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].

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.

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