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Deletion Polymorphism of the Angiotensin-Converting Enzyme Predicts Left Ventricular Hypertrophy After Renal Transplantation
Insertion/Deletion Polymorphism of the Angiotensin-Converting Enzyme Predicts Left Ventricular Hypertrophy After Renal Transplantation R. Fedor, L. Asztalos, L. Lo˝csey, L. Szabó, I.S. Mányiné, M. Fagyas, E. Lizanecz, and A. Tóth ABSTRACT Background. Kidney transplant recipients show a higher risk for cardiovascular complications, such as left ventricular hypertrophy and heart failure, leading to the premature death in many cases. Methods. We investigated the contribution of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism to the development of left ventricular hypertrophy (LVH), an indicator of heart disease progression among kidney transplant recipients. Results. We observed a significant correlation between graft function and left ventricular mass index. The occurrence of LVH or severe LVH was significantly greater among patients with at least one D-allele (ID or DD). Conclusion. The use of ACE inhibitors or angiotensin receptor blockers seemed to be advantageous for patients with the ID and especially, the DD genotype. ARDIOVASCULAR complications, including left ventricular hypertrophy (LVH),1 are the main cause of late mortality among kidney transplant recipients.2 Hypertension, immunosuppressive therapy, anemia, and kidney function are believed to be involved in the development of LVH, in addition to genetic factors, such as angiotensin converting enzyme (ACE) insertion/deletion (I/D) polymorphism.3,4 ACE is a key enzyme in the renin–angiotensin– aldosterone system. Beside regulating renal function and blood pressure, it is also involved in the modulation of cardiac growth. ACE I/D polymorphism affects the concentration and activity of the enzyme in the blood.5 Our aim was to correlate ACE I/D polymorphisms and LVH among kidney transplant patients.
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PATIENTS AND METHODS ACE I/D polymorphism was determined based on a previously described method.5 Two-dimensional guided M-mode echocardiography was performed to estimate LVH.6 Echocardiographic parameters and left ventricular mass index (LVMI) were analyzed retrospectively based on 3 times: within 4 months (Echo 1, 0.29 ⫾ 0.08 years), 12 months later (Echo 2, 1.20 ⫾ 0.24 years), and at the last follow-up after transplantation (Echo 3, 7.17 ⫾ 2.53 years). All 27 patients involved in the study received primary kidney transplantations from cadaveric donors and gave signed informed consent. The study was approved by our Local Ethics Committee (No. 2829-2008).
The results are expressed as mean values ⫾ standard deviations or percentages. Statistical differences (P ⬍ .05) between mean values were assessed by student’s t test for continuous variables and by 2 ⫻ 2 contingency table chi-square test for categorical variables.
RESULTS
Significant correlation was observed between kidney function and LVMI (Fig 1A). The occurrence of LVH was defined as an LVMI ⬎95 g/m2 in female and 115 g/m2 in male subjects; Echo 1, II— 67%, ID—100%, and DD— 86%; Echo 2, II— 67%, ID— 82%, and DD— 86%; Echo 3, II— 67%, ID—76%, and DD— 86% (Fig 1B). Severe LVH was noted when LVMI was ⬎122 g/m2 in females and 149 g/m2 in male subjects: Echo 1, II— 0%, ID— 82%, and DD—57%; Echo 2, II—33%, ID—59%, and DD—57%; Echo 3, II—33%, ID—53%, and DD—71%; Fig 1C); it was significantly lower among patients with the II genotype. There were no differences regarding other recorded clinical From the University of Debrecen (R.F., L.A., L.L., L.S.), Medical and Health Science Center, Department of Surgery and the Institute of Cardiology (I.S.M., M.F., E.L., A.T.), Division of Clinical Physiology, Debrecen, Hungary. Address reprint requests to Roland Fedor, MD, University of Debrecen, Medical and Health Science Center, Department of Surgery, Transplantation Center, Hungary, H-4032 Debrecen, Móricz Zs. krt. 22., Debrecen, Hungary. E-mail: [email protected]
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.03.064
Transplantation Proceedings, 43, 1259 –1260 (2011)
1259
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FEDOR, ASZTALOS, LÖCSEY ET AL
parameters among patients with different ACE genotype (data not shown). DISCUSSION
Cardiovascular complications are the major known cause of death in transplant recipients. They represent a significant obstacle to improving long-term morbidity and mortality after kidney transplantation. Although the occurrence of cardiovascular disease in this population is clearly related to the high prevalence of conventional risk factors, cardiovascular disease may also develop independently.7 Herein we sought to relate interindividual differences regarding the occurrence and severity of cardiovascular complications to genetic factors, such as ACE genotype. LVH is a common risk factor among renal transplant recipients, even children.8 It is believed to be reversed or ameliorated by treatment.9 Although the sample size was small, our results indicated a lower left ventricular mass index among patients with the II genotype. LVH and severe LVH were significantly more frequent in patients with ID and DD genotypes. Early determination of the ACE genotype might be advantageous for transplant recipients. The use of the ACE inhibitors or angiotensin receptor blockers could be beneficial for patients with the ID and DD genotypes. REFERENCES
Fig 1. Creatinine and ACE I/D polymorphism in occurrence and severity of LVH in renal transplant patients. LVMI (in g/m2) was plotted as the function of the actual creatinine level (in mol/L) in renal transplant patients (A; n ⫽ 81 determinations). Individual data was fitted by a linear regression (solid line) and 95% confidence intervals are also shown (dotted lines). (B, C) Correlation between the genotypes (I/D) of ACE and the presence (B) and severity (C) of LVH upon consecutive determinations (Echo 1, within 4 months of transplantation; Echo 2, 1 year later; Echo 3, about 7 years after transplantation).
1. Levy D, Garrison RJ, Savage DD, et al: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Engl J Med 322:1561, 1990 2. United States Renal Data System (USRDS): 2010 annual data report. Available at: http://www.usrds.org/atlas.htm 3. Koc M, Özener IC, Tezcan H, et al: Left ventricular hypertrophy and angiotensin-converting enzyme gene polymorphism in renal allograft recipients. Transplant Proc 32:542, 2000 4. Hernández D, Lacalzada J, Salido E, et al: Regression of left ventricular hypertrophy by lisinopril after renal transplantation: role of ACE gene polymorphism. Kidney Int 58:889, 2000 5. Fedor R, Asztalos L, Löcsey L, et al: Insertion/deletion polymorphism of angiotensin-converting enzyme as a risk factor for chronic allograft nephropathy. Transplant Proc 42:2304, 2010 6. Lang RM, Bierig M, Devereux RB, et al: Recommendations for chamber quantification: A report from the American Society of Echocardiography’s guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 18:1440, 2005 7. Gill JS: Cardiovascular disease in transplant recipients: current and future strategies. Clin J Am Soc Nephrol 3:S29, 2008 8. Becker-Cohen R, Nir A, Rinat C, et al: Risk factors for cardiovascular disease in children and young adults after renal transplantation. Clin J Am Soc Nephrol 1:1284, 2006 9. Iqbal MM, Rashid HU, Banerjee SK, et al: Changes in cardiac parameters of renal allograft recipients: a compilation of clinical, laboratory, and echocardiographic observations. Transplant Proc 40:2327, 2008
C
PATIENTS AND METHODS ACE I/D polymorphism was determined based on a previously described method.5 Two-dimensional guided M-mode echocardiography was performed to estimate LVH.6 Echocardiographic parameters and left ventricular mass index (LVMI) were analyzed retrospectively based on 3 times: within 4 months (Echo 1, 0.29 ⫾ 0.08 years), 12 months later (Echo 2, 1.20 ⫾ 0.24 years), and at the last follow-up after transplantation (Echo 3, 7.17 ⫾ 2.53 years). All 27 patients involved in the study received primary kidney transplantations from cadaveric donors and gave signed informed consent. The study was approved by our Local Ethics Committee (No. 2829-2008).
The results are expressed as mean values ⫾ standard deviations or percentages. Statistical differences (P ⬍ .05) between mean values were assessed by student’s t test for continuous variables and by 2 ⫻ 2 contingency table chi-square test for categorical variables.
RESULTS
Significant correlation was observed between kidney function and LVMI (Fig 1A). The occurrence of LVH was defined as an LVMI ⬎95 g/m2 in female and 115 g/m2 in male subjects; Echo 1, II— 67%, ID—100%, and DD— 86%; Echo 2, II— 67%, ID— 82%, and DD— 86%; Echo 3, II— 67%, ID—76%, and DD— 86% (Fig 1B). Severe LVH was noted when LVMI was ⬎122 g/m2 in females and 149 g/m2 in male subjects: Echo 1, II— 0%, ID— 82%, and DD—57%; Echo 2, II—33%, ID—59%, and DD—57%; Echo 3, II—33%, ID—53%, and DD—71%; Fig 1C); it was significantly lower among patients with the II genotype. There were no differences regarding other recorded clinical From the University of Debrecen (R.F., L.A., L.L., L.S.), Medical and Health Science Center, Department of Surgery and the Institute of Cardiology (I.S.M., M.F., E.L., A.T.), Division of Clinical Physiology, Debrecen, Hungary. Address reprint requests to Roland Fedor, MD, University of Debrecen, Medical and Health Science Center, Department of Surgery, Transplantation Center, Hungary, H-4032 Debrecen, Móricz Zs. krt. 22., Debrecen, Hungary. E-mail: [email protected]
© 2011 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/–see front matter doi:10.1016/j.transproceed.2011.03.064
Transplantation Proceedings, 43, 1259 –1260 (2011)
1259
1260
FEDOR, ASZTALOS, LÖCSEY ET AL
parameters among patients with different ACE genotype (data not shown). DISCUSSION
Cardiovascular complications are the major known cause of death in transplant recipients. They represent a significant obstacle to improving long-term morbidity and mortality after kidney transplantation. Although the occurrence of cardiovascular disease in this population is clearly related to the high prevalence of conventional risk factors, cardiovascular disease may also develop independently.7 Herein we sought to relate interindividual differences regarding the occurrence and severity of cardiovascular complications to genetic factors, such as ACE genotype. LVH is a common risk factor among renal transplant recipients, even children.8 It is believed to be reversed or ameliorated by treatment.9 Although the sample size was small, our results indicated a lower left ventricular mass index among patients with the II genotype. LVH and severe LVH were significantly more frequent in patients with ID and DD genotypes. Early determination of the ACE genotype might be advantageous for transplant recipients. The use of the ACE inhibitors or angiotensin receptor blockers could be beneficial for patients with the ID and DD genotypes. REFERENCES
Fig 1. Creatinine and ACE I/D polymorphism in occurrence and severity of LVH in renal transplant patients. LVMI (in g/m2) was plotted as the function of the actual creatinine level (in mol/L) in renal transplant patients (A; n ⫽ 81 determinations). Individual data was fitted by a linear regression (solid line) and 95% confidence intervals are also shown (dotted lines). (B, C) Correlation between the genotypes (I/D) of ACE and the presence (B) and severity (C) of LVH upon consecutive determinations (Echo 1, within 4 months of transplantation; Echo 2, 1 year later; Echo 3, about 7 years after transplantation).
1. Levy D, Garrison RJ, Savage DD, et al: Prognostic implications of echocardiographically determined left ventricular mass in the Framingham heart study. N Engl J Med 322:1561, 1990 2. United States Renal Data System (USRDS): 2010 annual data report. Available at: http://www.usrds.org/atlas.htm 3. Koc M, Özener IC, Tezcan H, et al: Left ventricular hypertrophy and angiotensin-converting enzyme gene polymorphism in renal allograft recipients. Transplant Proc 32:542, 2000 4. Hernández D, Lacalzada J, Salido E, et al: Regression of left ventricular hypertrophy by lisinopril after renal transplantation: role of ACE gene polymorphism. Kidney Int 58:889, 2000 5. Fedor R, Asztalos L, Löcsey L, et al: Insertion/deletion polymorphism of angiotensin-converting enzyme as a risk factor for chronic allograft nephropathy. Transplant Proc 42:2304, 2010 6. Lang RM, Bierig M, Devereux RB, et al: Recommendations for chamber quantification: A report from the American Society of Echocardiography’s guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 18:1440, 2005 7. Gill JS: Cardiovascular disease in transplant recipients: current and future strategies. Clin J Am Soc Nephrol 3:S29, 2008 8. Becker-Cohen R, Nir A, Rinat C, et al: Risk factors for cardiovascular disease in children and young adults after renal transplantation. Clin J Am Soc Nephrol 1:1284, 2006 9. Iqbal MM, Rashid HU, Banerjee SK, et al: Changes in cardiac parameters of renal allograft recipients: a compilation of clinical, laboratory, and echocardiographic observations. Transplant Proc 40:2327, 2008