Disordered FGF23 and Mineral Metabolism in Children with CKD

Portale, Anthony A.; Wolf, Myles; Jüppner, Harald; Messinger, Shari; Kumar, Juhi; Wesseling‐Perry, Katherine; Schwartz, George J.; Furth, Susan L.; Warady, Bradley A.; Salusky, Isidro B.

doi:10.2215/cjn.05840513

Cited by 132 publications

(115 citation statements)

References 47 publications

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“…Similar observations were recently made in a cohort of children with CKD. 27 This interpretation fits with results showing a decreased cellular response to FGF-23 in animal models of nephrotic proteinuria. Indeed, despite high plasma levels of FGF-23, phosphorylation of FRS2a, a major downstream target of FGF receptor, 19 was decreased in proteinuric animals.…”

Section: Discussionsupporting

confidence: 86%

“…24,25 Recent reports also indicate that FGF-23 increases in parallel to albuminuria in IgA nephropathy 26 and that children with glomerular diseases display higher FGF-23 levels than those with non-glomerular diseases. 27 Finally, decreased Klotho expression appears to be an early event in CKD. [28][29][30] We hypothesized that proteinuria indirectly modulates kidney phosphate handling via a toxicity that decreases Klotho expression and that thereby alters FGF-23 signaling, or via a direct competitive effect for endocytosis in the proximal tubule.…”

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confidence: 99%

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Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling

Seigneux

Courbebaisse

Rutkowski

et al. 2015

Journal of the American Society of Nephrology

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Proteinuria and hyperphosphatemia are cardiovascular risk factors independent of GFR. We hypothesized that proteinuria induces relative phosphate retention via increased proximal tubule phosphate reabsorption. To test the clinical relevance of this hypothesis, we studied phosphate handling in nephrotic children and patients with CKD. Plasma fibroblast growth factor 23 (FGF-23) concentration, plasma phosphate concentration, and tubular reabsorption of phosphate increased during the proteinuric phase compared with the remission phase in nephrotic children. Cross-sectional analysis of a cohort of 1738 patients with CKD showed that albuminuria$300 mg/24 hours is predictive of higher phosphate levels, independent of GFR and other confounding factors. Albuminuric patients also displayed higher plasma FGF-23 and parathyroid hormone levels. To understand the molecular mechanisms underlying these observations, we induced glomerular proteinuria in two animal models. Rats with puromycin-aminonucleoside-induced nephrotic proteinuria displayed higher renal protein expression of the sodium-phosphate co-transporter NaPi-IIa, lower renal Klotho protein expression, and decreased phosphorylation of FGF receptor substrate 2a, a major FGF-23 receptor substrate. These findings were confirmed in transgenic mice that develop nephrotic-range proteinuria resulting from podocyte depletion. In vitro, albumin did not directly alter phosphate uptake in cultured proximal tubule OK cells. In conclusion, we show that proteinuria increases plasma phosphate concentration independent of GFR. This effect relies on increased proximal tubule NaPi-IIa expression secondary to decreased FGF-23 biologic activity. Proteinuria induces elevation of both plasma phosphate and FGF-23 concentrations, potentially contributing to cardiovascular disease.

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Section: Discussionsupporting

confidence: 86%

mentioning

confidence: 99%

Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling

Seigneux

Courbebaisse

Rutkowski

et al. 2015

Journal of the American Society of Nephrology

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“…In CRIC, few patients (,6%) showed an isolated increase in PTH (.65 pg/ml but normal FGF23), emphasizing the primacy of elevations in FGF23 in this patient group (3). Consistent findings have been reported in pediatric CKD cohorts using the same assay (35) and other adult nondialysisdependent CKD cohorts using the Kainos iFGF23 assay (36). This temporal sequence is also borne out in longitudinal studies in murine models of progressive CKD (37).…”

Section: Does Fgf23 Measurement Add Value For Patients With Ckd? Ckd supporting

confidence: 77%

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Smith

2014

Clinical Journal of the American Society of Nephrology

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The emergence of fibroblast growth factor 23 as a potentially modifiable risk factor in CKD has led to growing interest in its measurement as a tool to assess patient risk and target therapy. This review discusses the analytical and clinical challenges faced in translating fibroblast growth factor 23 testing into routine practice. As for other bone mineral markers, agreement between commercial fibroblast growth factor 23 assays is poor, mainly because of differences in calibration, but also, these differences reflect the variable detection of hormone fragments. Direct comparison of readout from different assays is consequently limited and likely hampers setting uniform fibroblast growth factor 23-directed targets. Efforts are needed to standardize assay output to enhance clinical use. Fibroblast growth factor 23 is robustly associated with cardiovascular and renal outcomes in patients with CKD and adds value to risk assessments based on conventional risk factors. Compared with most other mineral markers, fibroblast growth factor 23 shows better intraindividual temporal stability, with minimal diurnal and week-to-week variability, but substantial interindividual variation, maximizing discriminative power for risk stratification. Conventional therapeutic interventions for the CKD-mineral bone disorder, such as dietary phosphate restriction and use of oral phosphate binders or calcimimetics, are associated with variable efficacy at modulating circulating fibroblast growth factor 23 concentrations, like they are for other mineral metabolites. Dual therapy with dietary phosphate restriction and noncalcium-based binder use achieves the most consistent fibroblast growth factor 23-lowering effect and seems best monitored using an intact assay. Additional studies are needed to evaluate whether strategies aimed at reducing levels or antagonizing its action have beneficial effects on clinical outcomes in CKD patients. Moreover, a better understanding of the mechanisms driving fibroblast growth factor 23 elevations in CKD is needed to inform the use of therapeutic interventions targeting fibroblast growth factor 23 excess. This evidence must be forthcoming to support the use of fibroblast growth factor 23 measurement and fibroblast growth factor 23-directed therapy in the clinic.

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“…They did, however, find independent associations of elevated FGF-23 with these outcomes, even in a subgroup of patients with eGFR between 30-90 (16). This difference might be due to the longer follow-up time in our study, because recent data in children with predialysis CKD have shown that FGF-23 concentrations increased early and progressively as GFR declined, and preceded any increase in serum phosphorus (34). Unfortunately, FGF-23 is not reported in our registry, so we were not able to test whether this hormone was associated with graft failure.…”

Section: Discussionmentioning

confidence: 83%

Mineral Metabolism in European Children Living with a Renal Transplant

Bonthuis¹,

Busutti²,

Stralen³

et al. 2015

Clinical Journal of the American Society of Nephrology

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Background and objectives Data on mineral metabolism in pediatric renal transplant recipients largely arise from small single-center studies. In adult patients, abnormal mineral levels are related to a higher risk of graft failure. This study used data from the European Society for Paediatric Nephrology/European Renal AssociationEuropean Dialysis and Transplant Association Registry to study the prevalence and potential determinants of mineral abnormalities, as well as the predictive value of a disturbed mineral level on graft survival in a large cohort of European pediatric renal transplant recipients.Design, setting, participants, & measurements This study included 1237 children (0-17 years) from 10 European countries, who had serum calcium, phosphorus, and parathyroid hormone measurements from 2000 onward. Abnormalities of mineral metabolism were defined according to European guidelines on prevention and treatment of renal osteodystrophy in children on chronic renal failure.Results Abnormal serum phosphorus levels were observed in 25% (14% hypophosphatemia and 11% hyperphosphatemia), altered serum calcium in 30% (19% hypocalcemia, 11% hypercalcemia), and hyperparathyroidism in 41% of the patients. A longer time since transplantation was associated with a lower risk of having mineral levels above target range. Serum phosphorus levels were inversely associated with eGFR, and levels above the recommended targets were associated with a higher risk of graft failure independently of eGFR.Conclusions Abnormalities in mineral metabolism are common after pediatric renal transplantation in Europe and are associated with graft dysfunction.

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Disordered FGF23 and Mineral Metabolism in Children with CKD

Cited by 132 publications

References 47 publications

Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling

Proteinuria Increases Plasma Phosphate by Altering Its Tubular Handling

The Use of Fibroblast Growth Factor 23 Testing in Patients with Kidney Disease

Mineral Metabolism in European Children Living with a Renal Transplant

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