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Published in: BMC Nephrology 1/2022

Open Access 01-12-2022 | Nephrectomy | Research

Evaluation of cerium oxide as a phosphate binder using 5/6 nephrectomy model rat

Authors: Akiko Hashimoto, Jiaqi Gao, Yuki Kanome, Yukihiro Ogawa, Masaharu Nakatsu, Masahiro Kohno, Koji Fukui

Published in: BMC Nephrology | Issue 1/2022

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Abstract

Background

The number of chronic kidney disease (CKD) patients continues to increase worldwide. CKD patients need to take phosphate binders to manage serum phosphorus concentrations. Currently, several types of phosphate binder, including lanthanum carbonate, are used. However, they each have disadvantages.

Methods

In this study, we evaluated cerium oxide as a new phosphate binder in vitro and in vivo. First, cerium oxide was mixed with phosphoric acid at pH 2.5 or 7.0, and residual phosphoric acid was measured by absorption photometry using colorimetric reagent. Second, cerium oxide was fed to 5/6 nephrectomy model rats (5/6Nx), a well-known renal damage model. All rats were measured food intake, water intake, feces volume, and urine volume, and collected serum and urine were analyzed for biochemical markers.

Results

Cerium oxide can adsorb phosphate at acidic and neutral pH, while lanthanum carbonate, which is a one of popular phosphate binder, does not dissolve at neutral pH. Cerium oxide-treatment reduced serum phosphate concentrations of 5/6Nx rats without an increase in serum alanine transaminase levels that would indicate hepatotoxicity, and cerium oxide-treatment maintained serum creatinine and blood urea nitrogen levels, while those of normal 5/6Nx rats increased slightly.

Conclusions

These results suggest that cerium oxide can be a potential phosphate binder. Decreased body weight gain and increased water intake and urine volume in 5/6Nx rats were thought to be an effect of nephrectomy because these changes did not occur in sham operation rats. Additional investigations are needed to evaluate the longer-term safety and possible accumulation of cerium oxide in the body.
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Literature
1.
go back to reference Lysaght MJ. Maintenance Dialysis Population Dynamics: Current Trends and Long-Term Implications. J Am Soc Nephrol. 2002;13(suppl 1):S37-40.CrossRef Lysaght MJ. Maintenance Dialysis Population Dynamics: Current Trends and Long-Term Implications. J Am Soc Nephrol. 2002;13(suppl 1):S37-40.CrossRef
2.
go back to reference Imai E, Horio M, Watanabe T, Iseki K, Yamagata K, Hara S, et al. Prevalence of chronic kidney disease in the Japanese general population. Clin Exp Nephrol. 2009;13:621–30.CrossRef Imai E, Horio M, Watanabe T, Iseki K, Yamagata K, Hara S, et al. Prevalence of chronic kidney disease in the Japanese general population. Clin Exp Nephrol. 2009;13:621–30.CrossRef
3.
go back to reference Hanafusa N, Abe M, Joki N, Hoshino J, Kikuchi K, Goto S, et al. 2020 Annual Dialysis Data Report, JSDT Renal Data Registry. Nihon Toseki Igakkai Zasshi. 2021;54:611–57.CrossRef Hanafusa N, Abe M, Joki N, Hoshino J, Kikuchi K, Goto S, et al. 2020 Annual Dialysis Data Report, JSDT Renal Data Registry. Nihon Toseki Igakkai Zasshi. 2021;54:611–57.CrossRef
4.
go back to reference Hruska KA, Mathew S, Lund R, Qiu P, Pratt R. Hyperphosphatemia of chronic kidney disease. Kidney Int. 2008;74:148–57.CrossRef Hruska KA, Mathew S, Lund R, Qiu P, Pratt R. Hyperphosphatemia of chronic kidney disease. Kidney Int. 2008;74:148–57.CrossRef
5.
go back to reference Marchais SJ, Metivier F, Guerin AP, London GM. Association of hyperphosphataemia with haemodynamic disturbances in end-stage renal disease. Nephrol Dial Transplant. 1999;14:2178–83.CrossRef Marchais SJ, Metivier F, Guerin AP, London GM. Association of hyperphosphataemia with haemodynamic disturbances in end-stage renal disease. Nephrol Dial Transplant. 1999;14:2178–83.CrossRef
6.
go back to reference Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int. 2007;71:438–41.CrossRef Block GA, Raggi P, Bellasi A, Kooienga L, Spiegel DM. Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. Kidney Int. 2007;71:438–41.CrossRef
7.
go back to reference Hutchison AJ, Maes B, Vanwalleghem J, Asmus G, Mohamed E, Schmieder R, et al. Efficacy, tolerability, and safety of lanthanum carbonate in hyperphosphatemia: a 6-month, randomized, comparative trial versus calcium carbonate. Nephron - Clin Pract. 2005;100:8–19.CrossRef Hutchison AJ, Maes B, Vanwalleghem J, Asmus G, Mohamed E, Schmieder R, et al. Efficacy, tolerability, and safety of lanthanum carbonate in hyperphosphatemia: a 6-month, randomized, comparative trial versus calcium carbonate. Nephron - Clin Pract. 2005;100:8–19.CrossRef
8.
go back to reference Komaba H, Kakuta T, Suzuki H, Hida M, Suga T, Fukagawa M. Survival advantage of lanthanum carbonate for hemodialysis patients with uncontrolled hyperphosphatemia. Nephrol Dial Transplant. 2015;30:107–14.CrossRef Komaba H, Kakuta T, Suzuki H, Hida M, Suga T, Fukagawa M. Survival advantage of lanthanum carbonate for hemodialysis patients with uncontrolled hyperphosphatemia. Nephrol Dial Transplant. 2015;30:107–14.CrossRef
9.
go back to reference Brennan A, Akehurst R, Davis S, Sakai H, Abbott V. The Cost-Effectiveness of Lanthanum Carbonate in the Treatment of Hyperphosphatemia in Patients with End-Stage Renal Disease. Value Heal. 2007;10:32–41.CrossRef Brennan A, Akehurst R, Davis S, Sakai H, Abbott V. The Cost-Effectiveness of Lanthanum Carbonate in the Treatment of Hyperphosphatemia in Patients with End-Stage Renal Disease. Value Heal. 2007;10:32–41.CrossRef
10.
go back to reference Shigematsu T, Mune, Negi, Mima, Sakaguchi, Orita, et al. The management of hyperphosphatemia by lanthanum carbonate in chronic kidney disease patients. Int J Nephrol Renovasc Dis. 2012;5:81.CrossRef Shigematsu T, Mune, Negi, Mima, Sakaguchi, Orita, et al. The management of hyperphosphatemia by lanthanum carbonate in chronic kidney disease patients. Int J Nephrol Renovasc Dis. 2012;5:81.CrossRef
11.
go back to reference Xu J, Zhang YX, Yu XQ, Liu ZH, Wang LN, Chen JH, et al. Lanthanum carbonate for the treatment of hyperphosphatemia in CKD 5D: Multicenter, double blind, randomized, controlled trial in mainland China. BMC Nephrol. 2013;14:1–11.CrossRef Xu J, Zhang YX, Yu XQ, Liu ZH, Wang LN, Chen JH, et al. Lanthanum carbonate for the treatment of hyperphosphatemia in CKD 5D: Multicenter, double blind, randomized, controlled trial in mainland China. BMC Nephrol. 2013;14:1–11.CrossRef
12.
go back to reference Zhang C, Wen J, Li Z, Fan J. Efficacy and safety of lanthanum carbonate on chronic kidney disease-mineral and bone disorder in dialysis patients: a systematic review. BMC Nephrol. 2013;14:226.CrossRef Zhang C, Wen J, Li Z, Fan J. Efficacy and safety of lanthanum carbonate on chronic kidney disease-mineral and bone disorder in dialysis patients: a systematic review. BMC Nephrol. 2013;14:226.CrossRef
14.
go back to reference Goldsmith DR, Scott LJ, Cvetković RS, Plosker GL. Sevelamer hydrochloride: a review of its use for hyperphosphataemia in patients with end-stage renal disease on haemodialysis. Drugs. 2008;68:85–104.CrossRef Goldsmith DR, Scott LJ, Cvetković RS, Plosker GL. Sevelamer hydrochloride: a review of its use for hyperphosphataemia in patients with end-stage renal disease on haemodialysis. Drugs. 2008;68:85–104.CrossRef
15.
go back to reference Chertow GM, Burke SK, Dillon MA, Slatopolsky E. Long-term effects of sevelamer hydrochloride on the calcium × phosphate product and lipid profile of haemodialysis patients*. Nephrol Dial Transplant. 1999;14:2907–14.CrossRef Chertow GM, Burke SK, Dillon MA, Slatopolsky E. Long-term effects of sevelamer hydrochloride on the calcium × phosphate product and lipid profile of haemodialysis patients*. Nephrol Dial Transplant. 1999;14:2907–14.CrossRef
16.
go back to reference Akizawa T, Origasa H, Kameoka C, Kaneko Y, Kawasaki S. Randomized Controlled Trial of Bixalomer Versus Sevelamer Hydrochloride in Hemodialysis Patients With Hyperphosphatemia. Ther Apher Dial. 2014;18:122–31.CrossRef Akizawa T, Origasa H, Kameoka C, Kaneko Y, Kawasaki S. Randomized Controlled Trial of Bixalomer Versus Sevelamer Hydrochloride in Hemodialysis Patients With Hyperphosphatemia. Ther Apher Dial. 2014;18:122–31.CrossRef
17.
go back to reference Hatakeyama S, Murasawa H, Narita T, Oikawa M, Fujita N, Iwamura H, et al. Switching hemodialysis patients from sevelamer hydrochloride to bixalomer: a single-center, non-randomized analysis of efficacy and effects on gastrointestinal symptoms and metabolic acidosis. BMC Nephrol. 2013;14:222.CrossRef Hatakeyama S, Murasawa H, Narita T, Oikawa M, Fujita N, Iwamura H, et al. Switching hemodialysis patients from sevelamer hydrochloride to bixalomer: a single-center, non-randomized analysis of efficacy and effects on gastrointestinal symptoms and metabolic acidosis. BMC Nephrol. 2013;14:222.CrossRef
18.
go back to reference Yokoyama K, Hirakata H, Akiba T, Fukagawa M, Nakayama M, Sawada K, et al. Ferric Citrate Hydrate for the Treatment of Hyperphosphatemia in Nondialysis-Dependent CKD. Clin J Am Soc Nephrol. 2014;9:543–52.CrossRef Yokoyama K, Hirakata H, Akiba T, Fukagawa M, Nakayama M, Sawada K, et al. Ferric Citrate Hydrate for the Treatment of Hyperphosphatemia in Nondialysis-Dependent CKD. Clin J Am Soc Nephrol. 2014;9:543–52.CrossRef
19.
go back to reference Yokoyama K, Fukagawa M, Akiba T, Nakayama M, Ito K, Hanaki K, et al. Randomised clinical trial of ferric citrate hydrate on anaemia management in haemodialysis patients with hyperphosphataemia: ASTRIO study. Sci Rep. 2019;9:8877.CrossRef Yokoyama K, Fukagawa M, Akiba T, Nakayama M, Ito K, Hanaki K, et al. Randomised clinical trial of ferric citrate hydrate on anaemia management in haemodialysis patients with hyperphosphataemia: ASTRIO study. Sci Rep. 2019;9:8877.CrossRef
20.
go back to reference Floege J, Covic AC, Ketteler M, Mann JFE, Rastogi A, Spinowitz B, et al. Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients. Nephrol Dial Transplant. 2015;30:1037–46.CrossRef Floege J, Covic AC, Ketteler M, Mann JFE, Rastogi A, Spinowitz B, et al. Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients. Nephrol Dial Transplant. 2015;30:1037–46.CrossRef
21.
go back to reference Kendrick J, Parameswaran V, Ficociello LH, Ofsthun NJ, Davis S, Mullon C, et al. One-Year Historical Cohort Study of the Phosphate Binder Sucroferric Oxyhydroxide in Patients on Maintenance Hemodialysis. J Ren Nutr. 2019;29:428–37.CrossRef Kendrick J, Parameswaran V, Ficociello LH, Ofsthun NJ, Davis S, Mullon C, et al. One-Year Historical Cohort Study of the Phosphate Binder Sucroferric Oxyhydroxide in Patients on Maintenance Hemodialysis. J Ren Nutr. 2019;29:428–37.CrossRef
22.
go back to reference Davis RL, Abraham JL. Lanthanum deposition in a dialysis patient. Nephrol Dial Transplant. 2009;24:3247–50.CrossRef Davis RL, Abraham JL. Lanthanum deposition in a dialysis patient. Nephrol Dial Transplant. 2009;24:3247–50.CrossRef
23.
go back to reference Shitomi Y, Nishida H, Kusaba T, Daa T, Yano S, Arakane M, et al. Gastric lanthanosis (lanthanum deposition) in dialysis patients treated with lanthanum carbonate. Pathol Int. 2017;67:389–97.CrossRef Shitomi Y, Nishida H, Kusaba T, Daa T, Yano S, Arakane M, et al. Gastric lanthanosis (lanthanum deposition) in dialysis patients treated with lanthanum carbonate. Pathol Int. 2017;67:389–97.CrossRef
24.
go back to reference Tabuchi M, Takeshima F, Akazawa Y, Nakao K. Early Gastric Cancer with Diffuse Lanthanum Deposition. Intern Med. 2019;58:447–8.CrossRef Tabuchi M, Takeshima F, Akazawa Y, Nakao K. Early Gastric Cancer with Diffuse Lanthanum Deposition. Intern Med. 2019;58:447–8.CrossRef
25.
go back to reference Takatsuna M, Takeuchi M, Usuda H, Terai S. Case of early-stage gastric cancer identified in the gastric mucosa with lanthanum phosphate deposition. Endosc Int Open. 2019;07:E893–5.CrossRef Takatsuna M, Takeuchi M, Usuda H, Terai S. Case of early-stage gastric cancer identified in the gastric mucosa with lanthanum phosphate deposition. Endosc Int Open. 2019;07:E893–5.CrossRef
26.
go back to reference Nakagawa S, Ogura M, Akiba T, Iwamoto H, Shibamoto T. DEVELOPMENT OF NONALUMINUM PHOSPHATE BINDER HYDROUS CERIUM OXIDE (Ceα(OH)4–2α·nH2O). Am Soc Artif Intern Organs. 1985;31:155–9. Nakagawa S, Ogura M, Akiba T, Iwamoto H, Shibamoto T. DEVELOPMENT OF NONALUMINUM PHOSPHATE BINDER HYDROUS CERIUM OXIDE (Ceα(OH)4–2α·nH2O). Am Soc Artif Intern Organs. 1985;31:155–9.
27.
go back to reference Malaki M. Acute encephalopathy following the use of aluminum hydroxide in a boy affected with chronic kidney disease. J Pediatr Neurosci. 2013;8:81.CrossRef Malaki M. Acute encephalopathy following the use of aluminum hydroxide in a boy affected with chronic kidney disease. J Pediatr Neurosci. 2013;8:81.CrossRef
28.
go back to reference Ogura M, Iwamoto H, Akiba T, Nakagawa S. Development of non-aluminum phosphate binder -Hydrous cerium oxide. J Japanese Assoc Dial Physicians. 1986;19:775–8. Ogura M, Iwamoto H, Akiba T, Nakagawa S. Development of non-aluminum phosphate binder -Hydrous cerium oxide. J Japanese Assoc Dial Physicians. 1986;19:775–8.
29.
go back to reference Yoshida M, Nishizaki I, Komura E, Hosomi R, Fukunaga K. Effect of difference in dietary protein on serum phoshorus and tissue lanthanum concentration in rats administered lanthanum carbonate. Trace Nutr Res. 2019;36:29–34. Yoshida M, Nishizaki I, Komura E, Hosomi R, Fukunaga K. Effect of difference in dietary protein on serum phoshorus and tissue lanthanum concentration in rats administered lanthanum carbonate. Trace Nutr Res. 2019;36:29–34.
30.
go back to reference Ji L, Masuda S, Saito H, Inui KI. Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int. 2002;62:514–24.CrossRef Ji L, Masuda S, Saito H, Inui KI. Down-regulation of rat organic cation transporter rOCT2 by 5/6 nephrectomy. Kidney Int. 2002;62:514–24.CrossRef
31.
go back to reference Kyoko B, Midori Y, Ryoji H, Akihiko M. Sequential Alterations in Clinical Biochemical Indicators of Renal Function in 5/6 Nephrectomized Rats: Basic Study for Renal Toxicity Using 5/6 Nephrectomized Rats. J Toxicol Sci. 1998;23:433–42.CrossRef Kyoko B, Midori Y, Ryoji H, Akihiko M. Sequential Alterations in Clinical Biochemical Indicators of Renal Function in 5/6 Nephrectomized Rats: Basic Study for Renal Toxicity Using 5/6 Nephrectomized Rats. J Toxicol Sci. 1998;23:433–42.CrossRef
32.
go back to reference Liu F, Li Y, Wang F, Jiang Y-F, Jiang Y-S. Shenfushu Granule and Atropine Attenuate Microvasculature Loss in Rat Models with 5/6 Nephrectomy. Ren Fail. 2012;34:600–9.CrossRef Liu F, Li Y, Wang F, Jiang Y-F, Jiang Y-S. Shenfushu Granule and Atropine Attenuate Microvasculature Loss in Rat Models with 5/6 Nephrectomy. Ren Fail. 2012;34:600–9.CrossRef
33.
go back to reference Ben-Dov IZ, Pappo O, Sklair-Levy M, Galitzer H, Ilan Y, Naveh-Many T, et al. Lanthanum carbonate decreases PTH gene expression with no hepatotoxicity in uraemic rats. Nephrol Dial Transplant. 2006;22:362–8.CrossRef Ben-Dov IZ, Pappo O, Sklair-Levy M, Galitzer H, Ilan Y, Naveh-Many T, et al. Lanthanum carbonate decreases PTH gene expression with no hepatotoxicity in uraemic rats. Nephrol Dial Transplant. 2006;22:362–8.CrossRef
34.
go back to reference Nemoto Y, Kumagai T, Ishizawa K, Miura Y, Shiraishi T, Morimoto C, et al. Phosphate binding by sucroferric oxyhydroxide ameliorates renal injury in the remnant kidney model. Sci Rep. 2019;9:1732.CrossRef Nemoto Y, Kumagai T, Ishizawa K, Miura Y, Shiraishi T, Morimoto C, et al. Phosphate binding by sucroferric oxyhydroxide ameliorates renal injury in the remnant kidney model. Sci Rep. 2019;9:1732.CrossRef
35.
go back to reference Santamaría R, Díaz-Tocados JM, Pendón-Ruiz de Mier MV, Robles A, Salmerón-Rodríguez MD, Ruiz E, et al. Increased phosphaturia accelerates the decline in renal function: a search for mechanisms. Sci Rep. 2018;8:13701.CrossRef Santamaría R, Díaz-Tocados JM, Pendón-Ruiz de Mier MV, Robles A, Salmerón-Rodríguez MD, Ruiz E, et al. Increased phosphaturia accelerates the decline in renal function: a search for mechanisms. Sci Rep. 2018;8:13701.CrossRef
36.
go back to reference Hutchison AJ, Barnett ME, Krause R, Kwan JTC, Siami GA. Long-Term Efficacy and Safety Profile of Lanthanum Carbonate: Results for up to 6 Years of Treatment. Nephron Clin Pract. 2008;110:c15-23.CrossRef Hutchison AJ, Barnett ME, Krause R, Kwan JTC, Siami GA. Long-Term Efficacy and Safety Profile of Lanthanum Carbonate: Results for up to 6 Years of Treatment. Nephron Clin Pract. 2008;110:c15-23.CrossRef
37.
go back to reference Rombolà G, Londrino F, Corbani V, Falqui V, Ardini M, Zattera T. Lanthanum carbonate: a postmarketing observational study of efficacy and safety. J Nephrol. 2012;25:490–6.CrossRef Rombolà G, Londrino F, Corbani V, Falqui V, Ardini M, Zattera T. Lanthanum carbonate: a postmarketing observational study of efficacy and safety. J Nephrol. 2012;25:490–6.CrossRef
38.
go back to reference Kasiske BL, O’Donnell MP, Garvis WJ, Keane WF. Pharmacologic treatment of hyperlipidemia reduces glomerular injury in rat 5/6 nephrectomy model of chronic renal failure. Circ Res. 1988;62:367–74.CrossRef Kasiske BL, O’Donnell MP, Garvis WJ, Keane WF. Pharmacologic treatment of hyperlipidemia reduces glomerular injury in rat 5/6 nephrectomy model of chronic renal failure. Circ Res. 1988;62:367–74.CrossRef
39.
go back to reference Suárez-Luque S, Mato I, Huidobro JF, Simal-Lozano J. Determination of major metal cations in milk by capillary zone electrophoresis. Int Dairy J. 2007;17:896–901.CrossRef Suárez-Luque S, Mato I, Huidobro JF, Simal-Lozano J. Determination of major metal cations in milk by capillary zone electrophoresis. Int Dairy J. 2007;17:896–901.CrossRef
40.
go back to reference Kumari M, Kumari SI, Grover P. Genotoxicity analysis of cerium oxide micro and nanoparticles in Wistar rats after 28 days of repeated oral administration. Mutagenesis. 2014;29:467–79.CrossRef Kumari M, Kumari SI, Grover P. Genotoxicity analysis of cerium oxide micro and nanoparticles in Wistar rats after 28 days of repeated oral administration. Mutagenesis. 2014;29:467–79.CrossRef
Metadata
Title
Evaluation of cerium oxide as a phosphate binder using 5/6 nephrectomy model rat
Authors
Akiko Hashimoto
Jiaqi Gao
Yuki Kanome
Yukihiro Ogawa
Masaharu Nakatsu
Masahiro Kohno
Koji Fukui
Publication date
01-12-2022
Publisher
BioMed Central
Published in
BMC Nephrology / Issue 1/2022
Electronic ISSN: 1471-2369
DOI
https://doi.org/10.1186/s12882-022-02904-6

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