Renal dysfunction in patients with cirrhosis: Where do we stand?

Table 1 International Ascites Club definition and diagnostic criteria for hepatorenal syndrome[7,116]

1996 criteria
Major criteria
Chronic or acute liver disease with advanced hepatic failure and portal hypertension
Serum creatinine > 1.5 mg/dL or 24-h creatinine clearance of < 40 mL/min
Absence of shock, ongoing bacterial infection, and current or recent treatment with nephrotoxic drugs. Absence of gastrointestinal fluid losses (repeated vomiting or intense diarrhea) or renal fluid losses
No sustained improvement in renal function defined as a decrease in serum creatinine to < 1.5 mg/dL or increase in creatinine clearance to 40 mL/min or more following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline
Proteinuria < 500 mg/dL and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease
Minor criteria
Urine volume < 500 mL/d	Urine osmolality > plasma osmolality
Urine sodium < 10 mEq/L	Urine red blood cells < 50 per high power field

Table 2 Acute kidney injury network and risk, injury, failure, loss, and end stage criteria for the diagnosis of acute kidney injury[117]

AKIN criteria	Urine output	RIFLE criteria
Serum creatinine	(common to both AKIN and RIFLE)	Class	Serum creatinine or GFR
Stage 1
Increase of more than or equal to 0.3 mg/dL (≥ 26.5 μmol/L) or increase to more than or equal to 150% to 199% (1.5- to 1.9-fold) from baseline	Less than 0.5 mL/kg per hour for more than 6 h	Risk	Increase in serum creatinine × 1.5 or GFR decrease > 25%
Stage 2
Increased to more than 200% to 300% (≥ 2- to 2.9-fold) from baseline	Less than 0.5 mL/kg per hour for more than 12 h	Injury	Serum creatinine × 2 or GFR decreased > 50%
Stage 3
Increased to more than 300% (≥ 3-fold) from baseline, or more than or equal to 4.0 mg/dL (≥ 354 μmol/L) with an acute increase of at least 0.5 mg/dL (44 μmol/L) or on RRT	Less than 0.3 mL/kg per hour for 24 h or anuria for 12 h	Failure	Serum creatinine × 3, or serum creatinine > 4 mg/dL (> 354 μmol/L) with an acute rise > 0.5 mg/dL (> 44 μmol/L) or GFR decreased > 75%
		Loss	Persistent acute renal failure = complete loss of kidney function > 4 wk
		End-stage kidney disease	ESRD > 3 mo

For conversion of creatinine expressed in SI units to mg/dl, divide by 88.4. For both AKIN stage and RIFLE criteria, only one criterion (creatinine rise or urine output decline) needs to be fulfilled. Class is based on the worst of either GFR or urine output criteria. GFR decrease is calculated from the increase in serum creatinine above baseline. For AKIN, the increase in creatinine must occur in < 48 h. For RIFLE, AKI should be both abrupt (within 1–7 d) and sustained (more than 24 h). AKI: Acute kidney injury; AKIN: Acute Kidney Injury Network; ESRD: End-stage renal disease; GFR: Glomerular filtration rate; RIFLE: Risk, injury, failure, loss, and end stage; RRT: Renal replacement therapy.

Table 3 Formulas for estimating the glomerular filtration rate: modified diet in renal disease-4, modified diet in renal disease-6, chronic kidney disease epidemiology collaboration (mL/min per 1.73 m²)[118-120]

MDRD-4 formula (1)	186 × [creatinine (mg/dL)] -1.154 × [age (yr)] 0.203 × (0.742 if patient is female) × (1.21 if patient is black)
MDRD-6 formula (2)	170 × sCr (mg/dL)-0.999 × age-0.176 × 1.180 (if black) × 0.762 (if female) × serum urea nitrogen-0.170 × albumin 0.138
CKD-EPI equation (3)	141 × min (sCr/κ, 1)α× max (sCr/κ, 1)-1.209 × 0.993 Age × 1.018 (if female) × 1.159 (if black)

MDRD: Modified diet in renal disease; CKD-EPI: Chronic kidney disease epidemiology collaboration.

Table 4 Recomendations for renal function evaluation in subgroups of patients with cirrhosis

Differentiate prerenal kidney disease, hepatorenal syndrome and acute tubular necrosis	Angeli et al[5] algorithm
Acute kidney injury	Modified cirrhosis–acute kidney injury classification sCr increase ≥ 0.3 mg/dL (≥ 26.4 μmol/L) or more than 150% (1.5 fold from baseline) within 48 h from the first measurement[12]
Chronic kidney disease	KDOQI[49] guidelines Glomerular filtration rate below 60 mL/min for more than three months, calculated using the modified diet in renal disease-6 formula chronic kidney disease epidemiology collaboration Cys C-Cr equation[51]
Critically ill cirrhotic patients	RIFLE score[18,19] MBRS score[61,62] combining mean arterial pressure, bilirubin, respiratory failure and sepsis
Candidates for liver transplantation	Exogenous filtration markers If there is suspicion for parenchymal disease and Glomerular filtration rate is between 30-60 mL/min consider renal biopsy
Advanced cirrhosis	Cystatin C
Difficulties in differentiation of acute tubular necrosis	NGAL
All patients with cirrhosis in every stage of liver disease	Renal resistive index estimation by renal duplex doppler ultrasound

KDOQI: Kidney disease outcomes quality initiative.

Table 5 Recomendations for management of patients with cirrhosis

First line therapy
Recognize and withdraw all causes of acute kidney disease
Resolve primary liver disease
Encounter hypoalbuminemia with albumin infusion and tension ascites with repeated paracentesis plus albumin
Have a high level of suspicion and treat spontaneous bacterial peritonitis
Be vigilant and have into close monitoring patients win acute kidney injury network stage 1 and sCr > 1.5 mg/dL (133 μmol/L) or initial acute kidney injury network stage > 1
If there is no improvement within 2 d, proceed to specific treatment measures
Second line therapy
Patients hospitalized at the ward	If the diagnosis of hepatorenal syndrome has been placed:
	Give albumin and terlipressin in continuous infusion
	If there is improvement within 4 d continue with oral midrodrine
	When terlipressin is unavailable:
	Give midrodrine plus octreotide plus albumin
Patients admitted to intensive care unit	Norepinephrine plus albumin
Third line therapy
Patients who qualify for transplant	Consider liver or simultaneous liver kidney transplantation
	Give therapeutic bridges – Dialysis, transjugular intrahepatic portosystemic shunt
Patients who do not qualify for transplant	Continue the combination of terlipressin plus albumin
	Dialysis, TIPS

Table 6 Scheme for terlipressin and albumin administration[5,97]

Terlipressin is given as an intravenous bolus 1 to 2 mg every four to six hours

Albumin is given for two days as an intravenous bolus 1 g/kg per day (100 g maximum) followed by 25 to 50 g /d until terlipressin therapy is discontinued

Table 7 Published guidelines on selection criteria for simultaneous liver-kidney transplantation

Davis et al[121], 2007

Patients with CKD with CrCl (preferentially iothalamate) of ≤ 30 mL/min for > 3 mo

Patients with AKI and/or HRS on dialysis for ≥ 6 wk

Patients with prolonged AKI with kidney biopsy showing fixed renal damage

SLK was not recommended in patients with AKI not requiring dialysis

Eason et al[122], 2008

Patients with CKD with GFR ≤ 30 mL/min > 3 mo

Patients with AKI/HRS with sCr ≥ 2 mg/dL and on dialysis ≥ 8 wk

Patients with evidence of CKD and kidney biopsy with > 30% GS or 30% fibrosis

Other criteria that was recommended to be considered: Presence of co-morbidities: Diabetes, Hypertension, age > 65 yr, renal size and duration of sCr > 2 mg/dL

Nadim et al[123], 2012

Persistent AKI ≥ 4 wk with one of the following:

Increase Scr ≥ 3-fold from baseline or on dialysis

GFR ≤ 35 mL/min (MDRD-6) or ≤ 25 mL/min (iothalamate)

CKD ≥ 3 mo with one of the following:

eGFR ≤ 40 mL/min (MDRD-6) or ≤ 30 mL/min (iothalamate)

Proteinuria ≥ 2 g/d

Kidney biopsy showing > 30% GS or > 30% interstitial fibrosis

Note: Higher GFR threshold with MDRD-6 was to account for the approximate 30%- 40% overestimation that has been described when compared to iothalamate.

CKD: Chronic kidney disease; CrCl: Creatinine clearance; HRS: Hepatorenal syndrome; AKI: Acute kidney injury; SLK: Simultaneous Liver-Kidney; sCr: Serum creatinine; GFR: Glomerular filtration rate; GS: Glomerulosclerosis; MDRD-6: Modification of diet in renal disease formula calculated using six variables of serum creatinine, serum urea, serum albumin, age, gender.