Redefining the pathogenesis of CKD-MBD: the critical role of FGF-23

Through signals between the kidney, parathyroid gland, and bone, alterations in kidney function lead to changes in serum biochemical values that accompany progressive skeletal disease. Abnormalities in mineral and bone metabolism occur early in the course of chronic kidney disease (CKD) and progress as renal function declines(1). Traditionally, these abnormalities have been ascribed to an early decline in 1,25(OH)2vitamin D (calcitriol) levels, leading to increases in serum PTH and subsequent alterations in calcium and phosphorus metabolism(1-3). However, recent studies have revealed that circulating values of fibroblast growth factor 23 (FGF-23), a key regulator of phosphorus and vitamin D metabolism, rise as renal function declines and may play a key initiating role in the development of abnormal mineral metabolism in patients with CKD(4). The importance of FGF-23 in the regulation of mineral metabolism was first identified in human genetic and acquired rachitic diseases such as autosomal dominant hypophosphatemic rickets (ADHR), tumor induced osteomalacia (TIO) and X-linked hypophosphatemic rickets (XLH)(5-8). In these conditions, increased levels of the protein are accompanied by impaired tubular phosphate reabsorption, hypophosphatemia, low (or inappropriately normal) levels of 1,25 (OH)2vitamin D, and impaired skeletal mineralization (rickets or osteomalacia)(9-13). Subsequently, animal studies confirmed that excess FGF-23, as occurs when FGF-23 is infused into rats with normal renal function, results in renal phosphate wasting through inhibition of renal phosphate cotransporters, NaPi2a and NaPi2c and direct suppression of 1α-hydroxylase activity(11). Moreover, a complete lack of either functional FGF-23 or its co-receptor, Klotho, results in phosphate retention, hyperphosphatemia, and increased circulating calcitriol levels(12–18). More recent studies have also implicated a role for FGF-23 in the regulation of PTH secretion–FGF-23 suppressing PTH secretion both in vitro and in vivo(19,20). In turn, FGF-23 expression is itself regulated by vitamin D, phosphate, and, potentially, PTH. In both animals and humans, the administration of 1,25(OH)2vitamin D increases circulating FGF-23 levels(21), apparently due to a direct action of vitamin D on FGF-23 via a vitamin D response element located upstream of the FGF-23 promotor(22). Sustained increases in dietary phosphorus are also associated with increasing FGF-23 levels and declining 1,25(OH)2vitamin D levels(23,24), while dietary phosphorus restriction reverses these trends(23,24). Parathyroid hormone (PTH) levels may also stimulate FGF-23 expression(25); findings in primary hyperparathyroidism(25), McCune-Albright syndrome(26), and Jansen’s disease(27), suggest that osteocytic stimulation by PTH directly increases skeletal FGF-23 release. The mechanism by which phosphate and PTH mediate changes in FGF-23 expression remain unknown and may be either direct effects on FGF-23 gene expression itself or mediated through other potential regulators of FGF-23. Circulating levels of FGF-23 are elevated as early as stage 2 CKD, before any changes in calcium, phosphorus, calcitriol, or PTH are apparent(4). Values rise progressively throughout the course of CKD and are markedly elevated in patients treated with maintenance dialysis(28,29). This rise