Lanthanum-Induced Mucosal Alterations in the Stomach (Lanthanum Gastropathy): a Comparative Study Using an Animal Model

Abstract

Lanthanum (La) carbonate (LC) is one of the most potent phosphate binders that prevents the elevation of serum phosphate levels in patients with end-stage renal diseases undergoing dialysis. LC binds strongly to dietary phosphate and forms insoluble complexes that pass through the gastrointestinal tract. La deposition in patients treated with LC is a recently documented finding particularly observed in gastric mucosa. We herein describe the detailed gastric mucosal lesions in 45 LC-treated patients and address the potential underlying pathologic mechanism using oral LC administration in rats. Microscopically, La deposition, as shown by subepithelial collections of plump eosinophilic histiocytes or small foreign body granulomas containing coarse granular or amorphous inclusion bodies, was found in the gastric mucosa of 44 (97.8%) of the 45 dialysis patients in the study cohort, which was most frequently associated with foveolar hyperplasia (37.8%). Using oral administration of rats with 1000 mg/day LC for 2 or more weeks, La deposition was consistently detectable in the gastric mucosa but not in other organs examined. In addition, various histologic alterations such as glandular atrophy, stromal fibrosis, proliferation of mucous neck cells, intestinal metaplasia, squamous cell papilloma, erosion, and ulcer were demonstrated in the rat model. Thus, orally administered LC can induce mucosal injury, designated here as La gastropathy, which may alter the local environment and result in La deposition in the gastric mucosa, thereby potentially inducing abnormal cell proliferation or neoplastic lesions.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Melamed ML, Eustace JA, Plantinga L, Jaar BG, Fink NE, Coresh J, Klag MJ, Powe NR (2006) Changes in serum calcium, phosphate, and PTH and the risk of death in incident dialysis patients: a longitudinal study. Kidney Int 70(2):351–357. https://doi.org/10.1038/sj.ki.5001542

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Covic A, Kothawala P, Bernal M, Robbins S, Chalian A, Goldsmith D (2009) Systematic review of the evidence underlying the association between mineral metabolism disturbances and risk of all-cause mortality, cardiovascular mortality and cardiovascular events in chronic kidney disease. Nephrol Dial Transplant 24(5):1506–1523. https://doi.org/10.1093/ndt/gfn613

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Shang D, Xie Q, Ge X, Yan H, Tian J, Kuang D, Hao C-M, Zhu T (2015) Hyperphosphatemia as an independent risk factor for coronary artery calcification progression in peritoneal dialysis patients. BMC Nephrol 16(1):107. https://doi.org/10.1186/s12882-015-0103-8

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Heaf JG, Nielsen LP (1984) Serum aluminium in haemodialysis patients: relation to osteodystrophy, encephalopathy and aluminium hydroxide consumption. Miner Electrolyte Metab 10(6):345–350

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Goodman WG (1985) Bone disease and aluminum: pathogenic considerations. Am J Kidney Dis 6(5):330–335. https://doi.org/10.1016/S0272-6386(85)80089-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB (2000) Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 342(20):1478–1483. https://doi.org/10.1056/NEJM200005183422003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Hutchison AJ, Wilson RJ, Garafola S, Copley JB (2016) Lanthanum carbonate: safety data after 10 years. Nephrology (Carlton) 21(12):987–994. https://doi.org/10.1111/nep.12864

    CAS  Article  Google Scholar 

  8. 8.

    Pennick M, Dennis K, Damment SJ (2006) Absolute bioavailability and disposition of lanthanum in healthy human subjects administered lanthanum carbonate. J Clin Pharmacol 46(7):738–746. https://doi.org/10.1177/0091270006289846

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Damment SJ, Pennick M (2007) Systemic lanthanum is excreted in the bile of rats. Toxicol Lett 171(1-2):69–77. https://doi.org/10.1016/j.toxlet.2007.04.005

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Bervoets AR, Behets GJ, Schryvers D, Roels F, Yang Z, Verberckmoes SC, Damment SJ, Dauwe S, Mubiana VK, Blust R, De Broe ME, D'Haese PC (2009) Hepatocellular transport and gastrointestinal absorption of lanthanum in chronic renal failure. Kidney Int 75(4):389–398. https://doi.org/10.1038/ki.2008.571

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Damment SJ, Cox AG, Secker R (2009) Dietary administration in rodent studies distorts the tissue deposition profile of lanthanum carbonate; brain deposition is a contamination artefact? Toxicol Lett 188(3):223–229. https://doi.org/10.1016/j.toxlet.2009.03.020

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Feng L, Xiao H, He X, Li Z, Li F, Liu N, Zhao Y, Huang Y, Zhang Z, Chai Z (2006) Neurotoxicological consequence of long-term exposure to lanthanum. Toxicol Lett 165(2):112–120. https://doi.org/10.1016/j.toxlet.2006.02.003

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    He X, Zhang Z, Zhang H, Zhao Y, Chai Z (2008) Neurotoxicological evaluation of long-term lanthanum chloride exposure in rats. Toxicol Sci 103(2):354–361. https://doi.org/10.1093/toxsci/kfn046

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Gramowski A, Jugelt K, Schroder OH, Weiss DG, Mitzner S (2011) Acute functional neurotoxicity of lanthanum(III) in primary cortical networks. Toxicol Sci 120(1):173–183. https://doi.org/10.1093/toxsci/kfq385

    CAS  Article  Google Scholar 

  15. 15.

    Hutchison AJ, Barnett ME, Krause R, Kwan JT, Siami GA, Group SPDLS (2008) Long-term efficacy and safety profile of lanthanum carbonate: results for up to 6 years of treatment. Nephron Clin Pract 110(1):c15–c23. https://doi.org/10.1159/000149239

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Zhang C, Wen J, Li Z, Fan J (2013) Efficacy and safety of lanthanum carbonate on chronic kidney disease-mineral and bone disorder in dialysis patients: a systematic review. BMC Nephrol 14(1):226. https://doi.org/10.1186/1471-2369-14-226

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Haratake J, Yasunaga C, Ootani A, Shimajiri S, Matsuyama A, Hisaoka M (2015) Peculiar histiocytic lesions with massive lanthanum deposition in dialysis patients treated with lanthanum carbonate. Am J Surg Pathol 39(6):767–771. https://doi.org/10.1097/PAS.0000000000000385

    Article  Google Scholar 

  18. 18.

    Makino M, Kawaguchi K, Shimojo H, Nakamura H, Nagasawa M, Kodama R (2015) Extensive lanthanum deposition in the gastric mucosa: the first histopathological report. Pathol Int 65(1):33–37. https://doi.org/10.1111/pin.12227

    CAS  Article  Google Scholar 

  19. 19.

    Tonooka A, Uda S, Tanaka H, Yao A, Uekusa T (2015) Possibility of lanthanum absorption in the stomach. Clin Kidney J 8(5):572–575. https://doi.org/10.1093/ckj/sfv062

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Goto K, Ogawa K (2016) Lanthanum deposition is frequently observed in the gastric mucosa of dialysis patients with lanthanum carbonate therapy: a clinicopathologic study of 13 cases, including 1 case of lanthanum granuloma in the colon and 2 nongranulomatous gastric cases. Int J Surg Pathol 24(1):89–92. https://doi.org/10.1177/1066896915613434

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Yabuki K, Shiba E, Harada H, Uchihashi K, Matsuyama A, Haratake J, Hisaoka M (2016) Lanthanum deposition in the gastrointestinal mucosa and regional lymph nodes in dialysis patients: analysis of surgically excised specimens and review of the literature. Pathol Res Pract 212(10):919–926. https://doi.org/10.1016/j.prp.2016.07.017

    Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Ban S, Suzuki S, Kubota K, Ohshima S, Satoh H, Imada H, Ueda Y (2017) Gastric mucosal status susceptible to lanthanum deposition in patients treated with dialysis and lanthanum carbonate. Ann Diagn Pathol 26:6–9. https://doi.org/10.1016/j.anndiagpath.2016.10.001

    Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Behets GJ, Dams G, Vercauteren SR, Damment SJ, Bouillon R, De Broe ME, D'Haese PC (2004) Does the phosphate binder lanthanum carbonate affect bone in rats with chronic renal failure? J Am Soc Nephrol 15(8):2219–2228. https://doi.org/10.1097/01.asn.0000133022.32912.95

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Bervoets AR, Oste L, Behets GJ, Dams G, Blust R, Marynissen R, Geryl H, De Broe ME, D'Haese PC (2006) Development and reversibility of impaired mineralization associated with lanthanum carbonate treatment in chronic renal failure rats. Bone 38(6):803–810. https://doi.org/10.1016/j.bone.2005.11.022

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) (2005) Guidance for industry, estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. https://www.fda.gov/downloads/drugs/guidances/ucm078932.pdf. Accessed 3 December 2017

  26. 26.

    Li H, Helander HF (1996) Hypergastrinemia increases proliferation of gastroduodenal epithelium during gastric ulcer healing in rats. Dig Dis Sci 41(1):40–48. https://doi.org/10.1007/BF02208582

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Loogna P, Franzen L, Sipponen P, Domellof L (2002) Cyclooxygenase-2 and Bcl-2 expression in the stomach mucosa of Wistar rats exposed to Helicobacter pylori, N'-methyl- N'-nitro- N-nitrosoguanidine and bile. Virchows Arch 441(1):77–84. https://doi.org/10.1007/s00428-001-0571-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Haratake J, Furuta A, Hashimoto H (1994) Immunohistochemical and ultrastructural study of hepatic sinusoidal linings during dichloropropanol-induced acute hepatic necrosis. Liver 14(2):90–97

    CAS  Article  Google Scholar 

  29. 29.

    Kanda Y (2013) Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48(3):452–458. https://doi.org/10.1038/bmt.2012.244

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE (2000) Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 356(9234):1000–1001. https://doi.org/10.1016/S0140-6736(00)02694-5

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Sanyal S, Marckmann P, Scherer S, Abraham JL (2011) Multiorgan gadolinium (Gd) deposition and fibrosis in a patient with nephrogenic systemic fibrosis—an autopsy-based review. Nephrol Dial Transplant 26(11):3616–3626. https://doi.org/10.1093/ndt/gfr085

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Kaewlai R, Abujudeh H (2012) Nephrogenic systemic fibrosis. AJR Am J Roentgenol 199(1):W17–W23. https://doi.org/10.2214/AJR.11.8144

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Davis RL, Abraham JL (2009) Lanthanum deposition in a dialysis patient. Nephrol Dial Transplant 24(10):3247–3250. https://doi.org/10.1093/ndt/gfp364

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Hoda RS, Sanyal S, Abraham JL, Everett JM, Hundemer GL, Yee E, Lauwers GY, Tolkoff-Rubin N, Misdraji J (2017) Lanthanum deposition from oral lanthanum carbonate in the upper gastrointestinal tract. Histopathology 70(7):1072–1078. https://doi.org/10.1111/his.13178

    Article  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Shitomi Y, Nishida H, Kusaba T, Daa T, Yano S, Arakane M, Kondo Y, Nagai T, Abe T, Gamachi A, Murakami K, Etoh T, Shiraishi N, Inomata M, Yokoyama S (2017) Gastric lanthanosis (lanthanum deposition) in dialysis patients treated with lanthanum carbonate. Pathol Int 67(8):389–397. https://doi.org/10.1111/pin.12558

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Greenson JK, Trinidad SB, Pfeil SA, Brainard JA, McBride PT, Colijn HO, Tesi RJ, Lucas JG (1993) Gastric mucosal calcinosis. Calcified aluminum phosphate deposits secondary to aluminum-containing antacids or sucralfate therapy in organ transplant patients. Am J Surg Pathol 17(1):45–50. https://doi.org/10.1097/00000478-199301000-00005

    CAS  Article  Google Scholar 

  37. 37.

    Greaves P (2012) Stomach (glandular). In: Greaves P (ed) Histopathology of preclinical toxicity studies: interpretation and relevance in drug safety studies, 4th edn. Academic Press, Amsterdam, pp 349–372

    Google Scholar 

  38. 38.

    Vaziri ND, Dure-Smith B, Miller R, Mirahmadi MK (1985) Pathology of gastrointestinal tract in chronic hemodialysis patients: an autopsy study of 78 cases. Am J Gastroenterol 80(8):608–611

    CAS  Google Scholar 

  39. 39.

    Marcuard SP, Weinstock JV (1988) Gastrointestinal angiodysplasia in renal failure. J Clin Gastroenterol 10(5):482–484. https://doi.org/10.1097/00004836-198810000-00003

    CAS  Article  Google Scholar 

  40. 40.

    Abu Farsakh NA, Roweily E, Rababaa M, Butchoun R (1996) Brief report: evaluation of the upper gastrointestinal tract in uraemic patients undergoing haemodialysis. Nephrol Dial Transplant 11(5):847–850. https://doi.org/10.1093/oxfordjournals.ndt.a027411

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Sotoudehmanesh R, Ali Asgari A, Ansari R, Nouraie M (2003) Endoscopic findings in end-stage renal disease. Endoscopy 35(6):502–505. https://doi.org/10.1055/s-2003-39672

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Quintero E, Ohning G, Guth PH (1994) Uremia in the rat affects gastric cell growth and differentiation. Dig Dis Sci 39(7):1464–1468. https://doi.org/10.1007/BF02088049

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Quintero E, Ohning GV, Del Rivero M, Wong HC, Walsh JH, Guth PH (1995) Gastrin mediates the increase in gastric cell growth in uremic rats. Am J Phys 268:G586–G591

    CAS  Google Scholar 

  44. 44.

    Arab HH, Salama SA, Omar HA, Arafa el SA, Maghrabi IA (2015) Diosmin protects against ethanol-induced gastric injury in rats: novel anti-ulcer actions. PLoS One 10(3):e0122417. https://doi.org/10.1371/journal.pone.0122417

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Vaziri ND, Yuan J, Nazertehrani S, Ni Z, Liu S (2013) Chronic kidney disease causes disruption of gastric and small intestinal epithelial tight junction. Am J Nephrol 38(2):99–103. https://doi.org/10.1159/000353764

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Ji R, Zuo XL, Yu T, Gu XM, Li Z, Zhou CJ, Li YQ (2012) Mucosal barrier defects in gastric intestinal metaplasia: in vivo evaluation by confocal endomicroscopy. Gastrointest Endosc 75(5):980–987. https://doi.org/10.1016/j.gie.2011.12.016

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors are grateful to Mr. Mitsuru Yokoyama, Shared-Use Research Center, University of Occupational and Environmental Health, for his technical assistance of electron microscopy.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Kei Yabuki.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Research Involving Human Participants and/or Animals

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study design involving humans was approved by the Ethics Committee of Medical Research, University of Occupational and Environmental Health, Japan (approval number H27-104). Informed opt-in/opt-out consent was obtained from all individual participants included in the study. All procedures performed in studies involving animals were in accordance with Guidelines for Proper Conduct of Animal Experiments by Science Council of Japan and approved by the Ethics Committee of Animal Care and Experimentation of the University of Occupational and Environmental Health, Japan (approval number AE15-011).

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yabuki, K., Haratake, J., Tsuda, Y. et al. Lanthanum-Induced Mucosal Alterations in the Stomach (Lanthanum Gastropathy): a Comparative Study Using an Animal Model. Biol Trace Elem Res 185, 36–47 (2018). https://doi.org/10.1007/s12011-017-1235-4

Download citation

Keywords

  • Dialysis
  • Lanthanum carbonate
  • Lanthanum deposition
  • Stomach
  • Histology
  • Rat