Acute kidney injury: pathogenesis and therapeutic interventions.

Introduction

Acute kidney injury (AKI), a significant global health concern, is marked by a swift deterioration in renal function, leading to high rates of mortality and morbidity. The incidence of AKI is on the rise, with causes ranging from trauma, sepsis, and surgery to nephrotoxic drugs, ischemia–reperfusion injury (IRI), and cirrhosis [ 1 , 2 ]. Estimates of AKI prevalence range from < 1% to 66%. Traditionally, AKI assessment relied on classifications such as RIFLE (Risk, Injury, Failure, Loss, and End-stage renal disease) [ 3 ], AKIN (Acute Kidney Injury Network) [ 4 ], KDIGO (Kidney Disease: Improving Global Outcomes) criteria [ 5 ], and CTCAE (Common Terminology Criteria for Adverse Events) [ 6 ]. Notably, the KDIGO classification stands as the most frequently employed tool in clinical practice. AKI is a prevalent complication linked to heightened mortality rates in liver diseases, acute myocardial infarction (AMI), and cancer patients [ 7 ]. Its occurrence fluctuates based on AKI criteria, disease types, treatments, and patient-specific factors. Furthermore, the frequency of hospital-acquired AKI exceeded that of community-acquired cases [ 8 ]. It is noteworthy that AKI frequently manifestes as a severe condition in critically ill cancer patients [ 9 , 10 ]. Globally, AKI almost affects 10–15% of hospitalized patients, 50% of critically ill patients in the intensive care unit(ICU), 22% of adults, and 34% of children. AKI frequently emerges as a complication during treatments, with its occurrence varying across diverse therapeutic modalities [ 11 ]. This discrepancy is exemplified by a range of approaches such as varied surgical techniques [ 12 – 18 ], concurrent chemoradiotherapy [ 19 , 20 ], allogeneic hematopoietic stem cell transplantation (HSCT) [ 21 ], immune checkpoint inhibitors (ICIs) [ 22 , 23 ], a combination of androgen deprivation therapy (ADT) with definitive radiotherapy [ 24 ], and surgery [ 25 ]. Of note, 20–50% of patients in cardiac surgery suffer from cardiac surgery-associated AKI, which was associated with postoperative morbidity and mortality [ 26 ]. Cardiopulmonary bypass (CPB) also leads to alterations in renal physiology [ 27 ]. Contrast-induced AKI (CI-AKI) is a common complication following coronary interventions, which are associated with elevated risks of mortality and morbidity [ 28 ]. 11–40% of patients with iodine contrast medium for diagnosis or treatment will develop AKI.

Extensive research has elucidated the intricate and dynamic interplay between cancer and AKI [ 29 – 31 ] (Table 1 ). Past research has indicated a higher prevalence of AKI in hematologic malignancies when contrasted with solid tumors. The predominant cancer-associated AKIs encompassed the hematological system (myeloma, leukemia, lymphoma), urinary system (urinary tract cancer, bladder cancer), and digestive system (hepatocellular carcinoma (HCC), gastrointestinal cancer) [ 8 , 32 – 34 ]. The existence of nephrotoxic effects in recipients of cancer therapeutics continues to serve as a significant limitation to the utilization and effectiveness of cancer treatments. AKI emerges as a crucial prognostic indicator for adverse outcomes in cancer patients [ 33 ]. Notably, in HCC individuals receiving transcatheter arterial chemoembolization (TACE), the presence of AKI amplifies the risk of mortality by 4.74 times compared to those unaffected by AKI [ 17 ]. Moreover, post-transplant allogeneic HSCT-induced AKI significantly escalates 5-year non-relapse mortality ( P < 0.001) [ 21 ]. Studies reveal that AKI in cancer patients is associated with a sevenfold increase in mortality [ 35 ]. Particularly in lung cancer cases, AKI predicts a 5-year survival rate of only 46.9% [ 36 ]. Consequently, AKI stands as a pivotal limitation in clinical therapy, emphasizing the urgent need to elucidate the underlying mechanisms of AKI for its early detection, prevention, or mitigation.

Previous studies have elucidated the intricate molecular interplay between clinical disorders and AKI. Drug-induced AKI is a well-recognized form of nephrotoxicity, recent advances in understanding novel mechanisms such as ferroptosis, mitochondrial regulation, and cell senescence have created new opportunities for addressing AKI. Furthermore, onco-nephrology is a new and evolving subspecialized area which attracted more and more attention. The incorporation of innovative therapeutic modalities like ICIs introduces increased complexity and diversity in managing AKI. Targeting mitochondria or signaling pathways is an emerging approach for AKI. More importantly, AKI not only has adverse effects on organs other than kidneys but also leads to elevated health-care costs. Therefore, subphenotyping is essential to facilitate personalized management strategies.

This review comprehensively overviews the pathophysiology of AKI and further elucidates the pathogenesis of AKI attributed to both clinical conditions and its treatments. Then it expounds on risk factors and causes, which makes a significant contribution by identifying predisposing factors from patient-specific sources. This review focuses on the diagnosis of AKI, finally summarizes therapeutic interventions, evaluates therapeutic gaps, and highlights the early diagnosis of AKI and how timely intervention paves the way to prevent and alleviate AKI.

Risk factors and causes

Common risk factors for acute kidney injury

The primary risk factors for AKI encompass volume depletion, haemodynamic instability, inflammation, exposure to nephrotoxic agents, and mitochondrial dysfunction. In cases of obstructive nephropathy, the density of lymphatic vessels is notably increased, acting as an independent predictor of renal function decline [ 37 ]. In addition, underlying co-morbidities such as type 2 diabetes mellitus (T2DM) and hypertension can further increase the risk of AKI. It has been reported that rhabdomyolysis, surgical procedures, and mechanical ventilation are all related to an increased risk of AKI [ 38 ]. As representative diseases, cancer is closely linked with the enhancement of AKI, Table 1 and Supplementary Table 1 showed the cancer patients-related risk profile for susceptibility to AKI.

Growing evidence indicates that patient variables significantly increase the risk of AKI in individuals with cancer or undergoing cancer-related therapies [ 32 ] (Table 1 and Supplementary Table 1 ). Advanced age and male gender are commonly recognized as independent risk factors for AKI in cancer patients. Additionally, conditions such as Diabetes mellitus (DM), chronic renal disease, or CKD are frequently reported as prevalent comorbidities. Factors such as metabolic syndrome, nutritional status, hypertension, dyslipidemia, increased body mass index (BMI), and lower albumin levels are considered key contributors to the heightened risk of AKI development [ 12 , 13 , 25 ]. A variety of organ-related conditions, such as shock, atrial fibrillation, and pneumonia, which were present prior to treatment, have been identified as independent predictors of AKI onset [ 8 , 11 , 12 ]. Notably, congestive heart failure, sepsis, and hypercalcemia are associated with substantially increased odds of AKI development in patients with solid tumors or multiple myeloma [ 35 ]. Baseline serum creatinine levels and estimated glomerular filtration rate (eGFR) also serve as valuable independent risk indicators for AKI occurrence in esophageal cancer patients. Furthermore, tobacco consumption is linked to a 3.029-fold increased risk of AKI in individuals with esophageal cancer [ 11 ].

Several researchers have delved into the influencing factors of AKI in cancer patients undergoing surgery, radiotherapy, immunotherapy, and HSCT. The quality and efficacy of treatment can directly impact outcomes and the risk of AKI, such as the duration of operation for esophageal cancer [ 11 ], the quality of TACE or the volume of hepatectomy-related transfusions contributing to AKI in HCC [ 17 ], and radical nephrectomy for renal cell carcinoma (RCC) [ 15 ]. Concurrent medications have emerged as significant predictors of AKI in cancer patients, with noteworthy associations observed between AKI and the simultaneous use of diuretics, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) [ 16 ], and Renin–angiotensin–aldosterone system inhibitor (RAASi) treatment [ 19 ]. Notably, the administration of three or more nephrotoxic drugs was linked to an increased risk of AKI in allogeneic HSCT patients [ 21 ]. In individuals receiving ICIs, the use of proton pump inhibitors (PPIs), nonsteroidal anti-inflammatory drugs (NSAIDs), fluindione, diuretics, and ACEI/ARBs was associated with a heightened risk of AKI [ 22 , 23 ]. Immune-related adverse events(irAEs) are common side effects of ICIs, with extrarenal irAEs linked to ICIs-induced AKI. In addition to the aforementioned factors, the occurrence of AKI was found to be dose-dependent, particularly in cases of higher cisplatin doses ≥ 70 mg/m 2 . Collectively, certain clinicopathological features, concurrent medication use, and underlying comorbidities are recognized as predisposing factors for AKI in cancer patients, aiding in the assessment of AKI occurrence.

Types and causes of acute kidney injury

Traditionally, AKI can be categorized into three types based on its pathophysiological mechanisms and the sites of anatomical injury: pre-renal, intrinsic renal, and post-renal injury. Specifically, intrinsic renal injury is implicated in renal AKI, which may involve the renal tubules, interstitium, renal vessels, and glomeruli. In general, AKI present at admission or developing within 48 h of admission is generally classified as community-acquired AKI, whereas AKI developing after this period is classified as hospital-acquired AKI. Broadly speaking, aetiological subtypes of AKI included ischemia-induced AKI, infection-related AKI, sepsis-induced AKI, contrast-induced AKI, and drug-induced AKI. Sepsis-induced AKI can be categorized into two distinct sub-phenotypes: AKI subphenotype 1(AKI-SP1) is characterized by a reparative, regenerative phenotype, and AKI subphenotype 2(AKI-SP2) is marked by an immune and inflammatory phenotype associated with blood bacteremia [ 39 ]. Therefore, the type of AKI varies in different clinical standards or etiology.

The causes of pre-renal acute kidney injury

Renal ischemia is a central mechanism underlying pre-renal AKI. Various factors can contribute to pre-renal AKI, including gastrointestinal symptoms, bleeding and tumor thrombus, hepatorenal syndrome, paraneoplastic syndrome, hypercalcemia, and nephrectomy-induced ischemic injury mediated by cancer. Additionally, treatment-related factors such as gastrointestinal effects and complications, including veno-occlusive disease (VOD) or sinusoidal obstruction syndrome following HSCT, can all lead to pre-renal AKI associated with renal hypoperfusion. Pre-operative dehydration may also be associated with the development of postoperative AKI [ 40 ].

The causes of intrinsic acute kidney injury

Intrinsic renal injury is the predominant cause of AKI. Intrinsic AKI, also referred to as intrarenal AKI, originates from damage within the kidney itself and can impact various renal structures, including the glomeruli, which may lead to glomerulonephritis; the tubules, which can result in acute tubular necrosis (ATN); and the interstitium, which can cause acute interstitial nephritis (AIN).

In patients with multiple myeloma (MM) [ 41 ] and lupus nephritis [ 42 ], free light chain casts can obstruct renal tubules, contributing to AKI. Other causes of intrinsic renal damage include conventional platinum-based chemotherapy and novel targeted therapy, or immunotherapy agents used in cancer treatment. The majority of intrinsic AKI cases are induced by nephrotoxic substances such as aminoglycosides, vancomycin, and amphotericin B. Additionally, renal ischemia, which may result from shock, surgical complications, or hemorrhage, primarily leads to tubular injury. Interstitial damage can also be caused by nephrotoxic drugs like beta-lactam antibiotics and NSAIDs, infections, and other autoimmune conditions such as systemic lupus erythematosus (SLE). In addition, vascular-related factors such as thrombotic microangiopathy (TMA) also induced AKI. Renal damage is commonly associated with TMA. Following an allogeneic hematopoietic cell transplant (HCT), endothelial damage serves as the primary instigator of AKI. This damage sets off a chain reaction that activates the coagulation system, resulting in thrombin production, fibrin formation, and platelet clumping. The development of AKI is also correlated with the activation of the coagulation system, as evidenced by elevated plasma levels of Plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), and D-dimer [ 43 ]. The rapid decline in renal function seems to be associated with factors like a neoplastic thrombus that causes blockage in the renal vein [ 44 ], clotting disorders [ 45 ], and thrombocytopenia. TMA is an uncommon complication of gemcitabine treatment [ 46 ]. Furthermore, proteasome inhibitors have the potential to reduce nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) levels in the nucleus, leading to VEGF inhibition, which is identified as one of the potential pathological factors contributing to TMA associated with AKI, potentially predisposing to TMA [ 47 ]. Hypoxic AKI arises from a mismatch in renal oxygenation, characterized by reduced oxygen supply and heightened oxygen consumption for tubular transport [ 194 ].

The causes of post-renal acute kidney injury

Urinary tract obstruction (UTO) is a primary cause of post-renal AKI, with anuria or oliguria often occurring rapidly following the obstruction. Tumor-induced obstruction or invasion of the urinary system could lead to local or post-renal obstruction and compromised renal function.

Special types of acute kidney injury

Aside from the typical risks and causes, various unique conditions are present in diverse clinical settings, such as AKI associated with coronavirus disease 2019 (COVID-19), pregnancy-related AKI (pAKI), neonatal AKI, tumor lysis syndrome (TLS) induced AKI, and sepsis-induced AKI.

COVID-19-associated acute kidney injury

COVID-19 is associated with a heightened risk of AKI [ 48 ]. A retrospective longitudinal multicenter cohort study indicated that patients with COVID-19-related AKI were generally younger, had a higher baseline eGFR, worse baseline comorbidity scores, elevated markers of illness severity, and longer hospital stay compared to those suffering from influenza-related AKI or other types of AKI [ 49 ]. In another cohort study involving veterans of African ancestry hospitalized with COVID-19 infection, it was found that variants of apolipoprotein L1 (APOL1) were linked to increased likelihood of AKI, greater AKI severity, and higher mortality rates, even among individuals with prior normal kidney function [ 50 ]. Substantial alterations in circulating levels of immune mediators [ 51 ] occurred in COVID-19-associated AKI, suggesting exacerbation of the immune response appears to play a role in the development of AKI. Given that long COVID has the potential to impact nearly every organ system [ 52 ], hence the relationship between AKI and long COVID has piqued our interest.

Pregnancy-related acute kidney injury

AKI during pregnancy can emerge from diverse causes and at different gestational stages. Prerenal and intrinsic AKI resulting from hemorrhage, which induces hypovolemia and renal ischemia, are the most prevalent types [ 53 ]. In the first and second trimesters, prerenal AKI is more frequent, often caused by septic abortions, hemorrhage, and hyperemesis gravidarum. Both hyperemesis gravidarum and septic abortions can result in hypovolemia and metabolic alkalosis, subsequently causing hypotension and renal ischemia, and ultimately resulting in AKI. In the third trimester, intrarenal AKI is the most frequent type of AKI in pregnancy, accounting for approximately 75% of cases. The primary causes of intrarenal AKI during this period are hypertensive disorders of pregnancy, such as preeclampsia and HELLP syndrome, as well as other rarer etiologies like TMA and acute fatty liver of pregnancy. Although rare, postrenal AKI may also occur during delivery or parturition.

Neonatal acute kidney injury

Neonatal AKI is a prevalent and independent risk predictor of increased mortality and prolonged hospitalization. Neonates, like pediatric and adult patients, can also be profoundly impacted by AKI. A meta-analysis compassing 201 studies from 45 countries systematically assesses the worldwide incidence of AKI in neonates and uncovered the incidence of any stage AKI was 30% and AKI-associated mortality was 30% [ 54 ]. Neonatal recurrent AKI was independently associated with longer LOS when compared with a single AKI episode [ 55 ].

Tumor lysis syndrome induced acute kidney injury

TLS is a dynamic metabolic complication associated with a heightened mortality rate, particularly evident in patients undergoing chimeric antigen receptor-T (CAR-T) cell therapy and bispecific T cell-engaging antibodies. TLS-induced AKI affects up to 64% of TLS patients, with an increased likelihood in cases of proliferative and/or chemosensitive malignancies harboring sizable tumor burdens. The abrupt and extensive breakdown of tumor cells leads to the release of intracellular components like potassium, phosphorus, and nucleic acids into the bloodstream, triggering TLS ( Fig. 1 ) . The excessive glomerular filtration capacity in normal kidneys can lead to blood clotting and metabolic disturbances like hyperphosphatemia, hyperkalemia, and hyperuricemia. TLS-induced AKI is characterized by crystal-driven damage caused by the deposition of uric acid and calcium phosphate in renal tubules [ 56 , 57 ], triggering inflammatory and pro-oxidative responses that harm the tubular epithelium. Elevated serum levels of uric acid are associated with hemodynamic changes resulting from poor autoregulation and renal vasoconstriction [ 58 ]. Conversely, uric acid may also contribute to AKI through mechanisms independent of crystal formation [ 59 ]. Besides, the increased release of extracellular histones during TLS led to significant endothelial changes in the mouse model. The activation of endothelial cells through Toll-like receptor 4 (TLR4) is involved in the pathways of histone-mediated damage. Heparin mitigates endothelial dysfunction during TLS by inhibiting extracellular histones [ 59 ]. It is crucial to differentiate between TLS and spontaneous TLS (STLS). STLS is a rare oncologic emergency, particularly in tumors with a larger burden and higher proliferation rates [ 60 , 61 ], triggered by extensive cancer cell lysis or necrosis without a specific cause [ 62 ], leading to normal or slightly elevated phosphate levels which are attributed to the utilization of phosphate in rapid tumor cell proliferation.

Sepsis-induced acute kidney injury

Infections are the primary cause of non-relapsed mortality after treatment with CAR-T cell therapy and bispecific T-cell-engaging antibodies. A multitude of factors, encompassing local inflammation, metabolic reprogramming [ 63 ], and microvascular endothelial dysfunction [ 64 ], contribute to the development of sepsis-induced AKI. Yang Y et al. suggest a significant link between septic AKI and certain cancer types [ 64 ], including bladder and retroperitoneal tumors. Surgical therapy increases the risk of inadequate organ perfusion during procedures. After undergoing nephrectomy, patients may encounter complications like intra-abdominal hypertension or abdominal infections. Moreover, AKI in tumor-related thrombotic microvascular disease and septic coagulation dysfunction can occur due to renal microvascular thrombosis with endothelial edema and microvascular blockage. The presence of these factors significantly heightens the likelihood of septic AKI in cancer patients. Taken together, grasping the risks and causes of AKI lays the foundation for a more precise diagnosis of the condition.

Pathophysiology of acute kidney injury

The causes of AKI are highly complex and varied [ 65 ]. Factors such as infection [ 66 ], sepsis [ 67 , 68 ], hypoxia [ 69 ], nephrotoxic drugs [ 70 ], rhabdomyolysis [ 71 ] and numerous others can all lead to AKI. While AKI is frequently multifactorial, haemodynamic instability, sepsis, and drug toxicity are frequently implicated. Regardless of the specific cause, multiple pathophysiological processes unfold simultaneously and in sequence, including endothelial dysfunction, alteration of the microcirculation, tubular injury, obstruction, venous congestion, and intrarenal inflammation. Epidemiologically, community-acquired AKI is more commonly of pre-renal origin and predominantly affects older individuals or those with pre-existing health conditions. It is often triggered by dehydration or the use of medications that compromise glomerular blood flow. Conversely, AKI that is acquired in the hospital setting is more often intrinsic in nature and typically presents with greater severity. AKI frequently occurs as a secondary issue among hospitalized patients, rather than being the main reason for their admission. It is often triggered by damage or impaired function in organs outside the urinary system. Sepsis stands out as a significant cause of AKI acquired during hospitalization, contributing to approximately 30–50% of such cases. In the context of sepsis, microbial constituents and substances released by the host function as alert signals, or alarmins, that engage with pattern recognition receptors (PRR). The renal endothelium, tubular epithelial cells (TECs), and immune cells all express PRR capable of recognizing a broad spectrum of injury-related molecular patterns. Stimulation of PRR elicits pro-inflammatory changes in renal cells and sets off pathways leading to programmed cell death. Meanwhile, immune cells are recruited to the location where alarmins are released, thereby fueling local inflammatory responses. IRI is likely the most thoroughly investigated experimental model of AKI. In clinical settings, it typically arises from severe renal hypoperfusion due to blood loss, septic shock, or other anatomical abnormalities that compromise renal blood flow. Multiple interacting etiologies contribute to AKI in clinical settings such as liver disease, heart failure, cancer, etc. Therapeutic manners also cause nephrotoxic injury including AKI. The pathophysiology of AKI secondary to cardiac surgery (coronary artery bypass grafting) might include hemodynamic instability, renal ischemia–reperfusion, systemic inflammatory response, or exposure to nephrotoxic medications. Exposure to the CPB circuit also leads to complement activation, hemolysis, and systemic inflammation. In this section, we mainly focus on clinical disorders, therapy-related nephrotoxicity, inflammation, and oxidative stress to share the underlying pathophysiological mechanisms of AKI.

The pathophysiological mechanism of acute kidney Injury induced by clinical conditions

The pathogenesis of acute kidney injury induced by liver disease

Individuals with cirrhosis are at an increased risk of developing all forms of AKI, including hepatorenal syndrome (HRS)-related AKI and non-HRS-AKI. HRS-AKI, a distinct form of AKI in individuals with advanced cirrhosis and ascites, is associated with an exceptionally high mortality risk. It stems from reduced renal blood flow due to changes in the arterial circulation and the overactivity of the body’s natural vasoactive systems including the renin–angiotensin–aldosterone system(RAAS), the sympathetic nervous system, and arginine vasopressin [ 72 ]. Systemic inflammation significantly contributes to the development of neurohumoral and vasodilatory imbalances, which subsequently result in functional AKI (HRS-AKI). In Japanese patients with cirrhosis, an imbalance in amino acids is strongly correlated with the development of AKI [ 73 ]. In the case of non-HRS-AKI, the predominant causes of AKI in patients with cirrhosis include hypovolemia, spontaneous bacterial peritonitis (SBP), bacterial infections (other than SBP), sepsis, upper gastrointestinal bleeding, and shock. Infections and sepsis can reduce blood flow to the kidneys. This can cause kidney damage in cirrhosis patients, who are already sensitive to changes in fluid volume. In the setting of cirrhosis or chronic liver disease, inflammation may result from damage-associated molecular patterns (DAMPs) in hepatocytes and the weakening of gut immunity due to pathogen-associated molecular patterns (PAMPs).

The pathogenesis of AKI induced by cardiovascular disease

Cardiorenal syndrome (CRS) is a complex, bidirectional condition marked by interdependent dysfunction of the heart and kidneys whereby the dysfunction of one organ, whether acute or chronic, can lead to dysfunction of the other organ in an acute or chronic manner. The underlying mechanism may involve hemodynamic dysregulation, a reduction in effective circulating volume, renal venous congestion, activation of the sympathetic nervous system and renin–angiotensin–aldosterone system (RAAS), inflammation, neurohormonal activation, and an imbalance in reactive oxygen species(ROS)/nitric oxide synthase(NOS) [ 74 ]. AKI in patients with atrial fibrillation might be induced by ATN and embolic events caused by hemodynamic instability and anticoagulation-related nephropathy.

Kidney involvement induced by cancer

Tumor infiltration of the kidney or kidney involvement can lead to AKI by causing compression and obstruction of the urinary tract, such as in cases of bladder cancer [ 14 ] and hematological malignancies [ 75 ]. 90% of lymphoma patients demonstrate bilateral interstitial lymphoma cell infiltration and an increase in renal size on radiographic imaging [ 76 ]. Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), infrequently infiltrates the kidneys but can also cause AKI due to lymphoma cell invasion of the renal interstitial space [ 77 ]. Furthermore, AKI can occur from tubular compression and disruption of renal microcirculation because of tumor infiltration. Lymphomatous invasion of the kidneys (LIK) may be presented with hematuria and proteinuria. Invasive cancers disrupting the renal parenchyma led to AKI by affecting the glomerular, tubulointerstitial, and microvascular structure. In patients with MM, light chain cast nephropathy (LCCN) represents a pivotal myeloma-related event contributing to AKI [ 41 ]. The presence of filtered free light chains (FLCs) within the glomerulus leads to excessive light chain excretion into the urine, which in turn compromises the resorptive capacity of the proximal tubules. Subsequently, the excess monoclonal FLCs interact with the Tamm Horsfall protein in the loop of Henle, leading to the formation of light chain casts. The obstruction of the tubules by these casts can result in tubular rupture and injury, which is often initiated by an immune response. Additionally, the generation of hydrogen peroxide by the FLCs further intensifies the renal injury, stimulating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and apoptosis signal-regulating kinase 1 (ASK1), as well as the Janus kinases(JAK) and signal transducer and activator of transcription proteins (STATs) pathway [ 78 ]. These processes drive tubulointerstitial fibrosis, inflammation, and apoptosis, amplifying the damage beyond mere tubular obstruction [ 79 , 80 ]. Both the physical blockade of the distal tubules and the FLC-induced injury to the proximal tubules collectively contribute to the development of AKI.

AKI resulted from cancer metastasis to the kidney, involving non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and HCC [ 81 , 82 ]. Renal carcinomatous lymphangitis also played a role in AKI occurrence [ 83 ]. Lymphostasis arises from compromised lymph circulation, impacting the removal of interstitial fluid. Failure in lymphatic vessels’ fluid clearance from the interstitial space hinders its return to the bloodstream. The release of cytokines and growth factors by damaged tubular cells triggers interstitial inflammation, accumulation of extracellular matrix, and eventual fibrosis. Disrupted calcium metabolism in cancer patients, including those with squamous cell carcinoma, renal carcinoma, genitourinary malignancies, breast cancers, pancreatic cancer [ 84 ], metastatic pancreatic neuroendocrine tumor [ 85 ], and human T-cell leukemia virus type 1-associated adult T-cell leukemia/lymphomas, often leads to AKI. It is important to note that elevated levels of calcium in the blood can lead to marked volume depletion through the stimulation of the calcium sensor located in the thick ascending limb of the loop of Henle, resulting in physiological effects resembling those induced by furosemide. Hypercalcemia triggers vasoconstriction of the afferent arteriole, leading to a decrease in intra-glomerular pressure. Furthermore, it results in the precipitation of calcium phosphate crystals and tubule blockage. Malignancy-associated hypercalcemia has been identified to be driven by three primary mechanisms [ 86 , 87 ]. Firstly, the abnormal secretion of parathyroid hormone-related peptide (PTHrP), particularly notable in squamous cancers, plays a crucial role in hypercalcemia by binding to the type I PTH/PTHrP receptor (PTHR-1) and activating pathways that promote increased calcium resorption from bones and reabsorption in the kidneys [ 88 ]. PTHrP stimulates bone resorption by activating osteoblasts to produce receptor activators of nuclear factor-kappa ligand (RANKL) and osteoclast precursors. Secondly, hypercalcemia can result from local osteolysis induced by tumor invasion of bone. Thirdly, absorptive hypercalcemia stems from the overproduction of vitamin D by malignancies in a PTH-independent manner, facilitated by the activation of 25-hydroxyvitamin-D3 1α-hydroxylase by tumor-associated macrophages. Moreover, hypercalcemia serves as a significant prognostic indicator for malignancy [ 89 ]. It is crucial to distinguish pseudo-hypercalcemia stemming from abnormal immunoglobulins [ 90 ].

Additionally, as renal complications in many diseases, including COVID-19, inflammatory bowel disease, lupus nephritis in childhood-onset SLE, age-related diseases such as Alzheimer's and Parkinson's disease, AKI remains the similar multiple interaction of pathophysiological mechanism following some other diseases.

The pathophysiological mechanism of acute kidney injury induced by therapeutic nephrotoxicity

Treatment manners, including surgery and medications (Supplementary Table 2), are leading causes of AKI in hospitalized patients, especially in critically ill settings. The mechanisms underlying drug-associated AKI are diverse, including direct tubular damage, tubulointerstitial inflammation, and intratubular crystal precipitation. Drug-induced nephrotoxicity can result in AKI via one of three main mechanisms: Initially, when drugs or their metabolites interact with the apical surface, traverse through it, or are secreted from the basolateral surface into the tubular lumen, they can induce dose-dependent proximal tubular injury and ATN. Second, tubular obstruction caused by crystals or casts containing drugs and their metabolites, is also dose-dependent. Third, interstitial nephritis is triggered by drugs and their metabolites, which is dose-independent. With the emergence of novel therapeutic tools like immunotherapy, it led to nephrotoxicity. Similarly, this section expounds on the recent developments regarding the pathogenesis of nephrotoxicity-induced AKI.

Platinum-based chemotherapy and acute kidney injury

Excessive accumulation of platinum in proximal tubule epithelial cells

Chemotherapy represents a conventional approach to treating cancer. Since 1978, cisplatin has occupied a pivotal role in chemotherapy regimens for various solid tumors, with cisplatin-induced AKI being an extensively studied mechanism (Fig. 2 ). The process of cisplatin being taken up by proximal tubule epithelial cells (PTEC) and being converted into a potent nephrotoxin initiates the development of cisplatin-induced nephrotoxicity, including AKI, through a transporter-dependent mechanism at the cellular membrane. Transporters involved in this process, such as organic cation transporter 2 (OCT2), copper transporter 1 (CTR1), and the less investigated volume-regulated anion channels (VRAC), are predominantly localized in the basolateral membrane of PTEC and play a crucial role in facilitating the accumulation and transport of platinum into kidney cells. Among these transporters, OCT2 has been extensively studied as a significant contributor to cisplatin uptake by modulating cellular sensitivity and urinary excretion of cisplatin, leading to 30% of nephrotoxicity [ 91 ]. Furthermore, genetic variations or deficiencies in OCT2 can influence its phenotypic activity, predisposition to toxicity, and response to drug treatments. Research has shown that a specific nonsynonymous single-nucleotide polymorphism (SNP), located in exon 4 of the OCT2 gene (rs316019), is associated with reduced cisplatin-induced nephrotoxicity in Caucasian cancer patients [ 91 , 92 ]. Consequently, OCT2 has been suggested as a potential target for protective therapeutic approaches against cisplatin-induced nephrotoxicity. Organic anion transporters (OATs) facilitate the entry of hydrophilic anions into cells through secondary or active transport processes, thereby maintaining the body's anion equilibrium. Furthermore, the elimination of cisplatin into the urine is governed by apically localized efflux transporters present in both proximal and distal tubules. These transporters comprise multidrug and toxin extrusion protein 1 (MATE1), multidrug resistance-associated proteins (MRPs), and P-type copper transporting ATPases (ATP7A). Tubular injury leads to the accumulation of platinum within the tubules, resulting in reduced glomerular filtration rate (GFR) and delayed urinary excretion of cisplatin [ 93 ]. Magnesium plays a crucial role as an essential modulator of cisplatin transporter expression [ 94 ]. A deficiency in magnesium following cisplatin injection reduces the expression of efflux transporters, leading to increased accumulation of cisplatin in tubular cells, thereby exacerbating the severity of AKI [ 95 ]. Collectively, these findings suggest a link between AKI and the abnormal accumulation of cisplatin in tubular cells.

DNA damage

Deoxyribonucleic acid (DNA) damage and the DNA damage response or repair (DDR) are critically implicated in cisplatin-induced AKI. Cisplatin accumulation in PTEC can form cross-links with DNA, disrupting its double-helical structure. Mixed lineage leukemia 1 (MLL1) is identified as a significant histone H3 lysine 4 methyltransferase and acts as a novel regulator of DDR, promoting apoptosis in cisplatin-induced renal proximal tubular cells and AKI. Specifically, MLL1 interacts directly with WD repeat domain 5(WDR5) to initiate DDR, involving phosphorylated ataxia telangiectasia mutated (ATM) kinases/ATM and Rad-3-related (ATR) kinases/and checkpoint kinase(Chk), and the expression of γ-H2AX. Subsequently, it activates p53 to induce cell cycle arrest and modulate E-cadherin expression, leading to apoptosis through activation of caspase-3 in murine renal proximal tubular cells [ 96 ]. Promotion of AKI by cisplatin occurs via the upregulation of apurinic/apyrimidinic endonuclease 2 (APE2), resulting in subsequent dysfunction of myosin heavy-chain 9 (MYH9) in the mitochondria of proximal tubule cells due to an additional role of APE2 in DDR [ 97 ]. In cisplatin-induced AKI, the reduction in miR-155 levels attenuates TEC apoptosis and DNA damage by upregulating telomeric repeat binding factor 1 (TRF1) and cyclin-dependent kinase 12 (CDK12), ultimately preventing telomere dysfunction and genomic DNA damage [ 98 ]. Cisplatin not only impacts mitochondrial DNA but also preferentially binds to proteins in the mitochondrial membrane, particularly the voltage-dependent anion channel [ 99 , 100 ].

Oxidative stress and mitochondrial dysfunction

Cisplatin-induced AKI is marked by oxidative stress, which stems from mitochondrial dysfunction and the accumulation of ROS [ 101 ]. These ROS interfere with a multitude of signaling pathways, including mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), nuclear factor erythroid 2-related factor 2 (Nrf2), iron metabolism, DDR, and cell death pathways [ 102 ]. Notably, the significant role of cisplatin-induced mitochondrial dysfunction as a key contributor is evident [ 103 – 108 ] (Fig. 3 ). In addition, mutations in transcription factors crucial for mitochondrial biogenesis, such as estrogen-related receptor alpha (ERRα) [ 109 ], and mitochondrial transcription factor A (TFAM) [ 110 ], have been linked to mitochondrial dysfunction exacerbating cisplatin-induced AKI. Sirtuin3 (Sirt3), the principal deacetylase residing in the mitochondrial matrix, is crucial for modulating mitochondrial function. In a murine model of cisplatin-induced AKI, the absence of Sirt3 led to the dysregulation of fatty acid oxidation (FAO) by deacetylating liver kinase B1 and activating AMP-activated protein kinase [ 111 ]. This cascade resulted in elevated ROS levels, culminating in renal tissue apoptosis and exacerbating kidney injury. Furthermore, NADPH Oxidase 2 (NOX2) and 4 (NOX4) mediated ROS production, serving as crucial inflammatory mediators in proximal tubular cell injury [ 112 ] and necroptosis [ 113 ] following cisplatin-induced AKI. In sum, the accumulation of ROS served as both an initiator and mediator in AKI, offering novel insights for potential clinical interventions [ 114 ].

Inflammation and immune infiltration

Besides inducing cytotoxic effects, cisplatin also triggers an inflammatory response that contributes to nephrotoxicity and exacerbates renal tissue damage (Fig. 4 ). Cisplatin can alter the immune microenvironment of the kidneys during AKI progression [ 115 , 116 ]. Hsing CH and colleagues demonstrated that cisplatin robustly activated glycogen synthase kinase-3β (GSK-3β) in vivo within the kidneys and in vitro in PTEC, leading to elevated cytokine/chemokine production, as well as the infiltration of inflammatory immune cells such as neutrophils, monocytes/macrophages, and T lymphocytes [ 117 ]. Significantly, exposure to cisplatin dose-dependently reduced the levels of renoprotective programmed death-ligand 1 (PD-L1) in primary renal PTEC, resulting in increased infiltration of CD4 + T cells and macrophages alongside reduced regulatory T cells (Treg) populations [ 118 ]. Cytokines and chemokines serve as key regulators in the development of cisplatin-induced AKI. Specifically, chemokine (C-X-C motif) ligand 1 (CXCL1)/C-X-C chemokine receptor (CXCR2) regulates inflammatory responses induced by cisplatin through the P38 and NF-κB signaling pathways both in vitro and in vivo [ 119 ]. Toll-like receptors (TLRs) also significantly contribute to AKI resulting from cisplatin exposure; for example, the nephrotoxic TLR4/NLR family pyrin domain containing-3 (NLRP3) pathway [ 120 ] and the renoprotective TLR-2 pathway [ 121 ]. Gal-3 is essential for the TLR-2-dependent activation of renal dendritic cells, stimulating the indoleamine 2, 3-dioxygenase 1 (IDO1)/kynurenine (KYN) pathway, which subsequently enhances the proliferation of immunosuppressive Tregs during kidney injury [ 122 ]. Furthermore, macrophage migration inhibitory factor (MIF) acts as an upstream pro-inflammatory cytokine, initiating the inflammatory cascade response, and activating macrophages, and T cells. In cisplatin-induced AKI, MIF instigates renal inflammation through a pathway that relies on CD74 and NF-κB signaling [ 123 ]. In recent years, increasing attention has been paid to the role of non-coding RNAs in cisplatin-induced AKI [ 124 , 125 ] (Table 2 ). Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach to modulate the inflammatory pathways mediated by miR-210/Serpine1 and miR-378/Fos in cisplatin-induced AKI [ 126 ]. It is proposed that cisplatin-induced nephrotoxicity results from a pro-inflammatory reaction.

Regulating PANoptosis and autophagy

The exposure to cisplatin leads to DNA damage, ROS generation, and inflammation, culminating in the activation of cell death pathways in tubular cells, notably the Notch signaling pathway [ 127 ]. In cisplatin-induced AKI, the predominant forms of tubular cell death are apoptosis and necroptosis. Aberrant apoptosis of renal TECs is primarily driven by endoplasmic reticulum (ER), death receptor, and mitochondrion-mediated apoptosis pathways, with the involvement of apoptotic factors such as cytochrome C (CytC) and cysteinyl aspartate-specific proteinase 3 (Caspase 3) [ 128 , 129 ]. Cisplatin induces the activation of multiple mediators associated with ER stress, including glucose-regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), phosphorylated c-Jun N-terminal kinase (p-JNK), protein kinase R-like ER kinase (PERK), activating transcription factor-6 (ATF-6), and inositol-requiring enzyme-1 (IRE-1) pathways. In the context of cisplatin-induced AKI, silencing of free fatty acid receptor 4 (FABP4) has been shown to reduce renal tubular cell death by mitigating ER stress [ 130 ]. Recent studies have increasingly highlighted the role of microRNAs (miRNAs) in mediating cisplatin-induced injury to renal TECs (Table 2 ), particularly in relation to apoptosis [ 98 , 131 – 139 ]. Yang et al. discovered that p53 suppresses mTOR activation through the upregulation of miR-199a-3p, consequently enhancing caspase-3 activity and promoting cell apoptosis [ 140 ]. Targeting microRNAs has been identified as a promising strategy to mitigate kidney damage, with notable candidates including miR-449 [ 141 ], miR-107 [ 142 ], and miR-34a [ 143 ]. Additionally, non-coding RNAs such as long non-coding RNAs (lncRNAs) Opa interacting protein 5-antisense RNA 1 (OIP5-AS1) and Prostate Cancer Associated Non-Coding RNA 1(PRNCR1) have been implicated in AKI caused by cisplatin exposure [ 144 , 145 ]. Necroptosis and necrosis are commonly observed in AKI following cisplatin administration. In kidneys treated with cisplatin, the activation of poly(ADP-ribose) polymerase 1 (PARP1) converges multiple pathways leading to cellular necrosis and inflammation, exemplified by the PARP1/TLR4/p38/Tumor Necrosis Factor-alpha (TNF-α) axis [ 146 ] and the receptor‐interacting protein kinase 1 (RIPK1)/RIPK3/mixed lineage kinase domain‐like protein (MLKL) pathway [ 147 ]. Furthermore, miR-500-3p has emerged as a pivotal regulator in cisplatin-induced necroptosis [ 148 ]. Pyroptosis, a lesser-explored pathway in cisplatin-induced AKI, involves NF-κB-mediated activation of the NLRP3/Caspase-1/Gasdermin D (GSDMD) pathway, as confirmed in the AKI model post-cisplatin treatment [ 149 ].

Ferroptosis, a newly recognized form of regulated cell death observed in cisplatin-induced nephropathy, is distinguished by iron-dependent lipid peroxidation (Fig. 5 ) [ 150 – 156 ]. The disruption of the balance between ROS and antioxidants, particularly the inadequacy of glutathione (GSH), enhances ferroptosis by inhibiting glutathione peroxidase 4 (GPX4). Myo-inositol oxygenase (MIOX), an enzyme present in proximal tubules, exacerbates cellular oxidative stress in AKI. Analysis of genomic DNA epigenetics has revealed that hypomethylation of the MIOX promoter induced by cisplatin might contribute to MIOX upregulation during AKI development [ 157 ]. Cisplatin-induced ROS production intensifies MIOX overexpression, leading to lipid hydroperoxidation in both in vivo and in vitro models exposed to cisplatin [ 158 ]. These findings underscore the significant regulatory role of MIOX in cisplatin-induced AKI. Recent studies have highlighted that activation of the vitamin D receptor (VDR) offers protection against cisplatin-induced renal damage by partially inhibiting ferroptosis, which is partly mediated through the trans-regulation of GPX4 [ 159 ]. Decreased levels of miR-214-3p have been demonstrated to protect renal TECs from ferroptosis and alleviate tubular damage in cisplatin-induced AKI, as evidenced in both cellular and animal models, by upregulating GPX4 and solute carrier family 7, member 11(SLC7A11) while downregulating Acyl-CoA synthetase long-chain family member 4(ACSL4) expression [ 160 ]. These combined findings further strengthen the link between ferroptosis, and AKI induced by cisplatin.

Autophagy has been confirmed to serve a dual role in cisplatin-induced AKI [ 161 ]. Initially, following cisplatin exposure, autophagy is activated to uphold cellular homeostasis. Nonetheless, the administration of high doses (≥ 50 μM) or prolonged cisplatin treatment markedly diminishes autophagic activity [ 162 ]. The role of mitophagy in cisplatin-induced AKI has generated inconsistent perspectives across both in vitro and in vivo studies [ 163 ]. Some studies have suggested that the knockdown of phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1) and Parkin RBR E3 ubiquitin -protein ligase (PRKN) worsened cellular injury and mitochondrial function, promoting a protective role against AKI [ 164 ]. Conversely, an alternative investigation put forth a contrasting perspective whereby Pink1 deficiency inhibited excessive mitophagy and dynamin 1-like (DNM1L)-mediated mitochondrial fission, potentially mitigating the impact of cisplatin-induced AKI in rats [ 165 ]. Certain signaling pathways regulate autophagy in reaction to cisplatin stimulation. Cisplatin can trigger Toll-like receptor 2 (TLR2) activation, leading to the phosphorylation of PI3K and Akt [ 166 ], or interact with heme oxygenase-1 (HO-1) pathways [ 121 ] to promote autophagy in renal tubular epithelial cells, thereby safeguarding them against cisplatin-induced AKI. Moreover, the Keap1-Nrf2 signaling pathway, known for its role in responding to oxidative stress, is implicated in the regulation of autophagy [ 167 ].

Other mechanisms

In addition to cell death, cell cycle regulation plays a vital role in this pathological process. Cisplatin-induced cellular damage triggers the activation of cyclin-dependent kinases 4/6 (CDK 4/6) in renal TECs, subsequently resulting in the phosphorylation of Rb1, leading to its inactivation under stress conditions. This cascade of events contributes to the dysfunction of renal TECs, cell death, and kidney injury, potentially occurring through both E2F1-dependent and -independent mechanisms [ 168 ]. Cellular senescence represents an irreversible state of cell cycle arrest characterized by changes at transcriptional, metabolic, and secretory levels, as well as alterations in cellular morphology and chromatin organization. Preliminary animal studies have highlighted the presence of cellular senescence in AKI, underscoring its significant impact on disease prognosis [ 169 ]. Yang and colleagues disclosed that the expression of SirT3, regulated by free fatty acid receptor 4 (FFAR4), has an anti-senescent influence via Gq subunit-mediated CaMKKβ/AMPK signaling cascade in cisplatin-exposed mice and TECs, underscoring the involvement of tubular FFAR4 in cellular senescence via the AMPK/SirT3 pathway [ 170 ]. Furthermore, their research team unveiled a reciprocal regulatory relationship between the aryl hydrocarbon receptor (AhR) and the methyltransferase enhancer of zeste homolog 2 (EZH2) in the kidneys of mice with cisplatin-induced AKI or in murine renal tubular epithelial TCMK-1 cells, accelerating tubular senescence in the context of cisplatin-induced AKI [ 171 ]. These innovative findings offer a fresh perspective on potential targeted therapies for AKI.

Apart from the extensively researched cisplatin, alternative chemotherapeutic treatments like carboplatin and oxaliplatin are known to induce lower levels of nephrotoxicity. Methotrexate, an antimetabolite, obstructs the metabolism of folic acid. Notably, in clinical settings, high-dose methotrexate (HDMTX) can lead to AKI in a range of 2% to 12% of patients [ 172 ]. Crystal nephropathy stands as the primary cause of nephrotoxicity induced by HDMTX. The precipitation of methotrexate and its metabolites in the renal tubules is triggered by acidic urine and a high concentration of methotrexate in these tubules. The development of intrarenal crystals can result in tubular obstruction, direct toxic injury to the renal tubular epithelium, and reduced perfusion due to vasoconstriction of the afferent arterioles, thus fostering the occurrence of AKI. Additionally, interactions between drugs can impede the excretion of methotrexate, leading to delayed clearance and subsequent nephrotoxic effects [ 173 ]. Conversely, the concurrent administration of levetiracetam and HDMTX is considered safe for adult lymphoma patients [ 174 ]. Therefore, addressing chemotherapy-related nephrotoxicity is crucial for reducing the risk of AKI.

Immunotherapy and acute kidney injury

The advent of immunotherapy has brought about a revolution in the field of oncology and immune disorders. Present-day immunotherapy encompasses CAR-T cell therapy, ICIs, and other forms of immunotherapy. The mechanisms by which immune therapy may contribute to the development of AKI have been extensively explored in several studies [ 175 – 177 ] (Fig. 6 ). CAR-T cells directly engage with and eradicate cancer cells, effectively countering the immune evasion strategies utilized by malignant cells. Both CAR-T cell therapy and bispecific T cell-engaging antibodies can trigger AKI, which is frequently associated with cytokine release syndrome (CRS), TLS, sepsis, or the infiltration of specific CAR-T cells into the kidneys. In recent years, drugs in the ICIs subgroup, including anti-cytotoxic T Lymphocyte antigen 4 (CTLA-4) antibodies (ipilimumab, tremelimumab), anti-programmed cell death protein 1 (PD-1) antibodies (nivolumab, pembrolizumab), and anti-PD-L1 antibodies (atezolizumab), have been approved for clinical use. The onset of kidney involvement, a rare complication and the most delayed irAEs associated with ICIs occurs due to neonatal Fc receptor-mediated transportation and receptor-mediated endocytosis, typically manifesting after a median duration of 14 weeks following the initiation of ICIs therapy and affecting 1% to 5% of patients undergoing such treatment. Kidney biopsies frequently reveal acute tubular interstitial nephritis (ATIN) as the most common manifestation of nephrotoxicity related to immune checkpoint blockade, although glomerular diseases have also been documented. In essence, immune checkpoint inhibitors are capable of inducing AKI via several mechanisms, including the loss of tolerance to self-antigens, reactivation of drug-specific effector T cells, and the production of autoantibodies directed against renal-specific antigens [ 178 ].

Cytokine release syndrome

CRS is a prevalent and potentially life-threatening complication that ensues following the administration of CAR-T cells and bispecific antibodies [ 179 ]. Approximately 75% of patients undergoing CAR-T cell therapy will experience CRS as a result of CAR-T cell expansion. The incidence of severe CRS significantly increases the risk of developing AKI by 5–tenfold [ 180 , 181 ]. Activated immune cells, primarily macrophages and CAR-T cells, produce substantial quantities of inflammatory cytokines, such as interleukin-1 receptor antagonist (IL-1RA), IL-2, interferon (IFN), IL-6, soluble IL-6R, IL-8, and granulocyte–macrophage colony-stimulating factor (GM-CSF). IL-6 specifically plays a critical role in CRS development. The elevated cytokine levels can induce vasodilation, reduced cardiac output, and intravascular volume depletion due to increased vascular permeability and space, resulting in diminished renal perfusion and subsequent AKI [ 182 ].

Furthermore, hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) is another syndrome within the spectrum of CRS that may be associated with AKI. This syndrome is believed to be influenced by elevated levels of IL-6 and IL-10 [ 183 ]. Prerenal physiology is often triggered by cytokine-mediated vasodilation and capillary leakage, leading to a significant accumulation of fluids in the third space. The systemic toxicity that may arise from CAR-T cells has the potential to cause AKI [ 184 ]. Just as in acute cardiorenal syndrome, where kidney perfusion is reduced resulting in prerenal AKI or progression to ischemic AKI, acute cardiomyopathy due to CRS can lead to hypotension, aggravating renal hypoperfusion.

The aberrant activation of self-reactive T-cells and drug-specific T cells

The initiation of ICIs can result in the abnormal activation of tissue-specific self-reactive T cells, potentially disrupting or compromising immune tolerance to renal self-antigens. The activated T lymphocytes migrate to the kidney as the site of local antigen presentation, infiltrate into the parenchyma, and release cytokines, leading to immune infiltration, inflammation, and kidney injury [ 185 , 186 ]. The immune profiling analysis of the kidney using imaging mass cytometry in patients with AKI-related ICIs showed an abundance of specific immune cells in the kidney tissue such as CD4 memory cells, T helper cells, and dendritic cells (DCs) [ 187 ]. The interaction between DCs and T cells, culminating in T cell activation, is a significant factor in the development of AKI. Additionally, a documented case of AKI linked to CTLA-4 haploinsufficiency, identified as acute granulomatous tubulointerstitial nephritis, led to the disruption of FOXP3 + regulatory T cells, heightened activity of effector T cells, and lymphocytic infiltration in various organs [ 188 ]. Furthermore, the expression of PD-L1 in TECs serves to shield them from aggressive autoimmunity mediated by T cells. In murine models, PD-L1 appears to be essential for the onset of AKI and immune-related AIN, given its prevalent expression in various renal pathologies not linked to ICIs therapy. Blocking antibodies against PD-L1 and PD-L2 hindered regulatory T-cells’ protective function, leading to AKI via ATN [ 189 , 190 ]. Conversely, blocking the PD-1 receptor on self-reactive T cells with antibodies disrupted the PD-1/PD-L1 signaling pathway, enabling T cell proliferation, maturation, and the production of cytotoxic molecules like granzyme B (GrzB) and perforin [ 191 ]. The widespread expression of PD-L1 in renal pathologies underscores its role in the development of AKI and immune-related AIN, irrespective of ICI therapy [ 192 ]. The delayed onset of AKI following ICI administration did not align with AIN induction through the creation of an immunogenic drug metabolite [ 193 ]. Yet, no evidence has been found for the detection of ipilimumab-, pembrolizumab-, or nivolumab-specific T cells in peripheral blood.

In the majority of studies investigating ICIs-associated AKI, patients who were taking medications associated with ATIN, such as PPIs, NSAIDs, and antibiotics, were identified [ 191 ]. These drugs, by binding to tubular antigens and acting as haptens, can instigate an immune response, either directly or indirectly. Subsequently, they become embedded in the renal parenchyma, leading to tubular injury and an immunological reaction. Upon administration of ICIs, these self-reactive T cells can become prominently activated. PPIs might serve as a latent trigger for hapten-reactive T cells, which are then further stimulated by ICIs, causing a loss of tolerance [ 194 ].

Other mechanisms

The administration of ICIs may lead to the generation of autoantibodies that target antigens expressed by podocytes, mesangial cells, or TECs [ 178 ]. A patient with metastatic melanoma developed nephrotic syndrome and an immune-complex glomerulopathy resembling lupus following treatment with ipilimumab. This individual also generated antibodies against double-stranded DNA and anti-nuclear antigens [ 195 ]. Moreover, Bacillus Calmette–Guérin (BCG) therapy may result in adverse effects such as AIN and local BCG disease (BCGitis) or disseminated BCG disease (BCGosis), with or without granulomas [ 188 , 196 ]. Tacrolimus-induced TMA -causing AKI without systemic features is a rare entity, particularly after non-renal solid organ transplantation such as heart–lung transplantation [ 197 ].

Targeted therapy and acute kidney injury

AKI induced by proteasome inhibitor

Carfilzomib (CFZ), a frequently used proteasome inhibitor for treating myelomas, has been associated with significant renal failure in patients. Efentakis et al. demonstrated that CFZ induced nephrotoxicity, triggering apoptosis, ROS generation, and inflammation pathways by activating serum/glucocorticoid-regulated kinase 1 (SGK-1) and mineralocorticoid receptors in mouse kidneys [ 198 ]. Additionally, the antioxidant system, lipid peroxidation, cytokine activation (IL-1β, IL-6, TNF-α), caspase-3, and Nrf2 downregulation play key roles in CFZ-induced renal impairment [ 199 ]. Notably, metabolomics studies have shown that CFZ causes the retention and dysfunction of metabolites, leading to local kidney injury by inhibiting nitric oxide (NO) production, resulting in elevated kidney resistance, increased oxidative stress, and modulation of inflammation [ 200 ].

AKI induced by Tyrosine kinase inhibitors (TKIs) and other inhibitors

TKIs such as vandetanib have been found to inhibit a number of human renal transporters, notably MATE-1 and MATE-2, essential for removing a variety of toxins and medications [ 201 ]. Agents that target MATE-1 and MATE-2 can impede the apical membrane of tubular cells, potentially leading to elevated drug concentrations within renal cells and exacerbating the renal toxic effects of certain drugs, particularly cisplatin [ 202 ]. AKI has primarily been associated with v-Raf murine sarcoma viral oncogene homolog B(BRAF) inhibitors due to instances of ATN, rhabdomyolysis, and TLS [ 203 ]. Epidermal Growth Factor Receptor (EGFR) inhibitors consist of three small-molecule TKIs (erlotinib, gefitinib, and afatinib) and two monoclonal antibodies (cetuximab and panitumumab). Each of these agents has been linked to the occurrence of AKI. EGFR, predominantly expressed in the distal and collecting tubules, plays a vital role in maintaining tubular integrity. Upon ATN, EGFR activation stimulates the growth and regeneration of TECs. Anti-EGFR medications may serve as a “second hit” in the development of AKI in individuals predisposed to renal dysfunction. AKI cases, including ATN, TLS, and ATIN, have been observed in patients receiving BRAF inhibitors. The likelihood of AKI was higher with concurrent use of trametinib and dabrafenib. Anaplastic lymphoma kinase(ALK) inhibitors have been linked to the development of peripheral edema and, in rare cases, electrolyte disorders and kidney failure [ 204 ]. In individuals undergoing anti-vascular endothelial growth factor (VEGF) therapy, TMA is the most frequently documented histopathological manifestation associated with AKI [ 205 ].

Radiotherapy and radiographic contrast agents-induced acute kidney injury

The kidneys are the most radiosensitive abdominal organ, yet the molecular pathomechanisms underlying radiotherapy nephropathy (RN) remain incompletely understood. Consequently, managing radiation exposure and contrast-induced AKI remains an ongoing challenge. Programmed cell death 4 (PDCD4) may play a role in radiotherapy-induced AKI in rectal cancer by upregulating FGR expression, activating the NF-κB signaling pathway, and triggering an oxidative stress response [ 206 ]. In radiation-induced kidney injury associated with cervical cancer, PARP1 interacts with X-ray repair cross-complementing 1 (XRCC1) to form a complex, which subsequently induces DNA damage and oxidative stress response in renal tubular cells [ 207 ]. Moreover, insulin-like growth factor-1 (IGF-1) and calcitonin gene-related peptide (CGRP) are involved in the development of radiotherapy nephropathy [ 208 ]. The pathogenesis of contrast-induced AKI may be related to the direct cytotoxicity of iodine contrast medium, medullary hypoxia, and ischemia, as well as oxidative stress. Contrast agents activate the classical Nlrp3 inflammasome in macrophages, leading to AKI through the regulation of inflammation. This process requires the involvement of IL-1, leukocyte recruitment, dipeptidase-1 (DPEP-1), and resident renal phagocytes. Upon recruitment of monocytes and macrophages to the kidneys, they interact directly with tubular cells to process contrast taken up from the urine. DPEP-1, an enzyme found on the brush border, plays a crucial role in the tubular reabsorption of contrast. The NLRP3 inflammasome is implicated in contrast-induced AKI by modulating the apoptotic pathway [ 209 , 210 ]. Recent renal proteomics analysis has identified 16 candidate proteins that could reveal novel mechanisms in the pathogenesis of contrast-induced AKI [ 211 ], offering new insights for potential therapeutic targets in the management of radiotherapy or contrast media-induced AKI.

Inflammatory response, oxidative stress, and tubular injury

Inflammatory response in pathogenesis of acute kidney injury

Historically, kidney dysfunction was primarily attributed to hemodynamic disturbances. Nevertheless, recent research has highlighted the intricate relationship between AKI, inflammation, and the immune system. The REALAKI study demonstrated that early-onset AKI is linked to the initial inflammatory response and injury-induced immunosuppression observed at the end of the first week following severe injuries like sepsis, trauma, surgery, and burns [ 212 ]. Injured renal cells release signals recruiting lymphocytes, which either perpetuate or inhibit renal injury. Both intrarenal and systemic inflammation are linked to AKI, implicating innate and adaptive immune systems in its pathogenesis. The development and progression of AKI are notably influenced by intricate intrarenal inflammatory pathways, which are propelled by both lymphocytes and innate immune cells [ 213 ]. Innate immune cells, such as granulocytes and macrophages, can trigger AKI by secreting pro-inflammatory mediators [ 214 ]. These cells can cause direct renal damage or indirectly through the recruitment of adaptive immune cells. Evidence from studies in both humans and mice has indicated that the complement system is activated during AKI. CD4 + and CD8 + T cells, B cells, and neutrophils are probably implicated in the development and progression of AKI. In contrast, regulatory T cells, double-negative T cells, and type 2 innate lymphoid cells appear to exert protective effects. Some other immune cells, such as macrophages and natural killer T cells, may exhibit both harmful and protective effects, contingent upon their specific subtype and/or the phase of AKI. The immune system not only contributes to the injury and repair processes during AKI but also mediates AKI-induced dysfunction in distant organs. Macrophages, as the most abundant immune cells residing in the kidney, can differentiate into pro-inflammatory and anti-inflammatory phenotypes. They dynamically influence the progression of AKI and the subsequent repair processes while also helping to maintain tissue homeostasis [ 215 , 216 ]. Macrophages influence the local inflammatory microenvironment by secreting extracellular vesicles (EVs) that carry pro-inflammatory or anti-inflammatory signaling molecules, thereby modulating tissue injury and repair. In rhabdomyolysis-induced AKI, necrotic muscle cells release substances that can activate platelets that could raise the production of macrophage extracellular traps (METs) by enhancing histone citrullination and intracellular ROS generation [ 217 ]. The primary signaling pathways involved in macrophage-mediated pro-inflammatory responses in AKI encompass the Notch, NF-κB, PI3K-AKT, JAK-STAT, and necroptosis pathways. Among these, Saa3hiCcl2hi monocyte-derived infiltrating macrophages have emerged as a pivotal effector subset, driving inflammation and directly interacting with renal cells [ 218 ]. During AKI, TECs acutely secrete IL-34, which activates resident macrophages and exacerbates tubular injury. T cells significantly influence the transition from AKI to CKD through their roles in injury and repair mechanisms. Importantly, T cells also participate in distant organ crosstalk during AKI, which affects overall outcomes. After AKI, TECs predominantly release signals that induce a T helper 1 (TH1) response, and renal myeloid cells polarize toward an IL-17-producing T helper (TH17) phenotype [ 219 ]. However, the role of T helper 2 (TH2) cells during AKI is still not well understood. Following renal injury, Tregs mitigate inflammation through various mechanisms. Gamma delta T cells (γδT cells) play a role in modulating the progression of kidney injury, but they are not indispensable for the development of AKI. IRI robustly recruits neutrophils and monocytes, leading to AKI. Dipeptidase-1 (DPEP1), a key neutrophil adhesion receptor, is highly expressed in renal proximal tubular cells and peritubular capillaries. DPEP1, along with CD44 and Intercellular adhesion molecule-1 (ICAM-1), plays a significant role in the recruitment of monocytes/macrophages to the kidney after IRI [ 220 ].

Damage-associated molecular patterns (DAMPs) have been recognized as substantial contributors to the development of AKI. Serum peroxiredoxin 1 (Prdx1) is a novel DAMP that mechanistically contributes to renal injury through activation of the Mincle/Syk/NF-κB signaling axis, thereby driving pro-inflammatory cascades [ 221 ]. In systemic inflammatory conditions induced by sepsis and cirrhosis, PAMPs and DAMPs potently activate innate immunity [ 222 ]. This immunostimulatory process engages multiple physiological systems, including complement activation, coagulation cascade initiation, and endothelial cell activation. The unabated inflammatory response mediated by PAMPs/DAMPs induces endothelial barrier dysfunction across vascular beds and parenchymal organs following regulated cell death (RCD). Subsequently, unregulated inflammatory mediators enter systemic circulation and exert detrimental effects on renal homeostasis, resulting in disruption of regional hemodynamic stability, impairment of renal vascular endothelial integrity, and mitochondrial dysfunction. These pathophysiological alterations manifest clinically as deteriorating renal function, biochemically characterized by elevated serum creatinine and urea nitrogen concentrations.

Oxidative stress and tubular injury

The pathological mechanisms underlying AKI are complex, with oxidative stress emerging as a major contributor. Like drug-induced and contrast-induced AKI, the kidney is highly susceptible to IRI under various clinical conditions, including hypotension, sepsis, and surgical procedures such as partial nephrectomy and kidney transplantation. IRI disrupts the cellular redox balance, triggering excessive production of ROS in the kidneys upon reperfusion. This triggers a series of events typical of IRI-induced AKI, such as mitochondrial damage, energy depletion, tubular apoptosis, and necrosis. Mitochondrial DNA (mtDNA) damage is recognized as a characteristic feature of AKI, with mtDNA depletion documented in both preclinical models and human patients with AKI. Mitochondrial ROS (mtROS) can worsen renal injury by suppressing mitochondrial transcription factor A (TFAM)-mediated maintenance of mtDNA. This suppression results in decreased mitochondrial energy metabolism and increased cytokine release. These findings suggest that addressing TFAM deficiencies could be a potential therapeutic approach for renal repair following IRI-AKI [ 223 ]. Oxidative stress is a key pathogenic mechanism of AKI, hence oxidative stress-related pathways are the key regulator in AKI, including the NOXs pathway, AMPK/PKC pathway, Nrf2/HO-1 pathway, Nrf2/SIRT3/SOD2 pathway, SIRT1/PGC-1α/FoxO1 pathway.

Previous studies uncovered accumulated signaling pathways involved in the occurrence and development of AKI [ 224 ], including inflammation, oxidative stress, and regulated cell death-related pathway. Oxidative stress and inflammation are intricately interconnected, forming a vicious cycle where oxidative stress triggers inflammation via various molecular mechanisms, including the NF-κB signaling pathway [ 225 ]. It is widely recognized that AKI is not always characterized by the loss of kidney epithelial cells, although cell death is common in severe cases of AKI. Importantly, there are intricate connections between different forms of regulated cell death, and even between regulated necrosis and inflammatory processes. Pathways of regulated cell death, including apoptosis and necrosis, have been identified as key events in the pathogenesis of AKI [ 226 ]. Apoptosis pathways mediated by mitochondrial autophagy, Bax/Bcl-2/caspase3, 9 pathway, MAPK pathway, PI3k/Akt/mTOR/Nrf2 pathway, and ER stress were the dominant contributors in various AKI. Notably, regulated necrosis pathways, such as ferroptosis, necroptosis, and proptosis, and mitochondrial permeability transition-mediated regulated necrosis, can directly induce AKI or contribute to its development by recruiting immune cells and triggering inflammatory responses [ 227 ]. Gasdermins E (GSDME)-mediated pyroptosis, mitochondrial damage, and inflammation played an important role in renal IRI, such as CHOP/Caspase3/GSDME mechanistic axis [ 228 ]. F-Box and WD Repeat Domain Containing 7 (FBXW7) exacerbates IR-AKI by promoting ferroptosis through downregulation of GPX4 expression [ 229 ]. mmu-lncRNA129814/hsa-lncRNA582795/miRNA-494-5p/IL-1α axis was found to modulate the progression of ischemic AKI [ 230 ]. In addition to the commonly employed pathways mentioned above, several emerging pathways have also been reported in the context of AKI. For example, the OPG/RANKL/RANK/TLR4 signaling cascade is implicated in the pathogenesis of sepsis-associated AKI [ 231 ]. The hypoxia-regulated pathway is also a significant contributor to the development of AKI. Hypoxic AKI is frequently observed in widely used warm ischemia–reperfusion (WIR) models, typically characterized by severe proximal tubular injury and accompanied by significant inflammation [ 232 ]. S100A16 worsens AKI by enhancing the ubiquitylation and degradation of glycogen synthase kinase 3β (GSK3β) and casein kinase 1α (CK1α) via the activation of HMG-CoA reductase degradation protein 1 (HRD1). TFAP2B, functioning as the transcription factor for S100A16, highlights the role of HIF-1α in regulating HRD1 transcription within the S100A16-HRD1-GSK3β/CK1α pathway during renal hypoxia injury [ 69 ]. FHL2 may be essential for protecting against ischemic AKI by enhancing the activation of HIF-1 and β-catenin signaling through its interactions with various protein partners [ 233 ]. The TWEAK/Fn14 axis is involved in the pathogenesis of rhabdomyolysis-induced AKI and the progression from AKI to CKD [ 71 ]. Collectively, a better comprehensive understanding of the pathophysiology of AKI is beneficial to establish the risk stratification for recognizing the susceptible subpopulation to AKI.

Diagnosis of acute kidney injury

Clinical criteria and biomarkers

Clinical criteria for diagnosis of acute kidney injury

AKI was classified according to three criteria sets (Table 3 ): RIFLE, AKIN, and KDIGO. For each definition, only the serum creatinine criteria were utilized, while urine output criteria were not considered. More importantly, early identification of AKI utilized the diagnosis of AKI and precise intervention. The AKI-Pro score, which encompasses factors such as female, baseline eGFR, aortic surgery, modified furosemide responsiveness index (mFRI), SOFA (Sequential Organ Failure Assessment) score, and AKI stage, represents a novel clinical tool. It offers valuable guidance for identifying early AKI patients who are at a heightened risk of experiencing AKI progression or succumbing to death [ 234 ].

Biomarkers-guided diagnosis for acute kidney injury

The biomarker related to AKI consisted of stress biomarkers, functional biomarkers, damage biomarkers, and cell cycle arrest biomarkers. Traditionally methods using only serum creatinine and urine output defined AKI, limited by certain factors. Novel biomarker-based diagnostics displayed superiority over the traditional methods(Table 4 ). Currently, cystatin C (CysC), serum creatinine(Scr), blood urea nitrogen (BUN), and urinary output are commonly employed as functional biomarkers for predicting AKI. In particular, damage biomarkers mainly included kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). The US Food and Drug Administration (FDA) has granted approval to KIM-1 as a biomarker for nephrotoxicity associated with several currently used drugs. Additionally, other biomarkers that signal nephrotoxic damage encompass alanine aminopeptidase (AAP), glutathione s-transferase (GST), and gamma-glutamyl transpeptidase (GGT). Urinary dickkopf-3 (DKK3), a glycoprotein produced by TECs in response to stress and known for its profibrotic effects, has demonstrated its potential in predicting postoperative AKI. It also offers valuable insights into persistent tubulointerstitial fibrosis and transient eGFR decline. Liver-type Fatty Acid-Binding Protein (L-FABP) primarily synthesized from the liver and also produced in other organs such as the kidney, can measured in urine to forecast the occurrence of AKI in patients who have undergone cardiac surgery or those in critical condition, with an apparent advantage over NGAL. The lysosomal enzyme N-acetyl-b-D-glucosaminidase (NAG) and the cytosolic protein lactate dehydrogenase (LDH) are also notable biomarkers. Given that G1 cell cycle arrest triggered by cellular stress is one of the early occurrences in AKI, urinary insulin-like growth factor-binding protein 7 (IGFBP7) and metalloproteinase inhibitor 2 (TIMP2) can be detected at the onset of AKI development. Previous research based on the physiology of AKI expanded mitochondrial-related biomarkers for predicting renal dysfunction [ 235 ]. Pannexin 1 (PANX1), a key regulator of ATP release, holds promise as a biomarker associated with mitochondrial dysfunction for diagnosing IRI-AKI [ 236 ]. Urinary full-length ATP synthase subunit beta (ATPSb) emerges as a highly sensitive and specific biomarker reflecting renal mitochondrial dysfunction in IRI-AKI [ 237 ]. Higher levels of mitochondrial DNA in urine can act as a proxy biomarker for kidney injury [ 238 ]. The kidney in older individuals is particularly susceptible to acute injury stemming from ischemia–reperfusion, toxic drugs, modified matrix proteins, systemic hemodynamics, and other factors. Non-coding RNA and microRNAs (miRNAs) are vital for maintaining renal homeostasis, and alterations in their expression patterns can serve as valuable indicators for AKI [ 239 ]. Additionally, some novel biomarkers for managing AKI are oncoming, such as ferroptosis-related gene Gclc [ 240 ], inflammatory biomarkers CXCL1 and TNFRSF12A [ 241 ], kidney-specific cfDNA methylation markers [ 242 ]. Higher levels of sTLR2 in the early stages of sepsis may emerge as a potential new indicator for predicting sepsis-associated AKI [ 243 ]. Plasma soluble urokinase plasminogen activator receptor (suPAR) and Scr are capable of specifically distinguishing critically ill children who are at a high risk of developing non-septic AKI and sepsis-associated AKI [ 244 ]. Among patients with moderate to severe AKI, urinary C–C motif chemokine ligand 14 (CCL14) demonstrated remarkable efficacy in predicting the persistence of AKI [ 245 ]. Urinary vanin-1 serves as an exceptional minimally invasive biomarker for the early prediction of cisplatin-induced AKI [ 246 ]. The levels of urine complement C3 and vitamin D-binding protein may serve as promising early indicators of adverse outcomes in patients who experience AKI following cardiac surgery [ 247 ]. There was also some biomarkers based on clinical laboratory tests for predicting AKI, like systemic immune-inflammation index (SII) [ 248 ], and high-sensitivity C-reactive protein (hsCRP) [ 249 ].

Role of imaging studies

Imaging modalities, including ultrasonography, X-ray, magnetic resonance imaging (MRI), or computed tomography (CT) often yield characteristic UTO images that support the diagnosis of AKI, particularly in cases of post-renal AKI, under most circumstances. Recently, renal contrast-enhanced ultrasonography (CEUS) and multiparametric MRI (mpMRI) seem to be the most potential imaging methods for evaluating renal microcirculation and oxygenation involved in AKI. Ultrasound molecular imaging, utilizing targeted microbubbles (TM) loaded with vascular cell adhesion molecule-1(VCAM-1) polypeptide, possesses the capability to precisely assess alterations in renal microcirculatory perfusion and inflammatory response. This innovative approach may emerge as a highly potential approach for the early detection of AKI [ 250 ]. In recent years, the application of renal MRI in the assessment of AKI has been on the rise, with its utilization in preclinical studies surpassing that in clinical studies. CF@P possesses antioxidant/anti-inflammatory properties by inhibiting pyruvate dehydrogenase kinase 4 (PDK4) and exhibited promising capabilities in T1-MRI and photoacoustic imaging for AKI management [ 251 ]. Given contrast-enhanced MRI (CE-MRI) of AKI significantly restricted by the inadequate targeting ability and potential toxicity of existing contrast agents, bovine serum albumin@polydopamine@Fe (BSA@PDA@Fe, BPFe) nanoprobe with self-purification capabilities and renal tubule-targeting properties for targeted CE-MRI of AKI [ 40 ]. BPFe is also employed for CE-MR angiography to visualize fine vessel structures. To position renal MRI as a vital tool for clinical research, the integration of multiparametric MRI (mpMRI) is indispensable [ 252 ], mpMRI provides comprehensive information on renal vasculature and function, including arterial spin labeling and intravoxel incoherent motion, as well as tissue oxygenation through blood oxygen level-dependent imaging. Moreover, it offers insights into tissue injury and fibrosis via diffusion tensor imaging, diffusion kurtosis imaging, T1 and T2 mapping, and quantitative susceptibility mapping [ 253 ]. When compared to mpMRI, amine-CEST has the potential to achieve the highest accuracy in diagnosing IRI-AKI [ 254 ]. PET/ 19 F MRI dual-modal imaging probes have been developed for monitoring ferroptosis and identifying the onset of cisplatin-induced AKI a minimum of 24 h earlier than conventional clinical or preclinical assays [ 255 ]. A tailored photoacoustic (PA) imaging probe (AB-DiOH) has also been created, which exhibits highly specific and sensitive reversible responses to hypochlorite (ClO-) and glutathione (GSH) [ 256 ]. This innovative probe allows for continuous, non-invasive monitoring of AKI through PA imaging, demonstrating superior detection sensitivity compared to traditional blood tests. However, there is a notable lack of clinical studies utilizing MRI to assess the degree and timing of renal recovery, and no clinical research has yet been carried out to assess the response to interventions in AKI using MRI.

The clinical pathology of acute kidney injury

The fundamental histopathological hallmarks of AKI are characterized by the loss of the epithelial phenotype in PTECs, which is manifested by the detachment of the brush border, the flattening and localized shedding of TECs, infiltration of inflammatory cells, and the formation of casts that are rich in Tamm-Horsfall protein [ 257 ]. The damaged TECs exhibit significant cellular adaptability. In the initial phase of AKI, some TECs are damaged and undergo cell death, while the surviving TECs initiate an adaptive repair process. ATN is the most common event. Collapsing glomerulopathy is the most frequent glomerular injury and is strongly linked to apolipoprotein L1 genotypes.

Differential diagnosis from chronic kidney diseases

Up to now, AKI and CKD have been clearly defined and categorized. This has in turn spurred enhanced research endeavors and given rise to more effective management strategies and recommendations. Firstly, medical history is a key point for differential diagnosis between AKI and CKD. Kidney injury or decline in kidney function lasting for at least 3 months is regarded as CKD. It’s important to urgently identify and timely intervention of AKI to prevent the transition from AKI to CKD. Secondly, the clinical phenotypes of the two renal impairments were distinct. Diagnosis from the clinical laboratory based on the KIDGO criteria showed the superior guideline to distinguish AKI from CKD, including functional parameters and structure change. The diagnostic criteria for GFR of below 60 mL/min per 1.73 m 2 and an albumin-creatinine ratio (ACR) at or above 30 mg/g were maintained. However, the inclusion of the phrase “with health implications” underscores the idea that while numerous kidney structural or functional abnormalities may exist, not all of them necessarily impact an individual's health. Thirdly, imaging diagnosis usually showed a smaller volume of kidney or other abnormalities of structure in CKD cases compared to AKI with normal kidney. Besides, serum O-sulfotyrosine levels enhanced the ability to distinguish AKI from CKD [ 258 ]. Collectively, although more efforts have standardized definitions and classification systems for AKI and CKD, recognition and awareness of both disorders facilitated timely interventions.

Therapeutic interventions

AKI is increasingly emerging as a significant issue for patients, primarily attributed to the extensive employment of nephrotoxic agents in healthcare settings. Currently, the early diagnosis of AKI remains a formidable challenge, and the existing therapeutic drugs are far from sufficient to meet the clinical demand. Medical management strategies for individuals with AKI typically encompass renal replacement therapy (RRT) and nutritional support. No definitive treatment has been established, even though various pharmacologic therapies including diuretics, vasoactive drugs, and growth factors have been documented in animal models or initial clinical trials [ 259 , 260 ]. Human Urine-Derived Stem Cells are protected from PTC injury and impeded macrophage polarization, as well as the secretion of pro-inflammatory interleukins, a novel potential cell therapy in AKI [ 261 ]. Macrophage autophagy safeguards against AKI by curbing renal inflammation via the MARCHF1- and MARCHF8-mediated degradation of T cell-interacting, activating receptors on myeloid cells 1(TARM1) [ 262 ]. Given the current situation, the discovery of novel therapeutic targets for AKI is of utmost urgency.

Supportive care strategies

Prerenal causes, originating from hypovolemia and decreased kidney blood flow, often respond well to fluid administration. Fluids are essential for maintaining kidney perfusion and compensating for impaired autoregulation mechanisms. Additionally, in various other scenarios, such as before surgery, fluids can be beneficial in preventing postoperative ATN. In the context of renal toxicity, particular attention must be paid to medications to prevent underdosing or adverse effects. Any drugs that may cause harm should be discontinued, and dose adjustments should be made based on renal function. For patients with AKI, it is crucial to promptly diagnose and treat associated complications such as metabolic acidosis, hyperkalemia, anemia, and fluid overload. Additionally, it is advisable to initiate stress-ulcer prophylaxis and take measures to prevent infections during the course of AKI. Fluid management is a crucial element for preventing and managing AKI. Traditionally, the focus has been on fluid resuscitation to ensure adequate renal perfusion. However, emerging evidence now cautions against the over-administration of fluids, considering that patients with AKI are highly vulnerable to volume overload [ 263 ]. In a cross-institutional feasibility trial conducted across seven ICUs in Europe and Australia, critically unwell individuals with AKI who were subjected to a conservative fluid management protocol experienced a lower overall fluid accumulation and fewer complications compared to those receiving usual care [ 264 ]. Of note, a more personalized approach to resuscitation is now preferred, taking into account the extent of hypovolemia. The volume of fluids administered should be precisely calculated to ensure adequate perfusion and oxygen delivery to the kidneys and other vital organs. Point-of-care ultrasound (POCUS) has emerged as a mainstream diagnostic tool for volume assessment, providing valuable insights into hemodynamics and organ congestion. The selection of fluid for resuscitation should be based on a comprehensive evaluation of the patient's volume status, electrolyte levels, the underlying cause of hypovolemia, comorbidities, and numerous other factors.

Pharmacological treatments

Therapies such as blood pressure control, glycaemic control (for diabetic patients), renin-angiotensin inhibition, and statins may be crucial in improving long-term cardiovascular and renal outcomes following AKI. Vasopressors represent another major category of treatment employed to elevate blood pressure. Moreover, timely administration of antibiotics in septic patients is crucial. Hypoxia-inducible factor (HIF) is reported to shield the kidney from acute ischemic harm and a novel HIF stabilizer, FG4592 (Roxadustat), has been introduced into clinical practice as an anti-anemia medication [ 265 ]. A newly synthesized covalent antagonist, H151, which targets both human and murine STING, has demonstrated protective effects against renal injury in cisplatin-induced AKI possibly achieved through mechanisms involving the amelioration of inflammation and mitochondrial dysfunction [ 266 ]. There were some clinical trials involving alleviating AKI [ 267 ]. Quinolinate phosphoribosyltransferase (QPRT), a key enzyme in de novo biosynthesis, helps to maintain renal NAD + levels and confers resistance to AKI [ 268 ]. Ilofotase alfa, a recombinant human alkaline phosphatase, has been demonstrated to provide renal protection. In patients with sepsis-associated AKI, it has been demonstrated to enhance survival rates and markedly decrease the occurrence of major adverse kidney events by 90 days (MAKE90) [ 269 ]. The oral administration of an FAAH inhibitor has been shown to effectively mitigate cisplatin-induced nephrotoxicity. Specifically, it can significantly reduce the DNA damage response, tubular injuries, and overall kidney dysfunction caused by cisplatin. The inactivation of FAAH thus emerges as a highly potential approach for the prevention of nephrotoxicity associated with cisplatin treatment [ 270 ]. Cardiac surgery-associated AKI (CSA-AKI) is a severe complication in patients who undergo cardiac surgery involving cardiopulmonary bypass (CPB), which is associated with increased postoperative adverse events and mortality rates. The VERTIGO trial aims to delineate the efficacy and safety profile of empagliflozin in the prevention of CSA-AKI [ 271 ].

Novel therapeutic approaches

Though medical research has made headway, the creation of new treatment methods for AKI is still in its nascent stages. These cutting-edge therapies have the potential to greatly enhance patient outcomes by focusing on the root causes and underlying mechanisms of AKI. A specialized photoacoustic (PA) imaging probe, AB-DiOH, exhibits high specificity and sensitivity in reversibly responding to ClO-/GSH [ 256 ]. This probe is employed to identify nephroprotective agents within natural products. Additionally, it has been discovered that the oral intake of astragalin may hold promise as a new therapeutic agent for the treatment of AKI through the inhibition of oxidative stress, ferroptosis, and cuproptosis. Berberine exerts a protective effect against IRI-induced AKI by inhibiting the intestinal biological barrier of Proteobacteria, reducing lipopolysaccharide (LPS) production, and eliciting an anti-inflammatory response via the regulation of the Sirt1-NF-κB-TLR4 pathway [ 272 ]. Dihydroartemisinin (DHA) has demonstrated its protective effect against AKI through the alleviation of oxidative stress and the reduction of inflammatory damage. These beneficial actions may be closely linked to its capacity to activate the Nrf2 pathway and modulate macrophage polarization [ 273 ]. Cullin 4B (CUL4B) exerts a kidney-protective role against AKI by restraining p53/PAI-1 signaling [ 274 ].

Therapeutic targeting of mitochondria is an emerging approach for AKI, including targeting mitochondrial energy metabolism, mitophagy, reducing ROS levels, disrupted mitochondrial fusion and fission. Mitochondrial energy metabolism involves several key processes, including pyruvate oxidation, FAO, the citric acid cycle, and the five complexes of oxidative phosphorylation. Mitochondrial damage can persist long after ischemia, perpetuating chronic inflammasome activation through the release of noxious molecules. Mitochondrial protection can be achieved during AKI using a mitoprotective agent like SS-31, fibroblast growth factor (FGF2), or compounds that activate the mitochondrial ATP-sensitive potassium channel. Additionally, the Drp1 inhibitor P110 can alleviate aberrant mitochondrial fragmentation and AKI by suppressing the interaction between Drp1 and Fis1 [ 275 ]. Replacing damaged mitochondria aids in restoring mitochondrial homeostasis [ 276 , 277 ]. Despite the promising potential, further research, including well-designed clinical trials, is critically needed. Nonetheless, mitochondrial replacement therapy undoubtedly provides a new and potentially revolutionary therapeutic approach for the management of AKI. Shen Z created a CD44-targeted and ROS-responsive CS-BR-mediated multifunctional liposome loading celastrol (CS-BR@CLT) for the targeted therapy of AKI, which exhibited multiple anti-AKI functions [ 278 ]. Its usage significantly ameliorates AKI attributable to ischemia–reperfusion and helps to preserve renal function by inhibiting apoptosis, protecting mitochondria, promoting autophagy, regulating macrophage polarization, and alleviating interstitial inflammation. Inhibition of CXCL5 may mitigate acute tubular injury and avert the subsequent progression from AKI to CKD [ 279 ].

Besides, targeting ER stress-related treatment mesencephalic astrocyte-derived neurotrophic factor (MANF) inhibited JNK/TLR4/NF-κB signaling [ 280 ]. WIP1 inhibitor (CCT007093) functions as a positive regulator of renal tubular pyroptosis, primarily mediated by phospho-p38 MAPK in sepsis-associated AKI [ 281 ]. Vaccines are anticipated to emerge as a groundbreaking approach for the prophylaxis and management of AKI. Pre-infusion of tolerogenic CD11c + DCs holds the potential to effectively replace the regulatory function of damaged intracellular pathways in cells (DIPC) on DCs and T-cells, thereby alleviating I/R-AKI [ 282 ]. The emergence of nanomedicine paved the way for improving AKI. The H 2 S-generating pre-nanozyme Pt 5.65 S demonstrates inducible antioxidant enzyme‐like activity within an acidic and inflammatory microenvironment. It also demonstrates protective effects against damage caused by ROS and reactive nitrogen species (RNS), even at extremely reduced doses, which significantly improved treatment outcomes in mouse models of kidney ischemia–reperfusion injury and cisplatin-induced AKI [ 283 ]. Managing ROS and inflammation is emerging as a potential strategy for mitigating AKI. Polyethylene glycol (PEG)-coated osmium nanozymes (Os) have shown promise in this regard. When combined with photothermal therapy (PTT) and chemotherapy, these nanozymes effectively regulate inflammation by scavenging ROS and generating oxygen, thereby alleviating cisplatin-induced AKI [ 284 ]. The nanoplatform offers provides a new therapeutic approach for addressing AKI caused by rhabdomyolysis. MPD NPs effectively rescued renal function in vivo by targeting ferroptosis to downregulate the antioxidant pathway, thereby mitigating oxidative stress and inflammatory responses and inhibiting renal tubular cell apoptosis [ 285 ]. Targeting ferroptosis with drugs offers a new and highly promising therapeutic avenue for the treatment of kidney diseases. Klotho, an anti-aging protein predominantly synthesized by TECs, is regarded as a potential anti-inflammatory molecule in AKI. Nanoparticle-mediated Klotho gene therapy for preventing the transition from AKI to CKD [ 286 ]. New therapeutic options are currently being investigated for different types of AKI. For sepsis-associated AKI, the potential benefits of alkaline phosphatase and L-carnitine are being explored. In hospitalized patients with AKI, the role of vitamin D is under study. Additionally, p53-targeted short-interfering RNA is being examined as a possible treatment for AKI following cardiac surgery.

Renal replacement therapy (dialysis)

Renal replacement therapy (RRT) is the primary treatment modality for AKI, particularly in cases associated with sepsis. Intermittent hemodialysis (IHD) and continuous RRT (CRRT) are the two main forms of RRT used to treat patients with severe AKI. The cornerstone of managing early AKI lies in preventive strategies, such as optimizing volume hemodynamics and status, as well as avoiding nephrotoxins. However, for severe AKI, RRT remains the sole therapeutic option. The optimal timing for initiating RRT has long been a subject of debate. Traditionally, RRT is initiated for the acute management of critical complications arising from AKI. The choice of the most suitable RRT option for critically ill patients with AKI remains a contentious issue. A secondary analysis of the Standard versus Accelerated Renal Replacement Therapy in AKI (STARRT-AKI) trial unveiled that among critically ill patients suffering from severe AKI, the commencement of CRRT was linked to a substantial decrease in the combined outcome of death or dependence on RRT at 90 days, compared to IHD [ 287 ]. Another secondary analysis of two multicenter randomized controlled trials, namely the AKIKI and IDEAL-ICU studies, indicated that using CRRT as the first modality did not appear to confer any benefits regarding survival or renal function restoration. In fact, it might have correlated with less positive outcomes in patients with less advanced disease when compared to IHD [ 288 ]. Unexpectedly, among critically ill patients with AKI, an expedited renal-replacement approach did not result in a decreased likelihood of death within 90 days compared to a standard strategy (STARRT-AKI ClinicalTrials.gov number, NCT02568722 ) [ 289 ]. The Worldwide Exploration of Renal Replacement Outcomes Collaborative in Kidney Disease (WE-ROCK) on a contemporary cohort of children weighing ≤ 10 kg treated with continuous kidney replacement therapy (CKRT) for AKI and/or fluid overload. ICU mortality rates are reduced when compared to those in prospective pediatric CRRT. The reasons for initiating treatment early are manifold. It can help to prevent severe electrolyte and acid–base disturbances, achieve better volume control, and avert uremic complications as well as rapid mortality due to the adverse effects of renal failure. Moreover, when determining whether to commence RRT, it is crucial to consider the trends in laboratory test results rather than relying solely on the creatinine threshold or blood urea nitrogen (BUN) level. However, starting RRT before it is truly necessary may expose patients to a variety of negative consequences. Surveillance and prevention of fluid overload during extracorporeal membrane oxygenation (ECMO) and CKRT are essential to reduce the risk of mortality [ 290 ]. The application of the oXiris filter in CRRT has been linked to diminished inflammatory damage and enhanced renal perfusion. However, in cases of sepsis-associated AKI, it does not appear to correlate with enhanced 28—day recovery of renal function or reduced 28-day all-cause mortality [ 291 ]. In a retrospective study conducted at a single center, low-effluent volume CRRT-PIRRT demonstrated comparable outcomes to standard effluent volume CRRT-PIRRT, aligning with the findings of previous observational research [ 292 ]. Artificial intelligence (AI) by establishing longitudinal, multimodal models improved early detection of AKI and prediction of CRRT requirement, facilitating timely interventions and thereby optimizing AKI management [ 293 ]. Despite the diverse ethical, climatic, geographic, and socioeconomic contexts in Asia that lead to the utilization of various RRT modalities, it is of paramount importance to ensure optimal care for all AKI patients.

Conclusions and perspectives

Recent advances in understanding the pathophysiology, risk factors, and causes of AKI highlight its significance in AKI genesis and development. Among them, onco-nephrology is an emerging and rapidly evolving subspecialty that delves into the intricate and multifaceted relationships between the kidneys and cancer. Prior research has elucidated the “two-hit” mechanism explaining the link between AKI and clinical conditions. For example, cancer acts as the initial insult or “first hit” to the kidney, with subsequent exposure to diverse treatments exacerbating toxicity and serving as the subsequent insult or “second hit” [ 294 ]. These discoveries underscore the critical interplay between remote malignancies and the kidney, with direct clinical relevance. Furthermore, they provide fresh perspectives on AKI management and treatment. Nonetheless, it is essential to recognize specific limitations. The complexity and dynamic nature of human tumors were inadequately captured in the animal model used. The traditional cisplatin-induced AKI mouse model lacks tumor presence. To enhance the relevance to clinical scenarios for this subgroup, it is essential to develop more comprehensive animal models that incorporate factors like appropriate dosing regimens of cisplatin, age, gender, genetic background, and tumor grafts, thus increasing model reproducibility and translatability significantly. Additionally, variations in AKI assessment criteria among previous studies may lead to inconsistencies in AKI evaluations.

Although AKI was well-defined and studied, it was clearly different from CKD. Nevertheless, there is a substantial deficiency in research, care, and guidance for patients who have abnormalities in kidney function and/or structure but do not meet the diagnostic criteria for either AKI or CKD. AKD is addressed and defined by functional or structural kidney abnormalities that have health implications and last for a duration of ≤ 3 months. AKD encompasses AKI, but more significantly, it also involves kidney functional abnormalities that are less severe than AKI or that evolve over a period exceeding 7 days [ 295 ]. Hence, future exploration of AKD is of importance. Timely detection and treatment of AKI are crucial to prevent its progression to AKD and mitigate long-term adverse outcomes [ 296 ]. The intensity and duration of early postoperative AKI are linked to a higher incidence of AKD, and early postoperative AKI has a strong association with AKD [ 297 ]. Pseudo-AKI occurrences pose challenges in clinical practices, particularly concerning the impact of diverse targeted agents, highlighted in recent literature [ 298 – 307 ] (Table 5 ). Notably, some tyrosine kinase inhibitors (e.g., sunitinib, sorafenib) and BCR-ABL inhibitors (e.g., dasatinib, nilotinib) have demonstrated potential for inducing pseudo-AKI in vitro, although clinical verification is lacking [ 301 , 308 ]. Lastly, subclinical AKI may manifest during cancer treatments, presenting symptoms like hypertension from renin-angiotensin axis activation, flank pain due to renal capsule stretching, and hematuria.

To date, a group of studies revealed that it’s essential to screen and utilize biomarkers in early cancer detection and pinpointing the highest-risk patients [ 309 ]. Currently, novel tumor markers have emerged, leveraging genetic mutations or epigenetic modifications frequently observed in cancer, including abnormal DNA methylation, exosomes, metabolites, mRNAs, or cell-free DNA (cfDNA), with urinary markers also being explored [ 310 ]. Therefore, a thorough comprehension of the fundamental mechanisms of cancer-associated AKI is crucial to advocate AKI-related biomarker screening for early detection and subsequent protective measures to maintain renal function during cancer progression and exposure to diverse therapies. While biomarkers for predicting AKI and small molecular inhibitors for AKI alleviation have emerged, it is vital to tackle the challenges linked to identifying AKI or subclinical AKI within the cancer context. Currently, only a limited number of novel biomarkers have been incorporated into conventional clinical management. Shi K et al. performed a meta-analysis and unveiled that CCL14 emerges as the optimal biomarker for predicting persistent AKI, particularly persistent stage 2–3 AKI [ 311 ]. With the advent of artificial intelligence (AI), its application has predominantly been centered on predicting AKI. However, more advanced methods are also being employed to categorize existing AKI into distinct phenotypes [ 312 ]. Early prediction of AKI by novel biomarkers or AI-based prediction models may provide a crucial opportunity for AKI prevention [ 313 ]. Postoperative acute kidney injury requiring dialysis (PO-AKID) is a serious adverse event strongly associated with acute morbidity and mortality, as well as long-term prognosis. A web-based risk calculator called the PO-AKID-teller can accurately predict an individual's risk for PO-AKID in an easy-to-understand way. This tool may help with informed decision-making, patient counseling, perioperative optimization, and longer-term care planning [ 314 ].

Timely intervention is critical for controlling AKI. Targeted therapies should be devised, focusing on the pivotal molecular pathways implicated in AKI pathogenesis. Uncertainty persists regarding the association between AKI and novel agents like CDK4/6 inhibitors, necessitating extensive prospective studies to elucidate incidence rates and risk factors for AKI in patients undergoing such therapies [ 315 ]. Likely, some innovative cancer treatments regarding small renal mass such as focal therapy and active surveillance and associated renal function detriments including AKI are arrived and paid more focus [ 316 ]. As for metastatic renal carcinoma, cytoreductive nephrectomy and metastasectomy showed different advantages [ 317 ]. Therapeutic targeting of mitochondria is an emerging strategy for AKI. Yet, additional studies are required prior to its application in clinical therapeutic contexts. Meanwhile, postponing the progression from AKI to CKD is a viable and manageable treatment approach. Specifically, Zn-D/DTH has been shown to reduce renal IRI and delay the transition from AKI to CKD by downregulating the TLR4/MyD88/NF-κB signaling cascade and reducing the expression of apoptotic caspases, thereby inhibiting inflammation and decreasing cell apoptosis [ 318 ]. Furthermore, recognizing high-risk individuals and clinical conditions, as well as high-risk situations and procedures, is an important step toward preventing AKI. Early detection of AKI may present a critical opportunity for AKI prophylaxis. Once considered a transient condition, AKI is now recognized as having significant long-term consequences. Acute alterations in kidney function are increasingly understood to be associated with the progression to CKD, adverse cardiovascular effects, persistent functional impairment, and increased mortality. The majority of significant “treatments” for AKI majority address complications of AKI rather than AKI itself. On the same note, AKI causes mutual damage within multi-organ injuries. During cardiac arrest, ischemia–reperfusion followed by successful cardiopulmonary resuscitation was prone to lead to AKI. Traditional complications of AKI, including electrolyte imbalances, uremia, and fluid overload, have long been identified as major factors contributing to adverse pulmonary outcomes in patients with AKI, respiratory complications/inflammatory lung injury. Moreover, AKI also led to intestinal injury, liver injury, and immunoparalysis. Likewise, the injuries of these organs also resulted in or exacerbated AKI. Most of these interventions are also highly debated. Among them, diuretics and bicarbonate are particularly contentious. Regarding diuretics, KDIGO advises against their use for treating AKI, except in cases of fluid overload. As for bicarbonate supplementation, the evidence from randomized controlled trials is extremely limited, which makes its efficacy highly questionable. It is crucial to establish a sustainable infrastructure that can provide appropriate care for all AKI patients.

In summary, AKI remains a catastrophic issue among hospitalized patients, particularly for those in critical condition. Although the development of biomarkers for early diagnosis is still ongoing, raising awareness of AKI is crucial for early detection. This early recognition is highly contingent upon the specific context and the resources available at the site where AKI occurs. These findings can provide the pathological mechanism of AKI and may establish novel therapeutic strategies. Undoubtedly, future investigations will identify additional biomarkers, targets, and therapies for AKI.

Supplementary Information

Supplementary Material 1: Table 1. The patients-related risk factor associated with AKI. Table 2. AKI-related anti-cancer drugs

Acknowledgements

We would like to acknowledge a scientific platform called BioRender ( https://app.biorender.com ), which was used by our team to make the figures presented in our manuscript. This platform has a helpful role in providing higher quality of the manuscript.

Authors’ contributions

Writing-original draft: XQX and TTZ. Funding acquisition: TTZ, YLS, YH, and WW. Writing-review, editing and visualization: SC. Visualization: XQX, TTZ, NT, and CYZ. Formal analysis and investigation: YMC and SYD. Data curation and investigation: ZGM, JL, and THZ. Resources and investigation: YH and WW. Conceptualization and supervision: PC and YLS. Project administration: YLS. All authors have read and approved the final manuscript.

Funding

This study was supported in part by National Natural Science Foundation of China (No. 82302632, Yali Song), Natural Science Foundation of Sichuan Province (No. 2025ZNSFSC0550, Yali Song) and the grants from the Clinical Research Center for Gastrointestinal Cancer In Hunan Province (No. 2021SK4016, Yi He and Wei Wang).

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable as no patients/participants were involved in this review.

Competing interests

All authors state that there are no potential competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Xiaoqin Xu and Tingting Zeng contributed equally to this work.

Contributor Information

Pan Chen, Email: chenpan@hnca.org.cn.

Yali Song, Email: songyl@scu.edu.cn.

References

1. Ostermann M, Lumlertgul N, Jeong R, See E, Joannidis M, James M. Acute kidney injury. Lancet. 2025;405(10474):241–56. 10.1016/S0140-6736(24)02385-7.

2. Patidar KR, Ma AT, Juanola A, Barone A, Incicco S, Kulkarni AV, et al. Global epidemiology of acute kidney injury in hospitalised patients with decompensated cirrhosis: the International Club of Ascites GLOBAL AKI prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2025;10(5):418–30. 10.1016/S2468-1253(25)00006-8.

3. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative w. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8(4):R204–12. 10.1186/cc2872

4. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. 10.1186/cc5713.

5. Section 2: AKI Definition. Kidney Int Suppl (2011). 2012;2(1):19–36. 10.1038/kisup.2011.32

6. Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0) to Evaluate the Severity of Adverse Events of Anticancer Therapies. Actas Dermosifiliogr (Engl Ed). 2021;112(1):90–2. 10.1016/j.ad.2019.05.009

7. Munch PV, Norgaard M, Jensen SK, Birn H, Schmidt H, Christiansen CF. Risk of and mortality after acute kidney injury following cancer treatment: a cohort study. Cancer Med. 2025;14(3): e70646. 10.1002/cam4.70646.

8. Cheng Y, Nie S, Li L, Li Y, Liu D, Xiong M, et al. Epidemiology and outcomes of acute kidney injury in hospitalized cancer patients in China. Int J Cancer. 2019;144(11):2644–50. 10.1002/ijc.31993.

9. Can W, Rong L, Lixia L. Incidence and risk factors of acute kidney injury in patients with malignant tumors: a systematic review and meta-analysis. BMC Cancer. 2023;23(1):1123. 10.1186/s12885-023-11561-3.

10. Seylanova N, Crichton S, Zhang J, Fisher R, Ostermann M. Acute kidney injury in critically ill cancer patients is associated with mortality: A retrospective analysis. PLoS ONE. 2020;15(5): e0232370. 10.1371/journal.pone.0232370.

11. Wang W, Wang T, Feng X, Sun L. Incidence and risk factors of acute kidney injury after esophageal cancer surgery: A nested case-control study. Int J Surg. 2017;39:11–5. 10.1016/j.ijsu.2017.01.043.

12. Murphy CF, Dunne T, Elliott JA, Kamarajah SK, Leighton J, Evans RPT, et al. Acute Kidney Injury After Esophageal Cancer Surgery: Incidence, Risk Factors, and Impact on Oncologic Outcomes. Ann Surg. 2022;275(5):e683–9. 10.1097/SLA.0000000000004146.

13. Sim JH, Kang SJ, Bang JY, Song JG. Comparison of the Effects of Laparoscopic and Open Surgery on Postoperative Acute Kidney Injury in Patients with Colorectal Cancer: Propensity Score Analysis. J Clin Med. 2021;10(7):1438. 10.3390/jcm10071438.

14. Kwon T, Jeong IG, Lee C, You D, Hong B, Hong JH, et al. Acute Kidney Injury After Radical Cystectomy for Bladder Cancer is Associated with Chronic Kidney Disease and Mortality. Ann Surg Oncol. 2016;23(2):686–93. 10.1245/s10434-015-4886-4.

15. Schmid M, Krishna N, Ravi P, Meyer CP, Becker A, Dalela D, et al. Trends of acute kidney injury after radical or partial nephrectomy for renal cell carcinoma. Urol Oncol. 2016;34(7):293.e1-e10. 10.1016/j.urolonc.2016.02.018.

16. Bai Y, Du Y, Ye P, Luo Y. Acute kidney injury after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with advanced ovarian cancer. Front Oncol. 2023;13:1094410. 10.3389/fonc.2023.1094410.

17. Mou Z, Guan T, Chen L. Acute Kidney Injury in Adult Patients With Hepatocellular Carcinoma After TACE or Hepatectomy Treatment. Front Oncol. 2022;12: 627895. 10.3389/fonc.2022.627895.

18. Tafuri A, Marchioni M, Cerrato C, Mari A, Tellini R, Odorizzi K, et al. Changes in renal function after nephroureterectomy for upper urinary tract carcinoma: analysis of a large multicenter cohort (Radical Nephroureterectomy Outcomes (RaNeO) Research Consortium). World J Urol. 2022;40(11):2771–9. 10.1007/s00345-022-04156-3.

19. Trevisani F, Di Marco F, Quattrini G, Lepori N, Floris M, Valsecchi D, et al. Acute kidney injury and acute kidney disease in high-dose cisplatin-treated head and neck cancer. Front Oncol. 2023;13:1173578. 10.3389/fonc.2023.1173578.

20. Patimarattananan T, Nongnuch A, Pattaranutaporn P, Unwanatham N, Jiarpinitnun C, Ngamphaiboon N. Risk and impact of delayed renal impairment in patients with locally advanced head and neck squamous cell carcinoma receiving chemoradiotherapy with cisplatin. Support Care Cancer. 2021;29(2):877–87. 10.1007/s00520-020-05566-y.

21. Sakaguchi M, Nakayama K, Yamaguchi H, Mii A, Shimizu A, Inai K, et al. Risk Factors for Acute Kidney Injury and Chronic Kidney Disease following Allogeneic Hematopoietic Stem Cell Transplantation for Hematopoietic Malignancies. Acta Haematol. 2020;143(5):452–64. 10.1159/000504354.

22. Liu C, Wei W, Yang L, Li J, Yi C, Pu Y, et al. Incidence and risk factors of acute kidney injury in cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Front Immunol. 2023;14:1173952. 10.3389/fimmu.2023.1173952.

23. Yan H, Tang M, Zhu W, Yang Y. Immune checkpoint inhibitor-associated acute kidney injury in patients with cancer: a systematic review and meta-analysis of risk factors. Clin Exp Nephrol. 2023;27(7):603–12. 10.1007/s10157-023-02344-y.

24. Sherer MV, Deka R, Salans MA, Nelson TJ, Sheridan P, Rose BS. Androgen deprivation therapy and acute kidney injury in patients with prostate cancer undergoing definitive radiotherapy. Prostate Cancer Prostatic Dis. 2023;26(2):276–81. 10.1038/s41391-021-00415-3.

25. Kim K, Bang JY, Kim SO, Kim S, Kim JU, Song JG. Association of preoperative hypoalbuminemia with postoperative acute kidney injury in patients undergoing brain tumor surgery: a retrospective study. J Neurosurg. 2018;128(4):1115–22. 10.3171/2016.11.JNS162237.

26. Udzik J, Pacholewicz J, Biskupski A, Walerowicz P, Januszkiewicz K, Kwiatkowska E. Alterations to Kidney Physiology during Cardiopulmonary Bypass-A Narrative Review of the Literature and Practical Remarks. J Clin Med. 2023;12(21):6894. 10.3390/jcm12216894.

27. Perez-Fernandez X, Ulsamer A, Camara-Rosell M, Sbraga F, Boza-Hernandez E, Moret-Ruiz E, et al. Extracorporeal Blood Purification and Acute Kidney Injury in Cardiac Surgery: The SIRAKI02 Randomized Clinical Trial. JAMA. 2024;332(17):1446–54. 10.1001/jama.2024.20630.

28. Cossette F, Trifan A, Prevost-Marcotte G, Doolub G, So DF, Beaubien-Souligny W, et al. Tailored hydration for the prevention of contrast-induced acute kidney injury after coronary angiogram or PCI: A systematic review and meta-analysis. Am Heart J. 2025;282:93–102. 10.1016/j.ahj.2025.01.002.

29. Hoste EAJ, Kellum JA, Selby NM, Zarbock A, Palevsky PM, Bagshaw SM, et al. Global epidemiology and outcomes of acute kidney injury. Nat Rev Nephrol. 2018;14(10):607–25. 10.1038/s41581-018-0052-0.

30. Rosner MH, Jhaveri KD, McMahon BA, Perazella MA. Onconephrology: The intersections between the kidney and cancer. CA Cancer J Clin. 2021;71(1):47–77. 10.3322/caac.21636.

31. Liu S, Zhao J, Wang F. Acute kidney injury in cancer patients. Clin Exp Nephrol. 2022;26(2):103–12. 10.1007/s10157-021-02131-7.

32. Kitchlu A, McArthur E, Amir E, Booth CM, Sutradhar R, Majeed H, et al. Acute Kidney Injury in Patients Receiving Systemic Treatment for Cancer: A Population-Based Cohort Study. J Natl Cancer Inst. 2019;111(7):727–36. 10.1093/jnci/djy167.

33. Kang E, Park M, Park PG, Park N, Jung Y, Kang U, et al. Acute kidney injury predicts all-cause mortality in patients with cancer. Cancer Med. 2019;8(6):2740–50. 10.1002/cam4.2140.

34. Jin J, Wang Y, Shen Q, Gong J, Zhao L, He Q. Acute kidney injury in cancer patients: A nationwide survey in China. Sci Rep. 2019;9(1):3540. 10.1038/s41598-019-39735-9.

35. Nazzal Z, Abdeljaleel F, Ashayer A, Salameh H, Hamdan Z. The Rate and Risk Factors of Acute Kidney Injury among Cancer Patients’ Admissions in Palestine: A Single-Center Study. Int J Nephrol. 2022;2022:2972275. 10.1155/2022/2972275.

36. Cho S, Kang E, Kim JE, Kang U, Kang HG, Park M, et al. Clinical Significance of Acute Kidney Injury in Lung Cancer Patients. Cancer Res Treat. 2021;53(4):1015–23. 10.4143/crt.2020.1010.

37. Wang Z, Hu D, Xu H, Zeng R, Yao Y. Increased Lymphatic Vessels: A Risk Factor for Severe Renal Function Loss in Obstructive Nephropathy Patients. Int J Med Sci. 2024;21(12):2305–14. 10.7150/ijms.100367.

38. Folkestad T, Brurberg KG, Nordhuus KM, Tveiten CK, Guttormsen AB, Os I, et al. Acute kidney injury in burn patients admitted to the intensive care unit: a systematic review and meta-analysis. Crit Care. 2020;24(1):2. 10.1186/s13054-019-2710-4.

39. Stanaway IB, Morrell ED, Mabrey FL, Sathe NA, Bailey Z, Speckmaier S, et al. Urinary proteomics identifies distinct immunological profiles of sepsis associated AKI sub-phenotypes. Crit Care. 2024;28(1):419. 10.1186/s13054-024-05202-9.

40. Myles PS, Bellomo R, Corcoran T, Forbes A, Peyton P, Story D, et al. Restrictive versus Liberal Fluid Therapy for Major Abdominal Surgery. N Engl J Med. 2018;378(24):2263–74. 10.1056/NEJMoa1801601.

41. Leung N, Rajkumar SV. Multiple myeloma with acute light chain cast nephropathy. Blood Cancer J. 2023;13(1):46. 10.1038/s41408-023-00806-w.

42. Stotter BR, Cody E, Gu H, Daga A, Greenbaum LA, Duong MD, et al. Acute kidney injury requiring kidney replacement therapy in childhood lupus nephritis: a cohort study of the Pediatric Nephrology Research Consortium and Childhood Arthritis and Rheumatology Research Alliance. Pediatr Nephrol. 2023;38(5):1653–65. 10.1007/s00467-022-05775-z.

43. Hingorani SR, Seidel K, Pao E, Lawler R, McDonald GB. Markers of coagulation activation and acute kidney injury in patients after hematopoietic cell transplantation. Bone Marrow Transplant. 2015;50(5):715–20. 10.1038/bmt.2015.2.

44. Sugase T, Akimoto T, Kubo T, Imai T, Otani-Takei N, Miki T, et al. Acute Kidney Injury Associated with Renal Cell Carcinoma Complicated by Renal Vein and Inferior Vena Cava Involvement. Intern Med. 2016;55(17):2447–52. 10.2169/internalmedicine.55.6724.

45. Wang Y, Qi K, Cheng H, Cao J, Shi M, Qiao J, et al. Coagulation Disorders after Chimeric Antigen Receptor T Cell Therapy: Analysis of 100 Patients with Relapsed and Refractory Hematologic Malignancies. Biol Blood Marrow Transplant. 2020;26(5):865–75. 10.1016/j.bbmt.2019.11.027.

46. Ryu H, Kang E, Park S, Park S, Lee K, Joo KW, et al. A case of gemcitabine-induced thrombotic microangiopathy in a urothelial tumor patient with a single kidney. Kidney Res Clin Pract. 2015;34(4):237–40. 10.1016/j.krcp.2015.06.001.

47. Lodhi A, Kumar A, Saqlain MU, Suneja M. Thrombotic microangiopathy associated with proteasome inhibitors. Clin Kidney J. 2015;8(5):632–6. 10.1093/ckj/sfv059.

48. Nadim MK, Forni LG, Mehta RL, Connor MJ Jr, Liu KD, Ostermann M, et al. COVID-19-associated acute kidney injury: consensus report of the 25th Acute Disease Quality Initiative (ADQI) Workgroup. Nat Rev Nephrol. 2020;16(12):747–64. 10.1038/s41581-020-00356-5.

49. Aklilu AM, Kumar S, Nugent J, Yamamoto Y, Coronel-Moreno C, Kadhim B, et al. COVID-19-Associated Acute Kidney Injury and Longitudinal Kidney Outcomes. JAMA Intern Med. 2024;184(4):414–23. 10.1001/jamainternmed.2023.8225.

50. Hung AM, Shah SC, Bick AG, Yu Z, Chen HC, Hunt CM, et al. APOL1 Risk Variants, Acute Kidney Injury, and Death in Participants With African Ancestry Hospitalized With COVID-19 From the Million Veteran Program. JAMA Intern Med. 2022;182(4):386–95. 10.1001/jamainternmed.2021.8538.

51. Medeiros T, Guimaraes GMC, Carvalho FR, Alves LS, Faustino R, Campi-Azevedo AC, et al. Acute kidney injury associated to COVID-19 leads to a strong unbalance of circulant immune mediators. Cytokine. 2022;157: 155974. 10.1016/j.cyto.2022.155974.

52. Al-Aly Z, Agarwal A, Alwan N, Luyckx VA. Long COVID: long-term health outcomes and implications for policy and research. Nat Rev Nephrol. 2023;19(1):1–2. 10.1038/s41581-022-00652-2.

53. Moronge D, Sullivan JC, Faulkner JL. Physiology of Pregnancy-Related Acute Kidney Injury. Compr Physiol. 2023;13(3):4869–78. 10.1002/cphy.c220026.

54. Meena J, Kumar J, Kocharlakota JP, Gupta H, Mittal P, Kumar A, et al. Acute Kidney Injury in Neonates: A Meta-Analysis. Pediatrics. 2024;154(1):e2023065182. 10.1542/peds.2023-065182.

55. Rutledge AD, Griffin RL, Vincent K, Askenazi DJ, Segar JL, Kupferman JC, et al. Incidence, Risk Factors, and Outcomes Associated With Recurrent Neonatal Acute Kidney Injury in the AWAKEN Study. JAMA Netw Open. 2024;7(2): e2355307. 10.1001/jamanetworkopen.2023.55307.

56. Ejaz AA, Mohandas R, Beaver TM, Johnson RJ. A Crystal-Independent Role for Uric Acid in AKI Associated with Tumor Lysis Syndrome. J Am Soc Nephrol. 2023;34(1):175. 10.1681/ASN.0000000000000018.

57. Chapman R, Shah S, D’Angelo A. Acute kidney injury following induction of chemotherapy: Diagnosis and management in critical care. J Intensive Care Soc. 2023;24(1):112–6. 10.1177/17511437221106441.

58. Lupusoru G, Ailincai I, Fratila G, Ungureanu O, Andronesi A, Lupusoru M, et al. Tumor Lysis Syndrome: An Endless Challenge in Onco-Nephrology. Biomedicines. 2022;10(5):1012. 10.3390/biomedicines10051012.

59. Arnaud M, Loiselle M, Vaganay C, Pons S, Letavernier E, Demonchy J, et al. Tumor Lysis Syndrome and AKI: Beyond Crystal Mechanisms. J Am Soc Nephrol. 2022;33(6):1154–71. 10.1681/ASN.2021070997.

60. Koura S, Parekh V, Parikh AD, Kaur K, Dunn BK. Spontaneous Tumor Lysis Syndrome Secondary to Metastatic Small Cell Lung Cancer. Cureus. 2023;15(2): e34557. 10.7759/cureus.34557.

61. Shafie M, Teymouri A, Parsa S, Sadeghian A, Zarei JN. Spontaneous tumor lysis syndrome in adrenal adenocarcinoma: a case report and review of the literature. J Med Case Rep. 2022;16(1):52. 10.1186/s13256-022-03263-4.

62. Kalter JA, Allen J, Yang Y, Willing T, Evans E. Spontaneous Tumor Lysis Syndrome in an Adenocarcinoma of Unknown Origin. Cureus. 2020;12(12): e12169. 10.7759/cureus.12169.

63. Peerapornratana S, Manrique-Caballero CL, Gomez H, Kellum JA. Acute kidney injury from sepsis: current concepts, epidemiology, pathophysiology, prevention and treatment. Kidney Int. 2019;96(5):1083–99. 10.1016/j.kint.2019.05.026.

64. Yang Y, Dong J, Chen X, Chen R, Wang H. Incidence, risk factors and clinical outcomes of septic acute renal injury in cancer patients with sepsis admitted to the ICU: A retrospective study. Front Med (Lausanne). 2022;9:1015735. 10.3389/fmed.2022.1015735.

65. Ronco C, Bellomo R, Kellum JA. Acute kidney injury. Lancet. 2019;394(10212):1949–64. 10.1016/S0140-6736(19)32563-2.

66. Batte A, Shahrin L, Claure-Del Granado R, Luyckx VA, Conroy AL. Infections and Acute Kidney Injury: A Global Perspective. Semin Nephrol. 2023;43(5): 151466. 10.1016/j.semnephrol.2023.151466.

67. van der Slikke EC, Star BS, van Meurs M, Henning RH, Moser J, Bouma HR. Sepsis is associated with mitochondrial DNA damage and a reduced mitochondrial mass in the kidney of patients with sepsis-AKI. Crit Care. 2021;25(1):36. 10.1186/s13054-020-03424-1.

68. Balkrishna A, Sinha S, Kumar A, Arya V, Gautam AK, Valis M, et al. Sepsis-mediated renal dysfunction: Pathophysiology, biomarkers and role of phytoconstituents in its management. Biomed Pharmacother. 2023;165: 115183. 10.1016/j.biopha.2023.115183.

69. Han S, Jin R, Huo L, Teng Y, Zhao L, Zhang K, et al. HIF-1alpha participates in the regulation of S100A16-HRD1-GSK3beta/CK1alpha pathway in renal hypoxia injury. Cell Death Dis. 2024;15(5):316. 10.1038/s41419-024-06696-5.

70. Perazella MA, Rosner MH. Drug-Induced Acute Kidney Injury. Clin J Am Soc Nephrol. 2022;17(8):1220–33. 10.2215/CJN.11290821.

71. Guerrero-Hue M, Vallejo-Mudarra M, Garcia-Caballero C, Cordoba-David GM, Palomino-Antolin A, Herencia C, et al. Tweak/Fn14 system is involved in rhabdomyolysis-induced acute kidney injury. Biomed Pharmacother. 2023;169: 115925. 10.1016/j.biopha.2023.115925.

72. Nadim MK, Kellum JA, Forni L, Francoz C, Asrani SK, Ostermann M, et al. Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting. J Hepatol. 2024;81(1):163–83. 10.1016/j.jhep.2024.03.031.

73. Miwa T, Utakata Y, Hanai T, Aiba M, Unome S, Imai K, et al. Acute kidney injury development is associated with mortality in Japanese patients with cirrhosis: impact of amino acid imbalance. J Gastroenterol. 2024;59(9):849–57. 10.1007/s00535-024-02126-7.

74. Lin H, Guo X, Wang M, Su X, Qiao X. Risk factors and early prediction of cardiorenal syndrome type 3 among acute kidney injury patients: a cohort study. Ren Fail. 2024;46(1):2349113. 10.1080/0886022X.2024.2349113.

75. Bridoux F, Cockwell P, Glezerman I, Gutgarts V, Hogan JJ, Jhaveri KD, et al. Kidney injury and disease in patients with haematological malignancies. Nat Rev Nephrol. 2021;17(6):386–401. 10.1038/s41581-021-00405-7.

76. Bach AG, Behrmann C, Holzhausen HJ, Katzer M, Arnold D, Spielmann RP, et al. Prevalence and patterns of renal involvement in imaging of malignant lymphoproliferative diseases. Acta Radiol. 2012;53(3):343–8. 10.1258/ar.2011.110523.

77. Ohara Y, Kobayashi N, Toda T, Matsui N. Renal infiltration of peripheral T-cell lymphoma, not otherwise specified, mimicking drug-induced acute interstitial nephritis. CEN Case Rep. 2023;12(2):146–51. 10.1007/s13730-022-00736-9.

78. Ying WZ, Wang PX, Aaron KJ, Basnayake K, Sanders PW. Immunoglobulin light chains activate nuclear factor-kappaB in renal epithelial cells through a Src-dependent mechanism. Blood. 2011;117(4):1301–7. 10.1182/blood-2010-08-302505.

79. Leung N, Bridoux F, Batuman V, Chaidos A, Cockwell P, D’Agati VD, et al. The evaluation of monoclonal gammopathy of renal significance: a consensus report of the International Kidney and Monoclonal Gammopathy Research Group. Nat Rev Nephrol. 2019;15(1):45–59. 10.1038/s41581-018-0077-4.

80. Ying WZ, Li X, Rangarajan S, Feng W, Curtis LM, Sanders PW. Immunoglobulin light chains generate proinflammatory and profibrotic kidney injury. J Clin Invest. 2019;129(7):2792–806. 10.1172/JCI125517.

81. Wen YK, Chen ML. Acute renal failure secondary to small cell lung cancer with tumor infiltration of the kidneys. Ren Fail. 2006;28(3):261–4. 10.1080/08860220600580423.

82. Miyamoto A, Kawakami T, Kakinuma M, Sato R, Fukuoka K, Karube M, et al. Extensive bilateral renal metastases of non-small cell lung carcinoma caused acute kidney injury resulting in end-stage renal disease. CEN Case Rep. 2021;10(2):194–8. 10.1007/s13730-020-00541-2.

83. Sannier A, Dupuis E, Berger AK, Bischofs C, Massy ZA, Seidowsky A. Acute kidney injury associated with lymphangitic carcinomatosis. Clin Kidney J. 2019;12(4):527–9. 10.1093/ckj/sfy099.

84. Pitarresi JR, Norgard RJ, Chiarella AM, Suzuki K, Bakir B, Sahu V, et al. PTHrP Drives Pancreatic Cancer Growth and Metastasis and Reveals a New Therapeutic Vulnerability. Cancer Discov. 2021;11(7):1774–91. 10.1158/2159-8290.CD-20-1098.

85. Behdadnia A, Jeddi M. Severe hypercalcemia due to metastatic pancreatic neuroendocrine tumor: a case report. J Med Case Rep. 2023;17(1):400. 10.1186/s13256-023-04042-5.

86. Guise TA, Wysolmerski JJ. Cancer-Associated Hypercalcemia. N Engl J Med. 2022;386(15):1443–51. 10.1056/NEJMcp2113128.

87. Almuradova E, Cicin I. Cancer-related hypercalcemia and potential treatments. Front Endocrinol (Lausanne). 2023;14:1039490. 10.3389/fendo.2023.1039490.

88. Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352(4):373–9. 10.1056/NEJMcp042806

89. Ramos REO, Perez Mak M, Alves MFS, Piotto GHM, Takahashi TK, Gomes da Fonseca L, et al. Malignancy-Related Hypercalcemia in Advanced Solid Tumors: Survival Outcomes. J Glob Oncol. 2017;3(6):728–33. 10.1200/JGO.2016.006890

90. Ashrafi F, Iraj B, Nematollahi P, Darakhshandeh A. Pseudohypercalcemia in Multiple Myeloma: A Case Report. Int J Hematol Oncol Stem Cell Res. 2017;11(3):246–9.

91. Ciarimboli G, Deuster D, Knief A, Sperling M, Holtkamp M, Edemir B, et al. Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is a target for protective interventions. Am J Pathol. 2010;176(3):1169–80. 10.2353/ajpath.2010.090610.

92. Filipski KK, Mathijssen RH, Mikkelsen TS, Schinkel AH, Sparreboom A. Contribution of organic cation transporter 2 (OCT2) to cisplatin-induced nephrotoxicity. Clin Pharmacol Ther. 2009;86(4):396–402. 10.1038/clpt.2009.139.

93. Mizuno T, Sato W, Ishikawa K, Terao Y, Takahashi K, Noda Y, et al. Significance of downregulation of renal organic cation transporter (SLC47A1) in cisplatin-induced proximal tubular injury. Onco Targets Ther. 2015;8:1701–6. 10.2147/OTT.S86743.

94. Saito Y, Okamoto K, Kobayashi M, Narumi K, Yamada T, Iseki K. Magnesium attenuates cisplatin-induced nephrotoxicity by regulating the expression of renal transporters. Eur J Pharmacol. 2017;811:191–8. 10.1016/j.ejphar.2017.05.034.

95. Kumar G, Solanki MH, Xue X, Mintz R, Madankumar S, Chatterjee PK, et al. Magnesium improves cisplatin-mediated tumor killing while protecting against cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol. 2017;313(2):F339–50. 10.1152/ajprenal.00688.2016.

96. Zhang C, Guan Y, Zou J, Yang X, Bayliss G, Zhuang S. Histone methyltransferase MLL1 drives renal tubular cell apoptosis by p53-dependent repression of E-cadherin during cisplatin-induced acute kidney injury. Cell Death Dis. 2022;13(9):770. 10.1038/s41419-022-05104-0.

97. Hu Y, Yang C, Amorim T, Maqbool M, Lin J, Li C, et al. Cisplatin-Mediated Upregulation of APE2 Binding to MYH9 Provokes Mitochondrial Fragmentation and Acute Kidney Injury. Cancer Res. 2021;81(3):713–23. 10.1158/0008-5472.CAN-20-1010.

98. Yin Q, Zhao YJ, Ni WJ, Tang TT, Wang Y, Cao JY, et al. MiR-155 deficiency protects renal tubular epithelial cells from telomeric and genomic DNA damage in cisplatin-induced acute kidney injury. Theranostics. 2022;12(10):4753–66. 10.7150/thno.72456.

99. Yang Z, Schumaker LM, Egorin MJ, Zuhowski EG, Guo Z, Cullen KJ. Cisplatin preferentially binds mitochondrial DNA and voltage-dependent anion channel protein in the mitochondrial membrane of head and neck squamous cell carcinoma: possible role in apoptosis. Clin Cancer Res. 2006;12(19):5817–25. 10.1158/1078-0432.CCR-06-1037.

100. Mapuskar KA, Steinbach EJ, Zaher A, Riley DP, Beardsley RA, Keene JL, et al. Mitochondrial Superoxide Dismutase in Cisplatin-Induced Kidney Injury. Antioxidants (Basel). 2021;10(9):1329. 10.3390/antiox10091329.

101. McSweeney KR, Gadanec LK, Qaradakhi T, Ali BA, Zulli A, Apostolopoulos V. Mechanisms of Cisplatin-Induced Acute Kidney Injury: Pathological Mechanisms, Pharmacological Interventions, and Genetic Mitigations. Cancers (Basel). 2021;13(7):1572. 10.3390/cancers13071572.

102. Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal. 2012;24(5):981–90. 10.1016/j.cellsig.2012.01.008.

103. Li J, Shi X, Chen Z, Xu J, Zhao R, Liu Y, et al. Aldehyde dehydrogenase 2 alleviates mitochondrial dysfunction by promoting PGC-1alpha-mediated biogenesis in acute kidney injury. Cell Death Dis. 2023;14(1):45. 10.1038/s41419-023-05557-x.

104. Wang S, Chen Y, Wu H, Li X, Xiao H, Pan Q, et al. Role of Transcription Factor EB in Mitochondrial Dysfunction of Cisplatin-Induced Acute Kidney Injury. Int J Mol Sci. 2023;24(3):3028. 10.3390/ijms24033028.

105. Wang S, Zhu H, Li R, Mui D, Toan S, Chang X, et al. DNA-PKcs interacts with and phosphorylates Fis1 to induce mitochondrial fragmentation in tubular cells during acute kidney injury. Sci Signal. 2022;15(725):eabh1121. 10.1126/scisignal.abh1121

106. Yu X, Xu M, Meng X, Li S, Liu Q, Bai M, et al. Nuclear receptor PXR targets AKR1B7 to protect mitochondrial metabolism and renal function in AKI. Sci Transl Med. 2020;12(543):eaay7591. 10.1126/scitranslmed.aay7591.

107. Zhou M, Dai Y, Ma Y, Yan Y, Hua M, Gao Q, et al. Protective Effects of Liquiritigenin against Cisplatin-Induced Nephrotoxicity via NRF2/SIRT3-Mediated Improvement of Mitochondrial Function. Molecules. 2022;27(12):3823. 10.3390/molecules27123823.

108. Xie W, He Q, Zhang Y, Xu X, Wen P, Cao H, et al. Pyruvate kinase M2 regulates mitochondrial homeostasis in cisplatin-induced acute kidney injury. Cell Death Dis. 2023;14(10):663. 10.1038/s41419-023-06195-z.

109. Tsushida K, Tanabe K, Masuda K, Tanimura S, Miyake H, Arata Y, et al. Estrogen-related receptor alpha is essential for maintaining mitochondrial integrity in cisplatin-induced acute kidney injury. Biochem Biophys Res Commun. 2018;498(4):918–24. 10.1016/j.bbrc.2018.03.080.

110. Guo Y, Ni J, Chen S, Bai M, Lin J, Ding G, et al. MicroRNA-709 Mediates Acute Tubular Injury through Effects on Mitochondrial Function. J Am Soc Nephrol. 2018;29(2):449–61. 10.1681/ASN.2017040381.

111. Li M, Li CM, Ye ZC, Huang J, Li Y, Lai W, et al. Sirt3 modulates fatty acid oxidation and attenuates cisplatin-induced AKI in mice. J Cell Mol Med. 2020;24(9):5109–21. 10.1111/jcmm.15148.

112. Chen HC, Hou HY, Sung JM, Shieh CC. Deletion of NADPH oxidase 2 attenuates cisplatin-induced acute kidney injury through reducing ROS-induced proximal tubular cell injury and inflammation. Front Med (Lausanne). 2023;10:1097671. 10.3389/fmed.2023.1097671.

113. Meng XM, Ren GL, Gao L, Yang Q, Li HD, Wu WF, et al. NADPH oxidase 4 promotes cisplatin-induced acute kidney injury via ROS-mediated programmed cell death and inflammation. Lab Invest. 2018;98(1):63–78. 10.1038/labinvest.2017.120.

114. Chou YN, Lee MM, Deng JS, Jiang WP, Lin JG, Huang GJ. Water Extract from Brown Strain of Flammulina velutipes Alleviates Cisplatin-Induced Acute Kidney Injury by Attenuating Oxidative Stress, Inflammation, and Autophagy via PI3K/AKT Pathway Regulation. Int J Mol Sci. 2023;24(11):9448. 10.3390/ijms24119448.

115. Huang W, Wang BO, Hou YF, Fu Y, Cui SJ, Zhu JH, et al. JAML promotes acute kidney injury mainly through a macrophage-dependent mechanism. JCI Insight. 2022;7(14):e158571. 10.1172/jci.insight.158571.

116. Tan RZ, Li JC, Zhu BW, Huang XR, Wang HL, Jia J, et al. Neuropeptide Y protects kidney from acute kidney injury by inactivating M1 macrophages via the Y1R-NF-kappaB-Mincle-dependent mechanism. Int J Biol Sci. 2023;19(2):521–36. 10.7150/ijbs.80200.

117. Hsing CH, Tsai CC, Chen CL, Lin YH, Tseng PC, Satria RD, et al. Pharmacologically Inhibiting Glycogen Synthase Kinase-3beta Ameliorates Renal Inflammation and Nephrotoxicity in an Animal Model of Cisplatin-Induced Acute Kidney Injury. Biomedicines. 2021;9(8):887. 10.3390/biomedicines9080887.

118. Liu J, Yang DC, Zhang J, Hsu SW, Weiss RH, Chen CH. A Novel Renoprotective Strategy: Upregulation of PD-L1 Mitigates Cisplatin-Induced Acute Kidney Injury. Int J Mol Sci. 2021;22(24):13304. 10.3390/ijms222413304.

119. Liu P, Li X, Lv W, Xu Z. Inhibition of CXCL1-CXCR2 axis ameliorates cisplatin-induced acute kidney injury by mediating inflammatory response. Biomed Pharmacother. 2020;122: 109693. 10.1016/j.biopha.2019.109693.

120. Gonzalez A, Garcia-Gomez-Heras S, Franco-Rodriguez R, Lopez-Miranda V, Herradon E. Cisplatin cycles treatment sustains cardiovascular and renal damage involving TLR4 and NLRP3 pathways. Pharmacol Res Perspect. 2023;11(4): e01108. 10.1002/prp2.1108.

121. Andrade-Silva M, Cenedeze MA, Perandini LA, Felizardo RJF, Watanabe IKM, Agudelo JSH, et al. TLR2 and TLR4 play opposite role in autophagy associated with cisplatin-induced acute kidney injury. Clin Sci (Lond). 2018;132(16):1725–39. 10.1042/CS20170262.

122. Volarevic V, Markovic BS, Jankovic MG, Djokovic B, Jovicic N, Harrell CR, et al. Galectin 3 protects from cisplatin-induced acute kidney injury by promoting TLR-2-dependent activation of IDO1/Kynurenine pathway in renal DCs. Theranostics. 2019;9(20):5976–6001. 10.7150/thno.33959.

123. Li J, Tang Y, Tang PMK, Lv J, Huang XR, Carlsson-Skwirut C, et al. Blocking Macrophage Migration Inhibitory Factor Protects Against Cisplatin-Induced Acute Kidney Injury in Mice. Mol Ther. 2018;26(10):2523–32. 10.1016/j.ymthe.2018.07.014.

124. Ding Y, Wan S, Liu W, Lu Y, Xu Q, Gan Y, et al. Regulation Networks of Non-Coding RNA-Associated ceRNAs in Cisplatin-Induced Acute Kidney Injury. Cells. 2022;11(19):2971. 10.3390/cells11192971.

125. Cao Y, Mi X, Zhang D, Wang Z, Zuo Y, Tang W. Transcriptome sequencing of circular RNA reveals a novel circular RNA-has_circ_0114427 in the regulation of inflammation in acute kidney injury. Clin Sci (Lond). 2020;134(2):139–54. 10.1042/CS20190990.

126. Zhang C, Ma P, Zhao Z, Jiang N, Lian D, Huo P, et al. miRNA-mRNA regulatory network analysis of mesenchymal stem cell treatment in cisplatin-induced acute kidney injury identifies roles for miR-210/Serpine1 and miR-378/Fos in regulating inflammation. Mol Med Rep. 2019;20(2):1509–22. 10.3892/mmr.2019.10383.

127. Soni H, Matthews AT, Pallikkuth S, Gangaraju R, Adebiyi A. gamma-secretase inhibitor DAPT mitigates cisplatin-induced acute kidney injury by suppressing Notch1 signaling. J Cell Mol Med. 2019;23(1):260–70. 10.1111/jcmm.13926.

128. Wang S, Zheng Y, Jin S, Fu Y, Liu Y. Dioscin Protects against Cisplatin-Induced Acute Kidney Injury by Reducing Ferroptosis and Apoptosis through Activating Nrf2/HO-1 Signaling. Antioxidants (Basel). 2022;11(12):2443. https://doi.org/10.3390/antiox11122443.

129. Zhang X, Xu Y, Zhang W, Yang B, Zhang Y, Jia Z, et al. TRAF1 improves cisplatin-induced acute kidney injury via inhibition of inflammation and metabolic disorders. Biochim Biophys Acta Gen Subj. 2023;1867(9): 130423. 10.1016/j.bbagen.2023.1304230.

130. Tan Z, Guo F, Huang Z, Xia Z, Liu J, Tao S, et al. Pharmacological and genetic inhibition of fatty acid-binding protein 4 alleviated cisplatin-induced acute kidney injury. J Cell Mol Med. 2019;23(9):6260–70. 10.1111/jcmm.14512.

131. Loren P, Lugones Y, Saavedra N, Saavedra K, Paez I, Rodriguez N, et al. MicroRNAs Involved in Intrinsic Apoptotic Pathway during Cisplatin-Induced Nephrotoxicity: Potential Use of Natural Products against DDP-Induced Apoptosis. Biomolecules. 2022;12(9):1206. 10.3390/biom12091206.

132. Xia Y, Pan W, Xiao X, Zhou X, Gu W, Liu Y, et al. MicroRNA-483-5p accentuates cisplatin-induced acute kidney injury by targeting GPX3. Lab Invest. 2022;102(6):589–601. 10.1038/s41374-022-00737-3.

133. Xiong X, Tang B, Ji T, Li X, Bai S. Ameliorative effects of miR-186 on cisplatin-triggered acute kidney injury via targeting ZEB1. Am J Transl Res. 2021;13(5):4296–308.

134. Yang Y, Li ZL, Wang FM, Tang RN, Tu Y, Liu H. MicroRNA26a inhibits cisplatin-induced renal tubular epithelial cells apoptosis through suppressing the expression of transient receptor potential channel 6 mediated dynamin-related protein 1. Cell Biochem Funct. 2020;38(4):384–91. 10.1002/cbf.3474.

135. Mao W, Zhang L, Wang Y, Sun S, Wu J, Sun J, et al. Cisplatin induces acute kidney injury by downregulating miR-30e-5p that targets Galnt3 to activate the AMPK signaling pathway. Environ Toxicol. 2023. 10.1002/tox.24054.

136. Ewees MGE, Orfali R, Rateb EE, Hassan HM, Hozzein WN, Alkhalfah DHM, et al. Modulation of mi-RNA25/Ox-LDL/NOX4 signaling pathway by polyphenolic compound Hydroxytyrosol as a new avenue to alleviate cisplatin-induced acute kidney injury, a mechanistic study in rats. Environ Toxicol Pharmacol. 2023;103: 104262. 10.1016/j.etap.2023.104262.

137. Wu J, Li DD, Li JY, Yin YC, Li PC, Qiu L, et al. Identification of microRNA-mRNA networks involved in cisplatin-induced renal tubular epithelial cells injury. Eur J Pharmacol. 2019;851:1–12. 10.1016/j.ejphar.2019.02.015.

138. Zhao Y, Lang Y, Zhang M, Liang S, Zhu X, Liu Z. miR-125b Disrupts Mitochondrial Dynamics via Targeting Mitofusin 1 in Cisplatin-Induced Acute Kidney Injury. Kidney Dis (Basel). 2022;8(2):137–47. 10.1159/000520140.

139. Han S, Lin F, Ruan Y, Zhao S, Yuan R, Ning J, et al. miR-132-3p promotes the cisplatin-induced apoptosis and inflammatory response of renal tubular epithelial cells by targeting SIRT1 via the NF-kappaB pathway. Int Immunopharmacol. 2021;99: 108022.

140. Yang A, Liu F, Guan B, Luo Z, Lin J, Fang W, et al. p53 induces miR-199a-3p to suppress mechanistic target of rapamycin activation in cisplatin-induced acute kidney injury. J Cell Biochem. 2019;120(10):17625–34. 10.1002/jcb.29030.

141. Qin W, Xie W, Yang X, Xia N, Yang K. Inhibiting microRNA-449 Attenuates Cisplatin-Induced Injury in NRK-52E Cells Possibly via Regulating the SIRT1/P53/BAX Pathway. Med Sci Monit. 2016;22:818–23. 10.12659/msm.897187.

142. Sun W, Zhu Q, Yan L, Shao F. Mesenchymal stem cells alleviate acute kidney injury via miR-107-mediated regulation of ribosomal protein S19. Ann Transl Med. 2019;7(23):765. 10.21037/atm.2019.11.89.

143. Sami DH, Soliman AS, Khowailed AA, Hassanein EHM, Kamel EM, Mahmoud AM. 7-hydroxycoumarin modulates Nrf2/HO-1 and microRNA-34a/SIRT1 signaling and prevents cisplatin-induced oxidative stress, inflammation, and kidney injury in rats. Life Sci. 2022;310: 121104. 10.1016/j.lfs.2022.121104.

144. Chang S, Chang M, Liu G, Xu D, Wang H, Sun R, et al. LncRNA OIP5-AS1 reduces renal epithelial cell apoptosis in cisplatin-induced AKI by regulating the miR-144-5p/PKM2 axis. Biomed J. 2022;45(4):642–53. 10.1016/j.bj.2021.07.005.

145. Li J, Fan X, Wang Q, Gong Y, Guo L. Long Noncoding RNA PRNCR1 Reduces Renal Epithelial Cell Apoptosis in Cisplatin-Induced AKI by Regulating miR-182-5p/EZH1. Kidney Blood Press Res. 2021;46(2):162–72. 10.1159/000510157.

146. Kim J, Long KE, Tang K, Padanilam BJ. Poly(ADP-ribose) polymerase 1 activation is required for cisplatin nephrotoxicity. Kidney Int. 2012;82(2):193–203. 10.1038/ki.2012.64.

147. Wu WF, Wang JN, Li Z, Wei B, Jin J, Gao L, et al. 7-Hydroxycoumarin protects against cisplatin-induced acute kidney injury by inhibiting necroptosis and promoting Sox9-mediated tubular epithelial cell proliferation. Phytomedicine. 2020;69: 153202. 10.1016/j.phymed.2020.153202.

148. Zhang S, Sun H, Kong W, Zhang B. Functional role of microRNA-500a-3P-loaded liposomes in the treatment of cisplatin-induced AKI. IET Nanobiotechnol. 2020;14(6):465–9. 10.1049/iet-nbt.2019.0247.

149. Jiang S, Zhang H, Li X, Yi B, Huang L, Hu Z, et al. Vitamin D/VDR attenuate cisplatin-induced AKI by down-regulating NLRP3/Caspase-1/GSDMD pyroptosis pathway. J Steroid Biochem Mol Biol. 2021;206: 105789. 10.1016/j.jsbmb.2020.105789.

150. Liu J, Han X, Zhou J, Leng Y. Molecular Mechanisms of Ferroptosis and Their Involvement in Acute Kidney Injury. J Inflamm Res. 2023;16:4941–51. 10.2147/JIR.S427505.

151. Ma Y, Huang L, Zhang Z, Yang P, Chen Q, Zeng X, et al. CD36 promotes tubular ferroptosis by regulating the ubiquitination of FSP1 in acute kidney injury. Genes Dis. 2024;11(1):449–63. 10.1016/j.gendis.2022.12.003.

152. Yang M, Liu YT, Han YC, Zhang W, Zhang H, Yang S. Mitochondrial Translocation of P66Shc Aggravates Cisplatin-induced AKI by Promoting Ferroptosis. Curr Med Chem. 2023;30(6):744–56. 10.2174/0929867329666220819112808.

153. Deng Z, Wang Y, Liu J, Zhang H, Zhou L, Zhao H, et al. WBP2 restrains the lysosomal degradation of GPX4 to inhibit ferroptosis in cisplatin-induced acute kidney injury. Redox Biol. 2023;65: 102826. 10.1016/j.redox.2023.102826.

154. Gong Q, Lai T, Liang L, Jiang Y, Liu F. Targeted inhibition of CX3CL1 limits podocytes ferroptosis to ameliorate cisplatin-induced acute kidney injury. Mol Med. 2023;29(1):140. 10.1186/s10020-023-00733-3.

155. Zeng F, Nijiati S, Liu Y, Yang Q, Liu X, Zhang Q, et al. Ferroptosis MRI for early detection of anticancer drug-induced acute cardiac/kidney injuries. Sci Adv. 2023;9(10):eadd8539. 10.1126/sciadv.add8539

156. Yu M, Lin Z, Tian X, Chen S, Liang X, Qin M, et al. Downregulation of Cx43 reduces cisplatin-induced acute renal injury by inhibiting ferroptosis. Food Chem Toxicol. 2021;158: 112672. 10.1016/j.fct.2021.112672.

157. Dutta RK, Kondeti VK, Sharma I, Chandel NS, Quaggin SE, Kanwar YS. Beneficial Effects of Myo-Inositol Oxygenase Deficiency in Cisplatin-Induced AKI. J Am Soc Nephrol. 2017;28(5):1421–36. 10.1681/ASN.2016070744.

158. Deng F, Sharma I, Dai Y, Yang M, Kanwar YS. Myo-inositol oxygenase expression profile modulates pathogenic ferroptosis in the renal proximal tubule. J Clin Invest. 2019;129(11):5033–49. 10.1172/JCI129903.

159. Hu Z, Zhang H, Yi B, Yang S, Liu J, Hu J, et al. VDR activation attenuate cisplatin induced AKI by inhibiting ferroptosis. Cell Death Dis. 2020;11(1):73. 10.1038/s41419-020-2256-z.

160. Zhou J, Xiao C, Zheng S, Wang Q, Zhu H, Zhang Y, et al. MicroRNA-214-3p aggravates ferroptosis by targeting GPX4 in cisplatin-induced acute kidney injury. Cell Stress Chaperones. 2022;27(4):325–36. 10.1007/s12192-022-01271-3.

161. Alassaf N, Attia H. Autophagy and necroptosis in cisplatin-induced acute kidney injury: Recent advances regarding their role and therapeutic potential. Front Pharmacol. 2023;14:1103062. 10.3389/fphar.2023.1103062.

162. Herzog C, Yang C, Holmes A, Kaushal GP. zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function. Am J Physiol Renal Physiol. 2012;303(8):F1239–50. 10.1152/ajprenal.00659.2011.

163. Su L, Zhang J, Gomez H, Kellum JA, Peng Z. Mitochondria ROS and mitophagy in acute kidney injury. Autophagy. 2023;19(2):401–14. 10.1080/15548627.2022.2084862.

164. Zhao C, Chen Z, Xu X, An X, Duan S, Huang Z, et al. Pink1/Parkin-mediated mitophagy play a protective role in cisplatin induced renal tubular epithelial cells injury. Exp Cell Res. 2017;350(2):390–7. 10.1016/j.yexcr.2016.12.015.

165. Zhou L, Zhang L, Zhang Y, Yu X, Sun X, Zhu T, et al. PINK1 Deficiency Ameliorates Cisplatin-Induced Acute Kidney Injury in Rats. Front Physiol. 2019;10:1225. 10.3389/fphys.2019.01225.

166. Shen Q, Zhang X, Li Q, Zhang J, Lai H, Gan H, et al. TLR2 protects cisplatin-induced acute kidney injury associated with autophagy via PI3K/Akt signaling pathway. J Cell Biochem. 2019;120(3):4366–74. 10.1002/jcb.27722.

167. Liao W, Wang Z, Fu Z, Ma H, Jiang M, Xu A, et al. p62/SQSTM1 protects against cisplatin-induced oxidative stress in kidneys by mediating the cross talk between autophagy and the Keap1-Nrf2 signalling pathway. Free Radic Res. 2019;53(7):800–14. 10.1080/10715762.2019.1635251.

168. Kim JY, Jayne LA, Bai Y, Feng M, Clark MA, Chung S, et al. Ribociclib mitigates cisplatin-associated kidney injury through retinoblastoma-1 dependent mechanisms. Biochem Pharmacol. 2020;177: 113939. 10.1016/j.bcp.2020.113939.

169. Lin X, Jin H, Chai Y, Shou S. Cellular senescence and acute kidney injury. Pediatr Nephrol. 2022;37(12):3009–18. 10.1007/s00467-022-05532-2.

170. Yang L, Wang B, Guo F, Huang R, Liang Y, Li L, et al. FFAR4 improves the senescence of tubular epithelial cells by AMPK/SirT3 signaling in acute kidney injury. Signal Transduct Target Ther. 2022;7(1):384. 10.1038/s41392-022-01254-x.

171. Wen L, Ren Q, Guo F, Du X, Yang H, Fu P, et al. Tubular aryl hydratocarbon receptor upregulates EZH2 to promote cellular senescence in cisplatin-induced acute kidney injury. Cell Death Dis. 2023;14(1):18. 10.1038/s41419-022-05492-3.

172. Widemann BC, Balis FM, Kim A, Boron M, Jayaprakash N, Shalabi A, et al. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol. 2010;28(25):3979–86. 10.1200/JCO.2009.25.4540.

173. Bain E, Birhiray RE, Reeves DJ. Drug-drug interaction between methotrexate and levetiracetam resulting in delayed methotrexate elimination. Ann Pharmacother. 2014;48(2):292–6. 10.1177/1060028013511951.

174. DeFino CE, Barreto JN, Pawlenty AG, Ruff MW, Carabenciov ID, Mara KC, et al. Lack of drug interaction between levetiracetam and high-dose methotrexate in patients with lymphoma. Pharmacotherapy. 2021;41(5):430–9. 10.1002/phar.2516.

175. Borowka M, Lacki-Zynzeling S, Nicze M, Kozak S, Chudek J. Adverse Renal Effects of Anticancer Immunotherapy: A Review. Cancers (Basel). 2022;14(17):4086. 10.3390/cancers14174086.

176. Franzin R, Netti GS, Spadaccino F, Porta C, Gesualdo L, Stallone G, et al. The Use of Immune Checkpoint Inhibitors in Oncology and the Occurrence of AKI: Where Do We Stand? Front Immunol. 2020;11: 574271. 10.3389/fimmu.2020.574271.

177. Sun Q, Hong Z, Zhang C, Wang L, Han Z, Ma D. Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends. Signal Transduct Target Ther. 2023;8(1):320. 10.1038/s41392-023-01522-4.

178. Sprangers B, Leaf DE, Porta C, Soler MJ, Perazella MA. Diagnosis and management of immune checkpoint inhibitor-associated acute kidney injury. Nat Rev Nephrol. 2022;18(12):794–805. 10.1038/s41581-022-00630-8.

179. Joseph A, Lafarge A, Azoulay E, Zafrani L. Acute Kidney Injury in Cancer Immunotherapy Recipients. Cells. 2022;11(24):3991. 10.3390/cells11243991.

180. Gupta S, Seethapathy H, Strohbehn IA, Frigault MJ, O’Donnell EK, Jacobson CA, et al. Acute Kidney Injury and Electrolyte Abnormalities After Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Diffuse Large B-Cell Lymphoma. Am J Kidney Dis. 2020;76(1):63–71. 10.1053/j.ajkd.2019.10.011.

181. Wu S, Lu J, Su D, Yang F, Zhang Y, Hu S. The advantage of chimeric antigen receptor T cell therapy in pediatric acute lymphoblastic leukemia with E2A-HLF fusion gene positivity: a case series. Transl Pediatr. 2021;10(3):686–91. 10.21037/tp-20-323

182. Jhaveri KD, Rosner MH. Chimeric Antigen Receptor T Cell Therapy and the Kidney: What the Nephrologist Needs to Know. Clin J Am Soc Nephrol. 2018;13(5):796–8. 10.2215/CJN.12871117.

183. Neelapu SS, Tummala S, Kebriaei P, Wierda W, Gutierrez C, Locke FL, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15(1):47–62. 10.1038/nrclinonc.2017.148.

184. Perazella MA, Shirali AC. Nephrotoxicity of Cancer Immunotherapies: Past, Present and Future. J Am Soc Nephrol. 2018;29(8):2039–52. 10.1681/ASN.2018050488.

185. Sury K, Perazella MA, Shirali AC. Cardiorenal complications of immune checkpoint inhibitors. Nat Rev Nephrol. 2018;14(9):571–88. 10.1038/s41581-018-0035-1.

186. Richards DM, Kyewski B, Feuerer M. Re-examining the Nature and Function of Self-Reactive T cells. Trends Immunol. 2016;37(2):114–25. 10.1016/j.it.2015.12.005.

187. Farooqui N, Zaidi M, Vaughan L, McKee TD, Ahsan E, Pavelko KD, et al. Cytokines and Immune Cell Phenotype in Acute Kidney Injury Associated With Immune Checkpoint Inhibitors. Kidney Int Rep. 2023;8(3):628–41. 10.1016/j.ekir.2022.11.020.

188. Kohatsu K, Suzuki T, Takimoto M, Matsui K, Hashiguchi A, Koike J, et al. Granulomatous interstitial nephritis with CTLA-4 haploinsufficiency: a case report. BMC Nephrol. 2022;23(1):367. 10.1186/s12882-022-02999-x.

189. Jaworska K, Ratajczak J, Huang L, Whalen K, Yang M, Stevens BK, et al. Both PD-1 ligands protect the kidney from ischemia reperfusion injury. J Immunol. 2015;194(1):325–33. 10.4049/jimmunol.1400497.

190. Manohar S, Kompotiatis P, Thongprayoon C, Cheungpasitporn W, Herrmann J, Herrmann SM. Programmed cell death protein 1 inhibitor treatment is associated with acute kidney injury and hypocalcemia: meta-analysis. Nephrol Dial Transplant. 2019;34(1):108–17. 10.1093/ndt/gfy105.

191. Murakami N, Borges TJ, Yamashita M, Riella LV. Severe acute interstitial nephritis after combination immune-checkpoint inhibitor therapy for metastatic melanoma. Clin Kidney J. 2016;9(3):411–7. 10.1093/ckj/sfw024.

192. Koda R, Watanabe H, Tsuchida M, Iino N, Suzuki K, Hasegawa G, et al. Immune checkpoint inhibitor (nivolumab)-associated kidney injury and the importance of recognizing concomitant medications known to cause acute tubulointerstitial nephritis: a case report. BMC Nephrol. 2018;19(1):48. 10.1186/s12882-018-0848-y.

193. Shingarev R, Glezerman IG. Kidney Complications of Immune Checkpoint Inhibitors: A Review. Am J Kidney Dis. 2019;74(4):529–37. 10.1053/j.ajkd.2019.03.433.

194. Marco T, Anna P, Annalisa T, Francesco M, Stefania SL, Stella D, et al. The mechanisms of acute interstitial nephritis in the era of immune checkpoint inhibitors in melanoma. Ther Adv Med Oncol. 2019;11:1758835919875549. 10.1177/1758835919875549.

195. Fadel F, El Karoui K, Knebelmann B. Anti-CTLA4 antibody-induced lupus nephritis. N Engl J Med. 2009;361(2):211–2. 10.1056/NEJMc0904283.

196. Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for bladder cancer–a current perspective. Nat Rev Urol. 2014;11(3):153–62. 10.1038/nrurol.2014.15.

197. Kattih Z, Iacono A, Saikus C, Esposito M, Kon Z, Korotun M. Tacrolimus-induced thrombotic microangiopathy (TMA) after heart and lung transplantation successfully treated with eculizumab. Transpl Immunol. 2025;88: 102169. 10.1016/j.trim.2024.102169.

198. Efentakis P, Lamprou S, Makridakis M, Barla I, Nikolaou PE, Christodoulou A, et al. Mineralocorticoid Receptor Pathway Is a Key Mediator of Carfilzomib-induced Nephrotoxicity: Preventive Role of Eplerenone. Hemasphere. 2022;6(11): e791. 10.1097/HS9.0000000000000791.

199. Qadri MM, Alam MF, Khired ZA, Alaqi RO, Khardali AA, Alasmari MM, et al. Thymoquinone Ameliorates Carfilzomib-Induced Renal Impairment by Modulating Oxidative Stress Markers, Inflammatory/Apoptotic Mediators, and Augmenting Nrf2 in Rats. Int J Mol Sci. 2023;24(13):10621. 10.3390/ijms241310621.

200. Barla I, Efentakis P, Lamprou S, Gavriatopoulou M, Dimopoulos MA, Terpos E, et al. An Untargeted Metabolomics Approach on Carfilzomib-Induced Nephrotoxicity. Molecules. 2022;27(22):7929. 10.3390/molecules27227929.

201. Morrissey KM, Stocker SL, Wittwer MB, Xu L, Giacomini KM. Renal transporters in drug development. Annu Rev Pharmacol Toxicol. 2013;53:503–29. 10.1146/annurev-pharmtox-011112-140317.

202. Shen H, Yang Z, Zhao W, Zhang Y, Rodrigues AD. Assessment of vandetanib as an inhibitor of various human renal transporters: inhibition of multidrug and toxin extrusion as a possible mechanism leading to decreased cisplatin and creatinine clearance. Drug Metab Dispos. 2013;41(12):2095–103. 10.1124/dmd.113.053215.

203. Wanchoo R, Jhaveri KD, Deray G, Launay-Vacher V. Renal effects of BRAF inhibitors: a systematic review by the Cancer and the Kidney International Network. Clin Kidney J. 2016;9(2):245–51. 10.1093/ckj/sfv149.

204. Bonilla M, Jhaveri KD, Izzedine H. Anaplastic lymphoma kinase inhibitors and their effect on the kidney. Clin Kidney J. 2022;15(8):1475–82. 10.1093/ckj/sfac062.

205. Glezerman IG, Salvatore SP, Chandran CB, Flombaum CD, Seshan SV. Clinicopathological spectrum of kidney diseases in cancer patients treated with vascular endothelial growth factor inhibitors: a report of 5 cases and review of literature. Hum Pathol. 2014;45(9):1918–27. 10.1016/j.humpath.2014.05.015.

206. Ma Q, Zheng L, Cheng H, Li X, Liu Z, Gong P. PDCD4-induced oxidative stress through FGR/NF-kappaB axis in rectal cancer radiotherapy-induced AKI. Int Immunopharmacol. 2024;132: 111779. 10.1016/j.intimp.2024.111779.

207. Zhang D, Zhang S, He Z, Chen Y. Cytosine-phosphate-guanine oligodeoxynucleotides alleviate radiation-induced kidney injury in cervical cancer by inhibiting DNA damage and oxidative stress through blockade of PARP1/XRCC1 axis. J Transl Med. 2023;21(1):679. 10.1186/s12967-023-04548-y.

208. Mahran YF, Al-Kharashi LA, Atawia RT, Alanazi RT, Dhahi AMB, Alsubaie R, et al. Radioprotective Effects of Carvacrol and/or Thymol against Gamma Irradiation-Induced Acute Nephropathy: In Silico and In Vivo Evidence of the Involvement of Insulin-like Growth Factor-1 (IGF-1) and Calcitonin Gene-Related Peptide. Biomedicines. 2023;11(9):2521. 10.3390/biomedicines11092521

209. Shen J, Wang L, Jiang N, Mou S, Zhang M, Gu L, et al. NLRP3 inflammasome mediates contrast media-induced acute kidney injury by regulating cell apoptosis. Sci Rep. 2016;6:34682. 10.1038/srep34682.

210. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703. 10.1056/NEJMoa1210093.

211. Deng YH, Wang XF, Wu X, Yan P, Liu Q, Wu T, et al. Differential renal proteomics analysis in a novel rat model of iodinated contrast-induced acute kidney injury. Ren Fail. 2023;45(1):2178821. 10.1080/0886022X.2023.2178821.

212. Bidar F, Peillon L, Bodinier M, Venet F, Monneret G, Lukaszewicz AC, et al. Immune profiling of critically ill patients with acute kidney injury during the first week after various types of injuries: the REALAKI study. Crit Care. 2024;28(1):227. 10.1186/s13054-024-04998-w.

213. Lee K, Jang HR, Rabb H. Lymphocytes and innate immune cells in acute kidney injury and repair. Nat Rev Nephrol. 2024;20(12):789–805. 10.1038/s41581-024-00875-5.

214. Meng XM, Wang L, Nikolic-Paterson DJ, Lan HY. Innate immune cells in acute and chronic kidney disease. Nat Rev Nephrol. 2025. 10.1038/s41581-025-00958-x.

215. Mu YF, Mao ZH, Pan SK, Liu DW, Liu ZS, Wu P, et al. Macrophage-driven inflammation in acute kidney injury: Therapeutic opportunities and challenges. Transl Res. 2025;278:1–9. 10.1016/j.trsl.2025.02.003.

216. Chen H, Liu N, Zhuang S. Macrophages in Renal Injury, Repair, Fibrosis Following Acute Kidney Injury and Targeted Therapy. Front Immunol. 2022;13: 934299. 10.3389/fimmu.2022.934299.

217. Okubo K, Kurosawa M, Kamiya M, Urano Y, Suzuki A, Yamamoto K, et al. Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury. Nat Med. 2018;24(2):232–8. 10.1038/nm.4462.

218. Peng Y, Fang Y, Li Z, Liu C, Zhang W. Saa3 promotes pro-inflammatory macrophage differentiation and contributes to sepsis-induced AKI. Int Immunopharmacol. 2024;127: 111417. 10.1016/j.intimp.2023.111417.

219. Moledina DG, Mansour SG, Jia Y, Obeid W, Thiessen-Philbrook H, Koyner JL, et al. Association of T Cell-Derived Inflammatory Cytokines With Acute Kidney Injury and Mortality After Cardiac Surgery. Kidney Int Rep. 2019;4(12):1689–97. 10.1016/j.ekir.2019.09.003.

220. Lau A, Rahn JJ, Chappellaz M, Chung H, Benediktsson H, Bihan D, et al. Dipeptidase-1 governs renal inflammation during ischemia reperfusion injury. Sci Adv. 2022;8(5):eabm0142. 10.1126/sciadv.abm0142

221. Li S, Zhang Y, Lu R, Lv X, Lei Q, Tang D, et al. Peroxiredoxin 1 aggravates acute kidney injury by promoting inflammation through Mincle/Syk/NF-kappaB signaling. Kidney Int. 2023;104(2):305–23. 10.1016/j.kint.2023.04.013.

222. Liu AB, Tan B, Yang P, Tian N, Li JK, Wang SC, et al. The role of inflammatory response and metabolic reprogramming in sepsis-associated acute kidney injury: mechanistic insights and therapeutic potential. Front Immunol. 2024;15:1487576. 10.3389/fimmu.2024.1487576.

223. Zhao M, Wang Y, Li L, Liu S, Wang C, Yuan Y, et al. Mitochondrial ROS promote mitochondrial dysfunction and inflammation in ischemic acute kidney injury by disrupting TFAM-mediated mtDNA maintenance. Theranostics. 2021;11(4):1845–63. 10.7150/thno.50905.

224. Deng K, Pei M, Li B, Yang N, Wang Z, Wan X, et al. Signal pathways involved in contrast-induced acute kidney injury. Front Physiol. 2024;15:1490725. 10.3389/fphys.2024.1490725.

225. Ren N, Wang WF, Zou L, Zhao YL, Miao H, Zhao YY. The nuclear factor kappa B signaling pathway is a master regulator of renal fibrosis. Front Pharmacol. 2023;14:1335094. 10.3389/fphar.2023.1335094.

226. Sanz AB, Sanchez-Nino MD, Ramos AM, Ortiz A. Regulated cell death pathways in kidney disease. Nat Rev Nephrol. 2023;19(5):281–99. 10.1038/s41581-023-00694-0.

227. Guerrero-Mauvecin J, Villar-Gomez N, Rayego-Mateos S, Ramos AM, Ruiz-Ortega M, Ortiz A, et al. Regulated necrosis role in inflammation and repair in acute kidney injury. Front Immunol. 2023;14:1324996. 10.3389/fimmu.2023.1324996.

228. Ma N, Lu H, Li N, Ni W, Zhang W, Liu Q, et al. CHOP-mediated Gasdermin E expression promotes pyroptosis, inflammation, and mitochondrial damage in renal ischemia-reperfusion injury. Cell Death Dis. 2024;15(2):163. 10.1038/s41419-024-06525-9.

229. Zhang LM, Liu XM, Guo DW, Li F, Hao J, Zhao S. FBXW7-Mediated Downregulation of GPX4 Aggravates Acute Kidney Injury Following Ischemia-Reperfusion. Inflammation. 2024. 10.1007/s10753-024-02137-9.

230. Yang L, Xu Y, Pan J, Li R, Lan C, Zhang D. Discovery of mmu-lncRNA129814/hsa-lncRNA582795 as a Potential Biomarker and Intervention Target for Ischemia Reperfusion Injury-Induced AKI. J Inflamm Res. 2024;17:4277–96. 10.2147/JIR.S465910.

231. Niu X, Wang C, Li H, Chen W. Role of OPG/RANKL/RANK/TLR4 signaling pathway in sepsis-associated acute kidney injury. BMC Nephrol. 2024;25(1):205. 10.1186/s12882-024-03648-1.

232. Heyman SN, Gorelik Y, Zorbavel D, Rosenberger C, Abassi Z, Rosen S, et al. Near-drowning: new perspectives for human hypoxic acute kidney injury. Nephrol Dial Transplant. 2020;35(2):206–12. 10.1093/ndt/gfz016.

233. Wang Y, Kuang Z, Xing X, Qiu Y, Zhang J, Shao D, et al. Proximal tubular FHL2, a novel downstream target of hypoxia inducible factor 1, is a protector against ischemic acute kidney injury. Cell Mol Life Sci. 2024;81(1):244. 10.1007/s00018-024-05289-x.

234. Su Y, Wang P, Hu Y, Liu WJ, Zhang YJ, Chen JQ, et al. AKI-Pro score for predicting progression to severe acute kidney injury or death in patients with early acute kidney injury after cardiac surgery. J Transl Med. 2024;22(1):571. 10.1186/s12967-024-05279-4.

235. Chen Y, Li Z, Zhang H, Chen H, Hao J, Liu H, et al. Mitochondrial metabolism and targeted treatment strategies in ischemic-induced acute kidney injury. Cell Death Discov. 2024;10(1):69. 10.1038/s41420-024-01843-5.

236. Su L, Zhang J, Wang J, Wang X, Cao E, Yang C, et al. Pannexin 1 targets mitophagy to mediate renal ischemia/reperfusion injury. Commun Biol. 2023;6(1):889. 10.1038/s42003-023-05226-x.

237. Whitaker RM, Korrapati MC, Stallons LJ, Jesinkey SR, Arthur JM, Beeson CC, et al. Urinary ATP Synthase Subunit beta Is a Novel Biomarker of Renal Mitochondrial Dysfunction in Acute Kidney Injury. Toxicol Sci. 2015;145(1):108–17. 10.1093/toxsci/kfv038.

238. Zhang M, Zhang Y, Wu M, Li Z, Li X, Liu Z, et al. Importance of urinary mitochondrial DNA in diagnosis and prognosis of kidney diseases. Mitochondrion. 2021;61:174–8. 10.1016/j.mito.2021.10.003.

239. Gupta S, Mandal S, Banerjee K, Almarshood H, Pushpakumar SB, Sen U. Complex Pathophysiology of Acute Kidney Injury (AKI) in Aging: Epigenetic Regulation, Matrix Remodeling, and the Healing Effects of H(2)S. Biomolecules. 2024;14(9):1165. 10.3390/biom14091165.

240. Li Y, Ma S, Wang Z, Shi M, Zeng R, Yao Y. Gclc as a Marker for Injured Distal Nephron in Ischemia-Reperfusion Induced Acute Kidney Injury. J Inflamm Res. 2024;17:527–40. 10.2147/JIR.S451402.

241. Li X, Zhou X, Ping X, Zhao X, Kang H, Zhang Y, et al. Combined Plasma Olink Proteomics and Transcriptomics Identifies CXCL1 and TNFRSF12A as Potential Predictive and Diagnostic Inflammatory Markers for Acute Kidney Injury. Inflammation. 2024;47(5):1547–63. 10.1007/s10753-024-01993-9.

242. You R, Quan X, Xia P, Zhang C, Liu A, Liu H, et al. A promising application of kidney-specific cell-free DNA methylation markers in real-time monitoring sepsis-induced acute kidney injury. Epigenetics. 2024;19(1):2408146. 10.1080/15592294.2024.2408146.

243. Yuan L, Zhou Y, Wang R, Huang X, Tang R, Yan F. Unveiling the role of sTLR2: A novel biomarker for predicting septic-associated AKI. Cytokine. 2024;184: 156798. 10.1016/j.cyto.2024.156798.

244. Xu J, Chen J, Li M, Jiang Z, Fang F, Hu J, et al. Utility of plasma suPAR to identify AKI and sepsis associated AKI in critically ill children. iScience. 2024;27(11):111247. 10.1016/j.isci.2024.111247

245. Fu Y, Zhang Z, He C, Jia L, Ge C, Long L, et al. Performance of urinary C-C motif chemokine ligand 14 and the renal resistive index in predicting persistent AKI. Ren Fail. 2024;46(2):2438855. 10.1080/0886022X.2024.2438855.

246. Uchino T, Iwano Y, Miyazaki Y, Nakajo M, Osawa M, Nagai E, et al. Evaluation of urinary vanin-1 for the early prediction of cisplatin-induced acute kidney injury during neoadjuvant chemotherapy for esophageal cancer. Cancer Chemother Pharmacol. 2024;95(1):11. 10.1007/s00280-024-04737-6.

247. Holthoff JH, Alge JL, Arthur JM, Ayub F, Bin Homam W, Janech MG, et al. Urinary Complement C3 and Vitamin D-Binding Protein Predict Adverse Outcomes in Patients with Acute Kidney Injury after Cardiac Surgery. Nephron. 2025;149(2): 66–76. 10.1159/000540664

248. Li Y, Huang H, Zhou H. Elevated postoperative systemic immune-inflammation index associates with acute kidney injury after cardiac surgery: a large-scale cohort study. Front Cardiovasc Med. 2024;11:1430776. 10.3389/fcvm.2024.1430776.

249. Ma K, Qiu H, Zhu Y, Lu Y, Li W. Preprocedural SII Combined with High-Sensitivity C-Reactive Protein Predicts the Risk of Contrast-Induced Acute Kidney Injury in STEMI Patients Undergoing Percutaneous Coronary Intervention. J Inflamm Res. 2022;15:3677–87. 10.2147/JIR.S370085.

250. Ren L, Zhao Y, Wang T, Tong Y, Zhao P, Nie F, et al. Ultrasound molecular imaging for early detection of acute renal ischemia-reperfusion injury. Bioeng Transl Med. 2024;9(4): e10638. 10.1002/btm2.10638.

251. He W, Ding C, Lin T, Wang B, Wang W, Deng Z, et al. An enzyme-mimicking reactive oxygen species scavenger targeting oxidative stress-inflammation cycle ameliorates IR-AKI by inhibiting pyruvate dehydrogenase kinase 4. Theranostics. 2024;14(19):7534–53. 10.7150/thno.101229.

252. Buchanan C, Mahmoud H, Cox E, Noble R, Prestwich B, Kasmi I, et al. Multiparametric MRI assessment of renal structure and function in acute kidney injury and renal recovery. Clin Kidney J. 2021;14(8):1969–76. 10.1093/ckj/sfaa221.

253. Wang B, Wang Y, Wang J, Jin C, Zhou R, Guo J, et al. Multiparametric Magnetic Resonance Investigations on Acute and Long-Term Kidney Injury. J Magn Reson Imaging. 2024;59(1):43–57. 10.1002/jmri.28784.

254. Tao Q, Zhang Q, An Z, Chen Z, Feng Y. Multi-Parametric MRI for Evaluating Variations in Renal Structure, Function, and Endogenous Metabolites in an Animal Model With Acute Kidney Injury Induced by Ischemia Reperfusion. J Magn Reson Imaging. 2024;60(1):245–55. 10.1002/jmri.29094.

255. Nijiati S, Zeng F, Zuo C, Zhang Q, Du C, Shi C, et al. Fe(II)-Targeted PET/(19)F MRI Dual-Modal Molecular Imaging Probe for Early Evaluation of Anticancer Drug-Induced Acute Kidney Injury. Mol Pharm. 2023;20(10):5185–94. 10.1021/acs.molpharmaceut.3c00531.

256. Zhang W, Chan C, Zhang K, Qin H, Yu BY, Xue Z, et al. Discovering a New Drug Against Acute Kidney Injury by Using a Tailored Photoacoustic Imaging Probe. Adv Mater. 2024;36(18): e2311397. 10.1002/adma.202311397.

257. Li ZL, Li XY, Zhou Y, Wang B, Lv LL, Liu BC. Renal tubular epithelial cells response to injury in acute kidney injury. EBioMedicine. 2024;107: 105294. 10.1016/j.ebiom.2024.105294.

258. Chen S, Liu YH, Dai DP, Zhu ZB, Dai Y, Wu ZM, et al. Using circulating O-sulfotyrosine in the differential diagnosis of acute kidney injury and chronic kidney disease. BMC Nephrol. 2021;22(1):66. 10.1186/s12882-021-02268-3.

259. Alaasam ER, Janabi AM, Al-Buthabhak KM, Almudhafar RH, Hadi NR, Alexiou A, et al. Nephroprotective role of resveratrol in renal ischemia-reperfusion injury: a preclinical study in Sprague-Dawley rats. BMC Pharmacol Toxicol. 2024;25(1):82. 10.1186/s40360-024-00809-8.

260. Geng X, Fu Z, Geng G, Chi K, Liu C, Hong H, et al. Astilbin improves the therapeutic effects of mesenchymal stem cells in AKI-CKD mice by regulating macrophage polarization through PTGS2-mediated pathway. Stem Cell Res Ther. 2024;15(1):427. 10.1186/s13287-024-04025-3.

261. Kuang Y, Fan C, Long X, Zheng J, Zeng Y, Wei Y, et al. The Renoprotective and Anti-Inflammatory Effects of Human Urine-Derived Stem Cells on Acute Kidney Injury Animals. Curr Stem Cell Res Ther. 2024;20(2):199–210. 10.2174/011574888X296559240326063705.

262. Huang XR, Ye L, An N, Wu CY, Wu HL, Li HY, et al. Macrophage autophagy protects against acute kidney injury by inhibiting renal inflammation through the degradation of TARM1. Autophagy. 2025;21(1):120–40. 10.1080/15548627.2024.2393926.

263. Messina A, Calatroni M, Castellani G, De Rosa S, Ostermann M, Cecconi M. Understanding fluid dynamics and renal perfusion in acute kidney injury management. J Clin Monit Comput. 2024. 10.1007/s10877-024-01209-3.

264. Vaara ST, Ostermann M, Bitker L, Schneider A, Poli E, Hoste E, et al. Restrictive fluid management versus usual care in acute kidney injury (REVERSE-AKI): a pilot randomized controlled feasibility trial. Intensive Care Med. 2021;47(6):665–73. 10.1007/s00134-021-06401-6.

265. Wu M, Chen W, Miao M, Jin Q, Zhang S, Bai M, et al. Anti-anemia drug FG4592 retards the AKI-to-CKD transition by improving vascular regeneration and antioxidative capability. Clin Sci (Lond). 2021;135(14):1707–26. 10.1042/CS20210100.

266. Gong W, Lu L, Zhou Y, Liu J, Ma H, Fu L, et al. The novel STING antagonist H151 ameliorates cisplatin-induced acute kidney injury and mitochondrial dysfunction. Am J Physiol Renal Physiol. 2021;320(4):F608–16. 10.1152/ajprenal.00554.2020.

267. Landoni G, Monaco F, Ti LK, Baiardo Redaelli M, Bradic N, Comis M, et al. A Randomized Trial of Intravenous Amino Acids for Kidney Protection. N Engl J Med. 2024;391(8):687–98. 10.1056/NEJMoa2403769.

268. Poyan Mehr A, Tran MT, Ralto KM, Leaf DE, Washco V, Messmer J, et al. De novo NAD(+) biosynthetic impairment in acute kidney injury in humans. Nat Med. 2018;24(9):1351–9. 10.1038/s41591-018-0138-z.

269. Pickkers P, Angus DC, Bass K, Bellomo R, van den Berg E, Bernholz J, et al. Phase-3 trial of recombinant human alkaline phosphatase for patients with sepsis-associated acute kidney injury (REVIVAL). Intensive Care Med. 2024;50(1):68–78. 10.1007/s00134-023-07271-w.

270. Chen C, Wang W, Poklis JL, Li PL, Lichtman AH, Gewirtz DA, et al. Mitigation of cisplatin-induced acute kidney injury through oral administration of FAAH Inhibitor PF-04457845. J Pharmacol Exp Ther. 2024. 10.1124/jpet.124.002282.

271. Coca A, Bustamante-Munguira E, Fidalgo V, Fernandez M, Abad C, Franco M, et al. EValuating the Effect of periopeRaTIve empaGliflOzin on cardiac surgery associated acute kidney injury: rationale and design of the VERTIGO study. Clin Kidney J. 2024;17(8):sfae229. 10.1093/ckj/sfae229

272. Huo A, Wang F. Berberine alleviates ischemia reperfusion injury induced AKI by regulation of intestinal microbiota and reducing intestinal inflammation. BMC Complement Med Ther. 2024;24(1):66. 10.1186/s12906-023-04323-y.

273. Jiang B, Liu J, Qu Z, Wang Y, Wang Y, Li Z, et al. Mechanism of dihydroartemisinin in the treatment of ischaemia/reperfusion-induced acute kidney injury via network pharmacology, molecular dynamics simulation and experiments. Int Immunopharmacol. 2025;144: 113705. 10.1016/j.intimp.2024.113705.

274. Liu K, Hao X, Gao Y, Cao Z, Hou M, Qin L, et al. CUL4B protects kidneys from acute injury by restraining p53/PAI-1 signaling. Cell Death Dis. 2024;15(12):915. 10.1038/s41419-024-07299-w.

275. Song Z, Xia Y, Shi L, Zha H, Huang J, Xiang X, et al. Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury. Cell Mol Biol Lett. 2024;29(1):31. 10.1186/s11658-024-00553-1.

276. Jabbari H, Roushandeh AM, Rostami MK, Razavi-Toosi MT, Shokrgozar MA, Jahanian-Najafabadi A, et al. Mitochondrial transplantation ameliorates ischemia/reperfusion-induced kidney injury in rat. Biochim Biophys Acta Mol Basis Dis. 2020;1866(8): 165809. 10.1016/j.bbadis.2020.165809.

277. Rossi A, Asthana A, Riganti C, Sedrakyan S, Byers LN, Robertson J, et al. Mitochondria Transplantation Mitigates Damage in an In Vitro Model of Renal Tubular Injury and in an Ex Vivo Model of DCD Renal Transplantation. Ann Surg. 2023;278(6):e1313–26. 10.1097/SLA.0000000000006005.

278. Shen Z, Wang X, Lu L, Wang R, Hu D, Fan Z, et al. Bilirubin-Modified Chondroitin Sulfate-Mediated Multifunctional Liposomes Ameliorate Acute Kidney Injury by Inducing Mitophagy and Regulating Macrophage Polarization. ACS Appl Mater Interfaces. 2024;16(45):62693–709. 10.1021/acsami.4c14169.

279. Chang TT, Li SY, Tsai MT, Chiang CH, Chen C, Chen JW. CXCL5 inhibition ameliorates acute kidney injury and prevents the progression from acute kidney injury to chronic kidney disease. Clin Sci (Lond). 2024;138(22):1451–66. 10.1042/CS20241713.

280. Zhu LR, Cui W, Liu HP. Molecular mechanisms of endoplasmic reticulum stress-mediated acute kidney injury in juvenile rats and the protective role of mesencephalic astrocyte-derived neurotrophic factor. J Pharm Pharmacol. 2024. 10.1093/jpp/rgae134.

281. Wang Y, Cui C, Zhao W, Tian X, Liu P, Wei L, et al. WIP1-mediated regulation of p38 MAPK signaling attenuates pyroptosis in sepsis-associated acute kidney injury. Immunobiology. 2024;229(5): 152832. 10.1016/j.imbio.2024.152832.

282. Wang P, Li C, Peng T, Ruan L, Wu A, Zhu J, et al. Tolerogenic CD11c(+)dendritic cells regulate CD4(+)Tregs in replacing delayed ischemic preconditioning to alleviate ischemia-reperfusion acute kidney injury. FASEB J. 2024;38(6): e23575. 10.1096/fj.202302299RR.

283. Jiang W, Hou X, Qi Y, Wang Z, Liu Y, Gao XJ, et al. pH-Activatable Pre-Nanozyme Mediated H(2)S Delivery for Endo-Exogenous Regulation of Oxidative Stress in Acute Kidney Injury. Adv Sci (Weinh). 2024;11(18): e2303901. 10.1002/advs.202303901.

284. Long Q, Liao F, Yi H, Wang M, Zhuang J, Zheng Y, et al. Biodegradable Osmium Nanoantidotes for Photothermal-/Chemo- Combined Treatment and to Prevent Chemotherapy-Induced Acute Kidney Injury. Adv Healthc Mater. 2024;13(7): e2302729. 10.1002/adhm.202302729.

285. Sun J, Shen H, Dong J, Zhang J, Yue T, Zhang R. Melanin-Deferoxamine Nanoparticles Targeting Ferroptosis Mitigate Acute Kidney Injury via RONS Scavenging and Iron Ion Chelation. ACS Appl Mater Interfaces. 2025;17(1):282–96. 10.1021/acsami.4c14815.

286. Li H, Ouyang Y, Lv H, Liang H, Luo S, Zhang Y, et al. Nanoparticle-mediated Klotho gene therapy prevents acute kidney injury to chronic kidney disease transition through regulating PPARalpha signaling in renal tubular epithelial cells. Biomaterials. 2025;315: 122926. 10.1016/j.biomaterials.2024.122926.

287. Wald R, Gaudry S, da Costa BR, Adhikari NKJ, Bellomo R, Du B, et al. Initiation of continuous renal replacement therapy versus intermittent hemodialysis in critically ill patients with severe acute kidney injury: a secondary analysis of STARRT-AKI trial. Intensive Care Med. 2023;49(11):1305–16. 10.1007/s00134-023-07211-8.

288. Gaudry S, Grolleau F, Barbar S, Martin-Lefevre L, Pons B, Boulet E, et al. Continuous renal replacement therapy versus intermittent hemodialysis as first modality for renal replacement therapy in severe acute kidney injury: a secondary analysis of AKIKI and IDEAL-ICU studies. Crit Care. 2022;26(1):93. 10.1186/s13054-022-03955-9.

289. Investigators S-A, Canadian Critical Care Trials G, Australian, New Zealand Intensive Care Society Clinical Trials G, United Kingdom Critical Care Research G, Canadian Nephrology Trials N, et al. Timing of Initiation of Renal-Replacement Therapy in Acute Kidney Injury. N Engl J Med. 2020;383(3):240–51. 10.1056/NEJMoa2000741

290. Raina R, Nair N, Pelletier J, Nied M, Whitham T, Doshi K, et al. Concurrent use of continuous kidney replacement therapy during extracorporeal membrane oxygenation: what pediatric nephrologists need to know-PCRRT-ICONIC practice points. Pediatr Nephrol. 2025;40(1):267–84. 10.1007/s00467-024-06311-x.

291. Zheng F, Wang YL, Zhou WY, Zhang J, Lu M, Pan NF, et al. Continuous renal replacement therapy with adsorbing filter oXiris in the treatment of sepsis associated acute kidney injury: a single-center retrospective observational study. BMC Nephrol. 2024;25(1):456. 10.1186/s12882-024-03897-0.

292. Napoli M, Gianfreda D, Matino S, Ria P, Zito A, Fonto G, et al. The role of a “volume sparing” strategy in kidney replacement therapy of AKI: a retrospective single-center study. J Nephrol. 2025. 10.1007/s40620-024-02142-z.

293. Tan Y, Dede M, Mohanty V, Dou J, Hill H, Bernstam E, et al. Forecasting acute kidney injury and resource utilization in ICU patients using longitudinal, multimodal models. J Biomed Inform. 2024;154: 104648. 10.1016/j.jbi.2024.104648.

294. Humphreys BD. Caught in the crossfire: cancer, cisplatin therapy, and kidney injury. Am J Physiol Renal Physiol. 2023;324(4):F362–3. 10.1152/ajprenal.00037.2023.

295. Yeh TH, Tu KC, Wang HY, Chen JY. From Acute to Chronic: Unraveling the Pathophysiological Mechanisms of the Progression from Acute Kidney Injury to Acute Kidney Disease to Chronic Kidney Disease. Int J Mol Sci. 2024;25(3):1755. 10.3390/ijms25031755.

296. Wang H, Lambourg E, Guthrie B, Morales DR, Donnan PT, Bell S. Patient outcomes following AKI and AKD: a population-based cohort study. BMC Med. 2022;20(1):229. 10.1186/s12916-022-02428-8.

297. Meersch M, Weiss R, Strauss C, Albert F, Booke H, Forni L, et al. Acute kidney disease beyond day 7 after major surgery: a secondary analysis of the EPIS-AKI trial. Intensive Care Med. 2024;50(2):247–57. 10.1007/s00134-023-07314-2.

298. Vanhoutte T, Sprangers B. Pseudo-AKI associated with targeted anti-cancer agents-the truth is in the eye of the filtration marker. Clin Kidney J. 2023;16(4):603–10. 10.1093/ckj/sfad011.

299. Brosnan EM, Weickhardt AJ, Lu X, Maxon DA, Baron AE, Chonchol M, et al. Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib. Cancer. 2014;120(5):664–74. 10.1002/cncr.28478.

300. Arakawa H, Omote S, Tamai I. Inhibitory Effect of Crizotinib on Creatinine Uptake by Renal Secretory Transporter OCT2. J Pharm Sci. 2017;106(9):2899–903. 10.1016/j.xphs.2017.03.013.

301. Zhao D, Chen J, Chu M, Long X, Wang J. Pharmacokinetic-Based Drug-Drug Interactions with Anaplastic Lymphoma Kinase Inhibitors: A Review. Drug Des Devel Ther. 2020;14:1663–81. 10.2147/DDDT.S249098.

302. Wijtvliet V, Roosens L, De Bondt C, Janssens A, Abramowicz D. Pseudo-acute kidney injury secondary to tepotinib. Clin Kidney J. 2023;16(4):760–1. 10.1093/ckj/sfac180.

303. Mohan A, Herrmann SM. Capmatinib-Induced Pseudo-Acute Kidney Injury: A Case Report. Am J Kidney Dis. 2022;79(1):120–4. 10.1053/j.ajkd.2021.04.009.

304. Vidal-Petiot E, Rea D, Serrano F, Stehle T, Gardin C, Rousselot P, et al. Imatinib Increases Serum Creatinine by Inhibiting Its Tubular Secretion in a Reversible Fashion in Chronic Myeloid Leukemia. Clin Lymphoma Myeloma Leuk. 2016;16(3):169–74. 10.1016/j.clml.2015.12.001.

305. Chappell JC, Turner PK, Pak YA, Bacon J, Chiang AY, Royalty J, et al. Abemaciclib Inhibits Renal Tubular Secretion Without Changing Glomerular Filtration Rate. Clin Pharmacol Ther. 2019;105(5):1187–95. 10.1002/cpt.1296.

306. Mach T, Qi A, Bouganim N, Trinh E. Targeted Cancer Therapies Causing Elevations in Serum Creatinine Through Tubular Secretion Inhibition: A Case Report and Review of the Literature. Can J Kidney Health Dis. 2022;9:20543581221106250. 10.1177/20543581221106246.

307. Topletz-Erickson AR, Lee AJ, Mayor JG, Rustia EL, Abdulrasool LI, Wise AL, et al. Tucatinib Inhibits Renal Transporters OCT2 and MATE Without Impacting Renal Function in Healthy Subjects. J Clin Pharmacol. 2021;61(4):461–71. 10.1002/jcph.1750.

308. McCormick A, Swaisland H. In vitro assessment of the roles of drug transporters in the disposition and drug-drug interaction potential of olaparib. Xenobiotica. 2017;47(10):903–15. 10.1080/00498254.2016.1241449.

309. Matuszczak M, Schalken JA, Salagierski M. Prostate Cancer Liquid Biopsy Biomarkers’ Clinical Utility in Diagnosis and Prognosis. Cancers (Basel). 2021;13(13):3373. 10.3390/cancers13133373.

310. Matuszczak M, Kiljanczyk A, Salagierski M. A Liquid Biopsy in Bladder Cancer-The Current Landscape in Urinary Biomarkers. Int J Mol Sci. 2022;23(15):8597. 10.3390/ijms23158597.

311. Shi K, Jiang W, Song L, Li X, Zhang C, Li L, et al. Persistent acute kidney injury biomarkers: A systematic review and meta-analysis. Clin Chim Acta. 2025;564: 119907. 10.1016/j.cca.2024.119907.

312. Tran TT, Yun G, Kim S. Artificial intelligence and predictive models for early detection of acute kidney injury: transforming clinical practice. BMC Nephrol. 2024;25(1):353. 10.1186/s12882-024-03793-7.

313. Zhang Y, Xu D, Gao J, Wang R, Yan K, Liang H, et al. Development and validation of a real-time prediction model for acute kidney injury in hospitalized patients. Nat Commun. 2025;16(1):68. 10.1038/s41467-024-55629-5.

314. Chen Q, Fu B, Yang J, Jin Z, Zhang L, Fan R, et al. PO-AKID-teller: an interpretable machine learning tool for predicting acute kidney injury requiring dialysis after acute type A aortic dissection surgery. Medcomm-FUTURE MEDICINE. 2024;3(1): e77. 10.1002/mef2.77.

315. Gupta S, Caza T, Herrmann SM, Sakhiya VC, Jhaveri KD. Clinicopathologic Features of Acute Kidney Injury Associated With CDK4/6 Inhibitors. Kidney Int Rep. 2022;7(3):618–23. 10.1016/j.ekir.2021.11.033.

316. Matuszczak M, Kiljanczyk A, Salagierski M. The Role of Focal Therapy and Active Surveillance for Small Renal Mass Therapy. Biomedicines. 2022;10(10):2583. 10.3390/biomedicines10102583.

317. Matuszczak M, Kiljanczyk A, Salagierski M. Surgical Approach in Metastatic Renal Cell Carcinoma: A Literature Review. Cancers (Basel). 2023;15(6):1804. 10.3390/cancers15061804.

318. Wang JH, Mao HB, Hu JB, Cheng S, Su H. Engineering of phosphatidylserine-targeting ROS-responsive polymeric prodrug for the repair of ischemia-reperfusion-induced acute kidney injury. J Control Release. 2024;376:1100–14. 10.1016/j.jconrel.2024.10.063.

Associated Data

Supplementary Materials

Supplementary Material 1: Table 1. The patients-related risk factor associated with AKI. Table 2. AKI-related anti-cancer drugs

Data Availability Statement

Not applicable.