Massive Aquaresis After Tolvaptan Administration and Albumin Infusion in a Patient with Alcoholic Cirrhosis

The management of hyponatremia in patients with end-stage liver disease is always a challenge for caring physicians because of limited options, poor responses, and risk of central pontine myelinolysis due to rapid correction of hyponatremia.¹ Tolvaptan, an oral competitive arginine vasopressin V2-receptor antagonist, is effective for treating euvolemic or hypervolemic hyponatremia, including cirrhosis-related hyponatremia, and is well tolerated.², ³ We describe a patient with alcoholic cirrhosis-associated hyponatremia who developed massive aquaresis after tolvaptan administration and intravenous albumin infusion.

A 40-year-old man with recently diagnosed alcoholic cirrhosis presented with a 2-day history of increasing lethargy and anasarca. He had been receiving frequent paracentesis despite taking spironolactone 100 mg daily and furosemide 40 mg daily. On examination, his blood pressure was 136/88 mm Hg. He was icteric and had a moderately distended abdomen with 2+ pitting edema in the lower extremities. Laboratory results were significant for a sodium concentration of 125 mEq/L, creatinine level of 0.6 mg/dL, albumin level of 2.7 g/dL, total bilirubin level of 19.1 mg/dL, and ammonia level of 50 mmol/L.

The patient was treated initially with oral lactulose solution for hepatic encephalopathy. His mental status improved, but his serum sodium level decreased to 120 mEq/dL when he started to consume more fluids despite a fluid restriction order. His urine sodium concentration was 94 mEq/L and urine osmolality was 754 mOsm/kg. Because of the lack of improvement in hyponatremia, tolvaptan 30 mg was given orally. His urine output increased to 200 to 300 mL per hour with an increase in serum sodium level and decrease in urine osmolality (Figure 1A-C). The patient then underwent paracentesis with removal of 3 liters of ascites. He received 25% albumin infusion at 50 mL/h for 6 hours starting 5 hours after tolvaptan administration. His urine output suddenly increased to 500 to 900 mL/h at the end of the albumin infusion. Because of massive polyuria, a large amount of hypotonic fluid was given intravenously to match the urine loss and prevent rapid correction of hyponatremia (Figure 1A). The aquaretic effect of tolvaptan abruptly stopped at 16 hours when urine output decreased to 115 mL/h from 400 mL/h at the previous hour. The urine output continued to decrease to 10 to 50 mL/h subsequently. Because of excessive hypotonic fluid administration, the patient's serum sodium level was 124 mEq/L at 24 hours after tolvaptan dosing.

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  Figure 1. 

  A, Hourly input (dash line) and urine output (solid line) after a single dose of tolvaptan given at time 0. The bar indicates 6-h intravenous 25% albumin infusion (50 mL/h). B, C, Time course of the change in serum sodium level and urine osmolality, respectively. The upward trend of serum sodium was leveled off after administration of intravenous hypotonic fluid. Tolvaptan caused a rapid decrease in urine osmolality. At 16 hours, urine osmolality increased as tolvaptan was weaned.

  
  
  
  
  
  
  
  
  
  
  
  
   

Our patient had an unusual response to a single dose of oral tolvaptan that produced a large amount of dilute urine. Such a massive aquaresis has not been reported. A meta-analysis found an average increase in water clearance of only 68 mL/h after tolvaptan treatment.³ However, in our patient, the maximum water clearance after tolvaptan treatment was 675 mL/h. Such an unexpected response required intensive monitoring of serum sodium levels and administrating hypotonic fluid intravenously to avoid rapid correction of hyponatremia.

We believe that the massive aquaresis observed in our patient was not caused by tolvaptan alone. The initial increase in serum sodium level, 5 mEq/L in the first 8 hours after tolvaptan, is slightly more than expected, probably because of poor fluid intake. However, the sudden and marked increase in urine output that began 10 hours after taking tolvaptan coincided with intravenous infusion of albumin. It is likely that this treatment transiently increased the oncotic pressure of the intravascular fluid, causing mobilization of the interstitial fluid, and increased the intravascular volume.⁴ As a result, renal perfusion and glomerular filtration increased. Because the collecting duct was deprived of aquaporins as the result of vasopressin receptor blockade by tolvaptan, the urine output markedly increased as the filtration rate increased.

We would like to bring this occurrence to the attention of physicians who are managing patients with hyponatremia-complicating cirrhosis with ascites and edema. Treatment with a combination of vasopressin receptor blockers and interventions that increase renal perfusion, such as albumin infusion in hypoalbuminemic patients, may induce massive aquaresis that could be life threatening.

References 

1. Lien YH, Shapiro JI. Hyponatremia: clinical diagnosis and management. Am J Med. 2007;120:653–658
2. Dixon MB, Lien YH. Tolvaptan and its potential in the treatment of hyponatremia. Ther Clin Risk Manag. 2008;4:1149–1155
3. Rozen-Zvi B, Yahav D, Gheorghiade M, Korzets A, Leibovici L, Gafter U. Vasopressin receptor antagonists for the treatment of hyponatremia: systematic review and meta-analysis. Am J Kidney Dis. 2010;56:325–337
4. Umgelter A, Wagner K, Reindl W, Nurtsch N, Huber W, Schmid RM. Haemodynamic effects of plasma-expansion with hyperoncotic albumin in cirrhotic patients with renal failure: a prospective interventional study. BMC Gastroenterol. 2008;8:39