The various approaches to the management of HRS have been based on the underlying pathophysiology.
- Simonetto DA
- Gines P
- Kamath PS.
Hepatorenal syndrome: pathophysiology, diagnosis, and management.
Diuretics should be discontinued, and fluid restriction may be needed to prevent dilutional hyponatremia, provided the volume status is satisfactory. Vasoconstrictors can reverse the dilatation of the splanchnic vessels, inhibit the activity of the entire vasoconstrictor system, and subsequently increase renal blood flow and perfusion. Transjugular intrahepatic portosystemic shunts can increase systemic circulation, decrease vasoconstriction, and increase renal perfusion and GFR but increases the risk of encephalopathy.
- Baraldi O
- Valentini C
- Donati G
- et al.
Hepatorenal syndrome: Update on diagnosis and treatment.
Hemodialysis and extracorporeal albumin dialysis have improved renal function in a small number of patients. The most definitive approach is liver transplantation which replaces the cirrhotic liver. However, an initial decrease in GFR often occurs with liver transplantation, often requiring hemodialysis and delaying the administration of medications, such as cyclosporine or tacrolimus. Furthermore, patients with HRS often have a short survival time and finding a liver donor can be difficult in the time period available; many patients die before transplantation. These approaches are discussed in more detail in the following paragraphs.
Medical management with vasopressors
Dilation of the splanchnic vasculature causes fluid accumulation in the abdomen and decreases effective arterial volume. Consequently, patients often receive vasoconstrictors during the initial management of HRS–AKI. Midodrine (a selective alpha 1 adrenergic agonist and systemic vasoconstrictor) combined with octreotide (a somatostatin analog/ splanchnic vasoconstrictor) can improve renal and systemic hemodynamics. A retrospective study of patients with HRS demonstrated that patients (n=60) treated with midodrine and octreotide and albumin have lower mortality (43% vs. 71%) and higher resolution rate of HRS (40% vs. 10%) than patients (n=21) who did not receive this treatment.
- Esrailian E
- Pantangco ER
- Kyulo NL
- et al.
Octreotide/Midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome.
Mahmoud and co-authors compared the outcomes of 60 patients with HRS–AKI treated with either midodrine/octreotide or norepinephrine.
- El-Desoki Mahmoud EI
- Abdelaziz DH
- Abd-Elsalam S
- et al.
Norepinephrine is more effective than midodrine/octreotide in patients with hepatorenal syndrome-acute kidney injury: a randomized controlled Trial.
The response rates based on reductions in creatinine were significantly higher in patients treated with norepinephrine (15/26, 57.6%) than with midodrine/octreotide (5/25, 20%). However, there was no difference in survival between the 2 groups. Saif et al. randomized 60 patients with type 1 HRS into treatment groups with either norepinephrine or terlipressin.
- Saif RU
- Dar HA
- Sofi SM
- et al.
Noradrenaline versus terlipressin in the management of type 1 hepatorenal syndrome: A randomized controlled study.
Reversal of type I HRS occurred in 16 patients (53%) treated with norepinephrine and 17 patients (57%) treated with terlipressin. Facciorusso et al. compared the efficacy of several pharmacological strategies for management of type 1 hepatorenal syndrome using a systematic review and network meta-analysis.
- Facciorusso A
- Chandar AK
- Murad MH
- et al.
Comparative efficacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network meta-analysis.
These investigators concluded that moderate quality evidence supported the use of terlipressin over placebo in the reduction of short-term mortality. Low quality evidence supported the use of norepinephrine, midodrine plus octreotide, or dopamine plus furosemide over placebo to reduce mortality. This meta-analysis supported the use of terlipressin over midodrine plus octreotide (OR 26.25, 95% CI 3.07-224.21) to reverse the hepatorenal syndrome. Wang et al. completed a systematic review and meta-analysis of 18 randomized control trials which included 1011 patients with hepatorenal syndrome.
Terlipressin in the treatment of hepatorenal syndrome: a systematic review and meta-analysis.
Terlipressin had a similar efficacy to norepinephrine but had more adverse events.
Wong et al. randomized 300 patients with type 1 HRS to treatment with terlipressin plus albumin or placebo in a special protocol assessment agreement with the Food and Drug Administration as a phase 3 registration trial.
- Wong F
- Pappas SC
- Curry MP
- et al.
Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome.
The primary endpoint was reversal hepatorenal syndrome which required two consecutive serum creatinine levels less than 1.5 mg/dL and survival without renal replacement therapy for at least 10 days. The baseline serum creatinine levels in these patients were 3.5±1.0 mg/dL. Thirty-two percent of the patients in the terlipressin group had reversal of their hepatorenal syndrome, and 17% of patients in the placebo group had reversal. By day 90, 51% of the patients in the terlipressin group had died, and 45% of the patients in the placebo group had died. Some patients in both groups received liver transplants. More adverse events, including respiratory failure, occurred in terlipressin group. The interpretation of this study is difficult. A significant percentage of patients in both groups died within 90 days. The study was undertaken in centers which could perform liver transplantation. Consequently, it is likely that centers with less expertise in chronic liver disease would have worse results. Belcher and coauthors analyzed this trial carefully and suggested that outcomes would improve if terlipressin was used earlier in HRS, if it were avoided in patients who are unlikely to benefit, and if there was significant attention to the patient's intravascular volume including avoiding excess albumin administration.
- Belcher JM
- Parada XV
- Simonetto DA
- et al.
Terlipressin and the treatment of hepatorenal syndrome: How the CONFIRM Trial moves the story forward.
These decisions are relevant to the use of any vasoconstrictor, including midodrine/octreotide and norepinephrine, but are not necessarily easy when managing a critically ill patient. Velez and associates analyzed the association between changes in the mean arterial pressure with vasoconstrictor therapy and reductions in creatinine levels.
- Velez JC
- Kadian M
- Taburyanskaya M
- et al.
Hepatorenal acute kidney injury and the importance of raising mean arterial pressure.
They found that patients treated with either midodrine/octreotide or norepinephrine with an increase in mean arterial pressure > 15 mmHg had a significant decrease in serum creatinine. Consequently, physicians using these medications should try to adjust the doses of medication to have a definite increase in mean arterial pressure.
Patients with cirrhosis and HRS–AKI often have large volumes of ascitic fluid and consequently have intra-abdominal hypertension. This increased pressure can have direct effects on renal vein pressure and on renal parenchyma, and logically paracentesis can reduce this pressure and potentially improve renal function. Mohmand and Goldfarb reviewed changes in renal function associated with the abdominal compartment syndrome.
Renal dysfunction associated with intra-abdominal hypertension and the abdominal compartment syndrome.
They noted that these patients had a decrease in mean arterial pressure, an increase in intra-abdominal pressure, a decrease in abdominal perfusion pressure, an increase in CVP, an increase in renal venous pressure, an increase in renal parenchymal pressure, and an increase in renal vascular resistance. All these changes contribute to reductions in GFR. Umgelter et al. measured changes in hemodynamic parameters using transpulmonary thermal dilution catheter and in the renal resistance index using ultrasound of the renal intralobular arteries following paracentesis.
- Umgelter A
- Reindl W
- Wagner KS
- et al.
Effects of plasma expansion with albumin and paracentesis on haemodynamics and kidney function in critically ill cirrhotic patients with tense ascites and hepatorenal syndrome: a prospective uncontrolled trial.
- Umgelter A
- Reindl W
- Franzen M
- et al.
Renal resistive index and renal function before and after paracentesis in patients with hepatorenal syndrome and tense ascites.
They noted a significant drop in intra-abdominal pressure, systemic vascular resistance, and the renal resistance index. Creatinine clearance increased and urine output increased; the timeframe for these studies was 6 hours. The mean the serum creatinine in these patients was 2.9 mg/dL.
Savino et al. measured the intra-abdominal pressure, cardiovascular hemodynamic parameters, and renal function in 25 patients with advanced cirrhosis admitted to the ICU with variceal bleeding, tense ascites, and peripheral edema.
- Savino JA
- Cerabona T
- Agarwal N
- Byrne D.
Manipulation of ascitic fluid pressure in cirrhotics to optimize hemodynamic and renal function.
In the patients with an elevated intra-abdominal pressure in this cohort, paracentesis decreased it from 33.5 to 19.1 cm of water. This was associated with a decrease in total peripheral resistance and an increase in cardiac index, stroke index, left ventricular stroke work, and right ventricular stroke work. There was a decrease in BUN and creatinine and an increase in creatinine clearance, urine volume, and osmolar clearance. The baseline serum creatinine in these patients was 1.41±0.44 mg/dL. The baseline urine sodium concentration was 51.2±33.4 mEq/L. Creatinine clearance was 46.2±18.2 cc/min. These patients were critically ill with variceal bleeding but did not have extremely abnormal renal function. This study does give a clear indication of the expected changes in hemodynamic parameters following acute reductions in intra-abdominal pressure.
Chang et al. used a murine model to study the effects of increased intra-abdominal pressure on renal function.
Hepatorenal syndrome: insights into the mechanisms of intra-abdominal hypertension.
Chronic liver disease was introduced in to these mice using carbon tetrachloride. After 12 weeks the mice had injections of albumin in the peritoneal cavity to increase intra-abdominal pressure to levels of 0, 5, 10, and 20 cm of water. Blood chemistries and renal histopathology were examined 24 hours later. BUN and serum creatinine increased in both the control group and the liver injury group with increasing levels of intra-abdominal pressure. Renal tissue in animals with an intraperitoneal pressure 20 cm of water revealed edema of the renal tubular epithelial cells, constriction of the renal tubular lumen, formed casts, and hyperemia in the interstitium. The histologic changes were more pronounced in animals with liver disease and at higher intraperitoneal pressures. These results developed within 24 hours of an increase in pressure.
The standard of care in these patients often involves large-volume paracenteses both as inpatients and as outpatients. Van Thiel et al. reported information on 40 patients with cirrhosis and chronic ascites using periodic peritoneal drainage over 72 hours.
- Van Thiel DH
- Moore CM
- Garcia M
- George M
- Nadir A.
Continuous peritoneal drainage of large-volume ascites.
This procedure involved the removal of 3 L of fluid every 6 hours; patient also received 25 g of albumin every 6 hours. The initial creatinine was 0.8 mg/dL; the final creatinine was 0.8 mg/dL. There were no episodes of peritoneal hemorrhage or infection associated with this procedure. Martin and co-authors also used an indwelling peritoneal catheter in 36 patients undergoing continuous large-volume paracentesis (up to 3 L every 8 hours).
- Martin DK
- Walayat S
- Jinma R
- et al.
Large-volume paracentesis with indwelling peritoneal catheter and albumin infusion: a community hospital study.
These patients received albumin replacement. An average of 16.5 L of ascitic fluid was removed over 72 hours. The initial serum creatinine was 1.37 mg/dL and a final serum creatinine was 1.21 mg/dL. There were no episodes of spontaneous bacterial peritonitis or major bleeding associated with this process. In these two studies, the patients had large volumes of ascitic fluid but did not have hepatorenal syndrome.
Large-volume paracenteses has the potential to reduce intravascular volume and therefore cardiac output and blood pressure. This could contribute to acute changes in renal function. Seethapathy et al. analyzed the outcome of 258 paracenteses done on 102 patients admitted to an academic liver transplant medical center.
- Seethapathy H
- Sharma S
- Zhao S
- et al.
Acute kidney injury following paracentesis among inpatients with cirrhosis.
Most of these paracentesis (67%) removed less than 5 L of ascitic fluid. The mean baseline creatinine is 1.25 mg/dL ±0.69 mg/dL. Acute kidney injury defined by a creatinine increase ≥0.3 mg/dL or ≥50% within 48 hours developed in 14 of the 258 paracenteses. A chart review indicated that only 4 of the 258 paracenteses (1.6%) were associated with new onset AKI without an alternative cause. All of the procedures in these cases had less than 5 L fluid removed. Hypotension defined by either a drop in systolic blood pressure or a drop in diastolic blood pressure occurred in 61 of the 258 paracenteses. This was more common in patients who had greater than 5 L removed but was not associated with AKI or a change in serum creatinine. These investigators concluded that therapeutic paracentesis had a low risk for the development of AKI. However, the ascitic fluid usually reaccumulates in these patients and requires repeat paracentesis.
An alternative approach to the management of patients with refractory ascites might involve continuous drainage through peritoneal-venous shunts or through a TIPS. Cade et al. measured the effects of vascular volume expansion with fresh frozen plasma, short-term reductions in intraperitoneal pressure with paracentesis, and placement of a LeVeen shunt on renal function in patients with severe hepatic cirrhosis and hepatorenal syndrome.
- Cade R
- Wagemaker H
- Vogel S
- et al.
Hepatorenal syndrome. Studies of the effect of vascular volume and intraperitoneal pressure on renal and hepatic function.
They noted that venous pressures decreased following the removal of ascitic fluid and GFR and urine flow increased. However, as ascitic fluid reaccumulated reducing intravascular volume, GFR and urine output decreased. The placement of LeVeen shunt resulted in a significant improvement in GFR and renal plasma flow. This study suggests that paracentesis has short-term beneficial and then adverse effects but continuous drainage of peritoneal fluid has long-term beneficial effects.
Allegretti et al. compared the effects on renal function of a transjugular intrahepatic portosystemic shunt versus large-volume paracentesis in patients with cirrhosis and refractory ascites.
- Allegretti AS
- Ortiz G
- Cui J
- et al.
Changes in kidney function after transjugular intrahepatic portosystemic shunts versus large-volume paracentesis in cirrhosis: a matched cohort analysis.
This study included 276 matched patients. There was a significant increase in the estimated GFR following TIPS placement in patients with a baseline estimated GFR less than 60 mL/min per 1.73 m². There was no difference in estimated GFR in patients with an estimated GFR greater than 60 at the baseline in patients undergoing a TIPS procedure versus recurrent large-volume paracentesis. The outcomes in a TIPS cohort included death in 30% and liver transplantation in 36%. The estimated GFR increased in 59%. The outcomes in the serial large-volume paracentesis cohort included death in 32% and liver transplantation in 14%. The estimated GFR increased in 31% of these patients. The entire cohort had an average of 5.5 ± 3.9 paracentesis over a 90-day during the baseline period. The mean creatinine was 1.7±1.3 mg/dL. Information on ascitic volume, peripheral edema, and intra-abdominal pressures were not available in this study.
Dialysis and liver transplantation
No guidelines have been established on the role of renal replacement therapy (RRT) in patients with HRS-AKI who do not have other indications for dialysis, such as uremic complications. A consensus developed by the Acute Dialysis Quality Initiative (ADQI) group suggested that survival in patients with HRS was very poor and thus RRT should be avoided; however, RRT should be considered in patients eligible for liver transplantation.
- Nadim MK
- Kellum JA
- Davenport A
- et al.
Hepatorenal syndrome: the 8th International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group.
Velez has critically reviewed the decision to use dialysis in patients with HRS.
Patients with hepatorenal syndrome should be dialyzed?.
He suggested that patients listed for liver transplantation should receive dialysis if needed. Patients undergoing evaluation for liver transplantation but without any clear decision should be considered with dialysis. The decision becomes much more difficult in patients who are ineligible for liver transplantation.
Studies have shown that patients with advanced cirrhosis and type 1 HRS who received a liver transplantation as a definitive treatment had a renal recovery rate of 76% and a 1-year survival rate of 97%. The best predictor of HRS non-reversal after liver transplantation is prolonged dialysis before proceeding to transplantation.
- Yadav K
- Serrano OK
- Peterson KJ
- et al.
The liver recipient with acute renal dysfunction: A single institution evaluation of the simultaneous liver-kidney transplant candidate.
In these cases, the possible evolution of structural renal damage may hinder ultimate renal recovery and patient survival after liver transplant. Therefore, patient with type 1 HRS who do not respond to vasoconstrictor therapy should be offered liver transplantation immediately.
- Chauhan K
- Azzi Y
- Faddoul G
- et al.
Pre-liver transplant renal dysfunction and association with post-transplant end-stage renal disease: A single-center examination of updated UNOS recommendations.