Fibroblast Growth Factor 23 and the Antiproteinuric Response to Dietary Sodium Restriction During Renin-Angiotensin-Aldosterone System Blockade

Humalda, Jelmer K.; Heerspink, Hiddo J.L.; Kwakernaak, Arjan J.; Slagman, Maartje C. J.; Waanders, Femke; Vervloet, Marc G.; Wee, Pieter M. ter; Navis, Gerarda; Borst, Martin H. de

doi:10.1053/j.ajkd.2014.07.022

Cited by 28 publications

(23 citation statements)

References 34 publications

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“…[58][59][60] Conversely, FGF-23 has no effect on phosphate uptake or phosphate-induced calcification, independent of phosphate concentration. 61 Dysregulation of FGF-23 expression might be more closely associated with cardiovascular complications due to volume overload, such as left ventricular hyper trophy and heart failure, than to ischaemic heart disease, as suggested by epidemiologic 62,63 and translational studies. 64 The risk of cardiovascular-associated morbidity and mortality in patients with ESRD is markedly reduced after kidney transplantation, but still remains high compared to that of the general population.…”

Section: Kidney Transplantationmentioning

confidence: 99%

Phosphate and FGF-23 homeostasis after kidney transplantation

Baia

Heilberg²,

Navis

et al. 2015

Nat Rev Nephrol

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Dysregulated phosphate metabolism is a common consequence of chronic kidney disease, and is characterized by a high circulating level of fibroblast growth factor (FGF)-23, hyperparathyroidism, and hyperphosphataemia. Kidney transplantation can elicit specific alterations to phosphate metabolism that evolve over time, ranging from severe hypophosphataemia (<0.5 mmol/l) to hyperphosphataemia (>1.50 mmol/l) and high FGF-23 levels. The majority of renal transplant recipients develop hypophosphataemia during the first 3 months after transplantation as a consequence of relatively slow adaptation of FGF-23 and parathyroid hormone levels to restored renal function, and the influence of immunosuppressive drugs. By 3-12 months after transplantation, phosphate homeostasis is at least partially restored in the majority of recipients, which is paralleled by a substantially reduced risk of cardiovascular-associated morbidity and mortality compared with the pre-transplantation setting. Many renal transplant recipients, however, exhibit persistent abnormalities in phosphate homeostasis, which is often due to multifactorial causes, and may contribute to adverse outcomes on the cardiovascular system, kidney, and bone. Dietary and pharmacologic interventions might improve phosphate homeostasis in renal transplant recipients, but additional insight into the pathophysiology of transplantation-associated abnormalities in phosphate homeostasis is needed to further optimize disease management and improve prognosis for renal transplant recipients.

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Section: Kidney Transplantationmentioning

confidence: 99%

Phosphate and FGF-23 homeostasis after kidney transplantation

Baia

Heilberg²,

Navis

et al. 2015

Nat Rev Nephrol

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“…We first assessed the relationship between FGF-23 as independent and residual proteinuria as dependent variable in univariate regression analysis as described earlier. [13] Subsequently, we studied the relationship between FGF-23 and residual proteinuria at the end of each treatment period in a model adjusted for “baseline” proteinuria, that is, proteinuria during regular sodium (RS) diet and placebo. Finally, we further adjusted for creatinine clearance, a potential confounder of the relation between FGF-23 and antiproteinuric response, and repeated these analyses with eGFR.…”

Section: Methodsmentioning

confidence: 99%

“…These observations add to previously documented independent associations between FGF-23 and markers of volume status, [12] and could at least partly explain the previously observed association between a higher FGF-23 level and an impaired antiproteinuric response to volume depletion. [13] Conversely, recent data suggest that changes in volume status may modulate FGF-23 concentrations at least in hemodialysis. [14] This suggests the presence of a feedback loop, where FGF-23 increases volume load, and an increase in volume may reduce FGF-23.…”

Section: Introductionmentioning

confidence: 99%

Response of fibroblast growth factor 23 to volume interventions in arterial hypertension and diabetic nephropathy

et al. 2016

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Fibroblast growth factor 23 (FGF-23) rises progressively in chronic kidney disease and is associated with adverse cardiovascular outcomes. FGF-23 putatively induces volume retention by upregulating the sodium-chloride cotransporter (NCC). We studied whether, conversely, interventions in volume status affect FGF-23 concentrations.We performed a post hoc analysis of 1) a prospective saline infusion study with 12 patients with arterial hypertension who received 2 L of isotonic saline over 4 hours, and 2) a randomized controlled trial with 45 diabetic nephropathy (DN) patients on background angiotensin-converting enzyme -inhibition (ACEi), who underwent 4 6-week treatment periods with add-on hydrochlorothiazide (HCT) or placebo, combined with regular sodium (RS) or low sodium (LS) diet in a cross-over design. Plasma C-terminal FGF-23 was measured by ELISA (Immutopics) after each treatment period in DN and before and after saline infusion in hypertensives.The patients with arterial hypertension were 45 ± 13 (mean ± SD) years old with an estimated glomerular filtration rate (eGFR) of 101 ± 18 mL/min/1.73 m2. Isotonic saline infusion did not affect FGF-23 (before infusion: 68 median [first to third quartile: 58–97] relative unit (RU)/mL, after infusion: 67 [57–77] RU/mL, P = 0.37). DN patients were 65 ± 9 years old. During ACEi + RS treatment, eGFR was 65 ± 25 mL/min/1.73 m2 and albuminuria 649 mg/d (230–2008 mg/d). FGF23 level was 94 (73–141) RU/mL during ACEi therapy. FGF-23 did not change significantly by add-on HCT (99 [74–148] RU/mL), LS diet (99 [75–135] RU/mL), or their combination (111 [81–160] RU/mL, P = 0.15).Acute and chronic changes in volume status did not materially change FGF-23 in hypertensive patients and DN, respectively. Our data do not support a direct feedback loop between volume status and FGF-23 in hypertension or DN.

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“…Interestingly, these FGF23-mediated effects on cardiovascular pathophysiology were augmented in animal models ingesting a low sodium diet (which stimulates aldosterone secretion), raising the possibility of an interaction between FGF23 and the renin-angiotensin-aldosterone axis in CKD-stimulated cardiovascular disease. Furthermore, Humalda et al demonstrated that humans with higher baseline FGF23 levels had a reduced antiproteinuric response to dietary sodium restriction and ACE inhibitor therapy, which has been associated with heighted cardiovascular and end-stage renal disease (ESRD) risk in CKD (36). …”

Section: Key Pathogenic Components Of the Ckd-mbdmentioning

confidence: 99%

The Kidney-Vascular-Bone Axis in the Chronic Kidney Disease-Mineral Bone Disorder

Seifert

Hruska

2016

Transplantation

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The last 25 years have been characterized by dramatic improvements in short-term patient and allograft survival after kidney transplantation. Long-term patient and allograft survival remains limited by cardiovascular disease and chronic allograft injury, among other factors. Cardiovascular disease remains a significant contributor to mortality in native chronic kidney disease as well, as cardiovascular mortality in chronic kidney disease more than doubles that of the general population. The chronic kidney disease-mineral bone disorder (CKD-MBD) is a syndrome recently coined to embody the biochemical, skeletal, and cardiovascular pathophysiology that results from disrupting the complex systems biology between the kidney, skeleton, and cardiovascular system in native and transplant kidney disease. The CKD-MBD is a unique kidney disease-specific syndrome containing novel cardiovascular risk factors, with an impact reaching far beyond traditional notions of renal osteodystrophy and hyperparathyroidism. This Overview reviews current knowledge of the pathophysiology of the CKD-MBD, including emerging concepts surrounding the importance of circulating pathogenic factors released from the injured kidney that directly cause cardiovascular disease in native and transplant chronic kidney disease, with potential application to mechanisms of chronic allograft injury and vasculopathy.

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Fibroblast Growth Factor 23 and the Antiproteinuric Response to Dietary Sodium Restriction During Renin-Angiotensin-Aldosterone System Blockade

Cited by 28 publications

References 34 publications

Phosphate and FGF-23 homeostasis after kidney transplantation

Phosphate and FGF-23 homeostasis after kidney transplantation

Response of fibroblast growth factor 23 to volume interventions in arterial hypertension and diabetic nephropathy

The Kidney-Vascular-Bone Axis in the Chronic Kidney Disease-Mineral Bone Disorder

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