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Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis: Summary statement of a First National Institutes of Health/Office of Rare Diseases conference

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Background

Autosomal recessive polycystic kidney disease/congenital hepatic fibrosis (ARPKD/CHF) is a developmental disorder of the kidneys and liver caused primarily, if not exclusively, by mutations in the PKHD1 gene.1, 2, 3, 4, 5 Fibrocystin/polyductin, the protein encoded by PKHD1, is expressed on the primary cilia of renal and bile duct epithelial cells and is believed to function to maintain the 3-dimensional tubular architecture.6 Kidney cysts in ARPKD are nonobstructive dilations of the collecting

Why a workshop on ARPKD/CHF?

The face of ARPKD/CHF has changed because of the wide availability of prenatal ultrasonography, which enables fetal diagnosis, permitting anticipatory treatment and, potentially, improved outcome. Recent advances in the molecular genetics and cell biologic study of polycystic kidney disease (PKD), on the basis of the identification of PKD genes, offer the potential to understand the functions of PKD proteins and to propose directed therapies. A workshop creates an opportunity for experts in the

Genetics and Cell Biology of ARPKD/CHF

PKHD1 is a large and complex gene, with a complicated transcription profile that likely generates multiple protein isoforms.3, 4 Mutations are distributed throughout the gene, and polymorphisms are common.5, 10 The current mutation detection rate is 80% to 85%.5, 10 There is marked allelic heterogeneity, and most affected patients appear to be compound heterozygotes. Denaturing high-performance liquid chromatography (DHPLC) has been successfully used for mutation screening.10 In general,

Developing symptomatic treatment and therapies directed at the basic defect in ARPKD/CHF

Therapies effective in animal models of PKD that may be effective in human PKD include angiotensin blockade (ACE inhibitors and ARBs), lipid-lowering medications (HMG CoA reductase inhibitors), vasopressin-2 receptor antagonists (V2RA; renal only), EGFR inhibitors (renal and liver), and dietary modifications (low protein, high soy protein, flaxseed oil, fish oil).30, 31

Studies indicate that deficiency of fibrocystin causes enhanced downstream effects of EGFR tyrosine kinase, making

The NIH ARPKD/CHF protocol

The National Human Genome Research Institute (NHGRI) at the NIH has an ongoing intramural research protocol on ARPKD/CHF. The objective of this protocol is to produce comprehensive longitudinal data on the kidney and liver disease in ARPKD/CHF that will in turn provide the basis for more focused studies and for novel therapeutic interventions in the future. The protocol enrolls children and adults with a clinical diagnosis of ARPKD/CHF, which requires the presence of characteristic kidney

Future directions

The most critical need in the field of ARPKD/CHF is to define the basic defect including the precise function of the fibrocystin protein more completely. In addition the acquisition of detailed longitudinal clinical data via the continued entry of new patients into the NIH ARPKD/CHF Protocol was endorsed as an important goal by the participants.

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      During cystogenesis, ARPKD kidney organoids showed a time-dependent enlargement of the tubule lumen, first proximally and later extended to distal regions (Figure 6C, left panels). This is well aligned with a proximal tubule origin of fetal renal cysts during the first and second trimester of pregnancy (Gunay-Aygun et al., 2006; Nakanishi et al., 2000; Woollard et al., 2007). Furthermore, there was a gradual reduction in the expression of segment-specific markers as cystogenesis progressed (Figure 6C, left panels).

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    Supported in part by the Intramural Research Program of the NIH, specifically, that of the National Human Genome Research Institute, and by the Office of Rare Diseases, Office of the Director, NIH, and ARPKD/CHF Alliance.

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