ORIGINAL ARTICLE

Age, Model for End-Stage Liver Disease Score,and Organ Functioning Predict PosttransplantTacrolimus NeurotoxicityAndrea DiMartini,1,2,5 Paulo Fontes,2,5 Mary Amanda Dew,1,3,4 Francis E. Lotrich,1 and Michael de Vera2,5

Departments of 1Psychiatry, 2Transplantation Surgery, 3Psychology, and 4Epidemiology, University ofPittsburgh Medical Center, Pittsburgh, PA; and 5Starzl Transplant Institute, Pittsburgh, PA

Calcineurin-inhibiting immunosuppressive medications are the mainstay of posttransplant immunosuppression. Although thesehighly beneficial drugs are critical for posttransplant survival, significant numbers of transplant recipients experience sideeffects, some requiring a switch to a different immunosuppressive regimen. Neurotoxicity is one of the most debilitating sideeffects because of its impact on mental status and cognition. As our center uses tacrolimus as the initial immunosuppressantfor all liver transplant (LTX) recipients, we were interested in those patients who required a switch because of neurotoxic sideeffects. Over a 5-year period, 827 adult LTX recipients received their first graft at our center. Ninety-four patients were no longeron tacrolimus by 2 months post-LTX (86 switched because of concerns over neurotoxicity, and 8 switched because of renalfunction concerns). Of those experiencing neurotoxic side effects, the majority (64%) had altered mental status, and 26% hadseizures (first onset post-LTX). On the basis of our prior work, we hypothesized that patients with a pre-LTX history ofexcessive alcohol use would be at higher risk for neurotoxic effects. We also hypothesized that the elderly and those who hadmore advanced illness (that is, higher Model for End-Stage Liver Disease scores) at LTX would be at risk as well. We foundthat patients with a pre-LTX diagnosis of alcoholic liver disease were not more likely to be switched from tacrolimus.Furthermore, we found that in addition to older age and higher Model for End-Stage Liver Disease scores, poorer hepaticfunctioning was significantly associated with a switch from tacrolimus. We discuss the implications of these findings and therelevance for future clinical care in these high-risk patients. Liver Transpl 14:815-822, 2008. © 2008 AASLD.

Received March 27, 2007; accepted November 28, 2007.

Until clinically effective tolerance-induction protocolscan allow substantial diminution of or liberation fromchronic nonspecific immunosuppression for trans-plant recipients,1 the toxic side effects of calcineurin-inhibiting immunosuppressive medications (tacroli-mus and others) will continue to be a clinicalchallenge. Neurotoxicity is one of the more disturbingof these side effects because of its potential impact onmental status and cognition. Calcineurin-inducedneurotoxicity can be severe and debilitating, requir-ing a mandatory switch to an alternative immuno-

suppressive medication. This complication-drivenmedication switch in the recipient’s primary immu-nosuppressive therapy can lead to subsequent acutecellular rejection episodes and eventual allograft dys-function. For most transplant recipients, neuropsy-chiatric symptoms of tacrolimus are mild and includetremulousness, headache, restlessness, insomnia,vivid dreams, hyperesthesias, anxiety, and agita-tion.2 The moderate to serious neuropsychiatric sideeffects (that is, cognitive impairment, coma, seizures,focal neurologic deficits, and delirium) occur less of-

Abbreviations: ALD, alcoholic liver disease; CNS, central nervous system; CT, computed tomography; EEG, electroencephalogram;HCV, hepatitis C virus; LTX, liver transplant; MELD, Model for End-Stage Liver Disease; MRI, magnetic resonance imaging; NASH,nonalcoholic steatohepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; SD, standard deviation. Supportedby grant number K23 AA0257 from the National Institute of Alcohol Abuse and Alcoholism, grant number R01 DK066266 from theNational Institute of Digestive Disorders and Kidney Diseases, and grant number K23 MH074012 from the National Institute of MentalHealth.Address reprint requests to Andrea DiMartini, M.D., Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213. Telephone:412-383-3166; FAX: 412-383-4846; E-mail: dimartiniaf@upmc.edu

DOI 10.1002/lt.21427Published online in Wiley InterScience (www.interscience.wiley.com).

LIVER TRANSPLANTATION 14:815-822, 2008

© 2008 American Association for the Study of Liver Diseases.

ten but can reach 21% to 32% in the early postoper-ative period.3

Our prior investigations at the Starzl Transplant In-stitute have helped to identify the profile of neuropsy-chiatric side effects of tacrolimus and have informedour hypotheses about recipients potentially at risk forneurotoxicity. In one study of 294 consecutive trans-plant recipients on tacrolimus (238 liver, 53 heart, 2double lung, and 1 heart-lung), those with preexistingcentral nervous system (CNS) damage (for example,strokes and multiple sclerosis) were at higher risk fordeveloping neurotoxic side effects.4 From this, it washypothesized that more serious neurotoxic side effects(focal neurologic abnormalities, speech disturbances,hemiplegia, and cortical blindness) may occur fromhigher CNS levels of tacrolimus in patients who have adisrupted blood-brain barrier.4 In addition, liver trans-plant (LTX) recipients appeared to be more susceptibleto neurotoxic side effects than heart and lung trans-plant recipients.4

In a randomized controlled trial of tacrolimus versuscyclosporine in LTX recipients, we identified that in theearly postoperative period, 35% of the recipients expe-rienced some cognitive impairment (based on neuro-psychiatric testing scores), with 29% of those on tacroli-mus experiencing moderate to severe cognitiveimpairment.5 Interestingly, we also found that those inthe tacrolimus group with a pretransplant diagnosis ofalcoholic cirrhosis appeared to be at higher risk forneuropsychiatric symptoms.6 Nevertheless, a large-scale study investigating multiple predictors of tacroli-mus neurotoxicity has not been done.

Therefore, we hypothesized that LTX recipients wouldbe at higher risk for tacrolimus neurotoxicity if they hadpossible preexisting CNS damage due to heavy alcoholexposure [that is, those with a pre-LTX primary or sec-ondary diagnosis of alcoholic liver disease (ALD)], afinding that we have preliminarily noted.6 Additionally,we considered 2 other variables possibly representing avulnerable CNS: (1) pre-LTX Model for End-Stage LiverDisease (MELD) scores, given that elevated MELDscores have been associated with post-LTX mental sta-tus changes,7 and (2) advanced age, which has beenassociated with impaired CNS “homeostatic reserve.”8

Because all adult LTX recipients at the Starzl Trans-plant Institute receive tacrolimus as their primary im-munosuppressant (that is, first choice after LTX), wewere able to test our hypothesized predictors in a largecohort by identifying those LTX recipients switched offtacrolimus because of neurotoxicity.

PATIENTS AND METHODS

All adult LTX recipients who received their first liverallograft over a 5-year period from June 1, 2001 to May31, 2006 and survived 2 months post-LTX were in-cluded in the study (n � 827). Immunosuppressantmedications at 2 months post-LTX were noted, andpatients in whom tacrolimus was discontinued becauseof neurotoxicity were identified. Our primary categori-

cal outcome in this study was simply whether a patientremained on tacrolimus or required a change to an-other immunosuppressant because of neurotoxicity. Inaddition, the clinical features of the neurotoxic symp-toms were retrospectively analyzed through the medicalrecords as well as documentation of electroencephalo-gram (EEG) results and brain imaging [computed to-mography (CT) and/or magnetic resonance imaging(MRI)] when done. The initial 2-month postoperativeperiod was chosen as the time frame for identifying theprimary immunosuppressive medication, as clinical ev-idence of serious tacrolimus neurotoxicity necessitat-ing a switch would usually develop in the first weekspost-LTX.9,10 Demographic and medical history vari-ables were also collected from the medical records. Inaddition, specific laboratory values of interest were col-lected, including tacrolimus blood levels, sodium, mag-nesium, total bilirubin, and creatinine. Because pa-tients’ blood samples were checked repeatedly, wechose to calculate the median value for each biochem-ical measure (either up until the switch from tacrolimusor throughout the total 2-month period for those notswitched) as the estimate of central tendency. Finally,we collected data on medical outcomes to compare the2 groups, including primary nonfunction, renal failurerequiring dialysis, and the times to acute cellular rejec-tion, retransplantation, or death.

Statistical Analysis

Continuous variables are presented as the mean �standard deviation, and categorical variables are pre-sented as proportions. Independent t tests were used totest continuous variables, and the chi-square test wasused for categorical variables. The time to specific med-ical outcomes was calculated by Kaplan-Meier survivalanalyses and compared by the log-rank test. MELDscores were log-transformed prior to analysis becauseof positive skewness. Untransformed scores are pre-sented in the tables and figures for clarity. We chosemedian values for the biochemical tests rather thanmean values, which could be affected by extreme valuesand not indicate central tendency.

To test our first hypothesis, we compared the propor-tion of patients switching immunosuppressants amongthose with a pre-LTX primary or secondary diagnosis ofALD versus patients with all other liver diagnoses. Wethen examined the proportions switching medicationsamong patients with other common liver disease diag-noses [that is, hepatitis C virus (HCV)] compared to allothers. In addition to age and MELD score at LTX, wealso examined gender, race, date of LTX, and biochem-ical values as potential predictors of our primary out-come in an exploratory univariate analysis. Colinearitywas checked between variables, and the final modelwas tested by logistic regression using variables thathad achieved P � 0.05 at the univariate level. Differ-ences between groups on specific medical outcomeswere also calculated. All analyses were performed withStatistical Package for Social Sciences version 12 forWindows.

816 DIMARTINI ET AL.

RESULTS

Cohort Characteristics

All 827 adult LTX recipients received tacrolimus astheir primary immunosuppressant. By 2 months post-LTX, 86 recipients (11%) had been removed from ta-crolimus because of neurotoxic side effects. Eight pa-tients were switched from tacrolimus because ofconcerns over renal toxicity and were not included inthe analyses. The majority of patients (93%) wereswitched to cyclosporine as their primary immunosup-pressant medication. Six patients received variouscombinations of sirolimus, mycophenolate, or azathio-prine. Twelve patients (14% of those switched) wereeventually switched back to tacrolimus anywhere frommonths to years later. The cohort was predominatelyCaucasian (90%) and male (61%), with ages rangingfrom 18 to 78 years of age (mean 54 � 11). MELD scoresat LTX ranged from 6 to 40 (mean 16 � 7). One hundredtwelve recipients received a living liver donation; 707recipients had deceased donor grafts. Thirty-three per-cent of the cohort had either a primary or secondarydiagnosis of ALD; of these, 42% were additionally coin-fected with HCV (Table 1).

The majority of patients (64%) had symptoms of al-tered mental status (including symptoms of stupor/coma, confusion/disorientation, agitation, and/or psy-chosis). Twenty-six percent experienced seizures (Table2). Of those switched from tacrolimus, 60% had an EEGperformed and 79% had CT and/or MRI imaging of thebrain to investigate the etiology of the mental statussymptoms (see Table 3). The most common finding onEEG was generalized, diffuse slowing (65%). Only 23%

showed either active or prodromal seizure activity.Twelve patients had characteristic abnormalities on ra-diological imaging (mostly MRI) of posterior reversibleleukoencephalopathy syndrome (low attenuation ofwhite matter on CT scan and/or corresponding hyper-intense lesions on T2-weighted MRI images). Interest-ingly, there were 3 patients who had both MRI and CTscanning where the MRI was read by the radiologist asbeing consistent with posterior reversible leukoenceph-alopathy syndrome yet the CT scan was either read asnormal or nonspecific. This suggests the better distin-guishing value of MRI in identifying such radiographicchanges.

Associations with Tacrolimus Switch

Of our 3 primary hypotheses, a previous diagnosis ofALD was not directly associated with a subsequent

TABLE 1. Total Cohort Demographics (n � 819)

Age (mean � SD) 54 � 11Gender (% male) 61Race (%)

Caucasian 90.4Black 4.4Asian 1.5Hispanic 1.6Middle Eastern 1.9

Married (%) 71Liver disease (%)

Alcoholic 19Alcohol and HCV 14HCV 23Cryptogenic 10NASH 5PBC 5PSC 8Other 16

MELD score (mean � SD) 16 � 7

Abbreviations: HCV, hepatitis C virus; MELD, Modelfor End-Stage Liver Disease; NASH, nonalcoholicsteatohepatitis; PBC, primary biliary cirrhosis; PSC,primary sclerosing cholangitis; SD, standard deviation.

TABLE 2. Neurotoxic Symptoms Among the 86

Patients Who Were Switched off Tacrolimus

% n

Altered mental status* 64 56Seizures 26 23Tremors/involuntary movements 19 17Dysarthria/aphasia 10 9Incoordination 3 3

NOTE: Percentages add to �100% as some patients hadmore than 1 symptom.*This included stupor/coma, confusion/disorientation,agitation, or hallucinations/psychosis.

TABLE 3. EEG and Radiological Imaging Results

Among the 86 Patients Who Were Switched off

Tacrolimus

% n

EEG (n � 52)Generalized slowing 65 34Seizure/seizure tendency 23 12Focal or other 6 3Normal 6 3

CT scans (n � 53)Low intensity 6 3Other* 53 28Normal 42 22

MRI scans (n � 45)High-intensity T2 signal 26 12Other* 62 28Normal 11 5

Abbreviations: CT, computed tomography; EEG,electroencephalogram; MRI, magnetic resonance imaging.*This category included radiographic changes consistentwith periventricular white matter changes, small vesseldisease, old infarcts, or volume loss.

POSTTRANSPLANT TACROLIMUS NEUROTOXICITY 817

switch from tacrolimus by 2 months post-LTX. How-ever, both older age and higher MELD scores were sig-nificantly associated with switching from tacrolimusdue to neurotoxicity (Table 4). The association betweenMELD score and tacrolimus switch was linear (see Fig.1). For age, there was a discreet cut point such thatabove 60 years of age the risk increased substantially(see Fig. 2). There was a significant correlation betweenage and MELD score (P � 0.013), although it was small(r � �0.06). When we controlled for MELD scores, theassociation between age and tacrolimus switch re-mained, and similarly, when we controlled for age, theassociation between MELD scores and tacrolimusswitch remained.

In addition, the date of transplant was significantlyassociated with being switched from tacrolimus suchthat within the 5-year cohort, those transplanted ear-lier (that is, closer to 2001) were more likely to remainon tacrolimus, whereas those transplanted more re-cently were more likely to be switched off tacrolimus.

To further examine liver disease diagnoses, we an-alyzed whether those with HCV were more likely to beswitched compared to all others. Although HCV wasassociated with a less likely chance of being switched(�2 � 6.1, P � 0.014), the association did not remainafter controlling for age, MELD score, and time ofLTX.

There were also notable differences in specific labo-

Figure 1. Percentage switched off tacrolimusby the Model for End-Stage Liver Disease(MELD) score.

TABLE 4. Potential Predictors of Continuing on Tacrolimus Versus Switching off Tacrolimus Because of

Neurotoxicity After Liver Transplantation

Remaining on

Tacrolimus

(n � 733)

Switched off

Tacrolimus

(n � 86)

Test

Statistic* P Value

ALD (%) 32 39 1.8 0.17MELD score, mean (SD) 15.6 (7.3) 18.7 (8.0) 3.6 0.000Age (years), mean (SD) 53 (11) 57 (11) 3.2 0.002Era of LTX (days), mean (SD) 911 (452) 747 (517) 3.1 0.002Gender (% male) 60 60 0.027 0.90Race (% Caucasian) 89 94 3.0 0.69Creatinine, mean (SD) 1.4 (1.0) 1.6 (0.9) 1.8 0.07Tacrolimus level (ng/mL)†, mean (SD) 9.7 (1.6) 9.5 (2.4) 1.5 0.14Total bilirubin, mean (SD) 3.7 (4.0) 5.5 (4.3) 3.7 0.000Magnesium, mean (SD) 1.5 (0.2) 1.7 (0.2) 9.2 0.000Sodium, mean (SD) 137 (2.4) 137 (3.5) 0.55 0.58

Abbreviations: ALD, alcoholic liver disease; LTX, liver transplant; MELD, Model for End-Stage Liver Disease; SD, standarddeviation.*�2 (1) was used for dichotomous variables, and a t test was used for independent variables.†Prior to switch for switched group.

818 DIMARTINI ET AL.

ratory values between groups (see Table 4). Because wewere investigating laboratory values that would predicta switch from tacrolimus, we report the median valueseither up until the switch from tacrolimus or through-out the total 2-month period for those not switched.Thus, the laboratory values reflect events before theswitch. We chose to investigate hypomagnesemia be-cause of its association with tacrolimus neurotoxicityand hyponatremia because of its association with im-munosuppression and central pontine myelinolysis. Al-though there was no difference between groups in me-dian sodium levels, the group switched off tacrolimushad significantly higher magnesium levels (1.7 versus1.5, P � 0.000) perhaps reflecting magnesium supple-mentation. In an attempt to keep patients on tacroli-mus, the dosage and blood levels were initially reducedin nearly all patients except when the clinical situationwas more urgent, necessitating an immediate switch.Although our immunosuppressive protocol haschanged over time, tacrolimus is the mainstay of ourtherapy, and we strive for a target whole blood level of 8to 15 ng/mL. Ninety percent had median tacrolimusvalues of 11.5 ng/mL or less, and only 5 patients hadmedian values greater that 15 ng/mL. No patient had amedian tacrolimus value greater than 18 ng/mL. Me-dian tacrolimus levels were not different betweengroups (see Table 4).

We also considered acute and chronic medical factorsthat may have contributed to our findings. Both acuterenal failure (represented by those who required dialy-sis within 2 months post-LTX) and chronic renal insuf-ficiency (represented by elevated median creatinine)were examined between groups. Although the creati-nine values were slightly but not significantly differentbetween groups, patients switched off tacrolimus weresignificantly more likely to require dialysis within 2months post-transplant (34% versus 22%, P � 0.02). Inaddition, liver function (represented by median totalbilirubin levels) was significantly worse for the switched

group. Older age was correlated with lower total biliru-bin levels, although this association was small (P �0.01, r � �0.09). Information on intraoperative hypo-tension was not available; however, we had data on thetotal number of packed cells used during the transplantoperation on 478 patients. The median number ofpacked cells used was 6 units and was not differentbetween groups.

There were also important differences in medicaloutcomes between groups. Patients switched offtacrolimus were slightly, although not significantly,more likely to have acute cellular rejection (37%versus 30%) by 1 year (see Fig. 3). However, they werenot more likely to have primary nonfunction (1%versus 1%), require retransplantation (12% versus9% at 5 years), or have received a donation from aliving donor (14% versus 14%). Of special concernwas the overall significantly poorer survival forthose switched off tacrolimus beginning at the pointof transplantation and continuing out to 5 yearspost-LTX (see Fig. 4). Although we considered thecontribution of age and pre-LTX MELD score tothis outcome in the switched group, in a multivariateCox regression including the variables of age andMELD score, being switched off tacrolimus still addeda significant contribution to poorer post-LTX out-comes.

We also investigated whether treatment with ananticonvulsant was associated with tacrolimusswitch. De novo anticonvulsant therapy was initiatedin 37 recipients by 2 months post-LTX (35 on phenyt-oin, 1 on valproic acid, and 1 on oxcarbazepine).Those on anticonvulsants were significantly morelikely to be switched off tacrolimus (P � 0.000) andrepresented patients that we suspect developed neu-rotoxic seizures necessitating both anticonvulsanttherapy and a tacrolimus switch. The majority (68%)were nearly simultaneously switched off tacrolimusand started on an anticonvulsant; therefore, a drug

Figure 2. Percentage switched off tacrolimusby age.

POSTTRANSPLANT TACROLIMUS NEUROTOXICITY 819

interaction between tacrolimus and the anticonvul-sant was an unlikely cause for the switch. It is of notethat 3 patients were already on cyclosporine beforedeveloping seizures and requiring anticonvulsanttherapy, highlighting the neurotoxic potential of cy-closporine as well.

DISCUSSIONAlthough elevated blood levels of tacrolimus2,11,12 andelectrolyte and other biochemical abnormalities3,13-15

have been associated with neurotoxicity, these chemicalderangements are correctable and often do not requirediscontinuing tacrolimus. Thus, our hypotheses werebased on the premise that beyond reversible chemicalderangements, core characteristics exist that can predicttacrolimus neurotoxicity and hence the need to switch toa different primary immunosuppressant. In addition, ourgroup had previously noted that neurotoxicity is mostlikely multifactorial.9 By identifying these risk factors, wemay be able to predict and possibly prevent this outcome.Furthermore, these results may lead to the developmentof studies on the potential mechanisms of tacrolimus-induced neurotoxicity.

As we hypothesized, older age and higher MELDscores at LTX did predict those who required a discon-tinuation of tacrolimus. Increased age is associatedwith increased sensitivity to a number of neuronallyactive medications.16 For several reasons, includingloss of neurons, altered receptor levels, impaired adapt-ability, and decreased homeostatic reserve, the olderbrain has elevated vulnerability to the effects of phar-macologic challenges.8 Additionally, increased suscep-tibility to blood-brain barrier disruption is evident inthe aged brain.17 Small changes associated with cere-brovascular disease, such as small lacunar infarcts,may further impair the blood-brain barrier.18

Neuropsychologic deficits have previously been foundto be higher in liver disease patients with elevated pre-LTX MELD scores.19 In a cohort of 80 LTX recipients,

MELD scores greater than 15 predicted post-LTX men-tal status changes occurring within the first postoper-ative month and lasting more than 3 days.7 The mech-anistic pathway resulting in these neural deficits is notclear. However, our results suggest that elevated pre-LTX MELD scores are additionally associated with in-creased vulnerability to post-LTX tacrolimus neurotox-icity. These findings are especially important given theprogressive trend toward a recipient population that isolder and has higher MELD scores than in the lastdecade.20

Our prior work in a small cohort of subjects6 alsoled us to hypothesize that patients with heavy pre-LTX alcohol exposure would have developed “vulner-able” brains and be at higher risk for tacrolimus neu-rotoxicity. Although we did not examine neurotoxicitydirectly, we did not find evidence in support of thishypothesis. However, because alcohol differentiallyaffects different organ systems (that is, the CNS andthe liver), using the diagnosis of ALD as a proxy foralcoholic brain damage may have masked a potentialassociation between alcohol-related structural or mi-crovascular brain abnormalities and a potential fortacrolimus neurotoxicity. A much more sophisticatedinvestigation, optimally using structural or func-tional imaging of the brain, may be required to resolvethis question.

Although not considered as a priori hypotheses, wefound poorer post-LTX hepatic functioning distin-guished those switched from tacrolimus. Thoseswitched had significantly higher bilirubin levels andslightly but not significantly higher creatinine levelsand were more likely to be on dialysis within 2 monthsfollowing LTX. As we had removed from the data setthose switched from tacrolimus because of concernsover renal toxicity, the patients in our analyses repre-sented those switched because of neurotoxicity. Thus,in addition to pre-LTX medical debility (that is, pre-LTXMELD scores), ongoing post-LTX hepatic and renal in-sufficiency may identify those prone to tacrolimus neu-

Days To Acute Cellular Rejection

25002000150010005000

Pe

rce

nt

Ac

ute

Ce

llu

lar

Re

jec

tio

n F

ree

1.0

0.8

0.6

0.4

0.2

0.0

Tacrolimus

Off Tacrolimus

Figure 3. Time to acute cellular rejection.

Days To Death

25002000150010005000

Cu

mu

lati

ve

Su

rviv

al

1.0

0.8

0.6

0.4

0.2

0.0

Tacrolimus

Off Tacrolimus

Figure 4. Survival: tacrolimus versus patients switched offtacrolimus.

820 DIMARTINI ET AL.

rotoxicity; this finding was noted in a previous studyfrom our center.9

One additional finding is that our prescribing prac-tices may have changed over time. More recently, ta-crolimus discontinuation is more common, and thissuggests a current lower clinical threshold to switch.The recent availability of other powerful, potentially lessneurotoxic non–calcineurin-inhibiting immunosup-pressants (that is, sirolimus) may have provided anadequate alternative to tacrolimus as the primary im-munosuppressant and a more recent impetus toswitch. Nevertheless, for the majority of our patients,tacrolimus was replaced with cyclosporine, which has asimilar neurotoxic profile.21 As we found, even after theswitch to cyclosporine, 3 patients developed new onsetseizures.

A striking finding was the poorer survival in the groupswitched off tacrolimus. Although this group was olderand had higher pre-LTX MELD scores, this did not fullyexplain their poorer outcomes. Perhaps some othermedical factors that we did not explore resulted in theirbeing switched off tacrolimus and also would explaintheir poorer survival. Nevertheless, this underscoresthe overall higher risk in this medically compromisedgroup.

There are several limitations to the present study.The retrospective design prevented us from charac-terizing the severity of the neurotoxic events necessi-tating the switch from tacrolimus. Thus, the severityof the events may have varied, and the decision toswitch may have differed by clinician. Nevertheless,that 26% of those switched also required the additionof an anticonvulsant suggests that the neurologicevents were significant and often severe. In addition,our clinical team has been stable for years, and pro-tocols for clinical care are routine. As this was aretrospective study, we also lacked detailed informa-tion on our patients’ past medical histories, informa-tion that may have further clarified the predictorsthat we found to be significant. For example, pre-transplant hepatic encephalopathy, a prior history ofa stroke, or a neurodegenerative disorder would beexpected to contribute to differences between groupsand may have further explained the association ofolder age with those requiring a switch. Finally, ourchoice of median laboratory values to represent thecentral tendency was an attempt to avoid the influ-ence of laboratory value outliers on mean values.However, we realize that median values may not fullyrepresent the biochemical influences either at thepoint of immunosuppressant medication switch orthroughout the 2-month period. These limitationsnotwithstanding, we have identified key variablespredicating those at risk for being intolerant of ta-crolimus.

Even with these considerations, this study is valid asan initial attempt to assess the variables related to theincidence of clinically relevant tacrolimus neurotoxicityin liver allograft recipients. The importance of theseparameters is especially relevant to the current clinical

arena, where older patients with higher MELD scoresare undergoing liver transplantation. The findings ofthis retrospective study emphasize the need for increas-ing awareness of this neurotoxicity-prone population,who should be carefully considered as a high-riskgroup for this undesirable calcineurin-inhibiting im-munosuppressant–driven complication. For our futureclinical care, these high-risk patients should be care-fully monitored for potential neurotoxic side effects,and a lower threshold to switch should be considered,especially when mental status changes persist post-LTX.

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