David S. Lirenman

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.

Randomized trial of problem-based versus didactic seminars for disseminating evidence-based guidelines on asthma management to primary care physicians.

Introduction: This randomized controlled trial (RCT) investigated the effectiveness of and satisfaction with small‐group problem‐based learning (PBL) versus a didactic lecture approach to guideline dissemination in asthma management controlling for confounders common in comparative educational interventions. Methods: Sites were selected as either lecture or PBL using simple randomization. All participants were exposed to similar educational resources to ensure treatment equivalency. Instruments included standardized program/speaker evaluation forms and a validated case‐based questionnaire with a visual analogue scale measuring the level of confidence of responses. The latter was presented immediately pre‐ and post‐intervention and 3 months later. The statistician was blinded to intervention groups. Results: Overall, 52 family physicians agreed to participate, 23 in the PBL sessions (mean 4.6 per group) and 29 in the didactic lecture sessions (mean 7.25). There was no significant difference between the groups with respect to the knowledge gained at each test administration. Participants rated the lecturer or facilitator equally well as having established a positive learning environment. PBL participants rated the perceived educational value of the program higher than did lecture participants (4.36 vs. 3.93; p =.04). Both groups experienced a significant increase in asthma‐related knowledge post‐intervention. Attrition rates for the 3‐month post‐test were 14% for PBL participants versus 32% for lecture‐based participants. Discussion: PBL was as effective in knowledge uptake and retention as lecture‐based continuing medical education (CME) programs. Further study is warranted to investigate whether the assessment of higher educational value or an increase in response rate to delayed testing is replicable in other RCTs addressing common confounders and if these factors influence future CME participation, changes in physician clinical behavior, or patient health outcomes.

Vasculopathy with renal artery stenosis in a child with sarcoidosis

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Childhood IgM nephropathy: comparison with minimal change disease.

The distinctiveness of IgM nephropathy (IgMN) as a clinicopathologic entity is controversial. Twenty-seven children (16 males, 11 females) with IgMN as defined immunohistochemically by diffuse mesangial staining of glomeruli for IgM were compared to a group of 63 children (40 males, 23 females) with minimal change disease (MCD). While mesangial expansion was significantly greater in IgMN than in MCD (p = 0.0014), there were no significant differences between the two groups with respect to the other biopsy factors. IgMN showed a significantly higher incidence of hypertension at presentation. More than 90% of patients in both groups presented with the nephrotic syndrome which in most initially responded to prednisone. Frequently relapsing/steroid-dependent nephrotic syndrome was the most common indication for biopsy in both groups. Approximately 60% of patients from both groups received cytotoxic therapy. Eight percent of IgMN and 7% of MCD patients failed to respond to therapy. Relapse rates and mean dose of prednisone at relapse were very similar in both groups prior to biopsy. Relapse rates diminished significantly after treatment in the postbiopsy interval, but mean dose of prednisone at relapse did not change appreciably over time. None of the patients developed renal failure or hypertension in the follow-up period. At last visit 23% of IgMN and 27% of MCD had proteinuria. The results indicate that IgMN and MCD are indistinguishable clinically in children who are biopsied for the nephrotic syndrome.

Diffuse Proliferative Lupus Glomerulonephritis: DETERMINATION OF PROGNOSTIC SIGNIFICANCE OF CLINICAL, LABORATORY AND PATHOLOGIC FACTORS

Clinical, laboratory and pathological factors in 35 females with diffuse proliferative lupus glomerulonephritis were analyzed to determine the prognostic significance of the individual variables. The clinical and laboratory variables were age, serum creatinine (Cr), serum C3, serum C4 and proteinuria at the time of biopsy while the biopsy ones included intraglomerular monocytic infiltration (NSE index), total glomerular deposits, extent of subendothelial deposits, extent of extraglomerular deposits, tubulo-interstitial inflammation, relative tubulo-interstitial volume and total pathologic score. Standard morphometric and counting procedures were used to determine the levels of all pathologic variables but pathologic score and extra glomerular deposits where grading estimates were done. Survival curves were determined by the life table method. Logrank and chi-square tests were used to establish levels of statistical significance. Seven patients developed established renal failure (Cr greater than or equal to 2.0 on two or more occasions at least 3 months apart) and nine showed significant deterioration of renal function (decrease in CrCl of 25% or more in between biopsy and last follow-up visit or an increase in serum Cr of 0.4 mg/dl or more over the follow-up period). The 5-year renal survival rate (absence of established renal failure) for the whole group was 77%. Serum Cr (p less than .005) and extent of extraglomerular deposits (p less than .025) were shown to be significant prognostic factors for renal survival. Of the seven patients who developed renal failure none had an NSE index greater than 3.0 and one had a C3 greater than or equal to 45 mg/dl. Statistically these factors were weak prognostic indicators (0.5 less than p less than .1). Multivariate analysis demonstrated that the extraglomerular deposit factor contributed significant additional prognostic information to that provided by Cr. Although not important as a prognostic factor on its own, the NSE index significantly improved the prognostic performance of serum Cr. The product of the NSE index and serum C3 proved to be a strong prognostic factor (p less than .005).

Renal-coloboma syndrome: Prenatal detection and clinical spectrum in a large family

Renal-coloboma syndrome includes abnormalities in the urogenital and ocular systems as its primary manifestations, although it can be associated with abnormalities in other systems as well. This syndrome is caused by mutations in the PAX2 gene and is transmitted as an autosomal dominant trait. We report a family in which at least 7 members have manifestations of renal-coloboma syndrome, including two in whom renal disease was diagnosed prenatally by ultrasound examination. A pathogenic frame-shift mutation (619insG) was found in the PAX2 gene in affected family members, who show remarkable variability in both the ocular and renal manifestations of the syndrome.

Sirolimus pharmacokinetics in pediatric renal transplant recipients receiving calcineurin inhibitor co-therapy

Abstract:  We have previously reported sirolimus (SRL) pharmacokinetics (PK) in pediatric renal transplant recipients on a calcineurin inhibitor (CNI)‐free protocol. We now report pediatric SRL PK in pediatric renal transplant patients receiving SRL + CNI. SRL was dosed to achieve target trough levels between 10 and 20 ng/mL. We performed 49 SRL PK profiles in pediatric renal transplant recipients receiving SRL in combination with either cyclosporine (CsA; 25 profiles), or tacrolimus (TCL; 24 profiles). Ten of the SRL + TCL profiles were obtained from children receiving SRL on a b.i.d. dosing regimen. All other SRL profiles were q.d. regimens. We calculated, the maximum concentration (Cmax), AUC, apparent clearance (aCL; dose/AUC) for dose in mg/m2, and mean residence time (MRT). SRL levels were measured at 6 and 7 time points for b.i.d. and q.d. dosing, respectively. Regression analysis of SRL trough values vs. AUC showed good correlation in the SRL q.d. + CsA, SRL q.d. + TCL, and SRL b.i.d. + TCL groups (r2 = 0.95, 0.68, and 0.44, respectively). SRL aCL corrected for body surface area was higher in children aged 0–5 yr receiving SRL with either CsA or TCL. SRL dosing schedule should be tailored to each patient. Higher SRL aCL may be present in younger children when administered with CNI.

ANCA-positive glomerulonephritis and IgA nephropathy in a patient on propylthiouracil

A 14-year-old girl developed acute renal failure after 3 years therapy with propylthiouracil (PTU) for Grave’s disease. Serologic evaluation showed antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 and myeloperoxidase. Renal biopsy showed a crescentic glomerulonephritis (GN) as well as evidence of IgA nephropathy (IgAN). PTU was discontinued and the patient was treated with prednisone and cyclophosphamide. ANCA became negative and renal function improved, but did not normalize. A second biopsy showed evidence of IgA nephropathy only. Propylthiouracil use has been associated with ANCA positive pauci-immune glomerulonephritis, but not with IgA nephropathy. An overlap syndrome between IgAN and ANCA-positive GN, however, has been described. This patient may have had a preexisting IgAN, with acute pauci-immune GN secondary to PTU, or this may be the first description of an overlap syndrome of IgAN and ANCA vasculitis all caused by PTU therapy.

Systemic lupus erythematosus and other autoimmune disorders in children with Noonan syndrome.

Elena Lopez-Rangel, Peter N. Malleson, David S. Lirenman, Benjamin Roa, Joanna Wiszniewska, and M.E. Suzanne Lewis* Department of Medical Genetics, British Columbia’s Children’s and Women’s Health Center, University of British Columbia, British Columbia, Canada Division of Rheumatology, British Columbia’s Children’s and Women’s Hospital, University of British Columbia, British Columbia, Canada Department of Pediatrics, Division of Pediatric Nephrology, British Columbia’s Children’s and Women’s Hospital, University of British Columbia, British Columbia, Canada Department of Molecular and Human Genetics, Baylor DNA Diagnostic Laboratory, Baylor College of Medicine, Houston, Texas Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas Department of Medical Genetics, British Columbia’s Children’s and Women’s Health Center, University of British Columbia, British Columbia, Canada

Identifying Educational Influentials for Formal and Informal Continuing Medical Education in the Province of British Columbia.

Background: The objective of this study was to identify physicians in the province of British Columbia (BC) who are perceived by their colleagues to be the most educationally influential. Methods: A cross‐sectional study using a previously validated survey tool was mailed to a randomly selected sample of 2300 BC registered primary care physicians. Follow‐up mailings were sent to nonresponders. Results: The survey response rate was 53%. A list of 375 educationally influential physicians (Els) was proportionately determined and tabulated by region. Implications: The top 5% of provincial Els were identified to serve as a resource for formal and informal continuing medical education (CME). Their names will be brought forward in response to selected requests for CME speakers.