The definition and diagnostic criteria for HRS established in 19945
were based on the following three concepts:
- renal failure in HRS is functional and caused by marked intrarenal arteriolar vasoconstriction;
- HRS occurs in patients with systemic circulatory dysfunction caused by extra‐renal vasodilatation;
- plasma volume expansion does not improve renal failure.
Four new concepts have emerged since then, these are:
(a) Extra‐renal arterial vasodilatation occurs mainly in the splanchnic vascular bed, whereas other vascular beds, such as those which supply the brain and the liver, may be vasoconstricted. This may contribute to the development of hepatic encephalopathy and hepatic failure, respectively.
(b) Cardiac output in patients with HRS may be low, normal or high, but it is insufficient for the patient's needs because of reduced peripheral resistances.
(c) The most common trigger for the development of type‐1 HRS is bacterial infection, mainly spontaneous bacterial peritonitis (SBP).
(d) Renal function can be improved by medical treatment in patients with HRS and is associated with improved survival.
Main pathophysiological and clinical aspects of HRS
- HRS is a functional renal failure caused by intrarenal vasoconstriction which occurs in patiens with end‐stage liver disease and circulatory dysfunction.
- Circulatory dysfunction is characterised by vasodilatation in the splanchnic circulation with a relatively low and insufficient cardiac output, leading to effective hypovolaemia.
- HRS may occur spontaneously with worsening liver function, or secondary to a precipitating event such as bacterial infection (eg, SBP).
- HRS can be improved by the administration of vasoconstrictors and albumin, or by TIPS.
Background for the new concepts
The first of these concepts was formulated following investigation conducted using Doppler ultrasonography or plethysmography both before and after 1994. These studies were performed in patients with varying degrees of severity of cirrhosis, and revealed arterial vasodilatation in the splanchnic circulation as well as arterial vasoconstriction in other areas such as the brain, kidneys and liver,6,7,8,9,10,11,12,13
whereas the cutaneous and muscular blood flow has been reported as low, normal or increased.13,14,15,16
The dilatation of the splanchnic vessels is mainly caused by local release of potent vasodilators such as nitric oxide (NO),17
which also render the splanchnic circulation resistant to various vasopressors including angiotensin II, norepinephrine, vasopressin and endothelin.18,19,20,21,22,23,24
The resistance of the splanchnic circulation to these vasopressor agents renders the control of arterial pressure in cirrhosis dependent on the extra‐splanchnic effects exerted by the endogenous vasoconstrictor systems. As arterial vasodilatation increases with progression of cirrhosis, the role of vasoconstrictors in maintaining haemodynamic stability becomes critical, and explains why cirrhotic patients with HRS are predisposed to develop renal, hepatic and cerebral vasoconstriction.
The second new concept—that is, that insufficient cardiac output contributes to renal hypoperfusion in patients with HRS—was first suggested by Tristani and Cohn,25
but it is only recently that this has been confirmed.26,27
The first study showed that the cardiac output of cirrhotic patients with SBP who developed progressive renal failure was relatively low, despite resolution of infection, when compared with a similar group of patients with SBP who did not develop renal failure.26
The second study compared non‐azotaemic cirrhotic patients who developed HRS with similar patients who did not, and showed that low cardiac output and high plasma renin activity (PRA) were independent predictors of HRS.27
Moreover, in patients developing HRS, the progression of circulatory dysfunction leading to arterial hypotension and renal failure occurred in the setting of a continued decrease in cardiac output and increase in PRA. These findings support the hypothesis that hyperdynamic circulation is essential to maintain central blood volume and renal perfusion in cirrhosis. Therefore, when cardiac output decreases, effective hypovolaemia occurs, leading to renal hypoperfusion and HRS. The mechanism leading to impaired or insuffient cardiac output in patients developing HRS is unknown. In recent years, a specific cardiac abnormality, characterised by attenuated systolic and diastolic responses to stimuli, changes in repolarisation and hypertrophy of the cardiac chambers, has become increasingly recognised—the so‐called “cirrhotic cardiomyopathy”.28
A fall in cardiac preload due to a decrease in venous return is another hypothesis that might justify the effectiveness of albumin infusion.27
HRS can be triggered by precipitating events. The most important of these are infection, bleeding and large‐volume paracentesis without albumin administration.29,30,31,32
The role of SBP has recently been emphasised. Table 1 compares the results of two studies29,30
assessing the prevalence of renal failure in cirrhotic patients with SBP and in those with infections unrelated to SBP, and shows that: (a) in spite of an effective antibiotic therapy, a significant proportion of cirrhotic patients with bacterial infection develop progressive renal failure. This almost exclusively occurs in patients with SBP; (b) in patients not responsive to antibiotic therapy, progressive renal failure occurs and is independent of the type of infection. Furthermore, changes in circulatory function, endogenous vasoactive systems and renal function in patients developing renal failure triggered by SBP are identical to those observed in patients with HRS unrelated to infection, suggesting that the pathogenesis of progressive renal failure in cirrhotic patients with infection is the same as that of HRS.
Table 1Incidence and course of renal failure in cirrhotic patients with severe bacterial infections without shock according to response to antibiotic treatment and to type of infection
The most important concept of HRS, however, arises from studies exploring new therapeutic strategies.33
Since type‐1 HRS is often associated with a rapid deterioration of liver function with increased levels of bilirubin and prothrombin time, it has traditionally been viewed as a manifestation of terminal hepatic failure. The demonstration that type‐1 HRS can be improved by vasoconstrictors34
or by TIPS,35,36
and that reversal of type‐1 HRS may be associated with improved survival, represents a major change in our understanding of the syndrome.
In conclusion, the main pathogenic mechanism in type‐1 HRS is a potentially reversible deterioration of systemic circulatory function, mostly due to splanchnic vasodilatation and renal vasoconstriction and often triggered by a precipitating event (fig 1). In addition to renal failure, the syndrome may be associated with other organ dysfunctions, such as decreased cardiac output, hepatic failure and encephalopathy.
Figure 1Schematic view of the pathogenetic mechanisms of hepatorenal syndrome in cirrhosis. Dotted arrows indicate that precipitating factors are frequent but not necessary. RAAS, renin–angiotensin–aldosterone system; SBP, spontaneous (more ...)