Pathophysiology and Management of the Hepatorenal Syndrome

Diagnostic Criteria of Hepatorenal Syndrome

During the past 20 years, three consensus meetings aimed to define diagnostic criteria of HRS were held. In 1996 Arroyo V et al. produced the first consensus definition of HRS. According to these criteria HRS was defined as a functional form of AKI that does not improve after plasma expansion with saline. The presence of an ongoing bacterial infection was an exclusion criteria for HRS. In the following years, several studies showed a very high incidence of AKI with the features of HRS after bacterial infections and in 2007 Salerno et al. modified the former criteria removing an ongoing bacterial infections among exclusion criteria. Furthermore, Salerno et al. suggested use of albumin (at the dosage of 1 g per kg per day) for plasma volume expansion in patients with suspected HRS, because albumin appeared to be the best plasma expander in patients with cirrhosis. More recently, with the development of AKI concept, it has become more evident that variations of SCr values are more important than a cutoff of SCr in predicting mortality. Indeed, several studies showed a high mortality rate for a small increase in SCr, questioning the cutoff of SCr of 2.5 mg/dL required for the diagnosis of type 1 HRS. As a result in 2016 Angeli P et al. introduced new criteria for the definition of AKI in patients with cirrhosis and removed any cutoff of SCr required for the diagnosis of HRS, while confirming the other criteria ( Box 128.1 ). According to these new observations, type 1 HRS also has been defined as HRS-AKI, whereas the classical type 2 HRS is considered to be a type of CKD in patients with cirrhosis (HRS-CKD).

In summary, new proposed criteria for the diagnosis of HRS-AKI are the following:

• Diagnosis of cirrhosis and ascites

• Diagnosis of AKI according to International Club of Ascites (ICA)–AKI criteria

• No response after 2 consecutive days of diuretic withdrawal and plasma volume expansion with albumin (1 g per kg of body weight)

• Absence of shock

• No current or recent use of nephrotoxic drugs (e.g., NSAIDs, aminoglycosides, iodinated contrast media)

No macroscopic signs of structural kidney injury, defined as follows:

• • Absence of proteinuria (>500 mg/day)

  • Absence of microhematuria (>50 RBCs per high-power field)

  • Normal findings on renal ultrasonography

One may argue that these criteria cannot rule out the presence of a subclinical renal damage and more sensitive biomarkers could be useful in this setting. Several urinary biomarkers have been developed in recent years; urinary neutrophil-gelatinase lipocalin is the most promising biomarker in the differential diagnosis of AKI in patients with cirrhosis. Nevertheless, further studies are needed before any of these biomarkers could be included in the diagnostic criteria of HRS.

Pathophysiology of Hepatorenal Syndrome

Peripheral Arterial Vasodilation Hypothesis

For several years the “peripheral arterial vasodilation hypothesis” (PAVH) represented the best pathophysiologic hypothesis of HRS ( Fig. 128.1 ). This hypothesis comes from the observation of an abnormal vasodilation in the splanchnic vascular bed in patients with cirrhosis. This abnormal vasodilation is the consequence of portal hypertension and is mediated by several vasodilators such as nitric oxide (NO), carbon monoxide (CO), glucagon, adrenomedullin, prostacyclin, and others in splanchnic circulation, leading to an abnormal vasodilation. This event causes a reduction in effective circulating volume and the activation of baroreceptors leading to activation of vasoconstrictors systems (sympathetic system, renin-angiotensin-aldosterone system, and nonosmotic production of vasopressin). Sympathetic nervous system activation causes an increase in heart rate and cardiac contractility, resulting in a global increase of cardiac output. Renin-angiotensin-aldosterone system activation causes an increase in distal absorption of sodium. Furthermore, the increase in sympathetic tone and angiotensin II stimulates sodium reabsorption in the proximal tubule. Finally, vasopressin is responsible of free water reabsorption in the distal tubule. Thus the effects of the activation of vasoconstrictors systems result in (1) an increase in cardiac output and (2) an expansion of body fluid resulting from sodium and water retention. In the early phases of the disease, these mechanisms restore the effective circulating volume. In this phase the so-called “hyperdynamic circulation” is the main feature. However, as liver disease worsens, the further increase in splanchnic vasodilation cannot be compensated for by a further increase in cardiac output. Thus the massive activation of the vasoconstrictor systems leads to abnormal renal sodium and water retention and arterial vasoconstriction in the kidney, which are responsible for the development of ascites, and, in the most advanced stages, dilutional hyponatremia, refractory ascites, and HRS. HRS usually develops in the most advanced stages of the disease, when there is an extreme reduction of the effective circulating volume and an extreme activation of the systemic vasoconstrictor systems.