It is important to avoid precipitants of renal failure in patients with chronic liver disease. The following are all measures that should reduce the incidence of hepatorenal syndrome:
• Prophylactic treatment to prevent spontaneous bacterial peritonitis in patients who have had a previous episode of spontaneous bacterial peritonitis.
• Use of salt-poor albumin as fluid replacement in patients undergoing large-volume paracentesis.
• Careful use of diuretics.
• Avoidance of nephrotoxic drugs (gentamicin, NSAIDs, X-ray contrast media).
• Optimal fluid management.
All of the drugs that have been investigated in hepatorenal syndrome have had one over-riding aim—to increase renal blood flow. This has been either indirectly, by splanchnic vasoconstriction, or directly by encouraging renal vasodilatation. One of the principle difficulties has been the lack of agents which act purely on the splanchnic circulation. Drugs which ‘spill over’ into the systemic circulation may actually exacerbate the intense vasoconstriction already present.
The use of splanchnic vasoconstrictors was first examined in 1968 by Cohn et al., in a study involving 10 cirrhotic patients, four of whom were oliguric, and one of whom was suffering from septic shock.22 Renal blood flow was measured in individual kidneys by a direct indicator-dilution technique, with a catheter advanced into a renal artery and a vein. Octapressin, a synthetic analogue of lysine vasopressin, when infused at low doses (0.004–0.02 units/min) produced an increase in renal blood flow (604–830 mL/min, P < 0.01), with an associated decrease in renal vascular resistance (8537–6967 dyne-sec/cm1, P < 0.05). At higher doses (0.1–0.5 units/min) renal vascular resistance climbed, and changes in renal blood flow were smaller.
In one patient, equipressor doses of noradrenaline and octapressin were compared. The latter had a far greater effect on renal blood flow, with an associated fall in renal vascular resistance. The same findings occurred when octapressin was compared with angiotensin amide in another patient.
In 1972, Kew et al. examined the effect of octapressin (dose range 0.001–0.016 units/mL) on 11 normotensive cirrhotic patients with abnormal renal perfusion, but only four patients had a reduced creatinine clearance.23 In five patients blood pressure rose by > 5 mmHg. Of these five patients, an increase in renal blood flow was observed in three. This group suggested that octapressin will only consistently improve renal perfusion in cirrhotic subjects who are hypotensive, and have a pressor response to the drug.
Ornipressin is similar to octapressin in that it is also a vasopressin analogue that preferentially leads to vasoconstriction of the splanchnic vasculature. This results in a redistribution of central blood volume, a rise in central blood pressure, and an increased renal perfusion pressure. These effects are reflected by a commensurate decrease in plasma renin and angiotensin, and improved renal clearance and sodium excretion.24
The first report outlining its use was in 1985. Lenz et al. described a patient with decompensated alcoholic liver cirrhosis and hepatorenal syndrome, in whom ornipressin was infused, 4.5 UI/h, over a 4-h period.25During the time that the patient received the drug there was an improvement in renal function and blood pressure. After stopping ornipressin all values returned to pre-treatment levels; ornipressin was therefore infused continuously until the patient underwent successful liver transplantation. In 1989 the same group extended their initial observations to a larger cohort of patients (n=9 and n=11, respectively).26, 27 In the first series, nine patients with decompensated alcoholic cirrhosis and renal impairment received ornipressin at a dose of 6 UI/h for 4 h. During the infusion, a 15% increase in creatinine clearance, an increase of 29% in urine volume and an increase of 30% in urinary sodium excretion was documented, as well as a significant fall in plasma renin. Six patients improved, but no long-term follow-up was provided, and three patients died whilst in the intensive care unit. In the second series, ornipressin at the same dose of 6 IU/h induced a 60% increase in systemic intravascular resistance and a marked suppression of both plasma renin activity (a 45% fall with respect to baseline values), and noradrenaline (a 55% fall). This indicated a significant improvement in circulatory function and was associated with a 27% fall in renal vascular resistance and a mild increase in renal perfusion and glomerular filtration rate (GFR) (175 ± 36 to 261 ± 24 mL/min and 18 ± 2 to 29 ± 3 mL/min, respectively). Nine out of the 11 patients improved during their stay on intensive care, but no data were presented regarding their final outcome. The two patients who deteriorated, died of hepatic encephalopathy. As a consequence of these results, Lenz proposed the use of ornipressin as an approach to the treatment of hepatorenal syndrome, particularly in patients awaiting liver transplantation.
In 1996 Salo et al. studied 20 patients with hepatorenal syndrome as defined by the International Ascites Club.28 A 2-h infusion of ornipressin at 6 IU/h in 11 patients resulted in a significant fall in plasma renin, and a rise in blood pressure. In the same 11 patients the combination of dopamine with ornipressin resulted in no significant additional effect. In four patients with hepatorenal syndrome given dopamine alone, no significant change was seen in any of the parameters studied. In the second part of their protocol performed on a further five patients, an intravenous infusion of noradrenaline plus prostacyclin failed to increase renal perfusion or glomerular filtration rate, and actually reduced the urinary volume and sodium excretion, associated with a rise in plasma renin.
In 1998, Guevara et al. further examined the role of ornipressin in the management of hepatorenal syndrome.29 Two protocols were employed; each was performed in a group of eight patients, using a combination of ornipressin and albumin administered for either 3 or 15 days. Ornipressin was administered intravenously as a stepped-dose infusion starting with 2 IU/h on the first day and increasing subsequently to 4 IU/h on the second day, and 6 IU/h on the third day. Albumin was infused at a dose of 20–60 g/day. The 3-day treatment with ornipressin and albumin was associated with normalization of renin–angiotensin and the sympathetic nervous system, together with a marked increase in atrial natriuretic factor, but with no change in systemic haemodynamics. However, the prolonged administration of the combination resulted in an increase in mean arterial pressure and normalization of renal function in the four patients who completed the 15-day regimen. These improvements were reflected by a marked fall in plasma renin activity, plasma aldosterone, noradrenaline concentrations and an increase in atrial naturetic peptide (ANP). The improvement in renal haemodynamics was not associated with an increase in natriuresis. hepatorenal syndrome did not recur after the cessation of therapy in patients who finished the 15-day therapy, despite a rebound increase in the activity of systemic vasoconstrictor factors. Three of these patients died at 12, 60 and 62 days after treatment was stopped; the remaining patient was alive 30 days after the end of therapy.
However, this treatment had significant complications; four patients had to prematurely stop therapy after a mean of 6 days because of serious side-effects, including ischaemic colitis, an infarcted tongue, asymptomatic ventricular extra systoles and bacteraemia due to a urinary tract infection.
Terlipressin (glypressin) is a synthetic analogue of vasopressin with intrinsic vasoconstrictor activity. It is slowly cleaved in vivo into vasopressin by enzymatic cleavage of the triglycyl residue. It has the advantage over vasopressin of a longer biological half life, allowing administration as a 4-hourly bolus.
In 1995 Hadengue et al. reported in abstract a double-blind crossover study with terlipressin, 1 mg/12 h intravenously, given for 48 h in 10 patients with hepatorenal syndrome.30 This regimen improved diuresis, creatinine clearance and was well tolerated. Bonnard et al. gave terlipressin at an initial dose of 4 mg/24 h for 7 days to 15 patients with hepatorenal syndrome.31 Ten patients responded with a decrease in serum creatinine from 298 ± 135 mmol/L to 140 ± 93 mmol/L at day 5. Mean urine output increased from 537 ± 294 mL/24 h to 1417 ± 503 mL/24 h. Nine of the patients died from liver failure and/or sepsis. Ganne-Carrie et al. described a case report of hepatorenal syndrome which was controlled by long-term low-dose terlipressin administration (2 mg/day), given for 2 months.32 Because hepatorenal syndrome repeatedly relapsed when treatment was discontinued, orthotopic liver transplantation was performed and renal function normalized. With the exception of limited cutaneous necrosis, the treatment was well tolerated.
In 1998, Hadengue et al. again showed, in a placebo controlled crossover study, that 2-day terlipressin administration (2 mg/day) increased the glomerular filtration rate in nine patients with carefully defined type 1 hepatorenal syndrome.33 Arterial pressure, creatinine clearance, urine output, levels of renin, aldosterone and vasopressin were all significantly altered during terlipressin administration. No side-effects were reported; there is no follow-up provided for after the study.
Octreotide is a long acting analogue of somatostatin, which has a variable effect on splanchnic haemodynamics. The data on its use in hepatorenal syndrome are limited to a recent publication by Angeli et al. and a series from Kaffy et al. of five patients with alcoholic cirrhosis.34, 35 In the latter, octreotide was infused at a rate of 25 μg/h; in the first four patients, the infusion was stopped after 5 days. All four patients died, three from hepatorenal syndrome and one from an alcoholic cardiomyopathy. It appeared that when the octreotide was stopped, hepatorenal syndrome recurred rapidly and did not respond to further octreotide infusion. Thus in the last patient, to avoid subsequent renal deterioration, the continuous infusion was replaced by a subcutaneous injection of 250 μg b.d. This continued for 5 months whilst the patient awaited liver transplant.
Angeli et al. demonstrated that combined long-term administration of midodrine, an oral α-adrenergic agent, and octreotide, led to an improvement in renal function after 10 days, and in its almost complete normalization after 20 days.34 Thirteen patients with type 1 hepatorenal syndrome were enrolled in the study. The cause of liver disease was alcoholic in six patients, hepatitis C virus related in eight patients and hepatitis B virus related in one patient. Five patients were treated with oral midodrine and parenteral octreotide. In addition, 50–100 mL of 20% human albumin solution was infused daily, for 20 days. Midodrine and octreotide were dosed to obtain a stable increase of at least 15 mmHg in mean arterial pressure. Eight patients were treated with the administration of non-pressor doses of dopamine (2–4 μg/kg/min) and the same daily amount of albumin. After 20 days of treatment with midodrine and octreotide, an impressive improvement in renal plasma flow, glomerular filtration rate, and urinary sodium excretion was observed. This was accompanied by a significant reduction in plasma renin activity, plasma vasopressin and plasma glucagon. No side-effects were observed. Of the five patients in this group, one was still alive after 472 days, two were successfully transplanted, with preserved renal function, and two died, one from terminal liver failure after 76 days and the other from pneumonia after 29 days. Seven out of the eight patients who were treated with dopamine experienced a progressive deterioration in renal function and died during the first 12 days. Only one patient had significant recovery of renal function, and underwent liver transplantation.
Dopamine is frequently prescribed to patients with renal impairment. At low dose (< 5 μg/kg/h) it increases renal blood flow. There have been five studies examining the use of dopamine in hepatorenal syndrome, including those of Hadengue, Salo and Angeli. Vincenti et al. were unable to identify any benefit of combined dopamine and prostaglandin A1 infusion in four patients with hepatorenal syndrome.36 Bennet et al. examined renal blood flow in 12 decompensated cirrhotic patients, seven of whom had hepatorenal syndrome, using a xenon133 washout technique during an intra-arterial infusion of subpressor doses of dopamine.37 In the patients with hepatorenal syndrome, dopamine appeared to improve the angiographic appearance of renal cortical vasculature, and cortical blood flow. No change was seen in GFR or urine output with 12–24-h infusions.
The role of noradrenaline as a vasoconstrictor in hepatorenal syndrome has been examined in only two studies—Salo et al., as described above, and one by Ames et al. in 1965, included here because of its historical interest.38 Nine patients with cirrhosis and variable renal impairment were subjected to brief infusions of noradrenaline. Only three patients developed a significant natriuresis. In the same cohort of patients, angiotensin II infusions produced an initial natriuresis in the patients with cirrhosis, on average 183 mmol/day. The degree of sodium loss appeared to be related to both the degree of pressor response, and the dose of angiotensin used. Tachyphylaxis was a consistent observation in the cirrhotic patients given angiotensin II, and aldosterone levels increased in these subjects. One normal control suffered a fatal cerebral haemorrhage during an infusion of angiotensin II, and as a consequence, the study was terminated.
Misoprostol, a synthetic analogue of prostaglandin E1, would potentially act on the renal circulation as a vasodilator, and its use in hepatorenal syndrome was examined by Fevery et al. in 1990.39 Four patients with hepatorenal syndrome received misoprostol at a dose of 0.4 mg q.d.s. orally, i.e. twice the recommended anti-ulcer dose. All four patients responded with a diuresis and a fall in creatinine, although only two patients had a natriuresis. Three patients died at days 10, 30 and 40 of bleeding, encephalopathy and pneumonia, respectively; the fourth patient underwent liver transplantation.
In a larger study by Gines et al., nine patients with renal impairment and/or hyponatraemia were given 200 μg misoprostol every 6 h for 4 days.40 No changes in GFR (59 ± 11 vs. 54 ± 11 mL/min), sodium excretion (4.0 ± 1.3 vs. 4.1 ± 2 uEq/min), and free water clearance (2.4 ± 0.8 vs. 2.1 ± 0.9 mL/min) were observed. An infusion of prostaglandin E2 in a further, similar group of nine patients had a similarly disappointing lack of effect on GFR and sodium excretion, and significantly decreased free water clearance.
Endothelin, a potent endogenous vasoconstrictor, is increased in patients with hepatorenal syndrome.11 The role of an endothelin A antagonist BQ123 was examined in a preliminary study of three cirrhotic patients with hepatorenal syndrome by Soper et al.41 Consecutive 10, 25, and 100 nmol/min infusions of BQ123 were given for 60 min. All three patients showed a dose-response improvement in inulin and para-aminohippurate (PAH) clearance, approaching 100% at the highest dose. All three patients subsequently died.
There has been one series of 12 patients (nine of whom had alcoholic cirrhosis) with hepatorenal syndrome where N-acetyl cysteine was used as an antioxidant. This treatment was well tolerated, with no side-effects. At baseline, following aggressive fluid replacement, the mean creatinine clearance was 24 ± 3 mL/min, rising to 43 ± 4 mL/min following the 5 days of therapy. This was associated with an increase in urine output, and a significant increase in sodium excretion from 1.2 ± 0.5 to 1.8 ± 0.6 mmol/h (P < 0/05). High survival figures of 67% (eight out of 12) at 1 month and 58% (seven out of 12) at 3 months were observed. This included two patients who underwent successful orthotopic liver transplantation after improvement in their renal function. Information on the aetiology of the patient's liver disease in the patients who survived was not provided.