Sirolimus in liver transplant recipients with renal dysfunction offers no advantage over low-dose calcineurin inhibitor regimens

Authors

  • Derek DuBay,

    1. Liver Transplant Unit, Multiorgan Transplant Program, University of Toronto and Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
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  • Rob J. Smith,

    1. Liver Transplant Unit, Multiorgan Transplant Program, University of Toronto and Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
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  • Kenneth G. Qiu,

    1. Liver Transplant Unit, Multiorgan Transplant Program, University of Toronto and Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
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  • Gary A. Levy,

    1. Liver Transplant Unit, Multiorgan Transplant Program, University of Toronto and Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
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  • Leslie Lilly,

    1. Liver Transplant Unit, Multiorgan Transplant Program, University of Toronto and Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
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  • George Therapondos

    Corresponding author
    1. Liver Transplant Unit, Multiorgan Transplant Program, University of Toronto and Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
    • George Therapondos, 11-1222 NCSB, MultiOrgan Transplant Program, Toronto General Hospital, University Health Network, 585 University Avenue, Toronto, Ontario, Canada
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    • Telephone: 416-340-4248; FAX: 416-340-4041


  • See Editorial on Page 601

Abstract

The purpose of this study is to review the clinical experience with sirolimus immunosuppression in liver transplant patients with calcineurin inhibitor–induced chronic renal insufficiency. The study design is a case-control retrospective series. Fifty-seven liver transplant patients with renal insufficiency that were started on sirolimus at greater than 90 days postoperatively and treated for more than 90 days were identified. A control group of 57 patients maintained on low-dose calcineurin inhibitors, matched for gender, year of transplant, and baseline creatinine clearance, was also identified. There were no significant differences in the absolute creatinine clearance values between the sirolimus and control groups from 6 months before sirolimus conversion to 12 months after sirolimus conversion. Patients exposed to calcineurin inhibitors for more than 5 years or those with an initial creatinine clearance of less than 30 mL/minute who were converted to sirolimus did worse than control patients maintained on low-dose calcineurin inhibitors. Progression to renal replacement therapy, episodes of acute and chronic rejection, and death were similar between the sirolimus and control groups. The overall prevalence of side effects was significantly higher in the sirolimus group compared with the control group, although these were generally tolerable in most patients. In conclusion, this study suggests that conversion to sirolimus in liver transplant patients with chronic renal insufficiency is associated with stabilization of renal function but confers no additional benefit to low-dose calcineurin inhibitor regimens and may in fact be disadvantageous in patients with a creatinine clearance of less than 30 mL/minute. Liver Transpl 14:651–659, 2008. © 2008 AASLD.

The development of chronic renal failure is a common complication following liver transplantation. A Scientific Registry of Transplant Recipients population-based analysis of 36,849 liver transplant patients demonstrated an 18.1% incidence of chronic renal failure (defined as a glomerular filtration rate of <29 mL/minute/1.73 m2 of body surface area) at 5 years postoperatively.1 The relative risk of mortality in this group of patients compared with patients without this complication was 4.55.1 There is also concern that recent changes in transplantation practices in the United States may increase the incidence of chronic renal failure following liver transplantation. The use of the Model for End-Stage Liver Disease score, which prioritizes liver recipients with acute renal dysfunction, and the trend to transplant older patients have both been shown to significantly predispose liver transplant patients to chronic renal failure in the postoperative period.1–3

The introduction of the calcineurin inhibitors cyclosporine and tacrolimus has significantly improved liver graft and patient survival at the cost of nephrotoxicity as a major side effect.3 Longitudinal studies of liver transplant patients with chronic renal insufficiency demonstrate that calcineurin inhibitor toxicity is the most common clinical4 and histologic4 diagnosis in patients who progress to end-stage renal disease. Both cumulative dose and duration of calcineurin inhibitor exposure are related to the degree of renal damage.5 The overwhelming majority of liver transplant patients are currently treated with calcineurin inhibitor–based immunosuppression in most transplant centers, so modification of the use of cyclosporine and tacrolimus is considered to be the most important intervention in altering the development of chronic renal failure.6

Sirolimus (rapamycin; Wyeth-Ayerst, Philadelphia, PA) is an immunosuppressive medication approved for renal transplantation in 1999, although several reports have also documented its use in liver transplantation.7 Sirolimus functions as an immunosuppressant by blocking interleukin-2–dependent pathways via interaction with a class of kinases known as the target of rapamycin.8 In contrast to calcineurin inhibitors, sirolimus monotherapy is not associated with nephrotoxicity,9 and its use has been proposed as a “calcineurin inhibitor sparing agent.” Prospective clinical trials with sirolimus in the immediate postoperative period were halted because of an increased incidence of hepatic artery thrombosis.7 However, sirolimus is still used to a variable degree in liver transplant patients with a contraindication to calcineurin inhibitors. One attractive application of sirolimus is in liver transplant patients with calcineurin-induced chronic renal insufficiency, although there are insufficient clinical data to support its theoretical renal-sparing effect.

The purpose of this study is to review the clinical experience with sirolimus in liver transplant patients with postoperative chronic renal insufficiency at the University of Toronto between 2001 and 2006. We hypothesized that conversion from a calcineurin inhibitor to sirolimus-based immunosuppression would lead to an improvement in renal function, and we compared this group of patients with a matched control group maintained on reduced-dose calcineurin inhibitors alone.

Abbreviations

ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blockade; CrCl, creatinine clearance; NS, not significant; OTTR, Organ Transplant Tracking Record; SEM, standard error of the mean.

PATIENTS AND METHODS

Ethics approval for this study was obtained from the Research Ethics Board of the University Health Network (protocol #07-0010-BE).

We carried out a retrospective review of the electronic charts of all liver transplant patients treated with sirolimus at our institution between January 2001 (the date on which sirolimus first became available to our patients) and June 2006. These patients were identified via the Organ Transplant Tracking Record (OTTR; HKS Medical Information Systems, Omaha, NE), which is an internal web-based transplantation database linked to the electronic medical record that encompasses all patients evaluated for a solid organ transplant at the University Health Network, University of Toronto. Data have been prospectively entered into OTTR since January 1999, and these include all medications, laboratory results, pathology, radiology, and all transcribed documentation.

Renal insufficiency was defined as a calculated creatinine clearance of less than 60 mL/minute and was calculated via the method proposed by Cockroft and Gault.10 The Cockroft-Gault formula is automatically calculated in the OTTR patient database and is felt to be the most appropriate method to use, given our patient population.

At the time of this study, our standard immunosuppression protocol included calcineurin inhibition at the time of transplant and corticosteroids for the first 3 months, with the additional use of induction therapy with anti-thymocyte globulin (rabbit; Genzyme Corp, Cambridge, MA) in living donor liver recipients. Antimetabolite drugs were added only if the desired levels of calcineurin inhibitors could not be achieved because of renal dysfunction.

Patients

Treatment with sirolimus was initiated in 114 patients between January 2001 and June 2006. Forty-six patients had a creatinine clearance above 60 mL/minute at the time at which sirolimus was initiated and were excluded because the reason for sirolimus initiation was unrelated to renal dysfunction. An additional 10 patients who started sirolimus in the early postoperative period (less than 90 days) were excluded to eliminate the study bias of resolving hepatorenal syndrome. One other patient who was treated with sirolimus for less than 90 days was also excluded. The final study population thus included 57 patients with a calculated creatinine clearance of less than 60 mL/minute who were started on sirolimus at least 90 days postoperatively and treated for a minimum of 90 days.

Conversion Protocol

A spot urinary protein was checked on patients considered for sirolimus conversion. Twenty-four–hour urine protein quantification was obtained on all patients with 1+ or more protein on the spot protein analysis. Patients with more than 500 mg of protein per day in the 24-hour urine protein were not considered for sirolimus conversion.

Two separate conversion protocols were generally followed, depending on the patient's immunosuppression regimen. For patients on calcineurin monotherapy, sirolimus was started at 1 mg daily, and the calcineurin dose was halved. At 1 week, the calcineurin inhibitor was stopped, and the sirolimus dose was adjusted on the basis of the serum levels. For patients on combination therapy, the calcineurin inhibitors were stopped, and sirolimus was started on the same day at 2 mg daily while the antimetabolite or steroid doses were maintained at their current levels. The sirolimus dose was adjusted to maintain trough levels of 5 to 15 μg/day.

Study Design

The study design was a case-control matched series. The control population was identified by the matching of gender, year of transplant, and creatinine clearance ± 15% in non–sirolimus-treated patients. Conversion to sirolimus was defined as the time of intervention. In 10 patients, there were no suitable controls identified with these parameters. One patient was matched with a non–gender-specific control transplanted in the same year, 7 patients were matched with patients transplanted 1 year earlier, and 2 patients were matched with controls transplanted 2 years earlier.

A transplant nephrologist saw 40 of the 57 patients prior to conversion to sirolimus as well as 28 of the 57 control group patients prior to the date of intervention, as evidenced by documented notes in the medical record. In each case, chronic calcineurin exposure was felt to significantly contribute to the decline in renal function. Renal biopsies were rarely performed.

We recorded transplant indication, duration and tolerability of sirolimus treatment, immunosuppression at time of transplant and intervention, postintervention immunosuppression levels, possible immunosuppression-related complications, episodes of rejection, retransplantation, renal replacement therapy, and death. Multiple serum creatinine and creatinine clearance measurements were recorded at 6 and 3 months before intervention, at the time of intervention, and at 3, 6, and 12 months post-intervention. Patients were censored when they were started on renal replacement therapy if this was required, and creatinine values were no longer recorded.

Statistical Analysis

All statistical analyses were performed with SPSS software (version 15, SPSS, Inc., Chicago, IL). The statistical significance of differences of proportions among groups was tested with the chi-square test. The Student t test was used to assess differences in continuous variables, whereas the analysis of variance test was used to test for differences in creatinine clearance at multiple time points between the sirolimus and control groups. Values are presented as mean ± standard error of the mean. A P value of <0.05 was taken to be significant.

RESULTS

The median creatinine clearance (range) at the time of liver transplant was 58.4 mL/minute (9.4-104.4) in the sirolimus group versus 58.1 mL/minute (22.6-124.9) in the control group. Thirty-two of the 57 patients in the sirolimus group and 31 of the 57 control patients had an estimated creatinine clearance of less than 60 mL/minute at the time of transplant. Sirolimus was started at the median postoperative time of 45 months (range 3-204 months), and the median duration of treatment was 18 months (range 4-46 months).

Group Demographics and Baseline Characteristics

The patients and controls were well matched at the time of intervention. The liver allograft function was felt to be satisfactory in all patients at the time of conversion to sirolimus and in the matched controls. There were no significant differences in gender, age, indication for liver transplant, and time from transplant to intervention (Table 1). Renal specific comorbidities were very common among both the sirolimus and control groups. Angiotensin converting enzyme inhibitors and angiotensin receptor blocker medications were used liberally in both groups. There were no significant differences in renal specific comorbidities or use of angiotensin inhibitors (Table 1).

Table 1. Baseline Demographics
 SirolimusControlSignificance
  1. Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blockade; CrCl, creatinine clearance; NS, not significant; SEM, standard error of the mean. *Other includes autoimmune hepatitis, hemochromatosis, and alpha-1 antitrypsin deficiency. †At the time of sirolimus conversion.

Total patients5757 
Age at transplant [years (range)]50.4 (23-70)53.4 (21-70)NS
Gender   
 Female25 (44%)26 (46%)NS
 Male32 (56%)31 (54%)NS
CrCl at transplant ± SEM (mL/minute)59.4 ± 3.058.9 ± 2.9NS
CrCl at intervention ± SEM (mL/minute)37.0 ± 1.637.3 ± 1.4NS
Etiology   
 Hepatitis C19 (33%)19 (33%)NS
 Hepatitis B3 (5%)6 (11%)NS
 Alcohol6 (11%)4 (7%)NS
 Primary biliary cirrhosis5 (9%)6 (11%)NS
 Primary sclerosing cholangitis6 (11%)5 (9%)NS
 Nonalcoholic steatohepatitis3 (5%)3 (5%)NS
 Cryptogenic5 (9%)3 (5%)NS
 Fulminant hepatic failure4 (7%)5 (9%)NS
 Other*6 (11%)6 (11%)NS
Renal-specific comorbidities†   
 Hypertension48 (84%)43 (75%)NS
 Diabetes mellitus32 (56%)36 (63%)NS
 Proteinuria0 (0%)3 (5%)NS
Angiotensin inhibitor medication use   
 ACEI   
  Pre-intervention30 (53%)22 (39%)NS
  Post-intervention19 (33%)15 (26%)NS
 ARB   
  Pre-intervention12 (21%)8 (14%)NS
  Post-intervention10 (17%)6 (11%)NS

There were no significant differences in the choice of calcineurin inhibitor or use of antimetabolite drugs (azathioprine or mycophenolate mofetil) between the sirolimus and control groups. The serum creatinine level and creatinine clearance values were similar in both the sirolimus and control groups at the time of liver transplant and at the time of intervention (Table 1). The measured median sirolimus level was 8.75 μg/L (range 5-13 μg/L) by 1 month post-conversion. All but 5 of the sirolimus-treated patients were completely withdrawn from calcineurin inhibitor therapy. One patient was continued on low-dose cyclosporine (serum cyclosporine level 2 hours post-dose C2 < 200 μg/L), and 4 patients were maintained on low-dose tacrolimus (serum levels < 4 μg/L). All of the control group patients were maintained on low-dose calcineurin inhibitors with the median C2 levels at 400 μg/L (range 100-700 μg/L), whereas the median serum trough tacrolimus levels were 6 μg/L (range 2.5-10.5 μg/L). There were no significant differences in steroid or antimetabolite adjuvant use between the sirolimus and control groups at the time of intervention (Table 2).

Table 2. Immunosuppression at the Time of Intervention
 SirolimusControlSignificance
  1. NOTE: Antimetabolite includes azathioprine or mycophenolate mofetil. Intervention denotes the time of sirolimus conversion. Abbreviation: NS, not significant.

Cyclosporine28 (49%)22 (39%)NS
Cyclosporine + antimetabolite10 (18%)14 (25%)NS
Tacrolimus13 (23%)12 (21%)NS
Tacrolimus + antimetabolite6 (11%)9 (16%)NS
Total5757 

Sirolimus Tolerability and Acute Cellular Rejection

Thirty-five of the 57 patients remained on sirolimus at the conclusion of the study. The primary reasons for cessation of sirolimus included progression to renal failure (7), death (3), perioperative withdrawal (3), recurrent shingles (2), headaches (2), oral ulcers (2), and other (3). Additionally, individual drug-related complications were similar between groups, although the overall percentage of patients experiencing drug-related side effects was significantly higher in the sirolimus group compared with the control group during this study (36 versus 24 patients, P = 0.025; Table 3). Serum albumin levels were not significantly altered with the use of sirolimus (Table 3). Four patients in the sirolimus group developed proteinuria within the first 12 months after initiating the medication. Sirolimus was stopped in the 1 patient with a 24-hour urinary protein over 500 mg. Renal replacement therapy was required in 1 of these 4 patients. Four patients in the control group developed proteinuria. The 24-hour urinary protein was over 500 mg in 2 of the 4 patients. These 2 patients both required renal replacement therapy and eventually received a renal transplant. The number of rejection episodes before or after sirolimus intervention was similar between groups (Table 4).

Table 3. Potential Sirolimus/Immunotherapy Drug–Related Complications
 SirolimusControlSignificance
  1. Abbreviations: NS, not significant; SEM, standard error of the mean.

Lower extremity edema13 (23%)6 (11%)P = 0.08
Anemia9 (16%)7 (12%)NS
Hernia7 (12%)3 (5%)NS
Headaches4 (7%)0NS
Dermatologic3 (5%)0NS
Deep venous thrombosis3 (5%)0NS
Shingles3 (5%)2 (4%)NS
Osteopenia2 (4%)4 (7%)NS
Diarrhea2 (4%)0NS
Oral ulcers2 (4%)0NS
Myalgias1 (2%)0NS
Gout1 (2%)2 (4%)NS
Pneumonitis1 (2%)0NS
Extremity numbness1 (2%)0NS
Depression1 (2%)5 (9%)NS
Alopecia01 (2%)NS
Nephrolithiasis01 (2%)NS
Total patients5757 
 With complications36 (63%)24 (42%)P = 0.025
 Without complications21 (37%)33 (58%) 
Serum albumin levels (g/L)   
 At conversion ± SEM36.7 ± 0.833.2 ± 0.9NS
 12 months post-conversion ± SEM37.4 ± 0.637.7 ± 0.8NS
Table 4. Rejection, Renal Replacement Therapy, and Death
 SirolimusControlSignificance
  1. NOTE: Intervention denotes the time of sirolimus conversion.

  2. Abbreviation: NS, not significant.

Acute rejection pre-intervention  NS
 Episodes1417 
 Patients12 (21%)12 (21%) 
Acute rejection post-intervention  NS
 Episodes32 
 Patients3 (5%)2 (4%) 
Chronic rejection4 (7%)2 (4%)NS
Retransplantation02 (4%)NS
Renal replacement therapy12 (21%)7 (12%)NS
Death7 (12%)8 (14%)NS

Renal Function

There was no significant difference in the requirement for renal replacement therapy or death between the sirolimus-treated and control groups (Table 4). The presence of poor renal function 12 months after sirolimus intervention proved to be a strong predictor of the eventual need for renal replacement therapy or death. Of the patients who required renal replacement therapy, 11 of 12 in the sirolimus group and all 8 of the control group patients had a creatinine clearance of <30 mL/minute at 12 months after intervention. Similarly, 4 of 7 sirolimus group deaths and 7 of 8 control group deaths occurred in patients who had a creatinine clearance of <30 at 12 months.

Creatinine Clearance Values (Sirolimus Versus Control Group; Fig. 1A)

The creatinine clearance of both the sirolimus [37 ± 1.6 versus 35 ± 14 mL/minute, P = not significant (NS)] and control groups (38 ± 1.4 versus 37 ± 1.6 mL/minute, P = NS) was unchanged at 12 months after intervention compared with the creatinine clearance at intervention. There were no significant differences in creatinine clearance values at any time point between the sirolimus and control groups. However, the change in creatinine clearance with respect to the time of intervention is graphically demonstrated in Fig. 1B and was significantly worse in the sirolimus group compared with the control group at 6 (P = 0.045) and 12 months after intervention (P = 0.001).

Figure 1.

(A) Creatinine clearance. (B) Relative change in creatinine clearance. Mean creatinine clearance was normalized to 1 at intervention. Time points illustrate relative changes in creatinine clearance from the point of intervention. *P = 0.045; **P = 0.001. Intervention denotes the time of conversion to sirolimus immunotherapy. Data are presented as the mean ± standard error of the mean. Abbreviations: post, post-intervention; pre, pre-intervention.

Creatinine Clearance Changes Stratified According to Creatinine Clearance Values at the Time of Sirolimus Initiation (Fig. 2A)

There were no significant differences in creatinine clearance values between the groups with baseline creatinine clearances of 30 to 45 or 45 to 60 mL/minute. However, at the lowest creatinine clearance stratification (less than 30 mL/minute), the sirolimus group (n = 17) demonstrated significantly worse creatinine clearance values at the 3-month (20 ± 1.4 versus 25 ± 1 mL/minute, P < 0.012) and 6-month (19 ± 2 versus 25 ± 1.5 mL/minute, P < 0.035) postintervention time points, although this improved at the 12-month postintervention time point such that the difference was no longer significant (20.5 ± 1.7 versus 24 ± 1.5 mL/minute, P = NS).

Figure 2.

(A) CCL stratified by CCL at the time of intervention. *P = 0.012; **P = 0.035. (B) CCL stratified by the time interval between the liver transplant and intervention. Intervention denotes the time of conversion to sirolimus immunotherapy. Abbreviations: CCL, creatinine clearance; post, post-intervention; pre, pre-intervention.

Creatinine Clearance Changes Stratified as a Function of the Time Interval Between Sirolimus Initiation and Transplant (Fig. 2B)

The creatinine clearance at 6 months prior to intervention was the lowest in the group started on sirolimus more than 5 years postoperatively and the highest in the group started on sirolimus within 2 years postoperatively (35 ± 3 versus 46 ± 4 versus 54 ± 4 mL/minute, P = 0.003). There were no significant differences in the creatinine clearance values between the sirolimus and control groups based on intervention soon after the transplant (less than 2 years) or at the intermediate dates (2-5 years). There is a single significant time point in the remote conversion group (greater than 5 years) at which the sirolimus group creatinine clearance was worse than that of the control group (26 ±2 versus 33 ± 2 mL/minute, P = 0.044).

DISCUSSION

The purpose of this study was to compare the 2 clinical approaches commonly used in liver transplant patients with chronic renal insufficiency to stabilize or minimize the decline in renal function. One approach is conversion from a calcineurin inhibitor to sirolimus, whereas the other approach is to simply reduce the calcineurin inhibitor dose. Patients who were changed to sirolimus because of chronic renal dysfunction were identified and were matched to a control group with equivalent demographics and renal function. Control patients had the dose of their calcineurin inhibitor reduced, and potentially nephrotoxic drugs were stopped. They also underwent evaluation by a transplant nephrologist. Overall, we observed that the patients in both the sirolimus and control groups in this study maintained a stable creatinine clearance level from the time of intervention, and this suggests that both approaches used in our center are valid therapeutic options. This study did not, however, demonstrate any substantial improvement in renal function with either of these 2 approaches.

Calcineurin inhibitors cause both acute functional nephrotoxicity and chronic structural nephrotoxicity. The acute nephrotoxicity associated with calcineurin inhibitors is due to afferent arteriolar vasospasm and resulting renal ischemia. The acute process is completely reversible with cessation of the offending drug.11 Chronic use of calcineurin inhibitors, however, leads to structural kidney damage via obliterative arteriopathy, tubular atrophy, interstitial fibrosis, and glomerular fibrosis12 and is reported to irreversibly reduce renal function.11 Although calcineurin inhibitor reduction or elimination is an attractive strategy to improve renal function, it is not clear that this approach can lead to a substantial improvement because of the structural damage sustained. Preservation of existing renal function may therefore be the only realistic goal of calcineurin inhibitor minimization/withdrawal and sirolimus initiation.

It is perhaps worth noting that the rate of progression to renal failure was higher in the sirolimus group compared with the control group (21% versus 12%), although this did not reach statistical significance. In addition, we also demonstrated a statistically significantly worse decline in renal function in those patients with a creatinine clearance of less than 30 mL/minute who received sirolimus compared with the patients on the reduced calcineurin protocol and with a similar creatinine clearance. Similar results were also reported by Sanchez et al.13 in a series of 27 liver transplant patients with calcineurin-induced chronic renal insufficiency converted to sirolimus monotherapy. The authors suggested that there was a critical creatinine clearance threshold of around 30 mL/minute, below which there would be no improvement in renal function, and they recommended starting sirolimus at a much earlier stage. In our study, the worse measurements were seen only at the postintervention 3-month and 6-month time points, and no significant differences were observed at 1 year post-intervention (Fig. 2A; initial creatinine clearance < 30) Although not statistically significant, preservation of renal function in the sirolimus group appeared maximal in the subgroup with the highest starting creatinine clearance (Fig. 2A; initial creatinine clearance = 45-60) ml/min.

We observed that the decline in creatinine clearance before intervention in the sirolimus group was higher compared with the decline in the control group (6.5 versus 2.1 mL/minute, P = NS), and this may have introduced a bias into our analysis. Although the sirolimus and control groups were highly matched at the time of intervention, it is possible that the patients treated by conversion to sirolimus had already been identified by their clinicians as a group of patients with rapidly declining renal function requiring more active intervention than a mere decrease in calcineurin dosing and thus more predisposed to having a worse renal outcome.

There were no significant differences in the liver retransplantation rate or death, and the potential immunosuppressive drug–related side effects were comparable between the sirolimus and control groups. The described side effects are reflective of the common sirolimus side effect profile reported in the literature.14 Although sirolimus was generally tolerated, there was a significantly increased number of side effects in that group compared with the control patients

Cotterell et al.15 suggested that exposure to calcineurin inhibitors for greater than 6 years reduces the likelihood of improvement in renal function following conversion to sirolimus in a series of liver transplant patients with chronic renal insufficiency. Our study also suggests a negative relationship between duration of exposure to calcineurin inhibitors and maintenance of renal function (Fig. 2B; >5 years post-transplant), although the decline in creatinine clearance in that group of sirolimus patients reached statistical significance only at one time point (6 months post-intervention). As expected, there was an inverse relationship between renal function and length of postoperative time.

Evidence in this field is beginning to accumulate and largely consists of small retrospective, uncontrolled case series with variable results. Cotterell et al.15 reported that 5 of 8 liver transplant patients with renal insufficiency experienced improvement in renal function after conversion to sirolimus, whereas the remaining 3 progressed to dialysis. Neff et al.16 reported that 9 of 14 liver transplant patients with renal insufficiency experienced improvement in renal function after conversion to sirolimus, with the baseline creatinine clearance of 40.1 mL/minute significantly improving to 51.4 mL/minute at 90 days post-intervention. Nair et al.17 reported that 7 of 16 liver transplant patients with renal insufficiency experienced improvement in renal function after conversion to sirolimus, with a trend in improvement in the creatinine clearance from a baseline of 43 mL/minute to 49 mL/minute at 6 months post-intervention. Similarly, Fairbanks et al.18 reported that 15 of 21 liver transplant patients with renal insufficiency experienced improvement in renal function after conversion to sirolimus, with the creatinine clearance significantly improving from a baseline of 34 mL/minute to 43 mL/minute at 67 weeks post-intervention. In a case series of 48 patients converted to sirolimus, Morard et al.19 reported an improvement in the glomerular filtration rate from 33 to 48 mL/minute in patients with severe renal insufficiency and an improvement in the glomerular filtration rate from 56 to 74 mL/minute in patients with moderate renal insufficiency.

In contrast, Backman et al.20 noted no significant difference in the glomerular filtration rate among 15 liver transplant patients with chronic renal insufficiency converted to a sirolimus-based immunosuppression, whereas substantial improvement was demonstrated in a similarly sized group of renal transplant recipients. Sanchez et al.13 reported on a case-control series of 35 liver transplant patients with chronic renal insufficiency converted to sirolimus immunosuppression at a median of 177 days post-transplant. There was no significant difference in the glomerular filtration rate or serum creatinine concentration at 1 or 2 years post-intervention in comparison with a matched control group maintained on low-dose calcineurin inhibitors. Similarly, Dhir et al.21 reported no change in renal function in a case series of 17 liver transplant patients with chronic renal insufficiency converted to sirolimus immunosuppression; serum creatinine values worsened from a baseline of 2.6 to 2.8 mg/dL at a mean follow-up of 38 weeks. Campbell and colleagues22 reported on a group of post–liver transplant patients with a mean creatinine of 1.2 mg/dL, of whom 79 were converted to sirolimus, and a control group of 100 patients was maintained on a standard calcineurin-based protocol. Conversion to sirolimus did not protect against the development of renal dysfunction in comparison with patients maintained on calcineurin inhibitors.

Our study represents the largest reported group of liver transplant patients with chronic renal insufficiency converted from calcineurin-based immunosuppression to sirolimus. Although it is retrospective in nature and includes a heterogeneous group of patients in the sirolimus group, it has clearly defined inclusion criteria and includes a control group carefully selected case by case to determine the effect of “best clinical practice,” which was considered to be low-dose calcineurin inhibitors ± antimetabolite therapy.

In summary, this study shows that conversion from a calcineurin inhibitor protocol to sirolimus in liver transplant patients with chronic renal insufficiency is safe and is associated with stabilization of renal function but confers no advantage over low-dose calcineurin inhibitors ± antimetabolites. Although episodes of acute and chronic rejection and death were similar in the sirolimus and control groups, the excess number of side effects seen in the sirolimus group makes the conservative approach of reduced calcineurin inhibition alone the preferable option.

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