Medical management of hepatorenal syndrome Nephrol Dial Transplant (2012) 27: 34–41 doi: /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 literature The 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

ADQI identified five topics relevant to the field of HRS Each topic, outlined a preliminary set of key questions and then assembled a diverse international panel Work group : 4~5 members with one acting as group facilitator, were convened with each work group addressing one key topic.

Using key terms relevant to the topic and electronic reference libraries Focus on human studies Limited to English language articles Published between January 1960 and December 2009 The 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 recommendations A systematic literature review of studies in HRS and AKI in patients with cirrhosis A comprehensive appraisal of prior studies Convening an expert panel to synthesize information and develop consensus-based recommendations Recommendation statements were incorporated if there was strong literature-based evidence if the expert panel voted that the recommendation was appropriate

Topics selected, work groups assembled and assigned Literature review Pre-conference 2½-day conference Identified supporting evidence Generated practice guideline and direction of future research Conference The reports were ed to each participant for comment and revision Final conference document Post- conference

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 antagonist Reduced complications in patients with advanced cirrhosis, including renal dysfunction Albumin 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 circulatory An 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 significantly Increased 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 analog Preferential effects on the V1 receptor Lower rate of ischemic complications The 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 weeks The aim is to improve renal function sufficiently to decrease the Scr <1.5 mg/dL (complete response) Renal function was improved in Type 1 HRS There 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 activity Potent vasoconstrictor of both the venous and arterial vasculature A 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 agonist Vascular 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 analogue High 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 remain Whether earlier introduction of this therapy would help prevent the development of HRS In 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