Hepatorenal syndrome

Table 1 Clinical types of HRS

Type 1

(1) 100% increase in serum creatinine to a level higher than 2.5 mg/dL or a 50% reduction of the initial 24-h creatinine clearance to a level

(2) Very poor short-term outcome

Type 2

(1) Serum creatinine > 1.5 mg/dL, without meeting the criteria for type 1 HRS

(2) Refractory ascites is usually present

(3) Prognosis is not as poor as with type 1

Table 2 Diagnostic criteria of hepatorenal syndrome¹

Major criteria (all must be present for the diagnosis of HRS)

(1) Advanced hepatic failure (acute or chronic liver disease) and portal hypertension

(2) Low GFR defined as serum creatinine > 1.5 mg/dL or creatinine clearance < 40 mL/min

(3) Absence of shock, significant volume losses, ongoing infection, or treatment with nephrotoxic medications

(4) Absence of a sustained improvement in renal function after cessation of diuretics and expansion of plasma volume with 1.5 L of isotonic fluids

(5) Urine protein excretion < 500 mg/dL with no ultrasonographic evidence of obstruction or parenchymal renal disease

Additional criteria (not necessary for the diagnosis, but provide supportive evidence)

(1) Urine volume < 500 mL/d

(2) Urine sodium < 10 mEq/L

(3) Urine osmolality greater than plasma osmolality

(4) Urine red blood cells < 50 per high-power field

(5) Serum sodium concentration < 130 mEq/L

¹Adapted from Arroyo et al[2].

Table 3 Non-invasive therapies

Authorand Year	n (# Type 1,# Type 2)	Study design	Intervention	Outcomemeasures	MeanbaselineSCr	Meanfollow-upSCr	Other results	Comments
Moreau et al[38] 2002	99 (99/0)	Multicenter, retrospective	Terlipressin (75% received albumin)	Reduction of SCr to < 130 μmol/L or a decrease of at least 20% at end of treatment)	272 ± 114 μmol/L	Responders: 138 ± 59 μmol/L Nonresponders: 382 ± 210 μmol/L	Renal function improved in 58% of patients.	Twenty-three patients had adverse events that may have been terlipressin-related. Three patients required RRT 40% survival at 1 mo.
Kiser et al[44] 2005	43 (32/11)	Observational (retrospective cohort)	Vasopressin (AVP) vs octreotide vs combination	Clinical response; SCr 1.5 mg/dL or less	3.9 ± 3.3 mg/dL	Responders: SCr decreased by 62% ± 9% Nonresponders: SCr increased by 46% ± 119%	42% complete response with AVP vs 38% with AVP and octreotide vs 0% with octreotide alone.	No adverse effects related to AVP. RRT rates: 50% in AVP group, 58% in combination group, and 31% in octreotide alone group.
Solanki et al[43] 2003	24 (24/0)	Randomized placebo- controlled single-blind	Terlipressin vs placebo (all patients received albumin) for 4-15 d	Reversal of HRS and survival at 15 d	Terlipressin: 2.9 ± 0.1 mg/dL Placebo: 2.2 ± 0.2 mg/dL	Terlipressin: 1.2 ± 0.2 mg/dL at d 15 Placebo: no survival at d 15 (SCr 3.9 ± 0.2 mg/dL on d 8)	In terlipressin group, 5 of 12 patients survived. None survived by d 15 in placebo group.
Ortega et al[39] 2002	21 (16/5)	Prospective, nonrandomized	Terlipressin with albumin vs without albumin for 4-14 d	SCr 1.5 mg/dL or lower	Terlipressin with albumin: 3.6 ± 1.5 mg/dL Terlipressin without albumin: 3.4 ± 0.3 mg/dL	Terlipressin with albumin: 1.5 ± 0.2 mg/dL Terlipressin without albumin: 3.4 ± 0.7 mg/dL	10 of 13 patients who received terlipressin and albumin responded. Of 8 patients who received terlipressin alone, 2 responded.	One patient had ischemic side effects (finger ischemia). At 1 mo, there was a 5% recurrence of HRS after complete response.
Pomier- Layrargues et al[61] 2003	19 (NS)	Randomized, double-blind, placebo- controlled, crossover	Placebo, then octreotide (Group 1) vs octreotide, then placebo (Group 2) (all patients received albumin)	20% decrease in SCr after 4 d	Group 1: 215 ± 32 μmol/ Group 2: 208 ± 16 μmol/L	Group 1: 222 ± 41 μmol/L after placebo; 270 ± 54 μmol/L after octreotide Group 2: 194 ± 34 μmol/L after octreotide; 204 ± 47 μmol/L after placebo	Treatment with octreotide was not effective.	The study included types 1 and 2 HRS patients (numbers in each group not specified). No side effects reported.
Colle et al[42] 2002	18 (18/0)	Chart review (retrospective analysis)	Terlipressin (some patients received albumin)	Decrease in SCr to < 130 μmol/L or decrease of at least 20% leading to a stable value; evaluation of predictive factors	Patients with improved SCr: 276 ± 47 μmol/L1 Patients without improved SCr: 295 ± 891μmol/L	Patients with improved SCr: 130 ± 13 μmol/L Patients with improved SCr: 411 ± 89 μmol/L	11 patients had improved renal function	Some of these patients were included in the Moreau study. Patients with improved renal function had less severe cirrhosis than patients without. Patients without a precipitating factor for HRS or who responded to terlipressin were more likely to survive.
Halimi et al[41] 2002	18 (16/2)	Multicenter pilot (retrospective)	Terlipressin for 2-16 d	> 30% decrease in baseline SCr	298 ± 124 μmol/L	145 ± 85 μmol/L	13 of 18 had improved renal function; 8 had a normal SCr at d 5	Three patients had ischemic side effects. One had severe bronchospasms after terlipressin administration, and subsequently died.
Guevara et al[49] 1998	16 (Type NS)	Open pilot study	Ornipressin and albumin for 3 vs 15 d	Efficacy	3-d arm: 2.9 ± 0.5 mg/dL 15-d arm: 3.0 ± 0.5 mg/dL	3-d arm: 2.2 ± 0.4 mg/dL 15-d arm: 0.7 ± 0.1 mg/dL	75% of patients had improved renal function.	Treatment was stopped in 4 patients on the 15-d protocol because of ischemic complications.
Angeli et al[62] 1999	13 (13/0)	Nonrandomized	Dopamine and albumin (Group A) vs midodrine, octreotride, and IV albumin (Group B)	Efficacy	Group A: 3.6 ± 0.6 mg/dL Group B: 5.0 ± 0.9 mg/dL	Group A: 5.1 ± 1.5 mg/dL at 15 d (only 1 patient survived to d 20) Group B: 3.3 ± 0.7 mg/dL at 20 d	All Group B patients had improved GFR. 7 of 8 patients in Group A had worsening renal function and died.	No significant side effects.
Holt et al[33] 1999	12 (NS)	Open label	N-acetylcysteine for 5 d	Efficacy	222 ± 27 μmol/L	169 ± 7 μmol/L		67% survival at 1 mo, and 58% at 3 mo (2 patients received liver transplants).
Mulkay et al[40] 2001	12 (12/0)	Pilot	Terlipressin for 1 wk to 2 mo	Safety and efficacy	3.4 mg/dL	1.8 mg/dL		Three patients received liver transplants, and had near-normal renal function. The other 9 died during follow-up. No ischemic complications.
Duvoux et al[48] 2002	12 (12/0)	Pilot	Noradrenalin (NA), albumin, and furosemide for at least 5 d	Safety and efficacy	2.6 ± 1.1 mg/dL pre- furosemide/ albumin; 3.9 ± 1.8 mg/dL after infusion (pre-NA)	1.6 ± 0.8 mg/dL	Reversal of HRS in 10 of 12 patients	Two patients had previously received terlipressin (underwent 48-h washout before starting NA). Transient myocardial ischemia was observed in 1 patient.
Hadengue et al[63] 1998	9 (9/0)	Double-blind, short-term, controlled crossover study	Terlipressin and placebo for 2 d in randomized order	Efficacy	Baseline CrCl: 15 ± 2 mL/min	CrCl after terlipressin (includes both groups): 27 ± 4 mL/min CrCl after placebo (includes both groups): 16 ± 3 mL/min		No side effects reported.
Uriz et al[37] 2000	9 (6/3)	Pilot	Terlipressin with albumin for 5-15 d	Reduction of serum creatinine to < 1.5 mg/dL	3.9 ± 0.7 mg/dL	1.5 ± 0.2 mg/dL	Reversal of HRS in 7 of 9 patients.	One patient did not complete the study due to pancreatitis. No ischemic complications.
Angeli et al[45] 1998	8 (0/8) + 17 cirrhotic patients without HRS	Open label	Midodrine (one dose)	Renal function and renal hemo- dynamics (acute effects)	GFR: 39.0 ± 6.4 mL/min	GFR: 45.1 ± 7.6 mL/min	No significant acute effect on renal hemodynamics or renal function.	This study looked at the acute effect of one dose of midodrine. The results include cirrhotic patients without HRS.
Gulberg et al[64] 1999	7 (7/0)	Nonrandomized	Orinpressin, dopamine, and albumin for 5-27 d	2× increase in Crcl (to > 40 mL/min)	Treatment success group: 4.6 ± 0.9 mg/dL, and improved to 1.3 ± 0.2 mg/dL	Treatment success group: 1.3 ± 0.2 mg/dL	HRS was reversed in 4 of 7 patients	Two responders had a relapse. One of them responded to retreatment, but treatment was stopped in the other because of a ventricular tachyarrhythmia. Treatment was stopped in another patient because of intestinal ischemia.
Kaffy et al[65] 1999	5 (NS)	Pilot	Octreotide for 5 d	Efficacy	194 μmol/L in 4 patients	96 μmol/L in 4 patients	Improvement of SCr in 4 of 5 patients,	but 4 of 5 patients eventually died. HRS rapidly recurred when octreotide was stopped, and did not respond to further octreotide infusion.

SCr: Serum Creatinine; RRT: Renal replacement therapy; NS: Not Specified; CrCl: Creatinine Clearance. Cr conversion from μmol/L to mg/dL: divide by 88.4.

Table 4 Invasive therapies

Author andYear	N (# Type 1,# Type 2)	Study design	Intervention	Outcomemeasures	Meanbaseline SCr	Meanfollow-up SCr	Other results	Comments
Brensing et al[50] 2000	31 (14/17); an additional 10 were too sick to receive TIPS	Phase II	TIPS	Safety and survival	(Of the 31 patients who received TIPS) 2.3 ± 1.7 mg/dL	Wk 4: 1.5 ± 1.2 mg/dL	Renal function improved within 2 wk after TIPS and subsequently stabilized.	Three-month survival rate was 81% (10% of non- shunted patients survived, but they were felt to be too sick to receive TIPS). There was 1 TIPS-related death.
Wong et al[46] 2004	14 (14/0)	Prospective	Midodrine, octreotide, albumin, and TIPS	Efficacy (serum creatinine < 135 μmol/L for at least 3 d)	Responders: 233 ± 29 μmol/L Nonresponders: 345 ± 83 μmol/L	Responders: 112 ± 8 μmol/L after medical therapy Nonresponders: 476 ± 139 μmol/L after medical therapy.	Renal function improved in 10 of 14 patients (71%) with medical therapy. Five responders received TIPS; their renal function continued to improve. Mean GFR was 96 ± 20 mL/min by 12 mo post-TIPS.	TIPS was performed in responders who were stable. Two of the five responders who did not receive TIPS underwent liver transplantation, and their SCr remained normal at the time of liver transplantation.
Alessandria et al[36] 2002	16 (0/11, and an additional 5 with “organic renal disease”)	Prospective, nonrandomized	Terlipressin for 7 d (and TIPS in stable patients)	Efficacy	2.4 ± 0.9 mg/dL	After terlipressin therapy: 1.8 ± 0.8 mg/dL After TIPS: 1.4 ± 0.3 mg/dL	Terlipressin: 8 of 11 HRS patients had improved renal function (and 7 of the 8 responders had reversal of HRS (SCr < 1.5 mg/dL) Subsequent TIPS: 8 of 9 patients (89%) who underwent TIPS had improved renal function by 1 mo.	Renal function improved significantly after TIPS in all patients who responded to terlipressin. One HRS patient who did not respond to terlipressin underwent TIPS and responded. In the non-HRS group (with “organic renal disease”, only one patient had an improved SCr (from 3.7 to 1.8 mg/dL) with terlipressin treatment.
Guevara et al[49] 1998	7 (7/0)	Prospective	TIPS	Efficacy	4.9 ± 0.8 mg/dL	1 wk after TIPS: 3.7 ± 1.0 mg/dL 1 mo after TIPS: 1.8 ± 0.4 mg/dL	Renal function improved in 6 of 7 patients.	Mean survival was 4.7 ± 2 mo.
Witzke et al[53] 2004	30 (NS)	Prospective	CVVHD (if mechanically ventilated) vs intermittent HD if not ventilated	Survival	N/A	N/A	8 of 15 patients who received HD survived. None of the ventilated patients (received CVVHD) survived.	Note that the sickest patients (on a ventilator) all received CVVHD.
Keller et al[54] 1995	26 (NS); an additional 81 patients had liver disease and renal failure, but were not diagnosed with HRS	Retrospective	HD	Risk factor evaluation and outcomes	N/A	N/A	7 of 16 patients with HRS who received HD survived, while only 1 out of 16 patients with HRS who did not receive HD survived.
Mitzner et al[55] 2000	13 (Type 1)	Prospective, randomized, controlled	MARS and HDF and standard medical therapy vs HDF and medical therapy	Survival	MARS + HDF: 3.8 ± 1.5 mg/dL HDF alone: 4.4 ± 1.3 mg/dL	MARS + HDF: 2.3 ± 1.5 mg/dL HDF alone: 3.8 ± 0.5 mg/dL	At one week: 62.5% mortality in the treatment group, and 100% mortality in the group who did not receive MARS.	None of these patients underwent liver transplantation or received TIPS or vasopressin analogues during the observation period.
Jalan et al[66] 2003	8 (5/2, and one patient without HRS)	Prospective, nonrandomized	MARS	Safety and efficacy	162 (51–312) μmol/L	108 (34–231) μmol/L	50% survival at 3 mo follow-up	All of the patients had alcoholic hepatitis and were encephalopathic. Renal function improved in all patients. Of the 5 patients with type 1 HRS, 3 remained anuric, but there was normalization of SCr in the other 2 patients. SCr was normalized in both patients with type 2 HRS by the end of treatment.
Mitzner et al[55] 2001	8 (NS)	Uncontrolled	MARS	Multiple organ function changes	380 ± 182 μmol/L	163 ± 119 μmol/L	Improvement in multiple organ functions

SCr: Serum creatinine; CrCl: Creatinine clearance; TIPS: Transjugular intrahepatic portosystemic shunt; NS: Not Specified; CVVHD: Continuous veno-venous hemodialysis; HD: Hemodialysis; MARS: Molecular adsorbents recirculating system; HDF: Hemodiafiltration. Cr conversion from μmol/L to mg/dL: divide by 88.4.