Influence of the new immunosuppressive combinations on arterial hypertension after renal transplantation
2002; Elsevier BV; Volume: 62; Linguagem: Inglês
10.1046/j.1523-1755.62.s82.16.x
ISSN1523-1755
Autores Tópico(s)Pregnancy and Medication Impact
ResumoInfluence of the new immunosuppressive combinations on arterial hypertension after renal transplantation. Arterial hypertension is highly prevalent after renal transplantation and may contribute to the risk of cardiovascular disease. Also, arterial hypertension has been reported to be an independent risk factor for graft failure. Immunosuppressive drugs such as corticosteroids, cyclosporine and tacrolimus may be important contributing factors to post-transplant hypertension. Recent data from multicenter trials and from conversion studies (cyclosporine to tacrolimus) suggest that renal transplant patients under tacrolimus-based therapy showed less arterial hypertension compared with cyclosporine treated patients. New immunosuppressive drugs, including mycophenolate mofetil and rapamycin, are not nephrotoxic and they do not have any hypertensive effect. New immunosuppressive combinations including mycophenolate mofetil in a triple therapy regimen (associated with corticosteroids and cyclosporine) can reduce blood pressure so that corticosteroids can be stopped or cyclosporine reduced or even eliminated. Non-nephrotoxic regimens using rapamycin (sirolimus) as basic immunosuppression, associated with azathioprine or mycophenolate mofetil, could reduce the incidence of post-transplant arterial hypertension. Also, in renal transplant patients initially immunosuppressed with rapamycin, cyclosporine and corticosteroids, after the elimination of CSA, a lower blood pressure is achieved. In summary, new protocols with mycophenolate mofetil and/or rapamycin may permit several combinations that offer important alternatives to classical immunosuppressive regimens to reduce the incidence and clinical impact of arterial hypertension after renal transplantation. Influence of the new immunosuppressive combinations on arterial hypertension after renal transplantation. Arterial hypertension is highly prevalent after renal transplantation and may contribute to the risk of cardiovascular disease. Also, arterial hypertension has been reported to be an independent risk factor for graft failure. Immunosuppressive drugs such as corticosteroids, cyclosporine and tacrolimus may be important contributing factors to post-transplant hypertension. Recent data from multicenter trials and from conversion studies (cyclosporine to tacrolimus) suggest that renal transplant patients under tacrolimus-based therapy showed less arterial hypertension compared with cyclosporine treated patients. New immunosuppressive drugs, including mycophenolate mofetil and rapamycin, are not nephrotoxic and they do not have any hypertensive effect. New immunosuppressive combinations including mycophenolate mofetil in a triple therapy regimen (associated with corticosteroids and cyclosporine) can reduce blood pressure so that corticosteroids can be stopped or cyclosporine reduced or even eliminated. Non-nephrotoxic regimens using rapamycin (sirolimus) as basic immunosuppression, associated with azathioprine or mycophenolate mofetil, could reduce the incidence of post-transplant arterial hypertension. Also, in renal transplant patients initially immunosuppressed with rapamycin, cyclosporine and corticosteroids, after the elimination of CSA, a lower blood pressure is achieved. In summary, new protocols with mycophenolate mofetil and/or rapamycin may permit several combinations that offer important alternatives to classical immunosuppressive regimens to reduce the incidence and clinical impact of arterial hypertension after renal transplantation. Arterial hypertension is a frequent and important complication after renal transplantation1First M.R. Neylan J.F. Rocher L.L. Tejani A. Hypertension after renal transplantation.J Am Soc Nephrol. 1994; 4: S30-S38PubMed Google Scholar, 2Morales J.M. Andres A. Rengel M. Rodicio J.L. Influence of cyclosporin, tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation.Nephrol Dial Transplant. 2001; 16: 121-124Crossref PubMed Scopus (93) Google Scholar, 3Textor S.C. Canzanello V.J. Taler S.J. et al.Cyclosporine-induced hypertension after renal transplantation.Mayo Clin Proc. 1994; 69: 1182-1193Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 4Zeier M. Mandelbaum A. Ritz E. Hypertension in the transplanted patient.Nephron. 1998; 80: 257-268Crossref PubMed Scopus (56) Google Scholar, 5Kasiske B.L. Ballantyne C.M. Cardiovascular risk associated with immunosuppression in renal transplantation.Transplant Rev. 2002; 16: 1-21Abstract Full Text PDF Scopus (18) Google Scholar. As in the general population hypertension has been associated with increased post-transplant cardiovascular morbidity and mortality5Kasiske B.L. Ballantyne C.M. Cardiovascular risk associated with immunosuppression in renal transplantation.Transplant Rev. 2002; 16: 1-21Abstract Full Text PDF Scopus (18) Google Scholar. In fact, cardiovascular disease is the leading cause of death in renal transplant patients with a functioning graft4Zeier M. Mandelbaum A. Ritz E. Hypertension in the transplanted patient.Nephron. 1998; 80: 257-268Crossref PubMed Scopus (56) Google Scholar,5Kasiske B.L. Ballantyne C.M. Cardiovascular risk associated with immunosuppression in renal transplantation.Transplant Rev. 2002; 16: 1-21Abstract Full Text PDF Scopus (18) Google Scholar, and arterial hypertension has been reported to be an independent risk factor for graft failure6Frei U. Schindler R. Wieters D. et al.Pre-transplant hypertension: A major risk for chronic progressive renal allograft dysfunction.Nephrol Dial Transplant. 1995; 10: 1206-1211PubMed Google Scholar, 7Opelz G. Wujciak T. Ritz E. the Collaborative Transplant Study Group Association of kidney graft failure with recipient blood pressure.Kidney Int. 1998; 53: 217-222Abstract Full Text PDF PubMed Scopus (528) Google Scholar, 8Mange K.C. Cizman B. Joffe M. Feldman H.L. Arterial hypertension and renal allograft survival.JAMA. 2000; 283: 633-638Crossref PubMed Scopus (253) Google Scholar. Therefore, hypertension requires an early and aggressive treatment. The incidence of hypertension after renal transplantation in the cyclosporine (CsA) era has varied from 50% to 80%4Zeier M. Mandelbaum A. Ritz E. Hypertension in the transplanted patient.Nephron. 1998; 80: 257-268Crossref PubMed Scopus (56) Google Scholar. In renal transplant recipients arterial hypertension may be caused by acute rejection, chronic allograft nephropathy, transplant renal artery stenosis, and immunosuppressive drugs such as corticosteroids and calcineurin inhibitors1First M.R. Neylan J.F. Rocher L.L. Tejani A. Hypertension after renal transplantation.J Am Soc Nephrol. 1994; 4: S30-S38PubMed Google Scholar, 2Morales J.M. Andres A. Rengel M. Rodicio J.L. Influence of cyclosporin, tacrolimus and rapamycin on renal function and arterial hypertension after renal transplantation.Nephrol Dial Transplant. 2001; 16: 121-124Crossref PubMed Scopus (93) Google Scholar, 3Textor S.C. Canzanello V.J. Taler S.J. et al.Cyclosporine-induced hypertension after renal transplantation.Mayo Clin Proc. 1994; 69: 1182-1193Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 4Zeier M. Mandelbaum A. Ritz E. Hypertension in the transplanted patient.Nephron. 1998; 80: 257-268Crossref PubMed Scopus (56) Google Scholar, 5Kasiske B.L. Ballantyne C.M. Cardiovascular risk associated with immunosuppression in renal transplantation.Transplant Rev. 2002; 16: 1-21Abstract Full Text PDF Scopus (18) Google Scholar. Other causes include pre-transplant hypertension in the recipient, donor hypertension, native kidneys, recurrent or de novo renal disease and increased body weight9Perez Fontan M. Rodriguez Carmona A. Garcia Falco T. et al.Early immunologic and non-immunologic predictors of arterial hypertension after renal transplantation.Am J Kidney Dis. 1999; 33: 21-28Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar. Corticosteroids, CsA and tacrolimus may be important contributing factors to post-transplant arterial hypertension. New immunosuppressive drugs such as mycophenolate mofetil (MMF) and—more recently—sirolimus are currently available to treat renal transplant patients, and new regimens combining old and new drugs have been started. However, information about the frequency and clinical impact of these strategies on hypertension is yet scarce. In this article I will review first the effects of immunosuppressive drugs on blood pressure, and second the influence of the new immunosuppressive regimens on the presence of arterial hypertension in renal transplant patients. Due to their immunosuppressive effect in preventing acute rejection and graft loss, corticosteroids continue to be useful in almost all transplant patients, although low doses and a rapid reduction in dosage are used10Hricik D.E. Lautman J. Bartucci M.R. et al.Variable effects of steroid withdrawal on blood pressure reduction in cyclosporine treated renal transplant recipients.Transplantation. 1992; 53: 1232-1236Crossref PubMed Scopus (87) Google Scholar. The efficacy of corticosteroids in post-transplant hypertension is well known1First M.R. Neylan J.F. Rocher L.L. Tejani A. Hypertension after renal transplantation.J Am Soc Nephrol. 1994; 4: S30-S38PubMed Google Scholar, 4Zeier M. Mandelbaum A. Ritz E. Hypertension in the transplanted patient.Nephron. 1998; 80: 257-268Crossref PubMed Scopus (56) Google Scholar, 5Kasiske B.L. Ballantyne C.M. Cardiovascular risk associated with immunosuppression in renal transplantation.Transplant Rev. 2002; 16: 1-21Abstract Full Text PDF Scopus (18) Google Scholar. Several factors such as sodium retention, increases in cardiac output and renal vascular resistance may induce arterial hypertension1First M.R. Neylan J.F. Rocher L.L. Tejani A. Hypertension after renal transplantation.J Am Soc Nephrol. 1994; 4: S30-S38PubMed Google Scholar,4Zeier M. Mandelbaum A. Ritz E. Hypertension in the transplanted patient.Nephron. 1998; 80: 257-268Crossref PubMed Scopus (56) Google Scholar. It has been demonstrated that the daily dose and cumulative dose of prednisone are related to blood pressure11Taler S.J. Textor S.C. Canzanello V.J. et al.Role of steroid dose in hypertension early after liver transplantation with tacrolimus and cyclosporine.Transplantation. 1996; 62: 1588-1592Crossref PubMed Scopus (60) Google Scholar,12Fryer J.P. Granger D.K. Leventhal J.R. et al.Steroid-related complications in the cyclosporine era.Clin Transplant. 1994; 8: 224-228PubMed Google Scholar. Currently, corticosteroids are not a major risk for arterial hypertension after renal transplantation due to the rapid reduction in dosage and mainly using new immunosuppressive regimens. In fact, one group estimated the incidence of arterial hypertension induced by corticosteroids was only 15% of their patient population13Veenstra D.L. Best J.H. Hornberger J. et al.Incidence and long-term cost of steroid-related side effects after renal transplantation.Am J Kidney Dis. 1999; 33: 829-833Abstract Full Text Full Text PDF PubMed Scopus (264) Google Scholar. However, it is clear that this drug therapy contributes to hypertension, since the elimination of corticosteroids in stable patients showed a reduction of blood pressure in most cases5Kasiske B.L. Ballantyne C.M. Cardiovascular risk associated with immunosuppression in renal transplantation.Transplant Rev. 2002; 16: 1-21Abstract Full Text PDF Scopus (18) Google Scholar. Cyclosporine A14Kahan B.D. Drug therapy: Cyclosporin.N Engl J Med. 1989; 321: 1725-1731Crossref PubMed Scopus (1581) Google Scholar or tacrolimus15Pirsch J.D. Miller J. Deierhoi M.H. et al.A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group.Transplantation. 1997; 63: 977-983Crossref PubMed Scopus (979) Google Scholar are the basic immunosuppressive regimens in the majority of renal transplant patients. It is well known that the immunosuppressive and nephrotoxic effects of CsA and tacrolimus appear to depend of calcineurin inhibition14Kahan B.D. Drug therapy: Cyclosporin.N Engl J Med. 1989; 321: 1725-1731Crossref PubMed Scopus (1581) Google Scholar,15Pirsch J.D. Miller J. Deierhoi M.H. et al.A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group.Transplantation. 1997; 63: 977-983Crossref PubMed Scopus (979) Google Scholar. Calcineurin is a protein phosphatase with important regulatory effects blocking the expression of T-cell activation genes14Kahan B.D. Drug therapy: Cyclosporin.N Engl J Med. 1989; 321: 1725-1731Crossref PubMed Scopus (1581) Google Scholar. Calcineurin is present in several tissues including the kidney, vascular smooth muscle and nervous system, all of which are targets for hypertension. It has been suggested that calcineurin inhibition in these tissues is the cause of the increase in sodium and water retention, vasoconstriction and sympathetic activity16Sander M. Lyson T. Thomas G.D. et al.Sympathetic neural mechanisms of cyclosporine-induced hypertension.Am J Hypertens. 1996; 9: S121-S127Crossref PubMed Scopus (75) Google Scholar. Both CsA and tacrolimus cause acute and chronic nephrotoxicity and arterial hypertension1First M.R. Neylan J.F. Rocher L.L. Tejani A. Hypertension after renal transplantation.J Am Soc Nephrol. 1994; 4: S30-S38PubMed Google Scholar. Mechanisms of these renal and vascular effects are believed to be multifactorial, including renal vasoconstriction of the afferent pre-glomerular arterioles, the increase in systemic vascular resistance, increase in sympathetic nervous tone, and activation of the renin-angiotensin system17Taler S.J. Textor S.C. Canzanello V.J. et al.Cyclosporine-induced hypertension: Incidence, pathogenesis and management.Drug Saf. 1999; 20: 437-457Crossref PubMed Scopus (118) Google Scholar,18Haas M. Mayer G. Cyclosporin A-associated hypertension-Pathomechanisms and clinical consequences.Nephrol Dial Transplant. 1997; 12: 395-397Crossref PubMed Scopus (28) Google Scholar. These may reflect an imbalance between vasoconstrictive factors, such as endothelin and thromboxane, and vasodilator factors, such as nitric oxide and prostacyclin, in CsA/tacrolimus treated patients17Taler S.J. Textor S.C. Canzanello V.J. et al.Cyclosporine-induced hypertension: Incidence, pathogenesis and management.Drug Saf. 1999; 20: 437-457Crossref PubMed Scopus (118) Google Scholar,18Haas M. Mayer G. Cyclosporin A-associated hypertension-Pathomechanisms and clinical consequences.Nephrol Dial Transplant. 1997; 12: 395-397Crossref PubMed Scopus (28) Google Scholar. The fact that the experimental administration of an endothelin receptor antagonist controlled CsA-induced hypertension strongly suggests that endothelin may play an important pathogenetic role in the development of hypertension19Takeda Y. Mitamori I. Wu P. et al.Effects of an endothelin receptor antagonist in rats with cyclosporine-induced hypertension.Hypertension. 1995; 26: 932-937Crossref PubMed Scopus (51) Google Scholar. Cyclosporine A-induced arterial hypertension has been described in autoimmune diseases and in renal, liver, heart and bone marrow transplantation14Kahan B.D. Drug therapy: Cyclosporin.N Engl J Med. 1989; 321: 1725-1731Crossref PubMed Scopus (1581) Google Scholar While the incidence of hypertension varies between 20 and 25% in patients with autoimmune disease18Haas M. Mayer G. Cyclosporin A-associated hypertension-Pathomechanisms and clinical consequences.Nephrol Dial Transplant. 1997; 12: 395-397Crossref PubMed Scopus (28) Google Scholar, hypertension in renal transplant patients using protocols with concomitant corticosteroids ranges between 50 and 80%18Haas M. Mayer G. Cyclosporin A-associated hypertension-Pathomechanisms and clinical consequences.Nephrol Dial Transplant. 1997; 12: 395-397Crossref PubMed Scopus (28) Google Scholar. CsA-induced hypertension also is characterized by nocturnal hypertension3Textor S.C. Canzanello V.J. Taler S.J. et al.Cyclosporine-induced hypertension after renal transplantation.Mayo Clin Proc. 1994; 69: 1182-1193Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar,17Taler S.J. Textor S.C. Canzanello V.J. et al.Cyclosporine-induced hypertension: Incidence, pathogenesis and management.Drug Saf. 1999; 20: 437-457Crossref PubMed Scopus (118) Google Scholar, and frequently is associated with some degree of renal dysfunction and with other cardiovascular risk factors such as hyperlipidemia4Zeier M. Mandelbaum A. Ritz E. Hypertension in the transplanted patient.Nephron. 1998; 80: 257-268Crossref PubMed Scopus (56) Google Scholar. It has been demonstrated that tacrolimus is as nephrotoxic as CsA15Pirsch J.D. Miller J. Deierhoi M.H. et al.A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group.Transplantation. 1997; 63: 977-983Crossref PubMed Scopus (979) Google Scholar. Nevertheless, tacrolimus has been associated with less systemic vasoconstriction and less arterial hypertension than CsA in liver transplant patients20Textor S.C. Weisner R. Wilson D.J. et al.Systemic and renal hemodynamic differences between FK506 and cyclosporine in liver transplant recipients.Transplantation. 1993; 55: 1332-1337Crossref PubMed Scopus (127) Google Scholar. In the most important U.S. and European pivotal studies comparing tacrolimus versus CsA (a classical formulation) there was no difference in the incidence of arterial hypertension reported as an adverse event Table 115Pirsch J.D. Miller J. Deierhoi M.H. et al.A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group.Transplantation. 1997; 63: 977-983Crossref PubMed Scopus (979) Google Scholar,21Mayer A.D. Dmitrewski J. Squifflet J.-P. et al.Multicentre randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection.Transplantation. 1997; 64: 436-443Crossref PubMed Scopus (614) Google Scholar. Although the use of antihypertensive medication was not statistically different in these trials, there was a tendency for lower values in the tacrolimus patients. Thus, in the U.S. study, by one year 39.4% of the tacrolimus and 30% CsA patients were off of all hypertensive drugs. Five year data from this study showed that the difference in antihypertensive drug use was significantly lower in tacrolimus patients: 81% versus 91.3% (P = 0.047)22Vincenti F. Jensik S.C. Filo R.S. et al.A long-term comparison of tacrolimus (FK506) and cyclosporine in kidney transplantation: Evidence for improved allograft survival at five years.Transplantation. 2002; 73: 775-782Crossref PubMed Scopus (322) Google Scholar. The most recent European multicenter study comparing tacrolimus with CsA microemulsion showed that the incidence of new-onset or worsening hypertension was less common in the tacrolimus group (16 vs. 23%, P = 0.032)23Margreiter R. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: A randomized multicentre study. The European Tacrolimus vs Ciclosporin-Microemulsion Renal Transplantation Study Group.Lancet. 2002; 359: 741-746Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar.Table 1Renal function (serum creatinine) and incidence of arterial hypertension at one year comparing tacrolimus versus CsA in multicenter trialsAuthors and referencesProtocolSerum creatinine μml/LArterial hypertension %Mayer et al21Mayer A.D. Dmitrewski J. Squifflet J.-P. et al.Multicentre randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection.Transplantation. 1997; 64: 436-443Crossref PubMed Scopus (614) Google ScholarS+Tacro+Aza20037S+CsA+Aza20039Pirsch et al15Pirsch J.D. Miller J. Deierhoi M.H. et al.A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group.Transplantation. 1997; 63: 977-983Crossref PubMed Scopus (979) Google ScholarS+Tacro+Aza14150S+CsA+Aza14152Margreiter et al23Margreiter R. Efficacy and safety of tacrolimus compared with ciclosporin microemulsion in renal transplantation: A randomized multicentre study. The European Tacrolimus vs Ciclosporin-Microemulsion Renal Transplantation Study Group.Lancet. 2002; 359: 741-746Abstract Full Text Full Text PDF PubMed Scopus (394) Google ScholarS+Tacro+Aza13916S+CsA Neoral+Aza14523Abbreviations are: S, steroids; Tacro, tacrolimus; AZA, azathioprine; CsA, cyclosporine; Neoral, (microemulsion). Open table in a new tab Abbreviations are: S, steroids; Tacro, tacrolimus; AZA, azathioprine; CsA, cyclosporine; Neoral, (microemulsion). Some authors also reported a decrease of mean arterial blood pressure in patients who were switched from CsA to tacrolimus because of hyperlipidemia, toxicity or rejection24Friemann S. Stopp K. Christ B. et al.Conversion to tacrolimus in hyperlipidemic patients.Transplant Proc. 1999; 31: S41-S44Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar,25Copley J.B. Staffeld C. Lindberg J. et al.Cyclosporine to tacrolimus: Effect on hypertension and lipid profile in renal allografts.Transplant Proc. 1998; 30: 1254-1257Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar. One study from The Netherlands examined 17 stable patients under CsA immunosuppression, and demonstrated that the mean daytime blood pressure values decreased from 149 ± 12 and 95 ± 8 mm Hg to138 ± 13 and 87 ± 9 mm Hg (P = 0.001) after they were switched to tacrolimus. The mean nighttime blood pressure values also significantly decreased. A return to CsA caused an increase in blood pressure to values similar to those during the first CsA period26Ligtenberg G. Hené R.J. Blankestijn P.J. Koomans H.A. Cardiovascular risk factors in renal transplant patients: Cyclosporin A versus tacrolimus.J Am Soc Nephrol. 2001; 12: 368-373PubMed Google Scholar. These data suggest that renal transplant patients under tacrolimus-based therapy showed less arterial hypertension compared with patients under CsA immunosuppression. Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, is a prodrug that is rapidly converted into mycophenolic acid after oral administration. MMF inhibits purine metabolism through inhibition of the enzyme inosine monophosphate dehydrogenase. MMF inhibits the proliferation of T and B cells and the synthesis of antibodies by B cells27Platz D.P. Sollinger H.W. Hullet D.A. et al.RS-61443, a new, potent immunosuppressive agent.Transplantation. 1991; 51: 27-31Crossref PubMed Scopus (209) Google Scholar. Associated with CsA and steroids, MMF demonstrated a reduction of acute rejection by approximately 50% in renal transplant patients28European Mycophenolate Mofetil Cooperative Study Group Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection.Lancet. 1995; 345: 1321-1325Abstract PubMed Google Scholar. The Federal Drug Administration approved its use in renal transplantation in 1995. Also, a recent study found that MMF reduced the incidence of chronic allograft failure and this effect was independent of acute rejection29Ojo A.O. Meier-Kriesche H.U. Hanson J.A. et al.Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection.Transplantation. 2000; 69: 2405-2409Crossref PubMed Scopus (398) Google Scholar, suggesting that MMF by its antiproliferative action may prevent chronic rejection. Renal and blood pressure data from all of the available literature support that MMF is not nephrotoxic and does not have any hypertensive effect27Platz D.P. Sollinger H.W. Hullet D.A. et al.RS-61443, a new, potent immunosuppressive agent.Transplantation. 1991; 51: 27-31Crossref PubMed Scopus (209) Google Scholar, 28European Mycophenolate Mofetil Cooperative Study Group Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection.Lancet. 1995; 345: 1321-1325Abstract PubMed Google Scholar, 29Ojo A.O. Meier-Kriesche H.U. Hanson J.A. et al.Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection.Transplantation. 2000; 69: 2405-2409Crossref PubMed Scopus (398) Google Scholar. Notably, MMF does not induce the presence of other cardiovascular risk factors, such as hyperlipidemia or diabetes5Kasiske B.L. Ballantyne C.M. Cardiovascular risk associated with immunosuppression in renal transplantation.Transplant Rev. 2002; 16: 1-21Abstract Full Text PDF Scopus (18) Google Scholar. Sirolimus (rapamycin) is a macrocyclic lactone isolated from Streptococus hygroscopicus30Sehgal S.N. Molnar-Kimbar K. Ocain T.D. Weichman B.M. Rapamycin. A novel immunosuppressive macrolide.Med Res Rev. 1994; 14: 1-22Crossref PubMed Scopus (167) Google Scholar. Although structurally homologous to tacrolimus and despite using the same binding protein, its mechanism of action is different. Sirolimus is a potent immunosuppressive agent that inhibits the mammalian target of rapamcycin (m-TOR), which plays an important role in cell cycling and does not inhibit calcineurin30Sehgal S.N. Molnar-Kimbar K. Ocain T.D. Weichman B.M. Rapamycin. A novel immunosuppressive macrolide.Med Res Rev. 1994; 14: 1-22Crossref PubMed Scopus (167) Google Scholar. Thus, it is anticipated that sirolimus will lack the nephrotoxic and hypertensive effects of calcineurin inhibitors31Andoh T.F. Burdmann E.A. Fransechini N. et al.Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506.Kidney Int. 1996; 50: 1110-1117Abstract Full Text PDF PubMed Scopus (180) Google Scholar,32Murgia M.G. Jordan S. Kahan B.D. The side effect profile of sirolimus: A phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients.Kidney Int. 1996; 49: 209-216Abstract Full Text PDF PubMed Scopus (222) Google Scholar. In addition to its action on immune cells, sirolimus inhibits growth-factor-induced proliferation of fibroblasts, endothelial cells, hepatocytes and smooth muscle cells33Kahan B.D. Camardo J.S. Rapamycin: Clinical results and future opportunities.Transplantation. 2001; 72: 1181-1193Crossref PubMed Scopus (211) Google Scholar. For both of these unique features, the non-calcineurin inhibitor immunosuppressive effect and suppression of growth-factor-induced smooth-muscle-cell proliferation and migration, sirolimus is considered to be an important non-nephrotoxic alternative to calcineurin inhibitor-based immunosuppression33Kahan B.D. Camardo J.S. Rapamycin: Clinical results and future opportunities.Transplantation. 2001; 72: 1181-1193Crossref PubMed Scopus (211) Google Scholar, 34Danovitch G.M. Immunosuppressive medications for renal transplantation: A multiple choice question.Kidney Int. 2001; 59: 388-402Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 35Backman L. Morales J.M. Is non-nephrotoxic immunosuppression a possibility?.Transplantation. 2000; 69: SS27-SS30PubMed Google Scholar. Sirolimus is not a nephrotoxic drug, at least not at the doses that are used in human transplantation, and it does not have any hypertensive effect. Experimentally, it has been demonstrated that high doses of sirolimus induced interstitial changes in the kidney31Andoh T.F. Burdmann E.A. Fransechini N. et al.Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506.Kidney Int. 1996; 50: 1110-1117Abstract Full Text PDF PubMed Scopus (180) Google Scholar. In a Phase I study sirolimus did not exacerbate the hypertensive response caused by corticosteroids and CsA32Murgia M.G. Jordan S. Kahan B.D. The side effect profile of sirolimus: A phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients.Kidney Int. 1996; 49: 209-216Abstract Full Text PDF PubMed Scopus (222) Google Scholar. However, in Phase III studies using sirolimus in combination with CsA, mild renal impairment and a higher frequency of arterial hypertension than control groups were observed (discussed later in this article)33Kahan B.D. Camardo J.S. Rapamycin: Clinical results and future opportunities.Transplantation. 2001; 72: 1181-1193Crossref PubMed Scopus (211) Google Scholar. It is possible that sirolimus can potentiate the nephrotoxic effects of cyclosporine, which would explain the increase of blood pressure33Kahan B.D. Camardo J.S. Rapamycin: Clinical results and future opportunities.Transplantation. 2001; 72: 1181-1193Crossref PubMed Scopus (211) Google Scholar. Currently, CsA or tacrolimus continues to be the choice for basic immunosuppression after renal transplantation34Danovitch G.M. Immunosuppressive medications for renal transplantation: A multiple choice question.Kidney Int. 2001; 59: 388-402Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar. The introduction of MMF and sirolimus permits several combinations. The most frequent regimens used in the United States and Europe are: cyclosporine, MMF and steroids or tacrolimus, and MMF and steroids34Danovitch G.M. Immunosuppressive medications for renal transplantation: A multiple choice question.Kidney Int. 2001; 59: 388-402Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar. To discuss the impact of the new combinations on blood pressure, data from the most important recently published multicenter trials are presented in this review only if information about arterial hypertension was available. Initial multicenter studies indicated that MMF associated with steroids and cyclosporine significantly reduces the incidence of acute rejection in renal transplant patients28European Mycophenolate Mofetil Cooperativ
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