FGF-23 and clinical outcomes in ADPKD patients

Summary

Principal Investigator: MYLES S WOLF
Abstract: DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is the most common life threatening hereditary disorder. Although progressive cyst enlargement leads to end-stage renal disease in 50 percent of affected individuals by the fifth decade, cardiovascular disease is the leading cause of death in ADPKD. Left ventricular hypertrophy is an important manifestation of cardiovascular disease in ADPKD with an incidence that is twice as high in ADPKD compared with essential hypertension. Understanding modifiable mechanisms of the high rates of left ventricular hypertrophy, cardiovascular events and mortality in ADPKD is essential to designing novel therapeutic strategies to improve clinical outcomes. An elevated level of the phosphate regulating hormone, fibroblast growth factor 23 (FGF23), is an independent risk factor for progression of chronic kidney disease (CKD), cardiovascular disease, and death, and published data by our group suggest a causal role for FGF23 in the pathogenesis of left ventricular hypertrophy. Although one study of ADPKD patients suggested that FGF23 levels are increased early in the course of disease, the mechanisms underlying FGF23 elevation in ADPKD are unknown. Furthermore, there are no data on FGF23 as a risk factor for left ventricular hypertrophy, CKD progression and clinical outcomes in ADPKD, and how these relationships differ versus other causes of CKD. In the first aim, we will determine whether FGF23 levels increase earlier and more markedly in adults and children with ADPKD compared with other etiologies of CKD or healthy subjects. We will compare FGF23 and other mineral metabolites from ~1000 adults with ADPKD in the HALT-PKD trial and 107 children with ADPKD in the statin-PKD trial with comparable data from non-ADPKD cohorts, including the Chronic Kidney Disease in Children (CKiD) and the Chronic Renal Insufficiency Cohort (CRIC) studies that are frequency matched by race and estimated glomerular filtration rate. In the second aim, we will perform the first ever bone biopsy study dedicated to ADPKD to investigate the regulation of FGF23 production by bone. We will assess standard bone histomorphometry and use novel translational techniques of bone research to precisely study subtle bone microarchitecture (using [unreadable]CT), total bone phosphate content (using Raman spectroscopy), and expression of FGF23 and DMP1, which is a critical molecular regulator of FGF23 in bone. In the third aim, we will examine FGF23 as a novel risk factor for kidney cyst enlargement, progression of CKD, left ventricular hypertrophy, and cardiovascular disease events. Extensive preliminary data support our hypotheses and our research team has the requisite expertise in clinical research, FGF23, analysis of bone biopsy data, and ADPKD to successfully complete these aims. By using data from 4 ongoing NIDDK- supported studies, we will efficiently characterize FGF23 in ADPKD in an effort to guide the design of novel interventions to improve outcomes in ADPKD.
Funding Period: 2012-09-30 - 2017-07-31
more information: NIH RePORT

Top Publications

  1. pmc αKlotho: FGF23 coreceptor and FGF23-regulating hormone
    Harald Juppner
    Endocrine Unit and Pediatric Nephrology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    J Clin Invest 122:4336-9. 2012
  2. ncbi The association of prevalent kidney stone disease with mortality in US adults: the National Health and Nutrition Examination Survey III, 1988-1994
    Jie Tang
    Division of Renal Disease and Hypertension, University of Colorado School of Medicine, Aurora, CO 80045, USA
    Am J Nephrol 37:501-6. 2013
  3. ncbi Vitamin D and kidney stone disease
    Jie Tang
    Division of Renal Disease and Hypertension, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
    Curr Opin Nephrol Hypertens 22:383-9. 2013
  4. pmc Vascular calcification in end-stage renal disease
    Kristen L Jablonski
    Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Center, Aurora, Colorado, USA
    Hemodial Int 17:S17-21. 2013
  5. pmc Fibroblast growth factor-23 and cardiovascular events in CKD
    Julia J Scialla
    University of Miami Miller School of Medicine, Miami, Florida
    J Am Soc Nephrol 25:349-60. 2014
  6. ncbi Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease
    Julia J Scialla
    University of Miami Miller School of Medicine, University of Miami, 1120 North West 14th Street, Suite 815, Miami, FL 33136, USA
    Nat Rev Nephrol 10:268-78. 2014

Detail Information

Publications6

  1. pmc αKlotho: FGF23 coreceptor and FGF23-regulating hormone
    Harald Juppner
    Endocrine Unit and Pediatric Nephrology Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    J Clin Invest 122:4336-9. 2012
    ..show that the cleaved form of αKlotho, the membrane-bound form of which is an FGF23 coreceptor, serves as a novel endocrine regulator of phosphate homeostasis, capable of inducing FGF23 production in osteocytes...
  2. ncbi The association of prevalent kidney stone disease with mortality in US adults: the National Health and Nutrition Examination Survey III, 1988-1994
    Jie Tang
    Division of Renal Disease and Hypertension, University of Colorado School of Medicine, Aurora, CO 80045, USA
    Am J Nephrol 37:501-6. 2013
    ..Kidney stone disease is associated with hypertension, diabetes, metabolic syndrome, kidney function decline, and increased cardiovascular (CV) events. However, its association with all-cause and CV mortality is unclear...
  3. ncbi Vitamin D and kidney stone disease
    Jie Tang
    Division of Renal Disease and Hypertension, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
    Curr Opin Nephrol Hypertens 22:383-9. 2013
    ..Vitamin D is important in maintaining calcium homeostasis, but its role in kidney stone disease and its effect on stone formation are still not clear...
  4. pmc Vascular calcification in end-stage renal disease
    Kristen L Jablonski
    Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Center, Aurora, Colorado, USA
    Hemodial Int 17:S17-21. 2013
    ..Further research is needed to determine if targeting these processes can ultimately reduce vascular calcification in this high cardiovascular risk population. ..
  5. pmc Fibroblast growth factor-23 and cardiovascular events in CKD
    Julia J Scialla
    University of Miami Miller School of Medicine, Miami, Florida
    J Am Soc Nephrol 25:349-60. 2014
    ..Thus, higher FGF-23 is independently associated with greater risk of cardiovascular events, particularly CHF, in patients with CKD stages 2-4. ..
  6. ncbi Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease
    Julia J Scialla
    University of Miami Miller School of Medicine, University of Miami, 1120 North West 14th Street, Suite 815, Miami, FL 33136, USA
    Nat Rev Nephrol 10:268-78. 2014
    ....

Research Grants30

  1. Disordered Mineral Metabolism in the CKiD Children: Role of FGF-23
    Anthony A Portale; Fiscal Year: 2013
    ....
  2. Regulatory Mechanisms In Intestinal Motility
    Kenton M Sanders; Fiscal Year: 2013
    ..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
  3. Renal Osteodystrophy and Vascular Calcification
    Keith A Hruska; Fiscal Year: 2013
    ..3) Determine the molecular basis for the interaction of skeleton with BMP-2/4 stimulated VSMC osteoblastic transition in CKD. ..
  4. The Aging Kidney: Chronic Injury, Impaired Functions and Clinical Outcomes
    Michael G Shlipak; Fiscal Year: 2013
    ....
  5. Mentored Patient Oriented Research in Mineral Metabolism
    MYLES S WOLF; Fiscal Year: 2013
    ....
  6. Role of FGF23 in Mineral Metabolism Across the Spectrum of Chronic Kidney Disease
    MYLES S WOLF; Fiscal Year: 2013
    ....
  7. Phosphorus and Vitamin D Metabolism and Cardiovascular Outcomes: The MESA Study
    Bryan R Kestenbaum; Fiscal Year: 2013
    ..Findings will help clarify optimal serum concentrations of phosphorous and vitamin D biomarkers with respect to cardiovascular health and inform clinical trials which target mineral metabolism to prevent and reduce CVD. ..
  8. STUDIES OF ORGAN TRANSPLANTATION IN ANIMALS AND MAN
    Arthur J Matas; Fiscal Year: 2013
    ..2. To maximize rehabilitation. The focus here is on minimizing complications and maximizing quality of life. ..
  9. North American Mitochondrial Disease Consortium (NAMDC)
    JOHN L THOMPSON; Fiscal Year: 2013
    ....
  10. Association of kidney disease, klotho and FGF23 with functional decline in HIV
    Michelle M Estrella; Fiscal Year: 2013
    ....
  11. HORMONAL CONTROL OF CALCIUM METABOLISM
    John T Potts; Fiscal Year: 2013
    ....
  12. Modifiable and Biochemical Predictors and Consequences of Acute Kidney Injury
    Amanda Hyre Anderson; Fiscal Year: 2013
    ..This study will make possible the identification of potentially modifiable, and thus, clinically-actionable, risk factors for AKI, and improve our understanding of the impact of AKI on the course of CKD. ..
  13. ASSESSING LONG TERM OUTCOMES OF LIVING DONATION
    Bertram L Kasiske; Fiscal Year: 2013
    ..In summary, it is critical to capitalize on the short term investment in ALTOLD with uninterrupted long-term follow up that will minimize participant dropout and maximize the knowledge we will gain from this valuable cohort. ..
  14. FGF23 and Cardiovascular Disease in CKD
    MYLES S WOLF; Fiscal Year: 2013
    ..Our long-term goal is to develop novel therapeutic and diagnostic strategies to improve the dismal clinical outcomes experienced by patients with CKD. ..
  15. Prevalence and Impact of Frailty among Dialysis Patients
    Kirsten L Johansen; Fiscal Year: 2013
    ..abstract_text> ..
  16. Dietary Acid Load, Subclinical Acidosis and Outcomes in Chronic Kidney Disease
    Julia J Scialla; Fiscal Year: 2013
    ....
  17. FGF-23 Regulation in Chronic Kidney Disease
    Katherine Wesseling-Perry; Fiscal Year: 2013
    ..The relationship between FGF-23 and skeletal mineralization will be assessed by immunohistochemical evaluation of bone in patients with CKD who undergo bone biopsy. ..
  18. Vitamin D hormones in CKiD: Prevalence of deficiency and clinical correlates.
    Juhi Kumar; Fiscal Year: 2013
    ..This K-23 study proposal aims to elucidate the role of novel risk factors for chronic kidney disease progression in one of the most vulnerable population to be afflicted by this disease. ..
  19. Hopkins Center for Eliminate Cardiovascular Health Disparities
    Lisa A Cooper; Fiscal Year: 2013
    ..abstract_text> ..
  20. Dysregulated Angiogenesis in ADPKD
    BERENICE YOLANDE GITOMER; Fiscal Year: 2013
    ..The results of these studies will impact future research directions in ADPKD. In particular, positive results of the proposed study should inform about the planning of a large, definitive, interventional study in patients with ADPKD. ..
  21. Clinical Trial to Slow the Progression of ADPKD
    Robert W Schrier; Fiscal Year: 2013
    ..The primary endpoint for Study B is a composite endpoint of time to the 50% reduction of baseline eGFR, eGFR <20 ml/min/1.73 m2, end stage renal disease (ESRD) or death. ..
  22. FGF-23 and the Risk of Stroke and Cognitive Decline
    Clinton B Wright; Fiscal Year: 2013
    ..We anticipate that the results of this study, in concert with our ongoing projects on FGF23 in more advanced CKD, will rapidly set the stage for randomized controlled trials. ..
  23. The Aging Kidney in HIV-Infection: biomarkers for early detection of injury
    Michael G Shlipak; Fiscal Year: 2013
    ..The third objective will be to evaluate longitudinally whether baseline and follow-up markers of kidney injury are independently associated with accelerated declines in kidney function during follow-up. ..