Nephrol Dial Transplant (2004) 19: 2906–2908 doi:10.1093/ndt/gfh352
Case Report
Sirolimus and angiotensin-converting enzyme inhibitors together induce tongue oedema in renal transplant recipients Giovanni Stallone1, Barbara Infante1, Salvatore Di Paolo1, Antonio Schena1, Giuseppe Grandaliano1, Loreto Gesualdo2 and Francesco Paolo Schena1 1
Department of Emergency and Organ Transplant, Division of Nephrology, University of Bari and 2Chair of Nephrology, University of Foggia, Italy
Keywords: angiotensin-converting enzyme inhibitors; renal transplantation; sirolimus; tongue oedema
Introduction 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) Correspondence and offprint request to: Francesco Paolo Schena, MD, Division of Nephrology, Department of Emergency and Organ Transplant, University of Bari, Policlinico, Piazza Giulio Cesare, 11, 70124 Bari, Italy. Email:
[email protected]
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.
Case We followed 52 patients, aged between 42 and 60 years, who received a cadaveric primary renal transplant in our Outpatient Division from May 2001 to February 2002. Of these, 15 patients, older than 45 years, had received kidneys from sub-optimal donors. We define as ‘sub-optimal’ a donor who was hypertensive or older than 55 years, or both. In these patients, after induction with anti-CD25 Abs (two doses on days 0
Nephrol Dial Transplant Vol. 19 No. 11 ß ERA–EDTA 2004; all rights reserved
Sirolimus and ACEi induce tongue oedema
and 4), our protocol to prevent acute allograft rejection consisted of corticosteroids (500 mg of methylprednisolone intraoperatively, then 200 mg of prednisone daily, tapered to 25 mg by day 8 and to 5 mg by month 3) and SRL (with an initial loading dose of 15 mg/day, in the second post-transplant day, then 5 mg/day with the dose adjusted to maintain whole blood trough levels between 12 and 20 ng/ml within 3 months posttransplant). During follow-up, the dose of SRL ranged from 2 to 5 mg/day, resulting in whole blood trough levels between 8 and 15 ng/ml. The conventional protocol included cyclosporine/ tacrolimus, mycophenolate mofetil and prednisone, and it was applied to the remaining 37 patients. Accompanying pharmacological treatments variably consisted of omeprazole, terazosin and amlodipine. For all patients, with or without hypertension or proteinuria, ACEi (ramipril at doses 2.5–5 mg/day) was used. Of the 52 patients, 31 had been taking ramipril before renal transplantation, but it was stopped at the moment of transplantation because of haemodynamic effects, and then reintroduced within the first month after surgery when renal function became stable. At 1 month after introduction of ramipril, corresponding to 2 months after surgery, five of the SRLtreated patients developed tongue oedema. The oedema was bilateral and only in the tongue. Its severity was moderate, and it was not life threatening. The patients did not have histories of allergic reactions. Moreover, although the presence of mucosal angioedema is a wellknown ACEi side effect, all patients had taken ramipril before renal transplantation without adverse clinical events. Differential leukocyte counts revealed normal levels of eosinophils; IgE levels as well as C1q inhibitor concentrations were within their normal ranges. Radiological examination by MRI disclosed no reason for the oedema. Mucosal herpes simplex, oral aphtous ulcers, oral moniliasis or stomatitis were not observed. Mycotic, viral and bacterial cultures from the oral cavity were negative. Interestingly, all five patients were taking 5 mg/day of SRL, resulting in whole blood trough levels between 16 and 20 ng/ml (mean 18.4±1.7 ng/ml) and 5 mg/day of ACEi. It is important to stress that in these five patients both drugs were administered at high doses; in fact, the SRL trough levels of the remaining 10 patients were in the low range (mean 14.2±1.9 ng/ml), and they took 2.5 mg/day of ACEi. Due to the persistence of the oedema, ACEi was stopped without reduction of SRL dosage. Two weeks after the discontinuation of ramipril, and without modification of SRL trough levels, the oedema resolved. Three months later (specifically, 6–8 months after transplantation), when SRL trough levels were established between 8 and 12 ng/ml, and its oral dosage between 2 and 4 mg/day, in accordance with our immunosuppressive approach for patients who had received kidneys from sub-optimal donors, ramipril at a dose of 2.5 mg/day was reintroduced in all patients. None showed side effects. At present all these patients continue their treatments with SRL and ACEi.
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This particular side effect was absent in the other patients on SRL therapy and in the 37 patients on a conventional immunosuppressive protocol.
Discussion A generalized oedematous state after renal transplantation may occur due to various factors, such as uraemic volume overload, renal function insufficient to support adequate fluid excretion, graft rejection episodes or cyclosporine toxicity. In contrast, the patients described here developed a distinct pattern of oedema limited to the tongue. However, tongue oedema may be heterogeneous. The hallmarks of a response to an allergenic xenobiotic agent are elevated eosinophilic cell counts, itching, or both. Neither of these, nor other laboratory findings were present to suggest such a response in our five patients. Various infections may be accompanied by tongue oedema, such as bacterial infiltration or viral epidemic nephropathy [9] with or without renal impairment, respectively. Rapid onset and involvement of the lips, larynx and bowel characterize the oedema of angioedema. The patients involved did not present any of these characteristics, and the time frame strictly argued against this type of disease. The mechanism leading to the tongue oedema in our five patients is uncertain and open to speculation. Rabbit endothelial cells exposed to SRL have been shown to release increased amounts of prostacyclin, compared with those exposed to tacrolimus [10]. An excess of prostaglandins can lead to inadequate vasodilatation and thus increase fluid collection in peripheral organs; this effect may in turn be synergized by ACEi treatment which interferes with the kallicrein–kinin system [11]. Moreover, the side effect we noted occurred when full doses of SRL and ACEi were being taken; therefore, we hypothesized that the two drugs act synergistically only when full doses of both are being taken. In fact, no side effects were noted when the dose of SRL was reduced and ACEi was reintroduced at 2.5 mg/day. Side effects of macrolide antibiotics usually appear 2–3 weeks after initiation of therapy, thus a delayed reaction to the macrocyclic compound SRL is still a possibility. Tongue oedema has not yet been reported in association with other macrocyclic compounds. This is not surprising, because the duration of therapy with macrolide antibiotics is usually shorter than with SRL. On the other hand, an adverse pharmacological reaction to enalapril has been described, with severe respiratory obstruction, secondary to lingual oedema [12]. The incidence of this condition among the population of users of this drug amounts to about 1 per thousand. It is important to be aware of this phenomenon to avoid burdensome and costly investigations of patients showing this symptom during combination treatment with high doses of SRL and ACEi. Finally, we suggest that this symptom should not prevent
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patients from being treated with this potentially promising combination after renal transplantation. Conflict of interest statement. None declared.
References 1. Sehgal SN. Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression. Clin Biochem 1998; 31: 335–342 2. Kimball PM, Kerman RK, Van Buren CT, Lewis RM, Kats S, Kahan BD. Cyclosporine and rapamycin affect protein kinase C induction of the intracellular activation signal, activator of DNA replication. Transplantation 1993; 55: 1128–1136 3. Groth CG, Backaman L, Morales JM et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999; 67: 1036–1044 4. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. Lancet 2000; 356: 914–921
G. Stallone et al. 5. Mohaupt MG, Vogt B, Frey FJ. Sirolimus-associated eyelid edema in kidney transplant recipients. Transplantation 2001; 72: 162–164 6. Klahr S, Morrissey J. Angiotensin II and gene expression in the kidney. Am J Kidney Dis 1998; 31: 171–178 7. Szabo A, Lutz J, Schleimer K et al. Effect of angiotensinconverting enzyme inhibition on growth factor mRNA in chronic renal allograft rejection in the rat. Kidney Int 2000; 57: 982–990 8. Amuchastegui SC, Azzollini N, Mister M, Pezzotta A, Perico N, Remuzzi G. Chronic allograft nephropathy in the rat is improved by angiotensin II receptor blockade but not by calcium channel antagonism. J Am Soc Nephrol 1998; 9: 1948–1955 9. Kontkanen M, Puustjarvi T, Kauppi P, Lahdevirta J. Ocular characteristics in nephropathia epidemica or Puumala virus infection. Acta Ophthalmol Scand 1996; 74: 621–627 10. Yatscoff RW, Fryer J, Thliveris JA. Comparison of the effect of rapamycin and FK506 on release of prostacyclin and endothelin in vitro. Clin Biochem 1993; 26: 409–414 11. Tschope C, Schultheiss HP, Walther T. Multiple interactions between the renin–angiotensin and the kallikrein–kinin systems: role of ACE inhibition and AT1 receptor blockade. J Cardiovasc Pharmacol 2002; 39: 478–487 12. Lacosta Nicolas JL, Garcia Cano J, Sanchez del Hoyo A. Clinical case of tongue angioedema caused by enalapril. An Otorrinolaringol Ibero Am 2002; 29: 275–279 Received for publication: 5.2.04 Accepted in revised form: 15.4.04
