Hyponatremia and hepatorenal syndrome HRS are severe complications that occur in patients with cirrhosis and ascites and are associated with lower survival than in patients with decompensated cirrhosis eg, those who have uncomplicated ascites, variceal hemorrhage, or encephalopathy.
Dilutional hyponatremia and HRS a type of renal failure unique to patients with cirrhosis represent manifestations of a continuum of pathophysiologic events stemming from portal hypertension and the resultant vasodilatation, which are the main mechanisms responsible for the development of ascites.
Making an accurate differential diagnosis is important both prognostically and therapeutically. We therefore review the pathophysiology, diagnosis, differential diagnosis, and management of hyponatremia and HRS in patients with cirrhosis. Vasodilatation of both the splanchnic and systemic circulations is one of the main factors contributing to the development of hyponatremia and HRS in cirrhosis Figure 1. Vasodilatation occurs after portal hypertension has led to the formation of portosystemic collaterals when factors that have not been well elucidated vascular endothelial growth factor being one of them trigger the production of nitric oxide and other vasodilators.
In advanced stages of cirrhosis, progressive vasodilatation leads not only to avid sodium retention with formation of ascites that is now refractory to diuretics but also to the nonosmotic release of antidiuretic hormone or arginine vasopressin AVP.
The biological effects of AVP in increasing water reabsorption are mediated through G protein—coupled receptors, specifically vasopressin 2 V2 receptors located on the basolateral membrane of principal cells of the collecting ducts.
When activated by AVP, V2 receptors enable translocation of selective water channels called aquaporins from the cytosol to the luminal plasma membrane of the collecting ducts, increasing water permeability.
This increase in water reabsorption exceeds that of sodium retention and leads to dilutional hyponatremia. V2 receptor antagonism has therefore been a potential target for drugs used in the treatment of this dilutional hyponatremia. Progressive vasodilatation also leads to further activation of vasoconstrictive systems mainly renin and angiotensin , resulting in renal vasoconstriction and decreased renal blood flow.
In addition, a relative decrease in cardiac output in this high-output cardiac failure state or cirrhotic cardiomyopathy may further contribute to decreased renal blood flow. Hepatorenal physiology as described above may be present in many patients with advanced cirrhosis who may develop HRS without an obvious precipitating event. However, more often than not, HRS is precipitated by factors that cause either a decrease in effective arterial blood volume, such as rapid fluid loss eg, excessive diuresis and gastrointestinal bleeding , or worsening vasodilatation induced by drugs eg, nitrates, carvedilol, and angiotensin-converting enzyme inhibitors or by a systemic inflammatory response eg, infection.
Hyponatremia in cirrhosis may be 1 hypervolemic or dilutional as a result of water retention in excess of sodium retention due to AVP activation secondary to vasodilatation and decreased effective circulatory volume or 2 hypovolemic as a result of sodium and fluid losses mainly overdiuresis.
It is important to distinguish between hypervolemic and hypovolemic hyponatremia in order to provide appropriate management. As hypervolemic hyponatremia results from increased sodium and water retention, patients often have dependent edema and tense refractory ascites. The clinical hallmark of systemic vasodilatation is low MAP; patients with dilutional hyponatremia are therefore usually hypotensive and may have creatinine levels above baseline.
On the other hand, in hypovolemic hyponatremia, patients are often dehydrated. They appear dry, with no ascites or edema. Hyponatremia is associated with a significantly higher risk of death with cirrhosis.
Kim and colleagues demonstrated serum sodium to be an important predictor of mortality, independent of MELD score among adult patients listed for liver transplantation.
The presence of dilutional hyponatremia is associated with severe ascites, spontaneous bacterial peritonitis, and HRS. In patients with cirrhosis and ascites, hyponatremia was found to be an independent predictor of decreased physical as well as mental component scores of the SF questionnaire that assesses HRQOL.
Pretransplant hyponatremia is an independent predictor of short-term mortality after liver transplantation. Apart from neurologic complications, pretransplant hyponatremia has been associated with an increased risk of renal failure and bacterial infections in the first month posttransplantation. Recognition of the type of hyponatremia hypervolemic vs hypovolemic is key in tailoring management. The easier type to treat is hypovolemic hypernatremia because removal of the precipitating factor mainly diuretics and administration of intravenous isotonic solutions to expand plasma volume often correct the abnormality.
On the other hand, treatment of hypervolemic hyponatremia is difficult and directed at decreasing excess free water in the circulation. Water restriction to 1 to 1. However, patient compliance is very poor, and the resultant effect on serum sodium levels is modest. Potential therapeutic targets for the management of hypervolemic hyponatremia in cirrhosis are shown in Figure 2. These include increasing renal excretion of solute-free water, increasing the effective arterial blood volume, and ameliorating systemic and splanchnic vasodilatation.
Vaptans, or V2 receptor antagonists, are a class of drugs that increase renal excretion of solute-free water by blocking water reabsorption, leading to voluminous hypotonic urine output. A recent meta-analysis of randomized, controlled trials of vaptans satavaptan, tolvaptan [Samsca, Otsuka], and lixivaptan for hyponatremia in patients with cirrhosis, in which the primary outcome was death, showed a small transient beneficial effect on hyponatremia but no effect on mortality or renal failure.
Tolvaptan is the only orally administered vaptan that is approved by the US Food and Drug Administration. Because significant elevations in liver enzymes have been observed with tolvaptan use in patients with autosomal dominant polycystic kidney disease, a black box warning was recently issued that precludes the use of this agent in patients with severe liver disease.
Interventions to correct the decreased effective arterial blood volume in patients with hyponatremia include withdrawal of diuretics and use of intravenous albumin. Infusion of albumin in a very small number of patients was found to be useful in short-term, nonrandomized studies.
However, the long-term benefit of albumin use remains unknown. Serum creatinine is an independent predictor of mortality in decompensated cirrhosis, such that it is a component of the MELD score, which is a robust predictor of 4-month mortality risk and, hence, is currently used for determining priority for orthotopic liver transplantation.
As mentioned previously, HRS is functional renal failure resulting from renal vasoconstriction, which in turn is a result of extreme vasodilation in the splanchnic and systemic vascular beds. HRS is a state of effective hypovolemia associated with low MAP, relatively decreased cardiac output, and reduced systemic vascular resistance.
HRS-1 is characterized by an abrupt deterioration in renal function a form of acute kidney injury [AKI] , often precipitated by a bacterial infection such as spontaneous bacterial peritonitis. HRS-2 is a more chronic form of renal dysfunction akin to chronic kidney disease [CKD] that is often associated with refractory ascites. Per the International Club of Ascites consensus conference in ,30 HRS is defined by a serum creatinine level of greater than 1. Although this definition may apply to patients with HRS-2, AKI in cirrhosis has been redefined very recently, and that definition is expanded below.
HRS-1 was defined by the International Club of Ascites as the doubling of initial serum creatinine concentration to a level greater than 2. This criterion has been recently revised as a result of a consensus conference among members of the International Club of Ascites in , taking into consideration that 1 the use of a creatinine cutoff of 1.
If the baseline measurement is unavailable, a serum creatinine measurement within the 3 months prior to admission can be considered as baseline. Although the more advanced the stage of AKI, the higher the mortality rate, progression of kidney injury to higher AKIN stages is the strongest independent predictor of mortality in hospitalized patients with cirrhosis. It should be noted, however, that creatinine-based equations eg, Modification of Diet in Renal Disease [MDRD] perform poorly in patients with cirrhosis, particularly in those with decompensated cirrhosis.
These patients may not have the recognized characteristics of patients with pure HRS, as they may have high MAP, and the use of vasoconstrictors in this setting would require investigation.
Making an accurate differential diagnosis is key in determining the most appropriate management. Prerenal azotemia responds to volume expansion, but vasoconstrictors and dialysis are not required. Acute tubular necrosis is treated with renal replacement therapy if indicated, but volume should not be expanded. HRS is caused by extreme vasodilatation with or without a precipitant with consequent renal vasoconstriction and is treated with vasoconstrictors and volume expansion.
Therefore, the first step in its diagnosis is to exclude the presence of structural kidney injury acute tubular necrosis, glomerulonephritis, and acute interstitial nephritis or obstructive kidney injury obstructive uropathy and to distinguish between prerenal azotemia and HRS the 2 functional types of AKI in cirrhosis.
Evidence of systemic inflammatory response syndrome and evaluation of volume status during physical examination are important. The presence of traditional urine biomarkers urine sediment, fractional excretion of sodium [FeNa], and urine albumin should be assessed as well as a renal ultrasound to exclude postobstructive uropathy.
Recent studies demonstrate the potential utility of urinary biomarkers in differentiating acute tubular necrosis from prerenal azotemia and HRS. Urinary neutrophil gelatinase—associated lipocalin, interleukin, liver-type fatty acid—binding protein, and urine albumin levels are highest in patients with acute tubular necrosis, lowest in patients with prerenal azotemia, and intermediate in those with HRS.
Interestingly, in a recent study, FeNa levels below 0. At times, the differential between acute tubular necrosis and HRS becomes difficult because, in advanced HRS, renal vasoconstriction may lead to tubular damage. Although the same precipitants of prerenal azotemia particularly those that worsen vasodilatation, such as infections may also precipitate HRS, in prerenal azotemia treatment of the precipitant and volume expansion should lead to resolution of AKI.
When the patient is clearly volume-depleted, volume expansion can be provided by intravenous saline solution eg, for overdiuresis or blood eg, for gastrointestinal hemorrhage. Once volume expansion and antibiotics have been initiated in those with suspected or confirmed infection , the course of AKI should be reevaluated in 24 to 48 hours.
If the serum creatinine level has improved significantly or returned to baseline, therapy should continue, as this is likely to be prerenal azotemia. If the creatinine level has decreased only slightly, patient management should be individualized and may include repeating the AKI workup. If the creatinine level is unchanged or has worsened, the patient likely has HRS, and specific therapy can be initiated.
It is important to note that at least 2 days of observation would have elapsed from the time of AKI diagnosis to the initiation of treatment for HRS. It is also important to remark that patients with HRS have advanced liver disease median Child-Pugh score, Liver transplantation is the definitive treatment for HRS because it is the only therapeutic option associated with improved survival.
Vasoconstrictors and Albumin Splanchnic and systemic vasodilatation and resultant renal vasoconstriction are the main mechanisms for development of HRS. Vasoconstrictors are used in conjunction with albumin in therapy for HRS.
Albumin acts as a plasma expander and, by binding vasodilator substances such as nitric oxide and by improving cirrhotic cardiomyopathy, may provide a beneficial effect that goes beyond volume expansion.
Vasoconstrictors that have been used in patients with HRS include terlipressin, norepinephrine, octreotide plus midodrine, and vasopressin.
In proof-of-concept studies, the use of these agents for more than 3 days has been associated with improvement in MAP, glomerular filtration rate, and serum sodium levels, with a decrease in plasma renin activity.
This is supported by a pooled analysis of 21 studies evaluating vasoconstrictor use in HRS that showed a strong association of increase in MAP with improvement in renal function. Terlipressin is a longer-acting vasopressin analogue with fewer side effects than vasopressin and is the vasoconstrictor for which there are more data regarding HRS. Terlipressin is administered at a dose of 1 mg every 4 hours.
If resolution of HRS is not observed after 10 days of therapy, use of terlipressin should be discontinued. Terlipressin is not yet available in the United States. However, there are alternatives. Two small randomized studies comparing terlipressin vs norepinephrine specifically in patients with HRS-1 have shown comparable effectiveness and side-effect profiles. Norepinephrine is given in doses of 0. The use of midodrine alone or octreotide alone is not associated with improvement in renal function in HRS.
Despite the lack of strong evidence, the combination of octreotide, midodrine, and albumin has been adopted as first-line therapy in countries where terlipressin is not available, such as the United States. Midodrine is given in doses of 7. Because this is a weak vasoconstrictor combination, if an improvement in MAP or creatinine level is not noted within 3 days after initiating midodrine and octreotide during which the dose should be escalated rapidly , then the patient should be transferred to the intensive care unit for administration of norepinephrine or vasopressin infusion.
Terlipressin is a vasopressin analogue, so vasopressin should be as effective as terlipressin. One retrospective study compared the use of vasopressin and octreotide for management of HRS and demonstrated higher recovery rates with the use of vasopressin.
All patients receiving vasoconstrictor therapies should be monitored for ischemic and cardiovascular complications. Vasoconstrictor therapies are not recommended in patients with preexisting ischemic heart disease, cerebrovascular disease, peripheral arterial disease, hypertension, or asthma. Other Therapies Transjugular intrahepatic portosystemic shunt TIPS and extracorporeal albumin dialysis have been evaluated in small studies as alternative therapies for HRS.
In one small, randomized, controlled trial, extracorporeal albumin dialysis was shown to reduce day mortality in patients with HRS as compared with venovenous hemofiltration alone. Hyponatremia and HRS are severe and ominous complications in patients with decompensated cirrhosis.
Early recognition and the initiation of appropriate therapy are keys to ensure reversal or even slowing of the process.
Because patients with HRS are often very sick and require treatment in an intensive care unit, coordinated multidisciplinary care with hepatologists, the transplant team, nephrologists, and critical care specialists is necessary to successfully bridge these patients to liver transplantation.
The authors have no relevant conflicts of interest to disclose. Hyponatremia and mortality among patients on the liver-transplant waiting list. Currently, a new family of drugs, known as vaptans, which act by antagonizing specifically the effects of arginine vasopressin on the V2 receptors located in the kidney tubules, is being evaluated for their role in the management of hyponatremia. The short-term treatment with vaptans is associated with a marked increase in renal solute-free water excretion and improvement of hyponatremia.
Long-term administration of vaptans seems to be effective in maintaining the improvement of serum sodium concentration, but the available information is still limited. Treatment with vaptans represents a novel approach to improving serum sodium concentration in cirrhosis.
Abstract Hyponatremia is a frequent complication of advanced cirrhosis related to an impairment in the renal capacity to eliminate solute-free water that causes a retention of water that is disproportionate to the retention of sodium, thus causing a reduction in serum sodium concentration and hypo-osmolality. Publication types Research Support, Non-U.
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