Pathogenesis and Treatment of Hepatorenal
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are important predictors of type-1 HRS. 24 The second study consisted of a longitudinal investigation of 66 nonazotemic cirrhotic patients with ascites.
43 Forty percent of patients developed HRS (type 1 or type 2). These patients were studied at inclusion and following the development of HRS. In the initial study, those patients who went on to develop HRS had significantly lower mean arterial pressure and cardiac output, and significantly higher plasma renin activity and norepinephrine concentration compared with those who did not develop HRS. Moreover, those who developed HRS had a further decrease in arterial pressure and cardiac output and an increase in renin and norepinephr- ine without changes in peripheral vascular resistance Figure 2 Peripheral arterial vasodilation hypothesis and renal dysfunction in cirrhosis. In initial phases, when cirrhosis is compensated, the increase in splanchnic arterial vasodilation is compensated by an increase in cardiac output (hyperdynamic circulation). The effective arterial blood volume and the activity of renin-angiotensin (RAAS), sympathetic nervous system (SNS), and plasma antidiuretic hormone (ADH) are normal despite a reduction in systemic vascular resistance. With the progression of liver disease, splanchnic arterial vasodilation increases but the cardiac output does not. An effective arterial hypovolemia therefore develops, leading to activation of the RAAS and SNS and ADH. Systemic vascular resistance does not decrease due to vasoconstriction of extrasplanchnic organs. Type-2 HRS could be the extreme expression of renal vasoconstriction. PATHOGENESIS AND TREATMENT OF HEPATORENAL SYNDROME/ARROYO ET AL 85
(Table 3). These findings strongly suggest that circula- tory dysfunction in cirrhosis is due to both an increase in arterial vasodilation and a decrease in cardiac function (Fig. 3), and that HRS occurs in the setting of severe reduction in effective arterial blood volume secondary to an impairment in cardiovascular function. In this study, baseline increased plasma renin activity and reduced cardiac output were found to be the only independent predictors of HRS. HRS IN CIRRHOSIS IS A COMPLEX SYNDROME THAT AFFECTS ORGANS OTHER THAN THE KIDNEY Traditionally, patients with HRS were considered to have mainly two different problems, a terminal and irreversible liver failure due to advanced cirrhosis and a functional renal failure secondary to renal vasoconstric- tion. The link between the diseased liver and the failing kidney was a deterioration in systemic hemodynamics. Table 3 Chronological Changes of Vasoactive Systems and Cardiovascular Function from Nonazotemic Cirrhosis with Ascites (NA) to Type-2 HRS* NA-1 NA-2
At Diagnosis of Type-2 HRS Mean arterial pressure (mm Hg) y 88 Æ 9 86 Æ 10 79 Æ 7
Plasma renin activity (ng/mL.h) y 3 Æ 2 7.5
Æ 3.7 11.9
Æ 4.8 Norepinephrine (pg/mL) y 221
Æ 256 412
Æ 155 628
Æ 320 Systemic vascular resistance (dynes.second/cm -5 )
Æ 256 1058
Æ 265 1014
Æ 276 Cardiac output (L/min) y 7.2
Æ 1.8 6.2
Æ 1.4 5.8
Æ 1.2 Heart rate (bpm) 87 Æ 15
84 Æ 12
80 Æ 14
Hepatic blood flow (mL/min) y 1123 Æ 328 1064
Æ 223 824
Æ 180 Hepatic venous pressure gradient (mm Hg) y 16.5
Æ 3 19 Æ 3 19.5 Æ 2
*Data from Ruiz-del-Arbol L, Monescillo A, Arocena C, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:439–447. NA-1, baseline measurement in nonazotemic cirrhotic patients who did not develop hepatorenal syndrome during the follow-up; NA-2, baseline measurement in nonazotemic cirrhotic patients who developed type-2 hepatorenal syndrome during the follow-up. bpm, beats per minute. y p < 0.01. Figure 3 Peripheral vasodilation hypothesis (top graph) and modified peripheral vasodilation hypothesis (bottom graph). According to this latter hypothesis, impairment in arterial blood volume in cirrhosis could be the consequence of a progression of splanchnic arterial vasodilation and a decrease in cardiac output. 86 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1 2008 During the last decade, however, increasing evidence suggest that HRS is a much more complex syndrome affecting organs other than the liver and the kidney. Moreover, data have been presented suggesting that the impairment in circulatory function affects the intrahe- patic circulation and that this may contribute to the severity of hepatic failure in HRS. Liver failure in HRS could, therefore, be partially reverted if circulatory dys- function is improved. Renal Failure HRS develops at the last phase of cirrhosis, when patients already present severe circulatory dysfunction, arterial hypotension, marked activation of the renin- angiotensin aldosterone system, sympathetic nervous system, and antidiuretic hormone, renal sodium and water retention, ascites, and dilutional hyponatremia. The mechanism of the renal vasoconstriction that causes HRS is complex. Since renal perfusion in decompen- sated cirrhosis correlates inversely with the activity of the renin-angiotensin and sympathetic nervous sys-
tems, 36,38,44,45 HRS is thought to be related to the extreme stimulation of these systems. The urinary ex- cretion of prostaglandin E2, 6-keto prostaglandin F1a (a prostacyclin metabolite), and kallikrein is decreased in patients with HRS, which is compatible with a reduced renal production of these vasodilatory substances. 46,47 Renal failure in HRS could, therefore, be the conse- quence of an imbalance between the activity of the systemic vasoconstrictor systems and the renal produc- tion of vasodilators. Additionally, once renal hypoperfu- sion develops, renal vasoconstriction could be amplified by the stimulation of other intrarenal vasoactive systems. For example, renal ischemia increases the generation of angiotensin-II by the juxtagomerular apparatus, the intrarenal production of adenosine (a renal vasoconstric- tor which in addition potentiates the vascular effect of angiotensin-II), and the synthesis of endothelin. Other intrarenal vasoconstrictors that have been involved in HRS are leukotrienes and F2-isoprostanes. 48 Renal
vasoconstriction in HRS is, therefore, related to the simultaneous effect of numerous vasoactive substances on the intrarenal circulation. Vasoconstruction of Cutaneous, Muscular, and Cerebral Circulation in HRS Brachial and femoral blood flows are markedly reduced in patients with HRS, indicating a vasoconstriction in the cutaneous and muscular arterial vascular beds. 36 The
resistive index in the mean cerebral artery is also in- creased in these patients, indicating cerebral vasocon- striction 39 (Fig. 4). The degree of vasoconstriction in these vascular territories in decompensated cirrhosis (patients with ascites with and without HRS) correlates directly with the degree of renal vasoconstriction and with the plasma levels of renin. Impairment in circula- tory function in cirrhosis is therefore associated with generalized nonsplanchnic arterial vasoconstriction. The clinical consequences of the decreased mus- cular blood flow in advanced cirrhosis have 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, 49 suggesting that they could be related to this reduction in muscular blood flow. Hepatic encephalopathy is common in patients with 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 observed in these patients. Cerebral vasoconstriction, however, could be an additional factor. Cardiac Dysfunction The normal response to arterial hypotension consists of a stimulation of the renin-angiotensin and sympathetic nervous systems. Angiotensin-II and the sympathetic nervous activity produce arterial vasoconstriction and increase the systemic vascular resistance. Moreover, these hormones also increase heart rate, ventricular contractility, and cardiac output. These two mechanisms increase arterial pressure to normal or near-normal levels. In patients with type-2 HRS, arterial vasodilation is followed by an appropriate response of the vasoactive neurohormonal systems. There is a marked increase in the plasma levels of renin and norepinephrine and vasoconstriction in the extrasplanchnic organs that maintains arterial pressure. 36,39 However, the cardiac response is clearly abnormal in these patients. Develop- ment of type-2 HRS is associated with a slight decrease in cardiac output. Moreover, despite the intense activa- tion of the sympathetic nervous activity, no change in heart rate is observed (Table 3). 43 These data clearly indicate that there is an impairment in cardiac inotropic and chronotropic functions in patients with type-2 HRS. In patients with type-1 HRS, the deterioration of cardiac function is even more evident. Type-1 HRS occurs in the setting of a severe decrease in cardiac output, which may reach values below normal. The heart rate remains unchanged despite a dramatic activation of the renin- angiotensin and sympathetic nervous systems. 42 The pathogenesis of the impaired cardiac re- sponse to arterial vasodilation in HRS is unknown. A specific cardiomiopathy characterized by attenuated sys- tolic and diastolic responses to stress stimuli, electro- physiological repolarization changes, and enlargement and hypertophy of cardiac chambers is common in patients with advanced cirrhosis. 50 This cirrhotic cardi- omiopathy has been thought to play a role in the PATHOGENESIS AND TREATMENT OF HEPATORENAL SYNDROME/ARROYO ET AL 87
pathogenesis of heart failure seen after the insertion of a transjugular intrahepatic portosystemic shunt (TIPS), 51,52
major surgery, or liver transplantation, 53,54
and in HRS. 42,43
Other features, however, suggest that the impairment in the cardiac inotropic function in HRS is not organic but is mainly functional in nature and related to a decrease in venous return. 55 First, the reduced cardiac output in patients with HRS occurs in the setting of a decrease in cardiopulmonary pressures, which is compatible with a fall in cardiac preload. Second, circulatory dysfunction in HRS can be reverted by the intravenous (I.V.) administration of albumin associated with vasoconstrictors or after the insertion of a TIPS. Both treatments increase venous return and cardiac output. Finally, expansion of plasma volume with albumin is highly effective in the prevention of type-1 HRS in patients with SBP. 56 The impairment in chro- notropic cardiac function is probably related to a down- regulation of b-adrenergic receptors secondary to the chronic stimulation of the sympathetic nervous system. Intrahepatic Vasoconstriction Angiotensin-II, noradrenaline, and vasopressin have powerful effects on the intrahepatic circulation. They produce arterial vasoconstriction and increase the intra- hepatic resistance to the portal venous flow at different levels (small portal venules, sinusoids, and small hepatic venules). In patients with cirrhosis these effects are increased due to a reduced intrahepatic synthesis of nitric oxide. 57 It is, therefore, not surprising that the stimulation of the endogenous vasoactive systems in HRS could be associated with an aggravation of portal hypertension and a marked reduction in hepatic blood flow.
42,43 This has been shown recently by Ruiz-del- Arbol et al. 43 They studied hepatic hemodynamics in a large series of nonazotemic cirrhotics with tense ascites when they had normal serum creatinine concentration and after a follow-up of several months when patients developed type-1 or type-2 HRS. The hepatic venous pressure gradient was significantly higher in the follow- up study than in the baseline study in patients developing type-1 HRS. Type-1 HRS was also associated with a dramatic reduction in hepatic blood flow. In patients developing type-2 HRS, significant differences were only observed in the hepatic blood flow (Table 3). In a second investigation from the same group, hepatic he- modynamics were assessed in patients with SBP at infection diagnosis and following infection resolution. 42 There was only a 1-week interval between the studies. Figure 4 Resistive index in the middle cerebral artery in patients with compensated cirrhosis, patients with ascites, and healthy subjects (upper graph). Relationship between the renal resistive index and the resistive index in the middle cerebral artery in cirrhotic patients (lower graph). (Reproduced with permission from Guevara M, Bru C, Gine`s P, et al. Increased cerebrovascular resistance in cirrhotic patients with ascites. Hepatology 1998;28:39–44.) 88 SEMINARS IN LIVER DISEASE/VOLUME 28, NUMBER 1 2008 Hepatic venous pressure gradient increased markedly in patients who developed type-1 HRS but not in patients with normal renal function. Changes in intrahepatic hemodynamics in the two studies correlated significantly with the increase in plasma renin activity. This finding suggests that circulatory dysfunction associated with hepatorenal syndrome adversely influences intrahepatic hemodynamics. Acute deterioration of hepatic function is a common event in patients with type-1 HRS. Variceal bleeding is also frequent in patients with severe bacterial infections and HRS. The intense reduction in hepatic blood flow and the increase in portal pressure associated with type-1 HRS could play a role in the development of these complications. Relative Adrenal Insufficiency Two recent studies indicate that relative adrenal dys- function is a common problem in patients with cirrhosis and acute-on-chronic liver failure secondary to severe sepsis. 58,59
In the first study, 58 adrenal insufficiency was detected in 80% of patients with HRS but only in 34% with serum creatinine below 1.5 mg/dL. A close rela- tionship, therefore, existed between adrenal insufficiency and HRS in patients with severe infection. Other fea- tures associated with adrenal insufficiency were severe liver failure, arterial hypotension and vasopressor de- pendency, and hospital mortality. Since normal adrenal function is essential for an adequate response of the arterial circulation to endogenous vasoconstrictors, adre- nal insufficiency could be an important contributory mechanism of circulatory dysfunction associated with HRS in patients with severe bacterial infections. The second study 59 recently showed that treatment with hydrocortisone in cirrhotic patients with severe sepsis and adrenal insufficiency is associated with a rapid improvement in systemic hemodynamics, reduction of vasoconstrictor requirements, and higher hospital sur- vival. The mechanisms of adrenal dysfunction in cir- rhosis with severe sepsis have not been explored. Since adrenal dysfunction is particularly prevalent in patients with HRS, a reduction in adrenal blood flow secondary to regional vasoconstriction is a possible mechanism. Cytokines directly inhibit adrenal cortisol synthesis. The inflammatory response associated with bacterial infec- tions is, therefore, another potential pathogenic mech- anism. TYPE-1 AND TYPE-2 HRS ARE NOT DIFFERENT EXPRESSIONS OF A COMMON SYNDROME BUT RATHER DIFFERENT ENTITIES 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 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 circu- latory function that spontaneously develops up to the final stages of the disease (Figs. 2, 3). 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 impair- ment 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 (Fig. 5). TREATMENTS FOR TYPE-1 HRS Liver Transplantation Liver transplantation is the treatment of choice for any patient with advanced cirrhosis, including those with type-1 and type-2 HRS. 60–63
Immediately after trans- plantation, a further impairment in GFR may be ob- served and many patients require hemodialysis (35% of patients with HRS as compared with 5% of patients without HRS). 60 Because cyclosporine or tacrolimus may contribute to this impairment in renal function, it has been suggested to delay the administration of these drugs until a recovery of renal function is noted, usually 48 to 96 hours after transplantation. After this initial impairment in renal function, GFR starts to improve and reaches an average of 30 to 40 mL/min by 1 to 2 months postoperatively. This moderate renal failure persists during follow-up, is more marked than that observed in transplantation patients without HRS, and is probably due to a greater nephrotoxicity of cyclosporine or tacro- limus in patients with renal impairment prior to trans- plantation. The hemodynamic and neurohormonal abnormalities associated with HRS disappear within the first month after the operation and patients regain a normal ability to excrete sodium and free water. Patients with HRS who undergo transplantation have more complications, spend more days in the in- tensive care unit, and have a higher in-hospital mortality rate than transplantation patients without HRS. The long-term survival of patients with HRS who undergo liver transplantation, however, is good, with a 3-year probability of survival of 60%. This survival rate is only PATHOGENESIS AND TREATMENT OF HEPATORENAL SYNDROME/ARROYO ET AL 89
slightly lower than that of patients without HRS (which ranges between 70% and 80%). 61 The main problem of liver transplantation in type-1 HRS is its applicability. Due to their extremely short survival, most patients die before transplantation. The introduction of the model for end-stage liver disease score, which includes serum creatinine, bilirubin, and the international normalized ratio, for listing has partially solved the problem since patients with HRS are gen- erally allocated the first places of the waiting list. Treat- ment of HRS with vasoconstrictors and albumin (see below) increases survival in a significant proportion of patients (and, therefore, the number of patients reaching liver transplantation), decreases early morbidity and mortality after transplantation, and prolongs long-term survival. Vasoconstrictors and Albumin The I.V. administration of vasoconstrictor agents (vaso- pressin, ornipressin, terlipressin, noradrenaline) or the combination of oral midodrine (an a-agonistic agent) and I.V. or subcutaneous octreotide during 1 to 3 weeks is an effective treatment of type-1 HRS. Twelve pilot studies including 176 patients with HRS (141 with type- 1 HRS) have so far been published on this topic. 64–75
In most patients, I.V. albumin was also given. The overall rate of positive response was 63.6% (112 patients). In nine of these studies (including 150 patients) a positive response was considered when there was reversal of HRS as defined by a decrease of serum creatinine below 1.5 mg/dL. This feature was observed in 96 patients (64%). A second important observation was that type-1 HRS does not recur after discontinuation of the treat- ment in most patients. Six studies including 74 patients have reported data on this feature. Fifty-two patients responded to therapy and HRS recurred in only 12. Yüklə 401,11 Kb. Dostları ilə paylaş:
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