Liver transplantation for dialysis dependent hepatorenal failure

Donald Richardson1, John Stoves1, Mervyn H. Davies2 and Alex M. Davison1

1 Departments of Renal Medicine and 2 Hepatology, St. James's University Hospital, Beckett Street, Leeds, UK

Correspondence and offprint requests to: D. Richardson, Department of Renal Medicine, St. James's University Hospital, Beckett Street, Leeds LS9 7TF, UK.

Introduction

Hepatorenal failure (HRS) complicating hepatic cirrhosis (frequently alcoholic), acute hepatitis, fulminant hepatic failure or hepatic malignancy is associated with a high mortality [1,2] (mean survival <2 weeks), is of uncertain pathogenesis, and no specific therapy is of proven effect. HRS remains a diagnosis of exclusion and treatment is supportive, awaiting either recovery of hepatic function, or in the case of irreversible liver disease, liver transplantation. We discuss these points taking as an example the case of HRS complicating alcoholic cirrhosis that demonstrates the success of supportive care (including continuous venovenous haemodiafiltration) followed by liver transplantation.

Case history

A 39-year-old male patient with alcoholic cirrhosis developed increasing jaundice 3 weeks after alcohol withdrawal. A weekly alcohol consumption of up to 60 units/week had been sustained for over 20 years. He was admitted to hospital with confusion and back pain. On examination there was jaundice, ascites, hepatomegaly, oedema, widespread stigmata of chronic liver disease (spider naevi, palmar erythema, gynaecomastia, testicular atrophy, and cushingoid appearance) and grade 1 encephalopathy (Table 1Go). Chest X-ray revealed a right-sided pneumonia and a raised right hemidiaphragm. Blood investigations on admission follow: Na 126 mmol/l, K 3.3 mmol/l, HCO3 10 mmol/l, urea 7.9 mmol/l, creatinine 312 µmol/l, albumin 25 g/dl, alkaline phosphatase 344 IU/l, AST 180 IU/l, ALT 68 IU/l, bilirubin 368 µmol/l, glucose 3.3 mmol/l, Hb 14.8 g/dl, WCC 17.6x109/l (neutrophils 15.3), platelets 160x109/l, PT 23.4 s, APTT 68 s, fibrinogen 1.1 g/l. Urine [Na]<10 mmol/l. A screen for paracetamol and salicylates was negative. There was no blood or protein on dipstick testing of urine. An ascitic tap showed a raised leucocyte count of 2160x106/l (normal <250x106/l) and a negative Gram stain. Blood and ascites cultured Streptococcus pneumoniae. Ultrasound showed a bright shrunken liver (compatible with cirrhosis), normal kidneys and gross ascites.


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Table 1. Stages of encephalopathy
 
A long-line was inserted and a central venous pressure of 19 mmHg recorded. Intravenous benzylpenicillin and N-acetylcysteine were commenced. The patient became increasingly hypoxic and confused and required continuous positive airway pressure ventilation. Urine output decreased to 15 ml/h with consequent increase in blood urea and creatinine. He was transferred to the intensive care unit. A paracentesis was undertaken and continuous venovenous haemodiafiltration was performed. Once his clinical status was stabilized he was transferred to the regional liver unit (Table 2Go) for assessment for liver transplantation (Table 3Go).


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Table 2. Indications for transfer of patients with liver failure to a transplant unit
 

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Table 3. Indications and contra-indications for liver transplantation
 
Intravenous salt-poor albumin solution 20% was given to maintain intravascular volume. An infusion of N-acetylcysteine and prophylactic fluconazole was commenced while awaiting urgent liver transplantation. Fluid removal on dialysis enabled continued nasogastric feeding.

Liver transplantation was performed within 48-h of transfer. The post-operative course was complicated by an initial deterioration in liver function tests. An hepatic arteriogram showed a filling defect in the right hepatic artery suggestive of non-occlusive thrombosis. Septicaemia secondary to an enterococcus further delayed recovery of renal function. Twelve days post-liver transplant urine output increased and dialysis support was discontinued on day 13. Renal function has continued to improve to a creatinine of 130 µmol/l at 1-year post-transplant.

Discussion

Aetiology
The liver and the kidneys are intricately involved in homeostasis and systemic conditions can affect and impair the function of both organs. Primary renal conditions have secondary effects on the liver and primary hepatic conditions can secondarily affect renal function. Simultaneous hepatic and renal failure may occur in many conditions (Table 4Go). In chronic hepatic failure, poor glomerular filtration rates have often been present for some time even though the serum creatinine may have been normal days before the onset of acute renal failure. Jaundiced patients and those with synthetic liver failure (low albumin) in whom jaundice may not be a feature (alpha 1 anti-trypsin deficiency, Budd-Chiari disease, the abstaining patient with alcoholic liver disease, end-stage burnt out chronic active hepatitis or viral-induced cirrhosis) are particularly susceptible to additional insults (Table 5Go). HRS is a functional problem and pathological abnormalities on microscopy are minimal and inconsistent [3]. Sodium reabsorption and concentrating function are relatively unimpaired as demonstrated by the low urine sodium in this case. The potential for recovery of renal function is supported by reports that renal allografts from donors with HRS can restore normal renal function [4]. In addition renal function is capable of returning to normal when the liver failure is successfully treated by liver transplantation [5]. Although the pathogenesis is poorly understood the major effect appears to be one of a reduction in renal perfusion [6,7]. Renal vasoconstriction is the likely functional basis of the renal failure though through as yet unknown mediators. Systemic haemodynamic changes in decompensated cirrhosis probably lead to a gradual reduction in the effective blood volume, thereby promoting compensatory activation of endogenous vasoactive systems including the renin-angiotensin system and the sympathetic nervous system with reduction in both renal perfusion and filtration fraction [8].


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Table 4. Causes of simultaneous hepatic and renal failure
 

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Table 5. Precipitants of renal failure in liver failure
 
Diagnosis
HRS is a diagnosis of exclusion made in the absence of clinical, laboratory or radiological evidence of other causes of renal failure in patients with liver disease.

Treatment
Vasopressin analogue (Ornipressin [9], Terlipressin [10]) therapy with volume expansion and transjugular intrahepatic portosystemic anastamosis [11] may be effective in reversing some of the haemodynamic changes that are seen in HRS although side-effects may occur. N-acetylcysteine has also been shown to be beneficial in small numbers of patients [12]. There is however no reproducibly effective long-term treatment for the hepatorenal syndrome other than successful treatment of the underlying liver disease. Prevention of precipitant events of renal failure is paramount. Sepsis should be actively sought and treated. Nephrotoxic drugs should be avoided. Angiotensin converting enzyme inhibitors and beta-blockers can inhibit the renin–angiotensin axis with a resultant decrease in mean arterial pressure and renal perfusion. Diuretics for the treatment of oedema and ascites, or lactulose used to limit protein absorption from the gut (and decrease hepatic encephalopathy) can induce profound hypovolaemia. Paracentesis can relieve inferior venocaval obstruction by decreasing intra-abdominal pressure, though reduction of intravascular volume must be avoided by simultaneous replacement of plasma expanders. Once correctable lesions are excluded and a therapeutic trial of volume expanders has been tried without success, careful restriction of salt and fluid intake should be undertaken to avoid pulmonary oedema. Supportive management and dialysis are the mainstay of therapy. Dialysis should be undertaken in selected patients with potentially reversible acute liver failure or those suitable for liver transplantation (Table 6Go). Indications for dialysis are listed in Table 7Go. Continuous haemodiafiltration produces less haemodynamic instability than intermittent dialysis [13]. Dialysis catheters should be inserted into vessels other than the right internal jugular and right femoral vein if possible. These vessels will be required for cannulation when going onto bypass at the time of liver transplantation. Anticoagulants for the dialysis circuit may initially be unnecessary or inadvisable because of the risk of bleeding. Prostacyclin [14] decreases platelet activation and decreases clotting within the filter but vasodilatation can cause hypotension. Use of low molecular weight heparin (Fragmin [15]) or heparin is usually deferred until the risk of bleeding has receded. Cerebral perfusion may be compromised in patients with HRS and the measurement of cerebral perfusion pressure using intra cranial pressure monitors in patients with fulminant hepatic failure (i.e. at higher risk of cerebral oedema) is recommended prior to the commencement of haemodialysis in ventilated (unconscious) patients. Cerebral perfusion can be optimised by nursing the patient in the supine position with the head no more than 20 degrees above horizontal [16]. The monitored use of inotropic drugs with measurement of cardiac output and systemic vascular resistance is often necessary in this patient group to maintain mean arterial pressure and cerebral perfusion pressure (minimum 50 mmHg).


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Table 6. Relative contra-indications to liver transplantation
 

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Table 7. Indications for haemodialysis
 
The management of combined hepatic and renal failure is relatively uncommon but is a medical emergency with a high mortality. Full supportive care should be offered to those carefully selected patients with irreversible liver failure in whom transplantation is an option and to those patients whose liver failure is acute/sub-acute and may recover. The development of dialysis-dependent renal failure in alcohol-related liver failure is a grave prognostic sign particularly in those requiring ventilatory support [17] (Table 8Go), but in carefully selected patients liver transplantation offers a viable treatment option.


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Table 8. Outcome in multi-organ failure (with hepatic failure as primary diagnosis). Adapted from [17]
 
Salient points

  1. HRS is a diagnosis of exclusion.
  2. Precipitants of renal failure should be avoided where possible.
  3. Sepsis should be sought meticulously and treated early.
  4. Management is supportive while awaiting recovery of renal function in reversible liver failure or transplantation in terminal liver failure.
  5. Continuous venovenous haemodialysis/haemodiafiltration is preferable to intermittent treatment modalities.
  6. Liver transplantation is currently the only successful treatment option for those who develop dialysis dependent renal failure secondary to alcohol related liver failure.

References

  1. Shear L, Klinerman J, Gabuzda GJ. Renal failure in patients with cirrhosis of the liver. 1. Clinical and pathological characteristics. Am J Med 1965; 39: 184–189[ISI][Medline]
  2. Epstein M. The hepatorenal syndrome: emerging perspectives of pathophysiology and therapy. J Am Soc Nephrol 1994; 4: 1735–1753[Abstract]
  3. Shear L, Ching S, Gabuzda GJ. Compartmentalisation of ascites and edema in patients with hepatic cirrhosis. N Engl J Med 1970; 282: 1391–1396[ISI][Medline]
  4. Koppel L, Coburn JW, Mims MM et al. Transplantation of cadaveric kidneys from patients with hepatorenal syndrome; evidence for the functional nature of renal failure in advanced liver disease. N Engl J Med 1969; 280: 1367–1371[ISI][Medline]
  5. Iwatsuki S, Popovtzer MM, Corma JL et al. Recovery from hepatorenal syndrome after orthoptic liver transplantation. N Engl J Med 1973; 289: 1155–1159[Medline]
  6. Epstein M, Berk DP, Hollender JNK et al. Renal failure in patients with cirrhosis: the role of active vasoconstriction. Am J Med 1970; 49: 175–185[ISI][Medline]
  7. Kew MC et al. Renal and intrarenal blood flow in cirrhosis of the liver. Lancet 1971; 2: 504–510[ISI][Medline]
  8. Moore K. The hepatorenal syndrome. Clin Sci 1997; 92: 433–443[ISI][Medline]
  9. Guevara M, Gines P, Fernandez-Esparrach G et al. Reversibility of hepatorenal syndrome by prolonged administration of ornipressin and plasma volume expansion. Hepatology 1998; 27: 35–41[ISI][Medline]
  10. Hadengue A, Gadano A, Moreau R et al. Beneficial effects of the 2 day administration of terlipressin in patients with cirrhosis and hepatorenal syndrome. J Hepatol 1998; 29: 565–570[ISI][Medline]
  11. Guevara M, Gines P, Bandi JC et al. Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome; effects on renal function and vasoactive system. Hepatology 1998; 28: 590–592[ISI][Medline]
  12. Holt S, Goodier D, Marley R et al. Improvement in renal function in hepatorenal syndrome with N-acetylcysteine. Lancet 1999; 353: 294–295[ISI][Medline]
  13. Davenport A, Will EJ, Davison AM. Effective renal replacement therapy in patients with combined acute renal and fulminant hepatic failure. Kidney Int 1993; 43 [Suppl]: S245–251[ISI]
  14. Davenport A, Will EJ, Davison AM. Comparison of the use of standard heparin and prostacyclin anticoagulation in spontaneous and pump driven extra-corporeal circuits in patients with acute renal and hepatorenal failure. Nephron 1994; 66: 431–437[ISI][Medline]
  15. Jeffrey RF, Khan RA, Douglas JT, Will EJ, Davison AM. Anticoagulation with low molecular weight heparin (Fragmin) during continuous haemodialysis in the intensive care unit. Artif Organs 1993; 17: 717–720[ISI][Medline]
  16. Davenport A, Will EJ, Davison AM. Effect of posture on intracranial pressure and cerebral perfusion pressure in patients with fulminant hepatic and renal failure after acetominophen self-poisoning. Crit Care Med 1990; 18: 286–287[ISI][Medline]
  17. Jones CH, Richardson D, Goutcher E et al. Continuous venovenous high-flux dialysis in multiorgan failure: a 5-year single center experience. Am J Kidney Dis 1998; 31: 227–233[ISI][Medline]




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