Proteinuria as a Predictor of Total Plasma Homocysteine Levels in Type 2 Diabetic Nephropathy

Abstract

OBJECTIVE -Patients with diabetes who manifest proteinuria are at increased risk for cardiovascular events. Some studies suggest that proteinuria exerts its cardiovascular effects at least partly through a positive association with total plasma homocysteine (tHcy). Modestly sized but better designed contrary studies find no such link through a limited range of serum creatinine and proteinuria. We tested the hypothesis that proteinuria independently predicts tHcy levels in a larger cohort of type 2 diabetic patients with nephropathy throughout a much broader range of kidney disease and proteinuria.RESEARCH DESIGN AND METHODS -Baseline data for the cross-sectional study were obtained from 717 patients enrolled in the multicenter Irbesartan Diabetic Nephropathy Trial. All subjects had type 2 diabetes, hypertension, and proteinuria and were between 29 and 78 years of age. Data included age, sex, BMI, serum creatinine and albumin, LDL and HDL cholesterol, triglyceride, proteinuria and albuminuria, plasma folate, B12, and pyridoxal 5Ј-phosphate (PLP) (the active form of B6), HbA 1c , and tHcy levels. Unadjusted and multivariable models were used in the analysis.RESULTS -Crude analyses revealed significant associations between tHcy and age (r ϭ 0.074; P ϭ 0.008), creatinine (r ϭ 0.414; P Ͻ 0.001), PLP (r ϭ Ϫ0.105; P ϭ 0.021), B12 (r ϭ Ϫ0.216; P Ͻ 0.001), folate (r ϭ Ϫ0.241; P Ͻ 0.001), and HbA 1c (r ϭ Ϫ0.119; P ϭ 0.003), with serum albumin approaching significance (r ϭ 0.055; P ϭ 0.072). Only serum creatinine, plasma folate, B12, serum albumin, sex, HbA 1c , and age were independent predictors of tHcy after controlling for all other variables.CONCLUSIONS -By finding no independent correlation between proteinuria (or albuminuria) and tHcy levels, this study improves the external validity of previous negative findings. Therefore, it is unlikely that the observed positive association between proteinuria and cardiovascular disease is directly related to hyperhomocysteinemia.

Association between serum homocysteine and markers of impaired kidney function in adults in the United States

“…Findings from previous studies of the association between albuminuria and homocysteine have been equivocal; some investigators have concluded that the association was due to an association of albuminuria with GFR [19,66] while others have concluded that the association was independent of GFR [67,68]. Our study differs from previous analyses in that we were able to assess the strength of the association in a larger sample of individuals with modest elevations in albumin excretion rate.…”

“…We had relatively few subjects in our sample with overt proteinuria. Our results are, therefore, not inconsistent with the observations from the IDNT study, a large clinical trial in subjects with established diabetic nephropathy, that overt proteinuria is not independently associated with elevated homocysteine, and the conclusion that in this condition, a low GFR is the main determinant of homocysteine levels [19].…”

“…The study group was limited to individuals aged 40 years and older because the main risk factor of interest, impaired renal function, is known to be associated with aging and more uncommon in younger adults. Also, the exclusion of younger adults created an age distribution for this study that closely corresponded to the age range of persons examined in previous studies of homocysteine concentration and its correlates or predictors [19,[66][67][68]. In contrast to measures of folate and vitamin B 12 status, the vitamin B 6 measure in our study represented dietary intake determined from a 24-hour recall of food consumption and does not necessarily reflect concentrations in cells or fluid.…”

“…To our knowledge only one general population study has investigated the strength of the association between markers of diminished renal function and elevated homocysteine, but that study focused on elevated homocysteine as a risk factor for albuminuria [18]. Several studies have examined the association between renal function and homocysteine in renal clinic patients [14,19], but extrapolation from such samples to the overall population is uncertain. Therefore, the present study was performed to assess the strength of the association between risk of elevated homocysteine and the presence of diminished kidney function in the community using data from the Third National Health and Nutrition Examination Survey (NHANES III, 1988.…”

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

“…Several epidemiological and clinical studies have shown that homocysteine is positively associated with microalbuminuria in individuals with diabetes [11,[33][34][35][36]. Two studies have reported a positive association between homocysteine and microalbuminuria in the general population [15,37].…”