Extrarenal manifestations of autosomal dominant polycystic kidney disease

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Extrarenal Manifestations of Autosomal Dominant Polycystic Kidney Disease Vicente E. Torres, MD

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UTOSOMAL DOMINANT polycystic kidney disease is a systemic disorder with cystic manifestations in the kidneys, liver, pancreas, seminal vesicles, and meninges; its noncystic manifestations affect mostly the vascular, cardiac, and connective tissues. The underlying genetic mechanisms are complex, heterogeneous, and incompletely understood. A two-hit tumor suppressor model of focal cyst formation is suggested by the clonal origin of the cysts, and because most PKD1 and PKD2 germline mutations are inactivating. Additional support for a two-hit hypothesis is the loss of heterozygosity in 20% to 30% of renal and hepatic cysts, the lack or very low rate of cyst formation in heterozygotes Pkd1⫹/⫺ and Pkd2⫹/⫺ knock-out mice, and the development of more severe cystic disease in compound heterozygotes Pkd2 ⫺/WS25 mice (WS25 is a hypermutable allele). Other genetic mechanisms may also play a role in the pathogenesis of ADPKD.1,2 Liver cysts are the most common extrarenal manifestation in patients with both PKD1 and PKD2 mutations. The severity of polycystic liver disease parallels that of PKD but exceptions to this rule are common. One genetically distinct form of autosomal dominant polycystic liver disease without kidney involvement exists. In the general population, liver cysts are found in 2% of individuals 40 to 70 years old and in 6% of those older than 70. Liver cysts are usually solitary; exceptionally, there are three or more. On the other hand, patients with ADPKD have a prevalence of liver cysts of 20% in the third decade of life that approaches 75% after the sixth decade. One-fourth of the patients with ADPKD

do not develop liver cysts. Liver cysts develop at a younger age in women; polycystic liver disease is more severe in women who have had multiple pregnancies than in those who have never been pregnant. The size of liver cysts in polycystic liver disease increases after menopause in women who receive estrogen replacement therapy, suggesting an important effect of estrogens on the development of polycystic liver disease.3 Liver cysts are usually asymptomatic and never cause liver failure. Symptoms, when they occur, are caused by the mass effect of the cysts, the development of complications, or rare associations of polycystic liver disease. Mass effects include abdominal distension and pain, early satiety, heartburn, and dyspnea. Symptoms can also be caused by extrinsic compression of the inferior vena cava (IVC), hepatic veins, or bile ducts by large or by many small- or mediumsized hepatic cysts. Treatment includes avoidance of estrogens and use of H2 blockers or proton pump inhibitors for symptomatic relief. Somatostatin analogues and estrogen antagonists have not been beneficial. Severe symptoms may require percutaneous aspiration and sclerosis, laparoscopic fenestration, combined hepatic resection and cyst fenestration, or liver transplantation. Any of these interventions should be tailored to individual patients.3 Cyst aspiration and sclerosis with alcohol or minocyline is the treatment of choice for symptoms caused by one or a small number of dominant cysts. Before instillation of the sclerosing agent, contrast media is injected into the cyst to rule out communication with the bile ducts. The procedure has minor complications. It has a

American Journal of Kidney Diseases, Vol 34, No 6 (December), 1999: pp xlv-xlviii

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VICENTE E. TORRES

Vicente E. Torres, MD Professor of Medicine Chair, Division of Nephrology Mayo Medical School Rochester, MN

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HE BALEARIC archipelago in the western Mediterranean has three main islands, the biggest of which, Majorca, is home to Palma, the capital of this province of Spain. Majorca is noted for its beauty, mild climate, and majolica products. Vicente Torres was born in Palma and received all his education through the college there. Understandably, he went to medical school in Barcelona, almost a warm stone throw away. Why he chose to pursue the rest of his training in Rochester, Minnesota, can only be explained by man’s relentless pursuit of excellence. An honor medical student, Torres received his medical degree Magna Cum Laude from the famous University of Barcelona, where he began his internal medicine training. In 1972, he became a research fellow in nephrology at the Mayo Graduate School

success rate (70% after a single treatment and an additional 20% after repeated treatment) that is inversely correlated with the size of the cyst(s). There is less experience with laparoscopic fenestration of hepatic cysts; the procedure is complicated by transient ascites in 40% of the patients, and the results are often short-lived. Thus, laparoscopic cyst fenestration is indicated only for the treatment of dominant cysts as an alternative to percutaneous sclerosis. Neither percutaneous sclerosis nor laparoscopic fenestration is helpful in patients with polycystic livers with many smalland medium-sized cysts. In most cases, part of the liver is spared allowing treatment with combined hepatic resection and cyst fenestration. Surgery and recovery from the procedure can be difficult, with complications such as transient ascites and bile leaks; the perioperative mortality is 2.5%. Only specialized centers and experienced surgeons should perform this procedure. This surgery has good long-term results in subjects with severe polycystic liver disease and is preferable to liver transplantation, which is re-

of Medicine in Rochester and completed further training in both internal medicine and nephrology. Torres was a National Kidney Foundation international fellow at the Mayo Medical School in 1973 and 1974. An astute person convinced the young Dr. Torres to join the faculty at Mayo, and the recruitment has paid off handsomely. Torres has become one of the leading world experts in polycystic diseases, particularly those grouped under autosomal dominant polycystic kidney disease. The extrarenal manifestations of this genetic disturbance are the subject of the accompanying article. Torres has also made significant contributions to the literature of inherited renal neoplasms, reflux nephropathy, and interstitial nephropathies. A frequent member of National Institutes of Health scientific evaluation committees, he serves on the editorial boards of Kidney and Kidney International. Sought after as an expert reviewer, he has reviewed for the American Journal of Kidney Diseases, the American Journal of Physiology, and the New England Journal of Medicine, among others. Torres and his wife Anna, a Catalonian, have two sons. One son is an organic chemist, the other a chef. Pleasant, quiet, and cerebral, Torres is a cinema buff. He and his wife particularly enjoy the dark humor and outrageous sensibility of filmmaker Pedro Almodo´var, another Spanish talent. —Manuel Marti´nez-Maldonado, MD

served for rare patients with severely affected liver parenchyma or with hepatic insufficiency.4 The cysts of polycystic liver disease can obstruct hepatic venous outflow by compression of the hepatic veins at their confluence with the intrahepatic IVC, leading to ascites. Magnetic resonance imaging (MRI) with spin-echo and gradient-echo images is useful in making the diagnosis. Venous catheterization for pressure measurements and venography may be needed to make the diagnosis or to detect superimposed thrombosis. Surgical decompression of the hepatic veins and IVC has a good outcome, whereas the outcome of patients with superimposed thrombosis is often poor.5 Polycystic liver disease may be complicated by hepatic cyst hemorrhage, infection, or rupture. Dilatation of bile ducts, congenital hepatic fibrosis, and cholangiocarcinoma are less frequently associated with ADPKD. Hemorrhagic cysts may cause fever and masquerade as cholecystitis or cyst infection. Infected cysts cause localized pain or tenderness, fever, leukocytosis,

EXTRARENAL MANIFESTATIONS OF ADPKD

elevated sedimentation rate, and high serum alkaline phosphatase. Computed tomography (CT) scan and MRI are helpful but have low specificity, whereas 111In white blood cell scans are more specific, but not always conclusive. The treatment includes percutaneous drainage and antibiotics that have good cyst penetration. Ruptured hepatic cysts cause acute abdomen and ascites. Dilation of biliary ducts may be associated with recurrent episodes of cholangitis. Congenital hepatic fibrosis is very rare in ADPKD and, contrary to the cystic disease, is not vertically transmitted.3 The most important noncystic manifestations of ADPKD include intracranial arterial aneurysms and dolichoectasias, dilatation of the aortic root, dissections of the thoracic aorta and cervicocephalic arteries, and cardiac abnormalities that affect not only the cardiac valves, but also the coronary arteries and, possibly, the myocardium. Common to these lesions is a disruption of the connective tissue framework responsible for the mechanical properties of these tissues. In the case of intracranial aneurysms and dolichoectasias, the internal elastic lamina, which is responsible for most of the tensile strength of the wall of the intracranial arteries, is abnormal. Dissections of the thoracic aorta and cervicocephalic arteries are the result of abnormal myoelastic lamellar structure of the arterial wall. PKD mutations may be responsible because polycystin 1 and polycystin 2 are strongly expressed in the medial myocytes of the elastic and large distributive arteries, as well as in the cardiac myocytes and valvular myofibroblasts.6 Cerebral aneurysmal rupture is the most feared extrarenal complication of ADPKD and leads to thunderclap headache, neck stiffness, and often loss of consciousness; mortality is approximately 50%. The prevalence of intracranial aneurysms in ADPKD depends on the age of the patient and the family history of intracranial aneurysms. Current screening procedures with either magnetic resonance angiography or spiral CT can detect virtually all aneurysms measuring 3 mm or more in diameter, with no significant risk. Presymptomatic screening with these techniques detects intracranial aneurysms in 6% of ADPKD patients that do not have a family history and in 21% who do have a family history of intracranial aneurysms. Most of these aneurysms

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are less than 6 mm in diameter. The benefit of the intervention depends on the morbidity and mortality from rupture or from surgery and on the rate of formation of de novo aneurysms. Aneurysmal rupture has a 50% mortality, surgical major morbidity and mortality range from 2% to 10%, and the rate of de novo aneurysm formation is approximately 2% per year. Therefore, the probability of rupture becomes the key factor in determining the benefit from elective surgery. A number of studies have suggested that the risk of rupture of intracranial aneurysms depends on the size and type of aneurysm (symptomatic versus asymptomatic, incidental versus concurrent). The risk of rupture of a truly incidental aneurysm less than 10 mm in diameter is much less than 1% per year. Therefore, the benefit from screening and elective surgery for these aneurysms would be marginal at best. A large international study involving 2,621 patients in 53 participating centers has shown that the likelihood of rupture of truly incidental aneurysms measuring less than 10 mm in diameter was exceedingly low but increased with the size of the aneurysm. On the other hand, the likelihood of rupture of concurrent aneurysms was higher and not dependent on size.7 Extrapolation of these results based on aneurysms in the general population to patients with ADPKD may be incorrect. However, in a small follow-up study of small (⬍6 mm) unruptured intracranial aneurysms in patients with ADPKD, no significant growth or rupture has been observed over 7 years.8 There is also evidence for familial clustering of thoracic aortic dissections in ADPKD. Until more information becomes available, it is reasonable to screen first-degree relatives of patients with this complication using either echocardiography or MRI. If aortic root dilation is found, yearly follow-up and strict blood pressure control with beta blockade should be recommended. When the diameter reaches 55 mm to 60 mm, aortic root replacement is indicated. In summary, it is now obvious that ADPKD is a systemic disorder with many extrarenal manifestations. Awareness of these manifestations is essential for the management of these patients, and their study may provide important clues for the understanding of the function of the PKD genes and polycystins.

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REFERENCES 1. Germino GG: Autosomal dominant polycystic kidney disease: A two-hit model. Hosp Pract 32:81-82, 91-92, 1997 2. Wu G, D’Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, Maeda Y, Le TC, Hou H, Jr, Kucherlapati R, Edelmann W, Somlo S: Somatic inactivation of PKD2 results in polycystic kidney disease. Cell 93:177-188, 1998 3. Torres VE: Polycystic liver disease, in Watson ML, Torres VE (eds): Polycystic Kidney Disease. Oxford, England, Oxford University Press, 1996, pp 500-529 4. Que F, Nagorney DM, Gross JB, Jr, Torres VE: Liver resection and cyst fenestration in the treatment of severe polycystic liver disease. Gastroenterology 108:487-494, 1995 5. Torres VE, Rastogi S, King BF, Stanson AW, Gross JB

Jr, Nagorney DM: Hepatic venous outflow obstruction in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 5:1186-1192, 1994 6. Griffin MD, Torres VE, Grande JP, Kumar R: Vascular expression of polycystin. J Am Soc Nephrol 8:616-626, 1997 7. International Study of Unruptured Intracranial Aneurysms Investigators: Unruptured intracranial aneurysms— Risk of rupture and risks of surgical intervention. New Engl J Med 339:1725-1733, 1998 8. Huston J III, Torres VE, Wiebers DO, Schievink WI: Follow-up of intracranial aneurysms in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 7:2135-2141, 1996