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A Simplified Method of Determining Effective Renal Plasma Flow
THE JOURNAL OF UROLOGY
Vol. 87, No. 2 February 1962 Copyright © 1962 by The Williams & Wilkins Co.
Printed in U.S.A.
A SIMPLIFIED METHOD OF DETERMINING EFFECTIVE REN AL PLASMA FLOW B. G. SMITH, *t, R. M. O'DELL
AND
J. U. SCHLEGEL
From Tulane University School of Medicine, Department of Surgery, Division of Urology, New Orleans, La.
Indirect measurement of the effective renal plasma flow is one of the major clinical tests for renal function. There has been an increased interest in the past few years in measuring effective renal plasma flow in each kidney simultaneously in patients with hypertension of suspected renal origin. Para-amino hippuric acid (PAH), phenol red, diodrast and hippuran have been used to measure clearances since at low plasma levels those substances are almost completely cleared from the plasma in a single passage through the kidney. 1 The standard laboratory analyses for these substances involve several different procedures that can introduce analytical error. At times, this procedure is neglected because of the con1plexity and time required for the study despite the valuable knowledge in regard to renal function that is obtained. There has been a continual search for a procedure that is less complicated and still accurate. It has been previously reported from this laboratory that I-131-labeled-hippuran when compared to PAH is accurate in determining effective renal plasma flow. 2 This procedure, however, requires a specialized pump that will give a continuous intravenous infusion of I-131hippuran to maintain constant blood levels. A further simplification has been made in that adequate blood levels can be obtained by giving I-131-labelecl-hippuran combined with epinephrine to delay absorption in a single intradermal injection. MA'I'ERIALS AND MSTHODS
Twenty-two female mongrel dogs and 18 patients of whom two were female and 16 were Accepted for publication July 25, 1961. This research was supported by Public Health Service Grant No H-4659, Abbott Laboratories and Louisiana Heart Association. * A Fellow under U. S. Public Health Training Grant No. CRT-5057. t Present address: Barnes Hospital, Division of Urology, St. Louis, Mo. 1 Smith, H. W.: The Kidney: Structure and function in health and disease. New York: Oxford University Press, 1951, chapt. 22, p. 1049. 2 Schlegel, J. U., Smith, B. G. and O'Dell, R. M,: Estimation of effective renal plasma flow using I-131-labeled hippuran. In press.
male varying in age from 11 to 72 years were included in the study. In the dog studies, the animals were anesthetized with 30 mg./kg. nembutal. A size 16 Foley catheter was inserted into the bladder to assure complete bladder drainage. Urine and blood were collected for blank values. An osmotic diuretic of 1000 cc 5 per cent dextrose in water containing 40 g. ureaphil (courtesy Abbott Laboratories) was given intravenously in the foreleg at a rate to maintain a urinary output of 2 cc/min. or greater. vVhen an adequate urinary output was obtained, clogs were given 30 uc I-131-labeledhippuran with epinephrine intradermally in the shoulder. The volume of solution given to both clogs and patients was 0.1 cc to 0.33 cc, depending on the decay of the labeled isotope, containing 0.01 cc 1 :1000 epinephrine in each 0.1 cc hippuran solution. In patients both total and differential clearances were measured. vVhen total renal function tests were done, a size 16 Foley catheter was placed in the bladder. In differential studies, size 7 whistle tip catheters were placed in each ureter through a cystoscope to a place where adequate drainage of urine was obtained. A size 16 Foley catheter was placed in the bladder after the cystoscope was removed. If bladder urine appeared, the site of leakage could be investigated and corrected. Blood and urine were collected for blanks. Patients were hydrated by giving 200 cc water by mouth every 30 minutes throughout the procedure. If a diuresis of 2 cc per minute or greater was not obtained by hydration alone, a solution of 1000 cc 5 per cent dextrose in water containing 80 g. ureaphil was given intravenously throughout the procedure. ·when an adequate urinary output was obtained, patients were given 100 uc I-131-labeled hippuran with epinephrine intradermally in the volar surface of the forearm immobilized on an arm board. After 1 hour to allow stabilization of I-131hippuran in the blood, the clearance periods were begun in both patients and dogs. At least
106
DETERMINATION OF EFFECTIVE RENAL PLASMA FLOW
constant inlra.venous int-usion
fntra.derma1 -----------............ .: 20Q,.____..,____ 0
30
'-:-
with
epinephrine
.... _--- ........ __
--.
__L_ _ _.J..___ _...J...__ _.....,L__ _L_------1
60
90
120
150
TIME llJ MIi-JUTES Fm. 1. Serum levels of I-131-labeled-hippuran obtained using constant intravenous infusion or single intradermal injection. 4 half-hour clearance periods were done collecting urine continuously and blood being drawn at the midpoint of each collection period. The Foley catheter was irrigated with air at the end of each collection period to assure complete bladder drainage. 1-131-labeled-hippuran levels in the serum and urine were obtained using model 132 analyzer computer (Nuclear, Chicago) to obtain counts/ ml./min. Three ml. serum and one ml. urine were counted for each clearance period. The difference in volume counted was used to obtain values in a closer range for more accuracy. 1-131labeled-hippuran clearances were obtained by using the standard formula: Volume urine ml/min. X Urine counts/ml/min. Serum counts/ml/min. RESULTS
In the 22 dogs studied, giving I-131-labeled hippuran with epinephrine intradermally, serum levels were relatively constant varying from 20-100 cts/ml./min. from one period to the next over four consecutive 30 minute periods in an individual animal. Eighteen patients also have had constant serum values ranging from 20 to 144 cts/min. over the 2 hour period. Figure 1 shows serum values of patients given I-131-labeled-hippuran intradermally as com-
pared to constant intravenous infusion. The points plotted are the mean serum values for each collection period for both intradermal and constant intravenous infusion patients. DISCUSSION
The fact is generally accepted, as Smith has stated, that constant, sustained blood levels of any substance are necessary for measurement of renal clearances. 1 For this reason, we have been primarily concerned with a simplified method of obtaining constant blood levels of I-131-hippuran. I-131-labeled-hippuran has been shown to be adequate for measurement of effective renal plasma flow. This method required a constant intravenous infusion of I-131-labeled-hippuran necessitating specialized equipment. The blood levels here were relatively constant from one clearance period to the next varying at a maximum from 10-100 cts/cc/min. Usually the count variation ranged from 30-50 cts/cc/min. However, even with variation as high as 110 cts/cc/min. values were adequate for clearances when compared with PAH clearances determined simultaneously. Since the indirect measurement of effective renal plasma flow is an estimation of normal clearances varying from 550-850 for P AH and hippuran, the exact value is not essential.
108
SMITH, O'DELL AND SCHLEGEL
Creatinine clearances and phenolsulfonphthalein excretion have been measured by giving a single subcutaneous injection. I-131-labeledhippuran clearances were attempted by a single subcutaneous injection but serum levels fell precipitously. Epinephrine was then added to the I-131-labeled hippuran solution to delay absorption which gave a more sustained blood level but still, the fall was too rapid. The intradermal injection of I-131-labeledhippuran with epinephrine has given as adequate and sustained blood levels as have been obtained by constant intravenous infusion. Renal clearances have been performed on patients by this method simultaneously with PAR and have been shown to be as adequate as with constant intravenous infusion. The difference in the level of serum counts/minute shown in the graph between intravenous and intradermal injection routes (fig. 1) is insignificant as it is a relative value rather than an absolute one. Immobilization of the part of the body at the site of injection is necessary for constant blood levels. vVhen immobilization was not done wide variations in serum levels were obtained. Massage at the site of injection in the dog is followed by a rapid rise in serum counts of 100-150 cts. It should be emphasized that blood should be drawn from the arm opposite the site of injection.
Blood drawn for the last clearance period on the same side of the injection of I-131-hippuran in one patient showed serum levels 4 times as great as the other three collection periods. Any analyzer that can count radioactive iodine such as is used for thyroid uptake can be used to count the samples. The only specialized equipment that is necessary is a. well-counter. After the ureteral or bladder catheters are placed, any personnel who can collect timed urine and blood samples can conduct the remainder of the study. In hypertensive studies when measurement of effective renal plasma flow is performed differentially, this method is being used exclusively in this laboratory. Its accuracy, ease and rapidity have been most gratifying. SUMMARY
Twenty-tv,-o dogs and 18 patients have been studied using I-131-labeled-hippuran with epinephrine intradermally for measurement of effective renal plasma flow. Serum levels obtained by intradermal route were as constant as serum levels obtained by constant intravenous infusion. The rapidity, ease and accuracy of the method for measuring the effective renal plasma flow have been emphasized.
If you plan to attend the ANNUAL MEETING of the AMERICAN UROLOGICAL ASSOCIATION, INC. in Philadelphia (May 14-17, 1962), please preregister early. Pre-Registration forms will be found in the advertising section, p. 4, in the front part of this journal. Merely pull out the Pre-Registration form, fill it in, and mail it.
Vol. 87, No. 2 February 1962 Copyright © 1962 by The Williams & Wilkins Co.
Printed in U.S.A.
A SIMPLIFIED METHOD OF DETERMINING EFFECTIVE REN AL PLASMA FLOW B. G. SMITH, *t, R. M. O'DELL
AND
J. U. SCHLEGEL
From Tulane University School of Medicine, Department of Surgery, Division of Urology, New Orleans, La.
Indirect measurement of the effective renal plasma flow is one of the major clinical tests for renal function. There has been an increased interest in the past few years in measuring effective renal plasma flow in each kidney simultaneously in patients with hypertension of suspected renal origin. Para-amino hippuric acid (PAH), phenol red, diodrast and hippuran have been used to measure clearances since at low plasma levels those substances are almost completely cleared from the plasma in a single passage through the kidney. 1 The standard laboratory analyses for these substances involve several different procedures that can introduce analytical error. At times, this procedure is neglected because of the con1plexity and time required for the study despite the valuable knowledge in regard to renal function that is obtained. There has been a continual search for a procedure that is less complicated and still accurate. It has been previously reported from this laboratory that I-131-labeled-hippuran when compared to PAH is accurate in determining effective renal plasma flow. 2 This procedure, however, requires a specialized pump that will give a continuous intravenous infusion of I-131hippuran to maintain constant blood levels. A further simplification has been made in that adequate blood levels can be obtained by giving I-131-labelecl-hippuran combined with epinephrine to delay absorption in a single intradermal injection. MA'I'ERIALS AND MSTHODS
Twenty-two female mongrel dogs and 18 patients of whom two were female and 16 were Accepted for publication July 25, 1961. This research was supported by Public Health Service Grant No H-4659, Abbott Laboratories and Louisiana Heart Association. * A Fellow under U. S. Public Health Training Grant No. CRT-5057. t Present address: Barnes Hospital, Division of Urology, St. Louis, Mo. 1 Smith, H. W.: The Kidney: Structure and function in health and disease. New York: Oxford University Press, 1951, chapt. 22, p. 1049. 2 Schlegel, J. U., Smith, B. G. and O'Dell, R. M,: Estimation of effective renal plasma flow using I-131-labeled hippuran. In press.
male varying in age from 11 to 72 years were included in the study. In the dog studies, the animals were anesthetized with 30 mg./kg. nembutal. A size 16 Foley catheter was inserted into the bladder to assure complete bladder drainage. Urine and blood were collected for blank values. An osmotic diuretic of 1000 cc 5 per cent dextrose in water containing 40 g. ureaphil (courtesy Abbott Laboratories) was given intravenously in the foreleg at a rate to maintain a urinary output of 2 cc/min. or greater. vVhen an adequate urinary output was obtained, clogs were given 30 uc I-131-labeledhippuran with epinephrine intradermally in the shoulder. The volume of solution given to both clogs and patients was 0.1 cc to 0.33 cc, depending on the decay of the labeled isotope, containing 0.01 cc 1 :1000 epinephrine in each 0.1 cc hippuran solution. In patients both total and differential clearances were measured. vVhen total renal function tests were done, a size 16 Foley catheter was placed in the bladder. In differential studies, size 7 whistle tip catheters were placed in each ureter through a cystoscope to a place where adequate drainage of urine was obtained. A size 16 Foley catheter was placed in the bladder after the cystoscope was removed. If bladder urine appeared, the site of leakage could be investigated and corrected. Blood and urine were collected for blanks. Patients were hydrated by giving 200 cc water by mouth every 30 minutes throughout the procedure. If a diuresis of 2 cc per minute or greater was not obtained by hydration alone, a solution of 1000 cc 5 per cent dextrose in water containing 80 g. ureaphil was given intravenously throughout the procedure. ·when an adequate urinary output was obtained, patients were given 100 uc I-131-labeled hippuran with epinephrine intradermally in the volar surface of the forearm immobilized on an arm board. After 1 hour to allow stabilization of I-131hippuran in the blood, the clearance periods were begun in both patients and dogs. At least
106
DETERMINATION OF EFFECTIVE RENAL PLASMA FLOW
constant inlra.venous int-usion
fntra.derma1 -----------............ .: 20Q,.____..,____ 0
30
'-:-
with
epinephrine
.... _--- ........ __
--.
__L_ _ _.J..___ _...J...__ _.....,L__ _L_------1
60
90
120
150
TIME llJ MIi-JUTES Fm. 1. Serum levels of I-131-labeled-hippuran obtained using constant intravenous infusion or single intradermal injection. 4 half-hour clearance periods were done collecting urine continuously and blood being drawn at the midpoint of each collection period. The Foley catheter was irrigated with air at the end of each collection period to assure complete bladder drainage. 1-131-labeled-hippuran levels in the serum and urine were obtained using model 132 analyzer computer (Nuclear, Chicago) to obtain counts/ ml./min. Three ml. serum and one ml. urine were counted for each clearance period. The difference in volume counted was used to obtain values in a closer range for more accuracy. 1-131labeled-hippuran clearances were obtained by using the standard formula: Volume urine ml/min. X Urine counts/ml/min. Serum counts/ml/min. RESULTS
In the 22 dogs studied, giving I-131-labeled hippuran with epinephrine intradermally, serum levels were relatively constant varying from 20-100 cts/ml./min. from one period to the next over four consecutive 30 minute periods in an individual animal. Eighteen patients also have had constant serum values ranging from 20 to 144 cts/min. over the 2 hour period. Figure 1 shows serum values of patients given I-131-labeled-hippuran intradermally as com-
pared to constant intravenous infusion. The points plotted are the mean serum values for each collection period for both intradermal and constant intravenous infusion patients. DISCUSSION
The fact is generally accepted, as Smith has stated, that constant, sustained blood levels of any substance are necessary for measurement of renal clearances. 1 For this reason, we have been primarily concerned with a simplified method of obtaining constant blood levels of I-131-hippuran. I-131-labeled-hippuran has been shown to be adequate for measurement of effective renal plasma flow. This method required a constant intravenous infusion of I-131-labeled-hippuran necessitating specialized equipment. The blood levels here were relatively constant from one clearance period to the next varying at a maximum from 10-100 cts/cc/min. Usually the count variation ranged from 30-50 cts/cc/min. However, even with variation as high as 110 cts/cc/min. values were adequate for clearances when compared with PAH clearances determined simultaneously. Since the indirect measurement of effective renal plasma flow is an estimation of normal clearances varying from 550-850 for P AH and hippuran, the exact value is not essential.
108
SMITH, O'DELL AND SCHLEGEL
Creatinine clearances and phenolsulfonphthalein excretion have been measured by giving a single subcutaneous injection. I-131-labeledhippuran clearances were attempted by a single subcutaneous injection but serum levels fell precipitously. Epinephrine was then added to the I-131-labeled hippuran solution to delay absorption which gave a more sustained blood level but still, the fall was too rapid. The intradermal injection of I-131-labeledhippuran with epinephrine has given as adequate and sustained blood levels as have been obtained by constant intravenous infusion. Renal clearances have been performed on patients by this method simultaneously with PAR and have been shown to be as adequate as with constant intravenous infusion. The difference in the level of serum counts/minute shown in the graph between intravenous and intradermal injection routes (fig. 1) is insignificant as it is a relative value rather than an absolute one. Immobilization of the part of the body at the site of injection is necessary for constant blood levels. vVhen immobilization was not done wide variations in serum levels were obtained. Massage at the site of injection in the dog is followed by a rapid rise in serum counts of 100-150 cts. It should be emphasized that blood should be drawn from the arm opposite the site of injection.
Blood drawn for the last clearance period on the same side of the injection of I-131-hippuran in one patient showed serum levels 4 times as great as the other three collection periods. Any analyzer that can count radioactive iodine such as is used for thyroid uptake can be used to count the samples. The only specialized equipment that is necessary is a. well-counter. After the ureteral or bladder catheters are placed, any personnel who can collect timed urine and blood samples can conduct the remainder of the study. In hypertensive studies when measurement of effective renal plasma flow is performed differentially, this method is being used exclusively in this laboratory. Its accuracy, ease and rapidity have been most gratifying. SUMMARY
Twenty-tv,-o dogs and 18 patients have been studied using I-131-labeled-hippuran with epinephrine intradermally for measurement of effective renal plasma flow. Serum levels obtained by intradermal route were as constant as serum levels obtained by constant intravenous infusion. The rapidity, ease and accuracy of the method for measuring the effective renal plasma flow have been emphasized.
If you plan to attend the ANNUAL MEETING of the AMERICAN UROLOGICAL ASSOCIATION, INC. in Philadelphia (May 14-17, 1962), please preregister early. Pre-Registration forms will be found in the advertising section, p. 4, in the front part of this journal. Merely pull out the Pre-Registration form, fill it in, and mail it.