Kevin E.C. Meyers

Design of the nephrotic syndrome study network (NEPTUNE) to evaluate primary glomerular nephropathy by a multidisciplinary approach

The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multi-center collaborative consortium established to develop a translational research infrastructure for Nephrotic Syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary studies program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy for detailed clinical, histopathologic, and molecular phenotyping at the time of clinically-indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and bi-annually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histologic data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for Nephrotic Syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.

Perceived barriers to adherence among adolescent renal transplant candidates.

Abstract:  Non‐adherence to medical regimens is a ubiquitous hindrance to quality health care among adolescent transplant recipients. Identification of potentially modifiable barriers to adherence when patients are listed for organ transplant would help with early intervention efforts to prepare adolescents for the stringent medication regimen post‐transplant. Fifty‐six adolescents listed for a kidney transplant, mean age 14.27 (s.d. = 2.2; range 11–18 yr), 73.2% male, 62.5% Caucasian participated in a semi‐structured interview, the Medical Adherence Measure, to assesses the patient’s knowledge of the prescribed regimen, reported adherence (missed and late doses), the system used to organized medications, and who holds the primary responsibility over medication management. Better knowledge of the medication regimen was associated with fewer missed doses (r = −0.48, p < 0.001). Patients who perceived more barriers had more missed (r = 0.38, p = 0.004) and late (r = 0.47, p < 0.001) doses. Patients who endorsed “just forget,” the most common barrier (56.4%), reported significantly more missed (z = −4.25, p < 0.001) and late (z = −2.2, p = 0.02) doses. Only one‐third of the transplant candidates used a pillbox to organize medications but these patients had significantly better adherence, z = −2.2, p = 0.03. With regard to responsibility over managing the regimens, adolescents missed fewer doses when their parents were in charge than when they were solely responsible, z = −2.1, p = 0.04. Interventions developed to prepare transplant candidates for a stringent post‐transplant regimen need to focus on ensuring accurate knowledge of as simple a regimen as possible. Use of an organized system such as a pillbox to establish a routine and facilitate tracking of medications is recommended with integration of reminders that may be appealing for this age group. Although individuation is developmentally normative at this age, parent involvement seems critical until the adolescent is able to manage the responsibility more independently.

Outcomes in pediatric solid‐organ transplantation

LaRosa C, Jorge Baluarte H, Meyers KEC. Outcomes in pediatric solid‐organ transplantation. 
Pediatr Transplantation 2011: 15:128–141.

NONCOMPLIANCE IN CHILDREN AND ADOLESCENTS AFTER RENAL TRANSPLANTATION

This study assesses the perceptions, knowledge, and attitudes of patients and parents attending the Pediatric Transplant Unit at the Johannesburg Hospital. Fifty-six children with renal transplants accompanied by their parents were assessed by means of a questionnaire. The childrens ages were 2.53 to 20.85 years. Eleven of twelve in the noncompliant group were male and nine were Black. The ages of the two groups of patients and distance traveled to the transplant center were similar. The noncompliant group of patients more often missed clinic visits (50% vs. 14%), P=0.0201; forgot to take their medications (50% vs. 23%); and took more medications (10.3 +/- 3.0 vs. 7.5 +/- 2.0) and remembered fewer of their names (4.0 +/- 3.5 vs. 6.5 +/- 2.5), P=0.0001 than the compliant group. The noncompliant patients knew less about their disease (50% vs. 8.3%) P=0.0141, allograft (53% vs. 33%), and immunosuppression (66% vs. 200%) P=0.0217, than the compliant patients. A total of 9% of the patients (5/56) were concerned about immunosuppressive side-effects, and indicated that this affected their compliance. Families wanted additional information, both pretransplant (52%) and posttransplant (45.5%). In addition, 85% wanted ongoing in-house education concerning transplantation and medications. Pediatric renal transplant patients and their families require ongoing education, support, medication evaluation, and compliance surveillance. Patients at high risk of noncompliance require directed additional intervention.

Efficacy and Safety of the Angiotensin Receptor Blocker Valsartan in Children With Hypertension Aged 1 to 5 Years

The efficacy and safety of valsartan were studied in 90 children (mean age: 3.2 years; 60% male; 30% black) with systolic blood pressure (SBP) ≥95th percentile. Nineteen percent received valsartan in addition to previous antihypertensive therapy. Subjects were randomly assigned to low-, medium-, or high-dose valsartan for 2 weeks (phase 1) and then reassigned randomly to placebo or to remain on the same valsartan dose for 2 additional weeks (phase 2). After this, subjects were enrolled into a 52-week, open-label phase during which valsartan was dosed to achieve SBP <95th percentile. Statistically significant reductions in SBP and diastolic blood pressure of ≈8.5 mm Hg and 5.7 mm Hg, respectively, were observed at the end of phase 1 in all of the valsartan dose groups. SBP and diastolic blood pressure were also significantly lower during phase 2 in valsartan recipients compared with placebo recipients. SBP <95th percentile was achieved in 77.3% of subjects during the open-label phase. Adverse events were minor and occurred at similar frequencies in each of the 3 dose groups in phase 1 and at equal frequencies in the valsartan and placebo arms in phase 2. Serious adverse events and drug-related adverse events occurred infrequently during both the double-blind (2.2% and 5.6%, respectively) and open-label (14.8% and 6.8%, respectively) portions of the study. Valsartan treatment had no demonstrable negative effects on growth and development. In this study, the first trial of an antihypertensive agent conducted in children <6 years of age, valsartan effectively lowered SBP and diastolic blood pressure compared with placebo.

Differing Effects of Rapamycin or Calcineurin Inhibitor on T‐Regulatory Cells in Pediatric Liver and Kidney Transplant Recipients

In a cross‐sectional study, we assessed effects of calcineurin inhibitor (CNI) or rapamycin on T‐regulatory (Treg) cells from children with stable liver (n = 53) or kidney (n = 9) allografts several years posttransplant. We analyzed Treg number, phenotype, suppressive function, and methylation at the Treg‐specific demethylation region (TSDR) using Tregs and peripheral blood mononuclear cells. Forty‐eight patients received CNI (39 as monotherapy) and 12 patients received rapamycin (9 as monotherapy). Treg numbers diminished over time on either regimen, but reached significance only with CNI (r =−0.424, p = 0.017). CNI levels inversely correlated with Treg number (r =−0.371, p = 0.026), and positively correlated with CD127+ expression by Tregs (r = 0.437, p = 0.023). Patients with CNI levels >3.6 ng/mL had weaker Treg function than those with levels <3.6 ng/mL, whereas rapamycin therapy positively correlated with Treg numbers (r = 0.628, p = 0.029) and their expression of CTLA4 (r = 0.726, p = 0.041). Overall, CTLA4 expression, TSDR demethylation and an absence of CD127 were important for Treg suppressive function. We conclude that rapamycin has beneficial effects on Treg biology, whereas long‐term and high dose CNI use may impair Treg number, function and phenotype, potentially acting as a barrier to attaining host hyporesponsiveness to an allograft.

Short sirolimus half-life in pediatric renal transplant recipients on a calcineurin inhibitor-free protocol.

Abstract:  Immunosuppression with SRL may provide an opportunity to avoid long‐term exposure to the nephrotoxicity of CNI. Thus, we have initiated an experimental protocol of IL‐2r antibody induction, prednisone, MMF and SRL in pediatric renal transplant recipients (median age 15.5 yr, IQR 8.5, range 1.3–21.7). The recipients were treated with daclizumab every 2 wk for the first 2 months, prednisone on a tapering schedule, MMF at 1200 mg/m2/day and SRL given b.i.d. The SRL was dosed to achieve defined target whole blood 12‐h trough levels. We performed 24 SRL PK profiles in 13 stable pediatric renal transplant recipients at 1 and 3 months post‐transplant. Half‐life (T1/2) and terminal T1/2 were 9.7 (7.1–24.6) and 10.8 (4.4–95.2) hours (median, range) respectively at month 1, and were 9.6 (5–17.8) and 12.1 (4.7–71.0) hours respectively at month 3. SRL trough levels correlated with AUC (r2 = 0.84, p < 0.001). There was no relationship between SRL and mycophenolic acid (MPA) AUC values (r2 = 0.04). During the first 3 months post‐transplant only one patient experienced severe neutropenia and another patient had subclinical (histologic) evidence of a mild acute rejection episode with no change in renal function. We conclude that the T1/2 of SRL in pediatric renal transplant recipients not treated with CNI is much shorter than what has been reported for adults, due to rapid metabolism. We conclude that children require SRL dosing every 12 h, higher doses and frequent drug monitoring to achieve target SRL concentrations.

Safety and Efficacy of a Calcineurin Inhibitor Avoidance Regimen in Pediatric Renal Transplantation

Thirty-four children were entered into a pilot trial of calcineurin inhibitor avoidance after living-donor kidney transplantation, the CN-01 study. Patients were treated with anti-CD25 mAb, prednisone, mycophenolate mofetil, and sirolimus. Twenty patients were maintained on the protocol for up to 3 yr of follow-up. One enrolled patient did not receive the transplant because of a donor problem, eight terminated because of one or more rejection episodes, four terminated because of adverse events, and one was lost to follow-up. Two grafts were lost, one as a result of chronic rejection and the other as a result of posttransplantation lymphoproliferative disorder. There were no deaths. The 6- and 12-mo acute rejection rates were 21.8 and 31.5%, respectively. GFR were stable throughout the course of the study, with a slight downward trend by 6 mo after transplantation followed by a slight upward trend to a mean of 70 ml/min thereafter. Early surveillance graft biopsies frequently showed focal interstitial mononuclear cellular infiltrates without overt vasculitis or tubulitis, but these infiltrates disappeared without treatment. Anti-HLA class I and II antibodies were detected in three patients before transplantation, and all three had acute rejections, including the two patients who lost their grafts. De novo anti-HLA Ab production occurred in only one patient after transplantation. There were two episodes of Epstein Barr virus-related posttransplantation lymphoproliferative disorder, one of which developed after the patient had been terminated from the study. It is concluded that calcineurin inhibitor-free immunosuppression can be safe and effective in pediatric living-donor renal transplantation. However, further modifications that are designed to lessen early rejection rates and decrease complications should be tested before this approach is used routinely.

Limited Evaluation of Microscopic Hematuria in Pediatrics

Objective. The purpose was to determine the value of the standard laboratory and radiologic evaluation of microscopic hematuria in children, and to determine the prevalence of idiopathic hypercalciuria in those children referred for evaluation of unexplained microscopic hematuria. Methods. This was a retrospective study of 325 children referred from 1985 to 1994 for the evaluation of asymptomatic microscopic hematuria. The diagnostic studies reviewed included serum creatinine, blood urea nitrogen, serum electrolyte studies, serum complement concentration, antinuclear antibody, urinalysis, urine calcium to creatinine ratios, urinary protein to creatinine ratio and/or 24-hour urinary protein excretion, renal ultrasounds, intravenous pyelograms, voiding cystourethrograms, and historical information. Results. All creatinine and electrolyte values were normal for age, and none of the biochemical tests obtained in the children with hypercalciuria was abnormal. Of the 325 patients with idiopathic microscopic hematuria, only 18 had abnormal renal ultrasound examinations and 9 voiding cystourethrograms showed low-grade reflux. Hypercalciuria was found in 29 patients. The family history was positive for urolithiasis in 16% of patients without hypercalciuria compared with 14% of patients with hypercalciuria. A positive family history of hematuria was reported in 25% of patients; 62 patients did not have hypercalciuria and 4 of the patients had hypercalciuria. Microscopic hematuria in children is a benign finding in the vast majority of children. Conclusions. Our data demonstrate that a renal ultrasound, voiding cystourethrogram, cystoscopy, and renal biopsy are not indicated in the work-up of microscopic hematuria, and microhematuria in the otherwise healthy child is a minimal health threat, rarely indicative of serious illness.

Solid-Organ Transplantation in Childhood: Transitioning to Adult Health Care

Pediatric solid-organ transplantation is an increasingly successful treatment for solid-organ failure. With dramatic improvements in patient survival rates over the last several decades, there has been a corresponding emergence of complications attributable to pretransplant factors, transplantation itself, and the management of transplantation with effective immunosuppression. The predominant solid-organ transplantation sequelae are medical and psychosocial. These sequelae have a substantial effect on transition to adult care; as such, hurdles to successful transition of care arise from the patients, their families, and pediatric and adult health care providers. Crucial to successful transitioning is the ongoing development of a sense of autonomy and responsibility for ones own care. In this article we address the barriers to transitioning that occur with long-term survival in pediatric solid-organ transplantation. Although a particular transitioning model is not promoted, practical tools and strategies that contribute to successful transitioning of pediatric patients who have received a transplant are suggested.