Etiology

HRS may develop spontaneously in patients with decompensated cirrhosis, but the prevalence of unprecipitated AKI is low. Often, it is precipitated by conditions leading to acute hemodynamic changes, including excessive diuresis, gastrointestinal bleeding, sepsis from infections like spontaneous bacterial peritonitis, drugs, or large volume paracentesis without albumin administration.[1] HRS may also develop in patients with severe alcohol-related hepatitis.[13]

Independent predictive factors of HRS occurrence are low serum sodium concentration and high plasma renin activity.[9]​​

Pathophysiology

Uncompensated hyperdynamic circulation is considered to be the hallmark of HRS-AKI, but the pathogenesis is complex, and involves macro- and microvascular dysfunction, systemic inflammation, and direct tubular damage.[5][14]​​​ Infection is one of the most common triggers of HRS.[8]

Four primary factors are involved in the vascular pathophysiology of HRS:[2][15]

  • Systemic vasodilation leads to a moderate lowering of blood pressure

  • Activation of the sympathetic nervous system leads to renal vasoconstriction and altered renal autoregulation, such that renal blood flow is much more dependent on mean arterial pressure

  • There is a relative impairment of cardiac function, such that although cardiac output is increased, it cannot increase adequately to maintain blood pressure. In cirrhosis, this is termed cirrhotic cardiomyopathy

  • There is increased formation of renal vasoconstrictors such as thromboxane A2, F2-isoprostanes, endothelin-1, cysteinyl-leukotrienes, although their exact role in the pathogenesis of HRS is unclear.

Systemic inflammation may also lead to HRS.[5][16]​ In one prospective study comprising 100 patients with cirrhosis from five French hospitals, systemic inflammatory response syndrome was observed in 41% of patients, of which 56% had an infection.[16]​ In patients with cirrhosis, inflammation is driven by pathogen associated molecular patterns (PAMPs), which include bacterial products, and damage associated molecular patterns (DAMPs), which include intracellular components released from injured hepatocytes.[5]​ When an overt bacterial infection is absent, PAMPs and DAMPs may drive inflammation and release proinflammatory cytokines by activating pattern recognition receptors (e.g., toll-like receptors).[5]​ This activation of proinflammatory response may increase the production of vasodilators such as nitric oxide, which in turn reduces systemic vascular resistance and effective arterial blood volume.[5]

Severe cholestasis may further impair renal function by worsening inflammation and macrocirculatory dysfunction or by promoting bile salt-related tubular damage.[14]

Adrenal insufficiency, cirrhotic cardiomyopathy, cholemic nephropathy, and elevated intra-abdominal pressure may also contribute to HRS.[5]

Classification

Classically, HRS was subdivided into type 1 and type 2 by the International Club of Ascites.[3]​ Briefly, type 1 HRS involved rapidly progressive acute kidney injury (AKI) with doubling of initial serum creatinine to a value of >2.5 mg/dL in <2 weeks and type 2 HRS was moderate renal failure that did not meet the type 1 criteria. The classification has since been updated to align with the Kidney Disease Improving Global Outcomes (KDIGO) guidelines.[4][5]​ The revised classification eliminates the prerequisite of doubling serum creatinine levels for starting the treatment of HRS-AKI (previously referred to type 1 HRS), as creatinine levels have been found to be inversely proportional to reversal of HRS.[4][6][7]

Revised International Club of Ascites classification

HRS-AKI[4]

  • A unique form of AKI

  • Requires a diagnosis of AKI according to International Club of Ascites Criteria (i.e., increase in serum creatinine ≥0.3 mg/dL within 48 hours; or a percentage increase serum creatinine ≥50% from baseline which is known, or presumed, to have occurred within the prior 7 days)

  • Previously referred to as type 1 HRS, but removes the fixed threshold of serum creatinine increase, which may allow for an earlier diagnosis.

HRS-non-AKI (HRS-NAKI)[5][8]​​

  • Renal impairment which fulfills the criteria for HRS, but not AKI

  • Previously referred to as type 2 HRS

  • Subcategories are defined by estimated glomerular filtration rate and duration as follows:

    • HRS-acute kidney disease (HRS-AKD)

      • Estimated glomerular filtration rate <60 mL/min/1.73 m² for <3 months in absence of other potential causes of other kidney disease

      • Increase in serum creatinine <50% using last available value of outpatient serum creatinine within 3 months as baseline.

    • HRS-chronic kidney disease (HRS-CKD)

      • Estimated glomerular filtration rate <60 mL/min/1.73 m² for ≥3 months in absence of other potential causes of other kidney disease.

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