Uric acid proximal tubule reabsorption

Ociasionally. a patient may experience hypercalcemia or liypcr-uiicemia after long-term use of a thia/idc or thia/idc-like diuretic. Tliis results from diuretic-induced reduction of the pti-irem s plasma volume and a concomitant compeasulory increase in the proximal tubule reabsorption of luminal fluid and solutes. In such a situation, mote Ca and uric acid than usual will be reabsorbed proximally. The seriousness of these two adverse cffccLs depends in part on the duration and extent of the plasma volume r uction. 

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

When probenecid (ColBENEMID) is given in sufficient amounts, it will block the active reabsorption of uric acid in the proximal tubules following its glomerular filtration, thereby increasing the amount of urate eliminated. In contrast, low dosages of probenecid appear to compete preferentially with plasma uric acid for the proximal tubule anionic transport system and thereby block its access to this active secretory system. The uricosuric action of probenecid, however, is accounted for by the drug s ability to inhibit the active reabsorption of filtered urate. 

A. Probenecid blocks active reabsorption of uric acid in the proximal tubules following glomerular filtration. It does not inhibit uric acid synthesis (B), stimulate tubular secretion (C), or inhibit the metabolism of purines (D). 

Mechanism of Action An antigout agent that competitively inhibits reabsorption of uric acid at the proximal convoluted tubule. Also, inhibits renal tubular secretion of weak organic acids, such as penicillins. Therapeutic Effect Promotes uric acid excretion, reduces serum uric acid level, and increases plasma levels of penicillins and cephalosporins. 

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. 

Uricosurics, such as probenecid or benz-bromarone (100 mg/day), promote renal excretion of uric acid. They saturate the organic acid transport system in the proximal renal tubules, making it unavailable for urate reabsorption. When underdosed, they inhibit only the acid secretory system, which has a smaller transport capacity. Urate elimination is then inhibited and a gout attack is possible. In patients with urate stones in the urinary tract, uricosurics are contraindicated. 

Most diuretics cause hyperuricemia. Increased reabsorption of uric acid (along with other solutes) in the proximal tubule as a consequence of volume depletion is one reason however, diuretics also compete with uric acid for excretory transport mechanisms. There is a small increased risk of acute gout in susceptible subjects (73). In the large outcome trials, about 3-5% of subjects treated with diuretics for hypertension developed clinical gout... 

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... 

Since the kidneys are the main depot for cadmium, they are of greatest concern for cadmium toxicity. Cadmium interferes with the proximal tubule s reabsorption function. This leads to abnormal actions of uric acid, calcium, and phosphorus. Amino aciduria (amino acids in the urine) and glucosuria (glucose in the urine) result in later stages, proteinuria (protein in the urine) results. When this happens, it is assumed that there is a marked decrease in glomerular filtration. Long-term exposure to cadmium leads to anemia, which may result from cadmium interfering with iron absorption. 

Renal handling of uric acid is complex and involves four sequential steps (1) glomerular filtration of virtually aU the uric acid in capillary plasma entering the glomerulus (2) reabsorption in the proximal convoluted tubule of about... 

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. 

Another transporter expressed in proximal tubule epithelial cells is URATl. URATl is responsible for the reabsorption of urate in the kidney. Gout, an inflammatory disease, results from elevated body levels of uric acid. It is believed that an inherited deficiency in URATl expression is a causative factor in the disease. Treatment includes administration of uricosuric agents such a probenecid and sulfinpyrazone increase uric acid excretion through inhibition of URATl. 

EFFECTS ON URINARY EXCRETION Since the late distal tubule and collecting duct have limited capacity to reabsorb solutes, blockade of Na+ channels in this part of the nephron only mildly increases the excretion rates of Na and Ck ( 2% of filtered load). Blockade of Na channels hyperpolarizes the luminal membrane, reducing the lumen-negative transepithelial voltage. Since the lumen-negative potential difference normally opposes cation reabsorption and facilitates cation secretion, attenuation of the lumen-negative voltage decreases the excretion rates of K+, H+, Ca +, and Mg +. Volume contraction may increase reabsorption of uric acid in the proximal tubule hence chronic administration of amiloride and triamterene may decrease uric acid excretion. Amiloride and triamterene have little or no effect on renal hemodynamics and do not alter TGF. 

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

Mechanism Uricosuric agents (probenecid, sulfinpyrazone) are weak acids that compete with uric acid for reabsorption by the weak acid transport mechanism in the S2 segment of the proximal renal tubule. At low doses, these agents may also compete with uric acid for secretion by the tubule and (occasionally) can even elevate serum uric acid concentration. Elevation of uric acid levels by this mechanism occurs with aspirin (another weak acid) over much of its dose range. 

Aspirin clearly increases bleeding tendency (by its antiplatelet effects). The answer is (D). Probenecid inhibits the reabsorption of uric acid in the proximal tubule. (Both secretion and reabsorption of weak acids occur in the proximal tubule, not the loop of Henle.) The answer is... 

Uricosuric inhibitor of renal weak acid secretion and reabsorption in segment of proximal tubule prolongs half-life of penicillin, accelerates clearance of uric acid. Used in gout. Sulfinpyrazole is similar. 

At least partial clarification is provided by recent work fo Zins and Weiner (59) which demonstrated a secretory flux for taurocholate in the proximal tubule which can be inhibited by the administration of p-aminohip-purate, a secreted substance. This flux, which presumably traverses the well-known mechanism for organic anion secretion, is normally overshadowed by the larger active reabsorptive process which occurs in the same tubular segment. This is not a unique example of bidirectional transport in a single tubular segment uric acid is similarly handled (60). 

This phenomenon is believed to be due to excretion by the kidneys of the uric acid passing in the plasma from extrahepatic tissues to the liver where uricase is located. Uric acid is completely filtered at the glomerulus and both actively reabsorbed and actively secreted in the proximal tubule (39, 40). In the dalmatian the reabsorptive process is deficient, and active secretion leads to the urinary excretion of uric acid. 

The treatment of the chronic gouty patient aims at maintaining the lowest possible blood uric acid level. This can be achieved either by preventing reabsorption of uric acid in the proximal tubules or by blocking uric acid biosynthesis through normal metabolic pathways. 

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. 

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