1. Following a single intravenous injection of inulin, values for the renal clearance of inulin (Cin = µν/P) show a steady decline, with diminishing values of plasma inulin concentrations.
2. Employing values of P 6 minutes before the mid‐point of the clearance period, in place of values 2½‐minutes before the mid‐point, does not eliminate this phenomenon.
3. Employing the formula Cin = µν/P, the fall in values for clearance is due to the fact that the renal excretion of inulin (µν) is not proportional to the plasma level (P), since the imposition of a linear relationship between the two variables results in lines which deviate significantly from the point of origin.
4. The lack of proportionality is shown not to be due to the sampling of venous blood as an estimate of arterial plasma inulin concentrations.
5. The dependence of the magnitude of the renal clearance of inulin upon the plasma concentration of inulin is found also in three subjects using the continuous infusion method of administration. This excludes the possibility that the results obtained, following a single injection of inulin, are distortions of a simple proportional relationship consequent upon the dynamics of distribution of inulin in the body following a single injection.
6. The results of the experiments, and those of other workers, are held to suggest strongly that, in man, inulin is reabsorbed by the tubules to a significant extent. Hence the use of inulin clearance as a measure of glomerular filtration rate involves a systematic error, which is estimated to be about 15 per cent. under the usual circumstances.
1. The assumption underlying methods for determining the renal clearance of inulin from the slope of the falling plasma curve of inulin concentration, following a single injection, is investigated.
2. The concept that, following the injection of inulin into the blood‐stream, equilibration occurs between the plasma and the extra‐vascular component of the volume of distribution is shown to be untenable. The conclusion that the falling plasma‐inulin concentration is exponentially related to time is consequently incorrect.
3. The errors introduced in the determination of the renal clearance of inulin from the slope of the falling plasma inulin‐time curve by the assumption of equilibration are discussed.
4. A formula is devised for the determination of the renal clearance of inulin incorporating functions which are demanded by the failure of the establishment of equilibration.
5. The formula is applied to the determination of the renal clearance of inulin in nine subjects possessing widely different clearance values. These calculated values are shown to agree closely with average values experimentally determined.
6. The calculative error introduced into the formula by the simplifying assumption that the volume of distribution of inulin is linearly related to time between defined limits of inulin dose and time, has been shown to be of no greater magnitude than the chemical error in the determination of inulin in the plasma.
7. The formula can be applied without the need for accurate collection of urine over short clearance periods. It necessitates merely the passage of urine approximately 35 and 120 minutes after the injection of a known amount of inulin, and two blood samples taken at the time of the passage of urine.
8. The simplicity of the method in comparison to those previously described is attained without loss of accuracy. The greater degree of precision in the measurement of the constituents of the formula than is possible in the direct estimation of the rate of renal excretion of inulin, renders values for clearance obtained by its use less susceptible to experimental error.
9. The relevance of the results obtained with inulin to the determination of the rate of glomerular filtration employing mannitol are discussed briefly.
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