Background
The number of dialysis patients in Japan reached 329,609 in 2016 [
1]. For dialysis patients, hyperphosphatemia is one of the critical complications because it significantly increases cardiovascular disease and mortality. To control the blood concentration of phosphoric acid, several types of oral phosphate binders have been developed, including lanthanum carbonate (LaC) (Fosrenol®; Shire Pharmaceuticals, Hampshire, UK), which has been authorized by the Ministry of Health, Labor and Welfare in Japan. LaC is the first non-calcium, non-resin phosphate binder for hyperphosphatasemia in patients with chronic kidney disease on hemodialysis. The use of LaC has increased in Japan since its launch in 2009 as it has fewer side effects than conventional medicines. Recently, it was reported that there are specific endoscopic findings caused by deposition of lanthanum (La) in the gastric mucosa of patients taking LaC [
2].
We previously reported that the daily dose and total dose of LaC were significantly correlated with La deposition in the gastroduodenal mucosa [
3]. However, it is still unknown why these phenomena appear in LaC users and what subsequent difficulties, if any, appear in patients with La deposition in the gastrointestinal mucosa. Although it was shown that patients on hemodialysis with anemia are at a high risk of small intestinal lesions in our previous study [
4], the relationships between La deposition and other factors were not investigated.
Murakami et al. investigated seven cases with the specific endoscopic features of La deposition in the gastric mucosa and described the whitish lesions as follows: an annular whitish mucosa, diffuse whitish mucosa, and whitish spots in the gastric mucosa [
5]. Although the endoscopic biopsy specimens from the above endoscopic features revealed La deposition histologically, it was uncertain whether these whitish lesions were pathologically consistent with La deposition.
We therefore conducted the two following clinical retrospective investigations: (1) comparative analysis of the clinical features of LaC users with and without La deposition in endoscopic biopsy specimens from gastric mucosa and (2) histological identification of the cause of the whitish lesions using biopsy specimens with La deposition by comparing the histological features of the endoscopic findings.
Discussion
To the best of our knowledge, this retrospective study is the first to investigate the clinical significance of La deposition in the gastric mucosa (as in Study 1), and the association between endoscopic features and histologic findings (as in Study 2).
In Study 1, the most important finding was that there was no significant difference between patients with and without La deposition in the gastric mucosa in terms of blood test findings. In addition, there was no significant difference between the patients taking LaC and those not taking LaC. The reason why the dialysis period is long in the LaC-taking patients was that patients who were on dialysis for longer periods were more likely to develop hyperphosphatemia and be required to take LaC. These results show that gastric La deposition may not cause clinical problems and LaC might be a safe treatment for hyperphosphatasemia in patients with chronic kidney disease on hemodialysis even if La deposits occur in the gastric mucosa. It was revealed that the total dose of LaC was significantly correlated with La deposition in the gastric mucosa. Although our result was similar to our previous report, this study differs in that the daily dose of LaC was not related to La deposition [
3]. We had predicted that the daily dose might not significantly affect La deposition when the period of LaC administration was longer. In addition, concomitant drugs (PPIs, H2RAs, NSAIDs, and gastric mucoprotective drugs) did not affect the deposition of La in the gastric mucosa. Although Shitomi et al. reported that the histological finding of
Helicobacter pylori infection might decrease the deposition of La [
5], Ban et al. reported that the lesions associated with
Helicobacter pylori infection, such as intestinal metaplasia, regenerative changes, and foveolar hyperplasia, were more frequently observed in mucosa with large quantities of La deposits [
6,
7]. Given that our present study also showed that the range of atrophic changes in the gastric mucosa was not associated with La deposition,
Helicobacter pylori infection may not be associated with the deposition of La in the gastric mucosa.
Study 2 revealed that the gastric endoscopic findings of La deposition reflected the infiltrated histiocytes, not the La deposition itself. The appearance of histiocytes must depend on the amount of La deposition, which acts as foreign matter to which histiocytes react. We suggest that the whitish lesions of La deposition reflect the existence of macrophages, similar to gastric xanthoma. La deposition was also detected from non-whitish normal mucosa. In summary, the specific features of La deposition reflect the body’s normal reaction to foreign bodies. However, the reason the histiocytic infiltration was divided clearly into two groups (less than 30% and more than 80%) is uncertain.
Although gastric La deposition may not cause clinical problems and LaC might be safe for hyperphosphatasemia in patients with chronic kidney disease on hemodialysis, it has been reported that several side effects of gastrointestinal symptoms have been associated with LaC, such as nausea, vomiting, and constipation [
9]. These symptoms might be caused by gastrointestinal motility dysfunction. As it has been reported that functional dyspepsia is caused, in part, by
Helicobacter pylori infection [
10], the gastrointestinal symptoms in hemodialysis patients taking LaC might be caused by La deposition even if there is no organic lesion. Although it has been reported in a pharmacological safety study of LaC that it has no significant effects on gastric emptying and intestinal transit time at high doses [
11,
12], an association between La deposition in the gastric mucosa has been loosely associated with gastric peristalsis. Because the present study did not investigate the relationship between the gastrointestinal symptoms and motility function, we should plan the next study to investigate gastric motility function in hemodialysis patients undergoing LaC treatment.
The present study had some limitations. First, the sample size was small, as this was a single-center retrospective study. In addition, there was some missing blood test data. Second, there may have been patients with gastric La deposition in the La-negative group in Study 1 because Study 2 revealed that La deposition was sometimes detected on biopsy specimens from normal gastric mucosa. Third, although La is often deposited at the duodenal mucosa [
8], we did not evaluate duodenal La deposition in the present study because of the low number of subjects or biopsy specimens. There might be a relationship between duodenal La deposition and some background factors. Fourth, in the histological assessment of histiocytic infiltration used in Study 2, it was difficult to remove the subjectivity of the pathologists.
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