Beatriz D. Kuizon

Growth Retardation in Children with Chronic Renal Failure

Growth retardation is a major obstacle to full rehabilitation of children with chronic renal failure (CRF). Several factors have been identified as contributors to impaired linear growth and they include protein and calorie malnutrition, metabolic acidosis, growth hormone resistance, anemia, and renal osteodystrophy. Although therapeutic interventions such as the use of recombinant human growth hormone, recombinant human erythropoietin, and calcitriol have made substantial contributions, the optimal therapeutic strategy remains to be defined. Indeed, growth failure persists in a substantial proportion of children with renal failure and those treated with maintenance dialysis. In addition, the increasing prevalence of adynamic lesions of renal osteodystrophy and its effect on growth have raised concern about the continued generalized use of calcitriol in children with CRF. Recent studies have shown the critical roles of parathyroid hormone–related protein (PTHrP) and the PTH/PTHrP receptor in the regulation of endochondral bone formation. The PTH/PTHrP receptor mRNA expression has been shown to be down‐regulated in kidney and growth plate cartilage of animals with renal failure. Differences in the severity of secondary hyperparathyroidism influence not only growth plate morphology but also the expression of selected markers of chondrocyte proliferation and differentiation in these animals. Such findings suggest potential molecular mechanisms by which cartilage and bone development may be disrupted in children with CRF, thereby contributing to diminished linear growth.

Infectious and catheter-related complications in pediatric patients treated with peritoneal dialysis at a single institution

Continuous ambulatory peritoneal dialysis (CAPD) and continuous cycling peritoneal dialysis (CCPD) are the predominant dialytic modalities for the majority of children while awaiting transplantation. Wide acceptability of peritoneal dialysis is hindered by infectious complications. A retrospective review of 367 pediatric patients treated with CAPD/CCPD for at least 3 months from September 1980 through December 1994 revealed that the peritonitis incidence ranged from 1.7 to 0.78 episodes per patient-year. No differences in peritonitis rates were observed between patients treated with CAPD or CCPD. Gram-positive organisms were responsible for the majority of peritonitis episodes. Age, sex, race, primary renal disease, presence of nephrotic syndrome, and serum albumin level were not associated risk factors. Longer time on treatment and diminished serum IgG level were associated with increased peritonitis incidence. Treatment was successfully completed at home in most cases. Almost half of the catheter losses were caused byStaphylococcus, Pseudomonas, and fungal peritonitis and tunnel/exit-site infections. Infectious complications are still the major causes of morbidity and treatment failure in patients treated with CAPD/CCPD. Thus, controlled studies are needed to assess methods for prevention or improvement of peritonitis rates in this patient population.

Impaired growth, delayed ossification, and reduced osteoclastic activity in the growth plate of calcium-supplemented rats with renal failure.

Linear growth is reduced in prepubertal children with adynamic renal osteodystrophy, suggesting that the proliferation and/or differentiation of epiphyseal growth plate chondrocytes is abnormal in this disorder. To examine this issue, in situ hybridization and histochemistry were used to measure selected markers of endochondral bone formation and bone resorption in the proximal tibia of subtotally nephrectomized rats fed a high calcium diet to induce biochemical changes consistent with adynamic osteodystrophy. Blood ionized calcium concentrations were higher and serum PTH levels were lower in nephrectomized, calcium-supplemented rats than in either intact or nephrectomized control animals. Linear growth and tibial length were reduced, but messenger RNA levels for type II collagen, type X collagen, and the PTH/PTHrP receptor did not differ from control values in nephrectomized rats given supplemental calcium. In contrast, both the width of epiphyseal cartilage and the height of the zone of hypertrophic cho...

Growth hormone and the skeleton in pediatric renal allograft recipients

Abstract Recombinant human growth hormone has been utilized to augment linear growth in pediatric renal allograft recipients. The skeletal changes that accompany growth hormone therapy have not been described in children. Thus, 23 stable prepubertal pediatric kidney recipients, aged 10±3 years, with a mean transplant time of 3.4±2.5 years and histological findings of normal bone formation and adynamic bone on bone biopsies were prospectively randomized into two groups. These comprised a treated group that received 12 months of growth hormone and a control group that did not receive any treatment. Anthropometric measurements and blood for serum calcium, phosphorus, parathyroid hormone (PTH), osteocalcin, and insulin-like growth factor-I (IGF-I) were obtained every 3 months. Measurements of bone mass by dual-energy X-ray absorptiometry were performed at the beginning and end of the study period. All patients underwent an initial and final bone biopsy procedure after double tetracycline labeling. Annual growth velocity increased and standard deviation scores for height improved in the treated group. Serum IGF-I levels increased in the treated group and the increase was evident in patients with normal bone formation who received growth hormone but not in patients with adynamic bone. Serum calcium, phosphorus, osteocalcin, and PTH levels did not differ between the treated and control groups. Bone mass did not change in the treated group, but declined after 12 months in the control group. Bone formation rates did not increase with growth hormone treatment. Thus, growth hormone therapy improves linear growth and maintains bone mass, but does not favorably affect bone formation rates in stable pediatric renal allograft recipients.

The Prevalence of Primary Pediatric Prehypertension and Hypertension in a Real-World Managed Care System

To assess the burden associated with hypertension, reliable estimates for the prevalence of pediatric hypertension are vital. For this cross‐sectional study of 237,248 youths aged 6 to 17 years without indication of secondary hypertension, blood pressure (BP) was classified according to age, sex, and height using standards from the Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents as prehypertension with at least 1 BP ≥90th percentile and as hypertension with 3 BPs ≥95th percentile. The prevalence of prehypertension and hypertension were 31.4% and 2.1%, respectively. An additional 21.4% had either 1 (16.6%) or 2 (4.8%) BPs ≥95th percentile. Based on this large population‐based study using routinely measured BP from clinical care, a remarkable proportion of youth (6.9%) has hypertension or nearly meets the definition of hypertension with 2 documented BPs in the hypertensive range.

High Blood Pressure in Overweight and Obese Youth: Implications for Screening

In the absence of evidence‐based guidelines for high blood pressure screening in asymptomatic youth, a reasonable strategy is to screen those who are at high risk. The present study aimed to identify optimal body mass index (BMI) thresholds as a marker for high‐risk youth to predict hypertension prevalence. In a cross‐sectional study, youth aged 6 to 17 years (n=237,248) enrolled in an integrated prepaid health plan in 2007 to 2009 were classified according to their BMI and hypertension status. In moderately and extremely obese youth, the prevalence of hypertension was 3.8% and 9.2%, respectively, compared with 0.9% in normal weight youth. The adjusted prevalence ratios (95% confidence intervals) of hypertension for normal weight, overweight, moderate obesity, and extreme obesity were 1.00 (Reference), 2.27 (2.08–2.47), 4.43 (4.10–4.79), and 10.76 (9.99–11.59), respectively. The prevalence of hypertension was best predicted by a BMI‐for‐age ≥94th percentile. These results suggest that all obese youth should be screened for hypertension.

The Skeletal Consequences of Growth Hormone Therapy in Dialyzed Children: A Randomized Trial

BACKGROUND AND OBJECTIVE The effects of recombinant human growth hormone on renal osteodystrophy are unknown; thus, the effects of growth hormone (GH) on bone histomorphometry were assessed in pediatric patients with ESRD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Thirty-three patients who underwent bone biopsy between July 1994 and May 1999 were randomly assigned to therapy with or without GH. Patients were stratified by bone formation rate; all patients with high bone turnover received intraperitoneal calcitriol. Serum biochemical values were obtained monthly, and bone biopsy was repeated after 8 months. RESULTS Median patient age was 11.7 years (interquartile range [IQR], 7.6, 14.1 years); 45% of patients were male, and 52% were prepubertal. Median dialysis duration was 0.4 (IQR, 0.3, 0.8) year. Bone formation rate per bone surface increased from 15.0 (9.6, 21.8) to 154.6 (23.7, 174.3) μm(2)/μm(3) per year (P=0.05) in patients with low bone turnover treated with GH, decreased from 103.3 (57.0, 173.4) to 60.3 (20.3, 13.7) μm(2)/μm(3) per year in patients with high bone turnover receiving standard therapy (P=0.03), and was unchanged in the other two groups. Bone formation rates were higher with GH, irrespective of underlying bone histologic features (P=0.05). Parathyroid hormone did not differ between groups. GH therapy resulted in greater increases in height SD scores (estimated mean difference in change ± SD, 0.324±0.076; P<0.001), irrespective of underlying bone histologic features. CONCLUSIONS GH therapy improves height in pediatric dialysis patients, irrespective of underlying bone histologic features. Bone formation rates are higher in GH recipients, and GH therapy alters the relationship between circulating parathyroid hormone values and bone turnover.

Intermittent Calcitriol Therapy and Growth in Children with Chronic Renal Failure

Intermittent calcitriol (1,25D) therapy has been used for the management of secondary hyperparathyroidism in children with chronic renal failure; however, the development of adynamic bone has been demonstrated in up to 40% of pediatric patients after 12 months of intermittent 1,25D therapy. To assess its effect on linear growth, we compared growth and biochemical data from 16 prepubertal patients with biopsy-proven secondary hyperparathyroidism during 12 months of intermittent 1,25D therapy and the preceding year of daily 1,25D therapy. While Z-scores for height remained stable during daily therapy, values decreased from –1.8 ± 0.32 to –2.0 ± 0.33, p < 0.01, during intermittent 1,25D therapy; the largest reductions were seen in those who developed adynamic bone. Reductions in growth may be due to the direct inhibitory effects of large intermittent doses of calcitriol on chondrocyte activity.

Implications of intermittent calcitriol therapy on growth and secondary hyperparathyroidism.

Abstract Secondary hyperparathyroidism is the most common skeletal lesion in pediatric patients undergoing maintenance dialysis. The present review summarizes a prospective randomized study that evaluated the biochemical and skeletal responses to intermittent calcitriol therapy in 33 pediatric patients on peritoneal dialysis with secondary hyperparathyroidism. Also, the effect of intermittent calcitriol therapy on linear growth was evaluated in 16 of 33 patients who had completed the clinical trial. Serum parathyroid hormone levels decreased by 62% from 648±125 pg/ml in patients treated with intermittent intraperitoneal (IP) calcitriol, and values remained unchanged from pre-treatment levels of 670±97 pg/ml with oral calcitriol therapy. Overall serum total and ionized calcium levels were higher in patients treated with IP calcitriol during the study. In contrast to these biochemical findings, the skeletal lesions of secondary hyperparathyroidism improved after 12 months of treatment in both groups and adynamic bone occurred in 33% of the patients. Z-scores for height decreased from –1.80±0.3 to –2.00±0.3, P<0.01, after 12 months of intermittent calcitriol therapy. Such findings suggest that an intermittent schedule of calcitriol administration adversely affects chondrocyte activity within epiphyseal cartilage in pre-pubertal children with end-stage renal disease.

CHAPTER 28 – Renal Osteodystrophy: Pathogenesis, Diagnosis, and Treatment

This chapter discusses the pathogenesis, clinical manifestations, and management of renal osteodystrophy in children with chronic renal failure and those treated with maintenance dialysis. Renal osteodystrophy is a disorder of bone and mineral metabolism that has long been recognized as a consequence of renal dysfunction. Disturbances in calcium and phosphorus homeostasis, reduced synthesis of 1,25-dihydroxyvitamin D 3 , altered metabolism of parathyroid hormone (PTH), and impaired renal clearance of PTH fragments and other substances—such as aluminum and β 2 -macroglobulin—develop during progressive renal impairment. These factors are fundamental in the pathogenesis of renal bone disease. Although it is well established that these skeletal lesions in adults primarily represent disturbances in bone remodeling, in children, they occur during longitudinal and appositional bone growth and modeling. Thus, the control of secondary hyperparathyroidism remains a critical element in the care of pediatric patients with renal failure to prevent potential serious long-term consequences, such as bone deformities and growth retardation.