Hepatorenal syndrome in children: a review

Abstract

Hepatorenal syndrome (HRS) occurs in patients with cirrhosis or fulminant hepatic failure and is a kind of pre-renal failure due to intense reduction of kidney perfusion induced by severe hepatic injury. While other causes of pre-renal acute kidney injury (AKI) respond to fluid infusion, HRS does not. HRS incidence is 5% in children with chronic liver conditions before liver transplantation. Type 1 HRS is an acute and rapidly progressive form that often develops after a precipitating factor, including gastrointestinal bleeding or spontaneous bacterial peritonitis, while type 2 is considered a slowly progressive form of kidney failure that often occurs spontaneously in chronic ascites settings. HRS pathogenesis is multifactorial. Cirrhosis causes portal hypertension; therefore, stasis and release of vasodilator substances occur in the hepatic vascular bed, leading to vasodilatation of splanchnic arteries and systemic hypotension. Many mechanisms seem to work together to cause this imbalance: splanchnic vasodilatation; vasoactive mediators; hyperdynamic circulation states and subsequent cardiac dysfunction; neuro-hormonal mechanisms; changes in sympathetic nervous system, renin-angiotensin system, and vasopressin. In patients with AKI and cirrhosis, fluid expansion therapy needs to be initiated as soon as possible and nephrotoxic drugs discontinued. Once HRS is diagnosed, pharmacological treatment with vasoconstrictors, mainly terlipressin plus albumin, should be initiated. If there is no response, other options can include surgical venous shunts and kidney replacement therapy. In this regard, extracorporeal liver support can be a bridge for liver transplantation, which remains as the ideal treatment. Further studies are necessary to investigate early biomarkers and alternative treatments for HRS.

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“…The S1-spike protein interacts with angiotensin-converting enzyme 2 (ACE2), a part of the RAAS, which is known as a multi-hormonal system, having a profound impact on the maintenance of electrolyte balance and blood pressure regulation [ 8 , 9 ]. The RAAS is defined as a two-arm, counter-regulatory system and is divided into classical and alternative axes [ 10 ].…”

“…In the classical axis, Angiotensin I (Ang I) is generated by the cleavage of a precursor peptide called angiotensinogen, and then is converted to Angiotensin II (Ang II) by ACE [ 10 ]. Ang II attaches to Ang II type 1 receptors (AT1R) and as a result, the ACE/Ang II/AT1R axis induces acute lung failure and also triggers aldosterone release from the adrenal gland [ 11 , 12 ].…”

“…Ang II attaches to Ang II type 1 receptors (AT1R) and as a result, the ACE/Ang II/AT1R axis induces acute lung failure and also triggers aldosterone release from the adrenal gland [ 11 , 12 ]. Along this pathway, Ang II activates Ang II type 2 receptors (AT2R), which have the opposite effects to Ang II/AT1R and acts to resolve inflammation, but AT2R expression is significantly lower during the human lifespan, except at the neonatal stage [ 10 , 13 ].…”

“…In the alternative axis, RAAS is balanced by ACE2, which is a homologue of ACE [ 14 ]. ACE2 can transform Ang II to Angiotensin 1–7 (Ang 1–7) and convert Ang I to Angiotensin 1–9, which can be further converted to Ang 1–7 [ 10 ]. Ang 1–7 is a specific Mas receptor (MasR) agonist and plays a central role in the alternative axis of the RAAS, ACE2/Ang 1–7/MasR [ 10 ].…”

“…ACE2 can transform Ang II to Angiotensin 1–7 (Ang 1–7) and convert Ang I to Angiotensin 1–9, which can be further converted to Ang 1–7 [ 10 ]. Ang 1–7 is a specific Mas receptor (MasR) agonist and plays a central role in the alternative axis of the RAAS, ACE2/Ang 1–7/MasR [ 10 ]. Binding Ang 1–7 to MasR exerts several protective effects, such as antioxidative, antiinflammatory, and antifibrotic effects, in addition to decreasing aldosterone secretion [ 15 , 16 ].…”