Autosomal Dominant Polycystic Kidney Disease: Presentation, Complications, and Prognosis

Autosomal Dominant Polycystic Kidney Disease: Presentation, Complications, and Prognosis Vera B. Delaney, MD, Sheldon Adler, MD, Frank J. Bruns, MD, Michael Licinia, MD, David P. Segel, MD, and Donald S. Fraley, MD • Fifty-three symptomatic adults with autosomal dominant polycystc kidney disease were studied retrospectively for a mean follow-up of 12 years (range 10 months to 33 years). Diagnosis was confirmed by either x-ray, ultrasound, laparotomy, or autopsy. Commonest presenting clinical findings were flank pain (30%), hypertension (21%), symptomatic urinary tract infection (UTI) (19%), gross hematuria (19%), and palpable masses (15%). A total of nine patients (17%) progressed to end-stage renal disease. Change in renal function measured using the reciprocal of plasma creatinine plotted against time was linear for each individual patient with a maximum functional decline of 0.7 mg/dL/yr (slope = - 0.07). Past the age of sixty renal failure was uncommon. Easily controlled hypertension developed in 64% attended by mild retinopathy. UTls were common (53%), often recurrent (61%), precipitated by instrumentation in 6 of 14 patients (43%), leading to death in two (33%). Renal calculi were extremely common (34%) and had no defined metabolic cause. The presence of hematuria (64%), gross or microscopic, bore no relationship to the decline in renal function. Pregnancy was normal in these patients with no increase in fetal or maternal morbidity or mortality. We conclude the following: (1) Renal functional deterioration is linear, less than previously reported, and bears no relationship to hematuria. (2) Hypertenson is common, easily treated, and causes minor end-organ damage. (3) Renal calculi are frequent. (4) Urinary tract instrumentation often induces infection with considerable morbidity and mortality and must be aVOided. (5) Pregnancy is not contraindicated if renal function is normal. (6) The prognosis for survival in this disease is better than previously reported. © 1985 by The National Kidney Foundation, Inc. INDEX WORDS:

Polycystic kidneys; renal calculi; hematuria.

A

DULT polycystic kidney disease accounts for approximately 8 % of patients undergoing dialysis and transplantation in the United States and Europe. 12 Many large series have been reported, but the majority were undertaken before 1970 3- 9 at a time when cyst punctures were performed 10 and diagnostic procedures such as retrograde pyelographyll were advocated. Both procedures distort the natural history of the disease. 11.12 A recent study from Switzerland 13 focused on the natural history of renal function in polycystic patients demonstrating a long period of stability in renal function followed by a steady decline in many of the cases. Their data have not been confirmed by other investigators. Controversy also remains concerning the relative polycythemia associated with the disease, the importance of hematuria as a prognostic sign, the incidence of renal calculi, fetal and maternal morbidity, and the prevalence of diverticular disease and its complications. The present study reviews 53 patients with From the Department of Medicine. Montefiore Hospital. University of Pittsburgh School of Medicine. Address reprint requests to Sheldon Adler, MD. Montefiore Hospital. 3459 Fifth Ave, Pittsburgh, PA 15213. © 1985 by The National Kidney Foundation, Inc. 0272-6386/85/020104-08$03.00/0

104

autosomal dominant polycystic kidney disease followed for a mean period of 12 years. The results show a markedly high incidence of renal calculi, a low incidence of fetal and maternal problems during pregnancy, no increase in diverticular disease, a lack of correlation between gross hematuria and renal failure, and a better prognosis for renal function than previously reported. 46 The results also show that, for anyone patient, once renal function starts to decline the rate of decline proceeds at a constant rate unless a superimposed problem intervenes. MATERIALS AND METHODS Fifty-three patients with adult polycystic kidney disease seen at Montefiore Hospital between 1947 and 1980 were studied retrospectively. All were adults and symptomatic. Four were black, the other 49 white. Asymptomatic family members, when discovered, were not added to the study group. The mean follow-up period was 12 years (range 10 months to 33 years). The clinical diagnosis of polycystic disease was suggested by history and physical examination and in every patient confirmed either by intravenous pyelogram (IVP) with tomograms. sonography, computed tomography (CT) scan with contrast, arteriography. laparotomy, or autopsy. The distribution of the cysts or the subsequent course confirmed the diagnosis in each case. Renal functional impairment was defined arbitrarily as a serum creatinine in excess of 2.5 mg/dL and end-stage renal disease as serum creatinine greater than 8.0 mg/dL ac-

American Journal of Kidney Diseases, Vol V, No 2, February 1985

105

NATURAL HISTORY ADULT POLYCYSTIC DISEASE

companied by uremic symptoms. Hypertension was defined as systolic or diastolic BPs exceeding 150 or 100 mm Hg on three or more occasions. Serial timduscopic examinations were carried out by renal physicians and classified using the KeithWagener-Barker classification. 14 Positive urine cultures in conjunction with symptoms of dysuria, frequency, and urgency were designated lower UTIs. Pyelonephritis was diagnosed when patients had positive urine cultures, fever, and flank pain with or without lower urinary tract symptoms. Perinephric abscess was identified by surgical or spontaneous drainage of pus from the perinephric area accompanied by local and systemic manifestations of severe infection. A diagnosis of renal calculus disease required passage or surgical removal of stones from the urinary tract or the presence of radio-opaque deposits on x-ray. Renal colic alone, with or without radiolucent filling defects, was not considered diagnostic of renal calculi. Creatinine was measured on the autoanalyzer. The chi-square and Student's t tests were used for all statistical evaluations. Linear regressions were performed using the least squares method. Curve fitting was performed after calculation of the regression coefficients. The coefficient of determination, r, is a measure of the quality of fit to a straight line with values closer to 1.00 indicating a better fit than those closer to zero.

RESULTS

Table 1. Presenting Clinical Findings in 53 Patients With Polycystic Kidney Disease Finding

Abdominal pain ± colic Hypertension UTI Gross hematuria Abdominal mass Abnormal urinary sediment Fatigue Subarachnoid hemorrhage

No. of Patients (%)

16 11 10 10 8 3 2 1

(30) (21) (19) (19) (15) (6) (4) (2)

Abdominal pain with or without renal colic was the most common presenting symptom. Hypertension, symptomatic UTI, gross hematuria, and palpable abdominal masses were also common. A definite family history of polycystic kidney disease was elicited in 66 % of patients. A history of a relative with unspecified kidney disease or dying at an early age from cerebral vascular hemorrhage was recorded in an additional 13 %.

Clinical Presentation

Renal Function

The age distribution of the 21 males and 32 females at presentation is shown in Fig 1. Table 1 summarizes their presenting signs and symptoms.

Figure 2 shows the state of renal function in each of the 53 patients. Four patients had renal impairment at diagnosis, nine patients came to dialysis, and an additional six patients died, five of whom had creatinines exceeding 6 mg/dL. Figure 3 shows the progression of renal disease in the 40 patients who had at least three plasma creatinine values determined for a minimum of 1 year. Whenever the reciprocal of the creatinine value was less than 0.6 the decline was linear against time (r = 0.87) for the group. This point is better shown in Fig 4. This figure shows the 13 patients with renal functional impainnent who were followed for at least 3 years. Note that in each case the decline in the reciprocal of the plasma creatinine was linear (r = 0.93). The mean age of these patients at the end of follow-up was 49 and the mean follow-up was 6.3 years. Nine were followed for at least 5 years. The average functional decline was 0.05 with a range between 0.03 and 0.07. Thus, the decline in renal function among individual patients was variable but could be predicted for each patient from the plot of the reciprocal of the plasma creatinine against time. The calculated range of slopes in the 40 patients shown in Fig 3 ranged from a slope of zero to a slope of - 0.07. Some patients showed no renal functional decline for as long as 33 years. Even in the most severe case, however, the rate of fall in renal func-

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Fig 1. Age and sex distribution at the time of presentation in 53 patients with autosomal dominant polycystic kidney disease.

106

DELANEY ET AL

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Causes of Death

Six patients died during the study. Three died of sepsis, two of cardiovascular disease, and one of cerebral hemorrhage. Except for one patient who died at age 21 from a ruptured berry aneurysm, all had significant renal failure and plasma creatinines exceeding 6 mg/dL. Urinary tract manipulation preceded death in two of the three patients who died from sepsis. Abdominal Pain and Abdominal Mass

Abdominal pain was the most common presenting symptom (30%), occurring in 62 % of the patients at some time during the course of their disease. It was more common in females (72 % v 48 %). Renal colic with stone passage was the presenting clinical feature in eight patients and occurred in a total of 18. In the remaining 15 patients the pain was nonspecific varying from an aching lumbar discomfort to diffuse colicky pain unrelated to exercise, food intake, or bowel movements. Urine cultures were negative during the bouts of pain. Abdominal pain antedated clinically palpable kidneys in 91 % of patients. Barium enemas were performed in three patients for abdominal pain associated with diarrhea. Although diverticulae were noted in two of these patients, age 49 and 50, there was no evidence of diverticulitis or other inflammatory bowel disease. Bilateral palpable kidneys were present in 38%; unilateral masses were found in an additional 21 %. The incidence of palpable kidneys was higher (P < 0.05) in patients with renal functional impairment (82 % v 35%).

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Fig 2. Renal function following diagnosis in 53 patients with autosomal dominant polycystic kidney disease. Serial plasma creatinine values were unavailable in 11 patients and are denoted by parallel broken lines.

tion did not exceed 7 % per year. A total of 28 patients were followed with reciprocal values for 5 yearS or longer. Regression analysis in this group showed correlation coefficients that varied from - 0.8 to 0.99 (mean of - 0.96) for each individual patient.

Calculi were detected in 18 of 53 patients (10 male and 8 female) and were multiple in 13 patients. Only one patient required surgery for obstruction. Stones were analyzed on multiple occasions in six patients. In three the stones were mainly calcium oxalate and in one uric acid. The other two patients had calcium oxalate stones on one occasion and uric acid or calcium phosphate stones on the other. The serum uric acid was elevated in one patient whose stones were not analyzed. In the remaining patients serum uric acid, calcium, phosphorus, and urinary calcium and uric acid excretion were normal. Hypertension

Hypertension on initial presentation occurred in 21 % of patients and developed subsequently in

107

NATURAL HISTORY ADULT POLYCYSTIC DISEASE 16 14 1.2 1.0

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another 43 %. Control was difficult in only one patient. Serial funduscopic examination revealed normal eye grounds in 44%, grade I K-W changes in 47%, and grade II changes in 9 %. No patients developed grade III or grade IV eye grounds. Using the Estes-Point score system 15 seven patients (21 %) had ECG evidence of left ventricular hypertrophy. A cardiothoracic ratio exceeding 0.5 on an x-ray was found in only one hypertensive patient. Urinary Tract Infections

Table 2 shows that 72 % of females and 24 % of males developed symptomatic urinary tract infections. Five males had pyelonephritis and one developed a perinephric abscess. More than half of the females (52 %) had pyelonephritis and three subsequently developed a perinephric abscess. Recurrence rate in the overall group was 61 %. The relationship of urinary tract instrumentation to infection is shown in Table 3. Of 14 patients instru12 1.0

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mented, six (43 %) developed symptomatic UTIs within five days of the procedure. Sterile urine cultures were obtained immediately prior to instrumentation in eight patients including four of the six who became infected following the procedure. No cultures were obtained in the remaining six patients. Three patients developed pyelonephritis that, despite parenteral antibiotic administration, led to death in two. Instrumentation was performed for various reasons. Ten patients had abdominal pain, five of whom had a history of renal calculi. Hematuria was the indication for instrumentation in three patients and acute urinary retention in one. Hematuria

Hematuria was detected in 64% of patients, 76% of whom had gross hematuria. Gross painless hematuria was the presenting symptom in ten patients (19 %) and developed in another 16 patients (30%) during the course of the disease. Lifethreatening hemorrhage developed in one patient necessitating nephrectomy. Nine patients maintained on hemodialysis with regular use of systemic heparinization had no increase in hematuria. Anemia

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Sex

No. of Patients

No. With Symptomatic UTI

Male Female

21 32

5

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23

12

YEARS FQLLOWED

Fig 4. Serial reciprocal plasma creatinine values in the 13 polycystic patients with renal functional impairment (1/Pcr < 0.8) who were followed for at least 3 years.

Symptomatic Urinary Tract Infection in Polycystic Kidney Disease No. With Pyelonephritis

No. With Perinephric Abscess

1 3

108

DELANEY ET AL Table 3. The Relationship of Urinary Tract Instrumentation to Infection in Polycystic Kidney Disease Patients Symptomatic at Risk UTI

Instrument

Cytoscopy Retrograde pyelogram Foley catheter

6

3

6

2

Pyelonephritis

Pregnancy

Twenty-seven patients had 55 pregnancies (Table 4) with no stillbirths or fetal abnormalities. There were nine pregnancy-related complications in seven patients each of whose age exceeded 34 years.

Death

0

Extrarenal Cysts

Twenty-three asymptomatic patients were screened by ultrasound for cysts in other organs. Ten (44 %) had multiple hepatic cysts and two (9 %) had multiple pancreatic cysts. No age difference was detected between those with liver cysts and those without. There was no increase in the incidence of hepatic cysts noted with declining renal function. Six of 16 patients (38 %) were found to have ovarian polycystic disease clinically confirmed by laparotomy in one and by autopsy in another.

2

lycystic kidney disease as compared with nonpolycystic individuals with comparable degrees of renal function (Fig 5). A single male patient had a Hct of 52 % when serum creatinine was 3.1 mg/ dL. With further decline in renal function to a creatinine of 17 mg/dL his Hct fell to 22 %. Proteinuria

Intermittent proteinuria was detected in 36 of 53 patients (68 %) during the course of the disease. Semiquantitative protein excretion as tested by albuminstix or sulfosalicyclic acid precipitation exceeded 2 + in only three patients who showed 3 + proteinuria. In each case specific gravity was 1.025 or greater. Subsequent urinalyses showed 1 + protein in two of these patients and 2 + in the other demonstrating, therefor~, only a moderate degree of intermittent protein loss. No patient had hypoproteinemia or hypoalbuminemia. Only two patients with adult polycystic kidney disease have been reported to have nephrotic syndrome and neither had a renal biopsy. 16

Intracranial Aneurysms

One normotensive patient had a subarachnoid hemorrhage with a berry aneurysm proven at autopsy. DISCUSSION

The diagnosis of autosomal dominant polycystic kidney disease was made in 53 patients by a combination of history, clinical examination, and special procedures. The initial constellation of symptoms appears to be consistent from series to series with abdominal pain, frequency, nocturia, dysuria,

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Fig 5. Mean linear relationship ± 1 SO of plasma creatinine to Hct in 27 nonpolycystic patients with chronic renal insufficiency. The Hct of 19 patients with polycystic kidney disease(e) are superimposed. A single patient (_) had a Hct of 52% when his plasma creatinine was 3.1 mg/dL. Repeat Hct when creatinine had risen to 17 mg/dL also is shown.

109

NATURAL HISTORY ADULT POLYCYSTIC DISEASE

Table 4. Total at Risk

Total With Pregnancy

Total No. of Pregnancies

32

27

55

Pregnancy in Polycystic Kidney Disease No of Fetal Abnormalities or Stillbirths

No. of Patients With PregnancyRelated Complications

No. of Complicated Pregnancies

o

7

9

hematuria, and palpable abdominal masses being the most common presenting complaints. The discovery of hypertension or abnormal urinalysis often led to the diagnosis in otherwise asymptomatic individuals. The prognosis for maintenance of adequate renal function was better than anticipated. In the present series of the 43 patients who reached their 35th year, none were symptomatically uremic and only 6 of 30 (20%) had become so by their 50th year. This contrasts with Dalgaard's series of 350 patients 4 in whom the incidence of uremia was 2 % by the age of 35 and 41 % by the age of 50 years. A further 6 of 25 patients (25 %) in the present series became uremic during the sixth decade. Of the seven patients who passed their 60th birthday five had normal plasma creatinines, suggesting that patients with this disease who survive to their 60th year without renal insufficiency are unlikely to require renal replacement therapy. Moreover, only 8 %of our patients became uremic within 10 years after the onset of symptoms compared with 38 % in Dalgaard's series. This difference is not due to an earlier age at diagnosis since the age distribution in both series was similar (Fig 1). Changes in renal function were highly variable from patient to patient (Fig 3). In individual patients, however, alinear relationship was found by plotting the reciprocal of the plasma creatinine against time . Asudden diversion from the initial slope was observed in only two patients. One developed biopsy-proven rapidly progressive glomerulonephritis 17 while the other developed a thiazide-induced interstitial nephritis. Concomitant pathologic processes may account for the inability of the two patients described by Grantham to maintain the constant expected linear relationship . 18 Our results are in accord with the recently published data of Franz and Reubi . \3 They also demonstrated that polycys-

No. of Complications

Toxemia (4) Hypertension (1) UTI (1) Hematuria (1) Acidosis (1) Transient decrease in GFR (1)

tic patients showed a prolonged period of stable renal function followed by a rate of decline predictable from the reciprocal of the plasma creatinine concentration. The predictability of slope in individual patients alerts the physician to superimposed pathology and allows determination of whether drugs or therapeutic regimens alter the natural history of the disease. 19 The prognosis for survival was better than predicted from the literature. Six patients (11 %) died and an additional nine patients required dialysis to sustain life. Even had these nine patients died, overall mortality rises only to 28 % in patients followed for an average of 12 years after the onset of symptoms. RaIl and Odel 6 studied 43 patients and found death occurred an average of9.3 years after the onset of symptoms. Nolan 20 found a 50% mortality 4 years after diagnosis compared with the 4 %rate found in the present series after the same time interval. No significant difference was noted in the present series in the average age of dialysis or death (mean 50 years) or length of follow-up period (mean 12 years) between the 15 patients that died and the remaining 38 patients. Neither age nor follow-up, therefore, account for the observed improved survival . Abdominal pain was the most common presenting complaint in this series and all others in ,the literature. The significant female preponderance was comparable with that found in Dalgaard's series. 4 The increased prevalence among females remains unexplained. A recent report 21 noted increased colonic perforation secondary to severe diverticulitis in polycystic patients maintained on hemodialysis as compared with other dialysis patients of comparable age. The lack of clinical evidence of diverticulitis in our patients , 24 of whom had reached or exceeded their sixth decade, was striking. This is consistent with an autopsy study

110

of 173 patients with adult polycystic kidney disease in which diverticulitis was not a fature. 4 In view of the difficulty in distinguishing clot colic from that due to stone passage, the incidence of renal calculi in this disease is difficult to assess from the literature . This difficulty is compounded by the occasional presence of calcification in the cyst wall. 22 Higgins 5 stated that acute renal colic was unusual but when present was always due to the passage of blood down the ureter. A recent review 23 also comments on the rarity of calculus disease. Dalgaard's Scandinavian series 4 and the American study by Ward et al,8 however, noted an incidence of 18 % and 20%, respectively-values much higher than the cited 1 % to 5 % incidence of stone formers in the general population. The incidence of 34 % in the present study is the highest recorded. There is no evidence that the incidence of renal calculi is high in Western Pennsylvania so the incidence of 34 % far exceeds that of the general population . A male predominance (47 % v 25%) was also noted by Dalgaard . Sixteen of our 18 patients had renal colic and radio-opaque defects suggestive of stones on x-ray. Since cysts may undergo wall calcification their inclusion as definite stone formers may be questioned. Even if these are excluded the incidence was still 30%. Anatomic distortion with stagnation of urine probably accounts for the high incidence of stones since other predisposing metabolic factors were absent. Gross hematuria was a frequent initial finding. Its onset, however, was not a sinister prognostic sign as a mean period of 8.5 years elapsed between the documented onset of hematuria and the development of renal insufficiency in those patients who developed the latter problem. This is identical to the follow-up period in the group of patients with hematuria who maintained normal plasma creatinines. These results contrast sharply with earlier data from Simon and Thompson ,7 summarized by Dalgaard,24 who observed only a 47% 5year survival rate after the onset of hematuria in a series of 115 patients. They concluded that the presence of hematuria predicted a poor prognosis for survival . Symptomatic UTis were common with an overall incidence of 53 % and a recurrence rate of 61 %. The incidence in other series ranges between 33 % and 50 %.48 Uncomplicated UTis have not been shown to hasten the onset of renal failure or to

DELANEY ET AL

shorten survival time. 13 In our series, however, infection of the urinary tract, often precipitated by instrumentation, contributed to the demise of three of the six patients who died during the course of the study (Table 3). In view of the high recurrence rate of infection, the recently reported failure of systemically administered antibiotics to achieve optimal concentrations in renal cysts 25 and the frequent precipitation of infection by any form of instrumentation of the urinary tract (Table 3), we recommend prolonged antibiotic treatment, diligent follow-up, and avoiding manipulation of the urinary tract. Hypertension developed in 64 % of the patients. In agreement with other reports,4-9 evidence of end-organ damage was rare and control relatively easy. It is possible that the mild vascular damage is due to a high-volume , low-renin form of hyeertension. 26.27 Erythrocytosis occurs in some patients with renal cystic disease , 28.29 and Chester and colleagues 30 noted a decrease in the transfusion requirements of polycystic patients compared with other patients with comparable degree of renal insufficiency. No difference in Hct was noted in the present series (Fig 5). Pregnancy in our series (Table 4) had a good prognosis . All 55 pregnancies went to term with delivery of normal infants. Seven patients, each of whom was 34 years or older, developed pregnancy-related complications that reversed upon delivery or soon thereafter. No permanent deleterious effect of the pregnancy was observed. These results contrast sharply to early series of MilIer 31 and of Morse 32 who reported low fetal salvage and significant maternal mortality in patients with polycystic kidney disease. A later series was more optimistic 33 with normal pregnancies in 82 % of those with subclinical disease. Preeclampsia complicated four pregnancies in patients with previously diagnosed hypertension , but the outcome was successful in each case. Thus, pregnancy in patients with adult polycystic kidney disease without renal failure seems to have a good prognosis. In conclusion, the present results show that autosomal dominant polycystic kidney disease has a better prognosis for survival and for maintenance of adequate renal function than has generally been reported. The decline in renal function is slow and for each patient is predictable from the reciprocal

111

NATURAL HISTORY ADULT POLYCYSTIC DISEASE

plot of plasma creatinine against time. Hematuria is not a poor prognostic sign. Pregnancy is not, in general, contraindicated or associated with increased maternal or fetal mortality. UTIs are common, often recurrent, and attended by a high morbidity and mortality particularly if precipitated by instrumentation of the urinary tract. The incidence

of renal calculi is high, but no evidence of increased diverticulitis was found. Hypertension, although common, is mild or moderate and easily controllable. These data, combined with the availability of end-stage renal therapy, permit the physician to give a more optimistic and precise prognosis to patients suffering from this disorder.

REFERENCES I. Advisory Committee to the Renal Transplant Registry: The eleventh report of the human renal transplant registry. JAMA 233:787-796, 1975 2. Jacobs C, Brunner FP, Chantler et al: Combined report on regular dialysis and transplantation in Europe VIII, 1976. Proc Eur Dial Transplant Assoc 14:18-24, 1977 3. Hatfield DM, Pfister RC: Adult polycystic disease of the kidneys (Potter type III). JAMA 222:1527-1531,1972 4. Dalgaard OZ: Bilateral polycystic disease of the kidneys. A follow up of two hundred and eighty-four patients and their families. Acta Med Scand 328, 1975 (suppl) 5. Higgins CC: Bilateral polycystic kidney disease: Review of 94 cases. Arch Surg 65:318-329, 1952 6. Rail JE, Odel HM: Congenital polycystic disease of the kidney: Review of the literature and data in 207 cases. Am J Med Sci 218:399-407, 1949 7. Simon HB, Thompson GT: Congenital polycystic disease. A clinical and therapeutic study of 366 cases. JAMA 159:657662, 1955 8. Ward IN, Draper Jw, Lavengood RW: A clinical review of polycystic disease in 53 patients. J Urol 98:48-53 , 1967 9. Segal AJ, Spataro RF, Barbaric ZL: Adult polycystic kidney disease: A review of 100 cases. J Urol 118:711-713, 1977 10. Lue YB, Anderson EE, Harrison JH: The surgical management of polycystic renal disease. Surg Gynecol Obstet 122:45-49, 1966 II. Bricker NS, Patton JF: Renal function studies in polycystic disease of the kidneys-With observations on the effects of surgical decompression. N Engl J Med 256:212-214, 1957 12. Waters WB, Hershman H, Klein LA: Management of infected polycystic kidneys. J Urol 122:383-385, 1979 13. Franz KA, Reubi FC: Rate of functional deterioration in polycystic kidney disease. Kidney Int 23:526-529. 1983 14. Keith NM. Wagener HP, Barker NW: Some different types of essential hypertension: Their cause and prognosis. Am J Med Sci 197:332-343, 1939 15. Romhilt DW, Estes EH Jr: A point-score system for the ECG diagnosis of left ventricular hypertrophy. Am Heart J 75:752-758. 1968 16. Ackerman GL: Nephrotic syndrome in polycystic renal disease. J Urol 105:7-9. 1971 17. Licina MG, Adler S, Bruns FJ: Acute renal failure in a patient with polycystic kidney disease. JAMA 245: 1664-1665, 1981

18. Grantham JJ: Polycystic kidney disease: A predominance of giant nephrons. Am J Physiol 244:F3-10, 1983 19. Mitch WE, Steinman TI, Walser M: The effect of protein restriction plus ketoacids on progression of chronic renal failure. Clin Res 31:437A, 1983 20. Nolan LE: Congenital polycystic disease of the kidneys. Urol Cutan Rev 49:734-737, 1945 21. 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 22. Olsson 0: Radiographic evaluation of the kidney, in Earley LE, Gottscalk CW (eds): Strauss and Welt's Diseases of the Kidney (ed 3). Boston, Little, Brown, 1979, pp 115-116 23. Martinez-Maldonado M: Adult polycystic kidney disease. The Kidney 9:1-4, 1976 24. Dalgaard OZ: Polycystic disease of the kidneys, in Early LE, Gottschalk CW (eds): Strauss and Welt's Diseases of the Kidney (ed 1). Boston, Little, Brown, 1963, pp 907-937 25. Muther RS, Bennett WM: Cyst fluid antibiotic concentrations in polycystic kidney disease: Differences between proximal and distal cysts. Kidney Int 20:519-522, 1981 26. Leenen GH, Galla SJ, Redmond DP, et al: Relationships of the renin-angiotensin-aldosterone system and sodium balance to blood pressure regulation in chronic renal failure of polycystic kidney disease. Metabolism 24:589-603, 1975 27. Nash DA: Hypertension in polycystic kidney disease without renal failure. Arch Intern Med 137:1571-1575,1977 28. Anderson ET, Walker BR: Polycystic kidney disease polycythemia and azotemia. JAMA 208:2472, 1969 29. Friend DG, Hoskins RG, Kirkin MW: Relative erythrocytemia (polycythemia) and polycystic kidney disease with uremia. N Engl J Med 1:17-19, 1961 30. Chester AC, Schreiner GE, Preuss HG: Polycystic kidney disease and other cystic disorders. Famous teachings in modern medicine. New York, Med Comm Inc, 1978 31. Miller WG: Pregnancy and polycystic disease of the kidneys. JObst Gynecol Brit Emp 60:868-871, 1953 ~2. Morris N: Pregnancy complicated by congenital polycystic disease of the kidney. JObst Gynecol Br Empire 59:822828, 1952 33. Landesman R, Scherr L: Congenital polycystic kidney disease in pregnancy. Obstet Gynecol 8:673-680, 1956