Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting

Abstract

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

Keywords: acute disease quality initiative; acute kidney injury; albumin; ascites; biomarker; cirrhosis; hepatorenal syndrome; international club of ascites; liver transplantation; renal replacement therapy; terlipressin.

Fig. 1.. Clinical course and outcomes of AKI in patients with cirrhosis.

AKI, AKD and CKD form a continuum whereby initial kidney injury can lead to recovery (adaptive repair), persistent renal injury, and/or eventually CKD (maladaptive repair). Multiple episodes of AKI may occur over the course of an illness within one individual. After AKI resolves, patients may still have abnormalities in kidney function and/or structure that fulfil the criteria for AKD. AKI is a subset of AKD, therefore, all patients with AKI are considered to have AKD. The absence of criteria for AKI, AKD or CKD represents no kidney disease (NKD). Liver or liver-kidney transplantation in select patients may occur at any time. Patients who meet HRS criteria are considered to have HRS-AKI, HRS-AKD or HRS-CKD based on the timing and duration of kidney dysfunction. Patients with HRS-AKD meeting AKI criteria are classified as having HRS-AKI. HRS for less than 90 days would be classified as HRS-AKD, while HRS persisting for more than 90 days would be classified as HRS-CKD. In contrast, a patient with pre-existing CKD (e.g., diabetic nephropathy) who develops HRS-AKI would be classified as having HRS-AKI on CKD. AKD, acute kidney disease; AKI, acute kidney injury; CKD, chronic kidney disease; HRS, hepatorenal syndrome. Adapted from Acute Disease Quality Initiative 29, www.ADQI.org, CC BY 2.0 (https://creativecommons.org/licenses/by/2.0/)

Fig. 2.. Contemporary concepts in the pathophysiology of AKI.

Multiple simultaneous mechanisms can contribute to the development of different phenotypes of AKI in patients with cirrhosis. Background susceptibility to renal injury varies across individuals, according to non-modifiable (e.g., comorbidity burden) and modifiable factors (e.g., sepsis) and includes liver-related (e.g., severity of liver disease, decompensating events), kidney-related (e.g., CKD, eGFR), cardiovascular (e.g., cirrhotic cardiomyopathy), comorbidities (e.g., hypertension, diabetes), and external factors (e.g., nephrotoxic drugs, sepsis, excessive diuretics or laxatives). The clinical condition of the liver, kidney, and heart, in addition to concomitant precipitating events and exposures (yellow arrows) may lead to a variety of clinical AKI phenotypes. The different phenotypes of AKI include presence of functional changes (i.e. increase serum creatinine and/or cystatin C, and decrease urine output), structural damage (i.e. albuminuria, urinary casts, urinary biomarkers) or both. The arrows show progression (red), regression or recovery (green) between the different phenotypes. ACEi, angiotensin converting enzyme inhibitor; ADH, anti-diuretic hormone; AKD, acute kidney disease; AKI, acute kidney injury; ATI, acute tubular injury; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; DAMPs, damage-associated molecular patterns; HBV, hepatitis B virus; LVP, large volume paracentesis; NKD, no kidney disease; NO, nitric oxide; NSBBs, non-selective beta-blockers; PAMPs, pathogen-associated molecular patterns; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species; SNS, sympathetic nervous system. Adapted from Acute Disease Quality Initiative 29, www.ADQI.org, CC BY 2.0 (https://creativecommons.org/licenses/bi/2.0/)

Fig 3.. Kidney-liver health assessment.

Kidney-liver health assessment is a ‘living’ process that should be repeated if the patient’s condition changes and following planned or unplanned exposure, both during hospitalization and post-AKI care in the outpatient setting. AKD, acute kidney disease; AKI, acute kidney injury; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; INR, international normalised ratio; MELD, model for end-stage liver disease; NKD, no kidney disease; NSAID, non-steroidal anti-inflammatory drug; NSBBs, non-selective beta-blockers. Adapted from Acute Disease Quality Initiative 29, www.ADQI.org, CC BY 2.9 (https://creativecommons.org/licenses/by/2.0/)

Fig. 4.. Proposed framework for evaluating AKI phenotypes based on combination of functional and damage markers.

At any given point in time, patients would fall into one of the four quadrants, based on the results of the representative functional and damage marker tests and could be assessed over time to see their transitions across the categories. The ability to detect a state of damage alone (right upper quadrant) represents a “subclinical” state from which loss of function might develop after several days or not at all. Markers of kidney damage may include albuminuria/proteinuria, hematuria, urinary casts, and biomarkers. Bottom left quadrant indicates an acute change in kidney filtration but without detectable kidney damage such as seen in patients with volume depletion. Patients who meet criteria for HRS may be either without evidence of damage (left lower quadrant) or have co-existing damage (right lower quadrant). Sequential assessments could provide information on which of the factors is prevalent for ongoing injury or resolution and offer opportunities for targeted intervention. It is expected that the process is dynamic, and patients may move from one phenotype to another during the course of their illness. Modified, with permission, from Acute Disease Quality Initiative 10, www.ADQI.org. AIN, acute interstitial nephritis; AKI, acute kidney injury; ATI, acute tubular injury; GN, glomerulonephritis; HRS, hepatorenal syndrome. Adapted from Acute Disease Quality Initiative 29, www.ADQI.org, CC BY 2.0 (https://creativecommons.org/licenses/by/2.0/)

Fig. 5.. Differential effects of various HRS-AKI treatments on vascular beds, cardiac function, and renal perfusion, as well as pulmonary effects.

Terlipressin (T) increases renal perfusion pressure but also decreases cardiac output. By increasing cardiac preload (through shunting of splanchnic blood to central blood), increasing cardiac afterload (due to increase in systemic vascular resistance), and effecting pulmonary vasculature^– (pulmonary artery dilation, pulmonary vein constriction, as well as possibly an increase in pulmonary capillary permeability), when combined with large doses of albumin, may be associated with an increased incidence of pulmonary oedema. Norepinephrine (N) has a positive inotropic effect and causes systemic vasoconstriction, which then also increases renal perfusion pressure. In contrast to terlipressin, norepinephrine constricts pulmonary arteries without any effect on the pulmonary vein. Midodrine (M) causes weak systemic vasoconstriction and octreotide (O) causes temporary splanchnic vasoconstriction, effects that lead to an only modest increase in renal perfusion. Adapted from Acute Disease Quality Initiative 29, www.ADQI.org/ CC BY 2.0 (https://creativecommons.org/licenses/by/2.0/)

Fig. 6.. Recommended structure of post-discharge follow-up according to the evaluation of the kidney axis (severity, duration, and recovery of AKI) and the liver axis (compensated vs. decompensated cirrhosis) at the time of hospital discharge.

Limited data are available to inform the timing and nature of monitoring for patients with cirrhosis who experience AKI or AKD in hospital. The post-discharge follow-up will depend on the state of kidney and liver health at the time of discharge. We suggest that these patients should have their kidney function checked within 1 month of hospital discharge, at a minimum, to confirm the extent of recovery or progression of kidney disease. Patients with persistent kidney dysfunction at 90 days should be formally assessed for the development or progression of CKD. Patients with less severe AKI or AKD can be monitored in primary care or by the base specialist with the degree of nephrology involvement in follow-up monitoring increasing with the duration and severity of AKI or AKD during hospitalization. Adapted, with permission, from Acute Disease Quality Initiative 24, www.ADQI.org. AKD, acute kidney disease; AKI, acute kidney injury; AKI-D, acute kidney injury treated with dialysis; CKD, chronic kidney disease; HTN, hypertension; NKD, no kidney disease; SCr, serum creatinine. Adapted from Acute Disease Quality Initiative 29, www.ADQI.org, CC BY 2.0 (https://creativecommons.org/licenses/by/2.0/)