SEARCH

SEARCH BY CITATION

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Background  Sirolimus is a potent immunosuppressive agent whose role in liver transplantation has not been well-described.

Aim  To evaluate the efficacy and side-effects of sirolimus-based immunosuppression in liver transplant patients.

Methods  Retrospective analysis of 185 patients who underwent orthotopic liver transplantation. Patients were divided into three groups: group SA, sirolimus alone (n = 28); group SC, sirolimus with calcineurin inhibitors (n =56) and group CNI, calcineurin inhibitors without sirolimus (n = 101).

Results  One-year patient and graft survival rates were 86.5% and 82.1% in group SA, 94.6% and 92.9% in group SC, and 83.2% and 75.2% in group CNI (P = N.S.). The rates of acute cellular rejection at 12 months were comparable among the three groups. At the time of transplantation, serum creatinine levels were significantly higher in group SA, but mean creatinine among the three groups at 1 month was similar. More patients in group SA required dialysis before orthotopic liver transplantation (group SA, 25%; group SC, 9%; group CNI, 5%; P = 0.008), but at 1 year, post-orthotopic liver transplantation dialysis rates were similar.

Conclusions  Sirolimus given alone or in conjunction with calcineurin inhibitors appears to be an effective primary immunosuppressant regimen for orthotopic liver transplantation patients. Further studies to evaluate the efficacy and side-effect profile of sirolimus in liver transplant patients are warranted.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Sirolimus was initially approved for renal transplantation by the Food and Drug Administration in 1999. Although sirolimus is not approved for use in orthotopic liver transplantation (OLT), a number of published reports have documented the safety of using this drug in liver transplant recipients. Using a combination of sirolimus and tacrolimus as immunosuppression, McAlister et al.1 reported 93% and 91% 1-year patient and graft survival rates among 52 OLT recipients. Subsequently, Trotter2 reported comparable patient and graft survivals among 200 liver transplant recipients who received sirolimus as part of a primary immunosuppression regimen that were not different from historical controls.

In contrast to calcineurin inhibitors (CNIs), neither nephrotoxicity nor neurotoxicity has been described with sirolimus.3 For these reasons, sirolimus has been used in liver transplant recipients with baseline renal insufficiency as a ‘CI-sparing’ agent.4, 5 The model for end-stage liver disease (MELD) is a numerical scale that is currently used in the United States for liver allocation. Its use has resulted in a higher proportion of patients with renal insufficiency at the time of liver transplant.6 As a result, the potential role for sirolimus in liver transplantation warrants further investigation. Furthermore, there is very limited data regarding the efficacy of sirolimus-based immunosuppression without CNI in the setting of OLT. The purpose of this study was to report our experience with sirolimus in liver transplant recipients who received sirolimus without CNIs or in combination with CNIs as part of the initial immunosuppressant regimen and to compare the outcomes with patient who received CNIs only.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Two hundred and fifteen adults underwent either cadaveric or living donor liver transplantation (LDLT) at the University of Southern California University Hospital between May 1996 and September 2002. One hundred and ten patients received sirolimus as part of the immunosuppression therapy immediately after OLT, and 105 patients did not receive sirolimus at all. As the goal of this retrospective analysis is to compare the efficacy of this regimen as an initial primary immunosuppression, 30 patients were excluded because sirolimus was either added to the immunosuppressant regimen more than 2 weeks but <3 months after OLT or discontinued within 3 months after OLT.

The remaining 185 patients were divided into three groups based on their initial primary immunosuppressant regimen and form the basis of this retrospective study – group SA (n = 28): sirolimus without CNIs; group SC (n = 56): combination CNIs and sirolimus; group CNIs (n = 101): CNIs without sirolimus. The assignment of an immunosuppression regimen was made by the senior liver transplant surgeons who generally favoured sirolimus for patients with renal insufficiency. All but 12 patients were given intraoperative methylprednisolone (500–1000 mg) followed by a steroid taper. Patients were tapered off steroids by the sixth month based on toxicity and rejection episodes. For patients who were not receiving sirolimus (group CNIs), the target levels for tacrolimus were 8–12 ng/mL for the first 3 months, then 5–8 ng/mL thereafter. Target levels for ciclosporin were 225–300 ng/mL for the first 3 months, then 150–225 ng/mL thereafter. For patients who were also receiving sirolimus (group SC), target levels for tacrolimus were 2–5 ng/mL for the first 3 months, then 2–3 ng/mL thereafter. Target levels for ciclosporin were 100–150 ng/mL during the first 3 months and below 100 ng/mL thereafter. Sirolimus was administered orally at a dose of 5–7 mg/day in group SA and at a lower dose, 2–4 mg/day, in group SC. Mycophenolate mofetil (1 g b.d.) was added to the immunosuppression regimen in 110 patients, generally after the first initial episode of acute cellular rejection (ACR). The proportion of patients in the three groups who received mycophenolate was comparable (data not shown). The demographic and clinical characteristics for patients in the three study groups were comparable (Table 1).

Table 1.  Comparison of demographic and clinical characteristics by study group
CharacteristicsSubgroup/statisticsGroup SA (n = 28)Group SC (n = 56)Group CNIs (n = 101)P-value*
  1. SA, sirolimus alone; SC, sirolimus with CNIs; CNIs, calcineurin inhibitors; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis; AIH, autoimmune hepatitis.

  2. * Rank analysis of variance for mean values; Fisher's exact test for proportions.

AgeMean ± s.d.55.2 ± 9.052.4 ± 12.353.3 ± 10.40.91
GenderMale, N (%)18 (64%)36 (64%)66 (65%)1.00
MELD scoreMean ± s.d.24.9 ± 9.820.2 ± 8.320.1 ± 7.40.95
Range8–429–466–45
Transplant type, N (%)Live donor7 (25)14 (25)22 (22)0.25
Cadaveric19 (68)42 (75)78 (77)
Combined liver/kidney2 (7)0 (0)1 (1)
Aetiology, N (%)HCV10 (36)26 (46)42 (42)0.64
HBV8 (29)10 (18)13 (13)0.14
Alcoholic liver disease1 (4)6 (11)11 (11)0.58
Cryptogenic cirrhosis7 (25)5 (9)12 (12)0.13
PSC0 (0)2 (4)5 (5)0.67
PBC0 (0)3 (5)9 (9)0.29
AIH1 (4)0 (0)6 (6)0.17
Others1 (4)4 (7)3 (3)0.42

Protocol liver biopsies were not routinely performed. Liver biopsies were performed for elevated liver tests. Treatment for ACR was initiated after histological confirmation. All patients were followed for at least 6 months and co-trimethoxazole was administered twice weekly for prophylaxis against pneumocystis carinii indefinitely. Cytomegalovirus (CMV) prophylaxis was limited to high-risk patients (CMV-positive donor/-negative recipient). This retrospective analysis was approved by the local institutional Review Board.

Statistical methods

The following end points were assessed: graft and patient survival, incidence of ACR at 1, 3, 6 and 12 months after transplantation, renal function including the need for dialysis after transplantation, haematological parameters, and incidence of vascular, biliary and wound healing complications. For functional graft survival, all patient deaths were treated as failures. Patients who underwent combined liver–kidney transplantation were excluded from analyses with respect to renal function and the need for dialysis. The lowest levels of haemoglobin, white cell and platelet counts between the first month after transplant and the patients’ last follow-up were used for comparison of haematological parameters. Patient characteristics and clinical characteristics at baseline among the three study groups were compared using anova for continuous variables and the chi-square test or Fisher's exact test (two-tailed) for categorical variables. The levels of the outcome parameters and the incremental changes of outcomes at various time points among the treatment groups were analysed using ancova with repeated measures and covariates. The changes in the levels of haematological parameters from baseline to the last follow-up within each study group were analysed using the paired t-test. For analysis of ACR, the survival analysis was used to derive the probability of ACR at various time points. For the analysis of patient and graft survival, the Cox regression model was used with adjustment for significant covariates. Adjusted hazard ratios or survival and their 95% confidence intervals were derived. The sas (Statistical Analysis System, Version 8.2, Cary, NC, USA) statistical software was used for all analyses.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

Patient survival

The overall patient survival was 86.5% (160 of 185 patients), 82.1% (23 of 28 patients) for group SA, 94.6% (53 of 56 patients) for group SC and 83.2% (84 of 101 patients) for group CNIs. In this study population, mortality was significantly associated with pre-transplant total bilirubin level, INR, MELD score, hypotension, sepsis and use of antibiotics and/or vasopressors (Table 2). After adjusting for these significant factors, patient survival was comparable among the three study groups (log-rank test: P = 0.1221). One-year patient actuarial survival rates were 83% in group SA, 96% in group SC and 85% in group CNIs.

Table 2.  Demographic and clinical factors associated with mortality
CharacteristicSubgroupMortality [died/in group; % (n)]Relative risk, % (95% CI)P-value
Age at transplant≥55 years12.4 (11/89)0.85 (0.41–1.8)0.67
<55 years14.6 (14/96)1.0
GenderMale12.5 (15/120)0.81 (0.39–1.7)0.65
Female15.4 (10/65)1.0
AetiologyHCV18.0 (14/78)1.8 (0.84–3.6)0.19
No HCV10.3 (11/107)1.0
HBV3.2 (1/31)0.21 (0.03–1.5)0.08
No HBV15.6 (24/154)1.0
Alcoholic liver disease0.0 (0/18)0.14
No alcoholic liver disease15.0 (25/167) 
Cryptogenic cirrhosis20.8 (5/24)1.7 (0.69–4.1)0.33
No cryptogenic cirrhosis12.4 (20/161)1.0
PSC14.3 (1/7)1.1 (0.17–6.8)1.0
No PSC13.5 (24/178)1.0
Autoimmune hepatitis28.6 (2/7)2.2 (0.65–7.6)0.24
No autoimmune hepatitis12.9 (23/178)1.0
Primary biliary cirrhosis16.7 (2/12)1.3 (0.33–4.7)0.67
No primary biliary cirrhosis13.3 (23/173)1.0
Others0.0 (0/8)0.60
No others14.1 (25/177) 
Tumour typeHCC17.4 (4/23)1.3 (0.50–3.5)1.0*
Cholangiocarcinoma0.0 (0/2)1.0*
No tumour13.1 (21/160)1.0
Pre-treatment historyDiabetes10.3 (4/39)0.71 (0.26–1.9)0.61
No diabetes14.4 (21/146)1.0
Hypertension9.5 (4/42)0.65 (0.24–1.8)0.45
No hypertension14.7 (21/143)1.0
Hypotension37.5 (6/16)3.3 (1.6–7.1)0.01
No hypotension11.2 (19/169)1.0
Sepsis24.4 (11/45)2.4 (1.2–5.0)0.02
No sepsis10.0 (14/140)1.0
Antibiotics22.5 (11/49)2.2 (1.1–4.5)0.05
No antibiotics10.3 (14/136)1.0
Pressors45.5 (5/11)3.9 (1.8–8.5)0.01
No pressors11.5 (20/174)1.0
Type of transplantLive donor11.6 (5/43)0.81 (0.32–2.0)1.0*
Liver and kidney transplant0.0 (0/3)1.0*
Cadaveric liver14.4 (20/139)1.0

Graft survival

The overall graft survival was 81.6% (151 of 185 patients), 82.1% (23 of 28 patients) for group SA, 92.9% (52 of 56 patients) for group SC and 75.2% (76 of 101 patients) for group CNIs. One-year functional graft survival rates were 83% in group SA, 94% in group SC and 78% in group CNIs (unadjusted P = 0.056 based on log-rank test). Graft success was significantly associated with 14 pre-treatment factors. After adjusting for the significant pre-treatment risk factors, graft survival was not significantly different among the three treatment groups. The adjusted graft failure ratio between group SA and group CNI was 2.4 (95% CI: 0.64–9.0; P = 0.19) and the adjusted graft failure ratio between group SC and group CNI was 0.48 (95% CI: 0.11–2.0; P = 0.31).

Acute cellular rejection

The incidence of histologically proven ACR during the 12-month period was similar among the three groups (log-rank: P = 0.46). At 6- and 12-month follow-up the cumulative probability of ACR was 0.21 in group SA, 0.35 in group SC and 0.33 in group CNI. The overall ACR was 20% (five of 25) in group SA, 35% (18 of 52) in group SC, and 31% (28 of 91) in group CNIs, P = 0.42 (Table 3).

Table 3.  Comparison of cumulative probability of acute cellular rejection (ACR) by study group
 Group SA (n = 25)Group SC (n = 52)Group CNI (n = 91)
  1. Values are expressed as cumulative probability of ACR (number of ACR cases).

  2. The survival analysis excluded three cases from group SA, two cases from group SC and 10 cases from group CNI due to missing data.

  3. Log-rank P-value comparing the survival experience is 0.45 and the chi-square P-value comparing the overall ACR percentage is 0.42.

Time interval
≤30 days0.08 (2)0.14 (7)0.09 (8)
≤90 days0.12 (3)0.28 (12)0.28 (24)
≤180 days0.21 (5)0.35 (18)0.33 (28)
≤365 days0.21 (5)0.35 (18)0.33 (28)
Overall ACR, % (number of cases)20 (5/25)35 (18/52)31 (28/91)

Renal function after liver transplantation

Mean serum creatinine levels at OLT were significantly worse among the patients who received sirolimus without CNIs (Table 4). At 1 month after the transplant, there was a significant decrease in serum creatinine from baseline in all three groups with the greatest reduction occurring in group SA. The incremental reduction was significant when comparing group SA (−1.1 ± 1.6) and group CNI (−0.20 ± 0.79; P < 0.001). By the third month, serum creatinine levels among the three groups were comparable and remained so at 12 months. When an adjustment was made for baseline serum creatinine among the three groups, the difference in the improvement in serum creatinine was no longer significant. Although there was a higher proportion of patients in group SA who required dialysis at the time of OLT, the proportion of patients who required dialysis 12 months after OLT was similar among the three groups.

Table 4.  Comparison of renal function after liver transplantation by study group
Time after OLTGroup SA, mean ± s.d. (n)Group SC, mean ± s.d. (n)Group CNI, mean ± s.d. (n)P-value*
  1. * Repeated measures analysis of covariance, adjusted for baseline creatinine level, showed no statistically significant differences for group, time and interaction between group and time.

  2. † By linear regression over time.

  3. ‡ Cochran-Mantel-Haenszel test adjusted for pre-treatment proportions.

  4. § Tested by Cochran-Armitage Trend test.

(A) Creatinine level (mg/dL)
Baseline2.3 ± 1.5 (28)1.5 ± 1.3 (56)1.3 ± 0.82 (101)<0.0001
1 month1.3 ± 0.80 (27)1.0 ± 0.56 (56)1.0 ± 0.51 (91)0.49
3 months1.2 ± 0.43 (26)1.1 ± 0.61 (55)1.1 ± 0.90 (83)0.76
6 months1.4 ± 0.89 (21)1.2 ± 0.47 (52)1.2 ± 1.2 (70)0.85
1 year1.4 ± 0.72 (14)1.4 ± 0.69 (35)1.2 ± 0.77 (60)0.76
P-value for trend†0.00410.36420.8793 
 Group SA, % (n of cases/total)Group SC, % (n of cases/total)Group CNI, % (n of cases/total)P-value for group differences‡
(B) Need for dialysis after OLT
Pre-treatment25 (7/28)9 (5/56)5 (5/10510.01
1 month22 (6/27)11 (6/56)8 (7/91)0.91
3 months0 (0/26)4 (2/55)5 (4/85)0.08
6 months5 (1/21)4 (2/52)3 (2/74)0.74
1 year7 (1/14)6 (2/36)3 (2/66)0.64
P-value for trend§0.00100.07680.0759 

Haematological changes

Changes in haematological parameters (haemoglobin, white blood cell and platelet counts) from the time of transplant to the time of the patients’ last follow-up were examined (Table 5). Patients who did not receive sirolimus experienced a significant improvement in their mean haemoglobin level (P = 0.018) while patients who received sirolimus did not. There was a significant improvement in the platelet count in all three study groups. Post-transplantation haemoglobin was lower in patients who received sirolimus only (P = 0.06). Post-transplantation white blood count and platelet count were not different among the three study groups.

Table 5.  Comparison of change in haematological parameters by study group
Haematological parameterGroup SA [n = 28; mean ± s.d. (n)]Group SC [n = 56; mean ± s.d. (n)]Group CNIs [n = 101; mean ± s.d. (n)]P-values among groups*
  1. * By Kruskal–Wallis test.

  2. † By linear regression to test zero slope.

  3. Rank anova with repeated measures analysis showed a significant treatment group effect (P = 0.032) for the lowest haemoglobin levels, but no significant difference in time or interaction effect. For WBC, no effect was significant at P = 0.05 level. For the lowest platelet count, only time effect was significant (P < 0.0001).

Lowest haemoglobin
 Before10.1 ± 2.2 (28)10.9 ± 1.5 (56)10.6 ± 1.8 (101)0.15
 After10.2 ± 1.8 (28)10.9 ± 1.5 (56)11.2 ± 1.6 (95)0.02
 Change0.04 ± 2.9 (28)0.02 ± 1.8 (56)0.5 ± 2.2 (95)0.319
 P-value†0.9420.9410.018 
Lowest WBC
 Before5.2 ± 1.7 (28)5.0 ± 2.0 (56)4.9 ± 2.2 (101)0.46
 After5.7 ± 4.1 (28)5.1 ± 1.9 (56)5.5 ± 2.3 (95)0.73
 Change0.5 ± 4.5 (28)0.1 ± 2.8 (56)0.6 ± 2.5 (95)0.35
 P-value†0.5210.7990.090 
Lowest platelet
 Before88.9 ± 68.7 (28)93.1 ± 85.2 (56)93.2 ± 60.2 (101)0.83
 After142 ± 80.7 (28)146 ± 70.6 (56)135 ± 78.0 (95)0.55
 Change53.4 ± 79.9 (28)53.1 ± 66.0 (56)41.4 ± 87.5 (95)0.147
 P-value†0.0100.0005<0.0001 

Complications

The incidence of hepatic artery thrombosis (HAT) was similar in the three groups (group SA, 3.6%; group SC, 1.8%; group CNIs, 3.0%; P = N.S.). The mean time at diagnosis was 16 days post-OLT (range: 1–36). One patient in group CNIs experienced portal vein thrombosis (PVT) that was diagnosed at 5 months post-OLT.

Biliary reconstruction techniques were duct-to-duct anastomoses in most patients. Roux-en-Y anastomoses were performed in three (7%) patients in group SA, six (10%) in group SC and 16 (15%) in group CNIs (P = N.S.). The incidence of biliary stricture was higher in patients who received a combination of sirolimus and CNI (group SC; 12.5%) compared with group SA (3.6%) and group CNIs (3.0%), but the difference did not reach statistical significance (P = 0.061). Bile leaks occurred at a similar rate (group SA, 7.1%; group SC, 7.1%; group CNIs, 5.9%; P = 0.85). There was no significant difference in complications in wound healing among the three groups (group SA, 6.4%; group SC, 6.4%; group CNIs, 4.8%; P = N.S.).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

In the setting of liver transplantation, sirolimus has been used primarily in conjunction with a CNI, as a CNI sparing agent. We found similar rates of ACR, 1-year graft and patient survival rates in patients receiving combination CNI and sirolimus, compared with patients receiving conventional CNI-based immunosuppression. These findings were in keeping with the results of prior experience.1, 7–10 To our knowledge, our study comprises one of the largest cohorts of OLT patients who received sirolimus alone without CNI. We found a comparable incidence of ACR, 1-year graft and patient survival rates in these patients to those who received sirolimus/CNI combination or conventional CNI-based immunosuppression. Watson et al.9 first reported the safety of sirolimus as primary immunosuppression in liver transplantation. In that pilot study, using a much lower dose of sirolimus, three of four patients who received sirolimus without CNIs, developed ACR within 3 months after OLT. In another series comprising nine patients who received sirolimus as initial primary immunosuppression and an additional five patients who were converted to sirolimus after CNIs was discontinued, six of 14 patients experienced mild to moderate ACR.5

One of the main potential benefits of using sirolimus in liver transplant recipients is the absence of nephrotoxicity associated with this drug. Among renal transplant recipients, mean serum creatinine levels were significantly lower among patients receiving sirolimus compared with patients who were treated with ciclosporin.8 This observation has been the basis of using sirolimus to prevent deterioration of renal function in liver transplant recipients, particularly in those with pre-existing renal impairment.5 The majority of the liver transplant patients who were given sirolimus have renal impairment. Several uncontrolled studies have shown improvement of renal dysfunction in liver transplant recipients following conversion from CNIs to sirolimus-based immunosuppression,4, 11–13 although this was not a uniform finding.10, 14 Our study showed that the mean serum creatinine levels improved more dramatically among patients receiving sirolimus at the outset, although this difference was no longer significant when baseline renal functions were adjusted. However, the serum creatinine level improved significantly 1 month after OLT compared to patients who received sirolimus without CNI.

A phase II trial was prematurely terminated by the FDA due to a higher incidence of HAT during the initial 6 months following OLT among patients receiving sirolimus (unpublished data). The underlying mechanism of sirolimus-associated HAT is unclear. There has been no increased incidence of HAT among our sirolimus-treated patients or in subsequent reports.15 Furthermore, there was no difference in the incidence of portal vein, hepatic vein, or lower extremity deep vein thrombosis among the three groups in this study.

The mechanism of sirolimus-associated bone marrow suppression is due to inhibition of specific cytokines and vascular growth factors.16 Reversible leucopoenia and thrombocytopenia have been reported among patients with sirolimus-based immunosuppression in liver11 transplant recipients. No haematological side-effects were reported among 205 liver transplant recipients who received sirolimus.17 In our study, sirolimus did not significantly affect platelet and white blood counts, but follow-up haemoglobin levels were lower among patients who received sirolimus in this study, which has not been described previously.

Biliary strictures occurred more often in our patients who received sirolimus in combination with CNI, although patients who received sirolimus alone had the lowest incidence of stricture. The proportion of recipients who received a split graft was similar among the three groups. The reason for this complication is not apparent. There is no direct evidence that sirolimus negatively impacts wound healing. However, the drug has antifibrotic effects, which could provide an explanation for impaired wound healing.18 Like others, we did not observe a higher incidence of wound dehiscence associated with sirolimus,15 but others have reported sirolimus may delay wound healing.17, 19

There are several inherent weaknesses of this retrospective study. There were no strict selection criteria for patients receiving sirolimus other than the risk of renal dysfunction or neurotoxicity during the perioperative period. Sirolimus was administered as a fixed dose without monitoring of trough levels as the optimal trough level in the setting of liver transplantation had not been established. Data on our patients’ lipid panels were not available. The incidence of hyperlipidaemia in OLT patients on sirolimus has been reported to be as high as 30%, more frequent in those patients receiving ciclosporin than tacrolimus concomitantly.20 Sirolimus-induced hyperlipidaemia in liver transplant recipients may not be dose-dependent.21

In conclusion, sirolimus, alone or in conjunction with low-dose CNIs, is safe and effective as an initial immunosuppression agent in liver transplantation. Patient and graft survival rates and the incidence of ACR were comparable with conventional CNI-based immunosuppression. Among patients with renal insufficiency, the greatest improvement in renal function was seen in patients who received sirolimus without CNIs. The incidence of HAT was no higher in patients who received sirolimus. Further studies with sirolimus in the liver transplant setting are warranted.

Acknowledgement

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References

No external funding was received for this study.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgement
  8. References
  • 1
    McAlister VC, Peltekian KM, Malatjalian DH, et al. Orthotopic liver transplantation using low-dose tacrolimus and sirolimus. Liver Transpl 2001; 8: 7018.
  • 2
    Trotter JF. Sirolimus in liver transplantation. Transplant Proc 2003; 35: S193200.
  • 3
    Murgia M, Jordan S, Kahan B. The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int 1996; 49: 20916.
  • 4
    Gilroy RK, McCashland TM, Mukherjee S, et al. Analysis of sirolimus in liver transplantation, the effect on chronic renal dysfunction, adverse events and allograft rejection. Hepatology 2002; 36: 185A.
  • 5
    Chang GJ, Mahanty HD, Quan D, et al. Experience with the use of sirolimus in liver transplantation-use in patients for whom calcineurin inhibitors are contraindicated. Liver Transpl 2000; 6: 73440.
  • 6
    Nair S, Verma S, Thuluvath PJ. Pre-transplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology 2002; 35: 117985.
  • 7
    Pridohl O, Heinemann K, Hartwig T, et al. Low-dose immunosuppression with FK 506 and sirolimus after liver transplantation: 1-year results. Transplant Proc 2001; 33: 3229.
  • 8
    Kniepeiss D, Iberer F, Grasser B, et al. Sirolimus in patients after liver transplantation. Transplant Proc 2003; 35: 8156.
  • 9
    Watson CJ, Friend PJ, Jamieson NV, et al. Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 1999; 67: 50514.
  • 10
    Poordad F, Flores P, Tran T, et al. Failure of sirolimus to impact major outcome variables in tacrolimus-based immunosuppression regimens in liver transplant recipients. Hepatology 2002; 36: 186A.
  • 11
    Nair S, Eason J, Loss G. Sirolimus monotherapy in nephrotoxicity due to calcineurin inhibitors in liver transplant recipients. Liver Transpl 2003; 9: 1269.
  • 12
    Gee I, Watson CJ, Alexander GJ, et al. Sirolimus improves long-term renal function after liver transplantation. Hepatology 2002; 36: 186A.
  • 13
    Cotterell AH, Fisher RA, King AL, et al. Calcineurin inhibitor-induced chronic nephrotoxicity in liver transplant patients is reversible using rapamycin as the primary immunosuppressive agent. Clin Transplant 2002; 16: 4951.
  • 14
    Dhir R, Quinn MK, Dennis V, et al. Conversion from a calcineurin inhibitor to sirolimus in liver transplant recipients with chronic renal insufficiency. Hepatology 2002; 36: 187A.
  • 15
    Dunkelberg JC, Trotter JF, Wachs M, et al. Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications. Liver Transpl 2003; 9: 4638.
  • 16
    Hong JC, Kahan BD. Sirolimus induced thrombocytopenia and leucopenia in renal transplant recipients: risk factors, incidence, progression, and management. Transplantation 2000; 69: 208590.
  • 17
    Montalbano M, Neff GW, Yamashiki N, et al. Sirolimus related side effects in liver transplanted recipients. Transplantation 2004; 78: 2648.
  • 18
    Sousa JE, Costa MA, Abizaid A, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries: a quantitative coronary angiography and three-dimensional intravascular ultrasound study. Circulation 2001; 103: 1925.
  • 19
    Guilbeau JM. Delayed wound healing with sirolimus after liver transplant. Ann Pharmacother 2002; 36: 13915.
  • 20
    Trotter JF, Wachs M, Bak T, et al. Dyslipidemia during sirolimus therapy in liver transplant recipients occurs with concomitant cyclosporine but not tacrolimus. Liver Transpl 2001; 7: 4018.
  • 21
    Firpi RJ, Tran TT, Flores P, et al. Sirolimus-induced hyperlipidaemia in liver transplant recipients is not dose-dependent. Aliment Pharmacol Ther 2004; 19: 10339.