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Background Inflammation signaled by Janus kinases (JAKs) promotes progression of diabetic kidney disease (DKD). Baricitinib is an oral, reversible, selective inhibitor of JAK1 and JAK2. This study tested the efficacy of baricitinib versus placebo on albuminuria in adults with Type 2 diabetes at high risk for progressive DKD. Methods In this Phase 2, double-blind, dose-ranging study, participants were randomized 1:1:1:1:1 to receive placebo or baricitinib (0.75 mg daily; 0.75 mg twice daily; 1.5 mg daily; or 4 mg daily), for 24 weeks followed by 4–8 weeks of washout. Results Participants (N = 129) were 63±9.1 (mean±standard deviation) years of age, 27.1% (35/129) women and 11.6% (15/129) African-American race. Baseline hemoglobin A1c (HbA1c) was 7.3±1% and estimated glomerular filtration rate was 45.0±12.1 mL/min/1.73 m2 with first morning urine albumin–creatinine ratio (UACR) of 820 (407–1632) (median; interquartile range) mg/g. Baricitinib, 4 mg daily, decreased morning UACR by 41% at Week 24 compared with placebo (ratio to baseline 0.59, 95% confidence interval 0.38–0.93, P = 0.022). UACR was decreased at Weeks 12 and 24 and after 4–8 weeks of washout. Baricitinib 4 mg decreased inflammatory biomarkers over 24 weeks (urine C–X–C motif chemokine 10 and urine C–C motif ligand 2, plasma soluble tumor necrosis factor receptors 1 and 2, intercellular adhesion molecule 1 and serum amyloid A). The only adverse event rate that differed between groups was anemia at 32.0% (8/25) for baricitinib 4 mg daily versus 3.7% (1/27) for placebo. Conclusions Baricitinib decreased albuminuria in participants with Type 2 diabetes and DKD. Further research is required to determine if baricitinib reduces DKD progression.

BACKGROUND Diabetic nephropathy imposes a substantial cardiovascular and renal burden contributing to both morbidity and excess mortality. Progression of chronic kidney disease (CKD) in diabetes mellitus is variable, and few biomarkers are available to predict progression accurately. Identification of novel predictive biomarkers may inform clinical care and assist in the design of clinical trials. We hypothesized that urinary and plasma protein biomarkers predict CKD progression independently of the known clinical markers such as albuminuria and estimated glomerular filtration rate (eGFR) in diabetic nephropathy. METHODS We studied 67 US veterans with CKD due to type 2 diabetes mellitus and 20 age-matched controls (no CKD, hypertension or cardiovascular disease). After clinical evaluation and the collection of blood and urine specimens for 24 biomarkers, we followed subjects prospectively for the next 2-6 years. CKD progression was defined in three ways: (i) clinically by examining eGFR versus time plots for each individual (slope progression), (ii) progression to end-stage renal disease (ESRD) and (iii) a composite outcome of ESRD or death. RESULTS Among 17 urinary and 7 plasma biomarkers evaluated, the relationship of the biomarkers with outcome was as follows: (i) for progression identified by eGFR plots, urinary C-terminal fibroblast growth factor (FGF)-23 emerged to have the strongest primary association (adjusted odds ratio [aOR] 2.08, P = 0.008); (ii) for ESRD, plasma vascular endothelial growth factor (VEGF) had an association (aOR: 1.44, P = 0.027) and (iii) for the composite outcome of death and ESRD, plasma C-terminal FGF-23 also had a robust direct association (aOR: 3.07, P = 0.008). CONCLUSION 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.