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.     

Congenital hypothyroidism in association with Caroli's disease and autosomal recessive polycystic kidney disease: patient report

Autosomal recessive polycystic kidney disease (ARPKD) is an important renal disease of childhood. Congenital hypothyroidism has been associated with glomerulocystic kidney disease, but to date no association has been made with ARPKD. To our knowledge this is the first reported case of congenital hypothyroidism in an infant with ARPKD.     

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.     

Congenital hepatic fibrosis: a very uncommon cause of pancytopenia in children

The disease presentation of autosomal recessive polycystic kidney disease (OMIM #263200, ARPKD) is highly variable and includes polycystic kidneys, pulmonary hypoplasia, and congenital hepatic fibrosis. The authors report an unusual case of ARPKD presenting with hepatosplenomegaly and cytopenia mimicking acute leukemia.     

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.     

Four pediatric patients with autosomal recessive polycystic kidney disease developed new‐onset diabetes after renal transplantation

NODAT is increasingly prevalent. Compared with adult recipients, NODAT is less prevalent in pediatric renal transplant recipients; however, some risk factors for its development in young patients have been defined. We report four pediatric renal transplant recipients with ARPKD who developed NODAT. We review the current pediatric NODAT literature and hypothesize that ARPKD may be an additional risk factor for NODAT.     

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.     

Successful transplantation in a child with rapid progression of autosomal recessive polycystic kidney disease associated with a novel mutation

Autosomal recessive polycystic kidney disease (ARPKD) is the most common pediatric renal cystic disease with liver involvement. The vast majority of patients with ARPKD carry mutations in the recently characterized PKHD1 gene on chromosome 6p12. A Turkish female demonstrated rapid growth of both kidneys after delivery. Accelerated growth of both kidneys and increasing respiratory distress necessitated right-sided nephrectomy at the age of three months. Because of persistent dyspnea and ongoing growth of the remaining kidney, the second kidney also had to be removed one month later. Biopsies taken from the kidney and the liver confirmed the diagnosis of ARPKD histologically. Renal ultrasound of the patient's consanguineous parents and her older brother showed normal results. PKHD1 mutation analysis yielded a novel homozygous missense mutation (c.1116C >G, F372L) in exon 14, coding for an Ig-like domain (TIG), possibly involved in the increased growth of the kidneys. Peritoneal dialysis was performed for 12 months. The patient had successful transplantation at the age of 15 months and is doing well with actual immunosuppression with cyclosporine, mycophenolate mofetil, and prednisolone. In conclusion, the present case clearly demonstrates the favorable outcome of a child with severe ARPKD after bilateral nephrectomy, pre-emptive dialysis, and successful transplantation.     

Prenatal diagnosis of autosomal recessive polycystic kidney disease]

OBJECTIVE: Prenatal ultrasonographic detection of autosomal recessive polycystic kidney disease (ARPKD) is of poor reliability, especially in early pregnancy. Molecular genetics allows earlier diagnosis, from 11 weeks of gestation; however, since only indirect diagnosis is possible--the ARPKD gene being localized on chromosome 6 but not identified--the feasibility of molecular diagnosis requires several conditions: definitive diagnosis in the index case, availability of index case and parents' DNA, genetic informativity of the family at the ARPKD locus. Results and limits of this method are analyzed, using a series of 56 requests for prenatal diagnosis. RESULTS: In eight of the 56 families ARPKD was excluded on the basis of histological (seven cases) and/or genetic (two cases) criteria. Molecular study was impossible in three families due to the lack of index case's DNA, and two other families were non-informative. Among the 43 families in which prenatal diagnosis was feasible, analysis of the haplotype of 35 fetuses issued from 29 families showed that 11 fetuses with the same haplotypes as that of the index case were affected, while 24 were not. No false positive or false negative result was reported. CONCLUSIONS: Early and reliable prenatal diagnosis of recessive polycystic kidney disease is possible in nearly 80% of affected families.     

Polycystic kidney disease in children

Polycystic renal diseases in children include 2 pathologically and genetically distinct diseases: autosomal recessive polycystic kidney disease (ARPKD), incorrectly called the "infantile form", characterized by a constant hepato-renal involvement, and autosomal dominant polycystic kidney disease, often termed the "adult form", which is more and more frequently detected in children as a result of advances in renal imaging techniques. The differential diagnosis is not based on age at discovery, clinical symptoms or renal imaging, which may all be similar in the 2 diseases, but on the presence, detected by either pathology or ultrasonography, of the biliary dysgenesis specific to ARPKD, and mainly on the mode of inheritance, confirmed by the results of ultrasonography in parents and grandparents.     

End‐stage renal disease due to ARPKD in the first months of life: Transplantation or dialysis? – Two case reports

Beil S, Drube J, Gluer S, Lehner F, Ehrich JHH, Pape L. End‐stage renal disease due to ARPKD in the first months of life: Transplantation or dialysis? – Two case reports.
Pediatr Transplantation 2010: 14:E75–E78. © 2009 John Wiley & Sons A/S. Abstract: ARPKD with renal insufficiency during the first months of life is a clinical challenge. We report on two children with ARPKD with massively enlarged kidneys requiring renal replacement therapy in early infancy. Patient 1 developed pulmonary insufficiency due to massively enlarged kidneys. At the age of six months the girl was listed for KT as “high urgency” on the Eurotransplant waiting list. A kidney from a deceased donor was pre‐emptively transplanted and simultaneous nephrectomy performed. No postoperative complications were observed, and the patient was discharged from in‐patient care 42 days after transplantation. Unexpectedly, she died at the age of one yr due to cerebral vascular spasms of unknown origin. Patient 2 was transferred at the age of three months to our clinic with life‐threatening pulmonary insufficiency. Pre‐emptive KT was not possible; therefore, bilateral nephrectomy was performed and PD begun. The boy is still doing well on PD one yr later. Pre‐emptive KT and bilateral nephrectomy followed by PD are two options for infants with ARPKD and excessive kidney enlargement. PD could be complicated and in some cases become impossible by peritoneal damage during nephrectomy. On the other hand, KT covers a high risk of infections caused by immunosuppression. The decision, which method to choose, should be driven by the individual situation of the patient and the expertise of the center.     

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.     

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.     

Predominant extrahepatic biliary disease in autosomal recessive polycystic kidney disease: a new association

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by dilation of ectatic renal collecting ducts, intrahepatic biliary dysgenesis, and portal fibrosis. Portal hypertension and recurrent bacterial cholangitis can dominate the clinical picture in long-term survivors. Predominant extrahepatic bile duct disease was revealed in four patients who underwent magnetic resonance cholangiopancreatography. All four patients had portal hypertension, although liver biochemistries did not suggest biliary disease. In two of the patients, cholangitis was clinically ascribed to the bile duct disease. Western blot analysis of plasma membranes from normal rat extrahepatic bile duct and kidney revealed the presence of polyductin as a single approximately 440 kDa protein. Although the exact function of polyductin in the extrahepatic duct is unknown, it may have a role in the development and control of lumenal size. Clinical management of patients with ARPKD should include consideration of potential problems related to extrahepatic bile duct disease.     

Appearance of autosomal recessive polycystic kidney disease in magnetic resonance imaging and RARE-MR-urography

Purpose. To describe the appearance of autosomal recessive polycystic kidney disease (ARPKD) on MRI and RARE-MR urography. Materials and methods. Seven boys and one girl (aged 3 months to 14 years, median 2.5 years) were evaluated. Images were obtained with 0.23-T and 1.5-T MR systems using T1-weighted (T1-W) spin-echo, T2-weighted (T2-W) turbo-spin-echo and RARE-MR-urography sequences. Signal intensities, morphological appearance of the affected kidneys and, specifically, the picture of the urinary tract on RARE-MR-urography were evaluated. Results. All children showed kidney enlargement, reniform but humpy kidney shape, homogeneously grainy renal parenchyma, normal renal pelvis and normal calyces. Signal intensity was hyperintense in T2-W images in all cases. In six cases (n = 7), T1-W images were hypointense. On RARE-MR urography a hyperintense, linear radial pattern was seen in the cortex and medulla which represents the characteristic microcystic dilatation of collecting ducts in ARPKD. Three boys and the girl presented with a few circumscribed small subcapsular cysts. Conclusions. In order to confirm the diagnosis of ARPKD, RARE-MR urography seems to be a non-invasive imaging tool that shows directly the microcystic dilated water-filled collecting ducts. Received: 14 September 1999/Accepted: 24 September 1999     

Hereditary polycystic kidney diseases in children: changing sonographic patterns through childhood

OBJECTIVE: To determine which US changes occur with time in children affected by autosomal recessive (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) and whether any of these changes correlate with the onset of renal failure. MATERIALS AND METHODS: We reviewed the US features of 29 patients (16 ARPKD, 13 ADPK) imaged by at least two US examinations. We analysed the size and echogenicity of the kidneys, corticomedullary differentiation (CMD), the presence, location and size of cysts and any other anomaly that developed with time. In order to determine whether a relationship could be found between any of the US changes and the onset of the renal failure (based on a glomerular filtration rate < 50 ml/min per 1.73 m2), a Pearson exact chi-square test was calculated. RESULTS: For ARPKD, renal size was above 4 standard deviations (SD) in 10 of 16 patients, but it remained stable during evolution (10/16). The kidneys appeared hyperechoic (16/16), without CMD in the majority (11/16) of patients. Changes in the appearance of CMD over time were observed in five patients. Small cysts (< 1 cm) were present at the time of diagnosis in seven patients, larger cysts (> 1 cm) in three. A diffuse microcystic pattern was observed in three patients. Diffuse hyperechoic foci developed in 14 patients--13 of whom had developed renal failure at the time of the examination or rapidly thereafter (statistical correlation P=0.0125). For ADPKD, renal size was between 0-2 SD in 7 of 13 patients and above 2 SD in the other 6. Renal echogenicity was normal in five, difficult to assess in five and the kidneys appeared hyperechoic without CMD in three patients. Cysts larger than 1 cm were present in 8 of 12 patients (> 3 cm in 5). In four patients, the cysts measured less than 1 cm. In the last child, the diagnosis had been made antenatally and the first cysts appeared at the age of 6 months. The size of the kidneys (13/13) and of the cysts (11/13) remained stable. No renal failure occurred. CONCLUSIONS: ARPKD may manifest with various US patterns and there may be evolution in the appearances over time. Our study confirms a significant relationship between the development of diffuse hyperechoic foci and the onset of renal failure. In older children, ARPKD and ADPKD may closely resemble each other. Large (> 3 cm) cysts are the US hallmark for the diagnosis of ADPKD; furthermore, fewer US changes occur with time during childhood in ADPKD.     

Combined liver and kidney transplantation and kidney after liver transplantation in children: Indication,postoperative outcome,and long‐term results

CLKT and sequential KALT are decided on a case‐by‐case basis in children for special indications such as ARPKD or PH1. We report on 21 children who underwent CLKT or KALT at our hospital between 1998 and 2013. Eleven children were diagnosed with PH1 and six with ARPKD. Other diagnosis were Joubert syndrome (n = 1), nephronophthisis (n = 1), CF (n = 1), and hepatocellular carcinoma (n = 1). Children (12 males, nine females) were aged 7.8 ± 6.2 yr (range, 10 months to 18 yr) at time of transplantation. Average wait time was 1.9 ± 0.9 yr (range, four months to 2.3 yr). Fifteen patients received dialysis prior to transplantation. In PH1 patients, four children received CLKT, five received KALT, and two infants have received only an LTx, whereas all six patients with ARPKD received CLKT. In patients with other indications, CLKT was performed in three cases and KALT in one girl. Cumulative 10‐yr survival of all 21 patients was 78.4%. At the time of transfer into adult care, 13 patients retained stable liver and kidney function. Regardless the underlying diagnosis, CLKT and KALT can be performed in children with good surgical outcomes and long‐term survival.     

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.     

Clinical and pathological features of a neonate with autosomal recessive polycystic kidney disease caused by a nonsense PKHD1 mutation

Background

Autosomal recessive polycystic kidney disease (ARPKD) is one of the most common hereditary nephropathies in childhood. We report a neonate with ARPKD presenting with oligohydramnios, enlargement and increased echogenicity of both kidneys shown by antenatal sonograms after a 29-week gestation and died within the first few hours of life.

Methods

The neonate was investigated pathologically post-mortem. PCR-DNA direct sequencing was performed to detect the exons of the PKHD1 gene for mutation analysis.

Results

Autopsy findings of the kidney and liver confirmed the diagnostic hypothesis. PKHD1 mutation analysis revealed that there was a homozygous nonsense mutation c.9319C>T (p.R3107X), which was found to be pathogenic, in exon 58 in the neonate.

Conclusions

The recurrence of PKHD1 mutation c.9319C>T (p.R3107X) in the ARPKD population might be a good evidence that it is disease associated. Given the limitations of antenatal ultrasound, PKHD1 mutation analysis is helpful for accurate genetic counseling and early prenatal diagnosis.     

MR cholangiography in children with autosomal recessive polycystic kidney disease

Background. Magnetic resonance cholangiography (MRC) is a relatively new, non-invasive imaging technique of the biliary tree that has shown good correlation with endoscopic retrograde cholangiopancreatography. The liver manifestation of autosomal recessive polycystic kidney disease (ARPKD) is congenital hepatic fibrosis (CHF). CHF may be accompanied by Caroli's disease, which is characterised by a non-obstructive dilation of the intrahepatic bile ducts. Objective. A prospective study was conducted to determine the presence and extent of Caroli's disease in children with ARPKD. Materials and methods. Seven children with ARPKD aged from 3.0 to 10.1 years were examined. CHF was confirmed in all biopsied cases (5 of 7). All children had been followed by repeated abdominal US examinations for many years. The MR examination included a morphological imaging study using a T2-weighted turbo spin-echo sequence and a heavily T2-weighted inversion-recovery turbo spin-echo sequence with three-dimensional maximum intensity projection (MIP) reconstructions for MRC. Results. The diagnosis of Caroli's disease could be made in one case by US; in two other children Caroli's disease was suspected, but the differentiation from hepatic cysts was not possible. By MRC, Caroli's disease could be diagnosed in three of seven children. Furthermore, MRC with MIP reconstructions demonstrated the extent of the disease by showing the entire biliary tree from different angles. Conclusions. MRC is a valuable method to establish the diagnosis and demonstrate the extent of Caroli's disease. Received: 5 January 1998 Accepted: 9 December 1998