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Apolipoprotein E alleles, dyslipemia and kidney transplantation
Apolipoprotein E Alleles, Dyslipemia and Kidney Transplantation B. Baye´s, M.C. Pastor, R. Lauzurica, N. Riutort, J. Bonal, J. Bonet, and R. Romero
C
ARDIOVASCULAR DISEASE is the main cause of morbidity and mortality in kidney transplant (KT) recipients.1 Hyperlipidemia is a known risk factor for cardiovascular disease. Polymorphism of the apolipoprotein E (Apo E) gene may affect plasma lipoprotein levels and composition and the risk of kidney disease. The aim of the present study was to ascertain the influence of the Apo E genotype on renal function and lipid profile in KT patients and analyze the effect of cerivastatin in relation to different phenotypes. PATIENTS AND METHODS Forty-five KT recipients who had their transplants for more than 1 year, with stable renal function (serum creatinine ⬍ 200 mol/L) and persistent hypercholesterolemia (total cholesterol ⱖ 6 mmol/ L), were included. Dietary counseling was indicated and treatment started with cerivastatin at 0.3 mg/d. Duration of the study was 3 months. Lipids were determined with a DAX 48 analyzer (Bayer). Apo E polymorphism was determined by PCR. Results are expressed as mean ⫾ SD. Statistical test results with a probability of ⬍.05 were considered statistically significant.
RESULTS
The Apo E genotype showed E3E3 in 31, E4E3 in 11, E4E4 in one, and E2E2 in two KT recipients. Allele frequency was: E2 4%, E3 81%, E4 14%, and was similar to that of the control group. Patients with the E4 allele had higher total cholesterol levels prior to treatment (total cholesterol in patients with the E3 allele 6.92 ⫾ 0.8 mmol/L vs E4 of 7.22 ⫾ 0.86 mmol/L; P ⬍ .05). The remaining lipid profile parameters (cholesterol HDL, LDL, TG, Apo B, and atherogenic index) showed no statistically significant differences. Following cerivastatin administration, the decreases in total cholesterol and LDL cholesterol were 20% and 18.9%, respectively, in patients with allele E4, with no statistical difference. KT patients with allele E4 have better renal function (Cl creatinine E3 56.11 ⫾ 13.17 mL/min vs Cl creatinine E4 70.15 ⫾ 22.14 mL/min) (P ⬍ .05). DISCUSSION
Dyslipemia is a very frequent cardiovascular risk factor in KT patients. Previous researchers have reported that apolipoprotein E plays a role in lipoprotein metabolism, and studies exist that show that the Apo E genotype could be responsible for between 1% and 14% of the variability in plasma total cholesterol and LDL cholesterol levels. As described in the literature,2 we found that patients with allele E4 presented higher cholesterol levels. The response to hypolipemiant treatment, both dietary and pharmacological, may be modulated by the genetic variability of the © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 373 (2002)
lipoprotein. A recent meta-analysis found the presence of allele 4 to be associated with a significantly better response by LDL cholesterol to dietary changes.3 It has also been reported that subjects with allele E4 respond significantly better to probucol.4 With fibrates, the Apo E phenotype does not appear to modulate the response to treatment.5 With respect to HMG CoA reductase inhibitors, Carmena et al6 described a lower response to treatment with lovastatin in male allele E4 carriers, which has not been confirmed by other authors. In our study with cerivastatin, we found no relationship between the Apo E phenotype and the diet-associated drug hypolipemiant response. Although contradictory results exist, recent studies have associated the Apo E polymorphism with the risk of kidney disease. The work by Oda7 suggests that allele E2 is a possible genetic predisposer to chronic renal failure in the Japanese population. On the other hand, the works of Kimura8 in diabetic patients and Chew9 in postoperative cardiac surgery report how allele E4 protects against the progression or development of kidney failure. In summary, it can be seen how KT patients with allele E4 have better renal function and higher cholesterol levels. The response to cerivastatin in these patients is not influenced by the allelic variability of apolipoprotein E. REFERENCES 1. Aakhus S, Dahl K, Wideroe TE, et al: Nephrol Dial Transplant 14:648, 1999 2. Sing CF, Davignon J: Am J Hum Genet 37:268, 1985 3. Lo ´pez Miranda J, Ordovas JM, Mata P, et al: J Lipid Res 35:1965, 1994 4. Eto M, Sato T, Watanabe K, et al: Atherosclerosis 84:49, 1990 5. Manttari M, Koskinen P, Ehnholm C, et al: Metabolism 40:217, 1991 6. Carmena R, Roederer G, Mailloux H, et al: Metabolism 42:895, 1993 7. Oda, H, Yorioka N, Ueda C, et al: Kidney Int 56(suppl 71):S25, 1999 8. Kimura H, Suzuki Y, Gejyo F, et al: Am J Kidney Dis 31:666, 1998 9. Chew ST, Newman MF, White WD, et al: Anesthesiology 93:325, 2000
From the Kidney Transplantation Unit and Department of Nephrology and Departments of Biochemistry, Hospital Universitari “Germans Trias i Pujol,” Badalona, Spain. Address reprint requests to Beatriz Baye´s, Department of Nephrology, Hospital Universitari “Germans Trias i Pujol” Crta del canyet, s/n 08916 Badalona, Spain. 0041-1345/02/$–see front matter PII S0041-1345(01)02808-1 373
C
ARDIOVASCULAR DISEASE is the main cause of morbidity and mortality in kidney transplant (KT) recipients.1 Hyperlipidemia is a known risk factor for cardiovascular disease. Polymorphism of the apolipoprotein E (Apo E) gene may affect plasma lipoprotein levels and composition and the risk of kidney disease. The aim of the present study was to ascertain the influence of the Apo E genotype on renal function and lipid profile in KT patients and analyze the effect of cerivastatin in relation to different phenotypes. PATIENTS AND METHODS Forty-five KT recipients who had their transplants for more than 1 year, with stable renal function (serum creatinine ⬍ 200 mol/L) and persistent hypercholesterolemia (total cholesterol ⱖ 6 mmol/ L), were included. Dietary counseling was indicated and treatment started with cerivastatin at 0.3 mg/d. Duration of the study was 3 months. Lipids were determined with a DAX 48 analyzer (Bayer). Apo E polymorphism was determined by PCR. Results are expressed as mean ⫾ SD. Statistical test results with a probability of ⬍.05 were considered statistically significant.
RESULTS
The Apo E genotype showed E3E3 in 31, E4E3 in 11, E4E4 in one, and E2E2 in two KT recipients. Allele frequency was: E2 4%, E3 81%, E4 14%, and was similar to that of the control group. Patients with the E4 allele had higher total cholesterol levels prior to treatment (total cholesterol in patients with the E3 allele 6.92 ⫾ 0.8 mmol/L vs E4 of 7.22 ⫾ 0.86 mmol/L; P ⬍ .05). The remaining lipid profile parameters (cholesterol HDL, LDL, TG, Apo B, and atherogenic index) showed no statistically significant differences. Following cerivastatin administration, the decreases in total cholesterol and LDL cholesterol were 20% and 18.9%, respectively, in patients with allele E4, with no statistical difference. KT patients with allele E4 have better renal function (Cl creatinine E3 56.11 ⫾ 13.17 mL/min vs Cl creatinine E4 70.15 ⫾ 22.14 mL/min) (P ⬍ .05). DISCUSSION
Dyslipemia is a very frequent cardiovascular risk factor in KT patients. Previous researchers have reported that apolipoprotein E plays a role in lipoprotein metabolism, and studies exist that show that the Apo E genotype could be responsible for between 1% and 14% of the variability in plasma total cholesterol and LDL cholesterol levels. As described in the literature,2 we found that patients with allele E4 presented higher cholesterol levels. The response to hypolipemiant treatment, both dietary and pharmacological, may be modulated by the genetic variability of the © 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 34, 373 (2002)
lipoprotein. A recent meta-analysis found the presence of allele 4 to be associated with a significantly better response by LDL cholesterol to dietary changes.3 It has also been reported that subjects with allele E4 respond significantly better to probucol.4 With fibrates, the Apo E phenotype does not appear to modulate the response to treatment.5 With respect to HMG CoA reductase inhibitors, Carmena et al6 described a lower response to treatment with lovastatin in male allele E4 carriers, which has not been confirmed by other authors. In our study with cerivastatin, we found no relationship between the Apo E phenotype and the diet-associated drug hypolipemiant response. Although contradictory results exist, recent studies have associated the Apo E polymorphism with the risk of kidney disease. The work by Oda7 suggests that allele E2 is a possible genetic predisposer to chronic renal failure in the Japanese population. On the other hand, the works of Kimura8 in diabetic patients and Chew9 in postoperative cardiac surgery report how allele E4 protects against the progression or development of kidney failure. In summary, it can be seen how KT patients with allele E4 have better renal function and higher cholesterol levels. The response to cerivastatin in these patients is not influenced by the allelic variability of apolipoprotein E. REFERENCES 1. Aakhus S, Dahl K, Wideroe TE, et al: Nephrol Dial Transplant 14:648, 1999 2. Sing CF, Davignon J: Am J Hum Genet 37:268, 1985 3. Lo ´pez Miranda J, Ordovas JM, Mata P, et al: J Lipid Res 35:1965, 1994 4. Eto M, Sato T, Watanabe K, et al: Atherosclerosis 84:49, 1990 5. Manttari M, Koskinen P, Ehnholm C, et al: Metabolism 40:217, 1991 6. Carmena R, Roederer G, Mailloux H, et al: Metabolism 42:895, 1993 7. Oda, H, Yorioka N, Ueda C, et al: Kidney Int 56(suppl 71):S25, 1999 8. Kimura H, Suzuki Y, Gejyo F, et al: Am J Kidney Dis 31:666, 1998 9. Chew ST, Newman MF, White WD, et al: Anesthesiology 93:325, 2000
From the Kidney Transplantation Unit and Department of Nephrology and Departments of Biochemistry, Hospital Universitari “Germans Trias i Pujol,” Badalona, Spain. Address reprint requests to Beatriz Baye´s, Department of Nephrology, Hospital Universitari “Germans Trias i Pujol” Crta del canyet, s/n 08916 Badalona, Spain. 0041-1345/02/$–see front matter PII S0041-1345(01)02808-1 373