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Home , Hepatorenal syndrome

Aliment Pharmacol Ther 2004; 20 (Suppl. 3): 24–28.

Review article: hepatorenal syndrome – definitions and diagnosis

R. MOREAU & D. LEBREC Laboratoire d’He´modynamique Splanchnique et de Biologie Vasculaire, INSERM U-481 and sevice d’He´patologie, Hoˆpital Beaujon, Clichy, France

criteria: (1) severe ; (2) glomerular hypofiltra- SUMMARY tion; (3) no other functional or organic causes; (4) Hepatorenal syndrome (HRS) is a severe complication of failure of plasma volume expansion; (5) no . cirrhosis that develops in the final phase of the disease. Additional diagnostic criteria may be present. The Two types of HRS exist. Type 1 is defined by a rapid diagnosis of HRS may be difficult in patients with severe reduction of renal function and in type 2 HRS the cirrhosis. Other types of acute renal failure may occur. reduction of renal function is slowly progressive. Type 1 For example, ischaemic or toxic tubular necrosis or HRS is diagnosed when the serum level sepsis may cause renal failure in these patients. increases by more than 50% of the baseline value to Furthermore, uncontrolled HRS may lead to ischaemic above 133 lmol/L. According to the International tubular necrosis; thus, these patients must be managed Club, HRS is defined by the presence of five as soon as possible in an intensive care unit.

the baseline value or to above 133 lmol/L (1.5 mg/dL). INTRODUCTION In patients with pre-existing renal impairment, acute Renal failure is characterized by the association of a renal failure is diagnosed when serum creatinine decrease in glomerular filtration, perturbation of extra- increases by more than 50% above baseline.6 cellular fluid volume, electrolyte and acid-base homoe- Acute renal failure resulting from renal hypoperfusion ostasis, and retention of nitrogenous waste from protein without renal cellular injury is called prerenal failure.1 catabolism.1 Acute renal failure is thought to be Renal dysfunction due to obstruction of the urinary out- common in patients with cirrhosis,2 but its exact flow tract is termed postrenal failure.1 Acute renal incidence is unknown. Patients with cirrhosis are failure due to a primary intrarenal cause is called predisposed to acute renal failure following complica- intrinsic renal failure. Intrinsic renal failure may be tions or the administration of drugs. Moreover, patients caused by either tubular necrosis, or with cirrhosis may develop a specific acute renal failure interstitial nephritis. called type 1 hepatorenal syndrome (HRS).2–5 HRS is a prerenal failure. There are two forms of HRS: type 1 is the severe and acute form, whereas type 2 is a moderate and chronic form.2 Prerenal failure is a Definitions preischaemic state; it may lead to ischaemic tubular In patients with cirrhosis without renal impairment at necrosis when the reduction in flow is sufficient to admission, acute renal failure is diagnosed when the result in the death of tubular cells. serum creatinine level increases by more than 50% of A recent multicentre retrospective study investigated 355 patients with cirrhosis and acute renal failure.7 A Correspondence to: Professor D. Lebrec, Laboratoire d’He´modynamique total of 206 patients (58.0%) had prerenal failure, Splanchnique et de Biologie Vasculaire, INSERM U-481 and sevice including 71 who had type 1 HRS; 148 (41.7%) had d’He´patologie, Hoˆpital Beaujon, 100 Boulevard du General, 92118 Clichy, France. ; ischaemic tubular injury E-mail: [email protected] occurred in 139 cases. Only one patient (0.3%) had

24 Ó 2004 Blackwell Publishing Ltd REVIEW: HEPATORENAL SYNDROME – DEFINITIONS AND DIAGNOSIS 25 postrenal failure. In this study, there was no case of acute sepsis-induced renal vasoconstriction, prerenal failure renal failure due to acute glomerulonephritis, confirming may be sensitive to fluid replacement. Patients with that this is an uncommon cause of acute renal failure in cirrhosis are susceptible to bacterial , in cirrhosis. Together, these findings indicate that renal particular spontaneous bacterial (SBP).11 hypoperfusion can explain more than 90% of cases of Septic and subsequent renal impairment occurs cirrhosis-associated acute renal failure. in 10% of patients with SBP. At the onset of SBP, 20–40% of patients have renal failure without shock. However, studies on SBP provide little information on Causes of prerenal failure the cause of this renal dysfunction. Prerenal failure may be rapidly reversible if the A total of 5% of patients hospitalized for acute upper underlying cause is corrected.1 Hypovolaemia (induced gastrointestinal haemorrhage8 and 30% of those admit- by haemorrhage or gastrointestinal or renal fluid losses) ted for SBP develop type 1 HRS during hospitalization.6 associated with shock or arterial is one Type 1 HRS also occurs in 10% of patients with ascites cause of prerenal failure. There is a short delay between treated by total paracentesis12 and in 25% of patients haemorrhage and the resulting renal dysfunction. with severe acute alcoholic .13 Acute upper gastrointestinal bleeding is a common Renal failure in patients with HRS is explained by complication of cirrhosis. Studies investigating acute marked renal vasoconstriction. However, the mecha- upper gastrointestinal bleeding in patients with cirrhosis nisms of renal vasoconstriction have not yet been fully show that 10–20% of patients have hypovolaemic elucidated. In type 1 HRS, there is a rapid increase in shock at inclusion. Prerenal failure is expected to occur serum creatinine. At diagnosis of HRS, there is no recent in patients with cirrhosis and gastrointestinal bleeding. history of circulatory shock, increased intestinal or However, the incidence of haemorrhage-induced renal renal fluid loss or nephrotoxic drug administration.2 In failure is unknown because the immediate impact of addition, there is no evidence for ongoing bleeding or shock or arterial hypotension on renal function was not sepsis. Finally, renal failure does not improve following an end-point in most studies. A retrospective study has administration of plasma expanders and discontinu- shown that 5% of patients with cirrhosis hospitalized for ation of .2 acute upper gastrointestinal bleeding have early renal The intravascular administration of iodinated radio- failure that lasts less than 7 days after index bleeding.8 contrast agents may cause prerenal failure by inducing Finally, it should be emphasized that patients admitted renal vasoconstriction.14 There are three important risk for haemorrhage may develop prerenal failure due to factors for radiocontrast-induced acute renal failure: other causes. Indeed, acute gastrointestinal bleeding chronic renal failure, diabetes and decreased effective predisposes patients with cirrhosis to bacterial infec- arterial blood volume. Nonazotemic patients with cir- tions9 which may induce prerenal failure or acute rhosis and ascites have decreased effective arterial blood tubular necrosis. On the other hand, a significant volume.2 They may also have ‘chronic renal impair- proportion of patients with cirrhosis admitted for acute ment’ or diabetes. Since patients with cirrhosis often upper gastrointestinal bleeding have received nonste- receive radiocontrast agents, they may develop prerenal roidal anti-inflammatory drugs (NSAIDs) in the week failure due to these agents. However, preliminary results preceding bleeding which may cause prerenal failure. show that radiocontrast agents did not impair renal Hypovolaemia and subsequent renal failure may be a plasma flow and glomerular filtration rate (GFR) in result of vomiting or diarrhoea.2 treatment to patients with cirrhosis.15 It should be noted that these mobilize tense or large ascites may induce prerenal results were obtained in a small series of patients, failure. Glycosuria is a cause of renal fluid loss, which however, one-third of whom did not have ascites. More may lead to renal dysfunction. information is needed on the effects of radiocontrast Severe sepsis is defined as the association of sepsis and agents on renal function in patients with cirrhosis. acute organ dysfunction. In the general population, Drugs such as nitrovasodilators or substances inhibiting patients with severe sepsis frequently develop prerenal the action of angiotensin II that are used in the treatment failure as a result of septic shock.10 Renal vasoconstric- of may induce renal dysfunction in tion plays a role in sepsis-induced prerenal failure.1 patients with cirrhosis and ascites. It has been shown that Since decreased intravascular volume is a mechanism of acute administration of the nitrovasodilator 5-mononi-

Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 3), 24–28 26 R. MOREAU & D. LEBREC trate induced decreases in effective arterial blood volume, disease is generally easy. In contrast, the diagnosis of arterial pressure, renal plasma flow and GFR.16 However, the cause of renal failure may be difficult. other studies did not show any increase in the incidence of prerenal failure in patients receiving long-term Clinical evaluation administration of 5-mononitrate isosorbide. Inhibition of angiotensin II action by inhibiting the angiotensin- A history of exposure to nephrotoxic medications, a converting enzyme with captopril or blocking type 1 recent history of angiography, and physical findings of angiotensin receptors with losartan or irbesartan may gastrointestinal haemorrhage or suggesting sepsis all induce marked arterial hypotension and of provide important diagnostic information. Anuria sug- postglomerular arterioles, causing prerenal failure in gests postrenal failure.1 The existence of arterial hyper- patients with cirrhosis and ascites. tension, which is an unexpected finding in cirrhosis, suggests glomerulonephritis. Macroscopic haematuria should suggest IgA nephropathy as a cause. Purpura, INTRINSIC RENAL FAILURE arthralgia, weakness, Raynaud’s syndrome, or leg ulcers suggest cryoglobulinaemia. Acute tubular necrosis Injury to the renal tubules may be ischaemic or toxic in evaluation origin. The mechanisms of renal failure are very similar in ischaemic and toxic tubular necrosis. The course of Diagnostic information may be obtained from the acute tubular necrosis can be divided into the initiation, urinanalysis.1 For example, pigmented granular casts maintenance and recovery phases. All causes of pre- are typical of ischaemic and toxic acute renal failure renal failure may lead to ischaemic tubular injury.1 and red cell casts typical of glomerulonephritis. Patients Administration of aminoglycoside antibiotics is thought with renal failure due to acute or subacute glomerulo- to be the most common cause of toxic tubular necrosis nephritis have significant proteinuria (around in patients with cirrhosis.2 The incidence of radiocon- 3 g/day).1 In contrast, proteinuria is absent or moder- trast agent-induced tubular necrosis is unknown in ate in other causes of acute renal failure.2 patients with cirrhosis. Ischaemia and toxins may Urine indices (, urinary sodium con- combine to cause renal failure in severely ill patients. centration and fractional excretion of sodium) may help distinguish prerenal failure (including type 1 HRS) from tubular necrosis.1 The tubular ability to reabsorb Acute glomerulonephritis sodium and to concentrate urine is preserved in Some cases of infectious acute glomerulonephritis have prerenal failure and impaired in tubular necrosis. Thus, been reported in patients with cirrhosis.17 The site of patients with prerenal failure have low urinary sodium was the oropharynx, the skin or the endocar- concentrations (below 20 mmol/L) and elevated urine dium. In patients with cirrhosis due to virus, osmolality (higher than 500 mOsm/kg). In contrast, cryoglobulinaemic membranoproliferative glomerulone- patients with tubular necrosis have high urinary phritis is a rare cause of acute renal failure.18 Macro- sodium concentrations (above 40 mmol/L) and urine scopic haematuria associated with acute renal failure osmolality below 350 mOsm/kg. However, the urinary may occur in certain patients with alcohol-induced sodium concentration may be low early in the course of cirrhosis and IgA nephropathy.19 In these patients, certain processes that lead to tubular necrosis such as acute renal failure is due to tubular necrosis and not sepsis, exposure to radiocontrast agents or obstruction. caused by glomerular lesions. Tubular necrosis may be In addition, some cases of HRS with elevated urinary caused by a direct toxic insult to the tubules by red sodium concentrations have been reported. blood cells that are present in the tubular lumen. These findings indicate that in clinical practice, it is difficult to differentiate type 1 HRS from other causes of acute renal failure. The International Ascites Club has DIAGNOSIS suggested that five major criteria be present to confirm Since acute renal failure mainly occurs in patients with the diagnosis of HRS:2 (1) severe cirrhosis; (2) glomer- decompensated cirrhosis, diagnosis of chronic ular hypofiltration; (3) no other functional or organic

Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 3), 24–28 REVIEW: HEPATORENAL SYNDROME – DEFINITIONS AND DIAGNOSIS 27 causes; (4) failure of plasma volume expansion; (5) no determine the diagnosis and treatment.1 Percutaneous proteinuria. Of these, one of the most important is the renal biopsy may be contraindicated in patients with lack of improved renal response following optimization cirrhosis and coagulation disorders and transjugular of intravascular volume in patients with type 1 HRS. renal biopsy has been shown to be a safe procedure in Indeed, although there is an increase in GFR following these patients.20 In addition to biopsy, a fluid replacement in most causes of prerenal failure, transjugular liver biopsy can confirm the diagnosis of GFR continues to rise despite fluid challenge in patients cirrhosis. with type 1 HRS. On the other hand, because patients with acute tubular necrosis do not respond to fluid CONCLUSION replacement, a lack of renal response to fluid challenge does not differentiate HRS from tubular necrosis.1, 2 In patients with cirrhosis, acute renal failure is mainly This is a limitation of the International Ascites Club due to prerenal failure and tubular necrosis. However, criteria. It should be emphasized that patients with type except for type 1 HRS, little is known about the 1 HRS have improved renal function following admin- incidence, natural course and treatment of the different istration of vasoconstrictors such as (Gly- causes of cirrhosis-associated acute renal failure. Studies pressinÒ),7 whereas vasoconstrictor therapy does not are needed, in particular for severe sepsis, radiocontrast- improve renal function in patients with acute tubular induced , and renal-replacement therap- necrosis. Thus, the renal response to vasoconstrictor ies, given that renal transplantation is not an option agents might be used to differentiate HRS from tubular except when combined with . necrosis.

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Ó 2004 Blackwell Publishing Ltd, Aliment Pharmacol Ther 20 (Suppl. 3), 24–28