Hepatorenal Syndrome (HRS)

📋 Key Information Summary

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Hepatorenal syndrome (HRS) is a functional renal failure occurring in patients with advanced cirrhosis and portal hypertension, characterised by intense renal vasoconstriction in the absence of structural kidney disease.
Diagnosis requires ICA-AKI criteria: serum creatinine rise ≥26.5 µmol/L within 48 hours or ≥50% increase within 7 days, after exclusion of shock, nephrotoxic drugs, hypovolaemia, and structural kidney injury.
A mandatory 48-hour diagnostic trial of diuretic withdrawal and volume expansion with albumin (1 g/kg/day, max 100 g/day for 2 days) is required before confirming HRS; failure to improve confirms functional renal failure.
HRS-AKI (formerly type 1) is rapidly progressive with doubling of serum creatinine within 2 weeks; HRS-NAKI (formerly type 2) is slower and associated with refractory ascites.
First-line vasoconstrictor therapy is terlipressin (bolus 1–2 mg IV 4–6 hourly, or continuous infusion 2–12 mg/day) combined with intravenous albumin (20–40 g/day after initial challenge); this is PBS-listed (Authority Required).
Where terlipressin is unavailable or contraindicated, noradrenaline 0.5–3 mg/hr continuous IV infusion plus albumin in an ICU setting is an evidence-based alternative.
Midodrine 7.5–12.5 mg PO TDS + octreotide 100–200 µg SC TDS + albumin is a second-line option where intravenous vasoconstrictors cannot be used.
NSAIDs, ACE inhibitors, ARBs, and aminoglycosides must be avoided as they precipitate or worsen HRS.
Liver transplantation is the only definitive treatment; simultaneous liver–kidney transplant is considered for patients with dialysis dependence ≥6 weeks or pre-existing CKD stage 4–5.
Renal replacement therapy is indicated only as a bridge to transplantation in suitable candidates; outcomes are significantly worse if transplanted while on RRT.
Aboriginal and Torres Strait Islander Australians have a disproportionately higher burden of liver disease and cirrhosis; timely specialist referral and culturally safe care pathways are essential.
Terlipressin carries risk of pulmonary oedema (especially in patients with cardiac dysfunction) and digital/peripheral ischaemia; careful volume status monitoring is mandatory.
Serum lactate, serum sodium, and bilirubin are important prognostic markers and guide transplant listing urgency.

Introduction & Australian Epidemiology

Hepatorenal syndrome (HRS) is a life-threatening complication of end-stage liver disease, defined as functional renal failure due to profound renal vasoconstriction in the setting of portal hypertension and splanchnic vasodilation. The kidneys in HRS are structurally normal; dysfunction is haemodynamic, and renal histology is typically unremarkable on biopsy.

HRS develops in approximately 18–40% of patients hospitalised with decompensated cirrhosis. In Australia, cirrhosis is the 11th leading cause of death overall, with rising incidence driven by increasing rates of metabolic dysfunction-associated steatohepatitis (MASH), harmful alcohol use, and chronic hepatitis B and C. The AIHW reports that liver disease mortality has increased by approximately 28% over the past decade, disproportionately affecting Aboriginal and Torres Strait Islander peoples and rural communities.

In Australian tertiary centres, HRS-AKI carries an untreated 2-week mortality exceeding 80%. Even with vasoconstrictor therapy, 30-day mortality remains 20–50%, underscoring the urgency of early recognition and the critical role of timely liver transplant assessment.

⚠️

Clinical urgency: Untreated HRS-AKI has a median survival of approximately 2 weeks. Early diagnosis and immediate vasoconstrictor therapy initiation, alongside urgent transplant referral, are essential.

Diagnosis

ICA-AKI Criteria in Cirrhosis

The International Club of Ascites (ICA) revised criteria require AKI staging based on serum creatinine changes from baseline:

AKI Stage	Serum Creatinine Criteria
Stage 1	Increase ≥26.5 µmol/L within 48 hours or ≥50% increase from baseline within 7 days
Stage 2	Increase ≥2× baseline creatinine
Stage 3	Increase ≥3× baseline or serum creatinine ≥353.6 µmol/L or initiation of RRT

Diagnostic Criteria for HRS

Diagnosis of HRS is one of exclusion. All of the following must be fulfilled:

Cirrhosis with ascites (documented by imaging or paracentesis)
AKI per ICA-AKI Stage 1 or above
No improvement of serum creatinine after at least 2 days of diuretic withdrawal and volume expansion with albumin (1 g/kg/day IV, maximum 100 g/day, for 2 days)
Absence of shock (no haemodynamic instability requiring vasopressors)
No current or recent nephrotoxic drug exposure (NSAIDs, aminoglycosides, IV contrast within prior 48–72 hours)
No macroscopic signs of structural kidney disease:
- Urine red blood cells <50 per high-power field
- Urine protein <500 mg/day (or urine protein:creatinine ratio <500 mg/g)
- Normal renal ultrasound (no hydronephrosis, no cortical thinning)
No sustained reversal with volume expansion alone

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Do not miss pre-renal azotaemia: Up to 50% of AKI episodes in cirrhosis are pre-renal (diarrhoea, over-diuresis, haemorrhage) and will respond to volume repletion. The 48-hour albumin challenge is mandatory to distinguish pre-renal AKI from true HRS.

Differential Diagnosis of AKI in Cirrhosis

Aetiology	Distinguishing Features	Response to Volume
Pre-renal (hypovolaemia)	Diarrhoea, haemorrhage, over-diuresis; low CVP	Yes — improves with albumin/crystalloid
Acute tubular necrosis (ATN)	Muddy brown granular casts, high FeNa (>2%), prior shock/ischaemia	No
Hepatorenal syndrome	Low urine sodium (<10 mEq/L), low FeNa (<1%), bland urine sediment	No — functional renal failure
Nephrotoxic injury	NSAIDs, aminoglycosides, IV contrast history	No
Intrinsic glomerulonephritis	Active urine sediment, proteinuria >500 mg/day, haematuria	No — requires renal biopsy

Investigations

ESSENTIAL

Serum creatinine (serial — 48-hr and 7-day trend)

MBS Item 66505 (renal function panel). Baseline must be established from most recent stable value prior to admission.

ESSENTIAL

Urinalysis and urine microscopy

MBS Item 69310 (urine microscopy). Exclude haematuria (<50 RBC/hpf) and casts. Urine dipstick for protein and blood.

ESSENTIAL

24-hour urine protein or spot urine protein:creatinine ratio

Must be <500 mg/day (<500 mg/g) to exclude glomerular disease.

AVAILABLE

Renal ultrasound with Doppler

MBS Item 55015. Exclude obstruction, assess kidney size and cortical thickness. Renal resistive index may be elevated but is non-specific.

AVAILABLE

Urine sodium and fractional excretion of sodium (FeNa)

Urine sodium <10 mEq/L and FeNa <1% support HRS (low specificity in cirrhosis).

AVAILABLE

Serum lactate, serum sodium, bilirubin, INR

Prognostic markers; hyponatraemia (<130 mEq/L) and hyperbilirubinaemia correlate with transplant-free survival. MBS Items 66505, 66512.

SPECIALIST

Renal biopsy (rarely required)

Considered only when intrinsic renal disease cannot be excluded clinically. High bleeding risk in cirrhosis; requires hepatology/nephrology consensus.

Classification & Treatment

Classification

Progressive

HRS-AKI (formerly Type 1)

Rapidly progressive AKI: serum creatinine doubles to ≥221 µmol/L within 2 weeks, or ≥50% reduction in 24-hr creatinine clearance to <20 mL/min. Frequently triggered by acute-on-chronic liver failure (ACLF), spontaneous bacterial peritonitis (SBP), or large-volume paracentesis without albumin replacement.

Setting: ICU or high-dependency unit; immediate vasoconstrictor therapy; urgent transplant referral

Chronic

HRS-NAKI (CKD/AKD, formerly Type 2)

Moderate, slowly progressive or stable renal impairment (serum creatinine 133–221 µmol/L) in the setting of refractory or recurrent ascites. Not driven by a precipitating event. Often spontaneous diuretic-resistant ascites precedes diagnosis by weeks to months.

Setting: outpatient hepatology/transplant workup; vasoconstrictor therapy if acute deterioration occurs

First-Line Vasoconstrictor Therapy: Terlipressin + Albumin

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Terlipressin

Glypressin® · Vasopressin analogue

Adult dose Initial bolus 1 mg IV; titrate to 2 mg IV every 4–6 hours (max 12 mg/day). Alternatively, continuous infusion 2–12 mg/day via syringe driver.

Paediatric dose Limited data. Not routinely recommended in paediatric HRS; discuss with paediatric hepatology.

Route Intravenous bolus or continuous infusion

Duration Continue until serum creatinine falls to within 26.5 µmol/L of baseline, or for a maximum of 14 days

Renal adjustment Not required (drug is not renally cleared)

Hepatic adjustment No dose change; use with caution in severe hepatic failure (haemodynamic instability risk)

PBS status ⛔ Authority Required (Specialist)

Key cautions Risk of pulmonary oedema (monitor daily weight, JVP, SpO₂); digital and peripheral ischaemia; cardiac arrhythmia; abdominal cramping. Contraindicated in severe ischaemic heart disease, peripheral vascular disease, uncontrolled hypertension.

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Albumin (Human, 20%)

Albumex® 20 · Octapharma · Colloid expander

Diagnostic challenge dose 1 g/kg/day IV (max 100 g/day) for 2 days to exclude pre-renal AKI

Treatment dose (with terlipressin) 20–40 g/day IV on days 1–2, then 20–40 g/day as needed while on vasoconstrictor therapy. Adjust based on serum albumin (>30 g/L target) and haemodynamic response.

Route Intravenous infusion (20% solution over 1–4 hours per unit)

Cautions Pulmonary oedema risk — especially in patients with cardiac dysfunction. Monitor fluid balance strictly. Do not use 4–5% albumin (insufficient oncotic pressure for this indication).

PBS status ⚠️ PBS Restricted Benefit (hospital use)

Alternative Vasoconstrictor Regimens

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Noradrenaline

Levophed® · α₁-agonist · ICU only

Adult dose Continuous IV infusion 0.5–3 mg/hr, titrated to achieve MAP increase of ≥10 mmHg from baseline or MAP ≥65 mmHg

Route Central venous catheter (ICU/HDU mandatory)

Combination Always combine with albumin 20–40 g/day IV

Duration Until serum creatinine returns to within 26.5 µmol/L of baseline or up to 15 days

PBS status ✔ PBS General Benefit (hospital)

Note Comparable efficacy to terlipressin in RCTs (Nadim et al., 2023). Preferred in centres without terlipressin access or in patients with cardiac contraindications to terlipressin.

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Midodrine + Octreotide

Gutron® / Sandostatin® · Oral + SC combination

Midodrine adult dose 7.5–12.5 mg PO TDS, titrated to increase MAP by ≥15 mmHg

Octreotide adult dose 100–200 µg SC TDS

Combination Always combine with albumin 20–40 g/day IV

PBS status — Midodrine ⛔ Authority Required (Specialist)

PBS status — Octreotide ⚠️ PBS Restricted Benefit

Efficacy Inferior to terlipressin/noradrenaline in head-to-head trials. Reserved for settings where IV vasoconstrictors are not available or feasible (e.g., rural/remote facilities awaiting transfer).

Medications to Avoid in Cirrhosis with Suspected/Acute HRS

⚠️

NSAIDs (ibuprofen, naproxen, diclofenac) — inhibit renal prostaglandin synthesis, precipitate AKI
ACE inhibitors and ARBs — abolish compensatory angiotensin-II-mediated renal efferent arteriolar tone, causing precipitous GFR decline
Aminoglycosides (gentamicin, tobramycin) — high nephrotoxicity risk in cirrhosis; avoid if any alternative exists
IV contrast — minimise exposure; if essential, pre-hydrate with normal saline and use low-osmolar or iso-osmolar agents only
Lactulose in excessive doses — can cause volume depletion and prerenal azotaemia

Definitive Therapy

Liver Transplantation

Liver transplantation is the only definitive treatment for HRS, restoring portal haemodynamics and reversing the splanchnic vasodilation that drives renal vasoconstriction. All patients with confirmed HRS should be assessed for transplant candidacy at the earliest opportunity.

HRS with recovery on vasoconstrictors: Transplant outcomes approach those of non-HRS patients; renal function often recovers fully post-transplant.
HRS without recovery (persistent AKI on RRT): Consider simultaneous liver–kidney transplant (SLK) if renal failure duration ≥6 weeks on RRT, or pre-existing CKD stage 4–5 (eGFR <30 mL/min for ≥90 days).
SLK rates in Australia are determined by state-based organ allocation services (DonateLife, Transplant Australia). Transplant centres include Royal Prince Alfred (Sydney), Austin Health (Melbourne), Princess Alexandra (Brisbane), Sir Charles Gairdner (Perth), and Flinders Medical Centre (Adelaide).
MELD and MELD-Na scores drive transplant listing priority. HRS patients with hyponatraemia often have very high MELD-Na scores, supporting earlier listing.

Renal Replacement Therapy (RRT)

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RRT is not a treatment for HRS: It does not reverse the underlying pathophysiology. RRT is indicated only as a bridge to liver transplantation in patients with confirmed transplant candidacy. Patients not eligible for transplant should generally not receive RRT for HRS alone; palliative care involvement is recommended.

Key considerations for RRT in HRS:

Continuous renal replacement therapy (CRRT) is preferred over intermittent haemodialysis due to better haemodynamic tolerance in cirrhotic patients.
Anticoagulation: regional citrate anticoagulation is preferred; avoid systemic heparin in patients with coagulopathy or active variceal risk.
Outcomes are significantly worse for patients transplanted while on RRT compared to those transplanted before RRT initiation — this underscores the importance of early vasoconstrictor therapy to prevent progression to dialysis dependence.
Peritoneal dialysis is occasionally used in stable patients but carries high infection risk in ascitic patients.

Emerging Therapies & Evolving Evidence

The therapeutic landscape for HRS is evolving rapidly:

Terlipressin — CONFIRM trial (2021): Established terlipressin + albumin superiority over albumin alone for HRS-AKI reversal, but with a signal of increased respiratory failure risk. Subsequent real-world analyses have refined patient selection (avoid in patients with significant pulmonary or cardiac comorbidities).
Serelaxin: A recombinant relaxin-2 analogue showing promise in early-phase trials for HRS via renal vasodilation; Phase III data pending.
Iptacopan and other complement inhibitors: Under investigation for complement-mediated kidney injury in ACLF-associated HRS; early-phase only.
Artificial liver support systems (e.g., MARS, Prometheus): May reduce bilirubin and ammonia but have not demonstrated survival benefit in HRS specifically; used as bridging in some European and select Australian centres.
Refined SLK criteria: Ongoing debate regarding the duration of RRT required before SLK listing (6-week rule); some centres now advocate earlier SLK for patients with irreversible kidney injury markers (e.g., kidney biopsy showing >30% interstitial fibrosis).

Special Populations

🤰 Pregnancy

Terlipressin: Contraindicated in pregnancy (Category C). Animal studies show uterotonic effects. Use noradrenaline + albumin as alternative if life-threatening HRS.

Albumin: Safe in pregnancy. Use standard dosing.

HRS in pregnancy is exceedingly rare but carries extremely high maternal mortality. Immediate multidisciplinary involvement (obstetrics, hepatology, ICU) is essential. Delivery may be necessary to resolve the underlying hepatic decompensation.

👶 Paediatrics

Paediatric HRS is rare, typically occurring in children with biliary atresia or metabolic liver disease post-Fontan circulation or in decompensated chronic liver disease.

Standard adult vasoconstrictor protocols are not validated in children. Paediatric hepatology and nephrology co-management is mandatory. Terlipressin dosing: limited paediatric data; case reports suggest 20 µg/kg IV bolus then 10 µg/kg/hr infusion.

Paediatric liver transplantation — assess via national transplant services. SLK in paediatrics is exceptionally rare.

👴 Elderly (≥65 years)

Terlipressin: Increased risk of cardiac ischaemia, digital ischaemia, and fluid overload in elderly patients. Start at lower doses (0.5 mg IV bolus) and titrate cautiously. Continuous cardiac monitoring recommended.

Transplant candidacy may be limited by comorbidities rather than age per se. Transplant centres assess physiological age, frailty indices, and social support.

🩺 Pre-existing CKD

Distinguish HRS-AKI superimposed on pre-existing CKD from progressive CKD alone. Vasoconstrictor therapy may still be attempted if acute component is suspected.

Patients with CKD stage 4–5 (eGFR <30 mL/min for ≥90 days) who develop HRS should be listed for simultaneous liver–kidney transplant (SLK).

🛡️ Immunocompromised

Patients on immunosuppression post-liver transplant or for autoimmune hepatitis: HRS risk persists if cirrhosis recurs. Vasoconstrictor therapy follows standard protocols. Ensure no active infection (especially SBP) before immunosuppressive dose adjustment.

Aboriginal and Torres Strait Islander Health Considerations

Aboriginal and Torres Strait Islander Health

Burden of disease

Aboriginal and Torres Strait Islander Australians experience liver-related mortality at 3–4× the rate of non-Indigenous Australians (AIHW, 2023). Cirrhosis is a leading cause of potentially preventable hospitalisations, driven by higher prevalence of harmful alcohol use, hepatitis B (particularly in remote NT communities), hepatitis C, and metabolic syndrome.

Geographic barriers

Many Indigenous Australians live in remote or very remote communities where tertiary hepatology, ICU, and transplant services are unavailable. Retrieval and transfer times may exceed 24–48 hours, during which HRS-AKI can be rapidly fatal. The Royal Flying Doctor Service (RFDS) and remote area health services must have clear escalation pathways for AKI in cirrhotic patients.

Terlipressin access

Terlipressin may not be stocked in remote hospitals or community health centres. Telehealth-guided initiation of midodrine + octreotide + albumin while arranging retrieval is a pragmatic approach. Advocacy for inclusion of terlipressin in remote facility emergency drug kits is ongoing.

Cultural safety

Engagement of Aboriginal Health Workers and Practitioners (AHW/AHPs), use of interpreter services, and recognition of family-centred decision-making processes are essential. Discussions about transplant candidacy, RRT, and end-of-life care must be culturally appropriate and unhurried. Liaison with Aboriginal Liaison Officers at tertiary centres is strongly recommended.

Transplant access

Indigenous Australians are under-represented on transplant waiting lists despite higher liver disease burden. Barriers include geographic isolation, delayed referral, comorbidity burden, and lower rates of formal advance care planning. Initiatives such as the National Indigenous Liver Disease Strategy and state-based ATSI transplant coordinators aim to address these inequities.

Hepatitis B in remote communities

Chronic hepatitis B prevalence in some remote Aboriginal communities exceeds 5% (compared to <1% in non-Indigenous populations). Ensuring HBV screening, vaccination, and antiviral treatment (entecavir, tenofovir — both PBS-listed) is critical for cirrhosis and HRS prevention. RHDAustralia and the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) provide treatment guidelines.

📚 References

1. Angeli P, Ginès P, Wong F, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut. 2015;64(4):531–537.
2. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of decompensated cirrhosis. J Hepatol. 2023;79(2):406–460.
3. Wong F, Pappas SC, Curry MP, et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome (CONFIRM trial). N Engl J Med. 2021;384(9):818–828.
4. Nadim MK, Kellum JA, Davenport A, et al. Hepatorenal syndrome: the 8th International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2012;16(1):R23.
5. Piano S, Schmidt HH, Ariza X, et al. Association between grade of acute on chronic liver failure and response to terlipressin and albumin in patients with hepatorenal syndrome. Clin Gastroenterol Hepatol. 2018;16(11):1792–1800.e3.
6. Singh V, Ghosh S, Singh B, et al. Noradrenaline vs terlipressin in the treatment of hepatorenal syndrome: a randomized study. J Hepatol. 2012;56(6):1293–1298.
7. Australian Institute of Health and Welfare. Liver and biliary disease in Australia. AIHW; 2023. Cat. no. PHE 319.
8. Biggins SW, Angeli P, Garcia-Tsao G, et al. Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome: 2021 Practice Guidance by the American Association for the Study of Liver Diseases. Hepatology. 2021;74(2):1014–1048.
9. Nadim MK, Durand F, Kellum JA, et al. Management of the critically ill patients with cirrhosis: a multidisciplinary perspective. J Hepatol. 2016;64(3):717–735.
10. RHDAustralia (Northern Territory Department of Health). Australian guidelines for the management of hepatitis B in Aboriginal and Torres Strait Islander peoples. 3rd ed. Darwin: RHDAustralia; 2022.
11. Kribben A, Gerken G, Haag S, et al. Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure (HELIOS study): a randomised controlled trial. Lancet. 2012;379(9816):309–316.
12. Australian Commission on Safety and Quality in Health Care. National Safety and Quality Health Service Standards. 2nd ed. ACSQHC; 2021.