Colitis Associated With Sevelamer Carbonate: A Case Report

Background

Drug-induced injury of the gastrointestinal (GI) tract is increasingly common but generally under-recognized (1). Nonabsorbable drugs exert their effect in the GI tract by binding a target molecule and forming an insoluble complex preventing absorption (2). Crystal deposition by ion-exchange resins (cholestyramine, sevelamer, and sodium polystyrene sulfonate) may result in mucosal damage. GI mucosal injury has been reported in the literature with sodium polystyrene sulfate and cholestyramine; however, there are few reports of sevelamer-associated GI mucosal injury. Sevelamer is an extensively used noncalcium-based phosphate binding agent used to lower serum phosphate levels in chronic kidney disease (CKD) and end-stage renal disease (ESRD) (3). Apart from lowering phosphate, it is also thought to have pleiotropic effects ranging from improvement in cholesterol levels to reduction of proinflammatory mediators and uremic toxins like p-cresol (4). It has a carbon polymer backbone and a nonabsorbable polymeric amine. The amine group of sevelamer becomes protonated in the intestines and binds to the dietary phosphate, preventing the absorption of phosphate. It is fairly well tolerated, with relatively milder GI side effects such as nausea, vomiting, constipation, flatulence, and diarrhea (3). There are, however, cases reports of GI mucosal injury secondary to sevelamer use.

Objective

We present a case of sevelamer-associated colitis to promote timely recognition and prevention of catastrophic complications.

Report

A 77-year-old woman with ESRD presented to the emergency department with shortness of breath, fatigue, and weakness for a few days. She did not report fever, chills, abdominal pain, or blood per rectum. Her medical history included congestive heart failure with preserved ejection fraction (60%–65%), hypertension, coronary artery disease, atrial fibrillation, peripheral vascular disease, type II diabetes mellitus, and ischemic colitis status post-stenting of celiac and superior mesenteric artery (SMA). Her medication list included aspirin, amlodipine, lisinopril, apixaban (5 mg, 2 times a day), gabapentin, amiodarone, isosorbide mononitrate, hydralazine, rosuvastatin, clopidogrel, insulin, and sevelamer (800 mg, 3 times a day with meals). Upon arrival to the emergency department, her vitals were stable with blood pressure of 157/75 mm Hg, pulse rate of 65 beats/min, and oxygen saturation of 95% on room air. Findings of the physical examination were unremarkable, with soft, nontender abdomen with no guarding or rigidity. Laboratory studies showed microcytic anemia with hemoglobin of 4.7 mmol/L (reference value 7.4–9.9 mmol/L). Upon review of her outpatient dialysis laboratory data, her hemoglobin had been trending down for few weeks before this presentation. Radiograph of the chest showed mild pulmonary vascular congestion. A fecal occult blood test was positive. She was admitted for further work-up of anemia and shortness of breath.

She received 6 units of packed red blood cells. Computed tomography angiogram of abdomen and pelvis was done to evaluate celiac/SMA stents, the findings of which were normal. She had esophagogastroduodenoscopy, which showed mild gastropathy. Colonoscopy revealed ulcers in the cecum and ileocecal valve, diverticulosis in the sigmoid colon, and small internal hemorrhoids (Figure 1). Cecal ulcer biopsy showed active colitis with ulceration and granulation tissue (Figure 2). Within ulcer slough, scattered irregularly shaped crystalline material with characteristic curvilinear cracking and yellow/pink bicolouration was noted, characteristic of sevelamer (Figure 3). The likely cause for enterocolitis was thought to be sevelamer. Sevelamer was immediately discontinued. Her hemoglobin was stable at 6.5 mmol/L (reference value 7.4–9.9 mmol/L) at the time of discharge.

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Discussion

Mineral bone disease is a prominent feature in CKD and is characterized by laboratory abnormalities in serum calcium, phosphate, and parathyroid hormone (5). Multiple studies have associated elevated serum phosphate levels with a more rapid decline in glomerular filtration rate, progression to end-stage kidney disease, and overall mortality (6–8). Sevelamer carbonate, a noncalcium-based phosphate binder, is an anion-exchange, nonabsorbable resin that has been widely used to treat hyperphosphatemia in patients with chronic kidney disease since it was first approved in 2000 (3). Although considered a generally well-tolerated therapy, some of its most common adverse effects involve the GI tract, including nausea, vomiting, constipation, and abdominal pain (9, 10). Although mucosal injury caused by ion-exchange resins such as polystyrene sulfate and cholestyramine has been described extensively, there is relatively few reports of sevelamer-associated GI injury (3).

In 2008, Madan et al. (11) first reported a case of lower GI bleed due to stercoral ulceration associated with sevelamer-induced constipation; however, they did not report any crystal deposition found on histopathology. Swanson et al. (12) later published a prospective study in which they first described the appearance of sevelamer crystals in the GI tract. They collected 15 specimens from 7 patients, of whom were all taking sevelamer. The samples were processed with periodic acid–Schiff–Alcian blue special staining with diastase. In addition, they crushed sevelamer tablets and put them through similar processing as the tissue samples. Sevelamer crystals were observed in all 15 specimens, with associated mucosal findings including chronic mucosal injury, acute inflammation, inflammatory polyps, ischemic injury, necrosis, and ulceration. The crystals found in the tissue samples were described as broad, curved, and irregularly spaced fish scales that appeared violet on hematoxylin–eosin stain and magenta on periodic acid–Schiff–Alcian blue special staining with diastase. The crushed sevelamer tablets had routine histologic examination revealing matching crystal morphology as those observed in the tissue samples (12). The mechanism through which sevelamer and other ion-exchange resins produce intestinal injury is not fully understood. It has been hypothesized that crystals produced by these resins trigger cell necrosis in intestinal epithelial cells and produce neutrophil necrosis and release of neutrophil extracellular traps, which produces intestinal barrier dysfunction and further necrosis. Kim et al. (13) performed an in-depth study of a patient with colon perforation following initiation and dose increase of sevelamer. Histologic examination of the colon biopsy confirmed broad, curved, and irregularly spaced “fish scales” crystals of different sizes. Through immunofluorescence and light microscopy, the authors were able to identify abundant neutrophil extracellular trap formation in proximity to small sevelamer crystals. The presence of sevelamer crystals on the damaged intestinal epithelium doesn't prove the causality, as it is important to consider and exclude other causes of mucosal injury. The aforementioned patient had a previous history of ischemic bowel disease, which makes the association with crystal deposition more challenging. Ischemic colitis, however, was considered less likely in her case, given her adherence to anticoagulation (apixaban, 5 mg 2 times a day) and patency of SMA and celiac stents on abdominal and pelvic computed tomography angiogram.

With an increase in polypharmacy and increased endoscopic evaluations of GI tract, identification of colorful medications including sevelamer in the tubular GI tract will only more frequently encountered. It is possible that sevelamer crystal–induced mucosal injury is under-recognized due to the relative rarity of severity, prompting further evaluation, nonspecific colonoscopic findings with subtle or absent histopathologic features, and failure to consistently identify sevelamer crystals in biopsied specimens (10). Sevelamer crystals and associated injury can be diagnosed on hematoxylin–eosin stain with awareness of the diagnostic pearls and pitfalls as discussed in this report. A table summarizing reported cases of GI mucosal injury associated with Sevelamer is included in this manuscript (Table 1).

It is important for clinicians caring for patients with CKD and ESRD to recognize the potential association of sevelamer with significant GI mucosal injury. High index of suspicion and timely recognition of this phenomenon and early discontinuation of sevelamer can prevent catastrophic complications of mucosal injury, including but not limited to acute blood loss, colonic ulcerations, and perforations.