Treatment strategy for patients with hepatorenal syndrome. Terlipressin is widely used in Europe but is not available in many countries including the United States. [This figure appears in colour on the web.] 

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... are the neurological complications that can occur after a rapid correction of serum sodium levels. It has been known for many years that in patients without liver disease with hyponatremia of different etiologies the rapid correction of hyponatremia may lead to the development central pontine myelinolysis (CPM), a severe condition with high mortality in which shrinkage of cerebral tissues leads to demyelination of pontine and extrapontine neurons causing seizures and coma [33]. Studies in small series of patients and isolated reports have described the occurrence of neurological complications, particularly CPM, in patients with cirrhosis after OLT [34,35]. In most, if not all cases CPM was associated with a rapid increase in serum sodium levels after transplantation, exceeding 20 mEq/L or more during a period of 24 h [34]. Therefore, every effort should be made to avoid rapid increases in serum sodium concentration in patients with cirrhosis transplanted with low serum sodium levels. In the future, improvement of serum sodium levels before transplantation with the use of vasopressin receptor antagonists drugs may help prevent significant fluctuations in serum sodium levels and subsequent development of neurological complications posttransplantation (see below). The first step in the management of dilutional hyponatremia is fluid restriction and discontinuation of diuretics. Water restriction at 1000 mL/day helps prevent the progressive decrease in serum sodium concentration but usually does not correct hyponatremia in most cases [36]. Currently, several pharmaceutical companies are developing drugs that are active orally and act by selectively antagonizing the specific receptors (V2 receptor) of arginine vasopressin. These agents act in the distal collecting ducts of the kidneys, by increasing solute-free water excretion and, thus, improving serum sodium concentration in hyponatremic patients. Recent reports in patients with cirrhosis and ascites indicate that these drugs are effective in improving serum sodium concentration in hyponatremic patients [36,37]. Large Phase II and III multicenter clinical trials are currently being conducted in aims of learning more about the efficacy and safety of these drugs. These compounds if approved for clinical use could be useful in managing decompensated cirrhotic patients listed for OLT. HRS is a functional renal failure without any identifiable kidney pathology that occurs in about 10% of patients with advanced cirrhosis [9,38]. The diagnosis of HRS is currently made using criteria to exclude other causes of renal failure that can occur in cirrhosis (Table 1). HRS is commonly seen in patients awaiting OLT and remains one of the most challenging complications of cirrhosis to manage given that there are limited treatments. It may develop acutely or subacutely. Type 1 HRS is an acute and rapidly progressive form of renal failure (serum creatinine O 2.5 mg/dL) that may occur spontaneously or be precipitated by events such as SBP, alcoholic hepatitis or large volume paracentesis without albumin expansion. The expected survival of type 1 HRS is of only 2 weeks if not treated or transplanted [39]. In type 2 HRS, renal failure is usually less severe (serum creatinine 1.5–2.5 mg/dL) and shows little or no rapid progression compared to that of type 1 HRS. Prevention of HRS has been a major step improving care for patients listed for OLT. There are two clinical situations in which HRS can be prevented; SBP and alcoholic hepatitis [40,41] (Table 2). Although OLT is undoubtedly the best treatment for HRS, successful pharmacological therapy prior to OLT is equally important in assuring an optimal outcome similar to that of patients without HRS. Systemic vasoconstrictors with plasma expansion are the therapy of choice for HRS now that several uncontrolled studies have confirmed a beneficial role in HRS [42–51]. Vasoconstrictors are used because the initial event in the pathogenesis of HRS is an arterial splanchnic vasodilation causing activation of endogenous vasoconstrictors systems with subsequent renal vasoconstriction. Intravenous terlipressin along with albumin as a plasma expander is associated with a significant improvement of renal function and reduction of serum creatinine to less than 1.5 mg/dL in approximately 60–75% of patients treated for at least 5 days [42–48]. With this protocol, recurrence is uncommon. Unfortunately, terlipressin is not available in many countries including the United States and, therefore, other options such as alpha- adrenergic agonists are a reasonable alternative given that they are widely available. Midodrine, an alpha-adrenergic agonist in association with octreotide, a glucagon inhibitor, and albumin has also proved efficatious in HRS [49,50]. Noradrenaline, another alpha agonist, in combination with albumin expansion also improves renal function in HRS [51]. The recommended doses and duration of vasocon- strictor therapy are summarized in Fig. 3. In three studies, patients that responded to therapy of HRS (decrease of creatinine to ! 1.5 mg/dL) with terlipressin plus albumin and octreotide, midodrine and albumin had an increased survival compared to those that did not respond to this therapy [43,44,50]. The primary goal of phamacological therapy is normal- ization of renal function so that suitable transplant candidates can undergo OLT with less morbidity and have similar survival compared to that of patients without HRS. A recent study from our Unit revealed that patients treated sucessfully with vasopressin analogues and albumin before OLT had a similar post-transplantation outcome and survival similar to patients transplanted without HRS [52]. This study supports the concept that HRS should be treated aggresively before OLT because improvements in renal function are associated with better outcomes. TIPS may improve renal function in HRS. In one recent study of 14 patients with type 1 HRS treated with midodrine, octreotide, and albumin, 10 had a good response (serum creatinine remained stable at ! 1.5 mg/dL for 3 days) and were subsequently treated with TIPS if not contraindicated by INR O 2.0, serum bilirubin O 5 mg/dL, and a Child-Pugh score O 12 [50]. Five patients underwent TIPS with very good outcome with one of them successfully receiving living donor OLT. Interestingly renal function continued to improve and completely normalized in these five patients. Of the five that responded to vasoconstrictors and albumin but did not get TIPS, two underwent successful OLT, but three died as a consequence of liver failure, sepsis and arrhythmia. There was improved survival in all responders, but the real impact of TIPS in improving survival is difficult to assess given the low number of patients treated. OLT is the optimal treatment for suitable candidates with HRS. Unfortunately, transplantation for HRS is limited by the fact that many of these patients may die before the operation due to prolonged waiting in the list in most centers. Priority for OLT in the United States is based on the MELD score which includes three variables; bilirubin, serum creatinine and international normalized ratio (INR) [53]. This scoring system is objective, includes serum creatinine and predicts survival in cirrhotics. The score ranges from 6 to 40. Its role in predicting prognosis in patients with HRS has recently been confirmed in our Unit in 105 cirrhotic patients with HRS (P. Gin ́s, unpublished results). Patients with type 1 HRS with a MELD score R 20 showed an extremely poor outcome with a median survival of 1 month and those with type 2 HRS and a score ! 20 showed a slightly better outcome with a median survival of 11 months, while patients with type 2 HRS and a score O 20 had an intermediate outcome, with a median survival of three months. In the whole group, the two independent predictive factors of survival were MELD score and type of HRS. Other centers outside the United States have different allocation systems that give higher priority to patients with HRS. Regardless of the system used for organ allocation, patients with HRS must be appropriately treated before transplantation. Since cyclosporine and tacrolimus treatment may contribute to renal impairment post-operatively, these drugs should not be given until diuresis and improvement of renal function is observed, usually in 3–4 days after transplantation. Bacterial infections are one of the most feared problems that complicate the course of patients with advanced liver disease. It is estimated that they occur at admission or during hospitalization in 20–60% of patients [54]. A recent prospective study conducted in our Unit between 1998 and 2000 showed that among all admissions, bacterial infections were present in 32% of cases either at entry or during hospitalization [55]. Of these the majority were secondary to SBP (24%), other common causes included urinary tract infection, pneumonia and bacteremia secondary to invasive procedures. Only 39% of SBP were culture positive and among these 84% were due to Gram-negative bacteria. Aerobic Gram-positive bacteria, mostly Streptococcus viridans , Staphylococcus aureus and Enterococcus fecalis were isolated in approximately 20% cases [55]. The prevalence of SBP in hospitalized cirrhotic patients ranges between 10 and 30% [54]. The 1-year survival probability after an episode is only 40% and therefore, patients should be evaluated for OLT once they are cured [54,56]. The clinical spectrum of SBP is variable and ranges from no symptoms to fever, chills, abdominal pain, and/or hepatic encephalopathy to a severe picture of peritonitis. The diagnosis of SBP relies on the examination of peritoneal fluid. The diagnosis is made when the poly- morphonuclear cell count is greater than 250/mm 3 or when urine strips for leukocyte estearase are positive (3 or 4 C ) [11–13,54]. For this reason and because of the high prevalence of SBP in patients with ascites, ...