ABSTRACT
Kidney disease in cirrhosis is now viewed as a continuum encompassing acute kidney injury (AKI), acute kidney disease (AKD), and chronic kidney disease (CKD), rather than three different disorders. Contemporary diagnostic criteria for AKI integrate urine output (UO) parameters and acknowledge the intricate relationship and possibility of overlap between functional and structural as well as acute and chronic entities, including hepatorenal syndrome (HRS). AKI demonstrates a propensity for progression to AKD and CKD, particularly in the context of recurrent and severe insults. The diagnostic complexity is further compounded by limitations in serum creatinine measurements, prompting the integration of novel biomarkers and the need to accurately estimate glomerular filtration rate. The diagnosis, phenotyping, and management of AKI should be prompt and early; the initial step should always be volume and UO assessment. A personalized approach is needed and the possibility of co-existing structural or functional kidney disease should be borne in mind. The earlier concept of waiting for 48 hours to diagnose HRS has evolved and early diagnosis and prompt treatment are advised now. Kidney replacement therapy and simultaneous liver and kidney transplantation may be required in resistant cases.
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Keywords: Hepatorenal syndrome; Acute kidney disease; Chronic kidney disease; Cholemic; Acute-on-chronic liver failure; Sepsis
INTRODUCTION
In patients with cirrhosis, the intricate link between liver and kidney function is evident, with the classically described forms of kidney disease, acute kidney injury (AKI) and chronic kidney disease (CKD), significantly increasing mortality. Disease progression in decompensated cirrhosis precipitates kidney dysfunction [
1-
4]. Recent evidence has changed our understanding of kidney disease and supports a continuum model from AKI to CKD and stratifies them as functional and structural diseases [
5-
7]. Hepatorenal syndrome (HRS) exemplifies the complex spectrum of acute and chronic functional kidney pathology in decompensated cirrhosis [
8]. Recent understanding has also introduced acute kidney disease (AKD) as an intermediate phase (technically including AKI and arising either as a continuation of unresolved AKI or independently) [
5,
9,
10].
Figure 1 summarizes the spectrum of AKI-AKD-CKD in cirrhosis. In this comprehensive review, we aim to define different kidney diseases in cirrhosis, discuss their pathophysiology and natural history, explore the management, and provide algorithms for managing the AKI-CKD spectrum in cirrhosis.
DEFINITIONS
Baseline serum creatinine
The International Club of Ascites (ICA) established baseline serum creatinine (SCr) criteria in 2015, recommending the lowest value from the preceding three months [
11]. Current guidelines extend consideration to 12 months if that is unavailable [
12]. For multiple values, either median or admission-proximate values are used. Admission value serves as a baseline when prior data is unavailable. Alternatively, baseline creatinine may be back-calculated using an assumed estimated glomerular filtration rate (eGFR) of 75 mL/min [
12].
AKI in cirrhosis has evolved significantly in definition and staging over the past two decades. Historically, acute renal failure in cirrhosis was defined by a SCr >1.5 mg/dL, which overlooked milder GFR impairments and lacked a temporal criterion. The Acute Disease Quality Initiative (ADQI) defined AKI in 2012 as SCr elevation ≥0.3 mg/dL within 48 hours or ≥1.5 times baseline [
13]. ICA (2015) added a sevenday temporal criterion [
11]. Urine output (UO) criteria from the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines were not initially extrapolated to patients with cirrhosis. The important study by Amathieu and colleagues in 2017 showed that incorporating UO criteria alongside SCr significantly improved the classification of AKI in chronic liver disease patients, identified a high-risk subgroup previously misclassified by SCr alone, and revealed a strong association between UO-defined AKI and increased hospital mortality [
14]. Angeli et al. (2019) [
11] incorporated UO criterion of <0.5 mL/kg/hr over six hours. 24-hour UO trajectories significantly predicted AKI risk in cirrhosis. With only 20% achieving resolution, preventing progression to stage 3 AKI remains crucial in critically ill patients with cirrhosis [
14]. A prospective study showed baseline oliguria and declining UO independently predicted AKI progression/persistence by day seven, adjusting for inflammation, bilirubin, and infection. The Asian Pacific Association for the Study of the Liver (APASL) recommends incorporating UO criteria in defining AKI in acute-on-chronic liver failure (ACLF) [
15]. Nevertheless, these criteria are primarily applicable in ICU settings, where UO monitoring is feasible. Due to challenges associated with inaccurate measurement, UO reliability may be lower in patients with ascites or refractory ascites. AKI staging in ICA criteria involves three stages of progressive severity, with SCr >1.5 mg/dL further stratifying patients due to its prognostic significance, which is given in
Figure 2.
AKI in cirrhosis is a complex entity with multiple etiolo-gies, necessitating a thorough differential diagnosis to guide management. The primary categories include prerenal AKI, HRS-AKI, intrinsic renal disease, and post-renal obstruction. Pre-renal AKI arises from decreased renal perfusion without structural damage, often secondary to hypovolemia due to gastrointestinal bleeding, excessive diuresis, large-volume paracentesis (LVP) without albumin replacement, or infections such as spontaneous bacterial peritonitis (SBP). It is typically reversible with appropriate volume resuscitation; however, prolonged hypoperfusion can lead to ischemic acute tubular necrosis (ATN), a more severe and less reversible condition.
HRS-AKI represents a severe form of functional kidney impairment due to extreme renal vasoconstriction in re-sponse to systemic and splanchnic vasodilation. It occurs in advanced cirrhosis and ascites, leading to progressive kidney dysfunction that does not improve with volume resuscitation. Unlike structural kidney disease, HRS-AKI is not associated with significant parenchymal injury, though delayed intervention may contribute to permanent kidney damage. In contrast, ATN results from prolonged ischemia, nephrotoxins (such as aminoglycosides, contrast agents, or non-steroidal anti-inflammatory drugs [NSAIDs]), or sepsis-induced renal injury. This condition can be distinguished from HRS-AKI through urinary findings, including granular casts and elevated urinary biomarkers such as neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Patients with ATN typically present with a higher urinary sodium concentration differentiating it from the sodium retention characteristic of HRS-AKI. Post-renal AKI, though rare in cirrhosis, may occur due to urinary outflow obstruction from nephrolithiasis, prostatic hypertrophy, or malignancy. Diagnosis requires imaging studies such as renal ultrasound to detect hydronephrosis, and management focuses on relieving the obstruction.
The understanding of HRS as a pure functional disorder of the kidney progressed from the 2007 ICA guidelines through 2015 KDIGO-aligned updates and 2019 refinements incorporating UO [
8,
11,
12,
16]. Metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence increased significantly in the last two decades increasing the prevalence of structural kidney disease [
17]. Excluding patients with CKD with superimposed HRS would deny early treatment. The requirement for a 48-hour albumin administration has been removed (
Fig. 1).
HRS classification evolved from type 1 and 2 to durationbased categories: HRS-AKI (<7 days) and HRS-NAKI (non-AKI), including HRS-AKD (7–90 days) and HRS-CKD (>90 days) (
Fig. 1). However, even mild elevation in SCr in cirrhosis is associated with adverse outcomes, including progressive kidney dysfunction, decreased mean arterial pressure (MAP), worsening liver parameters, and increased mortality [
18]. AKD encompasses the phase following AKI where recovery is incomplete or slow (7–90 days) but can occur independently without a previous AKI episode and includes markers of kidney damage in its diagnosis like CKD, unlike AKI [
19]. By definition, AKI is a subset of AKD. CKD is characterized by a persistent reduction in eGFR to less than 60 mL/min/1.73 m² and/or evidence of kidney damage lasting more than three months [
20]. Combining eGFR with albuminuria provides more accurate prognostication for CKD and has been included in the diagnosis and staging of CKD [
21]. Persistent renal vasoconstriction inherent in HRS-NAKI can precipitate structural changes over time, blurring the distinction between functional and structural impairment. However, HRS-NAKI may reverse with liver transplantation (LT) alone due to restoration of normal kidney physiology. In contrast, structural CKD often requires simultaneous or sequential liver and kidney transplantation except in the case of structural IgA nephropathy. Complete recovery from HRS-AKI is now defined as the “return of SCr to within 0.3 mg/dL of baseline [
12].”
PATHOPHYSIOLOGY OF KIDNEY DISEASE IN CHRONIC LIVER DISEASE
Kidney in decompensated cirrhosis
In decompensated cirrhosis, hemodynamic imbalances affect multiple organs, particularly the heart and kidneys. Ascites, the most common decompensation, significantly impacts kidney injury [
22]. Patients with decompensated cirrhosis are at a higher risk compared to those with compensated cirrhosis. Progressive decline in systemic vascular resistance leads to apparent arterial hypovolemia. The approach to AKI in compensated cirrhosis should be same as that of patients without cirrhosis. Activation of systemic vasoconstrictor systems, especially the renin-angiotensin-aldosterone system (RAAS), is pivotal in maintaining arterial pressure and contributes to AKI development [
23]. Compromised gut barrier function, cirrhosis-associated immune dysfunction, endotoxemia, and increased damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) with elevated inflammatory cytokines further exacerbate this condition [
14,
24]. Sympathetic nervous system activation contributes to vasoconstriction.
Cardiac dysfunction significantly influences the development of HRS and poor outcomes in advanced cirrhosis. Low cardiac output and more importantly, reduced cardiac reserve predict HRS and mortality [
25-
27]. Cirrhotic cardiomyopathy, characterized by impaired contractile response to stress and altered diastolic relaxation, is a major determinant of kidney function and patient survival [
28]. While the pathogenesis remains unclear, adrenal insufficiency may play a role [
29]. The “window hypothesis” suggests that non-selective beta-blockers are beneficial from the onset of varices until advanced disease stages, beyond which they may overwhelm cardiac reserve, impede compensatory cardiac output increases, and impair renal functional reserve (RFR) [
26].
Additional factors such as hypoalbuminemia, hyponatremia, bacterial translocation, sepsis, and increased systemic (e.g., nitric oxide [NO], endothelin-1) and intrarenal vasoactive mediators aggravate intravascular hypovolemia [
30]. Abdominal compartment syndrome, inadvertent fluid restriction, unsupervised diuretic use, excessive laxative-induced diarrhea, use of iodinated-contrast media, and polypharmacy further exacerbate kidney injury [
31-
33]. The use of angiotensin II receptor antagonists and NSAIDs is particularly detrimental [
34,
35].
RAAS activation leads to renal vasoconstriction and sodium retention. Elevated endothelin-1 and angiotensin II levels promote oxidative stress, inflammation, and fibrosis in the kidneys [
36]. This potent vasoconstriction increases the risk of ischemic ATN. Multiple AKI etiologies often coexist: pre-renal (diuretics, decreased intake), acute tubular injury (cholestasis, nephrotoxins), glomerulonephritis, interstitial nephritis, and obstructive uropathy (midodrine-induced) [
12,
37].
Pathophysiology of ACLF centres on systemic inflammation and immune dysfunction, with DAMPs and PAMPs triggering inflammatory responses [
36]. AKI affects approximately 50% of ACLF patients, significantly increasing short-term mortality [
38]. AKI in ACLF is distinct, often characterized by inflammatory kidney injury rather than HRS [
2]. Cholemic nephropathy (CN) may contribute to AKI, particularly in patients with prolonged jaundice, with only a small proportion able to receive LT; sequential organ failure assessment (SOFA) and chronic liver failure (CLIF)-SOFA scores were effective prognostic tools in this population [
39]. A prospective study involving 639 admissions for acute decompensation found that AKI was present in 92% of ACLF cases, with AKI-on-CKD in 22%; CKD alone was uncommon (4% in ACLF, 3% without). Three-month survival was best predicted by model for end-stage liver disease (MELD)-sodium (MELD-Na) score, ACLF status, and urine NGAL levels [
40]. Patients with ACLF exhibit elevated levels of kidney damage biomarkers. Furthermore, those with severe ACLF show a diminished response to terlipressin and albumin therapy, as reported by Piano and colleagues [
41].
HBV-related ACLF studies demonstrate predominantly structural kidney injury with poor terlipressin response compared to decompensated cirrhosis [
42]. A large prospective study of AKI in ACLF (APASL) indicated that although AKI in ACLF involves greater structural damage, reversibility is also high [
38,
43]. CN often underdiagnosed in ACLF [
15]. Stage 3 AKI prevalence in ACLF increases from 13% to 33% within 30 days, with 59% requiring dialysis [
38]. Risk factors include MELD scores ≥35, bilirubin ≥23 mg/dL, and Asian Acute-On-Chronic Liver Failure Research Consortium (AARC) scores ≥11. Post-mortem findings reveal cholemic nephropathy (54%), ATN (31%), and combined pathology (15%). Dialysis improved survival in patients with stage-3 AKI, despite overall worse outcomes associated with AKI [
38].
AKI prevalence in hospitalized patients with cirrhosis doubled (15–30%) in the past decade [
44]. In critically ill patients with cirrhosis, AKI affects two-thirds, with non-resolution at day seven predicting CKD in 48.3% [
14]. Elevated urinary NGAL, renal tubular epithelial cells (RTEC), and granular casts independently predict non-resolution [
15,
45]. AKI non-resolution is associated with increased tubular and endothelial injury, impaired repair mechanisms, mitochondrial dysfunction, and monocyte-macrophage infiltration. The short-term prognosis of critically ill patients with cirrhosis requiring renal replacement therapy is poor, with a mortality rate exceeding 65%. Most of these patients also fulfill the criteria for ACLF according to the European Association for the Study of the Liver (EASL), American Association for the Study of Liver Diseases (AASLD) and the North American Consortia for the Study of End-stage Liver Disease (NACSELD) definitions [
1,
46-
48].
ACUTE KIDNEY INJURY-CHRONIC KIDNEY DISEASE SPECTRUM
Progression of acute kidney injury to chronic kidney disease
The AKI-to-CKD continuum demonstrates significant overlap and bidirectional progression [
9,
49]. The severity, frequency and number of AKI episodes are crucial determinants in the progression to CKD. AKI defined by clinical criteria might vary from histology and have structural changes [
50]. Approximately one-third of patients with cirrhosis experience this transition, with risk factors including higher MELD scores, multiple AKI episodes, and elevated cystatin C levels [
38,
51,
52]. Patidar et al. [
7] reported that 64% of patients with cirrhosis who progressed to AKD developed CKD, compared to 30.7% in those without AKD. Moreover, urinary biomarkers such as NGAL, interleukin-18, and KIM-1 have been shown to predict AKI progression and mortality. Tonon et al. [
49] found that nearly 30% of patients with cirrhosis developed AKD, with 13.8% progressing to CKD. Similarly, in hospitalized patients with cirrhosis, 40% developed AKI, and at three months follow-up, 25% of AKI survivors had progressed to CKD, compared to only 1% in the NAKI group [
53]. This raises the question of whether classification into these entities is just artificial and if it’s the same disease and its spectrum.
The evolution from AKI to CKD in ACLF remains poorly documented. While AKI frequently complicates ACLF, the progression to CKD remains inadequately characterized, largely due to competing mortality risks and LT [
54,
55]. Posttransplant kidney outcomes are confounded by immunosuppressive nephrotoxicity, obscuring the natural progression of CKD in ACLF.
AKI predisposes to future AKI episodes, creating a cycle of kidney injury that culminates in progressive nephron loss and CKD [
56,
57]. Each AKI episode contributes to cumulative nephron damage, which is exacerbated by ongoing inflammation in the tubulointerstitium, leading to maladaptive repair mechanisms [
58]. This is especially pronounced in ATN, marked by increased monocyte infiltration, RTEC proliferation, endothelial injury, and elevated tubular injury markers [
59]. Systemic vasodilation aggravates the kidney’s vulnerability, driving the transition from AKI to CKD.
AKI and CKD often coexist, each condition increasing the risk of the other. Patients with pre-existing CKD might be at higher risk of developing AKI, and CKD modifies the outcomes of AKI, with CKD patients experiencing lower mortality but higher rates of dialysis dependence at discharge [
60]. Earlier studies showed that CKD protects against AKI. In patients with ACLF, AKI tends to progress rapidly and shows reduced responsiveness to vasoconstrictor therapy [
55]. A higher prevalence of structural AKI and active urinary sediments proves this.
RFR represents the kidney’s capacity to increase the GFR in response to metabolic stimuli, such as protein intake or amino acid infusions [
61]. In cirrhosis, despite altered hemodynamics and high levels of NO, RFR can remain well-maintained [
61]. The trajectory after an AKI insult is influenced by the renal reserve, which might be affected by repeated and severe AKI episodes.
STRUCTURAL KIDNEY DISEASE STRATIFIED BY ETIOLOGY
Metabolic dysfunction-associated steatotic liver disease
MASLD has emerged as a significant independent contributor to CKD development and progression [
62]. Shared mechanisms such as insulin resistance, systemic inflammation, and metabolic dysregulation exacerbate CKD risk beyond traditional factors like obesity and hypertension. CKD has emerged as a significant independent risk factor, with a higher prevalence of cardiopulmonary dysfunction compared to other etiologies. Patients with MASLD had lower baseline GFR and higher biomarkers of kidney damage and experienced an accelerated worsening of both. From a therapeutic perspective, sodium-glucose cotransporter-2 inhibitor dapagliflozin, and GLP-1 analogues are being evaluated.
Both hepatitis B virus (HBV) and hepatitis C virus (HCV) infections significantly increase CKD risk and progression. HCV infection confers an elevated risk, mostly causing proteinuria rather than reducing eGFR, primarily through immune complex-mediated mechanisms manifesting as membranoproliferative glomerulonephritis and cryoglobulinemia [
63,
64]. HBV infection demonstrated three times more cumulative CKD incidence compared to non-infected persons [
65]. Membranous nephropathy, resulting from immune complex deposition and direct viral-mediated kidney injury, is common. Antiviral therapy for both infections shows promise in mitigating CKD progression.
Alcohol-associated hepatitis impacts the CKD spectrum, with AKI occurring in up to 65% of cases [
66]. AKI markedly increases mortality risk and often serves as a precursor to CKD development. Key molecular pathways implicated include apoptosis, inflammation, and hypoxia [
67,
68].
ASSESSMENT OF KIDNEY INJURY IN CIRRHOSIS
Biomarkers
Accurate assessment of kidney injury in cirrhosis is vital due to the limitations of conventional biomarkers and estimation methods [
69]. Novel biomarkers have been investigated to enhance diagnostic accuracy and improve patient outcomes (
Fig. 2). Recent studies have highlighted the role of biomarkers in differentiating HRS-AKI from other causes of AKI and in prognosticating outcomes. Fagundes and colleagues [
70] in 2012 had identified urinary NGAL as a key marker for distinguishing HRS from ATN. Belcher [
71] in 2014 further demonstrated that plasma and urinary NGAL levels correlated with the severity of kidney injury and outcomes in cirrhosis. Urinary NGAL at day 3 demonstrated high accuracy in differentiating ATN from other AKI types in cirrhosis and independently predicted AKI progression and 28-day mortality [
72]. Allegretti et al. [
73] in their prospective study of 213 patients with decompensated cirrhosis assessed urinary NGAL for differentiating ATN from other AKI types and predicting 90-day mortality. Among 161 AKI cases (35% prerenal AKI, 34% HRS, 30% ATN), NGAL levels were significantly higher in ATN (median 344 μg/g creatinine) than in prerenal AKI and HRS. Higher NGAL levels were associated with increased mortality, and NGAL outperformed MELD score in predicting 90-day transplant-free survival. Gambino et al. [
74], evaluated urinary NGAL (uNGAL) as a biomarker for differentiating AKI subtypes in cirrhosis, predicting response to terlipressin and albumin in HRS-AKI, and assessing in-hospital mortality risk. In 162 patients, uNGAL levels were significantly higher in ATN-AKI than other AKI types, with a cutoff of 220 ng/mL. Elevated uNGAL was also independently associated with nonresponse to HRS-AKI treatment and higher in-hospital mortality. Juanola and colleagues [
75] in 2022 validated urinary L-FABP as an independent predictor of 3-month mortality and development of ACLF in decompensated cirrhosis. Maiwall et al. [
76] in 2024 assessed the role of AARC score and uNGAL in ACLF-related mortality and terlipressin non-response. These studies emphasize the critical role of biomarkers in phenotyping and prognosticating AKI.
Table 1 provides a list of biomarkers and their importance. Serum and urine metabolomics, particularly tryptophan-kynurenine and transsulfuration pathways, might enhance AKI prediction and kidney replacement therapy (KRT) requirement assessment [
77,
78].
Early and accurate diagnosis of AKI in cirrhosis is challenging due to limitations with SCr levels (
Table 1) [
12,
16,
50,
52,
79-
81]. Traditional equations for estimating GFR (
Table 2) overestimate true kidney function in patients with cirrhosis. Newer equations incorporating cystatin C, like the CKD-EPI-CysC equation, offer improved accuracy but require further validation and wider adoption (
Table 2). Accurate eGFR calculations help in determining candidacy for simultaneous liver and kidney transplantation and optimizing drug dosing. Clinicians are encouraged to incorporate cystatin C measurements and make it a practice to calculate eGFR in cirrhosis.
Predictive modelling for AKI in cirrhosis remains critical for risk stratification. The PIRO model demonstrates strong predictive capability in ACLF but awaits validation beyond the Asia-Pacific region [
82]. A notable single-center analysis (n=397) with a mean MELD score of 17 developed a predictive model incorporating white blood cell count, SCr, and international normalized ratio [
83].
MANAGEMENT
The management of kidney disease lies in addressing the precipitating factors, individualizing fluid management, stopping nephrotoxic agents, choosing the right patient for albumin infusion and vasoconstrictors and early evaluation for LT. The EASL management algorithm for AKI in cirrhosis has been prospectively validated, demonstrating favorable response rates following timely initiation of terlipressin therapy for HRS-AKI [
46,
84]. LT remains the definitive curative option for HRS-AKI.
Figure 3 gives an overview of assessing and stratifying kidney disease in cirrhosis, while detailed algorithms for the management of AKI and CKD in cirrhosis are given in
Figure 4 and
Figure 5.
The evaluation of fluid status in cirrhosis patients with AKI is difficult due to altered hemodynamics and thirdspace fluid accumulation [
85]. Point-of-care ultrasound and echocardiography have emerged as valuable diagnostic tools, facilitating more accurate classification of HRS and enabling targeted therapeutic interventions. The choice, timing, and dose of fluids in AKI and CKD after careful assessment of volume status have been discussed in
Figure 4 and
Figure 5, respectively. Apart from volume resuscitation, albumin administration has many roles. In SBP, combination therapy with albumin and antimicrobials demonstrates superior outcomes [
14,
86,
87]. The same is not proven for non-SBP infections. In LVP, albumin prevents paracentesis-induced circulatory dysfunction, hyponatremia, and mortality [
88]. In HRS-AKI, the combination of terlipressin and albumin exhibits greater efficacy in improving kidney function compared to placebo, albeit with increased adverse events [
89]. Pre-dialysis albumin in hypoalbuminemia reduces intradialytic hypotension and optimizes fluid removal. However, early albumin administration in continuous renal replacement therapy (CRRT) showed no independent association with mortality or renal recovery [
15]. A randomized controlled trial (RCT) targeting serum albumin levels ≥3 mg/dL through daily infusions failed to demonstrate significant benefits in infection prevention, kidney function, or mortality in decompensated cirrhosis [
90]. While albumin demonstrated superior hemodynamic improvement and lactate clearance compared to PlasmaLyte in patients with cirrhosis with sepsis-induced hypotension, it was associated with increased pulmonary complications without affect-ing 28-day mortality [
87]. Additionally, outpatient albumin infusions with daily midodrine showed no significant advantage over placebo in pre-transplant patients with cirrhosis [
91].
The efficacy of vasoconstrictors, particularly terlipressin, in HRS-AKI has been evaluated in multiple RCTs, with varying degrees of success and concerns regarding safety in specific patient subsets. Martín-Llahí and colleagues [
92] in 2009 compared terlipressin plus albumin to placebo in patients with type 1 HRS (now classified as HRS-AKI), demonstrating a significant improvement in renal function with terlipressin. However, the trial also highlighted concerns regarding treatment-related adverse events, particularly ischemic complications, which remain a major limitation of terlipressin use. Singh and colleagues [
93] in 2012 compared terlipressin to norepinephrine and found that norepinephrine was not inferior to terlipressin in terms of efficacy for HRS reversal. The findings suggested that norepinephrine may be a viable alternative, particularly in ICU settings where close monitoring is feasible. Cavallin and colleagues [
94,
95] in 2015 and 2016 conducted studies that explored alternative vasoconstrictor regimens, including the combination of terlipressin with albumin versus midodrine and octreotide. The results suggested that while terlipressin remains the most potent agent, the midodrine-octreotide-albumin combination was less effective, reinforcing the superiority of terlipressin-based regimens despite concerns about adverse effects. The CONFIRM trial also mentioned the risks of terlipressin, revealing an increased incidence of respiratory failure and sepsis-related complications in patients receiving terlipressin [
96]. These findings have necessitated a more cautious approach with terlipressin. As a result, guidelines have emphasized the need for careful patient selection, avoiding terlipressin in those with advanced ACLF (e.g., high MELD-Na scores, significant respiratory distress, or sepsis). EASL and AASLD have highlighted alternative approaches in high-risk patients, including norepinephrine as a potentially safer alternative in intensive care settings.
Terlipressin and norepinephrine are both utilized in HRS treatment (
Fig. 4). Some studies have found comparable efficacy between the two agents in improving kidney function [
97]. However, recent research shows terlipressin achieves earlier and higher response rates and improves survival in ACLF [
98,
99]. Terlipressin is more effective than placebo in reversing HRS but has more adverse events, including respiratory failure [
89,
100]. Continuous infusion of terlipressin has fewer side effects than bolus administration [
101,
102]. Timely initiation of terlipressin improved outcomes in ACLF, the selection of patients who would respond to terlipressin is of prime importance [
103]. Any euvolemic patient presenting with suspected HRS can be started on terlipressin if not contraindicated otherwise, and it should not be started before volume resuscitation [
12]. While the overall efficacy of terlipressin in HRS reversal is well-established, these studies emphasize the importance of individualized treatment selection to minimize adverse events and optimize patient outcomes. The optimal strategy for HRS-AKI management remains an evolving field. Several key questions persist – Who is the right patient deserving of terlipressin? Can an alternative dosing strategy or a combination of vasopressors mitigate the risks associated with terlipressin? Should biomarkers guide patient selection? Integrating a personalized medicine approach, leveraging hemodynamic monitoring and predictive biomarkers, may improve outcomes in the future.
The optimal modality, initiation timing, MAP targets, endpoints, and application of kidney replacement therapy in various AKI types in cirrhosis are not well-defined. Early initiation of CRRT in critically ill patients might be helpful [
104]. Patients with cirrhosis are highly susceptible to intradialytic hypotension, particularly with intermittent dialysis [
105]. Sustained low-efficiency dialysis offers an effective alternative to CRRT in appropriate patients, especially in resourcelimited settings. Initiation of KRT should not be based solely on biomarkers but should be personalized, maintaining a lower threshold for patients with AKI Stage 3 and ACLF [
15]. While biomarkers can help detect acute glomerular and severe tubular damage, specific thresholds have yet to be determined.
A randomized trial demonstrated that a higher MAP target (80–85 mmHg) in patients with cirrhosis with septic shock improved kidney recovery and dialysis tolerance but did not confer survival benefits and resulted in more adverse events [
106]. Another study found that a MAP below 82.7 mmHg at CRRT initiation was associated with higher mortality [
107]. Higher MAP is linked to an increased likelihood of AKI reversal in decompensated cirrhosis patients. CRRT is preferred over intermittent dialysis due to better hemodynamic stability in patients prone to hypotension, particularly those with ACLF.
Challenges in CRRT for patients with cirrhosis include anticoagulation (citrate/heparin), volume management (ultrafiltration dose), and defining optimal initiation and cessation rules. Early CRRT initiation in ACLF patients with septic shock has demonstrated improved hemodynamic stability and enhanced 28-day transplant-free survival. The ELAIN trial revealed improved kidney function recovery with early CRRT initiation guided by uNGAL levels in critically ill patients; however, the study excluded patients with HRS-AKI [
108].
DIALIVE, a novel extracorporeal liver support system, demonstrated significant improvements in kidney function in patients with ACLF, as evidenced by the greater reduction in CLIF-C OF and ACLF scores compared to standard care, with a higher rate of ACLF resolution [
109]. By exchanging dysfunctional albumin and removing inflammatory mediators, DIALIVE directly targets key pathophysiological mechanisms underlying ACLF-related AKI but needs further validation. In contrast, albumin dialysis using the molecular adsorbent recirculating system and Prometheus in ACLF showed no significant survival benefit.
Transjugular intrahepatic portosystemic shunt (TIPS) has been shown to significantly improve kidney function and clinical outcomes in patients with functional kidney disease and refractory ascites, potentially preventing HRS development [
110,
111]. Kidney function improves after TIPS in patients with HRS-NAKI while combining midodrine, octreotide, and albumin with TIPS might improve kidney function in selected patients with HRS-AKI [
112,
113].
LT is the definitive treatment for HRS [
114] Studies indicate that living donor LT may offer superior outcomes compared to deceased donor transplantation [
115,
116]. Following LT, reversal of HRS occurs in 75–83% of patients; non-reversal is associated with prolonged pre-transplant dialysis and elevated creatinine levels [
114]. While patients with HRS may experience higher mortality rates after LT compared to those without HRS, long-term outcomes are generally favorable [
117]. However, the impact of stage of AKI (stage 3 AKI has poor outcome), number of AKI episodes, and therefore, timing of LT on post-transplant outcomes remains a significant challenge [
118-
121].
The prevalence of CKD, which is increasing among LT candidates, significantly affects post-transplant outcomes [
122]. Pre-transplant CKD increases the risk of mortality and progression after LT [
123]. Risk factors for developing CKD post-transplantation include diabetes, hypertension, and specific liver disease etiologies such as MASLD, HBV, and HCV [
124,
125]. Strategies to preserve kidney function should involve optimization of immunosuppressive regimens, including delayed introduction of calcineurin inhibitors [
126]. Induction therapy with basiliximab in patients with a risk of developing kidney disease requires further validation [
127]. Importantly, lack of response to vasoconstrictors and albumin has been identified as a predictor of CKD after LT, as demonstrated by Piano and colleagues in 2021 [
128].
Current allocation policies for simultaneous liver-kidney transplantation (SLKT) in cases of sustained AKI, CKD, and metabolic liver diseases may inadequately identify atrisk patients by overlooking factors such as patient age, specific phenotypes of sustained AKI, and comorbidities [
129,
130]. Although the MELD score inversely correlates with post-SLKT outcomes, this relationship needs reassessment in patients with sarcopenia and normal creatinine levels [
69,
131]. Improved allocation policies are necessary to better identify and prioritize patients who would benefit most from SLKT, as the rate of kidney graft loss is seen especially in patients with advanced cirrhosis. The liver-kidney safety net policy prioritizes kidney transplantation for patients with persistent kidney dysfunction following LT. Early kidney-after-LT has demonstrated survival outcomes equivalent to those of SLKT, although SLKT in patients with lower MELD scores may provide better in-hospital outcomes [
69]. Kidney-only transplantation in patients with compensated cirrhosis may be considered after proper evaluation, including HVPG assessment.
Emergency LT has variable outcomes in patients requiring RRT; an earlier study showed favourable outcome in grade 3 ACLF, while ELITA study showed otherwise [
119,
132]. In the Asia-Pacific region, significant kidney impairment often precludes transplant candidacy [
120]. Pre-transplant organ failure resolution significantly improves outcomes. A study reported a significantly elevated risk of adverse kidney outcomes in LT recipients with ACLF and an eGFR <30 mL/min/1.73 m² at transplantation, while another observed that kidney involvement was highly prevalent post-transplantation (90%), with a greater proportion of ACLF recipients developing kidney disease stage ≥3 at 12 months [
133,
134]. Thus, SLKT holds some promise in patients with ACLF and endstage kidney disease.
PERSPECTIVES
Recent insights blur distinctions between functional and structural kidney disorders, and they might co-exist, particularly in HRS with structural disease. ACLF, in contrast to decompensated cirrhosis, has renal impairment due to severe inflammation and immune dysregulation. Biomarker-guided risk stratification and phenotyping show promise in improving AKI outcomes, especially in identifying tubular injury, diagnosing cholemic nephropathy, and predicting terlipressin nonresponse. uNGAL-guided extracorporeal treatments warrant further exploration. Adjustments in AKI management include early albumin initiation, dynamic volume monitoring, and timely terlipressin use for HRS-AKI. CRRT may mitigate systemic inflammation in ACLF-associated AKI and improve immune function, while sub-stratification of Stage 3 AKI based on oliguria could refine posttransplant prognostication. The authors acknowledge that several aspects of the management of AKI and/or CKD in cirrhosis are either based on expert opinion or extrapolated from studies in the general population.
Future research should assess kidney health post-recovery or LT, focusing on the progression to acute or CKD. Multicentric trials are required to evaluate the efficacy of combined extracorporeal modalities, such as hemoperfusion and CRRT, in managing kidney injury refractory to conventional therapies.
FOOTNOTES
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Conflicts of Interest
The authors have no conflicts to disclose.
Figure 1.The natural history of kidney injury in cirrhosis is depicted, highlighting the continuum of AKI-AKD-CKD and their outcomes. The susceptibility factors, such as demographic characteristics (age and sex), metabolic dysfunction (diabetes, hypertension, dyslipidemia,) ASCVD, CAD, autoimmune diseases, extrahepatic manifestations of PBC, viral hepatitis, genetic and epigenetic factors, pre-existing AKD/CKD, and specific drugs, predispose individuals to kidney injury. The stages of AKI are categorized based on SCr rise within 48 hours, a percentage increase over 7 days, or reduced urine output. Progression to AKD is defined by an SCr increase of ≥50% from baseline, reduced GFR below 60 mL/min/1.73 m², or the presence of kidney damage markers within 90 days. CKD represents a sustained GFR <60 mL/min/1.73 m² or persistent markers of kidney damage beyond 90 days. By definition, markers of kidney damage are not defined in AKI, but they might be present. The outcomes range from complete recovery (return of SCr within 0.3 mg/dL of baseline) to partial recovery with adaptive repair mechanisms (such as epithelial redifferentiation and return of tubular function) to maladaptive repair (associated with vascular dysfunction and persistent inflammation), culminating in progression to CKD or death. HRS type 1 has been redefined as HRS-AKI, representing AKI (KDIGO criteria) in cirrhotic patients with ascites fitting HRS criteria, while HRS type 2, characterized by a slow, subacute or chronic rise in SCr without a defined timeline, has been renamed HRS-NAKI. HRS-NAKI encompasses HRS-AKD, where kidney dysfunction persists for <90 days following an acute insult, and HRS-CKD, where dysfunction lasts ≥90 days. ACLF, acute-on-chronic liver failure; AKD, acute kidney disease; AKI, acute kidney injury; ASCVD, atherosclerotic cardiovascular disease; CAD, coronary artery disease; CKD, chronic kidney disease; FQ, fluoroquinolone; GFR, glomerular filtration rate; HRS, hepatorenal syndrome; HRS-NAKI, HRS-non-AKI; KDIGO, kidney disease improving global outcomes; LVP, large volume paracentesis; NSAID, non-steroidal anti-inflammatory drug; PBC, primary biliary cholangitis; PICD, paracentesis-induced circulatory dysfunction; PPI, proton pump inhibitor; SBP, spontaneous bacterial peritonitis; SCr, serum creatinine; SIRS, systemic inflammatory response syndrome.
Figure 2.Classification and staging of kidney dysfunction in cirrhosis. The figure provides a framework for evaluating kidney dysfunction in cirrhosis. The diagnostic algorithm begins with an elevation in serum creatinine or a reduction in eGFR, prompting urine analysis and kidney ultrasound. Kidney dysfunction is classified into two main categories based on the KDIGO criteria: AKI – defined by KDIGO criteria and NAKI, which includes AKD and CKD when KDIGO AKI criteria are not met. If AKI criteria are fulfilled, further assessment is conducted to determine whether the dysfunction meets the diagnostic criteria for HRS-AKI. The HRS criteria include no improvement in kidney function after 24 hours of adequate volume resuscitation (or immediate diagnosis if euvolemic), presence of cirrhosis with ascites and absence of alternative explanations for kidney impairment. Patients who do not fit the criteria for AKI but have persistent renal dysfunction may fall into the categories of HRS-AKD or HRS-CKD, depending on the duration of kidney dysfunction. These are collectively referred to as HRS-NAKI (functional AKD/CKD) when HRS pathophysiology underlies renal dysfunction without fulfilling the criteria for AKI. The bottom panels detail the staging criteria for AKI and CKD: AKI Staging follows KDIGO definitions based on the severity of serum creatinine rise and urine output reduction. CKD staging is stratified according to eGFR categories (G1–G5), ranging from normal kidney function (>90 mL/min/1.73 m²) to end-stage kidney disease (<15 mL/min/1.73 m²). Albuminuria is further classified into A1 (normal to mild), A2 (moderate), and A3 (severe). AKD, acute kidney disease; AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HRS, hepatorenal syndrome; KDIGO, kidney disease improving global outcomes; NAKI, non-AKI; SCr, serum creatinine. Created in BioRender, Girish (2025) (
https://BioRender.com/j37j260).
Figure 3.This diagram illustrates the various biomarkers of kidney disease in the setting of cirrhosis. Pre-renal AKI is influenced by factors including diuretics, cardiac dysfunction, excess laxative use, and inadvertent fluid restriction, which lead to renal vasoconstriction and may progress to HRS-AKI. Tubular injury is marked by proximal tubule dysfunction with associated biomarkers such as KIM-1, L-FABP, and IL-18, as well as distal tubule and collecting duct dysfunction marked by biomarkers like NGAL and calprotectin. Toxic and ischemic causes of AKI include variceal bleeding (AVB), septic shock, high-dose vasopressors, and cholemic nephropathy. Glomerulopathy, associated with viral hepatitis (HCV/HBV) and IgA nephropathy, and interstitial nephritis due to oxidative stress and inflammation, are additional contributors. Metabolomic pathways highlight oxidative stress-related AKI, including the transsulfuration pathway and metabolites such as kynurenine and cystathionine. Biomarkers of glomerular filtration include serum creatinine and cystatin C, which reflect kidney dysfunction and damage. AKI, acute kidney injury; AVB, acute variceal bleeding; HBV, hepatitis B virus; HCV, hepatitis C virus; HMGB-1, high mobility group box-1; HRS-AKI, hepatorenal syndrome-associated acute kidney injury; IL-18, interleukin-18; KIM-1, kidney injury molecule-1; L-FABP, liver-type fatty acid-binding protein; NGAL, neutrophil gelatinase-associated lipocalin; PENK, proenkephalin. Created in BioRender, Girish (2025) (
https://BioRender.com/v27v115).
Figure 4.Approach to kidney disease in patients with chronic liver disease. The upper panel emphasizes key clinical components, including history, examination, biochemical markers (e.g., serum creatinine, bilirubin, albumin), and imaging findings (POCUS, Doppler studies). It is important to note the precipitating factors like infection, drugs, and volume shifts. Assessment of liver health (MELD, CTP, and other scores) and complications such as ascites, encephalopathy, and electrolyte imbalances are critical. The middle panel illustrates the continuum of kidney injury from AKI to CKD. The lower panel categorizes renal dysfunction into functional, structural, or mixed phenotypes (functional on structural). VExUS is not validated in cirrhosis. AARC, Asian Acute-On-Chronic Liver Failure Research Consortium; ABG, arterial blood gas; AKD, acute kidney disease; AKI, acute kidney injury; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AVB, acute variceal bleeding; CKD, chronic kidney disease; CLIF-SOFA, chronic liver failure-sequential organ failure assessment; CTP, Child–Turcotte–Pugh; CVP, central venous pressure; eGFR, estimated glomerular filtration rate; HBV, hepatitis B virus; HCV, hepatitis C virus; IAP, intra-abdominal pressure; IVC, inferior vena cava; LVP, large volume paracentesis; MAP, mean arterial pressure; MELD, model for end-stage liver disease; MELD, model for end-stage liver disease; MVP, moderate volume paracentesis; POCUS, point-of-care ultrasound; RARI, renal artery resistive index; VExUS, venous excess ultrasound. Created in BioRender, Girish (2024) (
https://BioRender.com/f56o341).
Figure 5.Approach to AKI in cirrhosis: This flowchart outlines a systematic approach to diagnosing, grading, and managing AKI in cirrhosis, incorporating KDIGO criteria. The algorithm stratifies AKI into functional and structural categories, emphasizing volume assessment through clinical, biochemical, and imaging parameters such as POCUS and venous congestion markers (e.g., IVC, HV, PV Doppler). Management pathways diverge based on the presence or absence of shock. Volume-depleted states are addressed with albumin-based resuscitation, and vasopressors such as terlipressin or noradrenaline are recommended for HRS-AKI after resuscitation. If they are fluidreplete (euvolemic), terlipressin can be started in a timely manner (within 24 hours). Hypervolemic patients might benefit from diuretics, which should be done based on clinical judgment (not included in the algorithm). Structural AKI might require kidney replacement therapy, therapeutic plasma exchange, or extracorporeal liver support, especially for ACLF. Non-response to treatment warrants reassessment of the underlying etiology, diagnostic refinement, and consideration of SLKT. Emerging biomarkers like uNGAL (level above 220 μg/dL) and monitoring of urine output are integral to guiding interventions and predicting recovery. While higher MAP is associated with better response rates, there is no definitive evidence linking it to improved clinical outcomes. Future considerations include the use of biomarkers for renal recovery prediction and tailoring therapeutic strategies. ABG, arterial blood gas; ACLF, acute-on-chronic liver failure; AKD, acute kidney disease; AKI, acute kidney injury; AVB, acute variceal bleeding; CKD, chronic kidney disease; CRRT, continuous renal replacement therapy; HRS, hepatorenal syndrome; HV, hepatic vein; IVC, inferior vena cava; KDIGO, kidney disease improving global outcomes; LT, liver transplantation; MAP, mean arterial pressure; MELD, model for end-stage liver disease; NGAL, neutrophil gelatinase-associated lipocalin; POCUS, point-of-care ultrasound; PV, portal vein; RARI, renal artery resistive index; SBP, spontaneous bacterial peritonitis; SLKT, simultaneous liver-kidney transplantation; TIPS, transjugular intrahepatic portosystemic shunt; uNGAL, urinary NGAL; VTI, velocity time integral. Created in BioRender, Girish (2025) (
https://BioRender.com/y80v353).
Figure 6.Approach to AKD/CKD in cirrhosis: This flowchart outlines the management framework for AKD/CKD in cirrhosis, separating HRS-NAKI (HRS-AKD and HRS-CKD; earlier HRS-2 – which is functional) and structural kidney injuries. HRS-NAKI involves volume assessment and correction using albumin and vasopressors, with terlipressin tried in overlapping HRS-AKI cases. Structural CKD management targets underlying causes, including metabolic dysfunction (e.g., MASLD managed with SGLT2 inhibitors and statins), viral hepatitis (HBV and HCV therapies with renal adjustment), and immune-related nephropathies (e.g., IgA nephropathy and corticosteroid consideration). Key recommendations address metabolic derangements (acidosis, hyperkalemia, etc.), dietary restrictions, exercise for sarcopenia, and cautious diuretic use tailored to kidney and liver function. TIPS may be considered for refractory ascites, but patient selection based on MELD and clinical judgement is essential. Advanced therapies include renal replacement therapy and liver transplantation, with criteria for SLKT outlined for specific metabolic diseases and severe CKD. Emerging therapies and trial data for structural kidney diseases are integrated into management considerations. aHUS, atypical hemolytic uremic syndrome; AKD, acute kidney disease; CKD, chronic kidney disease; GFR, glomerular filtration rate; HBV, hepatitis B virus; HCV, hepatitis C virus; HE; HRS-NAKI, hepatorenal syndrome-non-AKI; KALT, kidney after liver transplant; KDPI, kidney donor profile index; LVP, large volume paracentesis; MAP, mean arterial pressure; MASLD, metabolic dysfunction-associated steatotic liver disease; MMA, methylmalonic acidemia; MVP, moderate volume paracentesis; NSBB, non-selective beta-blockers; SGLT2, sodium-glucose cotransporter 2; SLKT, simultaneous liver-kidney transplantation; TIPS, transjugular intrahepatic portosystemic shunt. Created in BioRender, Girish (2025) (
https://BioRender.com/z58z274).
Table 1.Biomarkers of kidney disease in cirrhosis
Table 1.
|
Biomarker |
Significance |
|
A. Biomarkers of glomerular filtration defect |
|
Blood biomarkers |
|
|
SCr |
Most used; overestimates GFR, part of MELD. |
|
CysC |
Better marker of GFR, Early predictor of AKI; predicts CKD progression, MELD CysC predicts outcomes better. [79] |
|
FGF-23 |
Predictive of AKI, CKD, and AKI-CKD progression; marker of inflammation, oxidative stress, and fibrosis, needs validation in cirrhosis. |
|
PENK |
Marker of oxidative stress and GFR estimation; early prediction of AKI and CKD, needs validation in cirrhosis. [50] |
|
Urine biomarkers |
|
|
Urinary CysC |
Predict CKD progression. |
|
B. Biomarkers of tubulointerstitial inflammation |
|
Blood biomarkers |
|
|
NGAL |
Correlated with inflammation; differentiates ATN from HRS; important in deciding need for KRT; predicts AKI progression and poor outcomes. |
|
KIM-1 |
Marker of inflammation, apoptosis, and oxidative stress; indicate AKI onset. |
|
Urine biomarkers |
|
|
uNGAL |
Elevated in ATN and differentiates from HRS in cirrhosis; predicts AKI progression and poor outcomes; caution required in UTI patients. [16] |
|
uKIM-1 |
Elevated in AKI and CKD, especially in decompensated cirrhosis with AKI; higher levels indicate tubular inflammation and oxidative stress; predicts AKI-to-CKD transition. |
|
IL-18 |
Differentiates ATN from HRS (uNGAL better), Increased in inflammation, predictor of AKI-to-CKD transition. [80] |
|
Urinary angiotensinogen and urinary cytokeratin 20 |
Novel markers for progression; needs further validation. |
|
C. Biomarkers of failed repair |
|
Blood biomarkers |
|
|
MCP-1 |
Marker of failed renal repair and persistent inflammation. [81] |
|
Angiopoietin |
Dysregulation contributes to failed repair following AKI. [12] |
|
NLR |
Elevated levels associated with poor outcomes and failed renal repair in AKI patients. [52] |
|
D. Biomarkers of kidney fibrosis |
|
Blood biomarkers |
|
|
TIMP-1 |
Predict progression, adverse outcomes in AKI patients. [81] |
|
L-FABP |
Correlates with decline in eGFR; predicts mortality, differentiates HRS and ATN. [81] |
|
Chitinase-3-like protein |
Elevated levels predict AKI and CKD onset. |
|
Calprotectin |
Differentiate functional AKI from intrinsic AKI, needs validation. |
|
Urine biomarkers |
|
|
Urinary L-FABP |
Elevated levels predict kidney fibrosis and the transition from AKI to CKD. |
Table 2.Methods for estimation of glomerular filtration rate
Table 2.
|
Assessment Method |
Advantages |
Limitations |
|
SCr |
- Easily available. |
- Overestimates GFR in sarcopenia, fluid overload and cirrhosis. |
|
CysC |
- Earlier diagnosis of AKI (precede SCr changes by ~48 hours). |
- Not routinely available; inflammation alters value. |
|
MDRD and CKD-EPI eGFR equations |
- Widely used and familiar. |
- Require SCr to be in a steady state; inaccurate in AKI. |
|
- Less reliable if GFR < 40 mL/min/1.73 m² or ascites. |
|
CKD-EPI-CysC eGFR equation |
- Least bias if GFR < 60 mL/min/1.73 m² (in cirrhosis). |
- Requires CysC. |
|
- Recommended in cirrhosis. |
|
2021 CKD-EPI equation (race-neutral) |
- Acceptable accuracy in initial studies (cirrhosis). |
- Likely role in patients with low GFR and ascites. |
Abbreviations
Asian Acute-On-Chronic Liver Failure Research Consortium
American Association for the Study of Liver Diseases
Asian Pacific Association for the Study of the Liver
chronic kidney disease epidemiology collaboration
chronic liver failure-sequential organ failure assessment
continuous renal replacement therapy
damage-associated molecular patterns
European Association for the Study of the Liver
European Liver and Intestinal Transplant Association
fibroblast growth factor-23
glomerular filtration rate
hepatorenal syndrome-non-AKI
kidney after liver transplant
kidney disease improving global outcomes
kidney donor profile index
kidney replacement therapy
liver-type fatty acid binding protein
large volume paracentesis
metabolic dysfunction-associated steatotic liver disease
monocyte chemoattractant protein-1
modification of diet in renal disease
model for end-stage liver disease
neutrophil gelatinase-associated lipocalin
non-steroidal anti-inflammatory drug
non-selective beta-blockers
pathogen-associated molecular patterns
paracentesis-induced circulatory dysfunction
renal replacement therapy
spontaneous bacterial peritonitis
sodiumglucose cotransporter 2
systemic inflammatory response syndrome
simultaneous liver-kidney transplantation
tissue inhibitor of metalloproteinases-1
transjugular intrahepatic portosystemic shunt
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