New approaches to the autosomal recessive polycystic kidney disease patient with dual kidney–liver complications

Improved neonatal medical care and renal replacement technology have improved the long‐term survival of patients with ARPKD. Ten‐yr survival of those surviving the first year of life is reported to be 82% and is continuing to improve further. However, despite increases in overall survival and improved treatment of systemic hypertension and other complications of their renal disease, nearly 50% of survivors will develop ESRD within the first decade of life. In addition to renal pathology, patients with ARPKD develop ductal plate malformations with cystic dilation of intra‐ and extrahepatic bile ducts resulting in CHF and Caroli syndrome. Many patients with CHF will develop portal hypertension with resulting esophageal varices, splenomegaly, hypersplenism, protein losing enteropathy, and gastrointestinal bleeding. Management of portal hypertension may require EBL of esophageal varices or porto‐systemic shunting. Complications of hepatic involvement can include ascending cholangitis, cholestasis with malabsorption of fat‐soluble vitamins, and rarely benign or malignant liver tumors. Patients with ARPKD who eventually reach ESRD, and ultimately require kidney transplantation, present a unique set of complications related to their underlying hepato‐biliary disease. In this review, we focus on new approaches to these challenging patients, including the indications for liver transplantation in ARPKD patients with severe chronic kidney disease awaiting kidney transplant. While survival in patients with ARPKD and isolated kidney transplant is comparable to that of age‐matched pediatric patients who have received kidney transplants due to other primary renal diseases, 64–80% of the mortality occurring in ARPKD kidney transplant patients is attributed to cholangitis/sepsis, which is related to their hepato‐biliary disease. Recent data demonstrate that surgical mortality among pediatric liver transplant recipients is decreased to <10% at one yr. The immunosuppressive regimen used for kidney transplant recipients is adequate for most liver transplant recipients. We therefore suggest that in a select group of ARPKD patients with recurrent cholangitis or complications of portal hypertension, combined liver–kidney transplant is a viable option. Although further study is necessary to confirm our approach, we believe that combined liver–kidney transplantation can potentially decrease overall mortality and morbidity in carefully selected ARPKD patients with ESRD and clinically significant CHF.     

Liver disease in autosomal recessive polycystic kidney disease

Hepatic complications occur in a significant proportion of children with autosomal recessive polycystic kidney disease (ARPKD). PKHD1/fibrocystin, the defective gene in ARPKD, is expressed in the cilia of bile duct epithelium and leads to abnormalities in the rubric of the ductal plate malformation. Portal hypertension and biliary disease are the major liver problems seen in ARPKD. Complete blood counting, physical examination, ultrasonography and magnetic resonance (MR) cholangiography are indicated as screening procedures for hepatic disease in ARPKD. Medical and surgical interventions are potentially indicated for children with portal hypertension and/or biliary disease. A high index of suspicion for the diagnosis of cholangitis needs to be maintained in children with biliary disease. The implications of hepatic disease need to be considered in the decision-making regarding renal transplantation in ARPKD.     

Individualized concept for the treatment of autosomal recessive polycystic kidney disease with end‐stage renal disease

Management of children with autosomal recessive polycystic kidney disease (ARPKD) who develop end‐stage renal disease (ESRD) remains challenging because of concomitant liver disease. Patients with recurrent cholangitis are candidates for liver‐kidney transplantation, while the treatment for patients with splenomegaly and pancytopenia due to portal hypertension is controversial. Herein, we report 7 children who were treated using an individualized treatment strategy stratified by liver disease. Two patients with recurrent cholangitis underwent sequential liver‐kidney transplantation, while 4 patients with splenomegaly and pancytopenia but without recurrent cholangitis underwent splenectomy followed by isolated kidney transplantation. The remaining patient, who did not have cholangitis and pancytopenia, underwent isolated kidney transplantation. Blood cell counts were normalized after splenectomy was performed at the median age of 8.7 (range, 7.4‐11.7) years. Kidney transplantation was performed at the median age of 8.8 (range, 1.9‐14.7) years in all patients. Overwhelming post‐splenectomy infections and cholangitis did not occur during the median follow‐up period of 6.3 (range, 1.0‐13.2) years. The estimated glomerular filtration rate at the last follow‐up was 53 (range, 35‐107) mL/min/1.73 m². No graft loss occurred. Our individualized treatment strategy stratified by recurrent cholangitis and pancytopenia can be a feasible strategy for children with ARPKD who develop ESRD and warrants further evaluation.     

Pediatric liver transplantation for fibropolycystic liver disease

Fibropolycystic liver disease includes CHF, Caroli's syndrome, and Caroli's disease. Patients with Caroli's disease and Caroli's syndrome have an increased risk of recurrent cholangitis, intrahepatic calculi, biliary cirrhosis, and cholangiocarcinoma. The aim of this study was to examine the post-transplantation outcomes of children with fibropolycystic liver disease. Of the 158 children transplanted at Seoul National University Hospital, there were four patients with Caroli's syndrome, two patients with CHF, and one patient with Caroli's disease. One patient underwent combined liver/kidney transplantation. Associated renal manifestations included ARPKD in three children and nephronophthisis in one child. The indications for LT were recurrent cholangitis, decompensated cirrhosis, and refractory complications of portal hypertension. Both graft and patient survival rates were 100% at a median follow-up period of two yr after LT. Three children with growth failure achieved catch-up growth after LT. In three patients with ARPKD, mean serum creatinine levels increased from 0.53 mg/dL at the time of LT to 0.91 mg/dL at the last follow-up (p = 0.01). LT is an excellent option for children with complications from fibropolycystic liver disease. Renal function should be monitored cautiously after LT in the patients with ARPKD.     

Transjugular intrahepatic portosystemic shunt prior to renal transplantation in a child with autosomal-recessive polycystic kidney disease and portal hypertension: A case report

Autosomal-recessive polycystic kidney disease (ARPKD) can cause renal failure and portal hypertension in children. Portal hypertension may complicate the course of renal transplantation (Tx). We report the successful outcome of a patient with end-stage renal disease (ESRD) and portal hypertension treated with transjugular intrahepatic portosystemic shunt (TIPS), a minimally invasive endovascular technique of portosystemic shunt, prior to renal Tx.     

Pleuropulmonary blastoma in a child with autosomal‐recessive polycystic kidney disease

Autosomal‐recessive polycystic kidney disease (ARPKD) is a developmental disorder known to affect both the kidneys and the liver. Renal involvement results in progressive renal insufficiency and hypertension, while hepatic involvement can result in portal hypertension and cholangitis. Pulmonary abnormalities relate mainly to pulmonary insufficiency in those patients who present as neonates. We present a unique case of a child with ARPKD found to have a cystic lesion of the lung. Upon surgical resection, a pathological diagnosis of pleuropulmonary blastoma (PPB) was made. There are no previous reports in the literature describing the association of these two entities. Knowledge of this potential association is important in the clinical management of these children and may open new avenues of genetic research.     

先天性胆总管囊肿合并门脉高压症

目的 探讨先天性胆总管囊肿（ＣＣ）合并门脉高压的原因、类型及转归。方法 将１７例ＣＣ合并门脉高压与１３例ＣＣ不合并门脉高压者进行比较,项目包括病程、胆源性发热、胆总管囊肿的最大前后径、胆道压力、肝组织病理变化、病理图像分析,对门脉高压患儿进行随访。结果 门脉高压组（ＰＨ）胆源性发热发生率高,胆道压力高于非门脉高压组（ＮＰＨ）,门脉高压组肝组织病理观察发现：１４例肝小叶完整,门静脉及肝静脉分支走行正     

Hepatic porto-enterostomy or cholecystostomy in the treatment of extrahepatic biliary atresia. A study of 49 cases.

Hepatic porto-enterostomy or cholecystostomy (Kasai's procedure) was successful in restoring bile flow in 31 of 49 patients with "noncorrectable" extrahepatic biliary atresia. However, all but one of the 31 developed acute or chronic complications such as cholangitis, bile peritonitis, or portal hypertension. During a five-year follow-up period, 26 (53%) died while 9 of the 23 survivors continue to manifest chronic or recurrent cholangitis. Thirteen of the 19 survivors who are more than one year of age have developed portal hypertension. These complications limit the prognosis of infants with "noncorrectable" biliary malformations.     

Sclerosing cholangitis with neonatal onset

Sclerosing cholangitis is characterized by irregular narrowing of extrahepatic or intrahepatic bile ducts, and in adults is defined mainly by radiologic findings. We describe eight children with cholestasis from the first week of life, followed by early cirrhosis and portal hypertension. Histologic examination of the liver showed absence of interlobular bile ducts in the early cholestatic phase in two patients and biliary cirrhosis later in all patients. Radiologic examination by percutaneous cholecystography under ultrasound guidance, carried out at age 8 months to 9 years, disclosed abnormal intrahepatic bile ducts with rarefaction of segmental branches, stenosis, and focal dilation. The extrahepatic ducts were involved in six patients. No intestinal disease has been found in these patients.     

Impact of liver transplantation on renal function of patients with congenital hepatic fibrosis associated with autosomal recessive polycystic kidney disease

Congenital hepatic fibrosis (CHF) is an uncommon autosomal recessive malformation. It may be associated with extrahepatic manifestations such as polycystic kidney disease. The main consequence is portal hypertension and bleeding from varices. Despite liver transplantation as a therapeutic option for this patient, long-term impact of liver transplantation on renal functions of patients with autosomal recessive polycystic kidney disease with associated liver disease is not well known. In this study, we aimed to analyze the patient's renal function after liver transplantation by creatinine clearance, glomerular filtration rate, and renal resistive indexes. Between March 1997 and September 2002, three of 50 orthotopic liver transplantation (OLT) were performed because of CHF associated with ARPKD at Ege University Organ Transplantation and Research Center. Baseline immunosuppression consisted of prednisone and cyclosporine A (CSA). The mean follow-up of the patients was 2.1 yr. Blood urea and creatinine levels were decreased after operation in all patients and remained within the normal range at the sixth and 12th month, whereas the level of the third patient were increased at the 18th month. RRI values of patients were not found different at the sixth month whereas, RRI values of patients were decreased at the 12th month and remained unchanged at the 18th month of follow-up. During the study period hypertension developed in one patient at the 16th month and resolved with antihypertensive treatment and decreasing dosage of CSA. Kidney function has remained satisfactory in all of the patients despite the use of cyclosporine. OLT can provide good survival in patients with CHF associated with ARPKD.     

Association of congenital hepatic fibrosis with autosomal dominant polycystic kidney disease

The association of autosomal recessive polycystic kidney disease (ARPKD) with congential hepatic fibrosis (CHF) is well known; a rare occurrence is that of congenital hepatic fibrosis with autosomal dominant polycystic kidney disease (ADPKD). We report a family with ADPKD in which congenital hepatic fibrosis with severe portal hypertension (PHT) presented in a 4-year-old girl; the kidneys were initially normal. Typical changes of autosomal dominant polycystic kidney disease developed in the next decade and were also found in the mother and sister (neither of whom had any evidence of portal hypertension). Severe variceal bleeding was treated by sclerotherapy and beta receptor blocade.     

Survival of childhood polycystic kidney disease following renal transplantation: the impact of advanced hepatobiliary disease

Childhood PKD encompasses the diagnoses of AR and ADPKD, glomerulocystic disease, and syndromes such as tuberous sclerosis or Jeune's syndrome. Given the fact that a majority of PKD children with ESRD carry the diagnosis of ARPKD, natural history studies assessing the long-term prognosis of PKD patients following renal transplantation must focus on morbidity and mortality issues related to complications from congenital hepatic fibrosis. Using the NAPRTCS registry, we analyzed the patient and graft survival rates of 203 PKD patients and 7044 non-PKD patients undergoing renal transplantation between 1987 and 2001. Deceased PKD patients, all with a diagnosis of ARPKD, were further identified and characterized using a special questionnaire submitted to the principal investigators. Overall graft and patient survival rates were not significantly different between PKD and non-PKD patients. No differences in rates of acute rejection or time to first rejection were noted between PKD and non-PKD patients. The relative risk of living longer than 3 yr in the PKD patients was not significantly different from non-PKD patients (RR = 0.70, p = 0.28). Sepsis was identified as a likely factor in the cause of death in nine (64%) ARPKD patients and was comfirmed with a positive blood culture in four patients. Despite similar graft and patient survival rates among PKD and non-PKD children following renal transplantation, our results suggest that ARPKD transplant recipients appear to be at increased risk for sepsis that may be related to hepatic fibrosis and ascending cholangitis. The utility of early liver transplantation in ARPKD patients with significant hepatobiliary disease is discussed.     

Syndromatic Paucity of Interlobular Bile Ducts: Hepatic Histopathology of the Early and Endstage Liver

Morphologic findings of the liver in syndromatic paucity of intrahepatic bile ducts (SPIHBD) during infancy include paucity of interlobular bile ducts, features of “giant cell hepatitis,” dilated lymphatics and veins in the portal tract, perisinusoidal fibrosis, and bile duct epithelial changes with a concentric layering of mesenchymal cells around bile ducts reminiscent of renal dysplasia. The latter change is characteristic of SPIHBD. Although the disease is characterized by paucity of bile ducts, morphometric studies show paucity of interlobular bile ducts in less than half of the patients during infancy. Reduced numbers of portal tracts and increased percentage of portal tracts devoid of bile ducts are more constant findings. It was impossible to predict from the early biopsy which patients would develop more severe portal fibrosis. Later in the disease portal fibrosis is variable and unevenly distributed, being more severe near the hilum regardless of the prior performance of a Kasai-type operation or the state of patency of the extrahepatic bile ducts. Hypoplasia of the extrahepatic bile ducts is the usual finding in SPIHBD, but if atresia of extrahepatic bile ducts is associated with intrahepatic paucity of bile ducts, the hepatic histopathology is that of PIHBD. Recognition of PIHBD would avoid unwarranted surgical procedures.     

Syndromatic paucity of interlobular bile ducts: hepatic histopathology of the early and endstage liver

Morphologic findings of the liver in syndromatic paucity of intrahepatic bile ducts (SPIHBD) during infancy include paucity of interlobular bile ducts, features of "giant cell hepatitis," dilated lymphatics and veins in the portal tract, perisinusoidal fibrosis, and bile duct epithelial changes with a concentric layering of mesenchymal cells around bile ducts reminiscent of renal dysplasia. The latter change is characteristic of SPIHBD. Although the disease is characterized by paucity of bile ducts, morphometric studies show paucity of interlobular bile ducts in less than half of the patients during infancy. Reduced numbers of portal tracts and increased percentage of portal tracts devoid of bile ducts are more constant findings. It was impossible to predict from the early biopsy which patients would develop more severe portal fibrosis. Later in the disease portal fibrosis is variable and unevenly distributed, being more severe near the hilum regardless of the prior performance of a Kasai-type operation or the state of patency of the extrahepatic bile ducts. Hypoplasia of the extrahepatic bile ducts is the usual finding in SPIHBD, but if atresia of extrahepatic bile ducts is associated with intrahepatic paucity of bile ducts, the hepatic histopathology is that of PIHBD. Recognition of PIHBD would avoid unwarranted surgical procedures.     

Polycystic kidney disease and other genetic kidney disorders

Cystic kidney diseases encompass a range of genetic disorders in which the primary cilia of the cells are affected and thereby cysts form as a result. There are an increasing range of cystic renal diseases recognized due to the advances in genomics. The most common genetic kidney condition is autosomal dominant polycystic kidney disease (ADPKD). ADPKD leads to renal failure in adulthood. In children, hypertension is common and if treated, may slow down renal decline. The most common cystic kidney disease causing renal failure in children is autosomal recessive polycystic kidney disease (ARPKD). ARPKD also affects the liver. These conditions often have extra-renal features which also need to be addressed. Until recently, treatments were mainly supportive but now it is possible to slow down development of cyst formation and renal decline in ADPKD. This raises hope for treatment for other cystic renal conditions as more genes are identified and underlying mechanisms defined.     

Atypical morphologic presentation of biliary atresia and value of serial liver biopsies

BACKGROUND: Liver biopsy findings are important in diagnosing extrahepatic biliary atresia. Diffuse ductular proliferation is a characteristic finding. We describe four patients with conjugated hyperbilirubinemia in whom the initial liver biopsy findings showed a lack of ductular proliferation, despite subsequent development of biliary atresia. RESULTS: On initial biopsy, paucity of intrahepatic bile ducts was present in three of four patients, with a bile duct to portal space ratio of 0.3 to 0.4 (normal, 0.9-1.8). A normal bile duct to portal space ratio of 1.0 was observed in the fourth patient. Ductular proliferation became apparent in three subjects between 9 and 12 weeks of age, and biliary atresia was noted at the time of a Kasai portoenterostomy. The fourth child had well-developed biliary cirrhosis at liver transplantation. CONCLUSIONS: Changes characteristic of biliary atresia may appear even after 9 weeks of age. Bile duct paucity and normal bile duct to portal space ratio do not preclude the subsequent development of biliary atresia. Infants with unexplained conjugated hyperbilirubinemia and acholic stools should undergo sequential liver biopsies until clinical improvement occurs or until biliary atresia can be excluded from the differential diagnosis.     

Long-term prognosis of patients with extrahepatic biliary atresia successfully treated with surgery. Our experience

The long-term prognosis of extrahepatic biliary atresia after surgical restoration of bile flow is still controversial. An ongoing process of cirrhosis and the development of portal hypertension continue to create frequent and frustrating management problems. Clinical features, hepatic function, echotomography aspect, calcium-phosphorus metabolism and serum levels of 25-OH-D-3 were evaluated in 12 anicteric patients with extrahepatic biliary atresia successfully treated in a period from 1974 through 1987. Seven of these children had a total of 21 episodes of cholangitis. In five patients liver biopsy, obtained at the time of the external diversion closure, showed a biliary cirrhosis. Growth, development and hepatic function were normal in all children studied; one patient had esophageal varices. The serum levels of 25-OH-D3 in patients without oral supplementation of vitamin D are lower than normal. This deficit can be corrected by oral administration of vitamin D. Our study revealed that the children with successful portoenterostomy appeared to thrive normally and that they tolerated the relatively mild liver damage. We believe that Kasai operation should be done in all patients with extrahepatic biliary atresia and that the liver transplantation is to be reserved only in those with unsuccessful Kasai. In our experience external diversion was not useful to prevent cholangitis and moreover it complicates the hepatectomy in case of transplantation.     

Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF)

ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in congenital hepatic fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents.     

Post-operative abdominal CT scanning in extrahepatic biliary atresia

A retrospective review of the abdominal CT scans of 26 children with extrahepatic biliary atresia was performed, and the results were correlated with available surgical and pathologic data. Associated congenital anomalies or acquired abnormalities were identified in these patients. Congenital anomalies included polysplenia, venous anomalies and bowel stenosis. Acquired abnormalities developed secondary to cirrhosis, portal hypertension, intrahepatic biliary duct dilatation, and hepatic ischemia. Despite frequent episodes of ascending cholangitis in these children, no hepatic abscesses were identified by CT or by pathologic examination. In conclusion, abdominal CT scanning of children with extrahepatic biliary atresia can define congenital and acquired abnormalities and provide important anatomic data for the surgeons before liver transplantation.     

Hazards of hepatic portocholecystostomy in biliary atresia.

A hepatic portocholecystostomy (HPC) has been recommended to avoid postoperative cholangitis in the case of a patent distal extrahepatic bile duct (PDEBD) for the treatment of biliary atresia (BA). We investigated the efficacy and clinical problems of HPC in BA. The clinical records of eight patients with BA and PDEBD were reviewed. The diameter of the common bile duct was compared between the patients with BA and PDEBD and age-matched patients with neonatal hepatitis (NH). Five of 8 patients with PDEBD underwent HPC. One patient had to be converted to a cholecystojejunostomy because of common bile duct stenosis at 19 years of age. The other two patients underwent a reoperation by a hepatic portojejunostomy due to poor bile drainage after HPC. Another patient became jaundice-free one month after HPC, but died of sepsis due to bile leakage 3 months thereafter. The mean diameter of the common bile duct in BA with PDEBD was significantly smaller than that of NH (0.76 +/- 0.16 mm (n = 8) in BA vs. 1.90 +/- 0.39 mm (n = 11) in NH, p<0.01). HPC was thus found to be an excellent operative method for preventing postoperative cholangitis in BA, however, many clinical problems still need to be overcome for such a narrow distal duct.