The pathophysiological changes in cirrhosis are mostly associated with systemic vasodilatation and splanchnic hyperemia which is accompanied by reflex stimulation of the sympathetic system to maintain hemodynamic stability [8, 9]. As a result there is an increase in the circulating catecholamine and activation of the renin-angiotensin system (RAS) . The role of renal sympathetic nervous system stimulation in the etiology of intrarenal vasoconstriction is at best a contributing factor since renal sympathetic denervation did not reverse the vasoconstrictor response that was demonstrated in HRS [10].

The activation of RAS may play a serious role in the etiology of intrarenal vasoconstriction and eventful renal damage as well as in the propagation of hepatic fibrosis with further deterioration of hepatic function [11, 12]. Recent studies indicated that angiotensin II can activate the contraction of the hepatic stellate cells which results in increased intrahepatic resistance to portal blood flow with the development of portal hypertension. The clinical values of ACE inhibitors and/or angiotensin receptor blockers (ARB) in cirrhotic patients are still required to be evaluated since the results of recent clinical trials are not very promising [13, 14]. The issues related to the use of ARBs and ACE inhibitors in cirrhotic patients are related to the development of systemic hypotension which can further compromise renal perfusion and blood flow. A new scientific discovery of the presence of a homolog of ACE that is present in the heart, kidneys, and testis which can convert angiotensin II into angiotensin (1–7 and 1–9) both can oppose the effects of the parent agent on the vascular resistance and on the hepatic cells. The clinical applications of these agents may pave the way for new therapeutic interventions to prevent renal injury in liver cirrhosis [15].

The presence of cirrhotic cardiomyopathy in patients with ESLD is a well-documented phenomena which can be detected in all kinds of cirrhosis not only in alcohol-induced cirrhosis. The severity of cardiac involvement is clearly related to the severity of liver disease and it tends to improve within 6–12 months after successful liver transplantation [16]. The cardiac dysfunction can be partially explained by high plasma levels of brain natriuretic peptide in the presence of relative hypovolemia or low preload (due to vasodilatation) and it correlates very well with the severity of liver disease [17].

The contribution of high levels of circulating catecholamine in the etiology of cardiomyopathy in ESLD is undeniable and can lead to myocardial growth and myocardial fibrosis with impairment of myocardial relaxation. The hyperactivity of sympathetic system can result in beta-adrenergic receptor down-regulation and abnormality of the signal transduction with overall reduction in the response to sympathomimetic agents [18]. Recently, endogenous cannabinoids (EC) which are lipid-signaling molecules have been recently found to be upregulated in liver disease and considered to be a factor not only in pathogenesis of liver cirrhosis but also in cirrhosis-induced hyperdynamic circulation and/or cirrhotic cardiomyopathy [19].

In ESLD there is breakdown of intestinal mucosal barrier which results in translocation of bacteria and endotoxin from the intestinal tract to the systemic circulation by passing the hepatic filter through the porta-systemic shunting or due to impairment of hepatic de-toxification function. The presence of chronic low levels of endotoxemia in patients with ESLD is the underlying mechanism of the chronic inflammatory response and the resultant splanchnic and systemic vasodilatation [20]. The increased production of pro-inflammatory cytokines (TNF-α, IL-18) which is coupled with excessive production of nitric oxide (NO) can further impair the cardiac dysfunction. The contribution of cardiomyopathy to the pathogenesis of AKI and especially to HRS is still controversial, but cirrhotic patients demonstrate that an inability to increase cardiac output during stress (sepsis, surgery) may further impede the already compromised renal blood flow and lead to AKI. The presence of excessive vasoactive mediators in ESLD can lead directly or indirectly through activation of secondary mediators to low SVR and high intrarenal vascular resistance. These agents include endotoxin, NO, TNF-α, IL-18, endothelin, glucagon, and prostaglandins. The increased production of NO is due to up-regulation of the inducible nitric oxide synthase (iNOS) , possibly induced by high shear stress on the vascular beds of both systemic and splanchnic and the presence of access of endotoxin. The high levels of NO are not only related to increased production but also decreased NO removal. In a recent study by Serna et al. [21] the investigators demonstrated the presence of high dimethylarginine dimethylaminohydrolases (DDAHs) which indicates an increased breakdown of asymmetric dimethylarginine (ADMA) , the natural NOS inhibitor which results in further increased NO production with sustained mesenteric vasodilatation. A new theory is emerging to explain in the intrarenal vasospasm while there is widespread systemic and splanchnic vasodilatation, in which ADMA plays the pivotal role in the inhibition of intrarenal NO production resulting in the vasoconstriction [22, 23].

Other known mediators of the intrarenal vasodilatory response are PGs, which are normally increased whenever there is intrarenal vasoconstriction as demonstrated by increase in urinary excretion of these PGs, except in patients with HRS [24]. The finding that there is a low level of vasodilatory PGs prompted the administration of these agents to patients with HRS; however, the results are still disappointing and may be due to further deterioration in the SVR and decrease in renal perfusion pressure or simply they play minor role in the pathophysiology of AKI of ESLD.

The most common AKI in patients with ESLD is acute tubular necrosis (ATN) 35 % and prerenal azotemia 32 %, HRS-1 20 %, and HRS-2 6.6 % and the rest are miscellaneous causes.