Elevated levels are associated with higher mortality and greater risk of CKD progression.

 

Phosphorus plays an important role in human life. It is an essential building block of the human body as a component of the bony skeleton, adenosine triphosphate, nucleic acids, phospholipid membranes, and blood and urinary buffers.1

 

An intricate regulatory system assures the maintenance of normal phosphorus homeostasis under normal circumstances.2 The kidneys play a pivotal role in this system as the main organs responsible for phosphorus excretion. One of the many abnormalities in CKD is a derangement of mineral metabolism,3 with abnormalities affecting phosphorus being one of its centerpieces. Much attention has focused on hyperphosphatemia and its consequences in dialysis patients, even though they represent only a minority of all patients with CKD.4

 

This review will describe the physiology and pathophysiology of phosphorus metabolism, various adverse outcomes associated with phosphorus deregulation, and potential treatment strategies in patients with CKD who are not yet on dialysis.

 

Phosphorus metabolism

 

The human body contains approximately 700 grams of phosphorus contained in various inorganic and organic molecules.1 The majority of this (85%) is in the bones as hydroxyapatite and about 14% is contained in soft tissues.1 Only 1% is found in the extracellular fluid.2 The main sources of phosphorus intake are meats, dairy products, and particularly food additives. The daily amount of phosphorus consumption in an average Western diet is 800-1500 mg, with approximately 65% of this being absorbed in the small intestine.1

 

The main regulator of intestinal phosphorus absorption is 1,25-dihydroxy vitamin D (calcitriol) acting through the Na-phosphate co-transporter Npt2b in the intestinal epithelial cells.2 A physiologic plasma phosphorus level of 3.0-4.5 mg/dL is maintained chiefly through renal clearance; about 900 mg of phosphorus is excreted daily in the urine. About 90% of plasma phosphates are filtered in the glomerulus, and 80%-97% of the filtered load is reabsorbed, mostly in the proximal tubule; no phosphorus is secreted by the tubular cells.2

 

The main regulators of proximal tubular reabsorption are the plasma phosphorus level and various hormones with phosphaturic properties, the main ones being parathyroid hormone (PTH) 2 and fibroblast growth factor 23 (FGF-23).5 Plasma phosphorus level exerts a direct negative feedback effect on proximal tubular phosphate reabsorption.2 PTH blocks phosphate reabsorption in the proximal tubule through its action on the sodium-phosphate transporter Npt2a,6 and concomitantly increases 1-hydroxylation of 25(OH) vitamin D, thus raising levels of calcitriol; the net effect is thus an increase in urinary phosphate excretion but also a concomitant increase in intestinal phosphate (and calcium) absorption. PTH is produced in the parathyroid glands, with lower calcium, higher phosphorus and lower calcitriol levels all stimulating its production.5-7

 

FGF-23 also lowers  phosphate reabsorption in the proximal tubule through Npt2a (independent of PTH), but it blocks 1- hydroxylation of 25(OH) vitamin D, consequently lowering calcitriol levels; its effect is thus net hypophosphatemic, with higher urinary excretion and lower intestinal absorption of phosphorus.5 FGF-23 is produced in the bone; higher phosphorus and higher calcitriol stimulate its production.5

 

Pathophysiology

As glomerular filtration rate (GFR) decreases,9 several changes occur that affect phosphorus balance; the most important ones are a decrease in calcitriol level due to deficient 1-hydroxylation8 (and with consequently lower intestinal calcium absorption, hypocalcemia and stimulation of PTH production) and a decrease in the filtered amount of phosphorus (with consequent hypocalcemia, hyperphosphatemia and stimulation of PTH and FGF-23 production).10

 

The higher PTH and FGF-23 levels will enhance urinary clearance of phosphorus by lowering proximal tubular reabsorption, thus ensuring normal plasma levels, albeit at the expense of secondary hyperparathyroidism (the classical trade-off hypothesis),11 and also a higher FGF-23 level (which in itself results in further lowering the calcitriol levels and more stimulation of PTH production: trade-off hypothesis revisited).5

 

This regulatory mechanism is unable to compensate for phosphorus retention once GFR falls below approximately 40 mL/min per 1.73 m2; this is when a subtle rise in serum phosphorus occurs, albeit mostly without manifest hyperphosphatemia.1

 

Frank hyperphosphatemia becomes common once patients with CKD reach the need for dialysis where the lack of substantial kidney function combined with the inefficiency of thrice weekly dialysis treatments in facilitating phosphorus clearance10 result in a persistent positive phosphate balance unless the amount of absorbed phosphorus is diminished.

 

Outcomes

Examining the impact of serum phosphorus in CKD poses distinct challenges compared to similar studies in dialysis patients. The first is the lack of available data sources: in spite of the large numbers of patients with CKD, sizeable research databases are still missing.

 

The second is the differences in the bone-mineral milieu between patients with CKD and those on dialysis: as detailed above, serum phosphorus levels in patients with CKD are in general much lower. In vitro data suggests that the phenotypic transformation of aortic smooth muscle cells into osteoblast-like cells that are thought to be involved in the soft tissue and cardiovascular calcification mediated by hyperphosphatemia occurs at ambient phosphorus concentrations of about 6 mg/dL and above.

 

Such elevated plasma phosphorus levels are unusual in CKD, and it is pos-sible that the cardiovascular (CV) effects of hyperphosphatemia are more subtle in earlier stages of CKD, and thus more difficult to detect.

 

The third challenge is the presence of competing end points in CKD: while mortality is still of major interest, progression to dialysis is also regarded as an independent end point and is in fact the main focus of our clinical interventions in everyday practice.

 

Mortality       

In the wake of several studies showing a significant association between hyperphosphatemia and mortality in dialysis patients,12,13 three studies have examined the same issue in patients with CKD, and one in a non-CKD population (see table). Kestenbaum et al. examined 3,490 US veterans with CKD and showed that higher phosphorus was associated with higher mortality even after adjustment for several potential confounders.14

 

The second study was a secondary analysis from the Modification of Diet in Renal Disease (MDRD) study: Menon et al. examined 839 mostly nondiabetic patients and showed an association between higher phosphorus and all-cause and CV mortality, but the results were not statistically significant.17

 

The third study by Voormolen et al. examined 448 patients with CKD stage 4-5 and found a hazard ratio for all-cause mortality of 1.62 (95% CI: 1.02-2.59) associated with a 1 mg/dl higher phosphorus level.18 The fourth study was by Tonelli et al., who examined 4,127 participants with normal kidney function enrolled in the Cholesterol and Recurrent Events study, and showed that higher plasma phosphorus level was associated with higher all-cause mortality, CV mortality, fatal or non-fatal MI and new onset congestive heart failure.19

 

The mechanism behind the  observed associations could be phosphorus' calcification-inducing effects in the vascular bed13, 20 or the concomitant deleterious effects of other factors linked to hyperphosphatemia, such as secondary hyperparathyroidism.14

 

CKD progression

Three observational studies have examined the association between higher phosphorus and progression of CKD. My colleagues and I examined the association between phosphorus level and the incidence of dialysis or doubling of serum creatinine in 985 male US veterans with CKD and found that higher phosphorus was associated with a higher incidence of the renal end point; a 1 mg/dL higher phosphorus level was associated with an adjusted hazard ratio of 1.29.21

 

A second study by Norris et al. examined risk factors for progression of CKD in 1,094 black patients enrolled in the African American Study of Hypertension and Kidney Disease (AASK) and found phosphorus level to be one of several independent predictors of progressive CKD.22 The third study by Voormolen et al. described an association between higher serum phosphorus levels and faster decline in renal function (by examining slopes of estimated GFR) in 432 patients with CKD.18 The plausibility of these findings is strengthened by the results of studies in patients with CKD 23,24 and in laboratory animals 25-27 that showed an attenuation of the progression of CKD after dietary restriction of phosphorus.

 

Several mechanisms could be responsible for the observed associations; renal parenchymal calcification, a deleterious effect of SHPT, hemodynamic alterations and derangements in cellular energy metabolism have been suggested as plausible explanations. 27, 28

 

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.