Understanding acute kidney injury in cirrhosis: Current perspective

Table 1 Diagnosis of hepatorenal syndrome

Key points of diagnosis
Cirrhosis with ascites
Increase in serum creatinine ≥ 0.3 mg/dL (26.5 mol/L) within 48 hours or ≥ 50% from baseline value known or presumed to have occurred within the prior 7 days and/or urinary output ≤ 0.5 mL/kg for ≥ 6 hours
Absence of improvement in serum creatinine and/or urine output within 24 hours following adequate volume resuscitation (when clinically indicated)
Absence of strong evidence for alternative explanation as the primary cause of AKI

AKI: Acute kidney injury.

Table 2 Serum biomarkers, urinary biomarkers, and hemodynamic parameters to differentiate among pre-renal acute kidney injury, acute tubular necrosis, and hepatorenal syndrome

Parameters	Pre-renal AKI	Hepatorenal syndrome	Acute tubular necrosis	Comments
Clue to diagnose	History of fluid loss or overzealous use of diuretics	Presence of refractory ascites, hyponatremia	Presence of sepsis and hypotension	History cannot be always reliable to diagnose the subtypes of kidney injury
Urine sediments[73,74]	The lack of any casts suggests functional renal failure mostly pre-renal AKI[56]	Usually absent	Muddy brown casts and renal tubular epithelial cell casts	Should be interpreted by expert renal pathologists
	Sensitivity: 73%		RETC and granular cast
	Specificity: 75%		PPV: 100%
	However, bland, hyaline cast may be present		NPV: 40%
FENa[27,75]	< 1	< 1 for diagnosing HRS-AKI	Usually > 1	FENa is unable to distinguish between Pre-renal AKI and HRS-AKI
	Sensitivity: 90%	Sensitivity: 100%	Sensitivity: 89%	Not validated in patients on diuretics
	Specificity: 82%	Specificity: 14%	Specificity: 71%	FENa can be < 1 in patients with cirrhosis without AKI
	To differentiate between intrinsic vs pre-renal kidney injury	AASLD	FENa < 0.56 excludes ATN
		< 0.1 suggests HRS[46]
FEUrea[29]	< 21	< 28.7	> 33	No standardized cut-off in patients with cirrhosis
	Sensitivity: 90%	Sensitivity: 75%	< 34 to rule out ATN
	Specificity: 61%	Specificity: 83%	Sensitivity: 70%
	For PRA vs HRS	For non-HRS vs HRS	Specificity: 58%
NGAL-1[35,36,38,39]	< 110	< 100	> 194 mcg/g Cr
	Sensitivity: 88%		Sensitivity: 91%
	Specificity: 85%		Specificity: 82%
Renal artery resistive index[76,77]	Cannot differentiate between prerenal AKI and AKI-HRS	> 0.7 predicts HRS[76]	> 0.8 is suggestive of ATN[77]	RARI is higher in patients with cirrhosis and ascites compared to healthy individuals
		> 0.77 predicts HRS in cirrhosis	RARI is higher in ATN than in HRS.
		Sensitivity: 100%
		Specificity: 77%

AKI: Acute kidney injury; ATN: Acute tubular necrosis; Cr: Creatinine; FENa: Fractional excretion of sodium; HRS: Hepatorenal syndrome; NGAL: Neutrophilc-gelatinase associated lipocalin; NPV: Negative predictive value; PPV: Positive predictive value; PRA: Plasma renin activity; RARI: Renal artery resistive index.

Table 3 Commonly used kidney biomarkers in patients with cirrhosis

Newer markers	Role in differentiating between ATN and HRS	As a predictor of mortality	Role in diagnosing HRS-AKI	Comments
NGAL[35,36,38,39]	417 mg/g Cr in ATN and 76 ug/g Cr in HRS	uNGAL 110 ng/mL is associated with inpatient mortality[53]	Increased in 1-2 hours after ischaemic renal injury	Can be high in other diseases. Higher synthesis in the presence of sepsis. High in lupus nephritis, IgA nephropathy[41]
KIM-1[47,53]	Differentiate HRS from ATN; Cut-off: 15.4 ng/mL (AUC: 0.63); HRS: 3.1 pg/mL	No data	Early rise predicts AKI; Better marker than creatinine[53]	Not widely available
Cystatin C[42-45,55]	No data	Serum cystatin-C level of > 1.45 mg/L had the highest 90-day mortality (sensitivity and specificity of 66.7% and 68.4%)[44]. Cystatin-MELD score predicts mortality[45]	Predicts development of AKI in one year[55]; Serum cystatin-C > 1.47 mg/dL is an early marker of AKI in cirrhosis[44,45]	Higher reliability than Cr in patients with sarcopenia

AUC: Area under the curve; AKI: Acute kidney injury; ATN: Acute tubular necrosis; HRS: Hepatorenal syndrome; KIM-1: Kidney injury molecule-1; MELD: Model for end stage liver disease; NGAL: Neutrophil-gelatinase-associated lipocalin; RARI: Renal artery resistive index; uNGAL: Urinary neutrophil gelatinase-associated lipocalin.