Hepatorenal Syndrome

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Dr Wong KW …

Dr Wong KW
Sabah
Malaysia

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  • Patients with cirrhosis and ascites often develop a particular form of renal failure known as hepatorenal syndrome (HRS), which is due to a vasoconstriction of the renal circulation (1). The histologic appearance of the kidneys in HRS is normal, and the kidneys regain a normal or near-normal function after liver transplantation. Both findings demonstrate the functional nature of HRS. Besides changes in renal function, patients with HRS also show marked abnormalities in the systemic arterial circulation and activity of endogenous vasoactive systems, which probably play a major role in the development of renal hypoperfusion.

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  • 1. Hepatorenal Syndrome Wong KW
  • 2. Historical notes
    • Frerichs and Flint - two separate reports - 1863
      • development of oliguria in patients with chronic liver disease in the absence of proteinuria and with a normal renal histology
      • proposed the first pathophysiologic interpretation of HRS by linking the abnormalities of renal function to the disturbances present in the systemic circulation
  • 3. Historical notes
    • Hecker, Sherlock, Papper, and Vessin (1950’s)
      • emphasized the functional nature of renal failure, the coexistence of abnormalities in the systemic circulation, and the poor prognosis of the syndrome
      • Studies which showed kidneys from patients with HRS functioned normally after transplanted into patients with CRF
      • Renal failure rapidly reversed after OLT
  • 4. Historical notes
    • Epstein (1970’s) demonstrated renal failure in HRS
      • Extreme vasoconstriction of the renal circulation
  • 5. Pseudohepatorenal syndrome
    • Conn (1973) described
      • Concurrent hepatic and renal dysfunction secondary to
        • Infectious,
        • Systemic,
        • Circulatory,
        • Genetic,
        • After administration of drugs and toxins
      • Liver does not play the etiological role here
  • 6. Definition
    • “ Hepatorenal syndrome is a clinical condition that occurs in patients with chronic liver disease, advanced hepatic failure, and portal hypertension characterized by impaired renal function and marked abnormalities in the arterial circulation and activity of the endogenous vasoactive systems. In the kidney there is marked renal vasoconstriction that results in a low GFR, whereas in the extrarenal circulation there is predominance of arterial vasodilation, which results in reduction of total systemic vascular resistance and arterial hypotension.”
            • Arroyo V, Gine`s P, et al: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. Hepatology 23: 164–176, 1996
  • 7. Definition
    • Type 1: rapid spontaneous deterioration in renal function defined as doubling of creatinine to a level >221umol/l, or a >50% reduction of the baseline creatinine clearance
    • Type 2: insidious onset and slowly progressive deterioration in renal function
  • 8. Pathogenesis
    • Liver failure  portal hypertension   levels of circulating and vascular vasodilators
    • Systemic and splanchnic vasodilatation  low MAP  renal hypoperfusion
    • Stimulation of renal SNS and RAAS - by  EABV with stimulation of the central volume receptors,
    • Renal vasoconstriction  renal cortical hypoperfusion   GFR
    • Break down of balance between the renal vasoconstrictors and intrarenal vasodilators
  • 9. Pathogenesis Proposed pathogenesis of hepatorenal syndrome in cirrhosis according to the arterial vasodilation theory
  • 10. Pathogenesis
  • 11. Vasodilatation
    • Mechanism unknown
    • Presence of circulating vasodilator(s) due to cirrhosis
    • Glucagon, VIP, substance P, prostacyclin, and PAF been all studied
    • Nitric oxide -
      • NO syntase increased in cirrhotic rats with ascites
      • NO2/NO3 levels: control<cirrhosis<cirrhosis with ascites<HRS
      • Inhibition of NO synthesis in cirrhotic rats -  arterial pressure and SVR,  in CI, and reverses the impaired pressor response
  • 12. Pathogenesis
  • 13. Adaptive response to  EABV
    • Increases in levels of circulating vasoconstrictors
      • Arginine-vasopressin,
      • Hormones of RAAS
      • Noradrenaline
  • 14. Pathogenesis
  • 15. Cardiac dysfunction
    • Ruiz-del-Arbol et al. demonstrated reduction in CO at time of diagnosis of SBP in patients with cirrhosis and subsequently developed HRS
    • CO further  after resolution of infection in HRS group
            • Ruiz del Arbol et al. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with SBP. Hepatology 38: 1210-1218, 2003
  • 16. Cardiac dysfunction
    • 66 patients with cirrhosis and tense ascites - normal serum creatinine at baseline
    • 27 patients subsequently developed HRS
    • At baseline - arterial BP and CO significantly lower, RAAS and SNS activity significantly higher in HRS group
    • CO further decrease at onset of renal dysfunction
    • Suggest that  in CO or its cause in HRS occurrence
            • Ruiz del Arbol et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 42: 439-447, 2005
  • 17. Pathogenesis
    • The hallmark of HRS is intense renal vasoconstriction that starts at an early time point and progresses with worsening of the liver disease
    • Xenon washout and selective arteriography - significant reduction in calculated RBF and preferential reduction in cortical blood flow
            • Epstein et al (Am J Med 1970;49:170)
    • Postmortem angiography showed normalization and reversal of the vascular abnormalities of the kidneys
  • 18. Renal vasoconstriction
    • Major mediators:
      • RAAS 
      • Increased SNS activity 
      • Imbalance in renal eicosanoids: the vasodilating prostaglandins and the vasoconstricting thromboxanes
      • Increased endothelin
  • 19. Vasoactive factors
  • 20. Renal vasoconstriction
    • Urinary excretion of prostaglandin higher in patients with cirrhosis and ascites compared to normal, with subsequent decline in patients developing HRS
      • Rimola et al. J Hepatol 3: 111-117, 1986
      • Laffi et al. Gastroenterology 90:274-282, 1979
    • Administration of COX inhibitors - to patients with cirrhosis and ascites - precipitate to development of syndrome indistinguishable to HRS
      • Boyer et al. Gastroenterology 77:215-222, 1979
    • Immunohistochemical studies - reduced COX staining in renal medullary tissues
      • Govindarajan S, et al. Hepatology 7:654-659, 1987
  • 21. Endothelin
    • Endothelin infusions increase renal vascular resistance
    • Plasma ET levels higher in cirrhotics both with and without ascites compared to controls
    • Plasma ET levels 2x higher in patients with endotoxemia
    • Endotoxin stimulates synthesis
  • 22. Precipitating factors
    • Type 1 - a precipitating event identified in 70-100% of patients
    • Bacterial infections, large volume paracentesis without albumin infusions, GI bleed, and acute alcoholic hepatitis
    • Type 2, and some patients with type 1 - a precipitating event not identified
  • 23. Precipitating factors
  • 24. Incidence
    • Gines et al -
      • 1-year probability of HRS in cirrhotic patients 18%
      • 5-year probability 39%
        • Gastroenterology 105: 229-236, 1993
    • Moreau et al - retrospective, multicentre study of 423 patients with cirrhosis and ARF
      • ATN (35%), prerenal (32%), Type 1 HRS (20%), Type 2 HRS (6.6%)
          • Gastroenterology 122: 923-930, 2002
  • 25. Predicting factors
    • Doppler ultrasound with early detection of vasoconstriction predicts development of HRS in cirrhosis
    • Platt et al - on patients with cirrhosis with normal renal function
      • HRS developed in 26% of those with elevated resistive indices, 1% in those with normal indices
        • Platt et al. Hepatology 20: 362-369, 1994
  • 26. Predicting factors
    • Dilutional hyponatremia, low urinary Na, reduced plasma osmolality, low arterial BP
    • On multivariate analysis - 3 independent predictors:
      • Hyponatremia (<133mmol/l)
      • High renin activity
      • Absence of hepatomegaly
          • Gines A et al. Gastroenterology 105:229-236, 1993
  • 27. Diagnosis
    • Out of exclusion
    • Should be based on IAC criteria
    • Document a reduced GFR (<40ml/min), and rule out other causes of ARF
    • Exclude concurrent bacterial infection
    • Watt et al showed that only 59% of ARF in cirrhosis had HRS
        • Am J Gastroenterol. 97:2046-2050, 2002
  • 28. Exclusion
    • Infections: sepsis, leptospirosis
    • Toxins: Paracetamol, tetracycline
    • Circulatory: CHF, shock
    • Neoplasms: metastatic
    • Connective tissue disease: SLE, PAN
    • Amyloidosis
  • 29.  
  • 30. International Ascites Club
  • 31. General measures
    • Type 1 - admit
    • CVP to guide intravascular volume and fluid/albumin infusion
    • Stop diuretics
    • Paracentesis for tense ascites
    • Low salt, restrict fluid if hyponatremia
    • Rule out other causes of ARF
    • Rule out SBP
    • Realistic assessment of patient’s prognosis
    • Aggressive management for those awaiting liver transplantation or undergoing evaluation to determine candidacy for transplantation
  • 32. Therapeutic options RRT
  • 33. Pharmacological
    • Renal vasodilators - low dose dopamine, fenoldopam, prostaglandins, endothelin antagonist - none of the studies showed improvement in renal perfusion or GFR
    • Systemic vasoconstrictors - on the assumption that interrupting the splanchnic vasodilatation will relieve the intense renal vasoconstriction
      • Vasopressin analog, somatostatin analog, alpha adrenergic agonists
  • 34. Vasopressin analogues
    • Vasoconstrictor effect thought action on V1 receptor in the arterial smooth muscle wall
    • Used extensively in acute variceal bleeding in patients with cirrhosis and portal hypertension
    • Ornipressin with volume expansion or low dose dopamine shown to improve renal function and GFR
      • Ischemic adverse effects in up to 30% of patients
  • 35. Terlipressin
    • Terlipressin and albumin infusion - significant improvement in GFR, increase in arterial pressure, near normalization of neurohumeral level and reduction of creatinine in 42 - 77% of cases
    • Non-responders had more severe cirrhosis
    • 50% recurrence rate
    • Questions:
      • is it due to volume expansion?
      • Optimal duration of treatment?
  • 36. Other combinations
    • Octreotide(somotostatin) and midodrine with albumin infusion - growing data suggest the combination may be highly effective and safe
      • 13 patients with HRS
      • 5 given octreotide (100-200ug SC tid) and midodrine (7.5-12.5mg tid), 8 given dopamine
      • Both groups received iv albumin, similar clinical characteristics
      • Combined therapy - 2 died
      • 7 out of 8 in dopamine group died
      • Improvement in renal function observed in the combined therapy group
  • 37. Transjugular intrahepatic portosystemic shunt
    • Treatment of refractory ascites
    • Guevara et al - TIPS inserted in 7 patients with type 1 HRS
      • Renal function improved in 6 patients
      • Significant reduction in serum creatinine and increase in urine volume
      • Significant rise in GFR and RBF
      • 30d survival achieved in 5 patients
            • Guevara et al. Hepatology 28:416-422, 1998
    • Brensing et al - TIPS on 31 patients with no transplant option
      • Survival at 10 weeks - 53%
      • Dialysis discontinued in 4 out of 7 dialysis dependent patients
            • Gut 47: 288-295, 2000
  • 38. TIPS
    • A few unanswered questions:
      • Biochemical, neurohumeral parameters improved but not normalized
      • Maximum renal recovery delayed for 2 - 4 weeks, and renal sodium excretion still impaired
      • Those with advanced cirrhosis at risk of decompensation/encephalopathy not candidates for TIPS
      • Potential for worsening existing hyperdynamic circulation or precipitating an underlying acute heart failure
      • Combinations - midodrine + octreotide + TIPS, Terlipressin + TIPS
  • 39. RRT
    • Most literature supports the view that HD is ineffective in HRS
    • Morbidity and mortality not improved
    • May be useful in acute fulminant hepatitis
    • For those waiting for liver transplantation -
      • Failure to respond to vasoconstritors and TIPS
      • With volume overload, hyperkalemia, intractable metabolic acidosis
        • RRT as a bridge to liver transplantation
  • 40. Which modality?
    • Davenport et al and Detry et al - demonstrated CRRT better tolerated than intermittent HD
      • Better cardiovascular stability
      • Gradual correction of hyponatremia
      • Less fluctuation of ICP
      • Potential advantage of removing inflammatory cytokines
            • Davenport et al. Kidney Int Suppl 41: S245-251 1993
            • Davenport et al. Crit Care Med 21: 328-338 1993
            • Detry et al. Transplantation 67: 767-770 1999
  • 41. CRRT Vs HD
    • Witzke et al
      • 30 patients waiting for liver transplant
      • CRRT for those ventilated, HD for those not ventilated
      • 8 patients survived in the HD group at 30 days, none in CRRT
      • 3 survived at one year - all received liver transplantation, none needed post transplant HD
            • Witzke et al Which patients benefit from hemodialysis therapy in hepatorenal syndrome? J Gastroenterol Hepatol19:1369-1373, 2004
  • 42. MARS
    • Molecular Absorbent Recirculation System
      • Cell-free, modified dialysis technique to remove albumin-bound and water soluble substances using a combination of albumin rich dialysate and CRRT
      • Removing albumin-bound toxins which may have detrimental effects on hepatocytes and other organs
      • Removing water soluble cytokines and albumin bound vasoactive agents
  • 43. MARS
    • Mitzner et al -
      • 8 patients with type 1 HRS, not candidates for TIPS, compared with a well matched group treated with volume expansion and CRRT
      • MARS group - mean survival 25d
      • Control group - mean survival 4.6d
            • Liver Transpl 6:277-286, 2000
    • Another retrospective study
      • 8 patients - type 1 HRS with alcoholic hepatitis
      • Treated with MARS - improvement in urine volume, MAP, encephalopathy grade, Child score
      • 5 survived > 12 months, one received transplant
            • Mitzner et al. Ther Apher 5:417-422, 2001
    • Both studies - 5 - 6 MARS treatments
  • 44. Liver transplantation
    • Best treatment for suitable candidates with HRS
    • Post transplant - renal Na excretion and hemodynamic abnormalities normalize within 1 mo
    • Renal function before liver transplantation is an independent predictor of both short and long term posttransplant patient and graft survival
    • Post transplant - patients with HRS - sicker, longer hospitalizations, prolonged ICU stay, more dialysis treatment
  • 45. Liver transplantation
    • Post transplant renal recovery
      • Gonwa et al Transplantation 59:361-365, 1995
        • 7% with HRS developed ESRD vs 2% without HRS
      • Marik et al NDT 25:25, 2005
        • Post transplant reversal of HRS only 58%
        • Predictors of renal recovery: young recipients, nonalcoholic liver disease, low posttransplant bilirubin level
      • Combined LKT - ?in patients with prolonged RRT, history of previous renal failure, renal biopsy findings
  • 46. Prognosis
    • Untreated - 80% mortality in 2 weeks, 10% survived > 3mo
    • Particularly poor in those with apparent precipitating factors
    • Type 2 better median survival - approx 6 mo
    • Child C worse than Child B
    • MELD score - independent predictor of death from HRS
      • Score >20 median survival 1 mo
      • Score <20 - 8 mo (p<0.001)
            • Alessandria et al Hepatology 41:1282-1289, 2005
  • 47. Summary
    • HRS - a functional cause of acute renal failure - up to 38% of patients with advanced liver disease
    • If untreated - 100% mortality
    • A hyperdynamic circulation, peripheral vasodilatation and renal vasoconstriction essential to the pathogenesis of HRS
    • Diagnosis must be one of exclusion
    • Orthotopic liver transplant only long term therapy
    • Medical therapy, TIPS and RRT important interventions for those waiting transplant