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The Radioisotope Renogram in Polycystic Kidney Disease
THE JOURNAL OF UROLOGY
Vol. 93, No. 1 January 1965 Copyright © 1965 by The Williams & Wilkins Co. Printed in U.S.A.
THE RADIOISOTOPE RENOGRAlVI IN POLYCYSTIC KIDNEY DISEASE KENNETH H. DOOLITTLE The finding of less mature tissue in polycystic kidneys was the basis of Brigidi and Severi's7 neoplastic theory. They believed that this was a cystadenoma. Imperfect glomeruli and tubules were found in adenosarcoma of the kidney by Masson. 8 But the diffuse, bilateral, and nonmetastasizing characteristics of polycystic kidney disease argue against neoplastic origin. The arrested development theory is the fourth theory. During formation of the kidney, many primitive tubules and glomeruli form prior to mature, permanent ones, but atrophy as they are displaced as the mature ones develop. 6 Blind primitive tubules have been found to remain as blind tubules with cysts in fetal kidneys by Kampmeier. 9 Experirn.entally complete obstruction leads to eventual atrophy so that these blind tubules should atrophy rather than progress as does polycystic kidney disease. These theories were never satisfactory in explaining this disease. The only definite thing is that it is a congenital disease inheriting a mendelian dominant gene. Lambert in 194710 demonstrated by microscopic serial sections of tubules that the cysts were simply ballooning of the tubular wall occurring at any point along the course of the tubules. These findings were verified by finding inulin in the cyst fluid which had been previously injected intraperitoneally. Tubular function was proven by determining the urine-plasma ratio of endogenous creatinine of the cyst fluid. Lambert's findings were verified by Bricker and Patton.11 They aspirated cysts under direct vision with the
During the past hundred years four different theories have been proposed concerning the etiology of the cysts in polycystic kidney disease. All of these theories have as a significant element the idea that the cysts are caused by some type of obstruction. The radioisotope renogram has shown a delayed excretion pattern in some patients with this disease. An attempt is made to explain this pattern and possibly shed some light on the etiology of the cyst. HISTORY
The first theory of the etiology of the cysts was proposed by Virchow in 1869. 1 • 2 He believed that salts precipitated in the tubules would cause antenatal obstruction and dilatation of the tubule with cyst formation. Later Shukowsky and others proposed that congenital syphilis was responsible for inflammatory lesions which obstructed the tubules. 3 , 4 The mal-union theory, the second theory, had its basis when Rupffer 5 described the formation of convoluted tubule from the metanephron and the collecting tubule from the wolffian duct. This theory then assumed that abnormalities of development would either prevent union or result in faulty union of the convoluted tubule and collecting tubule. The main argument against this theory is the fact that the metanephronic blastema does not develop into a tubule until it has joined a collecting; tubule. 6 Accepted for publication June 15, 1964. Read at annual meeting of North Central Section, American Urological Association, Inc., Chicago, Illinois, September 11-14, 1963. 1 Newman, H. R.: Congenital polycystic kidney disease. Amer. J. Surg., 80: 410-418, 1950. 2 Vire how, R.: Ueber Hydrops renum cysticus congenitus. Virchow Arch. f. path. Anat., 46:
6 Bell, E. T.: Cystic disease of the kidneys. Amer. J. Path., 11: 373-418, 1935. 7 Brigidi, D. V. and Severi, A.: Contributo a.Ila patogenesi delle cisti renali. Lo Spermitale, 46:
1-2,5, 1880. 8 Masson, P.: The role of the neural crests in the embryonal adenosarcomas of the kidney. Amer. J. Cancer, 33: 1-32, 1938. 9 Kampmeicr, 0. F.: A hitherto unrecognized mode of origin of congeni ta! renal cysts. Surg., Gynec. & Obst., 36: 208-216, 1923. 10 Lambert, P. P.: Polycystic disease of the kidney. Arch. Path., 44: 34-58, 1947. 11 Bricker, N. S. and Patton, J. F.: Cystic disease of the kidney. A study of dynamics and chemical composition of cyst fluid. Amer. J. Med., 18:
506-507, 1869.
Shukowsky, W. P. and Ssinjoff, W.: Ueber Polycystische degeneration der nieren nanentlich im kindesalter. Arch. f. Kinderh., 58: 85-101, 3
1912.
4 Norris, H.. F. and Herman, L.: The pathogenesis of polycyst Kicidneys: Reconstruction of cystic elements in four cases. J. Urol., 46: 147-176,
1941. 5 Rupffer, C.: Untersuchungen i.iber dil entwicklung des harn-und Geschlechtrsystems. Arch. f. Mic hr. Anat., 1: 233-248, 1865.
207-219, 1955. 30
RADIOISOTOPE RENOGRAPHY IN POLYCYSTIC KIDNEY DISEASE
31
Fm. 1. Normal renograms
FIG. 2. Renogrnm with delayed excretion shows improvement after urea and P AH patient on the operating table before and after intravenous infusion of various substances. METHOD
In each of the 14 patients in the study the diagnosis of polycystic kidney disease had been made previously by means of excretory urography or retrograde pyelography, and further verified by surgical exploration in 3 cases. Most of the 14 patients had a family history of polycystic kidney disease. The radioisotope renogram is a chemical test of individual renal function with a characteristic pattern of 3 phases. 12-14 The initial vertical spike 12 Winter, C. C.: Further experiences with the radioisotope renogram. Amer. J. Roentgenol., 82:
862-866, 1959.
is the vascular phase; the later, more gradual rise is the secretory phase; and the drainage phase shows the curve returning toward the base line, rapidly at first, then tapering off (fig. 1). Seven of the 14 patients had a normal renogram curve, but the other seven had a delayed excretion pattern with a prolonged drainage phase. In an effort to explain this pattern, the renogram was altered. The renogram was first made in the claRsieal manner as originally described by Winter, then improved by Winter and Nor13 Winter, C. C.: A clinical study of a new renal function test. The radioactive diodrast renogram. J. Ural., 76: 182-196, 1956. 14 Taplin, G. V., Meredith, 0. M., Jr., Kade, H. and Winter, C. C.: The radioisotope renogram. J. Lab. & Clin. Med., 48: 886-901, 1956.
32
DOOLITTLE
TABLE 1. Renograms in 14 patients 11Yith polycystic kidney disease Standard After Urea
Normal Delayed excretion Improved Unchanged
7 7
After PAH
7
7
6 1
4 3
dyke. 15 - 18 Then the renogram was made after urea diuresis of 4 per cent urea in 5 per cent dextrose in water which speeds up the renogram. The third renogram was done after competitive blocking of the tubules by para-aminohippuric acid (P AH) to block tubular secretion of the hippuran (fig. 2). RESULTS AND COMMKNT
It was felt that with this program something could be learned about the cause of the abnormal renogram. If the pattern was due to actual obstruction of the tubule by the cysts, then speeding up the renograms would exaggerate this obstruction. If the hippuran diffused into the cysts, thereby remaining in the kidney, this would be corrected by giving the material less time for diffusion with the reduced transit time. If the material was actively secreted into the cysts by the tubular function, blockage of this should return the renogram toward normal. Seven of the 14 patients had a delayed excretion pattern. In six of these seven improvement was noted after urea diuresis. This demonstrated that cysts do not actually block the kidney tubule, otherwise the abnormal pattern would have been accentuated. Four of these 7 patients had improved drainage after PAH, suggesting 15 Tubis, M., Posnick, E. and Nordyke, R. A.: Preparation and use of I-131 labeled S(1dium iodohippurate in kidney function tests. Proc. Soc. Exper. Biol. & Med., 103: 497-498, 19(50. 16 Winter, C. C., :Nordyke, R. A. and Tubis, M.: Clinical experience with a new test agent for the radioiostope reno gram; sodium orthohippurate I-131 (hippuran I-131). J. Urol., 85: 92-94, 1961. 17 Winter, C. C.: Advances in the radiosiotope renogram test. J. Urol., 85: 683-687, 1961. 18 Morgan, .J. M., Ferrell, T ..J., Lyons, C. and Murdaugh, H. V., Jr.: The diagnosis of renal hypertension. The use of the radiorenogram and the role of kidney biopsy. Amer ..J. Cardiol., 9: 760-772, 19(i2.
some active excretion into the cysts (table 1). All renogram curves were depressed because of the blockage of the excretion of 80 per cent of the hippuran at this concentration by P AH. One patient with normal renograms had aspiration of the cysts after each renogram with no radioactivity found in the cyst fluid. The best way to actually prove that the radioactive hippuran entered the cyst is to recover it in the cyst fluid on aspiration. This has been advocated for the treatrnent of polycystic kidney disease,1 9 but, it is difficult to aspirate these cysts and even more difficult to find a patient who will submit to it. Another experiment would be to make renograms with urokon, which is filtered at the glomerulus only. If these showed improvement after urea diuresis this would be further evidence against true obstruction. CONCLUSION
The delayed excretion pattern of the radioisotope renogram was in1proved by urea diuresis. This demonstrates that obstruction is not the cause of the cysts in polycystic kidney disease and verifies Lambert's work which demonstrated intact tubules in polycystic kidney disease. I want to thank Dr. C. C. Winter for his stimulation of this project and interpretation of the renograms. All renograms were clone in his laboratory.
3:0 East Broad Street, Columbus 15, Ohio REFERENCES BRICKER, N. S. AND PATTON, J. F.: Renal function studies in polycystic disease of the kidneys. New Engl. .J. Med., 256: 212-214, 1957. DALGAARD, 0. Z.: Bilateral polycystic disease of the kidneys. Acta Med. Scand., suppl. 328 1957. ' ' FERGUSSON, J. D.: Observations of familiar polycystic disease of the kidney. Proc. Royal Soc. Med., 42: 806-814, 1949. PATTON, J. F. AND BRICKER, N. S:. Renal function studies in polycystic disease of the kidney a preliminary report. J. Urol., 72: 285-292, 1°954. PENDER, B. W.: Polycystic disease of the kidney. Practitioner, 186: 445-449, 1961. · 19 De La Pena, A.: Percutaneous needle puncture in the mana11:ement of polycvstic renal disease. J. Int. Coll. Surg., 35: 591-595, 1961.
Vol. 93, No. 1 January 1965 Copyright © 1965 by The Williams & Wilkins Co. Printed in U.S.A.
THE RADIOISOTOPE RENOGRAlVI IN POLYCYSTIC KIDNEY DISEASE KENNETH H. DOOLITTLE The finding of less mature tissue in polycystic kidneys was the basis of Brigidi and Severi's7 neoplastic theory. They believed that this was a cystadenoma. Imperfect glomeruli and tubules were found in adenosarcoma of the kidney by Masson. 8 But the diffuse, bilateral, and nonmetastasizing characteristics of polycystic kidney disease argue against neoplastic origin. The arrested development theory is the fourth theory. During formation of the kidney, many primitive tubules and glomeruli form prior to mature, permanent ones, but atrophy as they are displaced as the mature ones develop. 6 Blind primitive tubules have been found to remain as blind tubules with cysts in fetal kidneys by Kampmeier. 9 Experirn.entally complete obstruction leads to eventual atrophy so that these blind tubules should atrophy rather than progress as does polycystic kidney disease. These theories were never satisfactory in explaining this disease. The only definite thing is that it is a congenital disease inheriting a mendelian dominant gene. Lambert in 194710 demonstrated by microscopic serial sections of tubules that the cysts were simply ballooning of the tubular wall occurring at any point along the course of the tubules. These findings were verified by finding inulin in the cyst fluid which had been previously injected intraperitoneally. Tubular function was proven by determining the urine-plasma ratio of endogenous creatinine of the cyst fluid. Lambert's findings were verified by Bricker and Patton.11 They aspirated cysts under direct vision with the
During the past hundred years four different theories have been proposed concerning the etiology of the cysts in polycystic kidney disease. All of these theories have as a significant element the idea that the cysts are caused by some type of obstruction. The radioisotope renogram has shown a delayed excretion pattern in some patients with this disease. An attempt is made to explain this pattern and possibly shed some light on the etiology of the cyst. HISTORY
The first theory of the etiology of the cysts was proposed by Virchow in 1869. 1 • 2 He believed that salts precipitated in the tubules would cause antenatal obstruction and dilatation of the tubule with cyst formation. Later Shukowsky and others proposed that congenital syphilis was responsible for inflammatory lesions which obstructed the tubules. 3 , 4 The mal-union theory, the second theory, had its basis when Rupffer 5 described the formation of convoluted tubule from the metanephron and the collecting tubule from the wolffian duct. This theory then assumed that abnormalities of development would either prevent union or result in faulty union of the convoluted tubule and collecting tubule. The main argument against this theory is the fact that the metanephronic blastema does not develop into a tubule until it has joined a collecting; tubule. 6 Accepted for publication June 15, 1964. Read at annual meeting of North Central Section, American Urological Association, Inc., Chicago, Illinois, September 11-14, 1963. 1 Newman, H. R.: Congenital polycystic kidney disease. Amer. J. Surg., 80: 410-418, 1950. 2 Vire how, R.: Ueber Hydrops renum cysticus congenitus. Virchow Arch. f. path. Anat., 46:
6 Bell, E. T.: Cystic disease of the kidneys. Amer. J. Path., 11: 373-418, 1935. 7 Brigidi, D. V. and Severi, A.: Contributo a.Ila patogenesi delle cisti renali. Lo Spermitale, 46:
1-2,5, 1880. 8 Masson, P.: The role of the neural crests in the embryonal adenosarcomas of the kidney. Amer. J. Cancer, 33: 1-32, 1938. 9 Kampmeicr, 0. F.: A hitherto unrecognized mode of origin of congeni ta! renal cysts. Surg., Gynec. & Obst., 36: 208-216, 1923. 10 Lambert, P. P.: Polycystic disease of the kidney. Arch. Path., 44: 34-58, 1947. 11 Bricker, N. S. and Patton, J. F.: Cystic disease of the kidney. A study of dynamics and chemical composition of cyst fluid. Amer. J. Med., 18:
506-507, 1869.
Shukowsky, W. P. and Ssinjoff, W.: Ueber Polycystische degeneration der nieren nanentlich im kindesalter. Arch. f. Kinderh., 58: 85-101, 3
1912.
4 Norris, H.. F. and Herman, L.: The pathogenesis of polycyst Kicidneys: Reconstruction of cystic elements in four cases. J. Urol., 46: 147-176,
1941. 5 Rupffer, C.: Untersuchungen i.iber dil entwicklung des harn-und Geschlechtrsystems. Arch. f. Mic hr. Anat., 1: 233-248, 1865.
207-219, 1955. 30
RADIOISOTOPE RENOGRAPHY IN POLYCYSTIC KIDNEY DISEASE
31
Fm. 1. Normal renograms
FIG. 2. Renogrnm with delayed excretion shows improvement after urea and P AH patient on the operating table before and after intravenous infusion of various substances. METHOD
In each of the 14 patients in the study the diagnosis of polycystic kidney disease had been made previously by means of excretory urography or retrograde pyelography, and further verified by surgical exploration in 3 cases. Most of the 14 patients had a family history of polycystic kidney disease. The radioisotope renogram is a chemical test of individual renal function with a characteristic pattern of 3 phases. 12-14 The initial vertical spike 12 Winter, C. C.: Further experiences with the radioisotope renogram. Amer. J. Roentgenol., 82:
862-866, 1959.
is the vascular phase; the later, more gradual rise is the secretory phase; and the drainage phase shows the curve returning toward the base line, rapidly at first, then tapering off (fig. 1). Seven of the 14 patients had a normal renogram curve, but the other seven had a delayed excretion pattern with a prolonged drainage phase. In an effort to explain this pattern, the renogram was altered. The renogram was first made in the claRsieal manner as originally described by Winter, then improved by Winter and Nor13 Winter, C. C.: A clinical study of a new renal function test. The radioactive diodrast renogram. J. Ural., 76: 182-196, 1956. 14 Taplin, G. V., Meredith, 0. M., Jr., Kade, H. and Winter, C. C.: The radioisotope renogram. J. Lab. & Clin. Med., 48: 886-901, 1956.
32
DOOLITTLE
TABLE 1. Renograms in 14 patients 11Yith polycystic kidney disease Standard After Urea
Normal Delayed excretion Improved Unchanged
7 7
After PAH
7
7
6 1
4 3
dyke. 15 - 18 Then the renogram was made after urea diuresis of 4 per cent urea in 5 per cent dextrose in water which speeds up the renogram. The third renogram was done after competitive blocking of the tubules by para-aminohippuric acid (P AH) to block tubular secretion of the hippuran (fig. 2). RESULTS AND COMMKNT
It was felt that with this program something could be learned about the cause of the abnormal renogram. If the pattern was due to actual obstruction of the tubule by the cysts, then speeding up the renograms would exaggerate this obstruction. If the hippuran diffused into the cysts, thereby remaining in the kidney, this would be corrected by giving the material less time for diffusion with the reduced transit time. If the material was actively secreted into the cysts by the tubular function, blockage of this should return the renogram toward normal. Seven of the 14 patients had a delayed excretion pattern. In six of these seven improvement was noted after urea diuresis. This demonstrated that cysts do not actually block the kidney tubule, otherwise the abnormal pattern would have been accentuated. Four of these 7 patients had improved drainage after PAH, suggesting 15 Tubis, M., Posnick, E. and Nordyke, R. A.: Preparation and use of I-131 labeled S(1dium iodohippurate in kidney function tests. Proc. Soc. Exper. Biol. & Med., 103: 497-498, 19(50. 16 Winter, C. C., :Nordyke, R. A. and Tubis, M.: Clinical experience with a new test agent for the radioiostope reno gram; sodium orthohippurate I-131 (hippuran I-131). J. Urol., 85: 92-94, 1961. 17 Winter, C. C.: Advances in the radiosiotope renogram test. J. Urol., 85: 683-687, 1961. 18 Morgan, .J. M., Ferrell, T ..J., Lyons, C. and Murdaugh, H. V., Jr.: The diagnosis of renal hypertension. The use of the radiorenogram and the role of kidney biopsy. Amer ..J. Cardiol., 9: 760-772, 19(i2.
some active excretion into the cysts (table 1). All renogram curves were depressed because of the blockage of the excretion of 80 per cent of the hippuran at this concentration by P AH. One patient with normal renograms had aspiration of the cysts after each renogram with no radioactivity found in the cyst fluid. The best way to actually prove that the radioactive hippuran entered the cyst is to recover it in the cyst fluid on aspiration. This has been advocated for the treatrnent of polycystic kidney disease,1 9 but, it is difficult to aspirate these cysts and even more difficult to find a patient who will submit to it. Another experiment would be to make renograms with urokon, which is filtered at the glomerulus only. If these showed improvement after urea diuresis this would be further evidence against true obstruction. CONCLUSION
The delayed excretion pattern of the radioisotope renogram was in1proved by urea diuresis. This demonstrates that obstruction is not the cause of the cysts in polycystic kidney disease and verifies Lambert's work which demonstrated intact tubules in polycystic kidney disease. I want to thank Dr. C. C. Winter for his stimulation of this project and interpretation of the renograms. All renograms were clone in his laboratory.
3:0 East Broad Street, Columbus 15, Ohio REFERENCES BRICKER, N. S. AND PATTON, J. F.: Renal function studies in polycystic disease of the kidneys. New Engl. .J. Med., 256: 212-214, 1957. DALGAARD, 0. Z.: Bilateral polycystic disease of the kidneys. Acta Med. Scand., suppl. 328 1957. ' ' FERGUSSON, J. D.: Observations of familiar polycystic disease of the kidney. Proc. Royal Soc. Med., 42: 806-814, 1949. PATTON, J. F. AND BRICKER, N. S:. Renal function studies in polycystic disease of the kidney a preliminary report. J. Urol., 72: 285-292, 1°954. PENDER, B. W.: Polycystic disease of the kidney. Practitioner, 186: 445-449, 1961. · 19 De La Pena, A.: Percutaneous needle puncture in the mana11:ement of polycvstic renal disease. J. Int. Coll. Surg., 35: 591-595, 1961.