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Therapy of Hyperlipidemia With Lovastatin in Kidney Transplant Patients on Cyclosporine A Immunosuppression: Three-Year Experience
Therapy of Hyperlipidemia With Lovastatin in Kidney Transplant Patients on Cyclosporine A Immunosuppression: Three-Year Experience A. Kandus, D. Kovacˇ, D. Cˇerne, M. Koselj, S. Kaplan-Pavlovcˇicˇ, J. Buturovic´, R. Ponikvar, R. Kveder, J. Lindicˇ, and A.F. Bren
K
IDNEY TRANSPLANT patients have had a high mortality in atherosclerotic cardiovascular disease.1,2 Hyperlipidemia, especially increased concentrations of total and low-density lipoprotein (LDL) cholesterol, which is frequent in these patients,3–12 is the well-established risk factor for atherosclerotic disease.8,13 The strong arguments for lipid-decreasing therapy in the general population are also applicable to the treatment for kidney transplant patients.12,14 Moreover, effective lipid-decreasing treatment may also promote kidney graft survival.14 Lovastatin is highly effective in decreasing total cholesterol and LDL cholesterol,15–18 but it can cause damage to the skeletal muscles and liver in patients on cyclosporine A (CyA) immunosuppression.17,19 –22 The goal of our study was to evaluate the possibility of achieving the expected decrease of serum concentrations of total cholesterol, LDL cholesterol, and triglycerides with lovastatin, without causing signs of damage to the skeletal muscles and liver in kidney transplant patients treated with CyA. We also intended to evaluate the influence of lovastatin on the serum concentrations of high-density lipoprotein (HDL) cholesterol, lipoprotein (a) [Lp(a)], apolipoprotein A-I (Apo A-I) and apolipoprotein B (Apo B). PATIENTS AND METHODS Twelve patients (6 women, 6 men, ages 29 to 57 years, weight 59 to 107 kg, 10 to 105 months after transplantation) with serum concentrations of LDL cholesterol higher than 4.1 mmol/L after a 3-month lipid-decreasing diet participated in the study. Informed consent was obtained. All the patients had stable kidney graft function with serum creatinine levels less than 300 mmol/L, at least two nonlipid risk factors of atherosclerosis, and they were without signs of damage to skeletal muscles and liver at the beginning of the study. They received CyA and a maintenance dose of corticosteroides. Mean daily CyA dose was 2.3 6 1.1 (SD) mg/kg (range, 0.9 to 4.5 mg/kg). CyA trough blood concentration ranged from 43 to 247 ng/mL during the 36-month period of the study. CyA concentration was measured by radioimmunoassay using monoclonal antibody in the first 6-month period of the study. Subsequently, it was measured by fluorescence polarization immunoassay using monoclonal antibody. In the first 3 months, patients received lovastatin in daily doses of 20 mg. From the fourth through the sixth month, the daily dose of
lovastatin was increased to 30 mg in five patients who still had a concentration of LDL cholesterol higher than 3.5 mmol/L. From the seventh through the 36th month, all the patients received lovastatin in daily doses of 20 mg. Every 3 to 6 weeks the patients were examined, and laboratory parameters for kidney graft function (serum creatinine), possible liver damage (serum activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyl transpeptidase (GGT), possible myopathy (serum activity of creatine kinase [CK], serum myoglobin), CyA blood, and lipid serum concentrations were evaluated. Blood samples were taken from seated patients after a 12-hour fast. Lp(a), Apo A-I, and Apo B were measured only in the first 6-month period. From the seventh through the 36th month serum lipid concentrations were evaluated every 3 months. The quantitative electromyography was performed in all the patients before and after 6 months of the study. In the statistical analysis the Student’s t test for paired data was used. Significant differences were defined with a P value of less than .05.
RESULTS
After 3 months of lovastatin therapy in daily doses of 20 mg, the concentration of total cholesterol decreased by 31% (from 8.8 6 2.0 mmol/L to 6.1 6 1.9 mmol/L; P , .001), LDL cholesterol by 38% (from 6.3 6 1.7 mmol/L to 3.9 6 1.9 mmol/L; P , .001), and triglycerides by 21% (from 2.4 6 1.1 mmol/L to 1.9 6 0.8 mmol/L; P , .05). The concentration of HDL cholesterol did not change significantly. There were no additional significant changes in the concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides by the end of the sixth month in five patients who received lovastatin in a daily dose of 30 mg from the fourth through the sixth month, and in seven patients who received lovastatin in a daily dose of 20 mg from the fourth through the sixth month. Only 10 patients reached the end of the study. There From the Department of Nephrology and Institute of Clinical Chemistry, University Medical Centre, Ljubljana, Slovenia. Address reprint requests to A. Kandus, MD, PhD, Department of Nephrology, University Medical Centre, Zalosˇka 7, 1525 Ljubljana, Slovenia.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00253-X
Transplantation Proceedings, 30, 1307–1309 (1998)
1307
KANDUS, KOVACˆ, CˆERNE ET AL
1308
were no significant changes in the concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides in 10 patients from the fourth through the 36th month. The ratio of concentration of total cholesterol/HDL cholesterol decreased by 31% (from 7.4 6 3.0 to 5.1 6 2.8; P , .001) after the first 3 months. There were no additional significant changes in this ratio by the end of the sixth and the 36th months. The concentration of Lp(a), Apo A-I, and Apo B did not change significantly during the investigation period. None of the patients experienced acute rejection. One patient discontinued lovastatin therapy because of kidney graft loss, as a consequence of chronic rejection in the 34th month. The concentration of serum creatinine did not change significantly in 10 patients; none of the patients had onset of new disease with possible influence on the serum lipids. The quantitative electromyogram remained normal in all the patients after 6 months of lovastatin therapy. CK activity exceeded normal value (,2.08 mkat/L) in 3.7% of measurements (maximal value was 5.99 mkat/L). Serum concentration of myoglobin exceeded normal value (,90 mg/L) in 7.9% of measurements (maximal value was 198 mg/L). ALT exceeded normal value (,0.70 mkat/L) in 0.6% of measurements (maximal value was 2.57 mkat/L). AST exceeded normal value (,0.60 mkat/L) in 0.7% of measurements (maximal value was 1.27 mkat/L). GGT exceeded normal value (,0.62 mkat/L) in 6.5% of measurements (maximal value was 2.47 mkat/L). Some patients had mild transient symptoms and signs: muscle pain (without laboratory signs of muscle damage), insomnia, and diarrhea. Lovastatin therapy was not discontinued for these abnormalities. One patient abandoned lovastatin therapy because of persistent muscle pain in the 20th month. After 3 months of lovastatin therapy in daily doses of 30 mg, asymptomatic rhabdomyolysis occurred in one patient. The increased serum concentration of myoglobin to 1566 mg/L and CK activity to 40.33 mkat/L were not accompanied by the impairment of kidney graft function. Discontinuation of lovastatin therapy was followed by normalization of serum myoglobin concentration and CK activity. After 12 weeks, lovastatin therapy in daily doses of 20 mg was reintroduced. DISCUSSION AND CONCLUSIONS
The significant decrease in serum concentrations of total cholesterol, LDL cholesterol, and triglycerides after lovastatin therapy was close to the range found by others.23–26 HDL cholesterol did not change significantly, which is in accordance with others’ findings.23–26 After 6 and 36 months of lovastatin therapy in daily doses of 20 mg, the concentrations of lipids, mentioned above, were not significantly different from concentrations after the first 3 months of treatment. This could be explained by
the fact that the maximal therapeutic effect of lovastatin is achieved after 4 weeks of treatment.15 The decrease in concentrations of total cholesterol, LDL cholesterol, and triglycerides with lovastatin therapy in daily doses of 30 mg was not significantly more pronounced than the decrease with daily doses of 20 mg. It could be assumed that the lipid-decreasing effect of lovastatin is already maximal with a daily dose of 20 mg. This assumption is supported by the observation that lovastatin serum concentrations in patients on CyA immunosuppression were 4.2 to 7.8 times higher than in control subjects without CyA taking equal doses (20 mg) of lovastatin.22 In the majority of patients, the symptoms and laboratory abnormalities, probably adverse effects of lovastatin, were infrequent, mild, and transient, and did not demand discontinuation of lovastatin therapy. However, the patient who abandoned lovastatin therapy because of persistent muscle pain had only mild and transient laboratory signs of muscle damage. On the other hand, the patient with laboratory abnormalities indicating rhabdomyolysis was asymptomatic. The absence of skeletal muscle damage could only be assumed in an asymptomatic patient without laboratory abnormalities. It may be concluded that the expected decrease of serum concentrations of total cholesterol, LDL cholesterol, and triglycerides was achieved with lovastatin in daily doses of 20 mg without causing serious signs of damage to the skeletal muscles and liver in the majority of kidney transplant patients on CyA immunosuppression. The increase of lovastatin to a daily dose of 30 mg, accompanied by the risk of rhabdomyolysis, was without additional decrease in concentrations of lipids. Lovastatin therapy did not significantly change the concentrations of HDL cholesterol, Lp(a), Apo A-I, and Apo B. Regular examinations of patients with monitoring of serum myoglobin concentration, CK, and liver enzyme activity are strongly recommended during lovastatin treatment.
REFERENCES 1. Gunnarsson R, Lo ¨fmark R, Nordlander R, et al: Eur Heart J 5:218, 1984 2. Raine AEG, Margreiter R, Brunner FP, et al: Nephrol Dial Transplant 7(suppl 2):7, 1992 3. Cattran DC, Steiner G, Wilson DR, et al: Ann Intern Med 91:554, 1979 4. Gokal R, Mann JI, Moore RA, et al: Q J Med 48:507, 1979 5. Kasiske BL, Umen AJ: Medicine 66:309, 1987 6. Vathsala A, Weinberg RB, Schoenberg L, et al: Transplantation 48:37, 1989 7. Divakar D, Bailey RR, Frampton CM, et al: Nephron 59:423, 1991 8. Dru ¨eke TB, Abdulmassih Z, Lacour B, et al: Kidney Int 39(suppl 31):S-24, 1991 9. Irish AB, Simons LA, Savdie E, et al: Clin Transplant 6:403, 1992 10. Ong CS, Pollock CA, Caterson RJ, et al: Medicine 73:215, 1994
HYPERLIPIDEMIA 11. Guijarro C, Massy ZA, Kasiske BL: Kidney Int 48(suppl 52):S-56, 1995 12. Massy ZA, Kasiske BL: J Am Soc Nephrol 7:971, 1996 13. Kasiske BL: Am J Med 84:985, 1988 14. Arnadottir M, Berg A-L: Transplantation 63:339, 1997 15. Lovastatin Study Group II: JAMA 256:2829, 1986 16. Grundy SM: N Engl J Med 319:24, 1988 17. Tobert JA: Am J Cardiol 62:28J, 1988 18. Illingworth DR, Bacon SP, Larsen KK: Atherosclerosis Rev 18:161, 1988 19. Norman DJ, Illingworth DR, Munson J, et al: N Engl J Med 318:46, 1988
1309 20. East C, Alivizatos PA, Grundy SM, et al: N Engl J Med 318:47, 1988 21. Corpier CL, Jones PH, Suki WN, et al: JAMA 260:239, 1988 22. Kobashigawa JA, Murphy FL, Stevenson LW, et al: Circulation 82(suppl IV):IV-281, 1990 23. Kasiske BL, Tortorice KL, Heim-Duthoy KL, et al: Transplantation 49:95, 1990 24. Traindl O, Reading S, Franz M, et al: Nephron 62:394, 1992 25. Cheung AK, De Vault GA, Gregory MC: J Am Soc Nephrol 3:1884, 1993 26. Castelao AM, Grino ´ JM, Andre´s E, et al: Transplant Proc 25:1043, 1993
K
IDNEY TRANSPLANT patients have had a high mortality in atherosclerotic cardiovascular disease.1,2 Hyperlipidemia, especially increased concentrations of total and low-density lipoprotein (LDL) cholesterol, which is frequent in these patients,3–12 is the well-established risk factor for atherosclerotic disease.8,13 The strong arguments for lipid-decreasing therapy in the general population are also applicable to the treatment for kidney transplant patients.12,14 Moreover, effective lipid-decreasing treatment may also promote kidney graft survival.14 Lovastatin is highly effective in decreasing total cholesterol and LDL cholesterol,15–18 but it can cause damage to the skeletal muscles and liver in patients on cyclosporine A (CyA) immunosuppression.17,19 –22 The goal of our study was to evaluate the possibility of achieving the expected decrease of serum concentrations of total cholesterol, LDL cholesterol, and triglycerides with lovastatin, without causing signs of damage to the skeletal muscles and liver in kidney transplant patients treated with CyA. We also intended to evaluate the influence of lovastatin on the serum concentrations of high-density lipoprotein (HDL) cholesterol, lipoprotein (a) [Lp(a)], apolipoprotein A-I (Apo A-I) and apolipoprotein B (Apo B). PATIENTS AND METHODS Twelve patients (6 women, 6 men, ages 29 to 57 years, weight 59 to 107 kg, 10 to 105 months after transplantation) with serum concentrations of LDL cholesterol higher than 4.1 mmol/L after a 3-month lipid-decreasing diet participated in the study. Informed consent was obtained. All the patients had stable kidney graft function with serum creatinine levels less than 300 mmol/L, at least two nonlipid risk factors of atherosclerosis, and they were without signs of damage to skeletal muscles and liver at the beginning of the study. They received CyA and a maintenance dose of corticosteroides. Mean daily CyA dose was 2.3 6 1.1 (SD) mg/kg (range, 0.9 to 4.5 mg/kg). CyA trough blood concentration ranged from 43 to 247 ng/mL during the 36-month period of the study. CyA concentration was measured by radioimmunoassay using monoclonal antibody in the first 6-month period of the study. Subsequently, it was measured by fluorescence polarization immunoassay using monoclonal antibody. In the first 3 months, patients received lovastatin in daily doses of 20 mg. From the fourth through the sixth month, the daily dose of
lovastatin was increased to 30 mg in five patients who still had a concentration of LDL cholesterol higher than 3.5 mmol/L. From the seventh through the 36th month, all the patients received lovastatin in daily doses of 20 mg. Every 3 to 6 weeks the patients were examined, and laboratory parameters for kidney graft function (serum creatinine), possible liver damage (serum activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gammaglutamyl transpeptidase (GGT), possible myopathy (serum activity of creatine kinase [CK], serum myoglobin), CyA blood, and lipid serum concentrations were evaluated. Blood samples were taken from seated patients after a 12-hour fast. Lp(a), Apo A-I, and Apo B were measured only in the first 6-month period. From the seventh through the 36th month serum lipid concentrations were evaluated every 3 months. The quantitative electromyography was performed in all the patients before and after 6 months of the study. In the statistical analysis the Student’s t test for paired data was used. Significant differences were defined with a P value of less than .05.
RESULTS
After 3 months of lovastatin therapy in daily doses of 20 mg, the concentration of total cholesterol decreased by 31% (from 8.8 6 2.0 mmol/L to 6.1 6 1.9 mmol/L; P , .001), LDL cholesterol by 38% (from 6.3 6 1.7 mmol/L to 3.9 6 1.9 mmol/L; P , .001), and triglycerides by 21% (from 2.4 6 1.1 mmol/L to 1.9 6 0.8 mmol/L; P , .05). The concentration of HDL cholesterol did not change significantly. There were no additional significant changes in the concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides by the end of the sixth month in five patients who received lovastatin in a daily dose of 30 mg from the fourth through the sixth month, and in seven patients who received lovastatin in a daily dose of 20 mg from the fourth through the sixth month. Only 10 patients reached the end of the study. There From the Department of Nephrology and Institute of Clinical Chemistry, University Medical Centre, Ljubljana, Slovenia. Address reprint requests to A. Kandus, MD, PhD, Department of Nephrology, University Medical Centre, Zalosˇka 7, 1525 Ljubljana, Slovenia.
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/98/$19.00 PII S0041-1345(98)00253-X
Transplantation Proceedings, 30, 1307–1309 (1998)
1307
KANDUS, KOVACˆ, CˆERNE ET AL
1308
were no significant changes in the concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides in 10 patients from the fourth through the 36th month. The ratio of concentration of total cholesterol/HDL cholesterol decreased by 31% (from 7.4 6 3.0 to 5.1 6 2.8; P , .001) after the first 3 months. There were no additional significant changes in this ratio by the end of the sixth and the 36th months. The concentration of Lp(a), Apo A-I, and Apo B did not change significantly during the investigation period. None of the patients experienced acute rejection. One patient discontinued lovastatin therapy because of kidney graft loss, as a consequence of chronic rejection in the 34th month. The concentration of serum creatinine did not change significantly in 10 patients; none of the patients had onset of new disease with possible influence on the serum lipids. The quantitative electromyogram remained normal in all the patients after 6 months of lovastatin therapy. CK activity exceeded normal value (,2.08 mkat/L) in 3.7% of measurements (maximal value was 5.99 mkat/L). Serum concentration of myoglobin exceeded normal value (,90 mg/L) in 7.9% of measurements (maximal value was 198 mg/L). ALT exceeded normal value (,0.70 mkat/L) in 0.6% of measurements (maximal value was 2.57 mkat/L). AST exceeded normal value (,0.60 mkat/L) in 0.7% of measurements (maximal value was 1.27 mkat/L). GGT exceeded normal value (,0.62 mkat/L) in 6.5% of measurements (maximal value was 2.47 mkat/L). Some patients had mild transient symptoms and signs: muscle pain (without laboratory signs of muscle damage), insomnia, and diarrhea. Lovastatin therapy was not discontinued for these abnormalities. One patient abandoned lovastatin therapy because of persistent muscle pain in the 20th month. After 3 months of lovastatin therapy in daily doses of 30 mg, asymptomatic rhabdomyolysis occurred in one patient. The increased serum concentration of myoglobin to 1566 mg/L and CK activity to 40.33 mkat/L were not accompanied by the impairment of kidney graft function. Discontinuation of lovastatin therapy was followed by normalization of serum myoglobin concentration and CK activity. After 12 weeks, lovastatin therapy in daily doses of 20 mg was reintroduced. DISCUSSION AND CONCLUSIONS
The significant decrease in serum concentrations of total cholesterol, LDL cholesterol, and triglycerides after lovastatin therapy was close to the range found by others.23–26 HDL cholesterol did not change significantly, which is in accordance with others’ findings.23–26 After 6 and 36 months of lovastatin therapy in daily doses of 20 mg, the concentrations of lipids, mentioned above, were not significantly different from concentrations after the first 3 months of treatment. This could be explained by
the fact that the maximal therapeutic effect of lovastatin is achieved after 4 weeks of treatment.15 The decrease in concentrations of total cholesterol, LDL cholesterol, and triglycerides with lovastatin therapy in daily doses of 30 mg was not significantly more pronounced than the decrease with daily doses of 20 mg. It could be assumed that the lipid-decreasing effect of lovastatin is already maximal with a daily dose of 20 mg. This assumption is supported by the observation that lovastatin serum concentrations in patients on CyA immunosuppression were 4.2 to 7.8 times higher than in control subjects without CyA taking equal doses (20 mg) of lovastatin.22 In the majority of patients, the symptoms and laboratory abnormalities, probably adverse effects of lovastatin, were infrequent, mild, and transient, and did not demand discontinuation of lovastatin therapy. However, the patient who abandoned lovastatin therapy because of persistent muscle pain had only mild and transient laboratory signs of muscle damage. On the other hand, the patient with laboratory abnormalities indicating rhabdomyolysis was asymptomatic. The absence of skeletal muscle damage could only be assumed in an asymptomatic patient without laboratory abnormalities. It may be concluded that the expected decrease of serum concentrations of total cholesterol, LDL cholesterol, and triglycerides was achieved with lovastatin in daily doses of 20 mg without causing serious signs of damage to the skeletal muscles and liver in the majority of kidney transplant patients on CyA immunosuppression. The increase of lovastatin to a daily dose of 30 mg, accompanied by the risk of rhabdomyolysis, was without additional decrease in concentrations of lipids. Lovastatin therapy did not significantly change the concentrations of HDL cholesterol, Lp(a), Apo A-I, and Apo B. Regular examinations of patients with monitoring of serum myoglobin concentration, CK, and liver enzyme activity are strongly recommended during lovastatin treatment.
REFERENCES 1. Gunnarsson R, Lo ¨fmark R, Nordlander R, et al: Eur Heart J 5:218, 1984 2. Raine AEG, Margreiter R, Brunner FP, et al: Nephrol Dial Transplant 7(suppl 2):7, 1992 3. Cattran DC, Steiner G, Wilson DR, et al: Ann Intern Med 91:554, 1979 4. Gokal R, Mann JI, Moore RA, et al: Q J Med 48:507, 1979 5. Kasiske BL, Umen AJ: Medicine 66:309, 1987 6. Vathsala A, Weinberg RB, Schoenberg L, et al: Transplantation 48:37, 1989 7. Divakar D, Bailey RR, Frampton CM, et al: Nephron 59:423, 1991 8. Dru ¨eke TB, Abdulmassih Z, Lacour B, et al: Kidney Int 39(suppl 31):S-24, 1991 9. Irish AB, Simons LA, Savdie E, et al: Clin Transplant 6:403, 1992 10. Ong CS, Pollock CA, Caterson RJ, et al: Medicine 73:215, 1994
HYPERLIPIDEMIA 11. Guijarro C, Massy ZA, Kasiske BL: Kidney Int 48(suppl 52):S-56, 1995 12. Massy ZA, Kasiske BL: J Am Soc Nephrol 7:971, 1996 13. Kasiske BL: Am J Med 84:985, 1988 14. Arnadottir M, Berg A-L: Transplantation 63:339, 1997 15. Lovastatin Study Group II: JAMA 256:2829, 1986 16. Grundy SM: N Engl J Med 319:24, 1988 17. Tobert JA: Am J Cardiol 62:28J, 1988 18. Illingworth DR, Bacon SP, Larsen KK: Atherosclerosis Rev 18:161, 1988 19. Norman DJ, Illingworth DR, Munson J, et al: N Engl J Med 318:46, 1988
1309 20. East C, Alivizatos PA, Grundy SM, et al: N Engl J Med 318:47, 1988 21. Corpier CL, Jones PH, Suki WN, et al: JAMA 260:239, 1988 22. Kobashigawa JA, Murphy FL, Stevenson LW, et al: Circulation 82(suppl IV):IV-281, 1990 23. Kasiske BL, Tortorice KL, Heim-Duthoy KL, et al: Transplantation 49:95, 1990 24. Traindl O, Reading S, Franz M, et al: Nephron 62:394, 1992 25. Cheung AK, De Vault GA, Gregory MC: J Am Soc Nephrol 3:1884, 1993 26. Castelao AM, Grino ´ JM, Andre´s E, et al: Transplant Proc 25:1043, 1993