Hepato-Renal Syndrome (HRS) is a functional renal impairment that occurs in patients with advanced liver disease or fulminant hepatic failure. It is characterized by intense renal vasoconstriction leading to a marked reduction in glomerular filtration rate and renal plasma flow without major histologic kidney changes. HRS is classified into two types - type 1 is rapidly progressive while type 2 is slow in onset. The pathophysiology involves systemic vasodilation and subsequent renal vasoconstriction mediated by the sympathetic nervous system and various cytokines. Treatment involves pharmacologic interventions like terlipressin or TIPS to constrict systemic vessels. Liver transplantation remains the definitive treatment as it cures both liver and renal dysfunction.

1. Hepato-Renal Syndrome
Devawrat Buche
ICU Registrar
July 2018

2. Overview
• Introduction
• Definition
• Pathophysiology
• Incidence & predicting factors
• Diagnosis
• treatment
• prognosis

3. • In the late 19th century- Fredrichs (1861) and Flint (1863) -
association among advanced liver disease, ascites, and oliguric renal
failure in the absence of significant renal histologic changes
• Almost 100 yr later Hecker and Sherlock – defined the pathogenesis
of hepatorenal syndrome

4. Definition
• HRS is a reversible functional renal impairment that occurs in patients
with advanced liver cirrhosis or those with fulminant hepatic failure.
• It is characterized by marked reduction in GFR and RPF .
• The hallmark - intense renal vasoconstriction with predominant
peripheral arterial vasodilation.
• no major histologic changes, tubular function is preserved

5. Types :
Type 1 HRS
• rapidly progressive
• doubling of creatinine ( > 2.5 mg/dl ) ,or
• 50% reduction in creat clearance to < 20 ml/min
• in < 2 weeks
Type 2 HRS
• slow in onset
• gradual renal decline
• sr creat > 1.5 mg%

6. Type 3 HRS
• cirrhosis + superimposed AKI / CKD
Type 4 HRS
• Fulminant liver failure with HRS
Clinics of North America, 2006

7. Pathophysiology
• Hallmark : systemic vasodilation with renal vasoconstriction
• 4 inter-related pathways :
1. Peripheral arterial vasodilation with hyperdynamic circulation
and subsequent renal vasoconstriction;
2. Stimulation of the renal sympathetic nervous system
3. Cardiac dysfunction contributing to the circulatory derangements
and renal hypoperfusion;
4. Action of different cytokines( TNF ⍺ , IL 6 ) and vasoactive mediators
(NO) on the renal circulation and other vascular beds.

8. Liver cirrhosis
increased resistance to blood flow in liver bed
increased vasodilator production ( NO )
splanchnic & systemic vasodilation
unloading of baroreceptors in aortic arch & carotid body
stimulation of SNS. RAAS. Vasopressin release
renal vasoconstriction

9. Incidence
• Gines et al, estimated the 1-yr probability of HRS in patients with
cirrhosis at 18% and the 5-yr probability at 39%.
• Type 1 HRS ( 20 %) is more common cause than Type 2 HRS ( 6.6 % )
as a cause of renal failure in advanced cirrhosis
Moreau R, etal: Terlipressin in patients with cirrhosis and
type 1 hepatorenal syndrome: A retrospective multicenter
study. Gastroenterology 122: 923–930, 2002

10. Predicting factors
On multivariate analysis, independent predictors of HRS occurrence
were identified as :
• dilutional hyponatremia,
• low urinary sodium,
• reduced plasma osmolality, and
• Hypotension
• high plasma renin activity,
• absence of hepatomegaly
Gines A, Escorsell A, Gines P, Salo J, Jimenez W, et al.:
Incidence, predictive factors, and prognosis of the
hepatorenal syndrome in cirrhosis with ascites.
Gastroenterology 105: 229–236, 1993

11. OTHER PRECIPITANTS FOR HRS

12. Diagnosis
• The diagnosis of HRS is one of exclusion
• criteria outlined by the IAC
• Only the major criteria are necessary to make the diagnosis,
• Aim first to document a reduced GFR (40 ml/min) and second to
exclude other causes of renal failure.

13. Major criteria ( IAC , 2015)
• Presence of cirrhosis with ascites
• Diagnosis of AKI ( Sr Cr increase > 1.5 times baseline)
• no improvement in creatinine clearance after 48 hrs of diuretic
withdrawal &/or plasma expansion by albumin ( 1g/kg/d , upto
100g/d)
• absence of shock
• no current exposure to nephrotoxic drugs
• no macroscopic e/o renal damage – normal renal US, absence of
proteinuria > 500 mg/d, no microscopic hematuria

14. Additional critieria ( in 1996 definition )
• Urine volume < 500 ml/d
• Urine sodium < 10 mEq/L
• Urine osmolality > plasma osmolality
• Urine red blood cells < 50/high-power field
• Serum sodium concentration < 130 mEq/L

15. Treatment
• Patients with type 1 HRS require hospitalization,
• type 2 HRS can be treated on an outpatient basis.
• In hospitalized patients -- central venous access is helpful to assess
the intravascular volume status and guide fluid and albumin infusion
• Nutrition – salt restricted diet
• Type 1 HRS – has a dismal prognosis –aggressive treatment warranted
for those on transplant list or undergoing evaluation
• 4 major therapeutic interventions : Pharmacologic treatment, TIPS,
RRT ( including MARS ) , and liver transplantation

16. Pharmacological interventions
• Pharmacologic agents can be grouped into two broad categories: Renal
vasodilators and systemic vasoconstrictors
RENAL VASODILATORS :
• direct renal vasodilators : dopamine ( 2-5 mcg/kg/min), fenoldopam, PGs
• antagonizing the endogenous effect of renal vasoconstrictors : saralasin,
ACE inhibitors, and ET antagonists
• The effect seen was mostly due to systemic vasoconstriction– but was also
was associated with adverse effects
• Because of adverse effects and lack of benefit, the use of renal vasodilators
in HRS largely has been abandoned.

17. Systemic vasoconstrictors
• vasopressin analogs ( terlipressin, ornipressin )
• somatostatin analogs ( Octreotide )
• ⍺ agonists ( midodrine, NA )

18. • Vasopressin analogs – act on V1 receptors on arterial wall
• Terlipressin is extensively studied
• Dose : 0.5 – 2 mg, every 4 – 6 hourly
• The administration of terlipressin and albumin is associated with
significant improvement in GFR, increase in BP, near normalization of
neurohumoral levels, and reduction of serum creatinine in 42 to 77% of
cases
• Type 2 HRS-better response, longer survival seen
• However, the survival advantage of terlipressin is short lived -m80% of
patients who do not receive a transplant will succumb within 3 months
of therapy.
• Major drawback – unavailability in many countries inc. USA

19. Octreotide – synthetic somatostatin analog
• inhibits release of glucagon & vasodilator peptides
• combination with albumin – proved to be inferior to vasopresin
combination in HRS.
Midodrine – alpha agonist
• scant data
• oral formulation in combination with albumin
• Dose : 7.5 – 12.5 mg , oral, 8 hourly
• improved hemodynamics, no effect on renal parameters.
Pomier-Layrargues G ETAL : Octreotide in hepatorenal syndrome: A
randomized, double-blind, placebo-controlled, crossover study. Hepatology
38: 238–243, 2003
Angeli P, etal : Acute effects of the oral administration of midodrine, an alpha-
adrenergic agonist, on renal hemodynamics and renal function in cirrhotic
patients with ascites. Hepatology 28: 937–943, 1998

20. TIPS
The possible mechanisms :
• reduction of portal pressure,
• suppression of hepatorenal reflex,
• improvement of the circulating volume,
• or, ?? improvement of cardiac function
• 2 studies found improved renal parameters and non significant
survival in patients
1.Guevara M, etal: Transjugular intrahepatic portosystemic shunt in
hepatorenal syndrome: Effects on renal function and vasoactive systems.
Hepatology 28: 416–422, 1998
2. Brensing KA, etal : Long term outcome after transjugular intrahepatic
portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal
syndrome: A phase II study. Gut47: 288–295, 2000

21. PROBLEMS ASSOCIATED WITH TIPS
1. the clinical, biochemical, and neurohumoral parameters, although
improved, still do not normalize after TIPS,
2. the maximum renal recovery is delayed to 2 to 4 wk after TIPS
insertion, and the renal capacity to excrete sodium still is impaired. The
cause is not clear.
3. patients with advanced cirrhosis are at risk for worsening liver failure
and/or HE.
4. TIPS has the potential for worsening the existing hyperdynamic
circulation or precipitating an underlying acute heart failure

22. RRT
RRT may be considered in :
• who are waiting for a liver transplant and did not respond to
vasoconstrictors or TIPS
• developed volume overload,
• intractable metabolic acidosis, or
• hyperkalemia,
• efficacy, safety, and best modality of RRT in HRS has not been studied
appropriately.

23. CRRT is better tolerated than intermittent hemodialysis
• by better cardiovascular stability,
• gradual correction of hyponatremia, and
• less fluctuation in intracranial pressure.
• potential advantage of removing inflammatory cytokines, TNF- ⍺ and
IL-6, implicated in the development of HRS
1. McClain CJ, etal: Cytokines in alcoholic liver disease. Semin Liver Dis 19: 205–219, 1999
2. Witzke O, etal: Which patients benefit from hemodialysis therapy in hepatorenal syndrome? J
Gastroenterol Hepatol 19: 1369–1373, 2004
3. Gonwa TA, etal : Renal replacement therapy and orthotopic liver transplantation: The role of
continuous veno-venous hemodialysis. Transplantation 71: 1424–1428, 2001

24. MARS
• The molecular adsorbent recirculating system (MARS) is a cell-free,
modified dialysis technique that is able to remove both albumin-
bound and water-soluble substances by using a combination of
albumin-enriched dialysate and CRRT .
The advantage of using MARS
• removing albumin-bound toxins (e.g., bile acids), which have a
detrimental effect on hepatocytes
• ability to remove both water-soluble cytokines (TNF-⍺ and IL-6) and
albumin-bound vasoactive agents (e.g., NO), both of which have been
implicated in the pathogenesis of HR

25. • Scant data
• Mitzner et al. showed that MARS improved clinical and biochemical
parameters as well as survival in 8 patients who had type 1 HRS and
were not candidates for TIPS insertion compared with a well-matched
group of patients who were treated with volume expansion and CRRT
• Despite improved survival, the overall survival still was low, with 7-d
survival of 37% and 30-d survival of 25%.
Mitzner SR, etal : Improvement of hepatorenal syndrome with extracorporeal
albumin dialysis MARS: Results of a prospective, randomized, controlled clinical
trial. Liver Transpl 6: 277–286, 2000

26. Liver Transplantation
• Liver transplantation remains the best treatment
• it offers a cure to both the diseased liver and the renal dysfunction.
• renal sodium excretion and hemodynamic abnormalities normalize
within 1 month
• renal resistive indices decrease to normal values during the first post-
transplantation year
• Renal function before liver transplantation is an independent
predictor of both short-term and long-term post-transplantation
patient and graft survival
Nair S, Verma S, Thuluvath PJ: Pretransplant renal function
predicts survival in patients undergoing orthotopic liver
transplantation. Hepatology 35: 1179–1185, 2002

27. • pre-transplantation treatment of HRS with vasopressin analogues
confers a slightly better 3-yr survival than those without HRS (100
versus 83%)
• After transplantation, renal failure still persists at 6 wk and is more
pronounced than those without pre-transplantation HRS
• Predictors of renal recovery included younger recipients, non-
alcoholic liver disease, and low post-transplantation bilirubin.
Restuccia T etal : Effects of treatment of hepatorenal syndrome before transplantation on
posttransplantation outcome. A case-control study. J Hepatol 40: 140–146, 2004
Marik PE, Wood K, Starzl TE: The course of type 1 hepatorenal syndrome post liver
transplantation. Nephrol Dial Transplant 25: 25,2005

28. Prognosis
• Untreated type 1 HRS carries a grim prognosis: Mortality is as high as
80% in 2 wk, and only 10% of patients survive 3 months
• The prognosis is particularly poor in patients with apparent
precipitating factors.
• type 2 HRS have a much better median survival, approximately 6 mo .
• severity of liver disease- patients with Child-Pugh class C disease
have a worse outcome .
• MELD score was an independent predictor of death from HRS -
median survival of patients with a MELD score of > 20 being only 1
month Vs.8 months , with a MELD score < 20
Alessandria C, et al: MELD score and clinical type predict prognosis
in hepatorenal syndrome: Relevance to liver transplantation.
Hepatology 41: 1282– 1289, 2005

29. Survival probabilityin HRS

30. Prevention of HRS
• Ascites : Albumin supplementation during paracentesis
• SBP – Norfloxacin as prophylaxis for primary SBP
• severe acute alcoholic hepatitis – oral pentoxiphylline
Arroyo etal, NEJM 1999; 341,407
Akriviadis E et al, Gastroenterology, 2000

31. THANK YOU !!