Colitis Associated With Sevelamer Carbonate: A Case Report
Sevelamer carbonate is an anion-exchange, nonabsorbable resin that is commonly used to treat hyperphosphatemia in patients with advanced chronic kidney disease and end-stage renal disease. It is generally well-tolerated with only mild gastrointestinal symptoms such as abdominal pain, nausea, vomiting, and constipation. There have been few case reports of gastrointestinal mucosal injury resulting from sevelamer crystal deposition. The severity of presentation varies from acute inflammation to polyp formation, necrosis, ulceration, and intestinal perforation. We report a 77-year-old woman with end-stage renal disease who was found to have mucosal injury from sevelamer crystal deposition resulting in colitis and ulceration.
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.
We present a case of sevelamer-associated colitis to promote timely recognition and prevention of catastrophic complications.
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.
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).
|Christina Tieu et al. (14)||A 74-year-old woman with ESRD presented with abdominal pain, rectal pain, and blood-tinged stool. Sevelamer was associated with rectosigmoid ulcers that led to her symptoms.|
|T Lai et al. (10)||A 47-year-old man with ESRD presented with recurrent abdomen pain with nausea and was found to have multiple circumferential lesions on the colon. Pathologic review of histology demonstrated ragged colonic mucosa with ulcerative debris and nonpolarizing crystalline material at the sites of ulceration, morphologically consistent with the phosphate binder, sevelamer carbonate.|
|Preethi Chintamaneni et al. (2)||A 61-year-old woman with ESRD with hematochezia. Work-up revealed a large ulceration in the sigmoid colon, and histologic images revealed sevelamer crystals embedded in the colonic mucosa, consistent with sevelamer crystal-mediated injury.|
|KC Keri et al. (3)||A 35-year-old patient with ESRD and HIV with lower GI bleed. Imaging showed ischemic gangrene of bowel wall. Histopathology was consistent with transmural ischemic necrosis with deposition of fibrin thrombi and sevelamer crystals.|
|Meeta Desai et al. (15)||A 45-year-old woman with intermittent abdominal cramping and rectal bleeding. Histology was most consistent with acute inflammation and ulceration associated with crystal fragments|
|Jin Hee Lee et al. (16)||A 29-year old man with ESRD due to IgA nephropathy presented with a low-grade fever and watery diarrhea tinged with blood. CT of the abdomen showed an occlusive mass in the rectum. Sigmoidoscopy with a biopsy showed the mass as a lump of mucous material with the entire lumen covered with exudate. The subsequent histopathology examination revealed a colonic mucosal injury and characteristic “fish scale”-like sevelamer crystals in the exudate|
|Tessa S. Schoot et al. (17)||A 67-year-old woman with lower GI bleeding after starting sevelamer. Sigmoidoscopy revealed multiple deep ulcers and mucosal edema. Histologic examination showed deposition of Sevelamer crystals in these rectal ulcers.|
|Sudheer Nambiar et al. (18)||A 56-year-old woman with ESRD on sevelamer presented with GI bleed. She had a right hemicolectomy found to have sevelamer-induced mucosal ulceration and crystal deposition in the colonic mucosa.|
|Pearl Princess Uy et al. (19)||A 33-year-old man with ESRD on sevelamer carbonate presented with hematochezia and was found to have rectosigmoid ulcers induced by sevelamer crystals. His hematochezia resolved after switching from sevelamer carbonate to lanthanum carbonate.|
|Pankaj Madan et al. (11)||A 62-year-old woman with ESRD with bleeding per rectum. Colonoscopy revealed stercoral ulcers in rectum and histologic examination of the ulcer showed denuded mucosa with acute and chronic inflammation.|
|Claudia Yuste et al. (20)||Three cases of lower GI bleed in patients with ESRD:|
Case 1: a 51-year-old woman with weakness and intermittent painful hematochezia. Endoscopic evaluation revealed a large ulcer in the ileocecal valve. Histologic evaluation of the ulcer consisted of focal erosion with bacterial material mixed with sevelamer crystals.
Case 2: a 53-year-old man with painless rectal bleeding. Sevelamer crystals seen in the ileocecal biopsy.
Case 3: a 76-year-old woman investigated for intermittent lower GI bleed. Endoscopic examination revealed chronic gastritis, diverticulosis, and several gastric and colonic polyps. Superficial erosions were found that were initially attributed to NSAIDs. However, her symptoms persisted after the discontinuation of NSAIDs until she received renal transplant that clearly coincided with sevelamer discontinuation. Histologic material was reexamined and superficial sevelamer crystals were found surrounded by mucous and detritus.
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.
Parfitt JR, Driman DK. Pathological effects of drugs on the gastrointestinal tract: a review. Hum Pathol. 2007;38:527-36. [PMID: 17367604] doi:10.1016/j.humpath.2007.01.014 CrossrefMedlineGoogle Scholar
Chintamaneni P, Das R, Kuan S-F, et al. Hematochezia associated with sevalamer-induced mucosal injury. ACG Case Rep J. 2014;1:145-7. [PMID: 26157856] doi:10.14309/crj.2014.32 CrossrefMedlineGoogle Scholar
Keri KC, Veitla V, Samji NS. Ischemic colitis in association with sevelamer crystals. Indian J Nephrol. 2019;29:191-3. [PMID: 31142966] doi:10.4103/ijn.IJN_80_18 CrossrefMedlineGoogle Scholar
Nikolov IG, Joki N, Maizel J, et al. Pleiotropic effects of the non calcium phosphate binder sevelamer. Kidney Int Suppl. 2006;70:S16-23. [PMID: 17136111] doi:10.1038/sj.ki.5001994 CrossrefMedlineGoogle Scholar
Patel L, Bernard LM, Elder GJ. Sevelamer versus calcium-based binders for treatment of hyperphosphatemia in CKD: a meta-analysis of randomized controlled trials. Clin J Am Soc Nephrol. 2016;11:232-44. [PMID: 26668024] doi:10.2215/CJN.06800615 CrossrefMedlineGoogle Scholar
Norris KC, Greene T, Kopple J, et al. Baseline predictors of renal disease progression in the African American study of hypertension and kidney disease. J Am Soc Nephrol. 2006;17:2928-36. [PMID: 16959828] doi:10.1681/ASN.2005101101 CrossrefMedlineGoogle Scholar
Schwarz S, Trivedi BK, Kalantar-Zadeh K, et al. Association of disorders in mineral metabolism with progression of chronic kidney disease. Clin J Am Soc Nephrol. 2006;1:825-31. [PMID: 17699293] doi:10.2215/CJN.02101205 CrossrefMedlineGoogle Scholar
Voormolen N, Noordzij M, Grootendors DC, et al. High plasma phosphate as a risk factor for decline in renal function and mortality in predialysis patients. Nephrol Dial Transplant. 2007;22:2909-16. [PMID: 17517792] doi:10.1093/ndt/gfm286 CrossrefMedlineGoogle Scholar
Ketteler M, Rix M, Fan S, et al. Efficacy and tolerability of sevelamer carbonate in hyperphosphatemic patients who have chronic kidney disease and are not on dialysis. Clin J Am Soc Nephrol. 2008;3:1125-30. [PMID: 18450923] doi:10.2215/CJN.05161107 CrossrefMedlineGoogle Scholar
Lai T, Frugoli A, Barrows B, et al. Sevelamer carbonate crystal-induced colitis. Case Rep Gastrointest Med. 2020;2020:4646732. MedlineGoogle Scholar
Madan P, Bhayana S, Chandra P, et al. Lower gastrointestinal bleeding: association with Sevelamer use. World J Gastroenterol. 2008;14:2615-6. [PMID: 18442219] doi:10.3748/wjg.14.2615 CrossrefMedlineGoogle Scholar
Swanson BJ, Limketkai BN, Liu TC, et al. Sevelamer crystals in the gastrointestinal tract (GIT): a new entity associated with mucosal injury. Am J Surg Pathol. 2013;37:1686-93. [PMID: 24061514] doi:10.1097/PAS.0b013e3182999d8d CrossrefMedlineGoogle Scholar
Kim T, de Oliveira Silva Lautenschlager S, Qiuyue M, et al. Drug crystal-related gastrointestinal complications involve crystal-induced release of neutrophil and monocyte extracellular traps. Cells. 2020;9:2481. [PMID: 33203124] doi:10.3390/cells9112481 CrossrefMedlineGoogle Scholar
Tieu C, Moreira RK, Song LMWK, et al. A case report of sevelamer-associated recto-sigmoid ulcers. BMC Gastroenterol. 2016;16:20. [PMID: 26911806] doi:10.1186/s12876-016-0441-4 CrossrefMedlineGoogle Scholar
Desai M, Reiprich A, Khov N, et al. Crystal-associated colitis with ulceration leading to hematochezia and abdominal pain. Case Rep Gastroenterol. 2016;10:332-7. [PMID: 27482192] doi:10.1159/000446575 CrossrefMedlineGoogle Scholar
Lee JH, Park SH, Shin JH, et al. [Colonic mass secondary to sevelamer-associated rectal ulcer]. Korean J Gastroenterol. 2021;77:305-8. [PMID: 34158451] doi:10.4166/kjg.2021.037 CrossrefMedlineGoogle Scholar
Schoot TS, Römkens TE, Hoogeveen EK. Lower gastrointestinal bleeding in a patient receiving sevelamer: Case report. SAGE Open Med Case Rep. 2021;9:2050313X211000488. [PMID: 33796314] doi:10.1177/2050313X211000488 CrossrefMedlineGoogle Scholar
Nambiar S, Pillai UK, Devasahayam J, et al. Colonic mucosal ulceration and gastrointestinal bleeding associated with sevelamer crystal deposition in a patient with end stage renal disease. Case Rep Nephrol. 2018;2018:4708068. [PMID: 29682371] doi:10.1155/2018/4708068 CrossrefMedlineGoogle Scholar
Uy PP, Vinsard DG, Hafeez S. Sevelamer-associated rectosigmoid ulcers in an end-stage renal disease patient. ACG Case Rep J. 2018;5:e83. [PMID: 30568971] doi:10.14309/crj.2018.83 CrossrefMedlineGoogle Scholar
Yuste C, Mérida E, Hernández E, et al. Gastrointestinal complications induced by sevelamer crystals. Clin Kidney J. 2017;10:539-44. [PMID: 28852493] doi:10.1093/ckj/sfx013 CrossrefMedlineGoogle Scholar
Author, Article, and Disclosure Information
1Blue Ridge Nephrology Associates, Christiansburg, Virginia
2Dominion Pathology Associates, Roanoke, Virginia
3Michigan State University, Lansing, Michigan
4Sparrow Medical Group Nephrology, Lansing, Michigan
Prajwol Pant, MD; Blue Ridge Nephrology Associates, 2900 Lamb Circle, Suite 190, Christiansburg, VA 24073; e-mail, [email protected].