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

Yang Dong,Yiyun Wang,Qunzi Zhang,Niansong Wang,Teng Chen,Rui Xue,Jiejun Wen,Jianyong Yin,Rui Wu,Ying Fan,Shiqi Li,Li He

doi:10.3389/fphys.2019.00153

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.

Highlights

Acute kidney injury is a common syndrome that occurs in approximately 5% of hospitalizations and is often associated with various short- and long-term complications (Uchino et al, 2005)
We found a positive association between sNGAL/urinary neutrophil gelatinaseassociated lipocalin (uNGAL) level and tubulointerstitial fibrosis by histological quantification in unilateral ischemia-reperfusion (UIRI) mice with AKIto-chronic kidney disease (CKD) progression (r = 0.87, 0.93, P < 0.01) (Figure 9B)
Our data suggested that acute kidney injury (AKI) severity and the subsequent AKI-to-CKD progression are dependent on ischemia duration in this model, which is in accordance with previous studies showing that, multiple clinical factors such as medical condition, advanced age and genetic diversity play a role, AKI severity seems to be the most significant risk factor for poor long-term outcome (Ishani et al, 2011; Chawla et al, 2011, 2014; Chawla and Kimmel, 2012)

Summary

Introduction

Acute kidney injury is a common syndrome that occurs in approximately 5% of hospitalizations and is often associated with various short- and long-term complications (Uchino et al, 2005). IRI may be followed by a repair process that restores the kidney to normal morphology and function if the injury is mild but may lead to permanent damage, progressive fibrosis and CKD in cases of severe injury (Basile et al, 2012; Lameire et al, 2013). The duration of renal ischemia has been well recognized in clinical studies to be associated with the severity and progression of AKI. Many studies have used different ischemia/reperfusion (I/R) models to mimic human AKI and study the mechanism of progression from AKI to CKD. Few studies have provided a side-by-side comparison of AKI prognosis and AKIto-CKD progression among different I/R animal models with variable ischemia duration and episodes (Ishani et al, 2011; Chawla et al, 2011; Thakar et al, 2011)

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Discussion

Conclusion