The evolving landscape of acute kidney injury: research directions and changes in clinical practice
Article information
Abstract
Acute kidney injury (AKI) is a common and serious disease, needing a comprehensive and management-based approach. While traditional practice focused on management after occurrence, recent practice is expanding its focus to prevention and novel therapeutic strategies, using new discoveries in AKI research. New biomarkers have been approved along with therapeutic agents, which target different pathophysiological pathways of AKI. In this review, we first summarize the current understanding of AKI definition and epidemiology, including global disparities and recent changes related to pandemics. Next, we highlight recent research directions regarding biomarkers, therapeutic agents, continuous renal replacement therapy, digital healthcare and artificial intelligence, and global collaborations. The aim of this review is to provide a comprehensive view of the direction in which AKI research is heading and link these areas to changes that are happening in clinical practice, with a goal to push innovative research accomplishments.
Introduction
Acute kidney injury (AKI) is a common and serious condition characterized by the sudden loss of kidney function. This impairment can range from a mild decrease to complete renal failure, presenting differing levels of risk to patient health. AKI affects patients across various clinical settings, from hospital wards to intensive care units (ICUs), and is associated with increased mortality, prolonged hospital stays, increased health care costs, and a higher likelihood of chronic kidney disease (CKD) progression [1]. These consequences can be alleviated with appropriate interventions in the early course of kidney injury, highlighting the importance of timely management [2,3]. Due to its complex pathophysiological mechanism and its acuteness, AKI remains a challenging condition for healthcare, emphasizing the need for a more detailed understanding of its underlying pathways.
Over recent years, the understanding of AKI has evolved, driven by advancements in research and technology. New epidemiological patterns have emerged, reflecting changes in population demographics and healthcare practices. Since AKI is a highly acute illness, prevention, early detection, and long-term management are important factors in treating AKI, and they serve as key objectives for many studies. Showing synergistic effects with new findings in pathophysiology, novel biomarkers and therapeutic agents are being continuously identified. Continuous renal replacement therapy (CRRT) methods are becoming more advanced, offering new options for patients requiring long-term management. Thanks to rapid advancements in technology, researchers now focus on new tools such as artificial intelligence (AI) and digital devices which can potentially help early detection, continuous monitoring, and clinical decision-making. Combined with traditional practices, these research findings are gradually being adopted into clinical practice.
The purpose of this review is to provide a comprehensive overview of the latest trends in AKI. It will explore its epidemiology, highlight the most notable research advancements, and discuss expected transformations in clinical practice. By understanding these advancements, clinicians and researchers can better optimize treatment strategies and ultimately improve patient outcomes.
Acute kidney injury epidemiology
The epidemiology of AKI has undergone notable transformations in recent years, reflecting shifts in population demographics, healthcare systems, and external influences such as pandemics. These changes provide new insights into the burden of AKI globally and emphasize the need for tailored interventions.
Overview
The current definition of AKI is given by Kidney Disease: Improving Global Outcomes (KDIGO), which defines and classifies different stages of AKI according to serum creatinine (sCr) and urine output fluctuation, as they are surrogates of glomerular filtration rate (GFR), a widely accepted index of kidney function. The main causes of AKI include hypovolemia, sepsis, nephrotoxic drugs, cardiac surgery, and radiocontrast agents, which lead to decreased kidney perfusion and damage such as acute interstitial nephritis [1,4–7]. In a systematic review (2004–2012) of 154 studies using the KDIGO criteria, inpatient incidence of AKI was 21.6% in adults, and 33.7% in children (23.2% in total patients). The rates of stage 1, stage 2, and stage 3 AKI were 11.5%, 4.8%, and 4.0%, respectively. Dialysis was required in 2.3% of hospitalized patients. Mortality for hospitalized AKI patients was 23.9% in adults and 13.8% in children. Mortality was higher for severe AKI (stage 3, requiring dialysis), which showed mortality over 40% [8]. In 2015, the Acute Kidney Injury-Epidemiologic Prospective Investigation study measured the incidence of AKI in ICUs and found that 57.3% of ICU patients had AKI, and that AKI was associated with higher mortality and poor kidney function [9]. However, many epidemiological studies show highly varying results of AKI incidence. Absence of baseline creatinine information and different methods to replace baseline creatinine might be the limiting factor in reporting accurate AKI incidence. Furthermore, AKI incidence can vary based on population, societal settings, and clinical settings such as sepsis, contrast use, drug use, and cardiac surgery [10].
Conditions that are not captured in the AKI definition are recognized in the acute kidney disease (AKD) criteria. AKD is a more persistent and broader category of AKI. AKD without AKI is common and associated with a high risk of CKD progression and other comorbidities compared to patients absent from kidney disease [10–12].
Global disparities of acute kidney injury
The burden of AKI varies significantly between regions with different income statuses. In high-income countries or urban areas, AKI often occurs in older populations with multiple comorbid conditions, such as diabetes and cardiovascular disease. Advances in healthcare have led to better recognition and documentation of these AKI cases, resulting in an apparent increase in their incidence. In these countries, AKI is mostly hospital-acquired, resulting from exposure to nephrotoxins, surgery, cardiovascular procedures, and sepsis.
In contrast, in low-income countries, AKI is more common among the young. These countries have higher rates of community-acquired AKI, often due to infections, dehydration, and environmental exposures. The rate of community-acquired AKI is higher in rural areas than in urban areas in these countries [3]. In resource-limited settings, the lack of access to advanced diagnostic tools and therapeutic interventions often results in delayed diagnosis and worse outcomes. These disparities highlight the need for targeted investments in healthcare infrastructure, education in underserved regions, and global strategies to address both hospital-acquired and community-acquired AKI.
It is important to consider the differences in AKI epidemiology between regions when preparing strategies for management. Focusing only on the disease itself and standard treatment options may not be efficient in every setting. Being aware of limited resources and the need for community management is necessary [3].
Recent changes in acute kidney injury epidemiology
Recently, the incidence of acute AKI has been increasing in hospital settings worldwide, particularly in high-income regions. In the United States, analysis of data from the National Inpatient Sample and the National Health Interview Survey demonstrated that the total number of hospitalizations associated with AKI increased approximately fourfold between 2000 and 2014 [13]. Recent data demonstrated a sharp increase in AKI incidence after 2019 [14]. Comparable trends have been reported in other high-income regions. In Europe, population-based studies have demonstrated a steady rise in AKI incidence over the past two decades, largely attributed to aging populations, increased comorbidity burden, and greater exposure to complex medical and surgical interventions [15]. Likewise, studies from Asia-Pacific countries, including China and Japan, have reported increasing AKI incidence in both hospitalized and critically ill populations, particularly in ICU settings [16]. In Korea, the incidence of AKI among ICU patients increased from 7.4% to 8.3% between 2008 and 2015 [17]. In another aspect, not only has the actual incidence of AKI increased, but also the detection of AKI may have increased by using novel biomarkers such as tissue inhibitor of metalloproteinases-2 (TIMP-2)/insulin-like growth factor-binding protein 7 (IGFBP7), neutrophil gelatinase-associated lipocalin (NGAL), and serum cystatin C.
Pandemic-associated acute kidney injury
The coronavirus disease 2019 (COVID-19) pandemic has significantly affected kidney health, with AKI being a common complication. A systematic review initially showed that the incidence of AKI in COVID-19 hospitalized patients was 5.5% for China and Korea, and 28.6% for the United States and Europe [18]. However, broader global data reveals significant regional variations: studies from South America (notably Brazil) reported much higher incidences exceeding 50% in hospitalized cohorts, while reports from the Middle East and South Asia indicate rates between 15% and 35%, depending on the severity of the cases and local comorbidities [19,20]. COVID-19 can have direct and indirect effects on AKI through multiple pathophysiological pathways. Although controversial, direct viral tropism of the kidney has been identified. Additionally, the enhanced release of inflammatory mediators and a stimulated immune response can cause endothelial injury or activate existing risk factors such as glomerulonephritis. Indirect effects are explained by the general frailty response to AKI as it is a critical illness [21]. Furthermore, COVID-19–associated AKI carries long-term risks even after clinical recovery, including a higher predisposition to CKD and a sustained decline in GFR [22]. These findings highlight the critical need for ongoing monitoring and management of kidney function in COVID-19 survivors across all global regions. Other pandemics, such as Middle East respiratory syndrome and severe acute respiratory syndrome, are also associated with a higher risk of AKI and were shown to be associated with higher mortality [20].
Acute kidney injury research advancements
The field of AKI research is evolving rapidly, with numerous opportunities for breakthroughs in diagnosis, treatment, and prevention. Future research is expected to focus on both biological mechanisms, innovative tools, and systemic factors to improve patient outcomes globally.
Overview of key research directions
Prevention and long-term management
Prevention is a key priority in managing AKI and prevention strategies are becoming more proactive. Prevention strategies focus on stratifying patients more precisely than the currently used stage-based classification to identify high-risk patients. This can be done by combining existing measures with novel biomarkers that are continuously researched and gradually adapted into clinical practice. Although still in development stages, AI can also be potentially used for efficient stratification. For patients with high risk, hospitals can follow protocols to reduce exposure to nephrotoxins, optimize volume status, and ensure appropriate hemodynamic monitoring. For example, the practice of ‘sick-day protocols’ is widely endorsed to prevent further kidney damage [23]. Multidisciplinary care teams including nephrologists, intensivists, and pharmacists play a vital role in these efforts for prevention.
Novel biomarker-based tests such as TIMP-2/IGFBP7 allow clinicians to detect AKI at an earlier stage, even before significant changes in sCr levels occur. This enables a more preventive management strategy by incorporating these tests. In the PrevAKI trial, a preventive strategy using the KDIGO bundle after cardiac surgery reduced the rate of AKI by 15% (55.1% vs. 71.7%) [24]. Similarly, in the BigpAK trial, identifying high-risk patients and following the KDIGO bundle reduced the rate of AKI by 20% after major cardiovascular surgery (27.1% vs. 48%) [25]. These findings were further supported by the subsequent BigpAK-2 trial, a large multinational randomized clinical study including more than 1,100 patients undergoing major surgery across various surgical disciplines. In this adequately powered trial, a preventive care strategy guided by urinary TIMP-2/IGFBP7 in combination with clinical risk factors significantly reduced the incidence of moderate to severe AKI within 72 hours after surgery compared with usual care. These results reinforce the efficacy and safety of biomarker-guided KDIGO bundle implementation and highlight its potential as a scalable strategy to reduce postoperative AKI [26].
One of the most pressing research areas is understanding the long-term impact of AKI. Many patients who recover from AKI experience a decline in kidney function, leading to an increased risk of CKD or end-stage renal disease. To prevent this transition, molecular and cellular processes involved in the transition from AKI to CKD need further investigation. Also, developing predictive models identifying patients at high risk of progression can help stratify patients and guide post-AKI management strategies.
Complexity of acute kidney injury pathophysiology
AKI is traditionally divided into three categories based on the location of defectiveness: prerenal azotemia, intrinsic AKI, and postrenal AKI. Prerenal azotemia is AKI caused by a sudden decrease in renal perfusion, often due to hypovolemia and a decrease in cardiac output. Using nonsteroidal anti-inflammatory drugs, angiotensin converting enzyme inhibitors, and angiotensin II receptor blockers can accelerate prerenal azotemia by restricting the autoregulative capability of vasodilation and vasoconstriction of the afferent and efferent arterioles, resulting in decreased glomerular filtration. Decreased blood flow can induce oxygen deprivation of tubular epithelial cells, leading to direct cell damage and intrinsic AKI. Intrinsic AKI is characterized by direct injury of the kidney cell and includes acute tubular necrosis, acute interstitial nephritis, acute vasculitis, and acute glomerulonephritis. The main risk factors are sepsis, ischemia, and nephrotoxins such as drugs and contrast agents. Postrenal AKI is mainly caused by urinary tract obstruction [1].
Traditional treatment options of AKI mainly focused on controlling macrovascular renal perfusion through fluid management. However, with deeper understandings of AKI pathophysiology, clinicians can now delve deeper into the complex causes of intrinsic AKI and address specific pathways regarding microvascular complications and tubular injury. Since kidney tubular cells are highly metabolic cells, deprivation of oxygen by microvascular dysfunction can be critical. Also, increased oxidative stress and immune responses due to the release of pro-inflammatory cytokines can cause epithelial damage, associated with AKI development and progression. Identification of targets involved in these pathways and discovery of novel therapeutic agents with anti-inflammatory and immunomodulatory functions can guide a new era in AKI treatment [27].
Novel acute kidney injury biomarkers
KDIGO defines AKI using sCr and urine output. However, sCr can be affected by non-kidney-related factors such as muscle mass or exogenous intake and is a late marker of kidney function decline [19]. Biomarkers for kidney injury such as NGAL can detect kidney damage earlier than sCr. Thus, these biomarkers can be used to predict upcoming AKI. Further, these damage biomarkers suggest an additional subphenotype of AKI. Evidence suggests that 15%–20% of patients who do not fulfill the sCr diagnostic criteria for AKI are nevertheless likely to have acute tubular damage, which is associated with major adverse kidney events [28]. This emerging subphenotype is commonly referred to as subclinical AKI [29]. In 2014, the 10th Acute Dialysis Quality Initiative meeting suggested a model that takes use of both functional markers including sCr, cystatin C, urine output and damage markers including NGAL, kidney injury molecule-1 (KIM-1), liver-type fatty acid-binding protein (L-FABP), interleukin-18 (IL-18) to stratify AKI patients. This expands the diagnostic criteria of AKI, especially those with damage but without loss of function. This meeting suggested that the use of damage biomarkers including NGAL can be potentially used for classification, monitoring, prognosis, and management guidance [30]. Further stratification using damage biomarkers can identify high-risk patients in early stages and optimize treatment strategies for patients with AKI burden (Figs. 1, 2) [31].
Biomarkers of acute kidney injury based on mechanism.
CCL14, C-C motif chemokine ligand 14; IGFBP7, insulin-like growth factor-binding protein 7; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; L-FABP, liver-type fatty acid-binding protein; NAG, N-acetyl-β-D-glucosaminidase; NGAL, neutrophil gelatinase-associated lipocalin; suPAR, soluble urokinase plasminogen activator receptor; TIMP-2, tissue inhibitor of metalloproteinases-2.
Clinical adoption of novel biomarkers in a timeline.
2011: Liver-type fatty acid-binding protein (L-FABP) approval in Japan. 2014: Tissue inhibitor of metalloproteinases-2 (TIMP-2)/insulin-like growth factor-binding protein 7 (IGFBP7) approval by U.S. Food and Drug Administration (FDA). 2018: Biomarker panel including urine clusterin, cystatin C, kidney injury molecule-1, N-acetyl-β-D-glucosaminidase, neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin approved for phase 1 study by FDA. 2023: NGAL approval by FDA.
Cystatin C is a protein that acts as a cysteine protease inhibitor. It has a constant production rate and gets filtered in the glomerulus. In contrast to sCr, serum cystatin C level is not affected by muscle mass and protein intake, having an advantage in detecting kidney function regardless of age, sex, and race. Thus, in populations where sCr results might not accurately estimate GFR, serum cystatin C can be used [30]. Serum cystatin C was shown to outperform sCr in predicting AKI at early stages, having greater sensitivity and elucidating eGFR decrease that is not captured using sCr tests, allowing for a more timely detection and management [32–34]. However, serum cystatin C levels can also be influenced by several factors such as corticosteroid use and thyroid dysfunction, therefore requiring caution in interpretation. Further research is needed to validate its use in AKI patients [32]. TIMP-2 and IGFBP7 are cell cycle arrest proteins expressed in tubular cells during cellular stress. TIMP-2 and IGFBP7 both inhibit cell growth by inducing G1 cell cycle arrest [35]. Cell cycle arrest is a protective process to stop the proliferation of injured cells. In response to stress of the kidney, tubular cells can express TIMP-2 and IGFBP7 to initiate G1 cell cycle arrest to repress division of damaged cells [36]. In 2014, the U.S. Food and Drug Administration (FDA) approved the TIMP-2/IGFBP7 test in ICU patients, 21 years or older, to aid assessment of moderate to severe AKI risk. Prior to FDA approval, major studies had been carried out to identify TIMP-2/IGFBP7 as a biomarker of AKI [37,38]. The use of TIMP-2/IGFBP7 had been validated in multiple settings [39–41].
Other promising biomarkers include NGAL, L-FABP, and KIM-1. NGAL is a promising biomarker to detect subclinical AKI as it is rapidly upregulated and secreted by the kidney in response to ischemic or nephrotoxic injury. It is expressed by tubular epithelial cells, specifically the proximal tubule, the thick ascending loop of Henle, and the collecting ducts. Within tubular cells, NGAL is synthesized in the cytoplasm. After synthesis, NGAL is secreted into the tubular lumen [42]. NGAL was originally identified in the cytoplasmic granules of neutrophils. NGAL is highly elevated after inflammation or kidney injury and can be found in plasma and urine within 2 hours of AKI. Elevated levels of urinary NGAL have been shown to effectively predict AKI and long-term consequences such as renal replacement therapy (RRT) initiation and death [43]. Recently in December 2023, the NGAL test achieved clearance by the FDA as an aid to identify the risk of moderate to severe AKI within 48 to 72 hours in pediatric ICU patients (≥3 months to <22 years) without underlying kidney disease [44,45]. During tubulointerstitial damage of the kidney, urinary excretion of L-FABP is increased, reflecting stress of proximal tubular epithelial cells [46]. Urinary L-FABP can facilitate the early detection of AKI before an increase in sCr in various clinical settings including ICU, surgery, and post-contrast settings [47]. After several studies regarding L-FABP, the Ministry of Health, Labor and Welfare in Japan approved the use of urinary L-FABP in both AKI and CKD [48]. In AKI patients, the ectodomain shedding can increase urinary KIM-1 levels up to a 100-fold increase [49].
Despite these promising findings, their overall predictive performance has been heterogeneous across studies, and none have consistently demonstrated sufficient accuracy to guide clinical decision-making when used in isolation. Recent evidence further highlights these limitations. In the MARKISIO study, no biomarker demonstrated significant predictive accuracy for the need for RRT within 72 hours after severe AKI onset in ICU patients, underscoring the gap between biomarker elevation and clinically actionable outcomes [50]. These findings suggest that while biomarkers may detect kidney injury earlier than conventional measures, their ability to predict disease severity or guide therapeutic interventions remains limited.
Other biomarkers being investigated
Search for novel biomarkers has no boundaries. Based on AKI pathophysiology understandings, investigations of new biomarkers, both functional and damage, are being actively done. Although adoption into routine clinical practice will take time, novel biomarkers can potentially be used for early detection of AKI, further stratification of patients, and prediction of long-term prognosis, offering a more comprehensive view. A recent RUBY study identified and validated CCL14 as the most predictive of persistent stage 3 AKI with an area under the curve (AUC) of 0.83 [51]. In addition, emerging biomarkers such as proenkephalin, circulating dipeptidyl peptidase 3, N1-methyl-2-pyridone-5-carboxamide, and methylnicotinamide evaluated in the MARKISIO study needs further investigation on potential associations with AKI severity and outcomes [50]. Other potential biomarkers being studied include N-acetyl-β-D-glucosaminidase, soluble urokinase plasminogen activator receptor, and microRNA [52].
Omics-based biomarkers
Omics technologies—genomics, transcriptomics, proteomics, and metabolomics—are expanding the field of AKI research. Genomic analyses identify genetic predispositions to AKI, transcriptomics reveal upregulated and downregulated gene expressions during AKI development, while proteomics and metabolomics provide a detailed view of the molecular changes during kidney injury. Although genome-wide association studies (GWAS) aiming to discover single nucleotide polymorphisms associated with AKI have been tried, since AKI is a heterogeneous clinical syndrome associated with multiple risk factors, differences in etiology and physiology may limit the identification of genetic variants and reproducibility across different populations [53]. To resolve these challenges, strategies to increase sample size and include multiethnic populations can be important.
Genomics in AKI research focuses on identifying inherited and acquired genetic variations that influence susceptibility, progression, and outcomes of AKI. Genome-wide approaches such as GWAS and next-generation sequencing have been used to uncover single nucleotide polymorphisms and genetic loci that may predispose individuals to AKI or specific subtypes, although many associations have yet to reach genome-wide significance due to the complex, multifactorial nature of the syndrome and limited heritability attributable to common variants. Some GWAS studies in AKI after surgery or critical illness have suggested potential loci (but with low replication), highlighting both the promise and challenges of genetic studies in AKI. This underscores the need for larger, more diverse cohorts and integrated multi-omics analyses to enhance discovery of causal targets [53].
Proteomics offers a comprehensive profiling of proteins in tissues, plasma, and urine, allowing detection of early injury signals and dynamic changes in protein expression during AKI. Mass spectrometry-based methods have identified panels of protein biomarkers that correlate with tubular cell stress and predict the development or prognosis of AKI. For example, cell cycle arrest biomarkers TIMP-2 and IGFBP7 are established clinical predictors of AKI risk, and broader proteomic profiling has revealed inflammatory and extracellular matrix remodeling pathways associated with AKI development. Proteomic studies also reveal alterations in signaling pathways that reflect the underlying pathophysiology of different injury types and support the discovery of novel candidate markers and mechanistic targets [35,36].
Metabolomics captures the small-molecule metabolites that reflect biochemical pathway alterations during kidney injury and recovery. Untargeted metabolomic profiling has highlighted early changes in metabolites such as amino acids and energy metabolites in AKI models and clinical cohorts, identifying potential diagnostic biomarkers and disrupted metabolic networks. Integrated metabolomics with proteomic data in sepsis-associated AKI (SA-AKI) has uncovered core metabolite changes that precede functional decline, illustrating how metabolic reprogramming and energy dysregulation contribute to AKI pathogenesis and may offer early diagnostic or prognostic signatures [52].
Using single-cell RNA sequencing, creating a comprehensive atlas of gene expressions during AKI is possible at the single-cell level. This can identify novel AKI biomarkers and shed light on previously unrecognized pathophysiology. Some of the examples include SOX4 and CD24A gene enriched in proximal and distal tubule injury [54]. In another study, using transcriptomics, researchers found that overexpression of SLC2A1 gene was associated with ferroptosis of tubular epithelial cells, leading to AKI [55]. Unbiased kidney proteomics and transcriptomics identified matrix metalloproteinase 7 as a protein biomarker strongly associated with kidney function decline [56].
Novel therapeutic agents
Currently, the gold standard for AKI treatment is hemodynamic stabilization, fluid therapy, cessation of nephrotoxic drugs, and in some cases, CRRT. However, these strategies are mostly supportive, and there are no established pharmacotherapies for AKI. This makes AKI treatment depend more on the prediction and management of complications [1]. Thus, research focusing on new therapeutic agents that target complex AKI pathways is critical for increasing treatment options.
Emerging understandings of AKI pathophysiology revealed its complexity, showing that inflammatory responses and cellular dysfunction contribute to kidney injury mechanisms (Fig. 3). After inflammation that commonly occurs in ICU patients, inflammatory responses are produced by mediators such as tumor necrosis factor alpha, IL-6, IL-18, and extracellular adenosine triphosphate (ATP). These mediators can lead to cell damage and cause kidney impairment. Deactivating these inflammatory responses can be a possible treatment strategy.
Studies of novel AKI therapeutic agents based on mechanism and stage of trial.
Accessed through clinicaltrials.gov on April 3rd, 2025. Clinical trial names with the corresponding therapeutic agents shown in parentheses.
AKI, acute kidney injury; ALP, alkaline phosphatase; NR, nicotinamide riboside.
Immunomodulatory agents
Alkaline phosphatase (ALP) is an endogenous enzyme that acts by dephosphorylating endotoxins and extracellular ATP. While extracellular ATP is known to have pro-inflammatory effects, dephosphorylated endotoxins and dephosphorylated extracellular ATP show anti-inflammatory and renoprotective effects. Due to the role in inhibiting inflammatory responses, randomized controlled trials (RCTs) have tested the effects of using ALP as a therapeutic agent for treating AKI. In the STOP-AKI (Safety, Tolerability, Efficacy, and Quality of Life Study of Human Recombinant Alkaline Phosphatase in the Treatment of Patients With Sepsis-Associated Acute Kidney Infection) trial (NCT02182440) and the REVIVAL trial (NCT04411472), however, short-term effects on SA-AKI patients were not identified and long-term effects needed further investigation [57,58].
Reltecimod is an immunomodulatory agent that acts by binding to CD28 on T cells. Reltecimod was tested in patients with necrotizing soft tissue infections but the results showed little significance. A recent phase 3 trial (NCT03403751) for testing Reltecimod in SA-AKI patients was terminated [59].
RBT-1 was shown to have effects in reducing ischemia-reperfusion injury (IRI), which is one of the common causes of AKI. Ischemia is characterized by depleted oxygen which can lead to free radical production and increased inflammation [60]. Currently, a phase 3 trial (NCT06021457) is recruiting and planning to assess the effect of RBT-1 on reducing the risk of AKI after cardiopulmonary bypass.
Kidney is an important organ in producing activated vitamin D. Emerging evidence shows that vitamin D deficiency is associated with a higher risk of AKI, causing interstitial damage and stimulating renal fibrosis progression [61]. A recent phase 2 trial (NCT02962102) tested the effects of calcifediol and calcitriol in preventing AKI progression in severely ill patients.
TIN816 is a recombinant CD39 that can act by depleting extracellular ATP, which is a pro-inflammatory molecule. Trials to test the effects of TIN816 in SA-AKI patients (NCT05996835) and in patients undergoing cardiopulmonary bypass (NCT05524051) are ongoing [60].
Hemodynamic and cell metabolism agents
Hemodynamic management is important in treating AKI, considering that decreased renal perfusion can decrease glomerular filtration and potentially lead to cell damage. The renin-angiotensin-aldosterone system is a hormone system that plays a key role in regulating blood pressure and fluid balance. In settings of hypotension, excretion of renin is increased, which leads to the cleavage of angiotensinogen into angiotensin I, a precursor of angiotensin II. Angiotensin II is a vasoconstrictor, and its effect on the efferent arteriole can possibly increase GFR and prevent AKI. The effects of angiotensin II in patients with vasodilatory shock were previously demonstrated in the phase 3 ATHOS-3 trial [62]. However, the use of angiotensin II as a vasopressor to prevent AKI has not been widely tested. Currently, a phase 3 trial (NCT06615102) is ongoing with the aim of demonstrating the effects of angiotensin II in preventing post-cardiac surgery AKI.
Another hemodynamic agent is levosimendan. Levosimendan is a calcium-sensitizing agent that acts by increasing renal blood flow through vasodilation. A recent trial has shown that levosimendan is effective in patients with postoperative AKI after cardiac surgery [63].
Cellular metabolism impairment, including mitochondrial dysfunction, is also a key factor in AKI. Nicotinamide adenine dinucleotide (NAD+) is essential for cellular metabolism and longevity, acting as a cofactor for sirtuin 1 (SIRT1), which regulates chromatin structure, gene expression, and aging-related diseases. In mouse models of AKI, NAD+ levels rapidly decline and niacinamide supplementation has shown protective effects. Additionally, SIRT1 deficiency increases AKI susceptibility and SIRT1 overexpression provides protection, suggesting that targeting NAD+ and SIRT1 could be a promising therapeutic approach. A recent trial found therapeutic benefits of the combination of nicotinamide riboside, a NAD+ precursor vitamin, and pterostilbene, which is a potent sirtuin activator [62]. Trials testing the effects of niacinamide (NCT04750616) in reducing cardiac surgery-associated AKI (CSA-AKI) and the effects of nicotinamide (NCT04589546) in preventing AKI in patients with septic shock are ongoing.
In proximal tubular epithelial cells, p53, a DNA-binding transcription factor, activates genes responsible for growth arrest or cell death after exposure to IRI. RNA interference can inhibit gene expression by using synthetic double-stranded RNA called small interfering RNAs (siRNA), which can neutralize targeted messenger RNA. QPI-1002 is a siRNA that temporarily inhibits p53-mediated cell death and thus may allow injured renal tubule cells to repair. However, a significant difference of AKI incidence by using QPI-1002 in patients undergoing cardiac surgery was not shown in a phase 2 trial. Currently, a phase 3 trial (NCT03510897) is being recruited [64].
The complement system is a complex cascade of over 30 proteins of the innate immune system, and acts as a main effector of the adaptive immune system. Activation of the complement system can lead to cell damage. Eculizumab is a complement inhibitor that blocks the complement pathway. There has been evidence that eculizumab can improve outcomes of hemolytic uremic syndrome [65]. Another complement inhibitor, ravulizumab, is being tested in a phase 3 trial (NCT05746559) for its efficacy in preventing CSA-AKI in CKD patients.
Free radical oxygen is also emerging as a main factor of AKI, by its role in oxidizing proteins and lipids, damaging DNA, and inducing apoptosis. Antioxidants can be used in AKI patients to eliminate these oxygen radicals, improving glomerular function and reducing inflammation. Some of the antioxidants being studied are alpha-lipoic acid, selenium, and sodium-2-mercaptoethane sulphonate [27].
Mesenchymal stem cells (MSC) are proposed to provide therapeutic benefits by both immunomodulatory pathways and cell repair pathways. In immunomodulatory aspects, MSCs can exert chemokines and cytokines, and also deliver extracellular vesicles, affecting nearby cells. Specifically, MSC-derived extracellular vesicles have been highlighted for their effects on AKI. Results showed that MSC-EVs can alleviate AKI by reducing inflammation and apoptosis through various pathways such as nuclear factor kappa B inhibition [66]. While inhibiting inflammation, MSCs also contribute to renal tubule repair by upregulating Bcl-2 and vascular endothelial growth factor [60].
Continuous renal replacement therapy treatment
CRRT is frequently used in critically ill AKI patients. CRRT can sometimes be more effective than hemodialysis because it can clear solutes without abrupt fluid fluctuation. Research is investigating the optimal timing for CRRT initiation, the most suitable type of fluid for therapy, and the best strategies for managing CRRT to improve patient outcomes [67].
History of CRRT evolution has improved diverse CRRT modalities to treat AKI patients. The first form of CRRT was continuous arteriovenous hemofiltration by Peter Kramer in 1977. However, continuous arteriovenous hemofiltration relied on arterial blood pressure to drive filtration, limiting its use in critically ill patients, and was associated with arterial cannulation. Continuous venovenous hemofiltration improved continuous arteriovenous hemofiltration by introducing pump-driven filtration, increasing the ultrafiltration rate and clearance by convection. Next, continuous venovenous hemodialysis and continuous venovenous hemodiafiltration were introduced. Continuous venovenous hemodialysis used diffusion for clearance rather than the convection used in continuous venovenous hemofiltration. However, this has limitations for large molecules. Continuous venovenous hemodiafiltration, which uses both convection and diffusion, can effectively clear large molecules through convection and also take advantage of dialysate diffusion [68].
Recently, CRRT methods have become more advanced and are starting to support functions of various organs for multi-organ dysfunction syndrome [69]. Also, hemoperfusion devices were developed to use sorbents to allow adsorption of toxins. For example, polymyxin B showed positive effects for selective endotoxin adsorption in sepsis patients [68]. Hemoperfusion can be used for removing inflammatory mediators. The CYTOHEP study aims to investigate the effects of a hemoadsorption device, CytoSorb (CytoSorbents), that adsorbs bilirubin, vasoactive cytokines, and inflammatory mediators in AKI patients receiving CRRT [70]. A recent retrospective analysis showed that oXiris (Baxter) CRRT can effectively reduce inflammatory molecules such as procalcitonin, IL-6, and high-sensitivity C-reactive protein by adsorption in sepsis patients [71]. Selective cytopheretic device cartridge can remove activated leukocytes [72]. Ongoing research is expected to develop new biomaterials that allow improved adsorption, miniaturize devices, and integrate sensors and software systems to better monitor CRRT.
Digital healthcare
Artificial intelligence
AI models are being widely developed, holding potential to become an integral part of AKI management. Using vast amounts of real-time data extracted from electronic health records (EHRs), AI can identify complex patterns that are beyond human discernment. This capability allows AI to predict AKI risk before incidence, alerting clinicians to intervene early. These systems can also assist in decisions such as fluid management, drug dose, and hemodynamic monitoring. AI models can also predict the prognosis of AKI and CKD progression [73,74].
Different types of machine learning algorithms, including logistic regression, gradient boosting machine, XGBoost, convolutional neural network, and recurrent neural network, have been developed for timely AKI prediction (Table 1) [75,76]. One of the notable studies by Koyner et al. [77] used a gradient boosting machine to predict inpatient AKI and showed an AUC of 0.87. It is unclear whether neural networks such as convolutional neural network or recurrent neural network show better performance than relatively classical models such as logistic regression. However, considering that EHR data is sequential, adopting recurrent neural network models can be beneficial by allowing real-time prediction as shown in several studies [78–83].
Overview of AI models developed for AKI development prediction
However, when using AI in clinical settings, it is important to note that the compliance of clinicians may be low. This could potentially result from a lack of trust and low comfort levels working with these tools. To improve clinician acceptance, efforts such as integrating with EHR systems, increasing transparency by providing a rationale for the outcome, and considering trends of data instead of snapshots might be helpful [84,85]. Also, efforts to develop a light-weight model are needed. Although utilizing maximum factors may show high performance, heavyweight models are hard to manage and can only be used in hospitals with abundant resources. Thus, it is important to achieve similar performances using less data and computing power. Ethical considerations are also important when integrating AI into clinical workflows. Since clinical data is very sensitive, privacy must be protected during the process of data input and output. Also, AI can be vulnerable to bias, especially when the training data itself is biased. Efforts to mitigate these biases such as data augmentation are important for reliability.
Telemedicine and digital tools
Telemedicine and digital health tools can expand the scope of AKI management beyond hospital settings. Remote monitoring systems enable healthcare providers to track at-risk populations, such as patients with CKD or heart failure, in outpatient settings. Digital tools, including wearable devices and mobile apps, can support remote monitoring systems by providing continuous, real-time monitoring of parameters like blood pressure, fluid balance, and biomarkers. These innovations can help detect early signs of AKI and potentially reduce the need for hospitalizations. Also, these tools can particularly impact resource-limited areas, allowing a skilled professional to easily monitor patients and make decisions even in long-distance settings. In this context, when costs and accessibility issues are resolved, digital tools can be a key component in reducing regional disparities.
Global collaborations
Multinational randomized controlled trials
AKI research requires large-scale, collaborative efforts to address its diverse causes and outcomes. Future research is expected to emphasize multinational registries that collect comprehensive data on AKI incidence, treatment, and outcomes across various populations. Global collaborations and multinational registries will allow RCTs to include different population groups with large sample sizes, which can uncover differences in AKI vulnerability and elucidate complex pathways of AKI. Including multiethnic data is important, especially when performing GWAS, as genetic variants can differ between different populations. Harmonizing data collection methods and definitions of AKI to ensure consistency and comparability across studies is also important. Such collaborations will enhance the understanding of AKI globally and promote the development of universally applicable interventions.
Efforts to mitigate global disparities
Healthcare inequalities significantly impact AKI outcomes. Research into addressing these disparities is essential to ensure equitable care. Identifying social determinants of health that contribute to poor AKI outcomes will be needed. Also, to lower healthcare disparities, community-based interventions should be widely applied to effectively provide access to preventive and acute care in underserved regions. Finally, evaluating cost-effective strategies to implement diagnostic and therapeutic innovations can help rapidly introduce these innovations in low-resource settings. For example, urinalysis and salivary urea nitrogen dipstick test utilization is an inexpensive and feasible way to identify AKI in patients of low-income countries. Also, implementing awareness of AKI among healthcare providers is crucial. Education should include the prevalence of AKI in the community, diagnosis of AKI, and using available resources to manage AKI in a healthcare facility [86].
Changes in clinical practice
AKI is defined as a syndrome with high heterogeneity due to multiple causes and diverse complications. Using recent advances in research, clinical practice is expected to thoroughly stratify AKI patients into multiple subgroups and optimize treatment strategies. Novel biomarkers are being investigated, with the potential of giving information about patient risks and helping with timely management. Biomarker investigation can also broaden our knowledge base of AKI pathophysiology, which may lead to a new scope of therapeutic options. Incorporating AI for specific stratification is an ongoing research topic in this area.
Also, new technologies regarding therapeutic options such as drugs and CRRT are continuously being investigated. These investigations should not only consider high performance but also consider strategies to implement technologies with fewer resources and plans to make them blend well with local situations and community settings.
To fully realize the potential of the advancements outlined in this review, a multidisciplinary approach is essential. Clinicians, researchers, policymakers, and healthcare systems must collaborate focusing on the following topics:
• Focus on preventive strategies to reduce the incidence and burden of AKI.
• Advance the adoption of innovative diagnostics and treatments into routine practice.
• Develop large-scale global collaborations to unify data collection and research efforts.
• Ensure equitable access to AKI care across diverse populations and settings.
By fostering these efforts, the medical community can continue to make meaningful strides in improving outcomes for patients with AKI, ultimately reducing its global impact.
Conclusion
AKI remains a significant global health challenge, but recent advancements in research are paving the way for transformative improvements in its prevention, diagnosis, and management. The integration of novel biomarkers, omics technologies, and AI has shown the possibility to enhance our ability to detect and stratify AKI at earlier stages and offer patient-tailored treatment strategies. Meanwhile, emerging therapeutic approaches that target inflammatory pathways and cellular functions offer hope for better outcomes. Ongoing future changes in clinical practice are expected to adopt these research advancements and shift towards a more preventive and personalized paradigm. However, challenges such as healthcare disparities persist, and standardized global research efforts along with sustained focus and innovation are required to overcome these challenges.
Notes
Conflicts of interest
All authors have no conflicts of interest to declare.
Data sharing statement
The data presented in this study are available from the corresponding author upon reasonable request.
Authors’ contributions
Conceptualization, Methodology, Supervision: All authors
Investigation, Project administration, Resources: SK
Validation, Visualization: KK, SH
Writing–original draft: All authors
Writing–review & editing: All authors
All authors read and approved the final manuscript.