Emerging role of FGF 23 in CKD-MBD

Just released article (Evenepoel et al, cJASN 2010) provides additional support for a new paradigm for the pathogenesis of Chronic Kidney Disease Mineral Bone Disorder (CKD-MBD). In the old traditional paradigm of CKD-MBD, loss of functioning kidney mass in CKD causes low active vitamin D level which leads to increased PTH production either directly or indirectly via diminished GI calcium absorption. However, in our CKD practice, we often see hyperparathyroidism without low active vitamin D or hypocalcemia. According to new phosphate-centric paradigm, CKD causes a decrease in renal phosphate excretion which leads to increased Fibroblast Growth Factor 23 (FGF-23) from bone osteocytes. FGF-23 act on kidney to inhibit phosphate reabsorption and also suppress production of active vitamin D to lower GI absorption of phosphorous. FGF-23 overproduction due to mutations in FGF gene was originally described in Autosomal Dominant Hypophosphatemic Rickets (ADHR consortium, Nature Genetics 2000). Recently, there has been explosion of literature on FGF-23 in CKD including its potential role in increased mortality (Gutierrez et al, NEJM 2008), left ventricular hypertrophy (Gutierrez et al, Circulation 2009) and progression of CKD (Fliser et al, JASN 2007). However, causal relationship between excess FGF-23 and adverse outcomes, and the potential mechanisms remain to be proven.