Autosomal recessive polycystic kidney disease (ARPKD), historically called infantile PKD, is a major cause of morbidity and mortality in neonates, infants and young adults. Autosomal dominant polycystic kidney disease (ADPKD), historically referred to as adult PKD, is increasingly recognized as a significant cause of morbidity and mortality in children and young adults. ARPKD, a dual-organ disease with hepatic and renal involvement has an incidence of 1: 20,000 to 1: 40,000. All ARPKD patients are invariably afflicted with congenital hepatic fibrosis (CHF) of varying degrees of severity. Improved survival of ARPKD patients has led to recognition of significant clinical complications of CHF and the highly variable age at which it presents, ranging from early childhood to young adulthood. ADPKD, with an incidence as high as 1:400, affects more than 13 million individuals worldwide, and accounts for 7-10% of end stage kidney disease (ESKD) in adults. However, asymptomatic disease is increasingly recognized in infants and children and nearly equivalent numbers of ADPKD and ARPKD patients may be seen in academic pediatric nephrology clinics. The delineation of the basic molecular and cellular pathophysiology of ADPKD and ARPKD has seen remarkable progress in the last decade. This progress has led to the development of promising therapies currently being evaluated in clinical trials. Early diagnosis of ADPKD and ARPKD allows for optimal anticipatory care (for example, early blood pressure control). Given the predicted benefit of early intervention with new disease-specific therapeutics, screening at-risk youth, a previouslydiscouraged strategy, may now be warranted. This chapter will discuss central clinical characteristics essential for diagnosis and the care of children with ARPKD or ADPKD. We will also highlight recent insights in the molecular and cellular pathophysiology of PKD and the clinical translation into new therapies that promise to alter the natural history of disease for children with genetic PKD.

No abstract

AIMTo delineate changes in miRNA expression localized to the peri-cystic local microenvironment (PLM) in an orthologous mouse model of autosomal dominant polycystic kidney disease (ADPKD) (mcwPkd1(nl/nl)).METHODSWe profiled miRNA expression in the whole kidney and laser captured microdissection (LCM) samples from PLM in mcwPkd1(nl/nl) kidneys with Qiagen miScript 384 HC miRNA PCR arrays. The three times points used are: (1) post-natal (PN) day 21, before the development of trichrome-positive areas; (2) PN28, the earliest sign of trichrome staining; and (3) PN42 following the development of progressive fibrosis. PN21 served as appropriate controls and as the reference time point for comparison of miRNA expression profiles.RESULTSLCM samples revealed three temporally upregulated miRNAs [2 to 2.75-fold at PN28 and 2.5 to 4-fold (P ≤ 0.05) at PN42] and four temporally downregulated miRNAs [2 to 2.75 fold at PN28 and 2.75 to 5-fold (P ≤ 0.05) at PN42]. Expression of twenty-six miRNAs showed no change until PN42 [six decreased (2.25 to 3.5-fold) (P ≤ 0.05) and 20 increased (2 to 4-fold) (P ≤ 0.05)]. Many critical miRNA changes seen in the LCM samples from PLM were not seen in the contralateral whole kidney.CONCLUSIONPrecise sampling with LCM identifies miRNA changes that occur with the initiation and progression of renal interstitial fibrosis (RIF). Identification of the target proteins regulated by these miRNAs will provide new insight into the process of fibrosis and identify unique therapeutic targets to prevent or slow the development and progression of RIF in ADPKD.

No abstract

Polycystic kidney disease (PKD) and nephronophthisis are common manifestation of ciliopathies. PKD is the most common genetic renal condition; it affects 12.5 million people worldwide. PKD is a great example of decades of translational research leading to the discovery of novel treatments and significant number of clinical trials. This review will concentrate on the basic molecular and cellular pathophysiology that led to the development of therapeutic targets for PKD.

Renal cysts are present in a wide variety of hereditary renal diseases in children. The term polycystic kidney disease (PKD) refers to two specific hereditary diseases, distinguished by the usual age of onset and genetic cause: autosomal recessive polycystic kidney disease/congenital hepatic fibrosis (ARPKD/CHF, MIM *606702) and autosomal dominant polycystic disease (ADPKD-OMIM *601313 and OMIM *173910). ARPKD/CHF is characterized by cystic dilations of the renal collecting ducts and developmental defects of biliary ductal plate remodeling, resulting in varying degrees of congenital hepatic fibrosis. ARPKD/CHF is commonly diagnosed in utero or at birth but can remain silent well into adolescence and rarely into adulthood. ADPKD, the most common inherited renal disease is characterized by slow, progressive enlargement of fluid-filled cysts leading to renal failure by the fifth to sixth decade of life in addition to various extrarenal manifestations. ADPKD can manifest in utero, infants, and children and can be a significant cause of morbidity and mortality in this age group. Our understanding of the genetic basis of ARPKD and ADPKD, including mechanisms of transmission and genes involved continues to evolve. Despite

Autosomal Dominant Polycystic Kidney Disease (ADPKD), the most common renal genetic disease, is characterized by formation and progressive enlargement of fluid-filled cysts [1]. A dynamic Peri-cystic Local Micro-environment (PLM) created between the cysts becomes fibrotic over time. Due to progressive fibrosis, over 50% of ADPKD patients will reach End-stage Renal Disease (ESRD) requiring renal replacement therapy. Despite this connection between fibrosis and ESRD, there is no Food and Drug Administration (FDA)-approved therapy targeting fibrosis in ADPKD.