AKI as a systemic syndrome and its impact on other organ systems

Abstract

Acute kidney injury (AKI) affects approximately 15% of all hospitalized individuals and nearly half of those admitted to intensive care units and is increasingly recognized as a systemic syndrome whose consequences extend well beyond structural and functional changes confined to the kidney. Experimental studies highlight the role of inflammation and accumulation of metabolites as pivotal drivers in the cross-talk between the kidneys and distant organ systems during AKI. Whereas clinical data reveals an association between AKI and non-renal organ dysfunctions and complications. This review outlines the pathophysiological mechanisms underlying AKI-associated remote organ dysfunction, focusing on five key organ systems: the lungs, the brain, the heart, the liver and the immune system. We discuss the direct consequences of reduced kidney function alongside the repercussions of the inflammatory cascade triggered by kidney cell injury and the resulting clinical implications. Recognizing that multi-organ failure significantly influences patients’ morbidity and mortality, identifying specific pathways of organ cross-talk is essential to optimize clinical management. Finally, we evaluate novel endpoints for future AKI trials. Given that traditional long-term metrics, such as Major Adverse Kidney Events (MAKE), present significant design challenges in non-enriched populations, we analyze alternative and surrogate outcomes, including those directly related to the remote organ complications of AKI.

Background

Acute kidney injury (AKI) is now recognized as a major health problem affecting millions of patients globally. General estimates of the AKI incidence in the past varied, with data from different populations ranging from 114 to 174 people per 10,000 person-years, or approximately 13.3 million worldwide in 2017 [1, 2]. Reported AKI incidence is highest in low- and middle-income countries with AKI affecting approximately 15% of all hospitalized patients and about half of critically ill patients in the highest income areas [1, 2]. AKI is associated with not only increased mortality but also increased morbidity [3–5]. Patients who survive an episode of AKI have an increased risk of developing chronic kidney disease (CKD) [6–10]. Outcomes in AKI are affected not only by the original cause of the AKI, but also by the duration and severity of kidney dysfunction as well as the baseline status of the patient, including the presence of CKD.

Although kidney replacement therapy (KRT) is available, the cause of the high mortality rate in patients with severe AKI is still not fully elucidated. AKI is not an isolated organ failure of the kidney; rather, due to the kidney’s numerous functions, other organs are also affected. Injury of distant organs is considered an important cause of complication and mortality, given that multi-organ dysfunction is often observed in AKI patients and the number of organ dysfunctions is associated with increased mortality [11, 12]. Patients with a dialysis-dependent AKI have a considerably higher mortality rate compared to patients with end-stage kidney disease (ESKD) [13], suggesting that, in addition to impaired kidney function in AKI, other factors contribute to the poor prognosis. These data suggest that organ dysfunction induced by AKI plays a significant role in the prognosis of critically ill patients. Experimental studies have uncovered various mechanisms contributing to AKI-induced distant organ injury. Mechanisms involving the immune system, lungs, heart, liver, brain, and gut have been demonstrated. These mechanisms are organ-specific and diverse, encompassing immune cell responses, oxidative stress, and inflammatory cytokines. These organ interactions, established in animal studies, have been corroborated in clinical observational studies [12, 13].

This review article briefly outlines the molecular mechanisms of AKI-associated remote organ dysfunction, the epidemiology of complications, and the clinical outcomes reported in the literature. The final section discusses novel endpoints for AKI trials, taking into account organ interactions during AKI and the resulting complications.

Consequences of AKI

AKI is associated with an increase in hospital length of stay (LOS), ICU-LOS, and higher morbidity and short and long-mortality [2, 14]. The 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines provided a classification of AKI in three different stages of severity based on serum creatinine levels and hourly urine output (Table 1) [15]. A correlation with AKI stages can be observed, where KDIGO stage 1 shows a twofold increase in mortality whereas severe AKI (stage 2–3) shows an almost 7-fold increase in mortality [5]. Clinical presentation of AKI is highly heterogeneous and depends on the severity of the injury. Many symptoms can be explained by an acute loss of glomerular filtration capability, which leads to azotemia and accumulation of protons, electrolytes, toxins, and drugs. The accumulation of uremic toxins has a direct impact on other organ systems and can start a vicious cycle of nephrotoxicity leading to reduced glomerular filtration rate (GFR) with further accumulation of toxins and subsequent increased toxicity [16, 17]. The development of metabolic acidosis is associated with a particularly poor prognosis [18]. Uremic toxicity can lead to arrhythmias (e.g. due to hyperkalemia), tiredness (e.g. due to azotemia), and in some cases it can cause confusion or even coma (e.g. accumulation of toxins, drugs). Furthermore, reduced urine output can lead to fluid overload and congestion which can cause or worsen ventilatory problems and lead to venous congestion with direct impact on other organs such as the liver and the kidney itself. After the initial resuscitation phase reduced kidney function can also complicate fluid deresuscitation [19].

Table 1.

AKI severity stage according to KDIGO 2012 guidelines [15]

Stage	Serum creatinine	Urine output
1	1.5–1.9 times baseline OR ≥ 0.3 mg/dl (≥ 26.5mmol/l) increase	< 0.5 ml/kg/h for 6–12 h
2	2.0–2.9 times baseline	< 0.5 ml/kg/h for ≥ 12 h
3	3.0 times baseline OR Increase in serum creatinine to ≥ 4.0 mg/dl (≥ 353.6mmol/l) OR Initiation of renal replacement therapy OR, In patients < 18 years, decrease in eGFR to < 35 ml/min per 1.73 m2	< 0.3 ml/kg/h for ≥ 24 h OR Anuria for ≥ 12 h

eGFR = estimated glomerular filtration rate

Additionally, an episode of AKI may have longer-lasting effects on kidney function and increase the risk for the development or progression of CKD [20–23]. Even with apparent full recovery of kidney function the risk for ESKD stays elevated after single episodes of AKI [24–26]. The mechanisms underlying this progression are not solely explained by the loss of functioning nephrons but also by maladaptive repair mechanisms, disordered regeneration, and a vicious cycle of endothelial injury leading to hypoxia/ischemia and further endothelial injury [27–29]. As a result, AKI is regarded as a syndrome with multiple different consequences and not all clinical presentations of AKI can solely be explained by functional reductions of GFR [30]. Kidney cell injury and intrarenal inflammation play an important role in the pathophysiology of organ cross-talk in AKI and consequences thereof [31, 32]. AKI leads to (sterile) activation of kidney cells and local immune cells, including resident macrophages and dendritic cells, which causes the release of proinflammatory cytokines and subsequent systemic inflammation [32]. Over the past decades, the role of different immune cells (e.g. dendritic cells, macrophages), cytokines (e.g. interleukin-17 - IL-17, and tumor necrosis factor-alpha - TNF-α), and pattern recognition receptors (e.g. toll-like receptors - TLR) in development and progression of AKI was discovered. Moreover, epigenetic changes of fibroblasts, myofibroblasts, pericytes, and epithelial cells also play important roles in the progression of AKI and its consequences [33–37]. For example, after apparent recovery of kidney function profibrotic signaling might still persist locally [35, 38] and distantly through humoral pathways leading to long-term consequences in other organs [39]. This highlights AKI as a systemic syndrome with consequences going far beyond the acute complications resulting from acutely reduced GFR (Fig. 1).

Fig. 1.

Mechanisms of AKI-induced distant organ injuries. AKI=kidney injury; DAMPs= damage associated molecular patterns; IL-1 = interleukin-1; IL-6 = interleukin-6; IL-10 = interleukin-10; RAAS = renin-angiotensin-aldosterone system; ROS = reactive oxygen species; SNS= sympathetic nervous system; TLR2/4 = toll-like receptor 2/4; TNF-α = tumor necrosis factor-alpha

The following section will address the impact of AKI on the lung, the brain, the heart, the liver and the immune system. For each organ system, the pathophysiological mechanisms and preclinical findings, focusing on inflammation triggered by AKI, will be discussed alongside clinical evidence, patient outcomes, and therapeutic strategies. Organ-specific damage biomarkers relevant to each of these systems, both experimental and clinically implemented, are summarized in Table 2 to complement the discussion.

Table 2.

Biomarkers of organ injury

Organ/system	Biomarkers	Status	Purpose
Lung [40]	RAGE, SP-D, Ang-2	Experimental	Epithelial/endothelial injury; ALI
Brain [41, 42]	NfL, GFAP, UCH-L1, Tau S100B, NSE	Experimental Implemented	Brain dysfunction; prognosis Prognostication in TBI and cardiac arrest; still under evaluation for neuroprognostication in the critically ill
Heart [43]	BNP, cTn sST2, Galectin-3	Implemented Experimental	Diagnosis of HF/ACS Prognosis
Liver [44, 45]	Bilirubin, GGT, ALP AST, ALT miR-122, GLDH, K18/ccK18, HMGB-1	Implemented Implemented Experimental	Congestion Hepatocellular injury Hepatocellular injury
Infections [46]	PCT, CRP	Implemented	Infection and sepsis
Immune system [46]	IL-6, IL-8, IL-10	Experimental	Inflammation/immunoparalysis
Kidney [47]	SCr, UO, Cystatin C NGAL, TIMP-2·IGFBP7 CCL14, DKK3, proenkephalin A, KIM-1, L-FABP	Implemented Implemented Experimental	AKI diagnosis and staging, GFR estimation Not routinely. Early tubular injury/stress; risk stratification Persistent AKI, risk prediction, sub-phenotyping

ACS = acute coronary syndrome; AKI = acute kidney injury; ALI = acute lung injury; ALP = alkaline phosphatase; ALT = alanine aminotransferase; Ang-2 = angiopoietin-2; AST = aspartate aminotransferase; BNP = B-type natriuretic peptide; ccK18 = caspase-cleaved cytokeratin 18; CCL14 = C-C motif chemokine ligand 14; CRP = C-reactive protein; cTn = cardiac troponin; DKK3 = Dickkopf-3; GFAP = glial fibrillary acidic protein; GFR = glomerular filtration rate; GGT = gamma-glutamyl transferase; GLDH = glutamate dehydrogenase; HF = heart failure; HMGB-1 = high mobility group box 1; IGFBP7 = insulin-like growth factor-binding protein 7; IL = interleukin; K18 = cytokeratin 18; KIM-1 = kidney injury molecule-1; L-FABP = liver-type fatty acid-binding protein; miR-122 = microRNA-122; NfL = neurofilament light chain; NGAL = neutrophil gelatinase-associated lipocalin; NSE = neuron-specific enolase; PCT = procalcitonin; RAGE = receptor for advanced glycation end-products (soluble form, sRAGE); S100B = S100 calcium-binding protein B; SCr = serum creatinine; SP-D = surfactant protein D; sST2 = soluble suppression of tumorigenicity 2; Tau = tau protein; TBI = traumatic brain injury; TIMP-2 = tissue inhibitor of metalloproteinases-2; UCH-L1 = ubiquitin C-terminal hydrolase L1; UO = urine output

AKI and its impact on organ systems

Lung

During the course of AKI, several mechanisms—most notably fluid overload—may contribute to the development of acute lung injury (ALI) [48]. In a small single-center study of patients with severe dialysis-requiring AKI, 47% developed pulmonary complications, mainly presenting as acute respiratory distress syndrome (ARDS) [49]. Consistent with this observation, 70%–85% of patients with AKI admitted to the ICU required mechanical ventilation across multiple studies, reflecting the high burden of respiratory failure in this population [50]. Conversely, in patients with ALI requiring mechanical ventilation, impaired venous return, systemic venous congestion, and low preload-dependent cardiac output (CO) may reduce renal perfusion pressure, thereby decreasing GFR [51]. This generates a vicious cycle that poses a significant threat to patients, clinicians and healthcare systems (Fig. 2). Furthermore, both organs are highly susceptible to systemic inflammation, which acts as a key driver of pathological crosstalk [48].

Fig. 2.

Bidirectional cross-talk between the kidney and the distant organ systems. Key cross-talk mechanisms, clinical manifestations of AKI-induced injury, therapeutic strategies and patient outcomes. AKI = acute kidney injury; ALI = acute lung injury; ARDS = acute respiratory distress syndrome; BBB = blood-brain barrier; CKD = chronic kidney disease; CYP450 = cytochrome P450; DDS = dialysis disequilibrium syndrome; KRT = kidney replacement therapy; MV = mechanical ventilation; PRES = posterior reversible encephalopathy syndrome

Consequences of AKI

During AKI, impaired sodium and water excretion can lead to life-threatening fluid overload [52]. In this setting, increased intravascular volume raises hydrostatic pressure, possibly leading to ventricular dysfunction and cardiogenic pulmonary edema [53–55]. This process is rapidly exacerbated in patients with pre-existing heart failure. Edema alters cell-to-cell interactions within the lung and disrupts tissue architecture to varying degrees, resulting in ALI and the need for respiratory support [56]. Accordingly, patients requiring mechanical ventilation who develop AKI exhibit higher plateau and driving pressures, reduced respiratory system compliance, and lower PaO₂/FiO₂ ratios, indicating more severe impairment of pulmonary function [57, 58].

Beyond fluid overload and metabolic disturbances AKI may also trigger intrarenal inflammation and the resulting inflammatory mediator release may independently induce distant organ damage. Preclinical models of AKI, including ischemia-reperfusion injury, have elucidated the mechanisms underlying the pathological crosstalk between kidneys and other organs [59]. In preclinical models of AKI-induced ALI, it has been demonstrated that inflammation contributes to pulmonary edema by increasing pulmonary capillary leak [60]. Injured tubular cells may release Damage-Associated Molecular Patterns (DAMPs)—including mitochondrial DNA, HMGB-1, and histones—which activate TLR4 signaling on tubular epithelial cells, with systemic release of proinflammatory cytokines [60–62]. These mediators increase pulmonary endothelial permeability, recruit leukocytes into the pulmonary tissue, and promote the development of non-cardiogenic pulmonary edema [54, 60]. A recent study showed that, in preclinical models of AKI-induced ALI, neutrophil recruitment to the lungs was predominantly confined to the alveolar capillaries, where neutrophils formed characteristic “neutrophil trains”, differently from direct pulmonary injury, where neutrophils primarily accumulated within the alveolar space [63]. These findings suggest that pulmonary injury in AKI is not solely a consequence of fluid overload, hemodynamic instability, or metabolic disturbances, but also involves distinct inflammatory pathways that contribute to lung dysfunction and disease progression. Furthermore, AKI may impair edema resolution via downregulation of alveolar epithelial sodium channels, Na⁺/K⁺-ATPase, and aquaporin-5, which participate in alveolar fluid clearance [64]. From a pathophysiological perspective, these alterations may justify the lack of response to fluid removal in some patients with refractory pulmonary edema [50, 65].

Clinical implications

Pulmonary complications in the context of AKI represent a major determinant of prognosis [50, 66]. A recent large retrospective single-center cohort study demonstrated that the coexistence of AKI and ARDS is associated with substantially worse short-term outcomes than either condition alone. ICU mortality reached 21%, compared with 4%–9% in patients with isolated AKI or ARDS, and was accompanied by longer ICU stays, prolonged mechanical ventilation, and increased use of KRT [66]. Mortality was highest when ARDS developed after AKI compared to the reverse (29% vs. 14%), suggesting that the temporal sequence of organ injury may influence prognosis. However, the retrospective observational design precludes causal inference, and the long-term consequences of AKI-associated lung injury remain poorly defined.

Given its independent association with increasing mortality, addressing fluid overload appears of paramount importance [56]. Whenever feasible, personalized fluid stewardship, deresuscitative strategies following initial stabilization, or ultrafiltration should be adopted to achieve a neutral or even negative fluid balance [19, 67]. In parallel, lung-protective mechanical ventilation remains essential, not only to limit pulmonary injury, but also because it may reduce the risk of AKI development or progression [58].

Brain

The clinical association between AKI and cerebral dysfunction is consistently reported [68–71]. In the acute setting, uremic encephalopathy appears to affect up to 20% of patients with AKI admitted to the ICU [72], while a recent meta-analysis involving 158,694 patients reported a pooled delirium prevalence of 32%, increasing in parallel with AKI severity [73]. Conversely, the central nervous system has been reported to influence the course of AKI (Fig. 2), either through direct pathways or via immune system modulation [74].

Consequences of AKI

AKI might mediate acute brain injury through different mechanisms. The role of uremic toxins remains a subject of intense scrutiny. Urea and its metabolites accumulate due to both AKI and the administration of high protein nutrition in critically ill patients [75]. Preclinical models suggest that a uremic milieu may act as a potent stimulus for renal recovery [76]. Nonetheless, specific urea-cycle metabolites, such as guanidino compounds and protein-bound solutes, are known to alter synaptic transmission, induce direct cellular injury, and promote neuroinflammation [70, 77]. Toxic effects likely emerge only in the setting of elevated urea levels. In a secondary analysis of the AKIKI 2 trial, patients managed according to a ‘more-delayed’ KRT strategy (BUN > 140 mg/dL) spent more days in coma compared to those in the ‘delayed’ strategy group (BUN > 112 mg/dL), suggesting that prolonged exposure to higher levels of uremic toxins may exacerbate cerebral dysfunction [78]. Furthermore, rapid urea clearance, particularly during intermittent KRT, sharply reduces extracellular tonicity, creating an osmotic gradient that might cause cerebral edema and, clinically, a broad spectrum of neurological symptoms known as dialysis disequilibrium syndrome [79]. Altered mental status, headache, seizures, and visual disturbances during AKI may also be related to posterior reversible encephalopathy syndrome (PRES) [80]. Driven by fluid retention and renin-angiotensin-aldosterone system (RAAS) activation, AKI-induced hypertension can trigger PRES via impaired cerebral autoregulation. However, vascular endothelial injury and blood-brain barrier (BBB) disruption also cause parieto-occipital vasogenic edema independently of severe hypertension [80]. In this clinical scenario, MRI might be essential for differential diagnosis [80].

Furthermore, metabolic acidosis secondary to AKI can directly impair neuronal function. Activation of acid-sensing ion channels on neuronal membranes triggers an influx of calcium and sodium ions, leading to depolarization, neuronal injury, and potentially cell death [81]. AKI-associated electrolyte disturbances may propagate across a disrupted BBB, especially hyponatremia, contributing to generalized cerebral edema. Finally, a key mechanism impairing cognitive function in critically ill patients is the decreased clearance of neurotoxic drugs. Unlike antibiotic-associated neurotoxicity (e.g., Cefepime) [82], which is widely recognized and routinely considered in clinical practice, the neurotoxic effects of other commonly used drugs in critically ill patients, such as opioids, gabapentinoids, and antivirals may be less readily recognized [83–85]. Their clinical manifestations may be mistaken for uremic or septic encephalopathy or even for progression of the underlying infection, as exemplified by aciclovir neurotoxicity being misinterpreted as worsening herpes encephalitis [86].

Consistent with the mechanisms observed in other organ systems, preclinical models of AKI have demonstrated that systemic inflammation compromises the BBB integrity [87]. This increase in permeability allows various molecules that are typically excluded from the central nervous system to cross the BBB. Cytokines and inflammatory mediators can activate astrocytes and glial cells, amplifying local neuroinflammation [81, 87]. Uremic toxins may activate resident microglia which, upon pathological stimulation, promote inflammation and aberrant synaptic pruning. Additionally, AKI seems to downregulate organic anion transporter 3 on the basolateral membrane of the BBB, impairing clearance of toxic metabolites and drugs from the brain [78].

Clinical implications

The kidney-brain interaction contributes substantially to morbidity and mortality [71, 73, 78]. Patients with AKI-associated delirium require significantly higher rates of mechanical ventilation, vasopressor support, and KRT, and exhibit increased mortality compared to non-delirious AKI patients [73]. Additionally, AKI is associated with an increased long-term risk of stroke, post-stroke mortality, and dementia. However, the interpretation of these findings is constrained by the predominantly retrospective nature of current evidence [71].

From a therapeutic perspective, frequent neurological assessment to promptly identify changes in consciousness, together with regular reassessment and optimisation of treatment strategies, represents a key component of management, including during KRT. Two post hoc analyses have suggested a potential role for KRT in mitigating the association between AKI and acute neurological dysfunction [69, 78], including delirium. However, further prospective studies are required to determine whether KRT can directly influence neurological outcomes in patients with AKI.

Heart

The bidirectional interaction between the heart and kidneys has long been recognized as the cardiorenal syndrome (CRS) (Fig. 2) [88]. For the purpose of this review we will focus on type 3 CRS, where AKI precipitates acute cardiac dysfunction. Reported incidence of CRS type 3 varies widely, ranging from 0% to 29% [89]. In cohorts strictly excluding pre-existing cardiac comorbidities, the incidence reached 29% [90], whereas in unselected AKI cohorts lower rates were reported (17.1%) [91]. This marked heterogeneity, compounded by varying AKI definitions and the lack of specific biomarkers to distinguish AKI-induced cardiac injury from pre-existing conditions, precludes a reliable pooled incidence estimate [89].

Consequences of AKI

Fluid overload secondary to AKI can be particularly detrimental to the heart, especially when cardiac function is already impaired [92]. By increasing preload and ventricular filling pressures, fluid overload can impair myocardial contractility and reduce CO. Concurrently, the elevation of pulmonary pressures may lead to the development of pulmonary edema particularly where vascular leak is present such as complicating sepsis [55]. Early in this process, the RAAS and sympathetic nervous system are activated as compensatory mechanisms by both organs to maintain preload and afterload. By increasing sodium and water retention, peripheral vasoconstriction, and adrenergic tone, these mechanisms might actually worsen organ dysfunction. The ensuing venous congestion, in addition to the reduced CO, further reduces renal filtration capacity and delays renal recovery [93–95]. Interestingly, KRT may further challenge cardiac function by exacerbating preload-dependent reductions in CO following aggressive fluid removal, which may occur even in the absence of hypotension [96]. Metabolic acidosis also promotes cardiac dysfunction [97]. By reducing calcium sensitivity of contractile proteins it impairs myocardial contractility and by disrupting electrolytes transport across cardiomyocytes it fosters cardiac arrhythmias. Electrolyte disturbances associated with AKI, hyperkalemia in particular, are also relevant in this regard [98]. In addition, acidosis promotes pulmonary vasoconstriction, which may precipitate acute right ventricular dysfunction. Finally, preclinical studies have shown the contribution of uremic toxins to myocardial injury, inflammation, and remodeling [99, 100], but their role in humans remains to be investigated. Nevertheless, the precise pathogenesis of CRS type 3 has not yet been fully elucidated.

In preclinical models of AKI, elevated circulating levels of cytokines — specifically IL-1β, TNF-α and IL-6 — have been observed to exert a cardiodepressant effect [101]. By inducing cardiomyocyte apoptosis, leukocyte infiltration, oxidative stress and mitochondrial dysfunction, these mediators lead to a significant reduction in myocardial contractility [99]. Mitochondrial injury appears to be particularly relevant in this context, given the continuous ATP demand required for cardiomyocyte contraction and excitation-contraction coupling. Future research is required to evaluate whether these mechanisms could serve as novel therapeutic targets for enhancing myocardial recovery, independently of the contribution of KRT on traditional complications.

Clinical implications

Clinically, type 3 CRS manifests across distinct scenarios depending on the predominant pathophysiological driver [88, 99]: oliguric AKI with progressive fluid overload presenting as acute congestive heart failure and cardiogenic pulmonary edema; severe hyperkalemia or acid-base derangements triggering brady- or tachyarrhythmias; metabolic acidosis impairing myocardial contractility while blunting catecholamine responsiveness in critically ill patients. Beyond these acute short-term life-threatening events, AKI serves as an independent marker of long-term cardiovascular vulnerability. A recent systematic review and meta-analysis of 54 studies showed that AKI is associated with significantly increased risks of major adverse cardiovascular events, heart failure, myocardial infarction, stroke, and cardiovascular mortality, with excess risk evident even after stage 1 AKI [102].

Management of CRS type 3 requires an individualized approach that accounts for both the severity of AKI and the nature of the accompanying cardiac manifestation. Because acute heart failure with cardiogenic pulmonary edema appears to be the most frequent presentation [89], optimizing fluid balance, through loop diuretics or extracorporeal ultrafiltration when indicated, represents a central therapeutic objective [89, 99].

Liver

The liver and kidneys are the two principal organ systems responsible for detoxification and maintaining metabolic homeostasis. While kidney dysfunction secondary to hepatic failure —most notably hepatorenal syndrome—is a well-recognized, albeit incompletely understood, clinical entity, the converse relationship has received considerably less attention (Fig. 2). A prospective study of critically ill patients with AKI reported that approximately 28% of them subsequently developed hepatic dysfunction, which was associated with increased mortality [103]. However, contemporary evidence on this bidirectional organ interaction remains limited.

Consequences of AKI

As highlighted throughout this review, fluid overload in oligo-anuric AKI is a major determinant of distant organ injury. Hepatic dysfunction resulting from AKI-associated fluid overload may be mediated by acute heart failure, placing this interaction within the framework of type 3 CRS [104]. The underlying mechanisms include hepatic venous congestion secondary to elevated central venous pressure in right-sided heart failure and hepatocellular ischemia caused by reduced CO [105]. Beyond concomitant cardiac dysfunction, a prospective study of critically ill patients without cirrhosis demonstrated that fluid overload resulting from kidney failure and aggressive fluid resuscitation, together with increasing central venous pressure, were the principal determinants of elevated liver stiffness during ICU admission. In this acute setting, liver stiffness measured by transient elastography reflects hepatic congestion rather than structural fibrosis [106].

Beyond these hemodynamic mechanisms, experimental studies have shown that AKI can directly induce sterile hepatic inflammation [104, 107]. Increased circulating concentrations of proinflammatory cytokines, particularly IL-1, IL-6, and TNF-α, activate resident Kupffer cells, initiating a secondary intrahepatic inflammatory cascade [107, 108]. This response increases hepatic vascular permeability, promotes interstitial edema, and facilitates neutrophil and lymphocyte infiltration [108]. Oxidative stress further contributes to AKI-induced liver injury. In experimental models of renal ischemia–reperfusion injury, pre-treatment with glutathione significantly attenuated hepatic injury and reduced the subsequent rise in serum transaminase concentrations, underscoring the pathogenic role of reactive oxygen species [107].

In addition to impairing renal drug clearance, AKI alters hepatic drug metabolism. The systemic accumulation of proinflammatory cytokines, reactive oxygen species, and uremic toxins during AKI suppresses the activity of hepatic cytochrome P450 enzymes [104] which are responsible for the metabolism of most xenobiotics. Consequently, reduced hepatic metabolic capacity may result in unexpected drug accumulation and toxicity, particularly for medications with a narrow therapeutic index despite preserved liver function [104, 109].

Clinical implications

Although the mechanisms underlying their interaction remain unclear, the coexistence of hepatic dysfunction and AKI is associated with worse outcomes compared with patients presenting with AKI alone [110]. To date, no targeted therapeutic strategies exist specifically for AKI-induced hepatic dysfunction. Management relies on fundamental principles of organ support, including volume control, hemodynamic optimization to support cardiac function, and rigorous therapeutic drug monitoring to prevent toxicity. Regarding advanced interventions, extracorporeal hemoadsorption techniques aimed at mitigating the systemic cytokine burden represent a biologically plausible rationale; however, robust clinical evidence supporting their routine use in this specific context remains insufficient [111–113].

Immune system

Under physiological conditions, the kidney acts as an immunological organ contributing to immune homeostasis [114, 115]. Following kidney injury, an inflammatory cascade is initiated in the kidneys [116, 117]. As shown in preclinical models, this process amplifies locally and may propagate systemically, defining a possible new mechanism of distant organ damage induced by AKI (Fig. 1), including profound dysregulation of the immune system itself (Fig. 2) [118]. Clinically, AKI markedly increases patient frailty and susceptibility to de novo infections across diverse surgical and non-surgical populations [119–121]. Among AKI patients at ICU admission, de novo infections subsequently developed in 44% of those with AKI compared with 20% of patients without AKI, with the risk increasing in parallel with AKI severity [122].

Consequences of AKI

AKI may modulate the immune system in two different ways, including both hyperinflammation characterized by early, context-dependent activation of innate immune system, systemic cytokine release, and heightened inflammatory signaling [117] and immunoparalysis [123, 124] that mainly affects the innate immune system. Specifically, neutrophil function, including migration and phagocytosis, have been reported to be inhibited in the context of AKI [118]. This impairment could be partly mediated by resistin, an inflammatory cytokine and uremic toxin whose levels are significantly increased during AKI [125]. In patients with septic shock and AKI, neutrophil migration was reported to be more extensively suppressed compared to patients only with septic shock [125]. This immunosuppressive shift also involves antigen-presenting cell dysfunction: monocyte HLA-DR expression, a recognized marker of immunoparalysis, has been reported to be significantly lower in septic patients with AKI than in those without, independently of illness severity, mirroring a deeper state of immune depression associated with worse outcomes [126]. Conversely, when AKI occurs in a non-inflammatory setting – as mainly shown in preclinical models - the proinflammatory effect is prevalent [60, 87, 123].

Clinical implications

In the short term, sepsis represents a leading cause of death in critically ill patients with AKI [127]. This heightened vulnerability extends beyond the acute phase: survivors of dialysis-requiring AKI exhibit a 50%–70% higher incidence of severe sepsis compared to matched controls [120]. Crucially, this excess risk persists even after complete functional kidney recovery, indicating that AKI induces sustained immune dysregulation rather than a transient disturbance [120].

Beyond established infection prevention measures and timely, targeted antimicrobial therapy, no upstream interventions are currently available to specifically reverse AKI-associated immune dysregulation. Although hemoadsorption has demonstrated the potential to modulate elevated resistin concentrations and remove circulating inflammatory mediators in patients with septic shock, current evidence remains insufficient to support its routine clinical use in this setting [128]. Novel immunomodulatory approaches targeting maladaptive inflammatory pathways are under investigation, including recombinant CD39 (TIN816) as a potential therapeutic strategy in sepsis-associated AKI (CLEAR-AKI, NCT05996835).

Based on the aforementioned organ-crosstalks between the kidneys and other organs, the resulting organ dysfunction(s) and complications might be considered as endpoints in AKI trials. The following section considers how these consequences can inform the selection of primary and surrogate endpoints in AKI trials, and why traditional long-term kidney-centric metrics such as MAKE may not capture the full burden of the syndrome in non-enriched populations.

AKI trial endpoints: surrogate markers of AKI-associated complications

In considering optimal AKI trial endpoints, the purpose of the trial impacts endpoint options. AKI prevention and attenuation trials endpoints should ideally account for the incidence, severity, and duration of AKI allowing for gradation across the spectrum of AKI. Long-term outcomes (e.g. Major Adverse Kidney Events —MAKE—death, initiation of dialysis, and persistent kidney dysfunction) are not ideally suited as their incidence in non-enriched populations in prevention trials will be extremely low (< 5–10%). Thus, using this outcome would necessitate trials of several thousand patients to demonstrate efficacy [129]. Treatment trials should utilize patient-centered long-term outcomes (e.g. MAKE, hospital and dialysis free days) although depending on the cohort, clinical setting, and intervention, one component of MAKE may dominate the overall outcomes.

Importantly, when considering AKI as an outcome for a trial, short-term and transient changes in creatinine - and urine output-based endpoints are practical and will undoubtedly increase event rates, facilitating smaller and faster trials. However, it remains unclear how small changes in serum creatinine reliably predict long-term outcomes. While some epidemiology studies demonstrate links between Stage 1 AKI and adverse outcomes, the data is inconsistent [130–132]. However trials performed in critically ill patients, are different from those looking at community-acquired or ward-based AKI, and ICU investigations are better suited to look at more severe and persistent AKI and MAKE.

Furthermore, MAKE, especially mortality, is influenced by factors unrelated to AKI (e.g. post-operative sepsis or stroke), and mortality is a competing risk for long-term outcomes such as CKD and dialysis-dependence/ESKD [133]. Strategies for investigating CKD progression as an outcome after AKI include: ensuring adequate proportions of patients in each stage of AKI severity, matching patients based on age, baseline kidney function, and comorbidities, and frequent laboratory follow-up to analyze trajectory of kidney function [134]. Importantly, establishing baseline (pre-enrolment) kidney function can be problematic, depending on the availability of prior serum creatinine data, and this can impact AKI incidence, AKI severity, and the incidence of recovery. In patients without known CKD, when a reliable premorbid creatinine (or cystatin C) value is unavailable, the 2012 KDIGO guideline recommends estimating baseline creatinine either by back-calculation using the Modification of Diet in Renal Disease equation (assuming a baseline eGFR of 75 mL/min/1.73 m²) or using the lowest in-hospital creatinine value as a surrogate, provided unrecognized CKD has been excluded [15]. However, back calculation can both over and under estimate the incidence of AKI depending on the cohort. It is more likely to underestimate the incidence in younger healthy cohorts and over estimates in sicker and older cohorts [135, 136]. To overcome these issues, albuminuria may be used as a surrogate marker of CKD progression. The prospective, longitudinal, observational ASSESS-AKI study found that higher urine albumin-creatinine ratio 3 months after hospitalization with AKI was associated with increased risk of CKD progression (HR 1.53, 95% CI 1.45–1.62) [137].

Albuminuria could serve as a surrogate to predict patients at risk of CKD progression after AKI as well as a therapeutic target, such as with renin-angiotensin-aldosterone inhibitors, sodium-glucose cotransporter 2 inhibitors (SGLT2i) or glucagon-like peptide-1 receptor agonist (GLP-1) [137–142]. Other structural and functional biomarkers, including plasma soluble tumor necrosis factor receptor 1 and 2 (sTNFR1, sTNFR2), urine neutrophil gelatinase-associated lipocalin (uNGAL), urinary tissue inhibitor of metalloproteinase 2 and insulin-like growth factor–binding protein 7 (TIMP-2*IGFBP7), have been shown to predict CKD progression or recovery from AKI and may have a role as a surrogate outcome in AKI trials, however this requires future investigation and validation [143–149]. This is separate from the use of damage and stress biomarkers as an enrichment strategy to increase AKI incidence and severity [150–154].

In trials of patients with AKI who require dialysis, standardized definitions of recovery and dialysis dependence are lacking; as such, several definitions have characterized renal recovery or dialysis dependence including continued dialysis at hospital discharge, 28 days, and/or 90 days [155–157]. Dialysis dependence at 90 days is consistent with the definition of ESKD, and while this is certainly a patient-centered outcome, assessment before 90-days is equally relevant. Among these trials, definitions of recovery from dialysis dependence also vary, such as being alive without dialysis for 14 consecutive days as used in the LIBERATE-D trial, or lack of need for dialysis with a minimal creatinine clearance of 20 ml/min used in a post hoc analysis of the Acute Renal Failure Trial Network (ATN) study [155, 156]. Days alive and dialysis-free is a novel alternative endpoint that accounts for a patient-centered outcome as well as mortality associated with in-hospital AKI [155, 158–162]. However, this is inherently a composite outcome that treats death and dialysis dependence as equally important. Hierarchical composite endpoints and calculations of win ratios have been explored to account for the relative importance of different outcomes and provide more nuanced interpretations of results of AKI trials where death and dialysis-dependence are competing outcomes [133, 163]. Even among patients who no longer require dialysis after AKI, the risk of recurrent AKI and development of ESKD remains high, and future studies should investigate how to optimize care after incident AKI [164].

Systemic complications from AKI are often included in secondary, post hoc, or safety outcomes of AKI trials. Examples of systemic complications include prolonged mechanical ventilation, cardiac arrhythmias, exposure to hypotension / hemodynamic instability, delirium, infections, and bleeding. Table 3 describes outcomes from AKI trials related to other organ systems. Since AKI is associated with these complications and these influence patient outcome, these complications can also be used as a composite endpoint in treatment trials.

Table 3.

Novel endpoints for AKI trials

Outcome	Interaction with AKI	Examples from prior trials
Mechanical ventilation/Ventilator-Free Days	Fluid overload can lead to or exacerbate pulmonary edema, hypoxemia, and decreased lung compliance	Delayed initiation or conservative dialysis strategies do not appear to increase days on mechanical ventilation, with the caveat that protocols allowed for dialysis per clinician judgement [155, 161, 162, 174]
	Hypophosphatemia from prolonged CKRT can contribute to neuromuscular weakness	Hypophosphatemia during CKRT was associated with lower chance of successful extubation [175, 176] and fewer ventilator-free days [177]
Cardiac arrhythmias	Electrolyte abnormalities related to AKI can precipitate cardiac arrhythmias	Delayed initiation or conservative dialysis strategies do not appear to increase incidence of cardiac arrhythmias [155, 161]
Hemodynamics	Volume balance and dialysis can impact the need for vasoactive medications	Intermittent KRT modalities were associated with hypotension and/or cardiac arrhythmias during KRT [178]
		Accelerated or delayed dialysis initiation strategies were not associated with vasopressor-free days [159, 161]
Delirium/Coma	Accumulation of uremic toxins or neurotoxic medications/metabolites can contribute to delirium/coma	A more-delayed dialysis initiation strategy was associated with a lower chance of awakening among comatose patients with AKI [78]
Infections	Placement of dialysis catheters could increase risk for bloodstream infections	An accelerated dialysis initiation strategy was not associated with catheter-related bloodstream infections [159]
	Clearance by dialysis can affect antimicrobial drug levels	Patients on CKRT experience high rates of multi-drug resistant infections [179]
Postoperative bleeding	Accumulation of uremic toxins and fluid overload could contribute to bleeding after surgery	Postoperative AKI has been associated with increased risk of bleeding complications [180, 181]

AKI= Acute kidney ijury; CKRT= Continuous kidney replacement therapy; KRT = Kidney replacement therapy

Finally, given the high morbidity associated with hospital-acquired AKI, it is important for AKI trials to increase and expand the measurement of patient- and caregiver- centered outcomes for those who survive their critical illness. Length of stay and readmission rates, while often regarded as hospital quality metrics, also represent time patients spend in the hospital rather than at home and can be a useful outcome in AKI prevention and post-discharge AKI care trials [150, 165–167]. However, this endpoint should only be used in a context-specific manner (e.g. in the context of sepsis-associated AKI, but not for trials investigating cardiac surgery associated AKI). This endpoint should also differentiate between time at a non-hospital facility (e.g. skilled nursing facility or long-term acute care facility) and time at home.

Financial burden and impact on employment are equally life-changing patient-centered outcomes, but are seldom explored in AKI studies [158]. Health-related quality of life and physical function have frequently been shown to decrease after hospitalization with AKI [168–170]. Trials surrounding dialysis initiation for AKI, such as STARRT-AKI and AKIKI2 trials, have thus included measures of quality of life and activities of daily living as secondary outcomes [159–161]. To optimize post-ICU physical function, some studies have explored the feasibility and effects of early mobilization while on continuous kidney replacement therapy (CKRT) [171–173]. Future AKI trials should incorporate outcomes that pertain to patients’ and caregivers’ perceptions and experiences during and after hospitalization with AKI.

Conclusions

Although the molecular mechanisms are not fully elucidated, the literature consistently reports the association between the failing kidneys and other organ dysfunctions and that AKI-associated complications are associated with an increased morbidity and mortality. Unfortunately, no therapies directly targeting AKI exist; therefore, physicians can only apply preventive and supportive measures. As these AKI-associated complications directly influence the outcome of the patients, they may be considered as endpoints in AKI trials.

Abbreviations

AKI

Acute Kidney Injury

ALI

Acute Lung Injury

ARDS

Acute Respiratory Distress Syndrome

BBB

Blood Brain Barrier

BUN

Blood Urea Nitrogen

CKD

Chronic Kidney Disease

CO

Cardiac Output

CKRT

Continuous Kidney Replacement Therapy

CRS

Cardiorenal Syndrome

DAMPs

Damage Associated Molecular Patterns

ESKD

End Stage Kidney Disease

GFR

Glomerular Filtration Rate

GLP-1

Glucagon-like Peptide 1 receptor agonist

HMGB-1

High Mobility Group Box 1

ICU

Intensive Care Unit

IGFBP7

Insulin-like Growth Factor–Binding Protein 7

IL

Interleukin

KDIGO

Kidney Disease: Improving Global Outcomes

KRT

Kidney Replacement Therapy

LOS

Length of Stay

MAKE

Major Adverse Kidney Events

MRI

Magnetic Resonance Imaging

PRES

Posterior Reversible Encephalopathy Syndrome

RAAS

Renin-Angiotensin-Aldosterone System

SGLT2i

Sodium-Glucose Cotransporter 2 inhibitors

sTNFR1

Soluble Tumor Necrosis Factor Receptor 1

sTNFR2

Soluble Tumor Necrosis Factor Receptor 2

TIMP2

Tissue Inhibitor of Metalloproteinase 2

TLR

Toll-like receptor

TNF-α

Tumor Necrosis Factor alpha

uNGAL

Urine Neutrophil Gelatinase-Associated Lipocalin

Author contributions

AZ designed the review. BM, LF, HB, SM, JK, AL, AZ performed the literature search and drafted the manuscript. LF, SV, JK and AZ critically revised the manuscript for important intellectual content. BM and AZ finalized and revised the entire manuscript. BM created the figures of the manuscript. All the authors read and approved the final manuscript.

Funding

Open Access funding enabled and organized by Projekt DEAL. Not applicable.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

LF received funding and honoraria from Baxter and consulting fees from Astra Zeneca, Baxter and SphingoTec. HB is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation, 493624047 [Clinician Scientist CareerS Münster]). JK received research Funding from NIH, Astute Medical-Biomerieux, Bioporto Fresenius, SphingoTec; consulting fees from Alexion, Astra-Zeneca, Astute-Biomerieux, Bioporto, Seastar, Novartis, Guard Therapeutics, Vantive ; royalties – Wolters Kluwer (Handbook of Critical Care Nephrology). AZ received consulting fees from Astute-Biomerieux, Baxter, Bayer, Novartis, Chugai, Guard Therapeutics, AM Pharma, Paion, Viatris, Dropshot, Fresenius, research funding from Astute-Biomerieux, Fresenius, Baxter, DFG and speaker fees from Astute-Biomerieux, Fresenius, Baxter, Alexion, and Paion. BM, SM and AL declare no conflict of interest.