Microsoft word - hepatorenales syndrom.doc

Behandlung des hepatorenalen Syndroms mit
TERLIPRESSIN / ORNIPRESSIN
Bei Patienten mit Leberzirrhose ist die Einschränkung der Nierenfunktion im Allgemeinen funktioneller Natur, bedingt durch eine Fehlverteilung des Blutvolumens. Verursacht wird die Fehlverteilung des Blutvolumens durch periphere und splanchnische arterielle Vasodilatation. Als Verursacher dieser Vasodilatation sind systemisch und lokal wirkende Vasodilatoren im Gespräch, wie Stickstoffmonoxid (NO), Glukagon, Calcitonin-gene-related Peptide (CGRP), Substanz P, Vasoactives intestinales Peptid (VIP), Tumor Nekrose Faktor (TNF), Adrenomedullin und das nicht-adrenerge nicht-cholinerge Neurotransmittersystem. Die splanchnische Vasodilatation führt zu vermindertem vaskulärem Widerstand mit erhöhtem Blutvolumen in den Gefäßen des Mesenterialbereichs. Die Folge dieses Blutpoolings ist eine relative Hypovolämie im arteriellen System mit erniedrigtem systolischem und diastolischem Blutdruck. Es kommt zur kompensatorischen Aktivierung des Renin-Angiotensin- Aldosteron Systems (RAAS) und des sympathischen Nervensystems (SNS) und hieraus resultierend zur Minderperfusion lebenswichtiger Organe wie Lunge, Herz, Gehirn und Nieren. An der Niere kommt es zur Natrium- und Wasserretention, zur Verminderung der Durchblutung und der glomerulären Filtrationsrate. Patienten mit hepatorenalem Syndrom Typ I haben im Allgemeinen eine sehr schlechte Prognose mit 1-Monats-Letalitätsraten von bis über 80%. Eine etablierte medikamentöse Therapie des hepatorenalen Syndroms existiert bisher nicht. Eine medikamentöse Therapie scheint aber von besonderer klinischer Bedeutung, auch als Brücke zur Lebertransplantation. Ansätze für eine medikamentöse Therapie sind die Korrektur der splanchnischen Vasodilatation durch Behandlung mit Vasokonstriktoren und/oder Wiederauffüllung des verminderten effektiven Blutvolumens mit Plasmaexpandern. Fliesst aufgrund der medikamentös hervorgerufenen splanchnischen Vasokonstriktion weniger Blut in die Portalvene, reduziert sich der portalvenöse Druck, die porto-cavalen Umgehungskreisläufe werden entlastet, die zentrale und arterielle Hypovolämie wird korrigiert und die Aktivierung des RAAS und des SNS wird verringert, was letztlich zur Reduzierung des intrahepatischen und intrarenalen Gefäßwiderstandes führt. Die Konsequenz ist eine bessere Durchblutung der Organe – die Nieren eingeschlossen – und eine Verbesserung der hyperdynamen Kreislaufsituation. Bei der Gabe von Vasokonstriktoren wurden gute Ergebnisse mit Terlipressin erzielt (1-13, 16-24). Terlipressin reduziert die Serum Kreatininspiegel auf unter 1,5 mg/dl und verbessert die kardiovaskuläre Situation über einen Anstieg des mittleren arteriellen Drucks und einer Hemmung der Plasma Reninaktivität und der Plasma Aldosteron- und Noradrenalinspiegel (16, 22). Terlipressin bewirkt u.a. über die Vasokonstriktion der glomerulären Gefässe der Niere eine Erhöhung der glomerulären Filtrationsrate (2, 16, 18, 20, 22), der Natriurese (18, 20) und der Urinausscheidung (16, 18, 20), was sich günstig auf das hepatorenale Syndrom auswirkt (9 – 11, 16 – 18, 20, 22). Dabei ist die Beobachtung von besonderem Interesse, dass bei vielen der mit Terlipressin und Plasmaexpandern behandelten Patienten die Verbesserung der kardiovaskulären Situation auch nach Absetzen der Therapie bestehen blieb und das hepatorenale Syndrom sich nicht wiedereinstellte (2). Somit erhebt sich die Frage zum Mechanismus über den sich das hepatorenale Syndrom bei Nichtbehandlung kontinuierlich verschlechtert. Therapy of hepatorenal Syndrom with Terlipressin
[#1] Hepatorenal syndrome in cirrhosis: pathogenesis and treatment.
Arroyo V, Guevara M, Ginès P.
Liver Unit, Institute of Digestive Disease, Hospital Clinic, University of Barcelona, Villaroel
170, 08036 Barcelona, Spain. arroyo@medicina.ub.es
Gastroenterology 2002 May;122(6):1658-76
Publication Types:
PMID: 12016430 [PubMed - indexed for MEDLINE]
[#2] Complications of cirrhosis. II. Renal and circulatory dysfunction. Lights
and shadows in an important clinical problem.
Institute of Digestive Diseases and Hormonal Laboratory, Hospital Clinic Universitari, University of Barcelona, Spain. arroyo@medicina.ub.es J Hepatol 32 (1 Suppl): 157-170, 2000 The pathophysiology of circulatory and renal dysfunction in cirrhosis and the treatment of ascites and related conditions (hepatorenal syndrome and spontaneous bacterial peritonitis) have been research topics of major interest during the last two decades. However, many aspects of these problems remain unclear and will constitute major areas of investigation in the next millennium. The pathogenesis of sodium retention, the most prevalent renal function abnormality of cirrhosis, is only partially known. In approximately one third of patients with ascites, sodium retention occurs despite normal activity of the renin-aldosterone and sympathetic nervous systems and increased circulating plasma levels of natriuretic peptides and activity of the so-called natriuretic hormone. These patients present an impairment in circulatory function which, although less intense, is similar to that of patients with increased activity of the renin-aldosterone and sympathetic nervous systems, suggesting that antinatriuretic factors more sensitive to changes in circulatory function that these systems may be important in the pathogenesis of sodium retention in cirrhosis. The development of drugs that inhibit the tubular effect of antidiuretic hormone and increase renal water excretion without affecting urine solute excretion has opened a field of great interest for the management of water retention and dilutional hyponatremia in cirrhosis. Two families of drugs, the V2 vasopressin receptor antagonists and the kappa-opioid agonists, have been shown to improve free water clearance and correct dilutional hyponatremia in human and experimental cirrhosis with ascites. The first type of drugs blocks the tubular effect of antidiuretic hormone and the second inhibits antidiuretic hormone secretion by the neurohypophysis. On the other hand, two new treatments have also been proved to reverse hepatorenal syndrome in cirrhosis. The most interesting one is that based on the simultaneous administration of plasma volume expansion and vasoconstrictors. The second is transjugular intrahepatic porto-systemic shunt. The long-term administration (1-3 weeks) of analogs of vasopressin (ornipressin or terlipressin) or other vasoconstrictors together with plasma volume expansion with albumin is associated with a dramatic improvement in circulatory function and normalization of serum creatinine concentration in patients with severe hepatorenal syndrome. Of interest is the observation that in many of these patients, hepatorenal syndrome does not recur following discontinuation of the treatment, thus raising important questions about the mechanism by which hepatorenal syndrome follows a progressive course in most untreated cases. The pathogenesis of circulatory dysfunction in cirrhosis and the role of local mechanisms in the development of the splanchnic arteriolar vasodilation associated with portal hypertension will continue as important topics in clinical and basic research in Hepatology. Of special interest is the study of the mechanism by which circulatory function further deteriorates following complications such as severe bacterial infection or therapeutic interventions such as therapeutic paracentesis, and the adverse consequences of the impairment in circulatory function on renal and hepatic hemodynamics. Finally, although major advances have been made concerning the treatment and secondary prophylaxis of spontaneous bacterial peritonitis in cirrhosis, many aspects of the pathogenesis of this infection remain unclear. The mechanism of bacterial translocation and of the colonization of bacteria in the ascitic fluid are particularly important to design adequate measures for primary prophylaxis of this severe bacterial infection.
[#3] Hepatorenal syndrome.
Bataller R, Gines P, Arroyo V, Rodes J.
Liver Unit, Institut de Malalties Digestives, Hospital Clinic, Barcelona, Spain.
Clin Liver Dis 2000 May;4(2):487-507
Hepatorenal syndrome is a functional renal failure that occurs in cirrhotic patients with
advanced liver disease and ascites. The diagnostic criteria and clinical types of this syndrome
have recently been revised. Hepatorenal syndrome is caused by marked hypoperfusion of the
kidney as the result of renal vasoconstriction, which is thought to be the extreme manifestation
of an underfilling of the arterial circulation. This circulatory dysfunction is the consequence of
arterial vasodilation in the splanchnic circulation. Liver transplantation is the best treatment for
HRS, but its applicability is low because of the short survival of these patients. New therapies,
such as the use of systemic vasoconstrictors or TIPS, seem promising, but prospective
investigations are needed to delineate their role in the management of cirrhotic patients with
HRS.
Publication Types:
PMID: 11232202 [PubMed - indexed for MEDLINE] "Haemopressin® (Wirkstoff TERLIPRESSIN) hilft Leben retten"
Therapy of hepatorenal Syndrom with Terlipressin
[#4] Effect of terlipressine (glypressine) on hepatorenal syndrome (HRS) in
cirrhotic patients: Results of a pilot study.
Bonnard Ph., Bernard B., Halimi Ch., Mathurin Ph., Demontis R., di Martino V., Henry-Biabaud E., Mofredj A., Poynard T., Cadranel JF. Gastroenterology 114 (4), A 1214, 1998 (abstract).

[#5] Renal failure after upper gastrointestinal bleeding in cirrhosis: incidence,
clinical course, predictive factors, and short-term prognosis.
Cardenas A, Gines P, Uriz J, Bessa X, Salmeron JM, Mas A, Ortega R, Calahorra B, De
Las Heras D, Bosch J, Arroyo V, Rodes J.
Hepatology 2001 Oct;34(4 Pt 1):671-6
Liver Unit, Institut de Malalties Digestives, Hospital Clinic, University of Barcelona, Spain.
To assess the incidence, clinical course, predictive factors, and prognosis of renal failure in
patients with cirrhosis and gastrointestinal bleeding, 175 consecutive episodes of
gastrointestinal bleeding in 161 patients were analyzed. Renal failure occurred in 20 (11%)
episodes and was transient in 8 episodes and nontransient in 12. Renal failure was more
common in patients with cirrhosis than in a control population of bleeding patients without
cirrhosis matched by age and severity of the bleeding episode. Among 39 clinical and
laboratory variables obtained at admission or during hospitalization related with the bleeding
episode or with liver and renal function, the presence of hypovolemic shock, number of packed
red blood cells transfused, Child-Pugh class at admission, and baseline platelet count were
independent predictors of renal failure. The development of renal failure and hypovolemic
shock was the only independent predictors of in-hospital mortality. Mortality rate among the 20
episodes with renal failure was 55% (11 deaths) as compared with only 3% (5 deaths) in the
155 episodes without renal failure (P <.01). The development of nontransient renal failure
entailed a much greater mortality as compared with transient renal failure (10 of 12 [83%] vs. 1
of 8 [12%]; P <.01). In conclusion, renal failure is a common event in patients with cirrhosis
and gastrointestinal bleeding, the occurrence of which is mainly related to the severity of
bleeding and baseline liver function. Renal failure is a strong predictor of mortality in patients
with cirrhosis and gastrointestinal bleeding.
PMID: 11584362 [PubMed - indexed for MEDLINE]
MIT FREUNDLICHER EMPFEHLUNG VON
Pharma GmbH

[#6] Hepatorenal syndrome.
Cardenas A, Uriz J, Gines P, Arroyo V.
Liver Unit, Institut de Malalties Digestives, Hospital Clinic, Barcelona, Spain.
Liver Transpl 2000 Jul;6(4 Suppl 1):S63-71
Publication Types:
PMID: 10915194 [PubMed - indexed for MEDLINE]
[#7] Terlipressin may influence the outcome of hepatorenal syndrome
complicating alcoholic hepatitis.
Cervoni JP, Lecomte T, Cellier C, Auroux J, Simon C, Landi B, Gadano A, Barbier JP.
Service d'Hepato-Gastroenterologie, Hopital Laennec, Paris, France.
Am J Gastroenterol 1997 Nov;92(11):2113-4
Hepatorenal syndrome is a frequent complication associated with extremely short survival in
cirrhotic patients with alcoholic hepatitis. Vasopressin analogs have been reported to induce
transient regression of hepatorenal syndrome in patients with cirrhosis. However, treatment
withdrawal was followed by early recurrences in every case. We report the case of a 68-yr-old
woman with severe alcoholic hepatitis complicated by hepatorenal syndrome. Terlipressin
induced a prolonged recovery of renal function that was associated with improvement in
hepatic function.
Publication Types:
PMID: 9362205 [PubMed - indexed for MEDLINE] WITH COMPLIMENTS
Pharma GmbH
Therapy of hepatorenal Syndrom with Terlipressin
[#8] Review article: pharmacological treatment of the hepatorenal syndrome
in cirrhotic patients.
Dagher L, Patch D, Marley R, Moore K, Burroughs A.
Department of Liver Transplantation and Hepatobiliary Medicine, Royal Free Hospital,
London, UK.
Aliment Pharmacol Ther 2000 May;14(5):515-21
Renal failure is common in patients who are dying from end-stage cirrhosis, developing in 40-
80% of all patients. Where there is no anatomical or pathological cause for the renal failure, it
is termed the hepatorenal syndrome. When the hepatorenal syndrome develops, it will only
recover when there is some degree of improvement in liver function. Thus for most patients this
will occur only after liver transplantation, although the transplantation mortality is increased in
this group. Hepatorenal syndrome is a common complication of alcoholic hepatitis, and this
group is unusual in that with time and abstinence, significant recovery of liver function may
occur. There is therefore a need for supportive therapy to allow time for some recovery of liver
function in patients with alcoholic hepatitis and hepatorenal syndrome. Similarly, patients may
need support whilst waiting for liver transplantation. This article reviews the pathophysiology
and treatment of hepatorenal syndrome.
Publication Types:
PMID: 10792112 [PubMed - indexed for MEDLINE]
[#9] Restoration of the uricosuric effect of probenecid after
triglycylvasopressine administration in a gouty patient.
Decaux G, Soupart A, Musch W, Hannotier P, Prospert F.
Hopital Universitaire Erasme, Universite Libre de Bruxelles, Belgium.
Clin Nephrol 1998 Oct;50(4):262-5
A 35-year-old patient with severe gout and mild renal insufficiency presented very low urinary
urate excretion. Volume expansion induced by fludrocortisone combined or not with a
uricosuric drug (Benzbromarone) was unable to significantly increase his urate excretion. A
combined Probenecid (PB) and Pyrazinamide (PZA) test was performed. These drugs being
considered to affect renal tubular reabsorption or secretion. No significant modification of uric
acid fractional excretion (FE.uric acid) was observed after PB and PZA. When the same test
was performed after the administration of Triglycyl-lysine vasopressine (TGLV), a potent V1
receptor stimulator, we observed a three fold increase in FE.uric acid after PB intake (from 6 to
18%) followed by a decrease after PZA (from 18 to 5.6%). When TGLV was administered
alone their was no significant modification of uric acid fractional excretion. We propose that
TGLV decrease proximal tubular urate reabsorption that could only be detected when postsecretory reabsorption is blocked by an uricosuric drug. PMID: 9799074 [PubMed - indexed for MEDLINE]
[#10] Hepatorenal syndrome in cirrhotic patients: terlipressine is a safe and
efficient treatment; propranolol and digitalic treatments: precipitating and
preventing factors?
Duhamel C, Mauillon J, Berkelmans I, Bourienne A, Tranvouez JL.
Am. J. Gastroenterol. 95, 2984-2985, 2000
Publication Types:
PMID: 11051385 [PubMed - indexed for MEDLINE]
[#11] Natriuretic response to the combination of atrial natriuretic peptide and
terlipressin in patients with cirrhosis and refractory ascites.
Gadano A, Moreau R, Vachiery F, Soupison T, Yang S, Cailmail S, Sogni P, Hadengue A,
Durand F, Valla D, Lebrec D.
Laboratoire d'Hemodynamique Splanchnique, Unite de Recherches de Physiopathologie
Hepatique, INSERM U-24, Hopital Beaujon, Clichy, France.
J Hepatol 1997 Jun;26(6):1229-34
BACKGROUND/AIMS: Refractory ascites, which occurs in certain patients with cirrhosis, is
associated with a blunted natriuretic response to exogenous atrial natriuretic peptide (ANP).
Since this blunting seems to be related to ANP-induced arterial hypotension, a vasoconstrictor,
such as terlipressin (a vasopressin analogue), may restore natriuresis to exogenous ANP.
Moreover, since cirrhosis-elicited vasodilation is thought to play a role in sodium retention, a
vasoconstriction caused by terlipressin alone may lead to an increase in sodium excretion. This
study aimed to evaluate the natriuretic response to either a combination of ANP with
terlipressin or terlipressin alone in patients with cirrhosis and refractory ascites. METHODS:
Sixteen consecutive patients with cirrhosis and refractory ascites were randomly assigned to
receive either a combination of terlipressin (1-2 mg, i.v. bolus) with ANP (35 ng/kg, i.v. bolus
followed by 15 ng x kg(-1) x min(-1) for 60 min) (n=8) or terlipressin alone (1-2 mg, i.v. bolus)
(n=8). Sodium excretion and urine output, systemic, splanchnic and renal hemodynamics and
renal oxygen consumption were measured before and during treatments. RESULTS: Combined
therapy did not change arterial pressure but significantly increased urinary sodium excretion
and urine output. These effects were associated with a significant increase in glomerular
filtration rate and a decrease in renal oxygen consumption. Terlipressin alone significantly
increased arterial pressure but did not change urinary sodium excretion or urine output.
Therapy of hepatorenal Syndrom with Terlipressin Moreover, terlipressin did not change either glomerular filtration rate or renal oxygen consumption. CONCLUSIONS: The combination of exogenous ANP with terlipressin, but not terlipressin alone, increases sodium excretion in patients with cirrhosis and refractory ascites. Publication Types: • PMID: 9210608 [PubMed - indexed for MEDLINE]
[#12] Hepatorenal syndrome. Long-term treatment with terlipressin as a
bridge to liver transplantation.
Ganne-Carrie N, Hadengue A, Mathurin P, Durand F, Erlinger S, Benhamou JP.
Service d'Hepatologie, Hopital Beaujon, Clichy, France.
Dig Dis Sci 1996 Jun;41(6):1054-6
In patients with hepatorenal syndrome (HRS), 4-hr administration of a vasopressin analog has
recently been shown to benefit renal blood flow and renal function. However, long-term effects
and tolerance of this treatment have not been reported. We report a case of HRS that was
controlled by the vasopressin analog, terlipressin. Because HRS repeatedly relapsed when
treatment was discontinued, terlipressin, 2 mg/day was administered for 67 days, until liver
transplantation could be performed in a patient with normal renal function. Except for limited
cutaneous necrosis at an injection point, prolonged treatment with this vasopressin analog was
well tolerated.
PMID: 8654133 [PubMed - indexed for MEDLINE]

[#13] Disease of the month: Hepatorenal syndrome.
Gines P, Arroyo V.
Liver Unit, Institut de Malalties Digestives, Hospital Clinic, Barcelona, Catalunya, Spain.
gines@medicina.ub.es
J Am Soc Nephrol 1999 Aug;10(8):1833-1839
Publication Types:
•
PMID: 10446954 [PubMed - indexed for MEDLINE] "Haemopressin® (active ingredient TERLIPRESSIN) helps to save lives"

[#14] Long-term therapy and retreatment of hepatorenal syndrome type 1
with ornipressin and dopamine.
Gülberg V, Bilzer M, Gerbes AL.
Department of Medicine II, Klinikum Grosshadern, University of Munich, Munich, Germany.
veit.guelberg@lrz.uni-muenchen.de
Hepatology 1999 Oct;30(4):870-5
Peripheral vasodilation is considered an important factor in the pathophysiology of the
hepatorenal syndrome (HRS). Therefore, the aim of this study was to evaluate the therapeutic
potential of the vasoconstrictor ornipressin plus dopamine in the treatment of the most severe
form of HRS, namely HRS type 1. Seven cirrhotic patients (creatinine clearance 15 +/- 1
mL/min, UNaV 7 +/- 2 mmol/24 h) with HRS type 1 were included in the study after
normalization of central venous pressure with intravenous albumin and low-dose dopamine had
failed to prevent further deterioration of renal function. Ornipressin was given continuously
(intravenous 6 IU/h) in combination with dopamine (2-3 microgram/kg/min) until creatinine
clearance had increased to above 40 mL/min or adverse events prevented further treatment.
HRS was reverted in 4 of 7 patients after 5 to 27 days (creatinine clearance 51 +/- 4 mL/min,
UNaV 47 +/- 11 mmol/24 h) of treatment. Withdrawal was necessary in 1 patient after 15 days
because of intestinal ischemia. Treatment failure was observed in 2 of 7 patients (creatinine
clearance 19 +/- 10 mL/min, UNaV 8 +/- 3 mmol/24 h). Two of 4 responders had recidivant
HRS 2 and 8 months after initial therapy, respectively. HRS in 1 of these patients was reverted
with 18 days of ornipressin retreatment. The other patient had to be withdrawn from ornipressin
after 2 hours because of ventricular tachyarrhythmia. Altogether, 3 of 7 patients survived HRS
type 1, 1 after successful ornipressin therapy and liver transplantation, 1 with 2 successful
courses of ornipressin, and 1 with liver transplantation after ornipressin treatment had failed.
Thus, ornipressin plus dopamine can be a useful therapeutic option in patients with HRS type 1,
especially as bridge to liver transplantation.
PMID: 10498636 [PubMed - indexed for MEDLINE]

[#15] [Successful conservative therapy of hepatorenal syndrome with
vasopressin-1-receptor antagonist ornipressin]
[Article in German]
Gülberg V, Luppa P, Pauletzki J, Paumgartner G, Gerbes AL.
Medizinische Klinik II, Ludwig-Maximilians-Universitat, München.
Z Gastroenterol 1998 Dec;36(12):1053-8
A 47-year-old male patient with alcoholic cirrhosis Child-Pugh grade C was admitted to our
center for evaluation of liver transplantation. Serum creatinine had increased from 1.6 to 4.3
mg/100 ml within the previous two weeks, creatinine clearance was 12 ml/min, and urinary
sodium 12 mmol/24 h. The diagnosis of HRS type I was established. Diuretic treatment was
discontinued. Following albumin infusion, central venous pressure was increased to above 10
cm H2O and dopamine (2 micrograms/kg/min) infusion was started. However, renal function
Therapy of hepatorenal Syndrom with Terlipressin did not improve. An i.v. infusion of ornipressin (POR8, Sandoz; 6 IU/h) was started and dopamine infusion continued. During a four-hour interval, urinary volume and sodium excretion doubled. Therefore treatment was continued for three weeks. After 22 days, renal function had normalized (creatinine 1.2 mg/100 ml, creatinine clearance 65 ml/min, urinary sodium 62 mmol/24 h) and diuretic therapy was resumed. No adverse effects were observed. Ornipressin/dopamine infusion was discontinued and renal function remained normal. Three weeks later, the patient underwent liver transplantation with normal renal function. Ornipressin infusion had no effect on circulating endothelin, but decreased the activation of the renin-aldosterone system and of the sympathetic activity. So far, no noninvasive therapy of hepatorenal syndrome has been established. This is the first report of successful medical treatment of HRS type I with a three-week infusion of the vasopressin-l-receptor agonist ornipressin. PMID: 10025057 [PubMed - indexed for MEDLINE]
[#16] Beneficial effects of the 2-day administration of terlipressin in patients
with cirrhosis and hepatorenal syndrome.
Hadengue A, Gadano A, Moreau R, Giostra E, Durand F, Valla D, Erlinger S, Lebrec D Laboratoire d'Hemodynamique Splanchnique et de Biologie Vasculaire, INSERM and Service d'Hepatologie, Hopital Beaujon, Clichy, France. BACKGROUND/AIMS: A treatment to induce a sustained increase in glomerular filtration rate in patients with hepatorenal syndrome has not yet been identified. Thus, the aim of the present study was to investigate the effects of terlipressin for 2 days on the glomerular filtration rate in patients with cirrhosis and hepatorenal syndrome. METHODS: A double-blind, cross-over randomized study was performed in nine patients. Patients received terlipressin (2 mg/day for 2 days) and a placebo for 2 days in a randomized order. RESULTS: Terlipressin administration significantly increased creatinine clearance (from 15+/-2 ml/min to 27+/-4 ml/min) and urine output (from 628+/-67 ml/day to 811+/-76 ml/day), but did not significantly change urinary sodium concentrations. Urinary sodium excretion was not significantly different after placebo administration (0.6+/-0.1 mmol/24 h) and terlipressin administration (9.3+/-7.2 mmol/24 h). Terlipressin administration significantly decreased plasma concentrations of renin and aldosterone but not atrial natriuretic peptide levels. Placebo elicited no significant effects. CONCLUSIONS: This study shows that 2-day terlipressin administration increases the glomerular filtration rate in patients with cirrhosis and hepatorenal syndrome. MIT FREUNDLICHER EMPFEHLUNG VON
Pharma GmbH

[#17] A discussion of how terlipressin limits mortality in cases of bleeding
oesophageal varices.
Laboratoire d'Hemodynamique Splanchnique et de Biologie Vasculaire, Unite de Recherches de Physiopathologie Hepatique (INSERM), Hopital Beaujon, Clichy, France. Eur J Gastroenterol Hepatol 10(7): 549-552, 1998 (Jul) Bleeding oesophageal varices (BOV) are a potentially life-threatening complication of portal hypertension. While endoscopic sclerotherapy and banding ligation are often employed in an attempt to arrest bleeding, the use of vasoactive pharmacological agents to control haemorrhage has a number of advantages. While many of the available vasoactive agents control acute bleeding and may exert a beneficial influence over hepatic haemodynamics, terlipressin (triglycyl lysine-vasopressin) is the only agent that has been shown actually to decrease mortality in cases of BOV. It is hypothesized that this increase in survival rate is due to the apparently unique multifactorial influence of terlipressin over variceal haemostasis and blood flow, hepatic and gastric haemodynamics and renal function, combined with the likelihood of only minimal adverse events. [#18] Treatment with terlipressin as a bridge to liver transplantation in a
patient with hepatorenal syndrome.
Le Moine O, el Nawar A, Jagodzinski R, Bourgeois N, Adler M, Gelin M, Cremer M Department of Gastroenterology, Hopital Erasme, Universite Libre de Bruxelles, Belgium. Acta Gastroenterol Belg 61(2): 268-270, 1998 (Apr-Jun) Hepatorenal syndrome is a rapidly lethal complication of cirrhosis. The present case provides further evidence of the efficacy of terlipressin in this context even with concomitant treatment with propranolol. A 56 year old male with HBV related cirrhosis developed renal failure characteristic of hepatorenal syndrome. He was also taking propranolol for primary prophylaxis of variceal bleeding. Terlipressin 6 mg/day was administered during haemodialysis and after 1 week plasma creatinine dropped from 6.2 to 2.8 mg%. Daily urinary volume, plasma sodium and natriuresis dramatically increased during the treatment. Discontinuation of the treatment led to a rapid relapse of renal failure (plasma creatinine from 1.8 to 2.2 mg%) and the drug was readministered until a successful liver transplantation could be performed 1 month after the beginning of the treatment. The patient has now a near normal renal function 3 months after transplantation. "Haemopressin® (Wirkstoff TERLIPRESSIN) hilft Leben retten"
Therapy of hepatorenal Syndrom with Terlipressin [#19] Terlipressin in patients with cirrhosis and type 1 hepatorenal
syndrome: A retrospective multicenter study.

Moreau R, Durand F, Poynard T, Duhamel C, Cervoni JP, Ichai P, Abergel A, Halimi C,
Pauwels M, Bronowicki JP, Giostra E, Fleurot C, Gurnot D, Nouel O, Renard P, Rivoal M,
Blanc P, Coumaros D, Ducloux S, Levy S, Pariente A, Perarnau JM, Roche J, Scribe-Outtas M,
Valla D, Bernard B, Samuel D, Butel J, Hadengue A, Platek A, Lebrec D, Cadranel JF.

INSERM U-481 et Service d'Hepatologie, Hopital Beaujon, Clichy, France; Service d'Hepato-
Gastroenterologie, Groupe Hospitalier Pitie-Salpetriere, Paris, France; Service de Gastroenterologie,
Centre Hospitalier, Le Havre, France; Service d'Hepato-Gastroenterologie, Hopital Fontenoy, Chartres,
France; Centre Hepato-Biliaire, Hopital Paul Brousse, Villejuif, France; Service d'Hepato-
Gastroenterologie, CHU Hotel-Dieu, Clermont-Ferrand, France; Service d'Hepato-Gastroenterologie,
Centre Hospitalier, Senlis, France; Service de Medecine B, Centre Hospitalier, Abbeville, France;
Service d'Hepato-Gastroenterologie, CHU Nancy-Brabois, Vandoeuvre-les-Nancy, France; Unite de
Greffe, HUG-Hopital Cantonal, Geneve, Switzerland; Service d'Anesthesie-Reanimation, CHU de
Bordeaux, Centre Medico-Chirurgical de la Maison du Haut Leveque, Groupe Hospitalier Sud, Pessac,
France; Service de Gastroenterologie, Centre Hospitalier Jean Coulon, Gourdon, France; Service
d'Hepato-Gastroenterologie, Centre Hospitalier la Beauche, Saint-Brieuc, France; Service d'Hepato-
Gastroenterologie, Centre Hospitalier Victor Dupouy, Argenteuil, France; Service d'Anesthesie-
Reanimation-Urgences, Etablissement Public de Sante, Arpajon, France; Service d'Hepato-
Gastroenterologie, Hopital Saint-Eloi, Montpellier, France; Service d'Hepato-Gastroenterologie, CHU-
Hopital Civil, Strasbourg, France; Service d'Alcoologie, CHU-Hopital Jean Minjoz, Besancon, France;
Service d'Hepato-Gastroenterologie, Hopital Robert Debre, CHU de Reims, Reims, France; Service
d'Hepato-Gastroenterologie, Centre Hospitalier, Pau, France; Service de Medecine B, CHR Notre-Dame
de Bon-Secours, Metz, France; Service de Medecine Interne, Centre Hospitalier, Roanne, France;
Service d'Hepato-Gastroenterologie, Centre Hospitalier, Ussel, France; and Unite d' Hepatologie, Centre
Hospitalier Laennec, Creil, France.
Gastroenterology 2002 Apr; 122(4): 923-930
Background & Aims: Type 1 hepatorenal syndrome (HRS) is a severe complication of cirrhosis
associated with a short median survival time (<2 weeks). Although the administration of
terlipressin improves renal function, its effect on survival is unknown. This study investigated
predictive factors of survival in patients with type 1 HRS treated with terlipressin. METHODS:
Ninety-nine patients with type 1 HRS treated with terlipressin in 24 centers were
retrospectively studied. Terlipressin-induced improved renal function was defined as a decrease
in serum creatinine value to <130 &mgr;mol/L or a decrease of at least 20% at the end of
treatment. RESULTS: At inclusion, the Child-Pugh score was 11.8 +/- 1.6 (mean +/- SD).
Terlipressin (3.2 +/- 1.3 mg/day) was administered for 11 +/- 12 days. Renal function improved
in 58% of patients (serum creatinine decreased by 46% +/- 17% from 272 +/- 114
&mgr;mol/L). Median survival time was 21 days. Survival rate was 40% at 1 month.
Multivariate analysis showed that improved renal function and Child-Pugh score </=11 at
inclusion were independent predictive factors of survival (P < 0.0001 and 0.02, respectively).
Thirteen patients underwent liver transplantation (92 +/- 95 days after HRS onset), 10 of whom
had received terlipressin and had had improved renal function. CONCLUSIONS: This
retrospective uncontrolled study shows that in patients with type 1 HRS, terlipressin-induced
improved renal function is associated with an increase in survival. Thus, a randomized trial
investigating the effect of terlipressin on survival in patients with type 1 HRS should be
performed.
PMID: 11910344 [PubMed - as supplied by publisher]
[#20] Long-term terlipressin administration improves renal function in
cirrhotic patients with type 1 hepatorenal syndrome: a pilot study.

Mulkay JP, Louis H, Donckier V, Bourgeois N, Adler M, Deviere J, Le Moine O.
Department of Gastroenterology, Hopital Erasme, Universite Libre de Bruxelles (ULB),
Brussels, Belgium.
Acta Gastroenterol Belg 64 (1): 15-19, 2001
BACKGROUND: Hepatorenal syndrome (HRS) is a severe complication of liver cirrhosis.
Recently, ornipressin, a potent splanchnic vasoconstrictor, was reported to improve renal
function in patients with HRS. However, this treatment is associated with a high incidence of
vascular complications. Terlipressin is thought to be as effective as ornipressin with less
systemic complications.
AIMS: To evaluate the effectiveness and safety of terlipressin administration in cirrhotic
patients with type 1 HRS.
PATIENTS: Twelve consecutive patients fulfilling HRS criteria of the International Ascites
Club were included in the study. Median plasma creatinine and sodium, urine volume and
sodium before treatment were 3.4 mg% (2.5-4.0); 127 mEq/l (124-130), 500 ml/24 h (100-
1031) and 7 mEq/24 h (1-17).
METHODS: Terlipressin was administered i.v. 2 mg bid in 8 patients and tid in 4 others for at
least one week and up to 2 months.
RESULTS: After one week of treatment median plasma creatinine decreased to 1.8 mg% (1.3-
2.1) together with an increase in urine volume, sodium excretion, creatinine and free-water
clearance. Three patients underwent successful liver transplantation with a near normal renal
function after 34, 36 and 111 days. The 9 other patients died during follow-up (4 from sepsis, 2
from digestive bleeding and 3 from liver failure). No ischaemic complications were
encountered during the treatment.
CONCLUSIONS: Long-term terlipressin administration is safe and effective to control type 1
HRS. However, it does not cure the underlying disease and therefore, may only be considered
as a bridge to a definitive treatment as liver transplantation.


[#21] Hepatorenal Syndrome.
Planas R, Bataller R, Rodes J.
Liver Section, Gastroenterology Department, Hospital Universitari Germans Trias i Pujol,
Carretera del Canyet, 08916 Badalona, Spain.
Curr Treat Options Gastroenterol 2000 Dec;3(6):445-450
The management of the hepatorenal syndrome (HRS) constitutes a major challenge for
clinicians. Because HRS is a functional disorder due to advanced liver disease and is associated
Therapy of hepatorenal Syndrom with Terlipressin with a very low survival expectancy, orthotopic liver transplantation (OLT) is the only effective and permanent treatment for patients with HRS. However, OLT is not applicable to all cirrhotic patients despite the presence of HRS. In addition, because of the poor prognosis of HRS and the prolonged waiting lists in most transplant centers a significant proportion of these patients may die before OLT is possible. Therefore, there is a need for effective therapies for HRS that improve renal function and increase survival. Such treatments are of interest not only as a bridge to OLT but also as a therapy for patients who are not candidates for transplantation. Preliminary studies have suggested that the administration of splanchnic vasoconstrictors such as terlipressin in combination with volume expanders or the insertion of transjugular intrahepatic portosystemic shunts (TIPS) may improve renal function in patients with HRS. However, before these treatments are widely recommended further studies are necessary. PMID: 11096604 [PubMed - as supplied by publisher]

[#22] Terlipressin plus albumin infusion: an effective and safe therapy of
hepatorenal syndrome.
Uriz J, Gines P, Cardenas A, Sort P, Jimenez W, Salmeron JM, Bataller R, Mas A, Navasa M, Arroyo V, Rodes J Institut de Malalties Digestives, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomediques August Pi-Sunyer, Catalunya, Spain. BACKGROUND/AIM: Ornipressin, a vasopressin analog with potent splanchnic vasoconstrictor action, has been shown to reverse hepatorenal syndrome. However, its usefulness in clinical practice is limited by frequent ischemic complications. The aim of this study was to assess the efficacy of terlipressin, an analog of vasopressin with a low profile of side effects, plus albumin in this condition. METHODS: Nine consecutive patients with cirrhosis and hepatorenal syndrome were included in a pilot study of terlipressin (0.5-2 mg/4 h i.v.) therapy associated with iv albumin. RESULTS: Treatment (9 days, range 5-15) was associated with a marked reduction of serum creatinine (3.9+/-0.7 to 1.3+/-0.1 mg/dl, p<0.001, mean+/-SE). Reversal of hepatorenal syndrome (reduction of creatinine below 1.5 mg/dl) was observed in seven of the nine patients. There was a remarkable improvement in circulatory function, with an increase in mean arterial pressure (68+/-2 to 80+/-4 mmHg, p<0.05) and suppression of vasoconstrictor systems activity (plasma renin activity and plasma norepinephrine decreased from 23+/-12 ng/ml x h and 1549+/-373 pg/ml to 3.5+/-2 ng/ml x h and 373+/-98 pg/ml, respectively, p<0.01 for both). No patient developed signs of intestinal, myocardial or distal ischemia. CONCLUSIONS: Terlipressin associated with albumin appears to be a safe and effective treatment of hepatorenal syndrome. "Haemopressin® (active ingredient TERLIPRESSIN) helps to save lives"

[#23] Increased plasma levels of neuropeptide Y in hepatorenal syndrome.
Uriz J, Ginès P, Ortega R, Jimenez W, Cardenas A, Calahorra B, Sort P, Fernandez J, Bataller
R, Arroyo V, Rivera F, Rodes J.
Liver Unit, Institut de Malalties Digestives, Hospital Clinic, Barcelona, Spain
J Hepatol 2002 Mar;36(3):349-55
Background/Aims: To investigate the relationship between neuropeptide Y (NPY), a potent
renal vasoconstrictor peptide released upon marked stimulations of sympathetic nervous system
(SNS), and renal and circulatory function in cirrhosis.Methods: Plasma levels of NPY
(radioimmunoassay) and norepinephrine and renal function parameters were determined in 17
healthy controls, nine patients with cirrhosis without ascites, and 37 patients with cirrhosis and
ascites, of whom 12 had hepatorenal syndrome (HRS).Results: Patients with ascites showed
circulating levels of NPY similar to those of patients without ascites and controls (73plus
minus4, 76plus minus4 and 68plus minus4pmol/l, respectively; NS). However, patients with
HRS had significantly increased levels of NPY with respect to the other groups (110plus
minus6pmol/l; P<0.001). NPY levels correlated inversely with renal plasma flow and
glomerular filtration rate and directly with norepinephrine. In patients with HRS (n=6)
treatment with terlipressin and albumin was associated with a marked improvement in
circulatory and renal function and marked suppression of NPY and norepinephrine
levels.Conclusions: Patients with HRS have increased levels of NPY which are related to
circulatory dysfunction and SNS activation and may contribute to renal vasoconstriction.
PMID: 11867178 [PubMed - in process]
[#24] Das hepatorenale Syndrom; Pathophysiologie, Diagnostik und
Therapie.
Deutsches Ärtzteblatt 43, A2858-A2862, 2000 (review).
[#25] New challenge of hepatorenal syndrome: prevention and treatment.
Wong F, Blendis L.
Division of Gastroenterology, Department of Medicine, The Toronto General Hospital,
University of Toronto, Ontario, Canada.
Hepatology 34(6):1242-1251, 2001
Hepatorenal syndrome (HRS) remains one of the major therapeutic challenges in hepatology
today. The pathogenesis is complex, but the final common pathway seems to be that
Therapy of hepatorenal Syndrom with Terlipressin sinusoidal portal hypertension, in the presence of severe hepatic decompensation, leads to splanchnic and systemic vasodilatation and decreased effective arterial blood volume. Renal vasoconstriction increases concomitantly, renal hemodynamics worsens, and renal failure occurs. Renal failure was shown 15 years ago to be potentially reversible after liver transplantation. This potential reversibility together with increased understanding of the pathogenesis has led to successful preliminary attempts to reverse HRS nonsurgically with combinations of splanchnic vasoconstrictors and colloid volume expansion, insertion of transjugular intrahepatic portovenous shunt radiologically, and improved forms of dialysis. Recent classification of HRS into the acute onset or severe type 1 with virtually 100% mortality and the more insidious less severe type II promises to shed more light on the pathogenesis of HRS, especially on the currently unrecognized precipitating factors. It is hoped that this classification will be included in the necessary and carefully performed clinical trials, which should lead to clearer indications for the available therapies. The challenge now is to use all this information to improve our management of cirrhotic patients to prevent occurrence of HRS in the future. Publication Types: PMID: 11732014 [PubMed - indexed for MEDLINE] WITH COMPLIMENTS
MIT FREUNDLICHER EMPFEHLUNG VON
Pharma GmbH
"Haemopressin® (active ingredient TERLIPRESSIN) helps to save lives"
"Haemopressin® (Wirkstoff TERLIPRESSIN) hilft Leben retten"
Literature on terlipressin, ornipressin and hepatorenal syndrome
1. Arroyo V, Guevara M, Ginès P.: Hepatorenal syndrome in cirrhosis: pathogenesis and treatment. Gastroenterology 122(6), 1658-1676, 2002. 2. Arroyo V., Jimenez W.: Complications of cirrhosis. II: Renal and circulatory dysfunction. Lights and shadows in an important clinical problem. J. Hepatol. 32, Suppl. 1, 157-170, 2000 (review). 3. Bataller R, Gines P, Arroyo V, Rodes J.: Hepatorenal syndrome. Clin Liver Dis 4,487-507,2000. 4. Bonnard Ph., Bernard B., Halimi Ch., Mathurin Ph., Demontis R., di Martino V., Henry-Biabaud E., Mofredj A., Poynard T., Cadranel JF.: Effect of terlipressine (glypressine) on hepatorenal syndrome (HRS) in cirrhotic patients: Results of a pilot study. Gastroenterology 114 (4), A 1214, 1998 (abstract). 5. Cardenas A, Gines P, Uriz J, Bessa X, Salmeron JM, Mas A, Ortega R, Calahorra B, De Las Heras D, Bosch J, Arroyo V, Rodes J.: Renal failure after upper gastrointestinal bleeding in cirrhosis: incidence, clinical course, predictive factors, and short-term prognosis. Hepatology 34(4 Pt 6. Cardenas A, Uriz J, Gines P, Arroyo V.: Hepatorenal syndrome. Liver Transpl 6 (4 Suppl 1), S63- 7. Cervoni J.P., Lecomte T., Cellier C., Auroux J., Simon C., Landi B., Gadano A., Barbier J.P.: Terlipressin may influence the outcome of hepatorenal syndrome complicating alcoholic hepatitis. Am. J. Gastroenterol. 92, 2113-2114, 1997. 8. Dagher L, Patch D, Marley R, Moore K, Burroughs A.: Review article: pharmacological treatment of the hepatorenal syndrome in cirrhotic patients. Aliment Pharmacol Ther 14(5), 515-21, 2000 9. Decaux G., Soupart A., Musch W., Hannotier P., Prospert F.: Restoration of the uricosuric effect of probenecid after Triglycylvasopressine administration in a gouty patient. Clinical Nephrol. 50, 10. Duhamel C, Mauillon J, Berkelmans I, Bourienne A, Tranvouez JL: Hepatorenal syndrome in cirrhotic patients: terlipressine is a safe and efficient treatment; propranolol and digitalic treatments: precipitating and preventing factors?. Am.J. Gastroenterol. 95, 2984-2985, 2000. 11. Gadano A., Moreau R., Vachiery F., Soupison T., Yang S., Cailmail S., Sogni P., Hadengue A., Durand F., Valla D., Lebrec D.: Natriuretic response to the combination of atrial natriuretic peptide and terlipressin in patients with cirrhosis and refractory ascites. J. Hepatol. 26, 1229- 12. Ganne-Carrié N., Hadengue A., Mathurin P., Durand F., Erlinger S., Benhamou J.-P.: Hepatorenal syndrome: long-term treatment with terlipressin as a bridge to liver transplantation. Dig. Diseases and Sciences 41, 1054-1056, 1996. 13. Ginès P., Arroyo V.: Disease of the month: Hepatorenal syndrome. J. Am. Soc. Nephrol. 10, 14. Gülberg V, Bilzer M, Gerbes AL.: Long-term therapy and retreatment of hepatorenal syndrome type 1 with ornipressin and dopamine. Hepatology 30, 870-875,1999. 15. Gülberg V, Luppa P, Pauletzki J, Paumgartner G, Gerbes AL.: [Successful conservative therapy of hepatorenal syndrome with vasopressin-1-receptor antagonist ornipressin][Article in German]. Z Gastroenterol 36, 1053-1058, 1998. 16. Hadengue A., Gadano A., Moreau R., Giostra E., Durand F., Valla D. Erlinger S., Lebrec D.: Beneficial effect of the 2-day administration of terlipressin in patients with cirrhosis and hepatorenal syndrome. J. Hepatol. 29, 565-570, 1998. 17. Lebrec D.: A discussion of how terlipressin limits mortality in cases of bleeding oesophageal varices. Eur. J. Gastroenterol. Hepatol. 10, 549-552, 1998 (review). Therapy of hepatorenal Syndrom with Terlipressin 18. Le Moine O., el Nawar A., Jagodzinski R., Bourgeois N., Adler M., Gelin M., Cremer M.: Treatment with terlipressin as a bridge to liver transplantation in a patient with hepatorenal syndrome. Acta Gastroenterol. Belg. 61, 268-270, 1998. 19. Moreau R, Durand F, Poynard T, Duhamel C, Cervoni JP, Ichai P, Abergel A, Halimi C, Pauwels M, Bronowicki JP, Giostra E, Fleurot C, Gurnot D, Nouel O, Renard P, Rivoal M, Blanc P, Coumaros D, Ducloux S, Levy S, Pariente A, Perarnau JM, Roche J, Scribe-Outtas M, Valla D, Bernard B, Samuel D, Butel J, Hadengue A, Platek A, Lebrec D, Cadranel JF.: Terlipressin in patients with cirrhosis and type 1 hepatorenal syndrome: A retrospective multicenter study. 20. Mulkay JP, Louis H, Donckier V, Bourgeois N, Adler M, Deviere J, Le Moine O: Long-term terlipressin administration improves renal function in cirrhotic patients with type 1 hepatorenal syndrome: a pilot study. Acta Gastroenterol. Belg. 64, 15-19, 2001. 21. Planas R, Bataller R, Rodes J.: Hepatorenal Syndrome. Curr Treat Options, Gastroenterol 3; 22. Uriz J., Gines P., Cardenas A., Sort P., Jiminez W., Salmeron J.M., Bataller R., Mas A., Navasa M., Arroyo V., Rodes J.: Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. J. Hepatol. 33, 43-48, 2000. 23. Uriz J, Gines P, Ortega R, Jimenez W, Cardenas A, Calahorra B, Sort P, Fernandez J, Bataller R, Arroyo V, Rivera F, Rodes J.: Increased plasma levels of neuropeptide Y in hepatorenal 24. von Schrenck T., Wolf G.: Das hepatorenale Syndrom; Pathophysiologie, Diagnostik und Therapie. Deutsches Ärtzteblatt 43, A2858-A2862, 2000 (review). 25. Wong F, Blendis L.: New challenge of hepatorenal syndrome: prevention and treatment.

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