The Measurement of Glomerular Filtration Rate and Effective Renal Plasma Flow in Man by lothalamate 1251 and lodopyracet "3'I

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1 The Measurement of Glomerular Filtration Rate and Effective Renal Plasma Flow in Man by lothalamate 11 and lodopyracet "3'I By CHARLES M ELWOOD, MD, AND EUGENE M SIGMAN, MD SUMMARY In 21 patients, 9 simultaneous renal clearances of inulin and sodium iothalamate 11, and para-amino-hippuric acid (PAH) and iodopyracet 1311 were determined by a constant infusion technique The activities of iothalamate 11 and iodopyracet 131I were determined simultaneously in a dual-channel scintillation counter The concentrations of inulin and PAH were determined by standard chemical techniques The ratio of iothalamate 1I to inulin clearance ranged from 93 to 19 with a mean of 1 The ratio of iodopyracet 1311 to PAH clearance varied from 86 to 14 with a mean of 96 The chemical determination of PAH and inulin required approximately 8 hours of technician time as compared with 3 minutes by the radioactive technique The determination of the renal clearances of iothalamate 1I and iodopyracet 131I is an accurate and time-saving technique for the measurement of glomerular filtration rate and effective renal plasma flow Additional Indexing Words: Inulin PAH RENAL HEMODYNAMICS are most commonly measured by the clearances of inulin and para-aminohippuric acid (PAH) which reflect, respectively, the glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) The chemical determination of these compounds, however, requires considerable laboratory time and may be complicated by the presence of interfering substances The standard deviation of repeated inulin determinations on the same sample is approximately 5%1 Moreover, the measurement of inulin requires further modification when increased concentrations of glucose are present Although the chemical determination of PAH is simpler and more accurate than From the State University of New York at Buffalo, School of Medicine, and the Buffalo General Hospital, Departments of Internal Medicine and Urology, Buffalo, New York Paper was presented at the Third International Congress of Nephrology, Washington, District of Columbia, September 29, 1966 Investigation was supported by the John A Hartford Foundation, Inc 441 that of inulin, sulfonamides give the same color reaction The simplicity and accuracy with which the activity of gamma-emitting isotopes can be quantitated have facilitated the measurement of renal hemodynamics by the use of radio-labeled compounds whose clearances are the same as either inulin or PAH The availability of sodium iodide crystal scintillation counters equipped with dual-channel pulse-height analyzers has made possible the development of double-isotope techniques This paper reports the use of iothalamate 1J* and iodopyracet 1311* for the measurement of GFR and ERPF in man Methods Twenty-one patients with various diseases were selected so that all levels of renal function would be represented In 17 patients bladder clearances and in four patients individual kidney clearances were done Bladder clearances were performed twice on one patient Twenty-six studies were done in all Diuresis was initiated with an *Iothalamate 11 (Glofil) and iodopyracet 131I (Diodrast) were obtained from Abbott Laboratories, North Chicago, Illinois

2 AA42 ELWOOD, SIGMAN Table 1 Priming and Sustaining Doses Employed Drug Iothalamate 1I Iodopyracet 131I Stable iodopyracet Inulin PAH Priming 5,uc/kg 5,mc/kg 8 mg/kg 5 mg/kg 8 mg/kg Sustaining GFR x = ERPF x 1 = ERPF x 2 = GFR X = ERPF X 2 =,uc/min,uc/min mg/min mg/min mg/min oral water load of 1, ml and sustained by the ingestion of 5 ml/hr Clearances were performed in the fasting state by the continuous infusion technique2 Urines were collected from an inlying bladder catheter or a ureteral catheter during split renal function studies performed on four patients After an equilibration period of 1 hour, one to four 15-minute collections of urine were made Venous blood samples were withdrawn 6 minutes before the midpoint of each collection period through a three-way stopcock fitted to an indwelling, no 18, venous needle This allowed the repeated removal of blood samples without discomfort to the subject The clearances of iothalamate 11 and iodopyracet 131I were measured simultaneously with those of inulin and PAH The priming and sustaining dosages employed are given in table 1 The plasma activity of both iothalamate 11 and iodopyracet 1311 obtained by this dosage schedule was approximately 5 counts/min/ml Standard laboratory methods were used for the measurement of inulin3 and PAH4 The activities of iothalamate 1I and iodopyracet 1311 were measured to a statistical accuracy of 1% or better in an automatic gamma-counter equipped with a dual-channel pulse-height analyzer Clearances were calculated from the formula C= UV, where C is the clearance in ml/min, V the urine flow in ml/min, U the urine, and P the plasma concentration The activities of iothalamate 1I and iodopyracet 1311 were expressed in net counts/min/ml and those of inulin and PAH in mg/ml The free iodine content of iothalamate 11 and iodopyracet 131I was determined by paper chromatography on several but not all lots of radioisotopes and was found to be less than 15%* Results The results of 9 clearances from studies on 21 patients are shown in table 2 The mean *Determinations were made by Dr Howard J Glenn, Abbott Laboratories, North Chicago, Illinois iothalamate 1I/inulin clearance ratio was 1 and varied from 93 to 19 (fig 1) The mean iodopyracet 131I/PAH clearance ratio was 96 and ranged from 86 to 14 (fig 2) Discussion Smith and associates5 suggested that the ideal compound for the measurement of GFR should be completely filtrable at the glomerulus, not bound by plasma proteins, neither reabsorbed nor excreted by the renal tubules, and easily quantitated Inulin has been the substance thought to best meet these criteria, and recent micropuncture studies in the rat have indeed shown complete recovery from a distal site of inulin injected proximally6 Yet, the chemical determination of inulin remains troublesome This difficulty has been overcome by the use of radioactive compounds excreted by glomerular filtration Allyl inulin 1I is a satisfactory substitute, but the radioiodine tends to become detached from the parent molecule, and free iodine must be removed before use7 57Cobalt-labeled vitamin B12 provides an accurate measure of GFR but requires the prior injection of stable B12 to saturate protein-binding sites and the use of a factor to correct for this binding8 The renal excretion of the newer tri-iodinated benzoic acid derivatives used as contrast media appears to be solely by glomerular filtration The clearances of radioiodinated forms of the sodium (Hypaque9) and meglumine (Renografin') salts of diatrizoate and the sodium salt of its isomer, iothalamate (Conray11) have approximated those of inulin in man Evidence that iothalamate 131I is not excreted by the renal route in aglomerular fish and that changes in its concentration in tubular fluid during stop-flow studies on

3 MEASUREMENT OF GFR AND ERPF 443 Table 2 Simultaneous Clearances of lothalamate 1I, Inulin, Iodopyracet 131I, and PAH Study C -I iothal C Inulin C 1I C Inulin C 131i iodopy C PAH C 131I C PAH

4 444 ELWOOD, SIGMAN Table 2 (continued) C 1I C 1I C l1ji C 131J Study iothal C Inulin C Inulin iodopy C PAH C PAH Circulation, Volume XXXVI September 1967

5 MEASUREMENT OF GFR AND ERPF 445 Table 2 (continued) C 1I C 1I C 13IJ C 131J Study iothal C Inulin C Inulin iodopy C PAH C PAH C = Clearances calculated in ml/min IGO to 14 1' Io z 5 11 N -J _l J LI J 4 I- a Z 4 3 t 1 'Sr o 8 9 au INULIN CLEARANCE ML / MIN Figure 1 Simultaneous iothalamate 1I and inulin clearances

6 446 ELWOOD, SIGMAN '- 131 I mi/rmin * 2' o C PAH the dog parallel those of inulin strongly suggests that no difference exists between the renal handling of inulin and iothalamate12 Iodopyracet was the first substance widely used for the measurement of ERPF, but it was determined by a complicated chemical method which involved measurement of the amount of iodopyracet iodine present13 The finding that PAH and iodopyracet at low plasma concentrations had identical clearances and extraction ratios and that the chemical determination of PAH was much simpler led to the substitution of PAH for iodopyracet14 The introduction of gamma-emitting isotopes into clinical medicine has allowed further simplification of the measurement of ERPF Although PAH had no place in its molecular structure for the substitution of a m/ / min Figure 2 Simultaneous iodopyracet 1311 and PAH clearances gamma-emitting atom, ortho-iodo-hippurate (OIH), previously shown to have renal clearances identical with those of PAH,4 was easily labeled with radioiodine by the process of free substitution Contrary to expectations, the OIH 1311/PAH clearance ratio ranged from only 84 to 88, a finding that could be accounted for only in part by the presence of free iodine in commercially available preparations 15-7 This disappointment with OIH led us to reconsider the use of iodopyracet 131I for the measurement of ERPF, even though earlier studies had shown that clearances of tracer doses of iodopyracet l31i were consistently 2% to % lower than those of PAH18 A possible explanation for this discrepancy became apparent when radioactive tracer dos-

7 MEASUREMENT OF GFR AND ERPF ages, given with carrier amounts of stable iodopyracet, were found to have clearances similar to those of the stable fonn This observation suggested a strong but quantitatively limited affinity of some binding compound, possibly a plasma protein, for iodopyracet, so that at the very low plasma concentrations achieved with tracer doses, a significant proportion of the total iodopyracet would be tightly bound and not available for tubular extraction The critical plasma iodopyracet level, above which binding appeared to be of little significance, was found to be 1 p,g/ ml19 The use of carrier iodopyracet, calculated to produce a plasma concentration of 5 mg/ ml and tagged with tracer dosages of iodopyracet '31I, allowed us to achieve a mean iodopyracet/ PAH clearance ratio of 132 In the later series reported in this paper, the mean ratio was 96 and compared favorably with the obtained by Chasis and associates14 which formed the basis for their recommendation that PAH replace iodopyracet The iothalamate '1-iodopyracet 13l1 technique is identical to the inulin-pah method until the required urine and plasma samples are obtained At this point, pipetting of 1-ml aliquots into counting tubes is the only additional processing needed for the radioisotopic technique, since samples are changed automatically, once a predetermined count is attained, and activities are printed out directly on tape in counts per minute per milliliter The half hour needed to pipette samples and load the counter represents a marked saving in time over the usual 8 hours required for the chemical determination of inulin and PAH in our laboratory Acknowledgment The authors gratefully acknowledge the technical assistance of Mary Louise Kelly, Christine Marcinkiewicz, and Marni Butterfield References 1 WESSON, L G, JR: Glomerular and tubular factors in the renal excretion of sodium chloride, Medicine (Balt) 36: 281, SMITH, H W: Principles of Renal Physiology, New York, Oxford University Press, SCHREINER, G E: Determination of inulin by means of resorcinol, Proc Soc Exp Biol Med 74: 117, SMITH, H W, FINKELSTEIN, N, ALIMINOSA, L, CRAWFORD, B, AND GRABER, M: Renal clearances of substituted hippuric acid derivatives and other aromatic acids in dog and man, J Clin Invest 24: 388, SMITH, H W: The Kidney: Structure and Function in Health and Disease, New York, Oxford University Press, MARSH, D, AND FRASIER, C: Reliability of inulin for determining volume flow in rat renal cortical tubules, Amer J Physiol 29: 283, CONCANNON, J P, SUMMERS, R E, BREWER, R, COLE, C, WEIL, C, AND FOSTER, W D: I1 allyl inulin for the determination of glomerular filtration rate, Amer J Roentgen : 32, NELP, W B, WAGNER, H N, JR, AND REBA, R C: Renal excretion of vitamin B12 and its use in measurement of glomerular filtration rate in man, J Lab Clin Med 63: 48, BURBANK, M K, TAUXE, W N, MAHER, F T, AND HUNT, J C: Utilisation des substances marquees dans les e'preuves classiques de clearance renale, J Physiol (Paris) 55: 433, MoRRIs, A M, ELWOOD, CHARLES, SIGMAN, E M, AND CATANZARO, ANTONINO: Renal clearance of 1311 labeled meglumine diatrizoate (Renografin) in man, J Nucl Med 6: 183, SIGMAN, E M, ELWOOD, C M, AND KNOX, FRANKLYN: Measurement of glomerular filtration rate in man with sodium iothalamate 131I (Conray), J Nucl Med 7: 6, GRIEP, R J, AND NELP, W B: Mechanism of renal excretion of iodine-131-sodium iothalamate (Conray), J Nuel Med 7: 37, SMiTH, H W, GOLDRING, WILLIAM, AND CHASIS, HERBERT: Measurement of the tubular excretory mass, effective blood flow, and filtration rate in the normal human kidney, J Clin Invest 17: 3, CHASIS, H, REDISH, J, GOLDRING, W, RANGES, H AND SMITH, H W: Use of sodium P-aminohippurate for the functional evaluation of the human kidney, J Clin Invest 24: 583, TAUXE, W M, BURBANK, M K, MAHER, F T, AND HuNT, J C: Renal clearances, Proc Mayo Clin 39: 761, SCHLEGEL, J U, SMITH, B G, AND O'DELL, R M: Estimation of effective renal plasma flow using I131-labeled hippuran, J Appl Physiol 17: 8, SCHWARTZ, F D, AND MADELOFF, M S: Simultaneous renal clearances of radiohippuran and PAH in man, Clin Res 9: 28, SCHLUNGBAUM, W, AND BILLION, H: Die Bes-

8 448 timmung der effektiven Plasma-Nierendurchstrdmung mit radioaktivem, mit 1131 markiertem Perabrodil-M Strahlentherapie (Sonderb) 36: 145, BLOCK, J B, AND BURROWS, B A: Influence of serum protein binding on renal clearance of ELWOOD, SIGMAN I131-labeled Diodrast, J Lab Clin Med 56: 463, ELWOOD, C M, ARMENIA, J, ORMAN, D, MOR- Ris, A, AND SIGMAN, E M: Measurement of renal plasma flow by iodopyracet 1131, JAMA 193: 771, 1965 The Choice of Medicine as a Profession There was still another story my father used to tell me When out hunting in the hills of northern Alabama, one time when he was a young man, he put his shotgun carefully over a fence before attempting to climb it, as all good hunters do, pointing it away from any of the party Then he attempted to climb over the barbed wire fence himself, but he slipped and caught the seat of his trousers on a barb of the fence The trousers were ripped violently He felt a sharp pain A barb had caught his scrotum "My scrotum ripped, and then I saw the inside of my scrotum dangle out like a little worm" I remember his exact words, "I held the torn place to me and went to the nearest doctor The doctor cleaned it out and took a few stitches in it They put a dressing on it and it soon healed" This seemed sheer magic to me It seemed as if I, too, had been ripped by that barbed wire and as though the surgeon-magician thereby had made my birth possible many years later I felt almost as much obligated to that surgeon for the gift of life as I did to my father-merrill MOORE In FABRICANT, N D (Editor): Why We Became Doctors New York, Grune & Stratton, 1954, p 15