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Reappraising the spectrum of AKI and hepatorenal syndrome in patients with cirrhosis

An Author Correction to this article was published on 27 January 2020

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Abstract

The occurrence of acute kidney injury (AKI) in patients with end-stage liver disease constitutes one of the most challenging clinical scenarios in in-hospital and critical care medicine. Hepatorenal syndrome type 1 (HRS-1), which is a specific type of AKI that occurs in the context of advanced cirrhosis and portal hypertension, is associated with particularly high mortality. The pathogenesis of HRS-1 is largely viewed as a functional derangement that ultimately affects renal vasculature tone. However, new insights suggest that non-haemodynamic tubulo-toxic factors, such as endotoxins and bile acids, might mediate parenchymal renal injury in patients with cirrhosis, suggesting that concurrent mechanisms, including those traditionally associated with HRS-1 and non-traditional factors, might contribute to the development of AKI in patients with cirrhosis. Moreover, histological evidence of morphological abnormalities in the kidneys of patients with cirrhosis and renal dysfunction has prompted the functional nature of HRS-1 to be re-examined. From a clinical perspective, a diagnosis of HRS-1 guides utilization of vasoconstrictive therapy and decisions regarding renal replacement therapy. Patients with cirrhosis are at risk of AKI owing to a wide range of factors. However, the tools currently available to ascertain the diagnosis of HRS-1 and guide therapy are suboptimal. Short of liver transplantation, goal-directed haemodynamically targeted pharmacotherapy remains the cornerstone of treatment for this condition; improved understanding of the underlying pathogenic mechanisms might lead to better clinical outcomes. Here, we examine our current understanding of the pathophysiology of HRS-1 and existing challenges in its diagnosis and treatment.

Key points

  • Although various non-haemodynamic mechanisms of injury, such as endotoxin-mediated inflammation, bile acid-induced tubular toxicity and true tubular ischaemia, are now implicated in the pathogenesis of hepatorenal syndrome type 1 (HRS-1), renal vasoconstriction and reduced renal blood flow continue to be regarded as the quintessential mechanism of renal dysfunction.

  • The differential diagnosis of acute kidney injury (AKI) in patients with cirrhosis is broad, and ‘pure’ HRS-1 likely constitutes a minor subset of these cases; however, different pathogenic mechanisms can coexist and overlap of AKI aetiologies is conceivable.

  • Strictly functional HRS-1 may therefore exist alongside other haemodynamic and/or parenchymal forms of renal dysfunction in the same patient.

  • The current diagnostic International Club of Ascites criteria for HRS-1 provide a useful foundation to frame the diagnostic approach of AKI in patients with cirrhosis; however, one must remain cognizant of the limitations of those criteria and recognize that key aspects of the HRS-1 ‘phenotype’ are not routinely included and should be carefully considered during clinical evaluation.

  • The cornerstone of pharmacological therapy for HRS-1 is the use of vasoconstrictors with a goal-directed approach to target a substantial rise in mean arterial pressure by ~15 mmHg or to >85 mmHg.

  • As kidney function declines and the serum bilirubin increases during the course of HRS-1-associated AKI, the likelihood of successful reversal of HRS-1 with a vasoconstrictor decreases; early recognition of HRS-1 is therefore critical to initiating therapy at an early stage of AKI.

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Fig. 1: Mechanisms of renal dysfunction in patients with cirrhosis.
Fig. 2: A multisystemic view of the different pathophysiological processes involved in the development of renal dysfunction in HRS-1 and their potential interaction with other mechanisms of AKI in cirrhosis.
Fig. 3: Proposed model showing the temporal evolution of HRS-1.
Fig. 4: Massive ascites precludes optimal assessment of renal parenchymal echogenicity in patients with cirrhosis.
Fig. 5: The relationship between mean arterial pressure and kidney function among patients with HRS-1.
Fig. 6: Derangement in renal autoregulation in patients with HRS-1.
Fig. 7: Proposed diagnostic and therapeutic approach to AKI in patients with cirrhosis.

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Acknowledgements

Thanks to B. Siede from Medical Illustration at Ochsner Medical Center for her input on the figures.

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The authors researched data for the article, contributed to discussion of the article’s content, writing and review/editing of the manuscript before submission.

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Correspondence to Juan Carlos Q. Velez.

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J.C.V. has participated in Speaker Bureau and Advisory Board meetings for Mallinckrodt Pharmaceuticals, the manufacturer of terlipressin, and is a member of the Speaker Bureau of Otsuka Pharmaceuticals (in reference to products not discussed in this article). The other authors declare no competing interests.

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Nature Reviews Nephrology thanks A. Rosenkranz, A. Tolwani, H. Wadei and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Prerenal azotaemia

A reversible form of acute reduction in kidney function caused by hypoperfusion to the renal vessels triggered by volume depletion, impaired cardiac output or vasomotor derangement. Prerenal means ‘before the kidney’; azotaemia refers to an elevated blood urea nitrogen level.

Acute tubular necrosis

New onset of injury to the kidney tubular cells.

Splanchnic vasodilation

Relaxation of the arterial vascular bed supplying the abdominal viscera.

Portosystemic shunting

Abnormal connection between the portal vascular system and the systemic circulation that bypasses the liver.

Vascular rarefaction

Reduction in blood vessel density.

Autonomic dysfunction

Hyperactive or hypoactive sympathetic nervous system.

Transjugular intrahepatic portosystemic shunt

Artificial channel within the liver to create patent communication between the portal and the hepatic veins.

Abdominal compartment syndrome

Rise in intra-abdominal pressure that impairs organ perfusion and function.

Tubulorrhexis

Necrosis of the renal tubuli.

Cholestasis

State of reduced or abolished flow of bile from the liver into the gastrointestinal tract.

Acute-on-chronic liver failure

New onset of damage to the liver superimposed over pre-existing chronic damage to the liver.

Sarcopenia

Loss of muscle mass.

Hydronephrosis

Dilation of the pelvicalyceal system in the kidney that results from downstream obstruction of the urinary tract.

Parenchymal echogenicity

Increased brightness of tissue with respect to a standard parameter as determined by ultrasonography.

Acanthocytes

Distinct type of dysmorphic erythrocytes (with protrusions) found in the urine of patients with haematuric glomerular diseases.

Molecular adsorbent recirculating system

Extracorporeal support system that facilitates removal of albumin-bound toxins for patients with liver disease (‘liver dialysis’).

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Velez, J.C.Q., Therapondos, G. & Juncos, L.A. Reappraising the spectrum of AKI and hepatorenal syndrome in patients with cirrhosis. Nat Rev Nephrol 16, 137–155 (2020). https://doi.org/10.1038/s41581-019-0218-4

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