How Phosphorus Affects CKD Patients

Treatment of hyperphosphatemia

The rationale for lowering phosphorus level in CKD is not primarily to treat frank hyperphosphatemia (given the relative infrequency of it), but rather to treat secondary hyperparathyroidism. Given the association of higher phosphorus levels with mortality and progression of CKD, it is also possible that lowering plasma phosphorus may be beneficial in lowering these outcomes; but this would have to be proven in clinical trials first.

Strategies to lower plasma phosphorus in CKD include dietary phosphate restriction and the application of medications that inhibit the intestinal absorption of phosphorus. Dietary protein restriction (with concomitant restriction of phosphate intake) is already one of the strategies applied to alleviate progression of CKD. ³¹ Medications that inhibit the absorption of phosphorus include phosphate binders (calcium, magnesium, iron and lanthanum salts and sevelamer hydrochloride) and inhibitors of intestinal mucosal phosphate transport (nicotinamide).³⁰

None of these medications have been formally approved for therapy of hyperphosphatemia in CKD, thus their “off label” use would be based on data and experience drawn mostly from dialysis patients. It is beyond the scope of this review to detail the mechanism of action, advantages and disadvantages of each of these medications, especially given the lack of data from CKD-based clinical trials. It is worth remembering that the application of either one of the above treatments should be applied with the understanding that there is currently no consensus about what an ideal plasma phosphorus level should be in CKD. The K/DOQI guidelines on bone and mineral disorders recommend a plasma phosphorus concentration of 2.7-4.5 mg/dL,¹⁰ which corresponds to what is regarded as the “normal” range of plasma phosphorus.

It does not, however, address the results of more recent studies that suggest a graded in-crease in the risk of adverse outcomes associated with higher levels of phosphorus even within this “normal” range. One could also argue that it is not only the plasma phosphorus level that should serve as a therapeutic target in CKD, but also the plasma PTH level and/or the amount of phosphorus excreted in the urine. Further research is warranted to clarify these issues.

Summary

Frank hyperphosphatemia is a relatively rare occurrence in CKD, but higher levels of plasma phosphorus (even within the range regarded as “normal”) is associated with higher mortality and worsened progression of CKD. Lowering plasma phosphorus levels in CKD can be beneficial in treating SHPT, and could become an additional therapy to lower mortality and to alleviate progressive loss of kidney function.

Dr. Kovesdy is assistant professor of clinical internal medicine at the University of Virginia in Charlottesville and chief of nephrology at the Salem VA Medical Center in Salem, Va.

References

1. Yu AS. Renal transport of calcium, magnesium and phosphate. In: Brenner BM, editor. Brenner & Rector's The Kidney. 7th ed. Saunders; 2004.
2. Yangawa N, Nakhoul F, Kurokawa K, Lee DB. Physiology of phosphorus metabolism. In: Narins RG, editor. Maxwell and Kleeman's clinical disorders of fluid and electrolyte metabolism. 5th ed. McGraw-Hill; 1994. pp. 307-371.
3. Levin A, Bakris GL, Molitch M et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007;71:31-38.
4. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 Suppl 1):S1-S266.
5. Fukagawa M, Kazama JJ. FGF23: its role in renal bone disease. Pediatr Nephrol. 2006;21:1802-1806.
6. Kempson SA, Lotscher M, Kaissling B, et al. Parathyroid hormone action on phosphate transporter mRNA and protein in rat renal proximal tubules. Am J Physiol. 1995;268: F784-F791.
7. Kates DM, Sherrard DJ, Andress DL. Evidence that serum phosphate is independently associated with serum PTH in patients with chronic renal failure. Am J Kidney Dis. 1997;30:809-813.
8. Portale AA, Booth BE, Tsai HC, Morris RC Jr. Reduced plasma concentration of 1,25-dihydroxyvitamin D in children with moderate renal insufficiency. Kidney Int. 1982;21:627-632.
9. Yamamoto M, Igarashi T, Muramatsu M, et al. Hypocalcemia increases and hypercalcemia decreases the steady-state level of parathyroid hormone messenger RNA in the rat. J Clin Invest. 1989;83:1053-1056.
10. K/DOQI Clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis. 2003;42 (Suppl S3):1-202.
11. Bricker NS. On the pathogenesis of the uremic state. An exposition of the “trade-off hypothesis.” N Engl J Med. 1972;286:1093-1099.
12. Mucsi I, Hercz G. Control of serum phosphate in patients with renal failure—new approaches. Nephrol Dial Transplant. 1998;13:2457-2460.
13. Jono S, McKee MD, Murry CE, et al. Phosphate regulation of vascular smooth muscle cell calcification. Circ Res. 2000;29;87:E10-E17.
14. Kalantar-Zadeh K, Kuwae N, Regidor DL, et al. Survival predictability of time-varying indicators of bone disease in maintenance hemodialysis patients. Kidney Int. 2006;70:771-780.
15. Block GA, Klassen PS, Lazarus JM, et al. Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol. 2004;15:2208-2218.
16. Kestenbaum B, Sampson JN, Rud-ser KD, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005;16:520-528.
17. Menon V, Greene T, Pereira AA, et al. Relationship of phosphorus and calcium-phosphorus product with mortality in CKD. Am J Kidney Dis. 2005;46:455-463.
18. Voormolen N, Noordzij M, Grootendorst DC, et al. High plasma phosphate as a risk factor for decline in renal function and mortality in pre-dialysis patients. Nephrol Dial Transplant. 2007 May 21 (Epub ahead of print).
19. Tonelli M, Sacks F, Pfeffer M, et al. Relation between serum phosphate level and cardiovascular event rate in people with coronary disease. Circulation. 2005;112:2627-2633.
20. Chen NX, O'Neill KD, Duan D, Moe SM. Phosphorus and uremic serum up-regulate osteopontin expression in vascular smooth muscle cells. Kidney Int. 2002;62:1724-1731.
21. Schwarz S, Trivedi BK, Kalantar-Zadeh K, Kovesdy CP. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol. 2006;1(4):825-831.
22. Norris KC, Greene T, Kopple J, et al. Baseline predictors of renal disease progression in the African American Study of Hypertension and Kidney Disease. J Am Soc Nephrol. 2006;17:2928-2936.
23. Barsotti G, Morelli E, Giannoni A, et al. Restricted phosphorus and nitrogen intake to slow the progression of chronic renal failure: a controlled trial. Kidney Int Suppl. 1983;16:S278-S284.
24. Maschio G, Oldrizzi L, Tessitore N, et al. Effects of dietary protein and phosphorus restriction on the progression of early renal failure. Kidney Int. 1982;22:371-376.
25. Ibels LS, Alfrey AC, Haut L, Huffer WE. Preservation of function in experimental renal disease by dietary restriction of phosphate. N Engl J Med. 1978;298:122-126.
26. Karlinsky ML, Haut L, Buddington B, et al. Preservation of renal function in experimental glomerulonephritis. Kidney Int. 1980;17:293-302.
27. Lumlertgul D, Burke TJ, Gillum DM, et al. Phosphate depletion arrests progression of chronic renal failure independent of protein intake. Kidney Int. 1986;29:658-666.
28. Kraus ES, Cheng L, Sikorski I, Spector DA. Effect of phosphorus res-triction on renal response to oral and intravenous protein loads in rats. Am J Physiol. 1993;264(4 Pt 2):F752-F759.
29. Klahr S, Levey AS, Beck GJ, et al. Effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med. 1994;330:877-884.
30. Sampathkumar K, Selvam M, Sooraj YS, Gowthaman S, Ajeshkumar RN. Ex-tended release nicotinic acid—a novel oral agent for phosphate control. Int Urol Nephrol. 2006;38:171-174.