Sclerostin, Osteocytes, and Wnt Signaling in Pediatric Renal Osteodystrophy.

The pathophysiology of chronic kidney disease-mineral and bone disorder (CKD-MBD) is not well understood. Specific factors secreted by osteocytes are elevated in the serum of adults and pediatric patients with CKD-MBD, including FGF-23 and sclerostin, a known inhibitor of the Wnt signaling pathway. The molecular mechanisms that promote bone disease during the progression of CKD are incompletely understood. In this study, we performed a cross-sectional analysis of 87 pediatric patients with pre-dialysis CKD and post-dialysis (CKD 5D). We assessed the associations between serum and bone sclerostin levels and biomarkers of bone turnover and bone histomorphometry. We report that serum sclerostin levels were elevated in both early and late CKD. Higher circulating and bone sclerostin levels were associated with histomorphometric parameters of bone turnover and mineralization. Immunofluorescence analyses of bone biopsies evaluated osteocyte staining of antibodies towards the canonical Wnt target, ß-catenin, in the phosphorylated (inhibited) or unphosphorylated (active) forms. Bone sclerostin was found to be colocalized with phosphorylated ß-catenin, which suggests that Wnt signaling was inhibited. In patients with low serum sclerostin levels, increased unphosphorylated "active" ß-catenin staining was observed in osteocytes. These data provide new mechanistic insight into the pathogenesis of CKD-MBD and suggest that sclerostin may offer a potential biomarker or therapeutic target in pediatric renal osteodystrophy.

Envarsus XR® pharmacokinetics in adolescents post-kidney transplantation - A pilot study.

INTRODUCTION: Envarsus XR® (LCPT), a once daily dosage formulation of tacrolimus, is an FDA-approved medication in adult renal transplant recipients (RTRs). There are limited data on its pharmacokinetics (PK) in adolescent RTRs. We report here the PK profile of LCPT in adolescent RTRs. METHODS: The dose of LCPT was determined using a dose conversion ratio targeting 0.7 relative to the total daily immediate-release tacrolimus (IR-Tac) dose. On day 7 after converting to LCPT, patients had an abbreviated PK assessment with sampling at: 0 h (pre-dose), 8-, and 12-h post-dose. The PK data analysis was performed using Bayesian estimators. Our results were compared to those of published adult PK data for LCPT and pediatric PK data for IR-Tac and extended release tacrolimus (ER-Tac) formulation (Advagraf). RESULTS: PK data from three adolescent patients on LCPT were evaluated. The mean (±SD) area under the time-concentration curve (AUC) was 240 (±20.22) h*ng/mL. The mean Tmax was 9.01 ± 2.12 h, and the % fluctuation was 77.71 ± 3.96%. The AUC, Tmax , and % fluctuation were similar to reported results in adult patients taking LCPT. The AUC was higher and the Tmax was longer than what has been reported in pediatric patients taking IR-Tac and ER-Tac. In addition, the LCPT group showed a lower % fluctuation than patients receiving ER-Tac. CONCLUSION: The PK evaluation of LCPT in adolescent RTRs showed similar results to adults. Adolescents taking LCPT had a higher AUC, a more attenuated Tmax , and a lower fluctuation than that seen with ER-Tac in pediatrics.

Effects of Primary Kidney Disease Etiology on Renal Osteodystrophy in Pediatric Dialysis Patients.

Congenital diseases of the kidney and urinary tract (CAKUT) and glomerulonephritis are the main causes of chronic kidney disease (CKD) in children. Although renal osteodystrophy (ROD) and indices of mineral metabolism have been characterized in dialyzed children, the impact of primary kidney disease on ROD is unknown. We performed a cross-sectional study of bone biopsies performed in 189 pediatric dialysis patients aged 12.6 ± 5.4 years. Patients were classified into three groups according to primary kidney disease: CAKUT (n = 82), hereditary (n = 22), or glomerular disease (n = 85). Serum concentrations of calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 25(OH) vitamin D were measured at the time of biopsy. Fibroblast growth factor 23 (FGF23) levels were measured in a subset of 59 patients. Levels of calcium, phosphate, PTH, and 25(OH) vitamin D were similar across groups. CAKUT patients had higher serum ALP and lower C-terminal FGF23 levels. Bone turnover and bone volume parameters did not differ across groups. However, osteoid volume (OV/BV), osteoid surface (OS/BS), and osteoid maturation time (OMT) were highest in the CAKUT group and lowest in the hereditary group. Multiple regression analysis revealed that calcium, phosphate, ALP, and PTH were independently associated with OV/BV and osteoid thickness (O.Th). PTH was an independent factor affecting bone formation rate. The relationship between CKD etiology and bone histomorphometric variables was abrogated after adjustment for biochemical parameters in the multivariable models. Overall, bone histology differed according to CKD etiology in the unadjusted analysis; however, this association could not be confirmed independently of biochemical parameters. Although CAKUT patients had a greater mineralization defect with elevated serum ALP levels, longitudinal studies will be needed to elucidate mediation pathways that might be involved in the complex interplay of CKD-mineral bone disease (MBD). © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Bone marrow adiposity inversely correlates with bone turnover in pediatric renal osteodystrophy.

Bone marrow adiposity is associated with bone disease in the general population. Although chronic kidney disease (CKD) is associated with increased bone fragility, the correlation between marrow adiposity and bone health in CKD is unknown. We evaluated the relationship between bone marrow adipocytes and bone histomorphometry in 32 pediatric patients. We also evaluated the effects of growth hormone and calcitriol (1,25(OH)2D3)-two therapies commonly prescribed for pediatric bone disease-on marrow adiposity and bone histomorphometry. Finally, the adipogenic potential of primary human osteoblasts from CKD patients was assessed in vitro, both alone and in the presence of 1,25(OH)2D3. In cross-sectional analysis, marrow adipocyte number per tissue area (Adi.N/T.Ar) correlated with bone formation rate/bone surface (BFR/BS) in patients with high bone turnover (r = -0.55, p = 0.01) but not in those with low/normal bone turnover. Changes in bone formation rate correlated with changes Adi.N/T.Ar on repeat bone biopsy(r = -0.48, p = 0.02). In vitro, CKD and control osteoblasts had a similar propensity to transition into an adipocyte-like phenotype; 1,25(OH)2D3 had very little effect on this propensity. In conclusion, marrow adiposity correlates inversely with bone turnover in pediatric patients with high turnover renal osteodystrophy. The range of adiposity observed in pediatric patients with low/normal bone turnover is not explained by intrinsic changes to precursor cells or by therapies but may reflect the effects of circulating factors on bone cell health in this population.

Nephropathic Cystinosis: A Distinct Form of CKD-Mineral and Bone Disorder that Provides Novel Insights into the Regulation of FGF23.

BACKGROUND: The rare lysosomal storage disease nephropathic cystinosis presents with renal Fanconi syndrome that evolves in time to CKD. Although biochemical abnormalities in common causes of CKD-mineral and bone disorder have been defined, it is unknown if persistent phosphate wasting in nephropathic cystinosis is associated with a biochemical mineral pattern distinct from that typically observed in CKD-mineral and bone disorder. METHODS: We assessed and compared determinants of mineral homeostasis in patients with nephropathic cystinosis across the predialysis CKD spectrum to these determinants in age- and CKD stage-matched patients, with causes of CKD other than nephropathic cystinosis. RESULTS: The study included 50 patients with nephropathic cystinosis-related CDK and 97 with CKD from other causes. All major aspects of mineral homeostasis were differentially effected in patients with CKD stemming from nephropathic cystinosis versus other causes. Patients with nephropathic cystinosis had significantly lower percent tubular reabsorption of phosphate and fibroblast growth factor-23 (FGF23) at all CKD stages, and lower blood phosphate in CKD stages 3-5. Linear regression analyses demonstrated lower FGF23 levels in nephropathic cystinosis participants at all CKD stages when corrected for eGFR and age, but not when adjusted for serum phosphate. CONCLUSIONS: Nephropathic cystinosis CKD patients have mineral abnormalities that are distinct from those in CKD stemming from other causes. Persistently increased urinary phosphate excretion maintains serum phosphate levels within the normal range, thus protecting patients with nephropathic cystinosis from elevations of FGF23 during early CKD stages. These findings support the notion that phosphate is a significant driver of increased FGF23 levels in CKD and that mineral abnormalities associated with CKD are likely to vary depending on the underlying renal disease.

Measurement of serum phosphate levels using a mobile sensor.

The measurement of serum phosphate concentration is crucial for patients with advanced chronic kidney disease (CKD) and those on maintenance dialysis, as abnormal phosphate levels may be associated with severe health risks. It is important to monitor serum phosphate levels on a regular basis in these patients; however, such measurements are generally limited to every 0.5-3 months, depending on the severity of CKD. This is due to the fact that serum phosphate measurements can only be performed at regular clinic visits, in addition to cost considerations. Here we present a portable and cost-effective point-of-care device capable of measuring serum phosphate levels using a single drop of blood (<60 µl). This is achieved by integrating a paper-based microfluidic platform with a custom-designed smartphone reader. This mobile sensor was tested on patients undergoing dialysis, where whole blood samples were acquired before starting the hemodialysis and during the three-hour treatment. This sampling during the hemodialysis, under patient consent, allowed us to test blood samples with a wide range of phosphate concentrations, and our results showed a strong correlation with the ground truth laboratory tests performed on the same patient samples (Pearson coefficient r = 0.95 and p < 0.001). Our 3D-printed smartphone attachment weighs about 400 g and costs less than 80 USD, whereas the material cost for the disposable test is <3.5 USD (under low volume manufacturing). This low-cost and easy-to-operate system can be used to measure serum phosphate levels at the point-of-care in about 45 min and can potentially be used on a daily basis by patients at home.

Effects of erythropoietin on fibroblast growth factor 23 in mice and humans.

BACKGROUND: Erythropoietin (EPO) has been reported as a novel determinant of fibroblast growth factor 23 (FGF23) production; however, it is unknown whether FGF23 is stimulated by chronic exposure to EPO or by EPO administration in nonpolycystic chronic kidney disease (CKD) models. METHODS: We analyzed the effects of chronic EPO on FGF23 in murine models with chronically high EPO levels and normal kidney function. We studied the effects of exogenous EPO on FGF23 in wild-type mice, with and without CKD, injected with EPO. Also, in four independent human CKD cohorts, we evaluated associations between FGF23 and serum EPO levels or exogenous EPO dose. RESULTS: Mice with high endogenous EPO have elevated circulating total FGF23, increased disproportionately to intact FGF23, suggesting coupling of increased FGF23 production with increased proteolytic cleavage. Similarly, in wild-type mice with and without CKD, a single exogenous EPO dose acutely increases circulating total FGF23 out of proportion to intact FGF23. In these murine models, the bone marrow is shown to be a novel source of EPO-stimulated FGF23 production. In humans, serum EPO levels and recombinant human EPO dose are positively and independently associated with total FGF23 levels across the spectrum of CKD and after kidney transplantation. In our largest cohort of 680 renal transplant recipients, serum EPO levels are associated with total FGF23, but not intact FGF23, consistent with the effects of EPO on FGF23 production and metabolism observed in our murine models. CONCLUSION: EPO affects FGF23 production and metabolism, which may have important implications for CKD patients.

Clinical experience with the use of ferric citrate as a phosphate binder in pediatric dialysis patients.

BACKGROUND: Ferric citrate, an iron-based phosphate binder, has been shown to improve both hyperphosphatemia and iron deficiency in adult chronic kidney disease patients, but its use in the pediatric dialysis population has not been described. METHODS: This is a retrospective analysis of 11 unselected pediatric dialysis patients who received ferric citrate as a phosphate binder between 2015 and 2017. Time-averaged laboratory values were compared pre- and post-ferric citrate initiation using the Wilcoxon signed-rank test. RESULTS: The median age of this cohort was 13 years old (range 4-17 years old). Five patients were on hemodialysis, and six patients were on peritoneal dialysis. The median duration of ferric citrate therapy was 214 days (range 39-654 days), with a median time-averaged ferric citrate dose of 3.5 tablets per day (range 1.5-8.4 tablets per day). Compared to the pre-ferric citrate period, ferric citrate treatment was associated with decreased serum phosphate (6.5 to 5.2 mg/dl, p = 0.014), decreased phosphate age-related standard deviation score (SDS) (2.3 to 0.9, p = 0.019), increased transferrin saturation (26 to 34%, p = 0.049), increased ferritin (107 to 230 ng/ml, p = 0.074), and maintenance of hematocrit. CONCLUSIONS: In pediatric dialysis patients, ferric citrate may be able to concurrently lower phosphate levels and treat iron deficiency. However, larger studies are needed to further evaluate safety and efficacy in the pediatric chronic kidney disease population.

Fractures and Osteomalacia in a Patient Treated With Frequent Home Hemodialysis.

Bone deformities and fractures are common consequences of renal osteodystrophy in the dialysis population. Persistent hypophosphatemia may be observed with more frequent home hemodialysis regimens, but the specific effects on the skeleton are unknown. We present a patient with end-stage renal disease treated with frequent home hemodialysis who developed severe bone pain and multiple fractures, including a hip fracture and a tibia-fibula fracture complicated by nonunion, rendering her nonambulatory and wheelchair bound for more than a year. A bone biopsy revealed severe osteomalacia, likely secondary to chronic hypophosphatemia and hypocalcemia. Treatment changes included the addition of phosphate to the dialysate, a higher dialysate calcium concentration, and increased calcitriol dose. Several months later, the patient no longer required a wheelchair and was able to ambulate without pain. Repeat bone biopsy revealed marked improvements in bone mineralization and turnover parameters. Also, with increased dialysate phosphate and calcium concentrations, as well as increased calcitriol, circulating fibroblast growth factor 23 levels increased.

Effects of acute kidney injury and chronic hypoxemia on fibroblast growth factor 23 levels in pediatric cardiac surgery patients.

BACKGROUND: Fibroblast growth factor-23 (FGF23) levels are elevated in cardiopulmonary bypass (CPB)-associated acute kidney injury (AKI); however, it is unknown how much of the circulating FGF23 is intact and bioactive. Hypoxia may induce FGF23 production, yet its impact in humans is unknown. Pediatric cardiac surgery patients have both a high incidence of CPB-associated AKI and a high prevalence of chronic hypoxemia. METHODS: We assessed the effects of hypoxemia and CPB-associated AKI on C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 32 pediatric cardiac surgery patients with normal estimated glomerular filtration rate (eGFR). Plasma cFGF23 and iFGF23 were measured preoperatively and serially postoperatively. RESULTS: Despite normal renal and ventricular function, preoperative cFGF23 levels were high and elevated out of proportion to iFGF23 levels. Preoperative oxygen saturation measurements correlated inversely with FGF23 levels. Preoperative cFGF23 and oxygen saturation both predicted postoperative AKI. Postoperatively, cFGF23 and iFGF23 increased by 2 h postreperfusion; iFGF23 then returned to baseline, but cFGF23 remained elevated through 24 h postreperfusion. Group status (AKI vs. non-AKI) modified the effect of time on changes in iFGF23 levels but not cFGF23 levels. CONCLUSIONS: Preoperative cFGF23 may predict CPB-associated kidney dysfunction. Changes over time in cFGF23 and iFGF23 levels post-CPB differ. Chronic hypoxemia may affect FGF23 production in humans.

Osteocytic protein expression response to doxercalciferol therapy in pediatric dialysis patients.

BACKGROUND: Osteocytic protein expression is dysregulated in CKD and is affected by changes in mineral metabolism; however the effects of active vitamin D sterol therapy on osteocyte protein expression in advanced CKD is unknown. METHODS: Eleven pediatric patients with end stage kidney disease underwent bone biopsy, were treated for 8 months with doxercalciferol, and then underwent a second bone biopsy. Bone expression of fibroblast growth factor 23 (FGF23), dentin matrix protein 1 (DMP1), and sclerostin were determined by immunohistochemistry and quantified by Ariol Scanning. Western blot analysis and qRT-PCR was performed on bone abstracts of a subset of study subjects to determine the nature (i.e. size) of FGF23 and DMP1 in bone before and after therapy. RESULTS: As assessed by immunohistochemistry, bone FGF23, DMP1 and sclerostin protein all increased with therapy. In the case of FGF23, this increase was due to an increase in the full-length molecule without the appearance of FGF23 fragments. DMP1 was present primarily in its full-length form in healthy controls while 57kDa and 37kDa fragments of DMP1 were apparent in bone of dialysis patients at baseline and the 57 kDa appeared to decrease with therapy. CONCLUSION: Marked changes in osteocytic protein expression accompany doxercalciferol therapy, potentially impacting bone mineralization and the skeletal response to PTH. The effects of these bone changes on long-term outcomes remain to be determined.

High-resolution, whole-body vascular imaging with ferumoxytol as an alternative to gadolinium agents in a pediatric chronic kidney disease cohort.

BACKGROUND: Exposure to gadolinium-based contrast agents (GBCA) in patients with chronic kidney disease (CKD) has been associated with the development of a potentially fatal disorder, nephrogenic systemic fibrosis (NSF). Although contrast-enhanced computed tomography (CT) is an alternative to magnetic resonance imaging (MRI), it carries the risk of radiation exposure and further reduction of residual renal function. Therefore we sought to assess the feasibility of ferumoxytol as an alternative to GBCA for contrast-enhanced MR angiography (MRA) in a pediatric cohort with CKD. Ferumoxytol is a parenteral iron supplement that contains ultrasmall superparamagnetic iron oxide (USPIO) and is a potent relaxivity agent for MRI. METHODS: We describe the MRI findings in ten pediatric patients who needed detailed vascular mapping. Ferumoxytol (4 mg/kg) was administered intravenously for contrast-enhanced MRA. The patients tolerated the procedure without complications. RESULTS: Resulting studies were highly diagnostic and were pivotal in guiding patient management. The images were notable for clear delineation of multiple vascular occlusions. CONCLUSIONS: Given the concerns associated with the use of GBCAs in renal failure, ferumoxytol is an excellent alternative contrast agent in pediatric end stage renal disease (ESRD) patients. Future studies are needed in order to further evaluate safety and efficacy of ferumoxytol in this patient population.

Cortical and trabecular bone in pediatric end-stage kidney disease.

BACKGROUND: Cortical bone represents nearly 80 % of human bone mass and is the major determinant of bone strength; however, cortical bone parameters and their relationship to trabecular bone in the pediatric chronic kidney disease (CKD) population have not been evaluated. METHODS: Biochemical values and cortical and trabecular bone parameters were assessed in 22 pediatric dialysis patients: 12 with high and 10 with normal to low trabecular bone turnover. RESULTS: Trabecular bone turnover and osteoid volume correlated with parathyroid hormone (PTH) levels (r = 0.86, p < 0.01 and r = 0.93, p < 0.01, respectively). Internal cortical osteonal bone formation rate was directly related to alkaline phosphatase (r = 0.45, p < 0.05) and inversely related to insulin-like growth factor (IGF)-1 values (r = -0.55, p < 0.01), and internal cortical porosity was also related to serum alkaline phosphatase levels (r = 0.57, p < 0.01). A similar relationship was not found between external cortical bone formation rate and parameters of bone turnover and porosity, however. No relationship was found between trabecular and cortical bone formation rates. CONCLUSIONS: Secondary hyperparathyroidism was associated with increased external cortical, relative to internal cortical, osteonal activity in pediatric dialysis patients. The clinical consequences of these changes and their response to therapy for secondary hyperparathyroidism remain to be defined.

Antibacterial responses by peritoneal macrophages are enhanced following vitamin D supplementation.

Patients with chronic kidney disease (CKD), who usually display low serum 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), are at high risk of infection, notably those undergoing peritoneal dialysis (PD). We hypothesized that peritoneal macrophages from PD patients are an important target for vitamin D-induced antibacterial activity. Dialysate effluent fluid was obtained from 27 non-infected PD patients. Flow cytometry indicated that PD cells were mainly monocytic (37.9±17.7% cells CD14+/CD45+). Ex vivo analyses showed that PD cells treated with 25D (100 nM, 6 hrs) or 1,25D (5 nM, 6 hrs) induced mRNA for antibacterial cathelicidin (CAMP) but conversely suppressed mRNA for hepcidin (HAMP). PD cells from patients with peritonitis (n = 3) showed higher baseline expression of CAMP (18-fold±9, p<0.05) and HAMP (64-fold±7) relative to cells from non-infected patients. In 12 non-infected PD patients, oral supplementation with a single dose of vitamin D2 (100,000 IU) increased serum levels of 25D from 18±8 to 41±15 ng/ml (p = 0.002). This had no significant effect on PD cell CD14/CD45 expression, but mRNA for HAMP was suppressed significantly (0.5-fold, p = 0.04). Adjustment for PD cell CD14/CD45 expression using a mixed linear statistical model also revealed increased expression of CAMP (mRNA in PD cells and protein in effluent) in vitamin D-supplemented patients. These data show for the first time that vitamin D supplementation in vitro and in vivo promotes innate immune responses that may enhance macrophage antibacterial responses in patients undergoing PD. This highlights a potentially important function for vitamin D in preventing infection-related complications in CKD.

Lack of FGF23 response to acute changes in serum calcium and PTH in humans.

CONTEXT: 1,25-Dihydroxyvitamin D (1,25D) administration and long-term increases in phosphate, PTH, and calcium concentrations are associated with increases in circulating fibroblast growth factor 23 (FGF23); however, whether or not acute changes in serum calcium modulate short-term FGF23 release is unknown. OBJECTIVE/DESIGN: To assess the direct effect of acute changes in calcium and PTH on circulating FGF23 levels. SETTING: A university clinical and translational research center. PATIENTS/PARTICIPANTS: Twelve healthy volunteers and 10 dialysis patients. INTERVENTIONS: Calcium gluconate and sodium citrate were infused for 120 minutes on 2 consecutive days. MAIN OUTCOME MEASURES: Serum levels of ionized calcium, phosphorus, PTH, 1,25D, and plasma C-terminal FGF23 levels were obtained at 0, 13, 30, 60, 90, and 120 minutes during the infusions. RESULTS: During the calcium infusion, serum calcium concentrations increased from 1.33 ± 0.01 to 1.57 ± 0.04 mmol/L (P < .05 from baseline) and from 1.20 ± 0.05 to 1.50 ± 0.03 mmol/L (P < .05 from baseline) in healthy subjects and in dialysis patients, respectively, whereas serum calcium values decreased from 1.33 ± 0.01 to 1.03 ± 0.02 mmol/L (P < .05 from baseline) and from 1.26 ± 0.04 to 1.07 ± 0.03 mmol/L (P < .05 from baseline) in the two groups, respectively during the sodium citrate infusion. PTH levels decreased from 35 (29, 57) to 8 (2,10) pg/mL (healthy subjects) (P < .05 from baseline) and from 292 (109, 423) to 44 (28, 86) pg/mL (dialysis patients) (P < .05 from baseline) during the calcium infusion and rose from 31 (25, 56) to 122 (95, 157) pg/mL and from 281 (117, 607) to 468 (169, 928) pg/mL (P < .05 from baseline) during sodium citrate infusion. Serum 1,25D levels and plasma FGF23 values remained unchanged during both infusions in both groups. CONCLUSIONS: Short-term changes in calcium and PTH levels do not affect FGF23 concentrations in either healthy volunteers or dialysis patients.

Short daily hemodialysis is associated with lower plasma FGF23 levels when compared with conventional hemodialysis.

BACKGROUND: The utilization of short-term daily hemodialysis has increased over the last few years, but little is known on its effects on the control of serum phosphate and fibroblast growth factor 23 (FGF23) levels. METHODS: We therefore performed a cross-sectional study to compare FGF23 levels as well as other biochemical variables between 24 patients undergoing short daily hemodialysis using the NxStage System® and 54 patients treated with conventional in-center hemodialysis. FGF23 levels were measured using the second-generation Immutopics® C-terminal assay. RESULTS: Short daily hemodialysis patients were younger than patients on conventional hemodialysis but there were no differences between groups in the duration of end-stage renal disease nor in the number of patients with residual renal function. A greater number of short daily hemodialysis patients received vitamin D sterol therapy than did conventional in-center hemodialysis patients while there were no differences in the use of different phosphate binders and calcimimetic therapy between groups. Overall serum calcium, phosphorus and intact parathyroid hormone levels were similar between groups. While serum phosphorus levels correlated with FGF23 concentrations in each group separately [r=0.522 (P<0.01) and r=0.42 (P<0.01) in short daily and conventional in-center hemodialysis, respectively], FGF23 levels were lower [823 RU/mL (263, 2169)] in the patients receiving short daily hemodialysis than in patients treated with conventional hemodialysis [2521 RU/mL (909, 5556)] (P<0.01 between groups). CONCLUSIONS: These findings demonstrate that FGF23 levels are significantly lower in short daily hemodialysis patients and suggest that FGF23 levels may be a more sensitive biomarker of cumulative phosphate burden than single or multiple serum phosphorus determinations in patients treated with hemodialysis.

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.

Idiopathic juvenile osteoporosis: a cross-sectional single-centre experience with bone histomorphometry and quantitative computed tomography.

BACKGROUND: Idiopathic juvenile osteoporosis (IJO) is a rare condition of poorly understood etiology and pathophysiology that affects otherwise healthy children. This condition is characterized clinically by bone pain and vertebral fractures; spontaneous recovery is observed after puberty in the majority of cases. Although decreased trabecular bone turnover has been noted previously, cortical and trabecular bone characteristics as determined by quantitative computed tomography (QCT) and their relationship to bone histomorphometry are unknown. METHODS: All children with a clinical diagnosis of IJO who were followed in our center since 1995 and who had undergone at least one diagnostic bone biopsy were included in this cross-sectional analysis. RESULTS: Fifteen patients (11 males/4 females) with median ages of 5.8 and 10.2 years at first symptoms and at referral, respectively, were included in the analysis. Histomorphometric analysis demonstrated decreased trabecular bone turnover (BFR/BS) in the majority of patients with heterogeneous parameters of trabecular mineralization and volume. QCTresults demonstrated that bone mineral density (BMD) was reduced in both trabecular/lumbar and cortical/femoral bone: Z score: -2.1 (-3.6;-1.0) and -0.9 (-8.2;1.4)in the two compartments, respectively. In the eight patients who underwent both bone biopsy and QCT, cortical BMD was associated with trabecular separation and with trabecular bone formation rate (r = 0.898 and -0.881, respectively, both p < 0.05). CONCLUSIONS: This series confirms that IJO is characterized by impaired trabecular architecture that can be detected by both bone biopsy and QCT. The association between bone biopsy and QCT results may have implications for diagnosis, treatment, and follow-up of these children.

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)(2) D). In the kidney, synthesis of 1,25(OH)(2) D 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)(2) D. 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)(2) D 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)(2) D. These data indicate that FGF23 can inhibit extra-renal expression of CYP27B1 and subsequent intracrine responses to 1,25(OH)(2) D 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).