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Hyperhomocysteinemia in renal transplant recipients with cyclosporine
Hyperhomocysteinemia in Renal Transplant Recipients With Cyclosporine S.I. Kim, T.H. Yoo, H.Y. Song, J.H. Hwang, H.Y. Lee, D.S. Han, J.I. Moon, Y.S. Kim, K.I. Park, K.J. Paeng, and K.H. Choi
M
ODERATE elevation of homocysteine (Hcy), a sulfur amino acid in plasma, is an independent risk factor for atherosclerotic disease in the coronary, cerebral, and peripheral arterial vessels.1 Some studies have demonstrated that hyperhomocyst(e)inemia is present in patients with impaired renal function in renal transplant and (RTx) recipeints. It is also correlated with cardiovascular disease.2,3 However, in RTx recipients, the major determinants of plasma Hcy are still unclear. In order to investigate the factors influencing plasma concentrations of Hcy, we measured plasma Hcy levels and evaluated the relationship between Hcy levels and laboratory parameters by correlation analysis in RTx recipients treated with cyclosporine (CyA).
There was a significant inverse correlation between plasma Hcy concentrations and glomerular filtration rates (GFR) reflected by creatinine clearance (r ⫽ ⫺0.39, P ⬍ .05) or hemoglobin value (r ⫽ ⫺0.38, P ⬍ .05). However, there were no significant correlations between plasma Hcy concentrations and age, dose of CyA and steroids, or time since transplantation. DISCUSSION
RESULTS
We showed that RTx recipients had higher Hcy concentrations in plasma compared with healthy controls. This finding agrees with an observation of plasma Hcy in RTx recipients published by Arnadottir et al.5 Four of the 25 patients who presented with cardiovascular disease until this study had higher Hcy concentrations than the others. Abnormally high levels of plasma Hcy might be an effect of abnormal renal clearance of Hcy and/or abnormal Hcy metabolism in RTx recipients. In this study, GFR and plasma Hcy concentrations were inversely correlated in RTx recipients, indicating the biological importance of reduced GFR in this context. Hcy is ultrafiltrated in glomeruli, almost completely absorbed in tubuli, and degraded in kidney tissue.6 Van Guldener et al7 recently found that humans with normal kidneys return as much Hcy to the circulation as is ultrafiltrated in glomeruli. These compensatory mechanisms in the autoregulated, activated methyl cycle are likely to explain the association between GFR and plasma Hcy in RTx recipients. There is evidence that Hcy catabolism takes place in the kidney, most likely in the renal tubular cells.5 CyA, which has well-known tubular effects, might interfere with Hcy catabolism at this level. However, this hypothesis is not
Mean age of patients was 46 years and transplant duration averaged 52.2 months. Red blood cell (RBC) folate and serum vitamin B12 levels in RTx recipients were not significantly different from controls. The Hcy concentration in RTx recipients was markedly higher than in healthy controls (8.52 ⫾ 2.46 mol/L vs 21.67 ⫾ 10.87, P ⬍ .05; Table 1). Four patients had a history of cardiovascular signs and/or symptoms and Hcy concentrations were higher in those patients than in the other patients with a negative history (32.15 ⫾ 13.32 mol/L vs 12.08 ⫾ 8.39, P ⬍ .05).
From the Departments of Surgery (S.I.K., J.I.M., Y.S.K., K.I.P.) and Internal Medicine (T.H.Y., H.Y.S., J.H.H., H.Y.L., D.S.H., K.H.C.), College of Medicine, Institute of Kidney Disease, and Department of Chemistry (K.J.P.), College of Liberal Arts and Sciences, Yonsei University, Seoul, Korea. Address reprint requests to Dr K.H. Choi, Department of Internal Medicine, Yonsei University College of Medicine, CPO Box 8044, Seoul 120-752, Korea. E-mail: khchoi6@yumc. yonsei.ac.kr.
PATIENTS AND METHODS Twenty-five RTx recipients and 20 healthy controls were enrolled in this study. All patients were treated with azathioprine and prednisolone, as well as with CyA. No study participant received treatment with folate or vitamin B12. Blood samples were drawn after an overnight fast for analysis of plasma concentrations of Hcy. The plasma was stored frozen at ⫺70°C until measured by highperformance liquid chromatography (HPLC; HP 1090 II, Hewlett Packard, Waldbronn, Germany, Column: Lichrospher RP-C18) with a programmable fluorescence detector, as previously described.4 Blood CyA, vitamin B12, and folate concentrations were analyzed with a radioimmunoassay. Cardiovascular complications were evaluated by means of chest roentgenogram, electrocardiogram (EKG), and history of vascular disease. Student’s t test was used to compare differences between groups, and the Spearman rank correlation test for estimating relationships between variables.
0041-1345/00/$–see front matter PII S0041-1345(00)01473-1
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1878
Transplantation Proceedings, 32, 1878–1879 (2000)
HYPERHOMOCYSTEINEMIA IN RTX RECIPIENTS
supported by the lack of difference between plasma Hcy concentrations and CyA levels in CyA-treated RTx recipients. There was a significant negative correlation between hemoglobin and Hcy concentrations, indicating that additional mechanisms are operative in RTx recipients. Further studies are required to confirm this result and to evaluate the influence of Hcy on hemoglobin metabolism. In conclusion, plasma Hcy concentrations are significantly increased in CyA-treated RTx recipients and appear to be higher in patients with atherosclerotic cardiovascular diseases. The GFR and hemoglobin levels appear to be important determinants of plasma Hcy concentrations in CyA-treated RTx recipients.
1879
REFERENCES 1. Ducloux D, Fournier V, Rebibou JM, et al: Clin Nephrol 49:232, 1998 2. Moustapha A, Gupta A, Robinson K, et al: Kidney Int 55:1470, 1999 3. Massy ZA, Chadefaux-Vekemans B, Chevalier A: Nephrol Dial Transplant 9:1103, 1994 4. Fortin LJ, Genest J: Clin Biochem 28:155, 1995 5. Arnadottir M, Hultberg B, Vladov V, et al: Transplantation 61:509, 1996 6. Wollesen F, Brattstrom L, Refsum H, et al: Kidney Int 55:1028, 1999 7. van Guldener C, Donker AJ, Jakobs C, et al: Kidney Int 54:166, 1998
M
ODERATE elevation of homocysteine (Hcy), a sulfur amino acid in plasma, is an independent risk factor for atherosclerotic disease in the coronary, cerebral, and peripheral arterial vessels.1 Some studies have demonstrated that hyperhomocyst(e)inemia is present in patients with impaired renal function in renal transplant and (RTx) recipeints. It is also correlated with cardiovascular disease.2,3 However, in RTx recipients, the major determinants of plasma Hcy are still unclear. In order to investigate the factors influencing plasma concentrations of Hcy, we measured plasma Hcy levels and evaluated the relationship between Hcy levels and laboratory parameters by correlation analysis in RTx recipients treated with cyclosporine (CyA).
There was a significant inverse correlation between plasma Hcy concentrations and glomerular filtration rates (GFR) reflected by creatinine clearance (r ⫽ ⫺0.39, P ⬍ .05) or hemoglobin value (r ⫽ ⫺0.38, P ⬍ .05). However, there were no significant correlations between plasma Hcy concentrations and age, dose of CyA and steroids, or time since transplantation. DISCUSSION
RESULTS
We showed that RTx recipients had higher Hcy concentrations in plasma compared with healthy controls. This finding agrees with an observation of plasma Hcy in RTx recipients published by Arnadottir et al.5 Four of the 25 patients who presented with cardiovascular disease until this study had higher Hcy concentrations than the others. Abnormally high levels of plasma Hcy might be an effect of abnormal renal clearance of Hcy and/or abnormal Hcy metabolism in RTx recipients. In this study, GFR and plasma Hcy concentrations were inversely correlated in RTx recipients, indicating the biological importance of reduced GFR in this context. Hcy is ultrafiltrated in glomeruli, almost completely absorbed in tubuli, and degraded in kidney tissue.6 Van Guldener et al7 recently found that humans with normal kidneys return as much Hcy to the circulation as is ultrafiltrated in glomeruli. These compensatory mechanisms in the autoregulated, activated methyl cycle are likely to explain the association between GFR and plasma Hcy in RTx recipients. There is evidence that Hcy catabolism takes place in the kidney, most likely in the renal tubular cells.5 CyA, which has well-known tubular effects, might interfere with Hcy catabolism at this level. However, this hypothesis is not
Mean age of patients was 46 years and transplant duration averaged 52.2 months. Red blood cell (RBC) folate and serum vitamin B12 levels in RTx recipients were not significantly different from controls. The Hcy concentration in RTx recipients was markedly higher than in healthy controls (8.52 ⫾ 2.46 mol/L vs 21.67 ⫾ 10.87, P ⬍ .05; Table 1). Four patients had a history of cardiovascular signs and/or symptoms and Hcy concentrations were higher in those patients than in the other patients with a negative history (32.15 ⫾ 13.32 mol/L vs 12.08 ⫾ 8.39, P ⬍ .05).
From the Departments of Surgery (S.I.K., J.I.M., Y.S.K., K.I.P.) and Internal Medicine (T.H.Y., H.Y.S., J.H.H., H.Y.L., D.S.H., K.H.C.), College of Medicine, Institute of Kidney Disease, and Department of Chemistry (K.J.P.), College of Liberal Arts and Sciences, Yonsei University, Seoul, Korea. Address reprint requests to Dr K.H. Choi, Department of Internal Medicine, Yonsei University College of Medicine, CPO Box 8044, Seoul 120-752, Korea. E-mail: khchoi6@yumc. yonsei.ac.kr.
PATIENTS AND METHODS Twenty-five RTx recipients and 20 healthy controls were enrolled in this study. All patients were treated with azathioprine and prednisolone, as well as with CyA. No study participant received treatment with folate or vitamin B12. Blood samples were drawn after an overnight fast for analysis of plasma concentrations of Hcy. The plasma was stored frozen at ⫺70°C until measured by highperformance liquid chromatography (HPLC; HP 1090 II, Hewlett Packard, Waldbronn, Germany, Column: Lichrospher RP-C18) with a programmable fluorescence detector, as previously described.4 Blood CyA, vitamin B12, and folate concentrations were analyzed with a radioimmunoassay. Cardiovascular complications were evaluated by means of chest roentgenogram, electrocardiogram (EKG), and history of vascular disease. Student’s t test was used to compare differences between groups, and the Spearman rank correlation test for estimating relationships between variables.
0041-1345/00/$–see front matter PII S0041-1345(00)01473-1
© 2000 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
1878
Transplantation Proceedings, 32, 1878–1879 (2000)
HYPERHOMOCYSTEINEMIA IN RTX RECIPIENTS
supported by the lack of difference between plasma Hcy concentrations and CyA levels in CyA-treated RTx recipients. There was a significant negative correlation between hemoglobin and Hcy concentrations, indicating that additional mechanisms are operative in RTx recipients. Further studies are required to confirm this result and to evaluate the influence of Hcy on hemoglobin metabolism. In conclusion, plasma Hcy concentrations are significantly increased in CyA-treated RTx recipients and appear to be higher in patients with atherosclerotic cardiovascular diseases. The GFR and hemoglobin levels appear to be important determinants of plasma Hcy concentrations in CyA-treated RTx recipients.
1879
REFERENCES 1. Ducloux D, Fournier V, Rebibou JM, et al: Clin Nephrol 49:232, 1998 2. Moustapha A, Gupta A, Robinson K, et al: Kidney Int 55:1470, 1999 3. Massy ZA, Chadefaux-Vekemans B, Chevalier A: Nephrol Dial Transplant 9:1103, 1994 4. Fortin LJ, Genest J: Clin Biochem 28:155, 1995 5. Arnadottir M, Hultberg B, Vladov V, et al: Transplantation 61:509, 1996 6. Wollesen F, Brattstrom L, Refsum H, et al: Kidney Int 55:1028, 1999 7. van Guldener C, Donker AJ, Jakobs C, et al: Kidney Int 54:166, 1998