Monoexponential analysis of plasma disappearance of 99mTc-DTPA and 131I-iodohippurate: a reliable method for measuring changes of renal function.

Glomerular filtration rate and effective renal plasma flow were measured in 170 subjects using monoexponential analysis of plasma disappearance curves for 99mTc-DTPA and 131I-iodohippurate after single injection. In the current study population, glomerular filtration rate and effective renal plasma flow decreased with increasing age, were less in females than in males, and were less in hypertensives than in normotensives. Differences in glomerular filtration rate according to age and sex in the current study were similar to those reported using traditional creatinine clearance methodology. Monoexponential treatment of plasma isotope disappearance gave reproducible values for both glomerular filtration rate and effective renal plasma flow when measured either during the day or on a daily basis. Intraindividual coefficient of variation was less than 10% for both 99mTc-DTPA and 131I-iodohippurate clearances derived from monoexponential analysis. These results demonstrate that monoexponential analysis of plasma disappearance curves for 99mTc-DTPA and 131I-iodohippurate after a single injection is a useful method for evaluating changes in renal hemodynamics either during chronic drug therapy or acutely after single dose administration.

Assessment of glomerular filtration rate and effective renal plasma flow in cystic fibrosis.

A study was conducted to examine renal function in 10 healthy control subjects and eight patients with cystic fibrosis in stable condition. Sequential bolus injections of 99mTc-DTPA and 125I-OIH were administered to assess glomerular filtration rate and effective renal plasma flow, respectively. Blood was subsequently collected for 3 hours, and urine for 24 hours. Renal clearances of both radioisotope markers were virtually identical in patients and controls. Inasmuch as neither glomerular filtration rate nor effective renal plasma flow was enhanced in patients with cystic fibrosis, increased clearance of drugs in these patients is unlikely to be the result of enhanced glomerular filtration or tubular secretion.

o- and M-iodohippurate binding to plasma proteins as a model drug transport mechanism.

The pharmacokinetics of two isomers, o- and m-iodohippurate, were determined in rabbits and rats and the effect of protein binding on their elimination is demonstrated. Both isomers are rapidly eliminated by transport systems in the kidney and their clearance by the kidney approaches the renal plasma flow regardless of protein binding, m-Iodohippurate is more highly bound to plasma proteins than o-iodohippurate and its rate of elimination is enhanced in comparison with o-iodohippurate. In the case of these two isomers, the binding to plasma proteins should be considered as a transport mechanism and not as a storage depot.

[Integral index of the rate of blood clearance of labelled hippuran]. / Integral'nyi pkozatel' skorosti ochishcheniia krovi ot mechenogo gippurana.

Significant correlation between the values of the effective renal blood flow (RBF) and indices calculated on a curve of "blood" radioactivity was established. Based on a comparison between RBF values and indirect indices some equations were obtained characterizing mathematical dependence between them. A conclusion has been made that the integral index of blood clearance of labeled hippuran calculated by indirect indices, is more accurate and can be used in routine studies.

Comparison of measurement of effective renal plasma flow by single plasma sample and plasma disappearance slope/volume methods.

Numerous simplified methods for the estimation of ERPF have described, including the so-called slope/intercept (SI) methods, based on the analysis of the slope of certain segments of the 131I-OIH plasma disappearance curve and its y-axis intercept, and the single sample (SS) clearance method, based on theoretical volumes of OIH distribution at some fixed time after injection. Using ERPFs estimated from compartment analysis of the entire 60-min plasma disappearance curve, we have compared the errors of data calculated from use of eight SI methods made at various times along the disappearance curve with that from the optimum SS curve. The errors obtained from the SS method were approximately 50% less than those obtained from the SI methods. The errors of the SI methods are greater at both ends of the 60-min plasma curve than when samples are drawn near the mid-time. The SS method appears to be the method of choice for the estimation of ERPF using single injection techniques.

Comparative evaluation of renoscintigraphic properties and plasma clearance of 99MTc-DADS (99mTc-N,N'-bis/mercaptoacetamido ethylenediamine), 99mTc-DTPA and 131I-o-hippuran.

Plasma clearance of 99mTc-N,N'-bis (1,2-mercaptoacetamido) ethylenediamine (DADS), 99mTc-DTPA and 131I-o-hippuran (OIH) was determined in rabbits from blood-concentration decay curves after single i.v. injection of the compounds. Dynamic scintigraphy was performed using the same three compounds, and "activity" curves were compared as observed over kidney ROIs. Both clearance values and renoscintigraphic curves were similar for 99mTc-DADS and 99mTc-DTPA but evidently different from those of OIH. Biliary excretion of 99mTc-DADS was also observed. It appears that, in contrast to other authors, 99mTc-DADS cannot serve as a substitute for 131I-o-hippuran.

New formulas for the calculation of effective renal plasma flow.

Estimation of effective renal plasma flow (ERPF) can be made easily, inexpensively, and accurately by means of a single plasma concentration determination, sampled 44 min after injection of 131I-orthoiodohippurate (OIH). We originally established predictive regression equations based on a series of patients with a wide variety of diseases and a few normal potential kidney donors. The equation best fitting that data was parabolic in form and assumed a negative slope when high ERPF rates were encountered. This problem has been corrected by deriving new equations (parabolic and exponential) based on an expanded series which includes a large number of subjects with high ERPF. Errors of estimation are lower than those of the more classic para-aminohippuric acid (PAH) clearances and well within the exigencies of clinical practice.

Comparison of renal extraction efficiencies for radioactive agents in the normal dog.

The renal extraction efficiencies for various radioactive agents were measured in normal anesthetized dogs during 1 hr after a single intravenous injection. Radioassays were made on serial blood samples drawn simultaneously from the aorta upstream from the renal arteries and from one renal vein. As a reference substance [131I]o-iodohippurate was injected concurrently in all experiments. Blood clearances from serial venous samples and urinary excretion also were measured. Extraction efficiency from whole blood was calculated as (A-V) divided by A, where A = aortic concentration and V = renal venous concentration. This ratio for commercial [131I]o-iodohippurate fell steadily from 88% at 30 sec to 50% at 1 hr. For "purified" [131I]o-iodohippurate the fall was less marked, to 61% at 1 hr. The EE ratios for all other agents were stable after the first minute. The Tc-99m complexes of DTPA, glucoheptonate, and acetylcysteine had ratios averaging 27-29%. The ratios of Tc-99m DMS and Hg-197 chlormerodrin had much lower average values of 8 and 14%, respectively. None of the newer agents approached the extraction efficiency of [131I]o-iodohippurate.

Evaluation of effective renal plasma flow during renography.

A method to determine effective renal plasma flow that requires only a single injection of 131-iodine hippuran and eliminates the necessity of obtaining blood samples is described. Good correlation was obtained between this procedure and a method requiring a blood sample. The technique should prove useful in determining effective renal plasma flow when difficulty is encountered in obtaining blood. However, before it is used as a method in its own right it must be compared to an independent method of measuring effective renal plasma flow.

[Estimation of 131I-Iodohippurate-clearance by a simplified method using a single plasma sample (author's transl)]. / Die Bestimmung der 131J-Hippuranclearance nach einer vereinfachten Methode mit nur einer Blutentnahme.

Theoretical volumes calculated from the reciprocal of the plasma concentration after intravenous injection of 131I-Iodohippurate were compared in 95 patients with clearance values calculated by the 2-compartment-method and in 18 patients with conventional PAH-clearance. For estimating Hippurate-clearance from a single blood sampling the most favorable time is 45 min. after injection (r = 0.96; clearance < 400/ml/min.: r = 0.98). Clearance values may be derived from the formula: C = 0.4 + 7.26 V - 0.021 . V2 (V = injected activity/activity per l plasma taken 45 min. after injection). The simplicity, precision and reproducibility of the above mentioned clearance-method is emphazised.

Kinetics of 131 I-o-iodohippurate in rats.

The organ distribution of 131I-o-iodohippurate (OIH) was studied in rats in the time interval of 1--1440 min. The mean decrease of OIH in plasma was fitted with a function composed of three exponential terms. A three-compartment model describing kinetics of OIH in rats was suggested and its parameters were computed. Comparison of organ and plasma concentrations of OIH showed that the liver, up to 30 min, and the heart and lungs, up to 15 min after administration, form with plasma a common central compartment.

Error dependent on renal function when monoexponential equation assumed. Serum clearances of 125I-iothalamate and 131I-o-iodohippurate.

An example from the literature has been used to demonstrate errors involved in calculating drug clearance by inappropriate use of the apparent drug distribution volume Vdext. The Vdext is always an overestimate of the true volume of distribution in a multicompartment system, and the degree of overestimation in using it to calculate clearance for such a system will increase as renal function increases. Drug dosages calculated on the basis of overestimated clearance values may give rise to overdosage in normal individuals, or therapeutic failure in severely uremic patients. Problems associated with the use of an oversimplified pharmacokinetic model for clearance calculations are discussed, together with the concept of model-independent calculations.

Application of the gamma function for the calculation of effective renal plasma flow by [131I]hippuran clearance.

A simplified technique based on the gamma function was developed to determine the effective renal plasma flow (ERPF) by [131I]hippuran clearance. The method requires only one blood sample in addition to standard renography and the calculations can be performed on a small computer. A close correlation was found between the ERPF values obtained by the application of the gamma function and the values yielded by the conventional bi-exponential approach. The present method is well suited for clinical routine use in connection with standard renography.

The collateral blood flow and hippuran clearance of the rabbit kidney after occlusion of the renal artery.

The collateral blood flow to the rabbit kidney was determined by two methods: (1) measurement of the venous flow after clamping of the renal artery and (2) Hippuran clearance of the clamped kidney. The collateral blood flow was found to be 0.012 ml/min/g kidney equivalent to 0.2% of the entire blood flow to the rabbit kidney. Compared with collateral blood flow in other mammals (as humans and dogs) with a collateral flow of 6.2% of the normal flow, the collateral blood flow in the rabbit is very modest. The cranial ureteric artery contributes more than 90% of the entire blood flow, while capsular perforants, important in other mammals, play no role in the supply of the rabbit kidney. Only 50% of the collateral blood flow passes the tubular system. Flow to the medulla calculated from Hippuran clearance was 35% greater than flow to the cortical part of the kidney. The subcapsular cortical tubuli were able to absorb Hippuran from the peritoneal fluid and surrounding tissues after the kidney was dissected free from its surroundings and all vessels severed. Absorption corresponded to an arbitrary serum flow of 0.0002 ml/min/g.

A computer program for automatic recording and processing of renograms.

A program is described, which performs automatic uptake, plotting and processing of radio-hippuran renograms obtained from a gamma camera, using an on-line minicomputer system. The program is written in machine language for a ND 50/50 system equipped with a PDP8-L processor, but translation for other nuclear medicine EDP system is easy. Minimum configuration requirements are: (i) 4K processor with TTY; (ii) external clock; (iii) magnetic tape transport; and (iv) 4K + 4K buffered camera interface or additional 8K of storage plus camera interface. Camera interface is computer-controlled and includes two AD-converters, a display unit for buffer storage and interest-areas selection facility. Operation starts recording 40 scintiphotographs of 30 sec each. Then, kidney uptake curves are obtained by subtraction of blood and tissue background, and diagnostic parameters, such as the initial slope, the maximum uptake point and 50% activity time, are computed. The only manual intervention required is the computer-assisted selection of interest-areas of kidneys, and blood and tissue background. Time required is 20 min for uptake of renograms and 5 min for processing and output, thus allowing routine execution of good quality renography, including hardcopy printout of both kidney uptake curves and diagnostic paramerers.