Hepatorenal Syndrome

AKI & Hepatorenal Syndrome (HRS) – Garren Montgomery


  • Circulatory dysfunction: Portal HTN causes shear stress on portal vessels; endothelium releases vasodilators (NO, prostanoids). This causes splanchnic vasodilation and reduced effective blood volume (decreased MAP) which activates RAAS and the sympathetic nervous system. This results in avid sodium and water retention and severe renal vasoconstriction.
  • Inflammation: Bacterial translocation (as seen in SBP) results in increased circulating pro-inflammatory cytokines which can worsen splanchnic vasodilation and also thought to act directly on proximal tubular cells to cause further intrarenal RAAS activation and GFR
  • Definitions:
    • HRS-AKI (formerly type I HRS): Absolute # in Cr ≥0.3 mg/dl within 48h OR Percent # in Cr ≥50% using last available value of outpatient Cr within 3 months as baseline
      • HRS-NAKI (“non-AKI”): (formerly type II HRS):
      • HRS-AKD: eGFR<60 for <3 months in absence of other structural causes OR Percent # in Cr ≤50% using last available Cr over last 3 months as baseline
      • HRS-CKD: eGFR<60 for 3 months in absence of other structural causes
  • Diagnostic Criteria
    • Presence of cirrhosis with ascites
    • Diagnosis of AKI (see above)
    • No response or inadequate response at 48 hrs after volume expansion w/ albumin and withdrawal of diuretics
    • Absence of shock
    • No current or recent use of nephrotoxic drugs
    • Absence of proteinuria (<500 mg/d), absence of hematuria (<50 RBCs per HPF), normal renal ultrasound (this criterion would not be included if patient has known CKD such as diabetic or hypertensive nephropathy)
    • Suggestion of renal vasoconstriction with FeNa <0.2, FeUrea <20 (most sensitive diagnostic measure). UNa <20 is suggestive but not diagnostic given baseline sodium avidity in cirrhosis and inability to calculate FeNa
    • Cut off for ATN in cirrhosis is a FeNa >0.5, rather than 1 in the general population



  • Step 1: Exclude other obvious causes of renal injury
    • DDx: Pre-renal (most common), ATN (2nd most common), AIN, bile cast nephropathy, IgA nephropathy, cryoglobulinemia/MPGN (HCV), membranous nephropathy (HBV), post renal (rare)
    • Common precipitants of AKI: infection, overdiuresis, GI bleeding, recent LVP without subsequent volume expansion, nephrotoxic drugs/NSAIDs
    • Workup: BMP, UA w/ microscopy, Urine electrolytes (FeNa, FeUrea), urine protein/Cr ratio, renal ultrasound (to assess for chronicity) 
  • Step 2: Diuretic cessation/albumin challenge
    • STOP all diuretics, beta blockers, NSAIDs, ACE/ARBs, anti-hypertensives, vasodilators, nephrotoxins
    • START volume expansion with albumin 1g/kg/day (up to a max of 100 g/day) for 2 consecutive days
    • Infection is a common precipitant of HRS, assess for ascites and perform diagnostic para to r/o SBP
  • Step 3: Diagnosis of HRS
    • If no other clear cause of AKI is identified and SCr has not improved after 48 hours of diuretic cessation and volume expansion proceed promptly to treatment. If suspicion for HRS is high, therapy can be started before the 48h mark



  • Pharmacologic therapies: (in order of preference):
  • Terlipressin + albumin. Most effective combo based on clinical trials but not yet available in the U.S.
  • Norepinephrine (NE, levophed) + albumin (25-50 g/day).
    • Most likely to be used at VUMC, requires central access (PICC vs triple lumen) but can be administered on stepdown unit/8MCE.
    • Guidelines recommend NE to be dosed at 0.5-3 mg/hr. Would ask fellow, attending or pharmacist for baseline. VUMC protocol for ICU and stepdown:
      • Start NE gtt at 3mcg/min. If UOP is <200 or MAP <10mm Hg from baseline, increase gtt by 3mcg increments until those goals are met or max 20 mcg/min
      • Albumin will continue to be infused at 50gm per day until replete and then stopped or modified depending on decision on rounds.
      • The use of furosemide to supplement volume removal will be made on a clinical basis on rounds by the attending and resident on service.
  • Continue to hold diuretics. LVP is still generally considered safe even in HRS if indicated by tense ascites. This can be attending specific and would confirm prior to performing.
  • Therapy is generally continued until HRS is reversed or the hepatology attending deems it refractory to medical treatment
  • Complete response to therapy defined as return of SCr within 0.3 mg/dL of baseline
  • Patients with HRS-NAKI (formerly type II HRS) may respond to the above therapies, but recurrence of renal dysfunction after withdrawal of vasoconstrictors is the norm and thus current guidelines do not recommend them for this scenario
  • TIPS: Generally contraindicated for most HRS pts given high MELD scores and not much data to support its use, but may improve renal function in patients with HRS-NAKI with refractory ascites
  • RRT: Dialysis can be considered for those who fail to respond to pharmacologic therapy, particularly as a bridge to liver transplant. Decision to initiate should be individualized
  • Liver transplant: The best and most definitive treatment regardless of response to pharmacologic therapy


Prevention of HRS:

  • Ensure that pts receive albumin after LVP and when diagnosed with SBP. Ensure pts with cirrhosis with suspected UGIB receive ppx abx
  • Avoid NSAIDs. Stop ACE/ARBs if possible. Stop beta blockers in patients with refractory ascites and AKI, hyponatremia or hypotension.