1. It has been suggested that a dominant mutation in the mouse is a suitable model for the most frequent form of human vitamin D-resistant rickets, X-linked hypophosphataemia. The mutant mice have reduced tubular reabsorption of phosphate, hypophosphataemia, rachitic bone lesions, moderate dwarfism and mild hypocalcaemia. 2. The present work shows that male hypophosphataemic (HYP/Y) mice have a decrease in the tubular capacity to reabsorb calcium as compared with normal littermates (+/Y). This decrease appears to be related to the phosphate status of the animals, since it is much more pronounced when the animals are fed on a low phosphorus diet. 3. The decrement in the tubular reabsorption and plasma concentration of calcium in HYP/Y mice is not accompanied by an augmentation in the absolute urinary excretion of calcium. It is associated with an increase in the urinary excretion of cyclic AMP. Furthermore, removal of the thyroparathyroid glands leads to much larger fall in the plasma concentration of calcium in HYP/Y than in +/Y mice. 4. Thus HYP/Y mice, when compared with normal littermates, have decreased tubular reabsorption of calcium with no apparent increase in the mobilization of calcium from intestinal and body sources as reflected by the absence of an augmentation in the absolute amount of calcium excreted in the urine. These findings could account for a propensity to hypocalcaemia which would be partially compensated by secondary hyperparathyroidism. This could explain the increase in urinary cyclic AMP excretion and the exaggerated hypocalcaemic response to removal of the parathyroid glands observed in murine X-linked hypophosphataemia.

1. Previous studies have shown that in thyroparathyroidectomized rats injection of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) at doses that inhibit bone mineral retention (0.16 mmol = 10 mg of phosphorus/kg body wt. per day subcutaneously) leads to a decrease in the net tubular reabsorption of phosphate. 2. In the present work the tubular response to EHDP (0.16 mmol/kg body wt.) injected subcutaneously for 9 days has been localized by free-flow micropuncture in thyroparathyroidectomized rats. 3. The results show that the net tubular reabsorption of phosphate along the first portion of the (early) proximal tubule was markedly depressed in the EHDP-injected thyroparathyroidectomized rats compared with that in the pair-fed thyroparathyroidectomized control animals. In this latter group the delivery of phosphate to the distal tubule was larger than in the final urine, confirming previous reports. In the EHDP-injected thyroparathyroidectomized rats no difference in delivery of phosphate was found between the distal tubule and the final urine, suggesting that diphosphonate inhibited net reabsorption of phosphate in the terminal nephron. 4. The sites of the EHDP-induced changes in the tubular handling of phosphate were similar to those previously determined for the adaptive response to an increase in the supply of phosphate.

1. We have studied the effects of the diuretic tienilic acid (Ticrynafen) upon renal tubular transport of urate, in 11 healthy volunteers on a constant dietary intake. 2. Daily administration of tienilic acid for 10 days to six subjects reduced the mean body weight from 67·1 ± 4·7 kg to 64·5 ± 4·7 kg and a reversible fall in serum urate from a mean value of 0·34 ± 0·04 to 0·16 ± 0·01 mmol/l. Fractional urate excretion in the six subjects on the first day of therapy was 30·3 ± 5·6% and then fell to reach a new steady-state mean value of 17·4 ± 2·0%. 3. To evaluate the mechanism of the uricosuria, studies were performed during acute sustained water diuresis in five subjects to assess the effects of tienilic acid, pyrazinamide, probenecid and their combinations. 4. Fractional urate excretion increased markedly with tienilic acid from 11·2 ± 1·3% to 47·5 ± 5·7%. Pyrazinamide, 24·4 mmol (3 g) orally, decreased urate excretion to 5·1 ± 0·7% and markedly blunted the uricosuric effects but not the natriuresis of tienilic acid. Probenecid increased urate excretion to 26 ± 6·0 % and when given with tienilic acid increased urate excretion to 66·4 ± 2·6%. Addition of pyrazinamide to this combination decreased urate excretion to 19·6 ± 4·0%, which was greater than the effect with pyrazinamide alone. 5. We suggest that tienilic acid increased urate excretion by inhibiting reabsorption of both filtered and secreted urate. We have used our results to construct semi-quantitative estimates of the various components of urate transport in man.