Non‐resolution of acute kidney injury in the first week portends the development of chronic kidney disease in critically ill patients with cirrhosis

Abstract

BACKGROUND: Renal tubular epithelial cells (RTECs) cause maladaptive repair and perpetuate renal fibrosis. AIM: To evaluate urinary neutrophil gelatinase-associated lipocalin (NGAL) and RTEC as risk factors for non-resolution of acute kidney injury (AKI-NR) at day seven and chronic kidney disease (CKD) in critically ill patients with cirrhosis. METHODS: We performed urinary NGAL and microscopy at enrolment and day 7 in all patients. We assessed 17 renal injury, endothelial injury and repair markers, genes for mitochondrial biogenesis by qRT-PCR in RTEC, and post-mortem renal biopsies for understanding mechanisms of AKI non-resolution (n = 30). RESULTS: We enrolled 310 patients, aged 48.1 ± 11.6 years, 87% male, 90% alcoholic. Of these, 36% had RTEC at enrolment, and 53% had AKI-NR on day 7. On mean follow-up of 136 days (range 43-365), 150 (48.3%) developed CKD. The presence of RTEC or granular casts, NGAL and AKI-NR were independent predictors of CKD development on competing risk analysis. Higher MCP-1, renal endothelial injury, decrease in tubular repair markers and failure of mitochondrial biogenesis in RTEC were seen in patients with AKI-NR compared with AKI-R (p < 0.05). Renal biopsies showed infiltration with monocyte-macrophage, increased α-SMA, and tubulointerstitial fibrosis. CONCLUSION: Almost two-thirds of critically ill patients with cirrhosis have AKI, which resolves in only one-half at day seven and predicts the development of CKD. Higher NGAL, RTEC, or granular casts were independent predictors of AKI-NR and CKD development. Enhanced tubular and endothelial injury, decreased repair, monocyte-macrophage infiltration and mitochondrial dysfunction in RTEC are associated with AKI non-resolution and risk of renal fibrosis.