Renal failure in patients with cirrhosis was initially described as renal dysfunction characterized by progressive azotemia associated with marked abnormalities of the systemic arterial circulation and normal renal histology; this condition later came to be known as hepatorenal syndrome (HRS).1–3 We now know that such patients with cirrhosis can develop renal failure for a variety of reasons besides HRS, including bacterial infections, shock, the use of nonsteroidal anti-inflammatory drugs (NSAIDs), and intrinsic renal diseases. The initial management of patients with a rising serum creatinine level (SCr) depends on the cause. Therefore, the most important step in treating renal failure in a patient with cirrhosis is to identify its etiology. The aim of this article is to summarize the current approach to renal failure in patients with cirrhosis.
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The gold standard for measuring the glomerular filtration rate (GFR) in cirrhosis relies on clearance techniques of exogenous markers (i.e., inulin); however, these methods are cumbersome, expensive, and not widely available in all settings. Thus, renal failure in cirrhosis is established when SCr increases more than 1.5 mg/dL; this corresponds to a GFR of approximately 30 mL/minute.4–6 This definition, proposed by the International Ascites Club, is the most accepted one in the hepatology community.6 Nonetheless, it is well known that SCr is a suboptimal marker for renal function because it may overestimate GFR, mainly on account of decreased creatinine production or reduced muscle mass. Furthermore, a SCr level < 1.5 mg/dL does not necessarily exclude renal dysfunction.7 New attempts at defining renal failure in cirrhosis using the definition of acute kidney injury (AKI) have been proposed: AKI in cirrhosis is defined as an increase in SCr > 50% from the baseline or a rise in SCr ≥ 0.3 mg/dL in <48 hours8, 9 (Table 1). This definition has the advantage of detecting earlier phases of kidney dysfunction with the goal of implementing early therapy. Minor increases in SCr detected with the AKI definition are independently associated with increased mortality for hospitalized patients with cirrhosis.10, 11 Although the AKI classification helps to refine the definition of renal failure in cirrhosis, two preliminary studies have not demonstrated that the AKI definition alone, in comparison with the classic criterion (SCr > 1.5 mg/dL), is a better tool for detecting hospital mortality.12, 13 The combination of the AKI stage and the classic criterion perhaps provides better risk classification than either criterion alone.12, 13 However, more data are needed in this area.
|AKI||Rise in SCr ≥ 50% from the baseline or rise in SCr ≥ 0.3 mg/dL in <48 hours|
|Chronic kidney disease||GFR < 60 mL/minute for >3 months (calculated with the MDRD6 formula*)|
|Acute-on-chronic kidney disease||Rise in SCr ≥ 50% from the baseline or rise in SCr ≥ 0.3 mg/dL in <48 hours in a patient with cirrhosis and a GFR < 60 mL/minute for >3 months (calculated with the MDRD6 formula*)|
Etiology and Prognosis
Renal failure arising in patients with cirrhosis may have many causes (Table 2). These etiologies are mainly classified as (1) HRS, (2) renal failure associated with infections, (3) hypovolemia-induced renal failure, (4) intrinsic renal diseases, and (5) drug-induced renal failure. In an analysis of 463 hospitalized patients with cirrhosis and renal failure, the most frequent cause was bacterial infection (46%).14 Other causes included hypovolemia-induced renal failure (32%), HRS (13%), parenchymal nephropathy (9%), drug-induced renal failure (7.5%), mixed causes (8%), and other causes (2%).14 Patients with intrinsic renal disease had a 73% survival rate at 3 months, and this was followed by a 46% survival rate for patients with hypovolemia-related renal failure. Those with renal failure associated with infections and HRS had the lowest 3-month survival probabilities: 31% and 15%, respectively.14
|Spontaneous bacterial peritonitis|
|Urinary tract infection, pneumonia, skin infection, or any other bacterial infection|
|Hypovolemia-induced renal failure|
|GI bleeding (with or without shock)|
|Vomiting and diarrhea|
|Intrinsic renal diseases|
|Glomerulopathy: immunoglobulin A nephropathy, membranous nephropathy, membranoproliferative glomerulonephritis, polyarteritis nodosa, or cryoglobulinemia due to viral hepatitis|
|Chronic kidney disease due to diabetes, hypertension, or other causes|
|Drug-induced renal failure|
|Hemodynamically induced: nonsteroidal anti-inflammatory agents or angiotensin receptor blockers|
|Acute tubular necrosis: aminoglycosides, amphotericin B, or tenofovir|
|Acute interstitial nephritis: penicillin, rifampin, or sulfonamides|
There are no specific tests that help to tease out the different causes of renal dysfunction in patients with cirrhosis. However, in the majority of cases, a detailed clinical history, a physical examination, and an assessment of renal function with a thorough evaluation of urine and serum electrolytes will suffice for establishing the cause.15 A step-wise approach should be used in which essential data are obtained from the history, a physical examination, laboratory data, and a renal ultrasound examination15 (Table 3). Limited data indicate that urinary neutrophil gelatinase-associated lipocalin, a urinary biomarker, is useful in discriminating between HRS and intrinsic renal failure (i.e., acute tubular necrosis).16, 17 However, data on biomarkers in the assessment of renal failure in cirrhosis are scarce, and this approach to diagnosis cannot yet be routinely recommended. Because the diagnosis of HRS cannot be made with a specific test, its confirmation is currently made with criteria excluding other causes of renal failure that can occur in cirrhosis.18 A diagnostic algorithm is depicted in Fig. 1.
|Complete history to rule out:|
|NSAID use and high doses of diuretics or other drugs|
|GI fluid losses and GI bleeding|
|Diabetes and arterial hypertension|
|Physical examination to document:|
|Signs of infection|
|Blood count, serum C reactive protein, SCr, electrolytes, and liver tests|
|Regular urine analysis, urine electrolytes, and sediment|
|24-hour urine volume, sodium, and protein|
|Culture: ascites, blood, and urine|
|Chest X-ray to rule out pneumonia|
|Abdominal ultrasound to rule out obstructive uropathy or chronic kidney disease|
Bacterial infections are the most common cause of renal failure in cirrhosis. The pathogenesis is related to an exacerbation of the systemic arterial vasodilation already present in patients with cirrhosis because of bacterial products, cytokines, or vasoactive mediators that appear in relation with the infection.19 This hemodynamic effect occurs mainly in patients who develop spontaneous bacterial peritonitis and spontaneous bacteremia, but it may occur with any bacterial infection. Therefore, the possibility of a bacterial infection should be meticulously examined in any patient with cirrhosis and renal failure.
HRS is characterized by functional renal vasoconstriction leading to a severe reduction in GFR without any identifiable kidney pathology. Because of the lack of specific diagnostic markers, the diagnosis of HRS is made with accepted criteria that exclude other causes of renal failure18 (Table 4). It is extremely important that hypovolemic renal failure be ruled out via volume replacement with intravenous albumin. There are two types of HRS: in type 1, renal function deteriorates rapidly with an increase in SCr to a level > 2.5 mg/dL in <2 weeks. This type of HRS is associated with a very poor prognosis without treatment with a median survival time of only 2 weeks.20 In type 2, there is a steady impairment of renal function, with SCr levels usually ranging from 1.5 to 2.5 mg/dL. Patients with type 2 HRS typically have refractory ascites and have a median survival time of 6 months if they do not undergo transplantation.20 Patients with type 2 HRS may go on to develop type 1 HRS because of either disease progression or triggering factors such as bacterial infections and large-volume paracentesis. Patients who undergo large-volume paracentesis are at high risk of developing postparacentesis circulatory dysfunction (PCD). This is a circulatory derangement accompanied by activation of the renin-angiotensin system that occurs because of the removal of large amounts of ascites.21 This disorder, although clinically silent, may be associated with ascites re-accumulation, hyponatremia, HRS, and decreased survival.21,22 Approximately 20% of patients who undergo large-volume paracentesis develop HRS and/or solute-free water retention leading to hyponatremia.22 Intravenous albumin effectively prevents PCD. A recent meta-analysis showed that albumin significantly reduced the odds of PCD in comparison with patients not receiving albumin expansion after paracentesis (73% developed PCD without albumin, whereas only 17% of those who received albumin did).23 Other plasma expanders (i.e., dextran 70, saline solution, and polygeline) also reduce the occurrence of PCD after paracentesis; however, albumin is superior at preventing PCD in cases of large/tense ascites in which more than 5 L is removed.23 The recommended dose of intravenous albumin (20% solution) is 8 g/L of removed ascites.5
|Cirrhosis with ascites|
|SCr > 1.5 mg/dL|
|No improvement in SCr [decrease to a level < 1.5 mg/dL (133 μmol/L) after at least 2 days off diuretics and volume expansion with albumin (1 g/kg of body weight up to a maximum of 100 g/day)]|
|Absence of shock|
|No current or recent treatment with nephrotoxic drugs|
|Absence of signs of parenchymal renal disease as suggested by proteinuria (>500 mg/day) or hematuria (>50 red blood cells per high-power field) and/or abnormal renal ultrasound findings|
In hypovolemia-induced renal failure, the major mechanism responsible for renal hypoperfusion is a reduction in the intravascular volume, which, if severe, can lead to acute tubular necrosis. The main causes of hypovolemia in cirrhosis are gastrointestinal (GI) bleeding, overdiuresis due to excessive diuretic treatment, and GI fluid losses due to vomiting and/or diarrhea.24 Diuretic-induced renal failure is related to an imbalance between the fluid loss from the intravascular space caused by diuretic treatment and the passage of fluid from the peritoneal compartment to the general circulation. Renal function usually improves after the elimination of the precipitating cause and plasma volume expansion unless there is severe hypovolemic shock or associated causes of renal failure.
Intrinsic Renal Diseases
Intrinsic renal disease in cirrhosis is considered if there is proteinuria > 500 mg in 24 hours, abnormal urine sediment with >50 red cells per high-power field, or abnormal renal ultrasound findings in the absence of other causes of renal failure.4, 5 Most intrinsic renal diseases are related to common etiological factors of cirrhosis and are secondary to the deposition of circulating immunocomplexes in the glomeruli. Membranoproliferative glomerulonephritis, membranous glomerulonephritis, and focal segmental glomerular sclerosis are the most common causes of intrinsic renal disease in patients with hepatitis C. Membranous nephropathy is most prominent in patients with hepatitis B, whereas immunoglobulin A nephropathy is most often seen in patients with alcoholic cirrhosis. A kidney biopsy in the evaluation of renal failure in cirrhosis of unclear etiology may be useful in select cases because patients with concomitant intrinsic renal disease may require dialysis or simultaneous liver-kidney transplantation.
Drug-Induced Renal Failure
Drug nephrotoxicity in patients with cirrhosis may arise in patients taking diuretics, NSAIDs, antihypertensives, or drugs that can cause acute tubular necrosis and/or acute interstitial nephritis.25 Hemodynamically mediated renal failure is mainly caused by NSAIDs or angiotensin-converting enzyme inhibitors because these drugs can alter the equilibrium between vasodilator and vasoconstrictor factors in the renal microcirculation. Drug-induced acute tubular necrosis occurs mainly because of the use of aminoglycosides, amphotericin B, or tenofovir. Finally, interstitial nephritis may occur because of antibiotics such as penicillin, rifampin, and sulfonamides. In drug-induced interstitial nephritis, there is an inflammatory component affecting the renal tubules and interstitium that occurs as a hypersensitivity reaction to medications. In most cases, renal function will return to normal after discontinuation of the offending agent.