Ischemic Duration and Frequency Determines AKI-to-CKD Progression Monitored by Dynamic Changes of Tubular Biomarkers in IRI Mice

Abstract

Ischemia reperfusion injury (IRI) is one of the most common causes of acute kidney injury (AKI). However, the pathogenesis and biomarkers predicting the progression of IRI-induced AKI to chronic kidney disease (CKD) remain unclear. A side-by-side comparison between different IRI animal models with variable ischemic duration and episodes was performed. The dynamic changes of KIM-1 and NGAL continuously from AKI to CKD phases were studied as well. Short-term duration of ischemia induced mild renal tubule-interstitial injury which was completely reversed at acute phase of kidney injury, while long-term duration of ischemia caused severe tubular damage, cell apoptosis and inflammatory infiltration at early disease stage, leading to permanent chronic kidney fibrosis at the late stage. Repeated attacks of moderate IRI accelerated the progression of AKI to CKD. Different from serum and urine levels of KIM-1 that increased at acute phase of IRI then declined gradually in chronic phase, NGAL increased continuously during AKI-to-CKD transition. Severity and frequency of ischemia injury determines the progression and outcome of ischemia-induced AKI. Inflammation, apoptosis and fibrogenesis likely participate in the progression of AKI to CKD. Both KIM-1 and NGAL enable noninvasive and early detection of AKI, but NGAL is associated better with the process of AKI-to-CKD progression.

Sitagliptin ameliorates renal tubular injury in diabetic kidney disease via STAT3‐dependent mitochondrial homeostasis through SDF‐1α/CXCR4 pathway

“…The mesangial matrix index was calculated and graded as follows: 0 represents no lesion; 1 + represents sclerosis of <25% of the glomerulus; and 2+, 3+, and 4+ represent sclerosis of >25‐50, >50‐75, and >75% of the glomerulus, respectively 33 . Tubular injury was defined and calculated as follows: score 0: no tubular injury; score 1: < 10% of tubules injured; score 2:10%‐25% of tubules injured; score 3:25%‐50% of tubules injured; score 4:50%‐74% of tubules injured; score 5: > 75% of tubules injured, as previously described 36,37 . For IHC staining, sections were treated with diaminobenzidine or NovaRed substrate (DAKO Labs, K3468), followed by counterstaining with Mayer hematoxylin and examination.…”

The sympathetic nervous system in acute kidney injury

“…64 A single-centre study in 30 paediatric patients (1-6 years old) who underwent cardiac surgery reported lower GFR and higher AKI incidence based on serum creatinine measurements obtained 5 minutes and 2 hours after weaning from cardiopulmonary bypass. [66][67][68] Their use in studies on the role of sympathetic activation may improve translatability of experimental data. In contrast to experimental renal IR studies where conditions can be well standardized, the effects of sympatholytics may have been blurred by the complexity of clinical scenarios and factors such as patient age, genetic diversity, associated chronic diseases and diverse co-medications.…”

“…3 Currently, reverse translational approaches are taken to better match animal models of renal IR to clinical situations that cause AKI. [66][67][68] Their use in studies on the role of sympathetic activation may improve translatability of experimental data.…”

Potent Therapy and Transcriptional Profile of Combined Erythropoietin Derived Peptide CHBP and Caspase-3 siRNA against Kidney Ischemia/Reperfusion Injury in mice

“…Renal ischemia/reperfusion (IR) injury is a major cause of AKI, characterized by apoptosis, in ammation and immune responses associated damage (Bellomo et al, 2012;Dong et al, 2019). Recently, the innate repair mechanism in AKI has attracted great attention, which is highlighted by an innate repair receptor, a heterodimer of erythropoietin (EPO) receptor and β common receptor (EPOR/βcR) (Brines and Cerami 2012).…”