Extrarenal Manifestations of Autosomal Dominant Polycystic Kidney Disease

Extrarenal Manifestations of Autosomal Dominant Polycystic Kidney Disease Yves Pirson Although asymptomatic in most patients, extrarenal manifestations of ADPKD may become more clinically relevant with the increasing life expectancy of affected patients. They mainly encompass cysts in other organs than the kidney (liver: 94%, seminal vesicle: 40%, pancreas: 9%, arachnoid membrane: 8%, and spinal meningeal, 2%) and connective tissue abnormalities (mitral valve prolapse: 25%, intracranial aneurysms: 8%, and abdominal hernia: 10%). Their recognition may spare the patient from other, useless investigations (eg, when an arachnoid cyst is incidentally found) or lead to the implementation of prophylactic or therapeutic measures (eg, screening, sometimes followed by the treatment of an asymptomatic intracranial aneurysm in at-risk patients, or, in the presence of a severe polycystic liver disease, avoidance from estrogens and treatment aimed to slow cyst growth). Q 2010 by the National Kidney Foundation, Inc. All rights reserved. Index Words: Autosomal dominant polycystic kidney disease, Polycystic liver disease, Intracranial aneurysm

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s previously underlined by others, autosomal dominant polycystic kidney disease (ADPKD) is a systemic disease with multiple extrarenal manifestations encompassing both cystic involvement of other organs than the kidney and connective tissue abnormalities.1,2 Extrarenal involvement is observed in PDK1 as well PKD2 disease. There is a wide intrafamilial variability in the occurrence and severity of extrarenal manifestations with a parallel paucity of genotype-phenotype correlations. Although asymptomatic in most patients, extrarenal manifestations may become more clinically relevant with the increasing life expectancy of ADPKD patients because of improved general management including renal replacement therapy. This review focuses on recent advances in the knowledge of these manifestations, with emphasis on both the understanding of their pathophysiology and attendant therapeutic prospects.

Liver Involvement Liver abnormalities essentially consist of cystic involvement; other abnormalities are exceptionally observed.

Polycystic Liver Disease Polycystic liver disease (PLD) is by far the most frequent extrarenal abnormality in ADPKD. Liver cysts are detected later than renal cysts. Their frequency increases with age.

Their prevalence by magnetic resonance imaging is 58% in 15- to 24-year olds, 85% in 25- to 34-year olds, and 94% in 35- to 46-year-old subjects.3 Hepatic cysts are more prevalent, and hepatic cyst volume is larger in women than in men. Women who have multiple pregnancies or who have used oral contraceptive drugs or estrogen replacement therapy have worse disease, suggesting an estrogen effect on hepatic cysts growth.4 Liver cysts result from abnormal remodeling of the ductal plate.5 They arise from 2 different structures. Most of them originate from overgrowth of bile ductules called biliary microhamartomas that become disconnected from the bile duct from which they derive; they exhibit intraparenchymatous location. Other cysts result from dilatation of the peribiliary glands surrounding large intrahepatic bile ducts; they are located in the hepatic hilum or around large portal tracts. Most potential mechanisms leading to the development and growth of liver cysts share similarities with those implicated for kidney

From Department of Nephrology, Cliniques Universitaires St Luc, Bruxelles, Belgium. Address correspondence to Yves Pirson, MD, Department of Nephrology, Cliniques Universitaires St Luc, Avenue Hippocrate 10, 1200 Bruxelles, Brabant, Belgium. E-mail: yves. [email protected] Ó 2010 by the National Kidney Foundation, Inc. All rights reserved. 1548-5595/10/1702-0008$36.00/0 doi:10.1053/j.ackd.2010.01.003

Advances in Chronic Kidney Disease, Vol 17, No 2 (March), 2010: pp 173-180

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cysts, whereas some of them seem to be more specific for the liver. Just as in the kidney, a 2hit model of the initiation of cyst formation (a germline mutation in either PKD1 or PKD2 followed by a second, loss-of-function somatic mutation in the other gene copy) has been suggested, accounting for the monoclonality found in (at least some) hepatic cysts.6 Just as in the kidney tubules, primary cilia of cholangiocytes appear as mechanosensory organelles capable, when bended by bile flow, of modulating the intracellular levels of cyclic adenosine monophosphate (cAMP) and calcium, 2 key intracellular mediators of cholangiocyte secretory and proliferative activities.7 It was recently shown that the hepatic cyst epithelium of ADPKD patients displayed heterogeneous features that are normal in small cysts (,1 cm), are characterized by rare or shortened cilia in 1- to 3-cm cysts, and are characterized by the absence of both primary cilia and microvilli in large cysts (.3 cm).5 Recently, a role for micro-RNAs in cystic liver and kidney diseases, including ADPKD, was suggested by Lee and colleagues.8 They showed that the levels of the micro-RNA miR15a are decreased in the livers of patients with ADPKD and that suppression of miR15a in normal rat cholangiocytes accelerates cell proliferation through an increased expression of the cell-cycle regulator Cdc25A.8 The estrogen effect on hepatic cyst growth, suggested by the previously mentioned clinical findings, is strongly supported by recent laboratory works. Estrogens have indeed been shown to enhance the proliferative and secretory activities of cholangiocytes through binding to estrogen receptors and activating several growth factors.9 Moreover, liver cyst– derived epithelial cells from ADPKD patients proliferated when exposed to estrogens.7 Although PLD is asymptomatic in the vast majority of patients, some patients experience either acute or chronic sequelae of liver cystic disease. Acute complications of hepatic cysts can include either infection and/or hemorrhage. A cyst infection usually presents with fever (.38  C) and right-sided abdominal pain. Remarkably, all 10 episodes of liver cyst infection reported in a recent series occurred in patients who were undergoing dialysis.10 Laboratory features include a Creactive protein level .50 mg/L, leucocytosis,

and increased serum levels of alkaline phosphatase and g-glutamyl transferase; in addition, we recently showed that the CA19.9 level, which seems to correlate with hepatic cyst burden, is markedly increased with liver cyst infection and could become an interesting diagnostic tool.11 The localization of the infected cyst can be challenging even with imaging methods such as computed tomography scans, magnetic resonance imaging, or tagged white blood cells.12 The most promising tool appears to be positron emission tomography scanning, which tested positive in all 4 patients with an infected liver cysts reported by Salle´e and colleagues.10 The identification of the causative microorganism relies on blood culture and/or culture of percutaneous drained cyst fluid. Gram-negative enterobacteria or hemophilus are most often involved. Although drainage is not a prerequisite to successful treatment of a small infected cyst, it should be performed early in .5-cm diameter cysts and should be considered in any infected cyst should antibiotic therapy fail. An initial combination of antibiotics is recommended, and the regimen should include a fluoroquinolone such as ciprofloxacin and a ß-lactamine or an aminoside.10 Although the optimal duration of treatment has not been rigorously studied, we currently recommend a 6-week course of antibiotics. Severe abdominal pain in a patient with PLD may also be caused by cyst hemorrhage and can usually be distinguished from infection by a computed tomography scan. The specificity for infection of both CA19.9 serum level and a positron emission tomography scan remains to evaluated.10,11 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, compression of the inferior vena cava, portal-vein compression, or bile-duct compression presenting as obstructive jaundice.4 The management of symptomatic PLD has been previously reviewed13,14 and updated.4,15-17 Patients with severe disease should avoid estrogens. Rarely, symptomatic PLD requires interventions to reduce

Extrarenal Manifestations of ADPKD

cyst volume and hepatic size. The choice of procedure (percutaneous cyst aspiration with sclerosis, laparoscopic cyst fenestration, combined liver resection and cyst fenestration, and liver transplantation) is mainly dictated by the anatomy and distribution of cysts.18 Percutaneous cyst aspiration under ultrasound or computed tomography guidance is helpful to establish causality between a particular cyst and symptoms. The injection of a sclerosing agent can be subsequently performed. This procedure is best suited for deep-seated cysts (because the tissue pressure of the surrounding parenchyma helps to collapse the cyst).18 The optimal surgical treatment has been recently reappraised by an experienced team, with emphasis on the long-term postoperative outcome.17 In brief, cyst fenestration alone can be performed safely but only provides durable effect in highly selected patients (typically, the rare patients with a few, superficial, dominant cyst). Partial hepatectomy with remnant cyst fenestration has currently the broadest applicability for the majority of patients; it can be performed with acceptable morbidity and mortality, prompt and durable relief of symptoms, and maintenance of liver function.17 Liver transplantation is reserved for patients with severely disabling PLD with diffuse cystic involvement and absence of at least single sectoral preservation; this option of course requires lifelong immunosuppression. Liver transplantation is increasingly used with excellent results; combined liver-kidney transplantation is the best option for patient with concomitant advanced kidney failure.16,19 Advances in the elucidation of the mechanisms leading to liver cyst growth have paved the way for therapies aimed to delay, inhibit, or even reverse PLD. The mammalian target of rapamycin (mTOR) inhibitor sirolimus, which is currently tested in humans to slow kidney cyst, could have a similar effect on PLD; a retrospective study of ADPKD patients after kidney transplantation has indeed shown that treatment with the sirolimus regimen for an average of 19 months was associated with a 12% reduction in liver volume, whereas treatment with tacrolimus for a comparable duration was associated with a 14% increase.20 Octreotide, a somatostatin analog, has been shown to inhibit cAMP accumulation

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in bile ducts and to halt the expansion of hepatic cysts from PCK rat in vitro and in vivo.21 A clinical trial of octreotide for patients who are not candidates for or who decline surgery for severe PLD is currently in progress at the Mayo Clinic. The first results, communicated in abstract form, indicate that, among 28 patients receiving octreotide, liver volume decreased by 4.9% compared with an increase by 3.7% among 14 patients on placebo, a difference reaching statistical significance.22 The results of a clinical trial with another somatostatin analog, lanreotide, in 32 ADPKD patients (together with 22 patients with isolated PLD) has been just published, showing that 6 months of treatment also significantly reduces liver volume as compared with placebo-controlled patients.23

Other Abnormalities Mild dilatation of the commun bile duct has been reported in 40% of patients studied by computed tomography scan.24 A few cases of congenital hepatic fibrosis have been recognized in ADPKD. Spleen enlargement and variceal bleeding are prominent features. Congenital hepatic fibrosis may be associated with focal or diffuse cystic dilatation of the segmental bile ducts (Caroli syndrome). Interestingly, congenital hepatic fibrosis is not vertically transmitted along with the renal disease, but siblings can be affected.4

Vascular Involvement An association between ADPKD and vascular abnormalities such as intracranial aneuvrysm (ICA) has been known for many years. These abnormalities also include dolichoectasias, thoracic aortic and cervicocephalic artery dissections, and coronary artery aneuvrysms. Several studies, especially in transgenic animal models, have provided convincing evidence that these vascular abnormalities are caused by alterations in the arterial wall linked to mutations in PKD1 or PKD2.25 First, polycystins 1 and 2 (PC1/PC2), are detected in both vascular smooth muscle cells and endothelial cells of all major vessels including aorta and intracranial arteries.25 Second, animal models of ADPKD recapitulate and extent the vascular abnormalities observed in

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humans, with a interesting gene dosage effect. Homozygous mice with a targeted mutation in either Pkd1 or Pkd2 gene die in utero because of massive hemorrhage caused by focal vascular leaks and rupture of blood vessels.25 Mice with a hypomorphic PKD1 allele (PC1 expression reduced by about 75%) show dissecting aneurysms, often accompanied by large intramural bleeding; sequential examination of the aorta reveal that rupture of the vessel wall results from the combination of progressive weakening of the media and development of a tear in the intima.26 In vessels of Pkd21/- mice (PC2 expression reduced by 50%), smooth muscle cells exhibit increased rates of proliferation and apoptosis,27 and Pkd21/- mice have an increased rate of intracranial vascular abnormalities when they are induced to develop hypertension.28

ICA An asymptomatic ICA is found by screening in 8% of patients with ADPKD (ie, a rate 3 to 4 times above that found in the general population).29,30 Just as in the general population, 90% of them are found in the anterior circulation. Of note, most of them are small; the majority of them are ,6 mm in diameter. The only clinical characteristic clearly associated with the presence of ICA is a family history of ICA because the relative risk for harboring ICA is more than doubled among patients with a definite family history of ICA or subarachnoid hemorrhage (SAH) than in those without. This family clustering is in agreement with the finding that patients with mutations in the 5’ region of PKD1 are more likely to have ICA than are patients with 3’ mutations, especially in those with ICA rupture before 40 years old and in families with multiple cases of ICA or other vascular events.31 Fortunately, as in the general population, most ICAs remain asymptomatic. They may produce symptoms via 3 mechanisms: rarely compression of adjacent structures or focal brain ischemia caused by embolism and more often SAH caused by rupture. The profile of the patient with ADPKD admitted for ICA rupture, his clinical presentation, and guidelines for management have been reviewed elsewhere.29 Age at the time of ICA

rupture averaged 41 years old in our series.29 This is close to that observed in other familial forms of ICA but a decade lower than that reported in the sporadic form.29 Occasionally, ICA is the presenting manifestation of ADPKD. As expected from the mean age at rupture, more than half of our patients still had a normal renal function at that time, and a quarter had a blood pressure within the normal range.29 In contrast to the female predominance found in patients with ICA rupture in the general population,32 the male-to-female ratio in ADPKD patients suffering on ICA rupture was approximately equal in a combined series of 191 patients.33-35 Both an earlier age at rupture and the absence of female preponderance in ADPKD suggest that that the mechanisms leading to rupture differ from those involved in the sporadic form. More specifically, estrogens might not be as detrimental in this complication as they are in PLD. Whether there is a relationship between massive PLD and ICA rupture in ADPKD would be an interesting field of investigation. The cardinal feature of SAH is a sudden intense headache. Up to 38% of patients admitted for SAH have a history of acute and transient headache in the days or weeks before rupture.36 This ‘‘warning headache’’ is most likely caused by a first, limited leak from the ICA. The first diagnostic step to assess the possibility of SAH is a cerebral computed tomography scan. Once established, SAH should be further investigated and managed under the direction of a neurologic team. As in the general population, ICA rupture in ADPKD patients entails a combined mortality-morbidity rate of 35% to 55%.29 Given the grave prognosis of ruptured ICA and the possibility of detecting and repairing one before it ruptures, screening has to be considered. This risk of prophylactic treatment (surgical or endovascular) has to be balanced against the risk of rupture (death or disability) at some time later in life.30 The balance of risks also include the amount of anxiety before screening, the reassurance that can be given with a negative result, and the anxiety that can be caused by finding an ICA (eg, if a 3-mm ICA is found and is left untreated but followed up regularly).30 Clearly, widespread screening is not indicated because it yields mostly small

Extrarenal Manifestations of ADPKD

ICAs with a low risk of rupture.4 Indications for screening (Fig 1) in patients with good life expectancy include a family history of aneurysm or SAH, previous aneurysm rupture, preparation for major elective surgery, highrisk occupations (eg, airline pilots), and patient anxiety despite adequate information.4,29 Screening is preferably performed by magnetic resonance imaging; it can be done without gadolinium, allowing patients with a low glomerular filtration rate to be screened. When an asymptomatic aneurysm is found, a recommendation for whether to intervene depends on its size, site, and morphology; a history of SAH from another aneurysm; the patient’s age and general health; whether the ICA is coilable or clippable; and finally the experience of the neuroradiologist or the neurosurgeon.4 Because the risk of new ICA or enlargement of an existing one is very low in those with small (,7 mm) ICAs,37,38 conservative management is usually recommended; repeat imaging is advisable annually and at less frequent intervals once the stability of the ICA has been documented.4 The elimination of tobacco use and aggressive treatment of hypertension and hyperlipidemia is recommended. The risk of developing an ICA after an initial negative study is small at about 3% at 10 years in patients with a family history of ICAs.39 Therefore, rescreening of patients with a family history of ICA after 5 to 10 years seems reasonable.4

Intracranial Arterial Dolichoectasia This abnormality consists of elongation and dilatation of an arterial segment. It is found in 2% of ADPKD patients (vs 0.06% in the general population). In some cases, it is a sequela of dissection. It may cause stroke.40

Other Arterial Abnormalities A few cases of dissection of cervico encephalic arteries and thoracic aorta have been reported.4 An increased prevalence of coronary aneurysms has been shown in a single limited series.4 These complications are, however, uncommon, and their prevalence is unknown.

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Figure 1. Screening occult ICA in ADPKD patients. *See text for explanations.

Extrahepatic Cysts Arachnoid membrane cysts are found in 8% of ADPKD patients.41 They require no treatment because they are generally asymptomatic.41 They can, however, increase the risk of subdural hematoma. Chronic subdural hematoma may present as headaches and focal neurologic deficit and imposes surgical drainage.42 Spinal meningeal cysts are observed in 1.7% of ADPKD patients.43,44 They rarely present with features of intracranial hypotension (orthostatic headache, diplopia, and hearing loss ataxia) caused by cerebrospinal fluid leak. Pancreatic cysts are detected by ultrasonography in 9% of ADPKD patients over 30 years of age.45 They are almost always asymptomatic, with very rare occurrences of recurrent pancreatitis. The presence of cysts in the seminal tract is reviewed later.

Other Abnormalities Cardiac Abnormalities Mitral valve prolapse is found in about 25% of patients.46 Aortic insufficiency can occur in association with the aortic root. Although these lesions can progress with time, they rarely need valve replacement.4 Pericardial effusion occurs with an increased frequency in patients with ADPKD (35% vs 9% in a control group of patients with another chronic nephropathy), possibly

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as a result of increased compliance of the parietal pericardium. Although frequently moderate to large, these effusions are generally well tolerated and clinically inconsequential.47

Diverticular Disease Whether ADPKD is associated with colonic diverticula remains uncertain. It is not the case in patients before ESRD. After renal transplantation, however, an increased incidence of diverticulitis and colon perforation has been observed.48 Duodenal diverticulosis was reported in 8 ADPKD patients (4 of them in ESRD), suggesting an increased occurrence of this abnormality in ADPKD with ESRD. It might become clinically significant in a few patients, presenting as nausea, vomiting, abdominal pain, and malabsorption.49 Because diverticulosis may be attributable to smooth muscle dysfunction, such association could be explained by the presence of PC1 and PC2 in intestinal smooth muscle and the abnormal contractility of smooth muscle in Pkd21/- haploinsufficiency.49

Abdominal Hernias As compared with unaffected family members, patients with ADPKD have an increased prevalence of inguinal (13% vs 4%) and umbilical (7% vs 2%) hernias.1 This predisposition should be kept in mind when renal replacement therapy is contemplated because it may complicate peritoneal dialysis.50

Bronchiectasis A 3-fold-increased prevalence of bronchiectasis, detected by computed tomography scans, was recently reported in ADPKD patients as compared with control patients with another chronic kidney disease. Bronchiectasis was generally mild, and a clinical counterpart of this radiologic study was not provided.51 The expression of PC1 and PC2 in the motile cilia of airway epithelial as well as smooth muscle cells52 provides a rationale for this association.

Semen Abnormalities Seminal vesicle cysts are found in about 40% of male patients with ADPKD versus 2% in

the general population.53,54 Moreover, there have been some reports on semen quality abnormalities in ADPKD. In the single study analyzing in the same patients the presence of seminal cysts and semen abnormalities including hypospermia (volume ,2 mL), oligozoospermia (sperm concentration ,20 3 106 mL), asthenozoospermia (,50% of spermatozoa with forward motility), or teratozoospermia (,15% of normal forms), the latest were documented in 90% of patients, but they did not correlate with the presence of seminal cysts.54 In another study, immotile cilia in the tail of the sperm (9 1 0 instead of 9 1 2 microtubular structure of the axoneme) were observed in 4 ADPKD patients, with proven infertility in 3 of them.55 Semen abnormalities in ADPKD are probably related to the defective function of polycystins. Watnick and colleagues56 indeed found that PKD2 was localized at the distal tip of the sperm flagella in Drosophila and a targeted mutation in this gene caused male sterility.56 Despite this increased prevalence of both seminal cysts and sperm abnormalities, male infertility is not a common trait in ADPKD.54 Nevertheless, more attention should be paid to reproductive issues in ADPKD.57

Conclusions The extrarenal manifestations of ADPKD are numerous (Table 1). They do not impact life Table 1. The Frequency of Documented Extrarenal Manifestations of ADPKD % of Patients Cystic involvement Liver Arachnoid membrane Spinal meningeal Pancreas Seminal tract Connective tissue Intracranial aneurysm Mitral valve prolapse Abdominal hernia Bronchiectasis Pericardial effusion

Reference

94 at age .35 y 8

3 41

1.7 9 at age .30 y 39-43

43 45 53,54

8

29

25

46

About 10 37 35

1 51 47

Extrarenal Manifestations of ADPKD

expectancy of affected patients but may contribute significantly to morbidity. Their proper diagnosis is important for at least 2 reasons. First, because recognizing a benign condition as an extrarenal manifestation of ADPKD, even if relatively rare, may spare the patient from futile investigation and could reassure him/her. An example is the incidental finding of an arachnoid cyst. Second, because some of these manifestations implicate prophylactic or therapeutic measures. Thus, in patients with good life expectancy and a family history of ICA on subarachnoid hemorrhage, screening for ICA is recommended. In the presence of severe PLD, estrogens should be avoided, and treatment halting progression is from now on to be considered. No doubt that ongoing progresses in the understanding of the mechanisms governing the development of these complications will provide further therapeutic means in the future.

References 1. Gabow PA: Autosomal dominant polycystic kidney disease—More than a renal disease. Am J Kidney Dis 16:403-413, 1990 2. Perrone RD: Extrarenal manifestations of ADPKD. Kidney Int 51:2022-2036, 1997 3. Bae KT, Zhu F, Chapman AB, et al: Magnetic resonance imaging evaluation of hepatic cysts in early autosomal-dominant polycystic kidney disease: The Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort. Clin J Am Soc Nephrol 1:64-69, 2006 4. Torres VE, Harris PC, Pirson Y: Autosomal dominant polycystic kidney disease. Lancet 369:1287-1301, 2007 5. Torres V: Polycystic liver disease, in Watson ML, Torres VE (eds.): Polycystic Kidney Disease. Oxford, Oxford Medical Publications, 1996, pp 500-529 6. Everson GT, Matthew RG, Taylor MR, et al: Polycystic disease of the liver. Hepatology 40:774-782, 2004 7. Alvaro D, Onori P, Alpini G, et al: Morphological and functional features of hepatic cyst epithelium in autosomal dominant polycystic kidney disease. Am J Pathol 172:321-332, 2008 8. Lee SO, Masyuk T, Splinter P, et al: MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease. J Clin Invest 118:3714-3724, 2008 9. Alvaro D, Mancino MG, Onori P, et al: Estrogens and the pathophysiology of the biliary tree. World J Gastroenterol 12:3537-3545, 2006 10. Salle´e M, Rafat C, Zahar JR, et al: Cyst infections in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 4:1183-1189, 2009

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11. Kanaan N, Goffin E, Pirson Y, et al: Carbohydrate antigen 19.9 as a diagnostic marker for hepatic cyst infection in autosomal dominant polycystic kidney disease. Am J Kidney Dis, (in press) 2010 12. Alam A, Perrone RD: Managing cyst infections in ADPKD: An old problem looking for new answers. Clin J Am Soc Nephrol 4:1154-1155, 2009 13. Chauveau D, Fakhouri F, Grunfeld JP: Liver involvement in autosomal-dominant polycystic kidney disease: therapeutic dilemma. J Am Soc Nephrol 11: 1767-1775, 2000 14. Gigot JF, Metairie S, Etienne J, et al: The surgical management of congenital liver cysts. Surg Endosc 15: 357-363, 2001 15. Arnold HL, Harrison SA: New advances in evaluation and management of patients with polycystic liver disease. Am J Gastroenterol 100:2569-2582, 2005 16. Russell RT, Pinson CW: Surgical management of polycystic liver disease. World J Gastroenterol 13: 5052-5059, 2007 17. Schnelldorfer T, Torres VE, Zakaria S, et al: Polycystic liver disease: A critical appraisal of hepatic resection, cyst fenestration, and liver transplantation. Ann Surg 250:112-118, 2009 18. Torres VE: Treatment of polycystic liver disease: One size does not fit all. Am J Kidney Dis 49:725-728, 2007 19. Davis CL, Gonwa TA, Wilkinson AH: Identification of patients best suited for combined liver-kidney transplantation: Part II. Liver Transpl 8:193-211, 2002 20. Qian Q, Du H, King BF, et al: Sirolimus reduces polycystic liver volume in ADPKD patients. J Am Soc Nephrol 19:631-638, 2008 21. Masyuk TV, Masyuk AI, Torres VE, et al: Octreotide inhibits hepatic cystogenesis in a rodent model of polycystic liver disease by reducing cholangiocyte adenosine 3’,5’-cyclic monophosphate. Gastroenterology 132:1104-1116, 2007 22. Hogan M, Masyuk T, Kim B, et al: A pilot study of long-acting octreotide in the treatment of patients with severe polycystic liver disease. Am Soc Nephrol, (in press) 2010 23. van Keimpema L, Nevens F, Vanslembrouck R, et al: Lanreotide reduces the volume of polycystic liver: A randomized, double-blind, placebo-controlled trial. Gastroenterology 137:1661-1668, 2009 24. Ishikawa I, Chikamoto E, Nakamura M, et al: High incidence of common bile duct dilatation in autosomal dominant polycystic kidney disease patients. Am J Kidney Dis 27:321-326, 1996 25. Bichet D, Peters D, Patel AJ, et al: Cardiovascular polycystins: Insights from autosomal dominant polycystic kidney disease and transgenic animal models. Trends Cardiovasc Med 16:292-298, 2006 26. Hassane S, Claij N, Lantinga-van Leeuwen IS, et al: Pathogenic sequence for dissecting aneurysm formation in a hypomorphic polycystic kidney disease 1 mouse model. Arterioscler Thromb Vasc Biol 27: 2177-2183, 2007 27. Kip SN, Hunter LW, Ren Q, et al: [Ca21]i reduction increases cellular proliferation and apoptosis in vascular smooth muscle cells: relevance to the ADPKD phenotype. Circ Res 96:873-880, 2005

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28. Qian Q, Hunter LW, Li M, et al: Pkd2 haploinsufficiency alters intracellular calcium regulation in vascular smooth muscle cells. Hum Mol Genet 12: 1875-1880, 2003 29. Pirson Y, Chauveau D, Torres V: Management of cerebral aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 13:269-276, 2002 30. Rinkel GJ: Natural history, epidemiology and screening of unruptured intracranial aneurysms. J Neuroradiol 35:99-103, 2008 31. Rossetti S, Chauveau D, Kubly V, et al: Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype. Lancet 361:2196-2201, 2003 32. de Rooij NK, Linn FH, van der Plas JA, et al: Incidence of subarachnoid haemorrhage: A systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry 78:1365-1372, 2007 33. Lozano AM, Leblanc R: Cerebral aneuvrysms and polycystic kidney disease: A critical review. Can J Neurol Sci 19:222-227, 1992 34. Schievink WI, Torres VE, Piepgras DG, et al: Saccular intracranial aneurysms in autosomal dominant polycystic kdney disease. J Am Soc Nephrol 3:88-95, 1992 35. Chauveau D, Pirson Y, Verellen-Dumoulin C, et al: Intracranial aneurysms in autosomal dominant polycystic kidney disease. Kidney Int 45:1140-1146, 1994 36. Gambhir S, O’Grady G, Koelmeyer T: Clinical lessons and risk factors from 403 fatal cases of subarachnoid haemorrhage. J Clin Neurosci 16:921-924, 2009 37. Belz MM, Fick-Brosnahan GM, Hughes RL, et al: Recurrence of intracranial aneurysms in autosomaldominant polycystic kidney disease. Kidney Int 63: 1824-1830, 2003 38. Gibbs GF, Huston J 3rd, Qian Q, et al: Follow-up of intracranial aneurysms in autosomal-dominant polycystic kidney disease. Kidney Int 65:1621-1967, 2004 39. Schrier RW, Belz MM, Johnson AM, et al: Repeat imaging for intracranial aneurysms in patients with autosomal dominant polycystic kidney disease with initially negative studies: A prospective ten-year follow-up. J Am Soc Nephrol 15:1023-1028, 2004 40. Schievink WI, Torres VE, Wiebers DO, et al: Intracranial arterial dolichoectasia in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 8: 1298-1303, 1997 41. Schievink WI, Huston J III, Torres VE, et al: Intracranial cysts in autosomal dominant polycystic kidney disease. J Neurosurg 83:1004-1007, 1995 42. Wijdicks EF, Torres VE, Schievink WI: Chronic subdural hematoma in autosomal dominant polycystic kidney disease. Am J Kidney Dis 35:40-43, 2000 43. Schievink WI, Torres VE: Spinal meningeal diverticula in autosomal dominant polycystic kidney disease. Lancet 349:1223-1224, 1997

44. Coche E, Persu A, Cosnard G, et al: Multiple thoracic paraspinal meningeal cysts in autosomal dominant polycystic kidney disease. Am J Kidney Dis 41:E8, 2003 45. Torra R, Nicolau C, Badenas C, et al: Ultrasonographic study of pancreatic cysts in autosomal dominant polycystic kidney disease. Clin Nephrol 47: 19-22, 1997 46. Lumiaho A, Ikaheimo R, Miettinen R, et al: Mitral valve prolapse and mitral regurgitation are common in patients with polycystic kidney disease type 1. Am J Kidney Dis 38:1208-1216, 2001 47. Qian Q, Hartman RP, King BF, et al: Increased occurrence of pericardial effusion in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2:1223-1227, 2007 48. Andreoni KA, Pelletier RP, Elkhammas EA, et al: Increased incidence of gastrointestinal surgical complications in renal transplant recipients with polycystic kidney disease. Transplantation 67:262-266, 1999 49. Kumar S, Adeva M, King BF, et al: Duodenal diverticulosis in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 21:3576-3578, 2006 50. Goffin E, Pirson Y: Is peritoneal dialysis a suitable renal replacement therapy in autosomal dominant polycystic kidney disease? Nat Clin Pract Nephrol 5: 122-123, 2009 51. Driscoll JA, Bhalla S, Liapis H, et al: Autosomal dominant polycystic kidney disease is associated with an increased prevalence of radiographic bronchiectasis. Chest 133:1181-1188, 2008 52. Wu J, Du H, Wang X, et al: Characterization of primary cilia in human airway smooth muscle cells. Chest 136:561-570, 2009 53. Belet U, Danaci M, Sarikaya S, et al: Prevalence of epididymal, seminal vesicle, prostate, and testicular cysts in autosomal dominant polycystic kidney disease. Urology 60:138-141, 2002 54. Torra R, Sarquella J, Calabia J, et al: Prevalence of cysts in seminal tract and abnormal semen parameters in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 3:790-793, 2008 55. Okada H, Fujioka H, Tatsumi N, et al: Assisted reproduction for infertile patients with 9 1 0 immotile spermatozoa associated with autosomal dominant polycystic kidney disease. Hum Reprod 14:110-113, 1999 56. Watnick TJ, Jin Y, Matunis E, et al: A flagellar polycystin-2 homolog required for male fertility in Drosophila. Curr Biol 13:2179-2184, 2003 57. Vora N, Perrone R, Bianchi DW: Reproductive issues for adults with autosomal dominant polycystic kidney disease. Am J Kidney Dis 51:307-318, 2008