TGF- has been implicated as a major pathogenic factor in diabetic nephropathy. This randomized, double-blind, phase 2 study assessed whether modulating TGF-1 activity with a TGF-1-specific, humanized, neutralizing monoclonal antibody (TGF-1 mAb) is safe and more effective than placebo in slowing renal function loss in patients with diabetic nephropathy on chronic stable renin-angiotensin system inhibitor treatment. We randomized 416 patients aged ≥25 years with type 1 or type 2 diabetes, a serum creatinine (SCr) level of 1.3-3.3 mg/dl for women and 1.5-3.5 mg/dl for men (or eGFR of 20-60 ml/min per 1.73 m), and a 24-hour urine protein-to-creatinine ratio ≥800 mg/g to TGF-1 mAb (2-, 10-, or 50-mg monthly subcutaneous dosing for 12 months) or placebo. We assessed a change in SCr from baseline to 12 months as the primary efficacy variable. Although the Data Monitoring Committee did not identify safety issues, we terminated the trial 4 months early for futility on the basis of their recommendation. The placebo group had a mean±SD change in SCr from baseline to end of treatment of 0.33±0.67 mg/dl. Least squares mean percentage change in SCr from baseline to end of treatment did not differ between placebo (14%; 95% confidence interval [95% CI], 9.7% to 18.2%) and TGF-1 mAb treatments (20% [95% CI, 15.3% to 24.3%], 19% [95% CI, 14.2% to 23.0%], and 19% [95% CI, 14.0% to 23.3%] for 2-, 10-, and 50-mg doses, respectively). Thus, TGF-1 mAb added to renin-angiotensin system inhibitors did not slow progression of diabetic nephropathy.

In patients with severe CRI, a continuous intravenous infusion of bumetanide is more effective and less toxic than conventional intermittent bolus therapy. Continuous administration will probably be useful in patients with severe CRI who have not achieved an adequate natriuresis or who show evidence of drug toxicity with standard diuretic dosing regimens. A similar benefit may occur in selected diuretic-resistant patients with cardiac or hepatic disease, and studies in these patients seem warranted.

Furosemide and bumetanide share a number of characteristics including reduced natriuretic effects in azotemic patients. It has been presumed that this condition affects each drug equally. Previous studies, however, suggest dissimilar pathways of delivery to their sites of action. Though not rigorously tested, this potential disparity might cause them to differ when used in azotemia. We, therefore, assessed the pharmacokinetic and pharmacodynamic characteristics of intravenously administered furosemide and bumetanide in ten adult patients with stable, chronic renal insufficiency (mean creatinine clearance = 14.1 +/- 2.0 ml/min/1.73 m2) in a randomized, cross-over study during controlled sodium intake. Our goals were to assess differences in diuretic effectiveness and in so doing to determine the dose required to produce a maximal response. The mean diuretic doses of 172 and 4.3 mg for furosemide and bumetanide, respectively (ratio = 40:1) were sufficient to produce a maximum response. Despite similarities in maximal fractional excretion of sodium (18.2 +/- 2.6% with furosemide vs. 19.4 +/- 4.5% with bumetanide, P = 0.687) demonstrating an equal tubular responsiveness to both drugs, overall response as quantified by cumulative natriuresis in the initial eight hour period was 52% greater with furosemide (108 +/- 17 vs. 71 +/- 7 mEq; P = 0.042). The difference in total excreted sodium was accounted for by a preserved nonrenal clearance of bumetanide (113 +/- 12 compared to 53 +/- 5 ml/min for furosemide, P = 0.001) which resulted in relatively less bumetanide in serum available to be delivered into the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

The relationship of biomarkers with future progression of CKD is complex and depends in part on how CKD progression is defined. Biomarkers in the FGF-23 and VEGF-A pathways predicted patient progression independently of albuminuria levels in this patient cohort. Additional studies in other cohorts will help further validate this pilot study.