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

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Influence of the new immunosuppressive combinations on

arterial hypertension after renal transplantation

J

OSE´

M. M

ORALES

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

hyper-tension is highly prevalent after renal transplantation and may

tension may be caused by acute rejection, chronic

allo-contribute to the risk of cardiovascular disease. Also, arterial

graft nephropathy, transplant renal artery stenosis, and

hypertension has been reported to be an independent risk factor

immunosuppressive drugs such as corticosteroids and

for graft failure. Immunosuppressive drugs such as

corticoste-roids, 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 hyperten-multicenter trials and from conversion studies (cyclosporine

sion, native kidneys, recurrent or de novo renal disease

to tacrolimus) suggest that renal transplant patients under

ta-and increased body weight [9].

crolimus-based therapy showed less arterial hypertension

com-Corticosteroids, CsA and tacrolimus may be important

pared with cyclosporine treated patients. New

immunosuppres-sive drugs, including mycophenolate mofetil and rapamycin, are contributing factors to post-transplant arterial hyperten-not nephrotoxic and they do hyperten-not have any hypertensive effect. sion. New immunosuppressive drugs such as New immunosuppressive combinations including

mycopheno-late mofetil (MMF) and—more recently—sirolimus are

late mofetil in a triple therapy regimen (associated with

cortico-currently 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

post-scarce. In this article I will review first the effects of

transplant arterial hypertension. Also, in renal transplant

pa-immunosuppressive 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

combina-patients.

tions that offer important alternatives to classical immunosup-pressive regimens to reduce the incidence and clinical impact of arterial hypertension after renal transplantation.

EFFECTS OF IMMUNOSUPPRESSIVE DRUGS ON ARTERIAL HYPERTENSION

Corticosteroids Arterial hypertension is a frequent and important

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 hyper-a functioning grhyper-aft [4, 5], hyper-and hyper-arterihyper-al hypertension hhyper-as 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 pres-sure [11, 12]. Currently, corticosteroids are not a major risk for arterial hypertension after renal transplantation

Key words: cardiovascular disease, kidney graft, blood pressure,

cyclo-sporine, tacrolimus, mycophenolate mofetil, sirolimus. due to the rapid reduction in dosage and mainly using

new immunosuppressive regimens. In fact, one group

 2002 by the International Society of Nephrology

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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 200 37 S⫹CsA⫹Aza 200 39 Pirsch et al [15] S⫹Tacro⫹Aza 141 50 S⫹CsA⫹Aza 141 52 Margreiter et al [23] S⫹Tacro⫹Aza 139 16 S⫹CsA Neoral⫹Aza 145 23

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]. CsA-induced hypertension also is characterized by noc-by corticosteroids was only 15% of their patient

popula-tion [13]. However, it is clear that this drug therapy turnal hypertension [3, 17], and frequently is associated with some degree of renal dysfunction and with other contributes to hypertension, since the elimination of

cor-ticosteroids 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 nephro-toxic as CsA [15]. Nevertheless, tacrolimus has been Cyclosporine A [14] or tacrolimus [15] are the basic

immunosuppressive regimens in the majority of renal associated with less systemic vasoconstriction and less arterial hypertension than CsA in liver transplant pa-transplant patients. It is well known that the

immunosup-pressive and nephrotoxic effects of CsA and tacrolimus tients [20]. In the most important U.S. and European pivotal studies comparing tacrolimus versus CsA (a clas-appear to depend of calcineurin inhibition [14, 15].

Cal-cineurin is a protein phosphatase with important regula- sical formulation) there was no difference in the inci-dence of arterial hypertension reported as an adverse tory effects blocking the expression of T-cell activation

genes [14]. Calcineurin is present in several tissues in- event (Table 1) [15, 21]. Although the use of antihyper-tensive medication was not statistically different in these cluding the kidney, vascular smooth muscle and nervous

system, all of which are targets for hypertension. It has trials, there was a tendency for lower values in the tacroli-mus patients. Thus, in the U.S. study, by one year 39.4% been suggested that calcineurin inhibition in these tissues

is the cause of the increase in sodium and water retention, of the tacrolimus and 30% CsA patients were off of all hypertensive drugs. Five year data from this study showed vasoconstriction and sympathetic activity [16].

Both CsA and tacrolimus cause acute and chronic that the difference in antihypertensive drug use was sig-nificantly lower in tacrolimus patients: 81% versus 91.3% nephrotoxicity and arterial hypertension [1].

Mecha-nisms of these renal and vascular effects are believed to (P⫽ 0.047) [22]. The most recent European multicenter study comparing tacrolimus with CsA microemulsion be multifactorial, including renal vasoconstriction of the

afferent pre-glomerular arterioles, the increase in sys- showed that the incidence of new-onset or worsening hypertension was less common in the tacrolimus group temic vascular resistance, increase in sympathetic

ner-vous tone, and activation of the renin-angiotensin system (16 vs. 23%, P⫽ 0.032) [23].

Some authors also reported a decrease of mean arte-[17, 18]. These may reflect an imbalance between

vaso-constrictive factors, such as endothelin and thrombox- rial blood pressure in patients who were switched from CsA to tacrolimus because of hyperlipidemia, toxicity ane, and vasodilator factors, such as nitric oxide and

prostacyclin, in CsA/tacrolimus treated patients [17, 18]. or rejection [24, 25]. One study from The Netherlands examined 17 stable patients under CsA immunosuppres-The fact that the experimental administration of an

en-dothelin receptor antagonist controlled CsA-induced hy- sion, and demonstrated that the mean daytime blood pressure values decreased from 149 ⫾ 12 and 95 ⫾ 8 pertension strongly suggests that endothelin may play

an important pathogenetic role in the development of mm Hg to138⫾ 13 and 87 ⫾ 9 mm Hg (P ⫽ 0.001) after they were switched to tacrolimus. The mean nighttime hypertension [19].

Cyclosporine A-induced arterial hypertension has been blood pressure values also significantly decreased. A re-turn to CsA caused an increase in blood pressure to described in autoimmune diseases and in renal, liver,

heart and bone marrow transplantation [14] While the values similar to those during the first CsA period [26]. These data suggest that renal transplant patients under incidence of hypertension varies between 20 and 25%

in patients with autoimmune disease [18], hypertension tacrolimus-based therapy showed less arterial hypertension compared with patients under CsA immunosuppression. in renal transplant patients using protocols with

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concomi-NEW IMMUNOSUPPRESSIVE DRUGS: (discussed later in this article) [33]. It is possible that sirolimus can potentiate the nephrotoxic effects of cyclo-MYCOPHENOLATE MOFETIL AND SIROLIMUS

sporine, which would explain the increase of blood pres-Mycophenolate mofetil

sure [33]. Mycophenolate mofetil (MMF), the morpholinoethyl

ester of mycophenolic acid, is a prodrug that is rapidly

EFFECTS OF THE NEW IMMUNOSUPPRESSIVE converted into mycophenolic acid after oral

administra-COMBINATIONS ON POST-TRANSPLANT tion. MMF inhibits purine metabolism through inhibition

ARTERIAL HYPERTENSION of the enzyme inosine monophosphate dehydrogenase.

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 regi-patients [28]. The Federal Drug Administration approved mens used in the United States and Europe are: cyclospo-its use in renal transplantation in 1995. 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 combina-allograft 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

Protocols using MMF in combination with CsA not have any hypertensive effect [27–29]. Notably, MMF

or tacrolimus does not induce the presence of other cardiovascular risk

factors, such as hyperlipidemia or diabetes [5]. Initial multicenter studies indicated that MMF associ-ated with steroids and cyclosporine significantly reduces

Sirolimus 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 immuno-sirolimus will lack the nephrotoxic and hypertensive ef- suppressive regimens. An interesting protocol from Eu-fects 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, dou-patocytes 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 stan-sirolimus is considered to be an important non-nephro- dard dose of steroids. At one year this study demon-toxic 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) counterbal-doses 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. 79.9 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 withdrawal at three months post-transplant in patients arterial hypertension than control groups were observed

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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 155 30.3–32.3 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 115 17 S⫹CsA⫹Aza 133 33 Kreis et al [47] S⫹Rapa⫹MMF 79 40 S⫹CsA⫹MMF 88 47 Morales et al [48] S⫹Rapa⫹Aza/MMF 120–130 30 S⫹CsA⫹Aza/MMF 140–150 48 Kahan et al [49] S⫹CsA⫹Rapa (2 mg) 160 38 S⫹CsA⫹Rapa (5 mg) 171 34 S⫹CsA⫹Aza 133 23 McDonald et al [50] S⫹CsA⫹Placebo 146 44 S⫹CsA⫹Rapa (2 mg) 155 42 S⫹CsA⫹Rapa (5 mg) 162 47 Johnson et al [52] S⫹CsA⫹Rapa 158 16

S⫹CsA⫹Rapa (CyA withdrawn) 142 7

Velosa et al [53] S⫹Rapa⫹CsA 160 45

S⫹Rapa⫹CsA (withdrawn) 121 26

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 mg/kg/day) in 242 renal transplant patients [43]. Three antihypertensive drugs was lower in this group versus

groups were established: tacrolimus and steroids versus the maintenance group (at six months, 83 vs. 93%; P

tacrolimus, steroids and MMF 1 g versus tacrolimus, 0.01). However, this study was stopped because of excess

steroids and MMF 2 g. At 12 months the graft survival rejection in the prednisone withdrawal group (especially

rates were 90%, 92% and 93% and patient survival rates in the black population) [38].

100%, 97% and 97%, respectively. The acute rejection Another option for using MMF was to evaluate

proto-rate was lower in the group with MMF 2 g, while renal cols that stopped or reduced the dose of CsA. The

possi-function and the incidence of arterial hypertension were bility of CsA withdrawal in patients with triple therapy

similar between groups (Table 2). The Pittsburgh experi-including MMF was explored in a multicenter study from

ence comparing steroids and tacrolimus versus steroids, The Netherlands [39]. At six months after

transplanta-tacrolimus plus MMF also showed a reduction of acute tion 212 patients were randomized to stop CsA or to stop

rejection in the MMF arm, but was without differences steroids versus maintain steroid therapy, CsA and MMF.

in renal function and survival rates. Overall, 32% of Although at two years the patient and graft survival rates

patients were withdrawn from antihypertensive medica-were similar, the rapid CsA withdrawal resulted in a

tions [44]. significant increase of acute and chronic rejection, while

prednisone withdrawal was safe and showed a reduction

Protocols using sirolimus in mean arterial pressure (104⫾ 1.3 at 6 months vs. 101 ⫾

1.4 mm Hg at two years; P ⫽ 0.017). One single-center In the United States sirolimus was approved in combi-nation with CsA for preventing acute rejection, and regu-study in patients with steroids, MMF and elimination of

CsA at three months showed an improvement of renal latory authorities in Europe approved sirolimus as an alternative to CsA for long-term maintenance therapy function, a decline of systolic and diastolic blood

pres-sure, and a more favorable lipid profile compared with in renal transplant patients [45].

Sirolimus as basic immunosuppression. The true

ef-patients on triple therapy with MMF [40]. This study found

no difference in the incidence of acute rejection between fect of sirolimus on renal function and arterial hyperten-sion can be observed in the trials recently performed in the groups. Other experiences with a limited number of

patients either on a decreasing dose of CsA or replace- Europe. Sirolimus-based immunosuppression was evalu-ated as an alternative to CsA microemulsion-based im-ment of CsA by MMF due to nephrotoxicity showed an

improvement of renal function as well as a significant munosuppression in cadaveric renal transplantation. In the first open-label Phase II study, 83 renal transplant reduction of blood pressure [41, 42].

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Fig. 1. Systolic (A ) and diastolic (B ) blood pressure after cyclosporine elimination in a protocol with steroids, sirolimus and cyclosporine [52].

Symbols are (䊉) group A: steroids, sirotimus and cyclosporine; (䊊) group B (cyclosporine elimination); ( ) randomization. P ⬍ 0.05.

All patients also received steroids and azathioprine (Aza) respectively). Use of sirolimus was associated with a statis-tically significant reduction in the incidence of acute re-[46]. The results at one year exhibited excellent graft (98%

sirolimus vs. 90% CsA) and patient survival (100% vs. jection (30% vs. 17% vs. 12% at 6 months, respectively). Nevertheless, at 6 and 12 months, the mean serum creati-98%) rates, a similar acute rejection rate, and also had

a tendency to have a better renal function and a minor nine concentrations were significantly higher in patients in the two sirolimus groups than in those in the Aza group. incidence of arterial hypertension (Table 2). In the

sec-ond study of 78 patients, Aza was replaced by MMF 2 Arterial hypertension also was found more frequently in the sirolimus-CsA combinations (Table 2).

g/day in a design similar to previous study using sirolimus

versus CsA. At 12 months the graft (92% sirolimus vs. Another large study comparing placebo with sirolimus 2 or 5 mg/day with the same methodological design corrob-89% CsA) and patient survival (97% vs. 95%) rates again

were excellent and without statistical differences. Although orated not only the reduction of rejection (41% vs. 25% vs. 19% at 6 months), but also the worsening of renal function the number of acute rejections was a little bit high in

the sirolimus patients, renal function was better while the at six months in the sirolimus groups. However, in this trial hypertension was similar in all groups (Table 2) [50]. incidence of arterial hypertension was similar to that of

the CsA patients (Table 2) [47]. The results from these These unexpected and important findings of an eleva-tion of serum creatinine and high blood pressure in pa-two studies subsequently were pooled, at pa-two years

ex-hibiting no differences in graft (90% sirolimus vs. 89% tients under the sirolimus and CsA combination may be explained by the potentiation of the nephrotoxic effects CsA) and patient survival (94% vs. 94%) [48].

Remark-ably, renal function from week 10 through year 2 was of cyclosporine by sirolimus [45, 51]. In fact, it has been demonstrated that sirolimus augments CsA-induced re-significantly higher in the sirolimus-treated than in

CsA-treated patients (glomerular filtration rate 69 vs. 57 mL/m nal dysfunction due to a pharmacokinetic interaction [45]. Therefore, these trials strongly suggest that renal at 2 years, P⫽ 0.004). Also, patients under the sirolimus

regimen exhibited a lower incidence of hypertension (Ta- function and arterial hypertension should be closely monitored, and CsA doses should be reduced in patients ble 2). Mean systolic and diastolic blood pressure values

for sirolimus patients (N⫽ 31) were 132 and 79.2 mm Hg under sirolimus and CsA in combination.

Cyclosporine elimination under sirolimus

immunosup-respectively, whereas CsA patients exhibited mean

val-ues of 137 and 82.5 mm Hg. pression. As a consequence of the results on renal

func-tion described earlier, the most recently published

multi-Sirolimus in combination with cyclosporine. In the

largest, multicenter, randomized Phase III study (N re- center trial explored whether CsA could be eliminated from a sirolimus-CsA-steroids regimen at 90 days. An cipients⫽ 719), sirolimus at 2 or 5 mg/day was compared

with Aza in combination with CsA microemulsion and open-label study was conducted in Europe, The United States and Australia that included 525 renal transplant corticosteroids [49]. At 12 months the survival rate was

similar for grafts (97% sirolimus 2 mg, 96% sirolimus patients. At three months plus weeks, the eligible pa-tients (N ⫽ 430; who were without previous vascular 5 mg and 98% Aza) and patients (95%, 93% and 94%,

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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 immunosup-steroids 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 ste-roids. At 12 months the graft survival (96% vs. 97%) roids or reducing/eliminating CsA. Non-nephrotoxic pro-and 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 Jose´ M. Morales, M.D., Renal Transplant Unit, and steroids or sirolimus, steroids and with CsA

discon-Nephrology Department, Hospital 12 de Octubre, Carretera de Anda-tinued. At one year, the graft survival (93% vs. 95%) and lucia km 5.400, 28041 Madrid, Spain.

E-mail: jmorales@h12o.es patient survival (97% vs. 96%) rates were not different.

The acute rejection rate was also similar and, notably,

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