Inherited disorder of primary (sensory) cilia characterized by cystic expansion of the kidneys producing progressive kidney enlargement and renal insufficiency, in addition to various extrarenal manifestations.
A normal kidney is about the size of a fist – a polycystic kidney can grow to the size of an American football.
| Image credit: Indiana University School of Medicine
Contents
Inherited disorder of primary (sensory) cilia characterized by cystic expansion of the kidneys producing progressive kidney enlargement and renal insufficiency, in addition to various extrarenal manifestations.
Genetically heterogeneous group of disorders that are caused by mutations in genes with products that localize to the cilium–centrosome complex.
Ciliary function:
Motile cilia: Respiratory epithelial function, fertility, and determination of left-right orientation
Primary (or sensory) cilia: Antennae for cells, sensing the extracullar environment and transducing signals back to the cell to facilitate its response. These functions are critically important in cell proliferation, differentiation, and maintenance.
Structures and functions of motile and non-motile cilia: All cilia extend from a basal body that typically consists of triplet microtubules, and subdistal and distal appendages. Distal appendages (also known as transition fibres) tether the basal body to the base of the ciliary membrane. Immediately distal to the basal body is the transition zone, which contains doublet microtubules that are connected to the ciliary membrane via Y-shaped structures. Axonemes (the ciliary backbone) are composed of doublet microtubules. In motile cilia, axonemes usually contain associated structures and proteins (for example, the central pair and axonemal dyneins) that are required for ciliary motility. Nodal cilia are an exception as they are motile but lack a central pair of microtubules. Cilia may contain additional subdomains, including singlet microtubules at the distal end, and regions with specific protein compositions or functions (for example, the inversin domain (INV; involved in signalling). Key cell signalling functions and roles in motility are summarized. | PKD, polycystin. | Reiter, J. F., & Leroux, M. R. (2017). Genes and molecular pathways underpinning ciliopathies. Nature reviews. Molecular cell biology, 18(9), 533–547. https://doi.org/10.1038/nrm.2017.60
Ciliopathies cause a wide range of overlapping syndromes that include fibrocystic diseases of the kidney and liver as well as disparate abnormalities of other organ systems.
Polycystic kidney disease (PKD/PCKD):
Inherited disorder of primary (or sensory) cilia characterized by cystic expansion of the kidneys producing progressive kidney enlargement and renal insufficiency, in addition to various extrarenal manifestations.
ARPKD: Abnormality of renal tubular (collecting duct) development
ADPKD: Abnormality of renal tubule homeostasis
Other renal abnormalities: Nephronophthisis, glomerulocystic disease, and medullary sponge kidney
Summary of ADPKD and ARPKD | Kwatra, S., Krishnappa, V., Mhanna, C., Murray, T.E., Novak, R., Sethi, S.K., Kumar, D., & Raina, R. (2017). Cystic Diseases of Childhood: A Review. Urology, 110, 184-191 .
Renal and extrarenal manifestations in polycystic kidney disease: a) ADPKD is the most common form of PKD and is mainly caused by mutations in PKD1 and PKD2, which encode polycystin 1 and polycystin 2, respectively. ADPKD is usually an adult-onset disease that is characterized by the formation of fluid-filled cysts in various locations in the kidneys, but mostly in the distal regions. The histology image is of the kidney (stained with Malloy trichrome stain) of a 49-year-old patient with end-stage ADPKD. Small cysts and extensive fibrosis (blue) are visible. b) ARPKD is rarer and more severe than ADPKD and is caused by mutations in PKHD1 (encodes fibrocystin) and DZIP1L. ARPKD usually presents in utero, perinatally or in infancy and is characterized by the formation of cysts from the renal distal tubules and collecting ducts. Microscopically, cysts are fusiform dilatations of the aforementioned distal parts of the nephron, which are lined by a columnar or cuboidal epithelium. Respective dilated collecting ducts run perpendicular to the renal capsule (renal section is stained with H&E). Both diseases often progress to end-stage renal disease (ESRD) that requires renal replacement therapy. | GFR,glomerular filtration rate. | Bergmann, C., Guay-Woodford, L. M., Harris, P. C., Horie, S., Peters, D., & Torres, V. E. (2018). Polycystic kidney disease. Nature reviews. Disease primers, 4(1), 50. https://doi.org/10.1038/s41572-018-0047-y
Hepatic fibrocystic disease:
In both ARPKD and ADPKD, the liver is also involved with fibrocystic disease caused by ductal plate malformation (DPM), which manifests as characteristic liver pathologies
Congenital hepatic fibrosis (CHF) (in ARPKD)
Caroli syndrome
Polycystic liver disease
Hepatobiliary lesions in hepatorenal disease: a) Hepatobiliary lesions result from an architectural defect in the developing biliary tree. The normal ramifications of the portal venous system and the lattice-like network of associated biliary ducts (left) are disrupted owing to ductal plate malformation (DPM) (right), likely owing to a defect in terminal differentiation of cholangiocytes. b) The DPM results in marked cystic and fusiform dilatation of the intrahepatic biliary system (coronal T2-weighted image of the abdomen), nephromegaly with small cysts (arrowhead), cystic biliary disease (arrow) and marked splenomegaly (asterisk). c) The histopathological manifestation of the DPM is congenital hepatic fibrosis (section stained with haematoxylin and eosin), which is characterized by extensive fibrosis of the portal area (asterisk), ectatic, tortuous bile ducts (arrows) and hypoplasia of the portal vein (arrowhead). | Magnification is 40×. | Part a: Marchal G J, Desmet V J, Proesmans W C, et al. Caroli disease: high-frequency US and pathologic findings. | Part b, c: Bergmann, C., Guay-Woodford, L. M., Harris, P. C., Horie, S., Peters, D., & Torres, V. E. (2018). Polycystic kidney disease. Nature reviews. Disease primers, 4(1), 50. https://doi.org/10.1038/s41572-018-0047-y
Ciliopathy syndromes:
In addition, renal and hepatic fibrocystic disease may accompany abnormalities of other organ systems in ciliopathy syndromes:
Joubert syndrome
Meckel-Gruber syndrome
Orofaciodigital type 1 syndrome
Sensenbrenner syndrome
Jeune syndrome
Genes and phenotypic abnormalities associated with syndromic forms of PKD. Diseases are listed in the center; genes associated with them are shown on the left (gray). On the right are phenotypes found in these different disorders (yellow). Note the high degree of overlap in genes and phenotypes between the different disorders. | Harris, P. C., & Torres, V. E. (2009). Polycystic kidney disease. Annual review of medicine, 60, 321–337. https://doi.org/10.1146/annurev.med.60.101707.125712
Diagnosis
Autosomal dominant PKD (ARPKD):
Given that the number of renal cysts increases with age, a minimum number of unilateral or bilateral cysts is sufficient to make a presumptive diagnosis:
15-39 years: ≥ 3 Unilateral/bulateral cysts
40-59 years: ≥ 2 bilateral cysts
≥ 60 years: ≥ 4 bilateral cysts
Autosomal recessive PKD (ARPKD):
In utero, the diagnosis is suggested by the presence of oligohydramnios, kidney enlargement, and the absence of urine in the fetal bladder, findings typically detectable by US at 18–20 weeks gestation.
Differential diagnosis:
Nephronophthisis (NPHP): Autosomal recessive renal ciliopathy characterized by aspecific symptoms (i.e., urine concentration, polydipsia, and polyuria), and additional features of ciliopathy syndrome, such as retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders
Renal Cystic Dysplasia: Characterized by cysts in renal cortex, distended collecting ducts, and poorly developed medullary pyramids. Cystic renal dysplasia may be associated with several urologic abnormalities, including ureteropelvic and ureterovesicular junction obstruction, neurogenic bladder, ureterocele, and prune belly syndrome.
Other (rare) renal phenotypes: Horseshoe kidneys and lobulated kidneys. Moreover, cilium dysfunction can increase the risk of urinary tract infections and kidney stones.
Renal Cell Carcinoma (RCC)
A selection of gene mutations associated with the development of renal ciliopathies.
| Santoni, M., Piva, F., Cimadamore, A., Giulietti, M., Battelli, N., Montironi, R., Cosmai, L., & Porta, C. (2020). Exploring the Spectrum of Kidney Ciliopathies. Diagnostics, 10(12), 1099. https://doi.org/10.3390/diagnostics10121099
Summary of the biology, epidemiology, diagnosis and management of autosomal dominant polycystic kidney disease (PKD) and autosomal recessive PKD. | Polycystic kidney disease. Nat Rev Dis Primers 4, 51 (2018). https://doi.org/10.1038/s41572-018-0053-0
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