Decompensated Cirrhosis

Ascites

Ascites is the commonest manifestation of decompensated cirrhosis and marks a major prognostic inflection: median survival after its development is approximately 50% at 2 years, and all patients should be considered for transplant assessment if otherwise appropriate. The dominant mechanism is portal hypertension-induced splanchnic vasodilatation, largely nitric oxide mediated, producing a reduced effective arterial blood volume despite expanded total extracellular volume. This activates the renin–angiotensin–aldosterone system, sympathetic nervous system and non-osmotic vasopressin release, causing renal sodium and water retention. Hypoalbuminaemia contributes, but ascites in cirrhosis is fundamentally a haemodynamic and renal sodium-retentive disorder rather than simply an oncotic problem.

Classification and diagnostic approach

Grade	Definition	Typical implication
Grade 1	Mild; detectable only by ultrasound	Usually no diuretics unless progressive or symptomatic
Grade 2	Moderate; symmetrical abdominal distension	Sodium restriction and diuretics
Grade 3	Large or tense ascites	Large-volume paracentesis with albumin; then prevention of recurrence

All new-onset ascites, hospital admission with ascites, clinical deterioration, gastrointestinal bleeding, shock, fever or renal dysfunction should prompt diagnostic paracentesis. Coagulation tests are poor predictors of bleeding risk in cirrhosis; routine prophylactic fresh frozen plasma or platelets before paracentesis is not recommended unless there is disseminated intravascular coagulation or a specific procedural concern. Ascitic fluid should be sent for cell count and differential, albumin/total protein, culture inoculated directly into blood culture bottles, and cytology/amylase/triglyceride only when clinically indicated.

Parameter	Interpretation
SAAG = serum albumin − ascitic albumin	≥11 g/L indicates portal hypertension with approximately 97% diagnostic accuracy; <11 g/L suggests peritoneal malignancy, tuberculosis, pancreatitis or nephrotic causes
Ascitic total protein	<15 g/L in cirrhosis identifies higher risk of infection and hepatorenal physiology; high protein with high SAAG suggests cardiac ascites or Budd–Chiari syndrome
Neutrophils	≥250 cells/mm3 defines infected ascites, but detailed management belongs to SBP

Medical management

Dietary sodium restriction is central: target approximately 80–120 mmol sodium/day, equivalent to 4.6–6.9 g salt/day. Stricter restriction worsens nutrition and adherence without clear benefit. Fluid restriction is not routinely useful; reserve it for severe dilutional hyponatraemia, typically serum sodium <125 mmol/L, especially if symptomatic. Avoid non-steroidal anti-inflammatory drugs, unnecessary nephrotoxins and excessive antihypertensive therapy; ACE inhibitors and angiotensin receptor blockers are generally poorly tolerated in advanced ascites because renal perfusion is angiotensin-II dependent.

Drug strategy	Dose	Key points
Spironolactone monotherapy	Start 100 mg once daily; increase every 3–5 days to 200, 300, maximum 400 mg/day	First-line for first episode/moderate ascites; aldosterone antagonist, delayed onset 48–72 h; monitor hyperkalaemia, gynaecomastia
Combination therapy	Spironolactone:furosemide 100:40 mg ratio; maximum 400:160 mg/day	Maintains normokalaemia and accelerates natriuresis; preferred in recurrent or severe ascites
Weight-loss targets	≤0.5 kg/day without peripheral oedema; ≤1.0 kg/day with oedema	Excessive diuresis risks intravascular depletion, encephalopathy, hyponatraemia and renal impairment

Therapeutic response may be assessed by weight, abdominal girth, renal function and urinary sodium. A spot urinary sodium:potassium ratio >1 correlates with urinary sodium excretion >78 mmol/day and suggests adequate natriuresis. Diuretics should be reduced or stopped for significant renal dysfunction, serum sodium usually <125 mmol/L, severe muscle cramps, overt encephalopathy, or potassium <3.0 or >6.0 mmol/L.

Large-volume paracentesis and albumin

Large-volume paracentesis is first-line for tense ascites because it provides rapid symptom relief and is safer than aggressive diuresis. Albumin prevents post-paracentesis circulatory dysfunction, a syndrome of arterial underfilling associated with hyponatraemia, renal impairment and increased mortality. Give human albumin solution when more than 5 L is removed: 8 g albumin per litre of ascites drained, usually as 20% albumin. Albumin is not routinely required for taps <5 L unless acute-on-chronic liver failure or high renal risk is present.

Refractory ascites, TIPS and prognosis

Refractory ascites is ascites that cannot be mobilised or recurs early despite sodium restriction and maximal tolerated diuretics. It is subdivided into diuretic-resistant ascites, where there is inadequate natriuresis despite spironolactone 400 mg plus furosemide 160 mg/day, and diuretic-intractable ascites, where complications preclude effective dosing. Management includes repeated large-volume paracentesis with albumin, transplant evaluation and selected use of transjugular intrahepatic portosystemic shunt.

TIPS reduces portal pressure and improves ascites control compared with repeated paracentesis, but at the cost of increased hepatic encephalopathy and potential liver failure. It is most suitable for recurrent/refractory ascites with preserved liver reserve, commonly bilirubin <50 µmol/L, platelet count >75 × 10⁹/L, MELD generally <18, no severe cardiopulmonary disease, uncontrolled infection or recurrent encephalopathy. Covered stents have improved patency compared with bare metal stents. Long-term albumin has evidence from the ANSWER trial, in which albumin 40 g twice weekly for 2 weeks then 40 g weekly improved 18-month survival in uncomplicated ascites, but uptake varies by guideline, cost and local policy.

SBP

Spontaneous bacterial peritonitis is infection of ascitic fluid without an evident surgically treatable intra-abdominal source. It is a cardinal decompensating event in cirrhosis, occurring in approximately 10–30% of hospitalised patients with ascites and carrying in-hospital mortality of 10–20% despite treatment. Pathogenesis reflects cirrhosis-associated immune dysfunction, intestinal dysbiosis, increased gut permeability, impaired hepatic reticuloendothelial clearance, reduced ascitic opsonic activity, and bacterial translocation to mesenteric lymph nodes and systemic circulation. Low ascitic total protein, particularly <15 g/L, is a marker of poor opsonic capacity and increased SBP risk.

Microbiology and classification

Classically, SBP is monomicrobial and caused by enteric Gram-negative organisms, particularly Escherichia coli and Klebsiella pneumoniae, although Gram-positive organisms including streptococci and enterococci are increasingly recognised, especially in healthcare-associated infection and following quinolone exposure. Multidrug-resistant organisms are more common in nosocomial SBP and in patients with recent antibiotics or repeated admissions.

Entity	Ascitic PMN count	Culture	Clinical implication
Classical SBP	≥250 cells/mm3	Usually positive, monomicrobial	Treat immediately
Culture-negative neutrocytic ascites	≥250 cells/mm3	Negative	Managed identically to SBP
Monomicrobial non-neutrocytic bacterascites	<250 cells/mm3	Positive	Repeat paracentesis; treat if symptomatic or persistent
Secondary bacterial peritonitis	Often very high	Often polymicrobial	Requires imaging and surgical/source control consideration

Diagnosis

Diagnostic paracentesis is mandatory in all cirrhotic patients admitted with ascites, and urgently in those with fever, abdominal pain, worsening ascites, ileus, shock, encephalopathy, gastrointestinal bleeding, renal dysfunction, acidosis or unexplained clinical deterioration. SBP is diagnosed when the ascitic neutrophil count is ≥250 cells/mm³, irrespective of culture result. If the ascitic tap is bloody, a correction may be applied: subtract 1 PMN for every 250 red cells/mm³.

Ascitic fluid should be sent for cell count with differential, culture, albumin/protein and, when secondary peritonitis is suspected, glucose, lactate dehydrogenase and amylase. Culture yield is improved by bedside inoculation of 10 mL ascites into aerobic and anaerobic blood culture bottles; conventional culture alone is substantially less sensitive. Empirical treatment must not await culture results.

Features suggesting secondary peritonitis include polymicrobial culture, failure of PMN count to fall after 48 hours of antibiotics, severe localising abdominal signs, or Runyon-type biochemical features: ascitic protein >10 g/L, glucose <2.8 mmol/L, and LDH above the upper limit of normal for serum. CT abdomen and surgical review are required if suspected.

Treatment

Empirical therapy should cover enteric Gram-negative organisms and streptococci, with local resistance patterns guiding choice. Traditional first-line therapy is a third-generation cephalosporin. In nosocomial SBP, prior quinolone prophylaxis, recent beta-lactam exposure or septic shock, broader therapy such as piperacillin–tazobactam or a carbapenem may be appropriate, often with enterococcal/MRSA cover depending on epidemiology.

Intervention	Typical regimen	Key point
Cefotaxime	2 g IV every 8 hours for 5 days	Landmark evidence; excellent ascitic penetration
Ceftriaxone	2 g IV once daily for 5 days	Common practical alternative
Human albumin solution	1.5 g/kg IV day 1, then 1.0 g/kg IV day 3	Reduces renal failure and mortality in high-risk SBP
Repeat paracentesis	At 48 hours if poor response, resistant-risk or diagnostic uncertainty	PMN should fall by ≥25%; failure suggests resistance or secondary peritonitis

The pivotal Sort et al. trial demonstrated that albumin added to cefotaxime reduced renal impairment from 33% to 10% and mortality from 29% to 10%. Albumin is particularly indicated when serum creatinine is >88 µmol/L, blood urea nitrogen >10.7 mmol/L, or bilirubin >68 µmol/L, although many guidelines favour albumin for most confirmed SBP because hepatorenal syndrome prevention is central to outcome.

Prophylaxis

SBP recurrence after an index episode is approximately 70% at 1 year without prophylaxis; therefore secondary prophylaxis is mandatory until ascites resolves, transplantation, or death. Options include norfloxacin 400 mg orally once daily where available, ciprofloxacin 500 mg orally once daily, or co-trimoxazole 960 mg orally once daily. Choice should account for resistance, previous cultures, QT risk, tendinopathy, Clostridioides difficile, renal function and antimicrobial stewardship.

Primary prophylaxis is more selective. It is recommended after acute upper gastrointestinal bleeding in cirrhosis, typically ceftriaxone 1 g IV once daily for up to 7 days in advanced disease or high quinolone-resistance settings, because bacterial infection increases rebleeding and mortality. It is also considered in high-risk ascites: ascitic protein <15 g/L plus severe liver failure or renal dysfunction, for example Child-Pugh ≥9 with bilirubin ≥51 µmol/L, creatinine ≥106 µmol/L, urea ≥8.9 mmol/L, or sodium ≤130 mmol/L.

For examination purposes, the decisive diagnostic threshold is ascitic PMN ≥250/mm³; treatment is immediate third-generation cephalosporin-based therapy plus albumin in appropriate patients; and any SBP episode mandates long-term secondary prophylaxis and assessment for liver transplantation.

Varices

Pathophysiology and risk stratification

Varices are portosystemic collaterals that develop once the hepatic venous pressure gradient (HVPG) rises sufficiently to drive splanchnic-to-systemic shunting. Normal HVPG is approximately 1–5 mmHg; clinically significant portal hypertension is defined as HVPG ≥10 mmHg, while variceal haemorrhage usually requires HVPG ≥12 mmHg. Bleeding risk is determined by portal pressure, variceal wall tension, variceal radius, wall thickness, and mucosal features; Laplace’s law explains why large varices with thin walls and high intravariceal pressure are prone to rupture.

In cirrhosis, varices develop at an annual rate of approximately 5–10%, and small varices progress to large varices in 5–12% per year. First variceal bleeding carries a mortality of around 15–20% at 6 weeks, higher in Child-Pugh C disease, renal dysfunction, active bleeding at endoscopy, infection, and hepatocellular carcinoma. MRCP candidates should associate variceal bleeding with decompensation and a marked increase in short-term mortality.

Risk marker	Clinical implication
Large oesophageal varices	Higher rupture risk; requires primary prophylaxis
Red wale marks or cherry-red spots	Endoscopic stigmata of high bleeding risk
Child-Pugh C	High risk of first bleed and rebleeding; consider early TIPS in acute bleeding
HVPG >20 mmHg during acute bleed	Strong predictor of failure to control bleeding and mortality

Diagnosis, screening, and classification

Upper gastrointestinal endoscopy is the diagnostic standard. In compensated cirrhosis, Baveno VII criteria allow some patients to avoid screening endoscopy: liver stiffness <20 kPa and platelet count >150 × 10⁹/L indicate a very low probability of high-risk varices. In decompensated cirrhosis, endoscopy is generally required because non-invasive exclusion is less reliable.

Varix type	Key features	Preferred therapy if bleeding
Oesophageal varices	Most common; graded small, medium, large	Band ligation plus vasoactive drug
GOV1	Gastro-oesophageal varices extending along lesser curve	Treat similarly to oesophageal varices
GOV2	Extension into fundus	Cyanoacrylate/thrombin, TIPS or BRTO depending anatomy
IGV1	Isolated fundal gastric varices	Cyanoacrylate/thrombin; consider TIPS/BRTO
IGV2	Isolated ectopic gastric varices elsewhere	Specialist endoscopic or radiological therapy

Primary prophylaxis

Primary prophylaxis is indicated for medium/large varices, small varices with red signs, or small varices in Child-Pugh C cirrhosis. Options are non-selective beta-blockers or endoscopic variceal ligation (EVL). Non-selective beta-blockers reduce portal inflow through β1-mediated reduction in cardiac output and β2 blockade causing unopposed α-mediated splanchnic vasoconstriction. Carvedilol additionally blocks α1 receptors and produces greater HVPG reduction, but may precipitate hypotension in advanced decompensation.

Drug	Typical regimen	Important cautions
Propranolol	Start 20–40 mg twice daily; titrate to heart rate 55–60/min or maximum tolerated dose	Asthma, bradycardia, hypotension; avoid over-titration in refractory ascites or AKI
Nadolol	20–40 mg once daily; titrate similarly	Renal excretion; adjust in renal impairment
Carvedilol	6.25 mg once daily, increase to 6.25 mg twice daily; usual maximum 12.5 mg/day in cirrhosis	Avoid if systolic BP <90 mmHg, severe hyponatraemia, AKI, or refractory shock physiology

EVL is performed every 2–4 weeks until eradication, then surveillance at approximately 3–6 months and subsequently 6–12 monthly. EVL prevents bleeding but does not modify portal hypertensive physiology; non-selective beta-blockers may additionally reduce other decompensation events. Baveno VII therefore favours carvedilol in compensated cirrhosis with clinically significant portal hypertension, but in established decompensation treatment must be individualised.

Acute variceal haemorrhage

Management is simultaneous resuscitation, vasoactive therapy, antibiotics, early endoscopy, and risk-stratified rescue therapy. Over-transfusion increases portal pressure; a restrictive strategy targeting haemoglobin 70–80 g/L is standard, supported by the Villanueva trial, which showed improved survival with restrictive transfusion compared with liberal transfusion in acute upper gastrointestinal bleeding, particularly in cirrhosis. Correct shock, protect the airway if massive haematemesis or encephalopathy, and avoid routine correction of INR, as INR poorly reflects haemostasis in cirrhosis.

Intervention	Exam-critical details
Vasoactive therapy	Terlipressin 2 mg IV every 4 hours initially, then 1 mg every 4 hours after control; usually for 2–5 days. Alternatives: octreotide 50 micrograms IV bolus then 50 micrograms/hour infusion. Terlipressin half-life is approximately 0.9–2 hours; monitor for ischaemia, arrhythmia, hyponatraemia.
Antibiotics	Give immediately: e.g. ceftriaxone 1 g IV once daily for up to 7 days. Reduces infection, early rebleeding, and mortality.
Endoscopy	Perform within 12 hours after haemodynamic stabilisation. EVL is first-line for oesophageal varices.
Failure to control bleeding	Balloon tamponade or fully covered self-expanding metal oesophageal stent as bridge to definitive therapy, usually TIPS.

Early or pre-emptive TIPS within 24–72 hours should be considered in high-risk bleeding: Child-Pugh C 10–13, or Child-Pugh B with active bleeding at endoscopy. The landmark García-Pagán study demonstrated marked reductions in rebleeding and mortality with early TIPS in selected high-risk patients. TIPS is generally avoided in severe heart failure, uncontrolled sepsis, severe pulmonary hypertension, and advanced liver failure where futility is likely.

Secondary prophylaxis

After survival from a variceal bleed, rebleeding risk without prophylaxis is approximately 60% within 1 year. Standard secondary prophylaxis is combination therapy with a non-selective beta-blocker plus serial EVL until eradication. Combination therapy is superior to either strategy alone. Rebleeding despite optimal therapy, intolerance of beta-blockers, or high-risk anatomy should prompt consideration of TIPS. Proton pump inhibitors should not be continued routinely after EVL unless there is another indication; prolonged use is associated with infection risk in cirrhosis.

Hepatic Encephalopathy

Hepatic encephalopathy (HE) in cirrhosis is a potentially reversible neuropsychiatric syndrome caused by portosystemic shunting and hepatocellular failure, most commonly precipitated by infection, gastrointestinal bleeding, constipation, acute kidney injury, hypovolaemia/overdiuresis, electrolyte disturbance, sedatives/opioids, excess alcohol, or recent TIPS. For MRCP, HE should be regarded as a clinical diagnosis after exclusion of mimics, but its presence signifies decompensation and adverse prognosis.

Pathophysiology and classification

The central toxin is ammonia, generated by intestinal bacterial ureases and glutaminase activity and normally detoxified by hepatic urea-cycle metabolism. In cirrhosis, ammonia bypasses the liver via spontaneous or iatrogenic shunts and is partly buffered by skeletal muscle glutamine synthetase; sarcopenia therefore increases risk. Within astrocytes, ammonia is converted to glutamine, causing osmotic stress, mitochondrial dysfunction, oxidative/nitrosative injury and low-grade cerebral oedema. Typical histology is Alzheimer type II astrocytosis. Systemic inflammation amplifies ammonia neurotoxicity through cytokine-mediated blood–brain barrier dysfunction and microglial activation. Additional contributors include enhanced GABAergic tone, endogenous benzodiazepine-like ligands, hyponatraemia, manganese deposition in basal ganglia, and altered gut microbiota.

Classification	Categories	Clinical relevance
Underlying liver disorder	Type A: acute liver failure; Type B: portosystemic bypass without intrinsic liver disease; Type C: cirrhosis	Decompensated cirrhosis produces Type C HE; cerebral oedema is much less dramatic than in acute liver failure.
Time course	Episodic, recurrent, persistent	Recurrent HE usually means ≥2 overt episodes within 6 months and mandates secondary prophylaxis.
Severity	Covert HE: minimal HE and West Haven grade I; Overt HE: grades II–IV	Overt HE is exam-relevant and usually requires treatment and precipitant search.

Staging and diagnostic assessment

West Haven grade	Key features	Examination emphasis
Minimal	Normal bedside examination; impaired psychometric/neurophysiological tests	Psychometric hepatic encephalopathy score, Stroop/encephalApp, critical flicker frequency; relevant to driving/work safety.
I	Sleep reversal, impaired attention, irritability, subtle cognitive slowing	Asterixis may be absent; often labelled covert HE.
II	Lethargy, disorientation for time, inappropriate behaviour	Asterixis, dysarthria, ataxia common.
III	Somnolence but arousable, gross confusion, disorientation	Assess airway risk and aspiration; look for sepsis or bleeding.
IV	Coma	Use Glasgow Coma Scale for monitoring; intubation may be required.

Plasma ammonia is mechanistically important but diagnostically imperfect: venous levels are prone to artefact from tourniquet use, delayed processing and haemolysis; normal values vary by laboratory, commonly approximately 10–50 µmol/L. A normal ammonia level should prompt reconsideration of the diagnosis, but an elevated level is neither specific nor proportional to severity. Diagnosis requires exclusion of intracranial bleeding, alcohol withdrawal, Wernicke encephalopathy, hypoglycaemia, hypercapnia, uraemia, hyponatraemia, sepsis-associated encephalopathy and drug toxicity. Investigation should include glucose, U&E, LFTs, INR, FBC, CRP, cultures, diagnostic ascitic tap if ascites is present, and evaluation for gastrointestinal haemorrhage; CT brain is indicated with focal signs, trauma, anticoagulation, first presentation, or failure to improve.

Management

Initial management is supportive and directed at precipitants. Correct hypoglycaemia, hypoxia and severe electrolyte disturbance; stop benzodiazepines, opioids and other sedatives where possible. Treat infection promptly, manage variceal or non-variceal bleeding, reverse constipation, and correct hypovolaemia/AKI. Severe grade III–IV HE requires senior assessment for airway protection and high-dependency/ICU care.

Therapy	Dose and pharmacology	Key exam points
Lactulose	Usually 20–30 g orally, equivalent to about 30–45 mL, every 1–2 h until bowel action, then titrate to 2–3 soft stools/day; common maintenance 15–30 mL 2–4 times daily. If unsafe swallow: 300 mL lactulose in 700 mL water as retention enema every 4–6 h.	Non-absorbable disaccharide acidifies colonic contents, converts NH3 to NH4+, acts cathartically and alters microbiota. Overuse causes dehydration, hypernatraemia and worsened HE.
Rifaximin	550 mg twice daily or 400 mg three times daily depending on formulary; minimally absorbed rifamycin with broad gut activity.	Add for secondary prophylaxis after recurrent overt HE or inadequate lactulose response. In Bass et al., NEJM 2010, rifaximin reduced breakthrough HE over 6 months: 22.1% versus 45.9% with placebo; HR 0.42, and reduced HE-related hospitalisation: 13.6% versus 22.6%.
Polyethylene glycol	4 L PEG solution over approximately 4 h in selected inpatients.	May accelerate early improvement compared with lactulose in small trials, but lactulose remains standard first-line therapy in guidelines.
L-ornithine L-aspartate	Often 20 g/day IV or oral preparations such as 3–6 g three times daily.	Enhances ammonia detoxification via urea synthesis and glutamine formation; used variably, not universal first-line MRCP answer.
Neomycin/metronidazole	Neomycin 1 g 2–4 times daily; metronidazole 250 mg 2–3 times daily short term.	Generally avoided long term: nephrotoxicity/ototoxicity with neomycin; neuropathy with metronidazole.

Nutritional management is important: historical protein restriction is harmful. Current AASLD/EASL guidance supports 35–40 kcal/kg/day and 1.2–1.5 g protein/kg/day, preferably divided with a late-evening carbohydrate/protein snack; vegetable and dairy protein may be better tolerated than large meat loads. Consider branched-chain amino acids in protein-intolerant patients, although they do not replace lactulose/rifaximin.

Secondary prophylaxis is indicated after an overt episode: lactulose reduces recurrence substantially, and rifaximin is added after a second episode or if recurrence occurs despite adequate lactulose. Persistent or refractory HE should prompt assessment for large spontaneous portosystemic shunts, TIPS reduction/occlusion where appropriate, medication review, sarcopenia management, and transplant referral if consistent with overall prognosis.

Hepatorenal Syndrome

Definition, pathophysiology and diagnostic framework

Hepatorenal syndrome (HRS) is a functional renal failure syndrome occurring in advanced cirrhosis, severe alcoholic hepatitis, or acute-on-chronic liver failure, characterised by intense renal vasoconstriction without primary structural kidney disease. The central mechanism is severe splanchnic arterial vasodilatation driven by portal hypertension, nitric oxide, carbon monoxide, endocannabinoids and bacterial translocation. This causes reduced effective arterial blood volume, activation of the renin–angiotensin–aldosterone system, sympathetic nervous system and non-osmotic vasopressin release, culminating in renal cortical vasoconstriction, sodium avidity and low glomerular filtration. Cardiac dysfunction in cirrhosis and systemic inflammation amplify renal hypoperfusion.

The International Club of Ascites (ICA) now classifies HRS within acute kidney injury terminology. HRS is a diagnosis of exclusion; importantly, urine sodium and fractional excretion of sodium are no longer required because they perform poorly in cirrhosis, particularly with diuretics.

Entity	Key definition	Clinical significance
AKI in cirrhosis	Increase in serum creatinine ≥26.5 μmol/L within 48 h, or ≥50% from baseline within 7 days	Creatinine underestimates renal dysfunction in cirrhosis due to sarcopenia, bilirubin assay interference and increased tubular secretion
HRS-AKI	AKI in cirrhosis with ascites, not responding to diuretic withdrawal and plasma expansion, with no shock, nephrotoxins or structural renal disease	Formerly “type 1 HRS”; rapidly progressive and high short-term mortality
HRS-NAKI	Non-AKI renal dysfunction in cirrhosis: HRS-AKD or HRS-CKD	Formerly overlaps with “type 2 HRS”; often associated with refractory ascites

Diagnostic criteria and differential diagnosis

ICA diagnostic criteria for HRS-AKI require cirrhosis with ascites, AKI by ICA definition, absence of response after 2 consecutive days of diuretic withdrawal and albumin 1 g/kg/day up to 100 g/day, absence of shock, no current/recent nephrotoxic drugs, and no evidence of structural kidney injury. Structural renal disease is suggested by proteinuria >500 mg/day, microhaematuria >50 red cells/high-power field, abnormal renal ultrasound, or casts consistent with intrinsic renal disease.

Differential	Typical clues	Management implication
Pre-renal azotaemia	Over-diuresis, bleeding, diarrhoea; improves with volume/albumin	Correct precipitant; avoid vasoconstrictors unless HRS criteria met
Acute tubular injury	Sepsis, hypotension, nephrotoxins; granular casts; higher urinary biomarkers such as NGAL	Supportive care; vasoconstrictor response limited
Abdominal compartment physiology	Tense ascites, raised intra-abdominal pressure	Large-volume paracentesis with albumin replacement
Glomerulonephritis	Proteinuria/haematuria, low complement, active sediment	Nephrology assessment; biopsy only selected cases

Management

Immediate steps are withdrawal of diuretics, ACE inhibitors/ARBs, NSAIDs and aminoglycosides; treatment of precipitants such as spontaneous bacterial peritonitis, gastrointestinal bleeding or sepsis; avoidance of excessive crystalloid; and early discussion with hepatology, intensive care and transplant services. Albumin is central: after the diagnostic challenge above, albumin is continued with vasoconstrictors, commonly 20–40 g/day, titrated to volume status. Over-infusion can precipitate pulmonary oedema, particularly with terlipressin.

Treatment	Typical regimen	Key adverse effects/notes
Terlipressin + albumin	1 mg IV every 4–6 h; increase to 2 mg every 4–6 h if creatinine has not fallen by ≥25% by day 3. Alternative continuous infusion 2 mg/day, titrated up to 12 mg/day	First-line where available; ischaemia, arrhythmia, abdominal cramps, hyponatraemia, respiratory failure. Avoid or use extreme caution if hypoxic, severe cardiovascular disease, or ACLF grade 3
Noradrenaline + albumin	ICU infusion commonly 0.5–3 mg/h or 0.05–0.5 μg/kg/min, titrated to raise MAP by ~10–15 mmHg	Comparable efficacy in small trials/meta-analyses; requires monitored setting
Midodrine + octreotide + albumin	Midodrine 7.5–12.5 mg orally three times daily plus octreotide 100–200 μg SC three times daily	Less effective than terlipressin; used where terlipressin/noradrenaline unavailable

Response is usually defined as reduction of serum creatinine to ≤133 μmol/L or within 0.3 mg/dL of baseline; partial response is a ≥50% fall without full normalisation. Treatment is generally stopped after 14 days if there is no meaningful creatinine reduction. A rise in mean arterial pressure is a favourable pharmacodynamic marker, reflecting reversal of effective hypovolaemia.

Evidence is strongest for terlipressin plus albumin. The CONFIRM trial demonstrated verified HRS reversal in 32% with terlipressin versus 17% with placebo, but respiratory failure was more frequent, including fatal events, reinforcing careful patient selection and albumin stewardship. Earlier European trials showed HRS reversal in approximately 40–50% versus 10–15% with albumin alone. Current EASL/AASLD-aligned practice favours terlipressin plus albumin as first-line therapy where available, with noradrenaline an accepted alternative in critical care.

Definitive therapy, rescue strategies and prognosis

Liver transplantation is the definitive treatment and should be considered urgently; HRS increases MELD-Na and wait-list mortality. Simultaneous liver–kidney transplantation is reserved for prolonged severe renal dysfunction, established chronic kidney disease, or dialysis dependence according to local allocation rules. Renal replacement therapy is a bridge to transplantation or recovery, not definitive therapy; outcomes are poor when used in non-transplant candidates. TIPS may improve renal function in selected patients with refractory ascites and preserved hepatic reserve, but is generally unsuitable in severe hepatic failure, uncontrolled encephalopathy, significant pulmonary hypertension or advanced cardiac dysfunction.

Prognosis remains poor: untreated HRS-AKI has median survival measured in weeks, historically around 2 weeks for rapidly progressive disease. Examination questions often test recognition that HRS is not “renal failure from dehydration” but a circulatory and inflammatory complication of portal hypertension requiring albumin, vasoconstriction and transplant assessment.