In diabetes, much of the disease burden occurs in patients with diabetic nephropathy because they have the highest chance of developing not only renal failure, but also cardiovascular disease, severe retinopathy, and severe neuropathy. The association between renal and cardiovascular disease is seen even in individuals with early nephropathy [microalbuminuria (MA)], and exists regardless of the presence of diabetes. One hypothesis to explain the link between MA and cardiovascular disease is that extensive endothelial dysfunction (ED) represents the common antecedent to both.
ED can be defined as any change in endothelial properties that is inappropriate with regard to the preservation of organ function. Therefore, many types of ED exist, depending on which function is affected (e.g., the regulation of hemostasis and fibrinolysis, vasomotor activity, permeability to macromolecules, leukocyte adhesion, or vascular smooth muscle cell proliferation). Nitric oxide (NO) is a particularly important endothelium-derived mediator because of its vasodilator, anti-platelet, anti-proliferative, anti-adhesive, permeability-decreasing, and anti-inflammatory properties. Generalized ED (i.e., affecting many functions) is now considered a transducer of atherogenic risk factors, and is thought to play an important role both in the initiation and the progression of atherosclerosis. Therefore, an association of MA with generalized ED, if it exists, could explain the fact that MA strongly predicts cardiovascular disease.
MA in type 1 and 2 diabetes is usually1,2, but perhaps not always2, accompanied by ED with regard to the regulation of hemostasis, fibrinolysis, leukocyte adhesion, and NO synthesis and/or availability (i.e., ED is, at the very least, extensive). Whether this occurs in all vascular beds is extremely difficult to test in humans, but is obviously an important question. There are fewer data on the extent of ED in nondiabetic individuals with MA, but such ED has, as in diabetes, been suggested to involve the regulation of hemostasis, fibrinolysis, and leukocyte adhesion2,3,4,5. However, it is controversial whether NO synthesis and/or availability are impaired in nondiabetic individuals with MA5,6,7.
To investigate this issue more fully, we examined brachial artery, flow-mediated vasodilation (FMD; an estimate of endothelium-derived NO synthesis) in elderly individuals without and with MA in the population-based Hoorn Study.
METHODS
The population has been described in detail elsewhere8,9. MA was defined as urinary albumin-creatinine ratio (ACR) 
2 mg/mmol (based on a single first-voided morning urine sample). FMD and nitroglycerin-induced, endothelium-independent dilation (NID) were measured by ultrasound as described elsewhere9,10. We used multivariate linear regression to analyze associations of MA [present vs. absent and in four categories (<2, 2 to 5, 5 to 10, 10 mg/mmol)] with FMD and NID.
RESULTS
Table 1 shows the characteristics of the study population. Ninety-three individuals had MA (49 with diabetes; 53, 20, and 20 with ACR 2 to 5, 5 to 10, and 10 mg/mmol, respectively). FMD was 0.12 mm in the presence of MA and 0.18 in its absence (P=0.002; Table 2). After adjustment for age, sex, baseline arterial diameter, and increase in peak systolic velocity, FMD was 0.038 mm (95% CI, 0.001 to 0.075) lower in the presence of MA (P=0.04) and decreased linearly across MA categories [by 0.027 mm (0.007 to 0.046) per category increase of MA; P=0.007; Table 3, model 3]. Additional adjustments did not materially affect these results (Table 3, models 4–11). NID was similar in individuals with and without MA. All results were similar in individuals without and with diabetes [P for interaction of diabetes with MA in model 5 of Table 3= 0.9 (dichotomized) and = 0.62 (in categories), respectively], and whether or not individuals with ACR >30 mg/mmol (N=4) were excluded.
Table 1 - Characteristics of the study population according to the presence or absence of microalbuminuria.
Full table Table 2 - Brachial arterial properties according to the presence or absence of microalbuminuria.
Full table Table 3 - Flow-mediated, endothelium-dependent vasodilation (absolute change in diameter) and microalbuminuria: Adjusted analyses.
Full table DISCUSSION
The major new finding of this population-based study is that FMD is impaired in elderly individuals with MA whether or not they have type 2 diabetes. Together with previous data3,4,5,6, this supports the concept that ED is extensive even in nondiabetic individuals with MA and that such extensive ED, including impaired endothelial nitric oxide synthesis and/or availability, plays a role in the association of MA with cardiovascular disease risk in nondiabetic individuals.
It must be emphasized that prospective studies are needed to test whether ED actually explains the link between MA and cardiovascular disease. Of three previous studies that used plasma markers of ED4,11,12, two4,11 found no strong evidence in favor of this hypothesis, which may mean that ED was not measured with sufficient precision, that the types of ED tested were irrelevant with regard to cardiovascular risk in MA, or that ED, although associated with MA, does not explain the MA-cardiovascular disease link.
Because ED precedes and predicts the onset of MA3,4,11,12,13, it is tempting to postulate that ED causes MA. Alternatively, the association between ED and MA could be explained by a common antecedent that causes both, but the association persists when adjusted for common risk factors. Theoretically, ED could cause MA both directly by increasing glomerular pressure and glomerular basement membrane permeability, and indirectly by influencing mesangial cell and podocyte function in a paracrine fashion (e.g., through inflammatory mechanisms). Importantly, the molecular pathways by which ED causes MA have yet to be worked out2.
CONCLUSION
ED in individuals with MA is usually extensive (i.e., affects many aspects of endothelial function) regardless of the presence of diabetes. The close linkage between MA and ED is an attractive but unproven explanation for the fact that MA is a risk marker for atherothrombosis. ED predicts the occurrence of MA, but whether this is causal has not been determined.
References
- STEHOUWER, CDA, LAMBERT, J, DONKER, AJM, VAN HINSBERGH, VWM: Endothelial dysfunction and the pathogenesis of diabetic angiopathy. Cardiovasc Res 1997 34: 55–68, | Article | PubMed | ISI | ChemPort |
- STEHOUWER, CDA: Endothelial dysfunction in diabetic nephropathy: State of the art and potential significance for non-diabetic renal disease. Nephrol Dial Transplant 2004 19: 778–781, | PubMed |
- CLAUSEN, P, FELDT-RASMUSSEN, B, JENSEN, G, JENSEN, JS: Endothelial haemostatic factors are associated with progression of urinary albumin excretion in clinically healthy subjects: A 4-year prospective study. Clin Sci (Lond) 1999 97: 37–43, | PubMed |
- JAGER, A, VAN HINSBERGH, VWM, KOSTENSE, PJ, et al: C-reactive protein and soluble vascular cell adhesion molecule-1 are associated with elevated urinary albumin excretion but do not explain its link with cardiovascular risk. Arterioscler Thromb Vasc Biol 2002 22: 593–598, | PubMed |
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- DIERCKX, GFH, STROES, ESG, VAN BOVEN, AJ, et al: Urinary albumin excretion is related to cardiovascular risk indicators, not to flow-mediated vasodilation, in apparently healthy subjects. Atherosclerosis 2002 163: 121–126, | PubMed |
- HENRY, RMA, KOSTENSE, PJ, SPIJKERMAN, AMW, et al: Arterial stiffness increases with deteriorating glucose tolerance status. The Hoorn Study. Circulation 2003 107: 2089–2095, | PubMed |
- HENRY, RMA, KAMP, O, KOSTENSE, PJ, et al: Left ventricular mass increases with deteriorating glucose tolerance, especially in women: Independence of increased arterial stiffness or decreased flow-mediated dilation. The Hoorn Study. Diabetes Care 2004 27: 522–529, | PubMed |
- HENRY, RMA, FERREIRA, I, KOSTENSE, PJ, et al: Type 2 diabetes is associated with impaired endothelium-dependent, flow-mediated dilation, but impaired glucose metabolism is not. The Hoorn Study. Atherosclerosis 2004 174: 49–56, | PubMed |
- STEHOUWER, CDA, GALL, MA, TWISK, JWR, et al: Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes. Progressive, interrelated, and independently associated with risk of death. Diabetes 2002 51: 1157–1165, | PubMed | ISI | ChemPort |
- STEHOUWER, CDA, NAUTA, JJP, ZELDENRUST, GC, et al: Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non–insulin-dependent diabetes mellitus. Lancet 1992 340: 319–323, | Article | PubMed | ISI | ChemPort |
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