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

Abstract

SummaryBackgroundRenal tubular epithelial cells (RTECs) cause maladaptive repair and perpetuate renal fibrosis.AimTo 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.MethodsWe 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).ResultsWe 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.ConclusionAlmost 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.

APASL clinical practice guidelines on the management of acute kidney injury in acute-on-chronic liver failure

“…These patients have a higher prevalence of structural AKI and active sediment on urine microscopy suggesting tubular injury. In critically ill patients with cirrhosis, non-resolution of AKI at day 7 was associated with worse outcomes and higher progression to chronic kidney disease (CKD) [19]. The proximal tubules are the prime victim of injury in inflammation-related AKI.…”

“…In a prospective study, a higher prevalence of tubule epithelial cells and granular casts (fine and coarse) was observed in patients with ACLF compared to decompensated cirrhosis. The tubule epithelial cells drive tubulointerstitial inflammation and maladaptive repair, leading to renal fibrosis secondary to failure of mitochondrial repair [19]. Patients with non-resolution also showed predominance of macrophage and monocyte infiltration on kidney biopsies.…”

“…In the context of critically ill patients with inflammation or infection-driven AKI, the incidence of progression to CKD was observed in almost 50%. The presence and persistence of renal tubule epithelial cells and/or granular casts at enrollment and day 7 were independent predictors of CKD development [17,19]. Patients who failed to recover at day 7 had significant elevation in the tubular and endothelial injury markers and higher levels of monocyte-chemoattractant protein-1 (MCP-1) and defective function of the mitochondrial genes in the renal tubule epithelial cells [19].…”

“…The presence and persistence of renal tubule epithelial cells and/or granular casts at enrollment and day 7 were independent predictors of CKD development [17,19]. Patients who failed to recover at day 7 had significant elevation in the tubular and endothelial injury markers and higher levels of monocyte-chemoattractant protein-1 (MCP-1) and defective function of the mitochondrial genes in the renal tubule epithelial cells [19]. Persistent AKI or worsening of AKI are more likely in patients with higher stages of AKI (AKI stage 2 or 3); thus, they are more likely to progress to CKD.…”

“…NGAL had the best accuracy for the ATN diagnosis, along with urine IL-18, albumin, trefoil-factor-3 (TFF-3), and glutathione-S-transferase-π (GST-π) [77]. In critically ill patients with cirrhosis, urine NGAL predicted the need for RRT, non-response to terlipressin, non-resolution of AKI at day7, and the development of de-novo CKD [19]. In another study of 162 patients with decompensated cirrhosis and AKI, urine NGAL could determine ATN and non-response to terlipressin in HRS-AKI and was an independent predictor of in-hospital mortality [78].…”