Uric acid reabsorption

The answer is e. (Katzung, p 254.) Furosemide affects the re absorption of uric acid in the proximal tubule. It increases uric acid reabsorption... 

Loop diuretics can cause hyperuricemia and precipitate attacks of gout. This is caused by hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule. It may be prevented by using lower doses to avoid development of hypovolemia. 

Tiaprofen is a racemic propionic acid derivative but does not undergo stereoconversion. It has a short serum half-life (1-2 hours) with an increase to 2-4 hours in the elderly. This drug inhibits renal uric acid reabsorption and thus decreases serum uric acid slightly. It is available for oral and intramuscular administration. Its efficacy and adverse event profiles mirror those of other NSAIDs, but tiaprofen is not available in the USA. 

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. 

Two mechanisms responsible for phenylbutazone-induced acute oligo-anuric renal failure include 1) inhibition of uric acid reabsorption, leading to hyperu-ricosuria and, ultimately, bilateral ureteral obstruction due to uric acid stones [112] 2) an idiosyncratic reaction has been reported that results in acute tubular injury without uric acid precipitation [113]. 

Electrolyte imbalances K+, i Mg +, i Na+, i Cl, T uric acid reabsorption in the proximal tubules can precipitate gouty attacks. Other side effects include rash, T glucose, dizziness, photosensitivity, i BP, headache, T lipids. 

MOA Inhibit prostaglandin synthesis by decreasing activity of cyclo-oxygenase Decreases the deposition of urate crystals in joints by decreasing leukocyte motility Decreases the motility of PMN leukocytes Competitive inhibition of uric acid reabsorption at the proximal tubule Inhibits xanthine oxidase, thus preventing uric acid production... 

Approximately 90% of filtered uric acid is reabsorbed in the proximal tubule, probably by both active and passive transport mechanisms. There is a close linkage between proximal tubular sodium reabsorption and uric acid reabsorption, so states that enhance sodium reabsorption (e.g., dehydration) also lead to increased uric acid reabsorption. The exact site of tubular secretion of uric acid has not been determined this too appears to involve an active transport process. Postsecretory reabsorption occurs somewhere distal to the secretory site. 

The distal tubule secretes 80% of the uric acid content in urine. The reabsorption of most of the uric acid (98%) in the glomerular filtrate takes place in the proximal tubule. This reabsorption can be inhibited by thiazide diuretics, thus increasing uric acid excretion in urine. The chronic use of diuretics, however, by depleting the extracellular fluid volume provides a stimulus for uric acid reabsorption. Drugs that promote uric acid excretion (uricosuric drugs) include probenecid, sulfinpyrazole, and salicylates in high doses. In low doses salicylates depress uric acid excretion. 

Uricosuric diuretic A diuretic that increases uric acid excretion, usually by inhibiting uric acid reabsorption In the proximal tubule. Example ethacrynic acid... 

In most patients with gout, the flow of plasma in the kidney, the glomerular filtration rate, and the renal clearance are normal, and no excess urates are found. Some investigators have claimed that gout is associated with abnormal tubular reabsorption of uric acid (93% in patients with gout versus 91% in normal individuals), leading to an absolute increase in total uric acid reabsorption and an accumulation of uric acid in the blood. 

Bear in mind that on the scale of this figure the control ratio in normal individuals would be less than 0.1 and that this would drop to 0.02 after pyrazinamide. The data in our patient supports the use of pyrazinamide as an agent to suppress the secretion of urate but we are unable to say whether complete suppression is achieved with a 3 gram dose or to evaluate any possible independent effects on uric acid reabsorption. 

In 1961 Gutman and Yu proposed a three component system for the regulation of the renal excretion of uric acid in man. The first component of this system is filtration of plasma urate at the glomerulus. While this process is certain to be operative in the human kidney, its quantitative role in the renal excretion of uric acid in man depends upon the extent of urate binding to plasma proteins in vivo. This is a subject that is being discussed in another section of this symposium and will not be considered further in this paper. The second and third component of this system relate to uric acid reabsorption and secretion by the human nephron. Ample data is available to document that both of these processes are operable in the human kidney (Gutman and Yu, 1957 Gutman, et al., 1959), but the relative contribution of each to the final excretion of uric acid has been difficult to determine with conventional clearance techniques. However, a potential solution to this problem of bidirectional uric acid transport appeared in 1967 when Steele and Rieselbach introduced the "pyrazinamide suppression test . 

The test is performed by determining uric acid excretion before and after the administration of pyrazinamide or its metabolite pyrazinoic acid (PZA) in a dosage sufficient to give maximal suppression of uric acid excretion. The decrement in uric acid excretion after PZA administration is taken as a quantitative measure of uric acid secretion. In addition the difference between filtered load of uric acid and uric acid excretion at the time of maximal PZA effect is taken as a quantitative measure of uric acid reabsorption. These estimates of uric acid secretion and reabsorption assume the following conditions (Table 1) ... 

Secretion of uric acid must occur distal to uric acid reabsorption in the nephron. 

PZA must completely block uric acid secretion without altering uric acid reabsorption. 

All uric acid secretion occurs distal to uric acid reabsorption in the human nephron. 2) PZA completely blocks uric acid secretion and it has no effect on uric acid reabsorption and 3) If PZA is to be used to determine the mechanism responsible for a change in uric acid excretion following the administration of a drug, PZA does not interfere with the metabolism or transport of that drug. 

Urinary uric acid is thought to be derived from two sources uric acid filtered at the glomerulus and incompletely reabsorbed, and uric acid secreted by the renal tubules. The magnitude of the decrease in urinary uric acid which follows administration of pyrazinamide has been widely accepted as an estimate of the secretory component of urinary uric acid. This estimate is dependent upon the assumption that the site of uric acid reabsorption in the renal tubule is proximal to the site of its secretion. Recently, we have reported that total urinary uric acid excretion increases when urine flow rate increases, and have suggested that this was the result of decreased distal tiibular reabsorption of uric acid. 

Xanthinuria is a rare hereditary disorder characterized by a gross deficiency of xanthine oxidase activity in tissues with a resultant decrease in urinary uric acid excretion and a concomitant increase in the excretion of xanthine and hypoxanthine in the urine. The differential diagnosis of hypouricemia includes many disorders such as uricosuric drugs, a specific defect in uric acid reabsorption from the tubule as reported by Praetorius and Kirk (1) and the Fanconi syndrome such as heavy metal intoxication or Wilson s disease. These are associated with an increase in uric acid excretion however while the association of hypouricemia and hypouricosuria in conjunction with xanthinuria is an expression of xanthine oxidase impairment either primary or induced by enzyme blockers such as allopurinol. 

---