D iabetic nephropathy, especially related to type 2 diabetes, has become the single most important cause of ESRD worldwide. Although management of traditional risk factors such as hypertension, hyperlipidemia, and smoking to improve cardiovascular and renal outcomes continues to be important in patients with chronic kidney disease, there is growing recognition that nontraditional risk factors such as increased urinary albumin excretion, hypoalbuminemia, elevated serum creatinine levels, and/or decreased hemoglobin levels also may be important in the population with chronic kidney disease (1). The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study demonstrated significant benefits of treatment with losartan-versus placebo-based therapy in patients with type 2 diabetes and nephropathy (2). We aimed to explore further the risk predictors in the diabetic kidney disease population by developing ESRD and ESRD or death risk scores from risk predictors in the RENAAL study and to compare the ability of the ESRD risk score and its components to predict ESRD. Materials and Methods Study DesignRENAAL was a multinational, double-blind, randomized study that compared losartan versus placebo, in addition to conventional antihypertensive therapy (excluding angiotensin-converting enzyme inhibitors or other angiotensin II receptor antagonists), in 1513 patients with type 2 diabetes and nephropathy. Patients were followed for a mean of 3.4 yr. The study design (3) and results (2) have been reported. ESRD was defined as the need for long-term dialysis or renal transplantation. End points were classified by an expert end point classification committee that was blinded to study drug identification.

A series of basic carbamates of 4-hydroxyanisole was prepared and evaluated as progenitors of this melanocytotoxic phenol. All of the carbamates were relatively stable at low pH but released 4-hydroxyanisole cleanly at pH 7.4 at rates that were structure dependent. A detailed study of the N-methyl-N-[2-(methylamino)ethyl]carbamate showed that generation of the parent phenol followed first-order kinetics with t1/2 = 36.3 min at pH 7.4, 37 degrees C, and was accompanied by formation of N,N'-dimethylimidazolidinone. These basic carbamates are examples of cyclization-activated prodrugs in which generation of the active drug is not linked to enzymatic cleavage but rather depends solely upon a predictable, intramolecular cyclization-elimination reaction.

An attempt to develop a water-soluble carbonic anhydrase inhibitor focused on exploring structure-activity relationships in the thienothiopyransulfonamide class. The strategy to influence water solubility while retaining carbonic anhydrase activity involved the introduction of a hydroxyl moiety and adjusting the oxidation state of the sulfur on the thiopyran portion of the molecule. Compounds 4 and 17 best fit the criteria of aqueous solubility and inhibitory potency vs. human carbonic anhydrase II and are candidates for evaluation as topically effective antiglaucoma agents.

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Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Cox regression models were stratified on baseline proteinuria and included treatment, geographic region, ACE/ID genotype, and treatment ϫ genotype interaction. Within the placebo group, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P ϭ 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo, however, losartan reduced the risk of reaching the composite endpoint by 5. 8% (95% confidence interval, Ϫ23.3, 28.0), 17.6% (3.8, 29.4), and 27.9% (7.0, 44.1) among those with the II, ID, and DD genotypes, respectively. Similar trends were demonstrated for the individual endpoints. In conclusion, proteinuric type 2 diabetic patients with the D allele of the ACE gene have an unfavorable renal prognosis, which can be mitigated and even improved by losartan.