Original Investigation
Effect of intensive blood pressure control on the course of type 1 diabetic nephropathy

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Abstract

Diabetic nephropathy is the most common cause of end-stage renal disease in the United States. We undertook a study to assess the impact of assignment to different levels of blood pressure control on the course of type 1 diabetic nephropathy in patients receiving angiotensin-converting enzyme (ACE) inhibitor therapy. We also examined the long-term course of this well-characterized cohort of patients receiving ACE inhibitor therapy. One hundred twenty-nine patients with type 1 diabetes and diabetic nephropathy who had previously participated in the Angiotensin-Converting Enzyme Inhibition in Diabetic Nephropathy Study who had a serum creatinine level less than 4.0 mg/dL were randomly assigned to a mean arterial blood pressure (MAP) goal of 92 mm Hg or less (group I) or 100 to 107 mm Hg (group II). Patients received varying doses of ramipril as the primary therapeutic antihypertensive agent. All patients were followed for a minimum of 2 years. Outcome measures included iothalamate clearance, 24-hour creatinine clearance, creatinine clearance estimated by the Cockcroft and Gault formula, and urinary protein excretion. The average difference in MAP between groups was 6 mm Hg over the 24-month follow-up. The median iothalamate clearance in group I was 62 mL/min/1.73 m2 at baseline and 54 mL/min/1.73 m2 at the end of the study compared with a baseline of 64 mL/min/1.73 m2 and final 58 mL/min/1.73 m2 in group II. There were no statistically significant differences in the rate of decline in renal function between groups. There was a significant difference in follow-up total urinary protein excretion between group I (535 mg/24 h) and group II (1,723 mg/24 h; P = 0.02). Thirty-two percent of 126 patients achieved a final total protein excretion less than 500 mg/24 h. Patients from groups I and II had equivalent rates of adverse events. In patients with type 1 diabetes mellitus and diabetic nephropathy, the MAP goal should be 92 mm Hg or less for optimal renoprotection, if defined as including decreased proteinuria. With the combination of ACE inhibition and intensive blood pressure control, many patients can achieve regression or apparent remission of clinical evidence of diabetic nephropathy.

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Subjects and methods

This study is a prospective, randomized, clinical trial performed in 17 centers of the Collaborative Study Group. The study conforms to the recommendations for clinical trials, set out in the Declaration of Helsinki (Hong Kong revision, 1989) and was approved by the institutional review boards at each center. Before entering onto the study, all subjects were informed about the nature of, purpose of, and risks involved in the study and gave informed written consent.

Clinical management

At baseline of the present study, the observed MAP was similar between the randomized groups (Table 1). However, within 3 months of randomization, the distribution of MAP became significantly different between the two groups and remained so for the duration of the trial (Fig 1; P = 0.009).

. Follow-up mean arterial blood pressures in (○) group I and (▪) group II for baseline and each follow-up visit. Values represent medians for each group. Numbers below the figure represent the number of

Discussion

We conclude that the renal outcome of patients with type 1 diabetic nephropathy who are receiving ACE inhibitors is strongly influenced by the degree of blood pressure control achieved. The present study is the first to show that using an intent-to-treat protocol, random assignment to an MAP goal of 92 mm Hg or less leads to a better renal outcome than assignment to an MAP of 100 to 107 mm Hg, if defined as including a decrease in proteinuria. Patients who were able to keep their MAP controlled

Acknowledgements

Acknowledgment: The support and efforts of all the study coordinators and patients on this study made this work possible. The authors thank Neil Smith of Hoechst-Roussel Pharmaceuticals International for his unfailing encouragement and support.

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Supported in part by a grant from Hoechst-Roussel Pharmaceuticals International.

Address reprint requests to Julia Breyer Lewis, MD, Vanderbilt University School of Medicine, Division of Nephrology, S-3223 Medical Center North, Nashville, TN 37232-2372. E-mail: [email protected]

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