Hepatorenal syndrome (HRS) is a form of prerenal kidney failure occurring in patients with end-stage liver disease or acute liver failure. Two types of HRS have been identified. Type 1 is an acute and rapidly progressive form that often develops after a precipitating factor such as gastrointestinal bleeding or spontaneous bacterial peritonitis. Type 2 is a slowly progressive form of renal failure that often occurs spontaneously in chronic ascites settings. The hallmark of HRS is severe vasoconstriction of the renal circulation to compensate for the characteristic circulatory disorders of advanced cirrhosis (1,2). HRS diagnosis is based on criteria established by the International Ascites Club (IAC) (3). Although recently revised, they remain difficult to apply to young children because of the lack of specific pediatric criteria (4). HRS is a potentially reversible condition, but its natural prognosis is poor, especially for type 1. Liver transplantation (LT) is the only treatment that ensures long-term survival, and thus it remains the principal treatment in both adults and children (4,5). Vasoconstrictor therapy with vasopressin analogues, mainly terlipressin, has been shown to improve renal function and survival in adults (4). To our knowledge, there is no published data on the use of vasopressin analogues in the treatment of children with HRS. We report on 4 children with end-stage liver disease who received terlipressin treatment for renal failure compatible with HRS.
Patient renal parameters at baseline and before and with terlipressin are summarized in Table 1. All of the patients received continuous 24 hour/24 hour infusion of terlipressin (Glypressin 30 μg · kg−1 · day−1) and albumin (1 g · kg−1 · day−1). In all of the children, body weight was overestimated due to the presence of voluminous ascites.
She underwent Kasai operation for biliary atresia at 2 months of age with secondary failure at 5 years, and was registered on the LT waiting list. At
years she weighed 18 kg (mean; body mass index 15.7 kg/m2), was 107 cm (−0.75 SD) tall, and presented with hepatosplenomegaly and tense ascites. Serum liver tests were abnormal: total bilirubin 816 μmol/L (N < 17), albumin 27 g/L (N ≥ 35 g/L), prothrombin time 73% (N > 70%), clotting factor V (FV) 46% (N > 80%), alanine aminotransferase (ALAT) 3 × N, and gamma-glutamyltransferase (GGT) 4 × N. Child Pugh class was C. Spironolactone therapy was initiated. Patient condition deteriorated with hyperthermia without signs of sepsis or bacterial peritonitis. Intravenous broad-spectrum antibiotics were started on an empirical basis. Microbiological investigations remained negative, and antibiotics were withdrawn after 3 days. Thereafter, the patient presented gastrointestinal bleeding without circulatory failure. Endoscopy showed grade III esophageal varices, treated with sclerotherapy. Bleeding episode was followed by an acute renal dysfunction and oliguria (<1 mL · kg−1 · hour−1), which did not improve after adequate fluid expansion with blood or albumin infusions and spironolactone withdrawal. Urinary sediment was negative for hematuria, cylinders, or proteinuria, and renal ultrasound scan was normal. HRS was suspected, and terlipressin treatment was started. No side effect due to treatment was noted. Serum creatinine slightly decreased, urine output increased, and the patient underwent emergency LT 5 days later. Renal function gradually improved, and terlipressin was withdrawn 5 days after LT. Nine years after LT, kidney function tests are normal with tacrolimus immunosuppression.
A 13-year-old boy with cystic fibrosis and cirrhosis (Child Pugh class C) had experienced, from age 9 years, recurrent episodes of ascites treated with spironolactone. Gastrointestinal bleeding due to esophageal varice rupture was treated with sclerotherapy at age 12. Physical examination revealed tense ascites and hepatosplenomegaly. He weighed 34 kg (−1 SD; body mass index 17.8 kg/m2) and was 138 cm (−2 SD) tall. Serum liver tests showed PT 40%, FV 22%, total bilirubin 136 μmol/L, albumin 28 g/L, ALAT N, and GGT 8 × N. Hyponatremia was noted, and spironolactone was withdrawn. Ascites was managed with low-volume paracentesis associated with albumin infusions. There was no bacterial peritonitis. The patient was registered on the LT waiting list for refractory ascites and liver failure. Renal function deteriorated progressively in the 2 weeks following admission with oliguria. Urinary sediment was negative for hematuria, cylinders, or significant proteinuria, and a renal ultrasound scan was normal. Renal function did not improve after albumin infusion. HRS was suspected, and terlipressin treatment was started. No side effect due to treatment was noted. Renal function tests normalized as did urine output and natremia. Terlipressin was withdrawn 10 days after treatment onset. The patient later presented with gastrointestinal bleeding treated with octreotide infusions. Liver function deteriorated and he underwent emergency LT. He died 5 days after surgery due to severe Pseudomonas aeruginosa pneumonia.
A 5-month-old girl with biliary atresia had undergone Kasai operation at 3 months of age with no improvement of jaundice and a rapid progression toward end-stage liver cirrhosis (Child Pugh class C). She weighed 4.4 kg (−3 SD; body mass index 12.5 kg/m2) and was 59 cm (−2 SD) tall. She had hard hepatomegaly, enlarged spleen, and tense ascites. Serum liver tests showed ALAT 3 × N, GGT N, total bilirubin 516 μmol/L, albumin 28 g/L, prothrombin time 28%, and FV 15%. She had hyponatremia. Four days later, she had oliguria unresponsive to albumin infusions. There was no bacterial peritonitis. A moderate increase in s-Cr (serum creatinine) level was noted. Renal ultrasound scan was normal, and no traces of hematuria or cylinders were found in urinary sediment. HRS was suspected, and terlipressin treatment was started. Natremia improved; urine output and renal function tests normalized and remained stable after treatment withdrawal 9 days later. No adverse effect was noted. The patient developed uncontrolled sepsis and died.
A 6-month-old girl with biliary atresia and a polymalformative syndrome of unknown origin had undergone Kasai operation at 6 weeks of age with no improvement of jaundice and a rapid progression toward cirrhosis (Child Pugh class C). She weighed 5.4 kg (−2.25 SD; body mass index 17.8 kg/m2) and was 55 cm (−4.5 SD) tall. Physical examination showed hepatosplenomegaly and tense ascites. Serum liver tests showed ALAT 2 × N, GGT 3 × N, total bilirubin 476 μmol/L, albumin 27 g/L, prothrombin time 37%, and FV 41%. There was no bacterial peritonitis. Hyponatremia was noted, and spironolactone was withdrawn. Thereafter, the patient had oliguria and ongoing hyponatremia. Renal function did not improve despite albumin infusions. Urinary sediment was negative for hematuria, cylinders, or significant proteinuria, and renal ultrasound scan was normal. HRS was suspected, and terlipressin treatment was started. No adverse effect was noted. Natremia improved; renal function tests and urine output normalized. Terlipressin was withdrawn 12 days after treatment onset. Renal function remained persistently normal. Because of the polymalformative syndrome, the patient was declared a noncandidate for LT and died.
HRS is a severe complication of end-stage liver disease occurring less frequently in children than in adults (5,6). Reported HRS incidence is 5% for children, but may be underestimated because specific pediatric diagnostic criteria are lacking (7). HRS diagnosis, in both children and adults, is based on criteria established by the IAC (for adult criteria, see Table 2, Supplemental Digital Content 1, http://links.lww.com/MPG/A16) (3,4). These criteria, which aim to exclude other causes of renal failure in the severe liver disease setting, have recently been revised. They now rely mainly on the s-Cr level to estimate the degree of renal failure.
All of the patients reported here presented with end-stage cirrhosis and ascites. Patient 1 developed acute renal failure after gastrointestinal bleeding. No precipitating factor, such as bacterial peritonitis or sepsis, was found for the other 3 patients. Although patients 1, 3, and 4 all presented with acute deterioration of renal function compatible with HRS type 1, patient 2 developed a slowly progressive form of renal failure compatible with HRS type 2. All 4 children had major criteria of HRS with low glomerular filtration rates (GFR) (calculated creatinine clearance [c-CrCl] <40 mL/min and/or s-Cr > 133 μmol/L) (3). Patients 1 and 2 had s-Cr values > 133 μmol/L and c-CrCl values at 14 and 41 mL/min, respectively. Although patients 3 and 4, who were malnourished, did not meet s-Cr cutoff values for HRS, c-CrCl values for both were low at 9 mL/min and 6 mL/min, respectively. All 4 had normal renal ultrasound scans and urinary sediments and were treated with fluid expanders and withdrawal of diuretic treatment without any improvement in renal function. HRS was, therefore, suspected and treatment with terlipressin was started.
Terlipressin is a vasopressin analog that induces vasoconstriction of the splanchnic vascular bed, thereby improving systemic and renal perfusion. It has been shown to be effective in improving renal function and survival in adults with HRS (4,8). Its association with albumin as a plasma volume expander significantly increases its efficacy (9). Terlipressin is now recommended as a first-line treatment in HRS type 1, but the experience in its use in HRS type 2 is limited (4). To our knowledge, there is no report on its use to treat HRS in children, but it has been used as a rescue therapy for refractory shock in children and neonates (10,11). The doses of terlipressin used in these pediatric reports were extrapolated from adult patient reports and varied widely from a unique dose of 15 to 20 μg/kg to 20 μg/kg 4-hourly. All of the patients in our report received terlipressin as a continuous infusion at 30 μg · kg−1 · day−1 associated with albumin infusion until improvement of renal function. All of the patients responded to treatment with a rapid improvement or stabilization of renal function. For patient 1, terlipressin treatment served as a bridge to LT by stabilizing renal function. No adverse effect of terlipressin treatment was noted in any of the 4 children.
A major difficulty in applying current IAC diagnostic criteria to the pediatric population lies in the cutoff value for s-Cr, especially for infants and young children. Although s-Cr level usually has good specificity for low GFR, it is less useful in patients with liver failure and ascites (12,13). Significant change in renal function may not be reflected in increased s-Cr value because of decreased endogenous creatinine production, poor nutrition, and decreased muscle mass. Among our patients, only patients 1 and 2 reached an s-Cr level of 133 μmol/L. However, all of the patients doubled their s-Cr values compared with baseline values. The current diagnostic criteria may be adapted to older children. We suggest a slight modification of the current IAC diagnostic criteria for their application to infants and young children. Because these children have low baseline s-Cr value, we suggest that diagnosis of decreased GFR be based on a doubling of baseline s-Cr level without a lower cutoff limit for s-Cr level (Table 2). Terlipressin seems to be safe and effective in children with HRS. Further investigations are needed to confirm its effectiveness and safety with the proposed pediatric dosage and to validate pediatric diagnostic criteria.
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