Influence of the new immunosuppressive combinations on arterial hypertension after renal transplantation

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1 Kidney International, Vol. 62, Supplement 82 (2002), pp. S81 S87 Influence of the new immunosuppressive combinations on arterial hypertension after renal transplantation JOSÉ M. MORALES Nephrology Department. Hospital 12 de Octubre, Madrid, Spain Influence of the new immunosuppressive combinations on arte- tion in the cyclosporine (CsA) era has varied from 50% rial hypertension after renal transplantation. Arterial hyper- to 80% [4]. In renal transplant recipients arterial hypertension is highly prevalent after renal transplantation and may tension may be caused by acute rejection, chronic allocontribute to the risk of cardiovascular disease. Also, arterial hypertension has been reported to be an independent risk factor graft nephropathy, transplant renal artery stenosis, and for graft failure. Immunosuppressive drugs such as corticosteroids, immunosuppressive drugs such as corticosteroids and cyclosporine and tacrolimus may be important contribut- calcineurin inhibitors [1 5]. Other causes include pre- ing factors to post-transplant hypertension. Recent data from transplant hypertension in the recipient, donor hypertenmulticenter trials and from conversion studies (cyclosporine to tacrolimus) suggest that renal transplant patients under taand increased body weight [9]. sion, native kidneys, recurrent or de novo renal disease crolimus-based therapy showed less arterial hypertension compared with cyclosporine treated patients. New immunosuppressive Corticosteroids, CsA and tacrolimus may be important drugs, including mycophenolate mofetil and rapamycin, are contributing factors to post-transplant arterial hyperten- not nephrotoxic and they do not have any hypertensive effect. sion. New immunosuppressive drugs such as mycopheno- New immunosuppressive combinations including mycophenolate mofetil (MMF) and more recently sirolimus are late mofetil in a triple therapy regimen (associated with corticocurrently available to treat renal transplant patients, and steroids and cyclosporine) can reduce blood pressure so that corticosteroids can be stopped or cyclosporine reduced or even new regimens combining old and new drugs have been eliminated. Non-nephrotoxic regimens using rapamycin (siroli- started. However, information about the frequency and mus) as basic immunosuppression, associated with azathioprine clinical impact of these strategies on hypertension is yet or mycophenolate mofetil, could reduce the incidence of postscarce. In this article I will review first the effects of transplant arterial hypertension. Also, in renal transplant paimmunosuppressive drugs on blood pressure, and second tients initially immunosuppressed with rapamycin, cyclosporine and corticosteroids, after the elimination of CSA, a lower blood the influence of the new immunosuppressive regimens on pressure is achieved. In summary, new protocols with mycophe- the presence of arterial hypertension in renal transplant nolate mofetil and/or rapamycin may permit several combinapatients. tions that offer important alternatives to classical immunosuppressive regimens to reduce the incidence and clinical impact of arterial hypertension after renal transplantation. EFFECTS OF IMMUNOSUPPRESSIVE DRUGS ON ARTERIAL HYPERTENSION Arterial hypertension is a frequent and important Corticosteroids complication after renal transplantation [1 5]. As in the Due to their immunosuppressive effect in preventing general population hypertension has been associated acute rejection and graft loss, corticosteroids continue with increased post-transplant cardiovascular morbidity to be useful in almost all transplant patients, although and mortality [5]. In fact, cardiovascular disease is the low doses and a rapid reduction in dosage are used [10]. leading cause of death in renal transplant patients with The efficacy of corticosteroids in post-transplant hypera functioning graft [4, 5], and arterial hypertension has tension is well known [1, 4, 5]. Several factors such as been reported to be an independent risk factor for graft sodium retention, increases in cardiac output and renal failure [6 8]. Therefore, hypertension requires an early vascular resistance may induce arterial hypertension and aggressive treatment. [1, 4]. It has been demonstrated that the daily dose and The incidence of hypertension after renal transplanta- cumulative dose of prednisone are related to blood pressure [11, 12]. Currently, corticosteroids are not a major Key words: cardiovascular disease, kidney graft, blood pressure, cyclosporine, tacrolimus, mycophenolate mofetil, sirolimus by the International Society of Nephrology S-81 risk for arterial hypertension after renal transplantation due to the rapid reduction in dosage and mainly using new immunosuppressive regimens. In fact, one group

2 S-82 Morales: Immunosuppression and hypertension post-tx Table 1. Renal function (serum creatinine) and incidence of arterial hypertension at one year comparing tacrolimus versus CsA in multicenter trials Serum creatinine Arterial hypertension Authors and references Protocol lml/l % Mayer et al [21] S Tacro Aza S CsA Aza Pirsch et al [15] S Tacro Aza S CsA Aza Margreiter et al [23] S Tacro Aza S CsA Neoral Aza Abbreviations are: S, steroids; Tacro, tacrolimus; AZA, azathioprine; CsA, cyclosporine; Neoral, (microemulsion). estimated the incidence of arterial hypertension induced tant corticosteroids ranges between 50 and 80% [18]. by corticosteroids was only 15% of their patient population CsA-induced hypertension also is characterized by noc- [13]. However, it is clear that this drug therapy turnal hypertension [3, 17], and frequently is associated contributes to hypertension, since the elimination of corticosteroids with some degree of renal dysfunction and with other in stable patients showed a reduction of cardiovascular risk factors such as hyperlipidemia [4]. blood pressure in most cases [5]. Tacrolimus versus cyclosporine Calcineurin inhibitors: Cyclosporine and tacrolimus It has been demonstrated that tacrolimus is as nephrotoxic Cyclosporine A [14] or tacrolimus [15] are the basic as CsA [15]. Nevertheless, tacrolimus has been immunosuppressive regimens in the majority of renal associated with less systemic vasoconstriction and less transplant patients. It is well known that the immunosuppressive arterial hypertension than CsA in liver transplant paappear and nephrotoxic effects of CsA and tacrolimus tients [20]. In the most important U.S. and European to depend of calcineurin inhibition [14, 15]. Calcineurin pivotal studies comparing tacrolimus versus CsA (a clas- is a protein phosphatase with important regula- sical formulation) there was no difference in the inci- tory effects blocking the expression of T-cell activation dence of arterial hypertension reported as an adverse genes [14]. Calcineurin is present in several tissues in- event (Table 1) [15, 21]. Although the use of antihypertensive cluding the kidney, vascular smooth muscle and nervous medication was not statistically different in these system, all of which are targets for hypertension. It has trials, there was a tendency for lower values in the tacrolimus been suggested that calcineurin inhibition in these tissues patients. Thus, in the U.S. study, by one year 39.4% is the cause of the increase in sodium and water retention, of the tacrolimus and 30% CsA patients were off of all vasoconstriction and sympathetic activity [16]. hypertensive drugs. Five year data from this study showed Both CsA and tacrolimus cause acute and chronic that the difference in antihypertensive drug use was significantly nephrotoxicity and arterial hypertension [1]. Mechanisms lower in tacrolimus patients: 81% versus 91.3% of these renal and vascular effects are believed to (P 0.047) [22]. The most recent European multicenter be multifactorial, including renal vasoconstriction of the study comparing tacrolimus with CsA microemulsion afferent pre-glomerular arterioles, the increase in sys- showed that the incidence of new-onset or worsening temic vascular resistance, increase in sympathetic nervous hypertension was less common in the tacrolimus group tone, and activation of the renin-angiotensin system (16 vs. 23%, P 0.032) [23]. [17, 18]. These may reflect an imbalance between vasoconstrictive Some authors also reported a decrease of mean arteane, factors, such as endothelin and thrombox- rial blood pressure in patients who were switched from and vasodilator factors, such as nitric oxide and CsA to tacrolimus because of hyperlipidemia, toxicity prostacyclin, in CsA/tacrolimus treated patients [17, 18]. or rejection [24, 25]. One study from The Netherlands The fact that the experimental administration of an endothelin examined 17 stable patients under CsA immunosupprespertension receptor antagonist controlled CsA-induced hy- sion, and demonstrated that the mean daytime blood strongly suggests that endothelin may play pressure values decreased from and 95 8 an important pathogenetic role in the development of mm Hg to and 87 9mmHg(P 0.001) after hypertension [19]. they were switched to tacrolimus. The mean nighttime Cyclosporine A-induced arterial hypertension has been blood pressure values also significantly decreased. A return described in autoimmune diseases and in renal, liver, to CsA caused an increase in blood pressure to heart and bone marrow transplantation [14] While the values similar to those during the first CsA period [26]. incidence of hypertension varies between 20 and 25% These data suggest that renal transplant patients under in patients with autoimmune disease [18], hypertension tacrolimus-based therapy showed less arterial hypertension in renal transplant patients using protocols with concomi- compared with patients under CsA immunosuppression.

3 Morales: Immunosuppression and hypertension post-tx S-83 NEW IMMUNOSUPPRESSIVE DRUGS: (discussed later in this article) [33]. It is possible that MYCOPHENOLATE MOFETIL AND SIROLIMUS sirolimus can potentiate the nephrotoxic effects of cyclo- Mycophenolate mofetil sporine, which would explain the increase of blood pressure [33]. Mycophenolate mofetil (MMF), the morpholinoethyl ester of mycophenolic acid, is a prodrug that is rapidly converted into mycophenolic acid after oral administra- EFFECTS OF THE NEW IMMUNOSUPPRESSIVE tion. MMF inhibits purine metabolism through inhibition COMBINATIONS ON POST-TRANSPLANT of the enzyme inosine monophosphate dehydrogenase. ARTERIAL HYPERTENSION MMF inhibits the proliferation of T and B cells and the Currently, CsA or tacrolimus continues to be the synthesis of antibodies by B cells [27]. Associated with choice for basic immunosuppression after renal trans- CsA and steroids, MMF demonstrated a reduction of plantation [34]. The introduction of MMF and sirolimus acute rejection by approximately 50% in renal transplant permits several combinations. The most frequent regipatients [28]. The Federal Drug Administration approved mens used in the United States and Europe are: cyclospoits use in renal transplantation in Also, a recent rine, MMF and steroids or tacrolimus, and MMF and study found that MMF reduced the incidence of chronic steroids [34]. To discuss the impact of the new combinaallograft failure and this effect was independent of acute tions on blood pressure, data from the most important rejection [29], suggesting that MMF by its antiprolifera- recently published multicenter trials are presented in this tive action may prevent chronic rejection. review only if information about arterial hypertension Renal and blood pressure data from all of the available was available. literature support that MMF is not nephrotoxic and does not have any hypertensive effect [27 29]. Notably, MMF Protocols using MMF in combination with CsA does not induce the presence of other cardiovascular risk or tacrolimus factors, such as hyperlipidemia or diabetes [5]. Initial multicenter studies indicated that MMF associated Sirolimus with steroids and cyclosporine significantly reduces the incidence of acute rejection in renal transplant pa- Sirolimus (rapamycin) is a macrocyclic lactone isolated tients [28, 36]. Unfortunately, only the pivotal American from Streptococus hygroscopicus [30]. Although struc- study comparing MMF versus azathioprine associated turally homologous to tacrolimus and despite using the with steroids, CsA and antithimocyte globulin (ATGAM), same binding protein, its mechanism of action is differ- contains information about arterial hypertension [36]. ent. Sirolimus is a potent immunosuppressive agent that Renal function and the incidence of hypertension were inhibits the mammalian target of rapamcycin (m-tor), similar between the groups (Table 2). which plays an important role in cell cycling and does This reduction of acute rejection using MMF and CsA not inhibit calcineurin [30]. Thus, it is anticipated that opened the possibility to test steroid-sparing immunosirolimus will lack the nephrotoxic and hypertensive ef- suppressive regimens. An interesting protocol from Eufects of calcineurin inhibitors [31, 32]. In addition to its rope and Australia that used two different corticosteroid action on immune cells, sirolimus inhibits growth-factor- regimens associated with MMF and CsA recently was induced proliferation of fibroblasts, endothelial cells, he- reported [37]. This was a multicenter, randomized, doupatocytes and smooth muscle cells [33]. For both of these ble blind study that used a low dose of steroids in one unique features, the non-calcineurin inhibitor immuno- arm that was stopped at three months, plus MMF 2 g suppressive effect and suppression of growth-factor- and standard (by center) CsA doses. The control group induced smooth-muscle-cell proliferation and migration, received a standard CsA dose, 2 g MMF, and the stansirolimus is considered to be an important non-nephro- dard dose of steroids. At one year this study demontoxic alternative to calcineurin inhibitor-based immuno- strated an acceptable increase of the acute rejection rate suppression [33 35]. in the group administered the lower doses of steroids Sirolimus is not a nephrotoxic drug, at least not at the (25 vs. 15%; most rejections were Banff I) counterbaldoses that are used in human transplantation, and it does anced by a significant reduction of corticosteroid side not have any hypertensive effect. Experimentally, it has effects such as arterial hypertension (mean systolic blood been demonstrated that high doses of sirolimus induced pressure at one year 141 vs. 134 mm Hg, P 0.001; mean interstitial changes in the kidney [31]. In a Phase I study diastolic blood pressure 83 vs mm Hg, P 0.01 in sirolimus did not exacerbate the hypertensive response the control group vs. low/stopped steroids, respectively), caused by corticosteroids and CsA [32]. However, in hyperlipidemia and bone loss. Renal function and sur- Phase III studies using sirolimus in combination with vival figures were similar between groups. In a very simi- CsA, mild renal impairment and a higher frequency of lar trial from The United States, using corticosteroid arterial hypertension than control groups were observed withdrawal at three months post-transplant in patients

4 S-84 Morales: Immunosuppression and hypertension post-tx Table 2. Renal function and arterial hypertension in patients under new immunosuppressive combination using MMF and Rapa Serum creatinine Arterial hypertension Authors [references] Protocol lml/l % Sollinger et al [36] S CsA Aza ATGAM in all groups S CsA MMF 2g ATGAM 150 S CsA MMF 3g ATGAM 148 Squifflet et al [43] Tacro S 157 Overall 32.8% Tacro MMF 1g S 142 Tacro MMF 2g S 145 Groth et al [46] S Rapa Aza S CsA Aza Kreis et al [47] S Rapa MMF S CsA MMF Morales et al [48] S Rapa Aza/MMF S CsA Aza/MMF Kahan et al [49] S CsA Rapa (2 mg) S CsA Rapa (5 mg) S CsA Aza McDonald et al [50] S CsA Placebo S CsA Rapa (2 mg) S CsA Rapa (5 mg) Johnson et al [52] S CsA Rapa S CsA Rapa (CyA withdrawn) Velosa et al [53] S Rapa CsA S Rapa CsA (withdrawn) Abbreviations are: S, steroids; Tacro, tacrolimus, AZA, azathioprine, CsA, cyclosporine, Neoral, (microemulsion); ATGAM, antithimocyte globulin. receiving MMF and CsA, the number of patients with different doses of MMF associated with tacrolimus (0.2 antihypertensive drugs was lower in this group versus mg/kg/day) in 242 renal transplant patients [43]. Three the maintenance group (at six months, 83 vs. 93%; P groups were established: tacrolimus and steroids versus 0.01). However, this study was stopped because of excess tacrolimus, steroids and MMF 1 g versus tacrolimus, rejection in the prednisone withdrawal group (especially steroids and MMF 2 g. At 12 months the graft survival in the black population) [38]. rates were 90%, 92% and 93% and patient survival rates Another option for using MMF was to evaluate protorate 100%, 97% and 97%, respectively. The acute rejection cols that stopped or reduced the dose of CsA. The possifunction was lower in the group with MMF 2 g, while renal bility of CsA withdrawal in patients with triple therapy and the incidence of arterial hypertension were including MMF was explored in a multicenter study from similar between groups (Table 2). The Pittsburgh experi- The Netherlands [39]. At six months after transplantatacrolimus ence comparing steroids and tacrolimus versus steroids, tion 212 patients were randomized to stop CsA or to stop plus MMF also showed a reduction of acute steroids versus maintain steroid therapy, CsA and MMF. rejection in the MMF arm, but was without differences Although at two years the patient and graft survival rates in renal function and survival rates. Overall, 32% of were similar, the rapid CsA withdrawal resulted in a patients were withdrawn from antihypertensive medica- significant increase of acute and chronic rejection, while tions [44]. prednisone withdrawal was safe and showed a reduction in mean arterial pressure ( at 6 months vs. 101 Protocols using sirolimus 1.4 mm Hg at two years; P 0.017). One single-center In the United States sirolimus was approved in combination study in patients with steroids, MMF and elimination of with CsA for preventing acute rejection, and regustudy CsA at three months showed an improvement of renal latory authorities in Europe approved sirolimus as an function, a decline of systolic and diastolic blood pressure, alternative to CsA for long-term maintenance therapy and a more favorable lipid profile compared with in renal transplant patients [45]. patients on triple therapy with MMF [40]. This study found Sirolimus as basic immunosuppression. The true ef- no difference in the incidence of acute rejection between fect of sirolimus on renal function and arterial hypertension the groups. Other experiences with a limited number of can be observed in the trials recently performed in patients either on a decreasing dose of CsA or replace- Europe. Sirolimus-based immunosuppression was evaluated ment of CsA by MMF due to nephrotoxicity showed an as an alternative to CsA microemulsion-based imment improvement of renal function as well as a significant munosuppression in cadaveric renal transplantation. In reduction of blood pressure [41, 42]. the first open-label Phase II study, 83 renal transplant A multicenter, randomized European study compared patients were randomized to receive sirolimus or CsA.

5 Morales: Immunosuppression and hypertension post-tx S-85 Fig. 1. Systolic (A ) and diastolic (B ) blood pressure after cyclosporine elimination in a protocol with steroids, sirolimus and cyclosporine [52]. Symbols are ( ) group A: steroids, sirotimus and cyclosporine; ( ) group B (cyclosporine elimination); ( ) randomization. P All patients also received steroids and azathioprine (Aza) [46]. The results at one year exhibited excellent graft (98% sirolimus vs. 90% CsA) and patient survival (100% vs. 98%) rates, a similar acute rejection rate, and also had a tendency to have a better renal function and a minor incidence of arterial hypertension (Table 2). In the second study of 78 patients, Aza was replaced by MMF 2 g/day in a design similar to previous study using sirolimus versus CsA. At 12 months the graft (92% sirolimus vs. 89% CsA) and patient survival (97% vs. 95%) rates again were excellent and without statistical differences. Although the number of acute rejections was a little bit high in the sirolimus patients, renal function was better while the incidence of arterial hypertension was similar to that of the CsA patients (Table 2) [47]. The results from these two studies subsequently were pooled, at two years exhibiting no differences in graft (90% sirolimus vs. 89% CsA) and patient survival (94% vs. 94%) [48]. Remarkably, renal function from week 10 through year 2 was significantly higher in the sirolimus-treated than in CsAtreated patients (glomerular filtration rate 69 vs. 57 ml/m at 2 years, P 0.004). Also, patients under the sirolimus regimen exhibited a lower incidence of hypertension (Table 2). Mean systolic and diastolic blood pressure values for sirolimus patients (N 31) were 132 and 79.2 mm Hg respectively, whereas CsA patients exhibited mean values of 137 and 82.5 mm Hg. Sirolimus in combination with cyclosporine. In the largest, multicenter, randomized Phase III study (N recipients 719), sirolimus at 2 or 5 mg/day was compared with Aza in combination with CsA microemulsion and corticosteroids [49]. At 12 months the survival rate was similar for grafts (97% sirolimus 2 mg, 96% sirolimus 5 mg and 98% Aza) and patients (95%, 93% and 94%, respectively). Use of sirolimus was associated with a statistically significant reduction in the incidence of acute rejection (30% vs. 17% vs. 12% at 6 months, respectively). Nevertheless, at 6 and 12 months, the mean serum creatinine concentrations were significantly higher in patients in the two sirolimus groups than in those in the Aza group. Arterial hypertension also was found more frequently in the sirolimus-csa combinations (Table 2). Another large study comparing placebo with sirolimus 2 or 5 mg/day with the same methodological design corroborated not only the reduction of rejection (41% vs. 25% vs. 19% at 6 months), but also the worsening of renal function at six months in the sirolimus groups. However, in this trial hypertension was similar in all groups (Table 2) [50]. These unexpected and important findings of an elevation of serum creatinine and high blood pressure in pa- tients under the sirolimus and CsA combination may be explained by the potentiation of the nephrotoxic effects of cyclosporine by sirolimus [45, 51]. In fact, it has been demonstrated that sirolimus augments CsA-induced re- nal dysfunction due to a pharmacokinetic interaction [45]. Therefore, these trials strongly suggest that renal function and arterial hypertension should be closely monitored, and CsA doses should be reduced in patients under sirolimus and CsA in combination. Cyclosporine elimination under sirolimus immunosup- pression. As a consequence of the results on renal function described earlier, the most recently published multicenter trial explored whether CsA could be eliminated from a sirolimus-csa-steroids regimen at 90 days. An open-label study was conducted in Europe, The United States and Australia that included 525 renal transplant patients. At three months plus weeks, the eligible patients (N 430; who were without previous vascular

6 S-86 Morales: Immunosuppression and hypertension post-tx rejection, no dialysis dependency and good renal func- renal transplantation. Fortunately, MMF and sirolimus tion) were randomized to remain on the sirolimus-csa- do not have any hypertensive effect. New immunosupsteroids regimen or to a withdrawal of CsA and continua- pressive combinations including MMF in a triple therapy tion of sirolimus (blood levels 20 to 30 ng/ml) and ste- regimen can reduce blood pressure by stopping the steroids. At 12 months the graft survival (96% vs. 97%) roids or reducing/eliminating CsA. Non-nephrotoxic proand patient survival (97% vs. 98%) rates were excellent. tocols using sirolimus as a basic immunosuppression could Although there was a non-significant increase in the inci- reduce the incidence of hypertension. Also, in patients dence of acute rejection in patients in whom CsA was with sirolimus-csa-steroids, a lower blood pressure is eliminated (20% vs. 13%), renal function improved and achieved after the elimination of CsA. Therefore, new a lower blood pressure was observed in this group (Table regimens with MMF and sirolimus permitting several 2 and Fig. 1) [52]. combinations offer important alternatives to the classic One study conducted in Europe and the United States immunosuppressive protocols to improve the incidence included 246 patients, of whom 181 were selected (with and clinical impact of arterial hypertension after renal similar exclusions as the previous trial) and randomized transplantation. at two months to receive sirolimus (dose 2 mg/dl), CsA Reprint requests to José M. Morales, M.D., Renal Transplant Unit, and steroids or sirolimus, steroids and with CsA discon- Nephrology Department, Hospital 12 de Octubre, Carretera de Andatinued. At one year, the graft survival (93% vs. 95%) and lucia km 5.400, Madrid, Spain. patient survival (97% vs. 96%) rates were not different. jmorales@h12o.es The acute rejection rate was also similar and, notably, renal function improved in the patients with an early REFERENCES elimination of CsA therapy (Table 2). The incidence of 1. First MR, Neylan JF, Rocher LL, Tejani A: Hypertension after arterial hypertension was lower and lower systolic blood renal transplantation. J Am Soc Nephrol 4(Suppl 1):S30 S38, 1994 pressure values were obtained after CsA withdrawal ( Morales JM, Andres A, Rengel M, Rodicio JL: Influence of cyclosporin, tacrolimus and rapamycin on renal function and arte- 3.2 vs mm Hg), but the diastolic blood rial hypertension after renal transplantation. Nephrol Dial Transpressure values were similar between groups [53]. plant 16(Suppl 1): , 2001 These trials strongly suggest that in selected patients, 3. 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