Autosomal Dominant Polycystic Kidney Disease-The Last 3 Years

Autosomal dominant polycystic kidney disease: the last 3 years

Vicente E. Torres1 and Peter C. Harris11Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic,Rochester, Minnesota, USA

AbstractAutosomal dominant polycystic kidney disease is the most prevalent, potentially lethal monogenicdisorder. It has large inter- and intra-familial variability explained to a large extent by its geneticheterogeneity and modifier genes. An increased understanding of its underlying genetic, molecular,and cellular mechanisms and a better appreciation of its progression and systemic manifestationshave laid out the foundation for the development of clinical trials and potentially effective therapies.The purpose of this review is to update the core of knowledge in this area with recent publicationsthat have appeared during 2006–2009.

KeywordsADPKD; PKD1; PKD2; polycystic kidney disease; polycystin-1; polycystin-2

Scope of this ReviewAlthough there have been numerous reviews of this topic in recent years, the fast pace of thefield of polycystic kidney disease (PKD) justifies frequent re-evaluations and updates. Thepurpose of this review is to update the core of knowledge in this area with recent publications,which have appeared during 2006–2009. References are limited to these publications. Thereader is referred to earlier reviews for older references.1–3

Autosomal dominant PKD (ADPKD) is the most common of the inherited renal cystic diseases,a group of disorders characterized by the development of renal cysts and a variety of extrarenalmanifestations. It occurs worldwide and in all races with a prevalence estimated to be between1:400 and 1:1000. Age-adjusted male/female sex ratios greater than unity (1.2–1.3) for theyearly incidence rates of ADPKD-caused end-stage renal disease (ESRD) in Japan, Europe,and United States suggest a more progressive disease in men than in women. Consistent withthis, a survival analysis of 1391 parent/offspring pairs showed a significant male gender effect(hazard ratio 1.424; 95% confidence interval 1.180–1.719) on age at ESRD (58 and 57 yearsfor female and 54 and 54 years for male parents and offspring), but no difference betweenpairs.4

PKD Genes and ProteinsAutosomal dominant PKD is genetically heterogeneous with two genes identified, PKD1(chromosome 16p13.3) and PKD2 (4q21). The PKD1 and PKD2 proteins, polycystin-1 (PC1,∼ 460 kDa) and polycystin-2 (PC2, ∼ 110 kDa) constitute a subfamily (TRPP) of transient

Correspondence: Vicente E. Torres, Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester,Minnesota 55905, USA. [email protected]: The authors declared no competing interests.

NIH Public AccessAuthor ManuscriptKidney Int. Author manuscript; available in PMC 2010 January 27.

Published in final edited form as:Kidney Int. 2009 July ; 76(2): 149–168. doi:10.1038/ki.2009.128.

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receptor potential (TRP) channels (Figure 1).5 Although PC2 (or TRPP2) exhibitscharacteristic structural (six transmembrane domains) and functional (permeability to cations)features of a TRP channel, PC1 (or TRPP1) is a distant TRP homolog. Its final six-transmembrane region is similar to the PC2 transmembrane domains and may have PC2-independent nonselective cation channel activity.

PC1 (4303 aa) has the structure of a receptor or adhesion molecule and contains a large (3074aa) extracellular N-terminal region, 11 transmembrane (1032 aa), and a short (197 aa)intracellular C-terminal region (Figure 1). It interacts with PC2 through a coiled-coil domainin the C-terminal portion and with multiple other proteins at different extracellular andintracellular sites. The interacting partners and putative functions of these interactions are listedin Table 1. PC1 is found in the primary cilia, cytoplasmic vesicles, plasma membrane at focaladhesions, desmosomes, adherens junctions, and possibly endoplasmic reticulum and nuclei.

The extracellular portion of PC1 contains a G-protein-coupled receptor proteolytic site.Cleavage at this site results in a C-terminal fragment (150 kDa) and an N-terminal fragment(400 kDa), which remains tethered.12 Pkd1-null mice die in utero and exhibit renal andpancreatic cysts as well as placental, vascular, cardiac and skeletal malformations, but micewith a mutation expressing non-cleavable PC1 protein survive to P28 with enlarged cystickidneys.13 This may mean that newly synthesized PC1 can proceed through competing‘cleavage’ (critical in embryonic development) and ‘non-cleavage’ (critical for maintenanceof tubular integrity) pathways with different functions in vivo, or that the non-cleavablePkd1 mutation is a hypomorphic mutation with residual function.

Two non-mutually exclusive models have suggested that the C-terminal tail of PC1 can becleaved and migrate to the nucleus. In the first, PC1 normally sequesters the transcription factorSTAT6 on cilia, thereby preventing its activation. Interruption of luminal fluid flow (forexample, after ureteral clamping or renal injury) triggers the cleavage of the final 112 aminoacids. This p112 fragment interacts with STAT6 and the co-activator P100 and stimulatestranscriptional activity.14 In the second, mechanical stimulation of the primary cilium normallytriggers the cleavage and release of the entire C-terminal tail (p200). This p200 fragmentcontains a nuclear localization motif, binds β-catenin in the nucleus, and inhibits its ability toactivate T-cell factor-dependent gene transcription, a major effector of the canonical Wntsignaling pathway.9

PC1 normally forms a complex at the adherens junction with E-cadherin and α-, β-, and γ-catenins. Under conditions of calcium starvation, PC1 and E-cadherin are sequestered incytoplasmic vesicles. Calcium restoration triggers the recruitment of both proteins to reformingcell–cell contacts.10 PC1 has been proposed to regulate the mechanical strength of adhesionbetween cells by controlling the formation of stabilized, actin-associated, adherens junctions.15 PC1/E-cadherin complexes are disrupted in ADPKD, and E-cadherin is sequesteredinternally and replaced at the surface by N-cadherin.

PC2 (968 aa) contains a short N-terminal cytoplasmic region with a ciliary targeting motif,16

6 transmembrane domains, and a short C-terminal portion. An earlier accepted model of theC-terminal portion included a calcium-binding motif (EF-hand) and partially overlappingcoiled-coil domain and endoplasmic reticulum retention motif. A recent molecular modelingand biophysical analysis of the C-terminal portion predicts a globular EF-hand motif thatundergoes calcium-induced conformational changes, connected by a linker to a previouslyunidentified, elongated coiled coil, C-terminal to the position of the coiled-coil domain in theearlier accepted model (Figure 1). Residues within the newly identified coiled coil arenecessary for binding to PC2-interacting proteins PC1, TRPC1, and KIF3A and for PC2-PC2oligomerization. This domain includes the most C-terminal pathogenic PKD2-associated

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truncation variant (R872X).6 An N-terminal dimerization domain has also been identified.17

Table 2 lists the proteins known to interact with PC2 and the functional significance of theseinteractions.

The subcellular localization of PC2 has been controversial. It has been shown to localizepredominantly to the endoplasmic reticulum, but also to the plasma membrane, primary cilium,centrosome, and mitotic spindles in dividing cells. Its subcellular transport and localization arecontrolled by phosphorylation and multiple interactions with adapter proteins.31 Interactionwith PIGEA-14 (Polycystin-2 interactor, Golgi- and endoplasmic reticulum-associated proteinwith a molecular weight of 14 kDa) augments forward trafficking from the endoplasmicreticulum to the cis-Golgi, while interaction with PC1 facilitates its translocation to the plasmamembrane. Phosphorylation of PC2 by casein kinase 2 mediates binding to phosphofurin acidiccluster sorting protein-1 and -2 (PACS-1 and PACS-2), two connector proteins that mediateretrieval back to the trans-Golgi network (PACS-1) and the endoplasmic reticulum (PACS-2).

Recently PC1 and PC2, as well as fibrocystin (the protein mutated in autosomal recessivePKD), have been located in exosomes.32 These are small vesicles (50–100 nm in diameter)produced by the multivesicular body sorting pathway. Membrane proteins are uniquelypackaged into intraluminal vesicles within the multivesicular body, some of which are excretedwhen these multivesicular bodies fuse with the apical plasma membrane. They are producedby a variety of cell types and have profound biological effect in the immune system and in theembryonic node for left/right (L/R) axis determination. Urine contains a sub-population ofexosomes that contain large amounts of PC1, PC2, and fibrocystin. In vitro studies showedthat these exosomes preferentially adhere to primary cilia of kidney and biliary epithelial cellsin a rapid and highly specific manner and may represent a novel ‘urocrine’ signaling systemmediated through a subset of primary cilia.

Disease Variability: Genic, Allelic, and Gene Modifier EffectsGenic, allelic, and gene modifier effects contribute to the high phenotypic variability ofADPKD. PKD1- is more severe than PKD2-associated disease (age at ESRD 54.3 versus 74.0years for PKD1 and PKD2, respectively). The greater severity of PKD1 is due to thedevelopment of more cysts at an early age, not to faster cyst growth.33 Both PKD1 and PKD2can be associated with severe polycystic liver disease (PLD) and vascular abnormalities. Dueto the lesser severity of the renal involvement, the prevalence of PKD2 associated disease haslikely been underestimated in clinically studies. Population-based studies in communitieswhere disease ascertainment is likely to be more complete, such as in Olmsted County andNewfoundland, reveal relative frequencies of PKD2 (36 and 29%, respectively) which arehigher than in clinical studies (10–15%).34,35

PKD1 and PKD2 mutations are highly variable and usually private. The ADPKD MutationDatabase (http://pkdb.mayo.edu) lists 333 truncating PKD1 mutations identified in 417families with a total of 869 variants, including missense mutations and silent polymorphisms.Ninety-five PKD2 truncating mutations are listed in 178 families, with a total of 128 differentvariants.

A recent study screened the 202 probands in the Consortium for Radiologic Imaging Study ofPKD (CRISP) ADPKD population by denaturing high-performance liquid chromatography,followed by direct sequencing. Definite truncating mutations and probable (missense, atypicalsplicing and small in-frame changes) mutations were identified in 127 (62.9%) and 53 (26.2%)probands, respectively.36 Of these, 153 (85.0%) were in PKD1 and 27 (15.0%) in PKD2. Thirtypercent of mutations were recurrent; hence 70% were unique to a single family. In a subsequentstudy, a multiplex ligation-dependent probe amplification assay detected large deletions (n =3) or duplications (n = 1) in four probands, thus increasing the level of detection to 184 of 202



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http://pkdb.mayo.edu

(91.1%).37 The molecular basis of disease in approximately 9% of ADPKD in the CRISPpopulation remained unclear. A similar overall mutation rate (86%) was observed in a smallerstudy using a Transgenomic's SURVEYOR Nuclease and WAVE nucleic acid high sensitivityanalysis system (Omaha, NE, USA).38

Compared with genic (PKD1 vs PKD2) effects, the influence of allelic factors (mutation typeor location) on the severity of ADPKD is limited. Patients with mutations in the 5′ region ofPKD1 have more severe disease (18.9 vs 39.7% with adequate renal function at 60 years) andare more likely to have intracranial aneurysms and aneurysm ruptures than patients with 3′mutations. No clear correlations were found with mutation type in PKD1 or PKD2 or withmutation type or position in PKD2. More recently, however, hypomorphic or incompletelypenetrant PKD1 or PKD2 alleles have been described.39 These alleles alone may result in mildcystic disease; two such alleles cause typical to severe disease; and in combination with aninactivating allele may be associated with early-onset disease.

The large intra-familial variability of ADPKD highlights a role for genetic background indisease presentation. Bilineal inheritance of a PKD1 and PKD2 mutant allele or of PKD1 orPKD2 hypomorphic alleles can result in variable degrees of enhancement to single genephenotypes. Mosaicism can also modulate the disease presentation and result in marked intra-familial variability.37,40 Renal enlargement in utero or in infancy more typical of autosomalrecessive PKD may occur in a small proportion of cases. Most early-onset cases have beenlinked to PKD1, but recently a PKD2 family with perinatal death in two severely affectedinfants was described.41 The high risk of recurrence of ADPKD with early manifestations inaffected families suggests a common familial modifying background for early and severedisease expression (for example, mutations or variants in genes encoding other cystoproteins).The best-documented example (apart from hypomorphic PKD1 alleles) is the contiguousdeletion of the adjacent PKD1 and TSC2, characterized by childhood PKD with additionalclinical signs of tuberous sclerosis complex.

Other modifying loci likely account for more common and subtle intra-familial variability.Studies of candidate loci, selected because of presumed relevance to the pathogenesis ofADPKD or association with prognosis in other renal diseases, have been mostly disappointing.Most studies have not found an association between the I/D polymorphism in the angiotensin-I-converting enzyme (ACE) and early ESRD.42,43 Studies of other components of the renin–angiotensin system have been negative. The Glu298Asp polymorphism of endothelial nitricoxide synthase has been associated with earlier ESRD,44 but this has not been a consistentfinding. A functional length polymorphism in the promoter region of the human hemeoxygenase-1 (HO-1) gene that results in higher HO-1 expression and enzyme activity had noeffect on age at ESRD, despite the protective role of HO-1 in a variety of experimental modelsof renal injury and its upregulation in polycystic kidneys.45 Functional polymorphisms oftumor growth factor-β1 (TGF-β1), bradykinin receptors B1 and B2, epidermal growth factorreceptor (EGFR), and endothelin ET-A receptor genes and of the regulatory region of theVEGF gene did not have an effect on disease progression.46–48 ADPKD patients who are TThomozygotes for the −414 T/C polymorphism in the promoter region of the α-8 integrin chaingene (ITGA8) were reported to have an earlier onset of ESRD than those with a C allele (47vs 51 years of age).49

Despite these mostly negative results, identification of quantitative trait loci influencing theseverity of PKD remains important for understanding the pathogenesis and providing insightsinto potential therapies. High-density single-nucleotide polymorphism arrays allow themapping of quantitative trait loci in large, clinically and genetically well-characterizedpopulations using a genome-wide association study. The feasibility of this approach has beenillustrated by the identification of the first putative modifier of renal disease severity (mapping



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to chromosome 4) in PKD as the kinesin gene (Kif12) in the cpk mouse. Interestingly, Kif12transcription is regulated by hepatocyte nuclear factor-1β (HNF-1β) and mutations inHNF-1β cause an inherited syndrome characterized by renal cystic disease or dysplasia anddiabetes mellitus.50

Genetic MechanismsEvidence from animal models of ADPKD and analysis of cystic epithelia have shown that renalcysts may develop from loss of functional polycystin with somatic inactivation of the normalallele consistent with a two hit mechanism. However, dosage reduction of the protein in twoPkd1 animal models with hypomorphic alleles that generate <20% of the normally splicedproduct indicates that cysts can develop even if the protein is not completely lost.51

Furthermore, Pkd1 transgenic mice overexpressing the Pkd1 transgene in the kidneys 2- to 15-fold over Pkd1 endogenous levels develop renal cystic disease resembling human ADPKD.52 Transgenic mice overexpressing Pkd2 develop B-Raf and ERK activation, increased ratesof proliferation and apoptosis, and renal cysts detectable at 6 months and progressive with age.53 Transgenic mice overexpressing human PKD2 to the levels of 30–100% of the expressionof the endogenous mouse Pkd2 show mild tubular dilatation, microcysts (in a minority ofanimals at 8 months of age), and tubular cell vacuolization, disorganization of the renal cortex,and abnormal expression of extracellular matrix (ECM) in older animals.54 Transgenic ratsexpressing a truncated human PKD2 cDNA lacking almost the entire C terminus to levels 7-to 15-fold higher than those of endogenous Pkd2 mRNA develop PKD and retinal degeneration.55 These animal models suggest that multiple genetic mechanisms that result in an imbalancein the expression of polycystins can affect their function and lead to the development of PKD.

Centrosomal amplification occurs in kidneys from conditional Pkd1 knockout mice, Pkd2-knockout mice, PKD2-overexpressing mice, and from patients with ADPKD.56,57 Knockdownof Pkd1 expression using small interfering RNA induces centrosomal amplification, multipolarspindle formation, polyploidism, and mitotic catastrophe, followed by a convergence of thecell population toward a stable ploidy in which centrosomal amplification is significantlydecreased, but cytological abnormalities and aneuploidy remain common.56 The link betweenderailed levels of polycystin expression, centrosome integrity and genomic stability mayreconcile the haploinsufficiency, gene dose effect, and two-hit hypotheses of cystogenesis.This model is consistent with the evidence of cyst formation from a relative low number oftubules, the presence of apoptotic cells in both tubular and cystic cells in ADPKD kidneys, theclonality of cystic epithelia, and the high frequency of chromosomal anomalies and geneticaberrations in cystic cells from patients with ADPKD. It may also account for the low rate ofdevelopment of renal cell carcinoma in ADPKD, despite the frequency of hyperplastic polypsand microscopic adenomas, as recent evidence indicates that high levels of genomic instabilitymay inhibit tumorigenesis.58,59

Conditional knockouts of ciliogenic genes (Tg737 and Kif3a) or of Pkd1 at various time pointshave shown that the timing of ciliary loss or Pkd1 inactivation determines the rate ofdevelopment of cystic disease.60–63 Kidney development is not yet completed in newbornmice. Inactivation of Pkd1 before postnatal day 13 results in rapidly progressive cystic disease,whereas later inactivation causes much slower cyst development.61 The kidney-specificinactivation of Kif3a in newborn mice leads to rapid cyst development in the loops of Henle,whereas inactivation at postnatal day 10 or later does not, despite comparable loss of primarycilia.60 Cysts also develop rapidly in the corticomedullary region (pars recta and thickascending limbs of Henle) of adult mouse kidneys subjected to renal ischemic/reperfusioninjury to stimulate cell proliferation (but not in contralateral control kidneys), when Kif3a isconditionally inactivated.64 Analysis of pre-cystic tubules show that the loss of cilia results inaberrant planar cell polarity manifested by abnormalities in the orientation of cell division. The



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age-dependence, location, and induction of the cysts by ischemia-reperfusion injury suggestthat cyst formation is associated with increased rates of cell proliferation. However,inactivation of Pkd1 at postnatal day 14 or of Kif3a at postnatal dates 10–14, when the ratesof cell proliferation are higher than in the adult, but lower than in younger animals, fails toinduce cyst formation. This suggests that a certain threshold of cell proliferation must beexceeded or that increased cell proliferation is only one of the factors responsible for the higherrate of cyst formation in newborn compared with older mice. Another factor could be thetranscriptional programming of kidney cells, which is markedly different in the postnatal periodcompared with the adult.61,65 In summary, these observations in conditional knockouts indicatethat PKD1 and cilia are required to maintain the renal tubular structure in adult kidneys, thatcyst initiation can occur throughout the lifetime of an individual, and that cyst developmentoccurs much more rapidly when PKD1 is inactivated or cilia are lost in developing than inmature kidneys. Although they provide important insights, it is important to point out thatmassive and complete inactivation of PKD1 at a particular time point is not likely how thedevelopment of cystic disease starts in ADPKD and that consequently these are imperfectmodels for this disease.

PathogenesisThe polycystins are essential to maintain the differentiated phenotype of the tubular epithelium.Reduction in one of these proteins below a critical threshold results in a phenotypic switchcharacterized by inability to maintain planar polarity, increased rates of proliferation andapoptosis, expression of a secretory phenotype, and remodeling of the ECM. The molecularmechanisms responsible for this phenotypic switch are not known, but hypotheses abound.Treatment strategies based on them may help to establish their validity. Given the proposedparticipation of the polycystins in numerous signaling pathways at multiple subcellularlocations, they are likely to be complex.

Centrosomal dysfunction or amplification, activation of canonical β-catenin-dependent Wntsignaling, and inhibition of non-canonical β-catenin-independent Wnt signaling (that is,activation of c-jun N-terminal kinase, JNK, and transient changes in cytosolic calciumconcentrations) may be responsible for the loss of planar cell polarity, which may be key tothe transformation of a tubular into a cystic structure.

A recent study has shown that secreted Frizzled-related protein 4 (sFRP4) is upregulated inhuman ADPKD9,66 and in four different animal models of PKD (Pkd2−/−, Invs−/−, and pcymice, and Han:SPRD rat) and is detected in the urine of patients and animals with PKD, butnot in the urine of healthy individuals.66 sFRP4 is a member of a family of secreted moleculesthat antagonize Wnt signaling. Interestingly, it inhibits only select members of the canonicalWnt signaling pathway, possibly explaining why β-catenin can accumulate in PKD in thepresence of elevated sFRP4 concentrations. The sFRP4 promoter contains lymphoid enhancer-binding factor-1-, STAT3-, and cAMP-responsive element-binding sites. Because thelymphoid enhancer-binding factor-1-binding site can be stimulated by active β-catenin, it isconceivable that canonical Wnt signaling, not blocked by sFRP4, stimulates sFRP4 production.Cyst fluid and vasopressin stimulate, while a vasopressin V2 receptor antagonist has an amarked inhibitory effect on the expression of sFRP4 in inner medullary collecting duct cellsin vitro and in kidneys of pcy mice in vivo. Microinjection of sFRP4 into zebrafish embryosinduces pronephric cyst formation, heterotaxia, and abnormal body curvature. Therefore,increased sFRP4 expression in PKD is more likely to be disease-promoting than an adaptivemechanism to protect the kidney from the detrimental effects of uncontrolled canonical Wntsignaling.



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Many pathways that couple cell surface receptors (GPCRs, TKRs, integrins, and so on) andepithelial cell proliferation are activated in PKD. These include mitogen-activated proteinkinase/extracellular regulated kinase and mammalian target of rapamycin (mTOR). In addition,several studies have implicated the polycystins directly in the regulation of the cell cycle. PC1was reported to activate JAK2/STAT-1 signaling, upregulate p21waf (a cell cycle inhibitor),inhibit cyclin-dependent kinase 2 (Cdk2), and induce cell cycle arrest in G0/G1 in a PC2-dependent manner. PC2 was reported to bind Id2, a helix-loop-helix protein in a PC1-dependentmanner, and prevent its translocation to the nucleus and suppression of p21waf, thus preventingCdk2 activation and cell cycle progression. Consistent with these studies, p21waf levels havebeen found to be reduced in human and animal PKD tissues as well as in affected cell lines.67 However, a recent study has found a different Cdk inhibitor (p57KIP2) to be downregulated,along with upregulation of Cdk2, in primary tubular epithelial cells isolated from a PKD2transgenic rat.68

PC1 and PC2 may also suppress cell growth through the control of the protein synthesisinitiation machinery. PC1 interacts with tuberin to suppress mTOR and activation of thedownstream translation initiation factor eIF4E. PC2 interacts with pancreatic eIF2a kinase(PERK) in the endoplasmic reticulum and enhances PERK-dependent phosphorylation of thetranslation initiation factor eIF2a.28

Numerous studies have shown that increased tubular cell proliferation is accompanied byincreased apoptosis in PKD.69 The induction of resistance to apoptosis by PC1 has beenattributed to GiCPR activation of phosphatidylinositol 3-kinase (PI3K) and Akt. However, therole of PI3K and Akt in PKD remain uncertain, as PI3K and Akt activation, along withincreased apoptosis, have been shown in animal models of PKD.70 Interestingly,overexpression of PKD1 has been shown to induce G0/G1 phase arrest in cell cycle progressionand an increase in the rate of apoptosis in cancer cell lines.71 Although PC1 knockdown inMDCK cells is associated with increased rates of proliferation and apoptosis, it is alsoaccompanied by increased adhesion to collagen type I and resistance to anoikis (apoptosistriggered by loss of cell anchorage) probably due to increased expression of integrin-α2β1.72

Beyond the loop of Henle, tubular epithelial cells have the capacity to secrete as well as toreabsorb solutes and fluid. Normally, absorptive flux overshadows secretory flux. Sodiumchloride reabsorption in cortical collecting duct principal cells, arguably the main origin of thecysts in ADPKD, is driven by low intracellular sodium concentration generated by basolateralNa-K-ATPase. Sodium chloride enters the luminal membrane through the epithelial sodiumand chloride channels. Apical recycling of potassium occurs through renal outer medullary K(ROMK) channels. Water enters the cells across the luminal membrane through vasopressin-sensitive aquaporin-2 channels. Cystic epithelial cells are markedly different from normalcortical collecting duct principal cells. Chloride enters across basolateral NaK2Clcotransporters, driven by the sodium gradient generated by basolateral Na-K-ATPase, and exitsacross apical protein kinase A (PKA)-stimulated cystic fibrosis transmembrane conductanceregulator (CFTR). Basolateral recycling of potassium may occur through KCa3.1 (see below).73,74 Active accumulation of chloride within the cyst lumen drives sodium and water secretiondown transepithelial potential and osmotic gradients. This model for cyst fluid secretionrequires a paracellular pathway sealed by tight junctions impermeable to chloride. The basicbiochemical infrastructure of the tight junction remains intact even in late-stage cysts.75 Tightjunctions are composed of interacting proteins, including scaffolding proteins such as ZO-1and transmembrane proteins such as occludin and members of the claudin family. Most of theclaudin isoforms expressed in ADPKD cysts are of distal nephron and collecting duct origin.Claudin-2, normally expressed in proximal tubules, is absent from the cysts.



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Human and animal models of PKD show an abnormal expression of matrix-degrading enzymesand inhibitors of metalloproteinases, necessary for the remodeling of basement membranesand the surrounding ECM. Cyst-lining epithelia produce large amounts of structural (collagenI and III, laminin) and soluble ECM-associated proteins (TGF-β, big-H3, periostin), whichaccumulate around the cysts. Some ECM components (laminin, periostin) actively contributeto epithelial cell proliferation and cyst growth.

Periostin is a novel autocrine mitogen expressed at high levels by cyst-derived epithelial cells.It is secreted across apical and basolateral cell membranes and found in the ECM adjacent tothe cysts and within cyst fluid, but not in normal kidneys.76 Periostin binds αV-integrins(αVβ3- and αVβ5-integrins), that is highly expressed in ADPKD cells, and activates integrin-linked kinase (ILK). ILK inhibits GSK-3β, stabilizes β-catenin, increases nuclear β-cateninlevels, and activates T-cell factor/lymphoid enhancer-binding factor, a transcription factorinvolved in cell proliferation. ILK also activates Akt and lowers the expression of p27Kip1 acell cycle kinase inhibitor. The effect of periostin on cell proliferation is inhibited by αV-integrin-blocking antibodies.

Laminin-5 (α3, β3, γ2) is strongly expressed by ADPKD cells and in the pericystic ECM ofADPKD kidneys, whereas no laminin-5 expression can be detected in adult control kidneys.77 ADPKD cells in a three-dimensional gel culture produce and secrete laminin-5 that isincorporated into pericystic ECM. Addition of purified laminin-5 stimulates cell proliferationand cyst formation, whereas blocking antibodies against laminin-5 inhibit cell proliferationand cyst formation. Furthermore, a hypomorphic mutation of laminin-α5, a major tubularbasement membrane component, results in aberrant accumulation of laminin-5 and cysticdisease in mice.78

Disregulation of Intracellular Calcium and cAMP Signaling in PKDIncreasing experimental evidence suggest that the polycystins are localized in specializedstructures that sense the extracellular environment, such as primary cilia, focal adhesions andadherens complexes, that their function is important for the regulation of intracellular calciumhomeostasis, and that alterations in intracellular calcium and cAMP signaling play a centralrole in the pathogenesis of PKD.

The location of the polycystins that recently has received the most attention is the primarycilium. In tubular epithelial cells, the cilium projects into the lumen and is thought to have asensory role. The PC1–PC2 complex acts as a sensor on cilia that translates mechanical orchemical stimulation into calcium influx through PC2 channels. This in turn induces calciumrelease from intracellular stores. PC2 interacts with other TRP channels (TRPC1 and TRPV4),which may be the components of the mechanosensory apparatus in primary cilia. ADPKD cystcells lack flow-sensitive calcium signaling and show reduced endoplasmic reticulum calciumstores, store-depletion-operated entry and, under certain conditions, intracellular calciumconcentrations.

Although PC2 is found mainly in the endoplasmic reticulum and to a lesser extent in the plasmamembrane, PC1 is found mainly in the plasma membrane and possibly in the endoplasmicreticulum. Although it seems certain that PC2 and probably PC1 play an important role in theregulation of the endoplasmic reticulum calcium stores and intracellular calcium homeostasis,the precise mechanisms by which this regulation operates remain uncertain. Calcium releasefrom intracellular stores decreases gradually with overexpression, haploinsufficiency, orabsence of PC2. In cardiac myocytes, the N terminus of PC2 binds to RyR2, whereas the Cterminus interacts with the RyR2 in its open state inhibiting its channel activity.24 InadequateRyR2 inhibition in cardiac myocytes lacking PC2 results in a higher frequency of spontaneous



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oscillations, reduced sarcoplasmic reticulum calcium stores due to calcium leak, and reducedcalcium transient amplitude compared with wild-type cells. PC2 interacts with Syntaxin 5 (amember of a family of proteins, which function in vesicle targeting and fusion and regulationof the channel activity), inhibits its channel activity, and prevents leaking of calcium from theendoplasmic reticulum.25 Overexpression in LLC-PK1 cells of a truncated PC2 protein thatcauses PKD and retinal degeneration in transgenic rats is associated with reduced endoplasmicreticulum calcium stores. As in the case of cardiac myocytes lacking PC2, downregulation ofPC1 expression and cystic cell lines from PKD1 patients are associated with a higher frequencyof calcium oscillations, in this case due to increased activity of non-capacitative calcium entry.79 Heterologous expression of PC1 in MDCK cells also inhibits the leakage of calcium acrossthe endoplasmic reticulum membrane.80 ADPKD cyst cells exhibit reduced endoplasmicreticulum calcium stores, store-depletion-operated entry and, under certain conditions,intracellular calcium concentrations.81 Although most of these observations point to reducedintracellular calcium stores as a common feature in PKD, another study reported thatoverexpression of PC2 in HEK cells increases calcium leakage and reduces the amount ofreleasable calcium upon stimulation with IP3 in the endoplasmic reticulum, whereasknockdown of PC2 in MDCK cells has the opposite effect and increases the susceptibility toapoptosis.82

Increased levels of cAMP and expression of cAMP-dependent genes (such as AQP2 in thekidney) are a common finding in the kidneys of cpk, jck, pcy, KspCre;HNF1βflax/laxPkd2−/ws25 and γGT.Cre:Pkd1flax/flax mice and PCK rats,83-85 liver of PCK rats,86 vascular smooth muscle of Pkd2+/− mice, and choroid plexus of TG737orpk mice.87 In arecent study, renal cAMP levels and AQP2 expression were found to be similar in mice witha specific knockout of Pkd1 in collecting duct principal cells compared with controls; however,the renal cAMP levels in the control animals were very high compared with earlier studies.88 In view of the role of PC1 and PC2 in the regulation of intracellular calcium homeostasisand the importance of calcium in the regulation of cAMP metabolism by stimulation of calciuminhibitable adenylyl cyclase 6 and/or inhibition of calcium-dependent phosphodiesterase 1, ithas been suggested that alterations in intracellular calcium homeostasis account for theaccumulation of cAMP. Cyclic AMP in turn contributes to the development and progressionof PKD by stimulating CFTR-driven chloride and fluid secretion and cell proliferation. Whileunder normal conditions cAMP inhibits mitogen-activated protein kinase signaling and cellproliferation, in PKD or in conditions of calcium deprivation it stimulates cell proliferation inan Src-, Ras-, and B-raf-dependent manner. Cell proliferation may be further enhanced bystimulation of epidermal growth factor (EGF)-like factors present in cyst fluid, increasedinsulin-like growth factor-1 in cystic tissues, and by activation of mTOR, likely due to adisrupted tuberin-polycystin-1 interaction or to ERK- or Akt-dependent phosphorylation oftuberin that prevents its association with hamartin and inhibits its GTPase activating functionfor Rheb.

The abnormal proliferative response to cAMP is directly linked to the alterations in [Ca2+]i,as it can be reproduced in wild-type cells by lowering [Ca2+]i. Conversely, Ca2+ ionophoresor channel activators can rescue the abnormal response of cyst-derived cells.89 Upregulationof the vasopressin V2 receptor and high circulating vasopressin levels may contribute to theincreased cAMP levels. A bioactive lipid with the same biochemical and biological propertiesas forskolin, a widely known, potent adenylyl cyclase agonist, has been isolated and identifiedwithin the cyst fluid. It is conceivable that forskolin is synthesized by mural cyst epithelialcells, although an exogenous source cannot be ruled out.90



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DiagnosisThe diagnosis of ADPKD usually relies on imaging testing. Counseling should be done beforetesting. The risk for discrimination in terms of insurability and employment has been reduced,but not eliminated, by the passage into law of the Genetic Information Nondiscrimination Act(GINA) on 21 May 2008 (refs 91,92). GINA prohibits insurers from canceling, denying, refusingto renew, or changing the terms or premiums of coverage based on genetic information. It alsoprohibits employers from making hiring, firing, promotion, and other employment-relateddecisions based on genetic factors. Genetic information is defined as information about anindividual's genetic tests, genetic tests of family members, or occurrence of a disease in familymembers of the individual. GINA, however, applies only to individuals who are asymptomatic,does not prohibit underwriting based on information about current health status, and does notapply to life insurance, disability insurance, or long-term care insurance.

Renal ultrasound is commonly used because of cost and safety. Revised criteria have beenproposed to improve the diagnostic performance of sonography in ADPKD (Table 3): Thepresence of at least three (unilateral or bilateral) renal cysts and of two cysts in each kidneyare sufficient for diagnosis of at-risk individuals aged 15–39 years and 40–59 years,respectively.93 For at-risk individuals aged ≥60 years, four or more cysts in each kidney arerequired. Requirement of three or more cysts (unilateral or bilateral) has a positive predictivevalue of 100% in the younger age group and minimizes false-positive diagnoses, as 2.1 and0.7% of the genetically unaffected individuals younger than 30 years have one and two renalcysts, respectively. In the 30–39 years old, both the original (2 cysts in each kidney) and therevised (>3 cysts, unilateral or bilateral) criteria have a positive predictive value of 100%.

Although the specificity and positive predictive value of the sonographic criteria is very high,their sensitivity and negative predictive value when applied to PKD2 in the 15–29 (69.5 and78%, respectively), 30–39 (94.9 and 95.4%, respectively), and 40–59 (88.8 and 92.3%,respectively) years old groups are low. This is a problem in the evaluation of potential kidneydonors, where exclusion of the diagnosis is important.93 Because of this, Pei et al.93 proposedthat different criteria are used to exclude a diagnosis of ADPKD in an individual at risk froma family with an unknown genotype. They found that an ultrasound scan finding of normalkidneys or one renal cyst in an individual aged 40 years or older has a negative predictive valueof 100%. The absence of any renal cyst provides almost certainty for disease exclusion in at-risk individuals aged 30–39 years with a false-negative rate of 0.7%. The utility ofultrasonography for disease exclusion is limited in an at-risk individual who is younger than30 years and has a negative or indeterminate scan.

In latter scenario, a negative magnetic resonance imaging (MRI) or computed tomography(CT) scan may provide further assurance that he/she is not affected. As part of the donorevaluation, potential candidates in most transplant centers undergo contrast enhanced, three-dimensional CT, or MR angiographic imaging. The resolution of these techniques is muchhigher than that of ultrasound. Three millimeter rather than 10 mm cysts are readily detected.These high resolution imaging modalities show a prevalence of cysts in the general population,which is at least four times higher than observed by ultrasound. Therefore, the negativepredictive value of a negative high resolution CT or MR, although not quantifiable becausethe proper study has not been performed, is undoubtly much higher than that of ultrasound.

Recently Huang et al.94 proposed an algorithm that incorporates the use of DNA testing forthe evaluation of donors at 50% risk of ADPKD inheritance. This algorithm proposes thatpotential kidney donors who are less than 30 years old with <3 renal cysts or 30–39 years oldwith 1–2 renal cysts or 40–59 years old with multiple cysts in one kidney and 0–1 cyst in theother should have genetic testing. The algorithm does not differentiate between cysts detected



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by ultrasound, CT, or MRI. Given the high prevalence of renal cysts detectable by CT or MRin the general population (for example, 16–20, 21–25, and 31–55% of 18–29, 30–44, and 45–59 years old women and men, respectively, have at least two renal cysts detectable by MR),the application of this algorithm would require genetic testing in nearly one-half of potentialliving related kidney donors for ADPKD. The algorithm does not take into account either theinformation that may be available on the ADPKD phenotype of the family. The presence ofone affected family member who developed ESRD by the age of 60 years is highly predictiveof PKD1 (PPV 100%, sensitivity 75%). By contrast, the presence of one affected familymember who remained renal sufficient or developed ESRD after the age of 70 years is highlypredictive of PKD2 (PPV 95%, sensitivity 75%).95

There are limitations to genetic testing, either by linkage or mutation analysis.96 Linkageanalysis requires accurate diagnosis, availability and willingness of sufficient affected familymembers to be tested and is feasible in fewer than 50% of families. De novo mutation can alsocomplicate interpretation of results. Molecular testing by direct DNA sequencing is nowpossible with likely mutations identified in ∼90% of patients.36,97 However, as most mutationsare unique and up to one-third of PKD1 changes are missense, the pathogenicity of somechanges is difficult to prove.36,97

Renal ManifestationsMost manifestations are directly related to the development and enlargement of renal cysts. Astudy of 241 patients with an estimated glomerular filtration rate (GFR) ≥60 ml/min followedprospectively with yearly MR examinations by CRISP has provided invaluable information tounderstand how the cysts develop and grow.98 Total kidney volume and cyst volumes increasedexponentially. At baseline, total kidney volume was 1060 ± 642 ml and the mean increase over3 years was 204 ml (5.27%) per year. The rates of change of total kidney and total cyst volumes,and of the right and left kidney volumes, were strongly correlated. Baseline total kidney volumepredicted the subsequent rate of increase in renal volume and was associated with decliningGFR in patients with baseline total kidney volume above 1500 ml. These results have beenconfirmed by recent European study of 100 ADPKD patients with an estimated GFR ≥70 ml/min who underwent standardized MR examinations with un-enhanced sequences 6 monthsapart. These patients had a baseline total kidney volume of 1003 ± 568 ml and a calculatedannual growth rate of 5.36%.99

Another study used contrast enhanced CT to monitor volume changes in 13 patients with moreadvanced ADPKD (serum creatinine 1.2–3.0 mg per 100 ml) imaged twice 6 months apart.100 The volumes of kidneys, cysts, fully enhanced parenchyma, and faintly contrast-enhancedparenchyma (referred to as intermediate) were estimated. The intermediate volume wasconsidered to be renal parenchyma undergoing tubular atrophy and fibrosis. The ratio ofintermediate over parenchyma volume strongly correlated with GFR (r −0.81, P<0.001). Inaddition, there were significant correlations between percentage changes in intermediatevolume (absolute or relative to parenchyma) and GFR changes during the observation period(r −0.70 and −0.75, P<0.01), thus supporting a significant relationship between renal structuraland functional changes in ADPKD.

A study in Newfoundland identified all patients with ADPKD attending nephrology/urologyclinics in 1981.35 The members of 18 families who were at 50% risk for inheriting ADPKD(136 with PKD1 and 60 with PKD2) were followed prospectively for 22 years. Median age atinitiation of treatment for hypertension, stage 3 CKD, ESRD, and death were 46, 50, 53, and67 years for PKD1, respectively. Median age to hypertension treatment, stage 3 CKD, anddeath were 51, 66, and 71 years, respectively, whereas ESRD was infrequent, for PKD2. Causesof death were similar, except for uremia, which was more common in PKD1.



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Hypertension is the most common manifestation of ADPKD and a major contributor to renaldisease progression and cardiovascular morbidity and mortality. Ambulatory blood pressuremonitoring of children or young adults without diagnosed hypertension often reveals elevatedblood pressures, attenuated nocturnal blood pressure dipping, and exaggerated blood pressureresponse during exercise. A recent study stratified 65 children by blood pressure into threecohorts: hypertensive (≥95th percentile), borderline hypertensive (75–95th percentile), andnormotensive (≤75th percentile).101 Both the hypertensive and borderline hypertensivechildren had significantly higher left ventricular mass indices than normotensive children.Among normotensive children, indices were significantly higher in those within the upperquartile of the normal blood pressure. These observations suggest that target organ damagedevelops early in ADPKD and that antihypertensive treatment may be indicated in childrenwith ADPKD and borderline hypertension.

Several factors contribute to the development of hypertension in ADPKD. Activation of theintrarenal renin–angiotensin system likely plays an important role, whereas there is controversyon whether the circulating renin–angiotensin system is inappropriately activated.102

Expression of PC1 and PC2 in vascular smooth muscle and endothelium, along with enhancedvascular smooth muscle contractility103 and impaired endothelial dependent vasorelaxation,suggest that disruption of polycystin function in the vasculature are directly involved. PC1 inthe primary cilia plays a role in the translation of physiological changes in fluid shear stressinto cytosolic calcium and nitric oxide signals.104 Other factors include increased sympatheticnerve activity and plasma endothelin-1 levels and insulin resistance.

Endothelial vasodilatation and constitutive nitric oxide synthase activity are reduced insubcutaneous resistance vessels from patients with ADPKD and normal GFR. Flow-inducedvasodilation of the brachial artery has been found to be inconsistently impaired,105,106 whereaspulse wave reflection was amplified suggesting a predominant involvement of small resistancevessels.107 Reduced coronary flow velocity reserve and increased carotid intima-mediathickness in normotensive patients with normal GFR suggest that atherosclerosis starts earlyin the course of ADPKD.108

Reduced nitric oxide endothelium-dependent vasorelaxa-tion in ADPKD may be due toincreased plasma levels of asymmetric dimethylarginine (ADMA).109 Increased oxidativestress in the kidneys, reflected by increased plasma and urine levels of 13-hydroxyoctadecadienoic acid, may result in the oxidation of a cysteine residue in the activesite of NG, NG-dimethylarginine dimethylaminohydrolase (DDAH, an enzyme thatmetabolizes ADMA in the renal tubules), reduced renal clearance and increased circulatinglevels of ADMA, and inhibition of constitutive nitric oxide synthase. Even modest increasesin plasma ADMA levels have been associated with impaired endothelial function. Systemicinfusion of non-pressor doses of ADMA into healthy human individuals impairs vasodilatorresponses to acetylcholine, increases vascular resistance, and decreases renal blood flow.

In most patients, renal function is maintained within the normal range, despite relentless growthof cysts, until the fourth to sixth decade of life. By the time renal function starts declining, thekidneys usually are markedly enlarged and distorted with little recognizable parenchyma onimaging studies. At this stage, the average rate of GFR decline is approximately 4.4–5.9 ml/min/year. Several mechanisms account for renal function decline. CRISP has confirmed earlierstudies suggesting a strong relationship with renal enlargement and shown that kidney and cystvolumes are the strongest predictors of renal functional decline.98 CRISP also found that renalblood flow (or vascular resistance) is an independent predictor.110 This points to the importanceof vascular remodeling in the progression of the disease and may account for cases where thedecline of renal function seems to be out of proportion to the severity of the cystic disease.



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Other factors such as heavy use of analgesics may contribute to CKD progression in somepatients.

Pain, often associated to cyst hemorrhage, infection or stones, is the most frequent symptomreported by adult patients. 18-F-fluorodeoxyglucose (FDG) positron emission tomography hasbecome a promising agent for detection of infected cysts.111,112 FDG is taken up byinflammatory cells because of their high metabolic rate. Advantages of FDG positron emissiontomography include: rapid imaging (1 h); high spatial resolution; high target-to-backgroundratio; low radiation burden; and high inter-observer agreement. Disadvantages are higher costand limited availability. Its use to diagnose infections in kidneys may be difficult, particularlywhen GFR is normal, because FDG is filtered by the kidneys (it is not reabsorbed by the tubules)and appears in the collecting system. By the time positron emission tomography scans areacquired, the renal parenchyma is usually free of activity, but prominent activity can be seenin renal calyces. Dual energy CT is increasingly used to distinguish between calcium and uricacid stones.113,114

Extrarenal ManifestationsPolycystic liver disease is the most common extrarenal manifestation. It is associated with bothPKD1 and non-PKD1 genotypes. PLD also occurs as a genetically distinct disease in theabsence of renal cysts. Similar to ADPKD, ADPLD is genetically heterogeneous, with twogenes identified (PRKCSH and SEC63) accounting for approximately one-third of isolatedADPLD cases.

The liver cysts arise by excessive proliferation and dilatation of biliary ductules and peribiliaryglands. Scanning electron microscopy has shown that the cyst epithelium displaysheterogeneous features, being normal in small cysts (<1 cm), characterized by rare or shortenedcilia in 1–3-cm cysts, and showing absence of both primary cilia and microvilli in large cysts(>3 cm).115 Estrogen receptors, insulin-like growth factor 1, insulin-like growth factor 1receptors (IGF1-R), and growth hormone receptor are expressed in the epithelium lining thehepatic cysts, and estrogens and IGF1 stimulate hepatic cyst-derived cell proliferation.115,116 Growth is also promoted by growth factors and cytokines secreted into the cyst fluid.117

Comparative analyses of human kidney and liver cyst fluids have shown disparate cytokine/growth factor profiles. CXCR2 agonists, including interleukin-8, epithelial neutrophil-activating peptide, growth-related oncogene-α, are potent proliferative agents that were foundat high levels in liver but not kidney cyst fluids.118

The changes in the expression of certain microRNAs may contribute to the proliferativephenotype of the cystic epithelium in PLD.119 A microarray analysis found marked differencesin microRNA expression in cholangiocyte cell lines derived from PCK rats, as well as in livertissues from PCK rats and patients with PLD, compared with controls. Specifically, a reducedexpression of miR15a in the cystic tissues was associated with upregulation of its target, thecell-cycle regulator cell division cycle 25A (Cdc25A). Over-expression of miR15a incholangiocytes from PCK rats decreased Cdc25A levels, inhibited cell proliferation, andreduced cyst growth. Suppression of miR15a in normal rat cholangiocytes accelerated cellproliferation, increased Cdc25A expression, and promoted cyst growth.

As shown earlier for PKD, cAMP seems to play a major role in the progression of PLD. Twomain downstream effectors of cAMP are cAMP-guanine nucleotide exchange factor/Epac(Epac) and PKA. Although only PKA has been implicated in the proliferative response tocAMP in PKD, both effector pathways may be important in PLD.120 Epac1 and Epac2 isoformsand the PKA RIβ subunit are over-expressed in cultured PCK cholangiocytes. Epac-specificstimulation promotes the proliferation of both, normal and PCK cholangiocytes, whereas PKA-specific stimulation suppresses proliferation in normal cholangiocytes and enhances it in PCK



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cholangiocytes. The stimulatory effects of Epac and PKA activation on the proliferation ofPCK cholangiocytes were both dependent on MEK-ERK1/2 signaling. The increasedproliferation of PCK cholangiocytes in response to PKA stimulation, but not to Epacstimulation, was found to be associated with decreased intracellular calcium. Restoration ofcalcium levels blocked the PKA-dependent proliferation. As described earlier for renal cyst-derived cells, the effect of intracellular calcium restoration on slowing PKA-associatedproliferation was abolished by preincubation of PCK cholangiocytes with PI3K or AKTinhibitors.

Hepatic cysts are rare in children. Their frequency increases with age and may have beenunderestimated by ultrasound and CT studies. Their prevalence by MRI in the CRISP study is58, 85, and 94% in 15–24, 25–34, and 35–46 years old participants.121 Hepatic cysts are moreprevalent and hepatic cyst volume is larger in women than in men.

Typically, PLD is asymptomatic, but symptoms have become more frequent as the lifespan ofADPKD patients has lengthened with dialysis and transplantation. Symptoms may result frommass effect or from complications related to the cysts. Symptoms typically caused by massiveenlargement of the liver or by mass effect from a single or a limited number of dominant cystsinclude dyspnea, early satiety, gastro-esophageal reflux, and mechanical low back pain. Othercomplications caused by mass effect include hepatic venous outflow obstruction, inferior venacava compression, portal vein compression, or bile duct compression presenting as obstructivejaundice. Symptomatic cyst complications include cyst hemorrhage, infection, and rarelytorsion or rupture. FDG positron emission tomography scanning is a promising diagnostic toolfor cyst infection.111 Rupture of an infected liver cyst into the pericardium and bronchobiliaryfistulas are rare recently reported complications.122,123

The seminal vesicles, pancreas, and arachnoid membrane cysts are present in 40–60% (males),5, and 8% of patients, respectively. Epididymal and prostate cysts may also occur withincreased frequency. Sperm abnormalities and defective motility (asthenozoospermia or <50%of spermatozoa with forward motility) are common in ADPKD and rarely may be a cause ofmale infertility.124 Pancreatic cysts are almost always asymptomatic, with very rareoccurrences of recurrent pancreatitis and possibly chance associations of intraductal papillarymucinous tumor or carcinoma. Spinal meningeal diverticula may occur with increasedfrequency and rarely present with intracranial hypotension (orthostatic headache, diplopia,hearing loss, ataxia) due to cerebrospinal fluid leak.125

Vascular manifestations include intracranial aneurysms and dolichoectasias, thoracic aorticand cervicocephalic artery dissections, and coronary artery aneurysms. They are caused byalterations in the vasculature directly linked to mutations in PKD1 or PKD2.126 Intracranialaneurysms are very prevalent (6% with a negative and 16% with a positive family history ofaneurysms), but most never rupture. Valvular heart disease (mitral valve prolapse and aorticinsufficiency) occurs with increased frequency. Colonic diverticulosis and diverticulitis aremore common in ESRD patients with ADPKD than in those with other renal diseases. Therehave been reports of extracolonic diverticular disease.127 A rarely reported association ofADPKD is with idiopathic hypertrophic pyloric stenosis.128 This may represent a chanceassociation, but a deficiency in nitric oxide synthase could be the underlying cause of bothconditions. PC1 is expressed in the motile cilia of airway epithelial cells. Bronchiectasis aredetected by CT three times more frequently in ADPKD compared with control individuals (37vs 13%, P<0.002).129

Adpkd Diagnosed in Utero or At BirthMore fetuses are now diagnosed with ADPKD due to the routine use of fetal ultrasonography.A report from a single center on 29 consecutive cases detected between the 12th week of



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pregnancy and the first day of life between 1981 and 2006 showed that the prognosis is usuallyfavorable, at least during childhood.130 Clinical features in 26 children (three pregnancies wereterminated because of prenatal signs of poor prognosis) included oligoamnios in five andneonatal pneumothorax in three. At the last follow-up (mean duration: 76 months; range: 0.5–262 months), 19 children (mean age: 5.5 years) were asymptomatic, 5 (8.5 years) hadhypertension, 2 (9.7 years) proteinuria, and 2 (19 years) chronic renal insufficiency.

TreatmentCurrent therapy is directed toward limiting the morbidity and mortality from the complicationsof the disease and has been the focus of recent reviews.3,131–133 The discussion here is limitedto information that has become available in the last 3 years.

Although some studies have shown better preservation of renal function or reduction inproteinuria and left ventricular hypertrophy with ACEIs or ARBs compared with diuretics orcalcium channel blockers, others have been unable to detect a superiority of these drugscompared with β-blockers. Most studies have been limited by inadequate power, short follow-ups, wide ranges of renal function, and doses with inadequate pharmacological effects. Equallyuncertain is the optimal blood pressure target. Although ADPKD patients with a baseline GFRbetween 13 and 24 ml/min per 1.73 m2 assigned in the MDRD study to a low blood pressuretarget (<92 mm Hg) had faster decline in GFR than those assigned to a standard blood pressuregoal (<107 mm Hg), an extended follow-up of the patients with a baseline GFR between 25and 55 ml/min per 1.73 m2 showed a delayed onset of kidney failure and a reduced compositeoutcome of kidney failure and all-cause mortality in the low blood pressure group. An ongoingstudy (HALT-PKD) is designed to determine whether the combined therapy with an ACEI andan ARB is superior to an ACEI alone in delaying the progression of the cystic disease in patientswith CKD stage 1 or 2 or in slowing down the decline of renal function in patients with CKDstage 3. HALT-PKD will also determine whether a low blood pressure target (<110/75) issuperior to a standard blood pressure target (<130/80) in the group of patients with preservedfunction (NCT00283686; Clinical Trials.gov).

Several studies have suggested a beneficial effect of statins on endothelial function, renal bloodflow, and levels of interleukin-6 and C-reactive protein.134 Administration of lovastatin to cy/+ rats increased renal blood flow and ameliorated the renal cystic disease, but the beneficialeffects from the administration lovastatin and enalapril on the severity of the cystic diseasewere not additive.135

Dietary supplementation with long-chain n-3 polyunsa-turated fatty acids has been shown tohave beneficial anti-inflammatory effects in cy/ + rats. However, a small prospectiverandomized trial of eicosapentaenoic acids (EPA, 2.4 g daily for 2 years) in ADPKD patients(21 treated with EPA and 20 controls; mean plasma creatinine concentrations, 1.75 and 1.56mg per 100 ml; mean total kidney volumes, 1806 and 1563 ml) did not show a beneficial effecton rates of renal enlargement or functional decline.136

The management of chronic pain in a relatively small subset of patients for whom it may bedisabling is challenging. When conservative measures fail, surgical interventions ranging fromcyst aspiration and sclerosing agents to laparoscopic or surgical cyst fenestration can beconsidered. A nonrandomized, open label, uncontrolled trial of videothoracoscopic sympatho-splanchnicectomy is ongoing (NCT00571909). Laparoscopic renal denervation andnephropexy have provided good results in children with chronic flank pain and intermittentsevere episodes.137 Laparoscopic or retroperitoneoscopic nephrectomy is indicated forsymptomatic patients with ESRD. Renal artery embolization can also be considered in thesecases. It has been reported to produce a decrease in kidney size to 73.8% at 3 months and to



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53.4% of the original size at 1 year. Side effects include flank pain which resolves within 5days, fever which lasts an average of 8.2 days, nausea and vomiting.138–140

Transplantation is the treatment of choice for ESRD in ADPKD. Complications after transplantare no greater than in the general population. Complications directly related to ADPKD arerare. Whether ADPKD increases the risk for developing new onset diabetes mellitus aftertransplantation is controversial.141,142 When nephrectomy is indicated, hand-assistedlaparoscopic nephrectomy is associated with less intraoperative blood loss, less postoperativepain, and a faster recovery compared with open nephrectomy and is increasingly being used.143–145

Most cases of PLD require no treatment. Rarely, symptomatic PLD requires interventions toreduce cyst volume and hepatic size. The choice of procedure (percutaneous cyst aspirationwithout or with sclerosis, laparoscopic cyst fenestration, combined liver resection and cystfenestration, and liver transplantation) is dictated by the anatomy and distribution of the cysts.146 Hepatic artery embolization has been used mainly in Japan and can be considered for highlysymptomatic patients in whom the other options are not feasible or too risky.147

Widespread pre-symptomatic screening is not indicated because it yields mostly smallaneurysms with a low risk of rupture. Indications for screening in patients with good lifeexpectancy include family history of aneurysm or subarachnoid hemorrhage, previousaneurysm rupture, preparation for major elective surgery, high-risk occupations (for example,airline pilots), and patient anxiety despite adequate information. MR angiography does notrequire intravenous contrast material. CT angiography is a satisfactory alternative when thereis no contraindication to intravenous contrast. When an asymptomatic aneurysm is found, arecommendation on whether to intervene depends on its risk of rupture (determined by size,site, morphology, and before history of subarachnoid hemorrhage from another aneurysm),patient age and general health, and whether the aneurysm is coilable or clippable.148

Novel TherapiesA better understanding of the pathophysiology and the availability of animal models hasfacilitated the development of preclinical trials (Figure 2) and identification of promisingcandidate drugs for clinical trials (Table 4).

The effect of vasopressin, through V2 receptors, on cAMP levels in the collecting duct, themajor site of cyst development in ADPKD, and the role of cAMP in cystogenesis provided therationale for preclinical trials of vasopressin V2 receptor (VPV2R) antagonists. One of thesedrugs, OPC-31260, reduced the renal levels of cAMP and markedly inhibited cyst developmentin models of ARPKD, ADPKD, and nephronophthisis.110 An antagonist with high potencyand selectivity for the human VPV2R (tolvaptan) was also effective. Neither had an effect onliver cysts, consistent with the absence of VPV2R in the liver. High water intake by itself alsoexerted a protective effect on the development of PKD in PCK rats most likely due tosuppression of vasopressin.149 Genetic elimination of AVP in these rats yielded animals bornwith normal kidneys that remained relatively free of cysts unless an exogenous V2R agonistwas administered.150 An antagonist of the endothelin-1 ETB receptor (predominant endothelinreceptor subtype in the collecting tubules that inhibits AVP action and promotes diuresis)increased renal cAMP and aggravated the renal cystic disease in Pkd2WS25/− mice, presumablyby enhancing the action of AVP.151 Phase II clinical trials with tolvaptan have been completedand a phase III clinical trial is ongoing (NCT00428948).

Somatostatin acting on SST2 receptors inhibits cAMP accumulation not only in the kidney butalso in the liver.152 Octreotide, a metabolically stable somatostatin analog, halted the expansionof hepatic cysts from PCK rats in vitro and in vivo. Similar effects were observed in the kidneys.



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These observations are consistent with the inhibition of renal growth in a pilot study of long-acting octreotide for human ADPKD and provide support for ongoing clinical trials ofoctreotide and lanreotide for PKD and PLD (NCT00309283, NCT00426153, NCT00565097).

Correcting the alteration in intracellular calcium homeostasis thought to be responsible for theaccumulation of cAMP and the proliferative phenotype of the cystic epithelium is a logicalalternative strategy to inhibit the development of PKD. The aggravation of PKD in cy/ + ratsby the administration of calcium channel blockers is consistent with this strategy.153 Triptolideinduced cellular calcium release through a PC2-dependent pathway, increased p21 expressionand arrested growth in Pkd1−/− cells, and reduced cystic burden in Pkd1−/− embryonic miceand in kidney-specific conditional Pkd1 knockout mice.154,155 On the other hand, amlodipinehas been reported to have an antiproliferative effect in vascular smooth muscle cells byincreasing the expression of p21 (Waf1/Cip1).156 The administration of a type 2 calcimimeticcaused a slight reduction in interstitial fibrosis, but had no detectable effect on the levels ofrenal cAMP, renal expression of cAMP-dependent genes, and cystogenesis in the PCK rat andPkd2−/WS25 mouse, possibly due to the absence of calcium-sensing receptor in the outermedullary and cortical collecting ducts or the reduction in extracellular calcium.84

The transporters required for chloride-driven fluid secretion into the cysts (NaK2Clcotransporter, Na-K-ATPase, CFTR, and KCa3.1) have been targeted to inhibit cyst growth(Figure 2). CFTR inhibitors slowed cyst growth in an MDCK cell culture model, in metanephrickidney organ cultures, and in Pkd1flox/–;Ksp-Cre mice.157,158 These observations areconsistent with reports of families with both ADPKD and cystic fibrosis in which individualswith both diseases had less severe cystic disease than those with only ADPKD.159 CFTRinhibitors that achieve high concentrations in the kidney and urine may find a place in thetreatment of ADPKD, because their accumulation in the lung is minimal and CFTR inhibitionhas to exceed 90% to affect lung function, thus making the development of cystic fibrosis-likelung disease unlikely.

A KCa3.1 inhibitor, TRAM-34 (an analog of des-imidazolyl clotrimazole), inhibited forskolin-stimulated transepithelial chloride secretion in filter-grown polarized monolayers of MDCK,NHK, and ADPKD cells, as well as MDCK and ADPKD cell cyst formation and enlargementin collagen gels.73,74 Although the efficacy of KCa3.1 inhibitors in ADPKD still needs to beshown in animal models of the disease, it is encouraging that senicapoc (ICA-17043), anotherKCa3.1 inhibitor, has been used successfully in a phase 2 trial and has shown little or no toxicityin a phase 3 trial for sickle-cell disease.160

Targeting the NaK2Cl cotransporter or Na-K-ATPase to treat ADPKD seems less feasiblebecause of likely side effects and less predictable effects on cystogenesis. Inhibition of theNaK2Cl cotransporter could potentially be detrimental as hypokalemia has been associatedwith chronic stimulation of COX-2 and PGE2 production and may favor cyst development.Addition of relatively high concentrations of ouabain to basolateral but not apical membranesof ADPKD cell monolayers and intact cysts dissected from ADPKD kidneys inhibited fluidsecretion. However, nanomolar concentrations of ouabain, within the range of levels found inblood under normal conditions increase ERK phosphorylation and MEK-ERK-dependentproliferation of ADPKD cells, without a significant effect on normal human kidney cells.161

Patients with the contiguous PKD1-TSC2 gene syndrome show a more severe form of PKDthan those with ADPKD alone. This observation suggests a convergence of signaling pathwaysdownstream from PC1 and the TSC2 protein tuberin (Figure 2). Activation of mTOR inpolycystic kidneys and an interaction between PC1 and tuberin have been reported.162

Furthermore, studies in three rodent models of PKD have shown that the mTOR inhibitorssirolimus and/or everolimus significantly retard cyst expansion and protects renal function.



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69,162–165 Small retrospective studies of ADPKD patients after transplantation have shown asignificant reduction in the volume of the polycystic kidneys or polycystic liver in patientstreated with sirolimus compared with patients treated with calcineurin inhibitors.162,166

Prospective, randomized clinical trials of rapamycin and everolimus are in progress(NCT00346918, NCT00491517, NCT00286156, NCT00414440).

It has been suggested that AMP-activated protein kinase activation might have a beneficialeffect on the development of PKD as it directly phosphorylates and inhibits CFTR and inhibitsmTOR through phosphorylation of tuberin (Figure 2). Consistent with this, metformin has beenshown to reduce the growth of MDCK cysts and the cystic index of conditional kidney-specificPkd1 knockout mouse.167

One of the effects of mTOR inhibition is to inhibit the production of and the cellular responseto vascular endothelial growth factor. Vascular endothelial growth factor is present in ADPKDliver and kidney cyst fluids, and VEGF receptors 1 and 2 (VEGFR1 and VEGFR2) are presentin cystic tissues. The results of VEGF inhibition in PKD have been mixed. Administration ofthe VEGFR inhibitor SU-5416 had a significant protective effect on the development of cysticdisease in the liver, but not in the kidney, in a small number of Pkd2WS25/− mice.168 On theother hand, treatment of developing CD-1 mice with antibodies against VEGFR2 results in thedevelopment of renal cysts, suggesting that inhibition of VEGF signaling could promote renalcyst growth.169

Tumor necrosis factor-α, TNFR-I, and TNF-α-converting enzyme are overexpressed in cystictissues. The administration of TNF promotes cyst formation in Pkd2+/− mice, whereasetanercept had an inhibitory effect.18 An inhibitor of TNF-α-converting enzyme was shown toameliorate the polycystic disease in the bpk mouse, a recessive model of PKD. The aggravationof PKD by TNFα may be due to its enhancement of the expression of FIP2, a protein thatphysically interacts with polycystin 2 and prevents its transport to the plasma membrane andprimay cilium. Alternatively, TNFα also activates IKKb (inhibitor of kB kinase-b), whichphysically interacts and phosphorylates hamartin, suppressing TSC1-TSC2 function andactivating mTOR.119 (Figure 2).

Polycystic kidney disease has been described as ‘neoplasm in disguise’, Many drugs developedto suppress cell proliferation and treat neoplastic diseases have been shown in animal modelsto be effective and of potential value for the treatment of ADPKD. These include Erb-B1 (EGFreceptor) and Erb-B2 tyrosine kinase, Src kinase, MEK, and cdk inhibitors.170–172 Roscovitine,a cyclin-dependent kinase inhibitor, inhibited cystogenesis and improved renal function in twomurine models of PKD, acting through blockade of the cell cycle, transcriptional regulation,and inhibition of apoptosis.173 Similar to PC1, roscovitine has been shown to increase the levelsof p21, which is downregulated in PKD.67

Increased apoptosis accompanies increased cell proliferation in PKD, but it is unclear whetherit is a neutral or beneficial consequence of excessive proliferation or an important contributorto cyst formation and renal injury. A caspase inhibitor (IDN-8050) reduced epithelial cellapoptosis and proliferation, and inhibited the development of the cystic disease and renalinsufficiency in Han:SPRD rats.69 Double mutants with PKD (cpk mice) and a knockout ofcaspase 3 had less severe cystic disease and lived longer than cpk mice with intact caspase3.174

A number of studies have focused on the role of arachidonic acid metabolites and theirinhibitors on the progression of PKD. Prostaglandin E2 (PGE2) accumulates in cyst fluids andenhances cAMP production and growth of MDCK cysts in collagen gels.175 PGE2 may act onfour different G-protein-coupled receptors named E-prostanoid (EP) receptors 1–4. EP2 andEP4 are coupled to G stimulatory proteins and stimulate cAMP formation. EP3 is coupled to



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G inhibitory protein, inhibits cAMP formation, induces Rho activation and actinpolymerization, and antagonizes vasopressin action. EP1 activation induces inositol 3-phosphate formation and calcium release. Recently, the effects of PGE2 on cAMP formationand cystogenesis, in a three-dimensional cell-culture system of human epithelial cells fromnormal and ADPKD kidneys, have been shown to be mediated by EP2 receptor activation, thussuggesting a possible role for EP2 receptor antagonists in the treatment of ADPKD.175

Phospholipase A, COX-1 and COX-2 activities and the production of prostacyclin,thromboxane A2, and PGE2 are higher in cystic than wild-type kidneys. Endogenous andsteady state in vitro levels of prostanoids were 2–10 times higher in diseased compared withnormal kidneys. The administration of the COX-2 inhibitor NS-398 reduced cystic expansionby 18%, interstitial fibrosis by 67%, macrophage infiltration by 33%, cell proliferation by 38%,and presence of oxidized low-density lipoprotein by 59% compared with controls, but had noprotective effect on renal function.176

The production of 20-hydroxyeicosatetraenoic acid (20-HETE), an endogenous cytochromeP450 metabolite of arachidonic acid with mitogenic properties, is markedly increased inmicrosomes from bpk compared with wild-type mice.177 Daily administration of HET-0016,an inhibitor of 20-HETE synthesis, reduced kidney size by half and doubled survival.Transfection of principal cells isolated from wild-type mice with Cyp4a12 induced a four- tofivefold increase in cell proliferation, which was completely abolished when 20-HETEsynthesis was inhibited. These observations suggest that 20-HETE contributes to theproliferation of epithelial cells in the formation of renal cysts and provide another potentialtarget for intervention.

Strategies for Clinical TrialsIn planning clinical trials for ADPKD, the utilization of renal function as the primary outcomebecomes an issue. Decades of normal renal function, despite progressive enlargement andcystic transformation of the kidneys, characterize the natural history of ADPKD. By the timeGFR starts declining, the kidneys are markedly enlarged, distorted, and unlikely to benefit fromtreatment. On the other hand, early interventional trials would require unrealistic periods offollow-up if renal function was to be used as the primary outcome. The results of CRISP178

have shown that the rate of renal growth is exponential and a good predictor of functionaldecline. Extrapolation of total kidney volume in individual CRISP subjects back to an age of18 years is consistent with the volumes observed by direct measurement in a separate cohortof patients. The good fit between these extrapolated and measured values indicates that thetotal kidney volume growth rate is a defining trait for individual patients.178 The results of theCRISP study have been confirmed by a recent European study that has shown that increasesin kidney volume can be reliably measured over a 6 month period in early ADPKD, usingunenhanced MRI sequences.99 These observations provide a strong rationale for the utilizationof kidney volume as a surrogate marker of disease progression in clinical trials for ADPKD.

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125. Schievink WI, Palestrant D, Maya MM, et al. Spontaneous spinal cerebrospinal fluid leak as a causeof coma after craniotomy for clipping of an unruptured intracranial aneurysm. J Neurosurg2009;110:521–524. [PubMed: 19012477]

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127. Kumar S, Adeva M, King BF, et al. Duodenal diverticulosis in autosomal dominant polycystic kidneydisease. Nephrol Dial Transplant 2006;21:3576–3578. [PubMed: 16951424]

128. Tennakoon J, Koh TH, Alcock G. Pyloric stenosis in a newborn baby with polycystic kidneys. JPerinatol 2007;27:125–126. [PubMed: 17262047]

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131. Grantham JJ. Clinical practice. Autosomal dominant polycystic kidney disease. N Engl J Med2008;359:1477–1485. [PubMed: 18832246]



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135. Zafar I, Tao Y, Falk S, et al. Effect of statin and angiotensin-converting enzyme inhibition onstructural and hemodynamic alterations in autosomal dominant polycystic kidney disease model.Am J Physiol Renal Physiol 2007;293:F854–F859. [PubMed: 17581927]

136. Higashihara E, Nutahara K, Horie S, et al. The effect of eicosapentaenoic acid on renal function andvolume in patients with ADPKD. Nephrol Dial Transplant 2008;23:2847–2852. [PubMed:18372389]

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138. Ubara Y. New therapeutic option for autosomal dominant polycystic kidney disease patients withenlarged kidney and liver. Ther Apher Dial 2006;10:333–341. [PubMed: 16911186]

139. Sakuhara Y, Kato F, Abo D, et al. Transcatheter arterial embolization with absolute ethanol injectionfor enlarged polycystic kidneys after failed metallic coil embolization. J Vasc Interv Radiol2008;19:267–271. [PubMed: 18341960]

140. Bremmer MS, Jacobs SC. Renal artery embolization for the symptomatic treatment of adultpolycystic kidney disease. Nat Clin Pract Nephrol 2008;4:236–237. [PubMed: 18317502]

141. Hamer RA, Chow CL, Ong AC, et al. Polycystic kidney disease is a risk factor for new-onset diabetesafter transplantation. Transplantation 2007;83:36–40. [PubMed: 17220788]

142. Pietrzak-Nowacka M, Safranow K, Rozanski J, et al. Autosomal dominant polycystic kidney diseaseis not a risk factor for post-transplant diabetes mellitus. Matched-pair design multicenter study.Arch Med Res 2008;39:312–319. [PubMed: 18279704]

143. Lipke MC, Bargman V, Milgrom M, et al. Limitations of laparoscopy for bilateral nephrectomy forautosomal dominant polycystic kidney disease. J Urol 2007;177:627–631. [PubMed: 17222647]

144. Desai PJ, Castle EP, Daley SM, et al. Bilateral laparoscopic nephrectomy for significantly enlargedpolycystic kidneys: a technique to optimize outcome in the largest of specimens. BJU Int2008;101:1019–1023. [PubMed: 18190626]

145. Kramer A, Sausville J, Haririan A, et al. Simultaneous bilateral native nephrectomy and living donorrenal transplantation are successful for polycystic kidney disease: the University of Marylandexperience. J Urol 2009;181:724–728. [PubMed: 19091353]

146. Torres VE. Polycystic liver disease: One size does not fit all. Am J Kidney Dis 2007;49:725–728.[PubMed: 17533013]

147. Takei R, Ubara Y, Hoshino J, et al. Percutaneous transcatheter hepatic artery embolism for patientswith polycystic liver disease. Am J Kidney Dis 2007;49:744–752. [PubMed: 17533017]

148. Burns J, Brown RJ. Treatment of unruptured intracranial aneurysms: surgery, coiling, or nothing?Curr Neurol Neurosci Rep 2009;9:6–12. [PubMed: 19080747]

149. Nagao S, Nishii K, Katsuyama M, et al. Increased water intake decreases progression of polycystickidney disease in the PCK rat. J Am Soc Nephrol 2006;17:2220–2227. [PubMed: 16807403]

150. Wang X, Wu Y, Ward CJ, et al. Vasopressin directly regulates cyst growth in the PCK rat. J AmSoc Nephrol 2008;19:102–108. [PubMed: 18032793]

151. Chang MY, Parker E, El Nahas M, et al. Endothelin B receptor blockade accelerates diseaseprogression in a murine model of autosomal dominant polycystic kidney disease. J Am Soc Nephrol2007;18:560–569. [PubMed: 17202412]

152. Masyuk AI, Masyuk TV, Splinter PL, et al. Cholangiocyte cilia detect changes in luminal fluid flowand transmit them into intracellular Ca2+ and cAMP signaling. Gastroenterology 2006;131:911–920. [PubMed: 16952559]

153. Nagao S, Nishii K, Yoshihara D, et al. Calcium channel inhibition accelerates polycystic kidneydisease progression in the Cy/+ rat. Kidney Int 2008;73:269–277. [PubMed: 17943077]



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154. Leuenroth SJ, Bencivenga N, Igarashi P, et al. Triptolide reduces cystogenesis in a model of ADPKD.J Am Soc Nephrol 2008;19:1659–1662. [PubMed: 18650476]

155. Leuenroth SJ, Okuhara D, Shotwell JD, et al. Triptolide is a traditional Chinese medicine-derivedinhibitor of polycystic kidney disease. Proc Natl Acad Sci USA 2007;104:4389–4394. [PubMed:17360534]

156. Ohba T, Watanabe H, Murakami M, et al. Amlodipine inhibits cell proliferation via PKD1-relatedpathway. Biochem Biophys Res Commun 2008;369:376–381. [PubMed: 18298949]

157. Magenheimer BS, St John PL, Isom KS, et al. Early embryonic renal tubules of wild-type andpolycystic kidney disease kidneys respond to cAMP stimulation with cystic fibrosis transmembraneconductance regulator/Na(+),K(+),2Cl(−) Co-transporter-dependent cystic dilation. J Am SocNephrol 2006;17:3424–3437. [PubMed: 17108316]

158. Yang B, Sonawane ND, Zhao D, et al. Small-molecule CFTR inhibitors slow cyst growth inpolycystic kidney disease. J Am Soc Nephrol 2008;19:1300–1310. [PubMed: 18385427]

159. Xu N, Glockner JF, Rossetti S, et al. Autosomal dominant polycystic kidney disease coexisting withcystic fibrosis. J Nephrol 2006;19:529–534. [PubMed: 17048214]

160. Ataga KI, Smith WR, De Castro LM, et al. Efficacy and safety of the Gardos channel blocker,senicapoc (ICA-17043), in patients with sickle cell anemia. Blood 2008;111:3991–3997. [PubMed:18192510]

161. Nguyen AN, Wallace DP, Blanco G. Ouabain binds with high affinity to the Na,K-ATPase in humanpolycystic kidney cells and induces extracellular signal-regulated kinase activation and cellproliferation. J Am Soc Nephrol 2007;18:46–57. [PubMed: 17151336]

162. Shillingford JM, Murcia NS, Larson CH, et al. The mTOR pathway is regulated by polycystin-1,and its inhibition reverses renal cystogenesis in polycystic kidney disease. Proc Natl Acad Sci USA2006;103:5466–5471. [PubMed: 16567633]

163. Wahl PR, Serra AL, Le Hir M, et al. Inhibition of mTOR with sirolimus slows disease progressionin Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrol DialTransplant 2006;21:598–604. [PubMed: 16221708]

164. Wu M, Wahl PR, Le Hir M, et al. Everolimus retards cyst growth and preserves kidney function ina rodent model for polycystic kidney disease. Kidney Blood Press Res 2007;30:253–259. [PubMed:17596700]

165. Berthier CC, Wahl PR, Le Hir M, et al. Sirolimus ameliorates the enhanced expression ofmetalloproteinases in a rat model of autosomal dominant polycystic kidney disease. Nephrol DialTransplant 2008;23:880–889. [PubMed: 18042615]

166. Qian Q, Du H, King BF, et al. Sirolimus reduces polycystic liver volume in ADPKD patients. J AmSoc Nephrol 2008;19:631–638. [PubMed: 18199797]

167. Takiar V, Nishio S, King JD, et al. Metformin activation of AMPK slows renal cystogenesis. J AmSoc Nephrol 2008;19:26A.

168. Amura CR, Brodsky KS, Groff R, et al. VEGF receptor inhibition blocks liver cyst growth in pkd2(WS25/−) mice. Am J Physiol Cell Physiol 2007;293:C419–C428. [PubMed: 17475663]

169. McGrath-Morrow S, Cho C, Molls R, et al. VEGF receptor 2 blockade leads to renal cyst formationin mice. Kidney Int 2006;69:1741–1748. [PubMed: 16572116]

170. Wilson SJ, Amsler K, Hyink DP, et al. Inhibition of HER-2(neu/ErbB2) restores normal functionand structure to polycystic kidney disease (PKD) epithelia. Biochim Biophys Acta 2006;1762:647–655. [PubMed: 16797938]

171. Sweeney WE Jr, von Vigier RO, Frost P, et al. Src inhibition ameliorates polycystic kidney disease.J Am Soc Nephrol 2008;19:1331–1341. [PubMed: 18385429]

172. Omori S, Hida M, Fujita H, et al. Extracellular signal-regulated kinase inhibition slows diseaseprogression in mice with polycystic kidney disease. J Am Soc Nephrol 2006;17:1604–1614.[PubMed: 16641154]

173. Bukanov NO, Smith LA, Klinger KW, et al. Long-lasting arrest of murine polycystic kidney diseasewith CDK inhibitor roscovitine. Nature 2006;444:949–952. [PubMed: 17122773]

174. Tao Y, Zafar I, Kim J, et al. Caspase-3 gene deletion prolongs survival in polycystic kidney disease.J Am Soc Nephrol 2008;19:749–755. [PubMed: 18272845]



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175. Elberg G, Elberg D, Lewis TV, et al. EP2 receptor mediates PGE2-induced cystogenesis of humanrenal epithelial cells. Am J Physiol – Renal Physiol 2007;293:F1622–F1632. [PubMed: 17728378]

176. Sankaran D, Bankovic-Calic N, Ogborn MR, et al. Selective COX-2 inhibition markedly slowsdisease progression and attenuates altered prostanoid production in Han:SPRD-cy rats withinherited kidney disease. Am J Physiol - Renal Physiol 2007;293:F821–F830. [PubMed: 17537981]

177. Park F, Sweeney WE, Jia G, et al. 20-HETE mediates proliferation of renal epithelial cells inpolycystic kidney disease. J Am Soc Nephrol 2008;19:1929–1939. [PubMed: 18596124]

178. Grantham JJ, Cook LT, Torres VE, et al. Determinants of renal volume in autosomal-dominantpolycystic kidney disease. Kidney Int 2008;73:108–116. [PubMed: 17960141]



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Figure 1. Diagram of the PKD1 protein, polycystin-1 (left) and the PKD2 protein, polycystin-2, andtheir interaction through coiled-coil domains in the C-terminal tails (according to the revisedmolecular model)6Details of the domains and regions of homology are shown in the key. Recently, it has beenproposed that polycystin-1 may activate transcription directly by cleavage and translocationof the C-terminus to the nucleus, a process found in other transmembrane proteins. Thecleavage site in the GPS region and possible cleavage sites in the C-terminal tail of polycystin-1are marked with arrows. TRP, transient receptor potential.



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Figure 2. Diagram depicting putative pathways up- or downregulated in polycystic kidney diseaseand rationale for treatment with V2 receptor antagonists, somatostatin, triptolide; tyrosine kinase,src, MEK, TNFα, mTOR, or CDK inhibitors; metformin, and CFTR or KCa3.1 inhibitors (greenboxes)Dysregulation of [Ca2+]i, increased concentrations of cAMP, mislocalization of ErbBreceptors, and upregulation of EGF, IGF1, VEGF, and TNFα occur in cells/kidneys bearingPKD mutations. Increased accumulation of cAMP in polycystic kidneys may result from: (i)disruption of the polycystin complex, as PC1 may act as a Gi protein-coupled receptor; (ii)stimulation of Ca2+ inhibitable AC6 and/or inhibition of Ca2+-dependent PDE1 by a reductionin [Ca2+]i; (iii) increased levels of circulating vasopressin due to an intrinsic concentratingdefect; and/or (iv) upregulation of vasopressin V2 receptors. Increased cAMP levels contributeto cystogenesis by stimulating chloride and fluid secretion. In addition, cAMP stimulatesmitogen-activated protein kinase/extracellularly regulated kinase (MAPK/ERK) signaling andcell proliferation in an Src- and Ras-dependent manner in cyst-derived cells or in wild-typetubular epithelial cells treated with Ca2+ channel blockers or in a low Ca2+ medium. Activationof tyrosine kinase receptors by ligands present in cystic fluid also contributes to the stimulationof MAPK/ERK signaling and cell proliferation. Phosphorylation of tuberin by ERK (orinadequate targeting to the plasma membrane due to defective interaction with polycystin-1)may lead to the dissociation of tuberin and hamartin and lead to the activation of Rheb andmTOR. Upregulation of TNFα or downregulation of AMPK signaling may also stimulatemTOR signaling through inhibition of the tuberin–hamartin complex. Activation of AMPKmay also blunt cystogenesis through inhibition of CFTR and ERK. Upregulation of Wnt



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signaling stimulates mTOR and β-catenin signaling. ERK and mTOR activation promotes G1/S transition and cell proliferation through regulation of cyclin D1, phosphorylation ofretinoblastoma protein (RB) by CDK4/6-cyclin D and CDK2-cyclin E, and the release of theE2F transcription factor. AC-VI, adenylate cyclase 6; AMPK, AMP kinase; CDK, cyclin-dependent kinase; ER, endoplasmic reticulum; MAPK, mitogen-activated protein kinase;mTOR, mammalian target of rapamycin; PC1, polycystin-1; PC2, polycystin-2; PDE,phosphodiesterase; PKA, protein kinase A; R, somatostatin sst2 receptor; TSC, tuberoussclerosis proteins tuberin (TSC2) and hamartin (TSC1); V2R, vasopressin V2 receptor; V2RA,vasopressin V2 receptor antagonists.



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Table 1Proteins interacting with PC1 and putative functions

Polycystin-1 interacting protein Putative function Referencea

PC2 (TRPP2) A coiled-coil domain within the Cterminus of PC1 binds to the C terminusof PC2. This interaction stabilizes PC2and affects its trafficking and channelfunction

β-subunit of casein kinase II (CK2β) The PLAT domain of PC1 interacts withCK2β. CK2 phosphorylates andactivates the PC2 channel in a PC1–PC2complex

Hu et al.7

Polycystin L Functional significance not known Bui-Xuan et al.8

Tuberin Localizes PC1 to lateral membranes ofrenal epithelial cells

Heterotrimeric G proteins The C terminus of PC1 bindsheterotrimeric Gi/Go and c-Jun N-terminal kinase (JNK) and AP-1

Regulator of G protein signaling 7 (RGS7) The C terminus of PC1 binds RGS7, amodulator of G-protein-dependentsignaling, and inhibits its degradation

Janus kinase 2 (JAK2) PC1 binds and activates JAK2 in a PC2-dependent manner. This leads toactivation of STAT3 and upregulation ofthe cyclin-dependent kinase inhibitorp21waf1

Na+/K+ATPase α-subunit The C terminus of PC1 binds the Na+/K+ATPase α-subunit and modulates itsactivity

Cell–cell adherens junction components (E-cadherin, α, β, and γ-catenins)

Multiprotein complex that regulatescell–cell contacts and their interactionswith the cell cytoskeleton in epithelialcells

β-catenin The cleaved PC1 C-terminal tail bindsβ-catenin in the nucleus and inhibits itsability to activate T-cell factor–dependent gene transcription

Lal et al.9

Annexin A5 Interacts with the LRR domain of PC1and inhibits the recruitment of E-cadherin to reforming cell contacts incalcium-starved MDCK cells aftercalcium restoration

Markoff et al.10

Flotillin-2 Serves to organize the PCs andassociated E-cadherin and β-catenin intoa signaling membrane domain

Focal adhesion protein components (α2β1integrin, talin, paxillin, vinculin, α-actinin,focal adhesion kinase, c-src, p130-cas,nephrocystin, proline-rich kinase pyk-2, andtensin)

Multiprotein complex that regulatesextracellular matrix interactions with theplasma membrane and cell cytoskeletonin epithelial cells

Intermediate filament proteins (Vimentin,cytokeratins K8 and K18, and desmin)

Structural and signaling functions at celljunctional complexes

Human homolog of Drosophila Seven inAbsentia (Siah-1)

Promotes the degradation of PC1through ubiquitin–proteasome pathway

Homer-1a/Vesl-1S Synaptic remodeling/plasticityresponses of hippocampal neurons

Stokely et al.11

aOnly articles published during 2006–2009 are referenced.


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Table 2Proteins interacting with PC2 and putative functions


PC1 (TRPP1) A coiled-coil domain within the Cterminus of PC1 binds to the Cterminus of PC2. This interaction maystabilize PC1

PC2 Forms oligomers (possibly required toform a functional channel) throughboth C-terminal and N-terminaldimerization domains

Celic et al.6, Feng et al.17

PC2 interactor, Golgi- and endoplasmicreticulum–associated protein (PIGEA-14)

Regulates the intracellular location ofPC2 and induces its translocation tothe trans-Golgi network

Phosphofurin acidic cluster sortingprotein (PACS)-1 and PACS-2

Regulates the routing of PC2 betweenendoplasmic reticulum, Golgi, andplasma membrane compartments

Family of Rab11-interacting protein 2(FIP2)

Scaffold protein induced by TNFαthat interacts with PC2 and preventsits translocation to the primary cilium

Li et al.18

Pericentrin Centrosomal protein that interactswith PC2 and is required for assemblyof primary cilia

Collectrin Membrane protein in the primarycilium and vesicles near the basalbody of collecting duct cells involvedin intracellular and ciliary movementof vesicles and membrane proteins.Knockdown in metanephric cultureresults in cystic dilatation of uretericbud branches

Zhang et al.19

Kinesin-2 subunit KIF3A Binds and regulates the activity ofPC2 in primary cilia

Li et al.20

Kinesin-2 subunit KIF3B Acts as a linker between PC2 andfibrocystin and mediates theregulation of PC2 channel function byfibrocystin

Wu et al.21

Fibrocystin Fibrocystin interacts with the Nterminus of PC2 and prevents PC2downregulation

Kim et al.22

Epidermal growth factor receptor (EGFR) Activation of EGFR releases PC2from PIP2 inhibition through PLC-γ2-induced activation and PI3K-inducedconversion of PIP2 to PIP3

Phospholipase C-γ2 (PLC-γ2) See above

Mammalian Diaphanous (mDia1) Facilitates the movement of PC2 to acentralized position during celldivision and affects intracellularcalcium homeostasis during mitosis

Kidney injury molecule 1 (Kim 1) Member of the T-cellimmunoglobulin mucin family thatmay act as a ciliary chemosensormodulating the function of PC2

Kuehn et al.23

Inositol 1,4,5-trisphosphate receptor(IP3R)

PC2 physically interacts with IP3Rthrough its C terminus and modulatesits channel activity

Ryanodine receptor 2 (RyR2) The N terminus of PC2 binds theRyR2. The C terminus of PC2 bindsto RyR2 only in its open state,inhibiting its channel activity

Anyatonwu et al.24


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Syntaxin 5 Interacts with the N terminus of andinactivates PC2, preventing theleakage of calcium from endoplasmicreticulum stores

Geng et al.25

Transient receptor potential channel(TRPC1)

PC2 interacts with TRPC1 throughtwo distinct domains (C terminalcoiled-coil and transmembranedomains), possibly affecting store–operated calcium entry

Transient receptor potential channel(TRPC4)

PC2 interacts with TRPC4 (andTRPC1) in mesangial cells, possiblyforming store–operated calciumchannels

Du et al.26

Transient receptor potential channel(TRPV4)

Interacts with the C terminus of PC2and is an essential component of theciliary flow sensor in MDCK cells.However, TRPV4 knockout mice donot have renal cysts

Kottgen et al.27

Pancreatic ER-resident eIF2α kinase(PERK)

PC2 promotes PERK-mediatedphosphorylation of eukaryotictranslation initiation factor eIF2α andnegatively controls cell growth

Liang et al.28

Eukaryotic translation initiation factoreIF2α

See above Liang et al.28

Helix-loop-helix protein Id2 PC2 binds Id2 in a PC1-dependentmanner, preventing its translocationto the nucleus and suppression ofp21waf

CD2-associated protein (CD2AP) Mediates the association of PC2 withmultimeric intracellular andmembrane complexes in renal tubularepithelia

Hax-1 Links PC2 to F-actin-binding proteincortactin and actin cytoskeleton

Tropomyosin-1 A component of the actinmicrofilament network; interacts withthe C terminus of PC2

α1- and α2-actinin Components of cell–cell and cell–matrix contacts, interact with both N-and C-termini of PC2 and stimulatesits channel activity

Troponin-I A component of the actinmicrofilament network, interacts withthe C terminus of PC2

Homocysteine-induced endoplasmicreticulum protein (Herp)

Ubiquitin-like protein implicated inregulation of PC2 degradation

Liang et al.29

ATPase p97 Component of a protein complex thatretro-translocates ubiquitinatedsubstrates from the endoplasmicreticulum to the cytosol

Liang et al.29

Transcriptional coactivator with PDZ-binding motif (TAZ)

Interacts with the C terminus of PC2,links PC2 to an SCFβ-Trcp E3 ligasecomplex, and promotes ubiquitin-dependent PC2 proteolysis. TAZknockout mice develop PKD

Tian et al.30

aOnly articles published during 2006–2009 are referenced.


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Table 3Sonographic criteria for the diagnosis of ADPKD93

Age(years) Criteria PPV NPV

Original Ravine's PKD1 diagnostic criteria

15–29 ≥2 cysts, unilateral or bilateral 99.2 87.7

30–39 ≥2 cysts in each kidney 100 87.5


≥60 ≥4 cysts in each kidney 100 100

Revised unified diagnostic criteria

15–29 ≥3 cysts, unilateral or bilateral 100 85.5

30–39 ≥3 cysts, unilateral or bilateral 100 96.4



Revised criteria for exclusion of diagnosis

15–29 ≥1 cyst 96.6 90.8

30–39 ≥1 cyst 94.0 98.3

40–59 ≥2 cysts 96.7 100



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sed)

Ots

uka

Phar

m.

TEM

PO 3

/4 T

rial p

hase

3 N

CT0

0428

948

V2

rece

ptor

ant

agon

ist (

tolv

apta

n)M

ultic

ente

r, do

uble

-blin

d, p

lace

bo-c

ontro

lled

18–4

0 ye

ars o

ldG

FR≥6

0, T

KV

≥75

0 m

l15

00, K

idne

y vo

lum

ech

ange

(MR

I)20

07–2

011

(rec

ruiti

ng)

Ots

uka

Phar

m.

Oct

reot

ide

in A

DPK

Dph

ase

3 N

CT0

0309

283

Long

-act

ing

som

atos

tatin

(oct

reot

ide)

Ran

dom

ized

, sin

gle-

blin

d, p

lace

bo-c

ontro

lled

18–7

5 ye

ars o

ld, G

FR>4

066

, Kid

ney

volu

me

chan

ge (M

RI)

2006

–201

0 (r

ecru

iting

)M

ario

Neg

ri In

stitu

te

Oct

reot

ide

in se

vere

PLD

pha

se 2

–3N

CT0

0426

153

Long

-act

ing

som

atos

tatin

(oct

reot

ide)

Ran

dom

ized

, dou

ble-

blin

d, p

lace

bo-c

ontro

lled,

cros

sove

r>1

8 ye

ars o

ld, L

V>4

000

ml o

r hig

hly

sym

ptom

atic

PLD

42, L

iver

vol

ume

chan

ge (M

RI)

(kid

ney

volu

me

sec.

outc

ome)

2007

–201

0 (r

ecru

itmen

t clo

sed)

May

o C

linic

, Nov

artis

Lanr

eotid

e in

PLD

phas

e 2–

3N

CT0

0565

097

Long

-act

ing

som

atos

tatin

(lan

reot

ide)

Ran

dom

ized

, dou

ble-

blin

d, p

lace

bo-c

ontro

lled

>18

year

s old

, >20

live

rcy

sts

38, L

iver

vol

ume

chan

ge (C

T)20

07-(

recr

uitm

ent c

lose

d)R

adbo

ud U

nive

rsity

, Ips

en

SUIS

SE st

udy

phas

e 3

NC

T003

4691

8m

TOR

inhi

bito

r (si

rolim

us)

Mul

ticen

ter,

rand

omiz

ed, s

ingl

e-bl

ind,

pla

cebo

-co

ntro

lled

18–4

0 ye

ars o

ld, G

FR≥7

010

0, K

idne

y vo

lum

ech

ange

(MR

I)20

06–2

010

(rec

ruitm

ent c

lose

d)U

nive

rsity

of Z

uric

h

SIR

ENA

STU

DY

phas

e 2

NC

T004

9151

7m

TOR

inhi

bito

r (si

rolim

us)

Ran

dom

ized

, ope

n-la

bel,

cros

sove

r18

–80

year

s old

, GFR

≥70

16, K

idne

y vo

lum

ech

ange

(CT)

2007

–200

9 (r

ecru

iting

)M

ario

Neg

ri In

stitu

te

Siro

limus

in A

DPK

Dph

ase

1–2

NC

T002

8615

6

mTO

R in

hibi

tor (

siro

limus

)R

ando

miz

ed, o

pen-

labe

l, do

se c

ompa

rison

18–7

5 ye

ars o

ld45

, Lot

hala

mat

e G

FRch

ange

(rec

ruiti

ng)

Cle

vela

nd C

linic

Ever

olim

us in

AD

PKD

phas

e 3

NC

T004

1444

0m

TOR

inhi

bito

r (ev

erol

imus

)M

ultic

ente

r, ra

ndom

ized

, pla

cebo

-con

trolle

d, d

oubl

e-bl

ind

18–6

5 ye

ars o

ld,

GFR

≥60

400,

Kid

ney

volu

me

chan

ge (M

RI)

2006

–200

9 (r

ecru

iting

)N

ovar

tis

AD

PKD

Pai

n St

udy

phas

e 2

NC

T005

7190

9V

ideo

thor

acos

copi

c sy

mpa

tho-

spla

nchn

icec

tom

yN

onra

ndom

ized

, ope

n-la

bel,

unco

ntro

lled

>18

year

s old

,de

bilit

atin

g ki

dney

pai

n20

, Pai

n co

ntro

l and

qual

ity o

f life

2007

–201

0 (r

ecru

iting

)M

ayo

Clin

ic, P

KD

F

BP,

blo

od p

ress

ure;

CT,

com

pute

d to

mog

raph

y; E

SRD

, end

-sta

ge re

nal d

isea

se; G

FR, g

lom

erul

ar fi

ltrat

ion

rate

; MR

I, m

agne

tic re

sona

nce

imag

ing;

PLD

, pol

ycys

tic li

ver d

isea

se.


NIH


NIH


NIH


Torres and Harris Page 37a G

FR, e

stim

ated

or m

easu

red,

in m

l/min

or m

l/min

per

1.7

3 m

2 ; B

P in

mm

Hg.


Documents

Autosomal Dominant Polycystic Kidney Disease-The Last 3 Years