Barbara Gales

Relationship between Plasma Fibroblast Growth Factor-23 Concentration and Bone Mineralization in Children with Renal Failure on Peritoneal Dialysis

CONTEXT Fibroblast growth factor (FGF)-23 is produced in bone, and circulating levels are markedly elevated in patients with end-stage kidney disease, but the relationship between plasma levels of FGF-23 and bone histology in dialysis patients with secondary hyperparathyroidism is unknown. OBJECTIVE The aim of the study was to evaluate the correlation between plasma levels of FGF-23 and bone histology in pediatric patients with end-stage kidney disease who display biochemical evidence of secondary hyperparathyroidism. DESIGN We performed a cross-sectional analysis of the relationship between plasma FGF-23 levels and bone histomorphometry. SETTING The study was conducted in a referral center. STUDY PARTICIPANTS Participants consisted of forty-nine pediatric patients who were treated with maintenance peritoneal dialysis and who had serum PTH levels (1st generation Nichols assay) greater than 400 pg/ml. INTERVENTION There were no interventions. MAIN OUTCOME MEASURE Plasma FGF-23 levels and bone histomorphometry were measured. RESULTS No correlation existed between values of PTH and FGF-23. Bone formation rates correlated with PTH (r = 0.44; P < 0.01), but not with FGF-23. Higher FGF-23 concentrations were associated with decreased osteoid thickness (r = -0.49; P < 0.01) and shorter osteoid maturation time (r = -0.48; P < 0.01). CONCLUSIONS High levels of FGF-23 are associated with improved indices of skeletal mineralization in dialyzed pediatric patients with high turnover renal osteodystrophy. Together with other biomarkers, FGF-23 measurements may indicate skeletal mineralization status in this patient population.

Calcitriol and doxercalciferol are equivalent in controlling bone turnover, suppressing parathyroid hormone, and increasing fibroblast growth factor-23 in secondary hyperparathyroidism.

We compared the effects of calcitriol and doxercalciferol, in combination with either calcium carbonate or sevelamer, on bone, mineral, and fibroblast growth factor-23 (FGF-23) metabolism in patients with secondary hyperparathyroidism. A total of 60 pediatric patients treated with peritoneal dialysis were randomized to 8 months of therapy with either oral calcitriol or doxercalciferol, combined with either calcium carbonate or sevelamer. Bone formation rates decreased during therapy and final values were within the normal range in 72% of patients. A greater improvement in eroded surface was found in patients treated with doxercalciferol than in those given calcitriol. On initial bone biopsy, a mineralization defect was identified in the majority of patients which did not normalize with therapy. Serum phosphate concentrations were controlled equally well by both binders, but serum calcium levels increased during treatment with calcium carbonate, and serum parathyroid hormone levels were decreased by 35% in all groups. Baseline plasma FGF-23 values were significantly elevated and rose over fourfold with calcitriol and doxercalciferol, irrespective of phosphate binder. Thus, doxercalciferol is as effective as calcitriol in controlling serum parathyroid hormone levels and suppressing the bone formation rate. Sevelamer allows the use of higher doses of vitamin D. Implications of these changes on bone and cardiovascular biology remain to be established.

Fibroblast growth factor 23 inhibits extrarenal synthesis of 1,25-dihydroxyvitamin D in human monocytes

Vitamin D is a potent stimulator of monocyte innate immunity, and this effect is mediated via intracrine conversion of 25‐hydroxyvitamin D (25OHD) to 1,25‐dihydroxyvitamin D (1,25(OH)2D). In the kidney, synthesis of 1,25(OH)2D is suppressed by fibroblast growth factor 23 (FGF23), via transcriptional suppression of the vitamin D‐activating enzyme 1α‐hydroxylase (CYP27B1). We hypothesized that FGF23 also suppresses CYP27B1 in monocytes, with concomitant effects on intracrine responses to 1,25(OH)2D. Healthy donor peripheral blood mononuclear cell monocytes (PBMCm) and peritoneal dialysate monocyte (PDm) effluent from kidney disease patients were assessed at baseline to confirm the presence of mRNA for FGF23 receptors (FGFRs), with Klotho and FGFR1 being more strongly expressed than FGFR2/3/4 in both cell types. Immunohistochemistry showed coexpression of Klotho and FGFR1 in PBMCm and PDm, with this effect being enhanced following treatment with FGF23 in PBMCm but not PDm. Treatment with FGF23 activated mitogen‐activated protein kinase (MAPK) and protein kinase B (Akt) pathways in PBMCm, demonstrating functional FGFR signaling in these cells. FGF23 treatment of PBMCm and PDm decreased expression of mRNA for CYP27B1. In PBMCm this was associated with downregulation of 25OHD to 1,25(OH)2D metabolism, and concomitant suppression of intracrine induced 24‐hydroxylase (CYP24A1) and antibacterial cathelicidin (LL37). FGF23 suppression of CYP27B1 was particularly pronounced in PBMCm treated with interleukin‐15 to stimulate synthesis of 1,25(OH)2D. These data indicate that FGF23 can inhibit extra‐renal expression of CYP27B1 and subsequent intracrine responses to 1,25(OH)2D in two different human monocyte models. Elevated expression of FGF23 may therefore play a crucial role in defining immune responses to vitamin D and this, in turn, may be a key determinant of infection in patients with chronic kidney disease (CKD).

Early Skeletal and Biochemical Alterations in Pediatric Chronic Kidney Disease

BACKGROUND AND OBJECTIVES The relationship between parathyroid hormone, fibroblast growth factor 23 (FGF-23), and indices of bone turnover and mineralization in children with early CKD is unknown; thus, this study characterizes the features of renal osteodystrophy and their relationship to biochemical markers of mineral metabolism. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Fifty-two patients 2-21 years of age with predialysis CKD underwent tetracycline-labeled bone biopsy. Anthropomorphic measurements and biochemical values were obtained at the time of biopsy. RESULTS Serum phosphorus levels were increased in 4% of patients with stage 3 CKD and 43% of those with stage 4/5 CKD. Parathyroid hormone concentrations were elevated in 36% of patients with stage 2, 71% with stage 3, and 93% with stage 4/5 CKD, whereas FGF-23 values were elevated in 81% of all patients, regardless of CKD stage. Bone turnover was normal in all patients with stage 2, but was increased in 13% with stage 3 and 29% with stage 4/5 CKD. Defective mineralization was present in 29% of patients with stage 2, 42% with stage 3, and 79% with stage 4/5 CKD. Defective skeletal mineralization was associated with lower serum calcium levels and increased parathyroid hormone concentrations. CONCLUSIONS Elevated circulating FGF-23 levels and defects in skeletal mineralization early in the course of CKD suggest that factors other than the traditional markers of mineral deficiency play a crucial role in the development of renal bone disease.

Sevelamer Controls Parathyroid Hormone–Induced Bone Disease as Efficiently as Calcium Carbonate without Increasing Serum Calcium Levels during Therapy with Active Vitamin D Sterols

Little is known about the impact of various phosphate binders on the skeletal lesions of secondary hyperparathyroidism (2 degrees HPT). The effects of calcium carbonate (CaCO3) and sevelamer were compared in pediatric peritoneal dialysis patients with bone biopsy-proven 2 degrees HPT. Twenty-nine patients were randomly assigned to CaCO3 (n = 14) or sevelamer (n = 15), concomitant with either intermittent doses of oral calcitriol or doxercalciferol for 8 mo, when bone biopsies were repeated. Serum phosphorus, calcium, parathyroid hormone (PTH), and alkaline phosphatase were measured monthly. The skeletal lesions of 2 degrees HPT improved with both binders, and bone formation rates reached the normal range in approximately 75% of the patients. Overall, serum phosphorus levels were 5.5 +/- 0.1 and 5.6 +/- 0.3 mg/dl (NS) with CaCO3 and sevelamer, respectively. Serum calcium levels and the Ca x P ion product increased with CaCO3; in contrast, values remained unchanged with sevelamer (9.6 +/- 01 versus 8.9 +/- 0.2 mg/dl; P < 0.001, respectively). Hypercalcemic episodes (>10.2 mg/dl) occurred more frequently with CaCO3 (P < 0.01). Baseline PTH levels were 980 +/- 112 and 975 +/- 174 pg/ml (NS); these values decreased to 369 +/- 92 (P < 0.01) and 562 +/- 164 pg/ml (P < 0.01) in the CaCO3 and the sevelamer groups, respectively (NS between groups). Serum alkaline phosphatase levels also diminished in both groups (P < 0.01). Thus, treatment with either CaCO3 or sevelamer resulted in equivalent control of the biochemical and skeletal lesions of 2 degrees HPT. Sevelamer, however, maintained serum calcium concentrations closer to the lower end of the normal physiologic range, thereby increasing the safety of treatment with active vitamin D sterols.

Reduction of Serum Hepcidin by Hemodialysis in Pediatric and Adult Patients

BACKGROUND AND OBJECTIVES Hepcidin, the principal regulator of iron homeostasis, may play a critical role in the response of patients with anemia to iron and erythropoiesis-stimulating agent therapy; however, the contribution of hepcidin to iron maldistribution and anemia in hemodialysis (HD) patients and the ability of HD to lower serum hepcidin levels have not been fully characterized. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We measured serum hepcidin using a competitive ELISA in 30 pediatric and 33 adult HD patients. In addition, we determined serum hepcidin kinetics and calculated hepcidin clearance by measuring serum hepcidin before, during, and after HD in eight pediatric and six adult patients. RESULTS Hepcidin was significantly increased in pediatric (median 240.5 ng/ml) and adult HD patients (690.2 ng/ml) when compared with their respective control subjects (pediatric 25.3 ng/ml, adult 72.9 ng/ml). Multivariate regression analysis showed that serum hepcidin was independently predicted by ferritin and high-sensitivity C-reactive protein in the pediatric group and ferritin, percentage of iron saturation, and high-sensitivity C-reactive protein in the adult group. Hepcidin levels decreased after dialysis from 532 +/- 297 to 292 +/- 171 ng/ml. Hepcidin clearance by HD was 141 +/- 40 and 128 +/- 44 ml/min in pediatric and adult patients, respectively (NS). CONCLUSIONS These findings suggest that hepcidin may mediate the negative effects of inflammation on both disordered iron metabolism and erythropoiesis in HD patients and that intensification of HD could be used therapeutically to reduce hepcidin concentrations and thereby improve erythropoiesis-stimulating agent responsiveness.

Value of the New Bone Classification System in Pediatric Renal Osteodystrophy

BACKGROUND AND OBJECTIVES Although lesions of renal osteodystrophy have traditionally been defined by bone turnover, alterations in skeletal mineralization and volume are also prevalent and may contribute to significant morbidity in patients with chronic kidney disease (CKD). The study presented here was undertaken to compare the traditional spectrum of renal osteodystrophy defined by bone turnover to a new classification system that includes T (turnover), M (mineralization), and V (volume) and to determine the value of biochemical parameters as predictors of specific TMV lesions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Pediatric patients (n = 161) treated with peritoneal dialysis were enrolled into the study. RESULTS Increased bone turnover and abnormal mineralization were prevalent (57% and 48%, respectively); bone volume was normal or increased in all subjects. Predictive algorithms for different skeletal diagnoses were established by Classification and regression tree analysis. Serum parathyroid hormone (PTH) less than 400 pg/ml in combination with alkaline phosphatase values less than 400 IU/L provided the highest correct prediction rate for patients with both normal bone turnover and normal mineralization. Levels of PTH were higher and serum calcium levels were lower in patients with defective mineralization, irrespective of bone turnover. CONCLUSIONS Although no single biochemical marker is able to provide a complete assessment of renal osteodystrophy, a combination of serum calcium, alkaline phosphatase, and PTH levels may lead to a more precise noninvasive assessment of turnover and mineralization abnormalities in this population.

The Calcemic Response to Continuous Parathyroid Hormone (PTH)(1-34) Infusion in End-Stage Kidney Disease Varies According to Bone Turnover: A Potential Role for PTH(7-84)

CONTEXT Factors contributing to PTH resistance in dialysis patients remain elusive. OBJECTIVES The study assessed the skeletal and biochemical response to 46 h of PTH(1-34) infusion in dialysis patients. DESIGN The study was a prospective, controlled assessment of response to PTH(1-34). SETTING The study was performed at the University of California, Los Angeles, General Clinical Research Center. PARTICIPANTS Nineteen dialysis patients and 17 healthy volunteers were studied. INTERVENTION PTH(1-34) was infused at a rate of 8 pmol/kg x h for 46 h. Bone biopsy was performed in all dialysis patients. MAIN OUTCOME MEASURES Serum calcium, phosphorus, 1,25-dihydroxyvitamin D, PTH (four separate assays), and FGF-23 were determined at baseline and h 7, 23, 35, and 46 of the infusion. RESULTS Serum calcium levels rose in healthy volunteers (9.2 +/- 0.1 to 11.9 +/- 0.3 mg/dl; P < 0.01) and in dialysis patients with adynamic/normal bone turnover (9.0 +/- 0.3 to 10.7 +/- 0.7 mg/dl; P < 0.05) but did not change in dialysis patients with high bone turnover. Serum phosphorus levels declined in healthy volunteers (3.9 +/- 0.1 to 3.5 +/- 0.1 mg/dl; P < 0.05) but increased in all dialysis patients (6.7 +/- 0.4 to 8.0 +/- 0.3 mg/dl; P < 0.05). Full-length PTH(1-84) declined in all subjects; however, PTH(7-84) fragments declined only in healthy subjects and in dialysis patients with normal/adynamic bone but remained unchanged in dialysis patients with high bone turnover. CONCLUSIONS The skeleton of dialysis patients with high bone turnover is resistant to the calcemic actions of PTH. PTH(7-84) may contribute to this phenomenon.

Technical approach to iliac crest biopsy.

Bone histomorphometry has been the gold standard in the evaluation and diagnosis of renal osteodystrophy. The recent new definition of renal osteodystrophy as chronic kidney disease-mineral and bone disorder has once again highlighted the use of bone biopsy as a powerful and diagnostic tool to determine skeletal abnormalities in chronic kidney disease. The procedure of iliac crest bone biopsy has been proved safe and associated with very minimal morbidity. In this review, the clinical indications, preparation, instrumentation, and potential complications are discussed. Because current biochemical markers are poor predictors of bone turnover, volume, and mineralization, a wider use of bone biopsy and histomorphometry will lead to a better understanding of the bone and mineral disorders that are associated with chronic kidney disease.

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.