Elevated serum phosphate and fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular disease, kidney disease progression, and premature death in patients with chronic kidney disease (CKD). FGF23 levels increases early in children with CKD while serum phosphate levels are normal, are predictors of CKD progression, and are independently associated with left ventricular hypertrophy. Current treatment paradigms of CKD-Mineral Bone Disorder (CKD-MBD) are: phosphate binders to correct hyperphosphatemia when FGF23 levels are markedly elevated and 1,25D therapy that further raise FGF23 levels. A novel paradigm is to start phosphate binders earlier in CKD when serum phosphate is normal to lower already elevated FGF23. However, interventional studies with phosphate binders have demonstrated inconsistent results; most of them were small, short duration and used single interventions. Moreover, monotherapy with binders may be hampered by up-regulation of the intestinal sodium-phosphate co-transporter NPT2b. Nicotinamide (NAM) lowers serum phosphate and FGF23 levels in CKD patients by down-regulating NPT2b expression, rather than by binding dietary phosphate. As highlighted by a recent Symposium on Phosphate Homeostasis, defining novel approaches to reverse disturbances in phosphate and FGF23 in CKD is a high priority. Thus, the proposed U34 will develop the necessary study infrastructure, research plan, and scientific, logistic, and regulatory documents to conduct a 12-month randomized double blinded, four-arm parallel trial of sevelamer carbonate (SC) and NAM in 168 pediatric patients with CKD stages 3-4 recruited from eight participating sites. The proposed U34 will provide the infrastructure for the subsequent U01 that will pursue the following aims:
Specific Aim 1 : To determine the efficacy of SC and NAM to lower serum phosphate and FGF23 levels (co-primary endpoints).
Specific Aim 2 : To determine the safety and tolerability of SC and NAM.
Specific Aim 3 : In addition to these primary endpoints, we will evaluate the effects of the active interventions compared to placebo on the following variables: a) biomarkers of bone turnover and phosphate homeostasis and we will perform pre- and post-treatment bone biopsies study in a sub-cohort of 25 UCLA patients to assess bone mineralization and expression of FGF23; b) on left ventricular mass, as assessed by cardiac magnetic resonance imaging and c) on the rate of decline in GFR, directly measured by the plasma disappearance of iohexol (iGFR). If our hypotheses are confirmed, a new paradigm shift would emerge in the therapy of CKD- MBD, because phosphate binders will be used as first-line of treatment when serum phosphate levels are within the normal range rather than correcting 1,25D deficiency with active vitamin D which further increases FGF23 levels.
Fibroblast growth factor 23 (FGF23) are elevated in early stages of chronic kidney disease (CKD) in children and are associated with CKD progression, cardiovascular and bone diseases. Thus, strategies that will lower or limit the rise of FGF23 may lead to a new paradigm for the treatment of CKD-Mineral Bone Disorder with early intervention focused on targeting dietary phosphate intake to control FGF23 rather than correcting 1,25D deficiency with replacement therapy.
|Hanudel, Mark R; Salusky, Isidro B (2017) Treatment of Pediatric Chronic Kidney Disease-Mineral and Bone Disorder. Curr Osteoporos Rep 15:198-206|