IF The National Kidney Foundation
Alllerican Journal of Kidney Diseases
The Official Journal of
Vol XVI, No 5, November 1990
IN-DEPTH REVIEW
Autosomal Dominant Polycystic Kidney DiseaseMore Than a Renal Disease Patricia A. Gabow, MD • Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease, affecting a half million Americans. The clinical phenotype can result from at least two different gene defects. One gene that can cause ADPKD has been located on the short arm of chromosome 16. This discovery has made possible new methods for diagnosing the disorder in gene carriers prior to the development of renal cysts. Although renal cysts are clearly an important manifestation of the gene defect, other systemic manifestations are both common and clinically important. Cardiac valvular lesions, intracranial aneurysms, hepatic cysts, and diverticula are included in the array of systemic manifestations. Moreover, renal cysts are only one of a myriad of renal manifestations. Although ADPKD was long considered an adult cystic disease, it is also a common cause of childhood cystic disease and must be considered in the differential diagnosis in that setting. © 1990 by the National Kidney Foundation, Inc. INDEX WORDS: Polycystic kidney disease.
U
NTIL RECENTLY, Dalgaard's classic monograph, 1 which supplied considerable information regarding the inheritance and clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), served as the major source for nephrologists' understanding of this disorder. However, it is well to remember that this treatise emerged before the availability of modern genetic methodologies, newer imaging techniques, widespread use of antihypertensive therapy, and newer antibiotics, and that Dalgaard's study focused on end-stage disease, with one third of the described patients being diagnosed at autopsy. Nonetheless, nephrologists had little else to rely on given the general lack of interest in the disorder for the next three decades. However, new interest has arisen in recent years, producing insights into the genetics, the cellular alterations producing cyst growth and development, and the clinical manifestations of ADPKD. This disorder now promises to be the first kidney disease to be understood from the gene to the patient.
GENETICS
ADPKD is the most common genetic disease and affects 500,000 Americans. The hereditary nature of ADPKD has long been appreciated and Dalgaard's family studies clearly substantiated the autosomal dominant inheritance of the malady. 1 In autosomal dominant transmission, only affected individuals can pass the gene to their offspring; there are no skipped generations and each offspring of an affected subject has a 50% chance of From the Denver General Hospital and School of Medicine, University of Colorado Health Sciences Center, Denver, CO. Supported by Grant No.5 POI DK34039, Human Polycystic Kidney Disease (PKD), awarded by the Department of Health and Human Services, Public Health Service, National Institute of Diabetes and Digestive and Kidney Diseases, and the Clinical Research Center; and by Grant No. MORR-00051 from the General Clinical Research Centers Research Program of the Division of Research Resources, National Institutes of Health. Address reprint requests to Patricia Gabow, MD, Box C283, University of Colorado, 4200 E Ninth Ave, Denver, CO 80262. © 1990 by the National Kidney Foundation, Inc. 0272-6386/90/1605-0001$3.00/0
American Journal of Kidney Diseases, Vol XVI, No 5 (November), 1990: pp 403-413
403
404
inheriting the gene and hence the disease. As in any genetic disease, random cases can occur from spontaneous mutations. Since only 60% of individuals with ADPKD have a positive family history of the disease, it was suspected that spontaneous mutations contributed significantly to the ADPKD patient population. However, a negative family history most commonly reflects failure of diagnosis in the parent, rather than absence of the disease. This failure to diagnose ADPKD is substantiated by the Olmsted County experience in which half the cases of ADPKD in that population were diagnosed at autopsy.2 This low rate of diagnosis reflects the oligosymptomatic nature of the disorder in many patients. Patient information from our institution based on family studies suggests that the spontaneous mutation rate may be less than 10%, not the 40% suggested by family history information. Therefore, physicians should study parents of an affected subject before concluding that an affected individual represents a spontaneous mutation . It is also important to remember that even in the circumstance of a true spontaneous mutation, affected individuals still pass the gene on to their offspring with the same frequency. In 1985, a major breakthrough occurred in the genetics of ADPKD. Reeders et al, using gene linkage techniques, localized a gene for ADPKD to the short arm of chromosome 16. 3 With gene linkage, the gene itself was not found, but DNA markers near the gene were identified. With this technique, the form of the marker associated with the gene must be established for each family. Also in order to identify which form of the marker is linked with the ADPKD gene in that family, the unaffected and affected parent must have different markers and there must be at least two affected people in the family of the individual whose gene status is in question (Fig 1). Currently, the presence of the same marker in both parents is rarely a problem because of the polymorphic nature of the markers and the number of markers now available in the region of the gene. This discovery oflinkage markers with the ADPKD gene offered a method to alter the approach to diagnosis of the disorder and provided investigators with a tool to examine the phenotypic evolution of the disease in an individual with the ADPKD gene over time. Before the availability of gene linkage, an individual at risk for ADPKD (ie, an individual with an affected
PATRICIA A. GABOW
aa
II
III
ab
ab
aa
aa
ab
Fig 1. Pedigree of an ADPKD family. The linkage types are displayed. The affected male in the first generation is dead and his type has been deduced. In this family, the b type is segregating with the PKD gene. Thus, in the III generation, it can be deduced that the aa offspring (or fetus) has a 95% chance of being unaffected and the ab offspring (or fetus) has a 95% chance of being affected. Families can be uninformative in a variety of ways. For example, if the female in generation I or the unaffected spouse in generation II had been ab, the likelihood of carrying the ADPKD gene could not be established (affected subject marked by cross line). (Reprinted with permission. 5)
parent) could only be diagnosed as having the ADPKD gene when detectable renal cysts were visualized with imaging techniques; before cysts were detectable, a person could only be counseled about their 50% risk status. However, with this discovery and the availability of flanking markers for the ADPKD gene region, the likelihood of gene carrier status can be changed from 50/50 to 99/1 (Fig 1).4.5 The limitations of this method are its expense, which currently is about $2,000 per family in commercial genetics laboratories, and the requirement that other family members must agree to be tested to establish the diagnosis in one individual (Fig 1). When the gene on chromosome 16 itself is localized, as it appears will occur shortly, 6 only the individual to be tested will need to be involved, thus removing one disadvantage of the technique. The availability of this method of diagnosis has raised the question of which at-risk individuals should be tested with this method. The issue has recently been addressed in a National Kidney Foundation sponsored special report published in this journal. 5 Essentially, gene linkage analysis should be performed only as part of overall care; counseling should be provided to the patient. Ran-
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
dom, nonclinically directed testing should be avoided. The test may be particularly helpful in defining the gene status of young potential transplant donors and individuals whose family planning would be strongly influenced by knowledge of their gene status. Since the methodology can be used in prenatal testing, 7 individuals with a fetus at 50% risk for ADPKD should be informed of the availability of the test for prenatal diagnosis. With the advent of this technology, the issue of the preferred diagnostic method for ADPKD arose. The answer depends on whether the patient is symptomatic, the physician's need to define the severity and location of structural lesions, and the certainty with which an at-risk individual desires to know their gene status (Table 1). Only imaging techniques will provide information on the anatomic basis for symptoms and define the structural lesions. Moreover, imaging studies that demonstrate the classic pattern of ADPKD in an at-risk individual provide the patient with information on their gene status with essentially 100% assurance; that is to say, an individual in an ADPKD family who has the classic ultrasonographic findings has ADPKD. Computed axial tomography (CT) is slightly more sensitive for detecting small renal cysts than is ultrasonography,8.9 but the additional Table 1.
Methods of Diagnosis in ADPKD
Method
Limitation
Renal concentrating ability in algorithm Ultrasonography
Untested in children No anatomic information May miss 2% to 6% of patients with cysts Operator- and reader-dependent Will not identify precystic gene carriers May miss rare patient with small cysts Radiation and contrast exposure Difficult to perform in children Expense Will not identify precystic gene carriers Requires other family members' participation Requires physician understand interpretation of results Expense Provides no anatomic information of organs involved
CT scan
Gene linkage analysis
405
expense, contrast, and radiation exposure and its difficulty of performance in young children make ultrasonography the imaging test of choice in screening for ADPKD. In the absence of diagnostic imaging studies, gene linkage analysis will provide the most exact estimate of risk. Although gene linkage testing is now available, there is little information regarding patients' attitudes about its use. Patient attitudes toward gene testing have been examined by Sujanksy et al. 10 An overwhelming majority (97 %) of at -risk subjects state that they would use the test to define their own status. Similarly, a majority of affected individuals (88 %) would use the test to define the status in their offspring. Sixty-five percent would use the test to define the gene status of a fetus, but only 4 % of affected individuals stated that they would abort a fetus for ADPKD.1O This is substantially different from the attitudes of parents with children at risk for cystic fibrosis 11 and from individuals affected with Huntington's disease. 12 The difference may be due to the relatively more benign nature of ADPKD. This information underscores the importance of informed counseling in the use of this type of testing, particularly when applied to prenatal diagnosis. The genetics of ADPKD revealed a startling quirk when Kimberling et al discovered the first family whose gene for ADPKD was not found on chromosome 16. \3 Subsequently other similar families have been identified. 14-16 This genetic heterogeneity could explain some of the interfamily variability in this disease that gave rise to Dalgaard's impression that the disease's natural history was similar within a given family. The gene located on chromosome 16 has been called ADPKDl and the other gene on a yet to be identified chromosome has been called ADPKD2 or non-ADPKD1; the latter nomenclature is meant to convey the possibility that there may be even more than two ADPKD genes. ADPKD1 appears to account for more than 90% of all ADPKD in the Caucasian populationY However, it remains to be determined if this distribution between the genotypes is the same in all racial groups. Thus, ADPKD, which appeared clinically to be one disease, actually results from at least two different genetic defects. Given that the gene products are very likely to be different, it is reasonable to expect that the clinical manifestations will also be different. In fact, definition of the phenotypes of
406
PATRICIA A. GABOW
the different gene types will be of considerable importance to the clinician in counseling .
Table 3.
Cardiovascular Abnormalities in ADPKD
CLINICAL MANIFESTATIONS OF ADPKD
Group
In many ways, the name polycystic kidney disease has been an unfortunate choice, most importantly because it has inappropriately assigned the disorder as a renal disease. Clearly the disorder is a systemic disease with clinically important involvement of the cardiovascular system, the gastrointestinal tract, and the genitourinary system (Table 2) . Only by viewing the disorder as a systemic disease will clinicians appropriately manage their patients.
ADPKD subject Family member Control
Cardiovascular Manifestations of ADPKD
In 1984, Leier et al reported a retrospective analysis of cardiac valvular abnormalities in 62 ADPKD patients. IS Eleven individuals had cardiac valve abnormalities, six of which were determined at autopsy examination. The aortic valve was most frequently involved. IS Two of the 11 patients required aortic valve replacement. IS More recently, Hossack et al prospectively delineated the frequency of cardiac symptoms, signs, and valvular abnormalities, defined by echocardiographic and Doppler techniques, in 100 control subjects, 130 ADPKD family members without detectable renal cysts by ultrasonography, and 163 affected individuals. 19 Twenty-six percent of the ADPKD subjects had mitral valve prolapse (MVP), compared with 14% of the unaffected family members and 2% of the control subjects {Table 3).19 In addition, other valves were'" also affected, albeit less frequently (Table 3). The occurrence of MVP in ADPKD is associated with a symptom complex common in primary MVP; the ADPKD patients in this study had a significantly greater frequency of complaints of palpitations, atypical chest pain, and Table 2.
Extrarenal Manifestations of ADPKD Cardiovascular abnormalities Cardiac valvular abnormalities Intracranial aneurysms Gastrointestinal abnormalities Hepatic cysts Colonic diverticula Genitourinary abnormalities Ovarian cysts (?) Musculoskeletal abnormalities Gout (?) Hernias
Mitral Valve Aortic Valve Tricuspid Valve Prolapse Incompetence Prolapse (%)
(%)
(%)
26
8 3
6 2 0
14
2
regurgitant murmur and clicks than did unaffected family members or control subjects. 19 This information raises four questions for the clinician: (1) What is the significance of MVP in a member of an ADPKD family member who does not have renal cysts; (2) Which ADPKD patients should have examination for cardiac valvular abnormality; (3) Which ADPKD patients with MVP should receive subacute bacterial endocarditis (SBE) prophylaxis; (4) Are there clinically important consequences of cardiac valvular involvement in ADPKD? Unfortunately, there are few, if any, substantiated answers to these questions. However, the presence of MVP in a family member who does not have renal cysts should raise the suspicion of the diagnosis, as it may well be that this manifestation of the gene can precede renal cysts in some patients. Moreover, the diagnosis should be considered in ADPKD patients who have symptoms or signs compatible with MVP. However, it is important to note that 38 % of individuals with ADPKD who had MVP did not have either a murmur or a click on physical examination by a cardiologist. 19 Although there is debate regarding SBE prophylaxis in primary MVP, it seems reasonable to apply the general guidelines available in primary MVP to ADPKD. 20 The natural history of cardiac valvular abnormalities and particularly of MVP in ADPKD is important, but unstudied. Leier's study clearly indicates that at least some ADPKD patients with cardiac valvular lesions require valve replacement. Moreover, it is reasonable to assume that MVP in ADPKD would have the same or even more complications than primary MVP. The most recent longitudinal study of primary MVP in 300 subjects demonstrated that one third of all subjects experienced one or more of 118 major complications, including cardiac arrhythmia (85 patients), sudden death (two patients), endocarditis (18 patients), mitral valve surgery (28 patients), and cerebral vascular accidents (II patients) during a mean follow-up of 6.1 years.21 Other studies have demonstrated that male patients over 50 years of
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
age are most at-risk for these complications. 22 Thus, clinicians caring for ADPKD patients with MVP should be cognizant of these possible complications. Perhaps an even more common and equally important cardiac manifestation in ADPKD patients is left ventricular hypertrophy (LVH). Autopsy studies demonstrated a 49 % occurrence,1.23 and echocardiographic studies an 18 % incidence of LVH in ADPKD.19 Presumably this LVH is the result of the high frequency of hypertension and this is likely not to be specifically related to ADPKD. Intracranial Aneurysms
The other major vascular abnormality in ADPKD is intracranial aneurysms. The reported frequency of this association is highly variable, from 0% to 41 % in differing series. 24-27 These reported differences in frequency may reflect differences in methods of diagnosis and the population studied. Preliminary data from this institution in a prospective study suggest a 10% frequency of occurrence. 28 However, another retrospective study in our population has suggested different occurrence rates of aneurysms in different families. 29 This latter point is of great interest, as this could theoretically reflect different ADPKD genes in given families producing different phenotypes. Carotid angiography appears to remain the gold standard for diagnosing intracranial aneurysms; however, there is some information that demonstrates the utility of dynamic CT in identifying clinically significant aneurysms in the general population. 30 Previous decision analysis methodology suggested that screening for aneurysm in all ADPKD patients using carotid angiography was not indicated. 31 Such decision analysis should be reapplied using risk factors as they are identified, such as family history, and CT scan as the method of diagnosis. In addition to ADPKD patients' predilection for intracranial aneurysms, the high frequency of hypertension may place them at risk for hypertensive cerebral hemorrhage as well. 32 Gastrointestinal Manifestations of ADPKD
The most common gastrointestinal manifestation of ADPKD is hepatic cyst formation. 1.33,34 Just as renal cysts appear to be the end result of altered renal tubular proliferation and secretion, hepatic cysts appear to be the end result of these processes
407
in biliary epithelia. Although data from cyst puncture suggest a biliary origin of hepatic cyst epithelia,35-37 this origin of hepatic cysts remains to be definitively established. Although the gene defect responsible for renal cyst formation undoubtedly is responsible for hepatic cyst formation, the processes are not entirely concordant. Hepatic cysts occur in patients at least a decade later than renal cysts and appear extremely unusual before puberty.33,34 The mean age of ADPKD subjects with renal cysts and no hepatic cysts is 32.5 years, compared with a mean age of 42.3 years of ADPKD patients with both hepatic and renal cysts. 33 In addition, massive hepatic cystic disease appears to be predominantly a disorder of women,38-40 raising the question of the role of female steroid hormones in hepatic cystogenesis in ADPKD. This massive hepatomegaly can be debilitating in some women and has required percutaneous cyst decompression, surgical decompression, and partial hepatectomy in some circumstances. 39 As patients with ADPKD are surviving longer, it appears that sequelae from hepatic cysts may be more frequent than previously appreciated. In one series, 10% of ADPKD patients with end-stage renal disease (ESRD) died from complications of hepatic cysts, most importantly cyst infections and malignancy. 41 In 1980, Scheff et al reported on the association of colonic diverticula and ADPKD.42 In comparison to the 38 % and 32 % frequency of diverticula in age-matched control subjects and non-ADPKD dialysis patients, respectively, ADPKD dialysis patients had an 83 % occurrence of diverticula. Moreover, in that study, four of 10 ADPKD patients with colonic diverticula suffered a major complication of perforation, which did not occur in any patient in the other two groupS.42 In addition, review of the literature shows 53 patients who developed a diverticular complication while receiving renal replacement therapy; 15 or 28% of these patients had ADPKD.43-47 Twenty-seven of these 53 patients, including 13 of 15 ADPKD patients, died. Since ADPKD patients represent approximately 10 % of the dialysis population, ADPKD patients were significantly disproportionately represented in both the group that developed the complication of diverticula and the group that died (P
Alllerican Journal of Kidney Diseases
The Official Journal of
Vol XVI, No 5, November 1990
IN-DEPTH REVIEW
Autosomal Dominant Polycystic Kidney DiseaseMore Than a Renal Disease Patricia A. Gabow, MD • Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disease, affecting a half million Americans. The clinical phenotype can result from at least two different gene defects. One gene that can cause ADPKD has been located on the short arm of chromosome 16. This discovery has made possible new methods for diagnosing the disorder in gene carriers prior to the development of renal cysts. Although renal cysts are clearly an important manifestation of the gene defect, other systemic manifestations are both common and clinically important. Cardiac valvular lesions, intracranial aneurysms, hepatic cysts, and diverticula are included in the array of systemic manifestations. Moreover, renal cysts are only one of a myriad of renal manifestations. Although ADPKD was long considered an adult cystic disease, it is also a common cause of childhood cystic disease and must be considered in the differential diagnosis in that setting. © 1990 by the National Kidney Foundation, Inc. INDEX WORDS: Polycystic kidney disease.
U
NTIL RECENTLY, Dalgaard's classic monograph, 1 which supplied considerable information regarding the inheritance and clinical manifestations of autosomal dominant polycystic kidney disease (ADPKD), served as the major source for nephrologists' understanding of this disorder. However, it is well to remember that this treatise emerged before the availability of modern genetic methodologies, newer imaging techniques, widespread use of antihypertensive therapy, and newer antibiotics, and that Dalgaard's study focused on end-stage disease, with one third of the described patients being diagnosed at autopsy. Nonetheless, nephrologists had little else to rely on given the general lack of interest in the disorder for the next three decades. However, new interest has arisen in recent years, producing insights into the genetics, the cellular alterations producing cyst growth and development, and the clinical manifestations of ADPKD. This disorder now promises to be the first kidney disease to be understood from the gene to the patient.
GENETICS
ADPKD is the most common genetic disease and affects 500,000 Americans. The hereditary nature of ADPKD has long been appreciated and Dalgaard's family studies clearly substantiated the autosomal dominant inheritance of the malady. 1 In autosomal dominant transmission, only affected individuals can pass the gene to their offspring; there are no skipped generations and each offspring of an affected subject has a 50% chance of From the Denver General Hospital and School of Medicine, University of Colorado Health Sciences Center, Denver, CO. Supported by Grant No.5 POI DK34039, Human Polycystic Kidney Disease (PKD), awarded by the Department of Health and Human Services, Public Health Service, National Institute of Diabetes and Digestive and Kidney Diseases, and the Clinical Research Center; and by Grant No. MORR-00051 from the General Clinical Research Centers Research Program of the Division of Research Resources, National Institutes of Health. Address reprint requests to Patricia Gabow, MD, Box C283, University of Colorado, 4200 E Ninth Ave, Denver, CO 80262. © 1990 by the National Kidney Foundation, Inc. 0272-6386/90/1605-0001$3.00/0
American Journal of Kidney Diseases, Vol XVI, No 5 (November), 1990: pp 403-413
403
404
inheriting the gene and hence the disease. As in any genetic disease, random cases can occur from spontaneous mutations. Since only 60% of individuals with ADPKD have a positive family history of the disease, it was suspected that spontaneous mutations contributed significantly to the ADPKD patient population. However, a negative family history most commonly reflects failure of diagnosis in the parent, rather than absence of the disease. This failure to diagnose ADPKD is substantiated by the Olmsted County experience in which half the cases of ADPKD in that population were diagnosed at autopsy.2 This low rate of diagnosis reflects the oligosymptomatic nature of the disorder in many patients. Patient information from our institution based on family studies suggests that the spontaneous mutation rate may be less than 10%, not the 40% suggested by family history information. Therefore, physicians should study parents of an affected subject before concluding that an affected individual represents a spontaneous mutation . It is also important to remember that even in the circumstance of a true spontaneous mutation, affected individuals still pass the gene on to their offspring with the same frequency. In 1985, a major breakthrough occurred in the genetics of ADPKD. Reeders et al, using gene linkage techniques, localized a gene for ADPKD to the short arm of chromosome 16. 3 With gene linkage, the gene itself was not found, but DNA markers near the gene were identified. With this technique, the form of the marker associated with the gene must be established for each family. Also in order to identify which form of the marker is linked with the ADPKD gene in that family, the unaffected and affected parent must have different markers and there must be at least two affected people in the family of the individual whose gene status is in question (Fig 1). Currently, the presence of the same marker in both parents is rarely a problem because of the polymorphic nature of the markers and the number of markers now available in the region of the gene. This discovery oflinkage markers with the ADPKD gene offered a method to alter the approach to diagnosis of the disorder and provided investigators with a tool to examine the phenotypic evolution of the disease in an individual with the ADPKD gene over time. Before the availability of gene linkage, an individual at risk for ADPKD (ie, an individual with an affected
PATRICIA A. GABOW
aa
II
III
ab
ab
aa
aa
ab
Fig 1. Pedigree of an ADPKD family. The linkage types are displayed. The affected male in the first generation is dead and his type has been deduced. In this family, the b type is segregating with the PKD gene. Thus, in the III generation, it can be deduced that the aa offspring (or fetus) has a 95% chance of being unaffected and the ab offspring (or fetus) has a 95% chance of being affected. Families can be uninformative in a variety of ways. For example, if the female in generation I or the unaffected spouse in generation II had been ab, the likelihood of carrying the ADPKD gene could not be established (affected subject marked by cross line). (Reprinted with permission. 5)
parent) could only be diagnosed as having the ADPKD gene when detectable renal cysts were visualized with imaging techniques; before cysts were detectable, a person could only be counseled about their 50% risk status. However, with this discovery and the availability of flanking markers for the ADPKD gene region, the likelihood of gene carrier status can be changed from 50/50 to 99/1 (Fig 1).4.5 The limitations of this method are its expense, which currently is about $2,000 per family in commercial genetics laboratories, and the requirement that other family members must agree to be tested to establish the diagnosis in one individual (Fig 1). When the gene on chromosome 16 itself is localized, as it appears will occur shortly, 6 only the individual to be tested will need to be involved, thus removing one disadvantage of the technique. The availability of this method of diagnosis has raised the question of which at-risk individuals should be tested with this method. The issue has recently been addressed in a National Kidney Foundation sponsored special report published in this journal. 5 Essentially, gene linkage analysis should be performed only as part of overall care; counseling should be provided to the patient. Ran-
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
dom, nonclinically directed testing should be avoided. The test may be particularly helpful in defining the gene status of young potential transplant donors and individuals whose family planning would be strongly influenced by knowledge of their gene status. Since the methodology can be used in prenatal testing, 7 individuals with a fetus at 50% risk for ADPKD should be informed of the availability of the test for prenatal diagnosis. With the advent of this technology, the issue of the preferred diagnostic method for ADPKD arose. The answer depends on whether the patient is symptomatic, the physician's need to define the severity and location of structural lesions, and the certainty with which an at-risk individual desires to know their gene status (Table 1). Only imaging techniques will provide information on the anatomic basis for symptoms and define the structural lesions. Moreover, imaging studies that demonstrate the classic pattern of ADPKD in an at-risk individual provide the patient with information on their gene status with essentially 100% assurance; that is to say, an individual in an ADPKD family who has the classic ultrasonographic findings has ADPKD. Computed axial tomography (CT) is slightly more sensitive for detecting small renal cysts than is ultrasonography,8.9 but the additional Table 1.
Methods of Diagnosis in ADPKD
Method
Limitation
Renal concentrating ability in algorithm Ultrasonography
Untested in children No anatomic information May miss 2% to 6% of patients with cysts Operator- and reader-dependent Will not identify precystic gene carriers May miss rare patient with small cysts Radiation and contrast exposure Difficult to perform in children Expense Will not identify precystic gene carriers Requires other family members' participation Requires physician understand interpretation of results Expense Provides no anatomic information of organs involved
CT scan
Gene linkage analysis
405
expense, contrast, and radiation exposure and its difficulty of performance in young children make ultrasonography the imaging test of choice in screening for ADPKD. In the absence of diagnostic imaging studies, gene linkage analysis will provide the most exact estimate of risk. Although gene linkage testing is now available, there is little information regarding patients' attitudes about its use. Patient attitudes toward gene testing have been examined by Sujanksy et al. 10 An overwhelming majority (97 %) of at -risk subjects state that they would use the test to define their own status. Similarly, a majority of affected individuals (88 %) would use the test to define the status in their offspring. Sixty-five percent would use the test to define the gene status of a fetus, but only 4 % of affected individuals stated that they would abort a fetus for ADPKD.1O This is substantially different from the attitudes of parents with children at risk for cystic fibrosis 11 and from individuals affected with Huntington's disease. 12 The difference may be due to the relatively more benign nature of ADPKD. This information underscores the importance of informed counseling in the use of this type of testing, particularly when applied to prenatal diagnosis. The genetics of ADPKD revealed a startling quirk when Kimberling et al discovered the first family whose gene for ADPKD was not found on chromosome 16. \3 Subsequently other similar families have been identified. 14-16 This genetic heterogeneity could explain some of the interfamily variability in this disease that gave rise to Dalgaard's impression that the disease's natural history was similar within a given family. The gene located on chromosome 16 has been called ADPKDl and the other gene on a yet to be identified chromosome has been called ADPKD2 or non-ADPKD1; the latter nomenclature is meant to convey the possibility that there may be even more than two ADPKD genes. ADPKD1 appears to account for more than 90% of all ADPKD in the Caucasian populationY However, it remains to be determined if this distribution between the genotypes is the same in all racial groups. Thus, ADPKD, which appeared clinically to be one disease, actually results from at least two different genetic defects. Given that the gene products are very likely to be different, it is reasonable to expect that the clinical manifestations will also be different. In fact, definition of the phenotypes of
406
PATRICIA A. GABOW
the different gene types will be of considerable importance to the clinician in counseling .
Table 3.
Cardiovascular Abnormalities in ADPKD
CLINICAL MANIFESTATIONS OF ADPKD
Group
In many ways, the name polycystic kidney disease has been an unfortunate choice, most importantly because it has inappropriately assigned the disorder as a renal disease. Clearly the disorder is a systemic disease with clinically important involvement of the cardiovascular system, the gastrointestinal tract, and the genitourinary system (Table 2) . Only by viewing the disorder as a systemic disease will clinicians appropriately manage their patients.
ADPKD subject Family member Control
Cardiovascular Manifestations of ADPKD
In 1984, Leier et al reported a retrospective analysis of cardiac valvular abnormalities in 62 ADPKD patients. IS Eleven individuals had cardiac valve abnormalities, six of which were determined at autopsy examination. The aortic valve was most frequently involved. IS Two of the 11 patients required aortic valve replacement. IS More recently, Hossack et al prospectively delineated the frequency of cardiac symptoms, signs, and valvular abnormalities, defined by echocardiographic and Doppler techniques, in 100 control subjects, 130 ADPKD family members without detectable renal cysts by ultrasonography, and 163 affected individuals. 19 Twenty-six percent of the ADPKD subjects had mitral valve prolapse (MVP), compared with 14% of the unaffected family members and 2% of the control subjects {Table 3).19 In addition, other valves were'" also affected, albeit less frequently (Table 3). The occurrence of MVP in ADPKD is associated with a symptom complex common in primary MVP; the ADPKD patients in this study had a significantly greater frequency of complaints of palpitations, atypical chest pain, and Table 2.
Extrarenal Manifestations of ADPKD Cardiovascular abnormalities Cardiac valvular abnormalities Intracranial aneurysms Gastrointestinal abnormalities Hepatic cysts Colonic diverticula Genitourinary abnormalities Ovarian cysts (?) Musculoskeletal abnormalities Gout (?) Hernias
Mitral Valve Aortic Valve Tricuspid Valve Prolapse Incompetence Prolapse (%)
(%)
(%)
26
8 3
6 2 0
14
2
regurgitant murmur and clicks than did unaffected family members or control subjects. 19 This information raises four questions for the clinician: (1) What is the significance of MVP in a member of an ADPKD family member who does not have renal cysts; (2) Which ADPKD patients should have examination for cardiac valvular abnormality; (3) Which ADPKD patients with MVP should receive subacute bacterial endocarditis (SBE) prophylaxis; (4) Are there clinically important consequences of cardiac valvular involvement in ADPKD? Unfortunately, there are few, if any, substantiated answers to these questions. However, the presence of MVP in a family member who does not have renal cysts should raise the suspicion of the diagnosis, as it may well be that this manifestation of the gene can precede renal cysts in some patients. Moreover, the diagnosis should be considered in ADPKD patients who have symptoms or signs compatible with MVP. However, it is important to note that 38 % of individuals with ADPKD who had MVP did not have either a murmur or a click on physical examination by a cardiologist. 19 Although there is debate regarding SBE prophylaxis in primary MVP, it seems reasonable to apply the general guidelines available in primary MVP to ADPKD. 20 The natural history of cardiac valvular abnormalities and particularly of MVP in ADPKD is important, but unstudied. Leier's study clearly indicates that at least some ADPKD patients with cardiac valvular lesions require valve replacement. Moreover, it is reasonable to assume that MVP in ADPKD would have the same or even more complications than primary MVP. The most recent longitudinal study of primary MVP in 300 subjects demonstrated that one third of all subjects experienced one or more of 118 major complications, including cardiac arrhythmia (85 patients), sudden death (two patients), endocarditis (18 patients), mitral valve surgery (28 patients), and cerebral vascular accidents (II patients) during a mean follow-up of 6.1 years.21 Other studies have demonstrated that male patients over 50 years of
AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
age are most at-risk for these complications. 22 Thus, clinicians caring for ADPKD patients with MVP should be cognizant of these possible complications. Perhaps an even more common and equally important cardiac manifestation in ADPKD patients is left ventricular hypertrophy (LVH). Autopsy studies demonstrated a 49 % occurrence,1.23 and echocardiographic studies an 18 % incidence of LVH in ADPKD.19 Presumably this LVH is the result of the high frequency of hypertension and this is likely not to be specifically related to ADPKD. Intracranial Aneurysms
The other major vascular abnormality in ADPKD is intracranial aneurysms. The reported frequency of this association is highly variable, from 0% to 41 % in differing series. 24-27 These reported differences in frequency may reflect differences in methods of diagnosis and the population studied. Preliminary data from this institution in a prospective study suggest a 10% frequency of occurrence. 28 However, another retrospective study in our population has suggested different occurrence rates of aneurysms in different families. 29 This latter point is of great interest, as this could theoretically reflect different ADPKD genes in given families producing different phenotypes. Carotid angiography appears to remain the gold standard for diagnosing intracranial aneurysms; however, there is some information that demonstrates the utility of dynamic CT in identifying clinically significant aneurysms in the general population. 30 Previous decision analysis methodology suggested that screening for aneurysm in all ADPKD patients using carotid angiography was not indicated. 31 Such decision analysis should be reapplied using risk factors as they are identified, such as family history, and CT scan as the method of diagnosis. In addition to ADPKD patients' predilection for intracranial aneurysms, the high frequency of hypertension may place them at risk for hypertensive cerebral hemorrhage as well. 32 Gastrointestinal Manifestations of ADPKD
The most common gastrointestinal manifestation of ADPKD is hepatic cyst formation. 1.33,34 Just as renal cysts appear to be the end result of altered renal tubular proliferation and secretion, hepatic cysts appear to be the end result of these processes
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in biliary epithelia. Although data from cyst puncture suggest a biliary origin of hepatic cyst epithelia,35-37 this origin of hepatic cysts remains to be definitively established. Although the gene defect responsible for renal cyst formation undoubtedly is responsible for hepatic cyst formation, the processes are not entirely concordant. Hepatic cysts occur in patients at least a decade later than renal cysts and appear extremely unusual before puberty.33,34 The mean age of ADPKD subjects with renal cysts and no hepatic cysts is 32.5 years, compared with a mean age of 42.3 years of ADPKD patients with both hepatic and renal cysts. 33 In addition, massive hepatic cystic disease appears to be predominantly a disorder of women,38-40 raising the question of the role of female steroid hormones in hepatic cystogenesis in ADPKD. This massive hepatomegaly can be debilitating in some women and has required percutaneous cyst decompression, surgical decompression, and partial hepatectomy in some circumstances. 39 As patients with ADPKD are surviving longer, it appears that sequelae from hepatic cysts may be more frequent than previously appreciated. In one series, 10% of ADPKD patients with end-stage renal disease (ESRD) died from complications of hepatic cysts, most importantly cyst infections and malignancy. 41 In 1980, Scheff et al reported on the association of colonic diverticula and ADPKD.42 In comparison to the 38 % and 32 % frequency of diverticula in age-matched control subjects and non-ADPKD dialysis patients, respectively, ADPKD dialysis patients had an 83 % occurrence of diverticula. Moreover, in that study, four of 10 ADPKD patients with colonic diverticula suffered a major complication of perforation, which did not occur in any patient in the other two groupS.42 In addition, review of the literature shows 53 patients who developed a diverticular complication while receiving renal replacement therapy; 15 or 28% of these patients had ADPKD.43-47 Twenty-seven of these 53 patients, including 13 of 15 ADPKD patients, died. Since ADPKD patients represent approximately 10 % of the dialysis population, ADPKD patients were significantly disproportionately represented in both the group that developed the complication of diverticula and the group that died (P
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