Medical management of hepatorenal syndromeNephrol Dial Transplant (2012) 27: 34–41

doi: 10.1093/ndt/gfr736

Andrew Davenport1, Jawad Ahmad2, Ali Al-Khafaji3, John A. Kellum3, Yuri S. Genyk4 and Mitra K. Nadim5

2012/03/26 R2 鄭雅婷 / Supervisor 張智翔醫師

Hepatorenal syndrome (HRS) is defined as the occurrence of acute kidney injury (AKI) in patients with end-stage liver cirrhosis in the absence of another identifiable cause

Untreated, median survival is 2 weeks for patients with Type 1 HRS and 4–6 months in patients with Type 2 HRS

A consensus conference under the auspices of the Acute Dialysis Quality Initiative (ADQI) was held in 2010 Appraise the existing evidence Develop a set of consensus recommendations

to standardize care and direct further research

The ADQI methods comprise Systemic search for evidence with review and

evaluation of the available literatureThe establishment of clinical and physiologic

outcomes as well as measures to be used for comparison of different treatments

The description of the current practice and the rationale for the use of current techniques

Analysis of areas in which evidence is lacking and future research is required

Using key terms relevant to the topic and electronic reference libraries

Focus on human studiesLimited to English language articlesPublished between January 1960 and December

2009The majority of the work group resources were

devoted to review of randomized trials, as these were deemed to be most likely to provide data to support Level 1 recommendations with very high- or high-quality (A or B) evidence

A three-phase approach was used to construct the evidence-based recommendationsA systematic literature review of studies in HRS

and AKI in patients with cirrhosisA comprehensive appraisal of prior studiesConvening an expert panel to synthesize

information and develop consensus-based recommendations

Recommendation statements were incorporatedif there was strong literature-based evidenceif the expert panel voted that the

recommendation was appropriate

General management strategies

Patients with hypotensive may have a reduced cortisol response (hepatoadrenal syndrome) and thus covert hypoadrenalism should be considered and treated appropriately to improve response not only to vasopressors but also survival

Drugs reported to precipitate HRS in patients with cirrhosis should be avoided

Radiocontrast media have not been established as causing AKI in cirrhotics

Norfloxacin Reduction in SBP (7 versus 61%)Rreduction in the incidence of HRS (28 versus

41%)Oxypentifyllin

A tumor necrosis factor-a antagonistReduced complications in patients with

advanced cirrhosis, including renal dysfunctionAlbumin infusions have been reported to

decrease the incidence of HRS in patient with SBP

Type 1 HRS patients should be closely monitored and precipitating factors including bacterial infection should be actively sought and treated (not graded)

Drugs reducing renal perfusion or directly causing nephrotoxicity should be avoided (1C)

Exposure to contrast should be minimized to reduce contrast induced kidney injury (1D)

Intravascular volume expansion, which is often necessary to treat HRS, can potentially lead to worsening of ascites, pleural effusion or heart failure

Assessment of intravascular volume in HRS is difficult as the standard static hemodynamics measurements of CVP and PCWP are not reliable markers of circulatoryAn infusion of 20% albumin significantly increasing

central blood volume and cardiac index, without changes in CVP

The response to a fluid challenge in cirrhotics is likely to be abnormal, as any fluid bolus which initially expands the intravascular space, will subsequently expand the ‘third space’

Excessive administration of fluids should be avoided to prevent volume overload due to the presence of kidney injury and development or progression of dilutional hyponatremia (1D).

Traditional methods in predicting volum responsiveness and should not be relied on (1C).

Prospective studies, specifically of volume assessment with hemodynamic monitoring tools in patients with HRS

In advanced liver disease, volume expansion does not always resolve hypotension, most likely due to the increased vascular compliance in cirrhotics

The choice of intravenous fluids used in cirrhotics remains controversial

Volume expansion with albumin has been shown to reduce plasma renin, suggesting an improvement in the effective circulating volume

In randomized controlled clinical trials, albumin infusions reduced both the incidence of HRS and mortality

Studies have shown that the use of vasopressors with albumin improves renal function and mortality compared to vasopressor alone

In one randomized study in patients with SBP, albumin significantlyIncreased mean arterial pressure (MAP) and

suppressed plasma renin activity, compared to hetastarch

Serum nitrates increased with hetastarch but not with albumin

Less neurohumeral activation compared to other colloids

Less volume expanders post-large-volume paracentesis Plasma von Willebrand-related antigen fell significantly

Intravenous administration of albumin (initially 1 g of albumin/kg of body weight, up to a maximum of 100 g, followed by 20–40 g/day) in combination with vasopressor therapy (1A)

For up to 14 days (2D)

AKI due to abdominal compartment syndrome is well recognized with intra-abdominal pressures (IAP) typically >18 mmHg

Uncontrolled studies have reported an improvement in renal function in patients with HRS following paracentesis for raised IAP

Prospective studies are required to investigate the effect of reducing IAP on renal function in patients at risk of developing or with established HRS

Splanchnic vasodilatation plays a key role in the pathogenesis of HRS

The prospective trials focused on treatment if type 1 HRS with vasocontrictiors reported an improvement in renal function (but not a survival benefit)

Activation V1 receptor leads to vascular smooth muscle contraction

High density of V1 receptors in the splanchnic bed make this vasculature especially responsive to vasopressin

Distinctive vasopressin analogPreferential effects on the V1 receptorLower rate of ischemic complicationsThe most widely studied agent for Type 1 HRS

Several small studies have demonstrated that terlipressin significantly decreases plasma renin and aldosterone, with an improvement in glomerular filtration rate (GFR) in patients with type 1 HRS

The importance of albumin infusion to terlipressin therapy was emphasized in a prospective study of predominantly Type 1 HRS

Terlipressin dosages ranged from 2 to 12 mg/day in divided doses and 20–40 g/day of albumin.

The duration of therapy is usually ≤ 2 weeksThe aim is to improve renal function sufficiently to

decrease the Scr <1.5 mg/dL (complete response)Renal function was improved in Type 1 HRSThere are no studies on how best to discontinue

terlipressin therapy, and whether this affects HRS recurrence

Studies have focused on changes in Scr rather than titrating terlipressin to achieve a target MAP

In most studies, there were no overall survival benefits

More recent studies have focused on early predictors of response with a baseline serum bilirubin (<10 mg/dL) and an increase in MAP of 5 mmHg by Day 3 predicting response

Terlipressin may be beneficial in cirrhotics with ascites and renal impairment before they fulfill the diagnostic criteria for HRS, by decreasing plasma renin and norepinephrine and increasing GFR and natriuresis

Patients with additional comorbidities such as ischemic heart and peripheral vascular disease have typically been excluded from studies

A catecholamine but its alpha-adrenergic activityPotent vasoconstrictor of both the venous and

arterial vasculatureA pilot study Type 1 HRS used norepinephrine at

a dose titrated to achieve an increase in MAP of 10 mmHg or an increase in 4-h urine output to >200 mL

Reversal of HRS occurred in 83%, with improvement in urine output, sodium excretion, serum sodium concentration, creatinine clearance, MAP, plasma renin activity and aldosterone

Oral midodrine, an alpha-adrenergic receptor agonistVascular smooth muscle vasoconstriction

Subcutaneous octreotide : long-acting somatostatin analogue which is used reduce portal hypertension after variceal hemorrhage

Early studies in Type 2 HRS demonstrated no improvement in renal function with midodrine or octreotide

The combination of thrice daily midodrine 7.5–12.5 mg and octreotide 100–200 μg, and albumin, improved renal plasma flow, GFR and urinary sodium extraction in Type 1 HRS after 3 weeks of treatment

Ornipressin, a vaspressin analogueHigh rate of ischemic complications

(including ischemic colitis and tongue ischemia) requiring ornipressin withdrawal

N-acetyl cysteine reported to help reverse HRS in case reports, but awaits confirmation

Oxypentifylline, used in alcoholic hepatitis, has been reported to reduce the incidence of HRS, but has not been shown to improve renal function in established HRS

In type 1 HRS, patients optimally resuscitated with albumin (initially 1 g of albumin/kg of body weight for 2 days, up to a maximum of 100 g/day, followed by 20–40 g/day) in combination with a vasoconstrictor (1A), preferentially terlipressin (2C)

Therapy should be discontinued after 14 days in non-responders and only continued thereafter in partial responders while awaiting the outcome of salvage techniques (2D).

Prospective trials are required to determine the optimum mode of delivery of terlipressin (bolus versus infusion).

Comparative trials of vasoconstrictors are required to determine the merits of vasopressin analogs against norepinephrine

Although the introduction of terlipressin and albumin has improved the outlook for patients with HRS, only ~50% of patients respond to therapy

Questions remainWhether earlier introduction of this therapy would

help prevent the development of HRSIn patients with established HRS how best to

administer terlipressin and if targeting vasoconstrictor dosage to an absolute or relative increase in MAP improves response

The effects of changes in IAP on renal function have not been explored