Diane Hebert

Renal transplantation, chronic dialysis, and chronic renal insufficiency in children and adolescents. The 1995 Annual Report of the North American Pediatric Renal Transplant Cooperative Study

Abstract. The 1995 Annual Report of the North American Pediatric Renal Transplant Cooperative Study summarizes data voluntarily collected from 123 centers on 5,197 children and adolescents grouped into three cohorts: (1) patients who received renal transplants on or after 1 January 1987 (n = 3,066), (2) patients who were maintained on peritoneal dialysis (PD) or hemodialysis (HD) on or after 1 January 1992 (n = 1,488), and (3) patients treated for chronic renal insufficiency (CRI) on or after 1 January 1994 (n = 643). The transplant and dialysis information update previous registry data whereas the CRI information reflects 1st-year registry data. Three-year graft survival rates were 83% and 66% for living donor grafts and cadaver donor (CD) grafts, respectively. Triple drug maintenance therapy with prednisone, cyclosporine, and azathioprine was used by >70% of all transplant recipients through 5 years of follow-up. The 2-year CD survival has steadily improved from 65% in 1987 to 82% in 1992. Fifty malignancies have been reported, the majority of which are lymphoproliferative disorders. The 2-year patient survival posttransplantation is 95%. Mortality rates for the youngest patients have drastically improved over the past 2 years. Approximately two-thirds of patients in the dialysis cohort are maintained on PD; automated PD remains the preferred modality. Overall, the peritonitis rate is one infection every 13.3 patient months, the frequency of infection being greatest in the youngest patients. Whereas the primary reason for dialysis modality termination is transplantation, approximately 40% of the entire dialysis cohort (PD and HD) were not considered active transplant candidates. Baseline CRI data revealed the most common primary diagnoses to be obstructive uropathy (24%) and aplastic/hypoplastic/dysplastic kidneys (19%). The standardized height deficit in the CRI cohort was greatest in the youngest patients and those with the most impaired renal function.

Clinical and Laboratory Characteristics and Long-Term Outcome of Pediatric Systemic Lupus Erythematosus: A Longitudinal Study

OBJECTIVES To determine the frequency and characteristics of clinical signs, symptoms, laboratory findings, and medication use in children with pediatric systemic lupus erythematosus (pSLE) at presentation and during the course of the disease, and to examine correlations among disease manifestations, disease activity, and damage over time. STUDY DESIGN The study involved an analysis of medical records and the SLE database of an inception cohort of 256 patients with pSLE (female:male ratio, 4.7:1). RESULTS The most common clinical manifestations were arthritis (67%), malar rash (66%), nephritis (55%), and central nervous system (CNS) disease (27%). At diagnosis, patients with both renal and CNS disease had the highest SLE Disease Activity Index (SLEDAI) scores (P < .0001), but these scores were similar to those of the total group at 1 year (P = .11). Patients who developed renal and CNS disease more than 1 year after diagnosis had higher SLEDAI scores at disease onset. Some 34% of patients had Systemic Lupus International Collaborative Clinics Damage Index (SLICC-DI) scores >1 at a mean follow-up of 3.5 years. A greater proportion of patients with renal and CNS disease had SLICC-DI scores of >1, and these patients had higher mean scores compared with patients without major organ involvement (70% vs 11% [P < .0001] and 1.4 vs 0.1 [P < .0001], respectively). CONCLUSIONS Most of the patients in our cohort exhibited major organ involvement. These patients had the highest SLEDAI scores at diagnosis, which normalized at 1 year but preceded development of renal and CNS disease. The average SLICC-DI score was lower than that previously reported in patients with pSLE.

Contributions of the Transplant Registry: The 2006 Annual Report of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS).

Abstract:  This summary of the NAPRTCS 2006 Annual Report of the Transplant Registry highlights the significant impact the registry has had in advancing knowledge in pediatric renal transplantation worldwide. This cooperative group has collected clinical information on children undergoing a renal transplantation since 1987 and now includes over 150 participating medical centers in the USA, Canada, Mexico, and Costa Rica. Currently, the NAPRTCS transplant registry includes information on 9837 renal transplants in 8990 patients (NAPRTCS 2006 Annual Report). Since the first data analysis in 1989, NAPRTCS reports have documented marked improvements in outcome after renal transplantation in addition to identifying factors associated with both favorable and poor outcomes. The registry has served to document and influence practice patterns, clinical outcomes, and changing trends in renal transplantation.

LYMPHOPROLIFERATIVE DISORDERS AFTER ORGAN TRANSPLANTATION IN CHILDREN

BACKGROUND After organ transplant, patients are at risk of posttransplant lymphoproliferative disorders (PTLD). The purpose of this study was to analyze 26 pediatric cases of PTLD observed at our institution between 1988 and 1996, and to evaluate the validity of the Society for Hematopathology Workshop (SHPW) 1997 classification in our patient population. METHODS Charts were reviewed for analysis of incidence, clinical course, and outcome. Tissue samples were classified by a pathologist according to SHPW recommendations. RESULTS By morphology, 20 were monomorphic, 5 polymorphic, and 1 hyperplastic. Assessment of lineage by morphology, molecular studies, and immunophenotyping did not correlate in six cases. By immunophenotyping, 12 were B cell, 4 T cell, 8 mixed B/T cells, and 2 undetermined. The 20 patients evaluable for treatment efficacy were treated with various therapeutic combinations, including immunosuppressive drug reduction, acyclovir/ganciclovir, interferon-alpha, immunoglobulins, surgery, and local irradiation. No patient received systemic chemotherapy. Thirteen patients achieved complete remission and 3, partial; 1 died 5 days after starting therapy, and 3 of progressive disease. Adverse prognostic factors included low platelet or neutrophil counts; stage III-IV and SHPW morphology were marginally significant. CONCLUSIONS The majority of patients eligible for treatment can be cured with immunosuppressive drug reduction and antiviral drugs, along with surgery and irradiation when indicated. Systemic chemotherapy or innovative approaches may have a role in unresponsive cases. Morphologic SHPW grouping is feasible and seems to have clinical relevance. However, correlation with clonality and immunophenotyping is not always possible, necessitating modifications including segregation of descriptive morphology from clonality and cell origin.

Eculizumab and Refractory Membranoproliferative Glomerulonephritis

This letter to the editor discusses the use of eculizumab in refractory membranoproliferative glomerulonephritis. The response appears to be dramatic.

Compliance with cyclosporine in adolescent renal transplant recipients.

Abstract.  Inadequate compliance with prescribed medication regimens in children is complex and poorly understood. We measured the extent and pattern of noncompliance with cyclosporine in our adolescent renal transplant population and attempted to determine factors associated with poor compliance. After informed consent, each patient was provided cyclosporine capsules in a medication bottle equipped with an electronic monitoring device (MEMS-4) in the lid. Of the 24 patients eligible, 19 patients (8 female, 11 male) completed the study. Four (21%) patients took less than 80% of the prescribed cyclosporine doses. Five (26%) patients took drug holidays involving ≥3 consecutive doses. There was a trend towards improved compliance with the evening dose (88.5% vs. 93.4%, P = 0.09) and a downward trend in compliance over the course of the study (P = 0.17). None of the variables tested were found to be associated with noncompliance. Experienced physicians and nurses were able to identify 2 of the 4 individuals who were identified by MEMS as noncompliant. Additionally, 2 of the 4 noncompliant patients demonstrated low cyclosporine trough levels (<50 ng/ml). Noncompliance with cyclosporine regimens occurs commonly in adolescent renal transplant recipients. Unexpectedly low cyclosporine levels are strongly suggestive of noncompliance, whereas other variables, including prediction by physicians and nurses intimately involved in the care, were not reflective of noncompliance.

Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children

Pollock‐BarZiv SM, Finkelstein Y, Manlhiot C, Dipchand AI, Hebert D, Ng VL, Solomon M, McCrindle BW, Grant D. Variability in tacrolimus blood levels increases the risk of late rejection and graft loss after solid organ transplantation in older children.
Pediatr Transplantation 2010: 14:968–975.

Thromboembolism in paediatric lupus patients

Paediatric patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL), specifically lupus anticoagulants(LAC) are at high risk of developingthromboembolicevents (TE). Our objectiveswere to determine the prevalenceof TE in paediatricSLE patientswith LAC and to determine if anticoagulation was effective to decrease morbidity, and prevent recurrent TE. We reviewed data on 149 paediatric SLE patients treated over 10 years. In all, 24 patients (16%) were LAC positive, and 21 TE occurred in 13 of these LAC positive patients (54% incidence of TE in LAC positive patients). The events were cerebral venous thrombosis (9), arterial stroke (3), deep venous thrombosis (4), pulmonary embolism (2), other venous event (1) and other arterial events (2). The median duration between SLE diagnosis and first TE was 15.2 months (range 0-62), and the median age at first TE was 15.1 years (range11.4-18.4). Long-termanticoagulationwas prescribed, and eight patients (62%) were transferred to adult care on lifelong oral warfarin; four (31%) remain under our care on lifelong warfarin, and one patient died of causes unrelated to her TE. No patient has been identified with deficiencies of protein C, protein S or antithrombinIII. One patient is heterozygousfor Factor V Leiden, and one is heterozygous for both the Prothrombin 20210A mutation and the MTHFR (methylene tetrahydrofolate reductase) mutation. Four patients had recurrent TE (31%), and three were not anticoagulated at the time of their second event. One patient had two recurrences on therapeuticanticoagulation.Thromboembolic events are prevalent in the LAC positive paediatric SLE population, and consideration for lifelong anticoagulation must occur after an initial TE.

Risk factors for post-transplant lymphoproliferative disorder in pediatric patients : A case-control study

Abstract:  Post‐transplant Lymphoproliferative Disorder (PTLD) because of the Epstein–Barr Virus (EBV) is a major concern after pediatric transplantation. The group at greatest risk is EBV‐seronegative recipients who receive EBV‐seropositive organs. Additional risk factors remain to be determined, including those among EBV‐seropositive recipients. In this case‐control study, PTLD cases were biopsy‐proven over a period of 4 yr (1997–2000, inclusive). Each case was matched with 2 controls, based on the type of organ transplanted and the period of transplantation (±1 yr). Variables compared between cases and controls included those relating to the clinical and virologic profiles and immunosuppressive therapy. Twenty‐two cases of PTLD were diagnosed during the study period. PTLD cases occurred at a median of 22.8 months post‐transplantation (range 1–131). The median age of cases was 26.2 months (range 6.1–194) compared with 47.4 months (range 0.8–202.2) for controls (p = 0.93). Cases had a higher mean baseline EBV load compared with controls (3.1 log10 (s.d. ± 1.0) vs. 1.6 log10/106 PBMCs (s.d. ± 1.4), with every 1 log increase in viral load resulting in a three times increase in the likelihood of PTLD (p < 0.007). Close to one in four cases of PTLD were EBV‐seropositive pretransplantation. These seropositive recipients tended to be older patients with a trend to a worse outcome compared with their seronegative counterparts. The occurrence of PTLD was not associated with the use of any specific immunosuppressants. A significant proportion of PTLD cases occurred among EBV‐seropositive transplant recipients, with a tendency towards an unfavorable outcome. Besides EBV‐seronegative recipients who receive seropositive organs, some EBV‐seropositive pediatric patients are at risk of PTLD. Additional studies are warranted to further define the factors associated with PTLD in EBV‐seropositive transplant recipients.

Ethnic Differences in Pediatric Systemic Lupus Erythematosus

Objective. Prevalence and severity of systemic lupus erythematosus (SLE) in adults is suggested to be distinctly different between ethnic groups. The impact of ethnicity is not as well delineated in pediatric SLE (pSLE). We compared prevalence and extent of major organ involvement, disease activity, and damage in pSLE between different ethnic groups. Methods. Ethnic demographic profiles of an inception cohort of 265 patients with pSLE followed at Sick Kids Hospital in Toronto were determined and compared to the Metropolitan Toronto at-risk population. Patients were categorized into ethnic subsets based on self-designated ethnic origins. Disease characteristics including major organ involvement, disease activity, and damage measures were longitudinally determined and compared among ethnic groups. Results. Ethnicity data were available on 259/265 pSLE patients (99.6%); the majority were non-Caucasian (60%) compared to the Metropolitan Toronto at-risk population (40%) (p < 0.0001). Non-Caucasian patients were younger at diagnosis than Caucasian patients, Black patients being the youngest at diagnosis (12.6 vs 14.6 yrs; p = 0.007). Renal disease was significantly more common in non-Caucasian than in Caucasian pSLE patients (62% vs 45%; p = 0.01). There was a trend toward increased prevalence of central nervous system disease in Black patients compared to Asian patients (p = 0.108). There was no difference in gender ratio, SLE Disease Activity Index, or damage scores between ethnic groups. Conclusion. Non-Caucasian ethnicity is associated with increased pSLE disease prevalence. Non-Caucasian pSLE patients were significantly younger and more likely to have nephritis. However, disease activity and damage were strongly associated with major organ disease independent of the patient’s ethnicity.