A tendency toward phosphate retention begins early in renal disease, due to the reduction in the filtered phosphate load. Although this problem is initially mild with hyperphosphatemia being a relatively late event, phosphate retention is intimately related to the common development of cardiovascular disease risk in CKD, increased fibroblast growth factor (FGF)-23 levels, and secondary hyperparathyroidism (figure 1) [1-6]. These adaptive endocrine alterations are a potential concern because high circulating levels of parathyroid hormone (PTH) play an important role in the development of renal osteodystrophy [1,2,7], and elevated circulating FGF-23 concentrations are strongly associated with increased cardiovascular mortality and renal failure [7,8]. (See "Pathogenesis of renal osteodystrophy".)
From the viewpoint of calcium and phosphate balance, the hypersecretion of FGF-23 and PTH reflect the development of phosphate retention, and are initially appropriate. FGF-23 appears to be the initial hormonal abnormality leading to increased urinary phosphate excretion and suppression of 1,25(OH)2D. PTH increases in response to reductions in 1,25(OH)2D. By increasing bone turnover and calcium phosphate release from bone and enhancing urinary phosphate excretion (via a decrease in proximal reabsorption), PTH can correct both the hypocalcemia and the hyperphosphatemia. FGF-23 is also important in the renal adaptation to maintain phosphate excretion. The effect on renal phosphate handling is manifested by a progressive reduction in the fraction of the filtered phosphate that is reabsorbed, from the normal value of 80 to 95 percent to as low as 15 percent in advanced renal failure . As a result, phosphate balance and a normal serum phosphate concentration are generally maintained (at the price of elevated FGF-23 and hyperparathyroidism) until the glomerular filtration rate (GFR) falls below 25 to 40 mL/min [2,10].
At this relatively late stage, dietary phosphate restriction may still reduce the serum concentration of phosphate, FGF-23, and PTH, although not usually to normal [2,11]. As a result, oral phosphate binders are frequently required. This problem is exacerbated once maintenance dialysis is required; in this setting, there is essentially no phosphate excretion and oral phosphate binders must be given to limit phosphate absorption . In addition, levels of FGF-23 become extremely elevated, and the secondary hyperparathyroidism may contribute to the hyperphosphatemia by continuing to enhance the release of calcium phosphate from bone .
Hyperphosphatemia alone or in combination with a high serum calcium is associated with increased mortality in dialysis patients [13,14]. This relationship also exists in patients with less advanced kidney disease . (See "Patient survival and maintenance dialysis", section on 'Disorders of mineral metabolism'.)
When both calcium and phosphate levels are high (due in part to the increased intake of calcium [via calcium-based phosphate binders]), heterotopic deposition of hydroxyapatite in arteries, joints, soft tissues, and the viscera develops; when small arterioles are affected, tissue ischemia and calciphylaxis may occur [2,16]. Tumoral collections of calcium phosphate crystals may also be a consequence of hyperphosphatemia and increased calcium levels . (See "Vascular calcification in chronic kidney disease" and "Calciphylaxis".)