Autosomal Dominant Polycystic Kidney Disease


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.



AbouAlaiwi WA, Takahashi M, Mell BR et al. (2009) Ciliary polycystin‐2 is a mechanosensitive calcium channel involved in nitric oxide signaling cascades. Circulation Research 104(7): 860–869.

Alper SL (2008) Let's look at cysts from both sides now. Kidney International 74(6): 699–702.

Arnaout MA (2001) Molecular genetics and pathogenesis of autosomal dominant polycystic kidney disease. Annual Review of Medicine 52: 93–123.

Arnaout MA (2008) Cystic kidney diseases. In: Goldman L and Ausiello D (eds) Cecil Textbook of Medicine, 23rd edn, pp. 903–910. Philadelphia, PA: Saunders‐Elsevier Publishers.

Bae KT and Grantham JJ (2010) Imaging for the prognosis of autosomal dominant polycystic kidney disease. Nature Reviews. Nephrology 6(2): 96–106.

Bae YK, Qin H, Knobel KM et al. (2006) General and cell‐type specific mechanisms target TRPP2/PKD‐2 to cilia. Development 133(19): 3859–3870.

Baert L (1978) Hereditary polycystic kidney disease (adult form): a microdissection study of two cases at an early stage of the disease. Kidney International 13(6): 519–525.

Benzing T, Simons M and Walz G (2007) Wnt signaling in polycystic kidney disease. Journal of the American Society of Nephrology 18(5): 1389–1398.

Berbari NF, O'Connor AK, Haycraft CJ et al. (2009) The primary cilium as a complex signaling center. Current Biology 19(13): R526–535.

Canzanello VJ, Baranco‐Pryor E, Rahbari‐Oskoui F et al. (2008) Predictors of blood pressure response to the angiotensin receptor blocker candesartan in essential hypertension. American Journal of Hypertension 21(1): 61–66.

Carone FA, Nakamura S, Schumacher BS et al. (1989) Cyst‐derived cells do not exhibit accelerated growth or features of transformed cells in vitro. Kidney International 35(6): 1351–1357.

Chapman AB (2008) Approaches to testing new treatments in autosomal dominant polycystic kidney disease: insights from the CRISP and HALT‐PKD studies. Clinical Journal of the American Society of Nephrology 3(4): 1197–1204.

Chapman AB, Johnson AM and Gabow PA (1994) Pregnancy outcome and its relationship to progression of renal failure in autosomal dominant polycystic kidney disease. Journal of the American Society of Nephrology 5(5): 1178–1185.

Dere R, Wilson PD, Sandford RN et al. (2010) Carboxy terminal tail of polycystin‐1 regulates localization of TSC2 to repress mTOR. PLoS ONE 5(2): e9239.

Distefano G, Boca M, Rowe I et al. (2009) Polycystin‐1 regulates extracellular signal‐regulated kinase‐dependent phosphorylation of tuberin to control cell size through mTOR and its downstream effectors S6K and 4EBP1. Molecular and Cellular Biology 29(9): 2359–2371.

Ecder T and Schrier RW (2009) Cardiovascular abnormalities in autosomal‐dominant polycystic kidney disease. Nature Reviews. Nephrology 5(4): 221–228.

Gonzalez‐Perrett S, Kim K, Ibarra C et al. (2001) Polycystin‐2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+‐permeable nonselective cation channel. Proceedings of the National Academy of Sciences of the USA 98(3): 1182–1187.

Grantham JJ (2008) Clinical practice. Autosomal dominant polycystic kidney disease. New England Journal of Medicine 359(14): 1477–1485.

Happe H, Leonhard WN, van der Wal A et al. (2009) Toxic tubular injury in kidneys from Pkd1‐deletion mice accelerates cystogenesis accompanied by dysregulated planar cell polarity and canonical Wnt signaling pathways. Human Molecular Genetics 18(14): 2532–2542.

Harris PC and Rossetti S (2010) Molecular diagnostics for autosomal dominant polycystic kidney disease. Nature Reviews. Nephrology 6(4): 197–206.

Hogan MC, Masyuk TV, Page LJ et al. (2010) Randomized clinical trial of long‐acting somatostatin for autosomal dominant polycystic kidney and liver disease. Journal of the American Society of Nephrology 21(6): 1052–1061.

Hu J, Bae YK, Knobel KM et al. (2006) Casein kinase II and calcineurin modulate TRPP function and ciliary localization. Molecular Biology of the Cell 17(5): 2200–2211.

Ishimaru Y, Inada H, Kubota M et al. (2006) Transient receptor potential family members PKD1L3 and PKD2L1 form a candidate sour taste receptor. Proceedings of the National Academy of Sciences of the USA 103(33): 12569–12574.

Karner CM, Chirumamilla R, Aoki S et al. (2009) Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis. Nature Genetics 41(7): 793–799.

Kelleher CL, McFann KK, Johnson AM et al. (2004) Characteristics of hypertension in young adults with autosomal dominant polycystic kidney disease compared with the general U.S. population. American Journal of Hypertension 17(11 part 1): 1029–1034.

Klein IH, Ligtenberg G, Oey PL et al. (2001) Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. Journal of the American Society of Nephrology 12(11): 2427–2433.

Kleymenova E, Ibraghimov‐Beskrovnaya O, Kugoh H et al. (2001) Tuberin‐dependent membrane localization of polycystin‐1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. Molecular Cell 7(4): 823–832.

Koulen P, Cai Y, Geng L et al. (2002) Polycystin‐2 is an intracellular calcium release channel. Nature Cell Biology 4(3): 191–197.

Lantinga‐van Leeuwen IS, Leonhard WN, van der Wal A et al. (2007) Kidney‐specific inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. Human Molecular Genetics 16(24): 3188–3196.

Lin F, Hiesberger T, Cordes K et al. (2003) Kidney‐specific inactivation of the KIF3A subunit of kinesin‐II inhibits renal ciliogenesis and produces polycystic kidney disease. Proceedings of the National Academy of Sciences of the USA 100(9): 5286–5291.

Loghman‐Adham M, Soto CE, Inagami T et al. (2004) The intrarenal renin‐angiotensin system in autosomal dominant polycystic kidney disease. American Journal of Physiology. Renal Physiology 287(4): F775–F788.

Nauli SM, Alenghat FJ, Luo Y et al. (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nature Genetics 33(2): 129–137.

Nishio S, Tian X, Gallagher AR et al. (2010) Loss of oriented cell division does not initiate cyst formation. Journal of the American Society of Nephrology 21(2): 295–302.

Pei Y, Obaji J, Dupuis A et al. (2009) Unified criteria for ultrasonographic diagnosis of ADPKD. Journal of the American Society of Nephrology 20(1): 205–212.

Piontek K, Menezes LF, Garcia‐Gonzalez MA et al. (2007) A critical developmental switch defines the kinetics of kidney cyst formation after loss of Pkd1. Nature Medicine 13(12): 1490–1495.

Rossetti S and Harris PC (2007) Genotype‐phenotype correlations in autosomal dominant and autosomal recessive polycystic kidney disease. Journal of the American Society of Nephrology 18(5): 1374–1380.

Saburi S, Hester I, Fischer E et al. (2008) Loss of Fat4 disrupts PCP signaling and oriented cell division and leads to cystic kidney disease. Nature Genetics 40(8): 1010–1015.

Sharif‐Naeini R, Folgering JH, Bichet D et al. (2009) Polycystin‐1 and ‐2 dosage regulates pressure sensing. Cell 139(3): 587–596.

Shibazaki S, Yu Z, Nishio S et al. (2008) Cyst formation and activation of the extracellular regulated kinase pathway after kidney specific inactivation of Pkd1. Human Molecular Genetics 17(11): 1505–1516.

Shillingford JM, Piontek KB, Germino GG et al. (2010) Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. Journal of the American Society of Nephrology 21(3): 489–497.

Torres VE and Harris PC (2009) Autosomal dominant polycystic kidney disease: the last 3 years. Kidney International 76(2): 149–168.

Wallingford JB, Fraser SE and Harland RM (2002) Convergent extension: the molecular control of polarized cell movement during embryonic development. Development Cell 2(6): 695–706.

Wilson SJ, Amsler K, Hyink DP et al. (2006) Inhibition of HER‐2(neu/ErbB2) restores normal function and structure to polycystic kidney disease (PKD) epithelia. Biochimica et Biophysica Acta 1762(7): 647–655.

Further Reading

Albaqumi M, Srivastava S, Li Z et al. (2008) KCa3.1 potassium channels are critical for cAMP‐dependent chloride secretion and cyst growth in autosomal‐dominant polycystic kidney disease. Kidney International 74: 740–749.

Fischer E, Legue E, Doyen A et al. (2006) Defective planar cell polarity in polycystic kidney disease. Nature Genetics 38: 21–23.

Hanaoka K, Qian F, Boletta A et al. (2000) Co‐assembly of polycystin‐1 and ‐2 produces unique cation‐permeable currents. Nature 408: 990–994.

Hildebrandt F, Attanasio M and Otto E (2009) Nephronophthisis: disease mechanisms of a ciliopathy. Journal of the American Society of Nephrology 20: 23–35.

Prasad S, Media JP, Tam FW, Haylor JL and Ong AC (2009) Pkd2 dosage influences cellular repair responses following ischemia‐reperfusion injury. American Journal of Pathology 175: 1493–1503.

Takakura A, Contrino L, Zhou X et al. (2009) Renal injury is a third hit promoting rapid development of adult polycystic kidney disease. Human Molecular Genetics 18: 2523–2531.

Wallace DP, Quante MT, Reif GA et al. (2008) Periostin induces proliferation of human autosomal dominant polycystic kidney cells through alphaV‐integrin receptor. American Journal of Physiology. Renal Physiology 295: F1463–F1471.

Wilson PD (2004) Polycystic kidney disease. New England Journal of Medicine 350: 151–164.

Yang B, Sonawane ND, Zhao D, Somlo S and Verkman AS (2008) Small‐molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. Journal of the American Society of Nephrology 19: 1300–1310.

Yu S, Hackmann K, Gao J et al. (2007) Essential role of cleavage of Polycystin‐1 at G protein‐coupled receptor proteolytic site for kidney tubular structure. Proceedings of the National Academy of Sciences of the USA 104: 18688–18693.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Arnaout, M Amin(Sep 2010) Autosomal Dominant Polycystic Kidney Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006010.pub2]