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The renal blood flow and function were studied after acute ligation of the inferior caval vein craniad to the right renal vein in rabbits. Ths function as measured by th: extraction of EDTA and Hippuran diminished and often reached the lowest values on the fourth day. After tha fourth day, either renal function will return to normal values or renal failure will develop. The renal blood flow first diminished, then increased toward normal values which could occur rather early—four days—but mostly took 16 days. The low glomerular filtration rate is revealed roentgenologlca!ly by low density of the urogram and a weak nephrographic phase of the cortex during renal angiography. Segmental drainagz with several “water sheds” develops in thz inferior caval vein. The most important drainage of the renal veins is by way of the supra-renolumbar wins.

The aim of this study is to present a comparison between different mathematical models that can be used to represent renal function, as characterized by the I–hippuran method. Based on physiological considerations, a general model for renal function is established, and three special and less complex models are derived a priori by choosing special values for some of the parameters of the general model. The three special models have previously been investigated by other authors. A general‐purpose computer program has been developed to fit any of the four models to the kinetic data. Parameters inherently dependent on the detection technique are calculated by a special method independent of the estimation of the physiologically relevant model parameters. Output from the computer program is used to determine which model gives the most relevant interpretation of I–hippuran renographic curves. In accordance with recent examinations performed by other workers, the results seem to indicate that each kidney can be satisfactorily represented by an ordinary compartment in series with a “delay compartment.”

Summary Serial computer assisted blood background subtraction renograms have been performed in 8 patients with acute renal failure. One patient showed an initial tracing identical to that from a case with a bilateral nephrectomy; in 2 patients initial tracings were indistinguishable from those of cases of advanced chronic parenchymal renal disease; however all 3 patients made a complete recovery. In 3 patients symmetrical continuously rising renograms were obtained as previously reported in acute renal failue. In 2 patients asymmetrical renograms were obtained which could have been interpreted as indicating obstructive uropathy. Renography in acute renal failure must be interpreted with extreme caution. We are grateful to Professor A. Polak and Dr H. A. Lee for their advice.

The pig, especially the miniature pig, has in recent years been used increasingly frequently as a laboratory animal and experience shows that as such it is very useful in many circumstances. The aim of the present investigation was to study the renal function in unsedated and unrestrained pigs. Techniques for the implantation of central venous catheters, for cystostomy, for thyroidectomy and for open kidney biopsy are described. Implantation of central venous catheters and cystostomy are necessary procedures for making clearance studies in unsedated and unrestrained pigs possible. The following mean values for the renal function were obtained: ClIn 4.11 ml/min/kg, Cl51Cr-EDTA-p 3.82 ml/min/kg, Cl51Cr-EDTA-w.b. 3.89 ml/min/kg, ClPAH 21.4 ml/min/kg, Cl125I-hippuran 17.4 ml/min/kg, TmPAH 4.31 mg/min/kg and TRP over 80%.

The reliability of serial microdilution techniques was investigated by diluting serum containing [ 125 I] hippuran. Four different techniques were tested: 1) The Pasteur pipette; 2) Microtiter metal transfer diluters, used in 3 versions; 3) The Eppendorf pipette; 4) A semi-automatic diluter designed in our department. The semi-automatic diluter, the Eppendorf pipette and the modified automatic metal transfer diluter produced acceptable results. Because of its reliability, simplicity and low cost we prefer the semi-automatic diluter.

After a single injection with the mixture of125I-hippuran and169YB-EDTA complex, each blood sample was collected from the patients at the 7th and 17th-minute for the ERPF determination and at the 3rd and 4th hour the determination of GFR. By using the device GAMMA-NK-108 (Budapest) set to the photopeak of125I radiation, from 12 to 16 per cent of the radiation of169Yb had been recorded. That required a correction of the recorded counts for125I-hippuran. As in the photopeak of169Yb the influence of125I was eliminated, corrections in the determination of GFR were not required.

Four groups of canine kidneys were preserved by hypothermic perfusion for 24 hours in an attempt to compare the relative merits of using cryoprecipitated plasma or albumin as perfusates and of using pulsatile or non-pulsatile flow. All the kidneys were subsequently autotransplanted At 0, 3 and 24 hours during preservation the following parameters were measured: perfusate and urine flow, renal vascular resistance, perfusate serum glutamic oxaloacetic transamianase, lactic dehydrogenase, acid and alkaline phosphatases, ammonia, free fatty acids, clearances of creatinine, 131I hippuran, Na+ and K+. After reimplantation similar renal clearance studies were carried out. After transplantation overall kidney viability was assessed by recipient survival and by serum creatinine levels. The results obtained were subjected to statistical analysis and compared between the groups. It was found that perfusion with albumin solution gave a significantly higher perfusate flow rate (P

Autotransplantation has proved a suitable experimental model for the study of transplantation factors unrelated to immune response. Experimental autotransplantation of kidney enables us to assess the possible adverse effects of perfusion and ischaemia on the graft, to check the adequancy of the surgical anastomoses and to followup the function of the organ. The fate of autogenous renal graft which had been stored for 4 or 24 hours at +4°C has been studied in dogs by radiorenocystography, using131I-hippuran. The procedure lends itself to the follow-up of the adverse effects of perfusion and transplantation at praerenal (vascular), renal (glomerular and tubular) as well as subrenal (urinary passage) levels. The radiorenogramsin vivo convey accurate information on the prevailing state of renal transplants.

Methods currently available for measurement of renal blood flow with radio-nuclides in man include clearance-extraction ratio, indicator dilution, and inert-gas washout. Only the gas washout method, involving 133 Xe or 85 Kr, provides data on intrarenal distribution of blood flow; it also permits the measurement of renal blood flow of individual kidneys and may be used in oligoanuric patients. It necessitates selective catheterization of the renal artery and external counting. The gas washout technique represents to date the most satisfactory method of studying renal hemodynamics in man. However, several problems remain unresolved, among which are the assumption of instantaneous gas diffusion in any normal or pathological state, the effects of the intra-arterial bolus injection, the exact significance of the second component of the washout curve, and the value of data obtained by computer analysis of the curves.

A review of the wide spectrum of radiopharmaceuticals developed over the last 15 yr for application in the evaluation of diseases of the kidney and urinary tract is presented below. The radiolabeled contrast agents including Hippuran have been extensively applied for renal function assessment. The kinetics of clearance of many of these agents are not yet satisfactorily established, and there is no ideal agent for routine clinical application, particularly by external counting methods. Many agents for intrarenal blood flow measurement have been reported that have yet to be adapted for obtaining clinical information. Renal morphology has been studied using several radiopharmaceuticals that are either fixed in the renal tubules for a sufficiently long time (chlormerodrin, 99m Tc-Fe ascorbic acid) or cleared from the kidneys fairly rapidly (Hippuran). These agents suffer from several disadvantages because of suboptimum energy of the radiolabel for use with imaging equipment, or relatively high radiation dose, or slow rate of excretion with inadequate organ specificity. It is hoped that the development of new radiopharmaceuticals tagged with radionuclides that have ideal imaging characteristics ( 99m Tc or 111 In) and satisfactory renal clearances will provide a major breakthrough in the continuing search for satisfactory renal agents for imaging and function tests in the near future.

99m-Technitium radioactive colloid particles were suspended in an iodine-131 Hippuran radioactive fluid medium and placed into the bladders of 6 patients. Two normal patients and one with only one urinary tract infection voided the fluid and particles synchronously, while three with recurrent urinary tract infections eliminated the particles at a much slower rate than the fluid. A change in either the physical contour or secretory activity of the bladder urothelium is postulated as the cause of particle retention in these patients with chronic infections.

Slices of rabbit kidney cortex, pieces of lateral choroid plexus and of ciliary body with iris were incubated in a potassium-rich medium containing iodipamide and o-iodohippurate labelled with different isotopes as test substances for the L-and the H-system respectively. Cholic, deoxycholic, chenodeoxycholic, lithocholic and dehydrocholic acids and their glycine and taurine conjugates were added as inhibitors and their ability to suppress iodipamide uptake preferentially compared. The most selective inhibitor was free chenodeoxycholic acid, followed by deoxycholic. Considerable inhibition was caused at 100, μM by the dihydroxy acids. At this concentration uptake of quaternary cations as “toxicity indicators” was hardly affected. Non-ionic detergents were unselective inhibitors. Thus, bile acids have affinity for the liverlike anion transport system in the kidney, eye and choroid plexus.

The technique of the regional renogram and of the conventional renogram was applied to a group of 100 patients with known hypertension, and the results of the two tests were compared. The regional renogram revealed more changes of renal function than the conventional renogram. Twenty-three of the 100 patients exhibited unilateral abnormal regional renogram; ten of the 100 patients exhibited unilateral abnormal conventional renogram. The ten patients with abnormal conventional renogram had similar changes noted by the regional renogram. The latter is probably the more sensitive screening test. A small group of 23 patients had had both regional renogram and renal arteriogram. There may be a better correlation between the regional renogram and the renal arteriogram than between the latter and the conventional renogram.

1. An improved method is presented for quantifying all the information relating to individual kidney function that is contained in the renogram. 2. From the convolution theorem, functions are derived which are equivalent to the renograms that would be obtained by simultaneous injections of the indicator into each renal artery, fractionated according to renal blood flow. 3. The ‘pulse-input’ renograms so derived can have the blood background subtracted by a process of ‘kinetic discrimination’, which dispenses with the prior injection of human serum albumin. 4. The ‘pulse-input’ renograms with blood background subtracted are analysed by the techniques used in conventional indicator dilution methods. 5. The value of this approach in clinical and experimental work is illustrated by comparison of examples drawn from 400 consecutive studies of patients with normal data.

The increasing frequency of renal transplantation has stimulated the development of diagnostic methods of evaluating the functional integrity of the graft. Radionuclide techniques have achieved great popularity in this regard. Although clearance studies, fibrinogen uptake, and conventional probe renography have been used with success, the imaging studies of the kidney recently have been of particular interest. Sequential scintiphotography with 131 I Hippuran has been shown to facilitate the diagnosis of problems such as vascular thrombosis, acute tubular necrosis, acute and chronic rejection, urinary extravasation, and ureteral obstruction. Although the appearance of the kidney in any one study may be diagnostic, it is of much greater value to observe improvement or deterioration of function studies with bolus injections of 99m Tc pertechnetate to establish the patency of the newly anastomosed vascular pathways.

A review of methods used in performing radionuclide renal clearance is presented. Adequate radionuclide substitutes for inulin and paraaminohippurate (PAH) have made possible a variety of techniques for measuring glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). The major deterrents to the standard inulin and PAH clearance procedures, including difficult chemical determinations, continuous intravenous infusions, timed catheterized urine collections, and frequent blood sampling, have been varyingly eliminated by the newer radionuclide clearance techniques: chemical determinations are replaced by simple gamma counting; the need for continuous infusions is obviated by the ability to quantitate gamma activity at very high and very low concentrations; urine collections can be eliminated by the analysis of plasma disappearance or by measuring the infusion rate necessary to maintain a constant plasma level; frequent blood sampling can be minimized by external gamma monitoring or by utilizing established volumes of distribution and inter-compartmental clearance based on patient studies. An attempt is made to present superficially the basic concepts used in analyzing plasma disappearance after a single intravenous injection. Mathematical derivations are not presented in depth, although some considerations of the two-compartment system are given in the Appendix. Although there are few disadvantages in using the newer radionuclide techniques compared with the standard infusion methods, direction from an individual with a firm foundation and genuine interest in renal physiology is paramount in establishing these procedures as acceptable and reproducible substitutes for measuring GFR and ERPF.

Externally monitored radioisotopic renal function studies have proven to be diagnostically useful in a variety of urinary tract disorders. Controversy, however, concerning everything from equipment and patient preparation to information content and interpretation has surrounded the procedure since its inception. The theses presented here are that the choice of equipment is determined by the intended use, that a few major physiologic events determine the shape of the curves produced in the studies, that the information content exceeds what has been extracted to date, and that subtle renal abnormalities are better detected by intercomparison of a patient's two kidneys than by comparison to values derived from a selected normal population. Choice of patient preparation and interpretation of the results depend on understanding the physiology involved in the procedure.

1. The depression of p-aminohippurate and o-iodohippurate transport induced by uraemic serum in rabbit and rat renal cortex in vitro was confirmed. At the same time no change in oxygen consumption was observed. 2. The transport of the tetraethylammonium ion was unimpaired by uraemic serum from man or rat. 3. When sera from neomycin-treated uraemic rats were incubated with rabbit renal cortex, the uptakes of p-aminohippurate and of o-iodohippurate were 50% higher than when sera from untreated uraemic rats were used. 4. In rat uraemic serum, the levels of hippuric and indole acetic acids are markedly elevated. Administration of neomycin causes a substantial reduction in these levels. 5. The implications of these observations upon the impaired renal transport of hippurates produced by uraemic serum is discussed.

A mathematical model for renography is presented. The model is based solely upon physiological quantities. With the aid of this model the following information can be deduced: 1. (1) The individual clearance of the kidneys expressed in percent of total clearance. 2. (2) An estimate of the ratio of the urinary flow to the volume of the renal pelvis. This quantity is obtained by comparing the measured renogram with simulated renograms, in which the urinary flow and the volume of the renal pelvis are known. 3. (3) In additon the measurement procedure gives the ordinary renogram and a blood clearance curve. The solutions of the differential-difference equations involved, are presented. Oscillations (waves or steps) in the excretory phase, often observed in measured renograms, were predicted by the mathematical treatment and must be regarded as normal phenomena.

Plasma creatinine, IVP, GFR, and renography were analysed in 53 candidates for unilateral nephrectomy. Renography was used to determine how the function was distributed between the two kidneys. Twelve of 29 patients with normal plasma creatinine had decreased GFR. One-third of 74 individual kidneys showing normal function at IVP had GFR values below 30 ml/min. There was poor agreement between the radiological and renographic estimation of function distribution. In 6 of 14 patients who were not nephrectomized mainly because the other kidney had a reduced function, the kidney scheduled for removal had the major function. GFR and renography were particularly informative in cases with elevated plasma creatinine and normal IVP.

Forty-seven diabetic patients with duration of diabetes of 1 to 40 years and 31 normal subjects were investigated using classical renal clearance technique. Glomerular filtration rate (GFR) and renal plasma flow (RPF) were significantly increased in patients with juvenile diabetes mellitus of short duration. There was no correlation between GFR and serum glucose concentration, or between GFR and serum sodium concentration. A significant decrease in both GFR and RPF was found with increasing duration of diabetes. If consistent proteinuria was not present in the long-term diabetics, no reduction could be demonstrated in GFR and RPF.

By means of polygraphic recordings complete independence of the sequence of sleeping and waking and of the two sleep states (REM and NREM) could be demonstrated in twins extensively conjoined at the skulls. Functionally important connections in the circulation of the two babies were found during subsequent preoperative investigations. These observations are at variance with the hypothesis of an extraneuronal humoral sleep-inducing factor based on crossed-circulation experiments in animals; moreover they raise a new question about the transportation of the sleepregulating biogenic amines.

A new technique for iodine labelling of aromatic iodine compounds is described and applied to the preparation of 131I-labelled m-iodohippuric acid (m-IHA). Being stored in saline solution, labelled m-IHA is more stable with respect to formation of free radioiodide than o-iodohippuric acid (o-IHA). Detailed animal experiments in rats and dogs lead to the conclusion that there are no significant differences in the behaviour of o-IHA and mIHA.

Renal arteriography before and after infusion of 0.5 mg. of glucagon into the renal vascular bed using both routine and magnification roentgenographic techniques reveals vasodilatation lasting up to 120 minutes throughout the entire arterial tree with improved visualization of the small vessels. Measurement of renal blood flow by a dye dilution technique shows an average rise of 65 cc. min. with no change in appearance time but a concomitant fall in mean transit time. In association with the increase in renal blood flow, there is a fall in the PAH extraction ratio. These results suggest that glucagon might be a useful pharmacologic adjunct in renal arteriography, particularly because of its prolonged effect.

The authors demonstrate the advantage of the Pearson functions for describing the renal weighting function. The Pearson functions allow easy introduction of a timelag, and their shape is close to that of the dilution curves. The relations between the average characteristics of the input and output functions are examined and the weighting function is calculated by the moments method. The proposed representation is used to describe the renal weighting function of the data of Gomez (dye in man). A theoretical example enables the limits of validity of the moments method to be determined. The authors conclude with a specimen calculation of the renal impulsional response to hippuran 131 I.

In 11 newly diagnosed juvenile diabetics a clearly abnormal high glomerular filtration rate (GFR) has been found. During treatment with insulin the GFR fell towards the normal level. The normalization of GFR was associated with normalization of fasting growth hormone level, suggesting that the growth hormone hypersecretion in diabetics may play a role in mediating the high GFR observed in these patients. The results obtained in the various clearance tests, including dextran clearance, suggest that the mechanism responsible for the increase in GFR in untreated diabetes is probably an abnormality of the tone of the afferent and/or efferent vessels of the glomerulus and not structural defects in the capillary membrane.

A digital computer model of the radio-Hippuran renogram has been developed to simulate the normal renogram previously described for this laboratory. The parameters used correspond to previously established physiologic values whenever such data were available, e.g. plasma volume, effective renal plasma flow, renal transit time and cardiac output. The apparent Hippuran space and body background were determined from patient studies. Intercompartmental transfer and intra-renal mixing rates were of necessity computer derived from the best fit. The model gives an estimate within ±5 per cent of the mean normal renogram and the 30-min excretion. Model results do not correspond as closely to the apparent Hippuran space. A simultaneous good fit of all three results does not appear possible with any combination of parameters which differ greatly from the values used. The model successfully simulates disease states, such as reduction in renal blood flow, mechanical obstruction and renal artery stenosis.

Experiences of 39 radioisotope, renographic measurements are described concerning 31 patients suffering from renal tuberculosis of different stages. For no group of diseases including tuberculosis did renography prove to be pathognostic. The method is suitable only for semiquantitative measurement of certain functions of kidneys and the upper urinary tract, resp., but inadequate for qualitative diagnosis. The diagnosis of urogenital tuberculosis should be based, therefore, on bacteriological and radiological examinations. The isotope renography is nevertheless a useful supplementary method to estimate the degree of parenchymal destruction, and the draining activity of the upper urinary tract. The method is free from risk and rather, sensitive, giving a good control tool to follow up the effectiveness of the bacteriostatic treatment. The occurrence of false negative results is claimed in case of small ulcerative processes. Observing false positivity the patient should be further examined by other methods, owing to the possibility of a subclinical tuberculous process. The renograms of 7 patients are presented in detail.

SUMMARY The interpretation of the renogram is not straightforward. This is due to the complexity of the kidney and not to any complexity in the technique of renography. The commonly used empirical method of interpretation is discussed. The technique of Computer Assisted Blood Background Subtraction (C.A.B.B.S.) renography is described and a theory of the renogram is presented which leads to a rigorous method of quantitation. The ratio between the efficiencies with which the kidneys take up Hippuran can be obtained. This is equivalent to the ratio of the effective renal plasma flows. It is hoped to quantitate aspects of the mechanism of transport of Hippuran through the kidney in order to assess renal autoregulation and other aspects of nephron function.

Summary The use of 1311-Hippuran for the determination of the residual urine volume has been studied. It has been shown that a significant error is introduced into residual urine calculation by the small amounts of 1311-Hippuran which continue to be excreted in the urine for some hours after intravenous injection, even when renal function is good. The rise in activity over the bladder area appears to be linear with time in individual patients, but the slope is unpredictable. True residual urine volume can be calculated if readings of the activity in the bladder area and at the background site are taken at a short, measured interval after voiding, and again 30 minutes later. The use of such a corrective calculation has a number of practical advantages, and makes the determination more accurate. The activity measured over the umbilicus with the patient supine appears to give a satisfactory tissue background reading.

A theoretical analysis of the simplified radiohippuran kinetics in organism, with regard to the radiohippuran renogram evaluation, is presented. The biological processes are characterized by rate coefficients. The theoretical influence of main processes, which are involved in the kinetics, was shown on the form of radiohippuran renogram.

The reaction of o-iodohippuric acid with labeled iodide has been shown to afford exclusively labeled o-iodohippuric acid. The same compound has been synthesized from anthranilic acid. The rate of exchange was sufficiently rapid to permit the preparation of 132I and 128I labeled o-iodohippuric acid. The mechanism of the exchange is discussed.