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Background: Little information is available about the kidney's involvement in patients with β-thalassaemia major (TM). In particular, there are no studies reporting the outcome of renal function over time., Methods: In this retrospective study, we evaluated the changes in estimated glomerular filtration rate (eGFR) in 81 adult patients with TM followed for 10 years. Only patients who had an eGFR of >90 mL/min/1.73 m(2) at presentation were admitted to the study. All patients were regularly followed for at least 10 years., Results: At 10 years, 66 patients showed a mild decline in eGFR that remained, however, within a normal range (from 119.9 to 113.6 mL/min/1.73 m(2), P = 0.636). In the remaining 15 patients (18.5%), eGFR decreased to <90 mL/min (from 98.1 to 78.2 mL/min/1.73 m(2); P = 0.004). The repeated-measures models showed that the decline in eGFR over time was significantly higher (P = 0.0068) in patients with baseline phosphaturia >1000 mg/24 h (P = 0.0068), while eGFR tended to decline more rapidly in patients with baseline uricuria >700 mg/24 h than in those with lower uricuria (P = 0.0783). Univariate Cox's proportional regression models showed that abnormal levels of calcaemia were associated with the risk of kidney damage [hazard ratio (HR) 0.30, 95% confidence interval 0.09-0.97 for calcaemia 8.4-10.2 mg/dL versus HR not estimable for calcaemia <8.4 or >10.2 mg/dL]., Conclusions: In most adults with TM, the eGFR tends to remain within a normal range after 10 years. However, patients with elevated phosphaturia, elevated uricuria and/or abnormal levels of calcaemia show a significant decline in eGFR over time, suggesting that tubular damage acquired in childhood caused by either TM or its treatment may eventually result in abnormal eGFR. Further studies in a larger cohort of TM patients are needed to further elucidate the long-term impact of TM on renal function.

Background: Matrix extracellular phosphoglycoprotein (MEPE), first isolated from tumour-derived tissue from a patient with oncogenic hypophosphataemia, is a putative phosphatonin that has received much less attention than fibroblast growth factor-23. To date, its effect on renal tubular phosphate reabsorption remains undefined., Methods: A renal clearance study was performed in anaesthetized rats infused intravenously with a range of doses of MEPE., Results: MEPE had no effect on glomerular filtration rate (inulin clearance) but caused rapid, dose-dependent increases in absolute and fractional phosphate excretion, wholly attributable to reduced phosphate reabsorption. At a maximal dose, MEPE increased fractional phosphate excretion more than 2-fold, whereas no change was observed in time controls., Conclusion: The results lend support to the hypothesis that MEPE contributes to the phosphaturia of oncogenic hypophosphataemia and of hypophosphataemic rickets.

FGF-23 is involved in the pathogenesis of two similar hypophosphatemic diseases, autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced osteomalacia (TIO). We have shown that the overproduction of FGF-23 by tumors causes TIO. In contrast, ADHR derives from missense mutations in FGF-23 gene. However, it has been unclear how those mutations affect phosphate metabolism. Therefore, we produced mutant as well as wild-type FGF-23 proteins and examined their biological activity. Western blot analysis using site-specific antibodies showed that wild-type FGF-23 secreted into conditioned media was partially cleaved between Arg(179) and Ser(180). In addition, further processing of the cleaved N-terminal portion was observed. In constrast, mutant FGF-23 proteins found in ADHR were resistant to the cleavage. In order to clarify which molecule has the biological activity to induce hypophosphatemia, we separated full-length protein, the N-terminal and C-terminal fragments of wild-type FGF-23. When the activity of each fraction was examined in vivo, only the full-length FGF-23 decreased serum phosphate. Mutant FGF-23 protein that was resistant to the cleavage also retained the activity to induce hypophosphatemia. The extent of hypophosphatemia induced by the single administration of either wild-type or the mutant full-length FGF-23 protein was similar. In addition, implantation of CHO cells expressing the mutant FGF-23 protein caused hypophosphatemia and the decrease of bone mineral content. We conclude that ADHR is caused by hypophosphatemic action of mutant full-length FGF-23 proteins that are resistant to the cleavage between Arg(179) and Ser(180).

Hereditary 1 alpha,25-dihydroxyvitamin D-resistant rickets (HVDRR) is a genetic disease that results from mutations in the gene encoding the vitamin D receptor (VDR). In this study of two siblings showing classical features of HVDRR, cultured dermal fibroblasts were used to characterize their VDR and assess responsiveness to 1,25-dihydroxyvitamin D3 treatment. The VDR displayed normal affinity and binding capacity for [3H]1,25-dihydroxyvitamin D3; however, the cells failed to exhibit induction of 25-hydroxyvitamin D 24-hydroxylase activity when treated with hormone. A decreased affinity of liganded VDR for DNA cellulose suggested that the defect was localized to the DNA-binding domain. Exons 2 and 3 of the VDR gene, which encode the two zinc fingers in the DNA-binding domain, were amplified and sequenced by polymerase chain reaction. Both siblings exhibited a G to A missense mutation (CGG to CAG) in exon 3, which results in the replacement of Arg77 by Gln at the base of the second zinc finger. This mutation has been described previously in two unrelated cases of HVDRR by Sone et al. It is unclear at this time whether these kindreds might be distantly related and, therefore, harbor the same mutation, or whether this represents a mutational hot spot in the VDR gene.

Low duodenal vitamin D-dependent calcium-binding protein has been reported in juvenile Hyp mice. Levels of this protein improved in adult Hyp mice. This led to the search for possible abnormal intestinal calcium absorption in juvenile Hyp mice and for evidence that calcium malabsorption, if present, would exacerbate the bone disease. A balance study was performed in 10 sets of normal and Hyp male mice at 5 and 12 weeks of age. Twelve-week-old Hyp mice had balances (24-h intake minus excretion) of Ca, P, Mg, Na, and K that were not significantly different from those of 12-week-old normal mice. However, 5-week-old Hyp mice had a significantly lower balance of Ca with higher fecal Ca and lower urinary Ca. No balance was also lower due to higher fecal Na. The balances of P, Mg, and K were not significantly affected in young Hyp mice. Growth and mineralization of the femur were compared in normal and heterozygous female Hyp mice from 3.5-46 weeks of age. The femora of Hyp mice gained ash weight at a rate comparable to that for normal mice, except for a lag between 3.5 and 7 weeks. There was life-long hypophosphatemia and elevated plasma alkaline phosphatase. It was concluded that the period of low levels of duodenal vitamin D-dependent calcium-binding protein was associated with low intestinal absorption and low skeletal mineralization. This dysfunction of the intestine in juvenile, rapidly growing Hyp mice may exacerbate the bone disease.