A Re-Evaluation: Acute Kidney Injury (AKI) Patterns are Similar in Human Autopsy Kidneys and Rat Kidneys Despite Differences in Renal Tubule Structure

Document Type

Conference Proceeding

Publication Date

3-2020

Publication Title

Laboratory Investigation

Abstract

Background: Preclinical pharmaceutical studies have shown beneficial effects on rat AKI; however, based on several recent reviews, the studies have failed to show effects that benefit human AKI. While there are variations in the design of each study reviewed that may contribute to the discrepancy, differences in kidney structures and disease progression scenarios between human (short S3 renal tubule segment and AKI in aging kidneys that often occurs with diabetic/hypertensive damage) and animals (long S3 renal tubule segment and AKI models induced in rats that have non-injured kidneys) can also be two main possibilities to explain the outcome discrepancy. Using a specific injury marker of proximal tubules called kidney injury molecule-1 (KIM-1), this study compares AKI patterns between full sections of human autopsy kidneys and rat kidneys allowing for identification of kidney structural related differences in the AKI patterns. Despite the presence of renal autolysis in autopsy specimen KIM-1 has proven reliable for identifying AKI. Design: In the animal model, 28 rats underwent induced renal ischemia (resulting in varying levels of AKI, from mild to moderate to severe acute tubular injury). Their serum creatinine levels (sCr) were measured; and the kidneys were then stained for KIM-1 to allow for AKI evaluation. In humans, 52 autopsy cases from adult patients were retrospectively reviewed for sCr and KIM-1 expression in full kidney sections. Results: All control rat kidneys showed an absence of stains for KIM-1. In ischemic kidneys, with mild to severe ATI, there was dominant upregulation of KIM-1 expression in the S3 segment of ischemic rat models, followed by slightly less upregulation in the S2 segment and mild upregulation in the S1 segment of rat kidneys. In human autopsy kidneys, 19 normal kidneys stained negatively for KIM-1, and served as controls. Thirty-three cases stained positively for KIM-1, with dominant KIM-1 upregulation in the S3 segment, followed by less upregulation in the S2 segment, and the least upregulation in the S1 segment. KIM-1 staining scores (0, 1+, 2+ and 3+ intensity) were directly correlated with sCr in both the animal ischemic model and in the human autopsy kidney cases. Conclusions: Despite the structural difference in the S3 segment of human and rat renal tubules, our data indicates that the AKI patterns are similar between the human and rat models. This finding implies that the difference in structure may not be the main reason for the non-reproducibility of beneficial effects o

Volume

100

Issue

Suppl 1

First Page

6

Comments

United States and Canadian Academy of Pathology (USCAP) 109th Annual Meeting, February 29 - March 5, 2020, Los Angeles, CA

Last Page

6

DOI

10.1038/s41374-020-0378-7

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