The administration of vasoconstrictors associated with intravenous albumin is currently considered the treatment of choice for the management of type 1 HRS.1, 6 The rationale behind this therapy is the improvement of circulatory function through vasoconstriction of the extremely dilated splanchnic arterial bed, which subsequently improves arterial underfilling, reduces the activity of the endogenous vasoconstrictor systems, and increases kidney perfusion.1, 2 The available vasoconstrictors used for HRS include vasopressin analogues such as terlipressin and alpha-adrenergic agonists such as noradrenaline and midodrine (Table 2). Most published data concern the use of intravenous terlipressin. Results from recent randomized controlled studies and systematic reviews indicate that treatment with terlipressin together with albumin is associated with marked improvements of kidney function in approximately 40% to 50% of patients.7, 8 Moreover, a systematic review of randomized controlled studies has shown that vasoconstrictor therapy for HRS improves survival.9 Although there are no dose-finding efficacy studies, the treatment is typically started intravenously with 1 mg/4-6 hours, and the dose is increased up to a maximum of 2 mg/4-6 hours after 3 days if there is no response to therapy (defined as a reduction of the serum creatinine level > 25% of the pretreatment values). In responders, the goal is to achieve the lowest levels of serum creatinine possible. Treatment is stopped when there is no further reduction of creatinine. In nonresponders, the duration of treatment is based on the effect on serum creatinine. If there is no decrease in creatinine or if its level increases, treatment should be stopped after 3 to 4 days of the maximum dose of terlipressin. If the reduction in serum creatinine is very slow, treatment can be maintained as long as the serum creatinine level decreases and there are no side effects of therapy. Recent studies suggest that the administration of terlipressin as a continuous intravenous infusion may improve its efficacy and decrease adverse events.10, 11 However, data are limited, and more studies are needed to confirm these results. A response to therapy is considered when there is a marked reduction in high serum creatinine levels, at least below 1.5 mg/dL. The incidence of ischemic side effects secondary to treatment with vasoconstrictors that require the discontinuation of treatment is approximately 10%. The recurrence of HRS after the withdrawal of therapy occurs in less than 15% of patients, and retreatment with terlipressin is generally effective.
Table 2. Pharmacological Treatment for HRS
| Terlipressin: 1 mg/4–6 hours intravenously. The dose is increased up to a maximum of 2 mg/4–6 hours after 3 days if there is no response to therapy (defined as a 25% or greater reduction in serum creatinine compared to pretreatment levels). A response to therapy is defined as a decrease in serum creatinine levels below 1.5 mg/dL (133 μmol/L). The treatment is usually applied for 5 to 15 days.|
| Midodrine and octreotide: 7.5 mg of midodrine orally 3 times daily (increased to 12.5 mg 3 times daily if needed) and 100 μg of octreotide subcutaneously 3 times daily (increased to 200 μg 3 times daily if needed). The duration of treatment depends on the effects on serum creatinine.|
| Norepinephrine: 0.5–3 mg/hour as a continuous intravenous infusion aimed at increasing the mean arterial pressure by 10 mm Hg. The treatment is continued until the serum creatinine level decreases below 1.5 mg/dL.|
| Concomitant administration of albumin and vasoconstrictor drugs (1 g/kg of body weight on day 1 followed by 20–40 g/day).|
Vasoconstrictors other than terlipressin that have been used in the management of HRS include noradrenaline and midodrine plus octreotide, both in combination with albumin.6 They represent alternative treatments to terlipressin because of their low cost and wide availability. Administered as a continuous intravenous infusion, noradrenaline appears to be effective for the treatment of type 1 HRS, although studies are still limited, and the number of treated patients is relatively small. A recent randomized trial compared the safety and efficacy of treatment with terlipressin versus noradrenaline for patients with HRS.12 Approximately 40% of the patients responded to treatment in both groups, and the adverse event profiles were similar in all patients. Therefore, noradrenaline seems to be as effective and safe as terlipressin for the treatment of HRS.
The combination of oral midodrine and octreotide in association with albumin has been shown to improve kidney function in patients with HRS, although the number of treated patients is relatively small, and no randomized comparative studies with other vasoconstrictors have been performed. A small study of 14 patients with type 1 HRS analyzed the efficacy of a transjugular intrahepatic portosystemic shunt (TIPS) for patients with type 1 HRS after the improvement of systemic hemodynamics and kidney function with a combination of midodrine, octreotide, and albumin. Medical therapy improved kidney function and renal sodium excretion in 10 of the 14 patients before TIPS insertion. TIPS insertion in five of the responders further improved kidney function and renal sodium excretion.13 A relatively large retrospective study evaluated the effects of treatment with octreotide plus midodrine on kidney function and 1-month survival in 87 patients with type 1 HRS versus a control group (21 subjects).14 A significantly higher proportion of patients treated with octreotide plus albumin showed a sustained reduction in serum creatinine in comparison with the control group (40% versus 10%, P < 0.05), and the 1-month mortality rate was significantly lower (43% versus 71%, P < 0.05). Another recent study also analyzed the effects of the combination of octreotide and midodrine plus albumin on kidney function and survival in 75 patients with type 1 or 2 HRS versus a cohort of 87 controls.15 The results were similar to those of the previous study. Transplant-free survival was higher for the treatment group (median = 101 days) versus the control group (median = 18 days, P < 0.0001). Kidney function had significantly improved at 1 month in the treatment group [glomerular filtration rate (GFR) = 48 mL/minute] versus the controls (GFR = 34 mL/minute, P = 0.03), and the 1-month survival rate was significantly higher for the treatment group versus the control group.15 Therefore, both studies suggest that treatment with oral midodrine plus octreotide may represent an effective alternative to terlipressin for patients with HRS because it improves kidney function and is associated with increased short-term survival. Finally, a recent retrospective analysis evaluated post-LT outcomes of patients treated with octreotide, midodrine, and albumin.16 In that study, patients treated before LT were compared with a control cohort that underwent LT in the era before this therapy was used. Forty-three patients with HRS underwent LT (27 cases and 16 controls). There were no differences between the groups in the proportion of patients requiring hemodialysis before LT (48% of cases versus 50% of controls, P = 1.00). After LT, the mean GFRs were similar for the cases and controls at 1 month (57 versus 53 mL/minute/1.73 m2, P = 0.61) and at 1 year (P = 0.13). Eleven of the 27 cases responded to octreotide, midodrine, and albumin before LT. In comparison with the nonresponders, there was no difference in GFR 1 month after LT. There were no differences between the groups for patients requiring long-term hemodialysis after LT (7.7% of cases versus 12.5% of controls, P = 0.61). The results of this analysis suggest that a pre-LT treatment with a combination of midodrine and octreotide in association with albumin is not associated with an additional benefit in improving kidney function after LT.16
Thus, although some studies suggest that treatment with oral midodrine plus octreotide in combination with albumin is effective for patients with HRS, the number of treated patients is still limited, and the studies are retrospective. Therefore, large randomized comparative trials with other vasoconstrictors are needed.