Effect of chitosan chewing gum on reducing serum phosphorus in hemodialysis patients: a multi-center, randomized, double-blind, placebo-controlled trial

Tadao Akizawa, Yoshinari Tsuruta, Yoichi Okada, Yoshihiro Miyauchi, Akio Suda, Hiroshi Kasahara, Nobuhiro Sasaki, Yoshitaka Maeda, Takako Suzuki, Noriaki Matsui, Jun Niwayama, Toshiaki Suzuki, Hideaki Hara, Yasushi Asano, Sadao Komemushi, Masafumi Fukagawa, Tadao Akizawa, Yoshinari Tsuruta, Yoichi Okada, Yoshihiro Miyauchi, Akio Suda, Hiroshi Kasahara, Nobuhiro Sasaki, Yoshitaka Maeda, Takako Suzuki, Noriaki Matsui, Jun Niwayama, Toshiaki Suzuki, Hideaki Hara, Yasushi Asano, Sadao Komemushi, Masafumi Fukagawa

Abstract

Background: HS219 (40 mg chitosan-loaded chewing gum) is designed to bind salivary phosphorus as an add-on to available phosphorus binders. We performed a randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of HS219 in hemodialysis (HD) patients with hyperphosphatemia as an add-on to phosphorus binders.

Methods: Sixty-eight HD patients who were maintained on calcium carbonate (n=33) or sevelamer hydrochloride (n=35) were enrolled. The primary end point was a change in serum phosphorus levels. Secondary end points included changes in levels of salivary phosphorus, serum calcium, parathyroid hormone (PTH), and intact fibroblast growth factor (iFGF) 23.

Results: Sixty-three patients chewed either HS219 (n=35) or placebo (n=28) for 30 min, three times a day, for 3 weeks. HS219 was well tolerated and safe. However, HS219 was not superior to placebo with additional reduction of serum phosphorus with respect to phosphorus binders at the end of the chewing period. There were no significant effects of HS219 on reduction of salivary phosphorus, serum calcium, iPTH, or iFGF23 levels.

Conclusions: The chitosan-loaded chewing gum HS219 does not affect serum and salivary phosphorus levels in Japanese HD patients with hyperphosphatemia. Our findings do not support previous findings that 20 mg of chitosan-loaded chewing gum reduces serum and salivary phosphorus levels.

Trial registration: [corrected] ClinicalTrials.gov NCT01039428, 24 December, 2009.

Figures

Figure 1
Figure 1
Flow chart of patients enrolled in the study. The following populations were defined. (i) The full analysis set (FAS) included a subset of patients who subsequently received chewing gum and had any of the variables for efficacy measured. (ii) The safety analysis set (SAF) included a subset of patients who received one or more doses of the chewing gum.

References

    1. Nakai S, Watanabe Y, Masakane I, Wada A, Shoji T, Hasegawa T, Nakamoto H, Yamagata K, Kazama JJ, Fujii N, Itami N, Shinoda T, Shigematsu T, Marubayashi S, Morita O, Hashimoto S, Suzuki K, Kimata N, Hanafusa N, Wakai K, Hamano T, Ogata S, Tsuchida K, Taniguchi M, Nishi H, Iseki K, Tsubakihara Y. An overview of regular dialysis treatment in Japan (as of 31 December 2010) Ther Apher Dial. 2012;16:483–521. doi: 10.1111/j.1744-9987.2012.01143.x.
    1. Menon MC, Ix JH. Dietary phosphorus, serum phosphorus, and cardiovascular disease. Ann N Y Acad Sci. 2013;1301:21–26. doi: 10.1111/nyas.12283.
    1. Coladonato JA. Control of hyperphosphatemia among patients with ESRD. J Am Soc Nephrol. 2005;16:S107–S114. doi: 10.1681/ASN.2005060663.
    1. Tonelli M, Pannu N, Manns B. Oral phosphate binders in patients with kidney failure. N Engl J Med. 2010;362:1312–1324. doi: 10.1056/NEJMra0912522.
    1. Almirall J, Valenzuela MP. The safety of phosphate binders. Expert Opin Drug Saf. 2006;5:675–686. doi: 10.1517/14740338.5.5.675.
    1. Savica V, Calò L, Santoro D, Monardo P, Granata A, Bellinghieri G. Salivary phosphate secretion in chronic kidney disease. J Ren Nutr. 2008;18:87–90. doi: 10.1053/j.jrn.2007.10.018.
    1. Savica V, Calò 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. 2007;105:52–55. doi: 10.1159/000098544.
    1. Kao CH, Hsieh JF, Tsai SC, Ho YJ, Chang HR. Decreased salivary function in patients with end-stage renal disease requiring hemodialysis. Am J Kidney Dis. 2000;36:1110–1114. doi: 10.1053/ajkd.2000.19810.
    1. Sung JM, Kuo SC, Guo HR, Chuang SF, Lee SY, Huang JJ. Decreased salivary flow rate as a dipsogenic factor in hemodialysis patients: evidence from an observational study and a pilocarpine clinical trial. J Am Soc Nephrol. 2005;16:3418–3429. doi: 10.1681/ASN.2005040346.
    1. Mahvash NM, Kumar SKS. Measuring salivary flow: Challenges and opportunities. J Am Dent Assoc. 2008;139:35S–40S. doi: 10.14219/jada.archive.2008.0353.
    1. Baker WL, Tercius A, Anglade M, White CM, Coleman CI. A meta-analysis evaluating the impact of chitosan on serum lipids in hypercholesterolemia patients. Ann Nutr Metab. 2009;55:368–374. doi: 10.1159/000258633.
    1. Kaats GR, Michalek JE, Preuss HG. Evaluating efficacy of a chitosan product using a double-blinded, placebo-controlled protocol. J Am Coll Nutr. 2006;25:389–394. doi: 10.1080/07315724.2006.10719550.
    1. Cherniack EP. Potential applications for alternative medicine to treat obesity in an aging population. Altern Med Rev. 2008;13:34–42.
    1. Barreteau H, Delattre C, Michaud P. Production of oligosaccharides as promising new food additive generation. Food Technol Biotechnol. 2006;44:323–333.
    1. Savica V, Calò LA, Monad 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. 2009;20:639–644. doi: 10.1681/ASN.2008020130.
    1. Kohler PF, Winter ME. A quantitative test for xerostomia. The Saxon test, an oral equivalent of the Schirmer test. Arthritis Rheum. 1985;28:1128–1132. doi: 10.1002/art.1780281008.
    1. R Development Core Team. R Foundation for Statistical Computing. Vienna, Austria; 2009. R: A language and environment for statistical computing. URL .
    1. Jayakumar R, Nagahama H, Furuike T, Tamura H. Synthesis of phosphorylated chitosan by novel method and its characterization. Int J Biol Macromol. 2008;42:335–339. doi: 10.1016/j.ijbiomac.2007.12.011.
    1. Jing SB, Li L, Ji D, Takiguchi Y, Yamaguchi T. Effect of chitosan on renal function in patients with chronic renal failure. J Pharm Pharmacol. 1997;49:721–723. doi: 10.1111/j.2042-7158.1997.tb06099.x.
    1. Jones JM, Watkins CA, Hand JS, Warren JJ, Cowen HJ. Comparison of three salivary flow rate assessment methods in an elderly population. Community Dent Oral Epidemiol. 2000;28:177–184. doi: 10.1034/j.1600-0528.2000.280303.x.
    1. Navazesh M, Kumar SK. Measuring salivary flow: challenges and opportunities. J Am Dent Assoc. 2008;139(Suppl):35S–40S.
    1. Bots CP, Brand HS, Veerman EC, Valentijn-Benz M, Henskens YM, Valentijn RM, Vos PF, Bijlsma JA, Ter Wee PM, Van Amerongen BM, Nieuw Amerongen AV. Acute effects of hemodialysis on salivary flow rate and composition. Clin Nephrol. 2007;67:25–31. doi: 10.5414/CNP67025.
    1. Kho HS, Lee SW, Chung SC, Kim YK. Oral manifestations and salivary flow rate, pH, and buffer capacity in patients with end-stage renal disease undergoing hemodialysis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1999;88:316–319. doi: 10.1016/S1079-2104(99)70035-1.
    1. Dawes C. Salivary flow patterns and the health of hard and soft oral tissues. J Am Dent Assoc. 2008;139(Suppl):18S–24S.
    1. Bots CP, Brand HS, Veerman EC, Korevaar JC, Valentijn-Benz M, Bezemer PD, Valentijn RM, Vos PF, Bijlsma JA, ter Wee PM, Van Amerongen BM, Nieuw Amerongen AV. Chewing gum and a saliva substitute alleviate thirst and xerostomia in patients on haemodialysis. Nephrol Dial Transplant. 2005;20:578–584. doi: 10.1093/ndt/gfh675.
    1. Tomás I, Marinho JS, Limeres J, Santos MJ, Araújo L, Diz P. Changes in salivary composition in patients with renal failure. Arch Oral Biol. 2008;53:528–532. doi: 10.1016/j.archoralbio.2008.01.006.
    1. Bayraktar G, Kazancioglu R, Bozfakioglu S, Yildiz A, Ark E. Evaluation of salivary parameters and dental status in adult hemodialysis patients. Clin Nephrol. 2004;62:380–383. doi: 10.5414/CNP62380.
    1. Block GA, Persky MS, Shamblin BM, Baltazar MF, Singh B, Sharma A, Pergola P, Smits G, Comelli MC. Effect of Salivary Phosphate-Binding Chewing Gum on Serum Phosphate in Chronic Kidney Disease. Nephron Clin Pract. 2013;123:93.
    1. Oh MS, Uribarri J. What Can We Learn from the Saga of Chitosan Gums in Hyperphosphatemia Therapy? Clin J Am Soc Nephrol. 2014;9:967–970. doi: 10.2215/CJN.09230913.
    1. Komaba H, Fukagawa M. FGF23: a key player in mineral and bone disorder in CKD. Nefrologia. 2009;29:392–396.
    1. Nakatsuka K, Nagasue K, Okuno S, Nagasue K, Okuno S, Yoshihara A, Miura M, Miyauchi A, Kobayashi K, Miki T, Shoji T, Ishimura E, Nishizawa Y. FGF-23 in patients with end-stage renal disease on hemodialysis. Kidney Int. 2004;65:1943–1946. doi: 10.1111/j.1523-1755.2004.00604.x.

Source: PubMed

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