Growth hormone axis in chronic kidney disease

Chronic kidney disease (CKD) in children is associated with dramatic changes in the growth hormone (GH) and insulin-like growth factor (IGF-1) axis, resulting in growth retardation. Moderate-to-severe growth retardation in CKD is associated with increased morbidity and mortality. Renal failure is a state of GH resistance and not GH deficiency. Some mechanisms of GH resistance are: reduced density of GH receptors in target organs, impaired GH-activated post-receptor Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling, and reduced levels of free IGF-1 due to increased inhibitory IGF-binding proteins (IGFBPs). Treatment with recombinant human growth hormone (rhGH) has been proven to be safe and efficacious in children with CKD. Even though rhGH has been shown to improve catch-up growth and to allow the child to achieve normal adult height, the final adult height is still significantly below the genetic target. Growth retardation may persist after renal transplantation due to multiple factors, such as steroid use, decreased renal function and an abnormal GH–IGF1 axis. Those below age 6 years are the ones to benefit most from transplantation in demonstrating acceleration in linear growth. Newer treatment modalities targeting the GH resistance with recombinant human IGF-1 (rhIGF-1), recombinant human IGFBP3 (rhIGFBP3) and IGFBP displacers are under investigation and may prove to be more effective in treating growth failure in CKD

Adult Height in Patients with Advanced CKD Requiring Renal Replacement Therapy during Childhood.

BACKGROUND AND OBJECTIVES: Growth and final height are of major concern in children with ESRD. This study sought to describe the distribution of adult height of patients who started renal replacement therapy (RRT) during childhood and to identify determinants of final height in a large cohort of RRT children. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 1612 patients from 20 European countries who started RRT before 19 years of age and reached final height between 1990 and 2011 were included. Linear regression analyses were performed to calculate adjusted mean final height SD score (SDS) and to investigate its potential determinants. RESULTS: The median final height SDS was -1.65 (median of 168 cm in boys and 155 cm in girls). Fifty-five percent of patients attained an adult height within the normal range. Adjusted for age at start of RRT and primary renal diseases, final height increased significantly over time from -2.06 SDS in children who reached adulthood in 1990-1995 to -1.33 SDS among those reaching adulthood in 2006-2011. Older age at start of RRT, more recent period of start of RRT, cumulative percentage time on a functioning graft, and greater height SDS at initiation of RRT were independently associated with a higher final height SDS. Patients with congenital anomalies of the kidney and urinary tract and metabolic disorders had a lower final height than those with other primary renal diseases. CONCLUSIONS: Although final height remains suboptimal in children with ESRD, it has consistently improved over time

Diagnostic and therapeutic management of vesico-ureteral reflux in pediatric kidney transplantation-Results of an online survey on behalf of the European Society for Paediatric Nephrology

BackgroundVesico-ureteral reflux (VUR) is considered to be a risk factor for recurrent febrile urinary tract infections and impaired renal transplant survival. MethodsAn online survey supported by the European Society for Paediatric Nephrology was designed to evaluate current management strategies of VUR in native and transplanted kidneys of recipients aged Seventy-three pediatric transplant centers from 32 countries contributed to the survey. All centers performed urological evaluation prior to pediatric kidney transplantation (KTx) with subsequent interdisciplinary discussion. Screening for VUR in native kidneys (30% in all, 70% in selected patients) led to surgical intervention in 78% (11% in all, 89% in selected patients) with a decided preference of endoscopic intervention over ureterocystoneostomy. Following KTx, continuous antibiotic prophylaxis was applied in 65% of the patients and screening for allograft VUR performed in 93% of selected patients. The main management strategies of symptomatic allograft VUR were continuous antibiotic prophylaxis (83%) and surgical treatment (74%) (endoscopic intervention 55%, redo ureterocystoneostomy 26%). ConclusionsThis survey demonstrates the high variability in the management of VUR in pediatric KTx recipients, points to knowledge gaps, and might serve as a starting point for improving the care for patients with VUR in native and transplanted kidneys

Rituximab-associated hypogammaglobulinemia in children with idiopathic nephrotic syndrome: results of an ESPN survey

Background: There is paucity of information on rituximab-associated hypogammaglobulinemia (HGG) and its potential infectious consequences in children treated for idiopathic nephrotic syndrome (INS). Methods: A survey was distributed by the European Society Pediatric Nephrology to its members. It addressed the screening and management practices of pediatric nephrology units for recognizing and treating RTX-associated HGG and its morbidity and mortality. Eighty-four centers which had treated an overall 1328 INS children with RTX responded. Results: The majority of centers administered several courses of RTX and continued concomitant immunosuppressive therapy. Sixty-five percent of centers routinely screened children for HGG prior to RTX infusion, 59% during, and 52% following RTX treatment. Forty-seven percent had observed HGG prior to RTX administration, 61% during and 47% >9 months following treatment in 121, 210, and 128 subjects respectively. Thirty-three severe infections were reported among the cohort of 1328 RTX-treated subjects, of whom 3 children died. HGG had been recognized in 30/33 (80%) of them. Conclusions: HGG in steroid-dependent/frequently relapsing nephrotic syndrome (SDNS/FRNS) children is probably multifactorial and can be observed prior to RTX administration in children with SDNS/FRNS. Persistent HGG lasting >9 months from RTX infusion is not uncommon and may increase the risk of severe infections in this cohort. We advocate for the obligatory screening for HGG in children with SDNS/FRNS prior to, during, and following RTX treatment. Further research is necessary to identify risk factors for developing both HGG and severe infections before recommendations are made for its optimal management

Nutrition in children with CRF and on dialysis

The objectives of this study are: (1) to understand the importance of nutrition in normal growth; (2) to review the methods of assessing nutritional status; (3) to review the dietary requirements of normal children throughout childhood, including protein, energy, vitamins and minerals; (4) to review recommendations for the nutritional requirements of children with chronic renal failure (CRF) and on dialysis; (5) to review reports of spontaneous nutritional intake in children with CRF and on dialysis; (6) to review the epidemiology of nutritional disturbances in renal disease, including height, weight and body composition; (7) to review the pathological mechanisms underlying poor appetite, abnormal metabolic rate and endocrine disturbances in renal disease; (8) to review the evidence for the benefit of dietetic input, dietary supplementation, nasogastric and gastrostomy feeds and intradialytic nutrition; (9) to review the effect of dialysis adequacy on nutrition; (10) to review the effect of nutrition on outcome

Personalized therapy for mycophenolate: consensus report by the International Association of Therapeutic Drug Monitoring and Clinical Toxicology

When mycophenolic acid (MPA) was originally marketed for immunosuppressive therapy, fixed doses were recommended by the manufacturer. Awareness of the potential for a more personalized dosing has led to development of methods to estimate MPA area under the curve based on the measurement of drug concentrations in only a few samples. This approach is feasible in the clinical routine and has proven successful in terms of correlation with outcome. However, the search for superior correlates has continued, and numerous studies in search of biomarkers that could better predict the perfect dosage for the individual patient have been published. As it was considered timely for an updated and comprehensive presentation of consensus on the status for personalized treatment with MPA, this report was prepared following an initiative from members of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT). Topics included are the criteria for analytics, methods to estimate exposure including pharmacometrics, the potential influence of pharmacogenetics, development of biomarkers, and the practical aspects of implementation of target concentration intervention. For selected topics with sufficient evidence, such as the application of limited sampling strategies for MPA area under the curve, graded recommendations on target ranges are presented. To provide a comprehensive review, this report also includes updates on the status of potential biomarkers including those which may be promising but with a low level of evidence. In view of the fact that there are very few new immunosuppressive drugs under development for the transplant field, it is likely that MPA will continue to be prescribed on a large scale in the upcoming years. Discontinuation of therapy due to adverse effects is relatively common, increasing the risk for late rejections, which may contribute to graft loss. Therefore, the continued search for innovative methods to better personalize MPA dosage is warranted.Personalised Therapeutic