DEPRESSION OF THE EXOGENOUS CREATININE/INULIN OR THIOSULFATE CLEARANCE RATIOS IN MAN BY DIODRAST AND p-AMINOHIPPURIC ACID 1

Abstract

Exogenous creatinine is excreted by the renal tubules of the aglomerular fish (1 to 4), the glomerular dogfish (5, 6), teleost (7) and chicken (8), but not by the frog (9), turtle (10), dog (11 to 14), sheep (15), seal (16), rabbit (17) or cat (18). Among the mammals tubular excretion is recorded only in the anthropoid apes (19,20) and man (21).The evidence for tubular excretion in man, as initially advanced by Shannon, consists of the facts that (1) the exogenous creatinine/inulin clearance ratio exceeds 1.0 (ranging from 1.2 to 1.7) (21,22,23); (2) this ratio is depressed towards 1.0 by raising the plasma level of creatinine (21); (3) at all plasma levels, the creatinine/inulin clearance ratio is depressed towards 1.0 by phlorhizin (21) which is known to depress the tubular excretion of phenol red (24) and diodrast (25).Winkler and Parra (26) observed that after the ingestion of creatinine, both the creatinine clearance and the creatinine/sucrose clearance ratio behaved erratically and generally fell as the experiment proceeded, and they believed that this progressive fall with time represented the same phenomenon as the self-depression of the clearance at high plasma levels. Shannon and Ranges (27) have, however, presented evidence to refute this view. They have shown that (a) the creatinine/inulin clearance ratio does not fall markedly with time if the plasma level is maintained by the continuous infusion of creatinine, (b) a second dose of creatinine elevates the clearance ratio, after this has been depressed by the lapse of time, towards the values observed shortly after a first dose, and (c) this elevation occurs only if the ratio has been depressed by virtue of the prolonged circulation of creatinine in the body. These ob1Aided by a grant from the Commonwealth Fund.servations appear to exclude 'fatigue' and 'stimulation' of the excretory mechanism. They accord with the possibility suggested by the above investigators; namely, that in the body creatinine is converted in part to a compound which, though still giving the Jaffe reaction, is less readily excreted by the tubules; or, alternatively, to a compound which blocks excretion by virtue of a high competitive affinity for some component of the excretion mechanism. This latter possibility is rendered more plausible by the recent description of caronamide (28), a compound not excreted by the tubules but one which blocks the excretion of some other substances (phenol red, diodrast, penicillin, etc.).The evidence for the tubular excretion of exogenous creatinine in man has not been convincing to all writers (29) and it has seemed desirable to examine the matter further.Substances excreted by the renal tubules appear in general to interfere in the excretion of other substances, presumably by competition for some enzyme system or source of energy. Thus diodrast and hippuran depress the excretion of phenol red and vice-versa (30, 2A possible exception to this interference phenomenon is observed in the dogfish, where creatinine, though copiously excreted b...

Cardiovascular, Renal, and General Effects of Large, Rapid Plasma Infusions in Convalescent Men 1

“…As facilities for inulin or mannitol clearances were not available, creatinine clearance was used as a reflection of glomerular filtration, although it is generally felt that inulin or mannitol better measure this in man (31,32). Creatinine/inulin ratios recently published (33,34) suggest, however, that creatinine clearance is a fairly good measure of glomerular filtration, especially when PAH or diodrast is administered concurrently.…”

Thiosulphate Clearance in Pregnancy

“…Using the single injection method, they found that the thiosulphate/ inulin clearance ratio fell within the range of 0.7 to 1.3 (average 0.99 + 0.08) and that this ratio was independent of the plasma concentration between 6 and 60 mg. per 100 cc. The apparent identity of these clearances has been confirmed by Brun (3), Crawford (4), and Blegen, Qrning, and Aas (5), while Bj0rnboe, Dalgaard-Mikkelsen, and Raaschou (6) report that in three subjects the thiosulphate/inulin clearance ratio is higher when the urine is alkaline than when it is acid.…”

A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

“…This occurred at physiological (9) as well as increased creatinine plasma levels (14,17). Similarly, studies in humans, dogs, and chicken revealed that organic anions can inhibit renal creatinine secretion (5,8,27,29). Moreover, while cimetidine inhibits OCT, it can also inhibit transport mediated by OAT1 and OAT3 (1,6,19), and basolateral uptake of cimetidine is additively blocked by probenecid and tetraethylammonium, blockers of organic anion and cation transporters, respectively (15,36,38).…”