Epidemiology of Adult Polycystic Kidney Disease, Olmsted County, Minnesota: 1935–1980

Epidemiology of Adult Polycystic Kidney Disease, Olmsted County, Minnesota: 1935-1980 Carmen Garcia Iglesias, M.D., Vicente E. Torres, M.D., Kenneth P. Offord, M.S., Keith E. Holley, M.D., C. Mary Beard, R.N., M.P.H., and Leonard T. Kurland, M.D., Dr.P.H. Between January 1, 1935 and December 31 , 1980, adult polycystic kidney disease (APKD) was diagnosed in 40 residents of Olmsted County, Minnesota, resulting in an age- and sex-adjusted annual incidence rate of 1.38/ 100,000 person-years. In addition , 16 cases were detected at autopsy, increasing the rate to 2.06. It is estimated that 16 additional cases would have been discovered had all deaths come to autopsy, resulting in a rate of 2.75, or approximately twice the incidence rate of cases diagnosed during life . Because of improve-

S

INCE THE INITIAL description by Lejars in 1888,1 polycystic kidney disease has been the subject of numerous reports . 2 Polycystic kidney disease diagnosed in adulthood (APKD) is generally regarded as an autosomal dominant disorder with high penetrance . Knowledge of the demographic features of this illness are derived from reports of autopsies and extensive series of hospitalized patients. Many autopsy series lack strict diagnostic criteria 3- s and neither autopsies nor patient series can be related to delineated populations. Because of this , the published populationbased analysis by Dalgaard in 1956 9 has been the sole source of incidence and trend data . Dalgaard compared the incidence and course of APKD in the population of Copenhagen during two time periods, 1920-1934 and 1935-1953 . Differences observed between these two periods were explained by improvements in the social conditions and diagnostic techniques. Further and more dramatic advances in diagnostic methods that have occurred since 1953 might have resulted in earlier and more frequent diagnoses of the disease or associated From the Department of M edical Statistics and Epidemiology, the Division of Nephrology, and the Deparrment of Anatomic Pathology, Mayo Clinic and Foundation , Rochester, Minn . Dr. Iglesias was a Special Proj ects Associate in the Department of Medical Statistics and Epidemiology at Mayo Clinic at the time of this research, which was supported in part by Grant No. AM 30582, National Institutes of H ealth, Bethesda, Md. Address reprint requests to V icente E. Torres, M. D. , Division of Nephrology, Mayo Clinic, Rochester, MN 55905. © 1983 by the National Kidney Founda rioll . In c. 0272-6386/83/060630-0 7$02 .0010 630

ments in medical care and diagnostic techniques , APKD has been diagnosed earlier and more frequently in the recent decades. This , along with therapeutic advances, explains the improvement in kidney and patient survival for the patients diagnosed during 1956-1980, as compared to those diagnosed during 1935-1955. Normotension at diagnosis tended to be associated with better kidney and/or patient survival. Cardiovascular disease was the leading cause of death.

pathology. Similarly, improvement in treatment modalities, such as antihypertensive and antibiotic therapies, might also have significantly altered the course and increased survival and , thereby, enhanced the chance of diagnosis during life. The objective of the present study is to describe the incidence, clinical course , associated pathology, and outcome of APKD during the period 1935- 1980, in the population of Olmsted County, Minnesota, utilizing the Rochester epidemiology facilities centered at the Mayo Clinic.

BACKGROUND The feasibility of identifying essentially all diagnosed cases of a given disorder over several decades has led to numerous studies on incidence , long-term trends, and outcome of more than 100 diseases and syndromes in the population of the city Rochester and Olmsted County, Minnesota, which is 98 % white and predominantly of northern European extraction . 10 This is the result of an unusual set of circumstances : (1) The local populatio'n (currently 92 ,000 in Olmsted County) is relatively stable and almost exclusively utilizes the local health care facilities for its medical problems. (2) Most medical care is provided by the Mayo Clinic and its affiliated hospitals, the Olmsted Medical Group, and the Olmsted Community Hospital. The diagnoses from these and other sources in adjacent counties are routinely entered into a population-based centralized index. (3) The records-linkage and medical indexing system at Mayo Clinic , developed early in this century and automated for record retrievals in 1935 with American Journal of Kidney Diseases, Vol. II, No . 6, May 1983

ADULT POLYCYSTIC RENAL DISEASE UPDATED

the use of Hollerith punch cards, assures the identification of almost all local persons in whom a given disorder has been diagnosed. Diagnoses made at the Mayo Clinic and the Olmsted Medical Group , their affiliated hospitals and laboratories , and on house calls are indexed from the entries on the master sheet of each patient's record. During the period studied, more than 50% of all deaths in Olmsted County residents have come to autopsy. Details on the organization and procedures used for case identification and methods of analysis utilized for studies in the Rochester Epidemiology Program Project are presented elsewhere. to MATERIALS AND METHODS The medical records described above for Olmsted County residents with clinical or postmortem diagnoses of " polycystic kidney disease," " congenital kidney cysts ," and "multicystic kidney" in the years 1935 through 1980 were identified, retrieved , and reviewed for evidence of APKD. The medical records with the diagnosis of "solitary renal cyst" were also screened; a representative third of these records were reviewed and no cases were found among them. Only those cases fulfilling the diagnostic criteria below and having resided within the county for at least one year prior to the initial diagnosis of APKD were included. Anyone moving to Rochester to facilitate diagnosis or treatment of symptomatic disease was exeluded .

Diagnostic Criteria Clinical diagnoses were based on definite radiographic findings (excretory urography, angiography, and computed tomography), ultrasound, or surgical exploration. Autopsy diagnoses were accepted if the cysts were bilateral , with diffuse and homogeneous involvement of the renal cortex and medulla but without parenchymal dysplasia or urinary tract obstruction . Cases that did not meet these criteria were rejected even if there was involvement of the renal parenchyma by numerous cysts. Eight infants with polycystic renal disease but without evidence of renal dysplasia or urinary tract obstruction were also excluded, as the clinical and morphologic features were consistent with the diagnosis of polycystic kidney disease of the infantile type.

Review of Clinical and Autopsy Records The clinical records of the patients included in the study were reviewed, and clinical manifestations seen during the course of the disease, association with extrarenal pathology, and causes of death were recorded. The autopsy records of the patients in this study were also reviewed. In addition, gross and microscopic examination of the preserved kidneys and hepatic tissue was again performed. Information regarding evidence of extrarenal cysts, cardiovascular disease , diverticulosis, hepatic pathology, and neoplasms was recorded. Special effort was made to identify the parents, siblings, and descendants of the patients in the study. Medical records of these relatives were reviewed, and information was sought from next-of-kin and physicians concerning other identified relatives.

631

Incidence Incidence refers to the first diagnostic episode in a person 's life, and the incidence rate for a given study period is the ratio of the number of persons in a population experiencing such episodes to the number of person-years for the population during the period under study. Three different incidence rates for APKD have been defined, according to the mode of diagnosis. Incidence rate A ineludes symptomatic cases diagnosed during life, as well as those detected during family screening. Incidence rate B includes, in addition to the cases diagnosed during life, those first discovered at autopsy. For these cases we have used the date of death as the date of the first diagnostic episode. Because the autopsy rate is less than 100 percent, we have also estimated the additional number of cases that would have been detected had all deaths of Olmsted County residents been autopsied. Thus incidence rate C includes, in addition to the cases diagnosed during life and at autopsy, those that we estimate would have been diagnosed had an autopsy been performed. This estimation was obtained in the following manner: The number of deaths and autopsies by age and sex for the 13-year period of 1964-1976 was projected onto the 46-year study period 1935-1980 by mUltiplying the number for each age- and sex-group by 46/ 13. Having already abstracted cases first diagnosed at autopsy in the period 1935-1980, we then were able to find the age- and sex-specific rate of first diagnosis of APKD at autopsy. We then multiplied these rates by the age- and sex-specific number of deaths for Olmsted County residents in the period 1935-1980 to obtain estimates of the age- and sex -specific total number of cases first diagnosed at autopsy, given that all deaths had been autopsied. Incidence rates were adjusted to the 1970 US white population. Adjusted incidence rates may be thought of simply as a weighted average of the observed rates, where the weights sum to unity. For sex-specific, age-adjusted rates, the proportions in the appropriate age group , combining males and females , of the 1970 U.S. white population were used as weights. For age- and sex-adjusted rates, the proportions in the respective age and sex groups were used as weights. The age and sex adjustment facilitates the comparison of the incidence from different studies in that it imposes a common age and sex composition on the overall age- and sex-adjusted incidence rate.

Survival Analysis Estimation of both kidney and patient survival were performed by the method of Kaplan and Meier. II Expected patient survival is based on persons of like age and sex from the population in the west north central region of the United States. It considers death from all causes and is specific to the age, sex, and calendar year of birth of cases in the sample. Patients diagnosed by family screening or at autopsy were excluded from this analysis. End points for kidney survival were serum creatinine of 10 mg/dL , plasma urea of 200 mg/dL , onset of dialysis , or renal transplantation . The effect of different factors on kidney or patient survival was assessed using the log-rank test." Factors studied included age, blood group , time period, blood pressure, proteinuria, and initial renal function. All P values reported are two-tailed. The level of significance was taken to be 0.05.

632

IGLESIAS ET AL Table 1.

Age Group

Distribution of APKD Patients According to Mode of Detection, Age Group, and Sex Female

Sx

FS

0-9 (Total)

0

0

10-29 (Total)

8

30-49 (Total)

6

Grand Total

EA

Sx

FS

0

0

0

0

(0) 4

0

4

0

0

11

0

0

0

0

4

0

7

0

0

12

8

8

0 0

0

17

0

0

4

2

11

14

16

16

(18) 5

0 (11 )

6

19

0

5

7

0

0

(13)

(25) 8

(36)

EA

(18)

2

0

OA (0)

(7) 5

5

0

0

(12) 15

FS

(11 ) 2

0

Sx

0

(4) 0

EA

(5)

(7) 0

Total OA

(0)

(13)

50-69 (Total) 70+ (Total)

Male OA

8

34

6

(36)

(72)

Key: symptomatic (Sx), family screen (FS), observed at autopsy (OA), estimated at autopsy (EA).

RESULTS

Fifty-six Olmsted County residents who were diagnosed with APKD between 1935 and 1980 met our diagnostic criteria and were included in this study. In 34 cases, the diagnosis was made during the evaluation of clinical manifestations of the disease. In six cases, the diagnosis was obtained during the investigation of relatives of patients known to have adult polycystic kidney disease (family screen). In 16 patients, the diagnosis was made at the time of autopsy. Had all deaths in Olmsted County been autopsied, it is estimated that 16 additional autopsy cases would have been discovered. The distribution of the patients with APKD included in this study, according to the mode of detection, age-group, and sex, is shown in Table 1.

APKD diagnosed during life had alpha 1 antitrypsin deficiency (ZZ phenotype). Two patients also had radiologic evidence of medullary sponge kidney. In some patients diagnosed by family screen, clinical manifestations of the disease, especially hypertension and proteinuria, developed after the time of the diagnosis. Thirteen of the 40 patients diagnosed during life have died; the causes of death of these patients, as well as those diagnosed at autopsy, are shown by mode of diagnosis in Table 3 for the two time periods. Cardiovascular disease was the most frequent cause. In six patients the cause of death was directly related to a malignancy; in three, to a lymphoma. Uremia was a frequent cause during the early period, but it ceased to be a significant cause

Review of Clinical and Autopsy Records

The ages of the patients at the time of the diagnosis are shown in Fig. 1. On the average, the patients diagnosed by family screen were younger than those with a clinical diagnosis, whereas the patients diagnosed at autopsy were older. The clinical manifestations of the disease by mode of diagnosis are shown in Table 2. Although less commonly than in the symptomatic cases diagnosed during life, a positive family history was noted in 50 percent of the patients diagnosed at autopsy. The clinical spectrum of the disease appeared to be quite similar in both groups of patients. One of the 34 symptomatic patients with

.

90 80 70 III

'ijj 0

c:

60

0> II!

50

-.;

40

~

30

'6

<

20

••••

....

•••

I I

.1.

•

·1·

X II

I

10 0

Clinical diagnosis

Autopsy diagnosis

Diagnosis by family screen

Fig. 1. Age at diagnosis by mode of diagnosis (1935-1980).

ADULT POLYCYSTIC RENAL DISEASE UPDATED

Table 2.

633

Clinical Manifestations of APKD at any Time up to Completion of the Study, by Mode of Diagnosis Symptomatic Cases

Fam ily Screening Cases

26/34 (76%) 32/34 (94%)

6/6 (100%) 1/6(17%)

8/16 (50%) 11/16 (69%)

32/34 21/34 15/34 13/34 24/34 15/34

(94% ) (62%) (44%) (38%) (71%) (44%)

3/6 (50%) 1/6(17%) 0/6 (0) 0/6 (0) 4/6 (67%) 1/6 (17%)

11/16 (69%) 5/16 (31%) 1/16(6%) 8/16 (50%) 13/16 (81%) 3/16 (19%)

5/34 3/34 6/34 2/15 7/12"

(15%) (9%) (18%) (13%) (58%)

0/6 (0) 0/6 (0) 0/6 (0)

(N; 34)

Positive family history Abdominal/flank pain HypertenSion Diastolic > 90 mm Hg Diastolic> 100 mm Hg Gross hematuria Microhematuria only Proteinuria Urinary tract infection Angina pectorislmyocardial infarction Cerebrovascular accident Gout Diaphragmatic hernia Diverticulosis

Autopsy Cases

(N; 6)

(N; 16)

4/16 (25%) 9/16 (56%) 1/16(6%) 2/9 (22%) 7/9 (78%)

" Two patients had episodes of diverticulitis with colonic perforation .

of death after the advent of successful dialysis techniques. A total of 20 patients, including the 16 patients with the initial diagnosis at postmortem, had an autopsy performed . The autopsy findings are shown in Table 4. As expected , intracranial aneurysms and extrarenal cysts were frequently observed . Arteriosclerotic vascular disease and colonic diverticulosis were noted very frequently, but the significance of these observations is open to question because of the advanced age (70 years ± 19 SO) of these patients at the time of the autopsy.

adjusted annual incidence rate A (symptomatic plus family screen cases) was 1.38 per 100,000 person-years , whereas the annual incidence rate C (cases diagnosed during life plus observed and estimated autopsy cases) was 2.75 per 100,000 person-years, indicating that only 50 % of the paTable 4.

Autopsy Findings in Patients with APKD Mild Moderate Severe Incidencet

Intracranial aneurysm

3/16

(19)" Cysts Liver

11/20

(55)

Incidence

Pancreas

2120

The incidence rates of APKO in Olmsted County are shown in Table 5. The age- and sex-

Spleen

(10) 1120 (5%)

Table 3.

Causes of Death of Patients with APKD 1935-1957

1 4 0 2

All causes

8

4

1

7

3

1

o

o

1

1

o 2

o

o

o

6

5

10

4

12

4

20/20

Cerebral

6

8

2

16/16

Aortic

3

11

6

20/20

(100)

1958-1980

Clinical Autopsy Clinical Autopsy Diagnosis Diagnosis Diagnosis Diagnosis Total Cardiovascular death Malignancy Uremia Infection Other

Arteriosclerotic vascular disease Coronary

13" 6 4 4

2 29

" Includes four myocardial infarction, four cerebrovascular accidents, two subarachnoid hemorrhages, two pulmonary embolisms , and one ruptured aortic aneurysm .

(100) (100) Aortic aneurysm Thoracic

2/20

(10) Abdominal

3/20

(15) Diverticulosis

8/20

(40) "Examination of the brain was excluded in 4 of the 20 autopsies. tPercentages are given in parentheses.

634

IGLESIAS ET AL

Table 5.

Annual Incidence Rates per 100,000 Population of AKPD from Clinical and Autopsy Diagnoses

Age Group 0-9 10-29 30-49 50-69 70+ Total Age-adjusted' Age- and sex-adjusted'

Rate C (N = 72) Female Male Total

Rate B (N = 56) Total Female Male

Rate A (N = 40) Total Male Female 0 2.30 1.89 0.44 0

0 1.12 3 .14 1.99 0

0 1.76 2.50 1.16 0

0 2.49 1.89 1.31 5.31

0 1.12 3 .14 2.99 9 .58

0 1.86 2.50 2.09 7.01

0 2.46 1.93 1.75 12.65

0 1.13 3.16 3.48 20.70

0 1.85 2.53 2.56 15.86

1.33 1.33

1.47 1.46

1.40 1.40 1.38

1.87 1.88

2.06 2.31

1.96 2.07 2.06

2.40 2.46

2 .66 3.16

2.52 2.76 2.75

'Adjusted to the 1970 U.S. white population.

tients with APKD were clinically diagnosed during their lifetimes. The rates by sex show a slight preponderance for males. The rate for those clinically diagnosed was nil among those less than to years and greater than or equal to 70 . The rates were fairly unifor~ between ages to and 69 , with a suggestion of the highest rates between ages 30 and 49 years. The effect of the autopsied cases is a dramatic increase in the oldest age group and a slight effect on the group 50-69 years. Incidence rate B (cases diagnosed during life plus observed autopsy cases) was calculated for two periods of time, 1935-1955 and 1956-1980, and was compared to the values calculated from the data published by Dalgaard 9 for the population of Co-

penhagen for the periods 1920-1934 and 19351953 (Table 6). The age- and sex-adjusted incidences in Olmsted County were higher, particularly in the more recent study period. More diagnoses of APKD at an early age (less than 30 years) , especially in females , were made in Olmsted County than in Copenhagen. In addition, more diagnoses (in this case, autopsy diagnoses) were made in Olmsted County at advanced ages (greater than or equal to 70 years) . The incidence of APKD in the United States can be estimated through the extrapolation of the results in Olmsted County to the total U.S. population of 220,000,000, on the assumption that the rate in Olmsted County is representative of the na-

Table 6. Annual Incidence Rate B per 100,000 Population of APKD in Olmsted County Versus Copenhagen'

Copenhagen

Olmsted County

Age Group 0-9 10-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75+ Age-adjusted' sexAgeand adjusted'

1935-1957

1935-1953

1920-1934 F

M

F

M

0 0 .20 0 0 .64 0 .54 1.22 1.10 1.28 2.00 1.44 1.28 0.50 0 .66

0 0 0.20 0 0.90 1.22 0.54 2.84 1.76 1.36 1.16 0.74 0

0 .61

0.58

0 0 0.38 0.24 0.94 1.32 2.24 1.58 1.84 1.90 1.72 1.28 0 3.02 0.84

0 0 0.16 0.28 0 .68 1.54 2.22 2.28 1.00 3.08 1.18 1.44 1 .12 2.98 0 .77

0 .60

'Adjusted to the 1970 U.S . white population.

0 .80

1958-1980 M

F

F

M

0

0

0

0

2.62

0 .64

2 .41

1.38

2.07

0 .74

1.78

4.63

o

2.46

2.12

3.35

14.19

4.31

1.52

12.69

2.32

1.14

1.73

3.02

1.79

2.29

ADULT POLYCYSTIC RENAL DISEASE UPDATED

635

1.0

... :!l?!') ,.

lL.'t,

0.8

~

(21)

'.I,••• !!.~).. ,

._-,

,

0 .6

0

~

: (6) ..... :

""- -,:

:0 111 .c Q..

.

(11)

,: ...... ,

.

,

(7)--:(4)--' 0 .4

: ....... J ................ ..................

(2)·,

(1)

, ,

o

o

10

5

15

20

25

30

35

Kidney survival (n=34)

~---i; )-------ili-

0.2

Fig. 2. Actuarial kidney and patient survival among symptomatic cases of APKD (19351980).

(1)

Observed patient survival (n=34)

40

Years from diagnosis

tional rate. In the absence of any other populationbased data , this seems to be a reasonable approach to the effort to obtain such estimates. This estimate can be provided based on the incidence rates A and C in Table 5. On this basis , we would roughly expect new cases annually among the U.S. popula-

tion as follows: diagnosed during life , 3,000; and total (assuming 100 % autopsy) , 6,000. Survivorship

The overall kidney and patient survival curves for the 34 symptomatic cases are shown in Fig. 2.

1.0 ......

.. -... (12)

~

................... :

(7)

~

i

0 .8

:

(2)

(1)

. . . . .......,.,. ...... JIL. . . . . . . .

0 .6

1956·80 (n=24)

0.4

0.2

~

:0

'"

(2)

(1)

(1)

0

.c 1.0 0 ~

)

......

~

, ......................... ~...... ..... Expected· 1935·55 ( 12)

0 .8

(7)

1

,......

~........

:

0.6

Expected· 1956·80

............. 1956·80 (3) (n=24)

0.4

(4)

(4)

(4)

0 .2 (2)

Fig. 3. Actuarial kidney (upper panel) and patient (lower panel) survival among symptomatic cases of APKD (1935-1955 versus 1956-1980).

1935·55 (n=10)

0 0

5

10

15

20

Years from diagnosis

25

(2)

30

1935·55 (n=10)

636

IGLESIAS ET AL

The ten-year survival rate of patients with APKD was significantly less than expected. Neither patient nor kidney survival was found to be associated with the sex or blood group. As shown in Fig. 3, there was borderline significantly (p = 0.058) better kidney survival among the patients diagnosed more recently (1956-1980) than among those diagnosed between 1935 and 1955 (at ten years after diagnosis , 92 % versus 48 %, respectively). There was also nonsignificant improvement in patient survival (80% versus 40% at 10 years). The departure from the expected survival at ten years, however, was significantly greater for the earlier time period (p = 0.006). Since age and patient survival are generally related, patient survival from the time of diagnosis was examined and was found to be significantly better in the patients diagnosed at a young age (less than 35 years) than in those diagnosed later (greater than or equal to 35 years). Even after adjusting for the difference in expected patient survival at ten years, the difference between age

groups was still significant, with the departure below the expected lO-year survival being greater in the older group (p = 0.037) . The effect of age at the time of diagnosis on kidney survival did not achieve statistical significance . The presence of hypertension at the time of the diagnosis of APKD had an adverse and significant (p = 0 .037) influence on kidney survival (Fig. 4). Although very suggestive (82 .5% versus 53.5% survival at ten years), the difference in patient survival did not reach statistical significance, undoubtedly due to the small number of patients. The presence of impaired renal function (Cr ~ 1.3 mg/dL, or if Cr not measured, plasma urea ~ 45 mg/dL) or proteinuria (protein grade 2 +) at the time of the diagnosis of APKD also had borderline (p = 0 .064 and p = 0.088, respectively) adverse influence on kidney survival, but no particular detectable influence on patient survival (Fig. 5) . In addition, the departure from the expected patient survival was not detectably different for any of these groups, regardless of the presence of pro-

(7) (5) (4) ....... .........................................

10

0 .8 : (2)

(1)

.......... .... ...... .. .. .. ..•

Normotensive

0 .6

(n= 12)

04

0.2

Hypertensive (n=22)

(3)

~

:0 I'll .0 0

0::

0 1.0

········••·•·····•..................... ~~~ected • Normotensive

......................

0 .8

(3)

0 .6

Expected Hypertensive

L..-_ _ _ _.., (2)

0.4

(3)

(1)

(21

Normotensive (n=12)

0 .2

Hypertensive (n=22) 0

0

5

10

15

20

Years from diagnosis

25

30

Fig. 4. Actuarial kidney (upper panel) and patient (lower panel) sur· vival among symptomatic cases of APKD by blood pressure status at diagnosis (1935-1980). Hyperten· sion : diastolic blood pressure ~ 90 mm Hg at diagnosis; normotensive : diastolic blood pressure < 90 mm Hg at diagnosis.

637

ADULT POLYCYSTIC RENAL DISEASE UPDATED 113)

( 13 )

10

. ... "j.....• ~~1 ..........~~! ..........(.~~ ..........i. ~)••••...••• !.' 1

0.8

Grade 0-1 (n=20)

0 .6

""ri'! i·· · ····i4i·········i,--~--..,

0.4

Grade 2 -4 (n=13)

0 .2

~

fI '

:0

0

.0

10

<0

a: 0

II,

("

;. .

L ,(.;6 )

~~~.~~~~.~~

-r';'i[L:

(~;···L._ ... !~!...........;

0.8

1 s

Cr < 1.3/P Ur < 45

(2,

( 2)

(1 )

(3)

Expected .: ....••.. ' .•.•...

(9)

(2 )

S Cr > 1 3 / P Ur > 45

'"

(1,

( I,

0 .2

S Cr

~

1.3/P Ur

~

0

5

10

15

12)

S Cr < 1.3 / P Ur < 45

45

20

-

........... .

(2)

(n=26)

(n=7) 0

\

l. ..................... ~ ...~...

"" ~::;,"' '" '"

(I ,

0.4

Cr < 1.3/P Ur < 45

. . . .... .... '

~

,.........

:~)....... 1.. .. ~~~.~~:..............

0 .6

. :s

(I ,

25

30 0

5

10

15

20

25

30

Years from diagnosis Fig. 5. Actuarial kidney (left panels) and patient (right panels) survival among symptomatic cases of APKD, depending on the level of renal function and grade of proteinuria on urinalysis, at diagnosis. S Cr = serum creatinine (mg/dL); P Ur = plasma urea (mg/dL).

teinuria or impaired renal function at the time of the initial diagnosis. DISCUSSION

The distinction between true APKD and multiple benign simple cysts may be difficult. For this study, to make the diagnosis, we required bilateral cystic changes in the absence of urinary tract obstruction, with extensive, diffuse , and homogeneous involvement of the renal cortex and medulla . It is possible that , by following these strict morphologic criteria, some cases of true APKD have been excluded, since, as noted by Bernstein,13 cystic changes in autosomal dominant polycystic kidney disease are not always diffuse. Nevertheless, we considered it most important for this study to screen out all controversial cases, especially among those diagnosed at autopsy. That this goal was accomplished is supported by the following facts: (1) the spectrum of clinical manifestations of the patients diagnosed during life and at autopsy was similar; (2) the finding of a positive family history in 50 % of our patients diagnosed at autopsy is comparable to the frequency with which

a positive family history has been noted in major clinical series; 3-7 (3) extrarenal cysts and intracranial aneurysms were noted in our autopsy studies with a frequency similar to or higher than in other major autopsy series.3- 8.1 4- 19 The frequencies of APKD which have been reported in other studies are quite variable, depending on whether the quoted figures were derived from autopsy (l: 600) or clinical studies (1 :3,000) .20 However, such studies are based on case selection, which is highly variable; they cannot be compared with one another or with the results of our population-based study. In addition to selection biases in such series, there may be some overdiagnosis of polycystic kidney disease at autopsy due to the lack of strict diagnostic criteria. Even when the presence of extrarenal cysts has been required for the diagnosis of polycystic kidney disease, only 25% of the patients in one series were diagnosed prior to autopsy.21 We have for the first time projected the incidence rate of APKD by adding the cases diagnosed because of symptoms or family screening, those observed at autopsy, and those that would have been detected had all

638

deaths been autopsied. By comparing incidence rates A and C, it appears that only about half of the patients with APKD are diagnosed during life. This is in spite of the fact that the incidence rate B, based on cases diagnosed clinically and at autopsy, was considerably higher in Olmsted County than in Copenhagen. 9 The higher incidence in our study is most likely explained by the completeness of case ascertainment of diagnosed illness, by advanced diagnostic techniques developed in the last few decades, and the high proportion of deaths in the population of Olmsted County that have come to autopsy. In addition to the classic associations of APKD with extrarenal disorders such as hepatic cysts and intracranial aneurysms, several more recent reports have emphasized the association of this disorder with gout,22.23 arteriosclerotic cardiovascular disease,24 and colonic diverticulosis. 25 Indeed, these conditions were observed in our patients in frequencies which seem higher than those in the general population. 2627 Since these conditions are a significant cause of morbidity and mortality, it seems appropriate that the clinician be aware of these possible associations. It is uncertain, however, whether these disorders are associated with APKD by virtue of a linked genetic disorder or a common pathogenic factor, or whether they are just a consequence of hypertension or other manifestations of polycystic renal disease. One of the patients in our series had alpha\-antitrypsin deficiency. Although this association was likely coincidental, a previously reported association between these two disorders 28 might have interesting pathogenetic implications. Similarly, the association between APKD and medullary sponge kidney, observed in two of our patients, has been previously reported. 29 The analysis of survival led to some interesting findings. Not surprisingly, because of the development of dialysis and renal transplantation, the patients diagnosed in the second study period had a better survival than those diagnosed earlier. Probably because of the same reason, the presence of proteinuria or an elevation of serum creatinine or plasma urea did not have a detectable adverse influence on patient survival, whereas they were detrimental to kidney survival. More unexpected was the finding of a significant improvement in kidney survival in the patients diagnosed between 1956 and 1980 as compared to those whose disease was

IGLESIAS ET AL

detected between 1935 and 1955. In part, this improvement in kidney survival might be more spurious than real, due to earlier diagnoses of the disease with improved diagnostic techniques. On the other hand, this improvement in kidney survival might also be explained by a more frequent use of medical services and the introduction of new therapeutic modalities, such as an effective antihypertensive therapy with reserpine in the 1950s. 30 The contention that satisfactory control of hypertension may be essential to the amelioration of kidney and patient survival is supported by the finding that normotensive patients at the time of diagnosis had a borderline better prognosis than those with hypertension. Finally, better patient survival associated with cases younger than 35 years of age at diagnosis, even after adjusting for age-related differences in expected survival, might also be explained by earlier and more continuous medical attention. The results of this study suggest that the early diagnosis of APKD with modern techniques, together with adequate medical attention, may improve kidney and patient survival. At the same time, however, patients whose disease might in the past have gone unrecognized will now, because of more frequent use of medical services, better diagnostic techniques, and more frequent family screening, be diagnosed. It is, therefore, most important not to create an unwarranted pessimistic view of the prognosis of APKD in these patients, who should be aware of the frequently benign course of this disease.

REFERENCES 1. Lejars F. Du fros rein polykystique de l'adulte. Paris: Steinheill, 1888, pp 5-55 2. Gardner KD Jr (ed): Cystic Diseases of the Kidney. New York, Wiley, 1976 3. Braasch WF, Schacht FW: Pathological and clinical data concerning polycystic kidney. Surg Gynec Obstet 57:467-475, 1933 4. Oppenheimer GD. Polycystic disease of the kidney. Ann Surg 100:1136-1158, 1934 5. Rail JE, Odel HH: Congenital polycystic disease of the kidney: Review of the literature and data on 207 cases. Am J Med Sci 218:399-407, 1949 6. Fergusson JD: Observations on familial polycystic disease of the kidney. Proc Roy Soc Med 42:806-814, 1949 7. Simon HB, Thompson GJ: Congenital renal polycystic disease: A clinical and therapeutic study of three hundred sixtysix cases. JAMA 159:657-662, 1955 8. Higgins CC: Bilateral polycystic kidney disease: Review of 94 cases. AMA Arch Surg 65:318-329, 1952

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9. Dalgaard OZ: Bilateral polycystic disease of the kidneys: A follow-up of two hundred and eighty-four patients and their families. Acta Med Scand Suppl 328:1-255,1957 10. Kurland LT, Molgaard CA: The patient record in epidemiology. Sci Am 245:54-63, 1981 II. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. Journal of American Statistical Association 53:457-481, 1958

12. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163-170, 1966 13. Bernstein J: A classification of renal cysts , in Gardner KD Jr (ed); Cystic Diseases of the Kidney. New York, Wiley, 1976, pp 7-30 14. Suter W: Congenital aneurism of basal cerebral arteries and cystic kidneys. Schweiz Med Wochenschr 79:471-476, 1949 15. Brown RAP: Polycystic disease of the kidneys and intracranial aneurisms. The aetiology and interrelationship of the conditions: Review of recent literature and report of seven cases in which both conditions coexisted. Glasgow Med J 32:333-348, 1951 16. Bibelow NH: The association of polycystic kidneys with intracranial aneurysms and other dilated disorders. Am J Med Sci 225 :485-494, 1953 17. Poutasse EF, Gardner WJ, McCormack U: Polycystic kidney disease and intracranial aneurysm. JAMA 154:741744, 1954 18. Ditiefsen EML, Torjum AM: Intracranial aneurysm and polycystic kidneys. Acta Med Scand 168:51-54, 1960

639 19. Harrow BR, Sioane JA: Polycystic renal disease with renal and splenic artery aneurysms. J Urol 84:447-452, 1960 20. Danovitch GA: Clinical features and pathophysiology of polycystic kidney disease in man, in Gardner KD Jr (ed): Cystic Diseases of the Kidney. New York, Wiley, 1976, pp 125150. 21. Hatfield PM, Pfister RC: Adult polycystic disease of the kidneys (Potter Type 3). JAMA 222:1527-1531, 1972 22. Rivera JF, Martinez-Maldonado M, Ramirez de Arellano GA, et al: Association of hyperuricemic and polycystic kidney disease. Bol Assoc Med PR 57:251-262, 1965 23. Newcombe DS: Gouty arthritis and polycystic kidney disease. Ann Intern Med 79:605, 1973 24. Chapman JR, Hilson AJW: Polycystic kidneys and abdominal aortic aneurysms. Lancet 1:646-647, 1980 (Letter) 25. Scheff RT, Zuckerman G, Harter H, et al: Diverticular disease in patients with chronic renal failure due to polycystic kidney disease. Ann Intern Med 92:202-204, 1980 26. Hall AP, Barry PE, Dawber TR, et al: Epidemiology of gout and hyperuricemia. Am J Med 42:27-37, 1967 27. Hughes LE: Postmortem survey of diverticular disease of the colon. Gut 10:336-351, 1969 28. Pintacuda S. DiBlasi S, Morici G, et al: Rene policistico e deficit di alfal-antitripsina sierica [Polycystic kidney and serum alphal-antitrypsine deficiency]. Minn Med 72: 16971701, 1981 29. Hockley BJ: Case report: Combined polycystic and medullary sponge renal disease. Aust Radiol 22:315-318, 1978 30. Moyer JH: Cardiovascular and renal hemodynamic response to reserpine (Serpasil) and clinical results of using this agent for the treatment of hypertension. Ann NY Acad Sci 59:82-94, 1954