Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations

Abstract

Administration of the chemotherapeutic agent cisplatin leads to acute kidney injury (AKI). Cisplatin-induced AKI (CIAKI) has a complex pathophysiological map, which has been linked to cellular uptake and efflux, apoptosis, vascular injury, oxidative and endoplasmic reticulum stress, and inflammation. Despite research efforts, pharmaceutical interventions, and clinical trials spanning over several decades, a consistent and stable pharmacological treatment option to reduce AKI in patients receiving cisplatin remains unavailable. This has been predominately linked to the incomplete understanding of CIAKI pathophysiology and molecular mechanisms involved. Herein, we detail the extensively known pathophysiology of cisplatin-induced nephrotoxicity that manifests and the variety of pharmacological and genetic alteration studies that target them.

Keywords: AKI; acute kidney injury; cisplatin; cisplatin-induced acute kidney injury; nephrotoxicity.

Figure 1

Pathophysiological map of the key molecular pathways demonstrated to play a role in the pathogenesis of cisplatin-induced acute kidney injury (AKI). The mechanisms associated with cisplatin-induced AKI (CIAKI) are complex, and the relationship between the key pathways remains unknown. However, it is believed that the detrimental nephrotoxic effect of cisplatin in renal tissue is due to platinum accumulation. Cisplatin accumulation triggers increased production of tumor necrosis factor alpha (TNF-α) [33,34] and reactive oxygen species (ROS), stimulating inflammation [35], oxidative stress [36], vascular injury [31], and apoptotic pathways [37]. The apoptotic mechanisms then promote renal tissue damage leading to the key clinical manifestation of nephrotoxicity (a reduction in glomerular filtration rate (GFR)) resulting in CIAKI. Abbreviations: GSH, glutathione; CAT, catalase; SOD, superoxide dismutase; TNF-α, tumor necrosis factor alpha; ROS, reactive oxygen species; ER stress, endoplasmic reticulum stress; and GFR, glomerular filtration rate. IL-1, Interleukin 1; MCP-1, monocyte chemoattractant protein 1; CXCL1, C-X-C Motif Chemokine Ligand 1; KIM-1, Kidney Injury Molecule 1; sCr, Serum Creatinine; BUN, Blood Urea Nitrogen; NGAL, Neutrophil gelatinase-associated lipocalin. Figure adapted from “Cisplatin nephrotoxicity: mechanisms and renoprotective strategies” by N. Pabla and Z. Dong, 2008, Kidney International, Volume 73, P994-1007, Copyright [2008] by the Elsevier.

Figure 2

Graphical representation of key molecules and pathways involved in cisplatin transportation initiating nephrotoxic effects. Key transporters responsible for cellular uptake of cisplatin from the blood into PTECs resulting in a much greater platinum concentration compared to the blood. The key interventions trialed to date and their effectiveness in targeting CIAKI are also illustrated. Diagram details the cellular processes involved in the cellular uptake [57,58,59,60,61,62,63,64], efflux [65,66], and metabolism of cisplatin into a highly reactive thiol (nephrotoxin) [67] and the treatment targeted to prevent them.

Figure 3

Cisplatin-induced acute kidney injury effects on the renin angiotensin system. A large focus has been on inhibition or genetic deletion of AT1 and AT2 receptors, both of which show amelioration in CIAKI [64,120,123,124,125]. Additionally, both ACE and Angiotensin II inhibition have also shown ameliorating qualities. Targeting the renin angiotensin system (RAS) system to prevent CIAKI is a promising pathway in potential treatments. Abbreviations: NO, nitric oxide; ONOO⁻, peroxynitrite; O₂⁻, superoxide; eNOS, endothelial nitric oxide synthase; ACE, angiotensin converting enzyme; GFR, glomerular filtration rate.

Figure 4

Apoptotic pathways involved in CIAKI. Cisplatin stimulation of ROS leads to cytochrome release and effector caspase activation in the Intrinsic/mitochondrial pathway (red) [54,94,154], ER stress is involved in two mechanisms, through stimulation of PERK to promote ER stress induced caspase-3 activation (blue) [155]. Extrinsic apoptosis is caused by TNFR1 signaling caspase-8 (green).

Figure 5

Key cytokines and chemokines upregulated or downregulated following cisplatin treatment. This diagram represents the therapeutic avenues published targeting inflammatory pathways and the targeted cytokines and chemokines involved [32,34,45,46,49,53,175,176,177].

Figure 6

Functional expression of toll-like receptors in healthy human intrarenal cells and tissue. Basal expression of TLR1–10 has been reported in healthy human tissue [179]. However, determination of renal cell specific TLR expression remains limited. To date, TLR expression has been reported in intrarenal cells and structures, including: CDEC (TLR3 [199]), DTECs (TLR4 [200]), glomeruli (TLR2 [201]; TLR3 [199,202]; TLR7–9 [202,203]), mesangial cells (TLR1–4 [199,201]), peritubular arteriole (TLR2 [201] and TLR3 [199]) and capillary (TLR2 [201,204] and TLR4 [204]) endothelial cells, podocytes (TLR1–6 and 10 [205,206]), PTECs (TLR1–5 [204,207,208,209,210] and 9 [211]), tubules * (TLR2–4 [201,202,203,212] and TLR7–9 [203,213]), VSMCs (TLR3 [199]) and renal cortex (TLR2 [201] and TLR4 [212]), medulla (TLR2 [201] and TLR4 [212]), and pelvis (TLR4 [212]). * Tubules refers to literature that does not state the specific tubule on which TLR expression was reported. Abbreviations: collecting duct epithelial cell, CDEC; DTEC, distal tubule epithelial cell; PTEC, proximal tubule epithelial cell; toll-like receptor, TLR; vascular smooth muscle cell, VSMC.