The diagnosis of MPA-induced ascites was based on the results of investigations which excluded alternative causes, the timing of onset and resolution of ascites after discontinuation of therapy and finally the recurrence of symptoms and signs with re-challenge with EC-MPS. Taken together these observations strongly support causality to the suspected adverse drug reaction [
9]. MPA, as main constituent of EC-MPS and MMF, defines the largely similar side-effect profile of both drugs [
4]. A search in VigiBase, the World Health Organization global database of Individual Case Safety Reports identified from a total of 19,338 reports involving MPA 90 cases of ascites between the years 2000 and 2015. In 88 cases MPA was reported as a suspected drug. In 4 cases “ascites” was the only reported side-effect and in just 2 patients MPA was reported as the only suspected drug. Causality assessment or de- and re-challenge were not reported in the WHO database. To our knowledge there are no cases of severe ascites associated with MPA treatment reported in the scientific literature.
In the presented case we describe MPA-associated ascites formation with positive de-challenge after exclusion of various differential diagnoses. Upon re-challenge with MPA although the patient’s symptoms were highly suggestive of repeated ascites formation we were unable to obtain confirmation of ascites formation prior to drug cessation which was done elsewhere. The impact of MPA re-challenge is therefore not objectively proven, however the rapid resolution of ascites upon initial cessation of MPA strongly supports a causative association. The pathomechanism of the MPA-associated ascites formation in our patients is not clear. Gastrointestinal adverse effects are a common complication of MPA treatment [
4]. Known MPA-associated morphological gastrointestinal toxicity includes duodenal villous atrophy in renal transplant recipients [
10], mucosal damage of the stomach and erosive or ulcerative enterocolitis [
11]. Genetic polymorphisms of MPA metabolism and transport might account for individual differences in side effects. However, clinically severe ascites formation has not been published as a complication of MPA treatment. An increase in capillary permeability was considered as explanation. In rats treated with MMF elevated levels of nitric oxide were detected in the serum as well as in the duodenum. Histopathologic examinations showed villous atrophy and inflammatory cell infiltration. Gastrointestinal disorders among these animals were therefore attributed to local inflammatory reactions which were possibly caused by elevated NO and myeloperoxidase levels [
12]. However MPA is better known for its inhibitory effects on inflammation [
1,
4]. In a mouse model of pleurisy, MMF suppressed protein levels of inflammatory cytokines such as TNFα, IL1β, VEGFα and IL-17 [
4,
13]. In a model of encapsulating peritoneal sclerosis MMF reduced inflammation and neovascularization by inhibiting VEGF and TGFβ1 [
14]. Hence, this inhibition of vascular growth factors and inflammatory cytokines would rather lead to a decrease of vascularity, tightening of the blood-peritoneal-barrier, less vasodilatation, reduced capillary leakage and therefore less ascites formation. An inflammation-induced increase in capillary permeability is also not compatible with the high SAAG gradient, low protein content and lack of inflammatory cells in the transudative ascitic fluid in our patient.
In summary MPA treatment should be added to the differential diagnosis of severe ascites. Given the worldwide use of MPA as antimetabolite of choice in immunosuppressive regimens our observation might raise awareness in cases of unexplained ascites formation in transplant as well as non-transplant patients.
Patient perspective
“Shortly after the surgery when the ascites occurred I felt desperate and unsure about ever leaving the hospital again. It took many weeks until I was finally able to go home but still needed weekly paracenteses treatments as outpatient. During this time I decided to insist with my doctors to resolve this problem because I felt my life had become unbearable. I started studying the drug information sheets of my medication and read about the potential side effect of ascites. I also had an aunt who was a kidney transplant recipient and was treated with cyclosporine A and azathioprine for many years and after switching her to tacrolimus and MPA later in life she felt increased abdominal fullness and volume. With this personal experience and reading about the side effects I suggested to my doctors repeatedly a switch from tacrolimus to cyclosporine A. After this change I felt better in general but the ascites persisted. When the change of MPA to azathioprine was done I slowly felt a relieve of the abdominal tension. The re-challenge with MPA made me then feel “like a balloon” after just a couple of doses.”
“I have never regretted the decision to have a kidney and pancreas transplantation, despite the complicated course I would always do it again. The full glycemic control and cessation of dialysis are important assets in my life that I would not want to miss any more.”