Plasma creatinine as a determinant of plasma total homocysteine concentrations in the Hordaland Homocysteine Study: Use of statistical modeling to determine reference limits Amany K. Elshorbagy a, ⁎ , Abderrahim Oulhaj b , Svetlana Konstantinova c,d , Eha Nurk e , Per M. Ueland d,f , Grethe S. Tell c,d , Ottar Nygård d,f , Stein E. Vollset c,d,g , Helga Refsum a,e a Oxford Centre for Gene Function, Department of Physiology, Anatomy and Genetics, Oxford University, UK b Oxford Project to Investigate Memory and Ageing, Department of Physiology, Anatomy and Genetics, Oxford University, UK c Department of Public Health and Primary Health Care, University of Bergen, Norway d LOCUS for Homocysteine and Related Vitamins, University of Bergen, Norway e Institute of Basic Medical Sciences, Department of Nutrition, University of Oslo, Norway f Institute of Medicine, University of Bergen, Norway g Norwegian Institute of Public Health, Bergen, Norway Received 19 March 2007; received in revised form 29 May 2007; accepted 2 July 2007 Available online 11 August 2007 Abstract Objectives: We established population-based reference limits for plasma total homocysteine (tHcy) according to creatinine. Design and methods: In 7042 middle-aged and elderly subjects from the Hordaland Homocysteine Study, we used statistical modeling to establish nomograms for tHcy according to creatinine in the whole population and in folate-replete and healthy subgroups. Results: When plotted against creatinine, tHcy 97.5th percentile almost overlapped in men and women, and, in elderly, increased up to 8 μmol/ L from the 2.5th to 97.5th creatinine percentiles. Folate-replete subjects had tHcy upper limits ∼ 20% below the whole population at all creatinine levels. Healthy subjects had lower creatinine, but at a given creatinine level, tHcy was the same as in the whole population. Conclusions: tHcy difference between men and women is mostly explained by creatinine. The tHcy-reducing effect of folate is independent of creatinine. In elderly people, creatinine should be taken into account when assessing tHcy levels. © 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Keywords: Homocysteine; Creatinine; Reference intervals; Nomograms; Blood; Kidney function; Folate; Gender; Age; Creatine synthesis Introduction Homocysteine is an amino acid intermediate of methionine metabolism that at elevated plasma levels has been implicated as an independent risk factor for cardiovascular disease, birth defects, pregnancy complications, and cognitive decline in the elderly [1]. Furthermore, plasma total homocysteine (tHcy) is increasingly used in the assessment of folate and vitamin B12 deficiency [1]. Several studies have identified renal function as a major determinant of plasma tHcy concentrations [1,2].A slightly reduced glomerular filtration rate (GFR) increases tHcy within the reference interval [1]. Frank hyperhomocysteinemia is common among patients with chronic renal insufficiency, and almost invariably accompanies chronic renal failure [3]. The causes of hyperhomocysteinemia in renal failure are not clear. Defective urinary excretion has been ruled out as a possibility, since about 80% of plasma tHcy is bound to albumin and unavailable for filtration [4]. The remaining fraction under- goes tubular reabsorption after glomerular filtration [5], and only minute amounts of homocysteine are recovered in urine [6]. Yet tHcy levels correlate strongly with GFR [7,8]. Homo- cysteine uptake and metabolism by the kidney were demon- strated in rats [9], but studies in humans found no significant arteriovenous differences in tHcy across the kidney [10,11]. Available online at www.sciencedirect.com Clinical Biochemistry 40 (2007) 1209 – 1218 ⁎ Corresponding author. Fax: +441865285813. E-mail address: amany.elshorbagy@dpag.ox.ac.uk (A.K. Elshorbagy). 0009-9120/$ - see front matter © 2007 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2007.07.014