Urate Reabsorption Research Articles

On the mechanism of the paradoxical effect of salicylate on urate excretion.

In 1959 Yu and Gutman reported that aspirin in a dose of 2g/day or less resulted in decreased urate excretion while at doses greater than 3g/day, urate excretion was increased (1). They also found that alkalinization of the urine with bicarbonate increased both salicylate and urate excretion. These results were interpreted as showing that low concentrations of salicylate in tubular urine inhibited tubular secretion of urate and high concentrations inhibited both tubular secretion of urate and reabsorption of urate. Since the overall result of tubular transport of urate is net re-absorption, uricosuria appeared when tubular salicylate concentrations were sufficiently increased.KeywordsTubular SecretionSalicylate ConcentrationTubular TransportUrate TransportUrate ExcretionThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

The influence of D-glucose of phosphate absorption in the rat proximal tubule.

The present studies demonstrate that a tubular maximum for phosphate absorption is present in the proximal tubule in the rat. In addition, the presence of D-glucose in the solution on the luminal side of the renal tubular cells inhibits phosphate absorption. The effect of D-glucose on phosphate absorption requires the tubular absorption of D-glucose and does not appear to be due to an interaction between glucose and phosphate at the luminal surface of the renal tubular cells.

Effect of combined administration of furosemide and aspirin on urinary urate excretion in man.

Furosemide (20 mg) was administered intravenously to 7 healthy volunteers, before and after 4 days of oral administration of aspirin in uricosuric dosage (1 g daily). Aspirin prevented the decrease in urinary urate excretion induced by furosemide, without interfering with its natriuretic action. This finding is suggested to be the result of the opposite and independent effects of the two drugs on tubular reabsorption of urate.

Maternal haemoglobin concentration, haematocrit and renal handling of urate in pregnancies ending in the births of small-for-dates infants.

In nine patients who gave birth to babies below the fifth centile in weight, serum urate concentration and fractional reabsorption of urate were significantly higher than in 25 control patients whose babies were of normal birth weight. Haemoglobin concentration and haematocrit were also significantly increased in the small-for-dates group. All of these changes may reflect depletion of extracellular fluid volume.

Pyrazinoic acid and urate transport in the rat.

SummaryThese results indicate that urate secretion is inhibited by PZA and that the degree of inhibition is dose dependent. In the highest dose tested (1.6 mM/kg body wt/hr), PZA not only inhibits secretion but also inhibits urate absorption. Thus, PZA appears to inhibit both urate secretion and reabsorption. The inhibition of these processes is dose dependent but not necessarily of equal sensitivity.These studies were presented in part to the American Federation for Clinical Research, Southern Section meeting, New Orleans, LA, January 27–29, 1977, and national meeting, Washington, D.C., April 30-May 2, 1977, and have appeared in abstract form in Clin. Res. 24: 416A, 1976. The studies were supported in part by a Clinical Investigator award to Dr. Weinman and an Associate Investigator award to Dr. Frankfurt from the Veterans Administration, and were performed while Dr. Frankfurt was a Fellow in Nephrology of Baylor College of Medicine. Pyrazinoic acid was kindly supplied by Dr. George Fanelli of the Merck ...

Metabolic Disorders in Acute Myeloid Leukaemia

Metabolic balance studies were carried out in 17 unselected patients with acute myeloid leukaemia. Widespread metabolic disturbances were observed. Serum Na fell below 135 mmol/1 in 14 patients (82%) and 11 patients (64%) developed hypokalaemia. An increased osmolal clearance caused by a release of electrolyte and blast cell waste (i.e. urea, urate, etc.) during chemotherapy appeared to be the principle cause of natriuresis and hyperkaluria. Seven patients had proteinuria before and eight others developed it during antileukemic therapy. Nine patients (53%) developed proximal renal tubular dysfunction with aminoaciduria, hyperphosphaturia and incomplete reabsorption of urate. No significant relation was found between this widespread glomerulo-tubular dysfunction and lysozymuria. We suggest that antileukaemic drugs release unidentified substances from blast cells which are toxic to the kidney. Metabolic alkalosis in six patients (35%) was probably related to volume depletion and hypokalaemia, while two patients developed acidaemia with the onset of renal failure. Hypocalcemia in seven patients (41%) had a multifactorial basis: hyperphosphaturia, septicaemia, malnutrition and cytotoxic drugs were among the probable causes.

CLINICAL RELEVANCE OF COAGULATION AND RENAL CHANGES IN PRE-ECLAMPSIA

Changes in coagulation tests (fibrin/ fibrinogen degradation products, factor-VIII activity, and platelet-count) and in renal function (creatinine clearance and serum concentration, clearance, and fractional reabsorption of urate) were measured in late pregnancy. 10 patients with severe pre-eclampsia showed changes in both coagulation and renal function when compared with 13 normotensive controls. 18 patients with mild pre-eclampsia had changes in renal function only. Results from 5 patients with essential hypertension did not differ from those of the normotensive group. When results from the patients with severe pre-eclampsia were arranged in order of decreasing protein excretion, only renal-function tests correlated significantly with this ranking. It is suggested that, in the management of patients with established pre-eclampsia, assessment of renal function may be of greater practical value than measurement of the degree of coagulopathy.

The effect of probenecid on urate transport in the rat kidney.

p-(Dipropylsulfamyl)benzoic acid (probenecid) has been utilized in clinical practice and in experimental studies to decrease the tubular reabsorption of uric acid (1). Probenecid is also known to inhibit the secretion of organic acids in the kidney (2). Despite the extensive use of this agent, its separate effects on the urate reabsorptive and secretory processes have not been examined by direct techniques. The current investigations, therefore, were designed to examine the effects of probenecid on net urate transport, urate reabsorption, and urate secretion using clearance, microinjection, and precession techniques in the rat.Methods. Male Sprague-Dawley rats anesthetized with Inactin (Promonta, Hamburg, Germany), 100 mg/kg body wt intra-peritoneally, were used for all studies. Probenecid was dissolved in a solution of dilute NaOH to a final concentration of 10-20 mg/ml and was administered in a dose of 100 mg/kg body wt/hr intravenously. In control animals and in control periods of the clearance experim...

Effect of pharmacological inhibitors on urate transport during induced uricosuria.

1. The effect on urate excretion of administration of probenecid and pyrazinamide was observed in normal subjects under control conditions and after induction of uricosuria by exogenous urate loading by ribonucleic acid feeding in seven subjects, by volume loading with hypertonic sodium chloride solution infusion in 11 subjects and by partial inhibition of net urate reabsorption with uricosuric drugs in 20 subjects. 2. After ribonucleic acid feeding, the uricosuric response to probenecid was intact and ribonucleic acid feeding did not produce uricosuria after pyrazinamide. 3. After volume loading, the uricosuric response to probenecid was again intact, but infusion of sodium chloride solution still produced uricosuria after pyrazinamide administration. 4. After uricosuric drugs, the uricosuric response to probenecid was diminished. 5. These responses to probenecid and pyrazinamide may reflect different mechanisms of uricosuria. Response to pharmacological inhibitors of urate reabsorption or urate secretion may be useful for classification of induced and clinical uricosuric states.

Sites of urate transport in the rat nephron.

The rat has been used frequently for studying renal urate excretion (1–14, 16). This is clearly correlated with the fact that the overall renal handling of urate in this animal is comparable to that in man (5). Previous clearance studies have revealed that the net reabsorption of urate in the mammalian nephron is the result of bidirectional tubular transport (17). Recently several investigators have applied different micropuncture and microanalytical methods to the rat model to further elucidate the complicated pattern of bidirectional tubular transport (1, 3, 4, 7–10, 13, 14, 16). As a result of these studies, it is generally accepted that both a secretory and a reabsorptive mechanism for urate exist in the proximal tubule. In the distal nephron very little, if any, urate is transported. However, some controversy still remains concerning the quantitative correlation of reabsorption and secretion in the proximal tubule and the quantitative importance of the post-proximal reabsorption, i.e. loop reabsorption (14).

Evidence for two secretory mechanisms for organic acid transport in man.

Pyrazinamide administration markedly impairs the uricosuric response to probenecid in man and in the chimpanzee (1,2). This effect of pyrazinamide on probenecid uricosuria has been attributed to inhibition of urate secretion by pyrazinamide and used as evidence for post secretory reabsorption of urate (1). However, other forms of drug interaction between probenecid and pyrazinamide have not been excluded. Recent evidence from studies in the chimpanzee and man suggest that urate and hippurate are secreted by different transport mechanisms (2,3). The present study was designed to further investigate the mechanism of pyrazinamide inhibition of the uricosuric response to probenecid in man and to compare the Interactions between pyrazinamide and probenecid with those between PAH and probenecid.

Factors affecting urate reabsorption in the rat kidney.

1. Urate transport in the rat appears to be saturable. However, affinity of the transport system for urate is very low and transport far from saturated at physiological plasma concentrations. 2. Since increase of the nonionized fraction of uric acid by a factor of five failed to increase urate reabsorption, transport cannot be due to nonionic diffusion but rather involves ionized urate. 3. Increases in luminal flow rate markedly depress urate reabsorption in the loop of Henle, which results in wash out of medullary urate.

Effect of splanchnicotomy on the renal excretion of uric acid in anaesthetized dogs.

The renal excretion of uric acid was examined during acute i.v. urate (Ua) loading on unilaterally splanchnicotomized ("renal denervation") anaesthetized mongrel dogs. Glomerular filtration rate (GFR) in general was not different in innervated and denervated kidneys, whereas urine flow (V) and urinary excretion of sodium (UNaV) on the splanchnicotomized side were significantly increased at any plasma concentration of Ua. The excretion (UUaV) and tubular transport (TUa) of urate calculated for unit GFR were considerably increased and depressed, respectively, at normal plasma Ua level and during minor urate loading (plasma concentration up to 4.7 mg%). Above this plasma level, i.e. up to 24.6 mg%, no difference in net urate reabsorption between intact and sympathectomized organs was found. It is suggested that both reabsorption and secretion of Ua in denervated kidneys are diminished.

The effects of indanyloxyacetic acid (mk 196) on electrolyte excretion in the rat kidney.

A substituted derivative of ethacrynic acid, 6,7-dichloro-2-methyl-l-oxo-phenyl-5-indanyloxyacetic acid (MK 196), has been shown in preliminary studies to be a potent uricosuric and diuretic agent in the rat and monkey (1, 2). Prior studies from this laboratory have localized the nephron site of inhibition of urate reabsorption to the proximal convoluted tubule. The reabsorption of sodium in the proximal tubule, however, is not affected by MK 196, and the sodium diuresis results from impaired reabsorption in the ascending limb of the loop of Henle (1). The current studies were undertaken to examine further the changes in electrolyte excretion induced by this agent and to gain additional inferential information on the nephron site of action. Methods. Clearance studies. Male Sprague-Dawley rats weighing 200 to 400 g were used in all studies. Animals were anesthetized with Inactin (Promonta, Hamburg, Germany), 100 mg/kg body wt injected in-traperitoneally, and prepared for clearance studies as previously described (3). A solution of isotonic saline containing [methoxy-3H]inulin (25 μCi/ml) was infused at a rate of 1.2 ml/hr for the duration of the experiment. MK 196 was dissolved in distilled water containing an equal concentration of sodium bicarbonate and infused in a dose of 50 mg/kg body wt/hr in a volume of 1.2 ml/ hr. Control animals received the same solution without the drug. In the experimental animals, urinary losses of sodium and water were replaced with a volume of isotonic saline equal to the urine flow rate. Hematocrits were measured before and after the study to ensure the adequacy of volume replacement. After 60 to 90 min of equilibration, blood and urine samples were obtained. Free water clearance and reabsorption studies. Studies were performed in a separate group of animals that were lightly anesthetized with ether for placement of catheters, placed in restraining cages, and allowed to awaken.

Dissociation of urate from sodium transport in the rat proximal tubule

The tubular transport of urate and sodium was examined by clearance, free-flow micropuncture, intratubular microinjection and precession techniques in control rats and in rats receiving a new uricosuric diuretic, indanyloxyacetic acid (MK-196). The i.v. infusion of MK-196 (50 mg/kg of body wt/hr) resulted in significant increases in the fractional excretion of sodium (FENa) from 0.98 +/- 0.01 to 11.86 +/- 2.88% (P less than 0.001) and in FEurate from 14.1 +/- 1.03 to 56.0 +/- 2.86% (P less than 0.001). End-proximal tubular fluid to plasma inulin (TF/Pinulin) ratios were 2.43 +/- 0.15 and 2.51 +/- 0.10 in control and drug-treated animals, respectively (P = NS). Total urinary urate recovery after MK-196 administration was higher following microinjections of [2-14C] urate into early proximal tubule sites: 70.5 +/- 2.7% in controls vs. 84.9 +/- 0.9 (P less than 0.001), and after microinjections into late proximal tubule sites: 82.8 +/- 2.9% vs. 91.3 +/- 1.9 (P less than 0.05). Urinary precession of urate from inulin was demonstrable following placement of isotopes of these compounds on the surface of the kidney in controls, but was abolished by MK-196. This agent, therefore, inhibits the reabsorption and secretion of urate in the proximal convoluted tubule, the net effect being a marked increase in urinary urate excretion. By contrast, its inhibitory effect on sodium reabsorption is exerted at a site or sites distal to the accessible portion of the proximal tubule. The demonstration of reduced urate reabsorption and normal sodium reabsorption in the proximal tubule suggests that the reabsorption of these constituents of the glomerular filtrate is not intimately linked at this nephron site.

Urate reabsorption in proximal convoluted tubule of the rat kidney.

Urate reabsorption was examined in the rat utilizing clearance and in vivo microperfusion techniques. In control rats, the fractional excretion of urate averaged 12.5 +/- 1.3% of the filtered load, with 60-70% of perfused urate reabsorbed at 2 mm of perfused tubule length (urate efflux). Increasing the perfusion concentration of urate to 6, 12, and 25 mg/100 ml did not alter the fractional rate of reabsorption. The acute administration of chlorothiazide resulted in a fall in GFR and Curate such that the fractional excretion was unchanged from controls and averaged 13.3 +/- 2.0%, without an associated change in urate reabsorption from proximal perfusates despite the presence of significant inhibition of sodium and water reabsorption. By contrast, the chronic administration of chlorothiazide accompanied by a low-sodium diet resulted in a significantly lower fractions excretion rate of urate of 7.95 +/- 0.5% and a significant increase in reabsorption of sodium and water as well as urate from microperfusates, In control rats receiving an infusion of 5% mannitol in isotonic saline, urate secretion was demonstrated by the urinary precession of [2-14C]urate from [methoxy-3H]inulin following placement of these isotopes on the surface of the kidney. The additional infusion of chlorothiazide did not alter this pattern of isotope recovery in the urine.

Effect of vasopressin on uric acid excretion: evidence for distal nephron reabsorption of urate in man.

1. When changes in urine flow rate were induced by vasopressin administration in eight subjects, urate excretion decreased by a mean of 14% and was positively correlated with urine flow rate (r = 0.88, P less than 0.01). The effect of vasopressin on urate excretion was not influenced by prior changes in extracellular fluid volume. 2. Mannitol administration in a dose sufficient to prevent vasopressin-induced alterations in urine flow rate blocked the effect of vasopressin on urate excretion. 3. Alterations in urate excretion produced by changes in extracellular fluid volume could be distinguished from the urate-retaining effect of vasopressin-mediated decrease in urine flow. Urate retention after vasopressin was entirely attributed to a decrease in pyrazinamide-suppressible urate excretion, consistent with either decreased secretion or enhanced post-secretory reabsorption of urate. 4. Since diminished urine flow rate in the distal part of the nephron is more likely to lead to enhanced reabsorption of urate, these results provide additional evidence for urate reabsorption in the distal part of the nephron.

Renal transport of urate during diuretic-induced hypouricemia

The effect of two weeks administration of a uricosuric diuretic (SKF-62698) on renal urate handling has been examined in 11 normal men. Plasma urate concentrations had declined by more than 60 per cent after two weeks. Urate excretion per unit of glomerular filtration rate and urate clearance (C urate) per unit of glomerular filtration rate were increased after the administration of SKF-62698. The importance of intact tubular secretion of urate in producing these changes was assessed by administering pyrazinamide, an agent that curtails urate secretion, to each participant. The decrements in urate excretion and clearance produced by pyrazinamide both increased significantly, whereas the residual urate excretion rates and clearances not suppressible by pyrazinamide were only minimally altered by SKF-62698 treatment. These results suggest that the excretion of secreted urate was enhanced by prolonged administration of SKF-62698, probably secondary to the inhibition of postsecretory urate reabsorption. In addition, because the nonsuppressible urate excretion did not decline despite a 63 per cent reduction in the plasma urate, it is likely that the reabsorption of filtered urate also was impaired by SKF-62698.

Postsecretory reabsorption of urate in man.

These results are consistent with a model for renal tubular transport of urate in which there is reabsorption of both filtered and secreted urate. Urate secretion greatly exceeds total urate excretion, and most secreted urate is reabsorbed. At least a portion of urate reabsorption occurs at a site distal to or coextensive with the urate secretory site. There appear to be at least two distinct reabsorptive mechanisms for urate. The results of the flow rate and vasopressin studies are consistent with the hypothesis that urate reabsorption occurs in both the distal and the proximal tubule in man. The distal reabsorptive site appears to be quite small. It may be passive since it does not appear to be inhibited by uricosuric drugs. This reabsorptive site may account for less than 15% of total urate reabsorption. Both volume expansion and probenecid may inhibit urate absorption only in the proximal tubule. Thus reabsorption in the proximal tubule coud account for more than 90% of total urate reabsorption. Reabsorption at the postulated collecting duct reabsorptive site appears to be too small in magnitude to account for all reabsorptions of secreted urate. This could be explained if the reabsorptive site in the proximal tubule is coextensive with or distal to the secretory site. Alternatively, there might be two reabsorptive sites in the proximal tubule: a presecretory site accounting for the reabsorption of most filtered urate, and a site either coextensive or distal to the secretory site accounting for a major component of reabsorption of secreted urate. Finally urate reabsorption would also take place in the collecting duct, perhaps at a passive, flow-dependent site.

Distal permeability to urate and effects of benzofuran derivatives in the rat kidney.

Effects of benziodarone and benzbromarone on renal tubular permeability to urate-14C were investigated in anesthetized rats by microinjection and clearance experiments. Urate-14C and inulin-3H were injected into proximal and distal convolutions and their recovery was measured in urine collected serially. In control rats, total and direct recoveries were significantly lower after early proximal (72 and 52%, respectively) than after late proximal injections (83 and 63%), whereas distal recoveries were higher (94 and 69%). Delayed excretion (ca. 25%) did not change with site of injection. Total distal recoveries were always less than 100% (P smaller than 0.001) but increased to 98% at high loads. After proximal injections in drug-pretreated rats, total and direct recoveries increased significantly (P smaller than 0.001). Recoveries after distal injections did not change in benzbromarone-treated rats, whereas direct and delayed excretion, respectively, increased (87%) and decreased (9%) significantly (P smaller than 0.001) following benziodarone infusion. These findings demonstrate inhibition of proximal urate reabsorption by benzofuran derivatives. The results also suggest distal reabsorption of urate, presumably along the collecting ducts.