Search

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.

Background and Objectives High plasma concentration of fibroblast growth factor 23 (FGF23) is a risk factor for left ventricular hypertrophy (LVH) in adults with CKD, and induces myocardial hypertrophy in experimental CKD. We hypothesized that high FGF23 levels associate with a higher prevalence of LVH in children with CKD. Design, setting, participants, & measurements We performed echocardiograms and measured plasma C-terminal FGF23 concentrations in 587 children with mild-to-moderate CKD enrolled in the Chronic Kidney Disease in Children (CKiD) study. We used linear and logistic regression to analyze the association of plasma FGF23 with left ventricular mass index (LVMI) and LVH (LVMI ≥95th percentile), adjusted for demographics, body mass index, eGFR, and CKD-specific factors. We also examined the relationship between FGF23 and LVH by eGFR level. Results Median age was 12 years (interquartile range, 8–15) and eGFR was 50 ml/min per 1.73 m2 (interquartile range, 38–64). Overall prevalence of LVH was 11%. After adjustment for demographics and body mass index, the odds of having LVH was higher by 2.53 (95% confidence interval, 1.28 to 4.97; P Conclusions Plasma FGF23 concentration ≥170 RU/ml is an independent predictor of LVH in children with eGFR≥45 ml/min per 1.73 m2.

Background and objectives Plasma fibroblast growth factor 23 (FGF23) concentrations increase early in the course of CKD in children. High FGF23 levels associate with progression of CKD in adults. Whether FGF23 predicts CKD progression in children is unknown. Design, setting, participants, & measurements We tested the hypothesis that high plasma FGF23 is an independent risk factor for CKD progression in 419 children, aged 1–16 years, enrolled in the Chronic Kidney Disease in Children (CKiD) cohort study. We measured plasma FGF23 concentrations at baseline and determined GFR annually using plasma disappearance of iohexol or the CKiD study estimating equation. We analyzed the association of baseline FGF23 with risk of progression to the composite end point, defined as start of dialysis or kidney transplantation or 50% decline from baseline GFR, adjusted for demographics, baseline GFR, proteinuria, other CKD-specific factors, and other mineral metabolites. Results At enrollment, median age was 11 years [interquartile range (IQR), 8–15], GFR was 44 ml/min per 1.73 m 2 (IQR, 33–57), and FGF23 was 132 RU/ml (IQR, 88–200). During a median follow-up of 5.5 years (IQR, 3.5–6.6), 32.5% of children reached the progression end point. Higher FGF23 concentrations were independently associated with higher risk of the composite outcome (fully adjusted hazard ratio, 2.52 in the highest versus lowest FGF23 tertile; 95% confidence interval, 1.44 to 4.39, P =0.002; fully adjusted hazard ratio, 1.33 per doubling of FGF23; 95% confidence interval, 1.13 to 1.56, P =0.001). The time to progression was 40% shorter for participants in the highest compared with the lowest FGF23 tertile. In contrast, serum phosphorus, vitamin D metabolites, and parathyroid hormone did not consistently associate with progression in adjusted analyses. Conclusions High plasma FGF23 is an independent risk factor for CKD progression in children.

Compound heterozygous and homozygous (comp/hom) mutations in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium (Na(+))-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH), a disorder characterized by renal phosphate wasting resulting in hypophosphatemia, correspondingly elevated 1,25(OH)2 vitamin D levels, hypercalciuria, and rickets/osteomalacia. Similar, albeit less severe, biochemical changes are observed in heterozygous (het) carriers and indistinguishable from those changes encountered in idiopathic hypercalciuria (IH). Here, we report a review of clinical and laboratory records of 133 individuals from 27 kindreds, including 5 previously unreported HHRH kindreds and two cases with IH, in which known and novel SLC34A3 mutations (c.1357delTTC [p.F453del]; c.G1369A [p.G457S]; c.367delC) were identified. Individuals with mutations affecting both SLC34A3 alleles had a significantly increased risk of kidney stone formation or medullary nephrocalcinosis, namely 46% compared with 6% observed in healthy family members carrying only the wild-type SLC34A3 allele (P=0.005) or 5.64% in the general population (P

Summary Background and objectives In children with CKD, information is limited regarding the prevalence and determinants of fibroblast growth factor 23 excess and 1,25-dihyroxyvitamin D deficiency across the spectrum of predialysis CKD. This study characterized circulating concentrations of fibroblast growth factor 23 and 1,25-dihyroxyvitamin D, and investigated their interrelationships and associations with GFR and secondary hyperparathyroidism in children with CKD who were enrolled in the Chronic Kidney Disease in Children observational cohort study. Design, setting, participants, & measurements Plasma fibroblast growth factor 23 concentrations and determinants of mineral metabolism were measured in 464 children ages 1–16 years with predialysis CKD. GFR was measured by plasma disappearance of iohexol in 70% of participants and estimated by the Chronic Kidney Disease in Children estimating equation using serum creatinine and cystatin C concentrations in the remainder of the participants. Participants were grouped according to CKD stage and by 10-ml/min categories of GFR. Results Median GFR for the cohort was 45 ml/min per 1.73 m2 (interquartile range=33–57; range=15–109). Plasma fibroblast growth factor 23 concentration was above the normal range in 67% of participants (with higher levels observed among participants with lower GFR) before higher levels of serum parathyroid hormone and phosphorus were observed. Plasma fibroblast growth factor 23 levels were 34% higher in participants with glomerular disease than in participants with nonglomerular disease, despite similar GFR. Serum phosphorus levels, adjusted for age, were significantly lower at GFR of 60–69 ml/min per 1.73 m2 than higher GFR, but thereafter they became higher in parallel with fibroblast growth factor 23 as GFR declined. Serum 1,25-dihyroxyvitamin D concentrations were lower in those participants with low GFR values, high fibroblast growth factor 23 levels, 25-hydroxyvitamin D deficiency, and proteinuria. Secondary hyperparathyroidism was present in 55% of participants with GFR Conclusion In children with predialysis CKD, high plasma fibroblast growth factor 23 is the earliest detectable abnormality in mineral metabolism, and levels are highest in glomerular diseases.

Purpose of review Regulation of calcium and phosphorus levels in the fetus and neonate is critical for proper bone development and mineralization. Recent findings Parathyroid hormone-related peptide plays an important role in transferring calcium across the placenta into the fetal circulation. In contrast, the factors controlling placental phosphate transport have not yet been explored, and numerous studies have indicated that maternal and childhood vitamin D deficiency continues to be a significant clinical concern. Summary The molecular basis for mineral ion homeostasis in the fetus and child remains incompletely understood. More attention must be paid to identifying and treating maternal, neonatal, and childhood vitamin D deficiency.

We aim to review the biological properties of novel molecules that are members of a kidney-bone axis involved in the regulation of phosphate homeostasis. In addition, we describe how an improved knowledge of the mechanisms leading to changes in renal phosphate handling may lead to the development of novel therapeutic approaches.As yet, eight genes involved in the regulation of phosphate homeostasis have been identified through genetic studies. A key protein in this regulatory pathway is FGF23, which is made by osteocytes and activates renal KLOTHO/FGFR1 receptor heterodimers to inhibit renal phosphate reabsorption and 1,25-dihydroxyvitamin D synthesis. Gain-of-function mutations in FGF23, which render the hormone resistant to proteolytic cleavage, lead to increased phosphaturic activity. Furthermore, inactivating mutations in DMP1 and PHEX increase, through yet unknown mechanisms, FGF23 synthesis and thus enhance renal phosphate excretion. In contrast, loss-of-function mutations in FGF23 and KLOTHO, and abnormal O-glycosylation of FGF23 because of GALNT3 mutations, lead to diminished phosphate excretion. Extremely high levels of FGF23 are observed in chronic renal failure, which may contribute to the development of renal osteodystrophy.The analysis of rare genetic disorders affecting phosphate homeostasis led to the identification of several proteins that are essential for the renal regulation of phosphate homeostasis, although it is not yet completely understood how these proteins interact, and additional proteins are likely to contribute to these regulatory events.

Hyperphosphatemia, calcitriol deficiency, and secondary hyperparathyroidism (SHPT) are common complications of chronic kidney disease (CKD). Fibroblast growth factor-23 (FGF-23) is a novel phosphaturic hormone that also inhibits renal 1alpha-hydroxylase activity and thus may be involved in the pathogenesis of SHPT. Several hypotheses were tested: that FGF-23 increases as renal function declines; is linearly associated with serum phosphate levels; is associated with increased phosphaturia independent of parathyroid hormone (PTH); and is associated with decreased calcitriol levels independent of renal function, hyperphosphatemia, and vitamin D stores. FGF-23, PTH, 25(OH)D3, calcitriol, calcium, phosphate, and urinary fractional excretion of phosphate (Fe(PO4)) were measured in 80 CKD patients. Multiple linear regression was used to test the hypotheses. FGF-23 and PTH were inversely associated with estimated GFR (eGFR), whereas calcitriol levels were linearly associated with eGFR. Hyperphosphatemia and hypocalcemia were present in only 12 and 6% of patients, respectively, all of whose eGFR was30. Increased Fe(PO4) was associated with decreased eGFR, and both increased FGF-23 and PTH were independently associated with increased Fe(PO4). Increased FGF-23 and decreased 25(OH)D3 were independent predictors of decreased calcitriol, but the effects on calcitriol levels of renal function itself and hyperphosphatemia were completely extinguished by adjusting for FGF-23. It is concluded that FGF-23 levels increase early in CKD before the development of serum mineral abnormalities and are independently associated with serum phosphate, Fe(PO4), and calcitriol deficiency. Increased FGF-23 may contribute to maintaining normal serum phosphate levels in the face of advancing CKD but may worsen calcitriol deficiency and thus may be a central factor in the early pathogenesis of SHPT.

The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor belongs to a newly discovered family of G protein-coupled receptors. Members of this family, which have been isolated from mammals, include the receptors for PTH/PTHrP, calcitonin, secretin, growth hormone-releasing hormone, vasoactive intestinal polypeptide (types 1 and 2), gastric-inhibitory polypeptide, glucagon-like peptide 1, glucagon, corticotropin-releasing factor, and the pituitary adenylate cyclase-activating peptide. Very recently, a receptor with remarkable homology to these mammalian receptors was isolated from the insect Manduca sexta, which indicates considerable conservation of these related proteins during evolution. Thus far the cognate ligands for these receptors are 27- to 46-amino-acid residues in length. Members of this novel receptor family are characterized by seven membrane-spanning domains and at least two conserved sites for N-linked glycosylation. Furthermore, 48-amino-acid residues, including eight extracellular cysteines, are identical in all receptors, and many other residues are highly conserved. The PTH/PTHrP receptor is expressed in a large variety of fetal and adult tissues, binds two ligands (PTH and PTHrP) with high affinity, and activates at least two second-messenger systems (adenylate cyclase and phospholipase C).