Liver and kidney disease in ciliopathies

Abstract

Hepatorenal fibrocystic diseases (HRFCDs) are among the most common inherited human disorders. The discovery that proteins defective in the autosomal dominant and recessive polycystic kidney diseases (ADPKD and ARPKD) localize to the primary cilia and the recognition of the role these organelles play in the pathogenesis of HRFCDs led to the term "ciliopathies." While ADPKD and ARPKD are the most common ciliopathies associated with both liver and kidney disease, variable degrees of renal and/or hepatic involvement occur in many other ciliopathies, including Joubert, Bardet-Biedl, Meckel-Gruber, and oral-facial-digital syndromes. The ductal plate malformation (DPM), a developmental abnormality of the portobiliary system, is the basis of the liver disease in ciliopathies that manifest congenital hepatic fibrosis (CHF), Caroli syndrome (CS), and polycystic liver disease (PLD). Hepatocellular function remains relatively preserved in ciliopathy-associated liver diseases. The major morbidity associated with CHF is portal hypertension (PH), often leading to esophageal varices and hypersplenism. In addition, CD predisposes to recurrent cholangitis. PLD is not typically associated with PH, but may result in complications due to mass effects. The kidney pathology in ciliopathies ranges from non-functional cystic dysplastic kidneys to an isolated urinary concentration defect; the disorders contributing to this pathology, in addition to ADPKD and ARPKD, include nephronophithisis (NPHP), glomerulocystic kidney disease and medullary sponge kidneys. Decreased urinary concentration ability, resulting in polyuria and polydypsia, is the first and most common renal symptom in ciliopathies. While the majority of ADPKD, ARPKD, and NPHP patients require renal transplantation, the frequency and rate of progression to renal failure varies considerably in other ciliopathies. This review focuses on the kidney and liver disease found in the different ciliopathies.

Copyright 2009 Wiley-Liss, Inc.

Figures

Figure 1

Artist’s rendering of normal bile duct development in comparison with the ductal plate malformation and corresponding liver histopathology showing normal portal triad and congenital hepatic fibrosis. The ductal plate initially forms as a sleeve-like structure around the portal vein branches. Normal remodeling of the ductal plate involves resorption of parts of this structure and migration of the remodeled ducts centrally closer to the portal vein (left panel at bottom). The liver biopsy at 10× magnification shows a normal portal tract with sections of portal vein, bile duct, and hepatic artery. Defective remodeling, termed the ductal plate malformation, is characterized by retention of excessive numbers of bile duct remnants in their original peripheral interrupted ring-like position (right panel at bottom). The biopsy with CHF shows persistence of bile duct remnants (magnification = 40×). (Liver biopsies are from Potter’s pathology of the fetus, infant and child, 2nd edition, Ed: Gilbert-Barness E. Mosby Elsevier.)

Figure 2

Artist’s rendering and MRI images of kidneys, liver, and spleen in ARPKD and ADPKD. A: ARPKD kidneys preserve their reniform contour. CHF in ARPKD is often complicated by portal hypertension evidenced by the enlarged spleen on the MRI. The majority of ARPKD patients also have dilatations of the intra- and extra-hepatic biliary system. B: In contrast, ADPKD kidneys often have distorted contours due to macrocysts. Portal hypertension is not typical in ADPKD and the spleen is not enlarged. Liver cysts in ADPKD are isolated cysts that are not contiguous with the biliary tree. (ADPKD MRI is from Heptinstall’s pathology of the kidney, Ed: Jennette J., Olson J., Schwartz M., Silva F.)

Figure 3

Kidney disease in ciliopathies. A: Kidneys of an infant with ARPKD that are enlarged with preserved contours due to uniform microcystic non-obstructive dilatation of collecting ducts. B: Massivelyenlarged kidneys of an adult with ADPKD that display large macrocysts distorting the kidney contour. C: Kidneys of an individual who has renal failure due nephronophithisis. D: Intraveneous pyelography of Bardet–Biedl syndrome kidneys displaying clubbing, blunting, and distortion of renal calyces in the absence of distal obstruction. E: Kidneys of an individual with glomerulocystic kidney disease displaying small cysts mostly located in the renal cortex. F: Cystic dysplastic kidneys in an infant with Meckel–Gruber syndrome. G: Multicystic dysplastic kidneys. H: Intraveneous pyelography displaying medullary sponge kidney. Sizes of the kidneys are not to scale. (A, B, E, and F are from Bisceglia et al., 2006, C is from Hildebrandt and Zhou, 2007, D is from Alton DJ and McDonald MB, Radiology, 109: 659–663, 1973. G is from Zerres et al., 1984. H is from Heptinstall’s Pathology of the kidney, Ed: Jennette J., Olson J., Schwartz M., Silva F.)