Autosomal Dominant Polycystic Kidney Disease

Abstract

Autosomal dominant polycystic disease (ADPKD) is the most common monogenic disease in humans and is among the leading causes of kidney failure. Dominantly inherited germline mutations in 2 genes, PKD1 and PKD2 followed by a second somatic hit that annuls or reduces the function of the remaining normal allele lead to loss of tube diameter control, cyst formation and eventual kidney failure. The respective gene products, polycystin‐1 and polycystin‐2 form a receptor–ion channel complex that transduces mechanical and/or chemical signals into a calcium entry signal that regulates cell polarity, proliferation and movement. Localisation of this complex in the primary cilium has linked this sensory organelle to the regulation of tube size. Here we review the recent advances made in elucidating pathogenesis, diagnosis and management of this disease and the experimental therapies targeting the implicated signalling pathways.

Key Concepts:

  • ADPKD presents with tubular dilatations/cysts mainly affecting the kidney, liver and cardiovascular system, reflecting a defect in tube diameter control. Arterial hypertension is common and occurs early. Current therapy is largely conservative.

  • ADPKD is caused by commonly inactivating germline mutations in PKD1 or PKD2 combined with a second somatic hit that abolishes or reduces function of the remaining normal allele, an event enhanced by the genomic instability associated with the haploid state.

  • Wide variations in onset and progression of the disease are caused by the type of the impaired gene, hypomorphic alleles, mosaicism, combining an inactivating germline mutation with an acquired hypomorphic allele, stochastic fluctuations in expression level of the remaining normal allele and the genetic background.

  • Cerebral aneurysms are more common in ADPKD patients, occur at an earlier age and tend to rupture at a smaller size when compared to the general population.

  • Progressive loss of renal function occurs before standard markers of renal function are abnormal. Measurement of kidney volume in patients with normal renal function using MR imaging (MRI), CT, or ultrasonography is a more sensitive approach for following disease progression at any age.

  • DNA‐based diagnostics are useful when imaging studies are equivocal, in individuals with a negative family history, in the selection of a young transplant donor from an ADPKD family or to facilitate pre‐implantation genetic diagnosis.

  • The gene products of PKD1 and PKD2, polyctytsin‐1 (PC1) and polycystin‐2 (PC2), respectively, localise to primary cilia as well as to other membrane compartments. Defects in primary cilium structure causes cysts, as are mutations in several other ciliogenic genes supporting a critical role of the primary cilium in tube formation and maintenance.

  • PC1 and PC2 form a receptor‐ion channel complex that triggers calcium entry, which normally activates the planar polarity pathway and represses mitogenic pathways thus regulating tube diameter.

  • The abnormal mitogenesis and fluid secretion pathways that contribute to cyst growth are being targeted therapeutically.

Keywords: PKD1; PKD2; primary cilium; TRP channels; tube size; cyst formation; calcium signalling; Wnt pathway; kidney failure; cardiovascular disease

Figure 1.

(a) Photograph of a kidney with multiple macroscopic cysts from a patient with ADPKD (provided courtesy of Dr. Robert Colvin, Department of Pathology, Massachusetts General Hospital). (b) An ultrasound scan from a patient with autosomal dominant polycystic kidney disease. Cysts of different sizes appear as dark holes interspersed on a diminished bright parenchyma (provided courtesy of Dr. Javier M Romero and Jennifer A McDowell, Department of Radiology, Massachusetts General Hospital).

Figure 2.

Schematic representation of the sequence of events leading to renal cyst formation in a renal tubular segment in ADPKD. All ADPKD tubular epithelial cells contain a germline mutation in PKD1 or PKD2. An inactivating somatic (or functional) second hit in the normal allele in a cell (dark blue cell in (a)) disrupts signals that control tube diameter, leading to progressive focal tube dilation ((b) and (c)) and a cyst which separates from the tube of origin (d). As the cyst grows by a combination of cellular proliferation and apical fluid secretion, it compresses the adjacent tubule, leading to obstructive and ischaemic injury, further enhancing cyst growth, eventually leading to progressive loss of kidney function and end stage kidney disease.

Figure 3.

Schematic of polycystin‐1 and polycystin‐2. PC1 is a multidomain glycoprotein with 11 putative transmembrane (TM) segments, the C‐terminal six of which (coloured in orange) bear homology to the six transmembrane segments of PC2. The large (3074 residue) extracellular segment of PC1 contains multiple domains of unknown functions. The extracellular region of PC1 consists of short leucine‐rich repeats (LRR), followed by a putative carbohydrate binding WSC domain found in a fungal β‐1,3 exoglucanase and in Saccharomyces cervesiae cell wall integrity and stress‐response component (WSC) proteins. The first of 16 PKD domains then follows. Each PKD domain assumes an immunoglobulin‐like fold, but is unrelated to it evolutionary. A C‐type lectin domain and a low‐density lipoprotein receptor (LDL) A‐like domain (LDL‐A) are inserted between the first and second PKD domains. The 16th PKD domain is followed a ∼700‐residue segment of unknown function, first found in the sea urchin receptor for egg jelly (REJ), where it mediates the acrosomal reaction. A ∼50‐amino acid G protein‐coupled receptor proteolytic site (GPS) separates REJ from the first TM segment. GPS is normally cleaved into two fragments that remain associated. Failure of this cleavage in mice results in cystic kidneys postnatally (reviewed in Torres and Harris, ). A ∼120‐residue polycystin/lipoxingenase/alpha‐toxin domain (PLAT) is found in the first intracellular loop. The cytoplasmic tail also contains potential phosphorylation sites for PKA and PKC and a C‐terminal predicted coiled‐coil segment shown to bind to PC2. The nonselective cation channel PC2 has both its N‐ and C‐termini inside the cell. The intramembranous channel pore lies in an extracellular loop between the fifth and sixth TM segments of PC2 and is not conserved in PC1. The C‐terminal cytoplasmic tail of PC2 contains a predicted EF hand motif (EF), an endoplasmic reticulum (ER) retention signal and a predicted coiled‐coil (CC) domain that interacts with PC1.

Figure 4.

Signalling pathways that may be up‐ or downregulated in epithelial cells in polycystic kidney disease, and the sites currently targeted by experimental therapeutics. Upregulated pathways are in red, downregulated pathways are in blue and drug targets are in green. PC1/PC2 mediates calcium entry into the cell, which triggers calcium release from the endoplasmic reticulum (ER) via ryanodine receptor (RyR). PC2 interacts with PC1 to regulate store operated calcium channel (SOC) activity and with inositol 1,4,5‐trisphosphate (IP3) receptor (IP3R) to regulate calcium release from ER. Reduced PC1/PC2‐mediated calcium influx increases intracellular cAMP levels, which stimulate, via protein kinase A (PKA), chloride and water secretion across the luminal membrane through CFTR and the vasopressin‐sensitive aquaporin‐2 (AQP2) channels, respectively, and activate MAPK/ERK signalling, which may also be activated by the mislocalised tyrosine kinase receptors (TKR). Phosphorylation of tuberin by ERK, upregulation of TNFα or downregulation of AMPK signalling may dissociate the tuberin/hamartin complex, leading to activation of Rheb and mTOR. ERK and mTOR activation promotes G1/S transition and cell proliferation through upregulation of cyclin D and protein translation respectively. Upregulation of Wnt signalling also activates mTOR and the β‐catenin mitogenic pathway. SOC, store operated calcium channel; SERCA, sarcoplasmic reticulum calcium pump; R, G‐protein q (Gq)‐coupled receptors; PLCγ, phospholipase Cγ; AC‐VI, adenylate cyclase 6, the predominant AC in collecting duct principal cells; PDE, phosphodiesterase (PDE1 in collecting duct principal cells); PKA, protein kinase A; Fz, frizzled receptor; SR, somatostatin SST2 receptor; TSC, tuberous sclerosis proteins hamartin (TSC1) and tuberin (TSC2); p, proteosome; V2R, vasopressin V2 receptor; V2RA, vasopressin V2 receptor antagonist; TNFA, TNFα antagonist and i, inhibitor. Adapted from Torres and Harris , with permission from Nature Publishing Group.

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Arnaout, M Amin(Sep 2010) Autosomal Dominant Polycystic Kidney Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006010.pub2]