Lanthanum-Induced Mucosal Alterations in the Stomach (Lanthanum Gastropathy): a Comparative Study Using an Animal Model
- 446 Downloads
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.
KeywordsDialysis Lanthanum carbonate Lanthanum deposition Stomach Histology Rat
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.
Compliance with Ethical Standards
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).
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedPubMedCentralGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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 349–372Google Scholar
- 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 CrossRefPubMedGoogle Scholar
- 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–G591Google Scholar