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Fgf-23 and mortality risk in CKD
- 1. FGF 23 and Outcomes in Kidney Disease Arun Chawla John Tlcowsczki 8/25/11
- 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
- 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
- 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.
- 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
- 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.
- 35. Thank You for Your Time Questions???
- 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
- 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.
- 41. Copyright ©2010 American Society of Nephrology Figure 9. FGFR1 and Klotho expression are reduced in parathyroid glands from uremic rats in vivo
- 42. PTH – Vit D- FGF axis
- 43. PTH – Vit D- FGF in Kidney Disease
- 44. Causes of primary and secondary FGF23 excess and deficiency. Wolf M JASN 2010;21:1427-1435 ©2010 by American Society of Nephrology
Notas do Editor
- 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'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.