Pathogenesis and Treatment of Hepatorenal
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Pathogenesis and Treatment of Hepatorenal Syndrome
Vicente Arroyo, M.D., 1 Javier Fernandez, M.D., 1 and Pere Gine`s, M.D. 1 ABSTRACT
Hepatorenal syndrome (HRS) is a functional renal failure that frequently develops in patients with advanced cirrhosis and severe impairment in systemic circulatory function. Traditionally it has been considered to be the consequence of a progression of the splanchnic arterial vasodilation occurring in these patients. However, recent data indicate that a reduction in cardiac output also plays a significant role. There are two different types of HRS. Type-2 HRS consists of a moderate and steady or slowly progressive renal failure. It represents the extreme expression of the circulatory dysfunction that spontaneously develops in patients with cirrhosis. The main clinical problem in these patients is refractory ascites. Type-1 HRS is a rapidly progressive acute renal failure that frequently develops in closed temporal relationship with a precipitating event, commonly spontaneous bacterial peritonitis. In addition to renal failure, patients with type-1 HRS present deterioration in the function of other organs, including the heart, brain, liver, and adrenal glands. Type-1 HRS is the complication of cirrhosis associated with the worst prognosis. However, effective treatments of HRS (vasoconstrictors associated with intravenous albumin, trans- jugular intrahepatic portacaval shunt, albumin dialysis) that can improve survival have recently been introduced. KEYWORDS: Cirrhosis, type-1 HRS, type-2 HRS, pharmacological treatment, transjugular intrahepatic portacaval shunt, extracorporeal albumin dialysis CONCEPT
Hepatorenal syndrome (HRS) is a common problem in patients with advanced cirrhosis and ascites. The annual incidence of HRS in patients with cirrhosis and ascites has been estimated as 8%. It is characterized by an intense renal vasoconstriction, which leads to very low renal perfusion and glomerular filtration rate (GRF). The renal ability to excrete sodium and free water is also severely reduced and most patients present dilutional hyponatremia. 1–3
Renal histology shows no lesions suf- ficient to justify the impairment in renal function. HRS occurs in the setting of a severe circulatory dysfunction characterized by arterial hypotension and intense stim- ulation of the renin-angiotensin system, sympathetic nervous system, and antidiuretic hormone. It has been classically considered to be the consequence of an arterial vasodilation in the splanchnic circulation (peripheral arterial vasodilation hypothesis). However, recent data indicate that a reduction in cardiac output also plays a significant role. Cirrhotic patients with ascites, increased activity of the renin-angiotensin and sympathetic nerv- ous systems, and intense sodium retention and those with dilutional hyponatremia are predisposed to develop HRS. This syndrome may develop spontaneously or be 1 Liver Unit, Institute of Digestive and Metabolic Diseases, CIBER- EHD, Hospital Clinic, University of Barcelona, Spain. Address for correspondence and reprint requests: Vicente Arroyo, M.D., Liver Unit, Institute of Digestive and Metabolic Diseases, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain (e-mail: varroyo@clinic.ub.es). Complications of Cirrhosis; Guest Editor, Pere Gine`s, M.D. Semin Liver Dis 2008;28:81–95. Copyright # 2008 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-2008-1040323. ISSN 0272-8087. 81
precipitated by factors that induce renal hypoperfusion. Bacterial infections, especially spontaneous bacterial peritonitis (SBP), are by far the most frequent precip- itating causes of HRS. Due to the functional nature of renal failure, there is no specific diagnostic marker for HRS.
2,4,5 Thus, diagnosis relies on the exclusion of other causes of renal insufficiency. 6 There are two different types of HRS. Type-2 HRS consists of a moderate and steady functional renal failure. It represents the extreme expression of the circulatory dysfunction that spontaneously develops in patients with cirrhosis. The main clinical problem in these patients is refractory ascites. In contrast, type-1 HRS is a rapidly progressive acute renal failure that frequently develops in close temporal relationship with a precipitating event and occurs in the setting of deterio- ration in the function of other organs, including the heart, the brain, the liver, and possibly the adrenal glands. Type-1 HRS is the complication of cirrhosis associated with the worst prognosis and, for many years, it has been considered as a terminal event of the disease. However, effective treatments of type-1 HRS have been introduced recently. These treatments improve survival and make it possible for a significant number of patients to arrive to liver transplantation. The current article offers a review of the pathogenesis, clinical aspects, prevention, and treatment of type-1 and type-2 HRS. The reader interested in this topic should consult other reviews published recently, 7,8
as well as the reports of two consensus conferences on HRS organized by the Inter- national Ascitis Club in Chicago and San Francisco. 9,10
CLINICAL ASPECTS Diagnosis of Renal Failure in Cirrhosis The first step in the diagnosis of HRS is the demon- stration of a reduced GFR, and this is not easy in advanced cirrhosis. The muscle mass, and therefore, the release of creatinine, is reduced in these patients and they may present normal or only moderately in- creased serum creatinine concentration in the setting of a very low GFR. Similarly, urea is synthesized by the liver and may be reduced as a consequence of hepatic insuffi- ciency. Therefore, false-negative diagnosis of HRS is relatively common. 11–13 There is consensus to establish the diagnosis of HRS when serum creatinine has risen above 1.5 mg/dL. 9,10 A creatinine clearance of less than 40 mL/min, which was also a criteria for the diagnosis of renal failure in cirrhosis (Table 1), 9 has been excluded because errors in the urine collection may lead to high rate of false-positive diagnosis. The second step is the differentiation of HRS from other types of renal failure. For many years this was based on the traditional param- eters used to differentiate functional renal failure from acute tubular necrosis (urine volume, urine sodium concentration, and urine-to-plasma osmolality ratio). However, acute tubular necrosis in patients with cir- rhosis and ascites usually courses with oliguria, low urine sodium concentration, and urine osmolality greater than plasma osmolality. 14 On the contrary, relatively high urinary sodium concentration has been observed in patients with HRS and high serum bilirubin. 15 Based
on these data, these parameters have been removed from the diagnostic criteria of HRS (Table 2). 10 Because of the lack of specific tests, diagnosis of HRS is based on the exclusion of other disorders that can cause renal failure in cirrhosis (Tables 1 and 2). 9,10 Acute
renal failure of pre-renal origin due to renal (diuretics) or extrarenal fluid losses should be investigated. If renal failure is secondary to volume depletion, renal function improves rapidly after volume expansion, whereas no improvement occurs in HRS. Even if there is no history of fluid losses, renal function should be assessed after diuretic withdrawal and volume expansion to rule out any subtle reduction in plasma volume as the cause of renal failure. The diagnostic criteria of HRS proposed by the International Ascites Club in San Francisco in 2005 consider that volume replacement should be performed with I.V. albumin (1 g/kg body weight up to a maximum of 100 g), rather than with saline. 10 This proposal is Table 1 International Ascites Club’s Diagnostic Criteria of HRS*
Major criteria
Chronic or acute liver disease with advanced hepatic failure and portal hypertension
Low glomerular filtration rate, as indicated by serum creatinine of > 1.5 mg/dL or 24-hr creatinine clearance < 40 mL/min
Absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs; absence of gastrointestinal fluid losses (repeated vomiting or intense diarrhea) or renal fluid losses (weight loss > 500 g/day for several days in patients with ascites without peripheral edema or 1000 g/day in patients with peripheral edema)
No sustained improvement in renal function (decrease in serum creatinine to 1.5 mg/dL or less or increase in creatinine clearance to 40 mL/min or more) following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline
Proteinuria < 500 mg/day and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease Additional criteria
Urine volume < 500 mL/day Urine sodium < 10 mEq/L
Urine osmolality greater than plasma osmolality Urine red blood cells < 50 per high-power field
Serum sodium concentration < 130 mEq/L *Arroyo V, Gine`s P, Gerbes A, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 1996;23:164–176. 82 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1 2008 based on a randomized study showing that albumin is more effective as plasma expander than a saline solution of hydroxyethyl starch in patients with SBP. 16 The presence of shock before the onset of renal failure points toward the diagnosis of acute tubular necrosis. On the other hand, cirrhotic patients with infections may de- velop transient renal failure, which resolves after reso- lution of the infection. This occurs in approximately one third of patients. 17,18 Therefore, HRS in cirrhotic pa- tients with bacterial infections should be diagnosed in patients without septic shock and only if renal failure does not improve following antibiotic administration. Complete resolution of the infection, which was re- quired for the diagnosis of HRS in the initial proposal by the International Ascites Club in 1996 (Table 1), 9 is
of treatment with vasoconstrictors and albumin. 10 Cirrhotic patients are predisposed to develop renal fail- ure in the setting of treatments with aminoglycosides, 19 nonsteroidal anti-inflammatory drugs, 20 and vasodila- tors (renin-angiotensin system inhibitors, prazosin, nitrates). 21 Therefore, treatment with these drugs in the days preceding the diagnosis of renal failure should be ruled out. Finally, patients with cirrhosis can develop renal failure due to intrinsic renal diseases, particularly glomerulonephritis in patients with hepatitis B or C (deposition of immunocomplexes) or with alcoholic cirrhosis (deposition of IgA). These cases can be recog- nized by the presence of proteinuria, hematuria or both, or abnormal renal ultrasonography (small irregular kidneys with abnormal echostructure). Type-1 and Type-2 HRS: Clinical Characteristics and Prognosis As indicated previously, there are two types of HRS. 9,10
Type-1 HRS consists of a severe and rapidly progressive renal failure, which has been defined as doubling of serum creatinine reaching a level greater than 2.5 mg/dL in less than 2 weeks. Although type-1 HRS may arise spontaneously, it frequently occurs in close relationship with a precipitating factor, such as severe bacterial infection, mainly SBP, gastrointestinal hemorrhage, major surgical procedure, or acute hep- atitis superimposed to cirrhosis. The association of HRS, SBP, and other bacterial infections has been carefully investigated. 17,18,22–24 Type-1 HRS develops in $25% of patients with SBP despite a rapid reso- lution of the infection with non-nephrotoxic antibi- otics. Patients with severe circulatory dysfunction prior to infection or intense inflammatory response (high concentration of polymorphonuclear leukocytes in as- citic fluid and high cytokine levels in plasma and ascitic fluid) are prone to develop type-1 HRS after the infection. In addition to renal failure, patients with type-1 HRS induced by SBP show signs and symp- toms of rapid and severe deterioration of liver function (jaundice, coagulopathy, and hepatic encephalopathy) and circulatory function (arterial hypotension, very high plasma levels of renin and norepinephrine). 22–24 It is interesting to note that in contrast to SBP, sepsis related to other types of infection in patients with cirrhosis is rarely associated with type-1 HRS. In one study, sepsis unrelated to SBP induced type-1 HRS only in the setting of lack of response to antibiotics. 17 In most patients with sepsis unrelated to SBP re- sponding to antibiotics, renal impairment, which was also a frequent event, was reversible. In a second study, 18
with SBP, of 19% in patients with severe acute urinary tract infection, and of only 4% in patients with sepsis of other origin. Interestingly enough, as in SBP, some patients with severe urinary tract infection developed type-1 HRS despite the resolution of the infection. The mechanism for the higher frequency of HRS in SBP as compared with other bacterial infections is unknown. Without treatment, type-1 HRS is the complication of cirrhosis with the poorest prognosis with a median survival time after the onset of renal failure of only 2 weeks (Fig. 1). 3 Type-2 HRS is characterized by a moderate and slowly progressive renal failure (serum creatinine lower than 2.5 mg/dL). Patients with type-2 HRS show signs of liver failure and arterial hypotension but to a lesser extent than patients with type-1 HRS. The dominant clinical feature is severe ascites with poor or no response to diuretics (a condition known as refractory ascites). Patients with
type-2 HRS
are predisposed to develop type-1 HRS following infections or other precipitating events. 22–24 Median
survival of patients with type-2 HRS (6 months) is worse than that of patients with nonazotemic cirrhosis with ascites (Fig. 1). 25 Table 2 New Diagnostic Criteria of Hepatorenal Syndrome in Cirrhosis*
Cirrhosis with ascites Serum creatinine > 133 mmol/L (1.5 mg/dL)
No improvement of serum creatinine (decrease to a level of 133 mmol/L) after at least 2 days with diuretic withdrawal and volume expansion with albumin; the recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day
Absence of shock No current or recent treatment with nephrotoxic drugs
Absence of parenchymal kidney disease as indicated by proteinuria > 500 mg/day, microhematuria (> 50 red blood cells per high-power field), and/or abnormal renal ultrasonography *Salerno F, Gerbes A, Gine`s P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310–1318. PATHOGENESIS AND TREATMENT OF HEPATORENAL SYNDROME/ARROYO ET AL 83
PATHOGENESIS OF HEPATORENAL SYNDROME IN CIRRHOSIS Renal Dysfunction in Cirrhosis Is Related to Arterial Vasodilation: The ‘‘Classical Peripheral Arterial Vasodilation Hypothesis’’ The development of portal hypertension in cirrhosis is associated with arterial vasodilation in the splanchnic circulation due to the local release of nitric oxide and other vasodilatory substances. 26–29
According to the ‘‘peripheral arterial vasodilation hypothesis’’ (Fig. 2), HRS would be the extreme expression of this splanchnic arterial vasodilation, which would increase steadily with the progression of the disease. 30 In the initial phases of cirrhosis, the decrease in systemic vascular resistance is compensated by the development of a hyperdynamic circulation (increased heart rate and car- diac output). 31–33 However, as the disease progresses and arterial vasodilation increases, the hyperdynamic circu- lation is insufficient to correct the effective arterial hypovolemia (Fig. 2). 30 Arterial hypotension develops, leading to the activation of high-pressure baroreceptors, reflex stimulation of the renin-angiotensin and sympa- thetic nervous systems, increase in arterial pressure to normal or near-normal levels, sodium and water reten- tion, and ascites formation. The stimulation of antidiu- retic hormone occurs later during the course of the disease. Patients then develop solute-free water reten- tion and dilutional hyponatremia. At this stage of the disease, the renin-angiotensin and sympathetic nervous systems are markedly stimulated and arterial pressure is critically dependent on the vascular effect of the sym- pathetic nervous activity, angiotensin-II, and antidiuretic hormone (vasopressin). Since the splanchnic circulation is resistant to the effect of angiotensin-II, noradrenaline, and vasopressin due to the local release of nitric oxide and other vasodilators, 34,35 the maintenance of arterial pressure is due to vasoconstriction in extrasplanchnic vascular territories such as the kidneys, muscle, skin, and brain. 36–39
HRS develops in the final phase of the disease when there is an extreme deterioration in effective arterial blood volume and severe arterial hy- potension. The homeostatic stimulation of the renin- angiotensin system, the sympathetic nervous system, and antidiuretic hormone is very intense leading to renal vasoconstriction and marked decrease in renal perfusion and GFR, azotemia, and increased serum creatinine concentration. Cardiac Dysfunction Is Also Important: The ‘‘Revised Peripheral Arterial Vasodilation Hypothesis’’ Most hemodynamic studies in cirrhosis have been per- formed in nonazotemic patients with and without as- cites, and their findings have been extended to the entire population of decompensated cirrhosis. Based on these studies, it has been assumed that HRS develops in the setting of a hyperdynamic circulation, with low periph- eral vascular resistance due to the splanchnic arterial vasodilation and high cardiac output. However, in the few studies assessing cardiovascular function in patients with HRS or refractory ascites (most of them with type- 2 HRS), cardiac output was found to be significantly reduced compared with patients without HRS. 40,41 In
subjects, suggesting that circulatory dysfunction associ- ated with HRS is due not only to arterial vasodilation but also to a decrease in cardiac function. Two studies by Ruiz-del-Arbol et al support this idea. 42,43 Figure 1 Survival of patients with cirrhosis after the diagnosis of type-1 or type-2 HRS. HRS, hepatorenal syndrome. 84 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1 2008
In the first study, 42 systemic and hepatic hemo- dynamics and the endogenous vasoactive systems were measured in 23 cirrhotic patients with SBP at infection diagnosis and after SBP resolution. Eight patients de- veloped type-1 HRS. The remaining 15 patients did not develop renal failure. Development of type-1 HRS was associated with a significant decrease in mean arterial pressure and a marked stimulation of the renin-angio- tensin and sympathetic nervous systems, indicating a severe impairment in effective arterial blood volume. Peripheral vascular resistance did not change despite the intense stimulation of these endogenous vasocon- strictor systems, which is consistent with a progression of the arterial vasodilation already present in these patients. The most important result of the study, however, was the observation of a marked decrease in cardiac output in all cases. These changes were not observed in patients not developing renal failure. Impairment in systemic hemo- dynamics and type-1 HRS associated with SBP was, therefore, clearly related to the simultaneous occurrence of a decrease in cardiac output and an accentuation of the arterial vasodilation. Patients who developed type-1 HRS showed significantly higher values of cytokines, plasma renin activity, and sympathetic nervous activity and lower cardiac output and glomerular filtration rate at infection diagnosis than patients not developing renal failure. These results confirm previous studies showing that in patients with SBP the severity of the inflamma- tory response and the degree of impairment of systemic hemodynamics and renal function prior to the infection Yüklə 401,11 Kb. Dostları ilə paylaş:
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