Pyrazinamide tubular reabsorption

Glomemlar filtration rate (GFR) was estimated through endogenous creatinine clearance and the rate of urate filtration from GFR and semm urate. The pyrazinamide suppres-sible part of the urate excretion was the intial excretion (UV-ur) minus the minimum excretion during PZA suppression (UV-ur, min). The tubular reabsorption of filtered urate (TR-ur) was calculated from GFR and the minimum urate clearance during PZA... 

Patients with a proximal renal tubular acidification defect had a basal urate excretion not different from controls or hyperuricosuric patients. Their response to pyrazinamide was, however, more pronounced than in controls and hyperuricosuric patients. The calculated tubular reabsorption of filtered urate was higher than in both controls and hyperuricosuric patients. It is suggested that this may contribute to the higher serum urate and the lower urate clearance in stone formers with a proximal renal acidification defect compared to patients with a normal acidification of the urine that we have reported on previously (4). 

A pyrazinamide suppression test (Table l) indicated defective renal tubular reabsorption of urate. The clearance of urate and the ratio of the urate clearance... 

The results obtained by studying the effect of probenecid on the clearance of urate were consistent with the pyrazinamide test, indicating defective renal tubular reabsorption of urate. Administration of probenecid, which normally increases the urate clearance by two to five- fold (7), affected the uric acid clearance in the patient only slightly, increasing it from 55.3 ml/minute to 74.8 ml/minute. The ratio of the urate clearance to the inulin clearance increased from 65% to 84%. 

Secreted urate (Ts urate) was calculated as the amount of urate excreted per ml GFR before pyrazinamide minus the amount excreted per ml GFR after the drug was given (during the period where maximal suppression of urate was apparent). Tubular reabsorption (Tr) was expressed as a percent of filtered load. This was calculated as the amount of urate filtered (assuming no protein binding) minus the excreted urate at the point where maximal suppression was evident. Fractional excretion of urate was expressed as the percent of filtered load excreted during pyrazinamide administration. Urine samples for amino acid excretion were collected within three months of the urate studies while patients were off D-penicillamine. The amino acids were measured on a Phoenix amino acid analyser. 

To test the hypothesis that part or all of renal tubular reabsorption of urate occurs distal to urate secretion, pyrazinamide suppression tests were carried out after inhibition of urate reabsorption. Probenecid or sulfinpyrazone was used to block urate reabsorption. 

Most drugs act by reducing active transport rather than by enhancing it. Thus, drugs that promote uric acid loss (uricosuric agents, such as probenecid and sulfinpyrazone) probably inhibit active urate reabsorption, while pyrazinamide, which reduces urate excretion, may block the active tubular secretion of uric acid. A complicating observation is that a drug may primarily inhibit active reabsorption at one dose and active secretion at another, frequently lower, dose. For example, small amounts of salicylate will decrease total urate ex-... 

On June 6, this patient developed severe loin pain after he participated in two 150-m sprints at a town athletics meeting. After 5 days, he was referred to the outpatient clinic of our department. His serum creatinine and uric acid levels and FEUA, were 2.9mg/dl, 2.1 mg/dl, and 49.7%, respectively. His creatine phosphokinase (CPK) level was normal. When his serum creatinine level decreased to 1.58 mg/dl, a contrast medium was administered. A delayed computed tomography (CT) scan after 24 and 48 h confirmed patchy wedge-shaped contrast enhancement (Fig. 58). Under a diagnosis of ALPE, his body water balance (hydration) was controlled. In this patient, recovery was achieved 4 weeks after onset, and his serum creatinine and uric acid levels were then 1.0 mg/dl and 0.6 mg/dl, respectively. Furthermore, load tests with a uric acid reabsorption inhibitor (benzbromarone) and a uric acid excretion inhibitor (pyrazinamide) suggested presecretory reabsorption defect-related renal hypouricemia. A kidney biopsy 16 days after onset confirmed the recovery from acute tubular necrosis. 

The mechanisms involved in urate reabsorption are not well known. The reabsorptive mechanism in at least a few species represents active transport urate may be reabsorbed from tubular fluid of the Cebus monkey when the concentration of urate is smaller than in the plasma and smaller than that predicted by the transepithelial electrical potential difference at equilibrium. Furthermore, in man and the chimpanzee, the concentration of urate in urine becomes smaller than that in the plasma when the secretion of urate is inhibited by the administration of pyrazinoic or pyrazinamide (Roch-Ramel and Weiner, 1980, review). 

We were able to conduct three different studies of agents which interfere with renal transport of urate during continuous inulin infusions. The first such study (a pyrazinamide suppression test), is shown on the next slide. The data from these experiments will be shov/n as the ratio of urate clearance to inulin clearance. A ratio greater than 1.0 reflects tubular secretion while a lower ratio would suggest reabsorption. The time of day is on the horizontal axis labelled "hours". 

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