Hyponatremia in cirrhosis and end-stage liver disease: treatment with the vasopressin V₂-receptor antagonist tolvaptan

Abstract

Hyponatremia is common in patients with cirrhosis and portal hypertension, and is characterized by excessive renal retention of water relative to sodium due to reduced solute-free water clearance. The primary cause is increased release of arginine vasopressin. Hyponatremia is associated with increased mortality in cirrhotic patients, those with end-stage liver disease (ESLD) on transplant waiting lists, and, in some studies, posttransplantation patients. Clinical evidence suggests that adding serum sodium to model for ESLD (MELD) scoring identifies patients in greatest need of liver transplantation by improving waiting list mortality prediction. Hyponatremia is also associated with numerous complications in liver disease patients, including severe ascites, hepatic encephalopathy, infectious complications, renal impairment, increased severity of liver disease in cirrhosis, and increased hospital stay and neurologic/infectious complications posttransplant. Vasopressin receptor antagonists, which act to increase free water excretion (aquaresis) and thereby increase serum sodium concentration, have been evaluated in patients with hypervolemic hyponatremia (including cirrhosis and heart failure) and euvolemic hyponatremia (SIADH). Tolvaptan, a selective vasopressin V(2)-receptor antagonist, is the only oral agent in this class approved for raising sodium levels in hypervolemic and euvolemic hyponatremia. The SALT trials showed that tolvaptan treatment rapidly and effectively resolved hyponatremia in these settings, including cirrhosis, and it has been shown that this agent can be safely and effectively used in long-term treatment. Fluid restriction should be avoided during the first 24 h of treatment to prevent overly rapid correction of hyponatremia, and tolvaptan should not be used in patients who cannot sense/respond to thirst, anuric patients, hypovolemic patients, and/or those requiring urgent intervention to raise serum sodium acutely.

Fig. 1

Six-month survival among 126 critically ill patients with cirrhosis. From Jenq et al. [13], reproduced with permission

Fig. 2

Relative risk of death (with 95 % confidence intervals [CI]) according to serum sodium concentration after adjustment for MELD score among 6,769 registrants in the Organ Procurement and Transplantation Network (2005 and 2006). From Kim et al. [4] reproduced with permission

Fig. 3

a Correlation of MELD score and MELD-Na score calculated by Biggins et al. showing change in transplant allocation priority. The bisecting lines represent 121 transplantations performed within 6 months of listing. The 33 patients in the upper left quadrant would have been favored by MELD-Na scoring over those in the lower right quadrant, who are favored by use of MELD alone. From Biggins et al. [23] reproduced with permission. b Distribution of MELD scores and Meld-Na scores calculated by Kim et al. for 477 patients who died on the transplant waiting list. Dark shaded cells indicate patients with similar MELD and MELD-Na scores. Light shaded cells represent patients with MELD-Na scores that were higher than their MELD scores and in a range that may have resulted in their selection for transplantation. The probabilities of receiving a transplant were 18.5 % for MELD scores of 10–19, 58.4 % for scores of 20–29, and 70.4 % for scores of 30–39. According to these percentages, 32 more patients may have received transplants if MELD-Na scoring had been used, potentially preventing death in 7 % of those who died on the waiting list. From Kim et al. [4] reproduced with permission

Fig. 4

Algorithm for evaluation and treatment of hypo-osmolar patients. The grey arrow running down the center emphasizes that the presence of central nervous system dysfunction due to hyponatremia should always be assessed immediately, so that appropriate therapy can be started as soon as possible in symptomatic patients, even while the outlined diagnostic evaluation is proceeding. Values for osmolality are in mOsm/kg H₂O, and those referring to serum sodium concentration are in mEq/L. Δ change (in concentration), 1° primary, 2° secondary, AVP arginine vasopressin, CNS central nervous system, D/C discontinue, ECF extracellular fluid, N no, NNS normal (isotonic) saline solution, P _osm plasma osmolality, Rx treat/treatment, SIADH syndrome of inappropriate antidiuretic hormone secretion, Y yes; (modified from Verbalis (2009) Hyponatremia and hypo-osmolar disorders. This chapter was published in: Greenberg A, Cheung AK, Coffman T, et al., eds. Primer on Kidney Diseases, 5th ed. Philadelphia: Saunders; 52–59)

Fig. 5

Observed serum sodium concentration throughout the study treatment period (days 1–30) and 7 days after stopping (day 37) in patients receiving tolvaptan or placebo. Error bars are ±SE (standard error of the mean). *P < 0.001, tolvaptan versus placebo; ^† P < 0.01, tolvaptan versus placebo; ^‡ P < 0.05, tolvaptan versus placebo [49]