Kidney-organ interactions: recent advances and clinical implications

Abstract

Purpose of review

Critically ill patients often present with multiorgan dysfunction, and the kidney plays a central role in these pathophysiologic interactions. This review aims to provide an up-to-date summary of the most relevant kidney–organ cross-talks in the ICU, including lung, heart, liver, gut, and brain interactions, with emphasis on underlying mechanisms and clinical implications.

Recent findings

Recent large-scale observational studies and meta-analyses have strengthened the evidence for bidirectional interactions between the kidneys and other organs. In acute respiratory distress syndrome, for example, acute kidney injury contributes significantly to mortality, with inflammation, hemodynamic disturbances, and mechanical ventilation as key elements. Cardiorenal syndromes have been well classified, with venous congestion, immune response and renin–angiotensin–aldosterone system dysregulation identified as the most important drivers. At the core of these organ interactions – including impairments in liver metabolism, intestinal barrier integrity, and brain function – lies systemic inflammation, predominantly mediated by pro-inflammatory cytokines such as interleukin-6 and tumor necrosis factor-alpha, which activate endothelial and immune responses across organ systems and contribute to multiorgan dysfunction. Novel biomarkers and therapeutic interventions are being explored across organ systems.

Summary

Organ–kidney cross-talk is a hallmark of critical illness and significantly affects patient outcomes. Understanding these interactions is essential for early diagnosis, risk stratification, and tailored interventions. Integrating knowledge of organ-specific pathophysiology with kidney-centered management strategies holds promise for improving multiorgan recovery and reducing ICU mortality.

INTRODUCTION

Acute kidney injury (AKI) is common in critically ill patients and is associated with increased mortality [1]. The 2012 Kidney Disease Improving Global Outcomes (KDIGO) guidelines provide the most commonly used classification for AKI, based on serum creatinine levels and urine output [2]. However, these criteria offer limited insights into the underlying pathophysiological process behind the organ injury. The complex interplay between different organ systems during critical illness has gained increasing attention during recent years. The term organ-crosstalk refers to the bidirectional communication between organs via various ways such as soluble mediators, neural pathways, hemodynamic changes or therapeutic interventions influencing multiple systems. Critically ill patients often develop simultaneous dysfunction in multiple organ systems. The kidneys frequently are at the center of these complex interactions [3]. In critical illness (such as sepsis or shock), a disturbance in one organ can trigger maladaptive responses in others, creating a vicious cycle of injury. For example, AKI rarely occurs in isolation in the ICU and often co-exists with respiratory failure, cardiac dysfunction, or neurological injury, each exacerbating the other. Recent studies have increasingly focused on decoding these inter-organ connections to improve outcomes in critical care. This review examines key organ axes involving the kidneys – the lung–kidney, gut–kidney, heart–kidney, and brain–kidney interactions – in critically ill patients (Fig. 1). For each axis, we discuss mechanistic insights, clinical implications and possible therapeutic strategies.

FIGURE 1.

Schematic overview of pathophysiological mechanisms contributing to kidney-related organ crosstalk in critical illness. Created with BioRender.com.

LUNG–KIDNEY INTERACTIONS

Lung and kidney failure commonly co-occur in ICU patients. Acute respiratory distress syndrome (ARDS) is a common condition in the ICU [4], and approximately 30–40% of patients develop AKI [5^■■]. ARDS has been identified as an independent predictor of AKI in an observational trial in 2014 by Darmon et al. [6]. In a secondary analysis of the LUNG SAFE study, including data from 459 ICUs with 1974 patients, it could be shown that the coexistence of ARDS and AKI was associated with an increased mortality (50%) compared to patients with only ARDS (31%). Despite this association, it is often difficult to determine how much of this increased mortality is attributable to AKI or is just a reflection of disease severity. In a recent large investigation, Antonucci et al. analyzed multiple randomized controlled ARDS trials to better answer this question. They found in 5148 patients (included from 10 randomized controlled trials (RCTs) over 20 years), that the frequency of AKI remained relatively stable over the period of all these trials and that the overall excess 90-day mortality was 28.4%, highlighting the importance of this interaction [5^■■]. Another large retrospective single-center cohort study of nearly 77 000 ICU patients examined outcomes in patients with AKI, ARDS, or both. In particular, patients who developed ARDS after AKI had the highest mortality, highlighting that the temporal sequence of organ failure critically influences kidney–lung crosstalk [7].

Furthermore, an important observation is the bidirectional relationship between AKI and invasive mechanical ventilation (IMV) derived from multiple observational studies. While IMV is an independent predictor of AKI [8], some studies suggest that AKI is also associated with the requirement of IMV [9]. In a retrospective study the occurrence of AKI during IMV was associated with increased mortality, length of ICU stay and in general impaired respiratory function [10]. This association has also been demonstrated in critically ill COVID-19 patients. During the first wave, many cohorts observed relatively high rates of IMV and concomitant AKI. In contrast, these rates declined both during the second wave, together with a more liberal application of noninvasive ventilation strategies [11–13].

In summary, lung–kidney interactions are primarily driven by hypoxemia, hypercapnia, systemic inflammation, and hemodynamic disturbances [14,15]. Lung injury and associated biotrauma can trigger a systemic inflammatory cascade, with the release of pro-inflammatory cytokines that contribute to the development of AKI [14,16]. On the other hand, AKI may induce lung injury via a pronounced inflammatory reaction and also increased cytokines such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α), as shown in an animal model [17]. Beyond cytokine release, mitochondrial dysfunction plays a pivotal role in this kidney–lung crosstalk by amplifying oxidative stress, promoting cell death pathways, and releasing mitochondrial danger signals (DAMPs) that further propagate systemic inflammation [18]. Uremia is another potential mediator of kidney-lung organ crosstalk, leading to increased vascular permeability and impaired alveolar fluid clearance in the lungs [19].

Another main mechanistic driver of this organ interaction is hypoxemia and hypercapnia, which are directly influencing renal vascular resistance [3]. Hemodynamic consequences, particularly right heart strain in ARDS, may further compromise renal function through venous congestion. Elevated central venous pressure has been repeatedly associated with worsening renal outcomes. While high positive end-expiratory pressure (PEEP) improves alveolar recruitment and oxygenation, it may also elevate intrathoracic pressures, compress the vena cava, reduce cardiac output, and promote the activation of the sympathetic and renin-angiotensin system [15]. Despite these insights, clinical trials have yet to clarify optimal PEEP levels due to variability in outcomes and the need to balance lung and kidney protection [20]. Prone positioning, widely used in COVID-19 patients [21], has been shown to influence renal hemodynamics: in patients with acute lung injury it increased intra-abdominal pressure and renal vascular resistance, without significantly altering glomerular filtration or urine output in otherwise stable conditions [22]. However, in a recent porcine ARDS model it markedly reduced renal perfusion and was associated with glomerular thrombosis, suggesting that prolonged or severe proning may contribute to compromised renal function [23].

Kidney injury on the other hand is often associated with oliguria and fluid accumulation and may therefore worsen lung injury [24]. This implies the importance of individualized ventilatory strategies, fluid management, and careful consideration of hemodynamic parameters, including intrathoracic pressures and central venous congestion, to optimize patient outcomes. Future research should focus on refining therapeutic protocols to balance protective lung strategies with renal preservation and improving recovery in critically ill patients with concurrent lung and kidney injury.

HEART–KIDNEY INTERACTIONS

Heart failure has long been associated with an increased risk of AKI and worsening renal failure, potentially leading to chronic kidney disease, especially in patients with chronic heart failure. These interactions have been categorized into five different cardio-renal syndromes [25]. Types 1 and 2 describe heart-to-kidney interactions, while types 3 and 4 focus on kidney-to-heart interactions. Type 5 involves systemic conditions affecting both organs (Table 1).

Table 1.

Classification of cardio-renal syndromes based on the Consensus Conference of the Acute Dialysis Quality Initiative adapted from [25]

Type	Name	Definition	Examples
1	Acute cardiorenal syndrome	Acute worsening of cardiac function leading to acute kidney injury (AKI)	Acute decompensated heart failure → AKI
2	Chronic cardiorenal syndrome	Chronic cardiac dysfunction leading to progressive chronic kidney disease (CKD)	Chronic heart failure → CKD
3	Acute renocardiac syndrome	Acute worsening of kidney function causing acute cardiac dysfunction	AKI → acute heart failure, arrhythmia
4	Chronic renocardiac syndrome	Chronic kidney disease contributing to cardiac dysfunction	CKD → left ventricular hypertrophy, ischemic heart disease
5	Secondary cardiorenal syndrome	Systemic condition causing simultaneous heart and kidney dysfunction	Sepsis, diabetes, systemic inflammation

AKI, acute kidney injury; CKD, chronic kidney disease.

While the details of all cardiorenal interactions are beyond the scope of this review, critically ill patients are most exposed to types 1, 3, and 5 cardiorenal syndromes.

In type 1 cardiorenal syndrome, venous congestion appears to play a critical role, and effective decongestion strategies – often involving hemoconcentration – have been associated with improved survival. The roles of systemic inflammation and oxidative stress have also been increasingly recognized [26–28].

Sepsis, which is highly prevalent in intensive care units, is frequently associated with both AKI and myocardial injury, and is characteristic of type 5 cardiorenal syndrome [29^■]. The pathophysiology mainly involves systemic inflammation, oxidative stress, and microcirculatory dysfunction. While the role of systemic hemodynamics has been debated, sepsis-associated AKI is most often associated with normal or elevated renal blood flow. Alterations in the renin–angiotensin–aldosterone system contribute to abnormal renal blood flow distribution and disruption of glomerular filtration regulation [30]. Finally, venous congestion may also contribute to sepsis-associated AKI [31].

Recently, the cardiac consequences of AKI (corresponding to type 3 cardiorenal syndrome) have been increasingly recognized [32]. Animal models have shown that an episode of AKI can lead to acute but persistent myocardial damage, followed by secondary fibrosis and alterations in cardiac function. Patients who experience AKI have an increased risk of death and cardiovascular events in the months following the episode.

Two pro-inflammatory pathways – Galectin-3 [33] and Interleukin-33 [34] – appear to play key roles in cardiac injury after AKI. Inhibition or blockade of these mediators has been shown to prevent cardiac injury in animal models. Persistent activation of the renin–angiotensin system may also contribute to post-AKI cardiac dysfunction. Treatment with renin-angiotensin system inhibitors such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is associated with improved outcomes after an episode of AKI [35,36]. Sodium-glucose cotransporter-2 (SGLT2) inhibitors also appear to be associated with better outcomes in patients at risk for AKI [37]. An observational study suggested that veterans with diabetic kidney disease treated with SGLT2i after an episode of AKI had better survival [38], although there is no current evidence that initiating these medications after an AKI episode improves cardiovascular outcomes.

LIVER–KIDNEY INTERACTIONS

AKI frequently coexists with acute and chronic liver dysfunction in critically ill patients. Over 50% of patients with acute liver failure (ALF) and approximately 30–50% of hospitalized cirrhotic patients develop AKI, including hepatorenal syndrome (HRS), highlighting the clinical significance of this organ interaction [39].

The liver primarily influences kidney function through hemodynamic alterations, systemic inflammation and drug-related nephrotoxicity. In cirrhosis, portal hypertension causes profound splanchnic vasodilation, leading to a relative hypovolemia that triggers compensatory activation of the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system [40]. This, in turn, induces renal vasoconstriction, reduced glomerular filtration rate (GFR), and eventually manifests as HRS – a form of functional renal failure without intrinsic kidney damage [41]. Moreover, liver dysfunction – especially during acute liver failure or sepsis-related liver impairment – releases pro-inflammatory cytokines and oxidative stress mediators that directly injure renal endothelial and tubular cells [42]. Interestingly bile acids seem to damage tubular cells a condition called cholemic nephropathy [43]. In a recent animal model pharmacologically blocking of bile acid reabsorption in renal proximal tubular epithelial cells prevented cholemic nephropathy, with strong biological rationale [44,45^■■]. Additionally, serum bile acid levels were strongly correlated with KIM-1, a sensitive biomarker of renal injury, suggesting a promising direction for future targeted therapies [44]. Additionally, drug toxicity in patients with preexisting liver impairment further increases the risk for AKI, emphasizing the complexity of pharmacological management in these patients.

Conversely, AKI exerts significant hepatic effects. The development of metabolic acidosis is common during severe AKI, which has multiple effects on hepatic metabolism [46,47]. Another factor is the accumulation of uremic toxins and volume overload due to impaired renal clearance, which may provoke hepatic congestion. A central mediator of AKI-induced liver injury is also the systemic inflammatory response with the release of pro-inflammatory cytokines such as IL-6 and TNF-α [48].

A recent study examined urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a stratification tool in patients with cirrhosis and AKI [49]. Elevated uNGAL levels correlated with more severe renal injury and worse prognosis. This suggests uNGAL may help differentiate structural AKI from functional HRS, offering a means to better personalize management strategies in this high-risk population. These complex interactions were the focus of the 2023 joint consensus by the Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) and the diagnostic criteria for HRS-AKI were updated and emphasized the central role of systemic inflammation and organ cross-talk in kidney–liver dysfunction [45^■■].

GUT–KIDNEY INTERACTIONS

The literature specifically focusing on gut-kidney interactions is currently limited. As part of multiorgan failure critically ill patients often develop “gut failure”, characterized by loss of epithelial integrity (a leaky gut), due to splanchnic vasoconstriction and stress-induced cell death [50^■]. Another mechanism is the destruction of tight junctions leading to increased permeability [51]. Interestingly, in a murine sepsis model, gut hyperpermeability was attenuated when epithelial apoptosis was reduced through BCL-2 overexpression, which preserved tight junction protein expression and thereby maintained barrier integrity [52]. During this state of increased permeability bacteria and microbial products (e.g. endotoxins) can translocate from the gut lumen into systemic circulation and activate proinflammatory cytokines potentially exaggerating multi organ failure including the kidneys as a potential organ interaction.

Another important aspect of the gut during critical illness is dysbiosis – a change in the composition of gut microbiota that has long been recognized [53,54]. During sepsis inflammation leads to significant changes in the microbiome [55]. On the other hand, the microbiome is able to modulate the immune response [56]. Notably, short-chain fatty acids produced by gut bacteria under physiological conditions have been shown to improve septic AKI in animal models [57]. Antibiotics further complicate this interaction. Broad-spectrum antibiotic use, ubiquitous in most ICU patients, profoundly alters the gut microbiome by reducing microbial diversity and eliminating commensal bacteria, thereby facilitating overgrowth of pathogenic organisms and reducing short-chain fatty acid production [58].

On the other hand AKI can lead to an increase in urea and therefore increase ammonia and ammonium hydroxide in the gut, which can ultimately destroy the tight junctions and also cause bacterial translocation [59,60].

Another relevant mediator is gut-derived endotoxin. In inflammatory bowel disease, barrier disruption permits translocation of endotoxin (lipopolysaccharide) into the circulation; blood endotoxin levels are significantly elevated in inflammatory bowel disease (IBD) patients compared to controls [61]. LPS activates TLR4-driven cytokine cascades, amplifying systemic inflammation. These processes provide a plausible route by which intestinal disease can aggravate distant organ dysfunction, including kidney injury, via endotoxin-mediated endothelial and immune activation.

Finally, the alternative renin–angiotensin pathway has gained attention in bowel disease. The ACE2/Ang-(1–7)/Mas receptor axis is highly expressed in the intestinal epithelium and counterbalances the pro-inflammatory ACE/Ang II/AT1 pathway. Loss of ACE2 disrupts tryptophan transport, reshapes the microbiota, and predisposes to severe colitis [62]. Conversely, augmentation of the alternative axis (e.g., Ang-(1–7) administration or ACE2 activation) attenuates colitis severity and preserves barrier integrity in experimental models [63]. These data support the concept that modulation of the gut RAS may influence both local bowel disease and systemic inflammatory responses, with potential implications for kidney injury during critical illness.

Therefore, therapeutic interventions aiming for gut integrity such as early enteral nutrition [64], probiotic therapies [65], or selective digestive decontamination [66] might have the potential to positively affect kidney outcomes. A new Mendelian randomization study used genome-wide associations studies and provides genetic evidence supporting a causal relationship between gut microbiota composition and risk of kidney injury [49]. This work strengthens the rationale for microbiome-targeted therapeutic strategies in AKI.

BRAIN–KIDNEY INTERACTIONS

Encephalopathy is a classical complication of chronic kidney disease (CKD) [67]. In cohort studies patients with AKI commonly develop confusion. AKI is therefore associated with both ICU delirium [68] and with subsequent diagnosis of dementia [69]. Several studies support the fact that these observed associations are related to a causal relationship. First, an experimental model of bilateral nephrectomy in mice demonstrated both pathological and functional brain changes, along with significant impact on animal locomotor activities [70]. In addition, further studies have identified biological pathways explaining brain-kidney interaction and giving a solid biological plausibility to these observations [71,72].

It is worth mentioning that drug toxicity [73], sepsis and organ dysfunctions may induce or worsen preexisting AKI-associated encephalopathy [74–76]. Although role of these factors is important, we will focus in this overview on pathophysiological pathways by which AKI may directly participate to observed encephalopathy.

First, AKI, probably via release of proinflammatory mediators and endothelial activation [77], increasing blood barrier permeability [70].

Second, studies have demonstrated glial and astrocytic activation further enhancing release of cytokines and adding local sources of injury [78].

Third, AKI has been shown to decrease catecholamine degradation [79] while decreasing central level of catecholamines [71,72].

Accumulation of various compounds including Guanidino compounds, tryptophan metabolites and advances glycation end product have been suggested to contribute to uremic encephalitis via direct functional effects, induced neuron cell death or induction of inflammation [67].

Last, changes in brain water content as a consequence of osmolyte accumulation in advanced AKI is debated [70,80]. Nevertheless, large brain to plasma urea gradient after dialysis may lead to dialysis disequilibrium syndrome and cerebral edema that may further deteriorate neurological functions [80,81].

Mechanistically, urea transporters (UT-B1) are reduced and aquaporins (particularly AQP4 in astrocytes) are upregulated during chronic uremia, a pattern consistent with rapid osmotic water shifts across the blood–brain barrier and cerebral edema during dialysis [82].

Despite these experimental data strongly suggesting that kidney-brain cross-talk may initiate or enhance neurological dysfunction, both epidemiological studies in this field are scarce and prognostic studies assessing impact of renal dysfunction on neurological outcome are limited. In an observational cohort study, Storm et al. found AKI to be a major risk factor for poor neurological outcome after cardiac arrest [83]. Similar results were observed in other cohorts of cardiac arrest patients [84] or after traumatic brain injury [85]. Most of these studies were however performed in cohorts of limited sample size, and interpretation is frequently limited by difficulty to adjust for confounding and more precisely to the fact that AKI is a marker of severity of disease in most of these studies, independently of potential kidney-brain interaction.

Table 2 summarizes the key mechanisms of the different organs.

Table 2.

Summary of key mechanisms in organ-crosstalk with the kidney and potential clinical implications

Organ system	Organ → kidney (mechanisms)	Kidney → organ (mechanisms)	Potential clinical/therapeutic implications
Lung	ARDS → Inflammation↑ (↑IL-6, TNF-α), Hypoxemia/Hypercapnia, Venous congestion, High PEEP → RBF↓	AKI → Inflammation, Fluid overload → pulmonary edema,	PEEP titration balancing lung/kidney, conservative fluid management,
Heart	Heart Failure → CO↓, Venous congestion, RAAS activation (CRS Type 1/2), Inflammation↑, Oxidative stress↑	AKI → Venous pressure↑, RAAS & SNS activation, Galectin-3, IL-33 → Myocardial fibrosis	Decongestion, RAAS inhibition, SGLT2 inhibitors post-AKI,
Liver	Cirrhosis → HRS, Splanchnic vasodilation, RAAS activation, ↑Inflammation, Drug toxicity	AKI → Metabolic acidosis, Uremia, hepatic congestion, Inflammation↑	Avoid nephrotoxins, fluid management (including albumin if necessary), terlipressin (using biomarker enrichment), splanchnic decongestion (TIPS, liver transplantation),,
Gut	Gut leak → Endotoxin translocation, Cytokines↑, Sepsis, Dysbiosis → Inflammation↑	AKI → Urea↑ → Ammonia↑ → Mucosal injury, Permeability↑, Dysbiosis, Bacterial translocation↑	Support gut integrity (early EN, probiotics), monitor dysbiosis, limit uremia
Brain	Neuro-injury → Catecholamine surge, Neuroinflammation	AKI → Inflammation, BBB permeability↑, Catecholamine clearance↓, Neurotoxins → Encephalopathy	Delirium monitoring, neuroprotective sedation, prevent rapid urea/osmotic shifts

AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; BBB, blood-brain barrier; CO, cardiac output; CRS, cardiorenal syndrome; EN, enteral nutrition; HRS, hepatorenal syndrome; IL, interleukin; PEEP, positive end-expiratory pressure; RAAS, renin-angiotensin-aldosterone system; RBF, renal blood flow; SGLT2, sodium-glucose cotransporter 2; SNS, sympathetic nervous system; TIPS, transjugular intrahepatic portosystemic shunt; TNF-α, tumor necrosis factor alpha.

CONCLUSION

A shift toward recognizing the dynamic interdependence between organs – especially under conditions like sepsis, mechanical ventilation, and circulatory failure – is essential. Bridging experimental insights with clinical tools, such as biomarkers and organ-specific management strategies, may unlock new opportunities to intervene earlier in the trajectory of multiorgan failure.

KEY POINTS.

• Multiorgan failure is often initiated and perpetuated through bidirectional kidney interactions and acute kidney injury can actively worsen cardiac, pulmonary, hepatic, gastrointestinal, and neurologic function, creating feedback loops that drive critical illness.

• Experimental models are shaping our mechanistic understanding. Animal studies have revealed distinct pathways that have the potential to inform targeted interventions for future research

• Organ- and interaction-specific biomarkers may enable tailored AKI management and offer promise for differentiating AKI subtypes with potential to guide timing and type of organ support.