Design of Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor for Treatment of Diabetic Nephropathy (VA NEPHRON-D)

• Published in: Clinical journal of the American Society of Nephrology Vol. 4; no. 2; pp. 361 - 368
• Main Authors: Fried, Linda F, Duckworth, William, Zhang, Jane Hongyuan, O'Connor, Theresa, Brophy, Mary, Emanuele, Nicholas, Huang, Grant D, McCullough, Peter A, Palevsky, Paul M, Seliger, Stephen, Warren, Stuart R, Peduzzi, Peter
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01.02.2009
• Subjects: Angiotensin II Type 1 Receptor Blockers - adverse effects; Angiotensin II Type 1 Receptor Blockers - therapeutic use; Angiotensin-Converting Enzyme Inhibitors - adverse effects; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Diabetes and the Kidney; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - mortality; Diabetes Mellitus, Type 2 - physiopathology; Diabetic Nephropathies - drug therapy; Diabetic Nephropathies - etiology; Diabetic Nephropathies - mortality; Diabetic Nephropathies - physiopathology; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Glomerular Filtration Rate - drug effects; Humans; Hyperkalemia - chemically induced; Kidney Failure, Chronic - etiology; Kidney Failure, Chronic - mortality; Kidney Failure, Chronic - physiopathology; Kidney Failure, Chronic - prevention & control; Kidney Transplantation; Lisinopril - adverse effects; Lisinopril - therapeutic use; Losartan - adverse effects; Losartan - therapeutic use; Prospective Studies; Proteinuria - drug therapy; Proteinuria - etiology; Proteinuria - mortality; Proteinuria - physiopathology; Renal Dialysis; Research Design; Time Factors; Treatment Outcome; United States; United States Department of Veterans Affairs; United States
• ISSN: 1555-9041; 1555-905X
• DOI: 10.2215/CJN.03350708

Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can slow the progression of diabetic nephropathy. Even with ACEI or ARB treatment, the proportion of patients who progress to end-stage renal disease (ESRD) remains high. Interventions that achieve more complete blockade of the renin-angiotensin system, such as combination ACEI and ARB, might be beneficial. This approach may decrease progression of nondiabetic kidney disease. In diabetic nephropathy, combination therapy decreases proteinuria, but its effect in slowing progression is unknown. In addition, the potential for hyperkalemia may limit the utility of combined therapy in this population. VA NEPHRON-D is a randomized, double-blind, multicenter clinical trial to assess the effect of combination losartan and lisinopril, compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria. The primary endpoints are time to (1) reduction in estimated GFR (eGFR) of > 50% (if baseline < 60 ml/min/1.73 m(2)); (2) reduction in eGFR of 30 ml/min/1.73 m(2) (if baseline > or = 60 ml/min/1.73 m(2)); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m(2)); or (4) death. The secondary endpoint is time to change in eGFR or ESRD. Tertiary endpoints are cardiovascular events, slope of change in eGFR, and change in albuminuria at 1 yr. Specific safety endpoints are serious hyperkalemia (potassium > 6 mEq/L, requiring admission, emergency room visit, or dialysis), all-cause mortality, and other serious adverse events. This paper discusses the design and key methodological issues that arose during the planning of the study.