Introduction
Renal dysfunction is a widespread complication in individuals with clinically evident cirrhosis. Changes in renal physiology in acute liver failure or cirrhosis with ascites, in particular, can predispose an individual to a particular functional type of renal failure known as hepatorenal syndrome (HRS). Hecker and Sherlock published the first detailed description of HRS in 1956.
What Is Hepatorenal Syndrome (HRS)?
-
The progression of renal failure in patients suffering from advanced liver failure (acute or chronic) without recognizable causes of renal pathology is defined as HRS.
-
There is substantial evidence that circulatory dysfunction is crucial in the pathogenesis of HRS in cirrhosis. A reduction in adequate blood volume due to systemic vasodilation with decreased renal perfusion causes compensatory activation of the renin-angiotensin system, the release of arginine vasopressin (antidiuretic hormone), and vasoconstriction of the renal blood vessels.
-
As cirrhosis progresses, chronic circulatory stress enhances systolic heart failure, exacerbating arterial under-filling with reduced renal perfusion, further deteriorating cardiac and renal function.
What Is the Classification of Hepatorenal Syndrome?
The International Ascites Club released a consensus paper in 1996 that classified HRS into two types.
-
Type 1 HRS is distinguished by a rapid decline in renal function, defined as a doubling of serum creatinine (sCr) greater than 2.5 mg/dL or a halving of creatinine clearance to 20 mL/min in less than two weeks. Acute renal failure is the clinical presentation.
-
Type 2 HRS is defined by renal function deteriorating more slowly, with serum creatinine rising to more than 1.5 mg/dL or a creatinine clearance of 40 mL/min. The clinical picture is that of a patient with refractory ascites with stable renal failure.
-
Although acute kidney injury (AKI) from HRS usually resolves after liver failure or with effective liver transplantation, persistent AKI from HRS can lead to irreversible renal failure. The survival rate varies between HRS types, with an average survival time of 14 days in type I compared to six months in type II HRS.
-
There is substantial evidence that renal dysfunction in cirrhotic patients is also caused by infection or inflammatory-mediated injury to the renal tubules. Bacterial translocation from the intestine has increased cytokine, nitric oxide metabolite, and the production of toll-like receptors.
-
Neutrophil gelatinase-associated lipocalin is produced in renal tubules and is up-regulated following tubular inflammation or injury. In addition, serum and urine levels in HRS patients were considerably higher than in stable cirrhotic patients. These findings point to the importance of inflammation-mediated renal dysfunction in cirrhosis.
-
In patients with cirrhosis, selective decontamination of the intestine and eradicating bacterial translocation with norfloxacin reduces renal dysfunction and improves survival.
What Are the Diagnostic Criteria for Hepatorenal Syndrome?
Primary criteria (must include all the norms):
-
An acute or chronic liver disease characterized by advanced hepatic failure and portal hypertension.
-
Low glomerular filtration rate (GFR), as demonstrated by a 24-hour creatinine clearance of less than 40 mL/min or serum creatinine levels greater than 1.5 mg/dL.
-
Absence of shock, septicemia (blood infection), depletion of volume, and nephrotoxic exposure.
-
Following diuretic withdrawal or plasma volume expansion with 1.5 L of normal saline, there was no substantial progress in renal function (creatinine greater than g 1.5 mg/dL or 24-hr creatinine chloride (CrCl) greater than 40 mL/min).
-
Proteinuria less than 500 mg/dL.
-
There were no signs of obstructive uropathy or parenchymal renal disease on ultrasonography.
Additional requirements (not required but would help in diagnosis):
-
Less than 500 mL of urine per day.
-
Less than ten mEq/L sodium in the urine.
-
Urine osmolality exceeds plasma osmolality.
-
Urine red blood cells are less than 50 per high-power field.
-
Less than 130 mEq/L sodium in serum.
What Are the Other Causes of Renal Dysfunction?
-
Other than HRS, renal dysfunction can be categorized as prerenal, intrinsic or parenchymal, and postrenal dysfunction.
-
Patients with cirrhosis have several risk factors for prerenal dysfunction incorporating depletion of the volume, such as gastrointestinal losses from lactulose following diarrhea, renal losses from diuretics, and large-volume paracentesis.
-
Prerenal dysfunction leads to renal ischemia due to renal hypoperfusion, along with nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and contrast dye. In addition, acute tubular necrosis (ATN) is prevalent in cirrhotic patients and contributes to chronic prerenal dysfunction. Chronic hepatitis B and C can also lead to glomerular disease.
-
Acute interstitial nephritis (AIN) is a rare but significant cause of intrinsic renal dysfunction in cirrhotic patients. Penicillins, cephalosporins, and sulfonamides are the most commonly used drugs that cause AIN.
-
Although postrenal dysfunction is rare, imaging studies should be carried out to exclude obstructive nephropathy. Although renal biopsy is rarely performed, it may be beneficial in determining candidates for simultaneous liver or kidney transplant (SLKT). Small kidneys, poor cortical differentiation, and large-volume ascites are all contraindications to renal biopsy.
How Is Renal Function Assessed?
-
Creatinine levels in chronic liver diseases are affected by decreased hepatic creatine production and loss of muscle mass.
-
In clinical practice, serum creatinine level is used to assess renal function, but it overestimates the glomerular filtration rate (GFR) in patients with cirrhosis due to low creatinine production. It has been shown that measuring 24-hour creatinine clearance overestimates GFR and necessitates accurate urine collection.
-
Cystatin C (is present in all cells) is unaffected by muscle mass or hepatic production and is a good reflection of renal function due to its relatively constant production rate, with greater than 99 percent filtered by glomeruli but not reabsorbed or secreted.
What Is the Underlying Pathophysiology of the Hepatorenal Syndrome?
Over the last few years, knowledge of the various pathophysiological pathomechanisms of renal dysfunction in cirrhosis has advanced dramatically. Cirrhosis-related impairment in renal function can be seen in a variety of diseases, some of which are linked to abnormalities in renal function and others to renal damage.
-
HRS-AKI is caused by intra-renal vasoconstriction because of circulatory dysfunction in decompensated cirrhosis. The pathophysiology of HRS is intimately related to the development of ascites, which is thought to be a requirement for the onset of HRS. Schrier and colleagues proposed the peripheral arterial vasodilation hypothesis in 1988 for ascites.
-
According to this theory, intrahepatic vascular resistance increases due to structural alterations in fibrotic tissue, resulting in portal hypertension and overexpression of compensatory vasodilating factors.
-
Vasodilating factors build up in the splanchnic area and, eventually, in the systemic circulation. Ascites are caused by a pooling effect in the splanchnic vessels, which causes an increase in shear-wall stress and plasma transudation into the abdominal cavity. As a result, effective circulating blood volume and mean arterial pressure drop.
-
This stimulates the renin-angiotensin-aldosterone system as well as the sympathetic nervous system, resulting in hyperdynamic circulation (RAAS). Extremely high RAAS activation initiates water and sodium retention, aggravates the formation of ascites, and high levels of angiotensin II cause renal vasoconstriction.
-
In cases of hemodynamic stress, such as loss of volume or bacterial infections, RAAS activation and circulatory dysfunction may develop to the point where the renal function can no longer be retained, resulting in HRS-AKI.
What Is the Management of Renal Dysfunction?
-
Initial Management: The first step in treating these patients is to rule out any reversible or treatable conditions. Patients should care till their livers recover or are transplanted. A thorough search for precipitating factors (infection and gastrointestinal bleeding) should be performed and treated accordingly. Similarly, nephrotoxic drugs should be avoided. Patients should be challenged with fluid at first to evaluate the response and treat subclinical hypovolemia. Cirrhotic patients with acute gastrointestinal bleeding, poor liver function, or reduced renal function should be treated in intensive care units to preserve effective circulating blood volume and renal perfusion.
-
Pharmacologic Therapy: Pharmacologic therapy aims to enhance renal blood flow. This can be achieved by either increasing renal perfusion pressure or inducing renal vasodilation. Splanchnic vasoconstriction transfers some intravascular volume to the systemic circulation, improving circulatory function and effective arterial volume and thus improving renal perfusion and GFR. These agents can serve as a bridge to liver recovery or transplantation.
Conclusion
Renal dysfunction is normal in patients with decompensated cirrhosis and is a major contributor to an increase in mortality. The most familiar type of renal dysfunction is HRS. Newer pharmacologic agents may assist in managing renal dysfunction in cirrhosis, but liver transplant is the definitive therapy for HRS, and combined liver or kidney transplant is the choice of treatment for patients with end-stage liver disease who have irreversible renal dysfunction.
