EXPERIMENTAL AND CLINICAL TRANSPLANTATION

For patients on liver transplant waiting lists, hypo-natremia is associated with increased mortality before transplant and complications during the early posttransplant period. Conventional therapies, such as fluid restriction or hypertonic saline infusion, are of limited value. We describe 2 patients with high Model for End-Stage Liver Disease scores (> 30) who were referred to our unit for expedited liver transplant. While on waiting lists, these patients developed severe hyponatremia (< 125 mEq/L) that was refractory to conventional therapies. Low-dose, short-term tolvaptan therapy (15 mg/d for 5 d) was then administered, as a bridge therapy to transplant, resulting in prompt restoration of serum sodium levels without any major clinical event. One patient died a few days later as no suitable grafts were available. The other received a liver transplant, and the outcome was uneventful. In conclusion, our report demonstrates that a short-term, low-dose tolvaptan-based strategy promptly resolves hyponatremia in patients who are on expedited waiting lists for liver transplant, allowing surgery with improved sodium levels and possibly limiting peritransplant complications.

Key words : Expedited liver transplant, Hyponatremia, Waiting list

Hyponatremia, defined as serum sodium levels < 130 mEq/L, is an important issue in patients with end-stage liver disease (ESLD) as it may lead to major complications such as renal failure, hepatic encephalopathy, and infections, thus affecting overall survival.¹ Hyponatremia is considered mainly dilutional in ESLD, as it is generally associated with ascites, peripheral edema, and brain edema, with impaired cognition and decreased quality of life. Patients with ESLD usually have reduced renal sodium excretion and increased water retention as a result of systemic hemodynamic derangement and hypersecretion of arginine vasopressin.²

For patients who are on liver transplant waiting lists, hyponatremia raises particular concerns because of its association with increased risk of mortality.³ Given the important and independent role of natremia in prognosis, the inclusion of sodium levels in the Model for End Stage Liver Disease (MELD) scoring system has been suggested. Inclusion would allow an evidence-based approach to improve graft allocation for patients on waiting lists.⁴ European studies have consistently reported that neurologic, infection-related, and renal complications after transplant are common in ESLD hyponatremic patients, leading to reduced survival.^5,6

With this understanding, it is important to attempt to correct severe hyponatremia (< 125 mEq/L) in patients waiting for liver transplant to prevent mortality before transplant and posttransplant complications. In addition, central pontine myelinolysis, a condition occurring after liver transplant (related to the rapid correction of serum sodium levels), which has a rate of permanent disability and/or mortality of 75%, can occur in severely hyponatremic patients during the first 48 hours after transplant.⁷ In fact, these patients are subject to greater and more harmful variations in serum sodium concentrations during the perioperative phase.⁸ With the possibility of this serious neurologic complication, several transplant centers have required measures to counteract severe hyponatremia before patients undergo liver transplant.

However, management of hypervolemic hypo-natremia in the clinical setting of liver diseases is often difficult. Fluid restriction (< 1 L/d) associated with diuretic therapy withdrawal is the principal measure to counteract this clinical occurrence, but effects are usually modest. Intravenous hypertonic saline administration gives limited results, worsening ascites and edema.

Here, we report on an alternative strategy, the use of the vasopressin V2 receptor anatagonist tolvaptan, for the rapid correction of hypervolemic hyponatremia in 2 patients with MELD scores > 30 waiting for regional advanced (top of waiting list) liver transplant.

Patient 1
A male patient (age, 62 y) with hepatitis C virus-related ESLD was added to the liver transplant list with a MELD score of 28. During the next month, his hepatic condition deteriorated, leading to an increase in MELD score (> 30), and, despite liquid restrictions and diuretic therapy withdrawal, he developed severe hyponatremia (sodium level < 125 mEq/L), with normal creatinine level, diluted urine, plasmatic osmolality < 280 msm/kg, and urine sodium level < 20 mmol/L. The patient was hospitalized, and regional advanced liver transplant was requested, with attempts to correct the serum sodium level. Although hypertonic saline administration is known to have limited efficacy, it was undertaken nevertheless because of the possible deleterious effects of hyponatremia on a patient in the pretransplant and posttransplant setting. Infusion therapy resulted in an increase in serum sodium level (to 126 mEq/L); however, the effect was transient, and natremia returned to baseline levels despite further intravenous sodium administration (Figure 1). Subsequently, after the acquisition of patient informed consent, tolvaptan treatment was started (15 mg/d with free access to water). This resulted in a prompt increase in natremia, reaching a peak of 131 mEq/L 5 days later. After treatment was stopped, sodium levels remained above 125 mEq/L with fluid restriction only (Figure 1, panel A).

One week later, the patient died from multiorgan failure due to ESLD because an appropriate graft was not available for transplant, despite the level of urgency. Tolvaptan treatment did not result in any major biochemical changes in liver or kidney enzymes or cholestasis markers.

Patient 2
A 45-year-old male patient with hepatitis C virus-related liver cirrhosis was added to our center’s liver transplant list with a MELD score of 26. In the next month, his hepatic conditions worsened, and the patient reached a MELD score of 32. Regional advanced liver transplant was therefore requested. The patient developed severe hyponatremia, with sodium levels of < 125 mEq/L, which did not respond to liquid restriction and diuretic withdrawal. As in the previous patient, serum creatinine levels were normal with diluted urine and urine sodium level < 20 mmol/L. Plasmatic osmolality was < 280 mosm/kg. Patient 2 also received hypertonic saline infusion. Because the patient did not respond to hydrolytic infusion, after acquisition of informed consent, tolvaptan therapy was started (Figure 1, panel B). The treatment resulted in a prompt increase of serum sodium levels that persisted after therapy withdrawal. Five days later, the patient received a deceased-donor liver transplant. The early posto-perative period was uneventful. The patient was discharged 20 days after transplant. Short-term tolvaptan treatment did not result in any major clinical or biochemical events.

Vasopressin receptor antagonists (or vaptans) are a new family of drugs that prevent vasopressin action at its receptor site. Among these, tolvaptan is a competitive vasopressin V2 receptor antagonist that has been used to correct hyponatremia associated with congestive heart failure, antidiuretic hormone (vasopressin) secretion, and liver cirrhosis.^1,2 In an early study of patients with hyponatremia from different causes, tolvaptan resulted in a significant correction of sodium levels in cirrhotic patients.⁹ The safe use of tolvaptan in cirrhotic patients has, however, been recently challenged by a US Food and Drug Administration safety communication (http://www.fda.gov/Safety/MedWatch/SafetyIn ormation/SafetyAlertsforHumanMedicalProducts ucm350185.htm), which cautioned on the use of the drug in patients with underlying liver disease. In a trial of tolvaptan in patients with autosomal dominant polycystic kidney disease, significant liver toxicity was shown in nearly 1% of treated patients when the drug was administered at the maximally tolerated dose and constantly for 36 months.10 Based on these findings, it is recommended that treatment should be limited to 30 days, and the drug should be avoided in patients with underlying liver disease.

Given the possibility of serious liver toxicity with tolvaptan during long-term administration and the rapid reduction of its effects after discontinuation,¹¹ the use of this agent to treat cirrhosis-related chronic hyponatremia and its sequelae did not seem further justified. However, even with the transient effects, a recent study demonstrated that short-term tolvaptan therapy in patients with liver disease avoided potential liver injury and improved cognition, quality of life, and brain edema as assessed by a magnetic resonance imaging scan.¹²

In this study, we report our experience with tolvaptan as a bridge, short-term therapy for severe hyponatremia (< 125 mEq/L) in 2 patients with ESLD who were on the waiting list for regional advanced liver transplant because of high MELD scores (> 30). This treatment was started after patients did not respond to conventional therapies (liquid restriction and hypertonic saline administration) and because of the serious adverse events that could occur in patients with hyponatremia who are waiting for liver transplant and immediately after transplant. Moreover, we also considered the recent data that showed that, together with sodium level, a pretransplant MELD score ≥ 26 is an important additional risk factor for central pontine myelinolysis.¹³

Our observations indicate that (1) in ESLD patients, short-term (5 days), low-dose tolvaptan therapy resulted in a prompt restoration of sodium levels above 130 mEq/L after other therapeutic approaches demonstrated no improvements; (2) serum sodium levels were easily normalized with tolvaptan in patients with severe liver disease; and (3) tolvaptan therapy had no detrimental effects.

Before our patients started tolvaptan therapy, a major contributor to MELD score and severity of liver disease in our patients was related to bilirubin and international normalized ratio levels (in patients with both values > 10 mg/dL of total bilirubin and international normalized ratio levels of approximately 2.5 without correction). Moreover, severe cholestasis and coagulopathy are not absolute contraindications to tolvaptan therapy.

In conclusion, our brief report describes, for the first time, the use of a short-term low-dose tolvaptan-based strategy, as a bridge therapy for expedited liver transplant in patients with severe liver disease and hyponatremia so that sodium levels could be corrected before the surgical procedure, thus possibly limiting hyponatremia-related complications during the early posttransplant period. Although our preliminary results demonstrate the feasibility of this approach, these (the possible) beneficial effects require confirmation in a large randomized trial.

Volume: 15 Issue: 6 December 2017

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