Elevated levels of fibroblast growth factor 23 (FGF23) are independently associated with increased risks of mortality and end-stage renal disease in patients with chronic kidney disease stages 2 through 4. A study of over 3,800 patients found that higher FGF23 levels predicted death and renal failure even after adjusting for factors like age, kidney function, phosphate, and parathyroid hormone. The relationship between FGF23 and mortality risk was consistent across all levels of FGF23 and kidney function stages. In contrast, parathyroid hormone and the calcium-phosphate product were not independently associated with mortality when accounting for FGF23.

1. FGF 23 and Outcomes in Kidney Disease Arun Chawla, MD Hofstra NS LIJ School of Medicine Nephrology

2. Copyright ©2010 American Society of Nephrology Gutierrez, O. M. Clin J Am Soc Nephrol 2010;5:1710-1716 Figure 1. Classic versus more contemporary renditions of the "trade-off" hypothesis

3. Why FGF

4. Copyright ©2010 American Society of Nephrology Wolf, M. J Am Soc Nephrol 2010;21:1427-1435 Figure 3. Temporal aspects of disordered phosphorus metabolism in progressive CKD and after kidney transplantation

5. Copyright ©2010 American Society of Nephrology Gutierrez, O. M. Clin J Am Soc Nephrol 2010;5:1710-1716 Figure 1. Classic versus more contemporary renditions of the "trade-off" hypothesis

8. Copyright ©2010 American Society of Nephrology Wolf, M. J Am Soc Nephrol 2010;21:1427-1435 Figure 2. Physiologic actions of FGF23

10. 177 of the non diabetic CKD patients prospectively for a median of 53 months to assess progression of renal disease. revealed that FGF23 independently predicted progression of CKD after adjustment for age, gender, GFR, proteinuria, Ca, Phos and PTH. . Fliser D et al. JASN 2007;18:2600-2608 ©2007 by American Society of Nephrology

11. 56 patients with diabetic nephropathy with proteinuria The composite primary outcome was defined as death, doubling of serum creatinine, and/or dialysis need. Mean follow-up time was 30.7 ± 10 months. independent predictor of the primary outcome, even after adjustment for crcl and iPTH Clin J Am Soc Nephrol 6: 241–247, 2011

12. Kaplan-Meier curves of the incidence of the composite primary outcome according to serum FGF-23 in 55 diabetic nephropathy patients. Titan S M et al. CJASN 2011;6:241-247 ©2011 by American Society of Nephrology

14. Accelerated Mortality on Renal Replacement (ArMORR) study is a prospective cohort study of 10,044 subjects who began HD at any of the 1056 U.S. dialysis centers operated by Fresenius

15. Copyright © 2008 Massachusetts Medical Society. All rights reserved. Published by Massachusetts Medical Society. 2 Figure 1 Fibroblast Growth Factor 23 and Mortality among Patients Undergoing Hemodialysis. Gutierrez, Orlando; Mannstadt, Michael; Isakova, Tamara; Rauh-Hain, Jose; Tamez, Hector; Shah, Anand; Smith, Kelsey; Lee, Hang; Thadhani, Ravi; Juppner, Harald; Wolf, Myles New England Journal of Medicine. 359(6):584-592, August 7, 2008. Figure 1 . Odds Ratios (and 95% CIs) for Death According to Quartile of C-Terminal Fibroblast Growth Factor 23 (cFGF-23) Levels.Crude, case-mix adjusted, and multivariable adjusted odds ratios for death are shown according to quartile of cFGF-23 levels (quartile 1, 4010 RU per milliliter). The case-mix adjusted analysis included the following variables: age, sex, race or ethnic group, blood pressure, body-mass index, facility-specific standardized mortality rate, vascular access at initiation of dialysis (fistula, graft, or catheter), cause of renal failure, urea reduction ratio, and coexisting conditions. The multivariable adjusted analysis included the case-mix variables plus phosphate, calcium, log parathyroid hormone, albumin, creatinine, and ferritin levels. Quartile 1 was the reference group in all models. I bars represent 95% confidence intervals. Asterisks indicate P<0.05. R denotes reference.

17. Two-year survival curve (Cox proportional hazard), according to the serum FGF-23 quartile, adjusted for age, gender, diabetes, tobacco use, alfacalcidol use, dialysis vintage, serum albumin, tertile of phosphataemia, calcaemia and PTH values. Jean G et al. Nephrol. Dial. Transplant. 2009;24:2792-2796 © The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

19. Fibroblast Growth Factor 23 and Risks of Mortality and End-Stage Renal Disease in Patients With Chronic Kidney Disease Tamara Isakova, Myles Wolf et al for for the Chronic Renal Insufficiency Cohort (CRIC) Study Group

20. Study Design Objective: To evaluate FGF-23 as a risk factor for adverse outcomes in patients with CKD Prospective study of 3879 participants with CKD stages 2 through 4 who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) between June 2003 and September 2008. CRIC Study is a multicenter, prospective observational study of risk factors for CVD, progression of CKD and mortality. Main Outcome Measures: All-cause mortality and ESRD (Dialysis or Transplant).

21. Patient Selection Inclusion Criteria : individuals aged 21 to 74 years with an estimated GFR of between 20 and 70 mL/min/1.73m 2 Exclusion Criteria: inability to consent, pregnancy, institutionalization, enrollment in other studies, NYHA class III to IV heart failure, HIV, cirrhosis, myeloma, PCKD, renal cancer, recent chemotherapy or immunosuppressive therapy, organ transplant, or prior treatment with dialysis for at least 1 month. More than 90% of the participants were retained during the longitudinal observation period.

22. Table 1. Baseline Characteristics in All Participants and According to Quartiles of Fibroblast Growth Factor 23. Isakova, T. et al. JAMA 2011;305:2432-2439 Copyright restrictions may apply.

25. Results The mean (SD) estimated GFR at the baseline visit was 42.8 mL/min/1.73 m2 89% had normal phosphate levels (4.6 mg/dL) the median FGF-23 level was 145.5 RU/mL (≥ 3* than the median of 43 RU/mL in pts without sig CKD) During a median follow-up of 3.5 years, 266 participants died (20.3/1000 person-years) 410 reached ESRD (33.0/1000 person-years).

26. Table 2. Risks of Adverse Outcomes by Natural Log-Transformed Fibroblast Growth Factor 23 and Ascending Quartiles. Isakova, T. et al. JAMA 2011;305:2432-2439 Copyright restrictions may apply.

27. Figure 1. Multivariable-Adjusted Hazard Function for Death According to Measured (Untransformed) Levels of Fibroblast Growth Factor 23 Isakova, T. et al. JAMA 2011;305:2432-2439 the graded increase in risk of death persisted across the spectrum of FGF 23 levels

28. Figure 2. Stratified Analyses of Risk of Death by Fibroblast Growth Factor 23 Levels Isakova, T. et al. JAMA 2011;305:2432-2439 Copyright restrictions may apply. elevated FGF-23 levels were associated with homogenously greater risk of mortality

29. Unlike FGF-23, neither PTH (HR per SD of natural log-transformed parathyroid hormone, 1.1; 95% CI, 0.9-1.3) nor FePi (HR per SD of natural log-transformed FePi, 1.0; 95% CI, 0.9-1.1) was associated with mortality in fully adjusted models that excluded FGF 23.

30. FGF-23 and Risk of ESRD In contrast to mortality, adjustment for estimated GFR and CKD–specific risk factors attenuated the unadjusted association between FGF-23 and risk of ESRD. In the fully adjusted model, reduced eGFR was the strongest predictor of ESRD

31. Table 2. Risks of Adverse Outcomes by Natural Log-Transformed Fibroblast Growth Factor 23 and Ascending Quartiles. Isakova, T. et al. JAMA 2011;305:2432-2439 Copyright restrictions may apply.

32. Figure 3. Fibroblast Growth Factor 23 Levels and Risks of End-Stage Renal Disease and Death by Baseline Kidney Function Isakova, T. et al. JAMA 2011;305:2432-2439 Copyright restrictions may apply.

33. Conclusions An elevated level of FGF-23 is an independent risk factor for mortality in a referred population of patients with CKD stages 2 through 4. The effect was minimally confounded by other factors known to influence survival and was specific to FGF-23 among the mineral metabolites analyzed.

35. PTH – Vit D- FGF axis

36. PTH – Vit D- FGF in Kidney Disease

37. Causes of primary and secondary FGF23 excess and deficiency. Wolf M JASN 2010;21:1427-1435 ©2010 by American Society of Nephrology

38. Limitations lack of data on cause of death. Vitamin D levels were only available in subsets of participants. Serial FGF values Klotho??

40. Thank You