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Calcineurin-inhibiting immunosuppressive medications are the mainstay of post-transplant immunosuppression. While these highly beneficial drugs are critical for post-transplant survival, significant numbers of transplant recipients experience side effects, some requiring a switch to a different immunosuppressive regimen. Neurotoxicty is one of the most debilitating side effects due to its impact on mental status and cognition. As our center uses tacrolimus as the initial immunosuppressant for all liver transplant (LTX) recipients, we were interested in those patients who required a switch due to neurotoxic side effects. Over a 5-year period, 827 adult liver transplant recipients received their first graft at our center. Ninety-four patients were no longer on tacrolimus by 2 months post-LTX (86 switched due to concerns over neurotoxicity, 8 switched due to renal function concerns). Of those experiencing neurotoxic side effects the majority (64%) had altered mental status and 26% had seizures (first onset post-LTX). Based on our prior work we hypothesized that patients with a pre-LTX history of excessive alcohol use would be at higher risk for neurotoxic effects. We also hypothesized that the elderly and those who had more advanced illness (i.e. higher MELD scores) at LTX would be at risk as well. We found 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 MELD scores, poorer hepatic functioning was significantly associated with a switch off of tacrolimus. We discuss the implications of these findings and the relevance for future clinical care in these high risk patients.
Until clinically effective tolerance-induction protocols can allow substantial diminution of or liberation from chronic non-specific immunosuppression for transplant recipients [Starzl 2005], the toxic side effects of calcineurin-inhibiting immunosuppressive medications (tacrolimus and others) will continue to be a clinical challenge. Neurotoxicity is one of the more disturbing of these side effects due to its potential impact on mental status and cognition. Calcineurin-induced neurotoxicity can be severe and debilitating, requiring a mandatory switch to an alternative immunosuppressive medication. This complication-driven medication switch on the recipient’s primary immunosuppressive therapy can lead to subsequent acute cellular rejection episodes and eventual allograft dysfunction. For most transplant recipients neuropsychiatric symptoms of tacrolimus are mild and include tremulousness, headache, restlessness, insomnia, vivid dreams, hyperesthesias, anxiety, and agitation [Fung 1991]. The moderate to serious neuropsychiatric side effects (i.e. cognitive impairment, coma, seizures, focal neurologic deficits, and delirium) occur less often but can reach 21–32% in the early post-operative period [Bechstein 2000].
Our prior investigations at the Starzl Transplant Institute (STI) have helped to identify the profile of neuropsychiatric side effects of tacrolimus and have informed our hypotheses about recipients potentially at risk for neurotoxicity. In one study of 294 consecutive transplant recipients on tacrolimus (238 liver, 53 heart, 2 double lung, and 1 heart-lung), those with pre-existing central nervous system damage (e.g. strokes and multiple sclerosis) were at higher risk for developing neurotoxic side effects [Eidelman 1991]. From this it was hypothesized that more serious neurotoxic side effects (focal neurologic abnormalities, speech disturbances, hemiplegia and cortical blindness) may occur from higher central nervous system (CNS) levels of tacrolimus in patients who have a disrupted blood-brain barrier [Eidelman 1991]. In addition liver transplant recipients appeared to be more susceptible to neurotoxic side effects than heart and lung transplant recipients [Eidelman 1991].
In a randomized controlled trial of tacrolimus versus cyclosporine in liver transplant recipients, we identified that in the early post-operative period 35% of the recipients experienced some cognitive impairment (based on neuropsychiatric testing scores), with 29% of those on tacrolimus experiencing moderate to severe cognitive impairment [DiMartini 1991]. Interestingly we also found in that group those with a pre-transplant diagnosis of alcoholic cirrhosis appeared to be at higher risk for neuropsychiatric symptoms [DiMartini 1992]. Nevertheless a large scale study investigating multiple predictors of tacrolimus neurotoxicity has not been done.
Therefore we hypothesized that LTX recipients would be at higher risk for tacrolimus neurotoxicity if they had possible pre-existing CNS damage due to heavy alcohol exposure (i.e. those with a pre-LTX primary or secondary diagnosis of alcoholic liver disease - ALD), a finding that we have preliminarily noted [DiMartini 1992]. Additionally we considered two other variables possibly representing a vulnerable CNS (1) pre-LTX Model for End-Stage Liver Disease (MELD) scores, given that elevated MELD scores have been associated with post-LTX mental status changes [Kanwal 2003], and (2) advanced age, which has been associated with impaired CNS “homeostatic reserve” [Toescu 2005]. Since all adult LTX recipients at the STI receive tacrolimus as their primary immunosuppressant (i.e. first choice after LTX), we were able to test our hypothesized predictors in a large cohort by identifying those LTX recipients switched off of tacrolimus due to neurotoxicity.
All adult liver transplant recipients who received their first liver allograft over a 5 year period from June 1, 2001 to May 31, 2006 and survived 2 months post-LTX were included in the study (n=827). Immunosuppressant medications at 2 months post-LTX were noted and patients in whom tacrolimus was discontinued due to neurotoxicity were identified. Our primary categorical outcome in this study was simply whether a patient remained on tacrolimus or required change to another immunosupressant due to neurotoxicity. In addition, the clinical features of the neurotoxic symptoms were retrospectively analyzed through the medical records as well as documenting electroencephalogram (EEG) results and brain imaging (CT and/or MRI) when done. The initial two-month post operative period was chosen as the time frame for identifying the primary immunosuppressive medication, as clinical evidence of serious tacrolimus neurotoxicity necessitating a switch would usually develop in the first weeks post-LTX [Jain 2000, Wijdicks 1994]. Demographic and medical history variables were also collected from the medical records. In addition, specific laboratory values of interest where collected including tacrolimus blood levels, sodium, magnesium, total bilirubin, and creatinine. Since patients’ blood samples were checked repeatedly we chose to calculate the median value for each biochemical measure (either up until the switch off of tacrolimus or throughout the total 2 month period for those not switched) as the estimate of central tendency. Finally we collected data on medical outcomes to compare the two groups including primary non-function, renal failure requiring dialysis and the times to acute cellular rejection, re-transplantation, or death.
Continuous variables are presented as the mean + standard deviation (SD), and categorical variables are presented as proportions. Independent t-tests were used to test continuous variables and the chi-squared test was used for categorical variables. Time to specific medical outcomes was calculated by Kaplan-Meier survival analyses and compared by the log-rank test. MELD scores were log transformed prior to analysis due to positive skewness. Untransformed scores are presented in the tables and figures for clarity. We chose median values for the biochemical tests rather than mean values which could be affected by extreme values and not indicate central tendency.
To test our first hypothesis we compared the proportion of patients switching immunosuppressants among those with a pre-LTX primary or secondary diagnosis of ALD vs. patients with all other liver diagnoses. We then examined the proportions switching medications among patients with other common liver disease diagnoses (i.e. hepatitis C- HCV) compared to all others. In addition to age and MELD score at LTX, we also examined gender, race, date of LTX, and biochemical values as potential predictors of our primary outcome in an exploratory univariate analysis. Colinearity was checked between variables and the final model was tested by logistic regression using variables that had achieved a p < 0.05 at the univariate level. Differences between groups on specific medical outcomes were also calculated. All analyses were performed using Statistical Package for Social Sciences (SPSS) version 12 for Windows.
All 827 adult LTX recipients received tacrolimus as their primary immunosuppressant. By 2 months post-LTX, 86 recipients (11%) had been removed from tacrolimus due to neurotoxic side effects. Eight patients were switched from tacrolimus due to concerns over renal toxicity and were not included in the analyses. The majority of patients (93%) were switched to cyclosporine as their primary immunosuppressant medication. Six patients received various combinations of sirolimus, mycophenolate, or azathioprine. Twelve patients (14% of those switched) were eventually switched back to tacrolimus anywhere from months to years later. The cohort was predominately Caucasian (90%) and male (61%), with ages ranging from 18 to 78 years of age (mean 54 + 11). MELD Scores at LTX ranged from 6 to 40 (mean 16 + 7). One hundred twelve recipients received a living liver donation, 707 recipients had deceased donor grafts. Thirty three percent of the cohort had either a primary or secondary diagnosis of alcoholic liver disease, of these 42% were additionally co-infected with HCV (Table 1).
The majority of patients (64%) had symptoms of altered mental status (including symptoms of stupor/coma, confusion/disorientation, agitation and/or psychosis). Twenty-six percent experienced seizures (Table 2). Of those switched from tacrolimus 60% had an EEG performed and 79% had either CT and/or MRI imaging of the brain to investigate the etiology of the mental status symptoms (see Table 3). The most common finding on EEG was generalized, diffuse slowing (65%). Only 23% showed either active or prodromal seizure activity. Twelve patients had characteristic abnormalities on radiological imaging (mostly MRI) of the Posterior Reversible leukoEncephalopathy Syndrome (PRES) (low attenuation of white matter on CT scan and/or corresponding hyper-intense lesions on T2 weighted MRI images). Interestingly there were 3 patients who had both MRI and CT scanning where the MRI was read by the radiologist as being consistent with PRES yet the CT scan was either read as normal or non-specific. This suggests the better distinguishing value of MRI in identifying such radiographic changes.
Of our three primary hypotheses, a previous diagnosis of alcoholic liver disease (ALD) was not directly associated with a subsequent switch off of tacrolimus by 2 months post-LTX. However, both older age and higher MELD scores were significantly associated with switching off of tacrolimus due to neurotoxicity (Table 4). The association between MELD score and tacrolimus switch was linear (see Figure 1). For age there was a discreet cut-point such that above 60 years of age the risk increased substantially (see Figure 2). There was a significant correlation between age and MELD score (p=.013) although small (r = −0.06). When controlling for MELD scores the association between age and tacrolimus switch remained and similarly controlling for age the association between MELD scores and tacrolimus switch remained.
In addition, the date of transplant was significantly associated with being switched off of tacrolimus such that within the 5 year cohort those transplanted earlier (i.e. closer to 2001) were more likely to remain on tacrolimus while those transplanted more recently were more likely to be switched off of tacrolimus.
To further examine liver disease diagnoses we analyzed whether those with HCV were more likely to be switched compared to all others. Although HCV was associated with a less likely chance of being switched (χ2 =6.1, p=0.014), the association did not remain after controlling for age, MELD score and time of LTX.
There were also notable differences in specific laboratory values between groups (see table 4). Since we were investigating laboratory values that would predict a switch off of tacrolimus, we report the median values either up until the switch off of tacroliums or throughout the total 2 month period for those not switched. Thus the laboratory values reflect events before the switch. We chose to investigate hypomagnesemia due to its association with tacrolimus neurotoxicity and hyponatremia due to its association with immunsuppression and central pontine myelinolysis. While there was no difference between groups on median sodium levels, the group switched off of tacrolimus had significantly higher magnesium levels (1.7 vs. 1.5, p=0.000) perhaps reflecting magnesium supplementation. In an attempt to keep patients on tacrolimus the dosage and blood levels were initially reduced in nearly all patients except when the clinical situation was more urgent necessitating an immediate switch. Although our immunosuppressive protocol has changed over time, tacrolimus is the mainstay of our therapy and we strive for a target whole blood level of 8–15ng/mL. Ninety percent had median values of tacrolimus 11.5 ng/mL or less and only five patients had median values greater that 15 ng/mL. No patient had a median tacrolimus value greater than 18 ng/mL. Median tacrolimus levels were not different between groups (see Table 4).
We also considered acute and chronic medical factors that may have contributed to our findings. Both acute renal failure (represented by those who required dialysis within 2 months post-LTX) and chronic renal insufficiency (represented by elevated median creatinine) were examined between groups. Although the creatinine values were slightly but not significantly different between groups, patients switched off of tacrolimus were significantly more likely to require dialysis within 2 months post-transplant (34% vs. 22%, p=0.02). In addition liver function (represented by median total bilirubin levels) was significantly worse for the switched group. Older age was correlated with lower total bilirubin levels, although this association was small (p=0.01, r = −0.09). Information on intraoperative hypotension was not available, however we had data on the total number of packed cells used during the transplant operation on 478 patients. The median number of packed cells used was 6 units and was not different between groups.
There were also important differences in medical outcomes between groups. Patients switched off of tacrolimus were slightly, although not significantly, more likely to have acute cellular rejection (37% vs. 30%) by one year (see Figure 3). However they were not more likely to have primary non-function (1% vs. 1%), require re-transplantation (12% vs. 9% at 5 years), or have received a donation from a living donor (14% vs. 14%). Especially concerning was the overall significantly poorer survival for those switched off of tacrolimus beginning at the point of transplantation and continuing out to five years post-LTX (see Figure 4). While we considered the contribution of age and pre-LTX MELD score to this outcome in the switched group, in a multivariate Cox regression including the variables of age and MELD score, being switch off of tacrolimus still added a significance contribution to poorer post-LTX outcomes.
We also investigated whether treatment with an anticonvulsant was associated with tacrolimus switch. Denovo anticonvulsant therapy was initiated in 37 recipients by 2 months post-LTX (35 on phenytoin, 1 on valproic acid, 1 on oxcarbazepine). Those on anticonvulsants were significantly more likely to be switched off of tacrolimus (p=0.000) and represented patients that we suspect developed neurotoxic seizures necessitating both anticonvulsant therapy and a tacrolimus switch. The majority (68%) were nearly simultaneously switched off of tacrolimus and started on an anticonvulsant therefore a drug interaction between tacrolimus and the anticonvulsant was an unlikely cause for the switch. It is of note that three patients were already on cyclosporine before developing seizures and requiring anticonvulsant therapy highlighting the neurotoxic potential of cyclosporine as well.
While elevated blood levels of tacrolimus [Burkhalter 1994, Fung 1991, DiMartini 1996] and electrolyte and other biochemical abnormalities [Kilinc 2002, Wong 2003, Sokol 2003, Bechstein 2000] have been associated with neurotoxicity, these chemical derangements are correctable and often do not require discontinuing tacrolimus. Thus our hypotheses were based on the premise that beyond reversible chemical derangements, core characteristics exist that can predict tacrolimus neurotoxicity and hence the need to switch to a different primary immunosuppressant. In addition our group had previously noted neurotoxicity is most likely multifactorial [Jain2 2000]. By identifying these risk factors we may be able to predict and possibly prevent this outcome. Furthermore these results may lead to the development of studies on the potential mechanisms of tacrolimus-induced neurotoxicity.
As we hypothesized older age and higher MELD scores at LTX did predict those who required a discontinuation of tacrolimus. Increased age is associated with increased sensitivity to a number of neuronally active medications [Turnheim 2004]. For several reasons, including loss of neurons, altered receptor levels, impaired adaptability and decreased homeostatic reserve, the older brain has elevated vulnerability to the effects of pharmacologic challenges [Toescu 2005]. Additionally, increased susceptibility to blood-brain barrier disruption is evident in the aged brain [Shah 1997]. Small changes associated with cerebrovascular disease, such as small lacunar infarcts, may further impair the blood-brain barrier [Wardlaw 2003].
Neuropsychologic deficits have previously been found to be higher in liver disease patients with elevated pre-LTX MELD scores [Sorrell 2006]. In a cohort of 80 LTX recipients MELD scores greater than 15 predicted post-LTX mental status changes occurring within the first post-operative month and lasting more than 3 days [Kanwal 2003]. The mechanistic pathway resulting in these neural deficits is not clear. However, our results suggest that elevated pre-LTX MELD scores are additionally associated with increased vulnerability to post-LTX tacrolimus neurotoxicity. These findings are especially important given the progressive trend towards a recipient population which is both older and has higher MELD scores than in the last decade [OPTN/SRTR 2006 annual report].
Our prior work in a small cohort of subjects [DiMartini 1992] also led us to hypothesize that patients with heavy pre-LTX alcohol exposure would have developed ‘vulnerable’ brains and be at higher risk for tacrolimus neurotoxicity. Although we did not examine neurotoxicity directly, we did not find evidence in support of this hypothesis. However, since alcohol differentially affects different organ systems (i.e. the CNS and the liver) using the diagnosis of ALD as a proxy for alcoholic brain damage may have masked a potential association between alcohol related structural or microvascular brain abnormalities and a potential for tacrolimus neurotoxicity. A much more sophisticated investigation, optimally using structural or functional imaging of the brain may be required to resolve this question.
Although not considered as a priori hypotheses we found poorer post-LTX hepatic functioning distinguished those switched from tacrolimus. Those switched had significantly higher bilirubin levels, slightly but not significantly higher creatinine levels and were more likely to be on dialysis within 2 months following LTX. As we had removed from the dataset those switched from tacrolimus due to concerns over renal toxicity, the patients in our analyses represented those switched due to neurotoxicity. Thus in addition to pre-LTX medical debility (i.e. pre-LTX MELD scores), ongoing post-LTX hepatic and renal insufficiency may identify those prone to tacrolimus neurotoxicity, a finding noted in a previous study from our center [Jain 2000].
One additional finding is that our prescribing practices may have changed over time. More recently, tacrolimus discontinuation is more common, suggesting a current lower clinical threshold to switch. The recent availability of other powerful, potentially less neurotoxic non-calcineurin-inhibiting immunosuppressants (i.e. sirolimus) may have provided an adequate alternative to tacrolimus as the primary immunosuppressant and more recent impetus to switch. Nevertheless for the majority of our patients tacrolimus was replaced with cyclosporine which has a similar neurotoxic profile [Mueller 1994]. As we found, even after the switch to cyclosporine three patients developed new onset seizures.
A striking finding was the poorer survival in the group switched off of tacrolimus. While this group was older and had higher pre-LTX MELD scores this did not fully explain their poorer outcomes. Perhaps some other medical factors that we did not explore resulted in their being switched off of tacrolimus and also would explain their poorer survival. Nevertheless this underscores the overall higher risk in this medically compromised group.
There are several limitations to the present study. The retrospective design prevented us from characterizing the severity of the neurotoxic events necessitating the switch from tacrolimus. Thus the severity of the events may have been varied and the decision to switch may have differed by clinician. Nevertheless, that 26% of those switched also required the addition of an anticonvulsant suggests that the neurologic events were significant and often severe. In addition, our clinical team has been stable for years and protocols for clinical care are routine. As this was a retrospective study we also lacked detailed information on our patients past medical histories, information that may have further clarified the predictors we found to be significant. For example pre-transplant hepatic encephalopathy, a prior history of a stroke, or a neurodegenerative disorder would be expected to contribute to differences between groups and may have further explained the association of older age to those requiring a switch. Finally our choice of median laboratory values to represent central tendency was an attempt to avoid the influence of lab value outliers on mean values. However we realize median values may not fully represent the biochemical influences either at the point of immunosuppressant medication switch or throughout the 2 month period. These limitations notwithstanding we have identified key variables predicating those at risk for being intolerant of tacrolimus.
Even with these considerations, this study is valid as an initial attempt to assess the variables related to the incidence of clinically-relevant tacrolimus neurotoxicity in liver allograft recipients. The importance of these parameters is especially relevant to the current clinical arena, where older patients with higher MELD scores are undergoing liver transplantation. The findings of this retrospective study emphasize the need for increasing awareness on this neurotoxicty-prone population, who should be carefully considered as a high-risk group for this undesirable calcineurin-inhibiting immunosuppressant driven complication. For our future clinical care these high risk patients should be carefully monitored for potential neurotoxic side effects and a lower threshold to switch should be considered especially when mental status changes persist post-LTX.
This research is supported by grant nos. K23 AA0257 from the National Institute of Alcohol Abuse and Alcoholism, R01 DK066266 from the National Institute of Digestive Disorders and Kidney Diseases and K23 MH074012 from the National Institute of Mental Health.