed. Five-year graft survival for patients with MPGN II was significantly worse (50.0 +/- 7.5%) compared with the database as a whole (74.3 +/- 0.6%; P < 0.001). Living related donor organs had a significantly better 5-yr survival (65.9 +/- 10.7%) compared with cadaveric donor organs (34.1 +/- 9.8%; P = 0.004). The primary cause of graft failure in 11 (14.7%) patients was recurrent disease. Supplemental surveys were obtained on 29 (38%) of 75 patients. Analysis of these data indicated that recurrent disease occurred in 12 (67%) of the 18 patients with posttransplantation biopsies. Although there was no correlation between pretransplantation presentation, pre- or posttransplantation C3 levels, and either disease recurrence or graft failure, there was a strong association between heavy proteinuria and disease recurrence. The presence of glomerular crescents in allograft biopsies had a significant negative correlation with graft survival. At last follow-up, patients with recurrent disease had significantly higher serum creatinine and qualitatively more proteinuria than patients without biopsy-proven disease. These data indicate that recurrent MPGN II has a significant negative impact on renal allograft function and survival.

Long-term outcomes in pediatric renal transplant recipients who survive into adulthood.

Background. Long-term results in renal transplant recipients who underwent transplantation as children are often buried within the outcomes of adult centers, leaving a void in our knowledge regarding this unique cohort. The authors aim to describe the long-term outcomes of children who experienced renal failure and subsequently underwent transplantation during childhood and who have now reached adulthood, with an emphasis on social and economic rehabilitation. Methods. Two hundred seventeen children were identified who underwent transplantation between 1967 and 1999. Of those 217, 174 who were born before October 1982 and who would therefore have reached adulthood were selected for study. A questionnaire and consent form were sent to the surviving 132 patients of this subpopulation. Results. Fifty-seven adult survivors answered the questionnaire. No significant differences were found comparing the respondents to the nonrespondents. Nearly half of all respondents were severely short and 27% were obese. Questionnaire respondents had high rates of hypertension, bone and joint symptoms, fractures, hypercholesterolemia, and cataracts. Despite significant remaining health issues, 82% of respondents were employed, 95% reported their health as “fair” or “good,” 61% reported “no” or “minor” physical limitations, and 82% described themselves as “just as” or “more content than others.” Nearly 50% of the respondents were married, and the overwhelming majority reported satisfaction in their sexual lives. Conclusions. Despite a high retransplantation rate and the presence of significant morbidity, renal transplantation in children can lead to attainment of a productive and satisfying life, with a high degree of rehabilitation in adulthood.

Campath‐1H Use in Pediatric Renal Transplantation

Campath‐1H is a humanized, monoclonal antibody directed against CD52 determinants on the surface of human B‐ and T‐cells and monocytes. Reports of Campath‐1H use as induction in adult renal transplantation have been encouraging with low rejection rates and minimal adverse events. We report four high risk pediatric kidney transplant patients who received Campath‐1H for unique indications with variable results. Children ranged in age from 20 months to 16 years. Immunosuppression regimens varied. Three of four patients experienced acute rejection, two of which were C4d positive. Serial flow cytometry was performed on all four patients. The patient who received only Campath‐1H has an absolute lymphocyte count that remains less than 50% of baseline at 12‐months post‐transplant. In addition, in this patient CD3, CD4, CD8 and CD20 remain less than 50% of baseline. From this initial experience using Campath‐1H in pediatric renal transplantation we conclude that; (1) the use of Campath‐1H does not prevent recurrence of FSGS, (2) as seen in adults, lack of calcineurin inhibition when using Campath‐1H may increase the risk of antibody‐mediated rejection and (3) prolonged lymphocyte depletion remains even after a single dose of Campath‐1H in children.

Linear growth after pediatric liver transplantation

To determine growth patterns in a large cohort of unselected children undergoing liver transplantation, the outcomes of 294 orthotopic liver transplantations performed in 221 children at The University of Chicago between October 1984 and October 1992 were retrospectively reviewed; 66% were alive at the time of this analysis. The mean age at transplantation was 4.1 +/- 5.0 years; 44% of the children were male and 16% of the transplants were from living-related donors. The mean height z score at the time of transplantation was -1.6 +/- 1.8, and 39% of children had height z scores of < -2.0 at transplantation. When children with growth retardation at the time of transplantation (height z scores of < -2. 0) were compared with children with more normal growth, there were no significant differences in gender or re-transplantation rates, although children with growth retardation at transplantation were significantly younger than those with more appropriate growth (2.8 +/- 4.1 years vs 4.7 +/- 5.1 years, P <.05). The height z score of all children with biliary atresia at the time of transplantation was -1.9 +/- 1.7 compared with -1.2 +/- 2.0 in those children with underlying diseases other than biliary atresia. Catch-up growth was seen in 37% to 47% of children at any given time point after transplantation. Children with evidence of catch-up growth (growth velocity z score >0) 2 years after transplantation were more likely to be first-time transplant recipients, had more growth retardation at the time of transplantation, and were receiving lower doses of prednisone at 2 years after transplantation. Younger children were most likely to demonstrate catch-up growth after transplantation. In summary, a large proportion of children have growth retardation at the time of liver transplantation. This growth retardation is inversely correlated with age. Before transplantation, children with biliary atresia grow less well than children with other forms of liver disease. Up to one half of children demonstrate catch-up growth after liver transplantation. Growth after transplantation is proportional to the degree of growth retardation at transplantation and inversely correlated to age at transplantation. Children with poor growth after transplantation are more likely to be receiving higher doses of corticosteroid.

A Randomized Double-Blind, Placebo Controlled Trial of Steroid Withdrawal after Pediatric Renal Transplantation

In an effort to reduce rejection, extend allograft survival and minimize complications, we hypothesized that robust immunosuppression during the first 6 months after transplantation would allow for the safe withdrawal of steroids. A total of 274 pediatric subjects were enrolled and received an anti‐CD25 antibody, sirolimus, calcineurin inhibitor and steroids. At 6 months after transplantation, subjects were randomized to steroid withdrawal (n = 73) versus continued low‐dose steroids (n = 59). This study was stopped prior to target enrollment because of the incidence of post‐transplant lymphoproliferative disorder. At the time of study termination, 132 subjects had been randomized and were available for analysis. At 18 months after transplantation, there was no difference in the standardized height z score; however, the standardized height velocity was greater in the steroid withdrawal group compared to the control group (p = 0.033). There were no differences in acute rejection episodes between treatment groups. The 3‐year allograft survival rate was 84.5% in the control group and 98.6% in the steroid withdrawal group (p = 0.002). The immunosuppressive protocol utilized in this study allowed for the withdrawal of steroids without an increased risk of rejection or allograft loss. However, the complications associated with the use of this immunosuppressive protocol were too high to recommend its routine use in pediatric patients.

IgA Nephropathy in children and adults: comparison of histologic features and clinical outcomes

BACKGROUND While some studies have reported that IgA nephropathy has a relatively benign clinical course in children, others have shown that renal outcomes of paediatric patients with IgA nephropathy followed into adulthood are similar to those of patients diagnosed as adults. Some of this variability may be related to differences in histologic severity of cohorts of patients diagnosed as children versus adults. METHODS We retrospectively examined correlations between renal biopsy findings, clinical features at presentation and renal survival in 99 children and adolescents (<or=17 years old) with IgA nephropathy and compared these findings to those of 125 adults with IgA nephropathy. RESULTS Compared with adults, paediatric patients were more likely to have minimal histologic lesions (24% versus 14%) and less likely to have advanced chronic lesions (3% versus 17%). Similar fractions of paediatric and adult patients showed focal and diffuse glomerulonephritis (GN), respectively. Among these latter two groups, renal survival was significantly better in patients diagnosed as children than as adults by univariate and multivariate analyses. By multivariate analysis, other significant, independent predictors of renal survival were estimated percent interstitial fibrosis and histologic grade (diffuse versus focal GN). CONCLUSIONS In patients with proliferative IgA nephropathy, the clinical course is more likely to be benign when the disease is diagnosed in childhood versus adulthood. This difference can be accounted for only in part by more advanced disease at the time of biopsy in adults.

A national conference to determine research priorities in pediatric solid organ transplantation.

Abstract:  The need for evidence‐based practice guidelines requires high quality, carefully controlled clinical research trials. This multidisciplinary conference attempted to: identify urgent clinical and research issues, identify obstacles to performing clinical trials, develop concepts for organ‐specific and all‐organ research and generate a report that would serve as a blueprint for future research initiatives. A few themes became evident. First, young children present a unique immunologic environment which may lead to tolerance, therefore, including young children in immunosuppression withdrawal and tolerance trials may increase the potential benefits of these studies. Second, adolescence poses significant barriers to successful transplantation. Non‐adherence may be insufficient to explain poorer outcomes. More studies focused on identification and prevention of non‐adherence, and the potential effects of puberty are required. Third, the relatively naive immune system of the child presents a unique opportunity to study primary infections and alloimmune responses. Finally, relatively small numbers of transplants performed in pediatric centers mandate multicenter collaboration. Investment in registries, tissue and DNA repositories will enhance productivity. The past decade has proven that outcomes after pediatric transplantation can be comparable to adults. The pediatric community now has the opportunity to design and complete studies that enhance outcomes for all transplant recipients.

Pharmacokinetics of enteric-coated mycophenolate sodium in stable pediatric renal transplant recipients

Abstract:  This study aims to characterize the pharmacokinetics of mycophenolic acid (MPA) and its glucuronide metabolite (mycophenolic acid 7‐O‐glucuronide, MPAG) following single oral administration of enteric‐coated mycophenolate sodium (EC‐MPS, myfortic®) at an approximate dose level of 450 mg/m2 body surface area (BSA) to 25 stable renal transplant recipients (aged 5–16 yr), and to evaluate the safety and tolerability of EC‐MPS in this pediatric population. Patients had been maintained on a cyclosporine emulsion, Neoral®‐based immunosuppressive regimen for at least 3 months and had received their first or second renal transplant more than 6 months prior to entry into the study. After a brief lag phase (tlag 0.75 h), MPA was rapidly absorbed (tmax 2.5 h) and rapidly converted to MPAG (tmax 3.25 h), with relatively high plasma concentrations of MPAG (Cmax 67.7 μg/mL) compared with MPA (Cmax 36.3 μg/mL). The elimination half‐life for MPAG was slightly longer than for MPA (approximately 13 h vs. 8.5 h), and the apparent oral clearance of MPA was approximately 0.2 L/h/kg. The pharmacokinetics of MPA or MPAG were not affected by age, body weight or BSA, within the study population. The pharmacokinetic results for pediatric patients are comparable with those obtained previously in adults, although exposure based on AUC0−∞ was approximately 23% higher, and this finding may be a result of dosing on the basis of BSA, rather than body weight. The recommended dose of EC‐MPS in pediatric patients is 400–450 mg/m2 twice daily or, alternatively, approximately 10–14 mg/kg twice daily when used in combination with cyclosporine microemulsion.