Pathophysiology of childhood polycystic kidney diseases: new insights into disease-specific therapy

Abstract

ADPKD and ARPKD are a significant cause of morbidity and mortality in children and young adults. ADPKD with an incidence of 1:400–1,000 affects over 13 million individuals worldwide, and is a major cause of end-stage renal disease (ESRD) in adults. However, symptomatic disease is increasingly recognized in children. ARPKD is a dual organ hepatorenal disease with an incidence of 1:20,000 to 1:40,000 and a heterozygote carrier rate of 1 in 70. Currently, no clinically significant disease-specific therapy exists for ADPKD or ARPKD. The genetic basis of both ADPKD and ARPKD have been identified, and delineation of the basic molecular and cellular pathophysiology have led to the discovery that abnormal ADPKD and ARPKD gene products interact to create “polycystin" complexes” located at multiple sites within affected cells. The integrated signaling of such complexes leads to abnormal cellular proliferation, altered cellular transport, and abnormal matrix-vascular biology. This review will focus on the molecular and cellular basis of the abnormal cystic phenotype, and review the clinical translation of such basic data into new therapies, which promise to alter the natural history of disease for children with genetic PKDs.

Therapies for Childhood Polycystic Kidney Disease

“…As the name of the gene and the disease imply, ARPKD/CHF patients invariably have some degree of CHF along with cystic renal disease [2]. The variability of renal and hepatic disease previously noted does not appear to be related to the type or site of mutations in PKHD1 [5,31].…”

“…ARPKD/CHF previously referred to as infantile PKD, is a rare disease commonly diagnosed in utero or at birth, and occurs at a frequency of 1:20,000 live births [1]. ARPKD/CHF is characterized by non-obstructive fusiform dilations of the renal collecting ducts and varying degrees of biliary ectasia due to developmental biliary ductal plate malformations leading to congenital hepatic fibrosis [2][3][4][5]. ARPKD is highly variable with a wide clinical spectrum of disease that ranges from the severe classical presentation in utero, or at birth, of massively enlarged bilaterally cystic kidneys to the presentation in older children, teenagers, or young adults with manifestations of hepatic disease and negligible renal disease [4,6].…”

Polycystic Kidney Disease

“…• Cyst can cause urinary tract infec:ons, flank pain, lead to ESRD and if external cyst exist serious complica:ons such as ruptured cerebral aneurysm can occur (Silverman, 2015). • Eventually the disease will progress that renal replacement therapy of dialysis is needed and kidney tranpla:on (Silverman, 2015).…”

Polycystic Kidney Disease

“…• PKD is a systemic disorder that causes irreversible kidney func:on, and can cause cyst forma:on in the liver, pancreas, brain, and arteries (Silverman, 2015).…”