FGF 23 and Outcomes in Kidney Disease Arun Chawla John Tlcowsczki 8/25/11
Copyright ©2010 American Society of Nephrology Gutierrez, O. M. Clin J Am Soc Nephrol 2010;5:1710-1716 Figure 1. Classic v...
Why FGF
Copyright ©2010 American Society of Nephrology Wolf, M. J Am Soc Nephrol 2010;21:1427-1435 Figure 3. Temporal aspects of d...
Copyright ©2010 American Society of Nephrology Gutierrez, O. M. Clin J Am Soc Nephrol 2010;5:1710-1716 Figure 1. Classic v...
 
 
Copyright ©2010 American Society of Nephrology Wolf, M. J Am Soc Nephrol 2010;21:1427-1435 Figure 2. Physiologic actions o...
 
<ul><li>177 of the non diabetic CKD patients prospectively for a median of 53 months to assess progression of renal diseas...
<ul><li>56 patients with diabetic nephropathy with proteinuria </li></ul><ul><li>The composite primary outcome was defined...
Kaplan-Meier curves of the incidence of the composite primary outcome according to serum FGF-23 in 55 diabetic nephropathy...
 
Accelerated Mortality on Renal Replacement (ArMORR) study is a  prospective cohort study  of 10,044 subjects who began HD ...
Copyright © 2008 Massachusetts Medical Society. All rights reserved.  Published by Massachusetts Medical Society. 2 Figure...
 
Two-year survival curve (Cox proportional hazard), according to the serum FGF-23 quartile, adjusted for age, gender, diabe...
 
Fibroblast Growth Factor 23 and Risks of Mortality and End-Stage Renal Disease in Patients With Chronic Kidney Disease Tam...
Study Design <ul><li>Objective:  To evaluate FGF-23 as a risk factor for adverse outcomes in patients with CKD </li></ul><...
Patient Selection <ul><li>Inclusion Criteria : individuals aged 21 to 74 years with an estimated GFR of between 20 and 70 ...
Table 1. Baseline Characteristics in All Participants and According to Quartiles of Fibroblast Growth Factor 23. Isakova, ...
 
 
Results <ul><li>The mean (SD) estimated GFR at the baseline visit was 42.8 mL/min/1.73 m2 </li></ul><ul><li>89% had normal...
Table 2. Risks of Adverse Outcomes by Natural Log-Transformed Fibroblast Growth Factor 23 and Ascending Quartiles. Isakova...
Figure 1. Multivariable-Adjusted Hazard Function for Death According to Measured (Untransformed) Levels of Fibroblast Grow...
Figure 2. Stratified Analyses of Risk of Death by Fibroblast Growth Factor 23 Levels Isakova, T. et al. JAMA 2011;305:2432...
<ul><li>Unlike FGF-23, neither PTH (HR per SD of natural log-transformed parathyroid hormone, 1.1; 95% CI, 0.9-1.3) nor Fe...
FGF-23 and Risk of ESRD <ul><li>In contrast to mortality, adjustment for estimated GFR and CKD–specific risk factors atten...
Table 2. Risks of Adverse Outcomes by Natural Log-Transformed Fibroblast Growth Factor 23 and Ascending Quartiles. Isakova...
Figure 3. Fibroblast Growth Factor 23 Levels and Risks of End-Stage Renal Disease and Death by Baseline Kidney Function Is...
Conclusions <ul><li>An elevated level of FGF-23 is an independent risk factor for mortality in a referred population of pa...
Limitations <ul><li>lack of data on cause of death. </li></ul><ul><li>Vitamin D levels were only available in subsets of p...
Thank You for Your Time Questions???
 
<ul><li>descriptive statistics to compare clinical characteristics according to baseline FGF-23 levels and examined Spearm...
Results Extra <ul><li>FGF- 23 correlated with estimated GFR (r=−0.52; P.001), cystatinC (r=0.59; P.001), serum phosphate (...
Scatter plots and correlation coefficients of serum FGF-23 and other laboratorial variables. Titan S M et al. CJASN 2011;6...
Copyright ©2010 American Society of Nephrology Figure 1. FGF23 reduces PTH secretion in normal rat parathyroid glands A) P...
Copyright ©2010 American Society of Nephrology Figure 9. FGFR1 and Klotho expression are reduced in parathyroid glands fro...
PTH – Vit D- FGF axis
PTH – Vit D- FGF in Kidney Disease
Causes of primary and secondary FGF23 excess and deficiency. Wolf M JASN 2010;21:1427-1435 ©2010 by American Society of Ne...
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Fgf-23 and mortality risk in CKD

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  • Kaplan-Meier curves of the incidence of the composite primary outcome according to serum FGF-23 in 55 diabetic nephropathy patients.
  • 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. (P = 0.007; hazard ratio, 2.5 (1.3–5) for the fourth FGF-23 quartile versus the first quartile.)‏
  • Table 1. Baseline Characteristics in All Participants and According to Quartiles of Fibroblast Growth Factor 23
  • Table 2. Risks of Adverse Outcomes by Natural Log-Transformed Fibroblast Growth Factor 23 and Ascending Quartiles
  • The median fibroblast growth factor 23 (FGF-23) level within the lowest FGF-23 quartile (74 RU/mL) served as the referent value (hazard = 1.0). The model was stratified by center and adjusted for age; sex; race; ethnicity; estimated glomerular filtration rate; natural log-transformed urine albumin-to-creatinine ratio; hemoglobin; serum albumin; systolic blood pressure; body mass index; diabetes; smoking status; low-density lipoprotein; history of coronary artery disease, congestive heart failure, stroke, and peripheral vascular disease; use of aspirin, β-blockers, statins, and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers; and serum calcium, phosphate, and natural log-transformed parathyroid hormone. Tick marks on the x-axis indicate individual observations at corresponding levels of FGF-23. The solid black line represents the multivariable-adjusted hazard of mortality as a function of the measured (nontransformed) FGF-23 level. The dashed lines indicate the 95% confidence intervals.
  • The multivariable-adjusted hazard ratio (95% confidence intervals) of death per unit increment in standard deviation of natural log-transformed fibroblast growth factor 23 (FGF-23) is plotted for the entire cohort and according to strata of baseline covariates. See Figure 1 legend for adjusted variables. To covert calcium from mg/dL to mmol/L, multiply by 0.25; low-density lipoprotein from mg/dL to mmol/L, multiply by 0.0259; and parathyroid hormone from pg/mL to ng/L, multiply by 0.1053.
  • Table 2. Risks of Adverse Outcomes by Natural Log-Transformed Fibroblast Growth Factor 23 and Ascending Quartiles
  • Multivariable-adjusted risks of end-stage renal disease and death per unit increment in SD of natural log-transformed fibroblast growth factor 23 (FGF-23) in all participants and according to categories of baseline estimated glomerular filtration rate (GFR). See Figure 1 legend for adjusted variables. Error bars indicate 95% confidence intervals. HR indicates hazard ratio.
  • Scatter plots and correlation coefficients of serum FGF-23 and other laboratorial variables. The lines represent linear regression and 95% mean prediction interval. The boxes contain Spearman&apos;s correlation coefficients and P values. P FE, urinary fractional excretion of phosphate.
  • Causes of primary and secondary FGF23 excess and deficiency. Specific diseases and clinical settings and their characteristic metabolic features are listed in each quadrant corresponding to states of primary or secondary FGF23 excess or deficiency. The physiologic effects of FGF23 were originally identified in studies of rare hereditary and acquired diseases of primary FGF23 excess (left upper quadrant) and confirmed in human studies and animal models of FGF23 deficiency (right upper quadrant). Non–FGF23-dependent causes of phosphate wasting and impaired vitamin D signaling cause appropriate, secondary FGF23 deficiency (right lower quadrant), whereas CKD and deficiency of klotho, the FGF23 co-receptor, cause secondary FGF23 excess (left lower quadrant). Of all of the listed diseases and clinical settings, CKD is far and away the most common. *In contrast to absolute FGF23 deficiency, tumoral calcinosis can be caused by a defect in posttranslational glycosylation of FGF23, leading to high circulating levels of inactive C-terminal FGF23 fragments but absence of intact, biologically active FGF23. **Klotho deficiency differs metabolically from the other clinical settings in this quadrant in that 1,25 dihydroxyvitamin D (1,25D) levels are high as a result of lack of inhibition of the renal 1-α-hydroxylase by the faulty FGF23-klotho axis. Phenotypically, klotho deficiency causes a syndrome of tumoral calcinosis. ***In 1-α-hydroxylase deficiency, 1,25D levels are low, unlike the other clinical settings in this quadrant. ADHR, autosomal dominant hypophosphatemic rickets; XLH, X-linked hypophosphatemia; ARHR, autosomal recessive hypophosphatemic rickets; NaPi, sodium phosphate co-transporter; HHRH, hereditary hypophosphatemic rickets with hypercalciuria.
  • Fgf-23 and mortality risk in CKD

    1. 1. FGF 23 and Outcomes in Kidney Disease Arun Chawla John Tlcowsczki 8/25/11
    2. 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 &quot;trade-off&quot; hypothesis
    3. 3. Why FGF
    4. 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. 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 &quot;trade-off&quot; hypothesis
    6. 8. Copyright ©2010 American Society of Nephrology Wolf, M. J Am Soc Nephrol 2010;21:1427-1435 Figure 2. Physiologic actions of FGF23
    7. 10. <ul><li>177 of the non diabetic CKD patients prospectively for a median of 53 months to assess progression of renal disease. </li></ul><ul><li>revealed that FGF23 independently predicted progression of CKD after adjustment for age, gender, GFR, proteinuria, Ca, Phos and PTH. </li></ul>. Fliser D et al. JASN 2007;18:2600-2608 ©2007 by American Society of Nephrology
    8. 11. <ul><li>56 patients with diabetic nephropathy with proteinuria </li></ul><ul><li>The composite primary outcome was defined as death, doubling of serum creatinine, and/or dialysis need. </li></ul><ul><li>Mean follow-up time was 30.7 ± 10 months. </li></ul><ul><li>independent predictor of the primary outcome, even after adjustment for crcl and iPTH </li></ul>Clin J Am Soc Nephrol 6: 241–247, 2011
    9. 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
    10. 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
    11. 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.
    12. 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
    13. 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
    14. 20. Study Design <ul><li>Objective: To evaluate FGF-23 as a risk factor for adverse outcomes in patients with CKD </li></ul><ul><li>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. </li></ul><ul><li>CRIC Study is a multicenter, prospective observational study of risk factors for CVD, progression of CKD and mortality. </li></ul><ul><li>Main Outcome Measures: All-cause mortality and ESRD (Dialysis or Transplant). </li></ul>
    15. 21. Patient Selection <ul><li>Inclusion Criteria : individuals aged 21 to 74 years with an estimated GFR of between 20 and 70 mL/min/1.73m 2 </li></ul><ul><li>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. </li></ul><ul><li>More than 90% of the participants were retained during the longitudinal observation period. </li></ul>
    16. 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.
    17. 25. Results <ul><li>The mean (SD) estimated GFR at the baseline visit was 42.8 mL/min/1.73 m2 </li></ul><ul><li>89% had normal phosphate levels (4.6 mg/dL) </li></ul><ul><li>the median FGF-23 level was 145.5 RU/mL (≥ 3* than the median of 43 RU/mL in pts without sig CKD) </li></ul><ul><li>During a median follow-up of 3.5 years, 266 participants died (20.3/1000 person-years) </li></ul><ul><li>410 reached ESRD (33.0/1000 person-years). </li></ul>
    18. 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.
    19. 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
    20. 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
    21. 29. <ul><li>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. </li></ul>
    22. 30. FGF-23 and Risk of ESRD <ul><li>In contrast to mortality, adjustment for estimated GFR and CKD–specific risk factors attenuated the unadjusted association between FGF-23 and risk of ESRD. </li></ul><ul><li>In the fully adjusted model, reduced eGFR was the strongest predictor of ESRD </li></ul>
    23. 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.
    24. 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.
    25. 33. Conclusions <ul><li>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. </li></ul><ul><li>The effect was minimally confounded by other factors known to influence survival and was specific to FGF-23 among the mineral metabolites analyzed. </li></ul>
    26. 34. Limitations <ul><li>lack of data on cause of death. </li></ul><ul><li>Vitamin D levels were only available in subsets of participants. </li></ul><ul><li>Serial FGF values </li></ul><ul><li>Klotho?? </li></ul>
    27. 35. Thank You for Your Time Questions???
    28. 37. <ul><li>descriptive statistics to compare clinical characteristics according to baseline FGF-23 levels and examined Spearman correlations between FGF-23, estimated GFR, and other laboratory values. </li></ul><ul><li>Because reduced kidney function is an independent risk factor for ESRD we performed prespecified analyses stratified by baseline estimated GFR and tested for interaction with FGF-23. </li></ul><ul><li>We adjusted for use of phos binders and for use of vitamin D supplements and performed a sensitivity analysis that excluded participants who were receiving these agents at enrollment. </li></ul><ul><li>the lowest quartile defined as the reference group </li></ul>
    29. 38. Results Extra <ul><li>FGF- 23 correlated with estimated GFR (r=−0.52; P.001), cystatinC (r=0.59; P.001), serum phosphate (r=0.35; P.001), PTH (r = 0.37; P.001), FePi (r = 0.26; P.001), and Hb (r=−0.36; P.001). </li></ul><ul><li>After FGF-23, PTH was the next closest correlate of estimated GFR (r=−0.47; P.001). </li></ul><ul><li>In sensitivity analyses, the results were qualitatively unchanged when we censored at the time of ESRD; when we substituted cystatin C (HR per SD of natural logtransformed FGF-23, 1.4; 95% CI, 1.2-1.7) or iothalamate GFR instead of the MDRD eGFR; when we adjusted for vitamin D levels; when participants treated with phosphate binders, active vitamin D, or vitamin D supplements were excluded </li></ul>
    30. 39. Scatter plots and correlation coefficients of serum FGF-23 and other laboratorial variables. Titan S M et al. CJASN 2011;6:241-247 ©2011 by American Society of Nephrology
    31. 40. Copyright ©2010 American Society of Nephrology Figure 1. FGF23 reduces PTH secretion in normal rat parathyroid glands A) Parathyroid glands are incubated in 1.25 mM Ca and then shifted to 0.8 mM to show a functional response. The effect of addition of rat FGF23 is evaluated in low-Ca (0.8 mM) and high-Ca (1.5 mM) concentrations.
    32. 41. Copyright ©2010 American Society of Nephrology Figure 9. FGFR1 and Klotho expression are reduced in parathyroid glands from uremic rats in vivo
    33. 42. PTH – Vit D- FGF axis
    34. 43. PTH – Vit D- FGF in Kidney Disease
    35. 44. Causes of primary and secondary FGF23 excess and deficiency. Wolf M JASN 2010;21:1427-1435 ©2010 by American Society of Nephrology
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