Original Article
Plasma Endothelin Immunoreactivity in Liver Disease and the Hepatorenal Syndrome
N Engl J Med 1992; 327:1774-1778December 17, 1992
- Abstract
- Abstract
Background.
Severe renal vasoconstriction is central to the pathogenesis of renal failure in the hepatorenal syndrome. Endothelin-1 and endothelin-3 are potent, long-acting vasoconstrictors, and endothelin-1 has selective potency as a renal vasoconstrictor. These properties suggest a role for endothelins in the hepatorenal syndrome.
Methods.
We measured plasma endothelin-1 and endothelin-3 concentrations using specific radioimmunoassays in subjects with the hepatorenal syndrome, liver disease but normal renal function, chronic renal failure, acute renal failure, liver dysfunction and renal impairment, or normal liver and kidney function.
Results.
The patients with the hepatorenal syndrome had markedly elevated mean (±SE) plasma concentrations of endothelin-1 (36±5 ng per liter [14.5±1.8 pmol per liter]) and endothelin-3 (43±3 ng per liter [16.3±1.0 pmol per liter]) as compared with the normal subjects (endothelin-1, 4±1 ng per liter [1.7±0.2 pmol per liter]; and endothelin-3, 18±1 ng per liter [6.8±0.4 pmol per liter]; P<0.001) and with the patients in the other four groups (P<0.001 to P<0.05). The plasma endothelin-1, but not endothelin-3, concentrations in these four patient groups were significantly higher than in the normal subjects (P<0.001 to P<0.05). The concentrations of endothelin-1 in renal arterial plasma and renal venous plasma, measured in five patients with the hepatorenal syndrome and three with chronic liver disease and normal renal function, were 20±4 ng per liter (7.9±1.8 pmol per liter) and 24±4 ng per liter (9.5±1.5 pmol per liter), respectively (P<0.05).
Conclusions.
The increase in plasma endothelin-1 and endothelin-3 concentrations in patients with the hepatorenal syndrome is consistent with the hypothesis that these substances have a role in the pathogenesis of the disease. (N Engl J Med 1992;327:1774–8.)
Media in This Article
Figure 1
Plasma Endothelin Concentrations in the Study Subjects.Figure 2
Renal Arterial and Venous Endothelin-1 Concentrations in Five Patients with the Hepatorenal Syndrome (●) and Three Patients with Chronic Liver Disease (○).Article Activity
- Article
THE hepatorenal syndrome, a common complication of chronic and acute liver failure, is characterized in its most extreme form by intense renal vasoconstriction that mediates a potentially reversible form of acute renal failure.1 2 3 The cause of the renal vasoconstriction is not known, but is likely to be multifactorial, involving activation of the sympathetic and renin—angiotensin systems, endotoxemia, and altered eicosanoid production.4 5 6 7 8 9 10 Attempts to reverse the hepatorenal syndrome through the antagonism of some of these stimuli have been inconclusive, however.
The endothelins are a family of 21-amino-acid peptides that are synthesized as a propeptide, cleaved to form big endothelin, and then further cleaved by endothelin-converting enzyme to form the active peptide. Endothelin-1 is formed in vascular endothelium, and endothelin-3 in neural tissue (there is an endothelin-2, but its origin is uncertain, and it cannot be measured in plasma). The endothelins are potent, long-acting vasoconstrictors. The sensitivity of the renal vasculature to the constrictor actions of the endothelins,11 , 12 coupled with evidence that these peptides are involved in the regulation of renal function,13 14 15 raised the possibility that endothelins may be involved in the pathogenesis of the hepatorenal syndrome.
We therefore measured the plasma concentrations of endothelin-1 and endothelin-3 in patients with liver disease with and without the hepatorenal syndrome, as well as in patients with acute renal failure, chronic renal failure, chronic liver disease, and combined liver dysfunction and renal impairment. We also measured the renal arteriovenous differences in plasma endothelin-1 concentrations. Our results provide evidence that circulating endothelin-1 is an important mediator of the severe renal vasoconstriction that characterizes the hepatorenal syndrome.
Methods
Study Subjects
We studied five groups of patients with liver or renal disease (or both) and a group of normal subjects (Table 1Table 1
Clinical Characteristics of the Study Subjects.*). Group 1 consisted of 11 patients with the hepatorenal syndrome, caused by alcoholic hepatitis in 8, non-A, non-B hepatitis in 2, and primary biliary cirrhosis in 1. The hepatorenal syndrome was defined as the spontaneous development of renal failure in patients with decompensated liver disease in the absence of any other identifiable cause. Patients with liver disease and renal impairment who had received excessive diuretic therapy or who had gastrointestinal bleeding or sepsis were excluded. All 11 patients had a urinary sodium concentration of less than 20 mmol per liter at the time of the study, a finding compatible with functional renal failure. The possibility of hypovolemia was excluded by the intravenous administration of fluid and the monitoring of pulmonary-capillary wedge pressure or central venous pressure. Nine of the 11 patients subsequently died during the hospital stay.Group 2 consisted of 17 patients with liver disease but normal renal function. The disease was alcoholic liver disease in seven patients, non-A, non-B hepatitis in two, primary biliary cirrhosis in three, chronic active hepatitis in two, and cryptogenic cirrhosis in three. Four of the patients in group 2 died, two during their hospital stay.
Group 3 consisted of 12 patients with chronic renal failure, caused by hypertension in 5, systemic lupus erythematosus in 4, and miscellaneous causes in 3.
Group 4 consisted of seven patients with acute renal failure, caused by drugs in three, hypovolemia in two, sepsis in one, and multiple myeloma in one.
Group 5 consisted of 11 patients with liver dysfunction and renal impairment, caused by sepsis in 4, an overdose of acetaminophen in 3, hypovolemia in 2, extensive tumor in 1, and biliary obstruction in 1. Four of these patients died during their hospital stay. The criteria for inclusion in group 5 were abnormal results on liver-function tests (plasma bilirubin level, >1.5 mg per deciliter [25 μmol per liter]), renal impairment (plasma creatinine level, >1.6 mg per deciliter [140 μmol per liter]), and an identifiable event causing acute renal dysfunction. This group included three patients whose renal damage was presumed to be a direct consequence of an overdose of acetaminophen, two patients with chronic liver disease with renal impairment responsive to volume challenge, four patients with sepsis, one patient with liver dysfunction due to extensive tumor, and one patient with biliary obstruction.
Group 6 consisted of 11 normal subjects.
There was no evidence of systemic sepsis or bacterial peritonitis in any of the patients with the hepatorenal syndrome, liver disease but normal renal function, or chronic renal failure (groups 1, 2, and 3). Five patients with liver dysfunction and renal impairment (group 5) had previously documented or suspected sepsis, including one of the patients who had taken an overdose of acetaminophen. Except for those with chronic renal failure (group 3), none of the patients had taken diuretic drugs for at least five days. None of the patients with chronic or acute renal failure (groups 3 and 4) were undergoing dialysis at the time of the study. A single patient with liver dysfunction and renal impairment (group 5) underwent hemo-filtration before the collection of blood samples.
Blood samples for plasma endothelin-1 and endothelin-3 determinations were collected at random times, and medications were not withheld. Eight patients, five with the hepatorenal syndrome (group 1) and three with chronic liver disease but normal renal function (group 2), underwent cannulation of both the renal artery and the renal vein by the femoral route, with a Seldinger approach with a 7-French catheter.
The study protocol was approved by the ethics committee of King's College School of Medicine and Dentistry. All the subjects gave informed consent. Consent was obtained from both the patient and relatives when encephalopathy was present.
Sample Collection
Twenty milliliters of venous blood was collected in heparin-treated tubes containing 100 U of aprotinin (Trasylol, Miles Laboratories, Elkhart, Ind.) on ice and centrifuged within 15 minutes at 4°C; the plasma was stored at -70°C until assayed. Among the patients who underwent renal venous and arterial cannulation, blood was withdrawn from the main vessel. The renal vein was always cannulated first, and a small amount of Omnipaque 350 radiocontrast medium (iohexol, Nycomed, Oslo, Norway) was used to confirm localization after venesection. The renal artery was cannulated within 20 minutes after the renal vein.
Plasma Endothelin Assay
After thawing, the plasma was centrifuged at 850×g for 15 minutes to remove any cryo-precipitate. Three milliliters of plasma was acidified with 1.5 ml of 0.3 percent acetic acid, after the addition of 30 μl of 0.05 mol of diisopropyl fluorophosphate per liter in 2-propanol, and 300 μl of inhibitor solution (containing 300 μl of aprotinin, 0.16 mmol of sodium chloride, and 8.9 mg of EDTA). This was followed by the addition of 120 μl of 0.4 percent Triton X-305 (Sigma Chemical, St. Louis). After centrifugation, the sample was passed through a C8 Bond Elut column (Analytichem International, Harbor City, Calif.) pretreated with 0.1 percent trifluoroacetic acid (Pierce Chemical, Rockford, Ill.) in acetonitrile (Fisher Scientific, Norcross, Ga.), 0.1 percent trifluoroacetic acid in methanol, and 0.1 percent trifluoroacetic acid in water. After addition of the sample, the column was washed with 0.1 percent trifluoroacetic acid in water and 0.1 percent trifluoroacetic acid in 40 percent methanol, and the fraction containing endothelin was eluted with 2 ml of 70 percent methanol containing 0.1 percent trifluoroacetic acid and 0.01 percent Triton X-305. The sample was dried under vacuum and reconstituted in 0.1 ml of assay buffer. The results were corrected for the mean recovery of 70 percent of endothelin-1 and 79 percent of endothelin-3, as determined in our laboratory.
Endothelin-1 and endothelin-3 were measured in the plasma extracts by radioimmunoassay in phosphate-buffered saline containing 0.001 percent Triton X-305 and 0.034 percent ethylenegly-col-bis-(β-aminoethyl ester)N,N,N′,N′-tetraacetic acid. One replicate of each plasma extract was analyzed. Endothelin-1 and endothelin-3 and their respective antibodies were purchased from Peninsula Laboratories (Belmont, Calif). Endothelin-1 and endothelin-3 were iodinated according to the method of Hirata et al.16 As compared with endothelin-1, the cross-reactivities of endothelin-2, endothelin-3, big endothelin, angiotensin II, and atrial natriuretic hormone with the an ti—endothelin-1 antiserum were 7 percent, 7 percent, 17 percent, less than 0.001 percent, and less than 0.001 percent, respectively, according to the supplier. As compared with endothelin-3, the cross-reactivities of endothelin-1, endothelin-2, angiotensin II, and atrial natriuretic hormone with the anti—endothelin-3 antiserum were less than 2 percent, less than 1 percent, less than 0.001 percent, and less than 0.001 percent, respectively, according to the supplier. Phase separation was carried out with goat antirabbit anti-IgG (Calbiochem, San Diego, Calif). The intraassay and interassay variations were 5.8 and 14.5 percent, respectively, for the endothelin-1 assay, and 4.2 and 12.8 percent for the endothelin-3 assay.
Statistical Analysis
The results in each group were compared with the Mann—Whitney U test, and arteriovenous differences were compared with Student's paired t-test. Correlations within a group were compared with the Spearman rank test.
Results
Plasma endothelin-1 concentrations were higher in all five groups of patients than in the normal subjects (Table 2Table 2
Plasma Endothelin-1 and Endothelin-3 Concentrations in the Study Subjects.* and Fig. 1Figure 1Plasma Endothelin Concentrations in the Study Subjects.A). The mean plasma endothelin-1 concentration was highest in the patients with the hepatorenal syndrome (group 1), and the value in this group was significantly higher than the value in the other four patient groups (P<0.001). In the group with the hepatorenal syndrome, there was no correlation between the plasma endothelin-1 concentration and the plasma creatinine or bilirubin concentration. There was, however, a significant correlation between plasma bilirubin and plasma endothelin-1 concentrations in the group with chronic liver disease (group 2) (rs = 0.8, P<0.001).To assess the contribution of renal tissue to the circulating plasma endothelin-1 concentration, the arteriovenous difference was measured in five patients with the hepatorenal syndrome (group 1) and three patients with chronic liver disease but normal renal function (group 2). The mean (±SE) concentration of endothelin-1 in renal venous plasma (24±4 ng per liter [9.5±1.5 pmol per liter]) in these eight patients was significantly higher than the mean concentration in renal arterial plasma (20±4 ng per liter [7.9± 1.8 pmol per liter], P<0.05) (Fig. 2Figure 2
Renal Arterial and Venous Endothelin-1 Concentrations in Five Patients with the Hepatorenal Syndrome (●) and Three Patients with Chronic Liver Disease (○).).The plasma endothelin-3 values are also shown in Table 2 and Figure 1B. The mean values in the patients with the hepatorenal syndrome (group 1 ) and in those with liver dysfunction and renal impairment (group 5) were significantly higher than the mean value in the normal subjects (P<0.001). The mean value in the patients with the hepatorenal syndrome was also significantly higher than that in the other four groups of patients (P<0.05). There was no correlation between the plasma endothelin-3 concentration and the plasma creatinine or bilirubin concentration in any of the groups. There was, however, a significant correlation between plasma endothelin-1 and endothelin-3 concentrations in the six groups as a whole (rs = 0.54, P<0.01).
Discussion
The recent identification and characterization of the endothelins as a group of long-acting, potent vasoconstricting peptides produced by vascular endothelium have generated much interest in the potential effects of these peptides on renal function. Most interest has focused on endothelin-1, and increased plasma concentrations of endothelin-1 have been found both in patients with acute renal failure and in those with chronic renal failure.17
We found increased plasma endothelin-1 concentrations in patients with liver disease and patients with renal failure of diverse causes. The plasma concentrations were 5 to 16 times higher in the patients with the hepatorenal syndrome than in the normal subjects, and more than 4 times higher than in the patients with acute renal failure alone. In normal subjects, the plasma endothelin-1 concentration is thought to be too low for systemic effects.18 The situation in the kidney appears to be different, however, because the renal vasculature is particularly sensitive to the action of endothelin- 1. There are high-affinity receptors in the renal artery and renal medulla in pigs19 and on glomerular mesangial cells in rats.13 14 15 , 20 The systemic infusion of endothelin-1 decreases both renal blood flow and the glomerular filtration rate, as well as fractional sodium excretion.11 , 13 14 15 The plasma endothelin-1 concentrations that we found in our patients with the hepatorenal syndrome were of the same order of magnitude as the observed dissociation constant for endothelin-1 receptors on membranes obtained from porcine renal arterial tissue.19
The role of circulating endothelin-3 is unknown. It is a relatively weak renal vasoconstrictor as compared with endothelin-1 or endothelin-2. There is increasing evidence, however, implicating endothelin-3 in the release of endothelium-derived relaxing factor (nitric oxide).21 Whether the higher plasma concentrations of endothelin-3 in the patients with the hepatorenal syndrome contribute to the characteristic peripheral vasodilatation through the secondary release of nitric oxide remains to be investigated.
The observation that endothelin-1 concentrations in renal venous plasma were higher than those in the renal artery contrasts with that of Hemsen, who found that 90 percent of renal arterial endothelin-1 was extracted from the blood by the pig kidney in vivo.19 If this level of extraction occurs in normal humans, then our results indicate that the renal clearance of endothelin is altered in patients with decompensated liver disease, perhaps because of the decreased activity of endothelin-metabolizing enzymes, such as neutral endopeptidase, that are abundant in the kidney. Whereas the circulating concentrations of endothelin-1 in patients with the hepatorenal syndrome are close to the binding constant in the renal artery, the local concentrations of synthesized endothelin may be much higher, and they could act synergistically with other vasoactive agents. There may be other sites of endothelin-1 synthesis, such as the diseased liver itself, as well as the splanchnic and peripheral vasculature.15
Although most of the interest in endothelin has concentrated on its vascular effects, it is also a potent stimulus for the contraction of glomerular mesangial cells, which decreases the glomerular-capillary ultrafiltration coefficient. As a result, the glomerular filtration rate may decrease to values below those induced by the decline in renal blood flow alone.11 12 13 Injecting endothelin into the renal artery of rats sharply reduces the ultrafiltration coefficient,11 and it causes contractile responses in cultured mesangial cells.20 This action is important, since vasoconstriction is unlikely to be the sole determinant of impaired renal function in patients with the hepatorenal syndrome. Although renal blood flow is the most important determinant of glomerular filtration in patients with the hepatorenal syndrome, there is considerable overlap between the values for renal blood flow in these patients22 and the values in patients with decompensated liver disease but relatively normal renal function. This suggests that other factors modulating glomerular function, such as the ultrafiltration coefficient, are likely to be involved in the pathogenesis of renal failure in the hepatorenal syndrome.
Other potential mechanisms for increased endothelin production in liver disease and the hepatorenal syndrome include tissue hypoxia,23 oxidant injury,24 and bacterial endotoxemia.15 , 25 Whether the systemic endotoxemia that occurs in patients with the hepatorenal syndrome is an important stimulus for the production of endothelin is not known.
Endothelins have a short plasma half-life of one to two minutes in vivo, but it may be longer in patients with liver disease. Moreover, plasma endothelin-1 concentrations increase slightly in normal subjects when they assume an upright posture, as a homeostatic response to the lowering of arterial pressure.26 Thus, the higher plasma endothelin-1 concentrations in patients with liver disease and the hepatorenal syndrome may in part reflect a response to systemic vasodilatation.
In conclusion, we have demonstrated increased plasma endothelin-1 concentrations in patients with the hepatorenal syndrome and lesser increases in patients with liver disease, acute renal failure, or chronic renal failure. The patients with the hepatorenal syndrome or chronic liver disease had slightly higher endothelin-1 concentrations in renal venous plasma than in renal arterial plasma. These results are consistent with the hypothesis that increases in circulating endothelin, and possibly the renal generation of endothelin, may mediate the vasoconstriction and decreased glomerular filtration rate found in patients with the hepatorenal syndrome.
Supported by grants from the Center for Kidney and Urologic Diseases, Vanderbilt University.
Source Information
From the Department of Clinical Pharmacology, Royal Postgraduate Medical School (K.M.), and the Institute for Liver Studies, King's College School of Medicine and Dentistry (J.W., J.K., R.W.), both in London; and the Division of Nephrology and Center for Kidney and Urologic Diseases, Vanderbilt University, Nashville (M.F., K.B.). Address reprint requests to Dr. Moore at the Department of Clinical Pharmacology, Royal Postgraduate Medical School, Du Cane Rd., London W12 0NN, United Kingdom.
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