Hepatorenal syndrome (HRS-AKI)

Sources:

• ADQI & ICA 2024 Consensus: Acute kidney injury in patients with cirrhosis
• UpToDate: Hepatorenal syndrome: Clinical presentation and diagnosis | Hepatorenal syndrome: Treatment and prognosis
• Core IM Podcast: 5 Pearls Segment on HRS Part 1 | 5 Pearls Segment on HRS Part 2

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Executive Summary: Hepatorenal Syndrome (HRS-AKI)

1. Definition & Pathophysiology

• Core Concept: Functional renal failure caused specifically by AKI on Portal Hypertension. A patient with stable cirrhosis (no ascites) cannot develop HRS.
• Mechanism: Splanchnic vasodilation (Portal HTN) $\to$ Effective arterial underfilling $\to$ Severe renal vasoconstriction (RAAS/Sympathetic drive).

2. Diagnostic Criteria (2024 ADQI/ICA Update)

• Volume Challenge Update: The mandatory 48-hour albumin challenge is REMOVED.
  • Rule: Assess response to volume within 24 hours. If volume replete, initiate vasoconstrictors immediately.
• Baseline Creatinine Hierarchy:
  1. Lowest stable Cr in last 3 months (Preferred).
  2. Last 12 months.
  3. Admission Cr OR Back-calculation (eGFR 75).
• Differential Diagnosis:
  • HRS: Urine Na $<10–20$; FeNa $<0.2\%$; Bland sediment.
  • ATN: Urine Na $>40$; FeNa $>1\%$; Muddy brown casts.
  • Prerenal: Responds to fluids (HRS does not).

3. Management (Canadian Standard of Care)

• Hemodynamic Goal: Raise MAP by $10–15\text{ mmHg}$ (or target $>65\text{ mmHg}$) to restore renal autoregulation.

Agent	Status in Canada	Clinical Pearls
Norepinephrine	First Line	• Standard of Care in Canadian ICUs (Terlipressin unavailable). • Respiratory Safety: Positive inotropy helps heart handle increased afterload; avoids pulmonary venoconstriction.
Midodrine + Octreotide	Second Line	• Significantly inferior efficacy. • Use only as bridge to ICU or if ICU is inappropriate (Ward setting).
Terlipressin	Gold Standard	• Unavailable in Canada (Special Access only). • Contraindications: Hypoxia ($Sp{O}_2<90\%$), ACLF Grade 3, Ischaemia. • Risk: Respiratory failure.

• Albumin Safety: Administer only to achieve euvolemia. STOP immediately if volume overloaded. Systematic/fixed dosing causes respiratory failure.

4. Liver Transplantation & Prognosis

• Simultaneous Liver-Kidney (SLK) Criteria (Irreversibility):

  • HRS-AKD: Dialysis or eGFR $\le 25$ for $\ge 6$ weeks.

  • HRS-CKD: eGFR $\le 60$ for $>90$ days.

• Safety Net Policy: If Liver Transplant Alone is performed and kidneys fail (Dialysis/GFR<20) between 60–365 days post-op $\to$ Priority Kidney Listing.

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1. Pathophysiology: AKI on Portal Hypertension

Core Concept: HRS is functional renal failure resulting from haemodynamic changes driven by portal hypertension. It is distinct from structural kidney injury.

• Reframing: Think of HRS as AKI on Portal Hypertension rather than AKI on Cirrhosis. A patient with stable, compensated cirrhosis (no ascites/portal HTN) cannot develop HRS.

Mechanism Sequence:

1. Splanchnic Vasodilation: Portal hypertension triggers the release of vasodilators (e.g., Nitric Oxide) in the splanchnic circulation.
2. Arterial Underfilling: Pooling of blood in the gut reduces effective arterial blood volume.
3. Neurohormonal Activation: The kidneys perceive “hypovolaemia” and activate vasoconstrictor systems (RAAS, Sympathetic Nervous System, Arginine Vasopressin) to maintain blood pressure.
4. Renal Vasoconstriction: These systems cause severe clamping of renal vessels, leading to 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: An inability to increase cardiac output in response to stress contributes to renal hypoperfusion.

Precipitants:

• Infections (SBP is #1), GI bleeding, alcoholic hepatitis, and rapid volume depletion (over-diuresis, diarrhoea).
• NSAIDs: Cirrhotic kidneys rely entirely on prostaglandins to maintain afferent arteriolar patency against the high vasoconstrictor drive. NSAIDs remove this defence, precipitating immediate failure.

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2. Diagnosis (Updated 2024 Criteria)

Diagnosis is one of exclusion.

A. Terminology Update (2024 ADQI/ICA)

• HRS-AKI: Acute form (definitions below).
• HRS-AKD (Acute Kidney Disease): HRS lasting $<90$ days.
• HRS-CKD (Chronic Kidney Disease): HRS lasting $\ge 90$ days.
• The terms “Type 1” and “Type 2” are obsolete.

B. Establishing Baseline Creatinine

The 2024 consensus recommends this hierarchy to determine the reference Serum Cr:

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 the admission Cr OR a back-calculation using an eGFR of $75{\text{ mL/min/1.73 m}}^2$.

C. Diagnostic Criteria (ADQI / ICA 2024)

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

1. Cirrhosis with Ascites.
2. AKI Diagnosis (KDIGO):
   • Increase in Serum Cr $\ge 26.5\mu \text{mol/L}$ 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 (Note: use with caution as baseline UO is often low in cirrhosis).
3. No Response to Volume Resuscitation (The “24-Hour” Rule):
   • Absence of improvement in Serum Cr or UO within 24 hours following adequate volume resuscitation. The mandatory 48-hour albumin challenge is removed. If a patient is volume replete, do not delay vasoconstrictors.
4. Absence of Alternative Causes:
   • No shock; no nephrotoxins; no structural signs (Proteinuria $>500$ mg/day, Microhaematuria $>50$ RBC/hpf).

D. Differential Diagnosis

Clinical Pearls:

• Blood Pressure: If BP is elevated/normal-high, HRS is unlikely. Caveat that average MAP in HRS is $\sim 76\text{ mmHg}$; patient’s baseline BP should be taken into account.
• Serum Na: Normal/High Na ($>140\text{ mmol/L}$) argues against HRS (high ADH should cause hyponatraemia).
• Biomarkers:

Feature	Prerenal AKI	ATN	HRS-AKI
History	Fluid loss	Shock, toxins	Worsening portal HTN
Urine Na	$<20\text{ mmol/L}$	$>40\text{ mmol/L}$	$<10-20\text{ mmol/L}$
FeNa	$<1\%$	$>1-2\%$	$<0.1-0.2\%$
Urinalysis	Bland	Muddy Brown Casts	Bland
Response to Albumin	Improves	No improvement	No improvement

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3. Prevention

The 2024 consensus emphasizes “Kidney-Liver Health” assessment to identify risks.

• Albumin Indicated:
  • SBP: $1.5\text{ g/kg}$ day 1, $1.0\text{ g/kg}$ day 3.
  • Large Volume Paracentesis: $6–8\text{ g}$ per litre removed if $>5\text{ L}$ removed.
• Albumin NOT Indicated:
  • Systematic use for non-SBP infections (risk of pulmonary oedema with no survival benefit).
  • To correct hypoalbuminaemia solely to maintain levels $>30\text{ g/L}$.

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4. Management

Primary Goal: Initiate therapy immediately (do not wait 48h if volume replete). Target a rise in MAP of $10–15\text{ mmHg}$ (or to $>65\text{ mmHg}$).

A. Pharmacotherapy

1. Norepinephrine (Practical First Line)

• Role: The standard of care in Canadian ICUs (as Terlipressin is unlicensed/unavailable).
• Setting: Requires ICU admission and central venous access.
• Dosing: Continuous infusion ($0.5–3\text{ mg/hr}$) titrated to raise MAP by $10–15\text{ mmHg}$ (or target $>65\text{ mmHg}$).
• Evidence:
  • Efficacy: Meta-analyses suggest non-inferiority to Terlipressin for HRS reversal.
  • Safety (Respiratory Sparing): Lower risk of respiratory failure compared to Terlipressin due to distinct haemodynamics:
    • Terlipressin (V1 Agonist): Causes profound systemic vasoconstriction (increased Afterload/SVR) and splanchnic-to-central blood shifting (increased Preload). Crucially, it lacks inotropic properties, meaning the heart must pump against this sudden high resistance, precipitating pulmonary oedema. It may also cause direct pulmonary venoconstriction.
    • Norepinephrine (${\alpha }_1+{\beta }_1$ Agonist): While it also increases Afterload (${\alpha }_1$), its ${\beta }_1$-adrenergic effect provides positive inotropy (increased contractility), allowing the heart to compensate for the increased resistance. It also 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: $5–15\text{ mg}$ PO q8h (titrate to max tolerated BP).
  • Octreotide: $100–200\mu \text{g}$ SC q8h (or $50\mu \text{g/hr}$ IV).

3. Terlipressin (Evidence-Based Gold Standard)

• Status: The Gold standard globally (CONFIRM trial), but restricted in Canada (requires Special Access Programme).
• Dosing: Continuous IV infusion preferred (start $2\text{ mg/day}$, max $12\text{ mg/day}$).
• The CONFIRM Trial & Albumin Warning: (CONFIRM trial)
  • The Lesson: The CONFIRM trial showed a high rate of respiratory failure (14% vs 5%). Retrospective analysis suggests this was partly driven by the rigid protocol which mandated albumin dosing regardless of volume status.
  • The “Two-Hit” Injury: Respiratory failure likely resulted from the combination of Drug Effect (Terlipressin increasing preload/afterload) PLUS Protocol Effect (Excessive Albumin causing volume overload).
  • Albumin should be administered only to achieve euvolemia, then STOPPED.
• Crucial Contraindications:
  • Respiratory: Hypoxia ($Sp{O}_2<90\%$) or ACLF Grade 3 ($\ge 3$ organ failures).
  • Renal: Serum Cr $>440\mu \text{mol/L}$ ($5\text{ mg/dL}$).
  • Vascular: Severe ischaemic disease.

B. Adjunctive Albumin

• Dosing: $20–40\text{ g/day}$.
• Safety: Dose must be adjusted daily. STOP immediately if signs of volume overload or pulmonary oedema develop.
• Pearl: “No BP, No PP” – Diuretics often fail in HRS. Once MAP is raised by vasoconstrictors, diuretics can be reintroduced to manage volume overload.

C. Stopping Rules

Discontinue therapy if:

1. Success: Serum Cr returns to within $26.5\mu \text{mol/L}$ of baseline.
2. Futility: No improvement after 48 hours on maximum dose (or 3 days depending on guideline).
3. Safety: Severe adverse reaction (ischaemia, pulmonary oedema).
4. Duration: Maximum 14 days.

D. Other Interventions

• TIPS: Not recommended for HRS-AKI treatment (risk of heart failure/liver ischaemia).
• Beta-Blockers: Typically stopped during HRS-AKI as they interfere with MAP targets.

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5. Transplant (SLK) & Prognosis

Liver Transplantation is the definitive treatment for HRS. The decision to include a kidney (Simultaneous Liver-Kidney or SLK) depends on whether the renal failure is deemed irreversible.

A. SLK Listing Criteria (Defining “Irreversibility”)

Current policy uses time-based cut-offs to determine if the kidneys are salvageable.

1. HRS-CKD (Chronic Permanent Damage):
   • Definition: Renal dysfunction lasting $>90$ days.
   • SLK Criterion: eGFR $\le 60\text{ mL/min}$ for $>90$ days PLUS (ESRD on dialysis or eGFR $\le 30$ at listing).
2. HRS-AKD (Prolonged Acute/Subacute Damage):
   • Definition: Renal dysfunction lasting between 7 and 90 days.
   • SLK Criterion: Sustained AKI (Dialysis or eGFR $\le 25\text{ mL/min}$) for $\ge 6$ consecutive weeks.
   • Rationale: After 6 weeks of deep renal failure, native recovery post-liver transplant is highly unlikely, justifying a double transplant.

B. Safety Net Policy

• Context: For patients with HRS-AKI or HRS-AKD who do not meet the 6-week SLK cutoff but receive a Liver Transplant alone.
• Policy: If they remain on dialysis or have eGFR $<20\text{ mL/min}$ between 60–365 days post-transplant, they receive priority access to a kidney transplant (correcting the “under-transplantation” risk).

C. Prognosis & Palliative Care

• Context: Patients with HRS-AKI who are not transplant candidates.
• Outcomes:
  • With Dialysis: Survival is typically 3–6 months (often a “bridge to nowhere”).
  • Without Dialysis: Survival is measured in days to weeks.
• In severe HRS-AKI, systemic BP is often too low to tolerate haemodialysis (intradialytic hypotension), making RRT technically impossible even if desired.

D. Post-Discharge Follow-Up

• Goal: Detect the transition from HRS-AKI (reversible) $\to$ 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.