Hepatorenal Syndrome

Hepatorenal syndrome (HRS), a form of renal failure thought to be due to extreme vasoconstriction of renal circulation in patients with advanced liver disease, has confounded physicians for over a century. The International Ascites Club [1] defined HRS in 1994 as "a condition that occurs in patients with chronic liver disease, advanced hepatic failure, and portal hypertension characterized by impaired renal function and marked abnormalities in arterial circulation and activity of 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 hypertension". Of note is the fact that this condition may also develop in acute liver failure as in viral or alcoholic hepatitis. The diagnosis is currently made on a set of criteria aimed at demonstrating a low GFR and excluding other causes of renal failure.

Diagnostic criteria

Major criteria

1. 1. low glomerular filtration rate, as indicated by serum creatinine >1.5 mg/dl or 24-h creatinine clearance <40 ml/min.
2. absence of shock, ongoing bacterial infection, fluid loss, and current treatment with nephrotoxic drugs.
3. no sustained improvement in renal function (decrease in serum creatinine to 1.5 mg/dl or less or increase in creatinine clearance to 40 ml/min or more) following diuretic withdrawal and expansion of plasma volume with 1.5 L of a plasma expander.
4. proteinuria <500 mg/d and no ultrasonographic evidence of obstructive uropathy or parenchymal renal disease.
   

Additional criteria

1. 1. urine volume <500 ml/d.
2. urine sodium <10 mEq/L.
3. urine osmolality greater than plasma osmolality.
4. urine red blood cells <50 per high power field.
5. serum sodium concentration <130 mEq/L.
   

All major criteria must be present for the diagnosis of hepatorenal syndrome. Additional criteria are not necessary for the diagnosis, but provide supportive evidence.
HRS has been classified into two forms: Type I requires demonstration of doubling of serum creatinine to over 2.5 mg/dl or a 50% decline of creatinine clearance to less than 20 ml/min in a period of less than 2 weeks, whereas the renal failure is less severe in type II and the rate of decline of GFR does not meet the criteria proposed for type I. A severe decline in urine output is prominent in type I, but the creatinine values are usually lower and severe hyperkalemia, metabolic acidosis and pulmonary edema less frequent than with other causes of ARF without liver disease. Nonoliguric forms of this syndrome have also been described. Associated findings include a high cardiac output, low arterial pressure (MAP ~60-80 mm of Hg). The chief hemodynamic abnormality is a reduction in total systemic vascular resistance, almost exclusively due to dilation of the splanchnic circulation. The body tries to reverse this by compensatory stimulation of vasoconstrictor systems like the renin-angiotensin system and sympathetic nervous system. This leads to extreme vasoconstriction in organs that do not show initial vasodilation such as the renal bed and the limbs and cerebral circulation to a lesser degree. The role of portal hypertension was suggested by the observation that lowering of portal pressure by side-to-side portasystemic shunting reversed HRS. The mechanism, however, remains unclear.

No effective therapeutic modality is available for this condition associated with a 15% 2-week survival. Since the kidney is anatomically normal and the functional abnormalities are secondary to liver disease, liver transplant is the ideal treatment. The waiting times for transplant, however, are long and a significant proportion die before getting one. The point to note is that HRS is frequently encountered in association with acute liver disease such as viral hepatitis in developing countries. Both liver and kidney failure are potentially reversible in such a situation, and in any case, liver transplantation is not an option here. In view of these issues, availability of some pharmacologic therapy that ameliorates renal failure or reduces its severity giving time for recovery from liver failure to those with acute hepatitis or until a cadaver organ becomes available for those with cirrhosis could mean a difference between life and death. The logical therapeutic approach would aim to reverse the dilation of splanchnic circulation and renal vasoconstriction. Another approach would be reduction in the portal pressure.

Splanchnic circulation has a profusion of vasopressin-1 receptors. Ornipressin, a vasopressin-1 receptor antagonist, has been shown to increase systemic vascular resistance, GFR and renal plasma flow in cirrhotics, has a weaker antidiuretic activity than vasopressin, and case reports indicated its therapeutic potential in HRS. Gulberg et al [2] studied 7 cirrhotics with type I HRS (creatinine clearance 15+1 ml/min, urinary sodium excretion 7+2 mmol/day) after IV albumin and low-dose dopamine had failed to halt progressive renal functional deterioration. Ornipressin was given in continuous IV infusion (6 IU/hr) along with dopamine (2-3 mg/kg/min) until creatinine clearance had increased to over 40 ml/min or side effects appeared. HRS was reversed (creatinine clearance 51+4 ml/min) in 4 after 4-27 days of treatment, 2 failed to respond (creatinine clearance 19+10 ml/min) and treatment was stopped in 1 because of intestinal ischemia. 2 of the responders had second episodes of HRS. Both were treated again: one responded after 18 days whereas the other developed ventricular tachycardia. Of the 4 initial responders, 3 died of liver failure whereas the fourth underwent liver transplantation and was alive. One of the non-responders was transplanted but failed to recover renal function and the other died of HRS. A significant elevation in the mean arterial pressure and natriuresis were noted amongst the responders. Also, improvement in GFR was positively correlated to the duration of therapy.

Angeli et al [3] took a different approach to correct the same hemodynamic abnormalities. They noted that midodrine, a ðað-adrenergic agonist, improved systemic hemodynamics and renal perfusion in cirrhotics with ascites and normal renal function but not in those with HRS. This reduced response to vasoconstrictors is thought to be due to increased level of vasodilators of both endothelial (e.g. prostacyclin, nitric oxide) and non-endothelial (e.g. glucagon) origin. Endothelial vasodilators are important in maintenance of renal perfusion and interference with their action can further worsen renal failure. The authors therefore reasoned that midodrine should work in these cases when given in combination with inhibitor of glucagon release such as somatostatin or octreotide. Somatostatin also has adverse renal hemodynamic effect, leaving octreotide as potentially most useful agent in this situation. Five patients received midodrine-octreotide combination for 20 days along with 50-100 ml of 20% albumin/day. Octreotide was given subcutaneous at 100 mg and midodrine at 7.5 mg PO, both thrice a day. The doses were increased to 200 mg and 12.5 mg thrice a day if necessary and were titrated to obtain an increase in mean BP of at least 15 mm of Hg. Control group (n=8) received dopamine 2-4 mg/kg/day for the same duration. Both groups were well matched in terms of demographic parameters, liver and renal function. In the control group, 4 died in the first week and another 3 in the next 5 days. The remaining patient survived the study. The treatment group showed a significant decrease in heart rate, plasma renin activity, aldosterone, ADH and glucagon along with increase in RPF, GFR and urinary sodium excretion over the study period. Renal function improved in every patient. Treatment was continued for after completion of the study and the renal function continued to be good as long as this was done. The side effects noted were tingling and goose bumps in 2 and diarrhea in 1, but did not require discontinuation of treatment. The authors showed evidence of subclinical tubular injury as evidenced by elevated excretion of renal tubular enzymes g-glulamyltranspeptidase, a-glucosidase and lysozyme in the urine at day 5. The levels increased further at day 10 in the control group whereas they fell and came back to normal by day 20 in the treatment group. The tubular injury is likely due to the vasoconstriction and if untreated, can manifest as frank ATN. Interestingly, the treatment group also showed a parallel decrease in nitric oxide. As none of the drugs used has an effect on nitric oxide release or stability, the authors postulate that the decline was secondary to correction of the hyperdynamic circulation and therefore the shear stress on the endothelium.

Transjugular intrahepatic portasystemic shunting (TIPS) was introduced in the early 1990s for treatment of bleeding varices, and later was found to be effective for management of other complications of portal hypertension including diuretic-resistant ascites. First publications on the acute beneficial effects of TIPS for HRS appeared in 1993. Subsequently, several workers confirmed this effect in small number of cases. In one representative study, Guevera et al [4] studied 7 cases with HRS and showed a significant improvement in renal function (as measured by serum creatinine, GFR and renal plasma flow) at 30 days after TIPS. These changes were associated with a significant fall in plasma renin activity and aldosterone and norepinephrin, but not endothelin levels. The urinary sodium, however, did not increase significantly. The mean survival after TIPS was 4.7 months, with 2 patients surviving beyond 6 months. Of note, renal function did not improve in the 2 cases whose portal pressure gradient did dot decrease below 12 mm of Hg.

Brensig et al [5] recently reported the long-term results of non-surgical management of 41 patients with advanced cirrhosis and HRS who were excluded from liver transplantation. Of these, 31 (type I: 14, type II: 17) were eligible for TIPS, and the rest were excluded because of advanced liver failure (serum bilirubin> 15, Child-Pugh score>12 or severe encephalopathy). Patients received a therapeutic paracentasis and IV albumin infusion (8 g/L ascites volume) a day before TIPS. A marked reduction in portal pressure gradient from 21+5 to 13+4 mm of Hg was noted, and was followed by improvement in renal function (creatinine clearance 18+15 to 48+42 ml/min and sodium excretion 9+16 to 77+78 mmol/24 hours) within 2 weeks. Four out of 7 patients could be taken off dialysis. The renal function continued to deteriorate in the non-TIPS group. The 3,6,12 and 18 month survival rates were 81%, 71%, 48% and 35% in the TIPS and 63%, 56%, 39% and 29% in non-TIPS groups respectively. Survival in the 25% TIPS patients who did not respond was similar to the non-TIPS group. 83% of deaths following TIPS were due to progressive liver failure. Survival was better in those with lower bilirubin levels, type II HRS and whose ascites was mobilized within one month following TIPS. The first two were shown to predict survival independently on Cox regression analysis. Measurement of vasoactive mediators showed a significant decline in systemic and portal plasma renin activity and active renin levels. In contrast, the endothelin levels fell significantly in the portal but not in the systemic circulation. The authors attribute their good results in part to patient selection. Also, they used smaller diameter shunts leading to smaller decrements in portal pressure (35-45%) as opposed to earlier studies (50-60%). This precaution was taken to prevent worsening of liver function after TIPS.

1. Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, Reynolds TB, Ring-Larsen H, Scholmerich J: Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 23:164-176, 1996.
   
   
2. Gulberg V, Bilzer M, Gerbes AL: Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine. Hepatology 30:870-875, 1999.
   
   
3. Angeli P, Volpin R, Gerunda G, Craighero R, Roner P, Merenda R, Amodio P, Sticca A, Caregaro L, Maffei-Faccioli A, Gatta A: Reversal of type 1 hepatorenal syndrome with the administration of midodrine and octreotide. Hepatology 29:1690-1697, 1999.
   
   
4. Guevara M, Gines P, Bandi JC, Gilabert R, Sort P, Jimenez W, Garcia-Pagan JC, Bosch J, Arroyo V, Rodes J: Transjugular intrahepatic portosystemic shunt in hepatorenal syndrome: effects on renal function and vasoactive systems [see comments]. Hepatology 28:416-422, 1998 .
   
   
5. Brensing KA, Textor J, Perz J, Schiedermaier P, Raab P, Strunk H, Klehr HU, Kramer HJ, Spengler U, Schild H, Sauerbruch T: Long term outcome after transjugular intrahepatic portosystemic stent- shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study. Gut 47:288-295, 2000