Diabetic nephropathy is a significant cause of chronic kidney disease and end-stage renal failure globally Much research has been conducted in both basic science and clinical therapeutics, which has enhanced understanding of the pathophysiology of diabetic nephropathy and expanded the potential therapies available This review will examine the current concepts of diabetic nephropathy management in the context of some of the basic science and pathophysiology aspects relevant to the approaches taken in novel, investigative treatment strategies

/pdf/diabetic-nephropathy-complications-and-treatment-arovwpix56.pdf

Diabetic nephropathy - complications and treatment.

Fibroblast growth factor 23 (FGF23) is an osteocyte-derived hormone that regulates phosphate and vitamin D homeostasis. Through unknown mechanisms, certain intravenous iron preparations induce acute, reversible increases in circulating FGF23 levels that lower serum phosphate in association with inappropriately low levels of calcitriol, similar to genetic diseases of primary FGF23 excess. In contrast, studies in wild-type mice suggest that iron deficiency stimulates fgf23 transcription but does not result in hypophosphatemia because FGF23 is cleaved within osteocytes by an unknown catabolic system. We tested the association of iron deficiency anemia with C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 55 women with a history of heavy uterine bleeding, and assessed the longitudinal biochemical response over 35 days to equivalent doses of randomly-assigned, intravenous elemental iron in the form of ferric carboxymaltose (FCM) or iron dextran. Iron deficiency was associated with markedly elevated cFGF23 (807.8 ± 123.9 relative units [RU]/mL) but normal iFGF23 (28.5 ± 1.1 pg/mL) levels at baseline. Within 24 hours of iron administration, cFGF23 levels fell by approximately 80% in both groups. In contrast, iFGF23 transiently increased in the FCM group alone, and was followed by a transient, asymptomatic reduction in serum phosphate <2.0 mg/dL in 10 women in the FCM group compared to none in the iron dextran group. Reduced serum phosphate was accompanied by increased urinary fractional excretion of phosphate, decreased calcitriol levels, and increased parathyroid hormone levels. These findings suggest that iron deficiency increases cFGF23 levels, and that certain iron preparations temporarily increase iFGF23 levels. We propose that intravenous iron lowers cFGF23 in humans by reducing fgf23 transcription as it does in mice, whereas carbohydrate moieties in certain iron preparations may simultaneously inhibit FGF23 degradation in osteocytes leading to transient increases in iFGF23 and reduced serum phosphate.

Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women.

Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 176RXXR179/S180 proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene–environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.

https://www.pnas.org/content/pnas/108/46/E1146.full.pdf

Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice.

Context: Parenteral iron administration has been associated with hypophosphatemia. Fibroblast growth factor 23 (FGF23) has a physiological role in phosphate homeostasis via suppression of 25-hydroxyvitamin D [25(OH)D] activation and promotion of phosphaturia. We recently reported a case of iron-induced hypophosphatemic osteomalacia associated with marked FGF23 elevation. Objective: Our objective was to prospectively investigate the effect of parenteral iron polymaltose on phosphate homeostasis and to determine whether any observed change was related to alterations in circulating FGF23. Design, Setting, and Participants: Eight medical outpatients prescribed iv iron polymaltose were recruited. Plasma phosphate, 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)2D], PTH, FGF23, and urinary tubular reabsorption of phosphate were measured prior to iron administration and then weekly for a minimum of 3 wk. Results: Plasma phosphate fell from 3.4 ± 0.6 mg/dl at baseline to 1.8 ± 0.6 mg/dl at wk 1 (P < 0.0001) associated...

/pdf/fgf23-elevation-and-hypophosphatemia-after-intravenous-iron-4zm6lqmm5t.pdf

FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study.

Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia. Tumor resection leads to cure. We investigated the clinical characteristics of TIO, diagnostic methods, and course after tumor resection in Beijing, China, and compared them with 269 previous published reports of TIO. A total of 94 patients with adult-onset hypophosphatemic osteomalacia were seen over a 6-year period (January, 2004 to May, 2010) in Peking Union Medical College Hospital. After physical examination (PE), all patients underwent technetium-99m octreotide scintigraphy (99Tcm-OCT). Tumors were removed after localization. The results demonstrated that 46 of 94 hypophosphatemic osteomalacia patients had high uptake in 99Tcm-OCT imaging. Forty of them underwent tumor resection with the TIO diagnosis established in 37 patients. In 2 patients, the tumor was discovered on PE but not by 99Tcm-OCT. The gender distribution was equal (M/F = 19/20). Average age was 42 ± 14 years. In 35 patients (90%), the serum phosphorus concentration returned to normal in 5.5 ± 3.0 days after tumor resection. Most of the tumors (85%) were classified as phosphaturic mesenchymal tumor (PMT) or mixed connective tissue variant (PMTMCT). Recurrence of disease was suggested in 3 patients (9%). When combined with the 269 cases reported in the literature, the mean age and sex distribution were similar. The tumors were of bone (40%) and soft tissue (55%) origins, with 42% of the tumors being found in the lower extremities. In summary, TIO is an important cause of adult-onset hypophosphatemia in China. 99Tcm-OCT imaging successfully localized the tumor in the overwhelming majority of patients. Successful removal of tumors leads to cure in most cases, but recurrence should be sought by long-term follow-up. © 2012 American Society for Bone and Mineral Research.

Tumor-induced osteomalacia: An important cause of adult-onset hypophosphatemic osteomalacia in China: Report of 39 cases and review of the literature

Saccharated ferric oxide (SFO)-induced osteomalacia: In vitro inhibition by SFO of bone formation and 1,25-dihydroxy-vitamin D production in renal tubules

17 β-estradiol increases calcium content in fetal mouse parietal bones cultured in serum-free medium only at physiological concentrations

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Saccharated ferric oxide (SFO)-induced osteomalacia: In vitro inhibition by SFO of bone formation and 1,25-dihydroxy-vitamin D production in renal tubules

17 β-estradiol increases calcium content in fetal mouse parietal bones cultured in serum-free medium only at physiological concentrations