Elevated fibroblast growth factor 23 is a risk factor for kidney transplant loss and mortality.

An increased circulating level of fibroblast growth factor 23 (FGF23) is an independent risk factor for mortality, cardiovascular disease, and progression of chronic kidney disease (CKD), but its role in transplant allograft and patient survival is unknown. We tested the hypothesis that increased FGF23 is an independent risk factor for all-cause mortality and allograft loss in a prospective cohort of 984 stable kidney transplant recipients. At enrollment, estimated GFR (eGFR) was 51 ± 21 ml/min per 1.

Differential effects of vitamin d receptor agonists on gene expression in neonatal rat cardiomyocytes.

Purpose: Vitamin D receptor (VDR) activation is associated with cardiovascular benefits in chronic kidney disease patients, but whether VDR's hormone and prehormone exhibit similar effects requires more studies.

Methods: Neonatal rat cardiomyocytes were treated with VDR agonists (calcitriol and/or paricalcitol) and the prehormone calcidiol in the presence of aldo (1 μM). The expression of VDR target genes were determined by real-time PCR and Western blotting.

Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease.

Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4.

Diuretics, calciuria and secondary hyperparathyroidism in the Chronic Renal Insufficiency Cohort.

Background: Secondary hyperparathyroidism is a common complication of chronic kidney disease (CKD) that is associated with bone disease, cardiovascular disease and death. Pathophysiological factors that maintain secondary hyperparathyroidism in advanced CKD are well-known, but early mechanisms of the disease that can be targeted for its primary prevention are poorly understood. Diuretics are widely used to control volume status and blood pressure in CKD patients but are also known to have important effects on renal calcium handling, which we hypothesized could alter the risk of secondary hyperparathyroidism.

Association of serum phosphorus level with anemia in kidney transplant recipients.

Background: Anemia and mineral and bone disorders (MBD) are both important and common complications in kidney transplant recipients. Studies in patients with chronic kidney disease indicated a possible independent association of higher serum phosphorus with anemia, but similar associations have not been examined in kidney transplant recipients. We hypothesized that higher serum phosphorus is associated with anemia independent of other components of MBD.

FGF23 or PTH: which comes first in CKD ?

In the past 40 years, disordered mineral metabolism has been among the most intensely studied areas of nephrology. A June 2010 PubMed search for 'secondary hyperparathyroidism and kidney disease' yielded 5866 references. Among these are papers documenting the development and application of numerous therapeutic agents-including calcitriol, vitamin D analogs, phosphate binders, and cinacalcet-that remain in widespread use in the day-to-day management of dialysis patients worldwide.

Tertiary excess of fibroblast growth factor 23 and hypophosphatemia following kidney transplantation.

Hypophosphatemia caused by inappropriate urinary phosphate wasting is a frequent metabolic complication of the early period following kidney transplantation. Although previously considered to be caused by tertiary hyperparathyroidism, recent evidence suggests a primary role for persistently elevated circulating levels of the phosphorus-regulating hormone, FGF23. In the setting of a healthy renal allograft, markedly increased FGF23 levels from the dialysis period induce renal phosphate wasting and inhibition of calcitriol production, which contribute to hypophosphatemia.

Low socioeconomic status associates with higher serum phosphate irrespective of race.

Hyperphosphatemia, which associates with adverse outcomes in CKD, is more common among blacks than whites for unclear reasons. Low socioeconomic status may explain this association because poverty both disproportionately affects racial and ethnic minorities and promotes excess intake of relatively inexpensive processed and fast foods enriched with highly absorbable phosphorus additives. We performed a cross-sectional analysis of race, socioeconomic status, and serum phosphate among 2879 participants in the Chronic Renal Insufficiency Cohort Study.

Vitamin D deficiency, inflammation, and albuminuria in chronic kidney disease: complex interactions.

Objective: Vitamin D may promote cardiovascular health in general population and in chronic kidney disease (CKD) through inhibition of the renin-angiotensin system and anti-inflammatory effects. Although proteinuria is a marker of kidney and cardiovascular disease, few studies have examined vitamin D levels, inflammation, and proteinuria simultaneously in CKD. We evaluated the relationship between calcidiol (25D), calcitriol (1,25D), inflammation, and albuminuria in Study of Early Evaluation of Kidney Disease, a multicenter CKD cohort.

Pilot study of dietary phosphorus restriction and phosphorus binders to target fibroblast growth factor 23 in patients with chronic kidney disease.

Background: High levels of fibroblast growth factor 23 (FGF23) are associated with mortality and progression of chronic kidney disease (CKD). Reducing dietary phosphorus intake lowers FGF23 secretion in healthly individuals, but there is little data on its effects in patients with pre-dialysis CKD.

Methods: Using a 2×2 factorial design, we randomly assigned 16 normophosphataemic CKD stage 3-4 patients to receive a 2-week treatment with either lanthanum carbonate 1000 mg three times daily or placebo, and to ingest a tightly controlled diet containing 750 or 1500 mg of dietary phosphorus daily.

FGF-23: More than a regulator of renal phosphate handling?

Fibroblast growth factor 23 (FGF-23) is likely to be the most important regulator of phosphate homeostasis, which mediates its functions through FGF receptors and the coreceptor Klotho. Besides reducing expression of the sodium-phosphate cotransporters NPT2a and NPT2c in the proximal tubules, FGF-23 inhibits the renal 1α-hydroxylase and stimulates the 24-hydroxylase, and it appears to reduce parathyroid hormone (PTH) secretion in short-term studies. FGF-23 synthesis and secretion by osteocytes and osteoblasts is upregulated through 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and through an increased dietary phosphate intake.

Recent advances in the rapidly evolving field of fibroblast growth factor 23 in chronic kidney disease.

Purpose Of Review: In recent years, there has been an increasing awareness of the central regulatory role of fibroblast growth factor 23 (FGF23) in mineral metabolism and its particular prominence in patients with chronic kidney disease (CKD).

Recent Findings: FGF23 is a powerful predictor of adverse clinical outcomes in CKD that appears to be superior to existing mineral metabolism markers such as serum phosphate and parathyroid hormone. Interesting new data suggest a central role of bone health in the regulation of FGF23 secretion, whereas another important new study reported that virtually all circulating FGF23 in advanced renal failure is biologically intact.

Dietary phosphorus restriction in advanced chronic kidney disease: merits, challenges, and emerging strategies.

Hyperphosphatemia is an independent risk factor for mortality in patients on maintenance dialysis. Since phosphorus clearance by standard three times-weekly dialysis is insufficient to balance ongoing dietary phosphorus intake, strategies to prevent absorption of dietary phosphorus are essential for attenuating increased serum levels. Dietary phosphorus binders are used widely for this purpose but dietary phosphorus restriction is relatively underutilized, most likely because of the logistical complexity of instituting and monitoring a low phosphorus diet, and for fear of worsening protein-energy wasting, which itself is a potent risk factor for mortality.

Impact of poverty on serum phosphate concentrations in the Third National Health and Nutrition Examination Survey.

Objective: Increased serum phosphate is associated with adverse health outcomes. High intake of inexpensive processed and fast foods is common in impoverished communities, and is linked with excessive dietary phosphorus intake and elevated serum phosphate concentrations in chronic kidney disease patients. We examined the impact of socioeconomic status on dietary phosphorus intake and serum phosphate concentrations in the general population.

Racial differences in postprandial mineral ion handling in health and in chronic kidney disease.

Background: Increased serum phosphate is associated with cardiovascular disease. Compared with whites, blacks have significantly higher serum phosphate and increased risk of hyperphosphataemia in health and chronic kidney disease (CKD). While population-based studies suggest that diminished urinary phosphorus excretion in blacks may explain these differences, few physiological studies explored the potential mechanisms.

Forging forward with 10 burning questions on FGF23 in kidney disease.

The discovery of fibroblast growth factor 23 (FGF23) as the causal factor in the pathogenesis of rare forms of hypophosphatemic rickets is rapidly reshaping our understanding of disordered mineral metabolism in chronic kidney disease (CKD). Excessive production of FGF23 by osteocytes is an appropriate compensation to help maintain normal phosphorus metabolism in these patients. Beginning in early CKD, progressive increases in levels of FGF23 enhance phosphaturia on a per-nephron basis and inhibit calcitriol production, thereby contributing centrally to the predominant phosphorus phenotype of predialysis kidney disease: normal serum phosphate, increased fractional excretion of phosphate, and calcitriol deficiency.

Randomized evaluation of efficacy and safety of ferric carboxymaltose in patients with iron deficiency anaemia and impaired renal function (REPAIR-IDA): rationale and study design.

Background: Patients with iron deficiency anaemia (IDA) in the setting of non-dialysis-dependent chronic kidney disease (NDD-CKD) may benefit from treatment with intravenous (IV) iron. Ferric carboxymaltose (FCM) is a novel IV iron formulation designed to permit larger infusions compared to currently available IV standards such as Venofer(R) (iron sucrose).

Methods: The primary objective of REPAIR-IDA is to estimate the cardiovascular safety and efficacy of FCM (two doses at 15 mg/kg to a maximum of 750 mg per dose) compared to Venofer(R) (1000 mg administered as five infusions of 200 mg) in subjects who have IDA and NDD-CKD.

Diagnosis and management of mineral metabolism in CKD.

Background: Chronic kidney disease (CKD) affects over 26 million Americans and is frequently complicated early in its course by disordered mineral metabolism and metabolic bone disease. Since CKD-related bone loss is often indistinguishable from osteoporosis by standard bone densitometry, many CKD patients may be inappropriately treated with bisphosphonates rather than CKD-specific therapies.

Objective: To determine the prevalence of appropriate evaluation, diagnosis and management of metabolic bone disease among individuals with pre-dialysis CKD.

Vitamin D deficiency and anemia in early chronic kidney disease.

Vitamin D has a number of pleiotropic effects in a variety of tissues, in addition to its well-known effects on mineral metabolism. To determine whether it has an effect on erythropoiesis, we studied the association of the components of the vitamin D axis with the prevalence and severity of anemia in chronic kidney disease. We measured the concentrations of 25-hydroxyvitamin D (25D), 1,25-dihydroxyvitamin D (1,25D), and hemoglobin in a cross-sectional study of 1661 subjects in SEEK, a multi-center cohort study of chronic kidney disease patients in the United States, of whom 41% met the criteria for anemia.

Elevated FGF-23 in a patient with rhabdomyolysis-induced acute kidney injury.

Rhabdomyolysis-induced acute kidney injury (AKI) is characterized by hyperphosphataemia and hypocalcaemia. Despite appropriate secondary elevation of parathyroid hormone (PTH) in response to hypocalcaemia, rhabdomyolysis and AKI are associated with acute deficiency of 1,25-dihydroxycholecalciferol (1,25(OH)(2)D(3)), and yet, the mechanism responsible for such a deficiency remains unclear. Fibroblast growth factor 23 (FGF-23), a potent phosphaturic hormone that inhibits 25-hydroxyvitamin D(3)-1alpha-hydroxylase, could explain the deficiency of 1,25(OH)(2)D(3) in this setting.

Circulating fibroblast growth factor 23 in patients with end-stage renal disease treated by peritoneal dialysis is intact and biologically active.

Context: Fibroblast growth factor 23 (FGF23) regulates phosphorus homeostasis and vitamin D metabolism. Circulating FGF23 levels are elevated in inherited and acquired hypophosphatemic disorders that can cause rickets or osteomalacia. Particularly increased concentrations of FGF23 are observed in patients with chronic kidney disease (CKD), in which increased FGF23 is associated with more rapid disease progression, improved bone mineralization, the development of left ventricular hypertrophy, and increased mortality.

Adiposity, cardiometabolic risk, and vitamin D status: the Framingham Heart Study.

Objective: Because vitamin D deficiency is associated with a variety of chronic diseases, understanding the characteristics that promote vitamin D deficiency in otherwise healthy adults could have important clinical implications. Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear.