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No Effect of Unfractioned or Low. Molecular Weight Heparin Treatment on. Markers of Vascular Wall and Hemostatic. Function in Incipient Diabetic Nephropathy.
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No Effect of Unfractioned or Low Molecular Weight Heparin Treatment on Markers of Vascular Wall and Hemostatic Function in Incipient Diabetic Nephropathy BjARNE MYRUP, MD TONNY JENSEN, DMSC JORGEN GRAM, DMSC

CORNELIS KLUFT, DSC J0RGEN JESPERSEN, DMSC TORSTEN DECKERT, DMSC

OBJECTIVE — The high risk for cardiovascular disease in IDDM patients with nephropathy may be mediated by abnormal function of the vascular wall. We investigated whether heparin was able to modulate markers of vascular wall and hemostatic function in patients with incipient nephropathy. RESEARCH DESIGN A N D M E T H O D S — Thirty-five IDDM patients with incipient nephropathy were randomized to treatment with placebo, unfractioned heparin, or low molecular weight heparin in a double-blind trial. The treatment was given as 1 h of conventional intravenous high-dose treatment and in a conventional subcutaneous low-dose regime for 3 months. Transcapillary escape rate of albumin and plasma levels of von Willebrand factor, fibrinogen, prothrombin fragment 1 + 2, thrombin-antithrombin III complexes, tissue type plasminogen activator, tissue plasminogen activator inhibitor type 1, total cholesterol, HDL cholesterol, and triglycerides were measured before and after treatment. Of the patients, 31 completed the study. RESULTS — We found no significant effect of heparin on markers of vascular wall and hemostatic function by any of the treatments. CONCLUSIONS — Treatment with high- or low-dose heparin induced no modulation of markers of vascular wall or hemostatic function in IDDM patients with incipient diabetic nephropathy.

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atients with IDDM and clinical nephropathy face, besides deteriorating kidney function (1), a high risk of cardiovascular disease (2). When evaluating intervention in this group of patients both aspects should be taken into account. The explanation of the high risk of cardiovascular disease in diabetic nephropathy has been suggested to be a changed function of the vascular wall, as demonstrated by elevated transcapillary escape rate of albumin (TER) and elevated von Willebrand factor (3). Recently, we published

that 3 months of treatment with low molecular weight heparin (LMWH) reduced urinary albumin excretion in patients with incipient nephropathy (urinary albumin excretion in the range 30-300 mg/24 h) (4). A similar effect of unfractioned heparin (UFH) was also seen. The main purpose of the present study was, in the same patients, to evaluate whether these markers of vascular wall function were modified by heparin treatment. This could give hope for beneficial effects of such treatment on the risk of cardiovascular disease in these

From the Steno Diabetes Center (B.M., T.D.), Gentofte; Novo Nordisk (T.J.), Bagsvaerd; the Institute for Thrombosis Research (J.G., J.J.), South Jutland University Centre, Esbjerg, Denmark; and Gaubius Laboratory, PG-TNO (C.K.), Leiden, The Netherlands. Address correspondence and reprint requests to B. Myrup, MD, Centralsygehuset i Holbaek, DK-4300 Holbaek, Denmark. Received for publication 17 April 1997 and accepted in revised form 17 June 1997. Abbreviations: LMWH, low molecular weight heparin; PAI-1, plasminogen activator inhibitor 1; TER, transcapillary escape rate of albumin; t-PA, tissue-type plasminogen activator; UFH, unfractioned heparin.

DIABETES CARE, VOLUME 20, NUMBER 10, OCTOBER 1997

patients. In this aspect, we also measured fibrinogen, total cholesterol, HDL cholesterol, and triglycerides as risk markers of cardiovascular disease. We have earlier demonstrated a procoagulant activity in IDDM (5) and wanted furthermore to investigate whether this could be modified by heparin. To monitor coagulation, both prothrombin fragment 1 + 2 and thrombin-antithrombin III complexes were measured. Prothrombin fragment 1+2 reflects the rate of activation of prothrombin, while the formation of thrombin-antithrombin III complexes requires an efficient inactivation system. The level of thrombinantithrombin III complexes therefore describes both formation and inactivation of thrombin. To assess hemostatic balance, the fibrinolytic system was monitored by measuring the level of tissue-type plasminogen activator (t-PA) antigen and plasminogen activator inhibitor 1 (PAI-1).

RESEARCH DESIGN AND M E T H O D S — All patients were recruited from the outpatient clinic at the Steno Diabetes Center, where they had been seen three times annually for several years. All IDDM patients with incipient nephropathy aged 18-60 years and with a diabetes duration >5 years were identified. They were classified as IDDM patients based on age at onset below 35 years and the necessity for insulin treatment from onset to obtain ketosis-free control. Among these patients, only those with persistently elevated urinary albumin excretion (30-300 mg/24 h) during the last 18 months were considered for participation (n = 153). Exclusion criteria were hypertension and daily intake of angiotensin-converting enzyme inhibitors, which are known to reduce albuminuria or nonsteroid antiinflammatory drugs, apart from low-dose aspirin (