Recent advances in pathophysiology, diagnosis and management of hepatorenal syndrome: A review

Table 1 Methods of estimating glomerular filtration rate and the novel equations for diagnosis of acute kidney injury in cirrhosis

Ref.	Equation		Variables	Advantage
	Cr-based
Cockcroft et al[93]	Cockcroft-Gault	1976	Age, SCr, sex, weight
Levey et al[94]	MDRD-4	2006	Age, SCr, sex, ethnicity
Levey et al[95]	MDRD-6	2007	Age, SCr, sex, ethnicity, BUN, albumin
Levey et al[96]	CKD-Epi	2009	Age, SCr, sex, ethnicity
Kalafateli et al[54]	The royal free hospital	2017	Age, SCr, sex, ascites, BUN, Na, INR
	Cystatin C-based		Age, sex, cystatin C	Equations including cystatin C are more accurate in patients with sarcopenia and advanced liver disease
Hoek et al[97]		2003
Larsson et al[98]	CKD Epi-Cystatin C	2004
Inker et al[99]		2012
	Cr-Cystatin C-based		Age, sex, cystatin C, SCr, ethnicity
Stevens et al[100]	CKD EPI -Cr Cystatin C	2008
Inker et al[99]		2012
Mindikoglu et al[101]		2016

ACLF: Acute on chronic liver failure; AKI: Acute kidney injury; BUN: Blood urea nitrogen; CKD: Chronic kidney disease; INR: International normalized ratio; MELD: Model for end-stage liver disease; Na: Sodium; SCr: Serum creatinine; UTI: Urinary tract infection.

Table 2 Methods of estimating glomerular filtration rate and the novel biomarkers for diagnosis of acute kidney injury in cirrhosis

Ref.	Biomarker	Year Published-Patient population	Advantage(s)	Limitation(s)
Fagundes et al[102]	NGAL and/or IL-18	2012-Cirrhosis	Best supporting data; can differentiate HRS-AKI and ATN; predicts AKI progression; predicts mortality; NGAL has good performance in patients with ACLF	Increased in inflammation and infections (UTI); lack of standard cut-offs
Verna et al[103]		2012-Cirrhosis
Tsai et al[104]		2013-Cirrhosis
Gungor et al[105]		2014-Cirrhosis
Belcher et al[55]		2014-Cirrhosis
Barreto et al[106]		2014-Cirrhosis
Qasem et al[56]		2014-Cirrhosis
Treeprasertsuk et al[107]		2015-Cirrhosis
Ariza et al[57]		2015-Cirrhosis
Markwardt et al[59]	Cystatin C	2017-Cirrhosis	Predicts AKI progression; predicts short-term mortality; Used in combination with MELD score (MELD-cystatin score)	Increases in CKD
Maiwall et al[60]		2017-Cirrhosis
Jaques et al[108]		2019-Cirrhosis
Belcher et al[55]	KIM-1	2014-Cirrhosis	Predicts AKI progression; Predicts short-term mortality	Low sensitivity and specificity for differentiating causes of AKI
Ariza et al[57]		2015-Cirrhosis
Belcher et al[55]	L-FABP	2014-Cirhrosis	Predicts AKI progression; predicts short-term mortality	Increased in CKD; poor performance in differentiating causes of AKI
Jiang et al[109]		2018-Cirrhosis
Belcher et al[55]	Albumin	2014-Cirrhosis	Can differentiate HRS-AKI and ATN; good performance in ACLF; predicts short-term mortality; readily available	Decreased level in advanced cirrhosis

ACLF: Acute on chronic liver failure; AKI: Acute kidney injury; ATN: Acute tubular necrosis; CKD: Chronic kidney disease; HRS-AKI: Hepatorenal syndrome with acute kidney injury; IL-18: Interleukin 18; KIM-1: Kidney injury molecule 1; L-FABP: Liver-type fatty acid-binding protein; MELD: Model for end-stage liver disease; NGAL: Neutrophil gelatinase-associated lipocalin; SCr: Serum creatinine; UTI: Urinary tract infection.

Table 3 Results of studies using vasoconstrictor therapy in patients with hepatorenal syndrome with acute kidney injury

Ref.	Study design	Treatment	Alb	HRS reversal (%)	Mortality (%)
Uriz et al[110], 2000	Prospective	Terlipressin	Yes	77	Not defined
Halimi et al[111], 2002	Retrospective	Terlipressin	No	72	Not defined
Moreau et al[112], 2002	Retrospective	Terlipressin	Yes	58	Not defined
Ortega et al[75], 2002	Prospective	Terlipressin	Yes	77	Not defined
Duvoux et al[113], 2002	Prospective	NE	Yes	83	Not defined
Solanki et al[60], 2003	Randomized	Terlipressin vs placebo	Yes	42 vs 0	58 vs 100
Alessandria et al[64], 2007	Randomized	Terlipressin vs NE	Yes	83 vs 70	25 vs 20
Neri et al[65], 2008	Randomized	Terlipressin vs placebo	Yes	81 vs 19	27 vs 58
Sharma et al[66], 2008	Randomized	Terlipressin vs NE	Yes	50 vs 50	45 vs 45
Sanyal et al[67], 2008	Randomized	Terlipressin vs placebo	Yes	34 vs 13	57 vs 62
Martin-Llahi et al[68], 2008	Randomized	Terlipressin vs placebo	Yes	44 vs 9	74 vs 83
Singh et al[69], 2012	Randomized	Terlipressin vs NE	Yes	39 vs 43	70 vs 65
Cavallin et al[70], 2015	Randomized	Terlipressin vs MID plus OCT	Yes	70 vs 29	30 vs 32
Cavallin et al[71], 2016	Randomized	Terlipressin infusion vs terlipressin bolus	Yes	56 vs 46	59 vs 43
Boyer et al[72], 2016	Randomized	Terlipressin vs placebo	Yes	24 vs 15	33 vs 35
Wong et al[73], 2019	Randomized	Terlipressin vs placebo	Yes	29 vs 16	73 vs 71
Wong et al[81], 2021	Randomized	Terlipressin vs placebo	Yes	32 vs 16	51 vs 45

Alb: Albumin; HRS: Hepatorenal syndrome; HRS-AKI: Hepatorenal syndrome with acute kidney injury; MID: Midodrine; NE: Norepinephrine; OCT: Octreotide.

Table 4 Results of recent meta-analyses comparing terlipressin to other vasoconstrictor therapies in hepatorenal syndrome with acute kidney injury

Ref.	Study design	Number of studies	HRS reversal	Mortality benefit	Data quality
Facciorusso et al[76], 2017	Meta-analysis	13	Same as NE; better than Alb+OCT; better than Alb+MID+OCT	Possible short-term benefits	Very low to low
Isralesen et al[77], 2017	Meta-analysis	10	Same as NE; better than Alb+OCT; better than Alb+MID+OCT	No difference	Very low to low
Nanda et al[78], 2018	Meta-analysis	13	Same as NE; better than Alb+OCT; better than Alb+MID+OCT	No difference	Poor to good
Wang et al[79], 2018	Meta-analysis	18	Same as NE; better than Alb+OCT; better than Alb+MID+OCT	Confers short-term benefits	Low to high
Best et al[80], 2019	Meta-analysis	25	Same as NE; better than Alb+OCT; better than Alb+MID+OCT	No difference	Very low to low

Alb: Albumin; HRS: Hepatorenal syndrome; HRS-AKI: Hepatorenal syndrome with acute kidney injury; MID: Midodrine; NE: Norepinephrine; OCT: Octreotide.