Hyperphosphatemia as a complication of chronic kidney disease (CKD) was recognized nearly a century ago.1 The central role of altered phosphate metabolism in CKD as a cause of secondary hyperparathyroidism and renal osteodystrophy was exposed as part of the elegant experimental studies that provided the basis of the “intact nephron hypothesis.”2 The association of high serum phosphorus levels and increased mortality of patients with ESRD first noted in 19903 has since been confirmed and extensively studied.4,5 There is now considerable evidence, convincing on balance, that elevated serum phosphorus levels are a surrogate marker of cardiovascular disease (coronary, aortic, valvular, and vascular calcification) and hard clinical outcomes (cardiovascular and all-cause hospitalization and mortality) in CKD.4–6 Accrued evidence on the systemic complications of altered phosphate homeostasis in CKD has led to the proposal of a new syndrome of mineral and bone disorders (MBD) of CKD, termed CKD-MBD, which encompasses biochemical alterations, bone abnormalities, and vascular calcification.7 Renewed interest in the detrimental consequences of elevated serum phosphorus and the difficulties of its management in CKD has become the center of much recent debate and controversy fueled, at least in part, by the pharmaceutical industry.
Approximately two thirds of the daily phosphorus intake is absorbed in the small intestines, and normal phosphorus homeostasis is maintained by its subsequent appropriate excretion by the kidney.8 With decreasing kidney function, the initial adaptive changes for maintenance of normal serum phosphorus gradually become restricted, and hyperphosphatemia occurs at GFR of <30 ml/min per 1.73 m2. Available treatments for the control of phosphorus in CKD are restriction of dietary phosphorus intake, the use of phosphorus binders, and in ESRD the increased duration and frequency of dialysis.8,9 The dietary control of phosphorus has been difficult and implicated in contributing to malnutrition and thereby likely associated with increased mortality.10 The use of phosphorus binders, as with most dialysis therapies, has followed an empiric approach. Complications as a result of aluminum-based binders used initially led to the preferential use of calcium-based binders. The incriminated potential of increased calcium loads in vascular calcification then led to the introduction of noncationic binders, whose preferential use continues to be debated.9,11
The administration of phosphorus binders in close temporal proximity of meals, the exogenous source of phosphorus load, is the principal route of binder use. Consideration has also been given to the control of endogenous sources of phosphorus released from bone and the recirculation of absorbed phosphorus secreted in gastrointestinal fluids. The administration of binders between meals has been proposed but not studied, emphasized, or fully used.11 In this issue of JASN, Savica et al.12 propose a novel and promising approach to the control of hyperphosphatemia by the binding of salivary phosphorus. This supplemental approach is especially relevant because dietary restriction and the use of phosphorus binders control hyperphosphatemia only in approximately half of patients with ESRD.8–10
The role of saliva in initiating the digestive process notwithstanding, the salivary glands remain an orphan-child of gastroenterology and increasingly the domain of oral medicine. Knowledge of their function has been slow and remains rather fragmentary. Several of the functions of salivary glands are similar to those of renal tubular epithelia, an association commented on when the kidney was still considered a secretory organ.13 Salivary gland function is defined as a two-phase secretory process, which begins in the acini by the production of an isotonic fluid. The second phase occurs in the water-impermeable interlobular ducts that drain the salivary fluid, where sodium chloride is reabsorbed with increasing hypotonicity of salivary fluid and the active secretion of potassium, bicarbonate, magnesium, and phosphorus.14,15 As a result, compared with serum, the salivary fluid is hypotonic (0.50 to 0.75), low in urea nitrogen and sodium (0.3 to 0.5), and high in potassium (2 to 4×) and phosphorus (>3×), with a pH of approximately 5.6 to 7.0. These ratios are altered asymptotically toward serum levels at increasing rate of salivary flow after stimulation but retain their general proportionality to serum. Most salivary function studies in CKD have been of hemodialysis patients, in whom the reduced rate of salivary flow has been incriminated for increased thirst and oral lesions, whereas salivary composition maintains its relative proportionalities to serum, with a directional correlation to changes in serum concentrations.16,17 These changes are reflected in salivary divalent ion concentrations in ESRD as increased magnesium and phosphorus but not calcium content.18 The normally elevated salivary phosphorus level is nearly doubled in ESRD.18,19 It is this feature of saliva that Savica et al.12 capitalize for the control of hyperphosphatemia.
Chitosan, the active ingredient used in binding salivary phosphorus, is an abundant natural polymer glucosamine that is produced industrially by the deacetylation of chitin obtained from crustacean shells. It is a biocompatible compound of low toxicity with a structure that is similar to cellulose and is not cleaved by digestive enzymes—hence, the increasing biomedical applications of chitosan as dietary fiber for weight reduction and control of hyperlipidemia.20,21 To this now is added its ability to bind phosphorus.
In the study by Savica et al.,12 chitosan lowers serum phosphorus when used as a chewing gum preparation that contains 20 mg of chitosan and is chewed for 1 h twice daily. Chitosan was used as a supplemental approach to control the serum phosphorus level of 13 hemodialysis patients who continued their usual regimen of phosphate binders with meals and thrice-weekly hemodialysis. The dosage of chitosan used was relatively small (20 mg twice daily) compared with the much larger dosages (1.0 to 1.5 g/d) used for treatment of obesity and hypercholesterolemia.21 Increased usage, frequency, or dosage of chitosan gum deserves further examination for its potential capacity to control hyperphosphatemia alone rather than a supplement. Furthermore, the role of chitosan ingested with meals for the control of dietary phosphorus and its additional beneficial effect on the lipid profile would be worth exploring. Although in a study of 80 seemingly poorly dialyzed patients who had ESRD and were not on phosphorus binders oral chitosan (450 mg thrice daily) was said not to have an effect on serum phosphorus,22 the issue deserves further examination.
Of interest is the intriguing persistence of low serum phosphorus levels after 2 wk of discontinuing chitosan. The authors attribute this to a residual effect of chitosan bound to the intestinal tract because of its mucoadhesive properties.20 Of note, the parathyroid hormone (PTH) levels decreased and remained low during that period. PTH-released phosphorus from bone is a source of hyperphosphatemia and deserves closer scrutiny. The decrement in PTH level was NS in this study, but that may be due to the limitations of the assay and small number of patients. Under any circumstance, the observations of Savica et al. using chitosan chewing gum for the management of a clinically relevant and serious problem are most promising. Their preliminary results are impressive but will need further study.
Published online ahead of print. Publication date available at www.jasn.org.
See related article, “Salivary Phosphate-Binding Chewing Gum Reduces Hyperphosphatemia in Dialysis Patients,” on pages 639–644.
1. Marriott WM, Howland J: Phosphate retention as a factor in the production of acidosis in nephritis. Arch Intern Med 18 : 708– 711, 1916
2. Bricker NS, Morrin PA, Kime SW: The pathologic physiology of chronic Bright's disease: An exposition of the “intact nephron hypothesis.” J Am Soc Nephrol 8 : 1470– 1476, 1997
3. Lowrie EG, Lew NL: Death in hemodialysis patients: The predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 15 : 458– 482, 1990
4. Block GA, Klassen PS, Lazarus JM, Ofshun N, Lowrie EG, Chertow GM: Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. J Am Soc Nephrol 15 : 2208– 2218, 2004
5. Wald R, Sarnak MJ, Tighiouart H, Cheung AK, Levey A, Eknoyan G, Miskulin D: Disordered mineral metabolism in the hemodialysis patients: An analysis of cumulative effects in the Hemodialysis (HEMO) Study. Am J Kidney Dis 52 : 531– 540, 2008
6. Moe S, Chen NX: Mechanisms of vascular calcification in chronic kidney disease. J Am Soc Nephrol 19 : 213– 216, 2008
7. Moe S, Drueke T, Lamiere N, Eknoyan G: Chronic kidney disease-mineral bone disorder: A new paradigm. Adv Chronic Kidney Dis 14 : 3– 12, 2007
8. Uribarri J: Phosphorus homeostasis in normal health and in chronic kidney disease patients with special emphasis on dietary phosphorus intake. Semin Dial 20 : 295– 301, 2007
9. Kestenbaum B: Phosphate metabolism in the setting of chronic kidney disease: Significance and recommendations for treatment. Semin Dial 20 : 286– 294, 2007
10. Shinaberger CS, Greenland S, Kopple JD, Van Wyck D, Mehrotra R, Kaveskdy CP, Kalantar-Zadeh K: Is controlling phosphorus by decreasing dietary protein intake beneficial or harmful in persons with chronic kidney disease? Am J Clin Nutr 88 : 1511– 1518, 2008
11. National Kidney Foundation: K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 42[ Suppl 3]: S1– S201, 2003
12. Savica V, Calo LA, Monardo P, Davis PA, Granata A, Santoro D, Savica R, Musolino R, Comelli MC, Bellinghieri G: Salivary phosphate-binding chewing gum reduces hyperphosphatemia in dialysis patients. J Am Soc Nephrol 20 : 639– 644, 2009
13. Grantham JJ, Wallace DP: Return of the secretory kidney. Am J Physiol Renal Physiol 282 : F1– F9, 2002
14. Malamud D, Tabak L, eds.: Saliva as a diagnostic fluid Ann N Y Acad Sci 694 : 1– 348, 1993
15. Cook DI, Van Lennep EW, Roberts ML, Young JA: Secretion by the major salivary glands. In: Physiology of the Gastrointestinal Tract, 3rd Ed., edited by Johnson LR, New York, Raven Press, 1994 , pp 1061– 1117
16. Dahlberg WH, Screebny LM, King B: Studies of parotid saliva and blood in hemodialysis patients. J Appl Physiol 23 : 100– 108, 1967
17. Sung J, Kuo S, Guo H, Chuang S, Lee S: Decreased salivary flow rate as a dypsogenic factor in hemodialysis patients evidence from an observational study and a pilocarpine clinical trial. J Am Soc Nephrol 16 : 3418– 3429, 2005
18. Earlbaum AM, Quinton PM: Elevated divalent ion concentration in parotid saliva from chronic renal failure patients. Nephron 28 : 58– 61, 1981
19. Savica V, Calo LA, Caldarera R, Cavaleri A, Granata A, Santoro D, Savica R, Muraca U, Mallamace A, Bellinghieri G: Phosphate salivary secretion in hemodialysis patients: Implications for the treatment of hyperphosphatemia. Nephron Physiol 105 : 52– 55, 2007
20. Koide SS: Chitin-chitosan: Properties, benefits and risks. Nutr Res 18 : 1091– 1101, 1998
21. Jull AB, Mhurchu C, Bennett DA, Dunshea-Mooij CA, Rodgers A: Chitosan for overweight or obesity. Cochrane Database Syst Rev 16 : CD003892 , 2008
22. Jing S, Li L, Ji D, Takiguchi Y, Yamaguchi T: Effect of chitosan on renal function in patients with chronic renal failure. J Pharm Pharmacol 49 : 721– 723, 1997