Abstract
ALBUMIN DOSING WITH TERLIPRESSIN FOR THE TREATMENT OF HRS-AKI: A DOUBLE-EDGED SWORD.
Background:
Current guidelines for the diagnosis of HRS-AKI require the use of albumin as volume expander to exclude pre-renal azotemia. The treatment of HRS-AKI (hepatorenal syndrome) also recommends the use of terlipressin with albumin at a dose of 20-40g per day. However, the optimal dose of albumin to be given in the pre- and during treatment remains unclear. We evaluated total albumin use in the two largest placebo-controlled, randomized trials of terlipressin plus albumin versus placebo in patients with HRS-AKI.
Methods:
Pooled data from the two trials (CONFIRM-NCT02770716 and REVERSE-NCT01143246) were used to determine transplant-free survival (TFS) and HRS reversal by total albumin quartiles; total albumin included albumin given up to 14 days prior to randomization and concomitant albumin given during study treatment. TFS was analyzed using a Kaplan-Meier product limit method; HRS reversal was defined as serum creatinine ≤ 1.5 mg/dL by day 14 or discharge.
Results:
The 4 quartiles of total albumin dose given were ≤325g (Gp A), >325 to ≤456.25g (Gp B), >456.25 to ≤655g (Gp C), and > 655g (Gp D). HRS reversal rates for the terlipressin patients were 33.7%, 31.9%, 27.8% and 38.2% for Gp A to D respectively. Similarly, the placebo group had comparable proportions of patients who achieved HRS reversal, being 12.7%, 24.3%, 15.4% and 18.4% for Gp A to D respectively. Therefore, there was no dose-response relationship between total albumin use and HRS reversal for either treatment group. The TFS by day 90 for the terlipressin patients were 25.6%, 29.0%, 27.8% and 27.9% for Gp A to D respectively. The corresponding TFS by Day 90 for the placebo patients were 14.5%, 18.9%, 28.8% and 45.4%. Therefore, once again, there was no relationship between total albumin use and TFS by Day 90 in the terlipressin group. In contrast, TFS by Day 90 increased in the placebo group with increasing albumin dose used, being 14.5%, 18.9%, 28.8% and 45.4%. for Gp A to D respectively. Importantly, there was a significant difference in placebo versus terlipressin TFS at Day 90 in the >655 g albumin quartile (terlipressin 27.9% vs. placebo 45.5%, p=.044). The lower TFS by Day 90 amongst terlipressin patients who received more than655g of albumin appears to be related in part to death from respiratory failure/sepsis/septic shock (terlipressin 12.6% vs placebo 3.0%).
Conclusion:
These results demonstrate that there does not appear to be an easily identifiable optimal dose of albumin during terlipressin therapy. The relationship between albumin use and the balance between efficacy and safety is complex; this “double-edged sword” underscores the need for careful patient selection and monitoring of albumin use to avoid volume overload.