Abstract
BackgroundWe tested minocycline as an anti-proteinuric adjunct to renin-angiotensin-aldosterone system inhibitors (RAASi) in diabetic nephropathy (DN) and measured urinary biomarkers to evaluate minocycline’s biological effects.MethodsDesign: Prospective, single center, randomized, placebo-controlled, intention-to-treat pilot trial. Inclusion. Type 2 diabetes/DN; Baseline creatinine clearance > 30 mL/min; proteinuria ≥ 1.0 g/day; Age ≥30 years; BP <150/95 mm Hg; intolerant of/at maximum RAASi dose. Protocol. 3-wk screening; Baseline randomization; Urine and blood measures at months 1, 2, 4, and Month 6 study completion. Urine interleukin-6 (IL-6) and osteoprotegerin were measured in a subset. Primary outcome. Natural log of urine protein/creatinine (ln U P:Cr) ratio at Month 6 vs Baseline.Results30 patients completed the study. The 15% decline in U P: Cr in minocycline patients (6 month P:Cr ÷ Baseline P:Cr, 0.85 vs. 0.92) was not significant (p = 0.27). Creatinine clearance did not differ in the 2 groups. Urine IL-6:Cr (p = 0.03) and osteoprotegerin/Cr (p = 0.046) decrements were significant. Minocycline modified the relationship between urine IL-6 and proteinuria, suggesting a protective biological effect.ConclusionsAlthough the decline in U P:Cr in minocycline patients was not statistically significant, the significant differences in urine IL-6 and osteoprotegerin suggest that minocycline may confer cytoprotection in patients with DN, providing a rationale for further study.Trial RegistrationClinicaltrials.gov NCT01779089
Highlights
Diabetic nephropathy (DN) remains a major source of mortality and morbidity in patients with Type 2 diabetes (DM)
Urine interleukin-6 (IL-6) and osteoprotegerin were measured in a subset
Creatinine clearance did not differ in the 2 groups
Summary
Diabetic nephropathy (DN) remains a major source of mortality and morbidity in patients with Type 2 diabetes (DM). Combining drugs that inhibit multiple targets in the renin-angiotensin-aldosterone system induce unacceptably high rates of acute kidney injury and hyperkalemia [1,2,3]. Recent studies testing drugs with treatment targets outside of the renin-angiotensin-aldosterone system, including bardoxolone, ruboxistaurin, pimagedine, monoclonal anti-connective tissue growth factor antibody, and sulodexide either failed to demonstrate benefit, were unsafe, or were abandoned for economic reasons[4,5,6,7,8]. A safe and inexpensive medication whose therapeutic target lies outside of the renin-angiotensin-aldosterone pathway would be useful as adjunctive therapy for DN. We tested minocycline as an anti-proteinuric adjunct to renin-angiotensin-aldosterone system inhibitors (RAASi) in diabetic nephropathy (DN) and measured urinary biomarkers to evaluate minocycline’s biological effects.
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