JOURNAL CLUB

FGF23 Induces LVH 

Every once in while comes along a study that one knows will be a landmark paper. Christian Faul and Myles Wolf (1) just published such a study in the Journal of Clinical Investigation.  

Dr. Christian Faul (left) and Dr. Myles Wolf (right) 

Why is this study important?
This study goes a long way in proving a causal relationship between FGF23 and the pathogenesis of left ventricular hypertrophy in patients with advanced chronic kidney disease (CKD).

Cardiovascular disease (CVD) is a leading cause of death in patients with CKD. LVH becomes increasingly prevalent as CKD progresses. LVH in CKD patients contributes to diastolic dysfunction, congestive heart failure, arrhythmia, and sudden death. As the authors note, compared with a prevalence of 15%–21% in the general population, LVH affects 50%–70% of patients during intermediate stages of CKD and up to 90% of patients by the time they reach dialysis.

Some background on FGF23 (see Ref 2,3 for others)
1.  FGF23 is an endocrine hormone that regulates phosphorus homeostasis through binding to FGFR and klotho, its coreceptor in the kidney and parathyroid glands.

Source: Renal Fellows Network

2. The primary physiological actions of FGF23 are to augment phosphaturia by downregulating expression of sodium-phosphate cotransporters in the renal proximal tubule and to decrease circulating concentrations of 1,25-dihydroxyvitamin D by inhibiting renal expression of the 1,25-dihydroxyvitamin D–synthesizing CYP27B1 (1-α-hydroxylase) and stimulating expression of the catabolic CYP24 (24-hydroxylase).

3. Circulating concentrations of FGF23 increase progressively as the renal capacity for phosphorus excretion declines. FGF23 levels are often 2- to 5-fold above the normal range during early and intermediate stages of CKD, but can reach levels 1,000-fold above normal in advanced renal failure.

4. While compensatory increases in FGF23 levels help patients with CKD to maintain normal serum phosphate levels, despite even severely reduced renal function, recent prospective studies of CKD and non-CKD patients demonstrated a dose-dependent association between elevated FGF23 levels and greater risks of major cardiovascular events and mortality.

Faul and colleagues conducted 2 sets of studies – an analysis of the The Chronic Renal Insufficiency Cohort (CRIC) database, which is a large, nationally representative, racially diverse cohort of patients with CKD; and, a series of experimental studies -- both in vitro and in vivo.  The epidemiologic study confirmed that FGF23 levels and rates of LVH are elevated in CKD and that elevated FGF23 is independently associated with LVH. The experimental studies demonstrated that FGF23 directly induces pathological hypertrophy of isolated cardiomyocytes and that mice develop LVH after intraventricular or intravenous injection of FGF23.

Ascending quartiles of FGF23 and LVMI
 (P for linear trend < 0.001)

Key Findings
1. Each unit increase in lnFGF23 was associated with a 2.5-fold greater relative risk (RR) of eccentric hypertrophy and concentric hypertrophy (95% CI, 2.1–3.0; P < 0.001) compared with normal ventricular geometry.

2. Multivariable analyses demonstrated that elevated FGF23 was independently associated with increased LVMI (1.5 g m–2.7 greater LVMI per unit increase in lnFGF23, 95% CI, 0.8–2.2; P < 0.001) and conferred greater risk of eccentric and concentric LVH (RR 1.5 per unit increase in lnFGF23; 95% CI, 1.3–1.9; P < 0.001).

3. In the 411 CRIC participants, who had normal left ventricular geometry on their baseline echocardiogram and underwent a second study 2.9 ± 0.5 years later, elevated FGF23 is associated with increased risk of new-onset LVH in CKD.

4. The investigators compared the response of isolated neonatal rat ventricular cardiomyocytes (NRVMs) to 48 hours of treatment with FGF23 versus FGF2 at concentrations that induced hypertrophy in previous studies of FGF2. They observed that FGF23 induces hypertrophy and activates prohypertrophic gene programs in isolated neonatal cardiomyocytes.

Prevalence of type of LVH by FGF quartiles

5. Using RT-PCR to determine expression levels of established markers of pathological cardiac hypertrophy in NRVMs after FGF treatment, the investigators observed that expression of adult α–myosin heavy chain (α-MHC) decreased while expression of fetal β–myosin heavy chain (β-MHC) increased after FGF23 and FGF2 treatment. This switch from adult to fetal MHC isoforms indicates reactivation of fetal gene programs that are associated with cardiac hypertrophy. In addition, FGF23 and FGF2 treatment increased expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which are established markers of LVH.

6. Again, using RT-PCR, the investigators demonstrated that FGF23-mediated hypertrophy is FGFR dependent but klotho independent.

7. Activation of isolated NRVMs by FGF23 and FGF2 uses distinct signaling pathways.

8. The investigators injected recombinant FGF23 protein directly into the left ventricular myocardium of mice and demonstrated that direct myocardial delivery of FGF23 induces LVH in mice. Furthermore, intravenous injection of FGF23 increases serum levels and yields an LVH phenotype that is similar to that induced by direct intramyocardial injection of FGF23.

9. The investigators studied klotho-deficient (kl/kl) and klotho heterozygous (kl/+) mice and demonstrate that an established genetic animal model of elevated serum FGF23 levels develops LVH in a dose-dependent fashion.

10. FGFR activity is required for the development of LVH in a rat model of CKD.

Bottom Line: This is a terrific study. Beautifully written. Few if any limitations. Faul et al elegantly demonstrate that a component of cardiovascular risk in patients with CKD could be directly attributable to FGF23. 

Next steps? Randomized studies are now required to test whether dietary phosphorus restriction or administration of phosphate binders that reduce FGF23, or monoclonal antibodies or small molecules that block its actions, can slow the progression of LVH, reduce cardiovascular events, and improve survival in patients with CKD.

References

1. Faul C,  et al Goetz R, et al. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol. 2007;27(9):3417–3428. J Clin Invest. 2011; doi:10.1172/JCI46122

2. Wolf M. Forging forward with 10 burning questions on FGF23 in kidney disease. J Am Soc Nephrol. 2010;21(9):1427–1435.

3. Oliveira RB, et al. Early control of PTH and FGF23 in normophosphatemic CKD patients: a new target in CKD-MBD therapy? Clin J Am Soc Nephrol. 2010;5(2):286–291.