Abstract

Background:

Infections with multidrug-resistant organisms (MDR) are a common cause of organ failures and increased fatality in patients with cirrhosis. Sepsis is associated with increased oxidative stress with widespread endothelial, cellular injury and acute deficiency of vitamin C. Polymyxins used for MDR infections have increased incidence of nephrotoxicity. We aimed to evaluate the impact of vitamin C on outcomes of sepsis-associated acute kidney injury (SA-AKI).

Methods:

Patients with nosocomial acquisition or proven MDR infections underwent open-label randomization into two groups. Group 1-received iv vitamin C (25 mg/kg or 1.5 gram maximum every 6 hourly) for 5 days along with polymyxin antibiotics while group 2 (SMT) received iv antibiotics alone. Primary end-point was AKI progression at day 5. Intention-to-treat analysis was performed. In a subset of patients (n = 20), we performed ELISA of plasma levels of vitamin-c, syndecan-1- a marker of endothelial glycocalyx degradation, von willebrand factor (vWF), and ADAMTS13 (a disintegrin and metalloproteinase thrombospondin motif) as markers of endothelial injury and microcirculation.

Results:

A total of 100 patients, 50 in each group, with mean age 48.7±9.8 years, lactate 2.67±2.27 µmol/L, SOFA scores 11.1±3.6, 91% males, 60% alcohol-related were randomized. The KDIGO stage at enrolment was comparable 1:2:3 (68%:14%:18% vs. 64%:16%:20%; p=0.91). Pneumonia was the commonest infection in 61%. Culture-proven MDR infections were seen in 51% patients, commonest being Acinetobacter baumannii (45.1%) and Klebsiella pneumoniae (27.4%). On intention-to-treat analysis, at day 5, AKI progression was significantly lower in Vit-C+SMT (18% vs. 54%; p<0.001) with higher reversal of shock (56% vs. 22%; p=0.001), lactate clearance at 12 hrs. (60% vs. 32%; p=0.009) and 24 hrs. (56% vs. 34%; p=0.044), reduction in SOFA score at 48 hrs. (52% vs. 26%; p=0.013), and higher AKI recovery at day 14 compared to SMT (61.2% vs. 32%; p<0.001) respectively. The 28-day mortality, need of dialysis, duration of ICU stay and mechanical ventilation were not different. There were no major adverse events requiring Vitamin C discontinuation, 20% patients developed thrombocytopenia. At day 5, a significant reduction in ADAMTS13, syndecan-1 and elevation in vWF levels and Vitamin-c levels were observed in Vit-C+SMT vs. SMT group.(Figure)

Conclusion:

Vitamin C improves outcomes of SA-AKI in cirrhosis patients with MDR infections. Reduction in endothelial injury, stabilization of endothelial glycocalyx with improvement in microcirculation, and possible reduction in nephrotoxicity of polymyxin antibiotics could be potential mechanisms of the observed benefit.