Hepato renal syndrome

1. HEPATO RENAL SYNDROME
Dr Pukar Thapa

2. Sections
• Introduction
• Measurement of renal function
• Concept and diagnostic criteria for Acute kidney injury
• Hepatorenal sydrome
– Prevalence
– Diagnsotic criteria
– Pathophysiology
– Diagnosis
– Treatment
– Prevention

3. Introduction
• It is estimated that 20% of cirrhotic patients admitted to hospital have some
form of renal dysfunction, most cases of which are related to acute renal failure,
whereas chronic renal failure constitutes only 1% of case.
Yun Jung Choi. Prevalence of renal dysfunction in patients with cirrhosis according to ADQI-IAC working party proposal. Clinical and
Molecular Hepatology 2014;20:185-191
Six hundred and forty-three patients were admitted, 83 patients (12.9%) were
diagnosed with AKI, the most common cause for which was dehydration (30
patients).
Three patients had hepatorenal syndrome type 1 and 26 patients had prerenal-type
AKI caused by volume deficiency after variceal bleeding. In addition, 22 patients
(3.4%) were diagnosed with CKD, 1 patient with hepatorenal syndrome type 2, and 3
patients (0.5%) with AKI on CKD.

4. History of renal dysfunction in liver disease
• Frerichs, the founder of modern liver pathology, reported the presence of oliguria in
patients with ascites in 1877.
• Flint noted that in most cases of renal failure in cirrhosis, there were no significant
histological changes in the kidneys at autopsy.
• In 1956, Hecker and Sherlock described renal failure in 9 patients with liver disease
characterised by progressive oliguria, very low urinary Na excretion, hyponatraemia, but
no proteinuria.
• It was later established that the renal failure was functional, since the kidneys of these
patients could be successfully transplanted to other patients with chronic renal failure,
and the renal failure was reversible after liver transplantation.
• Using clearance techniques, the hallmark of the HRS was found in 1967 to be severe renal
vasoconstriction.
Charles KF Ng, Michael HM Chan, Morris HL Tai, *Christopher WK Lam. Hepatorenal syndrome. Department of Chemical Pathology, The Chinese
University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. Clin Biochem Rev Vol 28 February 2007

5. Kidney diseases associated with liver disease

6. • Creatinine is derived from creatine, which is a metabolic product of muscles.
• In the case of patients with advanced cirrhosis, the production of creatinine
from creatine is reduced because of significant muscle wasting in these
patients, adding to the inaccuracy in the use of serum creatinine concentration
as a measure of renal function.
• Hyperbilirubinemia and hemolysis in pts with cirrhosis may produce spuriously
low levels of Cr.
• It is for these reasons that experts and investigators started to explore the use
of a change in serum creatinine concentration or a change in GFR as a measure
of renal dysfunction.
S Creatinine as a marker of Renal dysfunction in
Liver cirrhosis

7. Cr-based GFR-estimating equations
• Cr-based GFR-estimating equations have major limitations in pts with
cirrhosis.[1,2]
• The majority of Cr-based GFR and Cr clearance–estimating equations used in
clinical practice were derived either from pts with CKD or pts without cirrhosis.
They also overestimate GFR in cirrhosis.[3,4]
1. Mindikoglu AL, Dowling TC, Weir MR, et al. Performance of chronic kidney disease epidemiology collaboration creatininecystatin C equation for
estimating kidney function in cirrhosis. Hepatology 2014;59:1532–1542.
2. Francoz C, Nadim MK, Baron A, et al. Glomerular filtration rate equations for liver-kidney transplantation in patients with cirrhosis: validation of current
recommendations. Hepatology 2014;59:1514–1521.
3. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31–41.
4. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation.
Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461–470.

8. GFR and Cr Clearance Estimating Equations Validated
in Pts With Cirrhosis

9. Royal Free Hospital Cirrhosis GFR
• A Cr-based GFR-estimating equation derived from 469 pts with LC, recently was
described.
• This Cr-based GFR model suggested improved performance in predicting
measured GFR compared with the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) Cr and MDRD equations.
• Blood urea and degree of ascites (moderate vs severe) are 2 of the parameters
used in this new model.
• Increased blood urea levels in the setting of GIB and the subjective nature of
assessing the degree of ascites among clinicians may limit the value of this
model and further validation is required.
Kalafateli M, Wickham F, Burniston M, et al. Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: the
royal free hospital cirrhosis glomerular filtration rate. Hepatology 2017;65:582–591.

10. Serum Cystatin C levels
• Several equations based on serum cystatin C levels have been developed by Larsson et al.
(LARSSON equation), Hoek et al. (HOEK equation), and Inker et al. [CKD-EPI cystatin C
equation (2012)] to estimate GFR.
• In recent equations by Inker et al. [CKD-EPI creatinine-cystatin C equation(2012)], both
serum creatinine and cystatin C more accurately estimated kidney function compared to
models that included serum creatinine or cystatin C alone in pts .
• The Cr–Cystatin C equation for cirrhosis was validated recently in an cohort of 129 pts
with decompensated cirrhosis in Europe.
1. Larsson A, Malm J, Grubb A, Hansson LO. Calculation of glomerular filtration rate expressed in mL/min from plasma cystatin C values in mg/L. Scand J Clin Lab
Invest 2004;64:25-30.
2. Hoek FJ, Kemperman FA, Krediet RT. A comparison between cystatin C, plasma creatinine and the Cockcroft and Gault formula for the estimation of
glomerular filtration rate. Nephrol Dial Transplant 2003;18:2024-2031.
3. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J
Med 2012;367:20-29.

11. • Compared with the CKD-EPI cystatin C (2012) and Cr–cystatin C (2012)
equations, the Cr–Cystatin C GFR Equation for Cirrhosis had significantly higher
accuracy and showed the best performance to discriminate pts with cirrhosis
who had a GFR <60mL/min .
These development may become relevant to establishing the DX of HRS more
precisely and selecting the most appropriate therapy and its timing, be it
vasopressors, LTA, or SLKT.
1. Inker LA, Schmid CH, Tighiouart H, et al. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 2012;367:20–29.
2. Mindikoglu AL, Dowling TC, Magder LS, et al. Estimation of glomerular filtration rate in patients with cirrhosis by using new and conventional filtration
markers and dimethylarginines. Clin Gastroenterol Hepatol 2016;14:624–632 e2.
Serum cystatin C levels

12. Urinary Findings in Pts with Renal Dysfunction
and Cirrhosis
Prerenal HRS ATN
Urine osmolarity
(mOsm/kg)
>500 >500 <350
Urine sodium (mmol/day) <20 <20 * >40
Fractional excretion of
sodium (FeNa %)
<1 >2
Urine sediment Bland and/or non-
specific
nil May show muddy
brown granular
casts
*: Urine sodium can be high if treated with diuretics.

13. Biomarkers
• Fagundes et al (n=241) reported that urinary neutrophil gelatinase associated lipocalin
(NGAL) levels were ↑ significantly in pts with LC and ATN compared with pts who had
prerenal azotemia and HRS.
• The value of uNGAL that better discriminated between pts with ATN and those with
classical HRS was 194 ug/g creatinine (SN 91%, SP 82%).
• A major limitation of urinary NGAL is that it increases in pts with a UTI and can show false-
positive results.
• Other biomarkers includes IL-18, KIM-1, liver-type fatty acid binding protein(L-FABP)
Fagundes C, Pepin MN, Guevara M, et al. Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of
kidney function in cirrhosis. J Hepatol 2012;57:2674–2273.

14. Examples of proteic biomarkers tested in AKI.
• Other novel biomarkers:
• MicroRNAs (miRNAs)
• Transforming Growth Factor beta 1 (TGF-b1)
• soluble urokinase-type plasminogen activator receptor (suPAR)

15. The Concept of Acute Kidney Injury
• The term acute kidney injury (AKI) was first used in 1918 to describe cases of acute
mercury poisoning.
• It was then forgotten for many decades and not used again until it was revived by a
group of intensive care physicians and nephrologists in 2004 to describe cases of
acute renal failure.
• The most interesting observation was that even trivial changes in renal function
could be associated with negative patient outcomes.
• Many of the patients would not be recognized as having renal failure, as the serum
creatinine concentration increase was not high enough, and yet these mild increases
in serum creatinine concentration were sufficient to cause permanent structural
renal damage in those patients who underwent renal biopsy.
Therefore acute kidney injury (AKI) became the preferred term rather than acute
kidney failure to describe the changes in renal function in these patients.
(Acute Dialysis Quality Initiative (ADQI)

16. • This classification of AKI provides
three levels of severity of renal
dysfunction and two levels of
clinical outcome.
• The ADQI not only wanted to use
a change in renal function as a
means of defining AKI, it also
wanted to have a definition of
AKI that would separate the mild
cases from the severe cases, as
this may have prognostic
significance.
The RIFLE Diagnostic Criteria for Acute Kidney Injury
Bellomo R, et al. Acute renal failure: definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International
Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8(4):R204-R212.)

17. RIFLE (drawback)
• This set of diagnostic criteria poses a problem when a patient presents with AKI
but for whom a baseline serum creatinine concentration has not been
measured to calculate the change in serum creatinine concentration.
• It was proposed that the baseline serum creatinine concentration should be
back-calculated from the GFR with use of the Modification of Diet in Renal
Disease formula assuming a normal baseline GFR of 75 mL/min/1.73 m2.

18. • Do not require a baseline
measurement of renal function.
• Eliminated the use of an
estimated GFR, thereby
removing one of the
inaccuracies of renal function
measurement.
• The AKIN criteria also stipulated
that for the urine output
criterion to be meaningful, the
patient’s fluid state must be
optimized and use of diuretics
stopped, and that there should
be no bladder neck obstruction.
The Acute Kidney Injury Network (AKIN)
Diagnostic Criteria for Acute Kidney Injury
(Mehta RL, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury.Crit Care 2007;11(2):R31.)

19. The Kidney Disease: Improving Global
Outcomes (KDIGO) Clinical Practice Guidelines
• Their definition of AKI is based on the RIFLE and AKIN definitions.
• Renal replacement therapy has been added as a diagnostic criterion for the severest
stage.

20. The Acute Dialysis Quality Initiative and the International
Ascites Club Diagnostic Criteria for Acute Kidney Injury for
Cirrhotic Patients
• The drawback is that these criteria do not provide staging of the AKI, and hence are
unable to include progression of AKI in the evaluation of prognosis.

21. The Acute Dialysis Quality Initiative and the International
Ascites Club Diagnostic Criteria for Acute Kidney Injury for
Cirrhotic Patients
•For the first time the term acute kidney injury was formally adopted to represent acute renal failure in
cirrhosis.
•Serum creatinine concentration, despite its many shortcomings, should be maintained as a measure
of renal function, because of its simplicity of use and the wide availability of the test.
•Concept of using a small change in serum creatinine concentration over a short time, such as an
increase of 0.3 mg/dL (26.4 μmol/L) in 48 hours or less as a marker of acute deterioration of renal
function.
•Finally, a consensus was reached that the baseline serum creatinine concentration should be a stable
serum creatinine over the previous 3 months.
•The groups also decided to discard the urine output diagnostic criterion, as oliguria is a cardinal
feature of cirrhosis with ascites.

22. The Revised Consensus Recommendations of the
International Ascites Club on the Diagnosis of Acute Kidney
Injury in Cirrhosis
• Angeli P, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club
of Ascites. Gut 2015;64(4):531-537.)
Exapmple:
Baseline creatinine: 0.8
AKI: 3.4
Partial response: 1.9
Complete response: 0.9

23. Hepatorenal syndrome
• The term “hepatorenal syndrome” was first used in 1939 to describe the
occurrence of renal failure after biliary surgery or hepatic trauma.
• Later it was extended to other types of acute renal failure in liver diseases.
• In 1996, the International Ascites Club proposed a new definition and diagnostic
criteria for HRS, and were revised in 2007.
Hepatorenal syndrome (HRS) is characterized as renal dysfunction secondary to a reduction in
renal blood flow (RBF) occurring in the setting of underlying cirrhosis and portal hypertension.
It is classified as either rapidly developing acute kidney injury (AKI), HRS type 1, or slowly
progressive chronic kidney disease (CKD), HRS type 2.
The diagnosis conveys a poor prognosis; the median survival for HRS types 1 and 2 is
approximately 1 and 6.7 months, respectively. (1)
1. Mindikoglu et al. New Developments in Hepatorenal Syndrome. Clinical Gastroenterology and Hepatology 2018;16:162–177

24. Prevalence of AKI and HRS in Pts With Cirrhosis
• Almost 50% of cirrhotic pts with ascites will develop AKI during the course of
their illness.
• In a prospective study conducted by Planas et al among 263 pts with DLC and
ascites, 8% of pts developed HRS (3% developed T1 and 5% developed T2 HRS)
during a mean follow-up period of 41 months.
• According Garcia et al, 19% of hospitalized pts with LC had AKI, and among those
with acute renal failure, approx 17% had HRS.
1. Planas R, Montoliu S, Balleste B, et al. Natural history of patients hospitalized for management of cirrhotic ascites. Clin Gastroenterol Hepatol 2006;4:1385–
1394.
2. Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008;48:2064–2077.
3. Montoliu S, Ballesté B, Planas R, et al. Incidence and prognosis of different types of functional renal failure in cirrhotic patients with ascites. Clin
Gastroenterol Hepatol 2010;8(7):616–622, quiz e80

25. Prevalence of AKI and HRS in Pts With Cirrhosis
• HRS constitutes a small fraction of all AKI cases that develop in cirrhotic pts.
Moreau et al.
N= 423 pts with LC and AKI
ATN= 35 %
Pre Renal AKI= 32 %
HRS (T1)= 20 %
HRS (T2)= 6.6 %
Belcher et al.
N= 188 pts with LC and AKI
ATN= 21 %
HRS= 9 %
1. Moreau R, Durand F, Poynard T, et al. Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: a retrospective multicenter study.
Gastroenterology 2002;122(4):923–930
2. Belcher JM, Sanyal AJ, Peixoto AJ, et al. Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology
2014;60:622–632

26. Prevalence of AKI and HRS in Pts With Cirrhosis
• HRS occurs in about 4% of patients admitted with decompensated cirrhosis,
with a cumulative probability of 18% at 1 year and 39% at 5 years.
• Patients with spontaneous bacterial peritonitis will have a one-in-three chance
of developing HRS.
1. Gines A, Escorsell A, Gines P, et al. Incidence, predictive factors, and prognosis of hepatorenal syndrome in cirrhosis. Gastroenterology 1993;105:229-36.
2. Gines P, Martin P-Y, Niederberger M. Prognostic significance of renal dysfunction in cirrhosis. Kidney Int Suppl 1997;61:S77-S82

27. The Traditional Diagnostic Criteria for
Hepatorenal Syndrome
Salerno F, et al. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56(9);1310-1318.)
With the advent of effective
vasoconstrictor therapy for HRS1,
clinicians have been concerned that
a delay in initiating therapy of 2
weeks or until the serum creatinine
concentration reaches 2.5 mg/dL
(220 μmol/L) may result in a reduced
response rate.
Higher serum creatinine levels at
the start of vasoconstrictor therapy
have been found to be one of the
predictors of nonresponse.

28. The Proposed New Diagnostic Criteria for Type 1 Hepatorenal
Syndrome, or Hepatorenal Syndrome–Acute Kidney Injury
From Angeli P, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club
of Ascites. Gut 2015;64(4):531-537.)

29. The Proposed New Diagnostic Criteria for Type 1 Hepatorenal
Syndrome, or Hepatorenal Syndrome–Acute Kidney Injury
• Consensus was finally reached that patients who presented with Stage 2 or Stage 3 AKI
and otherwise fulfilled all the diagnostic criteria for HRS1 as set down previously by the
IAC2 would receive a diagnosis of HRS-AKI.
• All patients whose renal dysfunction progressed despite therapeutic measures not
including vasoconstrictors would also be regarded as having HRS-AKI.
• This would permit clinicians to start vasoconstrictor therapy without having to wait for
the obligatory 2 weeks for the serum creatinine concentration to rise above 2.5 mg/dL
(220 μmol/L).
It is important to recognize that this revised definition of HRS-AKI no longer acknowledges
HRS1 and HRS2. HRS2 is now regarded as a type of CKD. However, patients can still have AKI
superimposed on CKD, such as the case of AKI complicating an episode of infection in a
patient withdiabetic nephropathy.

30. Types
• Corresponds to AKI-HRS
Type 1
• renal impairment which fulfills
the criteria of HRS but not AKI
(non-AKI-HRS)Type 2

31. Pathophysiology of Acute Kidney Injury and
Hepatorenal Syndrome
• The pathogenesis of splanchnic vasodilatation in cirrhosis. Ang II, Angiotensin II; CO, carbon
monoxide; ET, endothelin; IL6, interleukin-6; NO, nitric oxide; TNF, tumor necrosis factor.
Elevated levels of
tetrahydrobiopterin, a TNF-α-
stimulated cofactor and inducer of
endothelial nitric oxide synthase

32. The Consequences of Splanchnic and Systemic Arterial
Vasodilatation
• “splanchnic steal” syndrome reduction in the effective arterial blood volume
activation of the various compensatory vasoconstrictive neurohormonal systems,
including the renin-angiotensin-aldosterone system, the sympathetic nervous system, and
the nonosmotic stimulation of arginine vasopressin release induce renal sodium
and water retention so as to increase the intravascular volume.
The activation of these various vasoconstrictor systems may have a beneficial effect on the
systemic circulation; however, in the renal circulation, there is renal hypoperfusion related
to an increase in renal vascular resistance, thereby predisposing the kidneys to the
development of renal ischemia and ultimately renal failure.

33. Cardiac dysfunction
• Simultaneous to the activation of the various vasoconstrictor systems, there is
also an increase in cardiac output in order to maintain hemodynamic stability.
• This is achieved through increases in venous return, heart rate, and myocardial
contractility. (features of a hyperdynamic circulation in patients with advanced
cirrhosis, tachycardia, low blood pressure, and warm peripheries).
• With the liver cirrhosis becoming progressively more advanced, systemic
vascular resistance will continue to fall, and cardiac compensation will
ultimately reach a maximum, beyond which cardiac dysfunction will become
evident and will contribute to the extrahepatic complications of liver cirrhosis
such as renal failure.

34. Pathogenesis of renal failure in cirrhosis
• The cirrhotic patient with ascites has
splanchnic and systemic arterial
vasodilatation but renal
vasoconstriction. The presence of
inflammation and cirrhotic
cardiomyopathy can worsen the
systemic vasodilatation and renal
vasoconstriction.
• Altered renal autoregulation and
relative deficiency of intrarenal
vasodilators maintains the renal
vasoconstriction, leading to reduced
renal blood flow and decreased
glomerular filtration. Therefore the
cirrhotic patient is poised to develop
acute kidney injury (first hit). Any
factor that can worsen any of the
pathogenetic pathways can
accelerate the development of acute
kidney injury (second hit).
Prostaglandins
Kallikreins

35. The role of inflammation
• Pro-inflammatory cytokines and chemokines exercise a direct relevant role in
the developmemnt of HRS.
• In addition, inflammatory mediators can also induce cellular damage. These are
molecules that are either expressed by bacteria called pathogen-associated
molecular patterns (PAMPs) or released by dying cells called damage-associated
molecular patterns (DAMPs).
• This, when combined with the oxidative stress induced by a relative deficiency
of nitric oxide, will predispose the tubules to cellular damage.
• Finally, severe cholestasis may further impair renal function by worsening
inflammation and/or macrocirculatory dysfunction, or by promoting bile salt-
related direct tubular damage. (cholemic nephropathy)

36. Step 1: Diagnose AKI (in Cirrhotic pt with Ascites)
Baseline S Cr
• Stable S Cr for ≤ 3 months.
• If not available, a stable S
Cr closest to the current one.
• If no previous S Cr, use
admission S Cr.
Absence of shock

37. Step 2: Stage AKI
• Huelin et al found that based on the new AKI criteria, more than half of the pts (290 of 547
pts) with LC admitted to the hospital had AKI.
• Not surprisingly, HRS and ATN were more common in pts with stages 2 and 3 AKI
compared with pts with stage 1 AKI.
Huelin P, Piano S, Sola E, et al. Validation of a staging system for acute kidney injury in patients with cirrhosis and association with acute-on-chronic liver
failure. Clin Gastroenterol Hepatol 2017;15:438–445 e5.

38. General measures
Discontinue use of diuretics, beta blockers and potential
nephrotoxic drugs.
Reduce the dose of lactulose if diarrhea is excessive.
Pts who have actually lost blood should receive blood
transfusions.
A septic workup is mandatory .
Empiric antibiotic therapy be given.

39. Step 3: Response to treatment

40. Exclusion
24 hr urinary protein > 500 mg/day
Microhematuria with > 50 RBC/HPF
Abnormal renal findings on USG
Start Inj albumin @ 1gm/kg/day for 2 days
AKI resolved ?YES
Closely monitor
NO
AKI-HRS

41. Step 4: Treat AKI- HRS & Evaluate response

42. Pharmacologic treatment
• The goal of pharmacologic therapy is to reverse renal failure and prolong
survival until candidates undergo LT.
Direct renal vasodilators
(Dopamine, fenoldopam, and prostaglandins)
By antagonizing the endogenous effect of
renal vasoconstrictors
ACEi, and endothelin antagonist(BQ-123).
Unfortunately, none of the studies that used
renal VD showed improvement in renal
perfusion or GFR.
Because of lack of benefit, the use of renal VD
in HRS largely has been abandoned.
Systemic vasoconstrictors
Vasopressin analogue: terlipressin
Somatostanin analogue: octreotide
α-adrenergic agonists: midodrine, NE
They rely on the assumption that
interrupting the splanchnic VD will
subsequently relieve the intense renal
VC.

43. Albumin
• Albumin is the recommended solution as it not only has a volume expanding
property but also has been shown to have antioxidant and antiinflammatory
properties.
• Albumin that is circulating in pts with DLC is reduced in quantity and deficient in
quality.
The abnormal quality of the circulating albumin is related to a constant oxidative milieu of
the cirrhotic state, causing the circulating albumin to exist in an oxidized rather than a
reduced form, thereby reducing the ability of the albumin molecule to bind free radicals
and perform its scavenger and detoxification functions.
1. Wong F: Drug insight: the role of albumin in the management of chronic liver disease. Nat Clin Pract Gastroenterol Hepatol 4(1):43–51, 2007
2. Oettl K, et al: Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival.J Hepatol 59(5):978–
983, 2013.

44. Albumin
• The dose of albumin in HRS treatment has not been well established.
• Albumin has been used intravenously at the mean dose of 20–40 g/day.
• Treatment should be maintained until a complete response (SCr below 1.5
mg/dl) or for a maximum of 14 days either in case of partial response (decrease
of SCr ≥50 with a final value still higher than 1.5 mg/dl) or in case of non-
response.
EASL 2018

45. Terlipressin (vasoconstrictor)
Binds to the V1 receptors of the vascular
smooth muscle cells to cause vasoconstriction
in both the systemic circulation and the
splanchnic circulation.
Dilate intrahepatic vessels, thereby reducing
intrahepatic resistance to portal inflow.
Reduction in portal
pressure, which has a
direct beneficial effect on
renal function in cirrhosis
Kiszka-Kanewitz M, Henricksen JH, Hansen EF & MØller S. Effect of terlipressin on blood volume distribution in patients with cirrhosis. Scandinavian Journal of
Gastroenterology. 2004; 39: 286–492.

46. Terlipressin
• Terlipressin has been studied in several RCTs in pts with HRS1 comparing bolus
doses of terlipressin plus albumin versus either albumin alone or placebo with
or without albumin.
• All studies showed that terlipressin was able to significantly improve renal
function in 24-80% of pts. However, overall terlipressin is considered effective
in 40-50 % of cases.
• When all the terlipressin trials were evaluated by a meta-analysis, there was an
overall reduction of mortality by 29%.
1. Martín-Llahí M, et al: Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome: a randomized study. Gastroenterology
134(5):1352–1359, 2008.
2. Neri S, et al: Terlipressin and albumin in patients with cirrhosis and type I hepatorenal syndrome. Dig Dis Sci 53(3):830–835,2008.
3. Sanyal AJ, et al: A randomized, prospective, double-blind, placebocontrolled trial of terlipressin for type 1 hepatorenal syndrome. Gastroenterology
134(5):1360–1368, 2008.
4. Boyer TD, et al: Terlipressin plus albumin is more effective than albumin alone in Improving renal function in patients with cirrhosis and hepatorenal syndrome
type 1. Gastroenterology 2016 Feb 16.

47. Terlipressin
• In the most recent studies, rates of response (complete or partial response) to
this treatment range from 64 to 76%, with a complete response, from 46 to 56%.
• In two meta-analyses terlipressin plus albumin was proven to improve not only
renal function but also short-term survival in patients with HRS.
• Terlipressin was initially proposed to be administered by i.v. boluses at a starting
dose of 0.5–1 mg every 4–6 h, progressively increased to a maximum of 2 mg
every 4–6 h in case of a reduction of baseline SCr < 25%.
• Adding albumin to terlipressin is more effective than terlipressin alone. One
possible explanation is that albumin, by increasing volaemia, may counteract
the decrease in cardiac output associated with HRS.
EASL 2018
Gluud LL et al. Terlipressin for hepatorenal syndrome. Cochrane Database Syst Rev 2012:CD005162.
Facciorusso A et al. Comparative efficacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network
meta-analysis. Lancet Gastroenterol Hepatol 2017;2:94–102.

48. Terlipressin
• Nazar et al. have identified an ↑ in the MAP of >5 mmHg on Day 3 of RX and a S
bilirubin of <10 mg/dL as predictors of response to terlipressin.
• Boyer et al. identified baseline S Cr as an important predictor, as pts with a
baseline S Cr of 5 mg/dL or greater were unlikely to respond .
The median time to HRS reversal is 7 days with faster recovery in pts with lower
serum creatinine at presentation.
1. Nazar A, et al: Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology 51(1):219–
226, 2010.
2. Israelsen ME, et al: Acute kidney injury and hepatorenal syndrome in cirrhosis. J Gastroenterol Hepatol 30(2):236–243, 2015.
3. Boyer TD, et al: Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics. J
Hepatol 55(2):315–321, 2011.

49. • The most common side effects of terlipressin are diarrhoea, abdominal pain,
circulatory overload and cardiovascular ischaemic complications which have
been reported in up to 45–46% of patients when the drug was delivered by i.v.
boluses.
• The use of terlipressin is a/with a risk of developing ischemic side effects,
estimated at approx 30% . The use of a continuous infusion rather than bolus of
terlipressin is a/with significantly fewer A/E. and more stable lowering effect
on portal pressure.
• The rate of discontinuation because of side effects, mainly cardiovascular, is
around 20%.
• Thus, a careful clinical screening including electrocardiogram is recommended
before starting the treatment.
EASL 2018
Terlipressin (side effects)

50. Recurrence
• Recurrent HRS in responders, after the end of the treatment, has been reported
in up to 20% of cases.
• Re-treatment is usually effective, however, in some cases, continuous
recurrence occurs, thus a long-term treatment with terlipressin plus albumin
and a long-term hospitalisation are required.

51. Norepinephrine/Noradrenaline
• Noradrenaline, given by continuous i.v. infusion at the dose of 0.5–3 mg/h, has
been proven to be as effective as terlipressin regarding the increase in mean
arterial pressure, the reversal of renal impairment and one-month survival.
• However, the number of patients treated with noradrenaline remains too small
to definitively confirm its efficacy. In addition, in contrast to terlipressin, the use
of noradrenaline always requires a central venous line and, in most countries,
the transfer of the patient to an intensive care unit (ICU). (EASL 2018)
Sharma P, Kumar A, Shrama BC, Sarin SK. An open label, pilot, randomized controlled trial of noradrenaline vs. terlipressin in the treatment of type 1
hepatorenal syndrome and predictors of response. Am J Gastroenterol 2008;103:1689–1697.

52. Midodrine
• It is usually used in combination with octreotide, a nonspecific inhibitor of
vasodilators in the splanchnic circulation, and albumin.
• The general consensus is that the response to the combination can be very
slow, and the overall response rate is approx 40%.
Cavallin M, et al shown that terlipressin plus albumin is far superior to the combination of
midodrine, octreotide, and albumin in terms of HRS1 reversal.
The response rate in the terlipressin plus albumin group was 70.4%, significantly better than
the 28.6% (p = 0.01) in the group receiving the midodrine combination.
Cavallin M, et al: Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: a randomized trial.
Hepatology 62(2):567–574, 2015.

53. Type 2 HRS
• Vasoconstrictors, in particular terlipressin, in association with albumin, have also been
proposed in the treatment of type 2 HRS. The treatment has been proven to be effective
in most cases but, unfortunately, recurrence after the withdrawal of treatment is the
norm.
• The finding that the higher baseline values of SCr, the lower rate of response to
terlipressin plus albumin, probably reflects the presence of renal parenchymal damage
• Regarding inflammation, it has been recently shown that, for the same value of baseline
SCr, the rate of response is related to the number of extra-renal organ failures.
Piano S, Schmidt HH, Ariza X, Amoros A, Romano A, Sola E, et al. Impact of Acute-on-Chronic Liver Failure on response to treatment with terlipressin and albumin
in patients with type 1 hepatorenal syndrome. J Hepatol 2017;66:S572.
The most relevant factors that may impair the response to vasoconstrictors are:
a) the baseline value of SCr,
b) the degree of inflammation,
c) the degree of cholestasis.

54. Recommended dosages of various vasoconstrictiors
in the treatement of type 1 HRS

55. Non pharmacological treatments

56. Molecular Adsorbent Recirculating System
• MARS is a form of dialysis where albumin recirculates repeatedly to adsorb
various bacterial products and cytokines that are thought to be responsible for
maintaining the vasodilatory state of the splanchnic and systemic circulations of
advanced cirrhosis.
• Studies with MARS have shown the low overall survival, with 7-day survival of
37% and 30-day survival of 25%.
• However, it appears that MARS simply removes creatinine, artificially lowering
the S Cr without affecting GFR.
1. Mitzner SR, Stange J, Klammt S, et al. Improvement of hepatorenal syndrome with extracorporeal albumin dialysis MARS: results of a prospective,
randomized, controlled clinical trial. Liver Transpl 2000;6(3):277–286
2. Mitzner SR, Klammt S, Peszynski P, et al. Improvement ofmultiple organ functions in hepatorenal syndrome during albumin dialysis with the molecular
adsorbent recirculating system. Ther Apher 2001;5(5):417– 422
3. Wong F, et al: Molecular adsorbent recirculating system is ineffective in the management of type 1 hepatorenal syndrome in patients with cirrhosis with
ascites who have failed vasoconstrictor treatment. Gut 59(3):381–386, 2010.

57. TIPS
• TIPS was used in the MX of HRS1 and HRS2 more than a decade ago.
• As PHTN is the initiator of the hemodynamic changes that ultimately lead to renal
VC and ↓ GFR, it is not surprising that lowering the PP will improve renal function.
• The effect of TIPS insertion on improving UNa excretion and renal function in
cirrhotic pts with refractory ascites is well documented.
1. Wong F, Sniderman K, Liu P, Allidina Y, Sherman M, Blendis L. Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium
homeostasis in cirrhosis and refractory ascites. Ann Intern Med 1995;122(11):816–822
2. Jalan R, Redhead DN, ThomasHW, et al.Mechanisms of changes in renal handling of sodium following transjugular intrahepatic portal systemic stent-shunt
(TIPSS). Eur J Gastroenterol Hepatol 1996;8(11):1111– 1116

58. TIPS
• Studies evaluated the effect of TIPS insertion in pts with T1HRS and preserved liver
function as evidenced by a CP score < 12.[1,2]
• Reversal of HRS occurred in almost 50% within 3 months from TIPS insertion. Pts’ survival ranged
from 10-570 days, with 30 day survival achieved in 5 pts(71%).
• An important observation from these two studies is the slow and delayed recovery of renal function
following TIPS (within 2-4 wks), unlike VC therapy, in which responders have faster recovery of renal
function (1-2 wks).
• HE was a common complication. Another drawback of TIPS insertion in T1HRS pts is the fact that most
of these pts have advanced liver disease who usually have CI for TIPS, limiting the utility of TIPS in this
group.
• Nevertheless, the results of the studies suggest that TIPS insertion is a reasonable alternative in pts
not candidates for VC therapy.
1. Guevara M, Ginès P, Bandi JC, et al. Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems. Hepatology 1998;28(2):416–422
2. Brensing KA, Textor J, Perz J, et al. Long term outcome after transjugular intrahepatic portosystemic stent-shunt in nontransplant cirrhotics with hepatorenal syndrome: a phase II study. Gut
2000;47(2):288 295
3. Rössle M, Gerbes AL. TIPS for the treatment of refractory ascites, hepatorenal syndrome and hepatic hydrothorax: a critical update.Gut 2010;59(7):988–1000
There is insufficient data to advocate TIPS in HRS-AKI but it could be suggested in selected patients with HRS-
NAKI. (EASL 2018)

59. TIPS - contraindication
AASLD

60. Combination Therapy
• VC therapy in conjunction with TIPS was evaluated in studies.
• The first study included 14 T1HRS pts who received oral midodrine, octreotide, and
albumin, followed by TIPS insertion in stable pts who responded to the VC therapy.[1]
• All 5 pts who received combination therapy were alive 6-30 months following TIPS, with
only 1 pt requiring LT 13 months later. On the other hand, responders to VC who did not
receive TIPS either died (3 pts) or required a LT (2 pts).
• The second study, which included 11 T2HRS cases MX with sequential terlipressin and
TIPS, also showed improvement of kidney function following TIPS. [2]
However, due to the small number of cases and limited applicability of TIPS in pts
with advanced cirrhosis, it is hard to utilize this combination TX on large no of pts.
1. Wong F, Pantea L, Sniderman K. Midodrine, octreotide, albumin,and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome. Hepatology
2004;40(1):55–64
2. Alessandria C, Venon WD, Marzano A, Barletti C, Fadda M, Rizzetto M. Renal failure in cirrhotic patients: role of terlipressin in clinical approach to
hepatorenal syndrome type 2. Eur J Gastroenterol Hepatol 2002;14(12):1363–1368

61. Thirty-Day and 90-Day Survival following RX of
HRS by Treatment Modality

62. Renal replacement therapy
• Renal replacement therapy should be considered in the management of AKI,
whatever the type. As far as HRS-AKI, it should be considered in non-responders
to vasoconstrictors. RRT should also be considered in patients with end-stage
kidney disease.
• The indications for RRT are the same in patients with cirrhosis as in the general
population including:
– severe and/or refractory electrolyte or acid-base imbalance, severe or refractory
volume overload, and/or symptomatic azotaemia.

63. Renal replacement therapy
• A retrospective study showed that cirrhotic pts (N=80) with HRS1 who were
nonresponders to VC therapy and received RRT had significantly longer
hospital stays without any beneficial effects on short-term (30-day) or long-
term (180-day) survival.[1]
• The decision to initiate RRT in HRS pts is further complicated by the presence of
HE, hypotension, and coagulopathy, which have been a/with ↑ risks of
hemorrhage and hypotension and which directly contributed to mortality in
some cases.[2,3]
• Therefore, in HRS pts waiting for a LT, RRT is justifiable as a bridge to LT . In
HRS pts who are not candidates for LT, initiation of RRT is controversial .
1. Zhang Z, et al: Role of renal replacement therapy in patients with type 1 hepatorenal syndrome receiving combination treatment of vasoconstrictor plus
albumin. J Crit Care 30(5):969–974, 2015.
2. Wilkinson SP, Weston MJ, Parsons V, Williams R. Dialysis in the treatment of renal failure in patients with liver disease. Clin Nephrol 1977;8(1):287–292
3. Ellis D, Avner ED. Renal failure and dialysis therapy in children with hepatic failure in the perioperative period of orthotopic liver transplantation. Clin Nephrol
1986;25(6):295–303

64. Liver transplant
• Improvement of renal function is gradual over the course of several weeks
after LTA.
• Renal Na excretion and S Cr and neurohormonal levels normalize within 1
month of LT in the majority of pts.[1]
• The more recent literature has reported a renal recovery rate of 58% to 76%.
[2,3]
• For example, Marik and colleagues studied renal function recovery following LT
in 28 HRS pts. Complete recovery of kidney function occurred in only 58% within
4-110 days of LT, whereas another 15% partially recovered. Importantly, kidney
function never recovered in 25% of cases.[4]
1. Navasa M, Feu F, García-Pagán JC, et al. Hemodynamic and humoral changes after liver transplantation in patients with cirrhosis. Hepatology
1993;17(3):355–360
2. Wong F, et al: Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation. Liver Transpl 21(3):300–307,
2015.
3. Marik PE, et al: The course of type 1 hepatorenal syndrome post liver transplantation. Nephrol Dial Transplant 21(2):478–482,2006.
4. Marik PE, Wood K, Starzl TE. The course of type 1 hepato-renal syndrome post liver transplantation. Nephrol Dial Transplant 2005;21(2):478–482

65. Liver transplant
• Shorter HRS duration, younger recipients’ age, and immediate liver allograft function as
evidenced by lower post-LT day 7 bilirubin level are factors that favor renal recovery.[1]
• HRS pts who do not recover kidney function and remain on RRT post–LT have a dismal
prognosis, with a 1-year mortality rate of around 70%.[2]
• In those pts who do not recover their renal function, consideration should be given for
renal transplant as well.
• One important predictor of post–LT dialysis requirement in HRS cases is prolonged RRT
for more than 8 weeks prior to LT.[3]
• Guidelines from the UNOS recommended that a dialysis period of >8 weeks is an
indication for combined liver and kidney transplant in pts with LC and HRS1.[4]
1. Marik PE, Wood K, Starzl TE. The course of type 1 hepato-renal syndrome post liver transplantation. Nephrol Dial Transplant 2005;21(2):478–482
2. Ruiz R, Barri YM, Jennings LW, et al. Hepatorenal syndrome: a proposal for kidney after liver transplantation (KALT). Liver Transpl 2007;13(6):838–843
3. Ruiz R, Kunitake H, Wilkinson AH, et al. Long-term analysis of combined liver and kidney transplantation at a single center. Arch Surg 2006;141(8):735–
741, discussion 741–742
4. Eason JD, et al: Proceedings of consensus conference on simultaneous liver-kidney transplantation [SLK]. Am J Transplant 8(11):2243–2251, 2008.

66. Changes in UNOS Policy for SLK Allocation:2017
(United Network for Organ Sharing)
• Eligibility for SLK includes pts with hepatic failure and one of the following: (1) chronic
kidney disease (CKD), (2) sustained AKI, or (3) metabolic disease.
• CKD is defined as an eGFR < 60 mL/min for >90 days before listing, as well as an eGFR
<35mL/min at the time of listing.
• This definition is based on UNOS data, which demonstrate that pts with a pretransplant
dialysis time of >2 months or S cr > 2.5 mg/dL who received an SLKT had a significantly
improved survival at 1 and 5 yrs (86.2% & 70.1%, respectively) compared with those pts
receiving LTA (81.1% & 65.9%).[1]
• Sustained AKI is defined as requirement for HD and an eGFR <25 mL/min for 6
consecutive weeks.
1. Formica RN, Aeder M, Bole G, Kucheryavaya A, Stewart D, Hirose R, Mulligan D. Simultaneous liver-kidney allocation proposal to optimize appropriate
utilization of scarce resources. Am J Transplant 2016;16:758- 766.

67. SLK (EASL 2018)
• SLK can be indicated in patients with cirrhosis and CKD in the following conditions:
– a) estimated GFR (using MDRD6 equation) ≤40 ml/min or measured GFR using iothalamate
clearance ≤30 ml/min,
– b) proteinuria ≥2 g a day,
– c) kidney biopsy showing >30% global glomerulosclerosis or >30% interstitial fibrosis, or
– d) inherited metabolic disease.
• SLK is also indicated in patients with cirrhosis and sustained AKI irrespective of its
type, including HRS-AKI when refractory to drug therapy, in the following
conditions:
– a) AKI on RRT for ≥4 weeks or
– b) estimated GFR ≤ 35 ml/min or measured GFR ≤25 ml/min ≥4 weeks.
Beyond these two conditions, in a candidate with high priority for LT due to a high MELD score,
the option of SLK may be considered in the presence of risk factors for underlying undiagnosed
CKD (diabetes, hypertension, abnormal renal imaging and proteinuria >2 g/day).

68. POST TRANSPLANT SURVIVAL
• A study examining the effect of pre-LT renal function on survival found that an
average pre-LT SCr of 0.8 mg/dL was a/with a 5 year survival of 62%, whereas 5
year survival in pts with pre-LT SCr of 2.7 mg/dL was 42%.[1]
• Another study showed 5 year post-LT survival of pts with HRS was moderately
reduced compared to pts without HRS (60% vs. 68%).[2]
In a single center review by Doyle et al,(52 had SLKT and 80 recipients had LTA), SLKT
pts had better overall survival rates at 1 and 5 years compared with LTA (92.3% and
81.6% vs 73.3% and 64.3% respectively; p < 0.01). [3]
1. Nair S, Verma S, Thuluvath PJ. Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology.
2002;35:1179–1185.
2. Gonwa TA, Klintmalm GB, Levy M, Jennings LS, Goldstein RM, Husberg BS. Impact of pretransplant renal function on survival after liver transplantation.
Transplantation. 1995;59:361–365.
3. Doyle MB, Subramanian V, Vachharajani N, Maynard E, Shenoy S, Wellen JR, Lin Y, Chapman WC. Results of Simultaneous Liver and Kidney Transplantation: A
Single-Center Review. J Am Coll Surg. 2016;223:193–201.

69. Association between renal function at the time of deceased
donor liver transplant and survival after transplant.
Schiff’s 12th edition

70. A simplified schematic of spectrum of renal
dysfunction in cirrhosis
Schiff’s 12th edition

71. Prognosis - HRS
• Ginès and others have previously reported a 2-week mortality rate as high as
80% in untreated T1 HRS pts with only 10% of pts surviving for 3 months.[1,2]
• Prognosis of T2 HRS pts is slightly better, with a median survival of 6 months.[3]
• In recent years, however, there is a trend toward a slight improvement in HRS
prognosis.
• For example, in a multicenter study by Salerno et al that included 116 HRS pts,
and the 3-month survival was 20% and 40% for T1 and T2 HRS, respectively.[4]
1. Ginès A, Escorsell A, Ginès P, et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 1993;105(1):229–236
2. Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996;23(1):164–176
3. Ginès P, Guevara M, Arroyo V, Rodés J. Hepatorenal syndrome.Lancet 2003;362(9398):1819–1827
4. Salerno F, Cazzaniga M, Merli M, et al. Diagnosis, treatment and survival of patientswith hepatorenal syndrome: a survey on daily medical practice. J Hepatol 2011;55(6):1241–1248

72. Survival graph
• Short- and long-term survival: in patients with acute kidney injury (AKI) and cirrhosis.
Schiff’s 12th edition

73. Prevention of HRS–Acute Kidney Injury (AKI)
• Sort P et al did a study to assess the effect of albumin infusion on renal function and survival in pts with
SBP, 126 pts were randomized to receive either cefotaxime or cefotaxime with albumin.
• AKI developed in 21 pts in the cefotaxime group (33 %) and 6 in the cefotaxime-plusalbumin group (10
%) (P=0.002).
• Improved mortality from 29% to 10% with cefotaxime with albumin when compared with cefotaxime
alone. [1]
Use of Albumin in Spontanous Bacterial peritonitis
Bacterial infections are the commonest precipitants of AKI in LC, estimated to
occur in approx 30% of pts with SBP.
1. Sort P, et al: Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med
341(6):403–409, 1999.
2. Salerno F, La Mura V: Treatment of spontaneous bacterial peritonitis. Dig Dis 33(4):582–585, 2015.
Pts with SBP who benefit the most : Creatinine > 1 mg/dl, BUN > 30 mg/dL,
bilirubin of >4 mg/dl
(1.5 g per kg body weight within six hours of diagnosis and 1.0 g/kg body weight
on day three)

74. Antibiotic Prophylaxis Against Infection
• For cirrhotic pts with ascites who have never developed SBP, PP with
norfloxacin shown to significantly reduce the likelihood of developing HRS
and ↓ SBP occurrence.[1]
• Cirrhotic pts with GIB have a high incidence of bacterial infections, estimated to
be 22% to 40% within 48 hrs after admission.[2,3]
• Because infections, whether occult or proven, are the triggers for AKI in
cirrhosis, it stands to reason to recommend that pts with GIB be given antibiotic
prophylaxis.[3]
1. Soriano G, et al: Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology 103:1267–1272, 1992.
2. Pauwels A, et al: Systemic antibiotic prophylaxis after gastrointestinal hemorrhage in cirrhotic patients with a high risk of infection. Hepatology 24:802–
806, 1996.
3. Chavez-Tapia NC, et al: Meta-analysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding—an updated Cochrane review.
Aliment Pharmacol Ther 34(5):509–518, 2011.
Norfloxacin (400mg/day) should be given as prophylaxis of SBP to prevent HRS-AKI. (EASL 2018)

75. Prophylaxis Against Circulatory Dysfunction
• LVP of >5 L is a/with the deterioration of systemic hemodynamics and with
reduction in SVR and hence vasodilatation, the so-called postparacentesis
circulatory dysfunction,[1] and this is a/with an ↑ risk for ascites recurrence,
hyponatremia, AKI (20 %), and death.[2]
• Gines et al. found that LVP (4–6 L/day), performed without iv albumin
replacement, precipitated HRS in 21% of 53 cases [3]. In contrast, there were no
cases of HRS when LVP was performed with iv albumin replacement.
1. Ruiz-del-Arbol L, et al: Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis. Gastroenterology
113(2):579–586, 1997.
2. Salerno F, et al: Refractory ascites: pathogenesis, definition, and therapy of a severe complication in patients with cirrhosis. Liver Int 30(7):937–947, 2010.
3. P. Gines, L. Tito, V. Arroyo et al., “Randomized comparative study of therapeutic paracentesis with and without intravenous albumin in cirrhosis,”
Gastroenterology, vol. 94, no. 6,
pp. 1493–1502, 1988.

76. • References:
– Zakim 7th edition
– Schiff’s 12th edition
– Uptodate 21.6
– EASL 2018 (Clinical Practice Guidelines for the management of patients with decompensated
cirrhosis)
– Renal dysfunction in cirrhosis – AASLD
– Kidney bio-markers in cirrhosis - EASL