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Biomedical subjects

Harald Jüppner

Publications and source records attributed to Harald Jüppner.

At least 37 records · Page 2Linked to original sources
PubMed2005

Molecular diagnosis of pseudohypoparathyroidism type Ib in a family with presumed paroxysmal dyskinesia.

We describe 2 sisters diagnosed initially with paroxysmal kinesigenic choreoathetosis, a condition characterized by brief episodes of spasms precipitated by sudden movement. However, subsequent testing showed hypocalcemia, hyperphosphatemia, and elevated parathyroid hormone levels consistent with pseudohypoparathyroidism type Ib. This diagnosis was confirmed by genetic testing, which identified a 3-kilobase deletion on chromosome 20q13.3. Our report describes the neurologic presentation, metabolic derangement, and underlying genetic mutation in a family. It also reinforces the importance of metabolic testing in the evaluation of pediatric patients with movement disorders.

Child↗
PubMed2005

The role of fibroblast growth factor 23 for hypophosphatemia and abnormal regulation of vitamin D metabolism in patients with McCune-Albright syndrome.

McCune-Albright syndrome (MAS) is sometimes complicated by hypophosphatemia and abnormally low levels of 1,25(OH)(2)D in the presence of hypophosphatemia. Recently, fibroblast growth factor 23 (FGF-23) was reported as a phosphaturic and a causal factor of abnormal vitamin D metabolism. This abnormal phosphate and vitamin D metabolism is well known to be found in oncogenic and X-linked hypophosphatemia. We furthermore reported increased circulating plasma FGF-23 levels in patients with oncogenic and X-linked hypophosphatemia. To determine whether FGF-23 may be involved in the pathogenesis of MAS, we measured plasma FGF-23 levels in six MAS patients. As a control for hypophosphatemia, we also investigated the plasma FGF-23 levels in two patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH). We also investigated the correlation of plasma FGF-23 levels with serum phosphate and 1,25(OH)(2)D levels after short-term pamidronate therapy in three MAS patients. Plasma FGF-23 levels were significantly increased in patients with MAS compared to normal controls, whereas they were not increased in HHRH patients. Serum phosphate levels of the MAS patients were significantly lower than those observed in normal controls. Plasma FGF-23 levels showed significant negative correlation with serum phosphate concentrations. In three MAS patients, pamidronate therapy decreased plasma FGF-23 levels, which showed significant negative correlation with serum 1,25(OH)(2)D concentrations. These data suggested that FGF-23 is a possible causal factor for hypophosphatemia and abnormal vitamin D metabolism in MAS.

Adolescent↗
PubMed2005

First- and second-generation immunometric PTH assays during treatment of hyperparathyroidism with cinacalcet HCl.

BACKGROUND: First-generation immunometric assays for "intact" parathyroid hormone (iPTH) also measure large N-terminally truncated PTH fragments, whereas second-generation assays, such as the "bio-intact" PTH (biPTH) assay, measure only full-length biologically active PTH(1-84). This study compared iPTH and biPTH assays during cinacalcet treatment in subjects with secondary HPT receiving dialysis. METHODS: Four hundred and ten subjects were enrolled in a 26-week randomized, double-blind, placebo-controlled trial of oral cinacalcet (or placebo), 30 to 180 mg once daily, and efficacy was assessed using biPTH and iPTH assays. RESULTS: Compared with control treatment, cinacalcet improved the management of secondary HPT. Both biPTH and iPTH decreased by 38%+/- 3% during weeks 13 to 26 in the cinacalcet group; biPTH increased by 23%+/- 4% and iPTH increased by 9.5%+/- 3% in the control group (P < 0.001). Fifty-six percent of cinacalcet subjects and 10% of control subjects had a > or = 30% reduction in biPTH, and 61% and 11%, respectively, had a > or = 30% reduction in iPTH. Significant correlations between biPTH and iPTH levels were observed throughout the study. Both assays correlated similarly with bone-specific alkaline phosphatase levels. The ratio of biPTH to iPTH was maintained at 56% +/- 1% after treatment in both treatment groups. Increasing serum calcium levels were associated with a decreasing ratio of biPTH to (iPTH-biPTH). CONCLUSION: These data show that PTH can be monitored with either iPTH or biPTH assays during therapy with cinacalcet, and that cinacalcet therapy does not exert a major influence on the ratio between PTH(1-84) and large, N-terminally truncated PTH fragments.

Adult↗
PubMed2005

A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders.

Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040Ctwo head right arrowT) in exon 41 of the gene encoding the alpha1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric alpha1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.

Bone and Bones↗
PubMed2004

Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib.

Epigenetic defects in the imprinted GNAS cluster are associated with pseudohypoparathyroidism type Ib. In two kindreds with this disorder, we now report deletions that remove the differentially methylated region encompassing exon NESP55 and exons 3 and 4 of the antisense transcript. When inherited from a female, either deletion abolishes all maternal GNAS imprints and derepresses maternally silenced transcripts, suggesting that the deleted region contains a cis-acting element that controls imprinting of the maternal GNAS allele.

Base Sequence↗
PubMed2004

Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo.

Stimulatory heterotrimeric G protein (Gs) transduces signals from various cell-surface receptors to adenylyl cyclases, which generate cAMP. The alpha subunit of Gs (Gsalpha) is encoded by GNAS (Gnas in mice), and heterozygous Gsalpha inactivating mutations lead to Albright hereditary osteodystrophy. The in vivo role of Gsalpha in skeletogenesis is largely unknown, because of early embryonic lethality of mice with disruption of Gnas exon 2 (Gnas(E2-/E2-)) and the absence of easily detectable phenotypes in growth plate chondrocytes of heterozygous mutant mice (Gnas(+/E2-)). We generated chimeric mice containing wild-type cells and either Gnas(E2-/E2-) or Gnas(+/E2-) cells. Gnas(E2-/E2-) chondrocytes phenocopied PTH/PTHrP receptor (PPR)(-/-) cells by prematurely undergoing hypertrophy. Introduction of a transgene expressing Gsalpha, one of several gene products that include Gnas exon 2, into Gnas(E2-/E2-) cells prevented premature hypertrophy. Gsalpha mRNA expression detected by real-time RT-PCR analysis was reduced to approximately half that of the wild-type in both paternal and maternal Gnas(+/E2-) growth plate chondrocytes, indicating biallelic expression of Gsalpha in these cells. Hypertrophy of Gnas(+/E2-) chondrocytes was modestly but significantly premature in chimeric growth plates of mice containing wild-type and Gnas(+/E2-) cells. These data suggest that Gsalpha is the primary mediator of the actions of PPR in growth plate chondrocytes and that there is haploinsufficiency of Gsalpha signaling in Gnas(+/E2-) chondrocytes.

Animals↗
PubMed2004

Identification and characterization of the zebrafish and fugu genes encoding tuberoinfundibular peptide 39.

Although the PTH type 2 receptor (PTH2R) has been isolated from mammals and zebrafish, only its mammalian agonist, tuberoinfundibular peptide 39 (TIP39), has been characterized thus far. To determine whether zebrafish TIP39 (zTIP39) functions similarly with the zebrafish PTHR (zPTH2R) and human PTH2Rs and to determine its tissue-specific expression, fugu (Takifugu rubripes) and zebrafish (Danio rerio) genomic databases were screened with human TIP39 (hTIP39) sequences. A single TIP39 gene was identified for each fish species, which showed significant homology to mammalian TIP39. Using standard molecular techniques, we isolated cDNA sequences encoding zTIP39. The fugu TIP39 precursor was encoded by a gene comprising at least three exons. It contained a hydrophobic signal sequence and a predicted prosequence with a dibasic cleavage site, similar to that found in mammalian TIP39 ligands. Phylogenetic analyses suggested that TIP39 forms the basal group from which PTH and PTHrP have been derived. Functionally, subtle differences in potency could be discerned between hTIP39 and zTIP39. The human PTH2R and zPTH2R were stimulated slightly better by both hTIP39 and zTIP39, whereas zTIP39 had a higher potency at a previously isolated zPTH2R splice variant. Whole-mount in situ hybridization of zebrafish revealed strong zTIP39 expression in the region of the hypothalamus and in the heart of 24- and 48-h-old embryos. Similarly, zPTH2R expression was highly expressed throughout the brain of 48- and 72-h-old embryos. Because the mammalian PTH2R was also most abundantly expressed in these tissues, the TIP39-PTH2R system may serve conserved physiological roles in mammals and fishes.

Amino Acid Sequence↗
PubMed2004

New PTH assays and renal osteodystrophy.

Parathyroid hormone (PTH) levels have been used instead of bone histomorphometric analysis in renal failure, but the assessment of tetracycline-labeled bone biopsy remains the most reliable method to diagnose the different subtypes of renal osteodystrophy. The availability of the first-generation immunometric PTH assay (1(st) PTH-IMA) allowed the distinction between the different types of renal bone diseases. However, 1(st) PTH-IMA not only detects the intact hormone PTH(1-84), but also additional PTH truncated fragments. A second-generation immunometric PTH assay (2(nd) PTH-IMA) recognizes only PTH(1-84) and possible PTH fragments that are truncated at the carboxyl-terminus, but not PTH(7-84). In addition, whether assessment of the ratio PTH(1-84) and amino-terminally truncated PTH(1-84) fragments is a better predictor of bone turnover remains controversial. An initial study using the 2(nd) PTH-IMA suggested that the ratio between PTH(1-84) and amino-terminally truncated PTH(1-84) fragments more accurately predicts bone turnover in adult patients treated with hemodialysis. However, subsequent studies using the Scantibodies assay have failed to better predict the underlying bone disease in adults undergoing maintenance hemodialysis. Furthermore, a different 2(nd) PTH-IMA (Immutopics) with similar, but not identical, in vitro characteristics did not show a superior predictive value of the ratio in pediatric patients treated with peritoneal dialysis. Although the 2(nd) PTH-IMA may provide important new insights into the physiology of parathyroid gland function, at present, measurement of PTH using either 1(st) or 2(nd) PTH-IMAs provides similar accuracy for predicting bone turnover in patients treated with dialysis. Thus, the current data do not yet support the claim that 2(nd) PTH-IMAs provide an advantage over 1(st) PTH-IMAs for the diagnosis of the different subtypes of renal bone diseases.

Bone and Bones↗
PubMed2004

Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis.

Mutations in the fibroblast growth factor 23 gene, FGF23, cause autosomal dominant hypophosphatemic rickets (ADHR). The gene product, FGF-23, is produced by tumors from patients with oncogenic osteomalacia (OOM), circulates at increased levels in most patients with X-linked hypophosphatemia (XLH) and is phosphaturic when injected into rats or mice, suggesting involvement in the regulation of phosphate (Pi) homeostasis. To better define the precise role of FGF-23 in maintaining Pi balance and bone mineralization, we generated transgenic mice that express wild-type human FGF-23, under the control of the alpha1(I) collagen promoter, in cells of the osteoblastic lineage. At 8 wk of age, transgenic mice were smaller (body weight = 17.5 +/- 0.57 vs. 24.3 +/- 0.37 g), exhibited decreased serum Pi concentrations (1.91 +/- 0.27 vs. 2.75 +/- 0.22 mmol/liter) and increased urinary Pi excretion when compared with wild-type littermates. The serum concentrations of human FGF-23 (undetectable in wild-type mice) was markedly elevated in transgenic mice (>7800 reference units/ml). Serum PTH levels were increased in transgenic mice (231 +/- 62 vs. 139 +/- 44 pg/ml), whereas differences in calcium and 1,25-dihydroxyvitamin D were not apparent. Expression of Npt2a, the major renal Na(+)/Pi cotransporter, as well as Npt1 and Npt2c mRNAs, was significantly decreased in the kidneys of transgenic mice. Histology of tibiae displayed a disorganized and widened growth plate and peripheral quantitative computerized tomography analysis revealed reduced bone mineral density in transgenic mice. The data indicate that FGF-23 induces phenotypic changes in mice resembling those of patients with ADHR, OOM, and XLH and that FGF-23 is an important determinant of Pi homeostasis and bone mineralization.

Animals↗
PubMed2004

Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice.

Fibroblast growth factor-23 (FGF-23), a recently identified molecule that is mutated in patients with autosomal dominant hypophosphatemic rickets (ADHR), appears to be involved in the regulation of phosphate homeostasis. Although increased levels of circulating FGF-23 were detected in patients with different phosphate-wasting disorders such as oncogenic osteomalacia (OOM) and X-linked hypophosphatemia (XLH), it is not yet clear whether FGF-23 is directly responsible for the abnormal regulation of mineral ion homeostasis and consequently bone development. To address some of these unresolved questions, we generated a mouse model, in which the entire Fgf-23 gene was replaced with the lacZ gene. Fgf-23 null (Fgf-23-/-) mice showed signs of growth retardation by day 17, developed severe hyperphosphatemia with elevated serum 1,25(OH)2D3 levels, and died by 13 weeks of age. Hyperphosphatemia in Fgf-23-/- mice was accompanied by skeletal abnormalities, as demonstrated by histological, molecular, and various other morphometric analyses. Fgf-23-/-) mice had increased total-body bone mineral content (BMC) but decreased bone mineral density (BMD) of the limbs. Overall, Fgf-23-/- mice exhibited increased mineralization, but also accumulation of unmineralized osteoid leading to marked limb deformities. Moreover, Fgf-23-/- mice showed excessive mineralization in soft tissues, including heart and kidney. To further expand our understanding regarding the role of Fgf-23 in phosphate homeostasis and skeletal mineralization, we crossed Fgf-23-/- animals with Hyp mice, the murine equivalent of XLH. Interestingly, Hyp males lacking both Fgf-23 alleles were indistinguishable from Fgf-23/-/ mice, both in terms of serum phosphate levels and skeletal changes, suggesting that Fgf-23 is upstream of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (Phex) and that the increased plasma Fgf-23 levels in Hyp mice (and in XLH patients) may be at least partially responsible for the phosphate imbalance in this disorder.

Alleles↗
PubMed2004

Haplotype frequencies and linkage disequilibrium analysis of four frequent polymorphisms at the PTH/PTH-related peptide receptor gene locus.

The parathyroid hormone (PTH)/PTH-related peptide receptor is a critical component in the control of mineral ion metabolism and in bone development. This receptor is encoded by a single gene (PTHR1) on chromosome 3p21.1-p24.2, and mutations in this gene have been found in several clinical disorders of bone and mineral metabolism. To facilitate future genetic studies of this important gene, we determined haplotype frequencies and performed linkage disequilibrium (LD) analysis of four different polymorphisms at the PTHR1 locus. Combined analysis of Caucasian, African-American and Asian individuals indicated that LD exists between all but one pair of the four polymorphisms. However, the pattern of LD differed substantially among the three subpopulations; for example, LD between two closely spaced (154-bp apart) single nucleotide polymorphisms appeared to be present only in Asians. Depending on the population under study, genetic association studies may need to test even more closely spaced polymorphic markers when screening the PTHR1 locus. These findings may thus affect the design and interpretation of future genetic studies involving PTHR1.

Black or African American↗
PubMed2004

Special aspects of renal osteodystrophy in children.

Renal osteodystrophy represents a spectrum of skeletal lesions that range from high-turnover to low-turnover bone disease. Similar factors are involved in the pathogenesis of renal osteodystrophy in adult and pediatric patients with chronic kidney disease (CKD). However, growth retardation and the development of bone deformities are specific complications that occurred in pediatric patients with CKD. Metabolic acidosis, renal osteodystrophy, malnutrition, and disturbances in the insulin growth factor (IGF)/growth hormone (GH) are among the main factors involved and they are discussed briefly in this article. In addition to disturbances in bone remodeling, longitudinal bone growth occurs at the growth plate cartilage by endochondral ossification. Although young rats with experimental CKD have growth retardation, the characteristics of the growth plate are markedly different between animals with severe secondary hyperparathyroidism and those with calcium-induced adynamic osteodystrophy. These disturbances may suggest potential molecular mechanisms by which endochondral bone formation may be altered in renal failure, consequently leading to growth retardation.

Acidosis, Renal Tubular↗
PubMed2004

A form of Jansen's metaphyseal chondrodysplasia with limited metabolic and skeletal abnormalities is caused by a novel activating parathyroid hormone (PTH)/PTH-related peptide receptor mutation.

A novel heterozygous PTH/PTHrP receptor missense mutation (T410R) was identified in a male and his two sons who are all affected by a less severe form of Jansen's metaphyseal chondrodysplasia (JMC). JMC is a rare disorder that is typically characterized by severe growth plate abnormalities that lead to short-limbed dwarfism. Furthermore, affected individuals usually show significant hypercalcemia, despite normal or undetectable levels of PTH and PTHrP. In contrast, the three affected members of this new family showed only mild skeletal dysplasia, comparatively normal stature, and blood calcium concentrations either within or at the upper end of the normal range. However, PTH levels were suppressed, and urinary calcium excretion was elevated, which led to nephrolithiasis in both children. When expressed in COS-7 cells, the PTH/PTHrP receptor with the T410R mutation led to agonist-independent cAMP formation, which was less pronounced than that observed with the previously identified T410P mutant. Our findings indicate that a mild form of JMC has been identified that is characterized by less pronounced skeletal and laboratory abnormalities.

Adult↗
PubMed2004

Phenotypic and molecular genetic aspects of pseudohypoparathyroidism type Ib in a Greek kindred: evidence for enhanced uric acid excretion due to parathyroid hormone resistance.

The predominant feature of pseudohypoparathyroidism (PHP) is renal resistance to PTH. Pseudohypoparathyroidism type Ia (PHP-Ia) is caused by maternally inherited heterozygous mutations in the GNAS exons encoding the alpha-subunit of the stimulatory G protein (Gsalpha). Besides PTH resistance, PHP-Ia patients have Albright's hereditary osteodystrophy and often display resistance to additional hormones. Patients with PHP-Ib lack features of Albright's hereditary osteodystrophy, and PTH resistance is associated with loss of methylation at the maternal GNAS exon A/B. Most individuals with the autosomal dominant form of PHP-Ib have a 3-kb microdeletion within STX16 approximately 220 kb upstream of exon A/B. Here we report on the clinical and genetic aspects of a Greek PHP-Ib kindred with four affected members and three obligate carriers, who had the 3-kb deletion within STX16. Symptomatic hypocalcemia was present only in the proband, but PTH was elevated in all members who had inherited the 3-kb deletion maternally. In all affected family members, urinary phosphate excretion was normal, but 1,25-dihydroxyvitamin D levels were diminished. These findings confirm previous data regarding patient to patient variation in disease severity for autosomal dominant PHP-Ib. Furthermore, affected individuals displayed hypouricemia with increased fractional excretion of uric acid, suggesting possible involvement of PTH in the renal handling of this metabolite.

Adult↗
PubMed2003

Identification and characterization of two parathyroid hormone-like molecules in zebrafish.

Zebrafish (Danio rerio) have receptors homologous to the human PTH (hPTH)/PTHrP receptor (PTH1R) and PTH-2 receptor (PTH2R) and an additional receptor (PTH3R) with high homology to the PTH1R. To find natural ligands for zPTH1R and zPTH3R, we searched the zebrafish genomic database and discovered two distinct regions that, when translated (zPTH1 and zPTH2), showed high homology to hPTH. Isolation of cDNAs and determination of the intron/exon boundaries revealed genomic structures which were similar to known PTHs. Peptides consisting of the first 34 amino acids after the pre- and prosequences of the zebrafish PTHs (zPTHs) were synthesized and were shown to be fully active at the hPTH1R. zPTH2(1-34) was, however, approximately 30-fold less potent at the zPTH1R than hPTH(1-34), hPTHrP(1-36), and zPTH1(1-34). When tested with zPTH3R, zPTH1(1-34) and hPTHrP(1-36) showed similar potencies, whereas the potency of zPTH2(1-34) was moderately (3-fold) reduced. To determine whether other fishes have multiple PTHs, we searched the genomic database of the Japanese pufferfish (Takifugu rubripes) and identified zPTH1 and zPTH2 homologs. Phylogenetic analysis showed that PTHs from zebrafish and pufferfish are more closely related to each other than to known mammalian PTH homologs or to PTHrP and tuberoinfundibular peptide of 39 residues. This is consistent with evolution of two teleost PTH-like peptides occurring after the evolutionary divergence between fishes and mammals. Overall, the PTH system appears more complex in fishes than in mammals, providing evidence of continued evolution in nontetrapod species. The availability of multiple forms of fish PTH and their receptors provide additional tools for PTH ligand/receptor structure-function studies.

Amino Acid Sequence↗
PubMed2003

Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia.

BACKGROUND: Mutations in fibroblast growth factor 23 (FGF-23) cause autosomal dominant hypophosphatemic rickets. Clinical and laboratory findings in this disorder are similar to those in oncogenic osteomalacia, in which tumors abundantly express FGF-23 messenger RNA, and to those in X-linked hypophosphatemia, which is caused by inactivating mutations in a phosphate-regulating endopeptidase called PHEX. Recombinant FGF-23 induces phosphaturia and hypophosphatemia in vivo, suggesting that it has a role in phosphate regulation. To determine whether FGF-23 circulates in healthy persons and whether it is elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, an immunometric assay was developed to measure it. METHODS: Using affinity-purified, polyclonal antibodies against [Tyr223]FGF-23(206-222)amide and [Tyr224]FGF-23(225-244)amide, we developed a two-site enzyme-linked immunosorbent assay that detects equivalently recombinant human FGF-23, the mutant form in which glutamine is substituted for arginine at position 179 (R179Q), and synthetic human FGF-23(207-244)amide. Plasma or serum samples from 147 healthy adults (mean [+/-SD] age, 48.4+/-19.6 years) and 26 healthy children (mean age, 10.9+/-5.5 years) and from 17 patients with oncogenic osteomalacia (mean age, 43.0+/-13.3 years) and 21 patients with X-linked hypophosphatemia (mean age, 34.9+/-17.2 years) were studied. RESULTS: Mean FGF-23 concentrations in the healthy adults and children were 55+/-50 and 69+/-36 reference units (RU) per milliliter, respectively. Four patients with oncogenic osteomalacia had concentrations ranging from 426 to 7970 RU per milliliter, which normalized after tumor resection. FGF-23 concentrations were 481+/-528 RU per milliliter in those with suspected oncogenic osteomalacia and 353+/-510 RU per milliliter (range, 31 to 2335) in those with X-linked hypophosphatemia. CONCLUSIONS: FGF-23 is readily detectable in the plasma or serum of healthy persons and can be markedly elevated in those with oncogenic osteomalacia or X-linked hypophosphatemia, suggesting that this growth factor has a role in phosphate homeostasis. FGF-23 measurements might improve the management of phosphate-wasting disorders.

Adolescent↗
PubMed2003

Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers.

BACKGROUND: Hyperphosphatemia is a risk factor for the development of several different complications of chronic kidney disease (CKD), including secondary hyperparathyroidism and cardiovascular complications, due to the formation of calcium-phosphate deposits. Fibroblast growth factor-23 (FGF-23) is a recently discovered protein that is mutated in autosomal-dominant hypophosphatemic rickets, an inherited phosphate wasting disorder, and it may represent a novel hormonal regulator of phosphate homeostasis. We therefore hypothesized that FGF-23 levels may be altered in hyperphosphatemia associated with renal failure and that its concentration changes in response to different levels of phosphate intake. METHODS: Using a two-site enzyme-linked immunosorbent assay (ELISA) detecting the C-terminal portion of FGF-23, serum concentration was measured in 20 patients with different stages of renal failure (creatinine range 155 to 724 micromol/L), in 33 patients with end-stage renal disease (ESRD) on dialysis treatment, and in 30 patients with functioning renal grafts. Furthermore, six healthy males were given oral phosphate binders in combination with low dietary phosphate intake for 2 days followed by 3 days of repletion with inorganic phosphate. FGF-23 levels were determined at multiple time points. RESULTS: FGF-23 serum levels were significantly elevated in CKD with a strong correlation between serum creatinine and FGF-23 concentration. Independent correlations were also seen between FGF-23 and phosphate, calcium, parathyroid hormone (PTH), and 1,25(OH)2D3. No changes in serum FGF-23 levels were observed in volunteers following ingestion of oral phosphate binders/low dietary phosphate intake, which led to a decline in phosphate excretion or during the subsequent repletion with inorganic phosphate through oral phosphate and a normal diet. CONCLUSION: Circulating FGF-23 was significantly elevated in patients with CKD and its concentration correlated with renal creatinine clearance. In healthy volunteers, FGF-23 levels did not change after phosphate deprivation or phosphate loading.

Adult↗