Human Albumin Injection in Hepatorenal Syndrome (HRS)

UptoDate: Hepatorenal syndrome

The ideal therapy for hepatorenal syndrome is improvement of liver function from recovery of alcoholic hepatitis, treatment of decompensated hepatitis B with effective antiviral therapy, recovery from acute hepatic failure, or liver transplantation. The ability of liver function to improve with abstinence from alcohol and effective antiviral therapy of hepatitis B is remarkable.

However, when improvement of liver function is not possible in the short term, we recommend that medical therapy be instituted in an attempt to reverse the acute kidney injury associated with hepatorenal syndrome.

In patients with hepatorenal syndrome who are critically ill, we suggest initial treatment with norepinephrine in combination with albumin. Norepinephrine is given intravenously as a continuous infusion (0.5 to 3 mg/hr) with the goal of raising the mean arterial pressure by 10 mmHg, and albumin is given for at least two days as an intravenous bolus (1 g/kg per day [100 g maximum]). Intravenous vasopressin may also be effective, starting at 0.01 units/min and titrating upward as needed to raise the mean arterial pressure.

In patients with hepatorenal syndrome who are not critically ill, where terlipressin therapy is not available, we suggest initial treatment with a combination of midodrine, octreotide, and albumin. Midodrine is given orally (starting at 7.5 mg and increasing the dose at eight-hour intervals up to a maximum of 15 mg by mouth three times daily), octreotide is either given as a continuous intravenous infusion (50 mcg/hr) or subcutaneously (100 to 200 mcg three times daily), and albumin is given for two days as an intravenous bolus (1 g/kg per day [100 g maximum]), followed by 25 to 50 grams per day until midodrine and octreotide therapy is discontinued.

In patients who fail to respond to the above therapies, develop severely impaired renal function, and either are candidates for liver transplantation or have a reversible form of liver injury and are expected to survive, we recommend dialysis as a bridge to liver transplantation or liver recovery.

In patients treated with norepinephrine, terlipressin, or octreotide, we usually treat for a total of two weeks. However, we and others occasionally treat for longer durations (up to one month or more) if there is some but not complete improvement in renal function after two weeks of therapy. In patients who respond to therapy, we occasionally treat indefinitely with midodrine to maintain a higher mean arterial pressure (or until liver transplantation or resolution of liver injury). Many patients who recover from type 1 hepatorenal syndrome continue to have refractory ascites, and midodrine may be effective in such patients [42]. In contrast, if a patient has no improvement in renal function after two weeks, therapy with these drugs can be considered futile.

EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis

Management of hepatorenal syndrome

The most effective method currently available is the administration of vasoconstrictor drugs. Among the vasoconstrictors used, those that have been investigated more extensively are the vasopressin analogues particularly terlipressin. The rationale for the use of vasopressin analogues in HRS is to improve the markedly impaired circulatory function by causing a vasoconstriction of the extremely dilated splanchnic vascular bed and increasing arterial pressure.

Drug therapy of type 1 hepatorenal syndrome Terlipressin (1 mg/4–6 h intravenous bolus) in combination with albumin should be considered the first line therapeutic agent for type 1 HRS. The aim of therapy is to improve renal function sufficiently to decrease serum creatinine to less than 133 mcmol/L (1.5 mg/dl) (complete response). If serum creatinine does not decrease at least 25% after 3 days, the dose of terlipressin should be increased in a stepwise manner up to a maximum of 2 mg/4 h. Median time to response is 14 days and usually depends on pre-treatment serum creatinine, the time being shorter in patients with lower baseline serum creatinine. A serum bilirubin less than 10 mg/dl before treatment and an increase in mean arterial pressure of >5 mm Hg at day 3 of treatment are associated with a high probability of response to therapy. For patients with partial response (serum creatinine does not decrease <133 mcmol/L) or in those patients without reduction of serum creatinine treatment should be discontinued within 14 days. Recurrence after withdrawal of therapy is uncommon and retreatment with terlipressin is generally effective.

In most studies, terlipressin was given in combination with albumin (1 g/kg on day 1 followed by 40 g/day) to improve the efficacy of treatment on circulatory function.

Japan Society of Transfusion Medicine and Cell Therapy: Evidence-based Guidelines for the Use of Albumin Products 2017

Hepatorenal syndrome is referred to as acute renal failure in patients with end-stage liver cirrhosis or hepatic insufficiency, such as fulminant hepatitis, but represents functional pre-renal failure without any organic or pathological changes in renal tissues. Hepatorenal syndrome is classified into 2 types: type 1 showing rapidly progressive symptoms of renal failure and type 2 showing slowly progressive renal failure. Patients with hepatorenal syndrome has a low glomerular filtration rate (serum Cr >1.5 mg/dl or 24-hour CCr <40 ml/min), resulting in oliguria. In many cases, hepatorenal syndrome progresses in an irreversible manner, is associated with a mortality rate of ≥90%, and is one of the causes of death in end-stage liver cirrhosis. The use of terlipressin and albumin is recommended for the treatment of type-1 hepatorenal syndrome. Improvement of renal impairment is also noted in 83% of patients with coadministration of norepinephrine and albumin, which represents a beneficial  treatment regimen while waiting for a liver transplant.

Treatment with a hypertonic albumin solution and a vasoconstrictor is effective in improving type-1 hepatorenal syndrome. Albumin should be administered at a dose of 1 g/kg body weight on day 1 and 20 to 40 g/body weight on subsequent days, in combination with terlipressin and other drugs (evidence grade 1A).

Guideline	Recommended Dosages of Human Albumin Injection for SBP
UptoDate [Accessed 19 August 2019]	Critically ill For at least two days as an intravenous bolus (1 g/kg per day [100 g maximum]) Not critically ill Given for two days as an intravenous bolus (1 g/kg/day [100 g maximum]), followed by 25-50 g/day until terlipressin therapy is discontinued
Clinical Guidelines for Human Albumin Use (NHS Scotland 2016)	Day 1          : 1 g/kg HAS Day 2 – 16  : 20 – 40 g HAS / day Rx continued until serum creatinine falls below 130mol/l. NB. Where creatinine is rising despite Rx, 60g HAS /day may be clinically indicated.
EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis 2010	1 g/kg on day 1, followed by 40 g/day
Evidence-based Guidelines for the Use of Albumin Products (Japan Society of Transfusion Medicine and Cell Therapy 2017)	1 g/kg body weight on day 1 , then, 20 to 40 g/body weight on subsequent days
Guideline for the use of human albumin solution (Guy’s and St. Thomas’ 2015)	Day 1: 1g/kg Day 2 -14: 0.5g/kg The transfusions should stopped once patient’s condition has resolved.
Guidelines for Intravenous Albumin Administration at Stanford Health Care (Stanford Health Care 2017)	Suspected HRS Defined as acute renal dysfunction (serum creatinine >1.5 mg/dL or 132.6 mcmol/L) in the presence of cirrhosis 1 g/kg/day for 2 days (max. 100 g/day) *
	Confirmed HRS Defined as: ·         Serum creatinine >1.5 mg/dL in the presence of cirrhosis ·         Absence of shock, ongoing bacterial infection, and/or current treatment with nephrotoxic drugs ·         Absence of sustained improvement in renal function after discontinuation of diuretics and a trial of albumin 1 g/kg ·         Absence of proteinuria (<500 mg/day) or hematuria (<50 red cells per high-power field) ·         Absence of ultrasonographic evidence of obstructive uropathy or parenchymal renal disease 25-50 g* daily for a total of 72 hours (starting 1-2 days after initial diagnostic trial of albumin, if applicable), and consult nephrology and hepatology services to determine whether to continue Should be used in addition to midodrine and octreotide
Albumin – Adult – Inpatient Clinical Practice Guideline (University of Wisconsin Hospitals 2018)	Management of hepatorenal syndrome (HRS) / acute kidney injury (AKI) in patients with cirrhosis and probable non-structural injury (i.e. pre-renal azotemia): As fluid challenge (UW Health low quality evidence; strong recommendation) Condition Albumin Type Dose Recommended Clinically volume depleted 5% Initial dose is 12.5 - 25 g Clinical volume repletion is achieved 25% 1 g/kg per day for 2 days * (max.100 g/day) Assess for resolution or progression of AKI at 48 hours after initiating albumin therapy
	Treatment of Type 1 HRS with cirrhosis (UW Health high quality evidence; strong recommendation) 1 g/kg on day 1 (max.100 g/day), then 25 g/day The following duration of therapy for albumin is recommended: 1.     For patients that respond to vasoconstrictors and albumin as evidenced by a decrease in plasma creatinine, discontinue albumin when plasma creatinine has returned to or is close to baseline, or has not decreased further after 3 days of treatment 2.     In patients that do not respond to vasoconstrictors and albumin, discontinue albumin after a maximum of 7 days 3.     Discontinue albumin if patient is started on renal replacement therapy or the plasma albumin level is > 3 g/dL (30 g/L).

*Use 25%.

References: UptoDate: Hepatorenal syndrome [Accessed 19 August 2019] NHS Services Scotland: National Plasma Products Expert Advisory Group. Clinical Guidelines for Human Albumin Use. Weinacker A & Ang H. Guidelines for Intravenous Albumin Administration at Stanford Health Care. 2017. Stanford Health Care. Retter et al. Guideline for the use of human albumin solution (HAS). 2015. Guy’s and St. Thomas’ NHS Foundation Trust. Fish et al.  Albumin – Adult – Inpatient Clinical Practice Guideline. 2018.  University of Wisconsin Hospitals and Clinics Authority European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. Journal of Hepatology 2010 vol. 53 j 397–417.