3.1 In CKD patients (Stages 3 and 4), the serum level of phosphorus should be maintained at or above 2.7 mg/dL (0.87 mmol/L) (EVIDENCE) and no higher than 4.6 mg/dL (1.49 mmol/L). (OPINION)
3.2 In CKD patients with kidney failure (Stage 5) and those treated with hemodialysis or peritoneal dialysis, the serum levels of phosphorus should be maintained between 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L). (EVIDENCE)
Hyperphosphatemia leads to secondary hyperparathyroidism and elevated blood levels of PTH by: (a) lowering the levels of ionized calcium; (b) interfering with the production of 1,25(OH)2D3; and (c) by directly affecting PTH secretion.84,85
These processes lead to high-turnover bone disease and other adverse consequences of excess PTH (see Background).
Prolonged hyperphosphatemia causes soft-tissue and vascular calcification due at least in part to an increase in calcium-phosphate product86-89 and is associated with increased morbidity90,91 and mortality.92-95 In the case of vascular calcification, hyperphosphatemia exerts a direct calcifying effect on vascular smooth muscle cells.96 Calcification of coronary arteries, cardiac valves, and pulmonary tissues produces cardiac disease, the leading cause of death in patients with CKD.90,97-99 It is therefore imperative to prevent hyperphosphatemia and maintain serum phosphorus levels within the normal range.
Among the factors that contribute to secondary hyperparathyroidism in CKD patients are phosphate retention and/or elevated levels of serum phosphorus. Hyperphosphatemia is associated with increased morbidity and mortality in CKD patients.86-93 Therefore, the maintenance of normal serum levels of phosphorus in CKD patients is critical for the prevention of abnormalities in parathyroid hormone metabolism and for the reduction of morbidity and mortality.
The influence of phosphorus levels on PTH secretion has not been conclusively demonstrated in humans. While available experimental data support a direct role of phosphorus on PTH secretion,84,85 the data in humans are less straightforward. One study has shown elevated PTH levels in patients with serum phosphorus levels >6.2 mg/dL (2.0 mmol/L).90 On the other hand, other studies have failed to demonstrate consistent changes in PTH levels across a range of serum phosphorus levels,100 and no direct correlation between the level of serum phosphorus and PTH has been established.85 The lack of conclusive studies in humans is to be expected, given that many studies measuring serum PTH levels are confounded by the use of phosphate binders and vitamin D therapy. Such a study design precludes the evaluation of a direct association between serum phosphorus and PTH levels. Based on available evidence and upon clinical experience, it is the opinion of the Work Group that elevated phosphorus levels in CKD and dialysis patients contribute to the development of hyperparathyroidism.
In order to eliminate the potentially confounding influence on outcomes of aluminum-containing phosphate binders, only studies of dialysis patients, and only those published after 1990, were included in the data analysis. Four studies meet these criteria, and all are observational or cross-sectional in design.90,92,93,100 These studies correlate serum phosphorus levels with multiple end-points in patients treated with hemodialysis.
The 4 cross-sectional studies90,92,93,100 that met the inclusion criteria evaluated the association of serum phosphorus levels with extraskeletal outcomes. Two studies evaluated the relative risk of mortality associated with serum phosphorus levels in patients treated with hemodialysis. In 1 study, a reference serum phosphorus range of 4.6 to 5.5 mg/dL (1.49 to 1.78 mmol/L) was used92; the relative risk of mortality increased with serum phosphorus levels >6.5 mg/dL (2.10 mmol/L). In the other study, a reference range of 5 to 7 mg/dL (1.61 to 2.26 mmol/L) was used93; the relative risk of mortality increased with serum phosphorus levels less than or greater than this range. The increase in mortality was particularly significant for levels of phosphorus >7 mg/dL (2.26 mmol/L) or <3 mg/dL (0.97 mmol/L). Serum phosphorus levels <2.5 mg/dL (0.81 mmol/L) may be associated with abnormalities in bone mineralization such as osteomalacia.100
In another study, serum phosphorus levels >6.2 mg/dL (2.00 mmol/L) were associated with increased blood pressure, hyperkinetic circulation, increased cardiac work, and high arterial tensile stress.90 One study failed to find an association between serum phosphorus levels and quality of life.100
The available evidence supports an association between serum phosphorus levels both above and below the normal range with poor outcomes, including mortality. Given that the major goal of phosphorus control in patients with CKD is to prevent morbidity and mortality, it was the opinion of the Work Group that serum phosphorus should be maintained between 2.7 and 4.6 mg/dL (0.87 and 1.49 mmol/L) in CKD patients Stages 3 and 4, and between 3.5 and 5.5 mg/dL (1.13 and 1.78 mmol/L) in CKD patients Stage 5.
Cross-sectional studies have established a correlation between serum phosphorus levels and various extraskeletal outcomes, but this correlation does not rise to the level of causality. Further, the studies of higher methodological quality92,93 relied on data from 1990 or earlier, indicating that their results may have been confounded by the use of aluminum hydroxide and/or by less aggressive vitamin D therapy. To date, studies performed in dialysis patients have failed to conclusively demonstrate a reduction in morbidity or mortality through dietary intervention or the use of phosphate binders to lower serum phosphorus levels to the suggested target range.
This Guideline supports intensive control of serum phosphorus in patients with CKD. Most data indicate that fewer than 30% of dialysis patients are able to maintain phosphorus in the suggested target range. The goal should be to increase the percentage of patients in this target range. Successful implementation will require an increased dietitian-to-patient ratio, educational tools to increase patient compliance, as well as studies to further explore the feasibility of dialytic techniques that are better able to control serum phosphorus levels (such as nocturnal or daily hemodialysis), and the widespread availability and affordability of different phosphate binders, regardless of patient insurance.
Longitudinal studies of patients on dialysis are needed, evaluating the effects of controlling serum phosphorus in the target range on morbidity and mortality.