ORIGINAL ARTICLE: HEPATOLOGY
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Liver Disease in Autosomal Recessive Polycystic Kidney Disease: Clinical Characteristics and Management in Relation to Renal Failure
Topi T. Luoto, Mikko P. Pakarinen, yTimo Jahnukainen, and yHannu Jalanko
ABSTRACT Objectives: We correlated liver and kidney manifestations in a national cohort of patients with autosomal recessive polycystic kidney disease (ARPKD). Methods: A total of 27 consecutive patients with ARPKD were included. Hepatobiliary disorders were comparatively evaluated in 2 groups: children in group 1 (n ¼ 10) displayed renal failure as infants and those in group 2 (n ¼ 17) had normal kidney function through the first year of life. Results: Median follow-up time was 10.6 (range, 0.4–40) years. Portal hypertension was diagnosed in 13 patients (48%) at the median age 5.0 (1.5– 27.9) years. Esophageal varices developed in 8 patients (30%) at age 8.0 (2.1–11.9) years; 4 patients (15%) had variceal bleeding, and hypersplenism/splenomegaly occurred in 52%, similarly in both groups. Biliary tract dilatation was detected at 2.8 years in group 1 and at 7.9 years in group 2, significantly more frequently in group 1 (60% vs 18%, P ¼ 0.039), causing cholangitis in 2 (20%) versus none in group 2 (P ¼ 0.055). A total of 10 patients (37%) underwent cadaveric liver transplantation (LT) at a median age of 6.6 (1.0–20.0) years. In 1 patient LT was performed because of hepatoblastoma. Nine of these were combined liver–kidney transplantations (CLKT). Patients in group 1 required LT earlier (4.1 years vs 18.2 years, P ¼ 0.017) and more frequently (70% vs 18%, P ¼ 0.01). Overall survival beyond neonatal period was 85%. Two patients died because of infectious complications after CLKT, and 1 patient because of recurrent hepatoblastoma. Conclusions: Although correlation of renal and liver manifestations was variable, biliary dilatation was associated with early renal failure. CLKT may be a treatment for patients with ARPKD with marked hepatobiliary complications. Key Words: autosomal recessive polycystic kidney disease, combined liver–kidney transplantation, congenital hepatic fibrosis, liver disease, liver transplantation
Received November 5, 2013; accepted April 29, 2014. From the Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children’s Hospital, University of Helsinki and Helsinki University Central Hospital, and the yDepartment of Pediatric Nephrology and Transplantation, Children’s Hospital, University of Helsinki and Helsinki University Central Hospital, Finland. Address correspondence and reprint requests to Topi T. Luoto, Section of Pediatric Surgery, Children’s Hospital, Stenba¨ckinkatu 11, PL 281, 00029-HUS, Helsinki, Finland (e-mail: [email protected]). The study was supported by the Foundation for Pediatric Research, the Helsinki University Central Hospital Fund, and the Sigrid Juselius Foundation. The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000422
(JPGN 2014;59: 190–196)
A
utosomal recessive polycystic kidney disease (ARPKD) is one of the most common pediatric renal cystic diseases, with an incidence of 1 in 20,000 live births (1,2). It is caused by mutations in the PKHD1 gene encoding fibrocystin. Genetic defects in fibrocystin lead to fusiform dilatation of the renal collecting system, causing varying degrees of renal insufficiency that require kidney transplantation (KT) in a significant proportion of patients. Fibrocystin is also expressed in the liver, and its erroneous function results in abnormal development and distortion of the biliary tract (1–6). The condition has been termed congenital hepatic fibrosis (CHF), which can be an isolated lesion or occur in conjunction with Caroli syndrome (2,4,7). CHF is considered a ductal plate malformation, in which persistence of immature embryonic bile ducts stimulates the formation of excess fibrous tissue in portal areas. Increased periportal fibrosis may contribute to development of portal hypertension, which results in splenomegaly, hypersplenism, upper gastrointestinal varices, and ascites. Portal venopathy is a process leading to noncirrhotic portal hypertension, and recently it has also been associated with CHF (8,9). Lobular architecture is well preserved in ARPKD, and hepatocellular dysfunction rarely develops in these patients (2,3). The clinical spectrum of ARPKD is diverse, and renal and hepatobiliary disease components advance at varying rates. Two truncating mutations of the PKHD1 gene associate with the most severe manifestations (10). Genotype–phenotype correlation, especially regarding the progression of hepatic lesions, however, is poor (1,3,9–12). The role of liver disease usually becomes increasingly predominant with advancing age. Development of recurrent cholangitis associated with biliary tract dilatation and/ or complications of portal hypertension may necessitate liver transplantation (LT). Indications and optimal timing of KT, LT, and combined liver–kidney transplantation (CLKT) are unclear (2,13–18). In the present work, we analyzed clinical characteristics, treatment, and long-term outcomes of the ARPKD-related liver disease in relation to the onset of renal failure in a cohort of Finnish patients, focusing on the timing of hepatobiliary complications and transplantation therapy.
METHODS Study Population The medical records of children diagnosed as having ARPKD and born between January 1980 and July 2011 were reviewed. In our country, management of patients with ARPKD including liver and kidney transplantations is centralized to Children’s Hospital, Helsinki University Central Hospital. Diagnosis of
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ARPKD was based on family history, typical clinical findings, ultrasound (US) examination demonstrating echogenic microcystic kidneys and periportal fibrosis in the liver, and mutational analysis of the PKHD1 gene.
Liver Disease in Autosomal Recessive Polycystic Kidney Disease was assessed with the Kaplan-Meier method. SPSS version 21.0 (IBM SPSS Statistics, Armonk, NY) was used for statistical analyses (IBM SPSS, Armonk, NY). Level of statistical significance was set at 0.05.
Study Design In total, 33 patients with ARPKD were consecutively enrolled and followed up at our institution. A total of 27 patients survived the neonatal period and formed the actual study group. Collected data included demographics, family history, mutational status, renal function, renal transplantations, infections, medications, pathology reports, endoscopic examinations, surgical interventions, results of imaging studies, timing and characteristics of LTs, cause of death, and survival. Data on the following laboratory tests were collected half-yearly: hemoglobin, platelet and leukocyte levels, markers of cholestasis, liver synthesis and cell damage, renal function, electrolytes, urine samples, and amylase. Portal hypertension was defined as the presence of gastroesophageal varices and/or hypersplenism. The latter was defined as splenomegaly (defined by a pediatric radiologist) and blood platelet count constantly T, c.10412T>G, and c.107C>T. These mutations are found in 75% of the Finnish patients with ARPKD.
Patient Management Neonates with pulmonary hypoplasia needing respiratory support were treated with a conventional ventilator or high-frequency oscillation ventilation from 1995 onward. Peritoneal dialysis, hemodialysis, or hemofiltration was started when end-stage renal disease (ESRD) developed (glomerular filtration rate T and c.1486C>T (n ¼ 5), c.1486C>T and c.10412T>G (n ¼ 5), c.1486C>T and unknown (n ¼ 9), and c.10412T>G and unknown (n ¼ 1). In 13 patients, no mutational status was reported. Two of the 5 patients with 2 truncating mutations c.1486C>T died during the neonatal period of pulmonary hypoplasia. A total of 27 patients surviving the neonatal period formed the actual study group (Table 1), with a median follow-up time of 10.6 (0.4–40) years. A total of 16 patients (60%) had additional minor disorders, including inguinal hernia (n ¼ 5), umbilical hernia (n ¼ 3), psoriasis (n ¼ 2), and strabismus (n ¼ 2). Interestingly, 1 patient had dilatations and stenoses in pancreatic ducts and experienced 8 pancreatitis episodes (in 5 years) before and 3 episodes after CLKT (in 7 years). Overall, 20 patients developed ESRD. Five newborns required early nephrectomy and dialysis during the first week of life because of the massive size of the kidneys. In the remaining 15 patients, ESRD developed at a median age of 3.5 (range 0–18.0) years. Cumulative survival without ESRD at 1, 5, and 10 years was 62%, 50%, and 38%, respectively (Fig. 1). A total of 15 patients (56%) received KT at a median age of 4.1 (range 0.7–28.5) years, and 5 patients underwent kidney retransplantation because of graft failure (Fig. 2). In order to assess association of the onset of chronic renal insufficiency (CRI) (creatinine constantly more than normal range) with hepatobiliary complications and LT, the 27 survivors were divided in 2 groups based on the onset of CRI. Group 1 (n ¼ 10) included patients who developed CRI during the first year of life and group 2 (n ¼ 17) those with onset of CRI after the first year of life. TABLE 1. General characteristics of patients with ARPKD (n ¼ 27) Characteristic Boys Prenatal diagnosis Birth weight, g Pulmonary hypoplasia Growth retardation Arterial hypertension Recurrent pancreatitis Sepsis Renal insufficiency Nephrectomy Renal transplantation Renal retransplantation Exitus
n (%) 15 12 3425 10 16 22 1 7 18 7 15 5 4
(56) (44) (2240–4680) (37) (59) (81) (4) (26) (67) (26) (56) (19) (15)
ARPKD ¼ autosomal recessive polycystic kidney disease. Median (range).
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Proportion without ESRD
1.0
Neonatal death n=6
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ARPKD patients n = 33
0.8 Neonatal survivors n = 27
0.6 0.4 0.2
Primary CLKT n=4 Survival 3/4 (75%)
No transplantations n = 12 Survival 12/12 (100%)
Isolated KT n = 11
0.0 0
2
4
6
8
10
12
14
16
18
20
Time (years)
Isolated LT n=1 Survival 0/1 (0%)
FIGURE 1. Cumulative survival without ESRD (Kaplan-Meier curve). ESRD ¼ end-stage renal disease.
Portal Hypertension Portal hypertension was diagnosed in 13 patients (48%) at a median age of 5.0 (1.5–27.9) years (Table 2). Hepatomegaly was detected in 16 patients (59%), and hypersplenism in 48%. A total of 16 patients (59%) underwent gastroscopy for a median of 8.5 (range 1–19) times. Esophageal varices were found in 8 patients (30%) at a median age of 8.0 (2.1–11.9) years. Four patients experienced variceal bleeding episodes. All 8 patients with varices received sclerotherapy for a median of 8 (1–14) times. The median age at the first sclerotherapy session was 8.7 (2.4–12.2) years. One patient underwent a distal splenorenal shunt to control portal hypertension associated with variceal bleeding. Ascites was found in 5 patients (19%). When comparing groups 1 and 2, no statistically significant differences were found in the frequency or onset of portal hypertension or its complications. Overall, 14 patients (52%) developed symptoms related to the liver disease. Cumulative survival without
All (n ¼ 27) Age at end of follow-up, y Hepatomegaly, % Portal hypertension, % Age at diagnosis, y Hypersplenism, % Age at diagnosis, y Splenomegaly, % Age at diagnosis, y Varices, % Age at diagnosis, y Variceal bleeding, % Biliary tract dilatation, % Age at diagnosis, y Cholangitis, % Caroli syndrome, % Liver Tx, % Age at Tx, y Died, %
10.6 16 13 5.0 13 5.0 14 4.9 8 8.0 4 9 3.0 2 3 10 6.6 4
(0.4–40) (59) (48) (1.5–28) (48) (1.5–28) (52) (0.7–28) (30) (2.1–12) (15) (33) (1.0–13) (7) (11) (37) (1.0–20) (15)
liver symptoms at 1, 5, and 10 years was 100%, 72%, and 42%, respectively.
Biliary Tract Pathology Biliary tract dilatation was verified by US, magnetic resonance imaging, or computed tomography in 9 patients (33%) at a median age of 3.0 (1.0–12.7) years (Table 2). It was significantly more frequent in group 1 (60% vs 18%, P ¼ 0.039) and associated with cholangitis in 2 (20%) group 1 patients versus 0 in group 2 (P ¼ 0.055). Cholangitis was recurrent, needing continued antibiotic prophylaxis in 1 patient, whereas 1 had only a single episode. The imaging findings were pathognomonic for Caroli syndrome in 3 patients, who all belonged to group 1 (P ¼ 0.041). As shown in
Group 1 CRI before 1 y (n ¼ 10) 8.5 8 6 5.1 6 5.1 6 5.1 3 7.1 2 6 2.8 2 3 7 4.1 2
No transplantations n=5 Survival 4/5 (80%)
FIGURE 2. The outcome of 33 patients with ARPKD. ARPKD ¼ autosomal recessive polycystic kidney disease; CLKT ¼combined liver–kidney transplantation; KT ¼ kidney transplantation; LT ¼ liver transplantation.
TABLE 2. Characteristics and comparison of the liver disease in relation to CRI
CLKT n=5 Survival 4/5 (80%)
(1.0–15.0) (80) (60) (1.5–8.7) (60) (1.5–8.7) (60) (0.7–8.7) (30) (2.9–8.8) (20) (60) (1.0–3.5) (20) (30) (70) (1.0–11) (20)
Group 2 CRI after 1 y (n ¼ 17) 16.0 8 7 4.8 7 4.9 8 4.5 5 8.6 2 3 7.9 0 0 3 18.2 2
(0.4–40) (47) (41) (2.1–28) (41) (3.5–28) (47) (1.0–28) (29) (2.1–12) (12) (18) (2.0–13) (0) (0) (18) (13–20) (12)
P 0.170 0.124 0.440 0.836 0.440 0.668 0.695 1.000 1.000 0.571 0.613 0.039 0.262 0.055 0.041 0.013 0.017 0.613
CRI ¼ chronic renal insufficiency; Tx ¼ transplantation. CRI ¼ creatinine level constantly >100 mmol/L. Median (range).
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Table 2, biliary tract dilatation was also observed earlier in group 1 than in group 2, although the difference was not statistically significant (P ¼ 0.262). An US-guided core needle liver biopsy was obtained from 20 patients at a median age of 2.7 (0.03–17.3) years. Histopathological analysis showed CHF in all patients and cholestasis in 5 patients (25%). The pathological report on the explanted liver was available in 8 patients, revealing CHF in all. Portoportal septas and fibrotic areas covered 20% to 75% of the parenchymal area. The hepatocytes between the fibrotic areas were microscopically normal. Cholestasis, cystic dilatation of bile ducts, and hepatoblastoma were found in 4, 3, and 1 of the livers, respectively.
Biochemistry Overall, the evolution of laboratory indicators was comparable in groups 1 and 2. Platelet and leukocyte counts decreased significantly (P < 0.05 in both) during follow-up. Thrombocytopenia (T, c.1486C>T
c.1486C>T, unknown
c.1486C>T, c.10412T>G
c.1486C>T, c.1486C>T
c.1486C>T, c.1486C>T
2
3
4
5
6
7
8
9
10
ESRD, bilateral nephrectomy, and peritoneal dialysis at 1.5 y ESRD, bilateral nephrectomy, and hemodialysis/peritoneal dialysis at 2 wk ESRD, bilateral nephrectomy, and peritoneal dialysis/hemodialysis at 2 wk
ESRD, bilateral nephrectomy, and peritoneal dialysis at 3 y
KT at 2 y, function preserved
KT at 2 y, graft failure because of de novo membranoproliferative glomerulonephritis
KT at 1 y, gradual deterioration of graft function
KT at 11 y, delayed graft function, graft failure at 13 y
KT at 5 y, graft failure at 18 y
KT at 7 y, graft failure at 20 y
Kidney
CLKT at 0.9 y
CLKT at 1.7 y
CLKT at 2.5 y
CLKT at 4.1 y
LT at 5.2 y
CLKT at 8.0 y
CLKT at 10.6 y
CLKT at 13 y
CLKT at 18.2 y
CLKT at 20 y
Liver
Severe hepatomegaly, liver fibrosis 50%, cystic biliary tracts, liver nodules in US and MRI
Hepatosplenomegaly, esophageal and gastrointestinal bleedings, severe hypersplenism Hepatosplenomegaly, poor growth (3.3 SD), portal thrombosis, ascites Hepatosplenomegaly, splenorenal shunt at 10 y, repeated episodes of hyperammonemia, liver fibrosis 50%, cystic biliary tracts Severe hepatosplenomegaly, moderate hypersplenism, poor growth (2.6 SD), liver fibrosis 75%, cholestasis, cholangitis Dilatations and stenoses of pancreatic ducts, large pancreas, repeated episodes of pancreatitis, severe hepatosplenomegaly, poor growth (4.3 SD), liver fibrosis 40%, ascites Chronic cholangitis, severe hepatomegaly, ascites, suspicion of hepatoblastoma (AFP 6553 mg/L, several nodules in liver) Moderate hepatosplenomegaly, poor growth (2.8 SD), liver nodules (up to 36 mm), liver fibrosis 40%, large cysts of biliary tract Moderate hepatosplenomegaly, liver fibrosis 50%, cystic biliary tracts, poor growth (3.5 SD) Moderate hepatosplenomegaly, liver fibrosis 30%, moderate biliary tract dilatations
Findings before CLKT/LT
Death because of CMV infection and RDS at 1 y
Functioning grafts at 11 y
Functioning grafts at 9 y
Functioning grafts at 10 y
Death because of metastatic hepatoblastoma at 10 y
Functioning grafts at 15 y
Functioning grafts at 15 y
Functioning grafts at 20 y
Death because of septic infection at 25 y Functioning grafts at 25 y
Outcome
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CLKT ¼ combined liver–kidney transplantation; CMV ¼ cytomegalovirus; ESRD ¼ end-stage renal disease; KT ¼ kidney transplantation; LT ¼ liver transplantation; MRI ¼ magnetic resonance imaging; RDS ¼ respiratory distress syndrome; SD ¼ standard deviation; US ¼ ultrasound.
N/A
Mutations
1
Patient no.
TABLE 3. Characteristics of liver transplantations
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and cholangitis has been reported, but numbers vary depending on the definitions and imaging modalities (2,11,20,22). A study by Gunay-Aygun et al reported biliary abnormalities in 70% of patients when imaging was based on high-resolution ultrasonography and magnetic resonance cholangiopancreatography (MRCP), and in 40% dilatation was considered to be Caroli syndrome (20). Interestingly, only 1 of their 4 patients with cholangitis had biliary abnormalities (20). In our cohort, MRCP revealed intrahepatic biliary dilatation in the 2 children with cholangitis, and extrahepatic biliary dilatation was seen in 1 patient. One of these patients experienced a single cholangitis episode before KT, and 1 had recurrent episodes after KT. Increased risk of cholangitis and sepsis after isolated KT, especially in patients with ARPKD, has been noted. In a retrospective analysis of 203 patients with polycystic kidney disease and isolated KT, 9 patients (4.4%) died of sepsis posttransplant (22,23). Our cohort included 2 individuals with exceptional disease manifestations whose association with the genetic defect is not clear. A young girl experienced repeated episodes of pancreatitis before and after transplantations. The patient received a KT at age 1.4 years and CLKT at age 8.0 years. Pancreatitis has not been described, to our knowledge, in humans or in animals, although cases of pancreatic cysts have been reported (24,25). One boy with 2 truncating mutations was diagnosed as having hepatoblastoma. Previously only 1 case of hepatoblastoma associated with ARPKD had been reported (26). Three of our neonatal survivors have been homozygous for a truncating mutation c.1486C>T. In general, 2 truncating mutations have been regarded as incompatible with life (12). The indications for isolated KT versus CLKT remain controversial in patients with ARPKD. The liver synthetic capacity is stable in most patients; liver fibrosis and ductal dilatation remain moderate, and the signs of portal hypertension, such as leukopenia, thrombopenia, and esophageal varices, seldom cause major clinical problems when managed adequately. The morbidity and mortality after CLKT are higher than in isolated KT, which all favor the use of KT as the transplant option. Moreover, shortage of organs speaks for isolated KT. Thus, CLKT rate has been low in many large transplant centers and is evident in a recent literature survey, in which 116 patients with ARPKD received transplantation; 56% had undergone isolated KT, 34% had LT, and only 9% had received CLKT (2). In our center, 10 of 27 patients have so far received cadaveric LT; 9 of these were CLKT, and 6 recipients had previously undergone solitary KT. In 1 patient, LT was performed because of hepatoblastoma. Telega et al proposed a decision tree considering the risk/ benefit analysis for each individual patient with ARPKD with dual organ involvement (18). In general, the major posttransplant risks are related to surgery and immunosuppressive medication. For patients with ARPKD requiring KT, surgical mortality is the major issue, because the immunosuppressive medication and its complications are similar after KT and CLKT. In patients with solitary KT, portal hypertension (variceal bleeding, hypersplenism), cholangitis/ sepsis, and cholestasis may cause morbidity and mortality; however, surgical complications (primary nonfunction, hepatic artery or portal vein thrombosis, bile duct strictures) and liver rejection can result in morbidity/mortality in patients with CLKT. According to these proposed guidelines, CLKT should be considered in patients who have both severe renal disease and CHF with serious complications (18). In our experience, there are important additional items affecting the decision making: the present quality of life (impaired because of organomegaly, fear for bleedings, and poor nutrition/ growth), the immunological benefit of using organs from the same donor (better kidney graft survival) (27), and the wish of the patient and parents (after thorough information). www.jpgn.org
Liver Disease in Autosomal Recessive Polycystic Kidney Disease Although the study population represents almost all patients with ARPKD in Finland since 1980, the relatively small number of patients does not allow strong conclusions on the optimal therapy for ARPKD. Another limitation of the present study is that mutations were recorded inconsistently, precluding their use in data analyses. Also, abdominal imaging was not uniform. The use of MRCP and abdominal computed tomography varies greatly in different centers, making reliable comparison over time difficult. The range of biliary abnormalities is extensive, and not all findings are seen in US (20,28). Uniform definitions for the biliary tract changes and Caroli syndrome are needed to formulate more reliable guidelines. In conclusion, many patients with early ARPKD manifestations develop significant hepatobiliary manifestations, including complications of portal hypertension and biliary tract pathology and are successfully treated with CLKT. Acknowledgments: The authors thank the Paediatric Research Centre of Tampere University and Tampere University Hospital for the opportunity to use their working facilities.
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17. Herden U, Kemper M, Ganschow R, et al. Surgical aspects and outcome of combined liver and kidney transplantation in children. Transpl Int 2011;24:805–11. 18. Telega G, Cronin D, Avner ED. New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney–liver complications. Pediatr Transplant 2013;17:328–35. 19. Lampela H, Kosola S, Koivusalo A, et al. Endoscopic surveillance and primary prophylaxis sclerotherapy of esophageal varices in biliary atresia. J Pediatr Gastroenterol Nutr 2012;55:574–9. 20. Gunay-Aygun M, Font-Montgomery E, Lukose L, et al. Characteristics of congenital hepatic fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease. Gastroenterology 2013;144:112– 21. 21. de Ville de Goyet J, D’Ambrosio G, Grimaldi C. Surgical management of portal hypertension in children. Semin Pediatr Surg 2012;21:219–32. 22. Khan K, Schwarzenberg SJ, Sharp HL, et al. Morbidity from congenital hepatic fibrosis after renal transplantation for autosomal recessive polycystic kidney disease. Am J Transplant 2002;2:360–5.
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23. Davis ID, Ho M, Hupertz V, et al. Survival of childhood polycystic kidney disease following renal transplantation: the impact of advanced hepatobiliary disease. Pediatr Transplant 2003;7:364–9. 24. Williams SS, Cobo-Stark P, James LR, et al. Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease. Pediatr Nephrol 2008;23:733–41. 25. Buscher R, Buscher AK, Weber S, et al. Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidneyrelated and non-kidney-related phenotypes. Pediatr Nephrol 2013 October 10. [Epub ahead of print]. 26. Kummerfeld M, Klaunick G, Druckler E, et al. Hepatoblastoma in association with bilateral polycystic kidneys. J Pediatr Surg 2010;45: E23–5. 27. Jalanko H, Pakarinen M. Combined liver and kidney transplantation in children. Pediatr Nephrol 2014;29:805–14. 28. Goilav B, Norton KI, Satlin LM, et al. Predominant extrahepatic biliary disease in autosomal recessive polycystic kidney disease: a new association. Pediatr Transplant 2006;10:294–8.
Redheaded Wet Nurses Only 4% of the world population is redheaded. (Scotland can boast 13%.) Throughout history there have been many superstitions and spiritual beliefs about the redhead (most of them negative), and even the world of medicine did not escape these extraordinary conceits. As the Nurse is, so will the Child be, by means of the nourishment which it draweth from her and in sucking her it will draw in both the vices of her Body and her Mind . . .. As may be seen in red-haired Women whose Milk hath a source of stinking and bad scent. Francoise Mauriceau, Traite des Maladies des Femmes Grosses (1668) [Red-heads are] unfit for the office of a nurse; they are certainly of a sanguine temperament . . . and unfit as protectors of young children. W.P Dewees, Treatise on the Physical and Medical Treatment of Children Blanchard and Lea, Philadelphia (1853) The milk of a brunette is generally richer in sold constituents than that of a blond; for a which reason the former are preferred as wet nurses. . .a fair skin, with brilliant colour, light blue eyes, very light or red hair . . . have weak digestive powers . . . C.H.F. Routh, Infant Feeding and Its Influence on Life, Wood, New York (1879) —Contributed by Angel R. Colo´n, MD
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Liver Disease in Autosomal Recessive Polycystic Kidney Disease: Clinical Characteristics and Management in Relation to Renal Failure
Topi T. Luoto, Mikko P. Pakarinen, yTimo Jahnukainen, and yHannu Jalanko
ABSTRACT Objectives: We correlated liver and kidney manifestations in a national cohort of patients with autosomal recessive polycystic kidney disease (ARPKD). Methods: A total of 27 consecutive patients with ARPKD were included. Hepatobiliary disorders were comparatively evaluated in 2 groups: children in group 1 (n ¼ 10) displayed renal failure as infants and those in group 2 (n ¼ 17) had normal kidney function through the first year of life. Results: Median follow-up time was 10.6 (range, 0.4–40) years. Portal hypertension was diagnosed in 13 patients (48%) at the median age 5.0 (1.5– 27.9) years. Esophageal varices developed in 8 patients (30%) at age 8.0 (2.1–11.9) years; 4 patients (15%) had variceal bleeding, and hypersplenism/splenomegaly occurred in 52%, similarly in both groups. Biliary tract dilatation was detected at 2.8 years in group 1 and at 7.9 years in group 2, significantly more frequently in group 1 (60% vs 18%, P ¼ 0.039), causing cholangitis in 2 (20%) versus none in group 2 (P ¼ 0.055). A total of 10 patients (37%) underwent cadaveric liver transplantation (LT) at a median age of 6.6 (1.0–20.0) years. In 1 patient LT was performed because of hepatoblastoma. Nine of these were combined liver–kidney transplantations (CLKT). Patients in group 1 required LT earlier (4.1 years vs 18.2 years, P ¼ 0.017) and more frequently (70% vs 18%, P ¼ 0.01). Overall survival beyond neonatal period was 85%. Two patients died because of infectious complications after CLKT, and 1 patient because of recurrent hepatoblastoma. Conclusions: Although correlation of renal and liver manifestations was variable, biliary dilatation was associated with early renal failure. CLKT may be a treatment for patients with ARPKD with marked hepatobiliary complications. Key Words: autosomal recessive polycystic kidney disease, combined liver–kidney transplantation, congenital hepatic fibrosis, liver disease, liver transplantation
Received November 5, 2013; accepted April 29, 2014. From the Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, Children’s Hospital, University of Helsinki and Helsinki University Central Hospital, and the yDepartment of Pediatric Nephrology and Transplantation, Children’s Hospital, University of Helsinki and Helsinki University Central Hospital, Finland. Address correspondence and reprint requests to Topi T. Luoto, Section of Pediatric Surgery, Children’s Hospital, Stenba¨ckinkatu 11, PL 281, 00029-HUS, Helsinki, Finland (e-mail: [email protected]). The study was supported by the Foundation for Pediatric Research, the Helsinki University Central Hospital Fund, and the Sigrid Juselius Foundation. The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000422
(JPGN 2014;59: 190–196)
A
utosomal recessive polycystic kidney disease (ARPKD) is one of the most common pediatric renal cystic diseases, with an incidence of 1 in 20,000 live births (1,2). It is caused by mutations in the PKHD1 gene encoding fibrocystin. Genetic defects in fibrocystin lead to fusiform dilatation of the renal collecting system, causing varying degrees of renal insufficiency that require kidney transplantation (KT) in a significant proportion of patients. Fibrocystin is also expressed in the liver, and its erroneous function results in abnormal development and distortion of the biliary tract (1–6). The condition has been termed congenital hepatic fibrosis (CHF), which can be an isolated lesion or occur in conjunction with Caroli syndrome (2,4,7). CHF is considered a ductal plate malformation, in which persistence of immature embryonic bile ducts stimulates the formation of excess fibrous tissue in portal areas. Increased periportal fibrosis may contribute to development of portal hypertension, which results in splenomegaly, hypersplenism, upper gastrointestinal varices, and ascites. Portal venopathy is a process leading to noncirrhotic portal hypertension, and recently it has also been associated with CHF (8,9). Lobular architecture is well preserved in ARPKD, and hepatocellular dysfunction rarely develops in these patients (2,3). The clinical spectrum of ARPKD is diverse, and renal and hepatobiliary disease components advance at varying rates. Two truncating mutations of the PKHD1 gene associate with the most severe manifestations (10). Genotype–phenotype correlation, especially regarding the progression of hepatic lesions, however, is poor (1,3,9–12). The role of liver disease usually becomes increasingly predominant with advancing age. Development of recurrent cholangitis associated with biliary tract dilatation and/ or complications of portal hypertension may necessitate liver transplantation (LT). Indications and optimal timing of KT, LT, and combined liver–kidney transplantation (CLKT) are unclear (2,13–18). In the present work, we analyzed clinical characteristics, treatment, and long-term outcomes of the ARPKD-related liver disease in relation to the onset of renal failure in a cohort of Finnish patients, focusing on the timing of hepatobiliary complications and transplantation therapy.
METHODS Study Population The medical records of children diagnosed as having ARPKD and born between January 1980 and July 2011 were reviewed. In our country, management of patients with ARPKD including liver and kidney transplantations is centralized to Children’s Hospital, Helsinki University Central Hospital. Diagnosis of
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ARPKD was based on family history, typical clinical findings, ultrasound (US) examination demonstrating echogenic microcystic kidneys and periportal fibrosis in the liver, and mutational analysis of the PKHD1 gene.
Liver Disease in Autosomal Recessive Polycystic Kidney Disease was assessed with the Kaplan-Meier method. SPSS version 21.0 (IBM SPSS Statistics, Armonk, NY) was used for statistical analyses (IBM SPSS, Armonk, NY). Level of statistical significance was set at 0.05.
Study Design In total, 33 patients with ARPKD were consecutively enrolled and followed up at our institution. A total of 27 patients survived the neonatal period and formed the actual study group. Collected data included demographics, family history, mutational status, renal function, renal transplantations, infections, medications, pathology reports, endoscopic examinations, surgical interventions, results of imaging studies, timing and characteristics of LTs, cause of death, and survival. Data on the following laboratory tests were collected half-yearly: hemoglobin, platelet and leukocyte levels, markers of cholestasis, liver synthesis and cell damage, renal function, electrolytes, urine samples, and amylase. Portal hypertension was defined as the presence of gastroesophageal varices and/or hypersplenism. The latter was defined as splenomegaly (defined by a pediatric radiologist) and blood platelet count constantly T, c.10412T>G, and c.107C>T. These mutations are found in 75% of the Finnish patients with ARPKD.
Patient Management Neonates with pulmonary hypoplasia needing respiratory support were treated with a conventional ventilator or high-frequency oscillation ventilation from 1995 onward. Peritoneal dialysis, hemodialysis, or hemofiltration was started when end-stage renal disease (ESRD) developed (glomerular filtration rate T and c.1486C>T (n ¼ 5), c.1486C>T and c.10412T>G (n ¼ 5), c.1486C>T and unknown (n ¼ 9), and c.10412T>G and unknown (n ¼ 1). In 13 patients, no mutational status was reported. Two of the 5 patients with 2 truncating mutations c.1486C>T died during the neonatal period of pulmonary hypoplasia. A total of 27 patients surviving the neonatal period formed the actual study group (Table 1), with a median follow-up time of 10.6 (0.4–40) years. A total of 16 patients (60%) had additional minor disorders, including inguinal hernia (n ¼ 5), umbilical hernia (n ¼ 3), psoriasis (n ¼ 2), and strabismus (n ¼ 2). Interestingly, 1 patient had dilatations and stenoses in pancreatic ducts and experienced 8 pancreatitis episodes (in 5 years) before and 3 episodes after CLKT (in 7 years). Overall, 20 patients developed ESRD. Five newborns required early nephrectomy and dialysis during the first week of life because of the massive size of the kidneys. In the remaining 15 patients, ESRD developed at a median age of 3.5 (range 0–18.0) years. Cumulative survival without ESRD at 1, 5, and 10 years was 62%, 50%, and 38%, respectively (Fig. 1). A total of 15 patients (56%) received KT at a median age of 4.1 (range 0.7–28.5) years, and 5 patients underwent kidney retransplantation because of graft failure (Fig. 2). In order to assess association of the onset of chronic renal insufficiency (CRI) (creatinine constantly more than normal range) with hepatobiliary complications and LT, the 27 survivors were divided in 2 groups based on the onset of CRI. Group 1 (n ¼ 10) included patients who developed CRI during the first year of life and group 2 (n ¼ 17) those with onset of CRI after the first year of life. TABLE 1. General characteristics of patients with ARPKD (n ¼ 27) Characteristic Boys Prenatal diagnosis Birth weight, g Pulmonary hypoplasia Growth retardation Arterial hypertension Recurrent pancreatitis Sepsis Renal insufficiency Nephrectomy Renal transplantation Renal retransplantation Exitus
n (%) 15 12 3425 10 16 22 1 7 18 7 15 5 4
(56) (44) (2240–4680) (37) (59) (81) (4) (26) (67) (26) (56) (19) (15)
ARPKD ¼ autosomal recessive polycystic kidney disease. Median (range).
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Proportion without ESRD
1.0
Neonatal death n=6
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ARPKD patients n = 33
0.8 Neonatal survivors n = 27
0.6 0.4 0.2
Primary CLKT n=4 Survival 3/4 (75%)
No transplantations n = 12 Survival 12/12 (100%)
Isolated KT n = 11
0.0 0
2
4
6
8
10
12
14
16
18
20
Time (years)
Isolated LT n=1 Survival 0/1 (0%)
FIGURE 1. Cumulative survival without ESRD (Kaplan-Meier curve). ESRD ¼ end-stage renal disease.
Portal Hypertension Portal hypertension was diagnosed in 13 patients (48%) at a median age of 5.0 (1.5–27.9) years (Table 2). Hepatomegaly was detected in 16 patients (59%), and hypersplenism in 48%. A total of 16 patients (59%) underwent gastroscopy for a median of 8.5 (range 1–19) times. Esophageal varices were found in 8 patients (30%) at a median age of 8.0 (2.1–11.9) years. Four patients experienced variceal bleeding episodes. All 8 patients with varices received sclerotherapy for a median of 8 (1–14) times. The median age at the first sclerotherapy session was 8.7 (2.4–12.2) years. One patient underwent a distal splenorenal shunt to control portal hypertension associated with variceal bleeding. Ascites was found in 5 patients (19%). When comparing groups 1 and 2, no statistically significant differences were found in the frequency or onset of portal hypertension or its complications. Overall, 14 patients (52%) developed symptoms related to the liver disease. Cumulative survival without
All (n ¼ 27) Age at end of follow-up, y Hepatomegaly, % Portal hypertension, % Age at diagnosis, y Hypersplenism, % Age at diagnosis, y Splenomegaly, % Age at diagnosis, y Varices, % Age at diagnosis, y Variceal bleeding, % Biliary tract dilatation, % Age at diagnosis, y Cholangitis, % Caroli syndrome, % Liver Tx, % Age at Tx, y Died, %
10.6 16 13 5.0 13 5.0 14 4.9 8 8.0 4 9 3.0 2 3 10 6.6 4
(0.4–40) (59) (48) (1.5–28) (48) (1.5–28) (52) (0.7–28) (30) (2.1–12) (15) (33) (1.0–13) (7) (11) (37) (1.0–20) (15)
liver symptoms at 1, 5, and 10 years was 100%, 72%, and 42%, respectively.
Biliary Tract Pathology Biliary tract dilatation was verified by US, magnetic resonance imaging, or computed tomography in 9 patients (33%) at a median age of 3.0 (1.0–12.7) years (Table 2). It was significantly more frequent in group 1 (60% vs 18%, P ¼ 0.039) and associated with cholangitis in 2 (20%) group 1 patients versus 0 in group 2 (P ¼ 0.055). Cholangitis was recurrent, needing continued antibiotic prophylaxis in 1 patient, whereas 1 had only a single episode. The imaging findings were pathognomonic for Caroli syndrome in 3 patients, who all belonged to group 1 (P ¼ 0.041). As shown in
Group 1 CRI before 1 y (n ¼ 10) 8.5 8 6 5.1 6 5.1 6 5.1 3 7.1 2 6 2.8 2 3 7 4.1 2
No transplantations n=5 Survival 4/5 (80%)
FIGURE 2. The outcome of 33 patients with ARPKD. ARPKD ¼ autosomal recessive polycystic kidney disease; CLKT ¼combined liver–kidney transplantation; KT ¼ kidney transplantation; LT ¼ liver transplantation.
TABLE 2. Characteristics and comparison of the liver disease in relation to CRI
CLKT n=5 Survival 4/5 (80%)
(1.0–15.0) (80) (60) (1.5–8.7) (60) (1.5–8.7) (60) (0.7–8.7) (30) (2.9–8.8) (20) (60) (1.0–3.5) (20) (30) (70) (1.0–11) (20)
Group 2 CRI after 1 y (n ¼ 17) 16.0 8 7 4.8 7 4.9 8 4.5 5 8.6 2 3 7.9 0 0 3 18.2 2
(0.4–40) (47) (41) (2.1–28) (41) (3.5–28) (47) (1.0–28) (29) (2.1–12) (12) (18) (2.0–13) (0) (0) (18) (13–20) (12)
P 0.170 0.124 0.440 0.836 0.440 0.668 0.695 1.000 1.000 0.571 0.613 0.039 0.262 0.055 0.041 0.013 0.017 0.613
CRI ¼ chronic renal insufficiency; Tx ¼ transplantation. CRI ¼ creatinine level constantly >100 mmol/L. Median (range).
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Table 2, biliary tract dilatation was also observed earlier in group 1 than in group 2, although the difference was not statistically significant (P ¼ 0.262). An US-guided core needle liver biopsy was obtained from 20 patients at a median age of 2.7 (0.03–17.3) years. Histopathological analysis showed CHF in all patients and cholestasis in 5 patients (25%). The pathological report on the explanted liver was available in 8 patients, revealing CHF in all. Portoportal septas and fibrotic areas covered 20% to 75% of the parenchymal area. The hepatocytes between the fibrotic areas were microscopically normal. Cholestasis, cystic dilatation of bile ducts, and hepatoblastoma were found in 4, 3, and 1 of the livers, respectively.
Biochemistry Overall, the evolution of laboratory indicators was comparable in groups 1 and 2. Platelet and leukocyte counts decreased significantly (P < 0.05 in both) during follow-up. Thrombocytopenia (T, c.1486C>T
c.1486C>T, unknown
c.1486C>T, c.10412T>G
c.1486C>T, c.1486C>T
c.1486C>T, c.1486C>T
2
3
4
5
6
7
8
9
10
ESRD, bilateral nephrectomy, and peritoneal dialysis at 1.5 y ESRD, bilateral nephrectomy, and hemodialysis/peritoneal dialysis at 2 wk ESRD, bilateral nephrectomy, and peritoneal dialysis/hemodialysis at 2 wk
ESRD, bilateral nephrectomy, and peritoneal dialysis at 3 y
KT at 2 y, function preserved
KT at 2 y, graft failure because of de novo membranoproliferative glomerulonephritis
KT at 1 y, gradual deterioration of graft function
KT at 11 y, delayed graft function, graft failure at 13 y
KT at 5 y, graft failure at 18 y
KT at 7 y, graft failure at 20 y
Kidney
CLKT at 0.9 y
CLKT at 1.7 y
CLKT at 2.5 y
CLKT at 4.1 y
LT at 5.2 y
CLKT at 8.0 y
CLKT at 10.6 y
CLKT at 13 y
CLKT at 18.2 y
CLKT at 20 y
Liver
Severe hepatomegaly, liver fibrosis 50%, cystic biliary tracts, liver nodules in US and MRI
Hepatosplenomegaly, esophageal and gastrointestinal bleedings, severe hypersplenism Hepatosplenomegaly, poor growth (3.3 SD), portal thrombosis, ascites Hepatosplenomegaly, splenorenal shunt at 10 y, repeated episodes of hyperammonemia, liver fibrosis 50%, cystic biliary tracts Severe hepatosplenomegaly, moderate hypersplenism, poor growth (2.6 SD), liver fibrosis 75%, cholestasis, cholangitis Dilatations and stenoses of pancreatic ducts, large pancreas, repeated episodes of pancreatitis, severe hepatosplenomegaly, poor growth (4.3 SD), liver fibrosis 40%, ascites Chronic cholangitis, severe hepatomegaly, ascites, suspicion of hepatoblastoma (AFP 6553 mg/L, several nodules in liver) Moderate hepatosplenomegaly, poor growth (2.8 SD), liver nodules (up to 36 mm), liver fibrosis 40%, large cysts of biliary tract Moderate hepatosplenomegaly, liver fibrosis 50%, cystic biliary tracts, poor growth (3.5 SD) Moderate hepatosplenomegaly, liver fibrosis 30%, moderate biliary tract dilatations
Findings before CLKT/LT
Death because of CMV infection and RDS at 1 y
Functioning grafts at 11 y
Functioning grafts at 9 y
Functioning grafts at 10 y
Death because of metastatic hepatoblastoma at 10 y
Functioning grafts at 15 y
Functioning grafts at 15 y
Functioning grafts at 20 y
Death because of septic infection at 25 y Functioning grafts at 25 y
Outcome
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CLKT ¼ combined liver–kidney transplantation; CMV ¼ cytomegalovirus; ESRD ¼ end-stage renal disease; KT ¼ kidney transplantation; LT ¼ liver transplantation; MRI ¼ magnetic resonance imaging; RDS ¼ respiratory distress syndrome; SD ¼ standard deviation; US ¼ ultrasound.
N/A
Mutations
1
Patient no.
TABLE 3. Characteristics of liver transplantations
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and cholangitis has been reported, but numbers vary depending on the definitions and imaging modalities (2,11,20,22). A study by Gunay-Aygun et al reported biliary abnormalities in 70% of patients when imaging was based on high-resolution ultrasonography and magnetic resonance cholangiopancreatography (MRCP), and in 40% dilatation was considered to be Caroli syndrome (20). Interestingly, only 1 of their 4 patients with cholangitis had biliary abnormalities (20). In our cohort, MRCP revealed intrahepatic biliary dilatation in the 2 children with cholangitis, and extrahepatic biliary dilatation was seen in 1 patient. One of these patients experienced a single cholangitis episode before KT, and 1 had recurrent episodes after KT. Increased risk of cholangitis and sepsis after isolated KT, especially in patients with ARPKD, has been noted. In a retrospective analysis of 203 patients with polycystic kidney disease and isolated KT, 9 patients (4.4%) died of sepsis posttransplant (22,23). Our cohort included 2 individuals with exceptional disease manifestations whose association with the genetic defect is not clear. A young girl experienced repeated episodes of pancreatitis before and after transplantations. The patient received a KT at age 1.4 years and CLKT at age 8.0 years. Pancreatitis has not been described, to our knowledge, in humans or in animals, although cases of pancreatic cysts have been reported (24,25). One boy with 2 truncating mutations was diagnosed as having hepatoblastoma. Previously only 1 case of hepatoblastoma associated with ARPKD had been reported (26). Three of our neonatal survivors have been homozygous for a truncating mutation c.1486C>T. In general, 2 truncating mutations have been regarded as incompatible with life (12). The indications for isolated KT versus CLKT remain controversial in patients with ARPKD. The liver synthetic capacity is stable in most patients; liver fibrosis and ductal dilatation remain moderate, and the signs of portal hypertension, such as leukopenia, thrombopenia, and esophageal varices, seldom cause major clinical problems when managed adequately. The morbidity and mortality after CLKT are higher than in isolated KT, which all favor the use of KT as the transplant option. Moreover, shortage of organs speaks for isolated KT. Thus, CLKT rate has been low in many large transplant centers and is evident in a recent literature survey, in which 116 patients with ARPKD received transplantation; 56% had undergone isolated KT, 34% had LT, and only 9% had received CLKT (2). In our center, 10 of 27 patients have so far received cadaveric LT; 9 of these were CLKT, and 6 recipients had previously undergone solitary KT. In 1 patient, LT was performed because of hepatoblastoma. Telega et al proposed a decision tree considering the risk/ benefit analysis for each individual patient with ARPKD with dual organ involvement (18). In general, the major posttransplant risks are related to surgery and immunosuppressive medication. For patients with ARPKD requiring KT, surgical mortality is the major issue, because the immunosuppressive medication and its complications are similar after KT and CLKT. In patients with solitary KT, portal hypertension (variceal bleeding, hypersplenism), cholangitis/ sepsis, and cholestasis may cause morbidity and mortality; however, surgical complications (primary nonfunction, hepatic artery or portal vein thrombosis, bile duct strictures) and liver rejection can result in morbidity/mortality in patients with CLKT. According to these proposed guidelines, CLKT should be considered in patients who have both severe renal disease and CHF with serious complications (18). In our experience, there are important additional items affecting the decision making: the present quality of life (impaired because of organomegaly, fear for bleedings, and poor nutrition/ growth), the immunological benefit of using organs from the same donor (better kidney graft survival) (27), and the wish of the patient and parents (after thorough information). www.jpgn.org
Liver Disease in Autosomal Recessive Polycystic Kidney Disease Although the study population represents almost all patients with ARPKD in Finland since 1980, the relatively small number of patients does not allow strong conclusions on the optimal therapy for ARPKD. Another limitation of the present study is that mutations were recorded inconsistently, precluding their use in data analyses. Also, abdominal imaging was not uniform. The use of MRCP and abdominal computed tomography varies greatly in different centers, making reliable comparison over time difficult. The range of biliary abnormalities is extensive, and not all findings are seen in US (20,28). Uniform definitions for the biliary tract changes and Caroli syndrome are needed to formulate more reliable guidelines. In conclusion, many patients with early ARPKD manifestations develop significant hepatobiliary manifestations, including complications of portal hypertension and biliary tract pathology and are successfully treated with CLKT. Acknowledgments: The authors thank the Paediatric Research Centre of Tampere University and Tampere University Hospital for the opportunity to use their working facilities.
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17. Herden U, Kemper M, Ganschow R, et al. Surgical aspects and outcome of combined liver and kidney transplantation in children. Transpl Int 2011;24:805–11. 18. Telega G, Cronin D, Avner ED. New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney–liver complications. Pediatr Transplant 2013;17:328–35. 19. Lampela H, Kosola S, Koivusalo A, et al. Endoscopic surveillance and primary prophylaxis sclerotherapy of esophageal varices in biliary atresia. J Pediatr Gastroenterol Nutr 2012;55:574–9. 20. Gunay-Aygun M, Font-Montgomery E, Lukose L, et al. Characteristics of congenital hepatic fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease. Gastroenterology 2013;144:112– 21. 21. de Ville de Goyet J, D’Ambrosio G, Grimaldi C. Surgical management of portal hypertension in children. Semin Pediatr Surg 2012;21:219–32. 22. Khan K, Schwarzenberg SJ, Sharp HL, et al. Morbidity from congenital hepatic fibrosis after renal transplantation for autosomal recessive polycystic kidney disease. Am J Transplant 2002;2:360–5.
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23. Davis ID, Ho M, Hupertz V, et al. Survival of childhood polycystic kidney disease following renal transplantation: the impact of advanced hepatobiliary disease. Pediatr Transplant 2003;7:364–9. 24. Williams SS, Cobo-Stark P, James LR, et al. Kidney cysts, pancreatic cysts, and biliary disease in a mouse model of autosomal recessive polycystic kidney disease. Pediatr Nephrol 2008;23:733–41. 25. Buscher R, Buscher AK, Weber S, et al. Clinical manifestations of autosomal recessive polycystic kidney disease (ARPKD): kidneyrelated and non-kidney-related phenotypes. Pediatr Nephrol 2013 October 10. [Epub ahead of print]. 26. Kummerfeld M, Klaunick G, Druckler E, et al. Hepatoblastoma in association with bilateral polycystic kidneys. J Pediatr Surg 2010;45: E23–5. 27. Jalanko H, Pakarinen M. Combined liver and kidney transplantation in children. Pediatr Nephrol 2014;29:805–14. 28. Goilav B, Norton KI, Satlin LM, et al. Predominant extrahepatic biliary disease in autosomal recessive polycystic kidney disease: a new association. Pediatr Transplant 2006;10:294–8.
Redheaded Wet Nurses Only 4% of the world population is redheaded. (Scotland can boast 13%.) Throughout history there have been many superstitions and spiritual beliefs about the redhead (most of them negative), and even the world of medicine did not escape these extraordinary conceits. As the Nurse is, so will the Child be, by means of the nourishment which it draweth from her and in sucking her it will draw in both the vices of her Body and her Mind . . .. As may be seen in red-haired Women whose Milk hath a source of stinking and bad scent. Francoise Mauriceau, Traite des Maladies des Femmes Grosses (1668) [Red-heads are] unfit for the office of a nurse; they are certainly of a sanguine temperament . . . and unfit as protectors of young children. W.P Dewees, Treatise on the Physical and Medical Treatment of Children Blanchard and Lea, Philadelphia (1853) The milk of a brunette is generally richer in sold constituents than that of a blond; for a which reason the former are preferred as wet nurses. . .a fair skin, with brilliant colour, light blue eyes, very light or red hair . . . have weak digestive powers . . . C.H.F. Routh, Infant Feeding and Its Influence on Life, Wood, New York (1879) —Contributed by Angel R. Colo´n, MD
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