Chronic kidney disease (CKD) is a public health epidemic that increases risk of death due to cardiovascular disease. Left ventricular hypertrophy (LVH) is an important mechanism of cardiovascular disease in individuals with CKD. Elevated levels of FGF23 have been linked to greater risks of LVH and mortality in patients with CKD, but whether these risks represent causal effects of FGF23 is unknown. Here, we report that elevated FGF23 levels are independently associated with LVH in a large, racially diverse CKD cohort. FGF23 caused pathological hypertrophy of isolated rat cardiomyocytes via FGF receptor-dependent activation of the calcineurin-NFAT signaling pathway, but this effect was independent of klotho, the coreceptor for FGF23 in the kidney and parathyroid glands. Intramyocardial or intravenous injection of FGF23 in wild-type mice resulted in LVH, and klotho-deficient mice demonstrated elevated FGF23 levels and LVH. In an established animal model of CKD, treatment with an FGF-receptor blocker attenuated LVH, although no change in blood pressure was observed. These results unveil a klotho-independent, causal role for FGF23 in the pathogenesis of LVH and suggest that chronically elevated FGF23 levels contribute directly to high rates of LVH and mortality in individuals with CKD.

Background-Vitamin

Background-Fibroblast growth factor 23 (FGF-23) is a hormone that increases the rate of urinary excretion of phosphate and inhibits renal production of 1,25-dihydroxyvitamin D, thus helping to mitigate hyperphosphatemia in patients with kidney disease. Hyperphosphatemia and low 1,25-dihydroxyvitamin D levels are associated with mortality among patients with chronic kidney disease, but the effect of the level of FGF-23 on mortality is unknown.

Background-Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role.

Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 has been proposed as an early biomarker of disordered phosphorus metabolism in earlier stages of chronic kidney disease (CKD), but data from large, well-characterized CKD cohorts are lacking. We measured FGF23 in baseline samples from 3,879 participants in the Chronic Renal Insufficiency Cohort study, a nationally representative, diverse CKD cohort with mean (± sd) estimated glomerular filtration rate (eGFR) of 42.8 ± 13.5 ml/min/1.73m2. Serum phosphate (3.7 ± 0.7 mg/dl) and parathyroid hormone (PTH; median 54, interquartile range [IQR] 35 – 89 pg/ml) levels were in the normal range, but FGF23 (median 145, IQR 96 – 239 RU/ml) was markedly greater than in healthy populations and increased significantly with decreasing eGFR. FGF23 excess, defined as ≥ 100 RU/ml, was more common than secondary hyperparathyroidism (≥ 65 pg/ml) and hyperphosphatemia (≥ 4.6 mg/dl) in all strata of eGFR, and the eGFR threshold at which the slope of FGF23 increased (57.8; 95%CI: 55.4 – 60.8 ml/min/1.73m2) was higher than the corresponding threshold for PTH (46.9; 95%CI: 45.5 – 51.4 ml/min/1.73m2). Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increases in phosphate or PTH. These findings provide additional support for use of FGF23 as a sensitive early screening test to identify disordered phosphorus metabolism in CKD patients with normal serum phosphate levels.

Context High levels of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), associate with mortality in patients with end-stage renal disease (ESRD), but little is known about its relationship with adverse outcomes in the much larger population of patients with earlier stages of chronic kidney disease (CKD). Objective Evaluate FGF23 as a risk factor for adverse outcomes in patients with CKD. Design, Setting and Participants A prospective study of 3,879 participants with CKD stages 2 – 4 who enrolled in the Chronic Renal Insufficiency Cohort between June 2003 and September 2008. Main Outcome Measures All-cause mortality and ESRD. Results At enrollment, mean estimated glomerular filtration rate (eGFR) was 42.8 ± 13.5 ml/min/1.73m2, and median FGF23 was 145 (interquartile range [IQR] 96 – 239) reference units/ml (RU/ml). During a median follow-up of 3.5 (IQR 2.5 – 4.4) years, 266 participants died (20.3/1000 person-years) and 410 reached ESRD (33.0/1000 person-years). Higher FGF23 levels independently associated with a greater risk of death in adjusted analyses of FGF23 on a continuous scale (hazard ratio [HR] per SD of lnFGF23, 1.5; 95%CI 1.3 – 1.7) or in quartiles (quartile 1, reference; quartile 2, HR 1.3; 95%CI 0.8 – 2.2; quartile 3, HR 2.0; 95%CI 1.2 – 3.3; quartile 4, HR 3.0; 95%CI 1.8 – 5.1). FGF23 was not independently associated with ESRD in adjusted analyses of the entire cohort, however, the effect was modified by eGFR (P for interaction = 0.005), which was the strongest predictor for ESRD. FGF23 independently associated with significantly greater risk of ESRD among participants with eGFR 30 – 44 (HR 1.3 per SD of lnFGF23; 95%CI 1.04 – 1.6) and ≥ 45 (HR 1.7; 95%CI 1.1 – 2.4), but not < 30 ml/min/1.73m2. Conclusion Elevated FGF23 is an independent risk factor for ESRD in patients with relatively preserved kidney function and for mortality across the spectrum of CKD.

Hyperphosphatemia, calcitriol deficiency, and secondary hyperparathyroidism (SHPT) are common complications of chronic kidney disease (CKD). Fibroblast growth factor-23 (FGF-23) is a novel phosphaturic hormone that also inhibits renal 1␣-hydroxylase activity and thus may be involved in the pathogenesis of SHPT. Several hypotheses were tested: that FGF-23 increases as renal function declines; is linearly associated with serum phosphate levels; is associated with increased phosphaturia independent of parathyroid hormone (PTH); and is associated with decreased calcitriol levels independent of renal function, hyperphosphatemia, and vitamin D stores. FGF-23, PTH, 25(OH)D 3 , calcitriol, calcium, phosphate, and urinary fractional excretion of phosphate (Fe PO4 ) were measured in 80 CKD patients. Multiple linear regression was used to test the hypotheses. FGF-23 and PTH were inversely associated with estimated GFR (eGFR), whereas calcitriol levels were linearly associated with eGFR. Hyperphosphatemia and hypocalcemia were present in only 12 and 6% of patients, respectively, all of whose eGFR was <30. Increased Fe PO4 was associated with decreased eGFR, and both increased FGF-23 and PTH were independently associated with increased Fe PO4 . Increased FGF-23 and decreased 25(OH)D 3 were independent predictors of decreased calcitriol, but the effects on calcitriol levels of renal function itself and hyperphosphatemia were completely extinguished by adjusting for FGF-23. It is concluded that FGF-23 levels increase early in CKD before the development of serum mineral abnormalities and are independently associated with serum phosphate, Fe PO4 , and calcitriol deficiency. Increased FGF-23 may contribute to maintaining normal serum phosphate levels in the face of advancing CKD but may worsen calcitriol deficiency and thus may be a central factor in the early pathogenesis of SHPT.

Patients who receive paricalcitol while undergoing long-term hemodialysis appear to have a significant survival advantage over those who receive calcitriol. A prospective, randomized study is critical to confirm these findings.