Mycophenolate mofetil in cyclosporin-associated thrombotic microangiopathy.

Nephrol Dial Transplant (1998) 13: 3212–3213 Nephrology Dialysis Transplantation Case Report Mycophenolate mofetil in cyclosporin-associated thrombotic microangiopathy Leslie Lecornu-Heuze1, Didier Ducloux1, Jean-Michel Rebibou1, Laurent Martin2, Claude Billerey2 and Jean-Marc Chalopin1 1Department of Nephrology and Renal Transplantation, Hopital Saint Jacques and 2Department of Pathology, Hopital Minjoz, Besançon, France Key words: renal transplantation; cyclosporin; thrombotic microangiopathy Introduction Thrombotic microangiopathy is a syndrome in which thrombocytopenia and microangiopathic haemolytic anaemia occur together with acute renal failure and a characteristic renal vascular pathology [1]. Its prevalence in renal transplant recipients is estimated to be 4% [2]. Both experimental and clinical data suggest a direct role for cyclosporin A (CsA) in the pathogenesis of post-transplant thrombotic microangiopathy. Renal endothelial cell injury mediated through the inhibition of PGI2 is believed to be the pathogenetic mechanism of CsA-induced thrombotic microangiopathy [3,4]. Despite different therapeutic strategies, the prognosis of CsA-associated thrombotic microangiopathy remains poor. CsA withdrawal is the cornerstone of treatment. However, CsA withdrawal exposes the patient to a major risk of acute rejection. Although some authors have suggested that CsA reintroduction is possible, this attitude remains controversial because of the possible relapse of a life-threatening disease [5]. Some authors have reported successful conversion from CsA to Tacrolimus [6 ] but Tacrolimus has also been associated with thrombotic microangiopathy [7]. We describe a favourable course of CsA-associated thrombotic microangiopathy in three renal transplant recipients after CsA withdrawal and concomittant switch from azathioprine (AZA) to mycophenolate mofetil (MMF ). Case Table 1 summarizes the three case reports. Correspondence and offprint requests to: Didier Ducloux, Department of Nephrology and Renal Transplantation, Saint Jacques Hospital, Besançon, France. Discussion Allograft biopsies confirmed the diagnosis of thrombotic microangiopathy in cases 2 and 3. In case 1, biopsy was not performed but the laboratory parameters were typical of thrombotic microangiopathy. They all had thrombocytopenia and schizocytes with other signs indicative of haemolysis. Moreover, the stability of SCr argue against vascular rejection. We attributed the thrombotic microangiopathy to CsA because no patient had a past history of pre-transplant thrombotic microangiopathy, allograft biopsies did not demonstrate any signs of acute rejection and all the patients improved without rejection therapy after CsA withdrawal. No infection previously associated with thrombotic microangiopathy could be detected in any of the patients. In these cases, we decided to avoid the use of both CsA and Tacrolimus and to replace AZA by MMF. Large studies have demonstrated that MMF is superior to AZA as a post-transplant immunosuppressant [8]. MMF may have a CsA-sparring effect allowing CsA withdrawal without acute rejection in post-transplant thrombotic microangiopathy. None of the three patients have experienced acute rejection 8, 11 and 17 months after transplantation, respectively. Although not controlled, this report suggests that an immunosuppressive regimen with steroids and MMF could be effective when both CsA and Tacrolimus are contraindicated. Interestingly, Van Gelder et al. recently described a similar case report [9]. Because CsAinduced thrombotic microangiopathy is a rare condition, individual anecdotes are the only information we have on managing this problem. It should be noted that it was a first transplantation for the three patients and that none of them had panel reactive antibody. Moreover, all of them had received immunosuppressive induction with polyclonal antithymocyte globulins. Our conclusion might be not true for other patient categories. It is conceivable that MMF might have a favourable direct effect on the course of thrombotic microangiopa- © 1998 European Renal Association–European Dialysis and Transplant Association 11 months 8 months fibrin thrombi mesangiolysis fibrin thrombi in arterioles 108 mmol/l 57 mmol/l 17 months Nd References 1. Neild GH. Haemolytic uraemic syndrome. Nephron 1991; 59: 194–200 2. Hochsletler LA, Flanigan MJ, Lager DJ. Transplant-associated thrombotic microangiopathy: the role of IgG administration as initial therapy. Am J Kidney Dis 1994; 23: 444–450 3. Neild GH, Rocchi G, Imberti L. Effect of cyclosporin A on prostacyclin synthesis by vascular tissue. Thromb Res 1983; 32: 373–379 4. Brown Z, Neild GH. Cyclosporin inhibits prostacyclin production by cultured human endothelial cells. Transplant Proc 1987; 19: 1178–1180 5. Young BA, Marsh CL, Alpers CE, Davis CL. Cyclosporineassociated thrombotic microangiopathy/hemolytic uremic syndrome following kidney and kidney-pancreas transplantation. Am J Kidney Dis 1996; 28: 561–571 6. Richardson D, Jones CH, Newstead CG, Will EJ, Lodge JP. The successful conversion to tacrolimus (FK506) of a renal transplant recipient with cyclosporin-induced haemolyticuraemic syndrome. Nephrol Dial Transplant 1996; 11: 2498–2500 7. Ichihashi T, Naoe T, Yoshida H et al. Haemolytic uraemic syndrome during FK 506 therapy. Lancet 1992; 340: 60–61 8. Halloran P, Mathew T, Tomlanovich S, Groth C, Hooftman L, Barker C. Mycophenolate mofetil in renal allograft recipients. Transplantation 1997; 63: 39–47 9. Van gelder T, Klaassen RJL, van Riemdijk-van Overbeeke IC, Ijzermans JNM, Weimar W. Mycophenolate mofetil and prednisone as maintenance treatment after kidney transplantation. Transplantation 1997; 63: 1530–1531 10. Eugui EM, Allison AC. Immunosuppressive activity of mycophenolate mofetil. Ann NY Acad Sci 1993; 685: 309 HUS, haemolytic uraemic syndrome. Tr, Transplantation. 175 ng/ml 13 d 50 Patient 3 F APKD 186 ng/ml 2 months 41 Patient 2 M MPGN 125 ng/ml 3 weeks interstitial nephritis F 65 Patient 1 3213 thy. By inhibiting the proliferation of vascular smooth muscle cells [10], MMF may have a beneficial effect on TMA-induced myointimal proliferation. In addition, because neutrophil adhesion to endothelial cells contributes to endothelial damage in thrombotic microangiopathy, MMF, which interferes with the glycosylation of adhesion molecules [10], may interact with this pathway and limit vascular damage. To conclude, CsA-associated thrombotic microangiopathy is a serious complication in renal transplantation. Prompt CsA withdrawal with concomittant switch from AZA to MMF seems to be a safe and effective therapeutic option. anaemia schizocytes thromocytopenia LDH (1898 IU/l ) creatinine (375 mmol/l ) anaemia schizocytes thrombocytopenia LDH (1758 IU/l ) creatinine (155 mmol/l ) schizocytes thrombocytopenia LDH (940 IU/l ) 201 mmol/l Serum creatinine concentration at follow-up Time of HUS after Tr Nephropathy Gender A (...truncated)