# Serial Combination of Toxic and Ischemic Renal Damages Causes Subsequent Chronic, Irreversible, and Progressive Renal Disease in Rats

## TL;DR

Repeated kidney injuries in rats lead to chronic kidney disease with features like fibrosis and albuminuria, challenging the role of fibrosis in kidney dysfunction.

## Contribution

A novel rat model of serial acute kidney injuries leading to chronic kidney disease is developed and compared to traditional CKD models.

## Key findings

- Serial acute kidney injuries in rats lead to progressive fibrosis and albuminuria characteristic of CKD.
- Biomarkers NGAL, KIM-1, and RBP4 show distinct temporal patterns of renal injury.
- Interstitial fibrosis increases while glomerular filtration remains stable, challenging the traditional view of fibrosis as the main driver of dysfunction.

## Abstract

Chronic kidney disease (CKD) poses a global burden affecting over 10% of the adult population worldwide. Acute kidney injury (AKI) is an important cause of CKD, especially following severe and repeated episodes. However, the processes underpinning progressive and chronic renal deterioration after AKI are only incompletely understood. Thus, models reproducing this scenario are needed to study the pathophysiological mechanisms involved and identify biomarkers and molecular targets for diagnostic and therapeutic purposes. In this study, we developed a rat model of 3 serial AKIs leading to CKD, in which renal function, kidney structure and fibrosis, and urinary injury biomarkers were studied over a period of 9 months, alongside a traditional model of CKD caused by renal mass reduction. Our results show that consecutive AKIs eventually develop key features of CKD including progressive fibrosis and albuminuria. Renal injury biomarkers neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule 1 (KIM-1), and retinol binding protein 4 (RBP4) show distinct evolution patterns suggestive of specific but undetermined damages with different time courses. The chronic evolution of renal tissue degeneration and dysfunction following serial AKIs closely resembles those observed after extensive renal mass reduction, which indicates chronic degeneration. Finally, a clear dissociation in the evolution of interstitial fibrosis (progressively increasing) and of glomerular filtration (mainly stable) was observed in both models. This questions the consuetudinary paradigm ascribing an etiological role to fibrosis in progressive renal dysfunction.