See **Figure 13**.

#### **Figure 13.**

*Pathophysiological mechanisms of hepatorenal syndrome. A) The greater production of vasoconstrictors and less formation of local vasodilators determine the development of portal hypertension and splanchnic vasodilation, which allows the sequestration of blood in this territory. Splanchnic vasodilation generates an effective decrease in blood volume that stimulates an increase in cardiac output, in order to restore effective arterial blood volume. When the liver disease progresses, severe portal hypertension develops and, together with the bacterial translocation that mediates the release of PAMPs into the circulation, increases the inflammatory response that facilitates greater splanchnic vasodilation, causing a lower effective arterial blood volume and the consequent activation of the sympathetic and renin-angiotensin-aldosterone system, which facilitates the reabsorption of sodium and water, B) cirrhotic cardiomyopathy, there are multiple mechanisms that allow its development and condition a decrease in cardiac output, which conditions a decrease in mean arterial pressure, being a predictor of the development of hepatorenal syndrome. C) Bacterial overgrowth and bacterial translocation allow PMAPs to reach the enterohepatic circulation and precipitating factors and the progression of liver damage from the underlying disease allows the release of DAMPS, and both molecular patterns are presented to both Kupffer cells generating an intrahepatic inflammatory response and the presentation of these molecular patterns to dendritic cells and macrophages facilitates SIRS, the arrival of PAMPs and DAMPs to the kidneys allows them to filter and be captured by TLR2-4 of tubular cells, generating a damaging effect. D) Relative adrenal insufficiency that determines hemodynamic changes. E) Increased intra-abdominal pressure due to ascites, associated with changes in intrarenal hemodynamics such as renal venous congestion.*

#### **14.1 Diagnosis**

The diagnosis of hepatorenal syndrome is difficult and is made by ruling out since there is no laboratory or imaging study to confirm it with certainty.

Within the International Ascites Club criteria, defines AKI as increases in serum creatinine of ≥ 0.3 mg/dL within 48 hours or 50% increase within 7 days in hospitalized patients with no response after 2 days consecutive with the use of albumin (1 g/ kg of body weight), in the absence of shock, without the use of nephrotoxic drugs, absence of proteinuria (> 500 mg/day), absence of microhematuria (> 50 red blood cells per high-power field), and normal findings on renal ultrasound [60].

The aforementioned criteria should be reviewed because many patients with cirrhosis usually present hypotension without being in septic shock, and the presence of hematuria and proteinuria may be present secondary to IgA nephropathy or membranoproliferative glomerulonephritis due to C virus, and it should be considered that they are also exposed to use of antibiotics and analgesics. I believe that many of them have overlapping causes within the spectrum of hepatorenal syndrome [68].

In the analysis, there is no pathognomonic marker. In the past, it was reported that FENA <1% was an indicator of this disease; currently, the cutoff value seems to be lower <0.2% [69], in the advent of biomarkers the urinary NGAL <400 μg/L correlates with hepatorenal syndrome, and urinary NAGAL values >400 μg/L occur in acute tubular necrosis (ATN) [70].

#### **14.2 Treatment**

The initial treatment of AKI in the spectrum of cirrhosis is the use of albumin (1 g/kg of body weight) for 48 hours. Velez et. al [71] describe AKI phenotypes in cirrhosis based on the diameter of the inferior vena cava (IVC) evaluated by ultrasound, in the aforementioned work three groups are described: group with IVC diameter <1.3 cm, which is subdivided According to CVI collapse, it can be > 40%, which corresponds to the fluid depleted phenotype and this group would benefit from albumin replacement; in those with <40% collapse, it corresponds to the intraabdominal hypertension phenotype and would benefit from paracentesis. In the second group with IVC 1.3-2 cm corresponds to the fluid repleted phenotype, which would benefit from vasoconstrictors and in the third group corresponds to those with IVC > 2 cm and which is subdivided based on collapse >40% indicating a state of euvolemia, the use of vasoconstrictors would be a good therapeutic option and those with collapsibility <40% correspond to the fluid expanded phenotype where diuretics are indicated.

If after expansion with albumin the decrease in creatinine is not achieved, albumin should be maintained at 20–40 g and add Terlipressin 0.5–1 mg/4–6 hours, titrating the dose with 2-mg increment every day until reaching a maximum dose of 12 mg, an adequate response is defined when a 25% drop in initial creatinine is achieved, and in case of no response, Terlipressin can be administered for 14 days. It is recommended that infusion is better when compared with boluses every 6 hours. The predictive factors of poor response to Terlipressin are elevated total bilirubin values >10 mg/dl, lack of MAP increase of 5 mmHg on day 3, as well as NGAL >728 μg/L. (61.63).

The evidence on Terlipressin, norepinephrine, octreotide, and midodrine is extensive and exceeds the scope of the review.
