tailoring immunosuppressive therapy for renal transplant recipients

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Tailoring immunosuppressive therapy for renal transplant recipients Vanrenterghem YFCh. Tailoring immunosuppressive therapy for renal transplant recipients. Pediatr Transplantation 2001: 5: 467–472. # Munksgaard, 2002 Abstract: During the past decade several new potent immunosuppressive agents with different modes of action and different side-effect profiles have become available. Nowadays immunosuppression after renal transplantation is no longer one single regimen applicable to all patients. In the selection of the optimal immunosuppressive protocol, individual drug-related toxicity, recipient-related risk factors as well as donor organ characteristics have to be taken into account. This article will give an overview of the most recently developed immunosuppressive agents available for clinical use. Their individual mode of action and their different efficacy and safety profile will be described as basis for selection of each of these drugs in an attempt to tailor the optimal therapeutic regimen for the individual patient both in terms of short-term and long- term outcome. Yves F. Ch. Vanrenterghem Department of Nephrology, University Hospital Gasthuisberg, Leuven, Belgium Key words: kidney transplantation – immunosuppressive therapy Yves Vanrenterghem MD, PhD, Chairman Department of Nephrology, University Hospital Gasthuisberg, Herestraat 49, B3000 Leuven, Belgium Tel.: 32-16-344580 Fax. 32-16-344599 E-mail: [email protected] Accepted for publication 9 August 2001 With the introduction of CsA into clinical practice in the beginning of the 1980s, a major improve- ment in patient and graft survival after renal transplantation was seen. It soon became appar- ent that in contrast to the formerly used immunosuppressive agents such as azathioprine, corticosteroids and antilymphocyte globulins, this potent new immunosuppressive agent impaired renal function. This unexpected side-effect was, however, considered less important than the major benefits in terms of patient and graft survival and in terms of steroid sparing. In Europe CsA was mainly used with corticoster- oids, whereas in the US it was used with azathioprine in the so-called ‘triple drug therapy’. Over the past two decades these regimens have been used almost uniformly in all patients, irrespective of individual donor and recipient risk factors. In recent years new immunosuppres- sive agents with different modes of action and with different side-effect profiles have become available. Patients who in the past were consid- ered as less-ideal candidates for organ transplan- tation are no longer excluded from the waiting list. This policy resulted in a further increase in the waiting list, whereas the donor pool did not increase in parallel. Because of the growing gap between demand and supply, donors who in the past were considered as less suitable for organ donation have now become a substantial part of the donor pool. Nowadays immunosuppression is no longer one single regimen applicable to all patients. In the selection of the best immunosup- pressive protocol, individual drug-related toxi- city, recipient-related risk factors and also donor organ characteristics have to be taken into account. In this review article, the mode of action, the efficacy and the toxicity profile of the newer immunosuppressive agents will be briefly described. Some guidelines for tailoring the immunosuppressive therapy to the individual patient will be given. It must, however, be stressed that in most of the pivotal trials testing these new drugs adult transplant recipients have been used. Data in the specific pediatric transplant popula- tion are almost non-existent. Also, the doses Abbreviations: anti-IL-2 Ra antibody, anti-interleukin-2 receptor antibody; CsA, cyclosporin A; IMPDH, inosine 5- monophosphate dehydrogenase; IL-2, interleukin-2; mAbs, monoclonal antibodies; MMF, mycophenolate mofetil; MPA, mycophenolate acid; TGFb1, tumor necrosis factor b 1; TOR, target of rapamycin. Pediatr Transplantation 2001: 5: 467–472 Printed in UK. All rights reserved Copyright # Munksgaard 2001 Pediatric Transplantation ISSN 1397-3142 467

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Tailoring immunosuppressive therapy forrenal transplant recipients

Vanrenterghem YFCh. Tailoring immunosuppressive therapy for renaltransplant recipients.Pediatr Transplantation 2001: 5: 467–472. # Munksgaard, 2002

Abstract: During the past decade several new potent immunosuppressiveagents with different modes of action and different side-effect profileshave become available. Nowadays immunosuppression after renaltransplantation is no longer one single regimen applicable to all patients.In the selection of the optimal immunosuppressive protocol, individualdrug-related toxicity, recipient-related risk factors as well as donor organcharacteristics have to be taken into account. This article will give anoverview of the most recently developed immunosuppressive agentsavailable for clinical use. Their individual mode of action and theirdifferent efficacy and safety profile will be described as basis for selectionof each of these drugs in an attempt to tailor the optimal therapeuticregimen for the individual patient both in terms of short-term and long-term outcome.

Yves F. Ch. VanrenterghemDepartment of Nephrology, University HospitalGasthuisberg, Leuven, Belgium

Key words: kidney transplantation –

immunosuppressive therapy

Yves Vanrenterghem MD, PhD, Chairman

Department of Nephrology, University Hospital

Gasthuisberg, Herestraat 49, B3000 Leuven,

Belgium

Tel.: 32-16-344580

Fax. 32-16-344599

E-mail: [email protected]

Accepted for publication 9 August 2001

With the introduction of CsA into clinical practicein the beginning of the 1980s, a major improve-ment in patient and graft survival after renaltransplantation was seen. It soon became appar-ent that in contrast to the formerly usedimmunosuppressive agents such as azathioprine,corticosteroids and antilymphocyte globulins, thispotent new immunosuppressive agent impairedrenal function. This unexpected side-effect was,however, considered less important than themajor benefits in terms of patient and graftsurvival and in terms of steroid sparing. InEurope CsA was mainly used with corticoster-oids, whereas in the US it was used withazathioprine in the so-called ‘triple drug therapy’.Over the past two decades these regimens havebeen used almost uniformly in all patients,irrespective of individual donor and recipientrisk factors. In recent years new immunosuppres-sive agents with different modes of action and

with different side-effect profiles have becomeavailable. Patients who in the past were consid-ered as less-ideal candidates for organ transplan-tation are no longer excluded from the waiting list.This policy resulted in a further increase in thewaiting list, whereas the donor pool did notincrease in parallel. Because of the growing gapbetween demand and supply, donors who in thepast were considered as less suitable for organdonation have now become a substantial part ofthe donor pool. Nowadays immunosuppression isno longer one single regimen applicable to allpatients. In the selection of the best immunosup-pressive protocol, individual drug-related toxi-city, recipient-related risk factors and also donororgan characteristics have to be taken intoaccount.

In this review article, the mode of action, theefficacy and the toxicity profile of the newerimmunosuppressive agents will be brieflydescribed. Some guidelines for tailoring theimmunosuppressive therapy to the individualpatient will be given. It must, however, be stressedthat in most of the pivotal trials testing these newdrugs adult transplant recipients have been used.Data in the specific pediatric transplant popula-tion are almost non-existent. Also, the doses

Abbreviations: anti-IL-2 Ra antibody, anti-interleukin-2receptor antibody; CsA, cyclosporin A; IMPDH, inosine 5’-monophosphate dehydrogenase; IL-2, interleukin-2; mAbs,monoclonal antibodies; MMF, mycophenolate mofetil;MPA, mycophenolate acid; TGFb1, tumor necrosis factorb 1; TOR, target of rapamycin.

Pediatr Transplantation 2001: 5: 467–472

Printed in UK. All rights reserved

Copyright # Munksgaard 2001

Pediatric TransplantationISSN 1397-3142

467

referred to in this paper, therefore, are onlyrelevant for the adult population.

Selection based on the mode of action

When an appropriately processed and presentedantigen interacts with the T-cell receptor for thatspecific antigen, the resting T cell is activatedleading to de novo synthesis and secretion of IL-2and expression of high-affinity IL-2 receptors (1).The immunosuppressive properties of CsA andtacrolimus or FK-506 are mainly linked to theinhibition of the activity of calcineurin, a serine–threonine phosphatase that activates intracellulargene-promoting transcription factors involved inIL-2 and other cytokine gene activation (2). Todo so, CsA binds to the intracellular cyclophyllin,whereas tacrolimus binds to another cytoplasmicprotein called FK-binding protein. As both drugsblock the stimulated lymphocyte at the samelevel, and as side-effects such as nephrotoxicityare probably mediated through the same mechan-ism, both drugs should not be combined.

Anti-IL-2Ra mAbs such as the chimeric anti-body basiliximab (Simulect1, Novartis, Basle,Switzerland: t1/2 : 6.5 days), and the humanizedanti-Tac antibody daclizumab (Zenapax1,Roche, Basle, Switzerland: t1/2 : 20 days), blockthe interaction of IL-2 with its receptor. Thisbinding normally results in a rapid proliferationof the antigen-activated T cells (clonal expansion)leading to effector T-cells with helper, suppressoror cytotoxic abilities (3). The immunosuppressiveproperties of these mAbs have been demonstratedwhen given in the early post-operative period inassociation with other immunosuppressive agentssuch as calcineurin inhibitors and steroids.

The binding of IL-2 to its receptor will lead toactivation of an intracellular kinase complexresulting in the translation of mRNAs encodingregulators of the cell cycle. This kinase also calledTOR is inhibited by rapamycin, a recently testedcompound biochemically similar to tacrolimus.Rapamycin occupies the same intracellular recep-tor as tacrolimus (FK-binding protein) (4).Rapamycin has been tested in combination withCsA (both drugs interfere at completely differentlevels of the T-cell stimulation and proliferation)and more recently also in combination withtacrolimus. As CsA and tacrolimus bind to thesame intracellular protein, it was originallythought that both drugs could not be given incombination because of competition for the samebinding protein. It turned out later that whengiven in therapeutic concentrations, tacrolimusonly binds to a small part of the intracellular FK-

binding protein, leaving enough molecules avail-able for binding to rapamycin (5).

The final step in the T-cell proliferation is theintranuclear RNA and DNA synthesis. This stepis blocked by the purine synthesis inhibitors suchas azathioprine and MMF. The latter inhibits thede novo pathway of purine synthesis throughinactivation of the IMPDH enzyme (6). Incontrast to most other cell types, purine synthesisin lymphocytes is entirely dependent on the denovo pathway. For this reason the effect of MMFis mainly limited to dividing lymphocytes. Theimmunosuppressive properties of MMF havemainly been tested in combination with thecalcineurin inhibitors.

Selection based on efficacy

Most of the recent pharmacological and biologi-cal immunosuppressive agents have been tested incombination with one of the two calcineurininhibitors, CsA or tacrolimus. By combining thesedrugs it was hoped to further increase theirefficacy without increasing the toxicity. As patientand graft survival had reached a level that couldhardly be further improved, the incidence of acuterejection was used in most controlled trials as theprimary endpoint. In the two pivotal trialscomparing CsA and tacrolimus, no difference inpatient and graft survival was seen but patientstreated with tacrolimus had a significantly lowerincidence of acute rejections (7, 8). This differencewas still there when in a more recent trial CsA wasreplaced by the microemulsion formulationNeoral1, Novartis, Basle, Switzerland (9). Inthe Neoral-treated patients, biopsy proven rejec-tion after 6 months was 37.3% vs. 19.6% in thetacrolimus-treated patients (p ,0.001).

At a dose of 20 mg given prior to transplanta-tion and at day 4, basiliximab gives aCD25-receptor saturation for 30 days. In twoplacebo-controlled phase III trials, basiliximab incombination with steroids and CsA, significantlydecreased the incidence of acute rejection at 6 (–26to –31%) and 12 months (–23 to –29%); overallgraft and patient survival rates at 12 months,however, were similar with basiliximab andplacebo (10, 11). Daclizumab at a dose of 1 mg/kg given prior to transplantation and every2 weeks thereafter for a total of 5 doses, provideseffective CD25 saturation for a period of 90 days.A significant reduction in incidence of acuterejection episodes at 6 months was demonstratedin two placebo-controlled phase III studies, eitherin combination with steroids and CsA (28 vs. 47%)or with steroids, CsA and azathioprine (22 vs.

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35%) (12, 13). Moreover, in combination withtriple therapy, 6-month graft survival was sig-nificantly better in the daclizumab group. In thedouble-therapy trial, 6-month patient survivalwas significantly better in the daclizumab group.Whether daclizumab is superior to basiliximab interms of incidence of acute rejection and of graftand patient survival needs to be determined; onemight speculate that the slightly better resultsobtained with daclizumab in these trials is relatedto the more prolonged CD25-receptor saturationdue to a longer half-life and the longer dosingschedule in the daclizumab studies. Basiliximabhas the advantage that only two doses in the earlypost-operative days were given.

Three pivotal trials have tested the immuno-suppressive effect of MMF in combination withCsA (14–16). No difference in patient and graftsurvival was seen but the association of MMF in adaily dose of either 2 or 3 g reduced the incidenceof acute rejection by more than 50%. Morerecently, MMF in a daily dose of 1 and 2 g wasalso tested in combination with tacrolimus (17,18). In the US trial only the 2-g dose resulted in asignificant reduction of the incidence of acuterejection, whereas in the European trial the sameeffect was already seen with the 1-g dose.

Rapamycin was first tested in combination withCsA in renal transplant recipients (19, 20). In aphase II multicenter single-blind trial differentdoses of rapamycin (1, 3 and 5 mg/m2/day) werestudied in association with full-dose and reduced-dose CsA (19). A significantly lower incidence ofacute rejection was seen in the groups treated withrapamycin and full-dose CsA (8.5% at 6 months)as compared with the control group not receivingrapamycin (32%). In the groups receiving low-dose CsA this reduced incidence of rejection wasonly seen in non-African-Americans (10.7%). Thepublished experience with the use of rapamycin incombination with tacrolimus is limited to a fewpatients with type 1 diabetes mellitus receivingislet-cell transplantation and some liver transplantrecipients (5, 21). At present at least two multi-center trials evaluating the combination oftacrolimus and rapamycin in renal transplantpatients are under way. Preliminary experienceseems very promising. Two recent multicentertrials have evaluated rapamycin as an alternativefor calcineurin inhibitors, either in associationwith azathioprine and steroids or in associationwith MMF and steroids (22, 23). Rapamycin wasstarted in a dose of 16–24 mg/m2/day, followed by8–12 mg/m2/day. Then doses were adjusted toachieve steady-state trough levels of 30 ng/mL for2 months and 15 ng/mL thereafter. The incidence

of acute rejection of 41% in the patients treatedwith rapamycin and azathioprine may nowadaysbe considered as too high, when given togetherwith MMF the incidence was reduced to a moreacceptable level of 27.5%.

Selection based on side-effect profile

Nephrotoxicity is the major drawback of calci-neurin inhibitors. From a clinical point of view,both calcineurin inhibitors appear equallynephrotoxic. Both in the US- (7) and theEuropean-multicenter trial (8), no difference inrenal function was seen between the CsA- and thetacrolimus-treated patients. Based on a review ofthe literature and on his own experience, Mihatchconcluded that nephrotoxicity seems to be at leastas common in patients under tacrolimus as underCsA (24). Review of the protocol biopsies at 2 yrin the US-multicenter trial could also not revealany difference between the two groups (25).Whether the less pronounced stimulation of theproduction of the fibrogenic TGFa1 by tacroli-mus may result in less long-term renal damage isstill to be answered (26). Although both calci-neurin inhibitors induce arterial hypertension andhyperlipidemia, the effect is less pronounced fortacrolimus than for CsA. A 3-yr analysis of the UStrial results showed significantly lower levels ofserum cholesterol, triglicerides and LDL choles-terol in the tacrolimus-treated patients [198.9 vs.226.3 mg/dL, 158.5 vs. 193.4 mg/dL and 116.7 vs.138.7 mg/dL, respectively (27)]. Also in theEuropean trial, tacrolimus-treated patients hadsignificantly lower cholesterol and LDL choles-terol levels 1 yr after transplantation (28).Triglyceride levels were, however, not signifi-cantly different. A significant drop in serum lipidswas also documented in several studies afterconversion from CsA to tacrolimus (29). Also, inthese studies a lower systemic blood pressure wasseen in tacrolimus-treated patients. The diabeto-genic effect of calcineurin inhibitors is welldocumented (30). In the pivotal US-controlledtrial (7), the incidence of post-transplant diabetesmellitus was as high as 19.9% in the tacrolimus-treated patients vs. 4% in the CsA group. In theEuropean trial (6), the incidence was 8.3% and2%, respectively. In one-third of the tacrolimus-treated patients insulin could be stopped subse-quently. Risk factors for the development of post-transplant diabetes under tacrolimus therapy arethe tacrolimus dose and high trough levels, theconcomitant use of higher doses of steroids,advanced age of the recipients, the existence ofpretransplant prediabetes, obesity, and race. A

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subgroup analysis of the US trial results demon-strated that in particular African-Americans areat risk for post-transplant diabetes: 36.6% devel-oped diabetes at 12 months vs. 12.2% of theCaucasian-Americans (31). A higher percentageof the Caucasians could stop insulin therapy bythe end of the 2 yr. In more recent studies usinglower doses of tacrolimus, the incidence of de novodiabetes mellitus has further decreased. In the trialcomparing Neoral with tacrolimus, the incidenceof de novo diabetes was 4.5% in the tacrolimus-treated group and 2% in the Neoral-treated group(9). Pretransplant screening should now alsoinclude a glucose-tolerance test to detect patientsat special risk for post-transplant diabetes. Incontrast to CsA, tacrolimus does not inducehypertrichosis or gum hyperplasia (7, 8,29).

Both anti-IL-2 mAb preparations are safe andwell tolerated (no cytokine release syndrome) withcomparable incidence and pattern of infectionsand no increase in malignancies compared withthe placebo groups. Anaphylactic or allergicreactions and clinically significant antibody pro-duction has not been described until now. Bothagents are easy to administer via peripheral i.v.infusion during 15 min in an easy dosing schedule.

The combination of rapamycin with a full doseof CsA may result in over-immunosuppression asa high incidence of infectious complications wasseen in the patients receiving full-dose CsAtogether with 3 mg/m2/day of rapamycin (19).The recent trial combining rapamycin with CsAhas also shown an exacerbation of the CsA-induced toxic effects of renal dysfunction, hyper-tension and hyperlipidemia (20). Especially in thegroup receiving 5 mg/day of rapamycin in addi-tion to cyclosporin microemulsion, a higherincidence of hypercholesterolemia, hypertension,headache, hyperkalaemia and acne was foundthan in the control group receiving azathioprine.When used without CsA rapamycin seems not benephrotoxic. In both studies using rapamycinwithout CsA serum creatinine was significantlylower in the rapamycin-treated groups than in thecontrol groups treated withCsA (22, 23). Adverseevents more frequently seen with rapamycin werethrombocytopenia, hypercholesterolemia andhypertriglyceridemia (19, 20).

The side-effects of MMF are mainly of gastro-intestinal, hematological and infectious nature(14–16). Diarrhea and abdominal pain arefrequent side-effects. Diarrhea especially is inour experience the most frequent reason forstopping MMF. Although MMF was supposedto be lymphocyte selective, the controlled trialscomparing MMF with azathioprine have shown

an almost comparable incidence of leuco- andthrombocytopenia. Although the pivotal trialshave shown a trend for more CMV invasivediseases, the difference was not significant. In theEuropean trial more herpetic infections were seenin the MMF-treated groups than in the controlgroup (14). Interestingly, while in the threecontrol groups Pneumocystis Carinii infectionwas reported in 1–2.4% of the patients, no singlecase was seen in the MMF-treated groupssuggesting that MMF may have a protectiveeffect against Pneumocystis carinii infection.

Although it is well known that solid organtransplant recipients have an increased incidenceof malignancies and that this risk is correlatedwith the intensity of the immunosuppressivetherapy used, up to now none of the above-mentioned new immunosuppressive drugs havebeen associated with a particularly higher risk ofmalignancies.

Tailoring the immunosuppressive therapy

The availability of different immunosuppressiveagents with different modes of action anddifferent side-effect profiles allows the transplantphysician to tailor the immunosuppressivetherapy taking into account recipient-related aswell as donor-associated characteristics and riskfactors.

As the outcome of renal transplantation is moreand more determined by late patient death that isprimarily cardiovascular in origin, preferenceshould go to immunosuppressive regimens witha better cardiovascular risk profile. Over the past2 yr our standard induction immunosuppressiveprotocol consisted of tacrolimus in a starting dose0.2 mg/kg/day adapted to maintain trough levelsbetween 12 and 18 ng/mL for 3 months incombination with 1 g of MMF and 16 mg ofmethylprednisolone. The latter is tapered with2 mg per month. Withdrawal of steroids shouldbe considered in all patients. Recent studies haveshown that this may be possible in a highproportion of patients (32, 33). Especially inchildren, early withdrawal of steroids may have apositive impact on growth correction and socialrehabilitation.

Pediatric and adolescent renal graft recipientswhose immune system is still very potent,recipients who lost their first graft due toaggressive acute rejection, or recipients withhigh titers of circulating HLA-antibodies (.80%PRA) should receive a combination of very potentimmunosuppressive agents, including inductionwith one of the anti-IL-2Ra mAbs, tacrolimus,

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MMF and corticosteroids. Recipients of a com-bined kidney–pancreas allograft may also benefitfrom this potent induction protocol. By addinganti-IL-2Ra mAbs it may be possible to use lowerdoses of tacrolimus avoiding nephrotoxicity. Inour own recent experience this protocol usingtacrolimus trough levels between 5 and 10 ng/mLfrom the very beginning after transplantationresulted in a significantly better kidney functionthan when more conventional trough levels of10–20 ng/mL were used.

In patients at risk of developing post-transplantdiabetes, such as Afro-Americans, obese patientsor patients with a history of prediabetes pre-ference may go to CsA or its newer-formulationNeoral instead of tacrolimus.

Older transplant recipients whose immunesystem has become less competent may be treatedwith less aggressive regimens. Especially in theseolder patients receiving also kidneys from olderdonors calcineurin inhibitor sparing protocolsmay be used. In 1998, the Munich grouppublished preliminary results of a calcineurin-free induction protocol used in 12 patients olderthan 50 yr and receiving a kidney from an olderdonor (34). At present 55 patients (mean age6465 yr) were transplanted with the same induc-tion protocol (W. Land, personal communica-tion). Patients are treated with MMF 2 g/day,steroids started at 500 mg and tapered 20 mg/dayafter 1 week, and ATG (4 mg/kg/day) for10 days. Early acute rejection was seen in 14(25.5%) patients with one graft loss. One-yeargraft survival was 92.2%. Delayed graft functionwas seen in 33%. Patients who developed an acuterejection had a mean MPA trough level of2.661.8 ng/mL vs. 3.960.8 ng/mL (p ,0.001)for the patients who did not develop a rejection.

The absence of nephrotoxicity makes rapamy-cin an attractive alternative for the widely usedcalcineurin inhibitors, especially in patientsreceiving less optimal kidneys coming fromolder donors, non-heart beating donors andthose with less optimal preservation character-istics. On the other hand, the pronouncedhyperlipidemia seen in some patients may be anadditional risk factor in those categories ofpatients with an already increased cardiovascularmorbidity and mortality.

Soon after the introduction of CsA, there weremany discussions in the literature as to whether incase of initial non-function of the renal allograft,the start of this nephrotoxic drug should bepostponed. As the beneficial effect of postponingthe nephrotoxic calcineurin inhibitors in case ofinitial non-function has never been analyzed in a

prospective randomized trial, the policy in thisregard has been quite different from one center tothe other. The recent availability of potent non-nephotxic alternatives for calcineurin inhibitorsmay put a new light on this issue. Until now noprospective trials with these new drugs in patientswith initial non-function have been done.

The present discussion on the selection of theoptimal immunosuppressive protocol for theindividual patient has been based only on medicalconsiderations. This does, however, not meanthat in the final selection of which immunosup-pressive drugs will be chosen, economic factorsshould not be taken into account. The latterdiscussion, however, is out of the scope of thepresent overview.

Acknowledgments

Theauthor is theholderof the BaxterChair for RenalTransplantation

at the Catholic University of Leuven, Belgium.

References

1. WALDMANN TA. The interleukin-2 receptor. J Biol Chem1991: 266: 2681–2684.

2. JOHANSSON A, MOLLER E. Evidence that the immunosup-pressive effects of FK-506 and cyclosporine are identical.Transplantation 1990: 50: 1001–1007.

3. MAES BD, VANRENTERGHEM YF. Anti-interleukin-2recept-or monoclonal antibodies in renal transplantation.Nephrol Dial Transplant: 199: 2824–2826.

4. SEHGAL SN. Rapamune (sirolims, rapamycin). an over-view and mechanism of action. Ther Drug Monitor 1995:17: 660–665.

5. MCALISTER VC, GAO Z, PELTEKIAN K, et al. Sirolimus-tacrolimus combination immunosuppression. Lancet2000: 355: 376–377.

6. ALLISON AC, EUGUI EM. Purine metabolism and immu-nosuppressive effects of mycophenolate mofetil (MMF).Clin Transplant 1996: 10: 77–84.

7. PIRSCH JD, MILLER J, DEIERHOI MH, VINCENTI F, FILO RS.A comparison of tacrolimus (FK506) and cyclosporinefor immunosuppression after cadaveric renal transplan-tation. Transplantation 1997: 63: 977–983.

8. MAYER AD, DMITREWSKI J, SQUIFFLET JP, et al. Multicenterrandomized trial comparing tacrolimus (FK506) andcyclosporine in the prevention of renal allograft rejection.Transplantation 1997: 64: 436–443.

9. MARGREITER R, FOR THE EUROPEAN TACROLIMUS VS CICLO-

SPORIN-MICROEMULSION RENAL TRANSPLANTATION STUDY

GROUP. A prospective, randomized, multicentre studyto compare the efficacy and safety of tacrolimus andciclosporin-microemulsion in renal transplantation.Transplantation 2000: 69: S112(Abstract).

10. NASHAN B, MOORE R, AMLOT P, et al. Randomised trial ofbasiliximab versus placebo for control of acute cellularrejection in renal allograft recipients. Lancet 1997: 350:1193–1198.

11. KAHAN BD, RAJAGOPALAN PR, HALL M. Reduction of theoccurrence of acute cellular rejection among renal allo-graft recipients treated with basiliximab, a chimeric anti-

Immunosuppressive therapy

471

interleukin-2-recpetor monoclonal antibody. Transplan-tation 1999: 67: 276–284.

12. VINCENTI F, KIRKMAN R, LIGHT S, et al. Interleukin-2-re-ceptor blockade with daclizumab to prevent acute rejec-tion in renal transplantation. N Engl J Med 1998: 338:161–165.

13. NASHAN B, LIGHT S, HARDIE I, LIN A, JOHNSON JR. Reduc-tion of acute renal allograft rejection by daclizumab.Transplantation 1999: 67: 110–115.

14. EUROPEAN MYCOPHENOLATE MOFETIL COOPERATIVE STUDY

GROUP. Placebo-controlled study of mycophenolate mof-etil combined with cyclosporin and corticosteroids forprevention of acute rejection. Lancet 1995: 345: 1321–1325.

15. SOLLINGER HW, FORTHE US RENAL TRANSPLANT MYCOPHEN-

OLATE MOFETIL STUDY GROUP. Mycophenolate Mofetil forthe prevention of in primary cadaveric renal allograftrecipients. Transplantation 1995: 60: 225–232.

16. THE TRICONTINENTAL MYCOPHENOLATE MOFETIL RENAL

TRANSPLANT TRIAL STUDY GROUP. A blinded, randomizedclinical trial of mycophenolate mofetil for the preventionof acute rejection in cadaveric renal transplantation.Transplantation 1996: 61: 1029–1037.

17. VANRENTERGHEM Y, SQUIFFLET JP, FORSYTHE J, et al. Co-administration of tacrolimus and mycophenolate mofetilin cadaveric renal transplant recipients. Transplant Proc1998: 30: 1290–1291.

18. MILLER J. FOR THE FK506/MMF DOSE-RANGING KIDNEY

TRANSPLANT STUDY GROUP. Tacrolimus and mycopheno-late mofetil in renal transplant recipients: one year resultsof a multicenter, randomized dose ranging trial. Trans-plant Proc 1999: 31: 276–277.

19. KAHAN BD, JULIAN BA, PESCOVITZ MD, VANRENTERGHEM

Y, NEYLAN J. Sirolimus reduces the incidence of acuterejection episodes despite lower cyclosporine doses inCaucasian recipients of mismatched primary renalallografts: a phase II trial. Transplantation 1999: 68:1526–1532.

20. KAHAN BD, FOR THE RAPAMUNE US STUDY GROUP. Efficacyof sirolimus compared with azathioprine for reduction ofacute renal allograftrejection: a randomised multicentrestudy. Lancet 2000: 356: 194–.

21. SHAPIRO AM, LAKEY JR, RYAN EA, et al. Islet transplanta-tion in seven patients with type 1 diabetes mellitus usingglucocorticoid-free immunosuppressive regimen. N EnglJ Med 2000: 343: 230–238.

22. GROTH CG, BACKMAN L, MORALES JM, et al. Sirolimus(rapamycin) -based therapy in human renal transplanta-tion. Transplantation 1999: 67: 1036–1042.

23. KREIS H, CISTERNE JM, LAND W, et al. Sirolimus in asso-ciation with mycophenolate mofetil induction for the pre-

vention of acute graft rejection in renal allograft recip-ients. Transplantation 2000: 69: 1252–1260.

24. MIHATSCH MJ, KYO M, MOROZUMI K, et al. The side effectsof ciclosporine A and tacrolimus. Clin Nephrol 1998: 49:356–363.

25. SOLEZ K, VINCENTI F, FILO RS. Histopathologic findingsfrom 2-year protocol biopsies from a U.S. multicenterkidney transplant trial comparing tacrolimus versuscyclosporine. Transplantation 1998: 66: 1736–1740.

26. HUTCHINSON IV. An endothelin-transforming growthfactor beta pathway in the nephrotoxicity of immuno-suppressive drugs. Curr Opin Nephrol Hypertens 1998: 7:665–671.

27. JENSIK SC AND THE FK506 KIDNEY TRANSPLANT STUDY

GROUP. Tacrolimus (FK506) in kidney transplantation:three-year survival results of the US multicenter, ran-domized comparative trial. Transplant Proc 1998: 30:1216–1218.

28. CLAESSON K, MAYER AD, SQUIFFLET JP, et al. Lipoproteinpatterns in renal transplant patients: a comparison bet-ween FK506 and cyclosporine A patients. TransplantProc 1998: 30: 1292–1294.

29. FRIEMANN S, FEURING E, PADBERG W, ERNST W. Improve-ment of nephrotoxicity, hypertension, and lipid metabo-lism after conversion of kidney transplant recipients fromcyclosporine to tacrolimus. Transplant Proc 1998: 30:1240–1242.

30. WEIR MR, FINK JC. Risk for posttransplant diabetesmellitus with current immunosuppressive medications.Am J Kidn Dis 1999: 34: 1–13.

31. NEYLAN JF FOR THE FK506 KIDNEY TRANSPLANT STUDY

GROUP. Racial differences in renal transplantation afterimmunosuppression with tacolimus versus cyclosporine.Transplantation 1998: 65: 515–523.

32. VANRENTERGHEM Y, LEBRANCHU Y, HENE R, et al. Double-blind comparison of two corticosteroid regimens plusmycophenolate mofetil and cyclosporine for preventionof renal allograft rejection. Transplantation 2000: 70:1352–1359.

33. SALMELA K, VANRENTERGHEM Y, VAN HOOFF J, SQUIFFLET

JP, the European Tacrolimus/lMMF Renal Transplan-tation Study Group. Efficacy and safety of three monthsof Tacrolimus/steroids/MMF followed by a controlledwithdrawal of stroids or MMF. Results of a large,prospective, multicentre trial. Am J Transplantation2001: 1 (Suppl. 1): 246(Abstract).

34. ZANKER B, SCHNEEBERGER H, ROTHENPIELER U, et al. Myco-phenolate mofetil-based, cyclosporine-free induction andmaintenance immunosuppression. Transplantation1998: 66: 44–49.

Vanrenterghem

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