Thomas H. Steele

Renal resistance to parathyroid hormone during phosphorus deprivation.

Because previous studies have demonstrated that renal inorganic phosphate reabsorption is enhanced in rats after dietary phosphorus deprivation, we studied the effects of parathyroid hormone (PTH) upon inorganic phosphate reabsorption in acutely thyroparathyroidectomized rats stabilized on a low phosphorus diet to determine if the phosphaturic response to PTH is impaired during phosphorous depletion. Acutely thyroparathyroidectomized phosphorus-deprived rats responded only minimally to PTH, whereas similarly prepared animals stabilized on a high phosphorus diet exhibited a large phosphaturic response. Base-line urinary cyclic AMP values and PTH-induced increases in cyclic AMP excretion were similar in both groups. In other experiments, dibutyryl cyclic AMP elicited a greatly diminished phosphaturic response in phosphorus-deprived rats, as compared to their high phosphorus counterparts. These results indicate that the renal phosphaturic responses to PTH and cyclic AMP are impaired during dietary phosphorus deprivation. The impaired phosphaturia would contribute to phosphorus conservation and to the replenishment of inorganic phosphate stores after phosphorus depletion.

Influence of the Kidney Upon Urate Homeostasis in Health and Disease

Abstract The role of the kidney in the maintenance of urate homeostasis is reviewed, with particular emphasis upon the major contributions of Dr. Alexander B. Gutman to our understanding in this area. Data in support of various models of renal urate transport are presented, in conjunction with a discussion of the pyrazinamide suppression test and its limitations as a means of characterizing urate transport. It is proposed that postsecretory reabsorption of urate, as well as the rate of urate secretion, controls and modulates the final rate of urate excretion in man. The renal basis for some of the disturbances of urate homeostasis encountered clinically is also considered. The role of the kidney in the pathogenesis of the hyperuricemia observed in hypertension, toxemia of pregnancy, gout and renal failure is discussed, as well as three apparently distinct defects in tubular reabsorption of urate which lead to hypouricemia. It is emphasized that the mechanisms of renal urate handling in health, and the pathogenesis of the disordered states of renal urate homeostasis which are discussed, remain partially within the realm of speculation. A clearer understanding of the pathophysiologic mechanisms underlying disordered urate balance awaits more complete knowledge of normal physiology.

Diminished Renal Urate Secretion Per Nephron As a Basis for Primary Gout

Abstract In order to examine the role of the kidney in the pathogenesis of primary gout, the rate of uric acid turnover and renal transport were studied in 15 gouty patients. Uric acid turnover dat...

Origins of the Uricosuric Response

The acute effects of intravenous (i.v.) probenecid and chlorothiazide on renal urate handling were investigated in paired studies in normal men. Uricosuric responses to these agents were compared in the same subjects, both without and with pyrazinamide (PZA) pretreatment. Assuming that PZA selectively inhibits the tubular secretion of urate and that uricosuric agents act by increasing the excretion of filtered urate, then the uricosuric responses (the increment in urate excretion or clearance) should have been unaffected by PZA. Defined in this manner, however, uricosuric responses to probenecid and chlorothiazide were significantly decreased after PZA pretreatment. In order to determine whether PZA diminished other renal actions of chlorothiazide, changes in sodium and inorganic phosphorus excretion were examined. Chlorothiazide produced equivalent natriuretic and phosphaturic responses after PZA pretreatment, indicating that PZA does not interfere with at least some of the renal actions of chlorothiazide. In separate studies, PZA depressed urate excretion by at least 68% during the maintenance of chlorothiazide-induced natriuresis and phosphaturia, suggesting that chlorothiazide does not diminish the anti-secretory action of PZA. The results suggest that probenecid and chlorothiazide may derive their uricosuric properties by facilitating the excretion of both filtered and secreted urate. Possibly, increased excretion of secreted urate might occur through modulation of urate reabsorption at a site distal to tubular secretion, rather than by the direct acceleration of secretory transport. However, PZA-induced interference with the actions of probenecid and chlorothiazide on renal urate transport mechanisms cannot be excluded as a possible explanation for the present results.

Urate Secretion in Man: The Pyrazinamide Suppression Test

Abstract The relatively specific inhibition of the renal tubular secretion of urate after pyrazinamide administration has been used to estimate the contribution of tubular secretion to the urinary ...

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 (Curate) 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.

Intrinsic Renal Disease Leading to Abnormal Urate Excretion

Since approximately two thirds of daily urate production is normally excreted by the kidney, intrinsic renal disease resulting in abnormalities of urate excretion may have a profound effect upon urate homeostasis. Alterations in the pattern of urate excretion encountered in chronic renal failure are reviewed in depth, with a description of adaptive mechanisms for urate excretion which develop in residual nephrons, as exemplified by the remaining normal kidney of transplant donors. In addition, abnormalities in urate excretion in the presence of a normal complement of nephrons are described. Diminished urate excretion per nephron appears to be responsible for hyperuricemia in some patients with gout, while a variety of tubular defects resulting in excessive renal urate excretion have been documented as the basis for some cases of hypouricemia.

Comparison of urinary phosphate, urate and magnesium excretion following parathyroid hormone administration to normal man

Abstract A phosphaturic dose of parathyroid hormone (PTH) administered intravenously to 14 normal volunteers significantly decreased magnesium excretion and did not significantly alter urate excretion. Elevated plasma levels of endogenous PTH appear to mediate the increased excretion of phosphate per nephron observed in progressive chronic renal disease. In this setting, a similar pattern of urate and magnesium excretion is seen. Results of this study fail to support the concept that PTH might play a role in the enhanced urate and magnesium excretion per nephron of subjects with chronic renal failure.

Renal Urate Excretion in Normal Man

The development of our knowledge of the intrarenal process involved in the control of urate excretion in normal man is summarized. Although there are many gaps in our current knowledge, and different interpretations may be given to the available data, current evidence seems to favor the existence of extensive tubular reabsorption of urate following its glomerular filtration. Subsequently, tubular secretion of urate and the reabsorption of an unknown amount of the secreted urate probably take place. For reasons discussed, it seems most likely that the regulation and control of urate excretion are accomplished through modulations in tubular secretion, post-secretory reabsorption, or both.

Diuretics, urate excretion and sodium reabsorption: effect of acetazolamide and urinary alkalinization.

The uricosuric properties of acetazolamide were investigated in order to elucidate the relationship between changes in proximal tubular sodium reabsorption and urate excretion in man. Acetazolamide produced a modest uricosuric response which was not suppressible by pyrazinamide. Alkalinization of the urine with sodium bicarbonate elicited an even smaller increment in the urate clearance. If urinary alkalinization does play a role in the uricosuric response to acetazolamide, it probably decreases urate reabsorption within the distal nephron. The present studies, when taken together with previous work, suggest that alterations in proximal tubular sodium and water reabsorption probably do not play an important role in the normal control of urate excretion or in the pathogenesis of hyperuricemic states. Diuretic-induced hyperuricemia occurring during extracellular fluid volume depletion probably results from either diminished tubular secretion of urate, accelerated postsecretory urate reabsorption, or both.