High expression of a vascular stricture‐related marker is predictive of an early response to tolvaptan, and a low fractional excretion of sodium is predictive of a poor long‐term survival after tolvaptan administration for liver cirrhosis

Abstract

Tolvaptan is a newly available diuretic that has a specific function in water reabsorption inhibition. Given that spironolactone or furosemide induces the aggravation of cirrhotic hyponatremia and dehydration, tolvaptan affects the management strategy of liver cirrhosis. Representative predictive markers of its response include renal function-related markers such as urea nitrogen or creatinine. However, vascular function-related markers have not been well investigated. We investigated the effect of the vascular function-related marker asymmetric dimethylarginine (ADMA) and the effective arterial blood volume (EABV) marker, fractional excretion of sodium (FENa), on the early tolvaptan response and survival in liver cirrhosis. Methods: We prospectively recruited 49 patients who required add-on tolvaptan for refractory ascites or edema. Laboratory data were obtained immediately before and 1 day after tolvaptan administration. Patients exhibiting >1.5 kg weight loss after 1 week were categorized as early responders to tolvaptan. Patients were followed for a median of 200 days and were assessed for survival. Results: Early responders showed lower creatinine levels (<1.0 mg/dL), and higher ADMA levels (≥0.61 nmol/mL) than others in a multivariate analysis. Patients with a shorter survival were positive for hepatocellular carcinoma and had a low FENa (<0.35%). Conclusion: Early responders showed higher ADMA levels reflecting vascular stricture, suggesting that higher vascular tonus is required for a tolvaptan early response. Patients with a shorter survival showed a lower FENa, reflecting a lower EABV and suggesting that adequate EABV is required for the prolonged survival after tolvaptan administration.

Management of Cirrhotic Ascites under the Add-on Administration of Tolvaptan

“…Several studies have shown that the administration of tolvaptan had no effect on survival [57,80,81]. These studies showed prognostic factors, such as complications with HCC and low fractional excretion of sodium (FENa) [57], complications with HCC and Child-…”

“…A prospective multicenter non-interventional, post-marketing surveillance study of 340 Japanese patients showed that body weight reduction was predominant in younger patients with a preserved renal function with low creatinine levels and a high estimated glomerular filtration rate (eGFR) [ 53 ]. A preserved renal function, as reflected by the eGFR or creatinine level, was shown to be important in several other reports and should therefore be considered a crucial factor predicting the effect of tolvaptan [ 54 , 55 , 56 , 57 ]. While even in chronic kidney disease (CKD) patients (eGFR < 45 mL/min/1.73 m 2 ), urinary volume increased and body weight decreased; however, the effect was somewhat lower than in non-CKD patients [ 58 ].…”

“…In addition to low creatinine levels, a high serum concentration of a vascular tonus-related marker, namely asymmetric dimethylarginine (ADMA), has been shown to be a significant marker in one study [ 57 ]. ADMA is a vascular function-related marker reflecting reactive oxygen species (ROS) related vasoconstriction.…”

“…Several studies have shown that the administration of tolvaptan had no effect on survival [ 57 , 80 , 81 ]. These studies showed prognostic factors, such as complications with HCC and low fractional excretion of sodium (FENa) [ 57 ], complications with HCC and Child-Pugh class C [ 80 ], and a rapid and early decrease in a bioimpedance analysis (defined by intracellular water at 6 h after the first dose of tolvaptan) [ 81 ]. These factors are also convincing.…”