Hepatocardiorenal Syndrome: Integrating Pathophysiology with Clinical Decision-Making via Point-Of-Care Ultrasound

Hepatorenal syndrome (HRS) type 1 is a phenotype of acute kidney injury (AKI) that is specific to patients with advanced cirrhosis and ascites (HRS-AKI). It is conventionally defined as a form of acute (or acute on chronic) impairment in kidney function that is caused by renal hypoperfusion and is refractory to intravascular volume repletion [1]. Systemic inflammation, alterations in arterial circulation, and maladaptive activity of the endogenous vasoactive systems contribute to HRS-AKI [2]. Neurohormonal activation including the renin-angiotensin-aldosterone system and sympathetic nervous system plays a key role in the pathophysiology of HRS-AKI. Interestingly, these pathways are also known to contribute to impaired kidney function in patients with heart failure (i.e., cardiorenal syndrome). On the other hand, emerging data obtained from more advanced imaging studies point to the involvement of the heart in various stages of liver disease (i.e., cirrhotic cardiomyopathy) [3]. As such, while HRS was originally thought to be primarily a syndrome involving the liver and the kidney, in more recent years, the role of the heart in its pathophysiology has been recognized, which encompasses endothelial and circulatory dysfunction [4, 5]. It is within this context that HRS-AKI is proposed to represent a form of overlap syndrome where the pathophysiologic mechanisms linking the liver to the kidney may be intertwined with those connecting the heart to the liver as well as the cardiorenal pathways, hence the name hepatocardiorenal syndrome (HCRS) [6].

Peripheral and splanchnic vasodilatation is believed to be the primary cause of hyperdynamic circulation in patients with advanced cirrhosis [7, 8]. Initially, an increase in cardiac output maintains the blood pressure and tissue perfusion, but as the liver disease advances, the significant reduction in systemic vascular resistance exceeds the cardiac reserve, resulting in progressive underfilling of the arterial circulation and central hypovolemia. Therefore, progressive activation of the neurohormonal system ensues to restore and maintain the blood volume and arterial pressure. This leads to impairment of renal blood flow, decrease in glomerular filtration rate, reduction of urinary sodium excretion, and increased water retention, hence the tendency for the development of ascites and hyponatremia [9].

Cirrhotic cardiomyopathy, the untoward impact of cirrhosis on cardiac dysfunction, is increasingly recognized as an overlooked entity in this setting and may be present in as many as more than half of these patients [10]. It is characterized by systolic dysfunction as evidenced by a blunted increase in stress cardiac output, impaired diastolic relaxation, prolonged isovolumetric relaxation time, and several electrophysiological disturbances in the absence of a known cardiac disease [10]. Therefore, it is conceivable that the impairment in renal function that is seen in HRS would be in part related to cardiac dysfunction and cirrhotic cardiomyopathy because maladaptive neurohormonal activation is also central to the pathophysiology of cardiorenal syndrome, linking acute heart failure to low glomerular filtration rate as well as retention of sodium and water [11]. Figure 1 provides an overview of the pathophysiologic pathways linking the liver, the heart, and the kidney in HCRS.

The potential contributory role of cardiac dysfunction in the development of renal impairment in this setting is supported by the observation that it precedes HRS-AKI. For example, in a study by Ruiz-del-Arbol, those cirrhotic patients who subsequently developed HRS already had stigmata of cardiac dysfunction (e.g., lower stroke volume) prior to the decline in renal function [12]. Similarly, in another study, more patients with cirrhosis developed HRS-AKI in the group with baseline low cardiac index as measured by gated myocardial perfusion imaging [13]. Cardiorenal interactions after portosystemic shunting also provide evidence in favor of the contributory role of the heart in the setting of HRS-AKI. Despite unloading the portal system into the systemic circulation and potentially leading to enhanced congestion of the renal veins, transjugular intrahepatic portosystemic shunt has been shown to have a beneficial impact on renal function [14]. Cardiorenal interplay may be the key mediator of the observed renal effects of transjugular intrahepatic portosystemic shunt, as it significantly improves cardiac inotropy, leading to enhanced central blood volume and renal perfusion [15].

Finally, a study by Pelayo et al. [16] used data from right heart catheterization of patients who had been clinically diagnosed with HRS-AKI based on the current criteria. A significant subset of these patients was found to have elevated cardiac filling pressures and was therefore switched to diuretic therapy which was followed by significant improvement in their renal function. Improvement of renal function after diuresis in these patients who were diagnosed with HRS-AKI highlights the significant contribution of cardiac dysfunction to their renal dysfunction. This observation also highlights the importance of objective assessment of volume in these patients. Point-of-care ultrasound (POCUS) has gained much attention in this setting as it can provide crucial information that links the pathophysiology of HCRS to its management.

Effective management of HCRS or AKI in cirrhosis in general relies on accurately assessing a patient’s hemodynamic status. It is well established that conventional physical examination has low sensitivity for this purpose [17]. Bedside ultrasonography is a valuable tool for evaluating multiple aspects of the hemodynamic circuit. It can often be performed during the same session as the patient’s history is being taken, allowing for immediate integration of the findings into clinical decision-making. Unlike ordering multiple diagnostic tests such as chest radiographs, comprehensive echocardiograms, renal and liver Doppler, and then waiting for reports from physicians who might not be directly involved in patient care, POCUS allows clinicians to address specific, immediate questions crucial for patient management at the bedside. This approach eases the cognitive burden of clinical decision-making. While POCUS is not a substitute for comprehensive or consultative imaging, further imaging may or may not be necessary depending on the questions answered and the operator’s skill level. We refer to bedside hemodynamic assessment as the “pump, pipes, and leaks” protocol, indicating the evaluation of cardiac function, blood vessels, and tissue congestion (e.g., extravascular lung water and ascites) [18]. This section delves into how POCUS fits into the diagnostic approach for HCRS, illustrating how it guides management decisions and provides the reasoning behind each sonographic application discussed.

Obstructive nephropathy is an uncommon cause of AKI in cirrhosis, reported in cases of tense ascites and midodrine-induced increased vesical sphincter tone [19, 20]. However, excluding hydronephrosis with POCUS takes just a few minutes and helps narrow down the diagnostic possibilities. Additionally, POCUS identifies Foley catheter malfunction leading to bladder outlet obstruction and differentiates pelvic ascites from a distended urinary bladder, which can mislead automated bladder scanners [21]. When it comes to ascites, ultrasonography is often the primary imaging tool employed for its detection. It can identify as little as 100 cc of fluid, whereas the sensitivity of physical examination is notably reduced, especially in obese patients [22]. Additionally, POCUS can assist in guiding paracentesis and differentiating bowel pathology from ascites as the cause of abdominal distension [23].

Given the significant focus on empiric intravenous fluid administration in hospitalized patients with cirrhosis and AKI, weighing the potential harm of fluid administration against benefit is crucial, a concept known as fluid tolerance assessment [24]. Put simply, if a patient already shows signs of congestion (such as sonographic evidence of elevated left and/or right atrial pressures [RAPs]), administering fluids is less likely to improve renal function and can lead to iatrogenic fluid overload. This concept differs from fluid responsiveness, which has traditionally been emphasized in resuscitation-related studies. Fluid responsiveness suggests that a patient can increase stroke volume in response to fluid administration. However, demonstrating fluid responsiveness is not an indication for intravenous fluids, as it is a physiological state, and exhausting it can push the patient into a pathological spectrum. Moreover, being fluid responsive does not guarantee fluid tolerance. In a recent study involving critically ill mechanically ventilated patients, at least one sign of congestion was present in over 50% of both fluid responsive and fluid unresponsive groups [25]. Although this study did not specifically involve patients with cirrhosis, it raises concerns given that this population is prone to empiric volume expansion and its associated consequences. Lung and inferior vena cava (IVC) ultrasound are technically simpler sonographic applications, and we view them as the entry point for fluid tolerance assessment, as they reflect left and right heart pressures, respectively.

Considering the high prevalence of diastolic dysfunction in patients with cirrhosis and the increased risk of pulmonary complications during therapy, assessing the lungs for extravascular lung water is a sensible approach, especially for patients receiving or expected to receive intravenous fluids. However, the sensitivity of auscultation findings in detecting pulmonary congestion is limited across various clinical contexts, including heart failure, end-stage kidney disease, and critically ill patients [26‒28]. Lung POCUS provides a radiation-free alternative that outperforms auscultation in identifying extravascular lung water. The number of B lines, which are vertical hyperechoic artifacts observed on lung POCUS, correlates with pulmonary capillary wedge pressure, and detecting subclinical pulmonary congestion through POCUS carries prognostic importance [29‒32] (Fig. 2). Notably, POCUS surpasses chest radiography in detecting cardiogenic pulmonary edema [33]. However, as shown in Figure 3, B lines are not specific to cardiogenic pulmonary edema and must be interpreted within the clinical context. Additionally, lung POCUS is highly effective at detecting pleural effusions; one study found that anteroposterior chest radiographs missed nearly 40% of effusions visible on ultrasound in cirrhotic patients [34].

As elevated RAP is a contributing factor to venous congestion and subsequent AKI, known as congestive nephropathy, detecting an elevated RAP at the bedside should prompt caution in administering intravenous fluids to avoid exacerbating venous congestion [35]. In intensive care unit patients with central venous catheters, a transduced central venous pressure can be obtained to monitor RAP. For patients without catheters, IVC POCUS provides a noninvasive method of estimating RAP. In fact, IVC ultrasound is a standard component of echocardiography for this purpose. In spontaneously breathing patients, an IVC diameter of less than 2.1 cm with more than 50% collapse during a sniff suggests a RAP between 0 and 5 mm Hg. Conversely, an IVC diameter greater than 2.1 cm with less than 50% collapse during a sniff indicates a RAP of 10–20 mm Hg. If the vessel is either dilated but well collapsible or small but less collapsible, it suggests an intermediate RAP of 5–10 mm Hg [36]. In the context of cirrhosis, an observational study conducted by Velez et al. [37] using IVC POCUS highlighted the limitations of conventional bedside assessment. Among a cohort of 53 patients diagnosed with HRS type 1 based on “clinical” criteria, alternative, potentially treatable fluid disorders (volume depletion, expansion, or intra-abdominal hypertension) were identified in 64% of the patients using predefined IVC criteria. However, in real-world scenarios, IVC POCUS presents numerous challenges in patients both with and without cirrhosis. A small collapsible IVC cannot reliably distinguish between hypovolemia and euvolemia. Anyone with considerable POCUS experience would know that it is common to see nephrology clinic patients with stable renal function and completely collapsible IVCs. Moreover, the aforementioned collapsibility cutoffs to estimate RAP are largely obtained from non-acutely ill patients and using a sniff rather than quiet respiration is to standardize the magnitude of breath. However, in ill hospitalized patients, the strength of breath widely varies, and they may not be able to follow instructions (e.g., patients with hepatic encephalopathy). IVC-based estimation of RAP is also unreliable in mechanically ventilated patients [38]. Additionally, in patients with a high cardiac output state and vasodilation, which is common in cirrhosis, the IVC is typically small and collapsible unless cardiac filling pressures begin to rise [39]. In such cases, volume expansion is not the logically appropriate treatment, and early initiation of vasopressor therapy may be beneficial if the patient presents with AKI. Additionally, obtaining an optimal view of the IVC in patients with cirrhosis can be technically challenging due to structural alterations in the liver, as we are assessing the intrahepatic portion of the IVC. It is not uncommon to encounter echocardiography reports stating that the IVC is inadequately visualized in these patients and hence the RAP is indeterminate. Furthermore, in cases of increased intra-abdominal pressure, the IVC can appear small despite elevated RAP. Although narrowing of the intrahepatic IVC that improves with positional changes has been described as a sonographic indicator of intra-abdominal hypertension, its specificity is unclear [40]. In our experience, we have observed similar appearances in patients without significant ascites due to caudate lobe hypertrophy, and it is not always feasible to reposition the patient. In fact, “IVC scalloping,” or compression of the intrahepatic IVC due to an enlarged caudate lobe, has been identified as a specific marker for cirrhosis in one study [41]. Regardless, it is prudent to drain the ascites to improve renal perfusion if there is any suspicion of intra-abdominal hypertension, provided the procedural risk is acceptable. On the other hand, IVC can be dilated despite normal RAP in some patients with cirrhosis due to factors such as portosystemic collaterals draining into it [42]. Figure 4 highlights key factors influencing IVC ultrasound and RAP that POCUS users must consider, alongside intravascular volume and the cirrhosis-specific pitfalls mentioned earlier, for accurate interpretation and effective clinical integration of this parameter.

If accessing the IVC is challenging or it appears unreliable, assessing the internal jugular vein (IJV) for estimating RAP is an alternative. A recent study in patients with cirrhosis found that an IJV cross-sectional area collapsibility index of ≤24.8% was more effective at predicting a central venous pressure of ≥8 mm Hg, with 100% sensitivity and 97.1% specificity, outperforming IVC ultrasound. Additionally, the IVC was not well visualized in 18% of cases, highlighting the technical difficulty in this population [43]. However, caution is essential when using IJV POCUS due to potential pitfalls. These include errors from improper head elevation or rotation, excessive probe pressure on the vein, previous thrombosis, variations in right atrial depth (contrary to the traditional 5 cm assumption), and a multitude of techniques found in the literature, such as measuring the height of the venous column, respiratory diameter variation, cross-sectional area, and response to the Valsalva maneuver [44, 45].

When evaluating patients at presentation, if lung and IVC or IJV POCUS indicate fluid tolerance, administering intravenous albumin is reasonable. Conversely, if the patient shows signs of fluid intolerance or unimproved AKI despite initial volume resuscitation, focused cardiac ultrasound can be valuable for further assessment and exploring the HCRS pathophysiology.

Cardiac POCUS offers better insights into hemodynamic abnormalities and guides management. For example, a plethoric IVC or IJV could result from various conditions, such as pericardial effusion, right ventricular failure due to chronic pulmonary hypertension, pulmonary embolism, biventricular failure, tricuspid regurgitation, or pneumothorax from central venous catheter complications. Equating a plethoric IVC with “volume overload” does not always lead to appropriate management [46]. By carefully examining greyscale and color Doppler images, one can quickly determine the presence or absence of pericardial effusion, assess left ventricular (LV) systolic function (eyeballing the ejection fraction), identify significant valvular lesions (such as mitral regurgitation leading to pulmonary edema), and gross chamber enlargement (e.g., right ventricular dilation with compression on the LV or left atrial dilation in diastolic dysfunction) [47]. In this context, it is crucial to emphasize that a “hyperdynamic LV” does not equate to volume depletion. It can indicate hypovolemia, a euvolemic state, or a high cardiac output state, similar to a small collapsible IVC. A study in patients with sepsis and septic shock supports this idea, showing significantly higher LV ejection fraction (64% vs. 56%) and stroke volume (72 mL vs. 48 mL), along with lower arterial elastance and systemic vascular resistance in patients with cirrhosis compared to those without cirrhosis [48]. This suggests that volume depletion is not the primary factor driving a hyperdynamic heart in this population. The utility of focused cardiac ultrasound is enhanced by the ability to assess certain Doppler parameters when wielded by competent POCUS users.

This holds significance in scenarios such as evaluating fluid responsiveness and differentiating volume depletion from a high cardiac output state. In volume depletion, stroke volume is low with a hyperdynamic heart, whereas in high cardiac output states, stroke volume is high. This differentiation helps determine whether a patient would benefit more from intravenous fluids or vasopressors like norepinephrine and terlipressin. Administering intravenous fluids based on a small collapsible IVC in a patient with a high-output cardiac state can result in iatrogenic fluid overload, as these patients are prone to elevated cardiac filling pressures, leading to high-output cardiac failure, especially after initiating vasoconstrictor therapy and increasing cardiac afterload (Fig. 5). Additionally, recent findings indicate that seemingly fluid-tolerant individuals may not necessarily be fluid responsive. A study by Kenny et al. [49] on 41 hypoperfused emergency department patients revealed that even fluid-naïve individuals with sonographic estimates of low preload demonstrated high rates of fluid unresponsiveness (approximately 30%). Assessing stroke volume is also crucial in overt cardiac failure to evaluate cardiac index and the need for invasive monitoring, inotropes, or mechanical circulatory support. The sonographic estimation of stroke volume involves multiplying the diameter of the left ventricular outflow tract (LVOT) by the velocity time integral (VTI), which is obtained by tracing the Doppler envelope of blood flow exiting the LVOT (Fig. 6). The normal VTI range is approximately 18–22 cm for heart rates between 55 and 95 bpm [50]. Since the LVOT diameter is constant for a given person, LVOT VTI is often used as a surrogate for stroke volume in clinical practice. However, tilted cardiac views can introduce substantial errors due to inappropriate Doppler angles. Similarly, failing to average multiple readings, especially in cases of arrhythmia, may lead to gross underestimation or overestimation.

Diastolic dysfunction stands out as the most sensitive parameter for diagnosing cirrhotic cardiomyopathy, impacting individuals at an early stage. The prevalence is indeed significant; a systematic review revealed diastolic dysfunction in 44.6% of Child-Pugh class A patients, 62% of class B, and 63.3% of class C patients [51]. Therefore, the ability to assess LV filling pressures at the bedside adds an additional layer of safety to weigh the risks versus benefits of intravenous fluid administration. It’s worth noting that B lines on lung ultrasound are not specific to cardiogenic pulmonary edema; they can also be observed in conditions like pneumonia (e.g., aspiration in an encephalopathic patient or COVID-19), pulmonary fibrosis, and acute respiratory distress syndrome [52]. Assessing cardiac filling pressures would also be beneficial in this scenario to differentiate between cardiogenic and non-cardiogenic causes of increased extravascular lung water.

According to the Cirrhotic Cardiomyopathy Consortium, screening for elevated LV filling pressures is performed using a combination of four echocardiographic criteria – Septal e’ velocity (abnormal: <7 cm/s), E/e’ ratio (abnormal: ≥15), left atrial volume index (abnormal: >34 mL/m²), and tricuspid regurgitant jet velocity (abnormal: >2.8 m/s) [53]. The presence of three or more of these criteria constitutes advanced diastolic dysfunction. E indicates the early diastolic velocity of the Doppler trace at mitral valve leaflets and e’ indicates tissue Doppler measurement of the mitral annulus quantifying myocardial relaxation (Fig. 7). Care should be taken not to overly rely on individual components, as each has its limitations. For instance, transmitral flow can be affected by variations in cardiac preload; left atrial size may be elevated in high-output states (such as cirrhosis) without diastolic dysfunction; tricuspid jet velocity is unable to differentiate between precapillary (e.g., porto-pulmonary hypertension) and postcapillary pulmonary hypertension and can also be influenced by positive pressure ventilation. Among these, e’ (and the E/e’ ratio) serves as a relatively preload-independent marker of diastolic function, reflecting myocardial relaxation status. It has also shown reliability in predicting elevated LV filling pressures in mechanically ventilated patients [54]. Furthermore, a recent study found that an e’ value less than 7 cm/s was associated with terlipressin nonresponse in cirrhotic patients with AKI, potentially indicating the severity of cirrhotic cardiomyopathy and a reduced capacity to withstand increased afterload [39]. Of note, in this cohort, central venous pressure measured 9.8 mm Hg at ICU admission and 11.2 mm Hg after 24 h, making volume depletion an unlikely cause of AKI. Additionally, lung ultrasound scores were elevated at ICU admission, indicating a high prevalence of fluid intolerance.

The bedside evaluation of venous congestion is attracting attention in heart failure literature, recognizing its importance in congestive nephropathy [55]. While IVC and IJV POCUS aid in estimating RAP, they fall short in assessing its impact on venous circulation and subsequent organ congestion. In this context, venous excess ultrasound (VExUS) has emerged as a valuable bedside tool to diagnose venous congestion and monitor the effectiveness of decongestive therapy, owing to the dynamic nature of the Doppler waveforms. Hepatic, portal, and intrarenal venous Doppler waveforms are used for this purpose detailed elsewhere, particularly in the nephrology context [56, 57] (Fig. 8). While there are limited data on cirrhosis, hepatic and portal vein waveforms may be unreliable, necessitating renal parenchymal waveform (technically challenging of all three) assessment to establish congestive nephropathy. However, they are not entirely devoid of utility, as demonstrated in a previously described case where hepatic and portal waveforms diagnosed venous congestion in a patient with biopsy-proven cirrhosis and were used to monitor the efficacy of decongestive therapy (Fig. 9, 10) [58]. Femoral vein Doppler is emerging as a complement to VExUS and, being readily accessible and extrahepatic, may be employed in cirrhotic patients alongside renal parenchymal vein assessment [59]. Nevertheless, further research is needed to define the precise role of VExUS in cirrhosis.

Figure 11 outlines our multiorgan POCUS-based approach for this scenario. In brief, when evaluating a patient with AKI in the context of cirrhosis, we first perform a kidney ultrasound to rule out obstructive nephropathy and qualitatively assess the ascites volume and its potential to cause intra-abdominal hypertension. If intra-abdominal hypertension is suspected, paracentesis is considered. Next, we evaluate volume tolerance, assessing RAP with IVC and/or IJV POCUS, and extravascular lung water using lung POCUS. If the patient is fluid-tolerant at presentation, empiric albumin is administered. However, if the patient has already received albumin for 1–2 days before our evaluation, we use LVOT VTI to assess stroke volume and determine if the patient is truly volume-depleted or in a high cardiac output state. For cases of high output with hypotension or relative hypotension, norepinephrine or terlipressin is considered, and albumin administration is held. We also limit albumin if E/e’ is elevated. On the other hand, if the LVOT VTI is low with a hyperdynamic left ventricle, additional albumin is given, and conditions causing volume loss are addressed. If the patient is not volume tolerant based on IVC/IJV/lung POCUS findings, we assess cardiac function to differentiate between high-output cardiac failure and cirrhotic cardiomyopathy with LV systolic dysfunction and manage accordingly in collaboration with a multidisciplinary team.

POCUS plays a vital role in simplifying the diagnosis of AKI in cirrhosis by helping to identify different hemodynamic phenotypes. However, it is essential to recognize that a diagnostic tool alone cannot improve outcomes unless it is linked to an effective treatment. If POCUS enhances diagnostic confidence, reduces the time to an accurate diagnosis, and prevents unnecessary therapies; thus, avoiding potential patient discomfort (e.g., shortness of breath from fluid overload), it represents a significant advancement. Many of these POCUS parameters are not new and have long been integrated into clinical practice with proven diagnostic effectiveness. For instance, echocardiography is routinely performed in hospitalized patients with suspected volume disorders, and we rarely question whether this technique needs to be validated for every specific patient population. Similarly, lung ultrasound and Doppler indicators of venous congestion have been recognized for over 2 decades. What is innovative is the use of a focused, multiorgan POCUS approach at the bedside by the clinician to enhance decision-making, reduce fragmentation of care, and improve management efficacy. Future research should focus on studying the optimal use of POCUS in different phenotypes of complex diseases like HRS-AKI, developing protocols that link these findings to appropriate treatments, and evaluating the impact on practical outcomes. Such an approach has the potential to reveal previously unrecognized pathophysiologic mechanisms and reinforce emerging pathways, such as HCRS. That said, POCUS depends on the operator’s expertise, like other aspects of medicine such as history-taking and clinical judgment. Its efficacy is contingent upon the operator’s proficiency in acquiring, interpreting, and integrating images into the management plan. Overestimating one’s abilities or the equipment’s capabilities can result in suboptimal clinical care and potential harm to the patient. Therefore, nephrology professional societies should collaborate to establish universal training standards and competency assessment policies to ensure quality care.

The authors of this narrative review declare that the research was conducted in accordance with ethical guidelines and standards. All included studies were carefully selected from publicly available databases, ensuring compliance with ethical research principles. No primary data were collected for this review.

The authors have no relevant conflicts of interest to declare.

No funding was received for the preparation of this manuscript.

Dr. Koratala has drafted the initial draft. Dr. Kazory and Dr. Ronco have provided critical revisions and additions.