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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Case presentation
  5. Patient 1
  6. Patient 2
  7. Patient 3
  8. Patient 4
  9. Patient 5
  10. Patient 6
  11. Discussion
  12. References

Background : Sirolimus is a potent immunosuppressive medication that acts by inhibiting T-cell proliferation. It has been used in kidney transplantation because of its lack of nephrotoxicity. It is now being investigated in liver transplantation, but there are concerns about safety and long-term side effects such as dyslipidaemia. Hypertriglyceridaemia is a common adverse event seen with sirolimus use, and often does not respond to dose reduction or anti-lipemic drugs.

Method : We report six patients who have developed significant hyperlipidaemia while receiving sirolimus, in spite of therapeutic trough levels.

Conclusion : All six patients showed either resolution or improvement in lipid levels with discontinuation of sirolimus.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Case presentation
  5. Patient 1
  6. Patient 2
  7. Patient 3
  8. Patient 4
  9. Patient 5
  10. Patient 6
  11. Discussion
  12. References

Sirolimus (also known as Rapamycin or Rapamune) is a new immunosuppressive drug produced by the actinomycete Streptomyces hygroscopicus.1 It resembles tacrolimus (TAC) but acts by blocking interleukin-2-dependent T-cell proliferation in a calcineurin-independent manner. Ciclosporin (CsA) and TAC interfere with signal 1 of T-cell activation by binding to and inhibiting the Ca2+-calmodulin regulated protein serine-threonine phosphatase calcineurin.2 In contrast, sirolimus (SRL) interferes with T-cell activation and proliferation by binding to the kinase enzyme mammalian target of rapamycin (mTOR).2 While calcineurin inhibitors act between the G0 and G1 phases of the cell cycle, SRL inhibits progression from the G1 to S phases.2 It is an attractive agent in transplantation as its side-effect profile differs from that of calcineurin inhibitors, thus allowing use of lower doses of both agents with a potential for reduced adverse reactions. Unlike calcineurin inhibitors, SRL has not been implicated in significant neurotoxicity, nephrotoxicity, or diabetogenesis.2, 3 SRL also has been shown to inhibit the in vitro proliferation of some tumours including hepatomas, making it attractive for patients transplanted with primary liver tumours.4

However, SRL can cause dose-dependent hyperlipidaemia, thrombocytopenia and leucopenia.5, 6 Hyperlipidaemia has been reported in up to 50% of kidney transplant recipients who received SRL as part of their immunosuppressive therapy.7 The incidence of elevated lipid values in published reports of patients treated with SRL after liver transplantation ranges from 3.6 to 20%.8–10 Lipid abnormalities in liver transplant recipients likely contribute to the high frequency of cardiovascular events and mortality in these patients.

Reports of SRL use in liver transplantation are limited to descriptive reports.3, 10, 11 It has been used as rescue therapy for patients experiencing severe side effects from other immunosuppressants,3 in combination with other immunosuppressive protocols,10, 11 and as part of the primary immunosuppressive regimen.9

The purpose of this report is to describe six cases of liver transplant recipients who developed significant hyperlipidaemia while receiving SRL in combination with TAC or CsA. These patients are discussed in the context of the published literature on SRL-induced lipid abnormalities.

Patient 1

  1. Top of page
  2. Summary
  3. Introduction
  4. Case presentation
  5. Patient 1
  6. Patient 2
  7. Patient 3
  8. Patient 4
  9. Patient 5
  10. Patient 6
  11. Discussion
  12. References

A 50-year-old Caucasian male underwent orthotopic liver transplantation (OLT) for hepatitis C related cirrhosis. He was started on triple immunosuppressive therapy with TAC, SRL and corticosteroids. At 1-month post-OLT, serum triglyceride was 99, rose to 331 at month 3, then to 2409 by month 8. (Table 1). His prednisone dose was 2.5 mg daily at the time of these findings. Pravastatin was added to his medication regimen without improvement in lipid profile after approximately 3 weeks of treatment. The SRL dose was reduced and triglyceride level at month 10 was 1665. The lipid-lowering regimen was changed to gemfibrozil, and within 3 weeks he was admitted to the hospital with abdominal pain, presumably secondary to gemfibrozil. The patient's serum creatinine was elevated but creatinine phosphokinase, lipase, and amylase were normal. SRL and gemfibrozil were discontinued during this admission, and serum cholesterol and triglycerides promptly normalized 4 weeks later. Of note, the patient's high-density lipoprotein (HDL) cholesterol was low at the time of peak cholesterol and triglyceride values, and normalized after discontinuation of SRL. A detailed description of the timing of the events described is shown in Table 1.

Table 1.  Course of immunosuppression and lipid abnormalities in patient 1 (1–11 months after liver transplantation)
Parameters1234567891011
  1. * Therapy with a lipid-lowering agent.

  2. SRL, sirolimus; TAC, tacrolimus; N/A, not available.

SRL dose (mg)5555555522Off
SRL mean trough level (ng/mL)4.74.7N/AN/A9.19.2N/A11.410.82.3<2.0
SRL highest trough level (ng/mL)5.65.0N/AN/A9.19.3N/A12.910.82.3<2.0
TAC dose (mg)45766655544
TAC mean trough level (ng/mL)6.23.010.48.58.37.25.710.014.67.911.3
TAC highest trough level (ng/mL)10.27.810.410.48.38.75.710.014.68.311.3
Triglycerides (mg/dL)99N/A331N/AN/AN/AN/A2,4092,9701,665123
Cholesterol (mg/dL)206N/A188N/AN/AN/AN/A340413160182
Lipid-lowering agentNoneNoneNoneNoneNoneNoneNone****

Patient 2

  1. Top of page
  2. Summary
  3. Introduction
  4. Case presentation
  5. Patient 1
  6. Patient 2
  7. Patient 3
  8. Patient 4
  9. Patient 5
  10. Patient 6
  11. Discussion
  12. References

A 68-year-old Hispanic male underwent OLT for cryptogenic cirrhosis. Immunosuppression therapy consisted of prednisone, TAC and SRL. Twelve months after OLT, elevation in cholesterol and triglyceride level was noted (Table 2). The prednisone dose at that time was 5 mg daily and 1 year prior to OLT, the patient's cholesterol was 139 mg/dL and the triglyceride level was 110 mg/dL. The patient's weight had not increased, and he had no other apparent risk factors for fatty liver disease. Prednisone and SRL were discontinued 2 months later, without improvement in triglyceride level.

Table 2.  Course of immunosuppression and lipids abnormalities in patient 2 (1–17 months after liver transplantation)
Parameters1–67–91011121314151617
  1. SRL, sirolimus; TAC, tacrolimus; N/A, not available.

SRL dose (mg)5555555OffOffOff
SRL mean trough level (ng/mL)3.75.97.64.77.87.39.014.9<2.0<2.0
SRL highest trough level (ng/mL)6.85.97.84.78.97.39.026.4<2.0<2.0
TAC dose (mg)2788766444
TAC mean trough level (ng/mL)5.211.08.5N/A7.311.310.88.64.36.8
TAC highest trough level (ng/mL)24.111.010.6N/A10.111.311.713.54.36.8
Triglycerides (mg/dL)N/AN/A134N/AN/A583528459622536
Cholesterol (mg/dL)646489N/AN/A257231212198172
Lipid-lowering agentNoneNoneNoneNoneNoneNoneNoneNoneNoneNone

Patient 3

  1. Top of page
  2. Summary
  3. Introduction
  4. Case presentation
  5. Patient 1
  6. Patient 2
  7. Patient 3
  8. Patient 4
  9. Patient 5
  10. Patient 6
  11. Discussion
  12. References

A 44-year-old Hispanic male with a history of hypertension and diabetes mellitus underwent OLT in conjunction with aortic valve replacement and kidney transplantation for end stage liver disease secondary to hepatitis C, chronic renal failure and endocarditis. Post-OLT immunosuppression consisted of TAC, SRL and prednisone. His lipid profile showed a significant rise in triglycerides and a moderate increase in total cholesterol 4 months post-OLT (Table 3). The prednisone dose at the time was 10 mg daily. Peak triglyceride and total cholesterol levels were 913 and 377 mg/dL, respectively, at post-operative month 6. He was started on pravastatin with no response. His prednisone dose was also decreased during this time to 5 mg daily. SRL dose was reduced at month 5 and triglycerides and cholesterol continued to increase as shown in Table 3.

Table 3.  Course of immunosuppression and lipids abnormalities in patient 3 (1–10 months after liver transplantation)
Parameters12345678910
  1. * Therapy with a lipid-lowering agent.

  2. SRL, sirolimus; TAC, tacrolimus; N/A, not available.

SRL dose (mg)571010888OffOffOff
SRL mean trough level (ng/mL)1.85.65.68.911.711.615.017.5<2.0<2.0
SRL highest trough level (ng/mL)1.85.67.38.913.511.617.817.5<2.0<2.0
TAC dose (mg)8121313101110887
TAC mean trough level (ng/mL)5.37.66.04.511.211.111.510.811.78.8
TAC highest trough level (ng/mL)9.011.26.34.513.111.112.210.811.711.4
Triglycerides (mg/dL)13413194273604913874723320162
Cholesterol (mg/dL)64177208231328377376260173138
Lipid-lowering agentNoneNoneNoneNoneNone*****

Patient 4

  1. Top of page
  2. Summary
  3. Introduction
  4. Case presentation
  5. Patient 1
  6. Patient 2
  7. Patient 3
  8. Patient 4
  9. Patient 5
  10. Patient 6
  11. Discussion
  12. References

A 45-year-old Caucasian male developed severe liver decompensation secondary to chronic hepatitis C and underwent OLT with placement of an infrarenal aortic conduit for graft revascularization. He had an uncomplicated post-operative course, but developed hyperlipidaemia 4 weeks after transplant. A lipid-lowering agent was started the second month post-transplant but triglycerides continued to increase to 1750. SRL dose was decreased, and TAC was changed to CsA because of alopecia. Triglycerides (TGs) at last follow-up were 350 mg/dL (Table 4).

Table 4.  Course of immunosuppression and lipids abnormalities in patient 4 (1–6 months after liver transplantation)
Parameters123456
  1. * Therapy with a lipid-lowering agent.

  2. † Patient taken off TAC secondary to side effects.

  3. SRL, sirolimus; TAC, tacrolimus; N/A, not available.

SRL dose (mg)55653Off
SRL mean trough level (ng/mL)8.35.66.510.913<2.0
SRL highest trough level (ng/mL)8.56.38.012.4137.4
TAC dose (mg)3345Off†Off
TAC mean trough level (ng/mL)11.44.65.78.7<1.5<1.5
TAC highest trough level (ng/mL)10.95.96.59.3<1.5<1.5
Triglycerides (mg/dL)N/A4505193191,750350
Cholesterol (mg/dL)N/A242318303457256
Lipid-lowering agentNoneNone****

Patient 5

  1. Top of page
  2. Summary
  3. Introduction
  4. Case presentation
  5. Patient 1
  6. Patient 2
  7. Patient 3
  8. Patient 4
  9. Patient 5
  10. Patient 6
  11. Discussion
  12. References

A 54-year-old female underwent OLT for decompensated cirrhosis because of hepatitis C (HCV) and was started on TAC, SRL and corticosteroids post-operatively. The patient had insulin-dependent diabetes mellitus and mild obesity, but not hyperlipidaemia. She had a significant increase in TGs and cholesterol at month 3 after liver transplantation. SRL was discontinued with a subsequent significant decrease in cholesterol and triglyceride levels. No lipid-lowering agent was required (Table 5).

Table 5.  Course of immunosuppression and lipids abnormalities in patient 5 (1–5 months after liver transplantation)
Parameters12345
  1. * Therapy with a lipid-lowering agent.

  2. SRL, sirolimus; TAC, tacrolimus; N/A, not available.

SRL dose (mg)557OffOff
SRL mean trough level (ng/mL)5.78.415<2.0<2.0
SRL highest trough level (ng/mL)6.410.115.9<2.0<2.0
TAC dose (mg)128885
TAC mean trough level (ng/mL)6.97.58.812.16.2
TAC highest trough level (ng/mL)119.58.920.36.6
Triglycerides (mg/dL)201199561963298
Cholesterol (mg/dL)167202321219131
Lipid-lowering agentNoneNoneNoneNoneNone

Patient 6

  1. Top of page
  2. Summary
  3. Introduction
  4. Case presentation
  5. Patient 1
  6. Patient 2
  7. Patient 3
  8. Patient 4
  9. Patient 5
  10. Patient 6
  11. Discussion
  12. References

A 40-year-old Caucasian male with cryptogenic cirrhosis underwent OLT for severe decompensation. Lipid panel within 6 months of OLT revealed his cholesterol, low-density lipoprotein (LDL) and TG levels to be <120 mg/dL. He did not have overt diabetes before transplant. His body mass index (BMI) pre-OLT was 39, and the BMI post-OLT significantly decreased to 29. Three months after transplant, he developed hyperlipidaemia. SRL was discontinued at month 4, and both cholesterol and triglyceride levels normalized by 7 months post-OLT (Table 6).

Table 6.  Course of immunosuppression and lipids abnormalities in patient 6 (1–16 months after liver transplantation)
Parameters1–23–45–67–89–1011–1213–1415–16
  1. SRL, sirolimus; TAC, tacrolimus; N/A = not available.

SRL dose (mg)55OffOffOffOffOffOff
SRL mean trough level (ng/mL)4.19.1<2.0<2.0<2.0<2.0<2.0<2.0
SRL highest trough level (ng/mL)4.59.3<2.0<2.0<2.0<2.0<2.0<2.0
TAC dose (mg)21133332
TAC mean trough level (ng/mL)5.67.810.77.88.1109.911.5
TAC highest trough level (ng/mL)8.421.66.09.48.6109.913.3
Triglycerides (mg/dL)N/A845540219N/AN/AN/AN/A
Cholesterol (mg/dL)N/A207170184N/AN/AN/AN/A
Lipid-lowering agentNoneNoneNoneNoneNoneNoneNoneNone

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Case presentation
  5. Patient 1
  6. Patient 2
  7. Patient 3
  8. Patient 4
  9. Patient 5
  10. Patient 6
  11. Discussion
  12. References

The patients described in this report experienced significant lipid abnormalities with an immunosuppressive regimen which included SRL. Patient demographics are described in Table 7. All had severe hypertriglyceridaemia accompanied by moderate increases in total cholesterol. Two of the patients also exhibited decreases in HDL cholesterol, although this was below the desired range in only one. The pattern of hyperlipidaemia, characterized primarily by hypertriglyceridaemia, is consistent with other reports of dyslipidaemia in patients receiving SRL.12

Table 7.  Patients demographics
 Patient 1Patient 2Patient 3Patient 4Patient 5Patient 6
  1. HCV, hepatitis C virus; OLT, orthotopic liver transplantation; BMI, body mass index; M, male; F, female.

Age (years)516745455440
GenderMMMMFM
Liver diseaseHCVCryptogenicHCVHCVHCVCryptogenic
Diabetes mellitusNoNoYesNoYesNo
Pre-OLT hyperlipidaemiaNoNoNoNoNoNo
Family history of hyperlipidaemiaNoNoNo?NoNo
BMI before OLT222424242839
BMI after OLT262926202625
Steatosis on liver biopsy
 Pre-OLTNoNoNoNoYesNo
 Post-OLTNoNoYes??No

It has been suggested that SRL toxicity, including hypertriglyceridaemia, may be related to trough concentrations, with significantly increased risk with levels over 15 ng/mL.13 We noted an association between higher trough levels of SRL and hyperlipidaemia in two of the six patients. Patient 1, who did not respond to treatment with an HMG-CoA reductase inhibitor, improved somewhat following SRL dose-reduction. It is difficult to determine whether resolution of hyperlipidaemia resulted from discontinuation of SRL alone, or this combined with use of gemfibrozil, a fibric acid derivative more specific for treating hypertriglyceridaemia. The second patient eventually responded to treatment with an HMG-CoA reductase inhibitor. There was a downward trend in TGs and cholesterol since discontinuation of SRL. Response to HMG-CoA reductase inhibitors has been reported in renal transplant recipients,13 although hyperlipidaemia refractory to therapy has been observed.14 Corticosteroids did not appear to contribute significantly to hyperlipidaemia, as the patient with the most severe abnormality received the lowest dose of prednisone, and no significant improvement was noted when steroids were tapered down or off.

The mechanism of SRL-induced hyperlipidaemia is not well-understood, although effects on apoCIII and apoB100 have been proposed (See Figure 1).15, 16 Tur et al. studied 67 renal transplant recipients on low-dose steroids to determine the effects of different immunosuppressants on lipid parameters.15 Total cholesterol and triglycerides were significantly higher in transplant recipients than in healthy controls, regardless of immunosuppressive regimen. Treatment with either calcineurin inhibitors or SRL was associated with increases in apoCIII and apoB levels, although triglyceride and apoCIII levels were highest in the SRL group. Elevated apoCIII levels would be expected to result in excessive inhibition of lipoprotein lipase (LPL) activity, the protein responsible for hydrolysis of triglycerides into fatty acids.17, 18 A second study of five renal transplant recipients confirmed some of these findings, while contradicting others.16 The five renal recipients were on stable doses of CsA and prednisone before starting SRL. A significant elevation in total cholesterol (mean 44.3%) and triglycerides (mean 120%) was noted after 8 weeks of SRL therapy. Increases in LDL-apoB100 and, particularly in VLDLapoB100 because of reduced catabolism rather than increased synthesis of these apolipoproteins, correlated with the observed lipid abnormalities. As apoB100 is the main structural apolipoprotein necessary for assembly and secretion of triglyceride-rich VLDL from the liver,17, 18 an increase in ApoB100 values would likely lead to elevated plasma triglycerides. In contrast to the findings of the first study, no significant change in LPL activity was seen, perhaps explained by the use of lipid-lowering agents. Trotter et al., reported that hypercholesterolaemia and hypertriglyceridaemia in liver transplant recipients were significantly more common in CsA/SRL-treated patients than in patients treated with TAC/SRL.11 However, our observation of significant hypertriglyceridaemia in patients treated with a combination of TAC and SRL, underscores the importance of lipid monitoring regardless of the calcineurin inhibitor used. McAlister found that in 56 liver transplant recipients receiving a combination of SRL and TAC, hyperlipidaemia occurred less often when used at a specific concentration than previously reported in combinations with CsA and steroids.10 Hyperlipidaemia was found in two patients who did not tolerate lipid-lowering agents. Both patients had improvement with diet and with elimination of steroids.

image

Figure 1. Lipoprotein metabolism.

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The goal of adding SRL to a regimen of TAC and corticosteroids is to allow for a substantial reduction in the dose of TAC to levels unlikely to cause toxicity. The synergistic combination of CsA and SRL has been shown to reduce the incidence of acute rejection episodes in renal transplantation compared with a regimen consisting of azathioprine, CsA and steroids.4 The synergism seen when SRL and CsA are combined may be partially explained by their action in two sequential phases of the cell cycle.4 Additional benefits of this synergistic immunosuppressant combination include the potential for early withdrawal of corticosteroids after transplantation and reduction of calcineurin inhibitors. Clinicians should, however, be aware of the potential lipid abnormalities seen in patients treated with SRL and monitor patients appropriately. Further studies are needed to determine the most appropriate management of lipid abnormalities seen with this new immunosuppressant. It seems prudent to attempt treatment with fibric acid derivatives for patients with predominant hypertriglyceridaemia, although SRL dosage reduction or discontinuation may ultimately be necessary to achieve normalization of the lipid profile.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Case presentation
  5. Patient 1
  6. Patient 2
  7. Patient 3
  8. Patient 4
  9. Patient 5
  10. Patient 6
  11. Discussion
  12. References
  • 1
    Vazquez EM. Sirolimus: a new agent for prevention of renal allograft rejection. Am J Health-Syst Pharm 2000; 57: 43748.
  • 2
    Neuhaus P, Klupp J & Langrehr JM. mTORinhibitors: an overview. Liver Transpl 2001; 7: 47384.
  • 3
    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.
  • 4
    Price DJ, Grove JR, Calvo V, Avruch J, Bierer BE. Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. Science 1992; 257: 973.
  • 5
    Kahan BD. Sirolimus: a new agent for clinical renal transplantation. Transplant Proc 1997; 29: 4850.
  • 6
    Murgia MG, Jordan S & Kahan BD. The side effect profile of sirolimus: a phase I study in quiescent cyclosporine-prednisone-treated renal transplant patients. Kidney Int 1996; 49: 20916.
  • 7
    MadDonald ASfor the Rapamune Global Study Group. A world-wide, phase III, randomized, controlled, safety and efficacy study of a sirolimus/cyclosporine regimen for prevention of acute rejection in recipients of primary mismatched renal allografts. Transplantation 2001; 71: 27180.
  • 8
    Trotter JF, Wachs ME, Trouillot TE, et al. Dyslipidemia during sirolimus therapy in liver transplant recipients occurs with concomitant cyclosporine but not tacrolimus. Liver Transpl 2001; 7: 4018.
  • 9
    Watson CJE, Friend PJ, Jamienson NV, et al. Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 1999; 67: 5059.
  • 10
    McAlister VC, Peltekian KM, Malatjalian DA, et al. Orthotopic liver transplantation using low-dose tacrolimus and sirolimus. Liver Transpl 2001; 7: 7018.
  • 11
    Trotter JF, Washs M, Bak T, et al. Liver transplantation using sirolimus and minimal corticosteroids (3-day taper). Liver Transpl 2001; 7: 34351.
  • 12
    Brattström C, Wilczek H, Tyden G, Böttiger Y, Säwe J, Groth CG. Hypertriglyceridemia in renal transplant recipients treated with sirolimus. Transplant Proc 1998; 30: 39501.
  • 13
    Meier-Kriesche HU, Kaplan B. Toxicity and efficacy of sirolimus: relationship to whole blood concentrations. Clinical Therapeutics 2000; 22(Suppl. B): B93100.
  • 14
    Kahan BD, Podbielski J, Napoli KL, Katz SM, Meier-Kriesche HU, Van Buren CT. Immunosuppressive effects and safety of a sirolimus/cyclosporine combination for renal transplantation. Transplantation 1998; 66: 10406.
  • 15
    Tur MD, Garrigue V, Vela C, et al. Apolipoprotein CIII is upregulated by anticalcineurins and rapamycin: implications in transplantation-induced dyslipidemia. Transplant Proc 2000; 32: 27834.
  • 16
    Hoogeveen RC, Ballantyne CM, Pownall HJ, et al. Effect of sirolimus on the metabolism of ApoB100-containing lipoproteins in renal transplant patients. Clin Transpl 2001; 72: 124450.
  • 17
    Wilson JD. Plasma protein: apolipoproteins, receptors, and enzymes. In: WilliamsRH, ed. Textbook of Endocrinology, 9th edn. W.B. Saunders Company, 1998: 1103.
  • 18
    Witzum JL, Steinberg D. The hyperlipoproteinemias. In: CecilR, ed. Textbook of Medicine 2000, 21st edn. W.B. Saunders Company, 1090100.