Mycophenolate Mofetil-induced Multiple Ileal Ulcerations in a Renal Transplant Recipient: Diagnostic Challenges and Management

Abstract

We herein report a kidney transplant recipient with recurrent bleeding due to multiple ileal ulcerations associated with mycophenolate mofetil (MMF). Symptoms persisted despite surgical resection and embolization. Double-balloon enteroscopy revealed multiple ulcerations, and a biopsy helped exclude other causes. The discontinuation of MMF led to rapid symptom resolution and healing of the ulceration. Intestinal complications after renal transplantation vary, and MMF-induced enteritis, although rare, should be considered. This case highlights the diagnostic value of enteroscopy in identifying drug-induced small intestinal injuries and underscores the importance of including MMF in the differential diagnosis of post-transplant gastrointestinal bleeding.

Introduction

Mycophenolate mofetil (MMF) is indispensable for preventing allograft rejection after solid organ transplantation. Its mechanism of action involves selective inhibition of inosine monophosphate dehydrogenase (IMPDH), which effectively suppresses T- and B-lymphocyte proliferation (1). Although MMF has proven effective in preventing allograft rejection, it is associated with various adverse effects, with gastrointestinal complications being among the most common, reported in up to 45% of patients (2,3).

The gastrointestinal side effects of MMF typically manifest as diarrhea, nausea, and vomiting. More severe complications such as gastrointestinal ulceration have also been reported, although the exact incidence remains unclear (4). One report described a life-threatening condition caused by bleeding from a colonic diverticulum associated with MMF treatment (5). Although colonic involvement has been well documented, small intestinal ulceration is relatively rare and can present diagnostic challenges owing to its nonspecific presentation and difficulty in endoscopic access.

We herein report a case of multiple ileal ulcerations requiring repeated transfusions and surgical resection in a renal transplant recipient receiving MMF, highlighting the importance of considering this medication as a potential cause of unexplained gastrointestinal bleeding in the transplant population.

Case Report

A man in his 60s with a history of renal transplantation (4 years prior) presented with recurrent hematochezia for over 3 months. An initial evaluation at an outside hospital revealed contrast extravasation in the distal ileum on contrast-enhanced computed tomography (CT), prompting coil embolization and subsequent partial ileal resection due to refractory bleeding. Despite these interventions, he experienced three recurrent episodes of hematochezia, leading to a referral to our institution.

His medical history included obstructive arteriosclerosis (managed with balloon angioplasty), angina pectoris (post-left circumflex stenting), and end-stage renal disease (30 years of dialysis prior to transplantation). Medications included MMF 250 mg/day, which was started 4 years prior to transplantation, tacrolimus 1 mg/day, methylprednisolone 2 mg/day, and cardiovascular agents (carvedilol and nicorandil). The patient had been taking aspirin because of a history of stent placement. He switched from aspirin to prasugrel after the appearance of hematochezia. However, after ileal resection, prasugrel was discontinued, and no other antiplatelet or anticoagulant medications were administered. No other medications that could have led to gastrointestinal disorders were being taken.

A physical examination revealed a blood pressure of 112/67 mmHg, pulse rate of 90 beats/min, and SpO₂ of 99% (room air). The abdomen was soft and flat, with surgical scars in the midline and right lower quadrant. Mild tenderness was noted in the right lower quadrant, but no rebound tenderness or peritoneal signs were observed.

Laboratory findings included anemia (hemoglobin 11.5 g/dL) and hypoalbuminemia (3.4 g/dL) with regular inflammatory markers (C-reactive protein 0.46 mg/dL). Contrast-enhanced CT demonstrated mucosal hyperenhancement in the terminal ileum but no active bleeding (Fig. 1A, B).

Figure 1.

Contrast-enhanced computed tomography showing mucosal hyperenhancement in the terminal ileum without active bleeding. (A) Axial view showing mucosal hyperenhancement of the terminal ileum, highlighted by a yellow circle. (B) Coronal view showing similar mucosal hyperenhancement of the terminal ileum, outlined by a red circle.

Transanal double-balloon enteroscopy (DBE) was performed to investigate the source of the recurrent hematochezia. Mild nonspecific erythema was observed in the left colon, whereas multiple irregular, shallow ulcerations were identified in the ileum, extending 35-50 cm proximal to the ileocolic anastomosis (Fig. 2). The ulcerations exhibited sharp, well-demarcated margins, without active bleeding or fibrinoid exudates.

Figure 2.

Double-balloon enteroscopy findings of the ileum. The examination revealed multiple irregular, shallow ulcerations in the ileum, distributed within a segment extending from 35 to 50 cm distal to the ileocecal anastomosis.

Biopsies of the ulceration margins revealed scattered small intestinal crypts containing numerous Paneth cells. The interstitium showed moderate to severe inflammatory cell infiltration, with a variable mix of lymphocytes, eosinophils, plasma cells, and neutrophils. No granulomas, viral inclusion bodies [as determined by cytomegalovirus (CMV) and herpes simplex virus immunostaining], or evidence of malignancy were observed. A histopathological examination revealed that ischemic enteritis and inflammatory bowel disease (IBD) were unlikely. Stool cultures, a Clostridioides difficile toxin assay, T-SPOT.TB, and serum CMV antigen tests were negative, effectively ruling out infectious etiologies.

Following admission, the patient experienced recurrent hematochezia despite bowel rest. Serial hemoglobin levels fluctuated, necessitating intermittent transfusion. Repeat enteroscopy on days 19 and 28 confirmed persistent ileal ulcerations, without active bleeding.

On day 28, MMF-induced enteritis was suspected because of the temporal association between symptoms and immunosuppressive therapy. MMF was discontinued and immunosuppression was switched to mizoribine. Hematochezia resolved within 48 h, with the hemoglobin stabilizing at 13.8 g/dL. Follow-up DBE at one month demonstrated healing of ulceration with reduced mucosal friability (Fig. 3). The patient resumed oral intake and was discharged without recurrence. Aspirin was resumed, but the ulcerations did not worsen.

Figure 3.

Double-balloon enteroscopy performed one month after discontinuation of mycophenolate mofetil. Images show that the previously identified ileal ulcerations are healing, and mucosal fragility is decreasing.

Discussion

We encountered a man in his 60s with a history of renal transplant who developed multiple ileal ulcerations secondary to MMF therapy. Repeated transfusions and surgical resection are necessary. However, after DBE, MMF-associated enteritis was suspected. This led to the discontinuation of MMF, which improved the patient's condition.

MMF is an effective adjunct immunosuppressive agent for preventing acute rejection in renal transplantation. However, the adverse gastrointestinal effects of MMF are a significant concern. These are the most frequent problems associated with MMF therapy, occurring in up to 45% of renal transplant recipients (2,3). The pathophysiology of MMF-induced gastrointestinal injury involves IMPDH inhibition-mediated depletion of guanosine nucleotides, which suppress enterocyte proliferation and induce apoptosis in cryptepithelial cells, particularly within the stem cell niche (6).

Gastrointestinal complications are common after renal transplantation and can result in a variety of disorders, including graft-versus-host disease (GVHD), infectious causes, malignancy, de novo IBD, and medication-induced injuries (7). Diagnosing the cause of gastrointestinal disorders after renal transplantation is difficult because of the wide variety of differential diagnoses available. The present case manifested four years after the administration of MMF. The median duration of MMF-associated colitis was reported to be 44.3±33.5 months, with a wide range of 4 to 123 months (8). Therefore, MMF-associated gastrointestinal injury should be included in the differential diagnosis even if the patient has been on MMF for a prolonged period. Another reason why the diagnosis was problematic is that the symptoms were similar and non-specific. In addition, the fact that the lesion in this case originated in the small intestine and that the previous hospital provided insufficient endoscopic findings was a contributing factor. MMF-induced gastrointestinal complications include colitis. However, studies in rats have shown that MMF may target the jejunum and ileum and induce gastrointestinal injury (9). Severe enteropathy due to MMF has also been reported (10). Therefore, it is important to remember MMF-associated gastrointestinal injuries in enteritis.

This case highlights the importance of enteroscopy. The fact that we were able to recognize ulceration morphology using DBE and obtain pathological biopsy data was of great help in determining the treatment for our patient. DBE revealed multiple irregular ulcerations with sharp margins, distinct from Crohn's serpiginous ulcerations or CMV's “volcano" morphology. The absence of cobblestones or a longitudinal distribution did not suggest IBD or ischemia. Biopsy pathology ruled out ischemia, infection, and malignancy.

Few reports have documented the histological findings in MMF enteritis. Liapis et al. reported that the histological characteristic features of MMF colitis were the angulated architecture of distorted crypts and the epithelial flattening and dilation of damaged crypts in association with crypt abscesses containing apoptotic bodies (6). The histological findings of MMF colitis have been summarized as follows: (1) irregular or extensive atrophy of the crypt; (2) alterations of the crypts in terms of cryptic abscesses, neutrophils, eosinophils, and mucin inside the lumen of the crypt; (3) mild, moderate, or severe inflammatory infiltrates, mainly plasma cells and, in some cases, eosinophils (＞40 per high-power field); and (4) focal cryptitis, ulcerations, and erosions (6-8,11). Conversely, the histological characteristics of MMF colitis resemble those of IBD-like conditions, GVHD, and ischemia (6,8,11). Compared with MMF colitis and IBD-like conditions, GVHD is characterized by more apoptotic bodies and mild-to-moderate inflammation with mild or absent crypt distortion (6,8). Crypt angulation, crypt dilation with flattened epithelium or denudation, and crypt abscesses with apoptotic bodies in the lumen aid in differentiation from IBD (6,11). However, there is no consensus on the specific histological findings of MMF-associated enteritis, particularly in the small intestine. As there are no diagnostic definitions for endoscopic or histological findings, it is currently not possible to make a diagnosis based on endoscopic findings alone. DBE provides useful information, but it provides only one piece of information for the diagnosis. It is important to comprehensively consider the patient's medical history and clinical course.

In conclusion, we encountered a case of multiple ileal ulcerations requiring repeated transfusions and surgical resection in a renal transplant recipient who received MMF. Intestinal complications following renal transplantation are diverse and require a differential diagnosis. Although there have been few reports of severe small intestinal injury in MMF, a differential diagnosis is important. In such cases, DBE, which can provide endoscopic findings and biopsy pathology, can help in making a diagnosis. As information on the clinical features and endoscopic and histological findings of MMF-related enteritis is limited, it is expected that more cases will be reported in the future.

Author’s disclosure of potential Conflicts of Interest (COI).

H.S. and T.Y. have received honoraria and grants from FUJIFILM Medical. Other authors have no financial conflicts of interest.