Effects of Minocycline on Urine Albumin, Interleukin-6, and Osteoprotegerin in Patients with Diabetic Nephropathy: A Randomized Controlled Pilot Trial

<div><p>Background</p><p>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.</p><p>Methods</p><p><b>Design</b>: Prospective, single center, randomized, placebo-controlled, intention-to-treat pilot trial. <b>Inclusion</b>. 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. <b>Protocol</b>. 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. <b>Primary outcome</b>. Natural log of urine protein/creatinine (ln U P:Cr) ratio at Month 6 vs Baseline.</p><p>Results</p><p>30 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.</p><p>Conclusions</p><p>Although 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.</p><p>Trial Registration</p><p>Clinicaltrials.gov <a href="https://www.clinicaltrials.gov/ct2/show/NCT01779089" target="_blank">NCT01779089</a></p></div

Enrollment of subjects.

<p>Enrollment of subjects.</p

Spaghetti plots of the urine IL6: creatinine measurements of each patient in the study from baseline to 6 months (end of trial).

<p>Baseline urine values were not available for 3 subjects.</p

% change in 24-hour urine Il-6: creatinine measurements from baseline to 6 months in placebo and minocycline groups.

<p>The edges of the boxes represent the 25% and 75% percentiles, the middle lines represents the median, and the whiskers extend to the minimum and maximum values. The %change in urine IL-6: creatinine was significantly lower in the minocycline group vs. the placebo group (mean % change -0.13 vs. 0.60, P = 0.03).</p

Spaghetti plots of the urine protein: creatinine measurements of each patient in the study over the course of the trial.

<p>Spaghetti plots of the urine protein: creatinine measurements of each patient in the study over the course of the trial.</p

Percent change in 24-hour urine protein/creatinine measurements from baseline to 6 months in placebo and minocycline groups.

<p>The edges of the boxes represent the 25% and 75% percentiles, the middle lines represents the median, and the whiskers extend to the minimum and maximum values. The primary outcome, ln (6Month P:Cr/baseline P:Cr), was not significantly different between the groups (p = 0.27).</p

Relationship between changes in urine IL-6 and proteinuria in minocycline and placebo patients.

<p>The slope of the regression curve for placebo-treated patients is not different from zero (p> 0.05). The slope of the regression curve for minocycline-treated patients is different from zero (p< 0.05).</p

Ratio of proteinuria in minocycline vs. placebo group, adjusted for baseline proteinuria.^*

<p>Ratio of proteinuria in minocycline vs. placebo group, adjusted for baseline proteinuria.^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0152357#t003fn001" target="_blank">*</a>}</p

Adverse and Serious Events (AE, SAE).

<p>Adverse and Serious Events (AE, SAE).</p

Subject characteristics at 6 months.

<p>Subject characteristics at 6 months.</p