Hepatorenal syndrome and acute kidney injury in cirrhosis

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

AKI in cirrhosis is defined by change from baseline rather than a single high threshold. Creatinine may be low at baseline because of sarcopenia, so a rise of at least 26 micromol/L within 48 hours or at least 50% within seven days is clinically important under standard AKI criteria. Confirm the trend, inspect urine output and retrieve recent results. Do not wait for creatinine to reach a conventional 'renal failure' range before acting.

Initial reasoning separates reduced renal perfusion, intrinsic injury and obstruction. Bleeding, diarrhoea, vomiting and excess diuresis suggest volume loss; infection and SBP can cause vasodilatation and tubular injury; aminoglycosides, NSAIDs, contrast and some other medicines add renal stress. Proteinuria, haematuria, casts or an atypical history suggests intrinsic disease. Renal ultrasound addresses obstruction but does not diagnose HRS.

HRS-AKI arises from severe circulatory dysfunction in advanced portal hypertension, with renal vasoconstriction despite no primary structural renal explanation. Contemporary diagnosis requires cirrhosis with ascites, AKI, no shock, no current nephrotoxic exposure, no strong evidence of structural kidney injury and insufficient improvement after diuretic withdrawal and appropriate plasma-volume assessment or expansion. Albumin and vasoconstrictor decisions need experienced oversight because excess albumin can precipitate pulmonary oedema, while terlipressin can worsen respiratory failure, ischaemia and sepsis risk. Liver transplantation is the definitive treatment when suitable.

Key points

Small creatinine rises matter in cirrhosis because low muscle mass can conceal major loss of glomerular filtration behind a deceptively modest value.
Common causes include hypovolaemia, sepsis or SBP, haemorrhage, over-diuresis, nephrotoxins, acute tubular injury and urinary obstruction.
HRS-AKI describes functional renal failure in advanced liver disease after alternative explanations and lack of response to appropriate initial management are established.
Stop diuretics and nephrotoxic medicines initially, assess volume carefully, and replace documented losses without reflexively flooding a patient with tense ascites.
Diagnostic paracentesis is time-critical in decompensation because SBP may cause AKI without striking abdominal symptoms or fever.
Terlipressin with albumin is specialist therapy and a bridge to recovery or transplantation, not definitive correction of advanced cirrhosis.
The MHRA advises avoiding terlipressin in advanced renal dysfunction or ACLF grade 3 unless benefits outweigh risks and mandates respiratory monitoring.
Renal replacement therapy follows standard emergency indications but should be planned with transplant candidacy, prognosis and the person's goals in view.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Volume loss and haemorrhage

Diarrhoea, vomiting, over-diuresis, poor intake, large-volume losses and gastrointestinal bleeding commonly cause reversible renal hypoperfusion in cirrhosis.

Infection and inflammation

SBP, other sepsis and systemic inflammation worsen vasodilatation and may trigger HRS-AKI or direct tubular injury.

Intrinsic, obstructive and medicine injury

Nephrotoxins, acute tubular injury, glomerular disease and urinary obstruction should be excluded before functional hepatorenal physiology is diagnosed.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Splanchnic vasodilatation
Advanced portal hypertension expands the splanchnic vascular bed and reduces effective arterial volume despite total-body fluid excess.
2
Compensatory renal vasoconstriction
Neurohormonal activation retains sodium and water and progressively constricts renal circulation to preserve systemic pressure as cirrhosis advances.
3
Functional filtration collapse
In HRS-AKI, intense renal vasoconstriction causes a rapid fall in filtration without primary structural kidney damage, often after infection or circulatory stress.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Early biochemical AKIRed flag

A rising creatinine compared with a recent baseline is more informative than whether it remains inside the laboratory reference interval. Verify timing and check urine output promptly.

Hypovolaemic pattern

Recent haematemesis, melaena, diarrhoea, vomiting, poor intake, large-volume drainage without appropriate support or intensified diuretics suggests reduced effective volume and needs cautious correction.

Sepsis-associated injuryRed flag

Fever may be absent; new encephalopathy, hypotension, abdominal tenderness, hypothermia or unexplained decompensation can indicate infection or SBP and should trigger cultures and ascitic sampling.

Structural renal clues

Marked proteinuria, active urinary sediment, substantial haematuria, prolonged hypotension, recent nephrotoxin exposure or abnormal renal imaging argues against uncomplicated HRS and may need nephrology review.

Advanced circulatory failure

Low arterial pressure, refractory ascites, hyponatraemia and worsening hepatic function increase HRS probability, but none is sufficiently specific to bypass exclusion of shock and infection.

Treatment hazard phenotype

Baseline hypoxia, pulmonary oedema, severe coronary or peripheral vascular disease, ACLF grade 3 or very advanced renal failure predicts greater harm from terlipressin and albumin.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Serial creatinine and urine outputFirst step
Why
Confirm AKI, stage its evolution and judge response to initial measures.
Interpretation and limitations
Use the best recent baseline and standard change criteria rather than a fixed upper limit. Oliguria reinforces urgency, although urine collection can be unreliable without careful observation.
02
Urinalysis, microscopy and protein quantification
Why
Look for evidence of glomerular, interstitial or tubular kidney disease.
Interpretation and limitations
Significant protein, blood with dysmorphic cells, cellular casts or granular casts shifts the differential away from pure HRS. Bland urine is compatible with HRS but not diagnostic.
03
Diagnostic ascitic fluid analysis
Why
Exclude spontaneous bacterial peritonitis as a treatable driver of renal deterioration.
Interpretation and limitations
Obtain a cell count and culture before antibiotics when this does not delay treatment. At least 250 neutrophils/mm³ supports SBP even without fever or abdominal guarding.
04
Renal profile, blood count, cultures and lactate
Why
Define metabolic complications, bleeding and occult sepsis requiring immediate treatment.
Interpretation and limitations
Hyperkalaemia, acidosis, anaemia, inflammatory change or raised lactate changes urgency and may explain AKI. Interpret lactate in the context of impaired hepatic clearance and perfusion.
05
Renal tract ultrasound
Why
Identify hydronephrosis, retention and major structural abnormalities where obstruction is plausible.
Interpretation and limitations
Normal imaging helps exclude obstruction but cannot distinguish HRS from hypovolaemia or tubular injury. Bladder scanning may be needed before catheterising an oliguric patient.
06
Respiratory and cardiac assessment
Why
Establish whether albumin or terlipressin would create unacceptable fluid or ischaemic risk.
Interpretation and limitations
Record oxygen saturation, respiratory examination and fluid balance; obtain chest imaging, ECG or cardiac tests when clinically indicated. New hypoxia or pulmonary congestion demands reassessment before further vasoconstrictor or albumin exposure.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Prerenal hypovolaemia

Documented losses and improvement with careful volume replacement favour simple hypoperfusion rather than persistent HRS-AKI after reassessment.

Acute tubular injury

Prolonged shock, sepsis, nephrotoxins, urinary sediment and lack of haemodynamic response support structural tubular damage, though overlap is common.

Obstruction or chronic kidney disease

Hydronephrosis, abnormal kidney size, longstanding proteinuria or a stable previous creatinine pattern indicates an alternative or additional process.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01ActTreat AKI before labelling HRSFirst stepCreatinine has risen from baseline or urine output has fallen in a person with cirrhosis.

1Confirm the trend, perform ABCDE assessment, review blood pressure and losses, send blood and urine studies, obtain cultures and arrange prompt ascitic sampling when ascites is present.
2Withhold diuretics, NSAIDs and other plausible nephrotoxins, treat haemorrhage or sepsis using the appropriate emergency pathway, and replace documented volume loss with repeated clinical reassessment.
3Measure urine output, electrolytes and creatinine serially, seek early hepatology advice and involve nephrology for active sediment, persistent severe AKI or renal-replacement questions.

02DiagnoseEstablish HRS-AKI carefullyAKI persists despite correction of obvious precipitants and appropriate initial volume management.

1Verify cirrhosis with ascites, exclude shock, ongoing nephrotoxin exposure, urinary obstruction and convincing structural renal disease, and revisit whether infection or bleeding remains uncontrolled.
2Use specialist-directed albumin assessment or expansion according to the regional protocol, stopping or reducing exposure if congestion, oxygen requirement or pulmonary oedema emerges.
3If criteria remain consistent with HRS-AKI, agree vasoconstrictor treatment, level of monitoring, transplant assessment and stopping rules with hepatology and critical care.

03EscalateUse terlipressin safelyEscalationThe specialist team proposes terlipressin with albumin for confirmed or strongly suspected HRS-AKI.

1Assess oxygenation, fluid overload, infection, cardiac or peripheral ischaemia, ACLF grade and renal severity before the first dose, explicitly applying current MHRA high-risk cautions.
2Monitor blood pressure, heart rate, oxygen saturation, sodium, potassium, urine output and fluid balance; stop and seek urgent review for respiratory decline or ischaemic symptoms.
3Judge response by renal trajectory and overall physiology, not blood pressure alone, and plan transplantation, renal support or goals-of-care review rather than allowing ineffective therapy to continue indefinitely.

Key medicines and prescribing safety2 treatments · regimens, roles and cautions

Supports selected volume expansion and accompanies vasoconstrictor therapy in HRS-AKI after common reversible causes have been addressed.

Human albumin solution

Give only under the decompensated-cirrhosis or transplant-centre protocol, with indication-specific dosing based on weight, clinical context and response; reassess before every further administration.

Albumin is not harmless volume. Pulmonary oedema and respiratory failure can occur, especially with excess exposure; monitor oxygenation, examination, fluid balance and weight, and reduce or stop if overload develops.

Produces splanchnic vasoconstriction and may reverse HRS-AKI when combined with carefully managed albumin while definitive transplant decisions proceed.

Terlipressin

Initiate and titrate only through the current specialist HRS-AKI protocol; dosing and continuation depend on creatinine response, adverse effects and whether bolus or continuous infusion is selected.

Avoid or use only when benefit clearly outweighs risk in ACLF grade 3, very advanced renal dysfunction, hypoxia or significant ischaemic disease. Monitor for respiratory failure, sepsis, hyponatraemia and cardiac, mesenteric or peripheral ischaemia.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Electrolyte and acid-base disturbance

Reduced filtration and treatment changes cause hyperkalaemia, hyponatraemia, acidosis and arrhythmia risk, requiring close biochemical monitoring.

Respiratory and circulatory failure

Ascites, fluid administration and renal retention can cause pulmonary oedema, while persistent vasodilatation progresses to shock.

Multiorgan decompensation

Kidney failure worsens encephalopathy, infection tolerance and transplant prognosis and may necessitate critical-care or renal replacement support.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Measure creatinine, electrolytes, bicarbonate and urine output frequently enough to identify rapid progression or response, using the clinical setting and AKI stage to set frequency.
Repeat volume assessment using blood pressure, perfusion, weight, fluid balance, ascites, oedema, lung examination and oxygen requirement rather than centralising one surrogate marker.
During terlipressin, monitor oxygen saturation, respiratory symptoms, blood pressure, heart rate, sodium and potassium, and perform at least daily review for infection.
Document albumin exposure and stop or reduce it when pulmonary congestion or worsening hypoxia suggests fluid overload.
Track response against the locally defined creatinine endpoint and agreed stopping rules; lack of improvement should prompt diagnostic and transplant-plan review.
If renal replacement therapy is used, monitor conventional indications and access complications while regularly revisiting transplant eligibility and treatment goals.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Baseline hides severity

Creatinine production is reduced by sarcopenia, so apparently moderate values can represent profound renal dysfunction; dynamic change is the essential signal.

HRS remains exclusionary

No single biomarker proves HRS-AKI. A bland urine and normal ultrasound only narrow the differential after shock, infection, hypovolaemia and nephrotoxins are addressed.

SBP can be silent

Absence of fever or abdominal pain does not safely exclude spontaneous bacterial peritonitis in decompensated cirrhosis, making early paracentesis a renal-protective intervention.

Albumin has a ceiling

The same oncotic expansion intended to improve effective volume can produce lung congestion in a vasodilated, fragile patient; every dose needs a continuing indication.

Reversal is not cure

Improved creatinine after terlipressin can create time for transplantation or recovery from a precipitant, but it does not reverse the portal-hypertensive disease driving HRS.

11Common pitfallsFrequent interpretation and management errors.

01
Waiting for creatinine to become markedly abnormal despite a clear rise from a low cirrhotic baseline.
02
Calling AKI hepatorenal before performing urinalysis, assessing losses, excluding infection and checking for obstruction or nephrotoxin exposure.
03
Missing SBP because the patient has neither fever nor impressive abdominal tenderness.
04
Giving repeated crystalloid or albumin without reassessing lungs, oxygenation, weight and fluid balance.
05
Starting terlipressin in a hypoxic or severely overloaded patient without applying current MHRA risk restrictions.
06
Treating a transient creatinine improvement as an alternative to early transplant-centre discussion.