Jager A, Kostense P J, Nijpels G, Dekker J M, Heine R J, Bouter L M, Donker A J, Stehouwer C D
Institute for Research in Extramural Medicine, Vrije Universiteit, Department of Clinical Epidemiology, Amsterdam, The Netherlands.
Arterioscler Thromb Vasc Biol. 2001 Jan;21(1):74-81. doi: 10.1161/01.atv.21.1.74.
Microalbuminuria is a strong indicator of the risk of future cardiovascular disease and renal dysfunction. Slightly increased levels of homocysteine, an independent risk factor for atherothrombotic disease, have recently been found to be associated with the presence of (micro)albuminuria. However, it is unknown whether increased homocysteine levels precede the occurrence of (micro)albuminuria. Normoalbuminuric subjects (n=316, 66 with non-insulin-dependent diabetes mellitus [NIDDM]) of an age-stratified, sex-stratified, and glucose tolerance-stratified sample of a population-based cohort study were investigated at baseline and after a mean follow-up duration of 6.1 years. Development of (micro)albuminuria was defined as a mean albumin-to-creatinine ratio >2.0 mg/mmol at the follow-up examination. The cumulative incidence of (micro)albuminuria was 14. 0% (9.7 % to 18.3%) among nondiabetic subjects and 22.7% (12.9% to 32.5%) among NIDDM patients. Age-adjusted, sex-adjusted, and glucose tolerance status-adjusted logistic regression analyses showed development of (micro)albuminuria to be significantly associated with baseline homocysteine levels >19.0 micromol/L compared with homocysteine levels <9.1 micromol/L (odds ratio [OR] 5.1, 95% CI 1.1 to 23.0). For homocysteine levels of 9.1 to 14.0 micromol/L and 14.1 to 19.0 micromol/L, the values were OR 1.2 (95% CI 0.5 to 3.0) and OR 1.8 (95% CI 0.6 to 5.3), respectively. Additional adjustment for baseline insulin resistance, blood pressure, body mass index, presence of cardiovascular disease and retinopathy, current smoking, or estimates of glomerular filtration rate did not materially affect the results. Substituting homocysteine levels as a continuous variable for categories of homocysteine levels showed that a 5-micromol/L increase of the homocysteine level was associated with an increased risk of developing (micro)albuminuria (OR 1.38, 95% CI 0.97 to 1.95). Analyses performed in nondiabetic and diabetic subjects separately gave similar results among nondiabetic subjects. Among diabetic subjects, the association between homocysteine level and (micro)albuminuria could not be estimated, because there was an insufficient number of diabetic subjects with high homocysteine levels. Hyperhomocysteinemia is an independent determinant of the development of (micro)albuminuria among nondiabetic subjects, even after adjustment for estimates of glomerular filtration rate. We could neither confirm nor reject an association between homocysteine levels and the development of (micro)albuminuria among NIDDM subjects. These data suggest that homocysteine may play a pathophysiological role in the development of (micro)albuminuria.
微量白蛋白尿是未来心血管疾病和肾功能不全风险的有力指标。同型半胱氨酸水平略有升高，这是动脉粥样硬化血栓形成疾病的一个独立危险因素，最近发现它与（微量）白蛋白尿的存在有关。然而，尚不清楚同型半胱氨酸水平升高是否先于（微量）白蛋白尿的发生。在一项基于人群的队列研究中，对按年龄、性别和糖耐量分层的样本中的正常白蛋白尿受试者（n = 316，66例非胰岛素依赖型糖尿病 [NIDDM]）进行了基线调查，并在平均随访6.1年后进行了复查。（微量）白蛋白尿的发生定义为随访检查时平均白蛋白与肌酐比值>2.0 mg/mmol。非糖尿病受试者中（微量）白蛋白尿的累积发生率为14.0%（9.7%至18.3%），NIDDM患者中为22.7%（12.9%至32.5%）。经年龄、性别和糖耐量状态调整的逻辑回归分析显示，与同型半胱氨酸水平<9.1 μmol/L相比，基线同型半胱氨酸水平>19.0 μmol/L时，（微量）白蛋白尿的发生与基线同型半胱氨酸水平显著相关（比值比 [OR] 5.1，95%置信区间1.1至23.0）。对于同型半胱氨酸水平为9.1至14.0 μmol/L和14.1至19.0 μmol/L的情况，相应的值分别为OR 1.2（95%置信区间0.5至3.0）和OR 1.8（95%置信区间0.6至5.3）。对基线胰岛素抵抗、血压、体重指数、心血管疾病和视网膜病变的存在、当前吸烟情况或肾小球滤过率估计值进行进一步调整，并未对结果产生实质性影响。将同型半胱氨酸水平作为连续变量替代同型半胱氨酸水平类别进行分析表明，同型半胱氨酸水平每增加5 μmol/L，发生（微量）白蛋白尿的风险增加（OR 1.38，95%置信区间0.97至1.95）。分别在非糖尿病和糖尿病受试者中进行的分析在非糖尿病受试者中得出了类似的结果。在糖尿病受试者中，由于高同型半胱氨酸水平的糖尿病受试者数量不足，无法估计同型半胱氨酸水平与（微量）白蛋白尿之间的关联。高同型半胱氨酸血症是无糖尿病受试者中（微量）白蛋白尿发生的独立决定因素，即使在对肾小球滤过率估计值进行调整后也是如此。我们既不能证实也不能排除NIDDM受试者中同型半胱氨酸水平与（微量）白蛋白尿发生之间的关联。这些数据表明，同型半胱氨酸可能在（微量）白蛋白尿的发生中起病理生理作用。
