switch to 1.5 grams mmf monotherapy for cni-related toxicity in liver transplantation is safe and...

ORIGINAL ARTICLE

Switch to 1.5 Grams MMF Monotherapy for CNI-Related Toxicity in Liver Transplantation Is Safeand Improves Renal Function, Dyslipidemia,and HypertensionGiuseppe Orlando,1 Leonardo Baiocchi,2 Andrea Cardillo,1 Giuseppe Iaria,1 Nicola De Liguori,1

Linda De Luca,1 Benedetto Ielpo,1 Laura Tariciotti,1 Mario Angelico,2 and Giuseppe Tisone1

1Transplant and General Surgery Unit, S. Eugenio Hospital, and 2Department of Gastroenterology andHepatology, Tor Vergata University of Rome, Italy

Although mycophenolate mofetil (MMF) monotherapy has been successfully used in liver transplant recipients suffering fromcalcineurin-inhibitor (CNI)-related chronic toxicity, still no consensus has been reached on its safety, efficacy and tolerability.We attempted the complete weaning off CNI in 42 individuals presenting chronic renal dysfunction and/or dyslipidemia and/orarterial hypertension and simultaneously introduced 1.5 gm/day MMF. CNI could be completely withdrawn in 41 cases. A totalof 32 (75%) patients are currently on �1.5 gm/day of MMF. Mean follow-up from the introduction of MMF is 31.5 months andmean length of follow-up from the beginning of MMF monotherapy is 27.3 months. Renal function improved in 31/36 (89%)cases. Blood levels of cholesterol and triglycerides decreased in 13 of 17 (76%) and 15 of 17 (89%) patients, respectively.Arterial hypertension improved in 4 of 5 (80%) cases. A total of 8 patients showed a single episode of fluctuation of liver functiontests during tapering off CNI. This feature was interpreted as an acute rejection (AR), based on the resolution of the clinicalsetting after escalation of MMF daily dose to 2 gm. A further patient developed a biopsy-proven AR insensitive to MMFadjustment, requiring reinstitution of the CNI dose. No deaths or major toxicity requiring MMF discontinuation occurred. Inconclusion, low dose MMF monotherapy is safe, effective, and well tolerated. Liver Transpl 13:46-54, 2007.© 2006 AASLD.

Received May 20, 2006; accepted July 16, 2006.

Mycophenolate mofetil (MMF) is the semisynthetic esterprodrug of mycophenolic acid (MPA), which is a revers-ible inhibitor of the inosine-monophosphate-dehydro-genase, required for de novo synthesis of guaninenucleosides.1 The central immunological effect of MPAis the induction of a relatively selective inhibition of Band T lymphocyte proliferation. In addition, MPA inhib-its the production of a wide variety of cytokines, theglycosylation of adhesion molecules in leukocytes, andthe proliferation of arterial smooth-muscle cells.1-3 Fi-nally, MPA exert in vitro antiviral and antifibrotic ef-fects, which have been recently confirmed in hepatitis Cvirus� liver transplant (LT) recipients.3,4

MPA was first used in humans for the treatment of

psoriasis at the daily dose of 3 to 5 gm.5 In organtransplantation, the potential role of MMF as an immu-nosuppressant became clear in studies conducted onanimal models,3,6 whose promising results led to theintroduction of the drug in heart and kidney transplan-tation first, and liver, pancreas and intestine, later,mainly in reason of its nephro- and neurosparing prop-erties. In LT, the drug is normally used as part of mul-tidrug regimens, either ab initio to allow the utilizationof calcineurin-inhibitor (CNI) at lower doses in order toreduce CNI-related adverse events, or in itinere toachieve reduction or withdrawal of CNI in case of severechronic toxicity.1,7-12 In a few studies, MMF was givenin monotherapy after complete CNI withdrawal for

Abbreviations: MMF, mycophenolate mofetil; MPA, mycophenolic acid; LT, liver transplantation; CNI, calcineurin inhibitor; AR, acuterejection; GFR, glomerular filtration rate; CRD, chronic renal dysfunction.Address reprint requests to Professor Giuseppe Tisone, MD, Tor Vergata University of Rome, Surgical Clinic, S. Eugenio Hospital, VialeUmanesimo 10–00144 Rome, Italy, I-00149 Rome. Telephone: 39-06-51002280; FAX: 39-06-5922681; E-mail: [email protected]

DOI 10.1002/lt.20926Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 13:46-54, 2007

© 2006 American Association for the Study of Liver Diseases.

chronic renal dysfunction (CRD) and/or arterial hyper-tension and/or hyperlipidemia and/or de novo tu-mor.13-19 Thus far, no agreement has been reached onthe topic. Although an unacceptably high risk of severeacute rejection (AR) was described by Fairbanks andThuluvath15 and Stewart et al.,18 other authors docu-mented better results.13,14,16,17,19 Note that, in all tri-als, MMF was administered at the currently recom-mended fixed daily dose of 2 gm, MPA monitoring wasnot adopted, and MMF-related toxicity, involvingmainly the gastrointestinal tract and the bone marrow,was reported in 13 to 57% of cases.20,21

Our group has always adopted minimal immunosup-pressive regimens,22,23 given the well known tolero-genic properties of the liver. In the last decade, severalauthors suggested that, whichever solid organ is con-sidered, transplant recipients may be “overimmuno-suppressed” rather than being “immunomodulated.”24

This allows speculation that immunosuppressive regi-mens milder than those currently used might beequally effective, while preserving patients from short-and long-term drug toxicity. Therefore, we undertookthis study to evaluate whether, in patients with CNI-chronic toxicity, the conversion to 1.5 gm/day MMFmonotherapy could be as effective as the 2 gm/daystandard scheme, without exposing patients to an in-creased risk of immunological (rejection) and/or non-immunological adverse events.

PATIENTS AND METHODS

Patients

The prospective trial started in December 2002, afterthe approval from the institutional review board of TorVergata University of Rome (Rome, Italy). A written con-sent form was obtained from each patient. The studywas conducted in conformance with the principles ofthe Declaration of Helsinki and was single-armed. Thestudy population consisted of adult liver transplantedpatients presenting 1 or more of the following CNI-related adverse events: CRD, hyperlipemia, arterial hy-pertension, and gingival hyperplasia. All individualsmet the following criteria: recipient of a single LT, atleast 1 yr follow-up from surgery, stable graft function,and compliance with treatment. Exclusion criteriawere: previous causes of CRD and/or arterial hyperten-sion and/or hyperlipidemia, previous history of severeAR, white blood cell count �2,000/mm3, PLT �50,000/mm3, hemoglobin � 8 gm/dL, and malignancies.

The study sample was represented by a group of 42individuals of mean age 60.1 (range 35-67) yr, male/female ratio 34/8, transplanted between 1992 and2004. The mean time from transplantation to enroll-ment in the study was 70.5 � 35.1 months. At baseline,patients were receiving cyclosporine A (n � 37) or ta-crolimus (n � 5) in monotherapy and mean bloodtrough levels were 129 � 71 and 2.3 � 1.8 ng/mL,respectively. Of note, no patient was on maintenancesteroids, since they are not part of our standard immu-nosuppression maintenance protocol.22 Indication to

switch to MMF was CRD alone (n � 22), CRD withhyperlipemia (n � 10), hypercholesterolemia (n � 4),CRD, hypertension and hyperlipemia (n � 2), CRD andhypertension (n � 2), hypercholesterolemia and hyper-tension (n � 1), and gingival hyperplasia (n � 1). Fourpatients were receiving antihypertensive drugs, while 5were under statins. Patient characteristics are summa-rized in Table 1.

Treatment Protocol

MMF was introduced at the dose of 250 mg per os bidand progressively increased by 500 mg weekly, in orderto reach the full daily dose of 1,500 mg. Cyclosporine Aor tacrolimus were simultaneously tapered by 25% ofthe initial dose every month, independently of the bloodtrough levels. Weaning off CNI was conducted untilcomplete withdrawal was achieved, provided that liverfunction tests and patient conditions remained stable.Once-a-day dosing, or daily-spaced administrationwere not considered.

Monitoring

At baseline, all patients underwent physical examina-tion, extensive laboratory testing (kidney and liver func-tion tests, blood glucose, blood cell count, clotting func-tion, cholesterol, triglycerides, and uric acid), andsequential renal scintigraphy for the evaluation of glo-merular filtration rate (GFR).12 GFR was measured us-ing the Gates methodology,25 which allows clearancemeasurement in venous blood after injection of iodin-ated contrast medium.

Blood biochemistry was repeated monthly, as well aswhen the CNI dose was 50% of baseline and at time of

TABLE 1. Demographic Characteristics of

Patients at Baseline

Number of patients 42Age 60.1 (35–67)Male/female 34/8Indication to LT (%)

HCV-related end-stage liver disease 15 (36%)HBV-related end-stage liver disease 12 (29%)Alcoholic cirrhosis 7 (17%)Cryptogenetic cirrhosis 4 (9%)Primary biliary cirrhosis 3 (7%)Carcinoid tumor 1 (2%)

Time from LT to baseline (months) 70.5 � 35.1Immunosuppression at the time of

enrollment (%)CsA 37 (88%)Tac 5 (12%)

Blood trough levels at baseline(mean)CsA (ng/mL) 129 � 71Tac (ng/mL) 2.3 � 1.8

Abbreviations: HCV, hepatitis C virus; HBV, chronichepatitis B; CsA, cyclosporine A; Tac, tacrolimus.

MMF MONOTHERAPY FOR LT CNI-RELATED TOXICITY 47

LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases

withdrawal in successful cases. Thereafter, patientswere followed according to the standard protocol. Liverand kidney function tests, serum cholesterol, triglycer-ides, and GFR were monitored to evaluate the responseto treatment.

When a flare of transaminases and/or of cholestaticmarkers (gamma glutamyl transferase, alkaline phos-phatase, and bilirubin] by �2� the baseline values wasobserved, a closer surveillance was enforced (weeklyblood drawings). In absence of any amelioration on 2further controls, and after exclusion of other possiblecauses, the presumptive diagnosis of AR was formu-lated. This led to adaptation of MMF and/or CNI dailydose. When biochemical abnormalities did not respondto therapy adjustment, the patient underwent percuta-neous liver biopsy. Evidence of biopsy-proven severe ARdetermined the adoption of steroid standard treatmentand exclusion of the patient from the study. Adversereactions were collected prospectively, based on patientreports and objective clinical data at the outpatientvisit. Patients were clearly and extensively informedabout MMF side effects and were invited to report anychange in their well being.1

MPA-C0 trough levels were measured on every bloodsample, using the enzymatic immunoassay Emit 2000Mycophenolic Acid Assay (Syva, Dade-Behring, MiltonKeynes, UK). MPA levels were recorded to evaluate theirpossible correlations with immunological and nonim-munological adverse events, but were not taken in toaccount for clinical management of patients and adap-tation of MMF doses.

Definitions

CRD was defined as the diminution of the GFR by 20 to60 mL/minute from the time of LT and the presence ofpost-LT serum creatinine levels �1.5 mg/dL (the rangeof normality in our laboratory being 0.8-1.2 mg/dL).These findings had to be present, in patients with nor-mal pre-LT values and in absence of any urologic dis-ease, on 2 different samples, during the last 3 months.

Arterial hypertension was diagnosed when a bloodpressure �140/90 mmHg was recorded on 2 or moreconsecutive out patient visits during the last 6 months,or when the patient was under antihypertensive ther-apy.

Hyperlipidemia was defined as serum triglyceride lev-els �150 mg/dL and/or serum cholesterol �240 mg/dL, measured on 2 different occasions at least 1 monthapart during the last 6 months; as well as the presenceof statin treatment in patients with normal pre-LT val-ues and in absence of any known lipid disease.

Stable graft function was defined as normal orslightly elevated (�2 �) levels of transaminases andbilirubin due to nonimmunological reasons.

Leukopenia was defined as a white blood cell count�2,500/mm3,10 anemia as a hematocrit �25% or se-rum hemoglobin � 8 gm/dL, and thrombocytopenia asa platelet count �80,000/mm3.

Study Aims

The primary aim of the study was the improvement ofkidney function, lipid metabolism, and arterial hyper-tension at 1 yr from the introduction of MMF. Second-ary aims were the incidence of AR (presumptive or bi-opsy-proven) and of MMF-related toxicity.

Statistical Analysis

Data were collected and analyzed using the SPSS 10.0software package (SPSS, Chicago, IL). They are ex-pressed as mean � standard deviation. Improvementafter modification of the immunosuppressive regimenwas evaluated employing the Student’s t-test for paireddata in the comparison between baseline values andthose obtained at the most recent follow up. A P value �0.05 was considered statistically significant.

RESULTS

All patients complied with the treatment protocol. CNIcould be completely withdrawn in all but 1 patient, aftera mean time of 4.3 � 1.4 months. Interestingly, despitethe minimal immunosuppressive regimen adopted(�1.5 gm/day MMF) only 9 patients (22%) requiredadoption of therapy at the full dosage, for abnormalitiesin liver function tests, consistent with the diagnosis ofAR (Table 2). At present 33 of 42 (78%) patients arereceiving MMF at the dose of either 1 (n � 3) or 1.5 (n �30) gm/day. Patient F in Table 2 is the only individualwho did not achieved MMF monotherapy. During taper-ing, she developed signs of immunological activation(gamma-glutamyl-transferase and alkaline-phospha-tase 6�, transaminases 8� vs. baseline levels) thatwere insensitive to MMF adjustment. A percutaneousliver biopsy showed signs of moderate AR for whichcyclosporine A daily dose was increased (5� the formerdaily dose).

Thus far, the mean follow-up from the introduction ofMMF to the time of preparation of this article is 31.5�6.1 months and the mean length of follow-up in pa-tients on MMF monotherapy (from time of CNI with-drawal throughout time of data collection) is 27.3 � 6.4months.

Efficacy

In the 36 patients with CRD, baseline mean serumcreatinine and GFR values were 1.8 � 0.4 mg/dL and47.8 � 10.4 mL/minute, respectively. Renal functionimproved in 31 of 36 (89%) cases. In particular, asdepicted in Figure 1, creatinine dropped to 1.56 �0.4mg/dL (P � 0.05 vs. baseline) after 12 months and themean GFR rose to 57.6 � 17 mL/minute (P � 0.05 vs.baseline). The improvement in renal function was notdifferent when the group of patients converted to MMFwithin 6 months from the onset of CRD was comparedwith those who converted later. Of 36 patients, 32reached a 2-yr follow up. At this time point, mean cre-atinine level is 1.4 mg/dL � 0.2 and mean GFR is63.2 � 11 mL/minute (Fig. 1).

48 ORLANDO ET AL.


In patients with dyslipidemia, serum levels of triglyc-erides lowered in 14 of 17 patients (82%), while choles-terol lowered in 12 of 13 (92%). Triglycerides decreasedfrom 275 � 100 mg/dL at baseline to 165 � 82.1 mg/dL(P � 0.05) after 12 months. At 2-yr follow-up, no furtherimprovement was recorded. Cholesterol blood levelsdropped from 274.5 � 43.7 mg/dL at baseline to170.5 � 48 mg/dL (P � 0.05) and to 164 � 34 mg/dLafter 12 months and 2 yr, respectively (Fig. 2). Of the 5patients under statin therapy at baseline, only 2 arecurrently under medication. The remaining withdrewthe treatment after 4 (1�) and 5 months (2�) from MMFmonotherapy adoption.

Arterial hypertension improved in 80% of cases.Mean systolic blood pressure decreased during thestudy from 158 � 20 mmHg at baseline to 135 � 15mmHg (P � 0.05) after 12 months, and to 134 � 12mmHg after 24 months of MMF therapy. Mean diastolicblood pressure decreased from 97 � 20 mmHg at base-line to 85 � 12 mmHg (P � 0.05) after 12 months, and

to 83 � 11 mmHg after 24 months of MMF therapy. Ofthe 4 patients receiving antihypertensive therapy, 2could stop the treatment at 5 and 7 months from theconversion to MMF.

At the end of the study, there were no significantchanges in the mean values of liver function tests, glu-cose or hemoglobin levels, or platelets or white bloodcell counts.

Safety

No patient or graft loss was recorded during the study.A total of 8 patients developed a presumptive episode ofAR when they were under 1.5 gm/day of MMF. Thecorresponding MPA blood trough levels are depicted inTable 2. To our knowledge, the literature reports on

TABLE 2. MMF Daily Dose, MPA Blood Trough Levels, and Other Variables in Patients with AR

PatientIndication

to LT

Time fromLT to MMF

introduction(months)*

Time fromMMF

introductionto AR

(months)

AST-GGTpeak value

(U/L)MMF dailydose (gm)

Monotherapy at timeof AR (yes/no); CNI

blood trough level(ng/mL)

MPAtrough

levels atAR (�g/

mL) Treatment

A ALC 19 6 106–330 1.5 Yes; / 6.1 1 MMF dose to 2 gmB HBV 76 4 81–61 1.5 No; C0 23; C2 71 2.3 1 MMF dose to 2 gmC HCV 77 3 120–537 1.5 No; Tac 2 1.8 1 MMF dose to 2 gmD ALC 59 3 91–110 1.5 No; C0 42; C2 96 1.9 1 MMF dose to 2 gmE HCV 102 6 88–26 1.5 No; C0 75; C2 97 2.5 1 MMF dose to 2 gmF Carcinoid 17 4 316–897 2 No; C0 11; C2 80 7.2 1 CsA doseG HCV 32 3 103–137 1.5 No; C0 26; C2 74 7.1 1 MMF dose to 2 mgH HBV 85 4 98–393 1.5 No; C0 33; C2 56 2.9 1 MMF dose to 2 gmI PBC 129 3 112–185 1.5 No; C0 25; C2 31 1.5 1 MMF dose to 2 gm

Abbreviations: ALC, alcoholic cirrhosis; HBV, hepatitis B-related cirrhosis; HDV, hepatitis D-related cirrhosis; PBC, primarybiliary cirrhosis; CsA, cyclosporine A; MMF.*66.2 � 38, median 76 (vs. 72.6 � 35, median 73 reported in the 33 nonrejecting patients; P � not significant).

Figure 1. The 2 curves depict the improvement of creatinineblood level and GFR following discontinuation and withdrawalof CNI with concomitant introduction of MMF.

Figure 2. Improvement of lipid profile following discontinu-ation and withdrawal of CNI with concomitant introduction ofMMF.



only a few ranges for MPA concentrations (1-3.5 �g/mLfor LT patients,2 �3 �g/mL for kidney,26 and 2.5-4.5�g/mL for cardiac27), on which no agreement has beenreached. Clearly, when the MPA blood concentration ismatched with the occurrence of AR, no correlation canestablished, but MPA levels are always not only thera-peutic but may even be toxic. Management consisted inthe increase of the MMF daily dose to 2 gm, alwaysfollowed by clinical improvement, thus corroboratingthe original diagnosis of AR. As described earlier, afurther patient rejected while under 2 gm/day, forwhich we opted to increase the cyclosporine A dose.When the mean MPA trough levels during the first 12postoperative months of the group of patients who re-jected were compared with the mean MPA concentra-tions of patients who did not reject, no differences werefound (Fig. 3).

It is well known that the risk of AR decreases overtime after LT.15 When the group of patients who re-jected was compared with those who did not reject interms of length of follow-up from LT to the introductionof MMF, no differences were found (66.2 � 38 vs. 72.6 �35; P � n.s.]. The 2 groups were similar also in relationwith the mean individual MPA measured throughoutthe first year (mean value of 2.5 �g/mL of patients whorejected vs. 3.1 �g/mL of those who did not reject; P �n.s.). Note that all the episodes of rejection occurredwithin the first 6 months from MMF conversion.

Adverse Events

Although 7 patients (16%) developed nonimmunologi-cal adverse events, discontinuation of MMF was neverrequired. Disturbances occurred between the third andthe seventh months from the introduction of MMF. Pa-tient 1 suffered from reactivation of herpes zoster infec-

tion in the skin of the anterior upper abdominalmetamer. Treatment consisted in specific antiviral ther-apy and momentary reduction of MMF dose from 1.5 to1 gm. Patient 2 complained about asthenia for 3 weeksbefore reporting to physicians, followed by spontaneousremission. In 2 cases, nausea and vomiting requiredantiemetic drugs. Three further patients presented mildleukocytopenia associated with thrombocytopenia(1,650 leukocytes/mm3 and 65,000 thrombocytes/mm3, 2,050 leukocytes/mm3 and 57,500 thrombo-cytes/mm3, and 1,400 leukocytes/mm3 and 55,500thrombocytes/mm3, respectively), justifying the adap-tation of the MMF dose from 1.5 to 1 gm, in patients 5and 7; for patient 6, management was conservative.

As shown in Table 3, the MPA blood trough levelswere always above the therapeutic thresholds reportedin the English literature (mean value of 8.6 ng/mL).2,26,27

DISCUSSION

The present study shows that renal function, lipid bloodlevels, and arterial hypertension improve significantlywith the suspension of CNI therapy and its replacementwith low-dose MMF monotherapy. CNI withdrawal wasobtained in all but 1 patient and was followed by a clinicalimprovement in most cases. Interestingly, the time fromintroduction of MMF to amelioration of clinical parame-ters was short, given that major changes were alreadyevident after 3 months, when CNI had been lowered by 50to 75% of the initial dose and MMF monotherapy had notyet been achieved (Figs. 1 and 2). The rejection rate, put-ting together the histologically-proven and those tenta-tively diagnosed as mild AR on the basis of biochemicalparameters, was 21%.

The time from LT did not correlate with the incidenceof rejection. With regard to CRD, the time of onset didnot have any influence on the outcome. The incidenceof MMF-related acute toxicity was 16% and the mildside-effects never required discontinuation of the drug.

The impact of MMF administration on patients pre-senting chronic CNI-related toxicity has been discussedpreviously.3,9,13-19 However, the incidence of AR stillrepresents a matter of concern. Early experience withMMF monotherapy’s use as CNI-sparing agent was re-lated to an increased incidence of acute, severe duc-topenic, and steroid-resistant rejection also requiringretransplantation. For this reason, the authors dis-couraged this approach.18 In the same issue of theLancet and more recently, 4 studies in which MMF wasadministered as monotherapy14,16,17,19 and 2 studiesin which patients were still receiving small doses ofprednisolone9,13 showed more promising results (Table4). However, in 2004 the group of Baltimore reported anincidence of irreversible AR of 23% in a group of 13patients, leading to death (2�) and retransplantation(1�).15 In our experience, AR did not represent a majorclinical problem given that all episodes were success-fully managed with the adaptation of MMF or CNI doses(Table 2). However, it is needless to say that the highestcaution should be used when changing immunosup-

Figure 3. Comparison between the fluctuation of mean MPAconcentration in patients who rejected and those who did not.Data diverge at around the fourth and the ninth month fromMMF introduction, the rejecters featuring the paradox ofhigher MPA levels. Interestingly, all the episodes of acuterejection occurred between the third and the sixth month,whereas no immune adverse events were recorded during thesecond semester.

50 ORLANDO ET AL.


pressive therapy in patients with a well-functioninggraft.

As long as a large consensus on the safety and effec-tiveness of monotherapy is not achieved, alternativestrategies should be taken into account. These mayinclude the reduction of CNI instead of its completewithdrawal and the use of sirolimus (with or withoutMMF). As mentioned above, we observed a frank im-provement of the clinical setting already by the end ofthe third month after MMF introduction, when CNI wasstill tapering off. Therefore, total elimination of CNI maynot be necessary, especially in case of CRD, which isnormally unrelated to CNI trough levels and canprogress despite drug withdrawal.28 The only random-ized trial in which CNI discontinuation has been com-pared with CNI reduction showed a lower incidence ofrejection in the second arm (38% vs. 9%); however, allpatients received “protective” additional low-dose pred-nisone.12 The Innsbruck group described a 6% inci-dence of AR during a 4.8-yr follow up in 32 individualsenrolled in a single-arm trial in which CNI was reducedstepwise by at least 70% of the initial dose. In thediscussion, the authors firmly state that MMF mono-therapy was not considered for reasons of immunolog-ical safety.9 Also, Beckebaum et al.29 reported no rejec-tion at all at 3 months, in a trial enrolling 32 patients, inwhich CNI reduction was compared with no modifica-tion of CNI doses during the introduction of MMF. Morelimited experience has been gained on the use of siroli-mus, alone or in concomitance with MMF. To ourknowledge, the first work on the simultaneous use ofMMF and sirolimus has been published by the Grazgroup, who reported no AR during the successfulswitch from CNI to MMF � sirolimus in 7 patientsfeaturing CNI-derived nephro- and neurotoxicity. Meanfollow-up; however, was only 137 days.30 Later, a Dal-las team reported a trivial 2.8% incidence of AR in 35patients converted from CNI�MMF�steroids tosirolimus�MMF�steroids.31 Finally, the switch tosirolimus monotherapy was attempted by Fairbanks etal.32 in LT recipients suffering from CRD. This regimenprovided adequate immunosuppression with a low in-cidence of acute rejection (1/18) and minimal adverseevents.32

A criticism of our trial is that we did not measure thearea under the curve of MPA blood concentrations. Thislatter undoubtedly represents the optimal method foradjusting the dose of drugs presenting a narrow thera-peutic window and a high inter- and intraindividualvariability, such as MMF. However, when the studyprotocol was designed, it was decided to neglect thearea under the curve because it is tedious, very de-manding of skilled personnel time and laboratory re-sources, and requires considerable quantities of pa-tient’s blood, patient written consent, and at least 12hours of time to spend in a medical center. In addition,this methodology is still at an investigative stage andthere is no agreement about the number of time pointsrequired to draw the area under the curve in order to beeffective.26,27,33-35 Data obtained mainly in the field ofkidney and heart transplantation provide increasingevidence that a fixed dose regimen of MMF might nolonger be the best approach for the management ofpatients under MMF.27,33 We therefore decided to mea-sure MPA trough levels in the attempt to investigate anycorrelation with the clinical event itself (AR, side ef-fects). Our data on MPA monitoring are not conclusive,although they show a correlation between high troughlevels and drug toxicity. In fact, when rejection oc-curred, the MPA blood trough levels were always abovethe lowest threshold currently considered in therapeu-tic ranges (Table 2).2,35 In addition, it should be under-lined that 8 of 9 cases were still receiving CNI whenrejection occurred. On the contrary, the onset of non-immunological adverse events always correlated withtoxic MPA trough levels, whichever range was consid-ered (see Table 3 and above).35 At present, further studyis needed to identify the single sampling point of MPAwith the best correlation with side-effects including AR.It should be also stressed whether the therapeuticrange should be higher when MMF is given in mono-therapy.

A major limitation of our study is the lack of a com-parator arm of higher MMF dosing. However, at the timeof study design, the literature counted only 3 arti-cles13,14,18 on the topic, reporting conflicting and non-convincing results. In a retrospective study, Raimondoet al.14 first demonstrated in 1999 that both MMF

TABLE 3. Correlation Between Adverse Event, MMF Dose and MPA Concentration

Patient Adverse event

Time of onset from

the introduction of

MMF (months) MMF dose (gm)

MPA trough levels at

time of occurrence of

adverse events

1 Herpes zoster 6 1.5 12 ng/mL2 Asthenia 7 1.5 7 ng/mL3 Nausea, vomiting 5 1.5 8 ng/mL4 Nausea, vomiting 6 1.5 11 ng/mL5 Leukocytopenia, thrombocytopenia 3 1.5 5 ng/mL6 Leukocytopenia, thrombocytopenia 5 1 8 ng/mL7 Leukocytopenia, thrombocytopenia 7 1.5 9 ng/mL

NOTE: In all the cases, the occurrence of the adverse event is related with toxic blood concentrations of MPA.



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(89%

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(80%

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one

52 ORLANDO ET AL.


monotherapy and MMF in combination with low doseCNI represent a valuable tool in case of CRD; in partic-ular, they observed a trivial incidence of rejection (1/16; 6%) in patients under MMF monotherapy. The dis-couraging results of the trial reported by Stewart et al.18

and Schlitt et al.13 have been mentioned above. Wetherefore designed a pilot study, to test the workinghypothesis in a larger patient sample.

The current literature has highlighted the growingimportance of quality of life as a measure of outcomeand a tool to determine the therapeutic strategy.36,37 Ithas been proven that the number and dose of pre-scribed drugs influences patient quality of life and com-pliance. Therefore, the optimal immunosuppressiveregimen should use the fewest agents at the lowesteffective dose, to increase patient satisfaction and re-duce toxicity and costs while still preventing rejectionand maintaining graft function. Low dose MMF mono-therapy may successfully address this issue.

In conclusion, in LT recipients presenting CNI-relatedchronic toxicity, the switch to low-dose MMF mono-therapy is effective, safe, and well tolerated. MPAtrough levels correlate with the occurrence of nonim-munological adverse events but not with the occurrenceof AR. Therefore, the therapeutic range of MPA for LTpatients remains undefined. Longer follow-up is neededto rule out the long-term risk of acute or chronic rejec-tion.

ACKNOWLEDGMENT

Mrs. Susanna Boughton-Thomas provided invaluableassistance in revising the manuscript.

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54 ORLANDO ET AL.


switch to 1.5 grams mmf monotherapy for cni-related toxicity in liver transplantation is safe and...

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