Von Willebrand Factor and Development of Diabetic Nephropathy in IDDM

Stehouwer, Coen D.A.; Stroes, ES; Hackeng, W. H. L.; Mulder, Paul; Ottolander, G.J.H. den

doi:10.2337/diab.40.8.971

Cited by 77 publications

(59 citation statements)

References 17 publications

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“…It is difficult to measure these endothelial functions but the plasma concentration of vWF, a high molecular glycoprotein synthesized mainly by endothelial cells, may act as a non-specific marker of endothelial dysfunction [35,36]. Our findings are in agreement with most studies demonstrating elevated vWF in microor macroalbuminuric patients with NIDDM [16,37] and IDDM [7,8,38]. However, the possibility that the raised vWF may be secondary to renal impairment and delayed clearance of vWF cannot be excluded.…”

Section: Discussionsupporting

confidence: 82%

Macro-microangiopathy and endothelial dysfunction in NIDDM patients with and without diabetic nephropathy

et al. 1996

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Insulin-dependent diabetic (IDDM) patients with incipient and overt diabetic nephropathy are characterized by a higher incidence and prevalence of retinopathy and cardiovascular diseases than normoalbuminuric IDDM patients [1,2]. The relative cardiovascular mortality is approximately 40 times higher in diabetic nephropathy as compared to the age-matched population [1]. Furthermore, the prevalence of

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Section: Discussionsupporting

confidence: 82%

Macro-microangiopathy and endothelial dysfunction in NIDDM patients with and without diabetic nephropathy

et al. 1996

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“…Note that median values are reported, which minimizes the influence of occasional outliers. Microalbuminuria was defined (in advance [11,12]) as UAE of 15-200 (xg/min. (We chose 15 fxg/min as cutoff because the median UAE in healthy volunteers in our laboratory is 5.7 jxg/min, with >95% having an UAE <15 jxg/min [11].)…”

Section: Main Outcome Measuresmentioning

confidence: 99%

“…Clinical and laboratory studies. Detailed descriptions are given elsewhere (11,12,17). At; each examination, we recorded age, diabetes duration, body mass index (BMI), blood pressure (BP; diastolic phase V, to the nearest 5 nunilg; twice, after 15 min of .supine rest, using a D1ABICTES, VOL -M, MAY IMS m standard sphygmomanometer with an appropriately sized cuff), insulin dose, current smoking habits, and current medication.…”

mentioning

confidence: 99%

“…It actively regulates vascular tone and RESEARCH DESIGN AND METHODS Cohort study. Between June 1985 and August, 1989, 05 IDDM pat ients (fasting ('»peptide levels < 0.01 nntol/1) were recruited and gave informed consent, as previously reported (11,12). Clinical and labora tory data, as detailed below, were obtained at baseline (first examina tion) and after a median follow-up of;} years (second examination).…”

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confidence: 99%

“…This study was completed in 59 patients and showed that the development of microalbuminuria was paralleled by increases in the plasma vWF concentration, but we could not. determine whether such increases preceded the occurrence of microalbuminuria (11). To further investi gate the time course of the development of complications of diabetes in relation to changes in vWF, patients were invited for further follow-up examinations when, at; the second examination, they had normal UAE, no diabetic retinopathy on ophthalmoscopy, and fair glyeemie control (HbAk.…”

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confidence: 99%

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Endothelial Dysfunction Precedes Development of Microalbuminuria in IDDM

Stehouwer¹,

Fischer

Kuijk³

et al. 1995

Diabetes

Self Cite

175

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In patients with insulin-dependent diabetes niellitus (IDDM), microalbuminuria is a predictor of widespread severe microangiopathy and maeroangiopathy. Patients with microalbuniimiria show generalized dysfunction of tiie vascular endothelium, but it Is unknown whether endothelial dysfunction precedes the development of mi croalbuminuria. We examined a cohort of 17 IDDM pa tients at baseline and on three occasions during a follow-up of (median) 64 months (range 51-89 permeability, the balance between coagulation and fibrino lysis, the composition of the subendothelial matrix, and the mitogenesis of vascular smooth muscle and renal mesangial cells (4-6). In cross-sectional studies in IDDM, there is a close association between microalbuminuria and endothelial dysfunction. Thus, in patients with microalbuminuria, the vascular endothelium tends to increase, rather than deerease, vascular resistance (7,8); fails to restrict the passage of macromolecules (1,3); and loses its anticoagulant and profibrinolytic properties (9,10). In addition, there is an increase in the plasma concentration of markers of endothe lial injury and dysfunction, such as von Willebrand factor (vWF) (9,11), a glycoprotein involved in primary hemostasis and secreted mainly by endothelial cells.Some aspects of endothelial function have been reported to be disturbed in IDDM patients with normal urinary albumin excretion (UAE) (12-15), but whether these are of prognostic significance is not known. Answering that ques tion is important because it would increase our knowledge about the pathogenesis of microalbuminuria and allow early recognition of high-risk patients. Therefore, we wished to investigate whether endothelial dysfunction precedes the occurrence of microalbuminuria. To do this, we followed a group of IDDM. patients and measured UAE and plasma vWF concentration at regular intervals (as an estimate of endo thelial function). n insulin-dependent diabetes mellitus (IDDM), mi croalbuminuria predicts the development not only of diabetic nephropathy, but also of severe retinopathy, neuropathy, hypertension, and macro vascular disease (1,2). Microalbuminuria is thought to be a marker of wide spread vascular damage (1,3), which may underlie the pro pensity of microalbuminuria patients to develop severe extrarenal vascular disease.The endothelium is mi important locus of control of vascular functions. It actively regulates vascular tone and Received for publication 10 November UHM and accepted in revised form li)January IW H.ANOVA, analysis of variance; HP, blood pressure; BMI, body mass index; IDDM, iasuliiMlopendent diabetes mellitus; NIDDM, non-insuliiMlepondom diabetes mel litus; UAE, urinary albuntin excretion; vWP, von Willebrand factor.

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Effects of ACE inhibition on cardiovascular risk factors, insulin resistance, and microalbuminuria

Yudkin

1995

Clin Cardiol

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Summary:Hypertension is one of the three major risk factors for cardiovascular disease, but levels of blood pressure are by themselves poor predictors of cardiovascular risk. Among subjects with hypertension, a number of phenotypic characteristics are capable of predicting cardiovascular events, but in turn these variables are only weakly related to levels of blood pressure, and may indeed be found in the normotensive as well as the hypertensive population. Among the most powerful predictws of cardiovascular risk are left ventricular hypertrophy (LVH) and microalbuminuria, which may in part represent end-organ damage from elevated blood pressure, but which may also result from the consequence of a common antecedent to that of hypertension. Another common finding in hypertensive subjects is that of insulin resistance, where euglycemia is maintained only at the expense of elevated concentrations of insulin. Several studies, both in diabetic and in nondiabetic subjects, have shown an association between insulin resistance and cardiovascular risk, although it is as yet unclear whether this is independent of the obesity and dyslipidemia associated with insulin resistance. The renin-angiotensin system has been implicated in the etiology of both microalbuminuria and LVH. In insulin-dependent diabetic subjects with microalbuminuria, angiotensin-converting enzyme (ACE) inhibitors have been shown to retard progression to proteinuria and to lower albumin excretion to a greater degree than can be explained by the reduction of blood pressure alone; the same is true in studies of left ventricular mass regression in hypertensive subjects. The relationship between the renin-angiotensin system and insulin resistance is less clear, but ACE inhibitors appear to produce a reduction in insulin resistance, particularly in the non-fasting state. ACE inhibitors may achieve these effects via restoration of endothelial function. The ultimate test of the benefit of any antihypertensive agent is the demonstration of reductions in stroke and in cardiovascular events in large randomized, controlled studies. In the absence of such studies, the potential advantages of newer agents must be set against the proven efficacy of thiazides and beta blockers in providing around 50% reversibility of coronary heart disease risk and virtually 100% reversibility in stroke risk. To attempt to predict the likely efficacy of new agents, the effects of these drugs on a series of surrogate end points must be used. The observations of benefit from ACE inhibitors in terms of left ventricular mass regression and reductions in insulin resistance and in microalbuminuria might predict benefit in reducing major end points. It must be remembered, however, that risk markers such as microalbuminuria and insulin resistance may not represent mechanisms of damage, and thus reversibility of these variables may not necessarily produce better outcomes than can be achieved with older drugs. It is only with end point studies that such questions can be answered.

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Von Willebrand Factor and Development of Diabetic Nephropathy in IDDM

Cited by 77 publications

References 17 publications

Macro-microangiopathy and endothelial dysfunction in NIDDM patients with and without diabetic nephropathy

Macro-microangiopathy and endothelial dysfunction in NIDDM patients with and without diabetic nephropathy

Endothelial Dysfunction Precedes Development of Microalbuminuria in IDDM

Effects of ACE inhibition on cardiovascular risk factors, insulin resistance, and microalbuminuria

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