Acute kidney injury and hepatorenal syndrome in cirrhosis

Table 1 A brief overview of the consensus definitions of acute kidney injury

Criteria	Stage	Definition
RIFLE criteria/ADQI in 2004[15]		At least 1.5 × baseline serum creatinine within 7 d, decrease in urine output of 0.5 mL/kg/h for 6 h, decrease in GFR of at least 25%
	Stage 1 (R)	1.5 × baseline Cr, GFR decrease of 25%, UOP < 0.5 mL/kg/h for 6-12 h.
	Stage 2 (I)	2 × baseline serum creatinine, decrease of GFR < 50%, UOP < 0.5 mL/kg/h for 12 h
	Stage 3 (F)	3 × baseline serum creatinine, decrease of GFR of 75%, UOP < 0.3 mL/kg/h for 24 h, anuria for 12 h, or on RRT acutely
Acute Kidney Injury Network (AKIN) in 2007[16]		Definition: increase of at least 0.3 mg/dL in last 48 h, 1.5 × baseline creatinine in last 48 h, or UOP < 0.5 mL/kg/h for at least 6 h
	Stage 1	Increase of 0.3 mg/dL w/in 2 d, 1.5-2 × baseline serum creatinine within 2 d, or UOP < 0.5 mL/kg/h for 6-12 h
	Stage 2	2-3 × baseline serum Cr, UOP < 0.5 mL/kg/h for at least 12 h
	Stage 3	3 × baseline serum Cr, UOP < 0.3 mL/kg/h for 24 h, anuria for 12 h, on RRT
Kidney Disease Improving Global Outcomes (KDIGO) in 2012[17]		Increase in sCr of at least 0.3 mg/dL within 48 h, increase of at least 1.5 × baseline in the last 7 d, or urine output < 0.5 mL/kg/h for at least 6 h
	Stage 1	Increase of 0.3 mg/dL, 1.5-2 × baseline Cr, UOP < 0.5 mL/kg/h for 6-12 h
	Stage 2	2-3 × baseline serum Cr or UOP < 0.5 mL/kg/h for at least 12 h
	Stage 3	3 × baseline serum Cr, increase of 0.5 mg/dL above absolute level of 4.0 mg/dL, on RRT, UOP < 0.3 mL/kg/h for 24 h, or 12 h of anuria

GFR: Glomerular kidney function; UOP: Urine output; RRT: Renal replacement therapy; ADQI: Acute Dialysis Quality Initiative; Cr: Creatinine.

Table 2 The current and past consensus definitions of acute kidney injury in cirrhosis

Criteria	Stage	Definition
ADQI/ICA in 2010[19]		The absolute increase in serum Cr of at least 0.3 mg/dL or 1.5 × baseline serum creatinine
	Stage 1	Increase of 0.3 mg/dL within 48 h or 1.5-2 × baseline serum creatinine
	Stage 2	Increase of 2-3 × baseline serum Cr
	Stage 3	At least 3 × baseline serum Cr with an increase of 0.5 mg/dL or currently on RRT
ICA-AKI in 2015[14]		An absolute increase in serum Cr of at least 0.3 mg/dL within 48 h or 1.5 × baseline Cr level within the last 7 d
	Stage 1A	Increase of 0.3 mg/dL from baseline in 48 h, 1.5-2 × baseline serum creatine. Absolute value of serum Cr < 1.5 mg/dL
	Stage 1B	Increase of 0.3 mg/dL from baseline in 48 h, 1.5-2 × baseline serum creatine. Absolute value of serum Cr > 1.5 mg/dL
	Stage 2	Increase of 2-3 × baseline
	Stage 3	Greater than 3 × baseline Cr, Cr > 4 mg/dL with rise of > 0.5, or on RRT

RRT: Renal replacement therapy; ADQI: Acute Dialysis Quality Initiative; ICA: International Club of Ascites; AKI: Acute kidney injury; Cr: Creatinine.

Table 3 The previous and current definition and nomenclature of hepatorenal syndrome[14,19,21-23]

	Previous and current definition and nomenclature
Criteria to confirm of HRS vs other etiology of renal dysfunction	To diagnose HRS, patients must have: (1) The presence of ascites; (2) No improvement of creatinine after holding diuretics; (3) No improvement after 48 h of albumin supplementation (1 g/kg/d); (4) No signs of shock; (5) No recent nephrotoxic medications (antibiotics, contrast, NSAIDs); and (6) No signs of kidney disease (proteinuria, microhematuria, no findings on renal ultrasound)
HRS type 1 (most recent definition in 2007)	Rapid renal injury (within two weeks) defined by 2 × baseline serum creatinine to a value > 2.5 mg/dL or 50% reduction in creatinine clearance
HRS type 2	Moderate renal failure with creatinine ranging from 1.5 to 2.5 mg/dL that occurs progressively
Definition of HRS-AKI	Patients with the criteria above and ICA-AKI 2015 definition for AKI
Definition of HRS-CKD	Patients who meet the criteria in row 1 and the rise of serum creatinine and changes in urine output are all progressive (> 1 wk)
	Patients with HRS-CKD are known to have decreased urine output over weeks to months

ICA: International Club of Ascites; AKI: Acute kidney injury; HRS: Hepatorenal syndrome; CKD: Chronic kidney disease; NSAID: Non-steroidal anti-inflammatory drug.

Table 4 The most well-known novel biomarkers being studied for acute kidney injury in cirrhosis

Novel biomarker	Source	Benefits/Clinical uses	Limitations
Cystatin C[62-68]	Plasma, urine	Early biomarker of AKI, potential benefit with severity of disease. Unaffected with age, sarcopenia, gender, or sepsis. Unaffected by malignancy and serum bilirubin level. Multiple studies found it to be an independent risk factor of AKI and mortality	Increased levels in CKD. Influenced by low levels of albumin. Potentially influenced by elevated WBC and CRP. Takes longer time to result when compared to sCr
NGAL[18,67-79]	Urine	Found in kidney tubular cell that is released during damage or injury. Elevated in AKI in cirrhosis and potential predictor of mortality. Markedly elevated in ATN, mildly elevated in prerenal azotemia/CKD/HRS-AKI	Increased levels in CKD. Increased levels in infections, particularly urinary tract infections. Overlap with values in PRA, HRS, and other AKI types of AKI. Small quantities are made in the liver
IL-18[75,78,82-84]	Urine	Very similar to urinary NGAL. Markedly elevated in cirrhotic patients with ATN, in comparison to other AKI types. Found in monocytes and macrophages. A notable proinflammatory marker. Not confounded by CKD, sepsis or UTI	There are increased levels in PRA and HRS but significant overlap in values with limited clinical utility. Levels are increased in levels of inflammation in the kidney other than AKI
Kidney Injury Molecule-1[18,73,84-86]	Urine	Originally found in kidney tubular transmembrane protein. Not expressed in normal kidney tissue. Noted with increased levels in ATN in cirrhosis when compared to the other types of AKI in cirrhosis. High specificity for ischemic or nephrotoxic kidney injury	Elevated from inflammatory conditions. Found to have overlap between different forms of AKI. Confounded by presence of infection
L-FABP[87-93]	Urine	Found in kidney proximal tubule. Levels may be increased in AKI or AKI 2/2 sepsis. Potential utility in predictor in adverse outcomes including AKI in patients with chronic liver disease and other liver disease	Limited studies in cirrhosis. Found to be increased in CKD. Increased in acute liver injury and liver failure as well

AKI: Acute kidney injury; HRS: Hepatorenal syndrome; CKD: Chronic kidney disease; ATN: Acute tubular necrosis; UTI: Urinary tract infection; NGAL: Neutrophil gelatinase-associated lipocalin; PRA: Prerenal azotemia; CRP: C-reactive protein; WBC: White blood cell; sCr: Serum creatinine; IL: Interleukin.