The family of fibroblast growth factors (FGFs) regulates a plethora of developmental processes, including brain patterning, branching morphogenesis and limb development. Several mitogenic, cytoprotective and angiogenic therapeutic applications of FGFs are already being explored, and the recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in bile acid, glucose and phosphate homeostasis has sparked renewed interest in the pharmacological potential of this family. This Review discusses traditional applications of recombinant FGFs and small-molecule FGF receptor kinase inhibitors in the treatment of cancer and cardiovascular disease and their emerging potential in the treatment of metabolic syndrome and hypophosphataemic diseases.

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The FGF family: biology, pathophysiology and therapy.

The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs) Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS-MAPK, PI3K-AKT, PLCγ, and STAT intracellular signaling pathways Four structurally related intracellular non-signaling FGFs interact with and regulate the family of voltage gated sodium channels Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning FGFs also have roles in adult tissues where they mediate metabolic functions, tissue repair, and regeneration, often by reactivating developmental signaling pathways Consistent with the presence of FGFs in almost all tissues and organs, aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer © 2015 Wiley Periodicals, Inc

The Fibroblast Growth Factor signaling pathway

Epidemiology of cardiovascular disease in chronic renal disease

In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis. (Funded by Amgen; EVOLVE ClinicalTrials.gov number, NCT00345839.).

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Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis

Unique among fibroblast growth factors (FGFs), FGF19, -21, and -23 act in an endocrine fashion to regulate energy, bile acid, glucose, lipid, phosphate, and vitamin D homeostasis. These FGFs require the presence of Klotho/betaKlotho in their target tissues. Here, we present the crystal structures of FGF19 alone and FGF23 in complex with sucrose octasulfate, a disaccharide chemically related to heparin. The conformation of the heparin-binding region between beta strands 10 and 12 in FGF19 and FGF23 diverges completely from the common conformation adopted by paracrine-acting FGFs. A cleft between this region and the beta1-beta2 loop, the other heparin-binding region, precludes direct interaction between heparin/heparan sulfate and backbone atoms of FGF19/23. This reduces the heparin-binding affinity of these ligands and confers endocrine function. Klotho/betaKlotho have evolved as a compensatory mechanism for the poor ability of heparin/heparan sulfate to promote binding of FGF19, -21, and -23 to their cognate receptors.

http://www-heparin.rpi.edu/main/files/papers/413.pdf

Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members

Context: Tumoral calcinosis is a disease characterized by ectopic calcification and hyperphosphatemia due to enhanced renal tubular phosphate reabsorption. Fibroblast growth factor (FGF)23 was identified as a responsible factor in hypophosphatemic diseases caused by renal phosphate leak. Objective: The objective of the study was to analyze the involvement of FGF23 in the development of tumoral calcinosis. Design: Serum FGF23 level was evaluated in a patient with tumoral calcinosis by two kinds of ELISA: full-length assay that detects only full-length FGF23 with phosphate-lowering activity and C-terminal assay that measures full-length as well as C-terminal fragment of FGF23. FGF23 gene was analyzed by direct sequencing of PCR products, and mutant FGF23 was analyzed by Western blotting after expression in mammalian cells. Patients: A family of tumoral calcinosis patients were studied. Results: Serum FGF23 was extremely high when measured by C-terminal assay. In contrast, it was low normal by full-length as...

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A Novel Mutation in Fibroblast Growth Factor 23 Gene as a Cause of Tumoral Calcinosis

Adequate sympathetic nervous system activation is essential for the compensatory mechanisms of blood pressure maintenance during the hemodialysis (HD) procedure. Chronic sympathetic nervous system overactivity, however, may lead to the development of hypertension and cardiovascular disease in HD patients. The present review focuses on recent findings on the sympathetic nervous system activity in these patients. Sympathetic overactivity has been demonstrated directly by muscle sympathetic nerve activity recordings (MSNA) in chronic renal disease, but only rarely in HD patients. In the latter, sympathetic activity has mostly been assessed using indirect methodology. Decreased heart rate variability, increased blood pressure variability (BPV), and suppressed baroreflex function are believed to represent chronic sympathetic overactivity in HD patients. The HD procedure and ultrafiltration are associated with enhanced sympathetic activity and baroreflex activation. During most episodes of intradialytic hypotension, the baroreflex is adequately activated; sympathetic withdrawal with bradycardia, however, has been reported during excessive hypovolemia. Sympathetic overactivity is also believed to be a mechanism associated with intradialytic hypertensive episodes and refractory hypertension. While successful renal transplantation is associated with improvement of heart rate variability (HRV), improvement and restoration of baroreflex function, persistent sympathetic overactivity has been documented in transplanted patients using MSNA recordings. Decreased HRV and baroreflex function have been reported to be associated with increased mortality and morbidity in HD patients. The predictive value of sympathetic outflow assessed by MSNA has yet to be determined. Optimization of HD treatment, pharmacological interventions, and renal sympathetic denervation are several approaches targeting sympathetic overactivity to improve cardiovascular morbidity and mortality.

Sympathetic Nervous System Function and Dysfunction in Chronic Hemodialysis Patients

Background 
The mechanisms of intradialytic increases in blood pressure are not well defined. The present study was undertaken to assess the role of autonomic nervous system activation during intradialytic hypertensive episodes.


Methodology/Principal Findings 
Continuous interbeat intervals (IBI) and systolic blood pressure (SBP) were monitored during hemodialysis in 108 chronic patients. Intradialytic hypertensive episodes defined as a period of at least 10 mmHg increase in SBP between the beginning and the end of a dialysis session or hypertension resistant to ultrafiltration occurring during or immediately after the dialysis procedure, were detected in 62 out of 113 hemodialysis sessions. SBP variability, IBI variability and baroreceptor sensitivity (BRS) in the low (LF) and high (HF) frequency ranges were assessed using the complex demodulation technique (CDM). Intradialytic hypertensive episodes were associated with an increased (n = 45) or decreased (n = 17) heart rate. The maximal blood pressure was similar in both groups. In patients with increased heart rate the increase in blood pressure was associated with marked increases in SBP and IBI variability, with suppressed BRS indices and enhanced sympatho-vagal balance. In contrast, in those with decreased heart rate, there were no significant changes in the above parameters. End-of- dialysis blood pressure in all sessions associated with hypertensive episode was significantly higher than in those without such episodes. In logistic regression analysis, predialysis BRS in the low frequency range was found to be the main predictor of intradialytic hypertension.


Conclusion/Significance 
Our data point to sympathetic overactivity with feed-forward blood pressure enhancement as an important mechanism of intradialytic hypertension in a significant proportion of patients. The triggers of increased sympathetic activity during hemodialysis remain to be determined. Intradialytic hypertensive episodes are associated with higher end-of- dialysis blood pressure, suggesting that intradialytic hypertension may play a role in generation of interdialytic hypertension.

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Sympathetic activation and baroreflex function during intradialytic hypertensive episodes.

Background. Renal transplantation improves the uraemic autonomic dysfunction and heart rate variability (HRV). The effects of successful transplantation on blood pressure variability (BPV) and baroreflex function are not well defined. Methods. BPV, HRV and baroreceptor indices were determined in (1) 52 non-diabetic chronic haemodialysis patients, (2) 44 transplanted patients, 24 in the first year after renal transplantation (≤I year) and 20 at least 1 year (>1 year) after renal transplantation, and (3) 41 control individuals with normal renal function, age-matched to (1) and (2). Power spectrum analysis of interbeat intervals (IBI) and systolic blood pressure (SBP) was performed in the low-frequency (LF 0.04-0.15 Hz) and the high-frequency (HF 0.15-0.40 Hz) bands. Spontaneous baroreceptor sensitivity (BRS) was determined by the sequence (slope) and spectral (a coefficient) techniques. Results. In haemodialysis patients, BPV was increased, while HRV, BRS slope and LF a and HF a coefficients were markedly decreased as compared to control individuals. Renal transplantation was associated with normalization of BPV at short term (≤1 year) and long term and with improvement of HRV at a long-term (> 1 year) follow-up. In patients with long-standing functioning grafts (>1 year), baroreceptor indices were significantly increased and returned to values similar to those of the control subjects. Conclusions. Our data show that renal transplantation improves blood pressure and HRV and restores baroreflex function to near normal range on the long-term follow-up. These effects may contribute to the improvement of blood pressure control and survival after successful transplantation.

Restoration of baroreflex function in patients with end-stage renal disease after renal transplantation

Objectives The role of the baroreflex function in the pathogenesis of hemodialysis-associated hypotension is controversial. Complex demodulation technique (CDM), providing continuous assessment of the amplitude of cardiovascular oscillation over time, is particularly suitable to assess dynamic changes in autonomic nervous system and baroreceptor sensitivity (BRS) during dialysis. In the present study, CDM was used to determine the effects of dialysis treatment on BRS and to characterize BRS changes during acute intradialytic hypotension. Methods Continuous beat-to-beat blood pressure and interbeat intervals (IBIs) were monitored in 93 chronic patients without (n = 70) and with (n = 26) hypotension during 96 dialysis sessions. The amplitudes of SBP and DBP, IBIs, and BRS change in the low-frequency (around center frequency of 0.09 Hz) and high-frequency (around center frequency of 0.30 Hz) ranges were followed during the whole dialysis session. Results Hemodialysis treatment was associated with increased low-frequency BRS, especially in sessions without hypotension. Hypotensive episodes were associated with significant increases in both low-frequency BRS and high-frequency BRS, mainly in patients with severe hypotension. The magnitude of the increase in baroreflex indices was proportional to the decrease in blood pressure. Low-frequency IBI/high-frequency IBI ratio, a marker of sympatho-vagal balance, did not significantly change during hypotension. Conclusion Our study shows that the baroreflex mechanism is preserved and adequately activated during intradialytic hypotension. Other factors, such as ischemic heart disease, left ventricular dysfunction, and inadequate arteriolar tone, rather than failure of baroreflex function, are more likely to be responsible for dialysis-induced hypotension.

Rebecca Backenroth

Papers

A Novel Mutation in Fibroblast Growth Factor 23 Gene as a Cause of Tumoral Calcinosis

Sympathetic Nervous System Function and Dysfunction in Chronic Hemodialysis Patients

Sympathetic activation and baroreflex function during intradialytic hypertensive episodes.

Restoration of baroreflex function in patients with end-stage renal disease after renal transplantation

Baroreflex sensitivity and sympatho-vagal balance during intradialytic hypotensive episodes.