The first reports of renal failure occurring in individuals with chronic liver diseases were from the late 19th century by Frerichs and Flint. However, the hepatorenal syndrome was first defined as acute renal failure that occurred in the setting of biliary surgery. The syndrome was soon re-associated with advanced liver disease, and, in the 1950s, was clinically defined by Sherlock, Hecker, Papper and Vessin as being associated with systemic hemodynamic abnormalities and high mortality. Hecker and Sherlock specifically identified that individuals with HRS had low urinary output, very low sodium in the urine, and no protein in the urine. Murray Epstein was the first to characterize splanchnic vasodilation and renal vasoconstriction as the key alterations in hemodynamics in patients with the syndrome. The functional nature of the renal impairment in HRS was crystallized by studies demonstrating that kidneys transplanted from patients with hepatorenal syndrome returned to function in the new host, leading to the hypothesis that hepatorenal syndrome was a systemic condition and not a renal disease. The first systematic attempt to define hepatorenal syndrome was made in 1994 by the International Ascites Club, a group of liver specialists. The more recent history of HRS has involved elucidation of the various vasoactive mediators that cause the splanchnic and renal blood flow abnormalities of the condition.
The ﬁrst step in the diagnosis of HRS is the demonstration of a reduced GFR, and this is not easy in advanced cirrhosis. The muscle mass, and therefore, the release of creatinine, is considerably reduced in these patients and they may present normal 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 insuﬃciency. Therefore, false negative diagnosis of HRS is relatively common. There is consensus to establish the diagnosis of HRS when serum creatinine has risen above 1.5 mg/dl or creatinine clearance has decreased to less than 40 ml/min.The ﬁrst step in the diagnosis of HRS is the demonstration 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 increased 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 insufﬁciency. Therefore, false-negative diagnosis of HRS is relatively common. There is consensus to establish the diagnosis of HRS when serum creatinine has risen above 1.5 mg/dL. A creatinine clearance of less than 40 mL/min, which was also a criteria for the diagnosis of renal failure in cirrhosis has been excluded because errors in the urine collection may lead to high rate of false-positive diagnosis. A rising serum creatinine in a patient with cirrhosis or ALF is suﬃcient cause to investigate for possible HRS. In patients with advanced cirrhosis, the normal serum creatinine level is typically 0.6 to 0.8 mg/dL because of muscle wasting, and a serum creatinine above 1.4 mg/dL reﬂects a substantially decreased GFR.The ﬁrst step in the diagnosis of HRS is the demonstration of a reduced GFR, and this is not easy in advanced cirrhosis. The muscle mass, and therefore, the release of creatinine, is considerably reduced in these patients and they may present normal serum creatinine concentration in the setting of a very low GFR. Similarly, urea is synthesized by the liver andmay be reduced as a consequence of hepatic insuﬃciency. Therefore, false negative diagnosis of HRS is relatively common. There is consensus to establish the diagnosis of HRS when serum creatinine has risen above 1.5 mg/dl or creatinine clearance has decreased to less than 40 ml/min.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. 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 noimprovement 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. This proposal is 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.Ref – RCT – Abstract:The administration of albumin improves circulatory function, prevents hepatorenal syndrome, and reduces hospital mortality in patients with cirrhosis and spontaneous bacterial peritonitis. This randomized unblinded pilot study compared the effect of albumin (10 patients) and the synthetic plasma expander hydroxyethyl starch 200/0.5 (10 patients) on the systemic hemodynamics of patients with spontaneous bacterial peritonitis. Baseline measurements were performed within 12 hours after diagnosis of infection. Patients thenreceived 2 doses of the volume expander (1.5 g/kg body weight after baseline measurements and 1 g/kg body weight on day 3). Measurements were repeated after infection resolution. Treatment with albumin was associated with a signiﬁcant increase in arterial pressure and a suppression of plasma renin activity, indicating an improvement in circulatory function. This occurred in the setting of a signiﬁcant expansion of central blood volume (increase in cardiopulmonary pressures and atrial natriuretic factor) and an increase in systolic volume and systemic vascular resistance. In contrast, no signiﬁcant changes were observed in these parameters in patients treated with hydroxyethyl starch. Von Willebrand–related antigen plasma levels signiﬁcantly decreased in patients treated with albumin but not in those treated with hydroxyethyl starch. Serum nitrates and nitrites increased in patients treated with hydroxyethyl starch but not in those treated with albumin. These data suggest an effect of albumin on endothelial function. In conclusion, albumin but not hydroxyethyl starch improves systemic hemodynamics in patients with spontaneous bacterial peritonitis. This effect is due not only to volume expansion but also to an action on the peripheral arterial circulation. (HEPATOLOGY 2005;42:627-634.)The oncotic capacity of 1 g albumin is identical to that of 1 g HES 200/0.5. However, the pharmacokinetics and pharmacodynamics of both substances as well as the characteristics of the solutions are markedly different. In healthy subjects, the half-life of albumin is of 19 days, although it decreases to 9 days in patients with sepsis and perhaps even more in patients with SBP accumulating ascites. In contrast, in healthy subjects, the half-life of HESs ranges from 6 hours to 3 days. Albumin presents numerous biological effects in addition to its oncotic action, and this is probably not the case with HESs. Finally, albumin solutions are prepared at high concentrations (20%) in a saline solution containing 130-160 mEq/L sodium in the form of caprylate and acetyltryptophanate salts. Therefore, high doses of albumin can be given within a short period without inducing a significant water and sodium overload. In contrast, HES 200/0.5 is prepared at a 6% concentration in a sodium chloride solution. This limits the administration of high doses of this compound within a short period. For an identical amount of the active compound, in the current study the amount of water and sodium infused was 3.3 times higher and the amount of oncotic equivalents per unit of time 3 times lower in patients treated with HES 200/0.5.On the other hand, cirrhotic patients with infections may develop transient renal failure, which resolves after resolution of the infection. This occurs in approximately one third of patients.Therefore, HRS in cirrhotic patients 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 required for the diagnosis of HRS in the initial proposal by the International Ascites Club in 1996, is no longer accepted because it may delay the initiation of treatment with vasoconstrictors and albumin.Cirrhotic patients are predisposed to develop renal failure in the setting of treatments with aminoglycosides, nonsteroidal anti-inﬂammatory drugs, and vasodilators (renin-angiotensin system inhibitors, prazosin,nitrates). Therefore, treatment with these drugs in the days preceding the diagnosis of renal failure should be ruled out.
This is just a mathematical/statistical assumption made – to demostrate stage migration.Such changes should be taken into consideration when comparing treatment results of new studies with those obtained in the previous years, because changes in deﬁnitions may lead to a sort of stage migration, a phenomenon that is well known to bio-statisticians, and is characterized by an improvement in outcome in both stages involved. Indeed, if patients with infections unresponsive to a 2-day infusion of albumin have a mortality rate intermediate between classical HRS and pre-renal azotemia (with the values suggested in the ﬁgure), the migration of these patients towards the group of patients with HRS would decrease mortality in HRS from 80% to 65%, and that of pre-renal azotemia from 27.5% to 20%.
Now coming to the minor criteria:Differentiation of HRS from other types of renal failure. For many years this was based on the traditional parameters 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 cirrhosis and ascites usually courses with oliguria, low urine sodium concentration, and urine osmolality greater than plasma osmolality.On the contrary, relatively high urinary sodium concentration has been observed in patients with HRS and high serum bilirubin. Based on these data, these parameters have been removed from the diagnostic criteria of HRS.
Many disease states in which there are clinical indications of renal and hepatic disease but there is no relationship between the two, e.g. a systemic disease in which the agent causes both hepatic and renal damage.
Original –Hepatorenal syndrome may be classified on a clinical basis into two different clinical types: (1) type I hepatorenal syndrome, characterized by rapidly progressive reduction of renal function as defined by a doubling of the initial serum creatinine to a level greater than 2.5 mg/dL or a 50% reduction of the initial 24-hour creatinine clearance to a level lower than 20 mL/min in less than 2 weeks; and (2) type II hepatorenal syndrome, in which the renal failure does not have a rapidly progressive course.In type 1 HRS the serum creatinine level doubles to greater than 2.5 mg/dL within 2 weeks. The key features of type 1 HRS are its rapid progression and high mortality, with a median survival of only 1 to 2 weeks. Common precipitating events in type 1 HRS include bacterial infections, particularly spontaneous bacterial peritonitis; varicealhemorrhage; major surgery; and acute alcoholic hepatitis. Sometimes acute hepatic injury, superimposed on cirrhosis, may lead to liver failure and HRS. The hepatic injury can occur from acute viral hepatitis; drug-induced liver injury (acetaminophen; idiopathic drug-induced hepatitis); hepatic ischemia; ﬂare of chronic hepatitis B virus infection caused by an emergent resistant viral strain or withdrawal of antiviral therapy; or superimposed acute delta virus hepatitis. Early identiﬁcation of a precipitating event is clinically important because it is frequently preventable or treatable with speciﬁc medical therapy.In type 2 HRS, the serum creatinine increases slowly and gradually during several weeks or months with a reciprocal gradual reduction in glomerular inﬁltration rate (GFR). This generally occurs without a precipitating factor. The median survival of type 2 HRS is about 6 months, signiﬁcantly longer than for type 1. Nonetheless, type 2 HRS still has an extremely poor prognosis. Unless liver transplantation is performed, or a dramatic response to therapy of the underlying liver disease occurs (such as HBV related cirrhosis responding to antiviral therapy), many patients with type 2 HRS eventually progress to type 1 HRS because of a precipitating factor.The clinician should distinguish between type 1 and type 2 HRS. The former is associated with a rapidly fatal prognosis. Type 1 HRS must be urgently managed, with elimination of precipitating factors and evaluation for liver transplantation. In contrast, type 2 HRS permits less frantic evaluation and therapy. Both types are part of a spectrum of renal dysfunction in the setting of severe liver disease. Patients may progress from type 2 to type 1 HRS without an obvious precipitating factor other than worsening liver failure. The mechanisms of this progression are unknown.Clinical data suggest that type-1 and type-2 HRS are diﬀerent syndromes and not diﬀerent expressions of a common underlying disorder. Renal failure in type-1 HRS is severe and progressive whereas in type-2 it is moderate and steady. As expected, circulatory function is also stable in type-2 HRS whereas a rapidly progressive impairment in circulatory function occurs in type-1 HRS. Type-1 HRS is frequently associated to a precipitant event, mainly SBP. In contrast, type-2 HRS develops spontaneously in most cases. Finally, the main clinical consequence of type 1 HRS is severe hepatorenal failure and death whereas it is refractory ascites in type-2 HRS. Type-2 HRS probably represents the genuine functional renal failure of cirrhosis. It would be the extreme expression of the impairment in circulatory function that spontaneously develops during the course of the disease. In contrast, type-1 HRS mimics the acute renal failure associated with other conditions such as sepsis or severe pancreatitis, with features of multiorgan failure including acute impairment in cardiovascular, renal, hepatic and cerebral function and relative adrenal insuﬃciency
Now let us see the factors associated to hepatorenal syndrome. This will lead us to understand the pathophysiology of HRS, the dysfunction leading to HRS and thus the larger picture that HRS is part of a multiorgan failure
If we take a look at this pic, it shows the circulatory dysfunction in cirrhosis, leading in progression to the development of HRS.I’ll discuss these things in detail few slides down the way.
Studies in both laboratory animals and patients with cirrhosis suggest that bacterial translocation — that is, the passage of bacteria from the intestinal lumen to the mesenteric lymph nodes — may play an important role in impairing circulatory function in advanced cirrhosis. Bacterial translocation may elicit an inflammatory response, with increased production of proinflammatory cytokines (mainly tumor necrosis factor α and interleukin-6) and vasodilator factors (e.g., nit r ic oxide) in the splanchnic area; this response in turn may lead to vasodilatation of the splanchnic arterial vessels. Patients with cirrhosis and increased levels of lipopolysaccharide-binding protein or circulating levels of bacterial DNA (which may be considered surrogate markers of bacterial translocation) have increased serum levels of cytokines, reduced systemic vascular resistance, and increased cardiac output, as compared with those who have cirrhosis but do not have these markers of bacterial translocation. Moreover, the administration of norfloxacin, an antibiotic that results in selective intestinal decontamination and reduces bacterial translocation, ameliorates but does not normalize the hemodynamic abnormalities in patients with cirrhosis.
The development of portal hypertension in cirrhosis is associated to arterial vasodilation in the splanchnic circulation due to the local release of nitric oxide and other vasodilatory substances. Early in the course of the disease, the decrease in systemic vascular resistance is compensated by the development of a hyperdynamic circulation (increased heart rate and cardiac output). However, as the disease progresses and arterial vasodilation increases, the hyperdynamic circulation is insuﬃcient to correct the eﬀective arterial hypovolemia. Arterial hypotension develops, leading to activation of high pressure baroreceptors, reﬂex stimulation of the renin–angiotensin and sympathetic nervous systems, increase in arterial pressure to normal or near normal levels, sodium and water retention and the formation of ascites. The activation of antidiuretic hormone causes water retention and dilutionalhyponatremia, which occurs at later phases of decompensated cirrhosis. 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 sympathetic nervous activity, angiotensin-II and antidiuretic hormone. 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, the maintenance of arterial pressure is due to vasoconstriction in extra-splanchnic vascular territories such as the kidneys and brain. HRS develops at the latest phase of the disease when there is extreme deterioration in eﬀective arterial blood volume and severe arterial hypotension. The homeostatic stimulation of the renin–angiotensin system, the sympathetic nervous system and antidiuretic hormone is very intense leading to extreme renal vasoconstriction, a marked decrease in renal perfusion and GFR, azotemia and increased serum creatinine concentration.
Resistive index – measure of resistance to arterial flow Peak systolic velocity – low diastolic velocity / peak systolic velocityVasoconstriction in the cutaneous, muscular and cerebral circulations in HRS Brachial and femoral blood ﬂows have been found markedly reduced by echo-Doppler in patients with HRS in comparison to patients without HRS. These results suggest that HRS is associated to vasoconstriction in the cutaneous and muscular arterial vascular beds, although this must be conﬁrmed in studies using other techniques. The resistive index in the meancerebral artery is also increased in these patients indicating cerebral vasoconstriction. The degree of vasoconstriction in cutaneous, muscular and cerebral territories found in these studies correlated directly with the degree of renal vasoconstriction and with the plasma levels of renin.The clinical consequence of the decreased muscular blood ﬂow in advanced cirrhosis has not been explored. Patients with type-2 HRS and refractory ascites frequently present muscle cramps. Although the pathogenesis of this abnormality is unknown, muscle cramps disappear or improve following plasma volume expansion with albumin suggesting that they could be related to this reduction of muscular blood ﬂow. Hepatic encephalopathy is common in patients with type-1 HRS. There are many possible mechanisms of this complication, including the precipitating event of HRS, which can also cause hepatic encephalopathy, and the deterioration of hepatic function seen in these patients. Cerebral vasoconstriction, however, could be an additional factor.
type-1 HRS mimics the acute renal failure associated with other conditions such as sepsis or severe pancreatitis, with features of multiorgan failure including acute impairment in cardiovascular, renal, hepatic and cerebral function and relative adrenal insuﬃciencyClinical data suggest that type-1 and type-2 HRS are different syndromes and not different expressions of a common underlying disorder. Renal failure in type-1 HRS is severe and progressive whereas in type-2 it is moderate and steady. As expected, circulatory function is also stable in type-2 HRS, whereas a rapidly progressive impairment in circulatory function occurs in type-1 HRS. Type-1 HRS is frequently associated with a precipitant event, mainly SBP. In contrast, type-2 HRS develops spontaneously in most cases. Finally,the main clinical consequence of type-1 HRS is severe hepatorenal failure and death, whereas in type-2 HRS it is refractory ascites. Type-2 HRS probably represents the genuine functional renal failure of cirrhosis. It would be the extreme expression of the impairment in circulatory function that spontaneously develops up to the ﬁnal stages of the disease. In contrast, type-1 HRS appears to share similarities with acute renal failure associated with other conditions such as septic shock or severe pancreatitis. In fact, as indicated previously, features of multiorgan failure including acute impairment in cardiovascular, renal, hepatic, and cerebral function and relative adrenal insufﬁciency are common in patients with type-1 HRS but rare in patients with type-2 HRS.
it is surprising that there have been so few studies assessing the natural history of cirrhotic patients with ascites. Therefore, at present, it is not well-established how many of these patients will develop other ascitic complications, what their survival rate is, and whether there are clinical and laboratory data of value in predicting prognosis.Natural history of ascites (Hep C and alcohol) – Ramon Planos et al, Spain, CGH 06: Included are HCV and alcohol related cirrhosis (~ 50% each) with either grade 2 or 3 ascites. ~ 75% of alcoholics remained abstinent. N = 263, median f/u = 41 months, mean age ~ 61 yr. In ~ 82%, ascites is the first decompensation. During this f/u, ~ 26% developed SBP. The 5-year probability of DH, RA, and HRS development was 37.1%, 16.7%, and 11.4%, respectively. 1 yr mortality after grade 2 or 3 ascites is 15% and 5 yr mortality is 45%. If patients don’t develop DH/RA/HRS – 5 yr mortality is only 20%. But in case of development of DH, RA, HRS during follow up, the 5 yr mortality is 75%, 85% and 90%.The 1-year probability of survival after developing DH, RA, and type 2 HRS was ~ 25%, 30%, and 38%, respectively. The survival of cirrhotic patients with ascites is relatively high, and it is mainly influenced by age and Child-Pugh score at the time of ascites decompensation, as well as by DH development. Moreover, although the probability of RA and HRS development is relatively low, they are associated with a low survival rate.
Background: The aim of the study was to investigate the incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Methods: The study is a follow-up investigation in 234 nonazotemic patients with cirrhosis and ascites. Thirty-nine variables obtained at inclusion were analyzed as possible predictors of hepatorenal syndrome occurrence (Kaplan-Meier method, Mantel-Cox test, and step-wise Cox regression procedure). Median follow up is 17 months.Results: The probability of hepatorenal syndrome occurrence was 18% at 1 year and 39% at 5 years. Sixteen variables had predictive value for hepatorenal syndrome occurrence in the univariate analysis: history of ascites, hepatomegaly, nutritional status, blood urea nitrogen level, serum creatinine concentration, serum sodium and potassium concentration, serum and urine osmolality, urinary sodium excretion, free water clearance after a water load, glomerular filtration rate, arterial pressure, plasma renin activity, plasma norepinephrine concentration, and esophageal varices. Neither etiology (alcoholic vs. nonalcoholic) nor the Child-Pugh score had predictive value. A multivariate analysis disclosed only three independent predictors of hepatorenal syndrome occurrence: low serum sodium concentration, high plasma renin activity, and absence of hepatomegaly. Conclusions: The hepatorenal syndrome is a relatively frequent complication in cirrhotic patients with ascites that is associated with an extremely short survival. Liver size, plasma renin activity, and serum sodium concentration are predictors of hepatorenal syndrome occurrence in these patients.
Ten randomized trials on terlipressin alone or with albumin, octreotide plus albumin, and noradrenalin plus albumin were included. The total number of patients was 376. Overall, vasoconstrictor drugs used alone or with albumin reduced mortality compared with no intervention oralbumin (relative risk [RR], 0.82; 95% conﬁdence interval [CI], 0.70-0.96).
Hepatorenal syndrome<br />Speaker: Dr.S.Ragavendra Preceptors: Dr. AshutoshBiswas<br /> Dr. AnoopSaraya<br /> Dr. SandeepMahajan<br />
Historical Perspective…<br />Association between kidney dysfunction and liver diseases- Frerichs(1877). Observed oliguria with ascites<br />Absence of urinary protein and low urinary sodium excretion- Hecker and Sherlock (1956)<br />Functional nature- Koppel et al (1960). Done kidney Tx from HRS patients<br />Recovered renal dysfunction after liver Tx- Iwasukiet al (1970)<br />Later, Schroeder et al- renal vasoconstriction in HRS<br />
Hepatorenal syndrome (HRS)<br />International ascites club defined HRS as a syndrome that occurs in patients with cirrhosis, portal hypertension and advanced liver failure, characterized by impaired renal function with marked abnormalities in the arterial circulation and activity of endogenous vasoactive systems<br />Is a functional disorder<br />Kidneys - histologically normal<br />Arroyo V et al, Hepatology 1996;23:164e76<br />4<br />
International ascites club (IAC) diagnostic criteria<br />Major Criteria:<br />Chronic or acute liver disease with advanced hepatic failure and portal hypertension<br />Low GFR ~ S.cr >1.5mg/dl or 24 hrcreatinine clearance <40ml/min<br />Absence of shock, ongoing bacterial infections, and current or recent Rx with nephrotoxic drugs<br />Absence of GI fluid losses<br />Absence of renal fluid losses in response to diuretic therapy<br />No sustained improvement in renal function after diuretic withdrawal and expansion of plasma volume with 1.5 liters of isotonic saline<br />Proteinuria <500mg/day, and no USG e/o obstructive uropathy or parenchymal renal disease<br />Arroyo et al, Hepatol, 1996<br />5<br />
International ascites club (IAC) diagnostic criteria<br />Minor criteria<br />Urine volume <500ml/day<br />Urine sodium <10mmol/L<br />Urine osmolality > Plasma osmolality<br />Serum Na <130mmol/L<br />Urine RBC <50/hpf<br />6<br />Arroyo et al, Hepatol, 1996<br />
New IAC diagnostic criteria 2007<br />Salerno et al, Gut 2007<br />
Rationale for the proposed diagnostic criteria for HRS<br />Serum creatinine(> 1.5 mg%) to establish reduced GFR – consensus<br />Volume expansion to exclude pre-renal causes<br />Volume replacement: saline vs albumin <br />Shock preceding renal failure – a pointer towards “ATN”<br />Transient AKI due to sepsis – should resolve with antibiotics<br />Nephrotoxic drugs – commonly used<br />8<br />
Rationale for the proposed diagnostic criteria for HRS<br />Intrinsic renal disease and obstructive uropathy to be ruled out<br />Urine volume, Urine Na, urine : plasma osmolality – <br />Parameters traditionally used to differentiate functional renal failure from ATN<br />Removed from the revised diagnostic criteria<br />Reason: parameters not exclusive for either of the entities<br />10<br />
Causes of pseudo hepatorenal syndrome<br />11<br />
Types of HRS<br />Type-1 HRS: <br />Rapidly progressive reduction of renal function as deﬁned by doubling of the initial S.cr to a level >2.5 mg/dL in < 2 wk<br />Clinical pattern: acute renal failure<br />Type-2 HRS: <br />Moderate renal failure (S.cr ranging from 1.5 to 2.5 mg/dL) with a steady or slowly progressive course<br />Clinical pattern: refractory ascites<br />Salerno et al, Gut 2007<br />12<br />
Probability of survival: Type 1 vsType 2<br />Alessandria et al, Hepatol 2005<br />
Type 3 HRS<br />Recently defined type<br />85% of end-stage cirrhotics- intrinsic renal disease on Kidney Bx<br />Allessandria C. Hepatology 2005<br />Cirrhotics + pre existing renal dysfunction can develop superimposed HRS<br />Renal histology may be required to accurately diagnose cause of renal failure<br />May require liver-kid transplant.<br />Never studied in therapeutic trials.<br />15<br />
Type 4 HRS<br />> 50 % of ALF develop HRS.<br /><ul><li>Rarely refractory ascites and PHT
Very poor prognosis esp. if ALF acetaminophen-related.
S.creatinine: prognostic value<br />MELD <br />Score based on creatinine, bilirubin, INR<br />Predicts mortality in patients undergoing TIPS<br />Organ allocation based on the score<br />Gives an idea about the requirement of RRT post LT<br />Predicts short term and long term survival in ESLD<br />Predicts mortality in variceal bleeding, sepsis and alcoholic hepatitis<br />Predicts mortality in HCC resection, cardiac and abdominal surgeries<br />Refinements - ∆MELD, MELD-Na<br />17<br />
Prevention of HRS<br />SBP: IV albumin administration<br />Severe acute alcoholic hepatitis: Oral pentoxyphylline<br />Low protein ascites: Norfloxacin as 1o SBP prophylaxis<br />Large volume paracentesis: IV albumin to prevent paracentesis induced circulatory dysfunction (PICD)<br />
32<br />Arroyo V, et al N Engl J Med 1999;341:407<br />
Prevention of HRS<br />SBP: IV albumin administration<br />Arroyo V, et al N Engl J Med 1999;341:407<br />Severe acute alcoholic hepatitis: Oral pentoxyphylline<br />Akriviadis E et alGastroenterology 2000<br />Low protein ascites: Norfloxacin as 1o SBP prophylaxis<br />Large volume paracentesis: IV albumin to prevent PICD<br />
Management of HRS<br />Liver transplantation is the only definitive treatment option<br />Renal failure at time of transplant has poorer outcomes<br />Bridge to Liver Transplantation needed<br />
Initial Management checklist <br />Admission to monitored care setting with Vitals montiroing<br />Central line placement for CVP helpful, not mandatory<br />Routine blood and urine investigations<br />Abdominal USG<br />Diagnostic paracentesis<br />Discontinue diuretics<br />Plasma expansion with albumin<br />Evaluation for Orthoptic liver transplantation<br />36<br />
Randomized trials on type 1 or type 2 HRS<br />Treatments compared:<br />Terlipressin (+ albumin) vs no intervention, albumin or NA + albumin<br />Octreotide + albumin vs albumin<br />Terlipressin + albumin given as continuous or bolus infusion<br />
Other drugs<br />Noradrenaline + albumin<br />Results similar to terlipressin<br /> Cheaper<br />0.1 mcg/kg/min infusion (max 0.7)<br />Alessandria et al, J hepatology 2007<br />Midodrine and octreotide<br />Oral α adrenergic agonist + long acting s/c somatostatin analogue<br />Direct vasoconstrictor + inhibits endogenous vasodilators<br />5 mg tds + 100mcg tds s/c<br />Given along with albumin<br />OPD use. Not studied for Type 2<br />Angelip;Hepatology.1999<br />41<br />
Other drugs<br />Misoprostol<br />Synthetic-PGE1<br />Patients have low urinary levels of vasodilatoryprostaglandins<br />Evidence poor<br />Gines;J Hepatol.1993<br />Renal vasoconstrictor antagonists<br />Saralasin - Angitensin II receptor antagonist<br />-worsening hypotension, abandoned<br />Endothelin antagonists- non specific tezosentan<br />Endothelin A receptor antagonist(BQ123)<br />SoperCP;Lancet.1996<br />42<br />
TIPS(Transjugular intrahepatic portosystemic shunting)<br />Few studies available (case series)<br />Decreases portal pressure and consequently reduces renal sympathetic activity<br />Improvement in renal function and <br /> survival noted compared to no treatment<br /> (but may take several weeks)<br />Careful patient selection needed to <br /> optimize safety and efficacy<br />Guevara et al,hepatology 1998;28:416-22<br />
Renal replacement therapy<br />Paucity of data<br />Optimal method not known<br />Impact on prognosis not known<br />No studies in comparison with medical Rx<br />To be used in patients with an urgent indication of HD and for patients with no response to vasoconstrictor therapy<br />Available studies:<br />Keller et al, Ren Fail, 1995 – retrospective analysis, n = 26, better survival<br />Witzke et al, J GastroenterolHepatol, 2004– prospective observational study, n = 30, RRT not predictive of improved survival <br />
Artificial hepatic support<br />Detoxification treatment ~ form of artificial extracorporeal liver support.<br />Considered to be a bridge to liver transplantation<br />Liver dialysis devices – <br />Molecular Adsorbents Recirculation System (MARS)<br />Single Pass Albumin Dialysis (SPAD)<br />Prometheus system<br />45<br />
Molecular adsorbent recirculating system (MARS)<br />Most frequently used albumin dialysis system<br />Dialysate recirculated and perfused online through charcoal and anion exchanger columns<br />Improve systemic hemodynamics and renal perfusion.<br />Better than HD for sodium,creatinine, bilirubin and PT <br />46<br />
Liver transplantation<br />Treats the causative organ dysfunction<br />1 yr survival rate: not on HD – 78.8% , on HD – 73.7%<br />survival with s.cr at similar MELD scores (at 15-17 and 24-40)<br />Similar 2 yr and 5 yr survival among non HRS and HRS LT<br />Beneficial outcomes with renal protective immunosuppression<br />Schmitt et al, TransplInt 2009<br />Sharma et al, Liver Transpl 2009<br />Jeyarajah et al, Transplantation 1997<br />Lopez Lago et al, Transplant Proc 2007<br />
Liver-Kidney transplantation<br />Usual norms:<br />Preoperative HRS/ ATN usually don’t need KTP<br />Many times 1o renal disease can be managed medically <br />Factors contributing to renal failure:<br />Improved medical management leading to better survival<br />Long waiting time for transplant<br />Post-LT calcineurin inhibitors<br />
Liver-Kidney transplantation<br />Issues to be addressed pre-LT:<br />Will the ARF reverse?<br />Is there a way to predict who will recover?<br />What is the acceptable degree of recovery?<br />Patients of HRS who required prolonged HD (> 4 - 8 wks) may require KLT and better outcomes have been reported<br />Ruiz et al, Arch Surg 2006<br />
Liver-Kidney transplantation<br />Tanriover et al, Transplantation 2008<br />
Conclusion<br />Prevention is utmost important<br />Low threshold to diagnose and investigate renal failure in presence of liver dysfunction.<br />Early diagnosis and timely therapeutics can increase life expectancy for HRS patients while these are waiting for liver transplantation as a definitive treatment.<br />54<br />
Ques to be answered<br />Definitions..<br />Fluid therapy<br />Cvp based?<br />Do pts develop structural changes?<br />Therapy lacunae?<br />56<br />
Summary<br />Decompensated cirrhosis with renal failure<br />Rule out pre-renal causes: stop diuretics, volume expansion (NS or albumin), CVP measurement<br />Rule out intrinsic and obstructive renal disease: urine analysis, USG KUB, check out nephrotoxic drugs<br />Surveillance for sepsis, low threshold for antibiotics usage<br />Medical mx to increase urine output and improvizing KFT, optimization of diuretics and management of refractory ascites, dialyze as per clinical indication<br />TIPS/List for LT<br />
Triple therapy vs Terlipressin<br />HRS (n=37)<br />Type II (n=14)<br />Type I (n=23)<br />Terlipressin (n=12)<br />Terlipressin (n=4)<br />Triple (n=11)<br />Triple (n=10)<br />