A Multicentre Study of Acute Kidney Injury in Severe Sepsis and Septic Shock: Association with Inflammatory Phenotype and HLA Genotype

Didier Payen,Marc Busson,Fabienne Fieux,Valérie Faivre,Elie Azoulay,Dominique Charron,Pascale Loiseau,Matthieu Legrand,Anne-Claire Lukaszewicz,Bruno Megarbane,Etienne Gayat,Emmanuel A Burdmann

doi:10.1371/journal.pone.0035838

Abstract

BackgroundTo investigate the association between severity of acute kidney injury (AKI) and outcome, systemic inflammatory phenotype and HLA genotype in severe sepsis.Methodology/Principal FindingsProspective multicenter observational study done in 4 intensive care units in two university hospitals. Severe sepsis and septic shock patients with at least 2 organ failures based on the SOFA score were classified: 1) "no AKI", 2) "mild AKI" (grouping stage 1 and 2 of AKIN score) and 3) "severe AKI" (stage 3 of AKIN score). Sequential measurements: The vasopressor dependency index (VDI; dose and types of drugs) to evaluate the association between hemodynamic status and the development of early AKI; plasma levels of IL-10, macrophage migration inhibitory factor (MIF), IL-6 and HLA-DR monocyte expression. Genotyping of the 13 HLA-DRB1 alleles with deduction of presence of HLA-DRB3, -DRB4 and -DRB5 genes. We used multivariate analysis with competitive risk model to study associations. Overall, 176 study patients (146 with septic shock) were classified from AKIN score as "no AKI" (n = 43), "mild AKI" (n = 74) or "severe AKI" (n = 59). The VDI did not differ between groups of AKI. After adjustment, "mild and severe AKI" were an independent risk factor for mortality (HR 2.42 95%CI[1.01-5.83], p = 0.048 and HR 1.99 95%CI[1.30-3.03], p = 0.001 respectively). "Severe AKI" had higher levels of plasma IL-10, MIF and IL-6 compared to “no AKI” and mild AKI (p<0.05 for each), with no difference in mHLA-DR at day 0. HLA-DRB genotyping showed a significantly lower proportion of 4 HLA-DRB alleles among patients requiring renal replacement therapy (RRT) (58%) than in patients with severe AKI who did not receive RRT (84%) (p = 0.004).ConclusionsAKI severity is independently associated with mortality and plasma IL-10, MIF or IL-6 levels. Presence of 4 alleles of HLA-DRB in severe AKI patients seems associated with a lower need of RRT.

Highlights

Acute kidney injury (AKI) is common in intensive care patients and associated with a worse prognosis [1,2,3]
acute kidney injury (AKI) severity is independently associated with mortality and plasma IL-10, MIF or IL-6 levels
Presence of 4 alleles of HLA-DRB in severe AKI patients seems associated with a lower need of renal replacement therapy (RRT)

Summary

Introduction

Acute kidney injury (AKI) is common in intensive care patients and associated with a worse prognosis [1,2,3]. Several arguments challenge this view: not all septic shock patients develop AKI despite similar hypotension and hemodynamic resuscitation; fresh human renal biopsies after death fail to show important ischemic lesions; biopsies show frequent microvessel thrombosis, infiltration by immune cells, and apoptosis [6]; the recently introduced biomarker neutrophil gelatinase-associated lipocalin (NGAL) a metallo-protein from neutrophils, is a good predictor of severe AKI [7] with a large lipocalin gene expression during post-ischemic reperfusion [8] All of these observations suggest an important role of ‘‘renal immune toxicity.’’ Among these non hemodynamic factors, the intensity of the systemic inflammatory response and genetic factors are reasonable candidates during severe sepsis. To investigate the association between severity of acute kidney injury (AKI) and outcome, systemic inflammatory phenotype and HLA genotype in severe sepsis

Methods

Results

Discussion

Conclusion