Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting

Summary Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.


Introduction
2][3][4][5][6][7][8][9] In 2012, the Acute Disease Quality Initiative (ADQI) VIII and the International Club of Ascites (ICA) proposed diagnostic criteria for AKI 10 which were further revised in 2015 by the ICA. 11Over the last decade, there have been significant advances in the field. 12In 2023, a joint meeting of ADQI (ADQI XXIX) and the ICA was reconvened to refine the diagnostic criteria for AKI and hepatorenal syndrome (HRS), review their epidemiology and pathophysiology, explore the role of biomarkers in the diagnosis and prognostication of AKI, examine current and novel therapies for the prevention and treatment of AKI, and create a potential paradigm for the post-discharge care of patients who experience AKI or acute kidney disease (AKD), especially as they progress to chronic kidney disease (CKD).The goals of the meeting were to provide recommendations for clinical practice and identify knowledge gaps to inform a research framework for this clinically important area.

Methods
The ADQI-ICA consensus conference chairs (MKN, FD and RLM) convened a diverse international panel of clinicians representing hepatology, nephrology, intensive care, surgery, and pharmacology.The conference was held over 2 days and followed the established ADQI process (http://www.ADQI.org)using a modified Delphi method to achieve consensus. 13onference participants were divided into five working groups.In the pre-conference phase, each group identified a list of key questions and conducted a systematic literature search.During the conference, a series of plenary and breakout sessions were held where work groups developed consensus positions and recommendations that were refined through iterative discussions in plenary sessions.Statements were then proposed and supported by evidence, and by consensus where evidence was limited.][16] Following the meeting, the contributions of all groups were merged and reconciled by the steering group to generate this conference report following revision and approval by each of the participants.

Epidemiology and definition of kidney dysfunction in patients with cirrhosis
How should definitions for AKI, AKD, CKD and renal recovery in patients with cirrhosis be harmonized between kidney disease: Improving global outcomes (KDIGO) and ICA? Consensus statements-• In patients with cirrhosis, we recommend defining AKI using KDIGO criteria: increase in serum creatinine (SCr) ≥0.3 mg/dl (26.5 μmol/L) within 48 h or ≥50% from baseline value known or presumed to have occurred within the prior 7 days and/or urine output (UO) ≤0.5 ml/kg for ≥6 h (strong recommendation, grade A).

•
In patients with cirrhosis, we recommend defining AKD and CKD using KDIGO criteria (strong recommendation, grade A).

•
In patients with cirrhosis, we recommend defining complete recovery from AKI as a return of SCr to within 0.3 mg/dl (26.5 μmol/L) of baseline (strong recommendation, grade B).
Rationale: AKI, AKD and CKD are classified by KDIGO according to duration and severity of structural and functional abnormalities (Fig. 1). 17The ICA currently defines and stages AKI by KDIGO SCr criteria only 11 ; however, oliguria is a sensitive and early marker of AKI that is associated with worse outcomes in critically ill patients with cirrhosis. 9ost cases of AKI will fulfil both SCr and UO criteria but clinical judgement should be utilised, taking into consideration that UO at baseline may be low in patients with cirrhosis and ascites.Measurement of UO, especially, outside the intensive care unit (ICU) is often inaccurate, and the frequent use of diuretics may affect inter-pretation; however, when possible, close monitoring of UO should be performed in order to detect moderate to severe AKI earlier, and reduce fluid overload. 18Recently, a combination of damage and functional biomarkers was proposed by ADQI to be used, along with clinical information, to define AKI and improve diagnostic and staging accuracy, 19 but their role in patients with cirrhosis remains to be determined.CKD is defined as persistent glomerular filtration rate (GFR) <60 ml/min/1.73m 2 and/or markers of kidney damage for >3 months. 17Some individuals may have significant abnormalities of structure and/or function (GFR <60 ml/min/1.73m 2 or increase in SCr by >50%) within a duration of ≤3 months that do not fulfil the definitions of AKI or CKD; this period is described as AKD (Fig. 1). 20AKI is a subset of AKD, therefore, any patient with AKI, by definition, has AKD.
To date, a universal definition of post-AKI renal recovery is not available and remains controversial.22][23] However, it is important to appreciate that use of the creatinine criteria may result in overestimation of recovery by ignoring the loss of muscle mass that occurs during critical illness. 24at reference SCr value should be used to define AKI in patients with cirrhosis?
Consensus statements

•
We recommend using the lowest stable SCr value obtained in the previous 3 months for the diagnosis and staging of AKI.If no values are available in the previous 3 months, the most recent value up to 12 months prior may be used (strong recommendation, grade D).

•
In the absence of a known baseline SCr, we suggest using the lower of either SCr on admission or SCr back calculated from an estimated GFR (eGFR) of 75 ml/min/1.73m 2 as the reference value (weak recommendation, grade B).
Rationale: A SCr value is required to diagnose and stage AKI, to evaluate the extent of renal recovery, and to establish a reference point in studies examining the long-term consequences of AKI. 25 What is considered a baseline SCr remains controversial and is inconsistently defined in the general population, especially in patients without any previous values. 25,26The use of known SCr values is superior to imputation, 27 and therefore, all efforts should be made to identify a prior SCr level, preferably within the previous 3 months. 288][29][30] However, if significant fluctuations exist across multiple SCr values, clinical judgement is crucial to determine the SCr that best reflects the most appropriate baseline value.If no SCr values are available from the prior 3 months, the most recent SCr value up to 12 months prior may be used as a reference SCr, with attention paid to the clinical trajectory to ensure that decrements in kidney function on presentation are truly acute and not due to the presence of progressive CKD. 27Thus, it is imperative that all patients with presumed AKI be evaluated for the presence of pre-existing CKD using all available data (i.e.clinical history, physical exam, laboratory data, and renal ultrasound).
In the rare instance when no previous baseline SCr values are available, the ICA has suggested the first documented SCr value on hospital admission be used as the reference SCr. 11However, this may underestimate the incidence and severity of AKI, and potentially miss the diagnosis of community-acquired AKI, as the SCr may have already increased prior to hospitalization. 9In patients with no prior SCr value available, KDIGO recommends the lower value of the admission SCr or SCr derived from eGFR (assuming a baseline GFR of 75 ml/min/1.73m 2 ) be used to decide the reference SCr. 9,17,30,31This method was studied in a retrospective study of 3,458 patients with cirrhosis. 9The average SCr on the day of admission in patients who developed stage 3 AKI was 1.6 mg/dl, however, an imputed SCr derived from back-calculation was 1.0 mg/dl, a value closer to the known baseline SCr (1.1 mg/dl).There is currently no superior alternative, thus we propose that KDIGO recommendations be followed until a better methodology is verified.The above recommendations for baseline SCr are to facilitate the clinical diagnosis of AKI and should not replace clinical judgement, as AKI remains a clinical diagnosis.
What are the diagnostic criteria for AKI due to HRS (HRS-AKI)?

Consensus statements
• HRS-AKI is a phenotype of AKI that is specific to patients with advanced cirrhosis and ascites; it may also occur in the presence of tubular injury, proteinuria, and/or pre-existing CKD (not graded).

•
We recommend the following diagnostic criteria for HRS-AKI: a) cirrhosis with ascites; b) increase in SCr ≥0.3 mg/dl (26.5 μmol/L) within 48 h or ≥50% from baseline value, known or presumed, to have occurred within the prior 7 days and/or UO ≤0.5 ml/kg for ≥6 h; c) absence of improvement in SCr and/or UO within 24 h following adequate volume resuscitation (when clinically indicated); and d) absence of strong evidence for an alternative explanation as the primary cause of AKI (not graded).

•
We recommend against systematic administration of albumin for 48 h as a requisite for the diagnosis of HRS-AKI (strong recommendation, grade D).

•
We recommend replacing the historical terms HRS type 1 and 2 with the terms HRS-AKI, HRS-AKD and HRS-CKD, depending on the timing and duration of kidney dysfunction (strong recommendation, grade D).
Rationale: HRS phenotype describes renal dysfunction in patients with cirrhosis and ascites (a sine qua non in the diagnosis of HRS), caused by reduced renal perfusion through haemodynamic alterations in the arterial circulation and overactivity of the endogenous vasoactive systems (Fig. 2). 12,32,33Systemic inflammation contributes to neurohumoral and vasodilatory derangements resulting in functional AKI (HRS-AKI) that persists despite adequate fluid resuscitation and may be reversible with vasoconstrictive therapy.In patients with cirrhosis and ascites who present with AKI, HRS-AKI (Box 1) is an essential part of the differential diagnosis and may not always occur in isolation.Even where other aetiologies of AKI coexist, HRS-AKI may be the primary cause of AKI.Therefore, appropriate, and rapid work-up and diagnosis of the cause of AKI are crucial in ensuring timely recognition and treatment of HRS-AKI.Intravascular volume should be assessed [34][35][36] in all patients who present with AKI.In those with clinical and haemodynamic evidence of intravascular volume depletion, assessment of response to fluid resuscitation [34][35][36] should be completed within 24 h, to ensure early diagnosis and initiation of treatment for HRS-AKI.
In patients who are euvolemic or have evidence of intravascular fluid overload, 48 h of albumin infusion for the diagnosis of HRS-AKI is not appropriate and will lead to fluid accumulation.In addition, 48 h of systematic administration of albumin may also delay the initiation of terlipressin in patients who are euvolemic at baseline.Where volume status is equivocal and/or difficult to assess, to exclude any reduction in intravascular volume as the cause of AKI, a fluid challenge (250-500 ml of crystalloid or 1-1.5 g/kg of 20-25% albumin) may be prescribed and, if there is no improvement in SCr and/or UO within 24 h, a diagnosis of HRS-AKI should be considered.
Strong evidence for an alternative explanation such as septic shock requiring vasopressors, acute glomerular injury, obstruction, or nephrotoxin-induced AKI (where an improvement in renal function is expected after withdrawal of drugs) as the primary cause of AKI should be sought.Analysis of urinary sediment and damage markers may be useful to detect acute glomerular and/or severe tubular damage, although the thresholds for biomarkers remain to be determined (Table S2).Given the increasing prevalence of metabolic syndrome and diabetes-related kidney disease, isolated proteinuria might be related to comorbidities in the patient and pre-existing CKD and/or proteinuria does not rule out HRS-AKI.
We acknowledge that clinical uncertainty will persist in some cases and whilst enrolment in clinical trials requires that many uncertain cases are excluded (best interest of advancing science), clinical practice mandates that uncertainty is managed in the best interest of the patient.There will be cases where a provisional diagnosis of HRS-AKI is made on the best available evidence and is excluded later as more information becomes available.Since HRS-AKI can coexist with other causes of AKI, patients with co-existing structural damage may still respond to treatment with vasoconstrictors given the presence of altered haemodynamics.Thus, although a lack of HRS-AKI-targeted vasoconstrictor response should trigger re-evaluation for other causes of AKI, non-response does not exclude a coexisting diagnosis of HRS-AKI.
A rapid reduction in kidney function, previously referred to as HRS type-1, is most often precipitated by infections, in particular spontaneous bacterial peritonitis (SBP), however variceal bleed and large volume paracentesis (LVP) without sufficient albumin administration have also been implicated. 37Conversely, HRS type-2 was characterised by a slower and more chronic decline in renal function in the setting of refractory ascites.We recommend using the terminology HRS-AKI, HRS-AKD or HRS-CKD based on timing and duration of kidney dysfunction, instead of the historical HRS type-1 and type-2.HRS for less than 90 days would be classified as HRS-AKD, while HRS persisting for more than 90 days would be classified as HRS-CKD.Patients with HRS-AKD meeting AKI criteria are classified as having HRS-AKI.In contrast, a patient with pre-existing CKD (e.g., diabetic nephropathy) who develops HRS-AKI would be classified as having HRS-AKI on CKD.

What is the epidemiology and what are the outcomes of kidney dysfunction in patients with cirrhosis?
Consensus statement • AKI and AKD are common in patients with cirrhosis; prognosis depends on the severity of kidney and liver disease (not graded).
• Risk of de novo CKD is high following AKI and is associated with worse clinical outcomes (not graded).

Pathophysiology of AKI in patients with cirrhosis
The degree of liver, kidney, and cardiac derangement, together with concomitant precipitating events and exposures may lead to a variety of clinical phenotypes of AKI (Fig. 2). 12Susceptibility to AKI follows development of portal hypertension through increased intrahepatic resistance from liver fibrosis and vasodilation of splanchnic vascular beds secondary to bacterial translocation and systemic inflammation.Vasodilatation leads to a decrease in effective central blood volume that, in turn, leads to activation of sodium/water conservation and vasoconstrictive neurohumoral pathways.Progression of cirrhosis and portal hypertension leads to further vasodilatation and consequently increased activation of these neurohumoral systems, leading to ascites, extreme renal vasoconstriction and HRS-AKI.
Cardiac dysfunction may contribute to AKI development although the mechanisms are controversial.In the early phase of decompensated cirrhosis, the cardiac output (CO) increases but release of cardio-depressive substances leads to subclinical changes in the myocardium 46 and impairment of cardiovascular reflexes which, coupled with cardiodepression and diastolic dysfunction, is termed "cirrhotic cardiomyopathy". 47Small cohort studies have suggested that a relative reduction of CO results in renal hypoperfusion and might predict the development of HRS-AKI. 48,49Use of non-selective beta-blockers to prevent variceal bleeding has been associated with a greater risk of developing HRS-AKI and to increased mortality in selected patients with refractory ascites and documented inappropriate CO. [50][51][52][53] However, two recent studies demonstrated significantly higher CO in patients with HRS-AKI compared to those without. 54,55Consequently, the predominant pathophysiological mechanism behind HRS-AKI may not be directly related to reduced CO but rather driven by an inability to increase CO in response to stress, a hallmark of cirrhotic cardiomyopathy. 55Collectively these seemingly disparate findings suggest that perhaps there is a "window" during the development of HRS-AKI in which impaired cardiac response to stress leads to a low CO.Interventions which worsen this trajectory (e.g., nonselective beta-blockers, un-guided volume expansion) may in fact impede renal recovery.However, whether interventions that protect or improve CO result in improved renal function is currently unknown. 56stemic inflammation is common in patients with decompensated cirrhosis (Fig. 2). 57,58acterial/bacterial product translocation and/or overt infection, which is associated with release of PAMPs (pathogen-associated molecular patterns), are fundamental in the development of HRS-AKI, particularly in patients with acute-on-chronic liver failure (ACLF).PAMPs activate innate host immunity, and release of proinflammatory cytokines, vasodilators and reactive oxygen species which may all impair renal function. 59,60Renal tubular Toll-like receptor 4 is also upregulated in patients with AKI, likely through bacterial translocation. 61e toxic effect of bile acids on tubular cells has been documented and the mechanisms leading to toxicity have been demonstrated recently in animal models. 62However, in the absence of diagnostic tests, the thresholds of bile acids and serum bilirubin associated with AKI in patients with severe cholestasis remain largely unknown. 63

What are the determinants of susceptibility and trajectory for AKI and its recovery in patients with cirrhosis?
Consensus statement

•
Modifiable and non-modifiable factors affect susceptibility to AKI and determine the severity as well as the trajectory of recovery (not graded).
Rationale: Background susceptibility to AKI varies across individuals according to liver-(e.g.severity of liver disease, ACLF, decompensating events) and kidney-related factors (CKD, baseline kidney function), cardiovascular status (e.g.cirrhotic cardiomyopathy), concurrent comorbidities (e.g.hypertension, diabetes), and external elements which may be either modifiable (e.g., presence of infection, liver disease aetiology, nephrotoxins, volume depletion) or non-modifiable (e.g., comorbidity burden).The trajectory of post-AKI recovery is influenced by resolution of the precipitating events, the aetiology and severity of AKI, presence of underlying CKD, renal reserve, the severity of liver disease, degree of adaptative and maladaptive repair, and regenerative mechanisms. 64Adaptive repair is characterised by tubular proliferation, repair and regeneration of endothelial cells, which leads to resolution and return to normal kidney structure. 65Maladaptive repair is characterised by fibrosis, tubular loss and delayed resolution of inflammation with subsequent loss of functional renal reserve and has been shown to play a central role in the transition from AKI to CKD. 65 Factors associated with a switch from adaptive to maladaptive repair are thought to include advanced age, AKI phenotype, severity, duration and frequency of injury, and baseline kidney health. 66atients with decompensated cirrhosis are prone to develop repeated episodes of AKI following sepsis, hypovolemia and circulatory changes associated with LVP and may develop irreversible chronic kidney changes.While no data exist on maladaptive repair in HRS-AKI, there is recognition that HRS-AKI may not be an entirely functional entity due purely to haemodynamic derangements.[71][72][73]

Prevention and work-up of AKI in patients with cirrhosis
What are the approaches for prevention of AKI in patients with cirrhosis?
Consensus statements

•
We recommend strategies to mitigate the risk of AKI that include a personalised kidney-liver health (KLH) assessment to inform susceptibility to AKI, nephrotoxin stewardship, and liver-specific recommendations for anticipated and unanticipated exposures (best practice statement).

•
We recommend 20-25% albumin for the prevention of AKI following LVP and in patients with SBP (strong recommendation, grade B).The dose and duration of albumin administration should be guided by patients' haemodynamic and volume status (best practice statement).

•
We recommend against the systematic use of albumin in patients with decompensated cirrhosis for a) the prevention of AKI in patients with non-SBP infections, and b) solely to maintain a serum albumin concentration >3.0 g/dl (strong recommendation, grade A).
Rationale: A comprehensive KLH assessment offers opportunities for surveillance measures and targeted prevention strategies, both before an anticipated exposure and following an AKI-inducing event (Fig. 3). 749][80] Approximately 30% of patients with cirrhosis experience a potentially avoidable adverse drug event. 81Drug dosing can be particularly challenging in patients with cirrhosis as relatively lower SCr concentrations may lead to overestimation of GFR. 82e role of intravenous albumin in the prevention of AKI has been studied in several randomised-controlled trials (RCTs) (Table S3).In patients with SBP, treatment with antibiotics in addition to 20% albumin administration (at an arbitrary dose of 1.5 g/kg on day 1 and 1.0 g/kg on day 3) has been associated with lower rates of AKI and mortality compared to antibiotics alone. 834][85] Administration of albumin should consider the patient's haemodynamic and volume status.Whether all patients with SBP should receive routine albumin administration, or the optimal dose 86 and duration of albumin treatment for the prevention of AKI in patients with SBP, remain to be determined.Systematic administration of albumin in hospitalized patients with non-SBP infection [87][88][89][90] or the use of daily albumin to target an albumin level >3.0 g/dl 91 have been associated with higher risk of pulmonary oedema with no effect on AKI incidence or survival.RCTs on the long-term administration of 20-25% albumin in the outpatient setting in patients with uncomplicated ascites have led to conflicting results. 92,93The lack of survival benefit in MACHT may be because few patients completed the 12-month follow-up (10% in those receiving albumin and 20% in the placebo group), as many underwent liver transplantation (LT). 93Meanwhile, in the ANSWER trial, patients receiving albumin were seen more frequently compared to those in the control group, thus the observed survival benefit could have resulted from earlier detection and treatment of complications. 92Therefore, there is insufficient evidence to recommend long-term outpatient administration of albumin for the prevention of AKI in patients with uncomplicated ascites.
Compared to alternative treatments, administration of 20-25% albumin (6-8 g for every litre over 5 L of ascites removed) during LVP is associated with lower incidence of postparacentesis circulatory dysfunction, a known trigger for AKI, specifically HRS-AKI. 94,95n patients with refractory ascites, transjugular intrahepatic portosystemic shunt (TIPS) has been shown to be effective at controlling ascites and may thereby prevent the development of HRS-AKI. 96An implantable medical device, alfapump ® (Sequana Medical NV, Ghent, Belgium) enables mobilization of ascitic fluid to the bladder for urinary excretion and has been shown to reduce the frequency of LVPs in patients with refractory ascites.99][100] What diagnostic tools should be included in the work-up of patients with cirrhosis and AKI?
Consensus statements

•
We recommend using similar tools for the diagnostic work-up for AKI in patients with cirrhosis as used in those without cirrhosis (best practice statement).

•
We suggest using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR equation without the race variable, and preferably with cystatin C (CysC), for assessment of kidney function, though the performance at low GFR and in those with ascites may be suboptimal (weak recommendation, grade B).

•
In addition to SCr, we suggest complementary use of functional and damagerelated markers to aid in timely detection of AKI, characterisation of different AKI phenotypes and to guide treatment strategies (weak recommendation, grade B).
Rationale: The diagnostic evaluation of patients with cirrhosis and AKI includes clinical history, assessment of intravascular volume status, and detection of potential precipitants.Assessment of intravascular volume remains challenging as most currently available haemodynamic monitoring tools have not been studied in patients with cirrhosis. 34,352][103] Examination of urinary sediment is difficult in patients with elevated bilirubin levels due to staining of cells and casts.Additionally, significant interobserver variability and discordance with kidney biopsy have been reported. 68,104,105omplications from percutaneous renal biopsy are documented in up to 30% of cases compared to 0.9% in the general population; 106,107 however, low complication rates have been reported using the transvenous route, even in patients with coagulation disorders. 68,105,108sessment of kidney function: Diagnosis of AKI may be missed or delayed in patients with cirrhosis given SCr is influenced by reduced muscle mass, increased volume of distribution in the setting of fluid overload, 109 and interference with bilirubin. 110SCr may also be falsely lowered by large volume blood transfusions.2][113][114][115] In a large prospective study in patients with cirrhosis, the addition of CysC to the components of the model for end-stage liver disease (MELD) score was superior to MELD for prediction of overall mortality. 111In addition, CysC provides a better estimation of renal function, especially in patients with prolonged critical illness, and may help in drug dosing and management of nephrotoxic drugs. 24,116FR equations, such as MDRD or CKD-EPI equations, were developed and validated in patients with CKD and are inaccurate for the assessment of renal function in patients with AKI, as they require SCr to be in a 'steady state'.eGFR is one of the factors used to determine candidacy for simultaneous liver and kidney transplantation (SLKT), yet current equations tend to overestimate the true GFR by 10 to 20 ml/min/1.73m 2 , especially in those with a GFR <40 ml/min/1.73m 2 , ascites, or both. 117,118In patients with cirrhosis with a GFR <60 ml/min/1.73m 2 , use of the CKD-EPI-CysC eGFR equation demonstrated the least bias (overestimated GFR by 10.3 ml/min/1.73m 2 ) with acceptable precision and accuracy. 117Thus, efforts to enable increased, routine and timely use of CysC, especially to confirm eGFR in patients who are at risk of or have CKD, should be undertaken as this may also allow clinicians to better identify candidates for SLKT. 26,117,1191][122] In 2021, a new CKD-EPI equation, which included the removal of race as a variable, was introduced and widely implemented in the US as an important step in efforts to eliminate disparities in the care of patients with kidney disease; however, this equation has not been widely adopted outside the US. 119,123reliminary data suggest acceptable performance in patients with cirrhosis, though their role in patients with low GFR and ascites remains to be studied. 124A meta-analysis of studies on timed urine collection for GFR estimation by creatinine clearance in patients with cirrhosis demonstrated overestimation of true GFR, especially in those with low GFR (<60 ml/min/ 1.73 m 2 ). 125In patients without cirrhosis, the composite of timed urinary urea clearance and creatinine clearance (former tends to underestimate, and the latter overestimate, the true GFR) showed superior performance over CKD-EPI equations and creatinine clearance alone when compared to measured GFR, especially in patients with GFR <60 ml/min/1.73m 2126 ; however, this has not been studied in patients with cirrhosis.

AKI phenotyping: Role of biomarkers:
The combined use of functional (e.g., Scr, CysC) and damage (e.g., albuminuria, urinary neutrophil gelatinase-associated lipocalin [uNGAL]) biomarkers enables more accurate differential diagnosis of the aetiology and mechanisms of AKI in patients with cirrhosis and potentially enables the identification of AKI subphenotypes suitable for specific therapeutic interventions (Fig. 4). 127Biomarkers may also help to detect those at risk of AKI in whom interventions may limit renal damage. 113,128,129owever, in the absence of a detectable SCr rise (i.e., subclinical AKI), more data are required to define context-specific thresholds for damage-related markers that could act as precise diagnostic criteria for AKI.[132] Various markers have been assessed in patients with cirrhosis (Table S2). 71,133,134easurement of the fractional excretion of sodium (FENa) to differentiate ATI from HRS-AKI has been thought to be unhelpful since FENa <1% is common in patients with cirrhosis, even in the absence of AKI. 70,135However, if using a lower threshold of FENa of <0.1-0.2%(which may not be possible as many laboratories do not report urine sodium values <20 mEq/L) in combination with other urinary biomarkers and clinical judgement, the test may have improved specificity in identifying HRS-AKI. 70,72uNGAL is one of the most promising and widely studied injury biomarkers, with levels significantly increasing in a stepwise manner from HRS-AKI to ATI. [70][71][72][73]133,136,137 A uNGAL value of ~220-250 μg/g creatinine (Bioporto Diagnostics, Hellerup, Denmark) has been demonstrated to distinguish patients with ATI from other phenotypes, 69,72 with response rates to terlipressin seen in 70% of patients with uNGAL <220 μg/g of creatinine compared to only 33% in those with uNGAL >220 μg/g of creatinine. 136 Of note these studies have shown overlap between different phenotypes, which may be due to a combination of patient population heterogeneity, presence of underlying CKD, differences in assays used, results based on adjudicated gold standards rather than histopathological diagnosis, or reflecting possible progression along a continuum from functional to structural causes of AKI.Combining markers such as urinary kidney injury molecule-1, uNGAL, and CysC was better than using one marker alone in identifying HRS-AKI, especially after adding clinical parameters.138 Whether the target level of uNGAL that would differentiate between the AKI phenotypes, and/or response to terlipressin would be different with the new diagnostic criteria for HRS-AKI set forth by the authors remains to be determined.

Management of AKI in patients with cirrhosis
What strategies are applicable to the management of AKI in patients with cirrhosis?
Consensus statements

•
We recommend personalised strategies for the management of AKI based on the individual patient's kidney-liver health profile and AKI phenotype (best practice statement).

•
We recommend a combination of physical examination, imaging studies, and static and dynamic measurements to guide fluid management, with frequent reassessment throughout all phases of treatment to avoid volume overload (best practice statement).

•
We recommend crystalloids, preferentially balanced solutions, as first-line therapy for patients with AKI requiring fluid resuscitation, unless a specific indication exists for the use of other fluids (strong recommendation, grade B).

•
We recommend discontinuation of all fluids and initiation of diuretic therapy or RRT in patients with AKI who demonstrate signs or symptoms of volume overload (best practice statement).

•
There is insufficient evidence to support routine measurement of intra-abdominal pressure (IAP) in patients with tense ascites and AKI (not graded).

•
We recommend initiation of RRT be individualised, with consideration of clinical context and anticipated or observed life-threatening AKI-related complications (best practice statement).

•
We recommend expedited evaluation for LT in patients with decompensated cirrhosis following an episode of AKI (best practice statement).

•
There is insufficient evidence to recommend TIPS or extracorporeal liver support for the treatment of AKI (not graded).
5][36] No study has demonstrated superiority of a particular method, and therefore the choice of tool depends on the patient's location (ICU vs. general ward) and clinical discretion.Repeated assessment of volume status and close monitoring of UO should be undertaken so that complications of iatrogenic volume overload can be prevented.
Albumin is often used with the notion that it is more likely to maintain oncotic pressure than crystalloids; however, numerous RCTs in critically ill patients have failed to demonstrate any difference in 30-day or 90-day mortality or need for RRT between groups. 139,140In patients with advanced cirrhosis, not only does serum albumin concentration decrease, but its structure and anti-oxidant functions are also altered, reducing its capacity to bind to bacterial products and reactive oxygen species, potentially exacerbating systemic inflammation. 141Experimental studies suggest that infusion of normal "exogenous" albumin has beneficial effects on controlling systemic inflammation and improving circulatory status, which could also contribute to the prevention or reversal of AKI; however, this effect has not been observed in clinical practice. 142Results from two RCTs comparing albumin to crystalloids in patients with cirrhosis and sepsis-induced hypotension have been conflicting, which may be explained by differences in type of albumin solution (5% vs. 20%), type of crystalloid (0.9% saline vs. plasmalyte), and the short duration of the studies (7 vs. 28 days) (Table S3). 143,144Although the use of albumin was associated with a significantly greater improvement in haemodynamics in the short term, the response was not sustained and did not improve renal outcomes or need for RRT compared to crystalloids. 143,144teractions between ascites, IAP, and AKI are complex.In theory, IAP and intra-abdominal compartment syndrome related to large volume ascites may induce AKI by increasing central venous pressure and reducing right ventricular output, and thus CO. 95,145 In critically ill patients with HRS and tense ascites, paracentesis plus albumin infusion resulted in an increase in creatinine clearance, which correlated with the decrease in IAP. 145,146However, LVP which reduces IAP is also known to trigger circulatory changes that may contribute to impaired kidney function without the use of albumin. 147Currently, there is insufficient evidence to support routine measurement of IAP in patients with tense ascites and no evidence to support systematic LVP in patients with increased IAP. 148,1494][155] Early initiation of RRT should be considered in patients with signs or symptoms of intravascular volume overload without adequate response to diuretics (even in the absence of AKI) or in those in whom volume overload cannot be corrected without serious adverse effects. 35,155Patients with cirrhosis and AKI-related metabolic changes are prone to develop encephalopathy and, uremic symptoms can often overlap with hepatic encephalopathy.As such, initiation of RRT should be considered earlier, especially if encephalopathy persists despite treatment.Choice of RRT modality depends on availability, resources, and inherent risks with intervention. 154mong patients listed or undergoing evaluation for LT, initiation of RRT should be viewed as a tool to optimise a patient's condition and as a bridge to LT.For those who are not candidates for LT, we recommend discussion with the patient and/or caregivers regarding goals of therapy, and the poor long-term prognosis, as transplant-free survival is extremely low, especially in those with very high MELD scores. 40,156,157ansplantation: Episodes of AKI are associated with a high risk of short-term mortality, especially in patients with high MELD scores, and therefore patients may benefit from an expedited inpatient transplant evaluation. 156,1580][161] Current US policies for SLKT incorporate duration of AKI (eGFR ≤25 ml/min for ≥6 weeks, with or without dialysis) and CKD at the time of transplant and introduced a safety net approach which guaranteed prioritisation of kidney transplantation in patients with an eGFR ≤20 ml/min within 1 year following LT. 162However, factors such as aetiology of AKI, 163 older age, and comorbidities (such as diabetes) known to impact post-transplant renal recovery are not included.Biomarkers predictive of AKI recovery after LT could enhance decision-making algorithms regarding the need for SLK. 164,165Kidney transplant alone in patients on chronic dialysis may be a feasible option among selected patients with compensated cirrhosis without clinically significant portal hypertension, especially in the setting of a treatable aetiology of liver disease. 166ansjugular intrahepatic portosystemic shunt: While TIPS placement has been shown to improve GFR over time in patients with refractory ascites, a complication of portal hypertension that shares its pathophysiology with HRS-AKI, it has been studied only sparingly as a treatment for HRS-AKI. 167-171A RCT examining TIPS for the treatment of HRS-AKI is currently underway. 172tracorporeal liver support: Extracorporeal liver support such as adsorbent columns, albumin dialysis, and plasma exchange have been investigated for use in ACLF and treatment of HE, but not as AKI-specific therapies.173,174 Treatment of AKI in patients with ACLF may require targeting not only removal of known substances, such as creatinine and urea, but also removal of a wide spectrum of pathogenic factors and mediators of inflammatory response that are implicated in the pathophysiology of ACLF.[175][176][177] What strategies are specific to the management of HRS-AKI?

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We recommend initiating vasoconstrictor therapy (terlipressin as first-line agent), in combination with 20-25% albumin, immediately upon establishing a diagnosis of HRS-AKI (strong recommendation, grade A).

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We recommend LT, in select patients, as the definitive treatment for HRS-AKI regardless of response to vasoconstrictor-directed therapy (strong recommendation, grade A).
Rationale: Terlipressin is the most studied and consistently effective vasoconstrictor for the treatment of HRS-AKI and its use (preferably as a continuous infusion) 178 is recommended as a first-line agent (Table 2). 11,75-774][185] However, norepinephrine requires ICU admission and placement of a central venous catheter for continuous infusion.
Current guidelines recommend daily use of 20-25% albumin (20-40 g/day) during the treatment of HRS-AKI; however, the optimal dosing of albumin and length of administration are not well defined.Cautious use of albumin is recommended, with discontinuation if there is evidence of pulmonary oedema.
6][187][188] Re-evaluation for alternative causes of AKI should be considered if there is an increase in MAP ≥15 mmHg from baseline during vasoconstrictor treatment for HRS-AKI without improvement in SCr.What MAP goal (absolute value or an increase in MAP from baseline) should be targeted during treatment with vasoconstrictors requires further investigation.Whether the current definitions set forth here by the authors will improve the rates of HRS-AKI reversal remains to be determined.
Patients receiving vasoconstrictors should be monitored for adverse events (mainly ischaemic) which are usually mitigated by drug discontinuation, lowering the dose, or in the case of terlipressin, changing from bolus dosing to continuous infusion. 178Higher incidence of pulmonary oedema has been reported in patients receiving terlipressin compared to placebo, [189][190][191][192] which may be related to a combination of several pathways in an already critically ill patient population (Fig. 5). 193,194Cautious use of terlipressin is recommended in patients with evidence of volume overload, and temporary suspension of albumin together with administration of diuretics may prevent complete discontinuation of vasoconstrictor treatment. 190versal of HRS-AKI reduces the risk of CKD and need for RRT after LT 195 ; however, there is no improvement in transplant-free survival, thus the use of vasoconstrictors should be seen as a bridge to transplantation or renal recovery, rather than a definitive cure.Pharmacological treatment of HRS-AKI lowers the MELD score by lowering SCr, affecting waiting list priority.This can be detrimental for patients awaiting LT in regions with long waiting times and higher average MELD scores at time of transplant, especially when MELD score is updated at very close intervals. 156,192Some countries partially mitigate this issue by "holding" the SCr at its apex after the initiation of a vasoconstrictor or assigning extra points for those treated for HRS-AKI, regardless of treatment response, to ensure patients who are treated are not disadvanged. 196As new treatments and prognostic scores become available, revisions to transplant allocation policies will be needed to best serve this high-risk patient population.

Post-AKI/AKD outpatient follow-up in patients with cirrhosis
What are the key elements of an appropriate post-AKI/AKD care bundle following hospital discharge in patients with cirrhosis?
Consensus statements

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We recommend tailoring the care bundle for post-AKI/AKD outpatient follow-up according to the severity of both kidney and liver disease, with the delivery of care requiring close collaboration between hepatologists and nephrologists (best practice statement).

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We recommend personalised palliative care evaluation with goals including reduction in symptom burden, patient/caregiver wellbeing and goals of care discussions (best practice statement).
][199][200][201][202] The post-hospital discharge period is a critical time in which dynamic liver and kidney function changes impact outcomes including mortality, transplant candidacy, and quality of life. 203Almost half of patients with cirrhosis discharged after an episode of AKI are re-admitted within 3 months, with 22% of readmissions due to renal and metabolic issues such as AKI, anasarca, or hyponatremia. 204Patients with cirrhosis who are discharged after an episode of AKI should have, at a minimum, a KLH assessment within 1 month of discharge, the timing of which can be individualised according to the risk-phenotype of the patient at the time of discharge (Fig. 6). 205From the clinical point of view, the stage of cirrhosis should be assessed during the first outpatient visit, with a focus on evaluating the presence and severity of specific complications.7][208] Screening for albuminuria should be routine following an episode of AKI as it has been shown to identify those patients who are at a higher risk of CKD progression. 209H management focuses on five key domains that include education, medication management, disease-modifying interventions, and dynamic transplant and palliative care evaluations.Communication of future risk of CKD and recurrent AKI episodes helps the patient adhere to preventative measures and avoid further kidney insults. 210Medication reconciliation is crucial during the first outpatient visit since dose modifications and initiation of medications such as diuretics are frequently necessary. 211The routine postdischarge evaluation of the global domains of frailty in addition to assessment of symptom burden and health-related quality of life, can allow for potentially modifiable gaps to be identified and addressed. 212,213More than one-third of caregivers of patients with cirrhosis have been shown to be affected by one or more major adverse impacts on their own lives and a substantial portion of family members are forced to stop working to provide care. 2146][217][218] Recognising AKI as a marker of worse prognosis in cirrhosis, persistent kidney dysfunction following discharge can be a trigger for reassessing goals of care by a multidisciplinary team, especially for those patients who are not candidates for LT and with a life expectancy of less than a few months. 215In such instances, a palliative approach to care is important to ensure that patient's goals are elicited and translated into care that best meets their needs before an acute medical crisis occurs.

Paediatric perspective
AKI is common in children with cirrhosis and carries significant morbidity and mortality. 219,220Cholestatic diseases such as biliary atresia are the leading aetiology of paediatric cirrhosis, precluding direct extrapolation of evidence from adult patients.The reported prevalence of paediatric HRS-AKI (<10%) is likely a gross underrepresentation as none of the proposed consensus definitions of HRS-AKI have been validated in children.CysC is a superior test for AKI detection and should be explored in combination with damage-related biomarkers to improve diagnostic accuracy in paediatric cirrhosis. 221espite the different case-mix, the pathophysiology of HRS-AKI seems to be similar in children, thus paediatric HRS-AKI should be responsive to splanchnic vasoconstrictors like terlipressin. 222Paediatric cirrhotic cardiomyopathy, in part related to bile acids, contributes to the pathogenesis of AKI in cirrhosis and is associated with need for continuous RRT and post-transplant outcomes. 223,224

Conclusion and perspectives
AKI in patients with cirrhosis, especially HRS-AKI, is strongly associated with both shortand long-term adverse events.Over the last decade, there have been significant advances in our understanding of the pathophysiology and epidemiology of AKI in patients with cirrhosis.Our consensus recommendations are based not only on existing data but also on expert opinion, as much of the strength of evidence is poor and much evidence comes from studies in patients without cirrhosis.We acknowledge that some of the current literature contains limitations as many of the studies were performed prior to changes in the definition of HRS-AKI and further research is needed.However, utilising a multidisciplinary approach, we endeavoured to apply, as precisely as possible, lessons learned from AKI in the general population to the specific population of patients with cirrhosis.With the new diagnostic criteria for HRS-AKI, the integration (into routine practice) of appropriately selected biomarkers that can identify different sub-phenotypes of AKI should be increasingly explored, as this holds the key to further improvements in the care of patients with HRS-AKI.Consequently, it is imperative to develop research questions to address these knowledge gaps (Table S4).Overall, we believe that an integrated approach involving various specialties is imperative in the management of AKI in patients with cirrhosis, both in the inpatient and outpatient settings.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

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The lowest, stable serum creatinine value obtained in the previous 3 months may be used for the diagnosis and staging of AKI.If no values are available in the previous 3 months, the most recent value up to 12 months prior may be used.

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Hepatorenal syndrome-AKI (HRS-AKI) is a phenotype of AKI that is specific to patients with advanced cirrhosis and ascites, which may also occur in the presence of tubular injury, proteinuria, and/or pre-existing chronic kidney disease.

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The following diagnostic criteria for HRS-AKI should be: a) cirrhosis with ascites; b) increase in serum creatinine ≥0.3 mg/dl (26.5 μmol/L) within 48 h or ≥50% from baseline value, known or presumed, to have occurred within the prior 7 days and/or urine output ≤0.5 ml/kg for ≥6 h; c) absence of improvement in serum creatinine and/or urine output within 24 h following adequate volume resuscitation (when clinically indicated); and d) absence of strong evidence for an alternative explanation as the primary cause of AKI.

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The ADQI and ICA joint multidisciplinary consensus meeting recommends against systematic administration of albumin for 48 h as a requisite for the diagnosis of HRS-AKI.

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Vasoconstrictor therapy (terlipressin as first-line agent), in combination with 20-25% albumin, should be initiated immediately upon establishing a diagnosis of HRS-AKI.

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Cirrhosis with ascites  Terlipressin (T) increases renal perfusion pressure but also decreases cardiac output.By increasing cardiac preload (through shunting of splanchnic blood to central blood), increasing cardiac afterload (due to increase in systemic vascular resistance), and effecting pulmonary vasculature [231][232][233][234] (pulmonary artery dilation, pulmonary vein constriction, as well as possibly an increase in pulmonary capillary permeability), when combined with large doses of albumin, may be associated with an increased incidence of pulmonary oedema.Norepinephrine (N) has a positive inotropic effect and causes systemic vasoconstriction, which then also increases renal perfusion pressure.In contrast to terlipressin, norepinephrine constricts pulmonary arteries without any effect on the pulmonary vein.• Caution with the initial daily volume removed by the pump that may be increased progressively (removal <1 L/day recommended) • Not widely available in many countries AKI, acute kidney injury; CIN, contrast-induced nephrotoxicity; LVP, large volume paracentesis; MAP, mean arterial pressure; NSAID, non-steroidal anti-inflammatory drug; PRBCs, packed red blood cells; SCr, serum creatinine.

Fig. 1 .Fig. 2 .Fig 3 .Fig. 4 .Fig. 5 .
Fig. 1.Clinical course and outcomes of AKI in patients with cirrhosis.AKI, AKD and CKD form a continuum whereby initial kidney injury can lead to recovery (adaptive repair), persistent renal injury, and/or eventually CKD (maladaptive repair).Multiple episodes of AKI may occur over the course of an illness within one individual.After AKI resolves, patients may still have abnormalities in kidney function and/or structure that fulfil the criteria for AKD.AKI is a subset of AKD, therefore, all patients with AKI are considered to have AKD.The absence of criteria for AKI, AKD or CKD represents no kidney disease (NKD).Liver or liver-kidney transplantation in select patients may occur at any time.Patients who meet HRS criteria are considered to have HRS-AKI, HRS-AKD or HRS-CKD based on the timing and duration of kidney dysfunction.Patients with HRS-AKD meeting AKI criteria are classified as having HRS-AKI.HRS for less than 90 days would be classified as HRS-AKD, while HRS persisting for more than 90 days would be classified as HRS-CKD.In contrast, a patient with pre-existing CKD (e.g., diabetic nephropathy) who develops HRS-AKI would be classified as having HRS-AKI on CKD.AKD, acute kidney disease; AKI, acute kidney injury; CKD, chronic kidney disease; HRS, hepatorenal syndrome.Adapted from Acute Disease Quality Initiative 29, www.ADQI.org,CC BY 2.0 (https://creativecommons.org/licenses/by/2.0/)

Fig. 6 .•
Fig. 6.Recommended structure of post-discharge follow-up according to the evaluation of the kidney axis (severity, duration, and recovery of AKI) and the liver axis (compensated vs. decompensated cirrhosis) at the time of hospital discharge.Limited data are available to inform the timing and nature of monitoring for patients with cirrhosis who experience AKI or AKD in hospital.The post-discharge follow-up will depend on the state of kidney and liver health at the time of discharge.We suggest that these patients should have their kidney function checked within 1 month of hospital discharge, at a minimum, to confirm the extent of recovery or progression of kidney disease.Patients with persistent kidney dysfunction at 90 days should be formally assessed for the development or progression of CKD.Patients with less severe AKI or AKD can be monitored in primary care or by the base specialist with the degree of nephrology involvement in follow-up monitoring increasing with the duration and severity of AKI or AKD during hospitalization.Adapted, with permission, from Acute Disease Quality Initiative 24, www.ADQI.org.AKD, acute kidney disease; AKI, acute kidney injury; AKI-D, acute kidney injury treated with dialysis; CKD, chronic kidney disease; HTN, hypertension; NKD, no kidney disease; SCr, serum creatinine.Adapted from Acute Disease Quality Initiative 29, www.ADQI.org,CC BY 2.0 (https://creativecommons.org/licenses/by/2.0/) This conference was kindly supported by unrestricted educational grants from Mallinckrodt Pharmaceuticals, Grifols, Sphingotec GmbH, Baxter, Fresenius, BioPorto, Ocelot, Biotest and Sequana Medical.MKN has received consulting/advisory board fees from Mallinckrodt Pharmaceuticals, Ocelot and Baxter; JAK has received grant support and consulting fees from Astute Medical/BioMerieux, Novaratis; Fulltime employee, Spectral Medical; LF has received research support from Baxter and Ortho Clinical Diagnostics; MO has received research funding from Baxter, Biomerieux and La Jolla Pharma; ASA has received consulting/advisory board fees from Mallinckrodt Pharmaceuticals and Ocelot; JAN has received consulting fees from Baxter, Outset Medical, and Vifor Pharma; JCO has received consulting fees from Mallinckrodt Pharmaceuticals; SP has received consulting fees from Plasma Protein Therapeutics association, advisory board fees from Mallinckrodt Pharmaceuticals and speaking fees from Grifols and Medscape; LBV has received research support from W.L. Gore & Associates; ECV has received research support to institution from Salix; AAA's institution has received research funding from Baxter, Bioporto, and Medtronic; PA has received advisory board fees from Biovie, Biomarin, and speaking fees from Grifols, CSL Bhering and Kedrion; JMB has received consulting/advisory board fees from Mallinckrodt; PG has received research funding from Gilead & Grifols, has consulted or attended advisory boards for Gilead, RallyBio, SeaBeLife, Merck, Sharp and Dohme (MSD), Ocelot Bio and Behring, and received speaking fees from Pfizer; MK has received speaker fees from Baxter, Fresenius Medical Care and B.Braun; CR has been consultant or member of advisory board and/or Speaker Bureau for Asahi medical, Aferetica, Baxter, B.Braun, AKI and HRS-AKI may coexist with other causes of AKI.Examples of alternative causes of AKI include septic shock requiring vasopressors, drug-induced AKI, obstruction, or acute glomerular injury.Patients who meet HRS criteria are considered to have HRS-AKI, HRS-AKD or HRS-CKD based on timing and duration of kidney dysfunction.ADQI, Acute Disease Quality Initiative; AKD, acute kidney disease; AKI, acute kidney injury; CKD, chronic kidney disease; HRS, hepatorenal syndrome; ICA, International Club of Ascites.