Scientists have known for almost half a century that hepatorenal syndrome (HRS) results from an intense active vasoconstriction of the renal arteries in an otherwise healthy kidney in the setting of advanced cirrhosis, or less commonly, acute liver failure.
The effect of this renal vasoconstriction is to dramatically reduce glomerular filtration rate (GFR), leading to renal failure.
However, because of the absence of any structural abnormalities in the kidneys of patients suffering HRS, physicians have always considered the disease to be theoretically reversible.
Despite this, all previous pharmacological and non-pharmacological therapies used to reverse HRS have proven unsuccessful, with liver transplantation being the only procedure known to improve renal function in such patients.
It is believed that renal vasoconstriction in HRS patients is the final consequence of an extreme vasodilation of the splanchnic arterial circulation.
This results in a reduction of the effective arterial blood volume (that is, the blood volume that is sensed by the central part of the arterial circulation) and an abnormal distribution of arterial blood volume.
This ultimately leads to a reduction in blood flow to all extra-splanchnic areas, including the kidneys.
A new therapeutic approach to reversing HRS has been the use of vasoconstrictors such as vasopressin analogues.
Administration of these drugs has been shown to greatly improve circulatory function in HRS, along with increased arterial pressure and a near-normalization of the activity of the major endogenous vasoconstrictor systems (renin-angiotensin system and sympathetic nervous system).
In addition, these effects are also associated with improved renal function, with marked increases in renal plasma flow, GFR, urine volume and serum sodium concentration in about two-thirds of patients treated.
A pilot study has now examined the efficacy and safety of noradrenalin (NA) in the treatment of type 1 HRS (the clinical form characterized by rapidly progressive renal failure).
Between 1998 and 2000, 12 consecutive patients with type 1 HRS (7 men, 5 women; mean age 54 years; mean Child-Pugh score 11.3) were given intravenous NA (0.5-3 mg/h), in combination with intravenous albumin and furosemide.
NA was administered for an average of 10 days, at a mean dose of 0.8 mg/h.
| HRS reversal:|
Occurred in 83% of noradrenalin-treated patients.
| Hepatology |
In 10 of the 12 patients (83%), reversal of HRS was observed after a median of 7 days (range 5-10 days).
Serum creatinine levels fell from 358 ± 161 to 145 ± 78 µmol/l, while creatinine clearance rose from 13 ± 9 to 40 ± 15 ml/min and urinary sodium output increased from 8 ± 14 to 52 ± 72 mEq/d.
The changes in renal function under NA treatment were associated with an increase in mean arterial pressure (MAP; 65 ± 7 to 73 ± 9 mm Hg).
A marked reduction in active renin (565 ± 989 to 164 ± 196 ng/l) and aldosterone plasma concentrations (1,945 ± 1,931 to 924 ± 730 ng/ml) was also observed.
There was one episode of reversible myocardial hypokinesia (in a patient on 1.5 mg/h NA) that did not recur after a dose reduction.
The research group that carried out the study concludes that "NA combined with albumin and furosemide appears effective and safe for the treatment of type 1 HRS."
However, writing in an accompanying editorial, Dr Pere Ginès and Dr Mónica Guevara caution that this study, along with previous studies using vasoconstrictors for HRS "raise important questions from a therapeutic and pathophysiologic perspective that need to be addressed in future studies."