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Review
. 2021 Jul;32(7):1559-1567.
doi: 10.1681/ASN.2020101455. Epub 2021 May 28.

Potential Therapeutic Targets for Cisplatin-Induced Kidney Injury: Lessons from Other Models of AKI and Fibrosis

Sophia M Sears  1 , Leah J Siskind  1   2
Affiliations
Review

Potential Therapeutic Targets for Cisplatin-Induced Kidney Injury: Lessons from Other Models of AKI and Fibrosis

Sophia M Sears et al. J Am Soc Nephrol. 2021 Jul.

Abstract

The effectiveness of cisplatin, a mainstay in the treatment of many solid organ cancers, is hindered by dose-limiting nephrotoxicity. Cisplatin causes AKI in 30% of patients. Patients who do not develop AKI by clinical standards during treatment are still at risk for long-term decline in kidney function and the development of CKD. The connection between AKI and CKD has become increasingly studied, with renal fibrosis a hallmark of CKD development. To prevent both the short- and long-term effects of cisplatin, researchers must use models that reflect both types of pathology. Although a lot is known about cisplatin-induced AKI, very little is known about the mechanisms by which repeated low levels of cisplatin lead to fibrosis development. In this review, strategies used in various rodent models to prevent kidney injury, its progression to fibrosis, or both, are examined to gain mechanistic insights and identify potential therapeutic targets for cisplatin-induced kidney pathologies. Reviewing the results from these models highlights the diverse and highly complex role of cell death, cell senescence, endoplasmic reticulum stress, autophagy, and immune cell activation in acute and chronic kidney injuries. The use of several models of kidney injury is needed for development of agents that will prevent all aspects of cisplatin-induced kidney injury.

Keywords: acute kidney injury; chronic kidney disease; cisplatin; fibrosis.

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Figures

Figure 1.
Figure 1.
Mechanisms of cisplatin-induced AKI after a single high dose (20–30 mg/kg) of cisplatin. Pointed arrow heads denote promotion of process, solid block lines indicate inhibition of process. Supporting references: 19, 20, 31, 37, 38, 45, 46, and 58-60.
Figure 2.
Figure 2.
Mechanisms of cisplatin-induced fibrosis after repeated low dose (7–9 mg/kg) cisplatin treatment. Solid line arrows indicate relationships directly examined in the literature. Dotted line arrows represent relationships studied in other models of renal fibrosis that we propose may also be occurring in the RLDC model. Supporting references: 25-30, 39-42, 47-49, and 61-67.
Figure 3.
Figure 3.
Immune cell involvement in cisplatin-induced AKI and renal fibrosis, ointed arrow heads denote promotion of process, solid block lines indicate inhibition of process, lines with no arrow ending denote no effect on process. Supporting references: 59-67. CDDP, cisplatin.
See this image and copyright information in PMC

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