Sodium polystyrene sulfonate as an additional contributing factor to repeated gastric ulcers among other multiple factors in a patient undergoing hemodialysis: a case report

Abstract

Background

Sodium polystyrene sulfonate (SPS) is a cation-exchange resin used to treat hyperkalemia. Although colorectal ulcers are known side effects of long-term SPS use, few studies have reported SPS-associated gastric ulcers. Herein, we report a case of repeated gastric ulcers during SPS administration.

Case presentation

The patient was a 55-year-old man who was on SPS treatment of hyperkalemia since the initiation of hemodialysis (HD) at the age of 51 years. At the age of 54 years, he started taking vonoprazan fumarate after developing a bleeding duodenal ulcer. The patient underwent laparoscopic pylorus-preserving gastrectomy for four recurrent bleeding gastric ulcers. The resected specimen showed an ulcerative lesion in the pyloric curvature of the stomach, and pathological findings showed deposition of a basophilic crystalline substance resembling a cation-exchange resin at the base of the ulcer.

Conclusion

In this case, various factors, including diabetic gastroenteropathy, use of multiple calcium channel blockers and phosphate binders, obesity, and lifestyle, contributed to decreased gastrointestinal peristalsis. This may have promoted SPS deposition in the stomach, potentially leading to ulceration.

Background

Sodium polystyrene sulfonate (SPS) is a cation-exchange resin used to treat hyperkalemia. Colorectal ulcers are common side effects of SPS administration, and mucosal protection has been reported to decrease with its long-term oral use. Although the addition of sorbitol to SPS preparations was previously thought to be the cause of gastrointestinal problems, recent reports have suggested that SPS itself might be toxic [1]. In addition, according to a review of serious gastrointestinal adverse events associated with SPS use by Harel Z, et al., upper gastrointestinal injuries associated with SPS use occurred in 2 patients, whereas lower gastrointestinal injuries occurred in 56 patients. The colon was the most common (n = 44), followed by the small intestine (n = 12). Histopathological findings associated with SPS use were necrosis of the bowel wall (n = 36), ulcer formation (n = 28), and perforation (n = 5), with upper gastrointestinal injuries less frequently reported [2]. We report a case of recurrent gastric ulcer during SPS administration and discuss the pathogenesis of gastric ulceration.

Case presentation

The patient was a 55-year-old man who was on SPS treatment of hyperkalemia since the initiation of hemodialysis (HD) at the age of 51 years. In X-1, at the age of 54, he underwent endoscopic hemostasis for a bleeding duodenal ulcer and was started on oral vonoprazan fumarate. Upper gastrointestinal endoscopy showed that the initial ulcer has improved with endoscopic treatment and proton pump inhibitors administration. In February X, he underwent endoscopic hemostasis for an ulcer on the lesser curvature of the gastric pyloric antrum and was started on sodium alginate in addition to vonoprazan fumarate. Figure 1 shows an illustration of endoscopic hemostasis. In June X, the patient developed a second ulcer on the lesser curvature of the gastric pyloric antrum and underwent endoscopic hemostasis. In July X, endoscopic Congo red staining test revealed negative results; selective vagotomy was not indicated. Hematoxylin eosin staining of the gastric biopsy specimen collected at endoscopy showed no H. pylori-like rods; immunostaining for H. pylori showed no obvious organisms. In July and August X, a bleeding gastric ulcer recurred at the same site, for which endoscopic hemostasis was performed. He underwent laparoscopic pyloric gastrectomy and Roux-en-Y reconstruction for refractory bleeding gastric ulcers in October X.

Fig. 1

Endoscopic images during two bleeding gastric ulcers. The patient experiences multiple recurrent bleeding gastric ulcers. The left image shows an endoscopic image of a bleeding gastric ulcer in February X. The right image shows an endoscopic image of a bleeding gastric ulcer in July X

The patient’s past medical history included type 2 diabetes mellitus for 26 years, diabetic retinopathy and hypertension difficult to control with one Ca antagonist. He was regularly administered amlodipine (10 mg/day), azilsartan (40 mg/day), nifedipine CR (80 mg/day), doxazosin (2 mg/day), and isosorbide nitrate tape (40 mg/day) for hypertension. The patient was administered lanthanum carbonate (1000 mg/day), precipitated calcium carbonate (1000 mg/day), and alfacalcidol (0.5 μg/day) for chronic kidney disease (CKD)-mineral and bone disorder. Moreover, he was taking vonoprazan fumarate (20 mg/day) and 60 mL/day of sodium alginate (5%) oral solution for gastric ulcers, as well as mosapride citrate hydrate (1500 mg/day) and butyric acid bacteria for gastrointestinal symptoms such as constipation and lethargy associated with decreased gastrointestinal peristalsis. He was administered SPS dry syrup (76%, 2 packets/day) for hyperkalemia. Usually, in patients on dialysis, K levels drop if hemodialysis is performed sufficiently, and SPS is rarely used. However, in this patient's case, restricting his diet was difficult; he was on ARBs and β-blockers. In addition, he had constipation due to diabetic gastroenteropathy. Therefore, the K levels were always high and discontinuing SPS was difficult.

On admission, the clinical findings were as follows: Glasgow Coma Scale score, E4V5M6; blood pressure, 184/100 mmHg; heart rate, 79 beats/min; body temperature, 36.1 °C; oxygen saturation, 98% in ambient air; and respiratory rate, 16 breaths/min. Conjunctival anemia was not observed. The abdomen was flat and soft, without spontaneous pain or tenderness. Table 1 summarizes laboratory test results. After clipping of a bleeding gastric ulcer in February X, dynamic computed tomography of the abdomen showed a clip on the lesser curvature of the gastric antecubital region and localized edematous thickening of the wall in the same region; no obvious extravasation or free air was observed.

Table 1 Laboratory findings

After admission, he underwent laparoscopic pyloric gastrectomy and Roux-en-Y reconstruction in October X. Gross examination of the specimen revealed a 15 mm × 10 mm ulcerative lesion located 64 mm from the proximal and 44 mm from the distal margins of the gastric pylorus (Fig. 2a). Histopathological examination revealed an active ulcer extending into the submucosa at the site of the gastric ulcerative lesion (UI–II). Inflammatory exudates were observed at the base of the ulcer. Furthermore, hyperplasia of the glandular and juvenile regenerating epithelia were observed. A basophilic crystalline substance, possibly a cation-exchange resin, was observed at or near the base of the ulcer (Fig. 2b).

Fig. 2

a Gross examination of the specimen (185 mm × 150 mm). Gastric kyphosis measures 110 mm in length; duodenum measures 20 mm × 70 mm. A 15 mm × 10 mm ulcerative lesion (circle) is observed 64 mm from the proximal gastric pylorus and 44 mm from the distal gastric pylorus. b Histopathological examination of the gastric ulcerative lesion. An active ulcer extending into the submucosa is observed (UI–II). Inflammatory exudates are observed at the base of the ulcer, and hyperplasia of the glandular and juvenile regenerating epithelia are observed. A basophilic crystalline substance (yellow arrow), possibly a cation-exchange resin, is observed at or near the base of the ulcer

The patient was started on a liquid diet on postoperative day 3, which was gradually increase. He was discharged from the hospital on postoperative day 15 without recurrence of gastrointestinal bleeding, wherein, 1 month after surgery, vonoprazan fumarate was discontinued.

Discussion and Conclusion

Herein, the patient who had been taking SPS regularly developed bleeding gastric ulcers, wherein deposition of a basophilic crystal-like substance, which was thought to be a cation-exchange resin, was detected in the ulcer lesion. We discuss the cause of gastric ulcers during oral administration of cation-exchange resins, which are uncommon.

Adverse reactions to SPS, including perforation and mucosal necrosis of the small intestine, colonic ulcers, and necrosis of the colon, have been reported when it is administered orally after suspension in water or sorbitol solution; the package insert also alerts the public to such reactions [3, 4]. In general, the mechanisms of drug-induced gastrointestinal disorders are classified into direct mucosal irritation by drugs, disorders caused by pharmacological actions of drugs, or both. Mechanisms of SPS-induced gastrointestinal disorders include mechanical irritation by crystals and inflammation and fibrosis caused by reactions to foreign substances [5]. In an observational study by Laureati et al. on SPS-naive patients with CKD, SPS initiation was found to be associated with the occurrence of serious gastrointestinal adverse events (adjusted hazard ratio, 1.25; 95% confidence interval, 1.05–1.49), with ulcers and perforations being frequently observed [6]. In a previous study, Panarelli et al. reported cases of gastrointestinal perforations in which crystal-like substances were observed at the perforation site in patients taking cation-exchange resins, and the perforation sites often occurred in the sigmoid colon or rectum, where the contents tended to deposit [7].

Patients undergoing dialysis have a higher incidence of gastrointestinal symptoms and gastrointestinal ulcers than the do general population [8]. Gastric ulcers develop when there is an imbalance between offensive and defensive factors such as Helicobacter pylori involvement, stress from dialysis, hypergastrinemia [due to impaired metabolism of gastrin caused by renal failure and the large molecular weight of gastrin (approximately 700 kDa), which is not removed by dialysis], abnormal gastric acid secretion, gastric mucosal circulatory disturbance, severe uremia, secondary hyperparathyroidism, heparin use during dialysis, renal anemia, and nutritional disorders. In this case, the H. pylori IgG test indicated negative results. Moreover, hematoxylin eosin staining and immunostaining for H. pylori of the gastric biopsy specimen collected at endoscopy showed no obvious H. pylori-like rods, indicating no H. pylori involvement. The blood gastrin levels were within the normal range. Gastric acid secretion was sufficiently suppressed, as indicated by the negative Congo red staining. Nafamostat was used as an anticoagulant during dialysis because of a history of gastrointestinal bleeding. Since the Kt/V for the patient was 1.32–1.56, dialysis efficiency was good, and no uremia was observed. The patient's intact parathyroid hormone level was 241 pg/mL, which was well-controlled and within the target range.

The patient also had diabetes mellitus. Mechanisms underlying gastrointestinal neuropathy caused by diabetes mellitus are complex and multifactorial. Autonomic neuropathy can affect both afferent and efferent connections between the enteric and central nervous systems. In addition, increased apoptosis due to hyperglycemia decreases the number of enteric neurons, and decreased neuronal growth factor levels decrease the number of interstitial cells of Cajal. In addition, myopathological changes and reduced contractility of smooth muscles due to impaired signaling pathways have also been observed. Taken together, patients with diabetes are considered to have gastrointestinal motility disorders owing to the multiple factors mentioned above.

Another possible cause of gastrointestinal motility disturbance is the use of calcium channel blockers. Calcium ions are known to be involved in smooth muscle contraction, and the process of excitation at the muscle cell membrane requires the influx of calcium ions from outside the cell into the cell. A previous study using isolated human lower esophageal sphincter (LES) demonstrated that calcium ion influx through L-type calcium ion channels plays an important role in maintaining LES tension. [9] Furthermore, an epidemiological study conducted in community pharmacies in Japan and Australia, in which the first prescription of anti-reflux medication or recall of reflux symptoms by the patient was considered an outcome, suggested a risk of worsening gastrointestinal disease after calcium ion channel blockade in older patients with cardiovascular disease. [10, 11]

In summary, the patient had decreased gastrointestinal motility owing to obesity, diabetic gastrointestinal disease, and the use of phosphorus adsorbent medication and two calcium channel blockers. SPS crystals deposited in the stomach owing to its regular use resulted in a state of decreased gastrointestinal motility, causing mechanical stimulation of the gastric mucosa and leading to inflammation and fibrosis due to the reaction to the foreign substance, which was considered to have caused repeated gastric ulcers.

Our patient on HD who had been taking SPS regularly for 4 years developed multiple recurrent gastric ulcers. Deposition of a basophilic crystalline substance, possibly an ion exchange resin, was observed in the ulcer lesion. We considered that various factors caused SPS deposition in the stomach and the crystalline substance continued to irritate the gastric mucosa, which contributed to the development of bleeding gastric ulcers. However, the relationship between SPS deposition and ulcer formation is unclear, and the possibility that SPS was deposited after ulcer formation cannot be completely ruled out. The mechanism by which SPS promotes ulcer formation is still unclear and requires further research. In conclusion, when SPS is continuously used in patients undergoing HD, attention should be paid not only to colorectal ulcers but also to gastric ulcers.