Richard N. Fine

Pediatric Transplantation in the United States, 1995–2004

Solid organ transplantation is accepted as a standard lifesaving therapy for end‐stage organ failure in children. This article reviews trends in pediatric transplantation from 1996 to 2005 using OPTN data analyzed by the Scientific Registry of Transplant Recipients. Over this period, children have contributed significantly to the donor pool, and although the number of pediatric donors has fallen from 1062 to 900, this still accounts for 12% of all deceased donors. In 2005, 2% of 89 884 candidates listed for transplantation were less than 18 years old; in 2005, 1955 children, or 7% of 28 105 recipients, received a transplant. Improvement in waiting list mortality is documented for most organs, but pretransplant mortality, especially among the youngest children, remains a concern. Posttransplant survival for both patients and allografts similarly has shown improvement throughout the period; in most cases, survival is as good as or better than that seen in adults. Examination of immunosuppressive practices shows an increasing tendency across organs toward tacrolimus‐based regimens. In addition, use of induction immunotherapy in the form of anti‐lymphocyte antibody preparations, especially the interleukin‐2 receptor antagonists, has increased steadily. Despite documented advances in care and outcomes for children undergoing transplantation, several considerations remain that require attention as we attempt to optimize transplant management.

Nonadherence Consensus Conference Summary Report

This report is a summary of a ‘Consensus Conference’ on nonadherence (NA) to immunosuppressants. Its aims were: (1) to discuss the state‐of‐the‐art on the definition, prevalence and measurement of NA, its risk factors and impact on clinical and economical outcomes and interventions and (2) to provide recommendations for future studies. A two‐day meeting was held in Florida in January 2008, inviting 66 medical and allied health adherence transplant and nontransplant experts. A scientific committee prepared the meeting. Consensus was reached using plenary and interactive presentations and discussions in small break‐out groups. Plenary presenters prepared a summary beforehand. Break‐out group leaders initiated discussion between the group members prior to the meeting using conference calls and e‐mail and provided a summary afterward. Conclusions were that NA: (a) is more prevalent than we assume; (b) is hard to measure accurately; (c) tends to confer worse outcomes; (d) happens for a number of reasons, and system‐related factors including the patients culture, the healthcare provider and the setting and (e) it is not currently known how to improve adherence. This consensus report provided some roadmaps for future studies on this complicated, multifaceted problem.

The 1989 report of the North American Pediatric Renal Transplant Cooperative Study - This report is prepared under the auspices of the scientific advisory committee of the North American Pediatric Renal Transplant Cooperative Study

This report of the North American Pediatric Transplant Cooperative Study summarizes data contributed by 57 participating centers on 754 children with 761 transplants from 1 January 1989 to 16 February 1989. Data collection was initiated in October 1987 and follow-up of all patients is ongoing. Transplant frequency increased with age; 24% of the patients were less than 5 years, with 7% being under 2 years. Common frequent diagnoses were: aplastic/dysplastic kidneys (18%), obstructive uropathy (16%), and focal segmental glomerulosclerosis (12%). Preemptive transplant, i.e., transplantation without prior maintenance dialysis, was performed in 21% of the patients. Dialytic modalities pretransplant were peritoneal dialysis in 42% and hemodialysis in 25%. Bilateral nephrectomy was reported in 29%. Live-donor sources accounted for 42% of the transplants. Among cadaveric donors, 41% of the donors were under 11 years old. During the first post-transplant month, maintenance therapy was used similarly for live-donor and cadaver source transplants, with prednisone, cyclosporine, and azathioprine used in 93%, 83%, and 81%, respectively. Triple therapy with prednisone, cyclosporine, and azathioprine was used in 78%, 75%, and 75% of functioning cadaver source transplants at 6 months, 12 months, and 18 months as opposed to 60%, 63%, and 54% for live-donor procedures, with single-drug therapy being uncommon. Rehospitalization during months 1–5 occurred in 62% of the patients, with treatment of rejection and infection being the main causes. Additionally, 9% were hospitalized for hypertension. During months 6–12 and 12–17, 30% and 28% of the patients with functioning grafts were rehospitalized. Times to first rejection differed significantly for cadaver and live-donor transplants. The median time to the first rejection was 36 days for cadaver transplants and 156 days for live-donor transplants. Overall, 57% of treated rejections were completely reversible although the complete reversal rate decreased to 37% for four or more rejections. One hundred and fifty-two graft failures had occurred at the time of writing, with a 1-year graft survival estimate of 0.88 for live-donor and 0.71 for cadaver source transplants. In addition to donor source, recipient age is a significant prognostic factor for graft survival. Among cadaver donors, decreasing donor age is associated with a decreasing probability of graft survival. Thirty-five deaths have occurred; 16 attributed to infection and 19 to other causes. The current 1-year survival estimate is 0.94. There have been 9 malignancies.

Accelerated growth after recombinant human growth hormone treatment of children with chronic renal failure

We studied the effect of recombinant human growth hormone treatment on five boys, aged 4.6 +/- 1.8 years, who had chronic renal failure secondary to congenital renal diseases (mean creatinine clearance (+/- SD): 18.3 +/- 6.3 ml/min/1.73 m2 (0.32 +/- 0.11 ml/sec/1.73 m2]. Patients received 0.125 mg/kg of growth hormone three times per week for 1 year. Before beginning treatment, the children had a mean annual growth velocity of 4.9 +/- 1.4 cm/yr (range 3.0 to 6.3 cm/yr), with a mean standard deviation score for a height of -2.98 +/- 0.73 (range -2.16 to -3.59). At the end of therapy, the mean growth velocity had increased to 8.9 +/- 1.2 cm/yr (range 7.5 to 10.7 cm/yr), and the mean height standard deviation score improved to -2.36 +/- 0.83 (range -1.15 to -3.18). Bone age advancement was consistent with the period of growth. Routine laboratory determinations, including results of glucose tolerance testing, did not vary significantly from pretreatment levels. These preliminary data indicate that growth-retarded children with chronic renal failure can respond to exogenous growth hormone therapy with a marked acceleration in growth velocity.

PRETRANSPLANT DIALYSIS STATUS AND OUTCOME OF RENAL TRANSPLANTATION IN NORTH AMERICAN CHILDREN: A NAPRTC STUDY. NORTH AMERICAN PEDIATRIC RENAL TRANSPLANT COOPERATIVE STUDY

BACKGROUND There are no large studies of the effect of pretransplant dialysis status on the outcome of renal transplantation (Tx) in children. This study evaluated the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) registry data for the outcome of Tx in pediatric patients who either (1) received their transplants preemptively or (2) were maintained on dialysis before receiving their transplants. METHODS We compared graft survival and patient survival rates, incidence of acute tubular necrosis (ATN), acute rejection episodes, and causes of graft failure in peritoneal dialysis (PD) patients with those maintained on hemodialysis (HD) and those undergoing preemptive Tx (PTx). RESULTS Primary Tx was performed in 2495 children (59% male; 61% Caucasian; 1090 PD, 780 HD, 625 PTx) between 1/1/1992 and 12/31/1996. The overall graft survival rates of the PD and HD groups were similar, but were less than that of the PTx group (3-year: 82% PD and HD, 89% PTx, overall P = 0.0003). Improved graft survival in the PTx group was present only in recipients of grafts from living donors. There was no difference in the overall patient survival rate at 3 years, or in time to first acute-rejection episodes in the three groups. The incidence of ATN in the first 7 days post-Tx was higher in PD and HD patients than in PTx patients (11% PD and 12% HD vs. 2% PTx, P<0.001; HD vs. PD, P = NS). The major single cause of graft failure in each group was: PD, vascular thrombosis (200%); HD, chronic rejection (27%); PTx, acute and chronic rejection (21% each). CONCLUSION NAPRTCS data show that graft survival is improved in patients receiving PTx, compared with those receiving PD and HD. Graft loss resulting from vascular thrombosis is more common in children who receive PD than in those receiving HD.

Clinical trial of focal segmental glomerulosclerosis in children and young adults

This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.

Adherence to the immunosuppressive regimen in pediatric kidney transplant recipients: a systematic review

Dobbels F, Ruppar T, De Geest S, Decorte A, Van Damme‐Lombaerts R, Fine RN. Adherence to the immunosuppressive regimen in pediatric kidney transplant recipients: A systematic review. Pediatr Transplantation 2010: 14:603–613.

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.

Chronic renal insufficiency in children and adolescents: The 1996 annual report of NAPRTCS

Abstract. The 1996 annual report of the Chronic Renal Insufficiency Arm of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) summarizes descriptive data and highlights important features on 1,725 patients from 130 centers. This database contains information on patients with an estimated glomerular filtration rate (GFR) ≤75 ml/min per 1.73 m2 as calculated by the Schwartz formula, who were treated on or after 1 January 1994. Thus this report reflects 2 years of data entry. Analysis of the data revealed that nearly two-thirds of patients registered had a structural anomaly. On average, patients were 1.5 standard deviations below age- and sex-specific norms for height, and 0.6 standard deviations below weight norms. Mean serum creatinine for the entire group was 2.4 mg/dl and 68% of patients had a baseline GFR of at least 25 ml/min per 1.73 m2. The mean hematocrit for all children at registration was 33.3±6.3%, and did not vary among age groups. Overall, 30.9% of patients had a hematocrit <30%. Only 12.8% of patients were receving Epoetin therapy. Although still in infancy, the Chronic Renal Insufficiency Arm of the NAPRTCS database in providing important insights into this disorder.

Factors predictive of sustained growth in children after renal transplantation

To ascertain growth and rehabilitation of children after transplantation, the North American Pediatric Renal Transplant Cooperative Study collected growth data on renal transplant recipients. From January 1987 through December 1990, a total of 1553 children with one or more transplants were entered into the study by its 75 participating centers. Of these, the first 300 children with a functioning graft and 2 years of linear growth data form the cohort for this study. For the total cohort of 300 patients, the mean (+/- SEM) baseline height z score was -2.41 +/- 0.09, and the change in z score determined after 2 years was 0.18 +/- 0.06 (p < 0.01). Children in the age group from birth to 1 year had the maximal deficit and had the maximal improvement in z score, gaining about 1 SD (p < 0.01). For the 2- to 5-year-old group, the change in z score was about 0.5 SD (p < 0.001). No improvement in z score was noted for children 6 to 17 years of age. Each increase in serum creatinine concentration of 90 mumol/L (1 mg/dl) was associated with -0.17 decrease in the z score (p < 0.001). Gender, donor source, history of previous transplantation, and prior dialysis were not associated with a significant change in the z score; thus the increased rate of growth during the first 2 post-transplantation years occurred mainly in subjects less than 6 years of age.