Sirolimus and angiotensin-converting enzyme inhibitors together induce tongue oedema in renal transplant recipients.

Sirolimus (rapamycin; SRL) is a macrocyclin lactone with a novel mechanism of immunosuppression. Via its c-7 methoxy group, SRL cross-links the immunophilin FK binding protein 12 (a peptide-prolyl isomerase that acts as a folding catalyst) to the multifunctional serinethreonine kinase, the mammalian target of rapamycin [1]. By blocking co-stimulation signals, SRL prevents the activation of the inhibitory factor, kappa kinase, necessary for the generation of the c-Rel transcription factors of the NF-kB complex, and it possibly also modulates protein kinase C activity [2]. Both the therapeutic and the toxic effects of SRL are related to the same cellular actions. The reported pattern of the side effects of SRL in humans includes, but is not limited to, hyperlipidaemia, infections (such as Pneumocystis carinii pneumonia), headache, nausea, mild dizziness, lower limb oedema, diarrhoea, epistaxis and dose-dependent decreased platelet counts [3,4]. A single report describes an atypical oedema of the eyelid [5]. Angiotensin-converting enzyme inhibitors (ACEi) have been shown to prevent or blunt the progression of renal damage, both functional and morphological, by inducing the down-regulation of the intrarenal angiotensin II (Ang II) level through the relative inhibition of renal ACE activity [6]. The blocking of the intrarenal renin–angiotensin system (RAS), in turn, would potently contribute to the inhibition of the local formation of transforming growth factor-b 1 (TGF-b1) and the accumulation of TGF-b1-mediated extracellular matrix (ECM), both of which are related to the protective effects of ACEi on kidneys [6,7]. Ang II blockade has been recently shown to prevent the development of renal injury in animal models of chronic allograft rejection, by mechanism(s) independent of the reduction of systemic blood pressure [7,8]. These studies have demonstrated the protective effect of RAS antagonists in immunologically mediated diseases such as anti-glomerular basement membrane nephritis and chronic allograft rejection [7,8]. Furthermore, ACEi are extensively used in different clinical settings, such as hypertension, atherosclerosis and several renal diseases, in which immuno-pathogenetic mechanisms have been considered to play a crucial role. Such observations suggested to us that the therapeutic combination of SRL and ACEi may ameliorate graft survival via a different and independent mechanism. On the other hand, the benefits of the two drugs are counterbalanced by their side effects, probably resulting from their synergic action when both drugs were administered in full doses. We observed a particular side effect during combination therapy with SRL and ACEi in renal transplanted patients. We describe here, for the first time, the occurrence of tongue oedema in five renal transplant patients concomitantly with combined SRL and ACEi therapy.