hepatorenal syndrome

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pathophysiology

mechanism:

1. splanchnic vasodilation — portal hypertension triggers vasodilator release (nitric oxide) in the splanchnic circulation
2. arterial underfilling — blood pools in the gut, reducing effective arterial blood volume
3. neurohormonal activation — kidneys perceive hypovolaemia → activate RAAS, sympathetic nervous system, arginine vasopressin
4. renal vasoconstriction — severe clamping of renal vessels → reduced GFR
5. systemic inflammation — bacterial translocation and PAMPs (pathogen-associated molecular patterns) drive cytokine release, causing microcirculatory dysfunction and direct tubular injury
6. cirrhotic cardiomyopathy — inability to increase cardiac output in response to stress contributes to renal hypoperfusion

precipitants: infections (SBP is #1), GI bleeding, alcoholic hepatitis, rapid volume depletion (over-diuresis, diarrhoea)

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diagnosis (2024 ADQI/ICA criteria)

A diagnosis of exclusion.

terminology update

• HRS-AKI — acute form (criteria below)
• HRS-AKD (acute kidney disease) — HRS lasting <90 days
• HRS-CKD (chronic kidney disease) — HRS lasting ≥90 days
• the terms “type 1” and “type 2” are obsolete

establishing baseline creatinine

The ADQI/ICA 2024 consensus recommends this hierarchy:

1. preferred: lowest stable value in the previous 3 months
2. alternative: most recent stable value within the last 12 months
3. if no history: use the lower of admission Cr OR back-calculation using eGFR of $75 \text{ mL/min/1.73 m}^2$

diagnostic criteria

To diagnose HRS-AKI, the patient must meet all of the following:

1. cirrhosis with ascites
2. AKI diagnosis (KDIGO):
   • increase in serum Cr $\ge 26.5 \text{ } \mu\text{mol/L}$ within 48h OR $\ge 50\%$ increase from baseline within 7 days
   • and/or urine output $\le 0.5 \text{ mL/kg/h}$ for $\ge 6$ hours (use with caution — baseline UO is often low in cirrhosis)
3. no response to volume resuscitation within 24 hours:
   • withdraw diuretics and administer albumin ($1 \text{ g/kg/day}$, max 100 g) as the volume challenge
   • if already volume replete (clinical assessment, no evidence of hypovolaemia), initiate vasoconstrictors immediately — do not delay

4. absence of alternative causes:
   • no shock; no nephrotoxins; no structural signs (proteinuria >500 mg/day, microhaematuria >50 RBC/hpf)

differential diagnosis

feature	prerenal AKI	ATN	HRS-AKI
history	fluid loss	shock, toxins	worsening portal HTN
urine Na	<20 mmol/L	>40 mmol/L	<10–20 mmol/L
FeNa	<1%	>1–2%	<0.1–0.2%
urinalysis	bland	muddy brown casts	bland
response to volume	improves	no improvement	no improvement

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prevention

The 2024 consensus emphasises “kidney-liver health” assessment to identify risks.

albumin indicated:

• spontaneous bacterial peritonitis: $1.5 \text{ g/kg}$ day 1, $1.0 \text{ g/kg}$ day 3
• large volume paracentesis: $6\text{–}8 \text{ g}$ per litre removed if >5 L removed

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management

primary goal: initiate therapy immediately (do not wait 48h if volume replete). Target a rise in MAP of 10–15 mmHg (or to >65 mmHg).

pharmacotherapy

1. norepinephrine — first-line in Canada (terlipressin unavailable)

• setting: requires ICU admission and central venous access
• dosing: continuous infusion ($0.5\text{–}3 \text{ mg/hr}$) titrated to raise MAP by 10–15 mmHg (or target >65 mmHg)
• evidence: meta-analyses suggest non-inferiority to terlipressin for HRS reversal (Olson, PLoS One. 2024; Pitre, Crit Care Med. 2022)
• respiratory safety: lower risk of respiratory failure vs terlipressin — $\beta_1$ inotropy allows the heart to compensate for increased afterload, and norepinephrine lacks specific pulmonary vasoconstrictive effects

2. midodrine + octreotide — ward/bridge therapy

• role: significantly inferior efficacy. Use only if:
  • patient is awaiting ICU transfer (bridge)
  • ICU admission is deemed inappropriate (goals of care)
• dosing:
  • midodrine: $5\text{–}15 \text{ mg}$ PO q8h (titrate to max tolerated BP)
  • octreotide: $100\text{–}200 \text{ } \mu\text{g}$ SC q8h (or $50 \text{ } \mu\text{g/hr}$ IV)

3. terlipressin — evidence-based gold standard

• status: gold standard globally (CONFIRM trial, NEJM 2022), but restricted availability in Canada
• dosing: continuous IV infusion preferred (start $2 \text{ mg/day}$, max $12 \text{ mg/day}$)
• mechanism risk vs norepinephrine:
  • terlipressin (V1 agonist): profound systemic vasoconstriction (↑ afterload/SVR) and splanchnic-to-central blood shifting (↑ preload). Lacks inotropic properties → heart cannot compensate → precipitates pulmonary oedema. May cause direct pulmonary venoconstriction
  • norepinephrine ($\alpha_1 + \beta_1$): while also ↑ afterload ($\alpha_1$), $\beta_1$ provides positive inotropy → heart compensates for increased resistance

adjunctive albumin

• dosing during vasoconstrictor therapy: $20\text{–}50 \text{ g/day}$ (AASLD 2021: $1 \text{ g/kg}$ day 1, then $40\text{–}50 \text{ g/day}$; lower end $20\text{–}40 \text{ g/day}$ may be appropriate depending on volume status)
• diagnostic challenge (older criteria): $1 \text{ g/kg/day}$ × 2 days (max 100 g/day) — no longer mandatory under 2024 criteria

stopping rules

discontinue therapy if:

1. success: serum Cr returns to within $26.5 \text{ } \mu\text{mol/L}$ of baseline
2. futility: no improvement after 4 days on maximum tolerated dose (AASLD 2021)
3. safety: severe adverse reaction (ischaemia, pulmonary oedema)
4. duration: maximum 14 days

other interventions

• TIPS: not recommended for HRS-AKI (risk of heart failure/liver ischaemia)
• beta-blockers: hold when MAP <65 mmHg or AKI develops (AASLD 2021); reassess after recovery

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transplant & prognosis

Liver transplantation is the definitive treatment. The decision to include a kidney (simultaneous liver-kidney or SLK) depends on whether the renal failure is deemed irreversible.

SLK listing criteria (defining “irreversibility”)

HRS-CKD (chronic permanent damage):

• renal dysfunction lasting >90 days
• SLK criterion: eGFR ≤60 mL/min for >90 days plus (ESRD on dialysis or eGFR ≤30 at listing)

HRS-AKD (prolonged acute/subacute damage):

• renal dysfunction lasting 7–90 days
• SLK criterion: sustained AKI (dialysis or eGFR ≤25 mL/min) for ≥6 consecutive weeks
• rationale: after 6 weeks of deep renal failure, native recovery post-liver transplant is highly unlikely

safety net policy

For patients with HRS-AKI or HRS-AKD who do not meet the 6-week SLK cutoff but receive a liver transplant alone:

• if they remain on dialysis or have eGFR <20 mL/min between 60–365 days post-transplant → priority access to a kidney transplant

prognosis & palliative care

For patients with HRS-AKI who are not transplant candidates:

• with dialysis: survival typically 3–6 months (often a “bridge to nowhere”)
• without dialysis: survival measured in days to weeks
• even vasoconstrictor responders have high short-term mortality without transplant — HRS-AKI should trigger urgent transplant evaluation in all eligible patients
• in severe HRS-AKI, systemic BP is often too low to tolerate haemodialysis (intradialytic hypotension), making RRT technically impossible

post-discharge follow-up

• goal: detect transition from HRS-AKI (reversible) → HRS-CKD (permanent)
• action: assess “kidney-liver health” within 1 month of discharge
• tool: use cystatin C where possible; serum creatinine underestimates dysfunction due to sarcopenia