Acute kidney injury: pathogenesis and therapeutic interventions

Abstract

Acute kidney injury (AKI) is a prevalent clinical condition that is associated with unacceptably high morbidity and mortality, as well as the development of chronic kidney disease (CKD). The pathogenesis of AKI is highly complex and heterogeneous, primarily attributed to metabolic disturbances arising from the disease itself and the administration of medications related to treatment. In recent years, AKI in cancer patients is highly concerned. The emergence of AKI caused injuries and dysfunction of remote organs but also enhanced the health-care costs. It's essential for early recognition of AKI by biomarker or prediction models and further, take a timely intervention. This review aims to provide the pathophysiology of AKI covering the intricate mechanisms underpinning AKI in the dynamic context of the clinical setting, the tailored role of inflammation and ischemia, and the cellular and molecular crosstalk pathways involved. These events closely related to patients at high risk of AKI and underscore the characteristics that may make these patients more susceptible to injury. Furthermore, the diagnosis of AKI relies on clinical criteria, biomarkers, and imaging, but it should be distinguished from CKD. Finally, the review offers the therapeutic intervention in clinical practice and preclinical or clinical trials, focusing on the improvement of conventional therapy and advanced novel treatment strategies. Simultaneously, the challenge and future direction on early identifying renal impairment and performing renoprotection are also discussed, further supporting the novel discipline including onco-nephrology. The development of effective interventions that reduce nephrotoxicity is highly contingent upon a thorough understanding of the molecular pathophysiology of AKI.

Keywords: Acute kidney injury; Diagnosis; Pathophysiology; Risk; Therapy.

Fig. 1

The mechanism of tumor lysis syndrome (TLS). TLS led to electrolyte disturbance, such as hyperphosphatemia, hyperkalemia, and hyperuricemia. Further, hyperuricemia caused AKI by crystal-dependent injury or crystal-independent injury. Note: AKI: Acute kidney injury; NF-κB:Nuclear factor kappa-light-chain-enhancer of activated B cells. (figure was created in BioRender. Xu, X. (2025) https://BioRender.com/f8wgo85)

Fig. 2

The relationship between cisplatin and AKI. Cisplatin was absorbed and transported into the TEC by various of anion transporters resulting in accumulation of cisplatin. Then accumulated cisplatin metabolites into reactive thiol and induced AKI by diverse mechanisms such as DNA damage, ROS, mitochondria injury, immune environment disorders, and finally cell death. Note: AKI: Acute kidney injury; TEC: Tubule epithelial cells; MATE 1: Multidrug and toxin extrusion protein 1; OCT2: Organic cation transporter 2; MRPs: Multidrug resistance-associated protein; ATP7A: P-type copper transporting ATPases; OAT1/3: Organic anion transporter 1 and 3; CTR1: Copper transporter 1. (figure was created in BioRender. Xu, X. (2025) https://BioRender.com/f8wgo85)

Fig. 3

The molecular mechanism of cisplatin-induced AKI by various types of mitochondrial injury. It included mitochondrial dysfunction, fragmentation, fission, biogenesis, mitophagy, regulating mitochondrial metabolism disorder. Note: AKI: Acute kidney injury; ERRα: Estrogen-related receptor alpha; APE2: Apurinic/apyrimidinic endonuclease 2; MYH9: Myosin heavy-Chain 9; TFAM: Mitochondrial transcription factor A; ALDH2: Aldehyde dehydrogenase 2; PGC-1α: Peroxisome proliferator-activated receptor-gamma coactivator 1-alpha; TFEB: Transcription factor EB; DNA-PKcs: DNA-dependent protein kinase catalytic subunit; DRP1: Dynamin-related protein 1; PXR: Pregnane X receptor; AKR1B7: Aldo–keto reductase family 1, member B7; NRF2: Nuclear erythroid 2-related factor 2; Sirt3: Sirtuin 3; Sirt5: Sirtuin 5; PKM2:Pyruvate kinase M2. (figure was created in BioRender. Xu, X. (2025) https://BioRender.com/f8wgo85)

Fig. 4

The molecular mechanism of cisplatin-induced AKI by regulating immunity and inflammation. The immune cells including macrophage, dendric cells, T cells, neutrophil, Tregs were involved in AKI. Meanwhile, the cytokines and chemokines secreted from these immune cells also contribute to AKI after administrating cisplatin. Note: AKI: Acute kidney injury; DC: Dendritic cell; Treg: Regulatory T cells; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; GSK-3β: glycogen synthase kinase-3β; CXCL1: chemokine (C-X-C motif) ligand 1; CXCR2: CXC chemokine receptor 2; MyD88: Myeloid differentiation primary response 88; TLR4: Toll-like receptor 4; NLRP3: Nucleotide oligomerization domain-like receptor protein 3; IFN: interferon; IL: Interleukin; TNF-α: Tumor necrosis factor-α; MCP-1: Monocyte chemoattractant protein-1; Gal-3: Galectin 3; IDO1: Indoleamine 2,3-dioxygenase 1; KYN: Kynurenine; TLR: Toll-like receptor; iNOS: inducible nitric oxide synthase; JAML: junctional adhesion molecule-like protein; Mincle: Macrophage-inducible C-type lectin; NPY: Neuropeptide Y; Y1R: NPY receptor 1; SYK: spleen tyrosine kinase. (figure was created in BioRender. Xu, X. (2025) https://BioRender.com/f8wgo85)

Fig. 5

The molecular mechanism of cisplatin-induced AKI by ferroptosis. Cisplatin enters the PTECs, inactivated GPX4 and interfere with iron-dependent lipid peroxidation by several pathways. Note: AKI: Acute kidney injury; PTECs: proximal tubular epithelial cells; GPX4: glutathione peroxidase 4; MIOX: Myo-inositol oxygenase; GSH: glutathione; WBP2: WW domain binding protein-2; HSC70: Heat shock cognate protein 70; GSSG: Oxidized glutathione; FSP1: Ferroptosis suppressor protein 1; Ub: Ubiquitination; Cx43: Connexin 43; SLC7A11: Light chain subunit solute carrier family 7 member 11. (figure was created in BioRender. Xu, X. (2025) https://BioRender.com/f8wgo85)

Fig. 6

The mechanism of immunotherapy associated AKI. The left showed the Chimeric Antigen Receptor-T (CAR-T) cell therapy mediated AKI by activating T cells, macrophage, and dendric cells, then accompanied by relapsing some kinds of cytokines. The right indicated the immune checkpoint inhibitors (ICIs) resulted in AKI by loss of tolerance for self-antigen, activation of auto-reactive T cells or drug-specific T cells, producing autoantibodies. Note: AKI: Acute kidney injury; TEC: Tubular epithelial cell; CTLA-4: Cytotoxic T Lymphocyte antigen 4; PD-1: Programmed cell death protein 1; PD-L1: Programmed death- ligand 1. (figure was created in BioRender. Xu, X. (2025) https://BioRender.com/f8wgo85)