Intact ability to lower urine pH in nonacidotic adrenalectomized rats.

Distal acidification was assessed in adrenalectomized (ADX) rats in which the development of acidosis was prevented by oral supplementation with NaHCO3, with or without glucocorticoid replacement. Totally corticosteroid-deficient nonacidotic rats were capable of lowering their urine pH in response to Na2SO4 infusion from a baseline of 7.47 +/- 0.22 to 4.83 +/- 0.1 (p less than 0.001). A similarly intact ability to lower the urine pH was also demonstrated in glucocorticoid-replaced mineralocorticoid-deficient rats. Absolute ammonium excretion was lower in ADX animals compared to controls (0.79 +/- 0.08 vs. 0.46 +/- 0.06 microEq/min, p less than 0.01) but when corrected for the difference in GFR, ammonium excretion was the same in ADX and adrenal-intact rats. During bicarbonate loading and at similar blood and urine pH, and bicarbonate concentrations, the U-B pCO2 gradient was similar in mineralocorticoid-deficient and adrenal intact rats (44 +/- 5.1 vs. 36 +/- 2.6 mm Hg, respectively). Amiloride administration to mineralocorticoid-deficient rats led to a reduction in the U-B pCO2 gradient from 30 +/- 4.5 to 10 +/- 3.0 mm Hg (p less than 0.002). These results indicate that the ability to lower the urine pH and raise the urine pCO2 is intact in the nonacidotic ADX rat; ammonium excretion in this model is reduced in proportion to the observed reduction in GFR, and amiloride administration inhibits acidification in ADX rats. The data strongly suggest the presence of a major site of aldosterone-independent, sodium-dependent acidification mechanism likely located at the level of the cortical collecting tubule.

The critical importance of urinary concentrating ability in the generation of urinary carbon dioxide tension.

Measurement of urine to blood (U-B) carbon dioxide tension (P(CO2)) gradient during alkalinization of the urine has been suggested to assess distal H(+) secretion. A fact that has not been considered in previous studies dealing with urinary P(CO2) is that dissolution of HCO(3) in water results in elevation of P(CO2) which is directly proportional to the HCO(3) concentration. To investigate the interrelationship of urinary HCO(3) and urinary acidification, we measured U-B P(CO2) in (a) the presence of enhanced H(+) secretion and decreased concentrating ability i.e., chronic renal failure (CRF), (b) animals with normal H(+) secretion and decreased concentrating ability, Brattleboro (BB) rats, and (c) the presence of both impaired H(+) secretion and concentrating ability (LiCl treatment and after release of unilateral ureteral obstruction). At moderately elevated plasma HCO(3) levels (30-40 meq/liter), normal rats achieved a highly alkaline urine (urine pH > 7.8) and raised urine HCO(3) concentration and U-B P(CO2). At similar plasma HCO(3) levels, BB rats had a much higher fractional water excretion and failed to raise urine pH, urine HCO(3) concentration, and U-B P(CO2) normally. At a very high plasma HCO(3) (>50 meq/liter), BB rats raised urine pH, urine HCO(3) concentration, and U-B P(CO2) to the same levels seen in normals. CRF rats failed to raise urine pH, urine HCO(3), and U-B P(CO2) normally at moderately elevated plasma HCO(3) levels; at very high plasma HCO(3) levels, CRF rats achieved a highly alkaline urine but failed to raise U-B P(CO2). Dogs and patients with CRF were also unable to raise urine pH, urine HCO(3) concentration, and U-B P(CO2) normally at moderately elevated plasma HCO(3) levels. In rats, dogs, and man, U-B P(CO2) was directly related to urine HCO(3) concentration and inversely related to fractional water excretion. At moderately elevated plasma HCO(3) levels, animals with a distal acidification defect failed to raise U-B P(CO2); increasing the plasma HCO(3) to very high levels resulted in a significant increase in urine HCO(3) concentration and U-B P(CO2). The observed urinary P(CO2) was very close to the P(CO2) which would be expected by simple dissolution of a comparable amount of HCO(3) in water. These data demonstrate that, in highly alkaline urine, urinary P(CO2) is largely determined by concentration of urinary HCO(3) and cannot be used as solely indicating distal H(+) secretion.

Effect of acetazolamide and parathyroid hormone on HCO3 and PO4 excretion.

It has been recently demonstrated that parathyroid hormone (PTH) inhibits renal cortical carbonic anhydrase. Based on this in vitro study, it was suggested that PTH depresses proximal reabsorption of phosphate and bicarbonate reabsorption in vivo by inhibiting carbonic anhydrase. To test this hypothesis, we measured bicarbonate and phosphate excretion in four groups of dogs. Group I received PTH for 2 hours; group II received acetazolamide for 2 hours; group III received PTH for 2 hours and acetazolamide in the 2nd hour; and in group IV, acetazolamide was given for 2 hours with PTH ADDED IN THE 2ND HOUR. Acetazolamide administration resulted in maximal bicarbonate excretion in the 1st hour and maximal phosphate excretion in the 2nd hour. Addition of acetazolamide to animals receiving PTH or addition of PTH to animals receiving acetazolamide resulted in additional increases in bicarbonate and phosphate excretion. These data demonstrate that PTH induces bicarbonate and phosphate excretion regardless of whether carbonic anhydrase is intact or nearly 100% inhibited by acetazolamide. These data do not support the hypothesis that PTH inhibits bicarbonate and phosphate reabsorption by inhibiting carbonic anhydrase.

On the mechanism of lithium-induced renal tubular acidosis.

The effect of lithium chloride administration on urinary acidification was studied in dogs. Lithium-treated dogs developed hyperchloremic metabolic acidosis with alkaline urine. Bicarbonate loading resulted in a normal increase in urinary Pco2 in normal dogs but failed to produce the same response in lithium-treated dogs. The bicarbonate titration curve of lithium-treated dogs revealed a small leak of bicarbonate at low plasma levels of bicarbonate; at high plasma levels bicarbonate reabsorption was significantly higher in lithium-treated dogs. This pattern of bicarbonate reabsorption is identical to that described in classic distal renal tubular acidosis. Sodium sulfate administration resulted in a normal urinary acidification ilithium-treated dogs. It is possible that lithium administration induces distal renal tubular acidosis by allowing excessive back-diffusion of acid. This excessive back-diffusion of acid would result in a low urinary Pco2 during bicarbonate loading. Sodium sulfate administration, by increasing the negative intratubular potential, would restrict back-diffusion of hydrogen ion and thereby result in a normal acidification in lithium-treated dogs. We previously demonstrated that postureteral obstruction of the kidney fails to increase urinary Pco2 during bicarbonate loading and to lower urinary pH with sodium sulfate. It is possible that a low urinary Pco2 during HCO3 loading can occur as a consequence of either diminished hydrogen ion secretion (postobstructed kidney) or excessive back-diffusion of acid (lithium administration). Further studies are indicated to determine whether both mechanisms may be found in patients with distal renal tubular acidosis.

Lithium administration and phosphate excretion.

The phosphaturic effect of parathyroid hormone (PTH), cyclic adenosine monophosphate (cAMP), acetazolamide (Az), and HCO3 loading was studied in normal, thyroparathyroidectomized (TPTX), and Li-treated dogs. PTH administration to normal animals markedly increased fractional excretion (F) of PO4 but had a blunted effect on FPO4 in the Li-treated animals. Cyclic AMP likewise markedly increased FPO4 in the normal animals but had a markedly blunted effect in the Li-treated animals. Az led to a significant increase in FNa, FHCO3, and FPO4 in the normal animals. In the Li-treated dogs, Az induced a significant natriuresis and bicarbonaturia but failed to increase phosphaturia. HCO3 loading in normal dogs caused a significant phosphaturia while having little effect on FPO4 in Li-treated dogs. HCO3 loading to TPTX dogs was associated with a lower FPO4 as compared to normal HCO3-loaded animals. These data suggest that Li administration not only blocks the adenyl cyclase-cAMP system in the renal cortex, but it may also interfere with a step distal to the formation of cAMP, since the phosphaturic effect of both PTH and cAMP was markedly diminished in Li-treated animals.

Bicarbonate reabsorption in chronic renal failure.

Bicarbonate reabsorption was studied in dogs before and after induction of renal failure, produced by infarction of one kidney and removal of the contralateral kidney. Glomerular filtration rate and renal plasma flow decreased to 21 and 37% of control values, respectively. Fractional potassium excretion and fractional phosphate excretion increased significantly. Volume expansion resulted in a significant decrease of bicarbonate reabsorption in both control and uremic groups. At comparable levels of fractional chloride excretion, bicarbonate reabsorption was significantly higher in renal failure than in control animals. In the second group of dogs, following induction of renal failure, sodium bicarbonate was given orally in an amount sufficient to neutralize endogenous acid production. Bicarbonate reabsorption was again significantly higher than in control animals. Thyroparathyroidectomy had no effect on bicarbonate reabsorption. Absolute bicarbonate reabsorption and sodium reabsorption were lineraly related in control animals and in those in renal failure; the ratio of absolute bicarbonate reabsorption/abolute sodium reabsorption was significantly higher in renal failure than in control. These data demonstrate that renal failure is associated with enhanced bicarbonate reabsorption which is not related to the state of extracellular volume, the need to increase acid excretion or the concentrations of parathyroid hormone. These findings suggest that there are additional unknown factors controlling bicarbonate reabsorption in renal failure.