Introduction
Renal transplantation has become the cornerstone treatment for patients with end-stage renal disease (ESRD), conferring significant survival benefits and improvements in quality of life. However, the long-term survival of the transplanted organ necessitates rigorous immunosuppressive therapy, typically incorporating agents such as mycophenolate mofetil (MMF), tacrolimus, and corticosteroids. While these medications are effective in preventing allograft rejection, they are not without adverse effects, including gastrointestinal disturbances, hematologic abnormalities, and various mucosal manifestations, such as aphthous stomatitis. Aphthous ulcers are commonly observed in the general population, but their occurrence in transplant patients, especially as an adverse reaction to immunosuppressive drugs, requires prompt recognition and management. This case report explores the development of aphthous ulcers in a 57-year-old male renal transplant recipient, specifically attributed to MMF therapy, after the exclusion of other potential etiologies.
Case Presentation
The patient, a 57-year-old male with a longstanding history of hypertension and diabetes mellitus, which had led to chronic kidney disease (CKD), underwent a successful renal transplantation from a living donor. Postoperatively, he was placed on a conventional immunosuppressive regimen comprising MMF (500 mg twice daily), tacrolimus (target trough level 8-10 ng/mL), and prednisone (10 mg daily). Six months after transplantation, the patient presented to the outpatient clinic with complaints of recurrent, painful oral lesions localized predominantly on the buccal mucosa and the dorsum of the tongue. The lesions were described as shallow, ulcerated areas with a yellowish necrotic center and a surrounding erythematous halo. These ulcers were causing significant discomfort, impacting his ability to eat, speak, and maintain adequate nutrition.
In order to delineate the etiology of these ulcers, a comprehensive diagnostic approach was undertaken. A detailed clinical history revealed no previous history of recurrent oral ulcers, and the patient denied any constitutional symptoms, such as fever or weight loss. The lesion’s temporal association with the initiation of MMF therapy raised a strong suspicion for a drug-induced reaction. The differential diagnosis included viral etiology (e.g., herpes simplex virus [HSV] infection), autoimmune conditions (e.g., Behçet’s disease, systemic lupus erythematosus), and nutritional deficiencies (e.g., vitamin B12 or folate deficiency), all of which were systematically ruled out.
Laboratory workup included serological tests for HSV (IgM and IgG), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) to rule out viral etiologies, all of which returned negative results. Additionally, autoimmune markers, including antinuclear antibody (ANA), antiphospholipid antibodies, and rheumatoid factor, were unremarkable. Serum levels of vitamin B12, folate, and iron were within normal limits, further excluding nutritional deficiencies. Given the lack of findings suggestive of alternative causes, and the temporal onset of aphthous ulcers following MMF initiation, a diagnosis of MMF-induced aphthous stomatitis was made.
Management and Treatment
Given the significant impact of the aphthous ulcers on the patient’s quality of life and the suspicion that MMF was the causative agent, an alteration of the immunosuppressive regimen was deemed necessary. MMF was promptly discontinued, and the patient was transitioned to an alternative purine synthesis inhibitor, azathioprine (1 mg/kg/day), which was considered to have a more favorable side-effect profile with respect to mucosal lesions. Additionally, a topical corticosteroid (triamcinolone acetonide ointment) was prescribed to alleviate the inflammatory response and promote ulcer healing.
Within two weeks of initiating the new regimen, the patient reported a substantial reduction in pain and discomfort associated with the oral lesions. The ulcers began to shrink, and by the fourth week, they had completely healed without recurrence. Renal function remained stable, with no evidence of graft rejection, and the patient was able to resume a regular diet without difficulty. The transition to azathioprine was well-tolerated, and the tacrolimus dosage was maintained within the therapeutic range. The patient was followed up regularly to ensure continued graft function and to monitor for any potential adverse effects of the new immunosuppressive regimen.
Discussion
Aphthous stomatitis, although commonly occurring in the general population, is an often-overlooked side effect of immunosuppressive therapy in transplant recipients. Mycophenolate mofetil, a potent immunosuppressive agent, inhibits inosine monophosphate dehydrogenase (IMPDH), an enzyme crucial for purine synthesis in T and B lymphocytes. This mechanism, while essential for preventing graft rejection, has been implicated in several adverse effects, including mucosal toxicity. The exact pathophysiology underlying MMF-induced aphthous ulcers remains poorly understood, but it is hypothesized that MMF-induced suppression of the immune response may compromise mucosal integrity, leading to ulcer formation. Furthermore, the immunosuppressive effects of MMF could exacerbate existing latent viral infections or render the mucosa more susceptible to opportunistic pathogens, though no such viral etiology was identified in this case.
Drug-induced aphthous ulcers are a well-documented but infrequent complication of MMF therapy. Literature reports have described a range of oral manifestations, from mild lesions to severe, recurrent ulcers that can significantly impair a patient’s quality of life. While the overall incidence of aphthous ulcers in renal transplant recipients on MMF is not precisely defined, it is recognized that the drug is a key contributor to mucosal side effects in this patient population. Studies suggest that the risk of developing oral lesions is higher in patients receiving MMF in combination with other immunosuppressive agents such as tacrolimus, which can further contribute to mucosal irritation.
When drug-induced aphthous ulcers are suspected, the cornerstone of management is to identify and eliminate the offending agent. In cases where discontinuation of MMF is necessary, alternative immunosuppressive agents such as azathioprine or sirolimus may be considered. These agents, while not devoid of side effects, generally have a more favorable profile concerning oral mucosal toxicity. In this case, the switch to azathioprine resulted in the complete resolution of the ulcers without compromising graft function.
It is crucial for clinicians to remain vigilant in monitoring for oral manifestations in transplant recipients, as these lesions, though not life-threatening, can significantly impact a patient’s well-being and complicate post-transplant care. Early identification and management are key to minimizing morbidity and maintaining optimal graft function.
Conclusion
This case report highlights the importance of recognizing MMF as a potential cause of aphthous stomatitis in renal transplant recipients. After ruling out other etiologies and making a clinical diagnosis of drug-induced aphthous ulcers, the patient’s lesions resolved promptly following the discontinuation of MMF and transition to azathioprine. Clinicians managing renal transplant patients should be aware of this rare but significant side effect and be prepared to modify immunosuppressive therapy as needed to balance effective graft protection with the minimization of adverse effects. Monitoring for oral mucosal lesions, along with timely intervention, plays a crucial role in optimizing post-transplant care and patient quality of life.
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Dr. S. Farhan Ali
Drnb Resident Nephrology
Kauvery Hospital Chennai