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Bathobakae L, Phuu P, Yasin S, Bashir R, Escobar J, Yuridullah R, Melki G, Elagami M, Amer K, Cavanagh Y, Baddoura W. Sevelamer-induced Gastrointestinal Mucosal Injury: A Critical Review for Clinicians. J Community Hosp Intern Med Perspect 2024; 14:58-65. [PMID: 39839182 PMCID: PMC11745178 DOI: 10.55729/2000-9666.1424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 09/12/2024] [Accepted: 09/20/2024] [Indexed: 01/23/2025] Open
Abstract
Sevelamer is a non-absorbable polymer used to treat hyperphosphatemia in individuals with end-stage renal disease (ESRD) undergoing hemodialysis. The deposition of sevelamer crystals in the gastrointestinal (GI) tract, especially in the colon, can cause mucosal inflammation, pseudopolyps, ulceration, ischemia, or necrosis. Owing to its rarity and lack of physician awareness, the actual incidence and prevalence of sevelamer-induced gastrointestinal mucosal injury (SIGMI) remain unknown. The current evidence is retrospective, in the form of observational studies. This systematic review of case reports provides an overview of SIGMI, with a focus on its etiology, signs and symptoms, pathogenesis, diagnosis, and management. Electronic databases, including PubMed, Embase, and Google Scholar, were searched for published case reports, case series, and abstracts from inception to August 2023. The search yielded 1239 articles that were filtered using the study design, English language, and human subjects. After screening for duplicates and irrelevant articles, only 28 articles were included in the final review. Melena and abdominal pain were the most common complaints. Sevelamer was discontinued in all patients, and 27 (75%) experienced clinical improvement or symptom resolution. Eight patients (22%) required colectomy due to colonic perforation, malignant obstruction, or extensive necrosis. SIGMI is a unique complication of sevelamer use in patients undergoing hemodialysis. Prompt diagnosis and management are crucial to prevent life-threatening complications.
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Affiliation(s)
- Lefika Bathobakae
- Internal Medicine, St. Joseph’s University Medical Center, Paterson,
USA
| | - Phenyo Phuu
- St. George’s University School of Medicine,
Grenada
| | - Saif Yasin
- St. George’s University School of Medicine,
Grenada
| | - Rammy Bashir
- St. George’s University School of Medicine,
Grenada
| | - Jessica Escobar
- Health Sciences Library, St. Joseph’s University Medical Center, Paterson,
USA
| | - Ruhin Yuridullah
- Gastroenterology & Hepatology, St. Joseph’s University Medical Center, Paterson,
USA
| | - Gabriel Melki
- Gastroenterology & Hepatology, St. Joseph’s University Medical Center, Paterson,
USA
| | - Mohamed Elagami
- Gastroenterology & Hepatology, St. Joseph’s University Medical Center, Paterson,
USA
| | - Kamal Amer
- Gastroenterology & Hepatology, St. Joseph’s University Medical Center, Paterson,
USA
| | - Yana Cavanagh
- Gastroenterology & Hepatology, St. Joseph’s University Medical Center, Paterson,
USA
- Advanced & Surgical Endoscopy, St. Joseph’s University Medical Center, Paterson,
USA
| | - Walid Baddoura
- Gastroenterology & Hepatology, St. Joseph’s University Medical Center, Paterson,
USA
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Ma Q, Steiger S. Neutrophils and extracellular traps in crystal-associated diseases. Trends Mol Med 2024; 30:809-823. [PMID: 38853086 DOI: 10.1016/j.molmed.2024.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 05/16/2024] [Accepted: 05/21/2024] [Indexed: 06/11/2024]
Abstract
Crystalline material can cause a multitude of acute and chronic inflammatory diseases, such as gouty arthritis, silicosis, kidney disease, and atherosclerosis. Crystals of various types are thought to cause similar inflammatory responses, including the release of proinflammatory mediators and formation of neutrophil extracellular traps (NETs), processes that further promote necroinflammation and tissue damage. It has become apparent that the intensity of inflammation and the related mechanisms of NET formation and neutrophil death in crystal-associated diseases can vary depending on the crystal type, amount, and site of deposition. This review details new mechanistic insights into crystal biology, highlights the differential effects of various crystals on neutrophils and extracellular trap (ET) formation, and discusses treatment strategies and potential future approaches for crystal-associated disorders.
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Affiliation(s)
- Qiuyue Ma
- Key Laboratory of Microsystems and Microstructures Manufacturing (Ministry of Education), School of Medicine and Health, Harbin Institute of Technology, Harbin, China; Zhengzhou Research Institute, Harbin Institute of Technology, Zhengzhou, China
| | - Stefanie Steiger
- Renal Division, Department of Medicine IV, Ludwig-Maximilians-University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
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Di Rienzo G, Crafa P, Delsante M, Fiaccadori E, Pedrazzi G, Campanini N, Corradini E. Histopathological lesions of the gastrointestinal tract associated with the use of polystyrene sulfonate and sevelamer: a meta-analysis. Pathologica 2024; 116:216-221. [PMID: 39377503 PMCID: PMC11460155 DOI: 10.32074/1591-951x-994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 05/27/2024] [Indexed: 10/09/2024] Open
Abstract
Background Gastrointestinal severe adverse events such as ulceration and perforation have been reported for sodium or calcium polystyrene sulfonate and sevelamer. Howewer, their role in the pathogenesis is unclear. Chronic kidney disease is a well known risk factor, while the role of hypertension and/or diabetes is uncertain. Methods A meta-analysis of the published literature was conducted to review the clinical features, risk factors and histopathological findings of patients who experienced gastrointestinal adverse events after administration of polystyrene sulfonate or sevelamer. Results The meta-analysis indicated that patients were more likely to show necrosis and/or perforation when the resin used was polystyrene sulfonate compared to sevelamer (p < 0.001). Death was more likely in patients taking polystyrene sulfonate compared to sevelamer (p < 0.001). Discussion The results show that sevelamer is more likely to lead to inflammation or ulceration in the gastrointestinal tract than polystyrene sulfonate, which is more likely to be associated with severe gastrointestinal adverse events such as necrosis and/or perforation. Polystyrene sulfonate is significantly associated with death compared to sevelamer.
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Affiliation(s)
- Gianluca Di Rienzo
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Anatomic Pathology Unit, University Hospital of Parma, Parma, Italy
| | - Pellegrino Crafa
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Anatomic Pathology Unit, University Hospital of Parma, Parma, Italy
| | - Marco Delsante
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Enrico Fiaccadori
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - Giuseppe Pedrazzi
- Department of Neuroscience, Biophysics and Medical Physics Unit, University of Parma, Parma, Italy
| | - Nicoletta Campanini
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Anatomic Pathology Unit, University Hospital of Parma, Parma, Italy
| | - Emilia Corradini
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Anatomic Pathology Unit, University Hospital of Parma, Parma, Italy
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Darnell H, Brenner A, Kern C, Flomenhoft D, Lee E. Sevelamer-Induced Ischemic Enteritis. ACG Case Rep J 2024; 11:e01451. [PMID: 39021715 PMCID: PMC11254113 DOI: 10.14309/crj.0000000000001451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 06/24/2024] [Indexed: 07/20/2024] Open
Abstract
Sevelamer, a nonabsorbable dietary phosphate binder, is essential for patients with renal impairment since hyperphosphatemia is associated with an increase in all-cause mortality. Sevelamer is generally well tolerated; however, it is rarely been documented to cause gastrointestinal mucosal injury by forming sevelamer crystals and depositing within the gastrointestinal walls. We present a 35-year-old man with end-stage renal disease on peritoneal dialysis who developed abdominal pain and hematochezia. Initial imaging and endoscopic examination were concerning for ischemic enteritis, and histopathology revealed crystalloid structures surrounded by necrosis consistent with sevelamer-induced ischemic enteritis.
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Affiliation(s)
- Hannah Darnell
- Department of Internal Medicine, University of Kentucky, Lexington, KY
| | - Aaron Brenner
- Department of Digestive Diseases and Nutrition, University of Kentucky, Lexington, KY
| | - Cody Kern
- Department of Digestive Diseases and Nutrition, University of Kentucky, Lexington, KY
| | | | - Eun Lee
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY
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Le D, Crews DC, Grams ME, Coresh J, Shin JI. Association of Sevelamer Initiation with Gastrointestinal Bleeding Hospitalization in Individuals Requiring Hemodialysis. Am J Nephrol 2024; 55:450-462. [PMID: 38555633 PMCID: PMC11614033 DOI: 10.1159/000538253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 03/05/2024] [Indexed: 04/02/2024]
Abstract
INTRODUCTION Case reports have suggested a causative role between sevelamer use and subsequent gastrointestinal bleeding (GIB), but no large observational studies have evaluated this association. METHODS Using the United States Renal Data System database from 2015 to 2019, we examined the association between initiation of sevelamer (vs. non-sevelamer containing phosphate binders) and GIB hospitalization as well as all-cause mortality among individuals on hemodialysis. We emulated a target trial using Cox regression models and inverse probability of treatment weights to estimate the adjusted hazard ratios (HR) across outcomes and subgroups. RESULTS Among 21,354 new users of phosphate binders (11,276 sevelamer and 10,078 non-sevelamer) with baseline lab data (calcium, phosphorus, hemoglobin, and albumin), there were 2,811 GIB hospitalizations and 5,920 deaths after a median follow-up of 1.3 years. Compared with the initiation of non-sevelamer binders, sevelamer was not associated with an increased risk of GIB hospitalization (89 vs. 90 events per 1,000 person-years; IPTW-HR: 0.98, 95% CI: 0.91-1.06) or all-cause mortality (220 vs. 224 events per 1,000 person-years; IPTW-HR: 0.98, 95% CI: 0.93-1.03). Subgroup analyses (such as diabetes and anti-coagulation use) were generally consistent, and there was no association between sevelamer dose and GIB hospitalization. CONCLUSION Among patients requiring hemodialysis, sevelamer (vs. non-sevelamer) containing phosphate binders was not associated with increased risk of GIB hospitalization.
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Affiliation(s)
- Dustin Le
- Division of Nephrology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Deidra C. Crews
- Division of Nephrology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Morgan E. Grams
- Division of Precision Medicine, Department of Medicine, New York University, New York, NY
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Jung-Im Shin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
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Carlesimo M, Varron L, Thierry S. [An unusual ischemic colitis with crystals]. Ann Pathol 2024; 44:142-145. [PMID: 37635019 DOI: 10.1016/j.annpat.2023.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 08/03/2023] [Indexed: 08/29/2023]
Affiliation(s)
- Marie Carlesimo
- Institut multisite de pathologie des hospices civils de Lyon, groupement hospitalier Est, 59, boulevard Pinel, 69677 Bron Cedex, France.
| | - Loïg Varron
- Service de médecine interne, groupement hospitalier des portes de Provence, Quartier Beausseret, route de Sauze, 26200 Montelimar, France
| | - Sixte Thierry
- Service d'anatomie et cytologie pathologiques du centre hospitalier de Valence, 179, boulevard du Maréchal-Juin, 26000 Valence, France
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Shakeri H, Panarelli NC. Patterns of gastrointestinal injury in patients with chronic kidney disease: Comparison of cases with and without sevelamer crystals. Histopathology 2024; 84:624-632. [PMID: 38044854 DOI: 10.1111/his.15104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 11/02/2023] [Accepted: 11/12/2023] [Indexed: 12/05/2023]
Abstract
AIMS Sevelamer is a phosphate-binding resin implicated in gastrointestinal (GI) injury. This study aimed to investigate the role of sevelamer in GI injury among chronic kidney disease (CKD) patients. METHODS AND RESULTS The study included 17 CKD patients (cases) with and 18 CKD patients (comparisons) without sevelamer crystals in specimens. All cases were on sevelamer. Six comparison patients were also taking sevelamer, but crystals were absent in tissue sections. The comparison group was thus subclassified into patients who were and were not taking sevelamer. The frequency of underlying disorders was similar between two groups, including hypertension (cases = 82%; comparisons = 78%) and diabetes mellitus (cases = 53%, comparisons = 50%). The most common presentation was GI bleeding (cases = 41%, comparisons = 33%). Predominant histological patterns were also similar, with ulcers (cases = 42%; comparisons = 39%) and acute ischaemia (cases = 35%; comparisons = 28%) being predominant in both cohorts. Of note, sevelamer was present with amyloidosis and cytomegalovirus in one study case each. Two study patients who continued sevelamer had follow-up biopsies; one showed persistent ulceration and the other appeared normal. Crystals were absent in both. CONCLUSIONS GI injury in CKD patients in both groups had similar features regardless of presence of sevelamer, suggesting that it adheres to tissue rather than causes injury. The study highlights other histologically identifiable causes of intestinal injury, as well as injuries unassociated with sevelamer in patients undergoing therapy. Therefore, physicians should be cautious in attributing GI injuries to sevelamer to avoid overlooking other causes and unnecessary treatment discontinuation.
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Affiliation(s)
- Hania Shakeri
- Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
| | - Nicole C Panarelli
- Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
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Fistrek Prlic M, Jelakovic M, Brinar M, Grgic D, Romic I, Marusic Z, Ivandic E, Jelakovic B, Vukovic Brinar I, Krznaric Z. Case report: Sevelamer-associated colitis-a cause of pseudotumor formation with colon perforation and life-threatening bleeding. Front Med (Lausanne) 2023; 10:1097469. [PMID: 37181355 PMCID: PMC10174228 DOI: 10.3389/fmed.2023.1097469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 04/07/2023] [Indexed: 05/16/2023] Open
Abstract
Chronic kidney disease (CKD) is a very common chronic non-communicable disease. Phosphate and calcium metabolism disorders are one of the most common features of CKD. Sevelamer carbonate is the most widely used non-calcium phosphate binder. Gastrointestinal (GI) injury associated with sevelamer use is a documented adverse effect but is underrecognized as a cause of gastrointestinal symptoms in patients with CKD. We report a case of a 74-year-old woman taking low-dose sevelamer with serious gastrointestinal adverse effects causing colon rupture and severe gastrointestinal bleeding.
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Affiliation(s)
- Margareta Fistrek Prlic
- Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, Zagreb, Croatia
| | - Mislav Jelakovic
- Department of Gastroenterology, University Hospital Center Zagreb, Zagreb, Croatia
| | - Marko Brinar
- Department of Gastroenterology, University Hospital Center Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Dora Grgic
- Department of Gastroenterology, University Hospital Center Zagreb, Zagreb, Croatia
| | - Ivan Romic
- Department of Abdominal Surgery, University Hospital Center Zagreb, Zagreb, Croatia
| | - Zlatko Marusic
- Department of Pathology, University Hospital Center Zagreb, Zagreb, Croatia
| | - Ema Ivandic
- Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, Zagreb, Croatia
| | - Bojan Jelakovic
- Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Ivana Vukovic Brinar
- Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Zeljko Krznaric
- Department of Gastroenterology, University Hospital Center Zagreb, Zagreb, Croatia
- School of Medicine, University of Zagreb, Zagreb, Croatia
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D M, BG B, E S, S A, VO L, NA B. May polydextrose potentially improve gut health in patients with chronic kidney disease? Clin Nutr ESPEN 2022; 51:7-16. [PMID: 36184250 DOI: 10.1016/j.clnesp.2022.08.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/12/2022] [Accepted: 08/17/2022] [Indexed: 02/07/2023]
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Lenz B, Brink A, Mihatsch MJ, Altmann B, Niederhauser U, Steinhuber B, Wyttenbach N, Fischer H. Multiorgan Crystal Deposition of an Amphoteric Drug in Rats Due to Lysosomal Accumulation and Conversion to a Poorly Soluble Hydrochloride Salt. Toxicol Sci 2021; 180:383-394. [PMID: 33454789 PMCID: PMC8041455 DOI: 10.1093/toxsci/kfaa191] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Poor solubility of drug candidates mainly affects bioavailability, but poor solubility of drugs and metabolites can also lead to precipitation within tissues, particularly when high doses are tested. RO0728617 is an amphoteric compound bearing basic and acidic moieties that has previously demonstrated good solubility at physiological pH but underwent widespread crystal deposition in multiple tissues in rat toxicity studies. The aim of our investigation was to better characterize these findings and their underlying mechanism(s), and to identify possible screening methods in the drug development process. Main microscopic features observed in rat RO0728617 toxicity studies were extensive infiltrates of crystal-containing macrophages in multiple organs. Matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry revealed that these crystals contained the orally administered parent compound, and locality was confirmed to be intracytoplasmic and partly intralysosomal by electron microscopic examination. Crystal formation was explained by lysosomal accumulation of the compound followed by precipitation of the hydrochloride salt under physiological conditions in the lysosomes, which have a lower pH and higher chloride concentration in comparison to the cytosol. This study demonstrates that risk of drug precipitation can be assessed by comparing the estimated lysosomal drug concentration at a given dose with the solubility of the compound at lysosomal conditions.
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Affiliation(s)
- Barbara Lenz
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
| | - Andreas Brink
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
| | - Michael J Mihatsch
- Pathology, Institute of Medical Genetics and Pathology, University Hospital of Basel, University of Basel, 4031 Basel, Switzerland
| | - Bernd Altmann
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
| | - Urs Niederhauser
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
| | - Bernd Steinhuber
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
| | - Nicole Wyttenbach
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
| | - Holger Fischer
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland
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Ooishi M, Yamada S, Itoh T, Meguro S, Yagi H, Kosugi I, Iwashita T, Shinmura K, Misawa K, Hariyama T, Kawasaki H. Diagnosis of Ion-Exchange Resin Depositions in Paraffin Sections Using Corrective Light and Electron Microscopy-NanoSuit Method. Diagnostics (Basel) 2021; 11:diagnostics11071193. [PMID: 34209027 PMCID: PMC8304092 DOI: 10.3390/diagnostics11071193] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 06/25/2021] [Accepted: 06/27/2021] [Indexed: 12/28/2022] Open
Abstract
Ion-exchange resins are commonly used to treat complications such as hyperkalemia, hyperphosphatemia, and hypercholesterolemia. Gastrointestinal complications may occur as side effects of such treatments. Sodium and calcium polystyrene sulfonate (PS-Ca) are cation-exchange resins comprising an insoluble structure that binds to potassium ions in the digestive tract and exchanges them with sodium and calcium ions, respectively, to promote their elimination. PS crystals are rhomboid, refractive, and basophilic in hematoxylin and eosin staining. To differentiate PS crystals from other ion-exchange resin crystals such as sevelamer and cholestyramine, periodic acid-Schiff, Ziehl-Neelsen, and Congo red staining are usually performed. Here, correlative light and electron microscopy (CLEM)-energy-dispersive X-ray spectroscopy and the NanoSuit method (CENM) was applied to perform a definitive identification of ion-exchange resins. CENM could detect sulfur in PS crystals without destroying the glass slides. Notably, PS retained its ion-exchange ability to bind potassium in paraffin sections. Differential diagnosis of anion-exchange resins, such as sevelamer and cholestyramine, was possible using these characteristics. The phosphorus:carbon ratio was higher in sevelamer than in cholestyramine after soaking paraffin sections in a phosphate solution. Therefore, CENM may be used for the differential pathological diagnosis of ion-exchange resins in paraffin sections.
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Affiliation(s)
- Mako Ooishi
- Institute for NanoSuit Research, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; (M.O.); (T.H.)
| | - Satoshi Yamada
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; (S.Y.); (K.M.)
| | - Toshiya Itoh
- Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan;
| | - Shiori Meguro
- Department of Regenerative & Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; (S.M.); (H.Y.); (I.K.); (T.I.)
| | - Haruna Yagi
- Department of Regenerative & Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; (S.M.); (H.Y.); (I.K.); (T.I.)
| | - Isao Kosugi
- Department of Regenerative & Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; (S.M.); (H.Y.); (I.K.); (T.I.)
| | - Toshihide Iwashita
- Department of Regenerative & Infectious Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; (S.M.); (H.Y.); (I.K.); (T.I.)
| | - Kazuya Shinmura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan;
| | - Kiyoshi Misawa
- Department of Otolaryngology/Head and Neck Surgery, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; (S.Y.); (K.M.)
| | - Takahiko Hariyama
- Institute for NanoSuit Research, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; (M.O.); (T.H.)
| | - Hideya Kawasaki
- Institute for NanoSuit Research, Preeminent Medical Photonics Education & Research Center, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan; (M.O.); (T.H.)
- Correspondence: ; Tel.: +81-53-435-2504
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12
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Lee JH, Park SH, Shin JH, Hong SM, Park JH, Hwang SW, Yang DH, Byeon JS, Myung SJ, Ye BD, Yang SK. [Colonic Mass Secondary to Sevelamer-associated Rectal Ulcer]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2021; 77:305-308. [PMID: 34158451 DOI: 10.4166/kjg.2021.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 04/02/2021] [Accepted: 04/12/2021] [Indexed: 11/03/2022]
Abstract
The phosphorous balance is clinically important in increasing the long-term outcomes and preventing complications of end-stage renal disease. Sevelamer is a phosphate binder used widely to regulate hyperphosphatemia. On the other hand, gastrointestinal side effects increase with increasing sevelamer intake. A 29-year-old male with end-stage renal disease of IgA nephropathy on maintenance hemodialysis was admitted for diffuse alveolar bleeding and pneumonia. He presented with a low-grade fever and watery diarrhea tinged with blood. Initially, a Clostridioides difficile-associated diarrhea treatment was started with positive findings of Clostridioides difficile toxin and culture. Despite this, there was no improvement in the symptoms even with the appropriate antibiotic treatment. Computed tomography of the abdomen and pelvis revealed an occlusive mass in the rectum and secondary obstructive changes in the sigmoid colon. The initial suspicion was a malignancy or fungal infection. Sigmoidoscopy with a biopsy identified 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. The diagnosis of a sevelamer-induced rectal ulcer was made. We report this case of a sevelamer-associated rectal ulcer of the sigmoid.
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Affiliation(s)
- Jin Hee Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sang Hyoung Park
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Ho Shin
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seung-Mo Hong
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Hwa Park
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sung Wook Hwang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong-Hoon Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Seung-Jae Myung
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Byong Duk Ye
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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13
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Cockrell HC, Cottrell-Cumber S, Brown K, Murphy JG. Sevelamer crystals-an unusual cause of large bowel obstruction. J Surg Case Rep 2021; 2021:rjab228. [PMID: 34150192 PMCID: PMC8208801 DOI: 10.1093/jscr/rjab228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/11/2021] [Indexed: 11/16/2022] Open
Abstract
Sevelamer is a common phosphate binder used to manage hyperphosphatemia in end-stage renal disease. The medication has a well-documented gastrointestinal side-effect profile including nausea, vomiting and abdominal pain. There are few case reports of Sevelamer crystal deposition causing gastrointestinal mucosal injury, pseudotumor or obstruction. Here, we discuss a patient on Sevelamer who required operative management of a sigmoid obstruction. Surgical pathology showed pericolonic abscess with Sevelamer crystals.
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Affiliation(s)
- Hannah C Cockrell
- Department of Surgery, University of Mississippi Medical Center, Jackson, MS, USA
| | | | - Kathryn Brown
- Department of Pathology, Mississippi Baptist Hospital, Jackson, MS, USA
| | - Jason G Murphy
- Surgical Clinic Associates, Mississippi Baptist Hospital, Jackson, MS, USA
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14
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Kim Y, Kesar V, LeBel D. Unusual cause of colonic mucosal ulceration and gastrointestinal bleeding. Frontline Gastroenterol 2021; 13:269-270. [PMID: 35493629 PMCID: PMC8996096 DOI: 10.1136/flgastro-2021-101844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/09/2021] [Indexed: 02/04/2023] Open
Affiliation(s)
- Youseung Kim
- Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA
| | - Varun Kesar
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA
| | - David LeBel
- Department of Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, Virginia, USA
- Dominion Pathology Associates, Roanoke, Virginia, USA
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15
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Schoot TS, Römkens TEH, Hoogeveen EK. Lower gastrointestinal bleeding in a patient receiving sevelamer: Case report. SAGE Open Med Case Rep 2021; 9:2050313X211000488. [PMID: 33796314 PMCID: PMC7968023 DOI: 10.1177/2050313x211000488] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 01/25/2021] [Indexed: 11/15/2022] Open
Abstract
Phosphate binders such as sevelamer are widely used in patients with chronic kidney disease to lower serum phosphate levels. We present a case of a 67-year-old woman with lower gastrointestinal bleeding after 9 days of using sevelamer carbonate (Renvela®). Sigmoidoscopy revealed multiple deep ulcers (diameter 10-15 mm) and mucosal oedema. Histologic examination showed deposition of sevelamer crystals in these rectal ulcers. We hypothesized that the lower gastrointestinal bleeding was caused by deposition of sevelamer crystals. After cessation of sevelamer, gastrointestinal bleeding stopped. Deposition of sevelamer crystals in the gastrointestinal tract is a rare complication of sevelamer therapy. There are only 17 other recorded cases of gastrointestinal deposition of sevelamer crystals. This adverse effect should be considered in all patients taking sevelamer who present with gastrointestinal symptoms, such as gastrointestinal bleeding and abdominal pain. When sevelamer is discontinued, symptoms and mucosal damage appear to revert.
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Affiliation(s)
- Tessa S Schoot
- Department of Nephrology, Jeroen Bosch Ziekenhuis, ’s-Hertogenbosch, The Netherlands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Tessa EH Römkens
- Department of Gastroenterology and Hepatology, Jeroen Bosch Ziekenhuis, ’s-Hertogenbosch, The Netherlands
| | - Ellen K Hoogeveen
- Department of Nephrology, Jeroen Bosch Ziekenhuis, ’s-Hertogenbosch, The Netherlands
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16
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Sevelamer Induced Gastrointestinal Injury. Am J Med Sci 2021; 362:e1-e2. [PMID: 33546880 DOI: 10.1016/j.amjms.2020.12.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 12/17/2020] [Indexed: 11/20/2022]
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17
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Kim T, de Oliveira Silva Lautenschlager S, Ma Q, Eller K, Pollheimer MJ, Lazarin-Bidóia D, Nakamura CV, Anders HJ, Steiger S. Drug Crystal-Related Gastrointestinal Complications Involve Crystal-Induced Release of Neutrophil and Monocyte Extracellular Traps. Cells 2020; 9:cells9112481. [PMID: 33203124 PMCID: PMC7697008 DOI: 10.3390/cells9112481] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 11/05/2020] [Accepted: 11/07/2020] [Indexed: 12/14/2022] Open
Abstract
Ion-exchange resins are commonly used to manage complications of chronic kidney disease, such as hyperphosphatemia, hyperkalemia, and hypercholesterolemia. Occasionally, these drugs can irritate the gastrointestinal lining and cause life-threatening intestinal necrosis. Currently, the pathophysiology of drug crystal-induced intestinal necrosis is not well understood. We hypothesized that crystals of ion-exchange resins like sevelamer, polystyrene sulfonate, and cholestyramine can trigger the formation of neutrophil and monocyte extracellular traps by contributing to intestinal barrier dysfunction. Light and fluorescence microscopy of the colonic resection specimen from a patient with chronic kidney disease revealed severe intestinal necrosis, ulceration, sevelamer crystals, and inflammation upon oral intake of sevelamer, as well as the formation of neutrophil extracellular traps in proximity to small sevelamer crystals. Indeed, drug crystals reduced metabolic activity and induced barrier dysfunction and cell death in human intestinal epithelial cells in vitro. In addition, drug crystals triggered the release of neutrophil and monocyte extracellular traps. Taken together, these data raise the possibility that besides other factors including chronic kidney disease, diabetes mellitus, and hypertension, drug crystals may further amplify a pre-existing barrier dysfunction and necroinflammation in a crescendo of local intestinal necrosis and systemic inflammation/infection, as occasionally observed in patients on ion-exchange resin therapy.
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Affiliation(s)
- Tehyung Kim
- Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital Munich, 80336 Munich, Germany; (T.K.); (Q.M.)
| | | | - Qiuyue Ma
- Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital Munich, 80336 Munich, Germany; (T.K.); (Q.M.)
| | - Kathrin Eller
- Division of Nephrology, Department of Internal Medicine, Medical University Graz, 8036 Graz, Austria;
| | - Marion Julia Pollheimer
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria;
| | - Danielle Lazarin-Bidóia
- Postgraduate Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Paraná 5790, Brazil; (S.d.O.S.L.); (D.L.-B.); (C.V.N.)
| | - Celso Vataru Nakamura
- Postgraduate Program in Pharmaceutical Sciences, State University of Maringá, Maringá, Paraná 5790, Brazil; (S.d.O.S.L.); (D.L.-B.); (C.V.N.)
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital Munich, 80336 Munich, Germany; (T.K.); (Q.M.)
- Correspondence: (H.-J.A.); (S.S.); Tel.: +49-89-4400-53583 (H.-J.A.); +49-89-4400-52129 (S.S.)
| | - Stefanie Steiger
- Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital Munich, 80336 Munich, Germany; (T.K.); (Q.M.)
- Correspondence: (H.-J.A.); (S.S.); Tel.: +49-89-4400-53583 (H.-J.A.); +49-89-4400-52129 (S.S.)
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18
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Abstract
Hyperphosphatemia is a common and well-described complication of end-stage renal disease. Despite strict dietary constraints and compliance, phosphate binders such as calcium acetate and/or sevelamer carbonate are also needed to treat secondary hyperparathyroidism. This case vignette describes an underrecognized adverse effect of a phosphate binder, sevelamer carbonate, inducing colitis in a 47-year-old male with insulin-dependent diabetes complicated by end-stage renal disease. He presented for recurrent abdominal pain with associated nausea and was found to have multiple circumferential lesions on computed tomography including distal ascending, transverse, and proximal descending colon. Colonoscopy demonstrated nearly obstructing lesions worrisome for colonic ischemia or inflammatory bowel disease. Pathological 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. Sevelamer carbonate was discontinued, and the patient was transitioned to calcium carbonate with strict dietary restrictions. His symptoms improved with the cessation of sevelamer, and he was subsequently discharged home. He eventually underwent renal transplant without redevelopment of symptoms. Recognition of this underreported complication of sevelamer carbonate, phosphate binder, is of utmost importance in directing appropriate therapy with cessation of this medication in the setting of gastrointestinal complaints or more specifically enteritis and colitis. Clinicians providing care to end-stage renal patients taking either sevelamer and/or sodium polystyrene sulfonate should have increased awareness of the possible gastrointestinal side effects.
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19
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Dai L, Meijers BK, Bammens B, de Loor H, Schurgers LJ, Qureshi AR, Stenvinkel P, Evenepoel P. Sevelamer Use in End-Stage Kidney Disease (ESKD) Patients Associates with Poor Vitamin K Status and High Levels of Gut-Derived Uremic Toxins: A Drug-Bug Interaction? Toxins (Basel) 2020; 12:toxins12060351. [PMID: 32471179 PMCID: PMC7354623 DOI: 10.3390/toxins12060351] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/06/2020] [Accepted: 05/22/2020] [Indexed: 12/17/2022] Open
Abstract
Gut microbial metabolism is not only an important source of uremic toxins but may also help to maintain the vitamin K stores of the host. We hypothesized that sevelamer therapy, a commonly used phosphate binder in patients with end-stage kidney disease (ESKD), associates with a disturbed gut microbial metabolism. Important representatives of gut-derived uremic toxins, including indoxyl sulfate (IndS), p-Cresyl sulfate (pCS), trimethylamine N-oxide (TMAO), phenylacetylglutamine (PAG) and non-phosphorylated, uncarboxylated matrix-Gla protein (dp-ucMGP; a marker of vitamin K status), were analyzed in blood samples from 423 patients (65% males, median age 54 years) with ESKD. Demographics and laboratory data were extracted from electronic files. Sevelamer users (n = 172, 41%) were characterized by higher phosphate, IndS, TMAO, PAG and dp-ucMGP levels compared to non-users. Sevelamer was significantly associated with increased IndS, PAG and dp-ucMGP levels, independent of age, sex, calcium-containing phosphate binder, cohort, phosphate, creatinine and dialysis vintage. High dp-ucMGP levels, reflecting vitamin K deficiency, were independently and positively associated with PAG and TMAO levels. Sevelamer therapy associates with an unfavorable gut microbial metabolism pattern. Although the observational design precludes causal inference, present findings implicate a disturbed microbial metabolism and vitamin K deficiency as potential trade-offs of sevelamer therapy.
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Affiliation(s)
- Lu Dai
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 86 Huddinge, Stockholm, Sweden; (L.D.); (A.R.Q.)
| | - Björn K. Meijers
- Department of Microbiology Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven-University of Leuven, B-3000 Leuven, Belgium; (B.K.M.); (B.B.); (H.d.L.)
- Department of Nephrology, University Hospitals Leuven, B-3000 Leuven, Belgium
| | - Bert Bammens
- Department of Microbiology Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven-University of Leuven, B-3000 Leuven, Belgium; (B.K.M.); (B.B.); (H.d.L.)
- Department of Nephrology, University Hospitals Leuven, B-3000 Leuven, Belgium
| | - Henriette de Loor
- Department of Microbiology Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven-University of Leuven, B-3000 Leuven, Belgium; (B.K.M.); (B.B.); (H.d.L.)
| | - Leon J. Schurgers
- Department of Biochemistry, Cardiovascular Research School Maastricht, Maastricht University, 6200MD Maastricht, The Netherlands;
| | - Abdul Rashid Qureshi
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 86 Huddinge, Stockholm, Sweden; (L.D.); (A.R.Q.)
| | - Peter Stenvinkel
- Division of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, 141 86 Huddinge, Stockholm, Sweden; (L.D.); (A.R.Q.)
- Correspondence: (P.S.); (P.E.)
| | - Pieter Evenepoel
- Department of Microbiology Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven-University of Leuven, B-3000 Leuven, Belgium; (B.K.M.); (B.B.); (H.d.L.)
- Department of Nephrology, University Hospitals Leuven, B-3000 Leuven, Belgium
- Correspondence: (P.S.); (P.E.)
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20
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Salani M, Golper T. When ESKD complicates disease management: GI bleeding and other GI illnesses. Semin Dial 2020; 33:263-269. [DOI: 10.1111/sdi.12874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Megha Salani
- Department of Nephrology Vanderbilt University Medical Center Nashville TN USA
| | - Thomas Golper
- Department of Nephrology Vanderbilt University Medical Center Nashville TN USA
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21
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Floege J. Phosphate binders in chronic kidney disease: an updated narrative review of recent data. J Nephrol 2019; 33:497-508. [PMID: 31865608 DOI: 10.1007/s40620-019-00689-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/17/2019] [Indexed: 12/11/2022]
Abstract
Chronic kidney disease (CKD) is frequently accompanied by hyperphosphatemia. High serum phosphate usually requires dietary measures, adequate dialysis prescription and/or phosphate binders. For this narrative review a PubMed searched was undertaken to identify new publications on phosphate binders that had been published between January 2015 and July 2019. The present review summarizes this most recent information on dietary measures and their problems in treating hyperphosphatemia in CKD patients, overall effects of phosphate binders on cardiovascular mortality and morbidity, adherence to phosphate binder therapy as well as new data on specific aspects of the various phosphate binders on the market: calcium-containing phosphate binders, polymeric phosphate binders (sevelamer, bixalomer, colestilan), magnesium-containing phosphate binders, lanthanum carbonate, ferric citrate, sucroferric oxyhydroxide, and new compounds in development, in particular drugs targeting intestinal phosphate transporters.
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Affiliation(s)
- Jürgen Floege
- Department of Nephrology and Clinical Immunology, University Hospital, Rheinisch Westfälische Technische Hochschule (RWTH), Pauwelsstr. 30, 52057, Aachen, Germany.
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22
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Leonard CE, Zhou M, Brensinger CM, Bilker WB, Soprano SE, Pham Nguyen TP, Nam YH, Cohen JB, Hennessy S. Clopidogrel Drug Interactions and Serious Bleeding: Generating Real-World Evidence via Automated High-Throughput Pharmacoepidemiologic Screening. Clin Pharmacol Ther 2019; 106:1067-1075. [PMID: 31106397 DOI: 10.1002/cpt.1507] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 04/23/2019] [Indexed: 12/19/2022]
Abstract
Few population-based studies have examined bleeding associated with clopidogrel drug-drug interactions (DDIs). We sought to identify precipitant drugs taken concomitantly with clopidogrel (an object drug) that increased serious bleeding rates. We screened 2000-2015 Optum commercial health insurance claims to identify DDI signals. We performed self-controlled case series studies for clopidogrel plus precipitant pairs, examining associations with gastrointestinal bleeding or intracranial hemorrhage. To distinguish native bleeding effects of a precipitant, we reexamined associations using pravastatin as a negative control object drug. Among 431 analyses, 28 clopidogrel plus precipitant pairs were statistically significantly positively associated with serious bleeding. Ratios of rate ratios ranged from 1.13-3.94. Among these pairs, 13 were expected given precipitant drugs alone increased and/or were harbingers of serious bleeding. The remaining 15 pairs constituted new DDI signals, none of which are currently listed in two major DDI knowledge bases.
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Affiliation(s)
- Charles E Leonard
- Department of Biostatistics, Epidemiology, and Informatics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Meijia Zhou
- Department of Biostatistics, Epidemiology, and Informatics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Colleen M Brensinger
- Department of Biostatistics, Epidemiology, and Informatics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Warren B Bilker
- Department of Biostatistics, Epidemiology, and Informatics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Samantha E Soprano
- Department of Biostatistics, Epidemiology, and Informatics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Thanh Phuong Pham Nguyen
- Department of Biostatistics, Epidemiology, and Informatics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Young Hee Nam
- Department of Biostatistics, Epidemiology, and Informatics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jordana B Cohen
- Department of Biostatistics, Epidemiology, and Informatics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Renal-Electrolyte and Hypertension Division, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Sean Hennessy
- Department of Biostatistics, Epidemiology, and Informatics, Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.,Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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23
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Awad C, Gilkison K, Shaw E. Lanthanum phosphate binder-induced iron deficiency anaemia. BMJ Case Rep 2019; 12:12/3/e226157. [PMID: 30878952 DOI: 10.1136/bcr-2018-226157] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Lanthanum carbonate is a phosphate binder that is used to reduce serum phosphate levels in patients with end-stage renal disease (ESRD). Lanthanum forms insoluble lanthanum phosphate complexes that are supposed to pass through the gastrointestinal (GI) tract unabsorbed. Phosphate binders have been reported to deposit in the GI tract and can cause mucosal injury. There are few case reports of GI bleeding associated with phosphate binder deposits. This case report presents a patient with iron deficiency anaemia secondary to biopsy-proven lanthanum deposits in the upper GI tract. There were no overt signs of active GI bleeding. Patient's anaemia improved with discontinuation of the phosphate binder. Lanthanum could be a hidden cause of resistant anaemia among patients with ESRD through asymptomatic GI blood loss.
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Affiliation(s)
- Christina Awad
- Internal Medicine, US Air Force Hospital Lackland AFB, San Antonio, Texas, USA
| | - Karin Gilkison
- US Air Force Hospital Keesler AFB, Keesler AFB, Mississippi, USA
| | - Erwin Shaw
- US Air Force Hospital Keesler AFB, Keesler AFB, Mississippi, USA
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24
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Sevelamer-Associated Rectosigmoid Ulcers in an End-Stage Renal Disease Patient. ACG Case Rep J 2018; 5:e83. [PMID: 30568971 PMCID: PMC6277133 DOI: 10.14309/crj.2018.83] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Accepted: 08/06/2018] [Indexed: 11/30/2022] Open
Abstract
Sevelamer carbonate is a commonly prescribed anion-exchange resin administered orally to prevent hyperphosphatemia in patients with chronic kidney disease. We present a rare case of a 33-year-old man with end-stage renal disease and diabetic gastroparesis on sevelamer carbonate, who 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. Clinicians and pathologists must be aware of the possibility of drug-induced mucosal ulceration associated with sevelamer use as a potential etiology of a gastrointestinal bleed.
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25
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Okwara CJ, Gulati R, Rustagi T, Birg A, Hanson J, McCarthy D. Upper Gastrointestinal Bleeding of Unusual Causation. Dig Dis Sci 2018; 63:2541-2546. [PMID: 30178284 DOI: 10.1007/s10620-018-5260-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Chinemerem J Okwara
- Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico School of Medicine, MSC 10-5550, 87131, Albuquerque, NM, Mexico.
| | - Rishabh Gulati
- Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico School of Medicine, MSC 10-5550, 87131, Albuquerque, NM, Mexico
| | - Tarun Rustagi
- Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico School of Medicine, MSC 10-5550, 87131, Albuquerque, NM, Mexico
| | - Aleksandr Birg
- Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico School of Medicine, MSC 10-5550, 87131, Albuquerque, NM, Mexico
| | - Joshua Hanson
- Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM, Mexico
| | - Denis McCarthy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico School of Medicine, MSC 10-5550, 87131, Albuquerque, NM, Mexico
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26
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Sherman RA. Briefly Noted. Semin Dial 2018. [DOI: 10.1111/sdi.12661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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27
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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 PMCID: PMC5851163 DOI: 10.1155/2018/4708068] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 01/15/2018] [Accepted: 01/24/2018] [Indexed: 01/10/2023] Open
Abstract
End stage renal disease (ESRD) population account for 1.9 per patient year of hospital admissions annually. ESRD population are at increased risk of bleeding secondary to use of anticoagulation during hemodialysis and uremia induced platelet dysfunction. Gastrointestinal bleeding accounts for 3-7% of all deaths in ESRD population. Lower gastrointestinal bleeding refers to blood loss from a site in the gastrointestinal tract distal to the ligament of Treitz. It is usually suspected when a patient complains of hematochezia. It is different from patients presenting with hematemesis that suggests bleeding from upper gastrointestinal tract. Common causes of lower gastrointestinal bleed include diverticulosis, ischemia, hemorrhoids, neoplasia, angiodysplasia, and inflammatory bowel disease. ESRD patients are known to retain phosphate alone or in combination with calcium which has been associated with high mortality. Sevelamer is a phosphate binder used widely in ESRD population. The known side effects of sevelamer include metabolic acidosis, vomiting, nausea, diarrhea, dyspepsia, abdominal pain, constipation, flatulence, fecal impaction, and skin rash. We are reporting a unique case of a 56-year-old female with end stage renal disease on sevelamer hydrochloride who presented with gastrointestinal bleeding and underwent a right hemicolectomy found to have sevelamer-induced mucosal ulceration and crystal deposition in the colonic mucosa. This case report highlights the fact that, with widespread use of this medication in the patients with chronic kidney diseases, physicians should be aware of this underrecognized entity in the differential diagnosis of gastrointestinal bleed in ESRD patients.
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28
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29
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Sevelamer-Associated Rectosigmoid Ulcers in an End-Stage Renal Disease Patient. ACG Case Rep J 2018. [DOI: 10.14309/02075970-201805110-00008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Dzingarski D, Mladenovska K. Pharmacotherapy in chronic kidney disease hyperphosphatemia – effects on vascular calcification and bone health. MAKEDONSKO FARMACEVTSKI BILTEN 2017. [DOI: 10.33320/maced.pharm.bull.2017.63.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Hyperphosphatemia (HP) in patients with chronic kidney disease (CKD) leads to complications such as renal osteodistrophy, cardiovascular calcification and hemodynamic abnormalities, all of them having a serious impact on the survival rate and quality of life. Also, HP is a key pathogenic factor in the development of secondary hyperparathyroidism (SHPT) in CKD. Having in regard the significance of controlling serum phosphorus levels (Pi), in this paper, the needs and obstacles to successful pharmacological management of HP in CKD are presented, with an overview of major classes of phosphate binders (PBs) and other drugs affecting Pi level, such as active vitamin D sterols and calcimimetics (CMs). In addition, their effects on progression of cardiovascular calcification and bone health are elaborated. In this regard, a PubMed search was carried out to capture all abstracts and articles relevant to the topic of CKD, HP and mineral metabolism, bone disorders and vascular/valvular calcification (VC), published from January 2007 to August 2017. The search was limited to English language, with the search terms including drug name AND hyperphosphatemia or cardiovascular calcification or bone disorder. Comparative studies, clinical studies/trials and meta-analyses related to different classes/representatives of PBs, vitamin D analogues and CMs were reviewed and research data related to their efficacy and safety compared.
Keywords: chronic kidney disease, hyperphosphatemia, phosphate binders, active vitamin D sterols, calcimimetics, bone disorders, cardiovascular calcification
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Affiliation(s)
- Dimce Dzingarski
- Faculty of Pharmacy, University “Ss Cyril and Methodius”, Mother Theresa St. 47, 1000 Skopje, Republic of Macedonia
| | - Kristina Mladenovska
- Faculty of Pharmacy, University “Ss Cyril and Methodius”, Mother Theresa St. 47, 1000 Skopje, Republic of Macedonia
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