491
Articles Phenotype Recognition Clinicians' Contributions to Molecular Genetics KENNETH D. GARDNER, Jr, MD, Albuquerque, New Mexico
Medullary cystic disease, Alport's syndrome, and autosomal dominant polycystic kidney disease are inherited renal disorders whose genetic bases are better understood because of careful clinical observation. I explore the relationships among some clinical aspects of each of these conditions, the rapidly advancing field of molecular genetics, and the ethical issues that need to be addressed before gene identification becomes too widely applied as a diagnostic tool. (Gardner KD: Phenotype recognition-Clinicians' contributions to molecular genetics. West J Med 1992 May; 156:491-494)
he advent of techniques for gene location and identification has propelled hereditary disease toward the forefront of clinical medicine. Practitioners, long frustrated by an inability to provide anything but supportive therapy, now may anticipate opportunities for improved diagnosis and care when dealing with familial disease. Nephrology is in the vanguard of specialties affected by advances in molecular genetics. Three inherited renal diseases deserve the attention of all clinicians: medullary cystic disease, Alport's syndrome, and autosomal dominant polycystic kidney disease. These conditions are among the most prevalent of all inherited disorders. They, especially the last, contribute substantially to morbidity, affecting hundreds of thousands of people worldwide, and to health care costs, obligating annual expenditures in the hundreds of millions of dollars in the United States alone. The patterns of inheritance of these diseases are now better understood because practitioners were careful earlier to delineate their distinguishing clinical features. Furthermore, these conditions illustrate the credits and debits that derive from applying molecular biology to clinical medicine. They are examples of the symbiotic relationship that must exist between practitioner and molecular geneticist if the search for any mutated gene is to succeed. As a discipline molecular genetics is rapidly expanding the number of diagnostic tests whose clinical application and interpretation will rest with providers of health care, not with laboratory scientists. Clinicians need to know of these tests and to understand their limitations. They also need to appreciate the necessity of recognizing familial disease and how important it can be to document subtle and seemingly unimportant differences in initial manifestations among affected T
persons.
Molecular geneticists rely on clinicians to discern and describe phenotypes. The three heritable renal diseases reviewed are genetically heterogeneous: multiple gene effects appear to be responsible for the phenotypic expression that characterizes each disorder. Medullary cystic disease exemplifies the way in which answers to one question in the family history evolve to suggest that multiple gene effects are present. Alport's syndrome illustrates how such clinical observation has led molecular geneticists to the identification of mutated genes. Autosomal dominant polycystic kidney disease demonstrates some of the complexities that may arise when phenotypic identification is imperfect.
Medullary Cystic Disease From the 1940s to the 1960s, a number of reports documented the cases of children and young adults who had died of renal failure of unknown cause with scarred and shrunken kidneys at autopsy. Some kidneys contained cysts in the corticomedullary and medullary regions; others did not. The disorder was recognized as a distinct entity known as medullary cystic disease (MCD) in the United States and nephronophthisis in Europe.1 In some kindreds, cases of MCD were sporadic,2 whereas in others in which siblings were affected, MCD appeared to be familial, but the issue of heritability was unsettled.3 In the mid-1960s, I encountered two families in which MCD affected members in sequential generations, a pattern of inheritance consistent with that of a dominant trait.4 The disorder
appeared in roughly half the offspring of an affected parent and did so over three or more generations. When kidneys from members of these families were examined, no differences in morphology could be detected. Significant differences were found in ages at death, ranging from the first to the fifth decades. Half of the deaths occurred during the third decade of life (Figure 1). When attention was 10
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Co0) o- u- NCo C Age at death
PA.
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Figure 1.-Ages at death of 28 persons with medullary cystic disease are shown in the histogram (adapted from Gardner4). A bell-shaped distribution is present, with the greatest number of deaths occurring between 20 and 24 years of age.
From the Department of Medicine, University of New Mexico School of Medicine, Albuquerque. Reprint requests to Kenneth D. Gardner, Jr, MD, Box 535, Graduate Medical Education, University of New Mexico School of Medicine, Albuquerque, NM 87131.
PHENOTYPE RECOGNITION
492
presumptive evidence that different gene effects operate in an inherited disorder. It now is thought that more than one gene is responsible for MCD.
ABBREVIATIONS USED IN TEXT ADPKD = autosomal dominant polycystic kidney disease MCD = medullary cystic disease
paid to the number of generations within families in which MCD appeared-one versus more than one generation-an informative pattern was found (Figure 2). When only siblings were affected, deaths occurred at younger ages than when successive generations were affected. These data support the concept that MCD is familial and can be inherited as either a recessive or a dominant trait.I With dominantly transmitted disease (Figure 3), a significant difference was found between members of the two prototype families. Deaths from MCD in one family peaked between the ages of 20 and 24 years, in contrast to the second family, which had a peak in the fourth decade.4 Geneticists recognize such differences in ages at death as
Alport's Syndrome Alport's syndrome is a rare disease but one of the most common hereditary renal diseases. Affected persons characteristically have progressive renal failure, hematuria, erythrocyte urinary casts, high-tone nerve deafness, and ocular abnormalities. At one time, the method of inheritance was unclear. A defect of an autosomal dominant gene seemed likely, but in a number of families the ratio of affected to unaffected offspring deviated from the expected 1:1 ratio.5 Furthermore, male patients with Alport's syndrome seemed to die of renal failure more frequently and at younger ages than did affected female patients. Inheritance patterns were subsequently clarified by the data presented in modified form in Figure 4.5 It was noted 7
Affected Generations
One
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Figure 2.-Ages at death from medullary cystic disease of the same 28 persons shown in Figure 1 are distributed according to generations affected. Of 11 cases from families in which the disease was restricted to a single generation, the median age at death was younger than 20 years. Of 17 cases from families in which the disease affected persons in three or more successive generations, the median age at death was older than 25 years. The difference is statistically significant (P < .05; Student's t test).
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Age at death Figure 3.-Ages at death are shown in members of two families in which medullary cystic disease affected persons in two or more successive generations (the same cases shown in the stippled bars of Figure 2). The mean age at death was 22 years in family 1 and 32 years in family 2. The difference (P < .015) is statistically significant (Student's t test) (adapted from Gardner'
4).
D CD0 D 02C 3
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Age at death
s
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Figure 4.-Mean ages at death of male members in 36 families with Alport's syndrome are depicted. Two populations are suggested by distribution of the data: families in which male members die before the age of 30 years and families in which male members die after the age of 30 years (adapted from Tishler and Rosner5).
that although men in most of these families die before the age of 30, in some families they live for four to seven decades. This pattern of death among men suggested two genetic forms of the disorder: when affected by one form, men died at a younger age than when affected by the second, when they survived to the later decades of life. On histologic examination, splitting of the glomerular basement membrane occurs in a fraction of cases from both groups.6 As with MCD, lightmicroscopic changes in the kidneys do not correlate with clinical manifestations or ages at the time of death. In further searches for affected members, concentrating on patients with chronic hematuria and a family history of chronic glomerulonephritis,7 clinical geneticists have determined that Alport's syndrome exists primarily in X-linked forms but probably also exists in autosomal dominant and recessive forms.8 Recently, techniques of chromosomal linkage analysis identified multiple different mutations at the site of a gene responsible for collagen IV production in persons with X-linked Alport's syndrome.9 Thus, this syndrome is a genetically heterogeneous renal disorder for which several mutated genes have been identified; presumably more will be found. The story is not so clear-cut for polycystic disease,
THE WESTERN JOURNAL OF MEDICINE * MAY 1992 *
156
493
* 5
perhaps because its phenotypic expression has not been defined adequately. Autosomal Dominant Polycystic Kidney Disease Autosomal dominant polycystic kidney disease (ADPKD) is a heritable renal disease for which genetic heterogeneity was not suspected until the advent of linkage analyses. Two separate chromosomal locations are probable for the mutated genes that are thought to cause the disorder. Typically, ADPKD results in enlarging cystic kidneys, progressive azotemia, and death unless renal transplantation or dialysis is done. It affects approximately 500,000 persons in the United States and is more common in the general population than Huntington's disease, sickle cell anemia, or cystic fibrosis. Autosomal dominant polycystic kidney disease accounts for approximately 10% of cases of end-stage renal disease. Until a decade ago, it was considered a monogenic disorder-that is, a one gene:one phenotype disease. Events have proved that concept to be incorrect. More recently, molecular geneticists have successfully applied a technique called restricted fragment length polymorphism analysis to clarify the genetic basis of ADPKD. This technique makes use of restriction endonucleases, enzymes that recognize specific base pair sequences along DNA molecules, to cut DNA. Pieces of DNA obtained from affected and unaffected members of the same family are compared. Differences in the patterns of the DNA pieces obtained-polymorphisms in the restricted fragment lengths of DNA-are matched to carriers of the disease. Families are compared, consistencies are sought, and results are analyzed statistically to determine the likelihood of given patterns or given pieces of DNA being associated with the disorder being investigated. In theory, a fragment of DNA that always is found among those with a given phenotype and never in those without this phenotype would contain the suspect gene. Fragments of DNA that frequently, but not always, associate with a phenotype would likely be near the causative gene but might not include it. Base pair sequences in some of these latter fragments can be used as markers of the mutated gene's presumed location. The ADPKD was the third heritable disorder-after Huntington's disease and Duchenne muscular dystrophy-to have the site of its mutated gene localized to a specific chromosome through the use of this technique, called linkage analysis.10 In 1985 the short arm of chromosome 16 was identified by these techniques as the probable locus of a mutated gene responsible for ADPKD. II At that time it seemed likely that the gene itself soon would be identified and that diagnosis of the disorder before birth or before clinical disease developed would become possible. Even the distant possibility of a cure through gene therapy could be postulated. Commercial tests for ADPKD markers became available. These early expectations were dashed in 1988. Test kits were withdrawn. Kimberling and co-workers published a compelling demonstration that ADPKD did not link to markers on chromosome 16 in one large family under their observation.12 The finding meant that in this kindred, a mutated gene at a second chromosomal location must have produced the ADPKD phenotype. In subsequent studies, it has been found that the ADPKD phenotype does not link with markers on chromosome 16 in approximately 5% and 10% of all families. Paralleling the observations in MCD and Alport's
syndrome, clinical evidence of the disease appears at significantly different ages, depending on which genotype is involved. Persons carrying the gene that is located off chromosome 16, the PKD2 gene, do not succumb to renal failure during the sixth decade of life as is described for the PKDI-associated disorder. The PKD2 carriers live into their seventh to ninth decades and often die of nonrenal causes.'3 The genetics of ADPKD is still unclear. One problem has been summarized as follows: "The discovery that mutations in more than one gene may lead to indistinguishable phenotypes has posed problems for ADPKD diagnosis that is based on linkage analysis."'4 There is evidence that two renal phenotypes may exist and that all kidneys may not be alike in ADPKD. In polycystic kidneys, cysts are filled with fluids of varied composition. 15.16 For example, the concentration of sodium in cyst fluids ranges from 1 to more than 200 mmol per liter (1 to > 200 mEq per liter). Parallel differences in concentrations of the hydrogen ion and other crystalloids led investigators to speculate that cysts arise from different segments ofthe nephron and that they contain fluids whose compositions are reminiscent of the tubules or ducts from which they arose: high sodium, low potassium, and low hydrogen concentrations in cysts arising from the proximal or permeant segment of the nephron and low sodium, high potassium, and high hydrogen concentrations in cysts arising from the distal nephron. 15 The ultrastructural characteristics of cells that line the two types of cysts are different, supporting the idea that cysts in polycystic kidneys are different and are not simply extremes of a continuum. Instead of all ADPKD kidneys containing an admixture of high- and low-sodium (permeant and impermeant; proximal and distal) cysts, some ADPKD kidneys contain exclusively high-sodium cysts (Figure 5). 16 Although 250 0 Minimum
A Maximum U Mean
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Kidne' Figure 5.-Mean and range of sodium concentrations are shown for 5 to 25 aspirated cyst fluids from 15 kidneys in persons with autosomal dominant polycystic kidney disease. Fluids from kidneys 1 to 9 had sodium concentrations more than and less than 50 mmol per liter (50 mEq/liter). In contrast, in the cysts of kidneys 10 to 15, all measured sodium concentrations were more than 100 mmol per liter (100 mEq per liter). The likelihood is
Articles Phenotype Recognition Clinicians' Contributions to Molecular Genetics KENNETH D. GARDNER, Jr, MD, Albuquerque, New Mexico
Medullary cystic disease, Alport's syndrome, and autosomal dominant polycystic kidney disease are inherited renal disorders whose genetic bases are better understood because of careful clinical observation. I explore the relationships among some clinical aspects of each of these conditions, the rapidly advancing field of molecular genetics, and the ethical issues that need to be addressed before gene identification becomes too widely applied as a diagnostic tool. (Gardner KD: Phenotype recognition-Clinicians' contributions to molecular genetics. West J Med 1992 May; 156:491-494)
he advent of techniques for gene location and identification has propelled hereditary disease toward the forefront of clinical medicine. Practitioners, long frustrated by an inability to provide anything but supportive therapy, now may anticipate opportunities for improved diagnosis and care when dealing with familial disease. Nephrology is in the vanguard of specialties affected by advances in molecular genetics. Three inherited renal diseases deserve the attention of all clinicians: medullary cystic disease, Alport's syndrome, and autosomal dominant polycystic kidney disease. These conditions are among the most prevalent of all inherited disorders. They, especially the last, contribute substantially to morbidity, affecting hundreds of thousands of people worldwide, and to health care costs, obligating annual expenditures in the hundreds of millions of dollars in the United States alone. The patterns of inheritance of these diseases are now better understood because practitioners were careful earlier to delineate their distinguishing clinical features. Furthermore, these conditions illustrate the credits and debits that derive from applying molecular biology to clinical medicine. They are examples of the symbiotic relationship that must exist between practitioner and molecular geneticist if the search for any mutated gene is to succeed. As a discipline molecular genetics is rapidly expanding the number of diagnostic tests whose clinical application and interpretation will rest with providers of health care, not with laboratory scientists. Clinicians need to know of these tests and to understand their limitations. They also need to appreciate the necessity of recognizing familial disease and how important it can be to document subtle and seemingly unimportant differences in initial manifestations among affected T
persons.
Molecular geneticists rely on clinicians to discern and describe phenotypes. The three heritable renal diseases reviewed are genetically heterogeneous: multiple gene effects appear to be responsible for the phenotypic expression that characterizes each disorder. Medullary cystic disease exemplifies the way in which answers to one question in the family history evolve to suggest that multiple gene effects are present. Alport's syndrome illustrates how such clinical observation has led molecular geneticists to the identification of mutated genes. Autosomal dominant polycystic kidney disease demonstrates some of the complexities that may arise when phenotypic identification is imperfect.
Medullary Cystic Disease From the 1940s to the 1960s, a number of reports documented the cases of children and young adults who had died of renal failure of unknown cause with scarred and shrunken kidneys at autopsy. Some kidneys contained cysts in the corticomedullary and medullary regions; others did not. The disorder was recognized as a distinct entity known as medullary cystic disease (MCD) in the United States and nephronophthisis in Europe.1 In some kindreds, cases of MCD were sporadic,2 whereas in others in which siblings were affected, MCD appeared to be familial, but the issue of heritability was unsettled.3 In the mid-1960s, I encountered two families in which MCD affected members in sequential generations, a pattern of inheritance consistent with that of a dominant trait.4 The disorder
appeared in roughly half the offspring of an affected parent and did so over three or more generations. When kidneys from members of these families were examined, no differences in morphology could be detected. Significant differences were found in ages at death, ranging from the first to the fifth decades. Half of the deaths occurred during the third decade of life (Figure 1). When attention was 10
(m)8 0 o
E
0
v
8
(
0t _ -
0
_
CIM
oU) CM
0t cro
) h
Co0) o- u- NCo C Age at death
PA.
t0 o qt el
o.
e
Figure 1.-Ages at death of 28 persons with medullary cystic disease are shown in the histogram (adapted from Gardner4). A bell-shaped distribution is present, with the greatest number of deaths occurring between 20 and 24 years of age.
From the Department of Medicine, University of New Mexico School of Medicine, Albuquerque. Reprint requests to Kenneth D. Gardner, Jr, MD, Box 535, Graduate Medical Education, University of New Mexico School of Medicine, Albuquerque, NM 87131.
PHENOTYPE RECOGNITION
492
presumptive evidence that different gene effects operate in an inherited disorder. It now is thought that more than one gene is responsible for MCD.
ABBREVIATIONS USED IN TEXT ADPKD = autosomal dominant polycystic kidney disease MCD = medullary cystic disease
paid to the number of generations within families in which MCD appeared-one versus more than one generation-an informative pattern was found (Figure 2). When only siblings were affected, deaths occurred at younger ages than when successive generations were affected. These data support the concept that MCD is familial and can be inherited as either a recessive or a dominant trait.I With dominantly transmitted disease (Figure 3), a significant difference was found between members of the two prototype families. Deaths from MCD in one family peaked between the ages of 20 and 24 years, in contrast to the second family, which had a peak in the fourth decade.4 Geneticists recognize such differences in ages at death as
Alport's Syndrome Alport's syndrome is a rare disease but one of the most common hereditary renal diseases. Affected persons characteristically have progressive renal failure, hematuria, erythrocyte urinary casts, high-tone nerve deafness, and ocular abnormalities. At one time, the method of inheritance was unclear. A defect of an autosomal dominant gene seemed likely, but in a number of families the ratio of affected to unaffected offspring deviated from the expected 1:1 ratio.5 Furthermore, male patients with Alport's syndrome seemed to die of renal failure more frequently and at younger ages than did affected female patients. Inheritance patterns were subsequently clarified by the data presented in modified form in Figure 4.5 It was noted 7
Affected Generations
One
a)
en 53 _ E42-
'a) sSuccessive
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s I
0
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-
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Figure 2.-Ages at death from medullary cystic disease of the same 28 persons shown in Figure 1 are distributed according to generations affected. Of 11 cases from families in which the disease was restricted to a single generation, the median age at death was younger than 20 years. Of 17 cases from families in which the disease affected persons in three or more successive generations, the median age at death was older than 25 years. The difference is statistically significant (P < .05; Student's t test).
6
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Age at death Figure 3.-Ages at death are shown in members of two families in which medullary cystic disease affected persons in two or more successive generations (the same cases shown in the stippled bars of Figure 2). The mean age at death was 22 years in family 1 and 32 years in family 2. The difference (P < .015) is statistically significant (Student's t test) (adapted from Gardner'
4).
D CD0 D 02C 3
Kr 0
Age at death
s
N-
Lo
N
CD
C
T-
LO
4)
CMca cas ma e at deat Mean ages of males at death
COI Le
CM
LO
Figure 4.-Mean ages at death of male members in 36 families with Alport's syndrome are depicted. Two populations are suggested by distribution of the data: families in which male members die before the age of 30 years and families in which male members die after the age of 30 years (adapted from Tishler and Rosner5).
that although men in most of these families die before the age of 30, in some families they live for four to seven decades. This pattern of death among men suggested two genetic forms of the disorder: when affected by one form, men died at a younger age than when affected by the second, when they survived to the later decades of life. On histologic examination, splitting of the glomerular basement membrane occurs in a fraction of cases from both groups.6 As with MCD, lightmicroscopic changes in the kidneys do not correlate with clinical manifestations or ages at the time of death. In further searches for affected members, concentrating on patients with chronic hematuria and a family history of chronic glomerulonephritis,7 clinical geneticists have determined that Alport's syndrome exists primarily in X-linked forms but probably also exists in autosomal dominant and recessive forms.8 Recently, techniques of chromosomal linkage analysis identified multiple different mutations at the site of a gene responsible for collagen IV production in persons with X-linked Alport's syndrome.9 Thus, this syndrome is a genetically heterogeneous renal disorder for which several mutated genes have been identified; presumably more will be found. The story is not so clear-cut for polycystic disease,
THE WESTERN JOURNAL OF MEDICINE * MAY 1992 *
156
493
* 5
perhaps because its phenotypic expression has not been defined adequately. Autosomal Dominant Polycystic Kidney Disease Autosomal dominant polycystic kidney disease (ADPKD) is a heritable renal disease for which genetic heterogeneity was not suspected until the advent of linkage analyses. Two separate chromosomal locations are probable for the mutated genes that are thought to cause the disorder. Typically, ADPKD results in enlarging cystic kidneys, progressive azotemia, and death unless renal transplantation or dialysis is done. It affects approximately 500,000 persons in the United States and is more common in the general population than Huntington's disease, sickle cell anemia, or cystic fibrosis. Autosomal dominant polycystic kidney disease accounts for approximately 10% of cases of end-stage renal disease. Until a decade ago, it was considered a monogenic disorder-that is, a one gene:one phenotype disease. Events have proved that concept to be incorrect. More recently, molecular geneticists have successfully applied a technique called restricted fragment length polymorphism analysis to clarify the genetic basis of ADPKD. This technique makes use of restriction endonucleases, enzymes that recognize specific base pair sequences along DNA molecules, to cut DNA. Pieces of DNA obtained from affected and unaffected members of the same family are compared. Differences in the patterns of the DNA pieces obtained-polymorphisms in the restricted fragment lengths of DNA-are matched to carriers of the disease. Families are compared, consistencies are sought, and results are analyzed statistically to determine the likelihood of given patterns or given pieces of DNA being associated with the disorder being investigated. In theory, a fragment of DNA that always is found among those with a given phenotype and never in those without this phenotype would contain the suspect gene. Fragments of DNA that frequently, but not always, associate with a phenotype would likely be near the causative gene but might not include it. Base pair sequences in some of these latter fragments can be used as markers of the mutated gene's presumed location. The ADPKD was the third heritable disorder-after Huntington's disease and Duchenne muscular dystrophy-to have the site of its mutated gene localized to a specific chromosome through the use of this technique, called linkage analysis.10 In 1985 the short arm of chromosome 16 was identified by these techniques as the probable locus of a mutated gene responsible for ADPKD. II At that time it seemed likely that the gene itself soon would be identified and that diagnosis of the disorder before birth or before clinical disease developed would become possible. Even the distant possibility of a cure through gene therapy could be postulated. Commercial tests for ADPKD markers became available. These early expectations were dashed in 1988. Test kits were withdrawn. Kimberling and co-workers published a compelling demonstration that ADPKD did not link to markers on chromosome 16 in one large family under their observation.12 The finding meant that in this kindred, a mutated gene at a second chromosomal location must have produced the ADPKD phenotype. In subsequent studies, it has been found that the ADPKD phenotype does not link with markers on chromosome 16 in approximately 5% and 10% of all families. Paralleling the observations in MCD and Alport's
syndrome, clinical evidence of the disease appears at significantly different ages, depending on which genotype is involved. Persons carrying the gene that is located off chromosome 16, the PKD2 gene, do not succumb to renal failure during the sixth decade of life as is described for the PKDI-associated disorder. The PKD2 carriers live into their seventh to ninth decades and often die of nonrenal causes.'3 The genetics of ADPKD is still unclear. One problem has been summarized as follows: "The discovery that mutations in more than one gene may lead to indistinguishable phenotypes has posed problems for ADPKD diagnosis that is based on linkage analysis."'4 There is evidence that two renal phenotypes may exist and that all kidneys may not be alike in ADPKD. In polycystic kidneys, cysts are filled with fluids of varied composition. 15.16 For example, the concentration of sodium in cyst fluids ranges from 1 to more than 200 mmol per liter (1 to > 200 mEq per liter). Parallel differences in concentrations of the hydrogen ion and other crystalloids led investigators to speculate that cysts arise from different segments ofthe nephron and that they contain fluids whose compositions are reminiscent of the tubules or ducts from which they arose: high sodium, low potassium, and low hydrogen concentrations in cysts arising from the proximal or permeant segment of the nephron and low sodium, high potassium, and high hydrogen concentrations in cysts arising from the distal nephron. 15 The ultrastructural characteristics of cells that line the two types of cysts are different, supporting the idea that cysts in polycystic kidneys are different and are not simply extremes of a continuum. Instead of all ADPKD kidneys containing an admixture of high- and low-sodium (permeant and impermeant; proximal and distal) cysts, some ADPKD kidneys contain exclusively high-sodium cysts (Figure 5). 16 Although 250 0 Minimum
A Maximum U Mean
^ 200 c 150 75 E E E 100 .2 'o 0 c" 50
0
1
!
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2
.
41
3
4
. .
4i , i
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5
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Kidne' Figure 5.-Mean and range of sodium concentrations are shown for 5 to 25 aspirated cyst fluids from 15 kidneys in persons with autosomal dominant polycystic kidney disease. Fluids from kidneys 1 to 9 had sodium concentrations more than and less than 50 mmol per liter (50 mEq/liter). In contrast, in the cysts of kidneys 10 to 15, all measured sodium concentrations were more than 100 mmol per liter (100 mEq per liter). The likelihood is
