Nontraditional Cardiovascular Risk Factors in Chronic Kidney Disease: Have You Heard of FGF 23?

In the previous installment of this series, two important studies—SHARP and TNT—were summarized regarding the treatment of traditional cardiovascular risk factors in persons with chronic kidney disease.¹ Here, as promised, I review non-traditional risk factors unique to chronic kidney disease (CKD).

Have you heard of fibroblast growth factor 23 (FGF 23)? This is a good place to start with cardiovascular risk in CKD because FGF 23 levels rise early as kidney disease progresses. It is an endocrine hormone that regulates phosphorus metabolism.² The highest levels occur in persons with CKD.

You may say, so what? Well . . .  Isakova and coworkers² tested whether FGF 23 is a risk factor for death in end-stage renal disease.

From June 2003 to September 2008, 3879 patients with CKD stages 2 through 4 were enrolled. Of this cohort during follow-up, 266 died and 410 progressed to dialysis dependence. In these 676 unfortunate individuals, median FGF 23 levels were significantly higher than in the other members of the cohort. In fact, after adjustments for other risk factors (estimated glomerular filtration rates, for example) FGF 23 as a risk did not change (a 4.3-fold greater risk of death).

So: elevated levels of FGF are a new risk factor for death in CKD—a clinical situation replete with cardiovascular disease.

Let’s look at why this association may exist (that is, why an increased risk of death may be associated with elevated levels of FGF 23).
 
FGF 23 is a phosphate (PO-_⁴) homeostasis hormone. What might phosphate and its partner in cardiovascular crime, calcium (Ca++), have to do with heightened mortality in CKD?

FGF 23 rises in response to decreased renal excretion of PO-_⁴. For every level of PO-_⁴, cardiovascular risk rises!^3,4 In fact, elevated PO-_⁴ is a cardiovascular risk factor par excellence! A rise in PO-_⁴ is associated with left ventricular hypertrophy, increased arterial stiffness (decreased compliance), vascular calcification, and increased overall mortality.^3-5

How bad as non-traditional risk factors are synergistic elevations in FGF 23 and PO-_⁴? Coronary artery calcification is already present in asymptomatic persons with CKD 2! It may be that PO-₄ and FGF 23 are both contributing to an increase risk for cardiovascular disease in CKD, as measured by CT scan angiography Ca++ scores.
 
How should practice change in the face of these newly identified nontraditional cardiovascular risk factors in CKD?

Increased fractional excretion of urinary PO-₄ (a direct result of a decreased GFR and an elevated PO-₄)² and elevated serum PO₄ per se should be treated. Block and coworkers⁶ demonstrated that Sevelamer (a non-calcium containing PO-₄ binder) was associated with a significant survival benefit when compared with a calcium containing binder in “new to dialysis patients.” The end point of serial perturbations in CKD—FGF 23, then elevated PO-₄, then elevated parathyroid hormone levels, and finally arterial calcifications—is a marked increase in cardiovascular mortality.

It is time that this risk receives appropriate attention. How’s that for nontraditional risk factors and residual risks? 


Acknowledgment: The background for this material and the references was obtained from Martin KJ, Block GA, Budoff MJ. Healthy Kidneys, Healthy Heart: Reducing cardiovascular risks in patients with chronic kidney disease. Accessed February 10, 2013, at Medscape Education. 


1. Rutecki GW. Residual cardiovascular risks: don’t forget kidney and vascular disease. February 26, 2012. www.consultantlive.com
2. Isakova T, Xie H, Yang W, et al. Fibroblast Growth factor 23 and risks of mortality and end-stage renal disease in patients with chronic kidney disease. JAMA. 2011;305:2432-2439.
3. Moderator Martin KJ, Block GA, Budoff MJ. Healthy Kidneys, Healthy Heart: Reducing cardiovascular risks in patients with chronic kidney disease. Accessed February 10, 2013, at Medscape Education. 
4. Toussaint ND, Pedagogos E, Sven-Jean T, et al. Phosphate in early chronic kidney disease: associations with clinical outcomes and a target to reduce cardiovascular risk. Nephrology. 2012 May 11; [Epub ahead of print].
5. Russo D, Morrone LF, Brancaccio S, et al. Pulse pressure and presence of coronary artery calcification. Clin J Am Soc Nephrol. 2009;4:316-322.
6. Block GA, Raggi P. Bellasi A, et al. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int. 2007;71:438-441.