Phosphate-Lowering Therapy in CKD
Csaba P. Kovesdy, MD, FASN
This article is the first in a series that will discuss various aspects of hyperphosphatemia in patients with renal disease. Csaba P. Kovesdy, MD, chief of nephrology at the Salem VA Medical Center, in Salem, Va., is the series editor.
Phosphorus is an essential element that serves as a building block of the bony skeleton, adenosine triphosphate, nucleic acids, phospholipid membranes, and blood and urinary buffers.
The kidney is the main organ responsible for maintaining phosphorus homeostasis, and the development of CKD invariably leads to phosphorus retention, even though a series of adaptive responses (such as increases in parathyroid hormone and fibroblast growth factor [FGF]-23 levels) are set in motion to alleviate the impact of lower glomerular filtration rate on phosphorus balance.
Clinical manifestations of hyperphosphatemia usually become evident in patients with CKD once lack of substantial kidney function combines with inefficient phosphorus clearance by thrice-weekly dialysis. This results in a persistent positive phosphate balance unless the amount of absorbed phosphorus is reduced.
A variety of interventions are known to alleviate higher serum phosphorus levels. The question arises, though, about the benefit derived from lowering those levels.
The impact of hyperphosphatemia on survival has been examined in several large observational studies. Elevated serum phosphorus has been associated with increased mortality in dialysis patients (J Am Soc Nephrol. 2004;15:2208-2218 and Kidney Int. 2006;70:771-780) and in patients with non-dialysis-dependent CKD (NDD-CKD) (J Am Soc Nephrol. 2005;16:520-528 and Nephrol Dial Transplant. 2007;22:2909-2916).
These associations are especially surprising in the latter group, as frank hyperphosphatemia is rarely seen in patients who are not on dialysis; indeed, the studies referenced have found that the increase in mortality associated with higher serum phosphorus was evident even with levels that were still in “normal” range.
Challenging our understanding of normality when it comes to serum phosphorus levels, studies in patients with normal kidney function (and hence with supposedly normal phosphorus homeostasis) have also found that higher (albeit still within normal range) serum phosphorus was associated with increased mortality and cardiovascular event rates (Circulation. 2005;112:2627-2633).
In addition to the increased mortality described in previously cited studies, higher serum phosphorus was also found to be associated with more significant loss of kidney function in NDD-CKD (Clin J Am Soc Nephrol. 2006;1:825-831).