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Treatment of hyperphosphatemia in chronic kidney disease

BACKGROUND

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 chronic kidney disease (CKD), increased fibroblast growth factor-23 (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 [7,8]. (See "Overview of chronic kidney disease-metabolic bone disease (CKD-MBD)".)

From the viewpoint of calcium and phosphate balance, the hypersecretion of FGF-23 and PTH reflects 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-dihydroxycholecalciferol (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 [9]. 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 [2]. 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 [12].

Hyperphosphatemia alone or in combination with a high serum calcium has been associated with increased mortality in dialysis patients [13,14]. (See "Patient survival and maintenance dialysis", section on 'Disorders of mineral metabolism'.) This association has also been observed in some [15-17], though not all [18,19], studies of patients with less advanced kidney disease.

As an example, in a retrospective study of 6730 patients with CKD (defined as two abnormal serum creatinine measurements at least six months, but no more than two years, apart) who were not on dialysis and had not received a renal transplant, after adjusting for age, renal function, comorbidities, race, gender, hemoglobin concentration, serum calcium, and elemental calcium intake from medication, the serum phosphate was independently associated with mortality, with an estimated 23 percent increased risk of death for every 1 mg/dL increase in serum phosphate concentration [15].

                         

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Literature review current through: Mar 2014. | This topic last updated: Apr 2, 2014.
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