Autosomal dominant polycystic kidney disease: the last 3 years

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http://www.kidney-international.org & 2009 International Society of Nephrology

Autosomal dominant polycystic kidney disease: the last 3 years Vicente E. Torres1 and Peter C. Harris1 1

Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA

Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal monogenic disorder. It has large inter- and intra-familial variability explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of its underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have 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 publications that have appeared during 2006–2009. Kidney International (2009) 76, 149–168; doi:10.1038/ki.2009.128; published online 20 May 2009 KEYWORDS: ADPKD; PKD1; PKD2; polycystic kidney disease; polycystin-1; polycystin-2

SCOPE OF THIS REVIEW

Although there have been numerous reviews of this topic in recent years, the fast pace of the field of polycystic kidney disease (PKD) justifies frequent re-evaluations and updates. The purpose 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. The reader 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 extrarenal manifestations. It occurs worldwide and in all races with a prevalence estimated to be between 1:400 and 1:1000. Age-adjusted male/female sex ratios greater than unity (1.2–1.3) for the yearly incidence rates of ADPKDcaused end-stage renal disease (ESRD) in Japan, Europe, and United States suggest a more progressive disease in men than in women. Consistent with this, 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 years for female and 54 and 54 years for male parents and offspring), but no difference between pairs.4 PKD GENES AND PROTEINS

Correspondence: Vicente E. Torres, Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. E-mail: [email protected] Received 6 February 2009; accepted 25 February 2009; published online 20 May 2009 Kidney International (2009) 76, 149–168

Autosomal dominant PKD is genetically heterogeneous with two genes identified, PKD1 (chromosome 16p13.3) and PKD2 (4q21). The PKD1 and PKD2 proteins, polycystin-1 (PC1, B460 kDa) and polycystin-2 (PC2, B110 kDa) constitute a subfamily (TRPP) of transient receptor potential (TRP) channels (Figure 1).5 Although PC2 (or TRPP2) exhibits characteristic 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 (3074 aa) 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 domain in the C-terminal portion and with multiple other proteins at different 149

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NH2

Leucine-rich repeats

Signal sequence WSC domain

PKD repeat C-type lectin

LDL-A related

REJ module

GPS domain

Transmembrane region G-protein binding

PLAT domain

TRP channel homology

ER retention signal

Coiled coil EF hand

Polycystin–2

? Polycystin–1

? COOH

COOH

NH2

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

extracellular and intracellular sites. The interacting partners and putative functions of these interactions are listed in Table 1. PC1 is found in the primary cilia, cytoplasmic vesicles, plasma membrane at focal adhesions, desmosomes, adherens junctions, and possibly endoplasmic reticulum and nuclei. The extracellular portion of PC1 contains a G-proteincoupled 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 and pancreatic cysts as well as placental, vascular, cardiac and skeletal malformations, but mice with a mutation expressing non-cleavable PC1 protein survive to P28 with enlarged cystic kidneys.13 This may mean that newly synthesized PC1 can proceed through competing ‘cleavage’ (critical in embryonic development) and ‘non-cleavage’ (critical for maintenance of tubular integrity) pathways with different functions in vivo, or that the non-cleavable Pkd1 mutation is a hypomorphic mutation with residual function. Two non-mutually exclusive models have suggested that the C-terminal tail of PC1 can be cleaved and migrate to the nucleus. In the first, PC1 normally sequesters the transcription factor STAT6 on cilia, thereby preventing its activation. Interruption of luminal fluid flow (for example, after ureteral clamping or renal injury) triggers the cleavage of the final 112 amino acids. This p112 fragment interacts with STAT6 and the co-activator P100 and stimulates transcriptional activity.14 In the second, mechanical stimulation of the 150

primary cilium normally triggers the cleavage and release of the entire C-terminal tail (p200). This p200 fragment contains a nuclear localization motif, binds b-catenin in the nucleus, and inhibits its ability to activate T-cell factordependent gene transcription, a major effector of the canonical Wnt signaling pathway.9 PC1 normally forms a complex at the adherens junction with E-cadherin and a-, b-, and g-catenins. Under conditions of calcium starvation, PC1 and E-cadherin are sequestered in cytoplasmic vesicles. Calcium restoration triggers the recruitment of both proteins to reforming cell–cell contacts.10 PC1 has been proposed to regulate the mechanical strength of adhesion between cells by controlling the formation of stabilized, actin-associated, adherens junctions.15 PC1/Ecadherin complexes are disrupted in ADPKD, and E-cadherin is sequestered internally 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 the C-terminal portion included a calcium-binding motif (EF-hand) and partially overlapping coiled-coil domain and endoplasmic reticulum retention motif. A recent molecular modeling and biophysical analysis of the Cterminal portion predicts a globular EF-hand motif that undergoes calcium-induced conformational changes, connected by a linker to a previously unidentified, elongated coiled coil, C-terminal to the position of the coiled-coil domain in the earlier accepted model (Figure 1). Residues Kidney International (2009) 76, 149–168

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Table 1 | Proteins interacting with PC1 and putative functions Referencea

Polycystin-1 interacting protein

Putative function

PC2 (TRPP2)

A coiled-coil domain within the C terminus of PC1 binds to the C terminus of PC2. This interaction stabilizes PC2 and affects its trafficking and channel function The PLAT domain of PC1 interacts with CK2b. CK2 phosphorylates and activates the PC2 channel in a PC1–PC2 complex Functional significance not known Localizes PC1 to lateral membranes of renal epithelial cells The C terminus of PC1 binds heterotrimeric Gi/Go and c-Jun N-terminal kinase (JNK) and AP-1 The C terminus of PC1 binds RGS7, a modulator of G-protein-dependent signaling, and inhibits its degradation PC1 binds and activates JAK2 in a PC2-dependent manner. This leads to activation of STAT3 and upregulation of the cyclin-dependent kinase inhibitor p21waf1 The C terminus of PC1 binds the Na+/K+ATPase a-subunit and modulates its activity Multiprotein complex that regulates cell–cell contacts and their interactions with the cell cytoskeleton in epithelial cells

b-subunit of casein kinase II (CK2b) Polycystin L Tuberin Heterotrimeric G proteins Regulator of G protein signaling 7 (RGS7) Janus kinase 2 (JAK2) Na+/K+ATPase a-subunit Cell–cell adherens junction components (E-cadherin, a, b, and g-catenins) b-catenin Annexin A5 Flotillin-2 Focal adhesion protein components (a2b1 integrin, talin, paxillin, vinculin, a-actinin, focal adhesion kinase, c-src, p130-cas, nephrocystin, proline-rich kinase pyk-2, and tensin) Intermediate filament proteins (Vimentin, cytokeratins K8 and K18, and desmin) Human homolog of Drosophila Seven in Absentia (Siah-1) Homer-1a/Vesl-1S

The cleaved PC1 C-terminal tail binds b-catenin in the nucleus and inhibits its ability to activate T-cell factor–dependent gene transcription Interacts with the LRR domain of PC1 and inhibits the recruitment of E-cadherin to reforming cell contacts in calcium-starved MDCK cells after calcium restoration Serves to organize the PCs and associated E-cadherin and b-catenin into a signaling membrane domain Multiprotein complex that regulates extracellular matrix interactions with the plasma membrane and cell cytoskeleton in epithelial cells

Hu et al.7 Bui-Xuan et al.8

Lal et al.9 Markoff et al.10

Structural and signaling functions at cell junctional complexes

Promotes the degradation of PC1 through ubiquitin–proteasome pathway Synaptic remodeling/plasticity responses of hippocampal neurons

Stokely et al.11

a

Only articles published during 2006–2009 are referenced.

within the newly identified coiled coil are necessary for binding to PC2-interacting proteins PC1, TRPC1, and KIF3A and for PC2-PC2 oligomerization. This domain includes the most C-terminal pathogenic PKD2-associated 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 these interactions. The subcellular localization of PC2 has been controversial. It has been shown to localize predominantly to the endoplasmic reticulum, but also to the plasma membrane, primary cilium, centrosome, and mitotic spindles in dividing cells. Its subcellular transport and localization are controlled by phosphorylation and multiple interactions with adapter proteins.31 Interaction with PIGEA-14 (Polycystin-2 interactor, Golgi- and endoplasmic reticulum-associated protein with a molecular weight of 14 kDa) augments forward trafficking from the endoplasmic reticulum to the cis-Golgi, while interaction with PC1 facilitates its translocation to the plasma membrane. Phosphorylation of PC2 by casein kinase 2 mediates binding to phosphofurin acidic cluster sorting protein-1 and -2 (PACS-1 and PACS-2), two connector proteins that mediate retrieval back to the trans-Golgi network (PACS-1) and the endoplasmic reticulum (PACS-2). Kidney International (2009) 76, 149–168

Recently PC1 and PC2, as well as fibrocystin (the protein mutated in autosomal recessive PKD), 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 uniquely packaged into intraluminal vesicles within the multivesicular body, some of which are excreted when these multivesicular bodies fuse with the apical plasma membrane. They are produced by a variety of cell types and have profound biological effect in the immune system and in the embryonic node for left/right (L/R) axis determination. Urine contains a sub-population of exosomes that contain large amounts of PC1, PC2, and fibrocystin. In vitro studies showed that these exosomes preferentially adhere to primary cilia of kidney and biliary epithelial cells in a rapid and highly specific manner and may represent a novel ‘urocrine’ signaling system mediated through a subset of primary cilia. DISEASE VARIABILITY: GENIC, ALLELIC, AND GENE MODIFIER EFFECTS

Genic, allelic, and gene modifier effects contribute to the high phenotypic variability of ADPKD. PKD1- is more severe than PKD2-associated disease (age at ESRD 54.3 versus 74.0 years for PKD1 and PKD2, respectively). The greater severity of 151

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Table 2 | Proteins interacting with PC2 and putative functions Polycystin-2 interacting protein

Referencea

Putative function

PC1 (TRPP1)

A coiled-coil domain within the C terminus of PC1 binds to the C terminus of PC2. This interaction may stabilize PC1 PC2 Forms oligomers (possibly required to form a functional channel) through both C-terminal and N-terminal dimerization domains PC2 interactor, Golgi- and endoplasmic Regulates the intracellular location of PC2 and induces its translocation to the reticulum–associated protein (PIGEA-14) trans-Golgi network Phosphofurin acidic cluster sorting Regulates the routing of PC2 between endoplasmic reticulum, Golgi, and plasma protein (PACS)-1 and PACS-2 membrane compartments Family of Rab11-interacting protein 2 Scaffold protein induced by TNFa that interacts with PC2 and prevents its (FIP2) translocation to the primary cilium Pericentrin Centrosomal protein that interacts with PC2 and is required for assembly of primary cilia Collectrin Membrane protein in the primary cilium and vesicles near the basal body of collecting duct cells involved in intracellular and ciliary movement of vesicles and membrane proteins. Knockdown in metanephric culture results in cystic dilatation of ureteric bud branches Kinesin-2 subunit KIF3A Binds and regulates the activity of PC2 in primary cilia Kinesin-2 subunit KIF3B Acts as a linker between PC2 and fibrocystin and mediates the regulation of PC2 channel function by fibrocystin Fibrocystin Fibrocystin interacts with the N terminus of PC2 and prevents PC2 downregulation Epidermal growth factor receptor Activation of EGFR releases PC2 from PIP2 inhibition through PLC-g2-induced (EGFR) activation and PI3K-induced conversion of PIP2 to PIP3 Phospholipase C-g2 (PLC-g2) See above Mammalian Diaphanous (mDia1) Facilitates the movement of PC2 to a centralized position during cell division and affects intracellular calcium homeostasis during mitosis Kidney injury molecule 1 (Kim 1) Member of the T-cell immunoglobulin mucin family that may act as a ciliary chemosensor modulating the function of PC2 Inositol 1,4,5-trisphosphate receptor PC2 physically interacts with IP3R through its C terminus and modulates its (IP3R) channel activity Ryanodine receptor 2 (RyR2) The N terminus of PC2 binds the RyR2. The C terminus of PC2 binds to RyR2 only in its open state, inhibiting its channel activity Syntaxin 5 Interacts with the N terminus of and inactivates PC2, preventing the leakage of calcium from endoplasmic reticulum stores Transient receptor potential channel PC2 interacts with TRPC1 through two distinct domains (C terminal coiled-coil (TRPC1) and transmembrane domains), possibly affecting store–operated calcium entry Transient receptor potential channel PC2 interacts with TRPC4 (and TRPC1) in mesangial cells, possibly forming (TRPC4) store–operated calcium channels Transient receptor potential channel Interacts with the C terminus of PC2 and is an essential component of the (TRPV4) ciliary flow sensor in MDCK cells. However, TRPV4 knockout mice do not have renal cysts Pancreatic ER-resident eIF2a kinase PC2 promotes PERK-mediated phosphorylation of eukaryotic translation (PERK) initiation factor eIF2a and negatively controls cell growth Eukaryotic translation initiation factor eIF2a See above Helix-loop-helix protein Id2 PC2 binds Id2 in a PC1-dependent manner, preventing its translocation to the nucleus and suppression of p21waf CD2-associated protein (CD2AP) Mediates the association of PC2 with multimeric intracellular and membrane complexes in renal tubular epithelia Hax-1 Links PC2 to F-actin-binding protein cortactin and actin cytoskeleton Tropomyosin-1 A component of the actin microfilament network; interacts with the C terminus of PC2 a1- and a2-actinin Components of cell–cell and cell–matrix contacts, interact with both N- and C-termini of PC2 and stimulates its channel activity Troponin-I A component of the actin microfilament network, interacts with the C terminus of PC2 Homocysteine-induced endoplasmic Ubiquitin-like protein implicated in regulation of PC2 degradation reticulum protein (Herp) ATPase p97 Component of a protein complex that retro-translocates ubiquitinated substrates from the endoplasmic reticulum to the cytosol Transcriptional coactivator with Interacts with the C terminus of PC2, links PC2 to an SCFb-Trcp E3 ligase PDZ-binding motif (TAZ) complex, and promotes ubiquitin-dependent PC2 proteolysis. TAZ knockout mice develop PKD

Celic et al.6, Feng et al.17

Li et al.18

Zhang et al.19

Li et al.20 Wu et al.21 Kim et al.22

Kuehn et al.23

Anyatonwu et al.24 Geng et al.25

Du et al.26 Kottgen et al.27 Liang et al.28 Liang et al.28

Liang et al.29 Liang et al.29 Tian et al.30

a

Only articles published during 2006–2009 are referenced.

PKD1 is due to the development of more cysts at an early age, not to faster cyst growth.33 Both PKD1 and PKD2 can be associated with severe polycystic liver disease (PLD) and 152

vascular abnormalities. Due to the lesser severity of the renal involvement, the prevalence of PKD2 associated disease has likely been underestimated in clinically studies. Kidney International (2009) 76, 149–168

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VE Torres and PC Harris: Autosomal dominant PKD

Population-based studies in communities where disease ascertainment is likely to be more complete, such as in Olmsted County and Newfoundland, reveal relative frequencies of PKD2 (36 and 29%, respectively) which are higher than in clinical studies (10–15%).34,35 PKD1 and PKD2 mutations are highly variable and usually private. The ADPKD Mutation Database (http:// pkdb.mayo.edu) lists 333 truncating PKD1 mutations identified in 417 families 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 different variants. A recent study screened the 202 probands in the Consortium for Radiologic Imaging Study of PKD (CRISP) ADPKD population by denaturing high-performance liquid chromatography, followed by direct sequencing. Definite truncating mutations and probable (missense, atypical splicing 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. Thirty percent of mutations were recurrent; hence 70% were unique to a single family. In a subsequent study, a multiplex ligationdependent probe amplification assay detected large deletions (n ¼ 3) or duplications (n ¼ 1) in four probands, thus increasing the level of detection to 184 of 202 (91.1%).37 The molecular basis of disease in approximately 9% of ADPKD in the CRISP population remained unclear. A similar overall mutation rate (86%) was observed in a smaller study using a Transgenomic’s SURVEYOR Nuclease and WAVE nucleic acid high sensitivity analysis system (Omaha, NE, USA).38 Compared with genic (PKD1 vs PKD2) effects, the influence of allelic factors (mutation type or location) on the severity of ADPKD is limited. Patients with mutations in the 50 region of PKD1 have more severe disease (18.9 vs 39.7% with adequate renal function at 60 years) and are more likely to have intracranial aneurysms and aneurysm ruptures than patients with 30 mutations. No clear correlations were found with mutation type in PKD1 or PKD2 or with mutation type or position in PKD2. More recently, however, hypomorphic or incompletely penetrant PKD1 or PKD2 alleles have been described.39 These alleles alone may result in mild cystic disease; two such alleles cause typical to severe disease; and in combination with an inactivating allele may be associated with early-onset disease. The large intra-familial variability of ADPKD highlights a role for genetic background in disease presentation. Bilineal inheritance of a PKD1 and PKD2 mutant allele or of PKD1 or PKD2 hypomorphic alleles can result in variable degrees of enhancement to single gene phenotypes. Mosaicism can also modulate the disease presentation and result in marked intrafamilial variability.37,40 Renal enlargement in utero or in infancy more typical of autosomal recessive PKD may occur in a small proportion of cases. Most early-onset cases have been linked to PKD1, but recently a PKD2 family with perinatal death in two severely affected infants was described.41 The high risk of recurrence of ADPKD with Kidney International (2009) 76, 149–168

early manifestations in affected families suggests a common familial modifying background for early and severe disease expression (for example, mutations or variants in genes encoding other cystoproteins). The best-documented example (apart from hypomorphic PKD1 alleles) is the contiguous deletion of the adjacent PKD1 and TSC2, characterized by childhood PKD with additional clinical 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 of ADPKD 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 nitric oxide synthase has been associated with earlier ESRD,44 but this has not been a consistent finding. A functional length polymorphism in the promoter region of the human heme oxygenase-1 (HO-1) gene that results in higher HO-1 expression and enzyme activity had no effect on age at ESRD, despite the protective role of HO-1 in a variety of experimental models of renal injury and its upregulation in polycystic kidneys.45 Functional polymorphisms of tumor growth factor-b1 (TGF-b1), bradykinin receptors B1 and B2, epidermal growth factor receptor (EGFR), and endothelin ET-A receptor genes and of the regulatory region of the VEGF gene did not have an effect on disease progression.46–48 ADPKD patients who are TT homozygotes for the –414 T/C polymorphism in the promoter region of the a-8 integrin chain gene (ITGA8) were reported to have an earlier onset of ESRD than those with a C allele (47 vs 51 years of age).49 Despite these mostly negative results, identification of quantitative trait loci influencing the severity of PKD remains important for understanding the pathogenesis and providing insights into potential therapies. High-density single-nucleotide polymorphism arrays allow the mapping of quantitative trait loci in large, clinically and genetically well-characterized populations using a genome-wide association study. The feasibility of this approach has been illustrated by the identification of the first putative modifier of renal disease severity (mapping to chromosome 4) in PKD as the kinesin gene (Kif12) in the cpk mouse. Interestingly, Kif12 transcription is regulated by hepatocyte nuclear factor-1b (HNF-1b) and mutations in HNF-1b cause an inherited syndrome characterized by renal cystic disease or dysplasia and diabetes mellitus.50 GENETIC MECHANISMS

Evidence from animal models of ADPKD and analysis of cystic epithelia have shown that renal cysts may develop from loss of functional polycystin with somatic inactivation of the normal allele consistent with a two hit mechanism. However, dosage reduction of the protein in two Pkd1 animal models with hypomorphic alleles that generate o20% of the normally spliced product indicates that cysts can develop 153

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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 rates of 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 expression of the endogenous mouse Pkd2 show mild tubular dilatation, microcysts (in a minority of animals 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 rats expressing 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 imbalance in 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, PKD2overexpressing mice, and from patients with ADPKD.56,57 Knockdown of Pkd1 expression using small interfering RNA induces centrosomal amplification, multipolar spindle formation, polyploidism, and mitotic catastrophe, followed by a convergence of the cell population toward a stable ploidy in which centrosomal amplification is significantly decreased, but cytological abnormalities and aneuploidy remain common.56 The link between derailed levels of polycystin expression, centrosome integrity and genomic stability may reconcile 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 of tubules, the presence of apoptotic cells in both tubular and cystic cells in ADPKD kidneys, the clonality of cystic epithelia, and the high frequency of chromosomal anomalies and genetic aberrations in cystic cells from patients with ADPKD. It may also account for the low rate of development of renal cell carcinoma in ADPKD, despite the frequency of hyperplastic polyps and microscopic adenomas, as recent evidence indicates that high levels of genomic instability may inhibit tumorigenesis.58,59 Conditional knockouts of ciliogenic genes (Tg737 and Kif3a) or of Pkd1 at various time points have shown that the timing of ciliary loss or Pkd1 inactivation determines the rate of development of cystic disease.60–63 Kidney development is not yet completed in newborn mice. Inactivation of Pkd1 before postnatal day 13 results in rapidly progressive cystic disease, whereas later inactivation causes much slower cyst development.61 The kidney-specific inactivation 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 primary cilia.60 Cysts also develop rapidly in the corticomedullary region (pars recta and thick ascending limbs of Henle) of adult mouse 154

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kidneys subjected to renal ischemic/reperfusion injury to stimulate cell proliferation (but not in contralateral control kidneys), when Kif3a is conditionally inactivated.64 Analysis of pre-cystic tubules show that the loss of cilia results in aberrant planar cell polarity manifested by abnormalities in the orientation of cell division. The age-dependence, location, and induction of the cysts by ischemia-reperfusion injury suggest that 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 rates of cell proliferation are higher than in the adult, but lower than in younger animals, fails to induce cyst formation. This suggests that a certain threshold of cell proliferation must be exceeded or that increased cell proliferation is only one of the factors responsible for the higher rate of cyst formation in newborn compared with older mice. Another factor could be the transcriptional programming of kidney cells, which is markedly different in the postnatal period compared with the adult.61,65 In summary, these observations in conditional knockouts indicate that PKD1 and cilia are required to maintain the renal tubular structure in adult kidneys, that cyst initiation can occur throughout the lifetime of an individual, and that cyst development occurs much more rapidly when PKD1 is inactivated or cilia are lost in developing than in mature kidneys. Although they provide important insights, it is important to point out that massive and complete inactivation of PKD1 at a particular time point is not likely how the development of cystic disease starts in ADPKD and that consequently these are imperfect models for this disease. PATHOGENESIS

The 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 switch characterized by inability to maintain planar polarity, increased rates of proliferation and apoptosis, expression of a secretory phenotype, and remodeling of the ECM. The molecular mechanisms responsible for this phenotypic switch are not known, but hypotheses abound. Treatment strategies based on them may help to establish their validity. Given the proposed participation of the polycystins in numerous signaling pathways at multiple subcellular locations, they are likely to be complex. Centrosomal dysfunction or amplification, activation of canonical b-catenin-dependent Wnt signaling, and inhibition of non-canonical b-catenin-independent Wnt signaling (that is, activation of c-jun N-terminal kinase, JNK, and transient changes in cytosolic calcium concentrations) may be responsible for the loss of planar cell polarity, which may be key to the transformation of a tubular into a cystic structure. A recent study has shown that secreted Frizzled-related protein 4 (sFRP4) is upregulated in human ADPKD9,66 and in four different animal models of PKD (Pkd2/, Invs/, and pcy mice, and Han:SPRD rat) and is detected in the urine of patients and animals with PKD, but not in the urine of Kidney International (2009) 76, 149–168

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healthy individuals.66 sFRP4 is a member of a family of secreted molecules that antagonize Wnt signaling. Interestingly, it inhibits only select members of the canonical Wnt signaling pathway, possibly explaining why b-catenin can accumulate in PKD in the presence of elevated sFRP4 concentrations. The sFRP4 promoter contains lymphoid enhancer-binding factor-1-, STAT3-, and cAMP-responsive element-binding sites. Because the lymphoid enhancerbinding factor-1-binding site can be stimulated by active b-catenin, it is conceivable that canonical Wnt signaling, not blocked by sFRP4, stimulates sFRP4 production. Cyst fluid and vasopressin stimulate, while a vasopressin V2 receptor antagonist has an a marked inhibitory effect on the expression of sFRP4 in inner medullary collecting duct cells in vitro and in kidneys of pcy mice in vivo. Microinjection of sFRP4 into zebrafish embryos induces pronephric cyst formation, heterotaxia, and abnormal body curvature. Therefore, increased sFRP4 expression in PKD is more likely to be disease-promoting than an adaptive mechanism to protect the kidney from the detrimental effects of uncontrolled canonical Wnt signaling. Many pathways that couple cell surface receptors (GPCRs, TKRs, integrins, and so on) and epithelial cell proliferation are activated in PKD. These include mitogen-activated protein kinase/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. PC1 was 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-dependent manner, and prevent its translocation to the nucleus and suppression of p21waf, thus preventing Cdk2 activation and cell cycle progression. Consistent with these studies, p21waf levels have been 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 PKD2 transgenic rat.68 PC1 and PC2 may also suppress cell growth through the control of the protein synthesis initiation machinery. PC1 interacts with tuberin to suppress mTOR and activation of the downstream translation initiation factor eIF4E. PC2 interacts with pancreatic eIF2a kinase (PERK) in the endoplasmic reticulum and enhances PERK-dependent phosphorylation of the translation initiation factor eIF2a.28 Numerous studies have shown that increased tubular cell proliferation is accompanied by increased apoptosis in PKD.69 The induction of resistance to apoptosis by PC1 has been attributed to GiCPR activation of phosphatidylinositol 3-kinase (PI3K) and Akt. However, the role of PI3K and Akt in PKD remain uncertain, as PI3K and Akt activation, along with increased apoptosis, have been shown in animal models of PKD.70 Interestingly, overexpression of PKD1 has been Kidney International (2009) 76, 149–168

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shown to induce G0/G1 phase arrest in cell cycle progression and an increase in the rate of apoptosis in cancer cell lines.71 Although PC1 knockdown in MDCK cells is associated with increased rates of proliferation and apoptosis, it is also accompanied by increased adhesion to collagen type I and resistance to anoikis (apoptosis triggered by loss of cell anchorage) probably due to increased expression of integrina2b1.72 Beyond the loop of Henle, tubular epithelial cells have the capacity to secrete as well as to reabsorb solutes and fluid. Normally, absorptive flux overshadows secretory flux. Sodium chloride reabsorption in cortical collecting duct principal cells, arguably the main origin of the cysts in ADPKD, is driven by low intracellular sodium concentration generated by basolateral Na-K-ATPase. Sodium chloride enters the luminal membrane through the epithelial sodium and 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 normal cortical collecting duct principal cells. Chloride enters across basolateral NaK2Cl cotransporters, driven by the sodium gradient generated by basolateral Na-K-ATPase, and exits across apical protein kinase A (PKA)-stimulated cystic fibrosis transmembrane conductance regulator (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 secretion down transepithelial potential and osmotic gradients. This model for cyst fluid secretion requires a paracellular pathway sealed by tight junctions impermeable to chloride. The basic biochemical infrastructure of the tight junction remains intact even in late-stage cysts.75 Tight junctions are composed of interacting proteins, including scaffolding proteins such as ZO-1 and transmembrane proteins such as occludin and members of the claudin family. Most of the claudin 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. Human and animal models of PKD show an abnormal expression of matrix-degrading enzymes and inhibitors of metalloproteinases, necessary for the remodeling of basement membranes and the surrounding ECM. Cyst-lining epithelia produce large amounts of structural (collagen I and III, laminin) and soluble ECM-associated proteins (TGF-b, bigH3, periostin), which accumulate around the cysts. Some ECM components (laminin, periostin) actively contribute to 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 to the cysts and within cyst fluid, but not in normal kidneys.76 Periostin binds aV-integrins (aVb3- and aVb5integrins), that is highly expressed in ADPKD cells, and activates integrin-linked kinase (ILK). ILK inhibits GSK-3b, 155

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stabilizes b-catenin, increases nuclear b-catenin levels, and activates T-cell factor/lymphoid enhancer-binding factor, a transcription factor involved in cell proliferation. ILK also activates Akt and lowers the expression of p27Kip1 a cell cycle kinase inhibitor. The effect of periostin on cell proliferation is inhibited by aV-integrin-blocking antibodies. Laminin-5 (a3, b3, g2) is strongly expressed by ADPKD cells and in the pericystic ECM of ADPKD 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 is incorporated into pericystic ECM. Addition of purified laminin-5 stimulates cell proliferation and cyst formation, whereas blocking antibodies against laminin-5 inhibit cell proliferation and cyst formation. Furthermore, a hypomorphic mutation of laminin-a5, a major tubular basement membrane component, results in aberrant accumulation of laminin-5 and cystic disease in mice.78 DISREGULATION OF INTRACELLULAR CALCIUM AND cAMP SIGNALING IN PKD

Increasing experimental evidence suggest that the polycystins are localized in specialized structures that sense the extracellular environment, such as primary cilia, focal adhesions and adherens complexes, that their function is important for the regulation of intracellular calcium homeostasis, and that alterations in intracellular calcium and cAMP signaling play a central role in the pathogenesis of PKD. The location of the polycystins that recently has received the most attention is the primary cilium. In tubular epithelial cells, the cilium projects into the lumen and is thought to have a sensory role. The PC1–PC2 complex acts as a sensor on cilia that translates mechanical or chemical stimulation into calcium influx through PC2 channels. This in turn induces calcium release 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 cyst cells lack flowsensitive calcium signaling and show reduced endoplasmic reticulum calcium stores, store-depletion-operated entry and, under certain conditions, intracellular calcium concentrations. Although PC2 is found mainly in the endoplasmic reticulum and to a lesser extent in the plasma membrane, PC1 is found mainly in the plasma membrane and possibly in the endoplasmic reticulum. Although it seems certain that PC2 and probably PC1 play an important role in the regulation of the endoplasmic reticulum calcium stores and intracellular calcium homeostasis, the precise mechanisms by which this regulation operates remain uncertain. Calcium release from intracellular stores decreases gradually with overexpression, haploinsufficiency, or absence of PC2. In cardiac myocytes, the N terminus of PC2 binds to RyR2, whereas the C terminus interacts with the RyR2 in its open state inhibiting its channel activity.24 Inadequate RyR2 inhibition in cardiac myocytes lacking PC2 results in a 156

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higher frequency of spontaneous oscillations, reduced sarcoplasmic reticulum calcium stores due to calcium leak, and reduced calcium transient amplitude compared with wild-type cells. PC2 interacts with Syntaxin 5 (a member of a family of proteins, which function in vesicle targeting and fusion and regulation of the channel activity), inhibits its channel activity, and prevents leaking of calcium from the endoplasmic reticulum.25 Overexpression in LLC-PK1 cells of a truncated PC2 protein that causes PKD and retinal degeneration in transgenic rats is associated with reduced endoplasmic reticulum calcium stores. As in the case of cardiac myocytes lacking PC2, downregulation of PC1 expression and cystic cell lines from PKD1 patients are associated with a higher frequency of 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 across the endoplasmic reticulum membrane.80 ADPKD cyst cells exhibit reduced endoplasmic reticulum calcium stores, store-depletion-operated entry and, under certain conditions, intracellular calcium concentrations.81 Although most of these observations point to reduced intracellular calcium stores as a common feature in PKD, another study reported that overexpression of PC2 in HEK cells increases calcium leakage and reduces the amount of releasable calcium upon stimulation with IP3 in the endoplasmic reticulum, whereas knockdown of PC2 in MDCK cells has the opposite effect and increases the susceptibility to apoptosis.82 Increased levels of cAMP and expression of cAMPdependent genes (such as AQP2 in the kidney) are a common finding in the kidneys of cpk, jck, pcy, KspCre; HNF1bflox/floxPkd2/ws25 and gGT.Cre:Pkd1flox/flox mice and PCK rats,83–85 liver of PCK rats,86 vascular smooth muscle of Pkd2 þ / mice, and choroid plexus of TG737orpk mice.87 In a recent study, renal cAMP levels and AQP2 expression were found to be similar in mice with a 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 homeostasis and the importance of calcium in the regulation of cAMP metabolism by stimulation of calcium inhibitable adenylyl cyclase 6 and/or inhibition of calcium-dependent phosphodiesterase 1, it has been suggested that alterations in intracellular calcium homeostasis account for the accumulation of cAMP. Cyclic AMP in turn contributes to the development and progression of PKD by stimulating CFTRdriven chloride and fluid secretion and cell proliferation. While under normal conditions cAMP inhibits mitogenactivated protein kinase signaling and cell proliferation, in PKD or in conditions of calcium deprivation it stimulates cell proliferation in an Src-, Ras-, and B-raf-dependent manner. Cell proliferation may be further enhanced by stimulation of epidermal growth factor (EGF)-like factors present in cyst fluid, increased insulin-like growth factor-1 in cystic tissues, and by activation of mTOR, likely due to a disrupted tuberinKidney International (2009) 76, 149–168

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polycystin-1 interaction or to ERK- or Akt-dependent phosphorylation of tuberin that prevents its association with hamartin and inhibits its GTPase activating function for Rheb. The abnormal proliferative response to cAMP is directly linked to the alterations in [Ca2 þ ]i, as it can be reproduced in wild-type cells by lowering [Ca2 þ ]i. Conversely, Ca2 þ ionophores or channel activators can rescue the abnormal response of cyst-derived cells.89 Upregulation of the vasopressin V2 receptor and high circulating vasopressin levels may contribute to the increased cAMP levels. A bioactive lipid with the same biochemical and biological properties as forskolin, a widely known, potent adenylyl cyclase agonist, has been isolated and identified within the cyst fluid. It is conceivable that forskolin is synthesized by mural cyst epithelial cells, although an exogenous source cannot be ruled out.90

Table 3 | Sonographic criteria for the diagnosis of ADPKD93

DIAGNOSIS

(69.5 and 78%, 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 kidney donors, where exclusion of the diagnosis is important.93 Because of this, Pei et al.93 proposed that different criteria are used to exclude a diagnosis of ADPKD in an individual at risk from a family with an unknown genotype. They found that an ultrasound scan finding of normal kidneys or one renal cyst in an individual aged 40 years or older has a negative predictive value of 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 of ultrasonography for disease exclusion is limited in an at-risk individual who is younger than 30 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 donor evaluation, potential candidates in most transplant centers undergo contrast enhanced, three-dimensional CT, or MR angiographic imaging. The resolution of these techniques is much higher 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 negative predictive value of a negative high resolution CT or MR, although not quantifiable because the 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 for the evaluation of donors at 50% risk of ADPKD inheritance. This algorithm proposes that potential kidney donors who are less than 30 years old with o3 renal cysts or 30–39 years old with 1–2 renal cysts or 40–59 years old with multiple cysts in one kidney and 0–1 cyst in the other should have genetic testing. The algorithm does not differentiate between cysts detected by ultrasound, CT, or MRI. Given the high prevalence of

The diagnosis of ADPKD usually relies on imaging testing. Counseling should be done before testing. 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, refusing to renew, or changing the terms or premiums of coverage based on genetic information. It also prohibits employers from making hiring, firing, promotion, and other employment-related decisions based on genetic factors. Genetic information is defined as information about an individual’s genetic tests, genetic tests of family members, or occurrence of a disease in family members 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 not apply to life insurance, disability insurance, or long-term care insurance. Renal ultrasound is commonly used because of cost and safety. Revised criteria have been proposed to improve the diagnostic performance of sonography in ADPKD (Table 3): The presence of at least three (unilateral or bilateral) renal cysts and of two cysts in each kidney are sufficient for diagnosis of at-risk individuals aged 15–39 years and 40–59 years, respectively.93 For at-risk individuals aged X60 years, four or more cysts in each kidney are required. Requirement of three or more cysts (unilateral or bilateral) has a positive predictive value of 100% in the younger age group and minimizes false-positive diagnoses, as 2.1 and 0.7% of the genetically unaffected individuals younger than 30 years have one and two renal cysts, respectively. In the 30–39 years old, both the original (2 cysts in each kidney) and the revised (43 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 Kidney International (2009) 76, 149–168

Age (years)

Criteria

PPV

NPV

15–29 30–39 40–59 X60

Original Ravine’s PKD1 diagnostic criteria X2 cysts, unilateral or bilateral X2 cysts in each kidney X2 cysts in each kidney X4 cysts in each kidney

99.2 100 100 100

87.7 87.5 94.8 100

15–29 30–39 40–59 X60

Revised unified diagnostic criteria X3 cysts, unilateral or bilateral X3 cysts, unilateral or bilateral X2 cysts in each kidney X4 cysts in each kidney

100 100 100 100

85.5 96.4 94.8 100

15–29 30–39 40–59 X60

Revised criteria for exclusion of diagnosis X1 cyst X1 cyst X2 cysts X4 cysts in each kidney

96.6 94.0 96.7 100

90.8 98.3 100 100

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renal cysts detectable by CT or MR in 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 potential living related kidney donors for ADPKD. The algorithm does not take into account either the information that may be available on the ADPKD phenotype of the family. The presence of one affected family member who developed ESRD by the age of 60 years is highly predictive of PKD1 (PPV 100%, sensitivity 75%). By contrast, the presence of one affected family member who remained renal sufficient or developed ESRD after the age of 70 years is highly predictive of PKD2 (PPV 95%, sensitivity 75%).95 There are limitations to genetic testing, either by linkage or mutation analysis.96 Linkage analysis requires accurate diagnosis, availability and willingness of sufficient affected family members to be tested and is feasible in fewer than 50% of families. De novo mutation can also complicate interpretation of results. Molecular testing by direct DNA sequencing is now possible with likely mutations identified in B90% of patients.36,97 However, as most mutations are unique and up to one-third of PKD1 changes are missense, the pathogenicity of some changes is difficult to prove.36,97 RENAL MANIFESTATIONS

Most manifestations are directly related to the development and enlargement of renal cysts. A study of 241 patients with an estimated glomerular filtration rate (GFR) X60 ml/min followed prospectively with yearly MR examinations by CRISP has provided invaluable information to understand how the cysts develop and grow.98 Total kidney volume and cyst volumes increased exponentially. At baseline, total kidney volume was 1060±642 ml and the mean increase over 3 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 volume predicted the subsequent rate of increase in renal volume and was associated with declining GFR in patients with baseline total kidney volume above 1500 ml. These results have been confirmed by recent European study of 100 ADPKD patients with an estimated GFR X70 ml/min who underwent standardized MR examinations with unenhanced sequences 6 months apart. These patients had a baseline total kidney volume of 1003±568 ml and a calculated annual growth rate of 5.36%.99 Another study used contrast enhanced CT to monitor volume changes in 13 patients with more advanced 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-enhanced parenchyma (referred to as intermediate) were estimated. The intermediate volume was considered to be renal parenchyma undergoing tubular atrophy and fibrosis. The ratio of intermediate over parenchyma volume strongly correlated with GFR (r 0.81, Po0.001). In addition, there were 158

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significant correlations between percentage changes in intermediate volume (absolute or relative to parenchyma) and GFR changes during the observation period (r 0.70 and 0.75, Po0.01), thus supporting a significant relationship between renal structural and functional changes in ADPKD. A study in Newfoundland identified all patients with ADPKD attending nephrology/urology clinics 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 at initiation of treatment for hypertension, stage 3 CKD, ESRD, and death were 46, 50, 53, and 67 years for PKD1, respectively. Median age to hypertension treatment, stage 3 CKD, and death were 51, 66, and 71 years, respectively, whereas ESRD was infrequent, for PKD2. Causes of death were similar, except for uremia, which was more common in PKD1. Hypertension is the most common manifestation of ADPKD and a major contributor to renal disease progression and cardiovascular morbidity and mortality. Ambulatory blood pressure monitoring of children or young adults without diagnosed hypertension often reveals elevated blood pressures, attenuated nocturnal blood pressure dipping, and exaggerated blood pressure response during exercise. A recent study stratified 65 children by blood pressure into three cohorts: hypertensive (X95th percentile), borderline hypertensive (75–95th percentile), and normotensive (p75th percentile).101 Both the hypertensive and borderline hypertensive children had significantly higher left ventricular mass indices than normotensive children. Among normotensive children, indices were significantly higher in those within the upper quartile of the normal blood pressure. These observations suggest that target organ damage develops early in ADPKD and that antihypertensive treatment may be indicated in children with ADPKD and borderline hypertension. Several factors contribute to the development of hypertension in ADPKD. Activation of the intrarenal renin–angiotensin system likely plays an important role, whereas there is controversy on whether the circulating renin–angiotensin system is inappropriately activated.102 Expression of PC1 and PC2 in vascular smooth muscle and endothelium, along with enhanced vascular smooth muscle contractility103 and impaired endothelial dependent vasorelaxation, suggest that disruption of polycystin function in the vasculature are directly involved. PC1 in the primary cilia plays a role in the translation of physiological changes in fluid shear stress into cytosolic calcium and nitric oxide signals.104 Other factors include increased sympathetic nerve activity and plasma endothelin-1 levels and insulin resistance. Endothelial vasodilatation and constitutive nitric oxide synthase activity are reduced in subcutaneous resistance vessels from patients with ADPKD and normal GFR. Flowinduced vasodilation of the brachial artery has been found to be inconsistently impaired,105,106 whereas pulse wave reflection was amplified suggesting a predominant involvement of small resistance vessels.107 Reduced coronary flow velocity Kidney International (2009) 76, 149–168

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VE Torres and PC Harris: Autosomal dominant PKD

reserve and increased carotid intima-media thickness in normotensive patients with normal GFR suggest that atherosclerosis starts early in the course of ADPKD.108 Reduced nitric oxide endothelium-dependent vasorelaxation in ADPKD may be due to increased plasma levels of asymmetric dimethylarginine (ADMA).109 Increased oxidative stress 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 active site of NG, NG-dimethylarginine dimethylaminohydrolase (DDAH, an enzyme that metabolizes ADMA in the renal tubules), reduced renal clearance and increased circulating levels of ADMA, and inhibition of constitutive nitric oxide synthase. Even modest increases in plasma ADMA levels have been associated with impaired endothelial function. Systemic infusion of non-pressor doses of ADMA into healthy human individuals impairs vasodilator responses to acetylcholine, increases vascular resistance, and decreases renal blood flow. In most patients, renal function is maintained within the normal range, despite relentless growth of cysts, until the fourth to sixth decade of life. By the time renal function starts declining, the kidneys usually are markedly enlarged and distorted with little recognizable parenchyma on imaging 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 earlier studies suggesting a strong relationship with renal enlargement and shown that kidney and cyst volumes are the strongest predictors of renal functional decline.98 CRISP also found that renal blood flow (or vascular resistance) is an independent predictor.110 This points to the importance of vascular remodeling in the progression of the disease and may account for cases where the decline of renal function seems to be out of proportion to the severity of the cystic disease. Other factors such as heavy use of analgesics may contribute to CKD progression in some patients. Pain, often associated to cyst hemorrhage, infection or stones, is the most frequent symptom reported by adult patients. 18-F-fluorodeoxyglucose (FDG) positron emission tomography has become a promising agent for detection of infected cysts.111,112 FDG is taken up by inflammatory cells because of their high metabolic rate. Advantages of FDG positron emission tomography include: rapid imaging (1 h); high spatial resolution; high target-to-background ratio; low radiation burden; and high inter-observer agreement. Disadvantages are higher cost and limited availability. Its use to diagnose infections in kidneys may be difficult, particularly when 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 are acquired, the renal parenchyma is usually free of activity, but prominent activity can be seen in renal calyces. Dual energy CT is increasingly used to distinguish between calcium and uric acid stones.113,114 Kidney International (2009) 76, 149–168

EXTRARENAL MANIFESTATIONS

Polycystic liver disease is the most common extrarenal manifestation. It is associated with both PKD1 and nonPKD1 genotypes. PLD also occurs as a genetically distinct disease in the absence of renal cysts. Similar to ADPKD, ADPLD is genetically heterogeneous, with two genes identified (PRKCSH and SEC63) accounting for approximately one-third of isolated ADPLD cases. The liver cysts arise by excessive proliferation and dilatation of biliary ductules and peribiliary glands. Scanning electron microscopy has shown that the cyst epithelium displays heterogeneous features, being normal in small cysts (o1 cm), characterized by rare or shortened cilia in 1–3-cm cysts, and showing absence of both primary cilia and microvilli in large cysts (43 cm).115 Estrogen receptors, insulin-like growth factor 1, insulin-like growth factor 1 receptors (IGF1-R), and growth hormone receptor are expressed in the epithelium lining the hepatic 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-a, are potent proliferative agents that were found at high levels in liver but not kidney cyst fluids.118 The changes in the expression of certain microRNAs may contribute to the proliferative phenotype of the cystic epithelium in PLD.119 A microarray analysis found marked differences in microRNA expression in cholangiocyte cell lines derived from PCK rats, as well as in liver tissues from PCK rats and patients with PLD, compared with controls. Specifically, a reduced expression of miR15a in the cystic tissues was associated with upregulation of its target, the cellcycle regulator cell division cycle 25A (Cdc25A). Overexpression of miR15a in cholangiocytes from PCK rats decreased Cdc25A levels, inhibited cell proliferation, and reduced cyst growth. Suppression of miR15a in normal rat cholangiocytes accelerated cell proliferation, increased Cdc25A expression, and promoted cyst growth. As shown earlier for PKD, cAMP seems to play a major role in the progression of PLD. Two main downstream effectors of cAMP are cAMP-guanine nucleotide exchange factor/Epac (Epac) and PKA. Although only PKA has been implicated in the proliferative response to cAMP in PKD, both effector pathways may be important in PLD.120 Epac1 and Epac2 isoforms and the PKA RIb subunit are overexpressed in cultured PCK cholangiocytes. Epac-specific stimulation promotes the proliferation of both, normal and PCK cholangiocytes, whereas PKA-specific stimulation suppresses proliferation in normal cholangiocytes and enhances it in PCK cholangiocytes. The stimulatory effects of Epac and PKA activation on the proliferation of PCK cholangiocytes were both dependent on MEK-ERK1/2 signaling. The increased proliferation of PCK cholangiocytes in response 159

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to PKA stimulation, but not to Epac stimulation, was found to be associated with decreased intracellular calcium. Restoration of calcium levels blocked the PKA-dependent proliferation. As described earlier for renal cyst-derived cells, the effect of intracellular calcium restoration on slowing PKA-associated proliferation was abolished by preincubation of PCK cholangiocytes with PI3K or AKT inhibitors. Hepatic cysts are rare in children. Their frequency increases with age and may have been underestimated by ultrasound and CT studies. Their prevalence by MRI in the CRISP study is 58, 85, and 94% in 15–24, 25–34, and 35–46 years old participants.121 Hepatic cysts are more prevalent and hepatic cyst volume is larger in women than in men. Typically, PLD is asymptomatic, but symptoms have become more frequent as the lifespan of ADPKD patients has lengthened with dialysis and transplantation. Symptoms may result from mass effect or from complications related to the cysts. Symptoms typically caused by massive enlargement of the liver or by mass effect from a single or a limited number of dominant cysts include dyspnea, early satiety, gastroesophageal reflux, and mechanical low back pain. Other complications caused by mass effect include hepatic venous outflow obstruction, inferior vena cava compression, portal vein compression, or bile duct compression presenting as obstructive jaundice. Symptomatic cyst complications include cyst hemorrhage, infection, and rarely torsion or rupture. FDG positron emission tomography scanning is a promising diagnostic tool for cyst infection.111 Rupture of an infected liver cyst into the pericardium and bronchobiliary fistulas 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 with increased frequency. Sperm abnormalities and defective motility (asthenozoospermia or o50% of spermatozoa with forward motility) are common in ADPKD and rarely may be a cause of male infertility.124 Pancreatic cysts are almost always asymptomatic, with very rare occurrences of recurrent pancreatitis and possibly chance associations of intraductal papillary mucinous tumor or carcinoma. Spinal meningeal diverticula may occur with increased frequency 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 aortic and cervicocephalic artery dissections, and coronary artery aneurysms. They are caused by alterations in the vasculature directly linked to mutations in PKD1 or PKD2.126 Intracranial aneurysms are very prevalent (6% with a negative and 16% with a positive family history of aneurysms), but most never rupture. Valvular heart disease (mitral valve prolapse and aortic insufficiency) occurs with increased frequency. Colonic diverticulosis and diverticulitis are more common in ESRD patients with ADPKD than in those with other renal diseases. 160

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There have been reports of extracolonic diverticular disease.127 A rarely reported association of ADPKD is with idiopathic hypertrophic pyloric stenosis.128 This may represent a chance association, but a deficiency in nitric oxide synthase could be the underlying cause of both conditions. PC1 is expressed in the motile cilia of airway epithelial cells. Bronchiectasis are detected by CT three times more frequently in ADPKD compared with control individuals (37 vs 13%, Po0.002).129 ADPKD DIAGNOSED IN UTERO OR AT BIRTH

More 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 pregnancy and the first day of life between 1981 and 2006 showed that the prognosis is usually favorable, at least during childhood.130 Clinical features in 26 children (three pregnancies were terminated because of prenatal signs of poor prognosis) included oligoamnios in five and neonatal 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) had hypertension, 2 (9.7 years) proteinuria, and 2 (19 years) chronic renal insufficiency. TREATMENT

Current therapy is directed toward limiting the morbidity and mortality from the complications of the disease and has been the focus of recent reviews.3,131–133 The discussion here is limited to information that has become available in the last 3 years. Although some studies have shown better preservation of renal function or reduction in proteinuria and left ventricular hypertrophy with ACEIs or ARBs compared with diuretics or calcium channel blockers, others have been unable to detect a superiority of these drugs compared with b-blockers. Most studies have been limited by inadequate power, short followups, wide ranges of renal function, and doses with inadequate pharmacological effects. Equally uncertain is the optimal blood pressure target. Although ADPKD patients with a baseline GFR between 13 and 24 ml/min per 1.73 m2 assigned in the MDRD study to a low blood pressure target (o92 mm Hg) had faster decline in GFR than those assigned to a standard blood pressure goal (o107 mm Hg), an extended follow-up of the patients with a baseline GFR between 25 and 55 ml/min per 1.73 m2 showed a delayed onset of kidney failure and a reduced composite outcome of kidney failure and all-cause mortality in the low blood pressure group. An ongoing study (HALT-PKD) is designed to determine whether the combined therapy with an ACEI and an ARB is superior to an ACEI alone in delaying the progression of the cystic disease in patients with CKD stage 1 or 2 or in slowing down the decline of renal function in patients with CKD stage 3. HALT-PKD will also determine whether a low blood pressure target (o110/75) is superior to a standard blood pressure target (o130/80) in the group of Kidney International (2009) 76, 149–168

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VE Torres and PC Harris: Autosomal dominant PKD

patients with preserved function (NCT00283686; Clinical Trials.gov). Several studies have suggested a beneficial effect of statins on endothelial function, renal blood flow, and levels of interleukin-6 and C-reactive protein.134 Administration of lovastatin to cy/ þ rats increased renal blood flow and ameliorated the renal cystic disease, but the beneficial effects from the administration lovastatin and enalapril on the severity of the cystic disease were not additive.135 Dietary supplementation with long-chain n-3 polyunsaturated fatty acids has been shown to have beneficial antiinflammatory effects in cy/ þ rats. However, a small prospective randomized 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 1.56 mg per 100 ml; mean total kidney volumes, 1806 and 1563 ml) did not show a beneficial effect on rates of renal enlargement or functional decline.136 The management of chronic pain in a relatively small subset of patients for whom it may be disabling is challenging. When conservative measures fail, surgical interventions ranging from cyst aspiration and sclerosing agents to laparoscopic or surgical cyst fenestration can be considered. A nonrandomized, open label, uncontrolled trial of videothoracoscopic sympatho-splanchnicectomy is ongoing (NCT00571909). Laparoscopic renal denervation and nephropexy have provided good results in children with chronic flank pain and intermittent severe episodes.137 Laparoscopic or retroperitoneoscopic nephrectomy is indicated for symptomatic patients with ESRD. Renal artery embolization can also be considered in these cases. It has been reported to produce a decrease in kidney size to 73.8% at 3 months and to 53.4% of the original size at 1 year. Side effects include flank pain which resolves within 5 days, 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 transplant are no greater than in the general population. Complications directly related to ADPKD are rare. Whether ADPKD increases the risk for developing new onset diabetes mellitus after transplantation is controversial.141,142 When nephrectomy is indicated, handassisted laparoscopic nephrectomy is associated with less intraoperative blood loss, less postoperative pain, 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 to reduce cyst volume and hepatic size. The choice of procedure (percutaneous cyst aspiration without or with sclerosis, laparoscopic cyst fenestration, combined liver resection and cyst fenestration, 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 highly symptomatic patients in whom the other options are not feasible or too risky.147 Kidney International (2009) 76, 149–168

Widespread pre-symptomatic screening is not indicated because it yields mostly small aneurysms with a low risk of rupture. Indications for screening in patients with good life expectancy include family history of aneurysm or subarachnoid hemorrhage, previous aneurysm rupture, preparation for major elective surgery, high-risk occupations (for example, airline pilots), and patient anxiety despite adequate information. MR angiography does not require intravenous contrast material. CT angiography is a satisfactory alternative when there is no contraindication to intravenous contrast. When an asymptomatic aneurysm is found, a recommendation 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 THERAPIES

A better understanding of the pathophysiology and the availability of animal models has facilitated the development of preclinical trials (Figure 2) and identification of promising candidate drugs for clinical trials (Table 4). The effect of vasopressin, through V2 receptors, on cAMP levels in the collecting duct, the major site of cyst development in ADPKD, and the role of cAMP in cystogenesis provided the rationale for preclinical trials of vasopressin V2 receptor (VPV2R) antagonists. One of these drugs, OPC-31260, reduced the renal levels of cAMP and markedly inhibited cyst development in models of ARPKD, ADPKD, and nephronophthisis.110 An antagonist with high potency and selectivity for the human VPV2R (tolvaptan) was also effective. Neither had an effect on liver cysts, consistent with the absence of VPV2R in the liver. High water intake by itself also exerted a protective effect on the development of PKD in PCK rats most likely due to suppression of vasopressin.149 Genetic elimination of AVP in these rats yielded animals born with normal kidneys that remained relatively free of cysts unless an exogenous V2R agonist was administered.150 An antagonist of the endothelin-1 ETB receptor (predominant endothelin receptor subtype in the collecting tubules that inhibits AVP action and promotes diuresis) increased renal cAMP and aggravated the renal cystic disease in Pkd2WS25/ mice, presumably by enhancing the action of AVP.151 Phase II clinical trials with tolvaptan have been completed and a phase III clinical trial is ongoing (NCT00428948). Somatostatin acting on SST2 receptors inhibits cAMP accumulation not only in the kidney but also in the liver.152 Octreotide, a metabolically stable somatostatin analog, halted the expansion of hepatic cysts from PCK rats in vitro and in vivo. Similar effects were observed in the kidneys. 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 of octreotide and lanreotide for PKD and PLD (NCT00309283, NCT00426153, NCT00565097). 161

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Reduced in PKD TNF antagonist

CFTR inh KCa3.1 inh

TKIs

TNFα

KCa3.1

EGF IGF1 VEGF

K+

PKA

Src inh

Na+K+ATPase

CI

+

Na

MEK

MEK inh

RSK Rheb

AMPK

Metformin LKB1

2+

Ca

PKA

SOC

ERK TSC1 TSC2

ER

Ca2+

Src

B-Raf

IKKβ

–

Triptolide

PC2

Ras NKCC1

Increased in PKD

PC1

Nucleus

Myc jun phos cyclinD

Ca2+

2+

Ca

IP3

AM P PDE

mTOR

Protein synthesis

GSK3β

β-Catenin

Dvl

PKA cAMP ATP

AMP

PLCγ ATP

ADP

Na+K+ATPase

Frizzled Wnt sFRP4

Proteasome mTOR inhibitors

CDK inhibitors

Gi Ac-VI Gs V2R R Somatostatin

Gq R

Vasopressin

V2RA

Figure 2 | Diagram depicting putative pathways up- or downregulated in polycystic kidney disease and rationale for treatment with V2 receptor antagonists, somatostatin, triptolide; tyrosine kinase, src, MEK, TNFa, mTOR, or CDK inhibitors; metformin, and CFTR or KCa3.1 inhibitors (green boxes). Dysregulation of [Ca2 þ ]i , increased concentrations of cAMP, mislocalization of ErbB receptors, and upregulation of EGF, IGF1, VEGF, and TNFa occur in cells/kidneys bearing PKD 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 þ inhibitable AC6 and/or inhibition of Ca2 þ -dependent PDE1 by a reduction in [Ca2 þ ]i; (iii) increased levels of circulating vasopressin due to an intrinsic concentrating defect; and/or (iv) upregulation of vasopressin V2 receptors. Increased cAMP levels contribute to cystogenesis by stimulating chloride and fluid secretion. In addition, cAMP stimulates mitogen-activated protein kinase/extracellularly regulated kinase (MAPK/ERK) signaling and cell proliferation in an Src- and Ras-dependent manner in cyst-derived cells or in wild-type tubular epithelial cells treated with Ca2 þ channel blockers or in a low Ca2 þ medium. Activation of tyrosine kinase receptors by ligands present in cystic fluid also contributes to the stimulation of MAPK/ERK signaling and cell proliferation. Phosphorylation of tuberin by ERK (or inadequate 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 and mTOR. Upregulation of TNFa or downregulation of AMPK signaling may also stimulate mTOR signaling through inhibition of the tuberin–hamartin complex. Activation of AMPK may also blunt cystogenesis through inhibition of CFTR and ERK. Upregulation of Wnt signaling stimulates mTOR and b-catenin signaling. ERK and mTOR activation promotes G1/S transition and cell proliferation through regulation of cyclin D1, phosphorylation of retinoblastoma protein (RB) by CDK4/6-cyclin D and CDK2-cyclin E, and the release of the E2F 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, tuberous sclerosis proteins tuberin (TSC2) and hamartin (TSC1); V2R, vasopressin V2 receptor; V2RA, vasopressin V2 receptor antagonists.

Correcting the alteration in intracellular calcium homeostasis thought to be responsible for the accumulation of cAMP and the proliferative phenotype of the cystic epithelium is a logical alternative strategy to inhibit the development of PKD. The aggravation of PKD in cy/ þ rats by the administration of calcium channel blockers is consistent with this strategy.153 Triptolide induced cellular calcium release through a PC2-dependent pathway, increased p21 expression and arrested growth in Pkd1/ cells, and reduced cystic burden in Pkd1/ embryonic mice and in kidney-specific conditional Pkd1 knockout mice.154,155 On the other hand, amlodipine has been reported to have an antiproliferative effect in vascular smooth muscle cells by increasing the expression of p21 (Waf1/Cip1).156 The administration of a type 2 calcimimetic caused a slight reduction in interstitial fibrosis, but had no detectable effect on the levels of renal cAMP, renal expression of cAMP-dependent genes, and cystogenesis in the PCK rat and Pkd2/WS25 mouse, possibly due to the absence of calcium162

sensing receptor in the outer medullary and cortical collecting ducts or the reduction in extracellular calcium.84 The transporters required for chloride-driven fluid secretion into the cysts (NaK2Cl cotransporter, 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 metanephric kidney organ cultures, and in Pkd1flox/–;Ksp-Cre mice.157,158 These observations are consistent with reports of families with both ADPKD and cystic fibrosis in which individuals with both diseases had less severe cystic disease than those with only ADPKD.159 CFTR inhibitors that achieve high concentrations in the kidney and urine may find a place in the treatment of ADPKD, because their accumulation in the lung is minimal and CFTR inhibition has to exceed 90% to affect lung function, thus making the development of cystic fibrosis-like lung disease unlikely. A KCa3.1 inhibitor, TRAM-34 (an analog of desimidazolyl clotrimazole), inhibited forskolin-stimulated Kidney International (2009) 76, 149–168

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VE Torres and PC Harris: Autosomal dominant PKD

Table 4 | Currently active clinical trials for ADPKD

a

Enrollment target and primary outcome measure

Intervention

Study design

Eligibility

HALT-PKD Study A phase 3 NCT00283686

Lisinopril/telmisartan vs lisinopril/placebo and low vs standard BP target

15–49 years old, GFR 548, Kidney volume 460, BP X130/80, or change (MRI) treatment for HT

HALT-PKD Study B phase 3 NCT00283686

Lisinopril/telmisartan vs lisinopril/placebo

Effect of Statin on disease progression phase 3 NCT00456365 TEMPO 2/4 Trial phase 2 NCT00413777 TEMPO 3/4 Trial phase 3 NCT00428948 Octreotide in ADPKD phase 3 NCT00309283 Octreotide in severe PLD phase 2–3 NCT00426153

Pravastatin

Multicenter, randomized, doubleblind, placebocontrolled, 2  2 factorial assignment Multicenter, randomized, doubleblind, placebocontrolled Randomized, doubleblind, placebocontrolled

V2 receptor antagonist (tolvaptan)

Start–finish dates (status) Sponsor 2006–2013 (recruiting)

NIDDK

18–64 years old, GFR 470, Time to the 50% 2006–2013 25–60, BP X130/80, reduction in eGFR, ESRD, (recruitment or treatment for HT or death closed)

NIDDK

8–21 years old, Normal GFR

2006–2011 (recruiting)

University of Colorado

2005–2008 (recruitment closed) 2007–2011 (recruiting)

Otsuka Pharm. Otsuka Pharm.

2006–2010 (recruiting)

Mario Negri Institute

100, Kidney volume, LVMI, urine albumin, endothelial-dependent vasodilation 418 years old 48, Long-term safety Participation in prior (kidney volume sec. dose-finding studies outcome) 18–40 years old 1500, Kidney volume GFRX60, TKV change (MRI) X750 ml 18–75 years old, GFR 66, Kidney volume 440 change (MRI)

Multicenter, openlabel, dose comparison V2 receptor antagonist Multicenter, double(tolvaptan) blind, placebocontrolled Long-acting Randomized, singlesomatostatin blind, placebo(octreotide) controlled Long-acting Randomized, double- 418 years old, somatostatin blind, placeboLV44000 ml or (octreotide) controlled, crossover highly symptomatic PLD Lanreotide in PLD Long-acting Randomized, double- 418 years old, 420 phase 2–3 somatostatin (lanreotide) blind, placeboliver cysts NCT00565097 controlled SUISSE study phase 3 mTOR inhibitor Multicenter, 18–40 years old, GFR NCT00346918 (sirolimus) randomized, single- X70 blind, placebocontrolled SIRENA STUDY phase mTOR inhibitor Randomized, open- 18–80 years old, GFR 2 NCT00491517 (sirolimus) label, crossover X70 Sirolimus in ADPKD mTOR inhibitor Randomized, open- 18–75 years old phase 1–2 (sirolimus) label, dose NCT00286156 comparison 18–65 years old, Everolimus in ADPKD mTOR inhibitor Multicenter, GFRX60 phase 3 (everolimus) randomized, NCT00414440 placebocontrolled, doubleblind ADPKD Pain Study Videothoracoscopic Nonrandomized, 418 years old, phase 2 sympathoopen-label, debilitating kidney NCT00571909 splanchnicectomy uncontrolled pain

42, Liver volume change 2007–2010 (MRI) (kidney volume (recruitment sec. outcome) closed)

Mayo Clinic, Novartis

38, Liver volume change 2007(CT) (recruitment closed) 100, Kidney volume 2006–2010 change (MRI) (recruitment closed)

Radboud University, Ipsen University of Zurich

16, Kidney volume change (CT) 45, Lothalamate GFR change

2007–2009 (recruiting) (recruiting)

Mario Negri Institute Cleveland Clinic

400, Kidney volume change (MRI)

2006–2009 (recruiting)

Novartis

20, Pain control and quality of life

2007–2010 (recruiting)

Mayo Clinic, PKDF

BP, blood pressure; CT, computed tomography; ESRD, end-stage renal disease; GFR, glomerular filtration rate; MRI, magnetic resonance imaging; PLD, polycystic liver disease. a GFR, estimated or measured, in ml/min or ml/min per 1.73 m2; BP in mm Hg.

transepithelial chloride secretion in filter-grown polarized monolayers of MDCK, NHK, and ADPKD cells, as well as MDCK and ADPKD cell cyst formation and enlargement in collagen gels.73,74 Although the efficacy of KCa3.1 inhibitors in ADPKD still needs to be shown in animal models of the disease, it is encouraging that senicapoc (ICA-17043), another KCa3.1 inhibitor, has been used successfully in a phase 2 trial and has shown little or no toxicity in a phase 3 trial for sickle-cell disease.160 Targeting the NaK2Cl cotransporter or Na-K-ATPase to treat ADPKD seems less feasible because of likely side effects and less predictable effects on cystogenesis. Inhibition of the NaK2Cl cotransporter could potentially be detrimental as Kidney International (2009) 76, 149–168

hypokalemia has been associated with 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 membranes of ADPKD cell monolayers and intact cysts dissected from ADPKD kidneys inhibited fluid secretion. However, nanomolar concentrations of ouabain, within the range of levels found in blood under normal conditions increase ERK phosphorylation and MEK-ERK-dependent proliferation 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 PKD than those with ADPKD alone. This observation suggests a convergence of signaling 163

review

pathways downstream from PC1 and the TSC2 protein tuberin (Figure 2). Activation of mTOR in polycystic 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 inhibitors sirolimus and/or everolimus significantly retard cyst expansion and protects renal function.69,162–165 Small retrospective studies of ADPKD patients after transplantation have shown a significant reduction in the volume of the polycystic kidneys or polycystic liver in patients treated 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 beneficial effect on the development of PKD as it directly phosphorylates and inhibits CFTR and inhibits mTOR through phosphorylation of tuberin (Figure 2). Consistent with this, metformin has been shown to reduce the growth of MDCK cysts and the cystic index of conditional kidney-specific Pkd1 knockout mouse.167 One of the effects of mTOR inhibition is to inhibit the production of and the cellular response to vascular endothelial growth factor. Vascular endothelial growth factor is present in ADPKD liver and kidney cyst fluids, and VEGF receptors 1 and 2 (VEGFR1 and VEGFR2) are present in cystic tissues. The results of VEGF inhibition in PKD have been mixed. Administration of the VEGFR inhibitor SU-5416 had a significant protective effect on the development of cystic disease in the liver, but not in the kidney, in a small number of Pkd2WS25/ mice.168 On the other hand, treatment of developing CD-1 mice with antibodies against VEGFR2 results in the development of renal cysts, suggesting that inhibition of VEGF signaling could promote renal cyst growth.169 Tumor necrosis factor-a, TNFR-I, and TNF-a-converting enzyme are overexpressed in cystic tissues. The administration of TNF promotes cyst formation in Pkd2 þ / mice, whereas etanercept had an inhibitory effect.18 An inhibitor of TNF-a-converting enzyme was shown to ameliorate the polycystic disease in the bpk mouse, a recessive model of PKD. The aggravation of PKD by TNFa may be due to its enhancement of the expression of FIP2, a protein that physically interacts with polycystin 2 and prevents its transport to the plasma membrane and primay cilium. Alternatively, TNFa also activates IKKb (inhibitor of kB kinase-b), which physically interacts and phosphorylates hamartin, suppressing TSC1-TSC2 function and activating mTOR.119 (Figure 2). Polycystic kidney disease has been described as ‘neoplasm in disguise’, Many drugs developed to suppress cell proliferation and treat neoplastic diseases have been shown in animal models to be effective and of potential value for the treatment of ADPKD. These include Erb-B1 (EGF receptor) and Erb-B2 tyrosine kinase, Src kinase, MEK, and cdk inhibitors.170–172 Roscovitine, a cyclin-dependent kinase inhibitor, inhibited 164

VE Torres and PC Harris: Autosomal dominant PKD

cystogenesis and improved renal function in two murine 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 levels of p21, which is downregulated in PKD.67 Increased apoptosis accompanies increased cell proliferation in PKD, but it is unclear whether it is a neutral or beneficial consequence of excessive proliferation or an important contributor to cyst formation and renal injury. A caspase inhibitor (IDN-8050) reduced epithelial cell apoptosis and proliferation, and inhibited the development of the cystic disease and renal insufficiency in Han:SPRD rats.69 Double mutants with PKD (cpk mice) and a knockout of caspase 3 had less severe cystic disease and lived longer than cpk mice with intact caspase 3.174 A number of studies have focused on the role of arachidonic acid metabolites and their inhibitors on the progression of PKD. Prostaglandin E2 (PGE2) accumulates in cyst fluids and enhances cAMP production and growth of MDCK cysts in collagen gels.175 PGE2 may act on four different G-protein-coupled receptors named E-prostanoid (EP) receptors 1–4. EP2 and EP4 are coupled to G stimulatory proteins and stimulate cAMP formation. EP3 is coupled to G inhibitory protein, inhibits cAMP formation, induces Rho activation and actin polymerization, and antagonizes vasopressin action. EP1 activation induces inositol 3-phosphate formation and calcium release. Recently, the effects of PGE2 on cAMP formation and cystogenesis, in a three-dimensional cell-culture system of human epithelial cells from normal and ADPKD kidneys, have been shown to be mediated by EP2 receptor activation, thus suggesting 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 and steady state in vitro levels of prostanoids were 2–10 times higher in diseased compared with normal kidneys. The administration of the COX-2 inhibitor NS-398 reduced cystic expansion by 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 no protective effect on renal function.176 The production of 20-hydroxyeicosatetraenoic acid (20HETE), an endogenous cytochrome P450 metabolite of arachidonic acid with mitogenic properties, is markedly increased in microsomes 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 wildtype mice with Cyp4a12 induced a four- to fivefold increase in cell proliferation, which was completely abolished when 20-HETE synthesis was inhibited. These observations suggest that 20-HETE contributes to the proliferation of epithelial cells in the formation of renal cysts and provide another potential target for intervention. Kidney International (2009) 76, 149–168

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VE Torres and PC Harris: Autosomal dominant PKD

STRATEGIES FOR CLINICAL TRIALS

In planning clinical trials for ADPKD, the utilization of renal function as the primary outcome becomes an issue. Decades of normal renal function, despite progressive enlargement and cystic transformation of the kidneys, characterize the natural history of ADPKD. By the time GFR starts declining, the kidneys are markedly enlarged, distorted, and unlikely to benefit from treatment. On the other hand, early interventional trials would require unrealistic periods of follow-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 functional decline. Extrapolation of total kidney volume in individual CRISP subjects back to an age of 18 years is consistent with the volumes observed by direct measurement in a separate cohort of patients. The good fit between these extrapolated and measured values indicates that the total kidney volume growth rate is a defining trait for individual patients.178 The results of the CRISP study have been confirmed by a recent European study that has shown that increases in kidney volume can be reliably measured over a 6 month period in early ADPKD, using unenhanced MRI sequences.99 These observations provide a strong rationale for the utilization of kidney volume as a surrogate marker of disease progression in clinical trials for ADPKD. DISCLOSURE

The authors declared no competing interests.

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