Fibroblast Growth Factor 23 and Risks of Mortality and End-Stage Renal Disease in Patients With Chronic Kidney Disease

Abstract

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.

Relationship between Plasma Fibroblast Growth Factor‐23 Concentration and Survival Time in Cats with Chronic Kidney Disease

“…FGF‐23 predicts the progression of CKD in human patients,13, 27, 28 and FGF‐23 concentrations are also well established as being independently associated with case fatality in CKD patients at the start of hemodialysis,14, 29 and in earlier stages of CKD 27, 28. At present, just as has been debated for many years concerning PTH, it is unclear whether FGF‐23 is a uremic toxin, or whether it is a surrogate marker for other causes of uremic toxicity.…”

Competitive Interaction Between Fibroblast Growth Factor 23 And Asymmetric Dimethylarginine in Patients With CKD

“…2,5 Several cohort studies have examined the relationship between FGF-23 and renal outcomes. [10][11][12][13][14][15] In line with findings in the Chronic Renal Insufficiency Cohort cohort 11 and in the MMKD study 10 from analyses not considering the FGF-23-ADMA interaction, we confirmed that the FGF-23-CKD progression relationship was independent of (1) classic risk factors and (2) CKD-specific risk factors, such as proteinuria and the GFR, that are known to belong to the strongest predictors of CKD progression, as well as (3) major biomarkers of CKD mineral and bone disorder, including serum phosphate, 1,25(OH) 2 D, and PTH. These results further highlight the potential relevance of FGF-23 as a novel risk factor for evolution toward kidney failure in CKD.…”

“…in the United States, [11][12][13][14] as well as a large study in transplant recipients in Hungary, 15 have coherently associated high plasma FGF-23 with CKD progression toward kidney failure.…”

Renal Allograft Fibrosis: Biology and Therapeutic Targets

“…A promising CKD biomarker is fibroblast growth factor 23 (FGF-23), which is highly increased in CKD patients and associated with cardiovascular disease and mortality (380)(381)(382). Other potentially interesting molecules include the tubular injury markers NGAL (383-385), KIM-1 (385-388), TIMP-2 (389), IGFBP7 (389) and liver-type fatty acid-binding protein (L-FABP) (390,391).…”