Chronic kidney disease (CKD) is a public health epidemic that affects millions. It is associated with a dramatically increased risk of cardiovascular mortality that is associated with the abnormal phosphate, calcitriol (1,25-D) and parathyroid metabolism that constitute secondary hyperparathyroidism (sHPT). Although factors that exacerbate sHPT in stage 5 CKD (US prevalence ~300,000) are well defined, much less is known about factors that initiate its pathogenesis in stages 3-4 (US prevalence ~8,000,000). Fibroblast growth factor-23 (FGF-23) maintains normal serum phosphate levels by augmenting phosphaturia and inhibiting 1,25-D synthesis. We hypothesize that through its reversible inhibition of 1,25-D synthesis, xaggerated FGF-23 secretion may be a root cause of sHPT in CKD that is modifiable in clinical practice. An experienced investigative team will use a multi-disciplinary approach to examine the role of FGF-23 in sHPT across the spectrum of CKD. We will perform in-depth physiological studies on the GCRC to study FGF-23 physiology in detail in the fasting and postprandial states among healthy volunteers and CKD subjects. We will examine the clinical utility of several phosphorous reduction strategies in a randomized controlled trial of """"""""normophosphatemic"""""""" CKD patients.
The aim i s to establish the pathogenic primacy of phosphate loading, acting via increased FGF-23, in the development of sHPT even in the absence of hyperphosphatemia. Next, we will examine FGF-23 as a novel biomarker of overall phosphorous exposure in stage 5 CKD. We will test whether FGF-23 excess is associated with increased mortality on dialysis within ArMORR, a prospective cohort of 15,000 incident hemodialysis patients. All studies are IRB-approved and preliminary data support our hypotheses. Relevance: The overall purpose of this research application is to establish the importance of assessing and modifying net phosphorous exposure, marked by changes in FGF-23, in an effort to improve the dismal outcomes in CKD. Detailed examination of our hypotheses will provide novel insight into the role of FGF-23 in normal renal physiology and in CKD, and suggest novel therapeutic paradigms for ameliorating sHPT and perhaps, cardiovascular disease in CKD. The results will be of immediate clinical relevance for the millions of normophosphatemic CKD patients who outnumber hyperphosphatemic patients at least 10-fold but for whom current guidelines do not recommend aggressive phosphate reduction strategies. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK076116-01A1
Application #
7258512
Study Section
Kidney, Nutrition, Obesity and Diabetes (KNOD)
Program Officer
Eggers, Paul Wayne
Project Start
2007-07-01
Project End
2008-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
1
Fiscal Year
2007
Total Cost
$331,250
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Munoz Mendoza, Jair; Isakova, Tamara; Cai, Xuan et al. (2017) Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease. Kidney Int 91:711-719
Ahmad, Faraz S; Cai, Xuan; Kunkel, Katherine et al. (2017) Racial/Ethnic Differences in Left Ventricular Structure and Function in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort. Am J Hypertens 30:822-829
Middleton, John P; Wolf, Myles (2017) Second Chances to Improve ESRD Outcomes With a Second-Generation Calcimimetic. JAMA 317:139-141
Batacchi, Zona; Robinson-Cohen, Cassianne; Hoofnagle, Andrew N et al. (2017) Effects of Vitamin D2 Supplementation on Vitamin D3 Metabolism in Health and CKD. Clin J Am Soc Nephrol 12:1498-1506
Ali, Farah N; Josefson, Jami; Mendez, Armando J et al. (2016) Cord Blood Ferritin and Fibroblast Growth Factor-23 Levels in Neonates. J Clin Endocrinol Metab 101:1673-9
David, Valentin; Wolf, Myles (2016) Pruning the ricket thicket. J Clin Invest 126:473-6
Gutiérrez, Orlando M; Parsa, Afshin; Isakova, Tamara et al. (2016) Genetic African Ancestry and Markers of Mineral Metabolism in CKD. Clin J Am Soc Nephrol 11:653-62
David, Valentin; Martin, Aline; Isakova, Tamara et al. (2016) Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int 89:135-46
Singh, Saurav; Grabner, Alexander; Yanucil, Christopher et al. (2016) Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int 90:985-996
Lash, James P; Ricardo, Ana C; Roy, Jason et al. (2016) Race/Ethnicity and Cardiovascular Outcomes in Adults With CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic CRIC Studies. Am J Kidney Dis 68:545-553

Showing the most recent 10 out of 70 publications