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Published in: Clinical and Experimental Nephrology 1/2011

01-02-2011 | Original Article

Association between plasma homocysteine and microalbuminuria in persons without hypertension, diabetes mellitus, and cardiovascular disease

Authors: Charumathi Sabanayagam, Anoop Shankar

Published in: Clinical and Experimental Nephrology | Issue 1/2011

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Abstract

Background

Microalbuminuria and plasma homocysteine levels are both considered to be markers of endothelial dysfunction and shown to be predictors of cardiovascular disease (CVD) in epidemiological studies. However, previous studies examining the association between plasma homocysteine and microalbuminuria have suggested that this association is explained by confounding factors such as preexisting CVD, diabetes, hypertension, and reduced kidney function.

Methods

We examined the association between plasma homocysteine and microalbuminuria in a representative sample of US men and women aged ≥20 years, who were free of diabetes mellitus, hypertension, and CVD and who participated in the Third National Health and Nutrition Examination Survey (n = 3,948). Microalbuminuria was defined as urinary albumin-to-creatinine ratio ≥30 mg/g.

Results

Plasma homocysteine levels were positively associated with microalbuminuria in men but not in women (p-interaction <0.0001) after adjusting for age, race/ethnicity, smoking, drinking, body mass index, physical activity, glomerular filtration rate, blood pressure, high-density lipoprotein cholesterol, glycated hemoglobin, serum folate, serum vitamin B12, and C-reactive protein. In men, the multivariable odds ratio (OR) [95% confidence interval (CI)] of microalbuminuria comparing the highest to the lowest quartile of homocysteine was 5.17 (2.00–13.36); (p-trend = 0.005). Further, men in the highest quartile of homocysteine and age ≥60 years had >12-fold odds of microalbuminuria compared with men in the lowest homocysteine quartile and age <60 years. In contrast, in women, the multivariable OR (95% CI) comparing the highest to the lowest quartile of homocysteine was 0.96 (0.86–1.07); (p-trend = 0.41).

Conclusions

Among relatively healthy adults, plasma homocysteine levels are associated with microalbuminuria only in men.
Literature
1.
go back to reference Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms. J Am Soc Nephrol. 2006;17:2106–11.CrossRefPubMed Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardiovascular disease: analysis of potential mechanisms. J Am Soc Nephrol. 2006;17:2106–11.CrossRefPubMed
2.
go back to reference Feldt-Rasmussen B. Microalbuminuria, endothelial dysfunction and cardiovascular risk. Diabetes Metab. 2000;26(Suppl 4):64–6.PubMed Feldt-Rasmussen B. Microalbuminuria, endothelial dysfunction and cardiovascular risk. Diabetes Metab. 2000;26(Suppl 4):64–6.PubMed
3.
go back to reference Hillege HL, Fidler V, Diercks GF, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002;106:1777–82.CrossRefPubMed Hillege HL, Fidler V, Diercks GF, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002;106:1777–82.CrossRefPubMed
4.
go back to reference Hillege HL, Janssen WM, Bak AA, et al. Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med. 2001;249:519–26.CrossRefPubMed Hillege HL, Janssen WM, Bak AA, et al. Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med. 2001;249:519–26.CrossRefPubMed
5.
go back to reference Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202.CrossRefPubMed Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002;325:1202.CrossRefPubMed
6.
go back to reference Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med. 1999;131:363–75.PubMed Eikelboom JW, Lonn E, Genest J Jr, Hankey G, Yusuf S. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med. 1999;131:363–75.PubMed
7.
go back to reference Davies L, Wilmshurst EG, McElduff A, Gunton J, Clifton-Bligh P, Fulcher GR. The relationship among homocysteine, creatinine clearance, and albuminuria in patients with type 2 diabetes. Diabetes Care. 2001;24:1805–9.CrossRefPubMed Davies L, Wilmshurst EG, McElduff A, Gunton J, Clifton-Bligh P, Fulcher GR. The relationship among homocysteine, creatinine clearance, and albuminuria in patients with type 2 diabetes. Diabetes Care. 2001;24:1805–9.CrossRefPubMed
8.
go back to reference Fonseca VA, Reynolds T, Fink LM. Hyperhomocysteinemia and microalbuminuria in diabetes. Diabetes Care. 1998;21:1028.CrossRefPubMed Fonseca VA, Reynolds T, Fink LM. Hyperhomocysteinemia and microalbuminuria in diabetes. Diabetes Care. 1998;21:1028.CrossRefPubMed
9.
go back to reference Looker HC, Fagot-Campagna A, Gunter EW, et al. Homocysteine as a risk factor for nephropathy and retinopathy in Type 2 diabetes. Diabetologia. 2003;46:766–72.CrossRefPubMed Looker HC, Fagot-Campagna A, Gunter EW, et al. Homocysteine as a risk factor for nephropathy and retinopathy in Type 2 diabetes. Diabetologia. 2003;46:766–72.CrossRefPubMed
10.
go back to reference Smulders YM, Brouwer CB, Silberbusch J. Is plasma homocysteine related to albumin excretion rate in patients with diabetes mellitus? Diabetologia. 1999;42:382–3.CrossRefPubMed Smulders YM, Brouwer CB, Silberbusch J. Is plasma homocysteine related to albumin excretion rate in patients with diabetes mellitus? Diabetologia. 1999;42:382–3.CrossRefPubMed
11.
go back to reference Soedamah-Muthu SS, Chaturvedi N, Teerlink T, Idzior-Walus B, Fuller JH, Stehouwer CD. Plasma homocysteine and microvascular and macrovascular complications in type 1 diabetes: a cross-sectional nested case-control study. J Intern Med. 2005;258:450–9.CrossRefPubMed Soedamah-Muthu SS, Chaturvedi N, Teerlink T, Idzior-Walus B, Fuller JH, Stehouwer CD. Plasma homocysteine and microvascular and macrovascular complications in type 1 diabetes: a cross-sectional nested case-control study. J Intern Med. 2005;258:450–9.CrossRefPubMed
12.
go back to reference Wotherspoon F, Laight DW, Browne DL, et al. Plasma homocysteine, oxidative stress and endothelial function in patients with Type 1 diabetes mellitus and microalbuminuria. Diabetes Med. 2006;23:1350–6.CrossRef Wotherspoon F, Laight DW, Browne DL, et al. Plasma homocysteine, oxidative stress and endothelial function in patients with Type 1 diabetes mellitus and microalbuminuria. Diabetes Med. 2006;23:1350–6.CrossRef
13.
go back to reference Gonzalez-Clemente JM, Deulofeu R, Mitjavila J, et al. Plasma homocysteine is not increased in microalbuminuric patients with type 2 diabetes without clinical cardiovascular disease. Diabetes Care. 2002;25:632–3.CrossRefPubMed Gonzalez-Clemente JM, Deulofeu R, Mitjavila J, et al. Plasma homocysteine is not increased in microalbuminuric patients with type 2 diabetes without clinical cardiovascular disease. Diabetes Care. 2002;25:632–3.CrossRefPubMed
14.
go back to reference Abdella N, Mojiminiyi OA, Akanji AO. Homocysteine and endogenous markers of renal function in type 2 diabetic patients without coronary heart disease. Diabetes Res Clin Pract. 2000;50:177–85.CrossRefPubMed Abdella N, Mojiminiyi OA, Akanji AO. Homocysteine and endogenous markers of renal function in type 2 diabetic patients without coronary heart disease. Diabetes Res Clin Pract. 2000;50:177–85.CrossRefPubMed
15.
go back to reference Francis ME, Eggers PW, Hostetter TH, Briggs JP. Association between serum homocysteine and markers of impaired kidney function in adults in the United States. Kidney Int. 2004;66:303–12.CrossRefPubMed Francis ME, Eggers PW, Hostetter TH, Briggs JP. Association between serum homocysteine and markers of impaired kidney function in adults in the United States. Kidney Int. 2004;66:303–12.CrossRefPubMed
16.
go back to reference Jager A, Kostense PJ, Nijpels G, et al. Serum homocysteine levels are associated with the development of (micro)albuminuria: the Hoorn study. Arterioscler Thromb Vasc Biol. 2001;21:74–81.PubMed Jager A, Kostense PJ, Nijpels G, et al. Serum homocysteine levels are associated with the development of (micro)albuminuria: the Hoorn study. Arterioscler Thromb Vasc Biol. 2001;21:74–81.PubMed
17.
go back to reference Mason JB, Miller JW. The effects of vitamins B12, B6, and folate on blood homocysteine levels. Ann N Y Acad Sci. 1992;669:197–203.CrossRefPubMed Mason JB, Miller JW. The effects of vitamins B12, B6, and folate on blood homocysteine levels. Ann N Y Acad Sci. 1992;669:197–203.CrossRefPubMed
18.
go back to reference Mann JF, Sheridan P, McQueen MJ, et al. Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease––results of the renal Hope-2 study. Nephrol Dial Transplant. 2008;23:645–53.CrossRefPubMed Mann JF, Sheridan P, McQueen MJ, et al. Homocysteine lowering with folic acid and B vitamins in people with chronic kidney disease––results of the renal Hope-2 study. Nephrol Dial Transplant. 2008;23:645–53.CrossRefPubMed
19.
go back to reference Abdella NA, Mojiminiyi OA, Akanji AO, Moussa MA. Associations of plasma homocysteine concentration in subjects with type 2 diabetes mellitus. Acta Diabetol. 2002;39:183–90.CrossRefPubMed Abdella NA, Mojiminiyi OA, Akanji AO, Moussa MA. Associations of plasma homocysteine concentration in subjects with type 2 diabetes mellitus. Acta Diabetol. 2002;39:183–90.CrossRefPubMed
20.
go back to reference Jacques PF, Rosenberg IH, Rogers G, et al. Serum total homocysteine concentrations in adolescent and adult Americans: results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr. 1999;69:482–9.PubMed Jacques PF, Rosenberg IH, Rogers G, et al. Serum total homocysteine concentrations in adolescent and adult Americans: results from the third National Health and Nutrition Examination Survey. Am J Clin Nutr. 1999;69:482–9.PubMed
21.
go back to reference Cappuccio FP, Bell R, Perry IJ, et al. Homocysteine levels in men and women of different ethnic and cultural background living in England. Atherosclerosis. 2002;164:95–102.CrossRefPubMed Cappuccio FP, Bell R, Perry IJ, et al. Homocysteine levels in men and women of different ethnic and cultural background living in England. Atherosclerosis. 2002;164:95–102.CrossRefPubMed
25.
go back to reference American Diabetes Association Clinical Practice Recommendations 2001. Diabetes Care. 2001; 24(Suppl 1): S1–133. American Diabetes Association Clinical Practice Recommendations 2001. Diabetes Care. 2001; 24(Suppl 1): S1–133.
26.
go back to reference National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1–266.CrossRef National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39:S1–266.CrossRef
27.
go back to reference Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr. 1987;422:43–52.CrossRefPubMed Araki A, Sako Y. Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr. 1987;422:43–52.CrossRefPubMed
28.
go back to reference American Diabetes Association. Standards of Medical Care in Diabetes––2007. Diabetes Care. 2007;30:S4–41.CrossRef American Diabetes Association. Standards of Medical Care in Diabetes––2007. Diabetes Care. 2007;30:S4–41.CrossRef
29.
go back to reference Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–70.PubMed Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999;130:461–70.PubMed
30.
go back to reference Coresh J, Astor BC, McQuillan G, et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis. 2002;39:920–9.CrossRefPubMed Coresh J, Astor BC, McQuillan G, et al. Calibration and random variation of the serum creatinine assay as critical elements of using equations to estimate glomerular filtration rate. Am J Kidney Dis. 2002;39:920–9.CrossRefPubMed
31.
go back to reference Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: a meta-analysis. Stroke. 2010;41:1205–12.CrossRefPubMed Lee M, Hong KS, Chang SC, Saver JL. Efficacy of homocysteine-lowering therapy with folic acid in stroke prevention: a meta-analysis. Stroke. 2010;41:1205–12.CrossRefPubMed
32.
go back to reference Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008;299:2027–36.CrossRefPubMed Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008;299:2027–36.CrossRefPubMed
33.
go back to reference Chico A, Perez A, Cordoba A, et al. Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: a new link between diabetic nephropathy and cardiovascular disease? Diabetologia. 1998;41:684–93.CrossRefPubMed Chico A, Perez A, Cordoba A, et al. Plasma homocysteine is related to albumin excretion rate in patients with diabetes mellitus: a new link between diabetic nephropathy and cardiovascular disease? Diabetologia. 1998;41:684–93.CrossRefPubMed
34.
go back to reference Friedman AN, Hunsicker LG, Selhub J, Bostom AG. Proteinuria as a predictor of total plasma homocysteine levels in type 2 diabetic nephropathy. Diabetes Care. 2002;25:2037–41.CrossRefPubMed Friedman AN, Hunsicker LG, Selhub J, Bostom AG. Proteinuria as a predictor of total plasma homocysteine levels in type 2 diabetic nephropathy. Diabetes Care. 2002;25:2037–41.CrossRefPubMed
35.
go back to reference Ozmen B, Ozmen D, Turgan N, Habif S, Mutaf I, Bayindir O. Association between homocysteinemia and renal function in patients with type 2 diabetes mellitus. Ann Clin Lab Sci. 2002;32:279–86.PubMed Ozmen B, Ozmen D, Turgan N, Habif S, Mutaf I, Bayindir O. Association between homocysteinemia and renal function in patients with type 2 diabetes mellitus. Ann Clin Lab Sci. 2002;32:279–86.PubMed
36.
go back to reference Elias AN, Eng S. Homocysteine concentrations in patients with diabetes mellitus––relationship to microvascular and macrovascular disease. Diabetes Obes Metab. 2005;7:117–21.CrossRefPubMed Elias AN, Eng S. Homocysteine concentrations in patients with diabetes mellitus––relationship to microvascular and macrovascular disease. Diabetes Obes Metab. 2005;7:117–21.CrossRefPubMed
37.
go back to reference Hoogeveen EK, Kostense PJ, Jager A, et al. Serum homocysteine level and protein intake are related to risk of microalbuminuria: the Hoorn Study. Kidney Int. 1998;54:203–9.CrossRefPubMed Hoogeveen EK, Kostense PJ, Jager A, et al. Serum homocysteine level and protein intake are related to risk of microalbuminuria: the Hoorn Study. Kidney Int. 1998;54:203–9.CrossRefPubMed
38.
go back to reference Yi F, dos Santos EA, Xia M, Chen QZ, Li PL, Li N. Podocyte injury and glomerulosclerosis in hyperhomocysteinemic rats. Am J Nephrol. 2007;27:262–8.CrossRefPubMed Yi F, dos Santos EA, Xia M, Chen QZ, Li PL, Li N. Podocyte injury and glomerulosclerosis in hyperhomocysteinemic rats. Am J Nephrol. 2007;27:262–8.CrossRefPubMed
39.
go back to reference Yi F, Li PL. Mechanisms of homocysteine-induced glomerular injury and sclerosis. Am J Nephrol. 2008;28:254–64.CrossRefPubMed Yi F, Li PL. Mechanisms of homocysteine-induced glomerular injury and sclerosis. Am J Nephrol. 2008;28:254–64.CrossRefPubMed
41.
go back to reference Zhou J, Austin RC. Contributions of hyperhomocysteinemia to atherosclerosis: causal relationship and potential mechanisms. Biofactors. 2009;35:120–9.CrossRefPubMed Zhou J, Austin RC. Contributions of hyperhomocysteinemia to atherosclerosis: causal relationship and potential mechanisms. Biofactors. 2009;35:120–9.CrossRefPubMed
42.
go back to reference Shankar A, Wang JJ, Chua B, Rochtchina E, Flood V, Mitchell P. Positive association between plasma homocysteine level and chronic kidney disease. Kidney Blood Press Res. 2008;31:55–62.CrossRefPubMed Shankar A, Wang JJ, Chua B, Rochtchina E, Flood V, Mitchell P. Positive association between plasma homocysteine level and chronic kidney disease. Kidney Blood Press Res. 2008;31:55–62.CrossRefPubMed
43.
go back to reference Ambrosch A, Dierkes J, Lobmann R, et al. Relation between homocysteinaemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diabet Med. 2001;18:185–92.CrossRefPubMed Ambrosch A, Dierkes J, Lobmann R, et al. Relation between homocysteinaemia and diabetic neuropathy in patients with Type 2 diabetes mellitus. Diabet Med. 2001;18:185–92.CrossRefPubMed
44.
go back to reference Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015–22.CrossRef Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA. 2002;288:2015–22.CrossRef
45.
go back to reference Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41:1–12.CrossRefPubMed Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003;41:1–12.CrossRefPubMed
46.
go back to reference Coresh J, Byrd-Holt D, Astor BC, et al. Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to 2000. J Am Soc Nephrol. 2005;16:180–8.CrossRefPubMed Coresh J, Byrd-Holt D, Astor BC, et al. Chronic kidney disease awareness, prevalence, and trends among U.S. adults, 1999 to 2000. J Am Soc Nephrol. 2005;16:180–8.CrossRefPubMed
47.
go back to reference Mattix HJ, Hsu CY, Shaykevich S, Curhan G. Use of the albumin/creatinine ratio to detect microalbuminuria: implications of sex and race. J Am Soc Nephrol. 2002;13:1034–9.PubMed Mattix HJ, Hsu CY, Shaykevich S, Curhan G. Use of the albumin/creatinine ratio to detect microalbuminuria: implications of sex and race. J Am Soc Nephrol. 2002;13:1034–9.PubMed
48.
go back to reference Asnani S, Desouza C, Homan J, Murthy SN, McNamara DB, Fonseca V. Hormones and homocysteine. Minerva Endocrinol. 2002;27:141–55.PubMed Asnani S, Desouza C, Homan J, Murthy SN, McNamara DB, Fonseca V. Hormones and homocysteine. Minerva Endocrinol. 2002;27:141–55.PubMed
49.
go back to reference Ide T, Tsutsui H, Ohashi N, et al. Greater oxidative stress in healthy young men compared with premenopausal women. Arterioscler Thromb Vasc Biol. 2002;22:438–42.CrossRefPubMed Ide T, Tsutsui H, Ohashi N, et al. Greater oxidative stress in healthy young men compared with premenopausal women. Arterioscler Thromb Vasc Biol. 2002;22:438–42.CrossRefPubMed
50.
go back to reference Foody JM, Milberg JA, Robinson K, Pearce GL, Jacobsen DW, Sprecher DL. Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women. Arterioscler Thromb Vasc Biol. 2000;20:493–9.PubMed Foody JM, Milberg JA, Robinson K, Pearce GL, Jacobsen DW, Sprecher DL. Homocysteine and lipoprotein(a) interact to increase CAD risk in young men and women. Arterioscler Thromb Vasc Biol. 2000;20:493–9.PubMed
51.
go back to reference Sadeghian S, Fallahi F, Salarifar M, et al. Homocysteine, vitamin B12, folate levels in premature coronary artery disease. BMC Cardiovasc Disord. 2006;6:38.CrossRefPubMed Sadeghian S, Fallahi F, Salarifar M, et al. Homocysteine, vitamin B12, folate levels in premature coronary artery disease. BMC Cardiovasc Disord. 2006;6:38.CrossRefPubMed
Metadata
Title
Association between plasma homocysteine and microalbuminuria in persons without hypertension, diabetes mellitus, and cardiovascular disease
Authors
Charumathi Sabanayagam
Anoop Shankar
Publication date
01-02-2011
Publisher
Springer Japan
Published in
Clinical and Experimental Nephrology / Issue 1/2011
Print ISSN: 1342-1751
Electronic ISSN: 1437-7799
DOI
https://doi.org/10.1007/s10157-010-0361-5

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