The RENAAL Study is a double-blind, placebo-controlled trial to evaluate the renal protective effects of losartan in Type 2 diabetic patients with nephropathy. The study has enrolled 1513 patients and is expected to continue for 3.5 years after the last patient has been entered. Eligible patients must have a urinary albumin:creatinine ratio of at least 300 mg/g and serum creatinine between 1.3 to 3.0 mg/dL. Eligible hypertensive or normotensive patients are randomised to receive either losartan or placebo, in addition to their existing antihypertensive therapy. Medications that block angiotensin production or action, are excluded. The primary endpoint is a composite of the time to first event of doubling of serum creatinine, end-stage renal disease, or death; secondary endpoints include cardiovascular events, progression of renal disease, and changes in proteinuria; tertiary endpoints include quality of life, healthcare resource utilisation, and amputations. Patients include Caucasians (48.6%), Blacks (15.2%), Asians (16.7%), and Hispanics (18.2%). Baseline urinary albumin:creatinine ratio and serum creatinine levels average 1867 mg/g and 1.9 mg/dL, respectively. Mean systolic and diastolic blood pressures are 153 and 82 mmHg, respectively. RENAAL will document whether blockade of the AII receptor with losartan produces clinical benefits in patients with Type 2 diabetes and nephropathy.
Type 2 diabetes is becoming the leading cause of end-stage renal disease (ESRD) worldwide. Prevalence of ESRD and the antihypertensive response to renin-angiotensin system intervention are suggested to vary among different ethnicities. The Reduction in Endpoints in Non-insulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study, which included different ethnic groups, demonstrated a renoprotective effect of losartan. A post hoc analysis from RENAAL was performed where we examined in each ethnic group the ESRD risk, identified independent predictors for ESRD, effect of degree of baseline albuminuria, effect of 6-month antiproteinuric response to therapy on ESRD, and renoprotective effect of losartan assessed by albuminuria reduction and ESRD. Baseline albuminuria was the strongest predictor for ESRD in every ethnic group. Albuminuria reduction was associated with reduced risk of ESRD while losartan reduced albuminuria in every ethnic group. When accounting for independent predictors of ESRD, losartan exhibited renoprotection in all ethnic groups. In this type 2 diabetic population with nephropathy, baseline albuminuria is the predominant risk parameter for ESRD; early antiproteinuric effect of losartan predicts long-term renoprotection; and losartan appears to be renoprotective in all ethnic groups. Since the RENAAL study was not powered to determine ethnic responses, these results underline the need for prospective trials where the aim is renal protection among different ethnic groups.
The potent antithrombotic effects of rTAP in this model directly implicate de novo thrombin formation as a major source of thrombin activity within the highly thrombogenic residual thrombus. These findings suggest that direct inhibition of prothrombinase activity may be an effective strategy in the development of a new class of conjunctive agents.
SummaryAn in vivo thromboplastin (TP)-induced venous stasis thrombosis model in rabbits was used to compare the efficacy of standard heparin with the selective factor Xa inhibitors, recombinant tick anticoagulant peptide (rTAP) and recombinant antistasin (rATS), in prophylactic prevention of thrombus formation. Heparin significantly reduced TP-induced clot formation at doses of 55 and 100 U kg−1 h−1 yielding clot weights of 9 ± 4 and 6 ± 2%, respectively. Clot formation was significantly decreased by i.v. infusions of rTAP at doses of 21, 37 and 64 Μg kg−1 min−1 resulting in normalized clot weights of 13 ± 3, 8 ± 2 and 2 ± 1%, respectively. rATS was approximately 10-fold more potent than rTAP, reducing normalized clot weights to 16 ± 5, 2 ± 1 and 1 ± 0.8% at rATS doses of 1.25, 2.5 and 5.0 Μg kg−1 min−1, respectively. These data suggest that factor Xa-mediated inhibition of coagulation with rTAP and rATS is as effective as conventional anticogulant treatment with heparin in preventing venous thrombosis.
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