Regulation of renal bicarbonate reabsorption by extracellular volume.

The ability of the kidney to reabsorb bicarbonate is held to be a function of plasma CO(2) tension, carbonic anhydrase activity, and potassium stores. The effects of alterations of extracellular volume on bicarbonate reabsorption were studied in dogs whose arterial Pco(2) was kept constant at 40 mm Hg (range 35-45 mm Hg). The effect of extracellular volume expansion was studied in dogs receiving hypertonic bicarbonate and isotonic saline, isotonic saline alone (two of the animals in this group received HCl to lower the plasma bicarbonate concentration), and isotonic bicarbonate. The results were similar in each group. Extracellular volume expansion depressed bicarbonate reabsorption. This depression was related not to changes in glomerular filtration rate (GFR) or bicarbonate concentration, but to the increase of fractional sodium excretion. In addition, volume expansion with bicarbonate increased chloride excretion. Bicarbonate loading was performed in two groups of dogs in which effective expansion of extracellular volume was minimized by hemorrhage or acute constriction of the thoracic vena cava. Both groups demonstrated enhanced bicarbonate reabsorption relative to that seen in the volume-expanded groups. Release of the caval ligature promptly decreased bicarbonate reabsorption. Plasma potassium decreased in all animals studied, but the changes in bicarbonate reabsorption noted could not be related to the decrease. This study demonstrates that the state of effective extracellular volume is a major determinant of bicarbonate reabsorption by the kidney.

Characterization of acidification in the cortical and medullary collecting tubule of the rabbit.

Ouabain and lithium decrease acidification in open-circuited bladders by eliminating the electrical gradient favoring acidification. The effect of ouabain and lithium on acidification in cortical and medullary collecting tubules derived from starved New Zealand white rabbits was studied by using the techniques of isolated nephron microperfusion and microcalorimetric determination of total CO2 flux. Bath and perfusion solutions were symmetric throughout all studies, and solutions contained 25 meq of bicarbonate and were bubbled with 93.3% O2/6.7% CO2 gas mixtures. In cortical collecting tubules, ouabain (10(-8) M) addition to bath resulted in a decrease in both potential difference (PD), from -16.4 to -2.2 mV (P less than 0.001), and total CO2 flux (JTCO2), from +6.0 to 1.5 pmol/mm per min (P less than 0.005). In medullary collecting tubules neither PD nor JTCO2 changed with the addition of ouabain in either 10(-8) or 10(-4) M concentration. Replacement of 40 mM NaCl with 40 mM LiCl in both perfusate and bath in cortical collecting tubules resulted in decreases in both PD, from -11.6 to 0.4 mV (P less than 0.005), and JTCO2, from +10.8 to +4.2 pmol/mm per min (P less than 0.025). This substitution had no effect on medullary collecting tubules. When control flux rates were plotted against animal bladder urine pH, both medullary and cortical tubules showed good inverse correlation between these variables, with higher values of flux rate for the medullary tubules. The data support a role for transepithelial PD in acidification in the cortical collecting tubule and also suggest that both cortical and medullary segments of the collecting tubule participate when urinary acidification is increased during starvation in the rabbit.

Regulation of collecting tubule adenosine triphosphatases by aldosterone and potassium.

To examine the precise role of potassium and aldosterone on acid-base composition and on collecting tubule ATPases, glucocorticoid-replete adrenalectomized rats were replaced with zero, physiological, or pharmacological doses of aldosterone and were fed varying potassium diets to produce hypokalemia, normokalemia, or hyperkalemia. Radiochemical measurement of ATPase activities showed that collecting tubule H/K-ATPase changed inversely with potassium and not with aldosterone whereas H-ATPase changed directly with aldosterone but not with potassium. When both enzymes changed in the same direction, alterations in acid-base composition were profound; however, when these two acidifying enzymes changed in opposite directions or when only one enzyme changed, the effect on acid-base balance was modest. Serum bicarbonate was approximately 45 meq/liter when aldosterone was high and potassium was low; it was only 29 meq/liter when aldosterone was high but potassium was normal or when aldosterone was normal and potassium was low. Our observations may help explain the metabolic alkalosis of primary aldosteronism in which aldosterone excess and hypokalemia are combined and the metabolic acidosis of aldosterone deficiency in which hypoaldosteronism and hyperkalemia are paired. The present study also demonstrated that aldosterone plays the major role in controlling Na/K-ATPase activity in cortical collecting tubule. Hypokalemia stimulates Na/K-ATPase activity in the medullary collecting tubule; this stimulatory effect of hypokalemia supports the hypothesis that the enzyme is present on the apical membrane at this site.

Internephron heterogeneity for carbonic anhydrase-independent bicarbonate reabsorption in the rat.

The present experiments were designed to localize the sites of carbonic anhydrase-independent bicarbonate reabsorption in the rat kidney and to examine some of its mechanisms. Young Munich-Wistar rats were studied using standard cortical and papillary free-flow micropuncture techniques. Total CO2 (tCO2) was determined using microcalorimetry. In control rats both superficial and juxtamedullary proximal nephrons reabsorbed approximately 95% of the filtered load of bicarbonate. The administration of acetazolamide (20 mg/kg body weight [bw]/h) decreased proximal reabsorption to 65.6% of the filtered load in superficial nephrons (32% was reabsorbed by the proximal convoluted tubule while 31.7% was reabsorbed by the loop segment), and to 38.4% in juxtamedullary nephrons. Absolute reabsorption of bicarbonate was also significantly higher in superficial than in juxtamedullary nephrons after administration of acetazolamide (727 +/- 82 vs. 346 +/- 126 pmol/min; P less than 0.05). The infusion of amiloride (2.5 mg/kg bw/h) to acetazolamide-treated rats increased the fractional excretion of bicarbonate as compared with animals treated with acetazolamide alone (34.9 +/- 1.9 vs. 42.9 +/- 2.1%; P less than 0.01), and induced net addition of bicarbonate between the superficial early distal tubule and the final urine (34.8 +/- 3.0 vs. 42.9 +/- 2.1%; P less than 0.05). Amiloride at this dose did not affect proximal water or bicarbonate transport; our studies localize its site of action to the terminal nephron. Vasa recta (VR) plasma and loop of Henle (LH) tubular fluid tCO2 were determined in control and acetazolamide-treated rats in order to identify possible driving forces for carbonic anhydrase-independent bicarbonate reabsorption in the rat papilla. Control animals showed a tCO2 gradient favoring secretion (LH tCO2, 7.4 +/- 1.7 mM vs. VR tCO2, 19.1 +/- 2.3 mM; P less than 0.005). Acetazolamide administration reversed this chemical concentration gradient, inducing a driving force favoring reabsorption of bicarbonate (LH tCO2, 27.0 +/- 1.4 mM vs. VR tCO2, 20.4 +/- 1.0 mM; P less than 0.005). Our study shows that in addition to the superficial proximal convoluted tubule, the loop segment and the collecting duct show acetazolamide-insensitive bicarbonate reabsorption. No internephron heterogeneity for bicarbonate transport was found in controls. The infusion of acetazolamide, however, induced significant internephron heterogeneity for bicarbonate reabsorption, with superficial nephrons reabsorbing a higher fractional and absolute load of bicarbonate than juxtamedullary nephrons. We think that the net addition of bicarbonate induced by amiloride is secondary to inhibition of voltage-dependent, carbonic anhydrase-independent bicarbonate reabsorption at the level of the collecting duct, which uncovers a greater delivery of carbonate from deeper nephrons to the collecting duct. Finally, our results suggest that carbonic anhydrase-independent bicarbonate reabsorption is partly passive, driven by favorable chemical gradients in the papillary tubular structures, and partly voltage-dependent, in the collecting duct.

Relationship of urinary and blood carbon dioxide tension during hypercapnia in the rat. Its significance in the evaluation of collecting duct hydrogen ion secretion.

This study was designed to establish the relationship between urinary pCO2 and systemic blood pCO2 during acute hypercapnia and to investigate the significance of this relationship to collecting duct hydrogen ion (H+) secretion when the urine is acid and when it is highly alkaline. In rats excreting a highly alkaline urine, an acute increase in blood pCO2 (from 42 +/- 0.8 to 87 +/- 0.8 mmHg) resulted in a significant fall in urine minus blood (U-B) pCO2 (from 31 +/- 2.0 to 16 +/- 4.2 mmHg, P less than 0.005), a finding which could be interpreted to indicate inhibition of collecting duct H+ secretion by hypercapnia. The urinary pCO2 of rats with hypercapnia, unlike that of normocapnic controls, was significantly lower than that of blood when the urine was acid (58 +/- 6.3 and 86 +/- 1.7 mmHg, P less than 0.001) and when it was alkalinized in the face of accelerated carbonic acid dehydration by infusion of carbonic anhydrase (78 +/- 2.7 and 87 +/- 1.8 mmHg, P less than 0.02). The finding of a urinary pCO2 lower than systemic blood pCO2 during hypercapnia suggested that the urine pCO2 prevailing before bicarbonate loading should be known and the blood pCO2 kept constant to evaluate collecting duct H+ secretion using the urinary pCO2 technique. In experiments performed under these conditions, sodium bicarbonate infusion resulted in an increment in urinary pCO2 (i.e., a delta pCO2) which was comparable in hypercapnic and normocapnic rats (40 +/- 7.2 and 42 +/- 4.6 mmHg, respectively) that were alkalemic (blood pH 7.53 +/- 0.02 and 7.69 +/- 0.01, respectively). The U-B pCO2, however, was again lower in hypercapnic than in normocapnic rats (15 +/- 4.0 and 39 +/- 2.5 mmHg, respectively, P less than 0.001). In hypercapnic rats in which blood pH during bicarbonate infusion was not allowed to become alkalemic (7.38 +/- 0.01), the delta pCO2 was higher than that of normocapnic rats which were alkalemic (70 +/- 5.6 and 42 +/- 4.6 mmHg, respectively, P less than 0.005) while the U-B pCO2 was about the same (39 +/- 3.7 and 39 +/- 2.5 mmHg). We further examined urine pCO2 generation by measuring the difference between the urine pCO2 of a highly alkaline urine not containing carbonic anhydrase and that of an equally alkaline urine containing this enzyme. Carbonic anhydrase infusion to hypercapnic rats that were not alkalemic resulted in a fall in urine pCO(2) (from 122+/-5.7 to 77+/-2.2 mmHg) which was greater (P <0.02) than that seen in alkalemic normocapnic controls (from 73+/- 1.9 to 43+/-1.3 mmHg) with a comparable urine bicarbonate concentration and urine nonbicarbonate buffer capacity. CO(2) generation, therefore, from collecting dust H(+) secretion and titration of bicarbonate, was higher in hypercapnic rats that in normocapnic controls. We conclude that in rats with actue hypercapnia, the U-B p(CO(2)) achieved during bicarbonate loading greatly underestimates collecting duct H(+) secretion because it is artificially influenced by systemic blood pCO(2). the deltapCO(2) is a better qualitative index of collecting duct H+ secretion that the U-B pCO(2), because it is not artificially influenced by systemic blood pCO(2) and it takes into account the urine PCO(2) prevailing before bicarbonate loading.

Relationship of sodium reabsorption and glomerular filtration rate to renal glucose reabsorption.

Glucose reabsorption was measured in dogs in which sodium reabsorption was stimulated by obstruction of the thoracic inferior vena cava or inhibited by volume expansion with Ringer's lactate. Glucose reabsorption was much higher during periods of enhanced sodium reabsorption than during sodium diuresis. The relationship of glucose reabsorption to glomerular filtration rate was examined using data from animals that had fractional sodium excretion rates of less than 1%. Under this condition the relationship of glucose reabsorption to glomerular filtration rate is highly linear. When points obtained during sodium diuresis (C(Na)/GFR>0.1) are plotted on the same graph, glucose reabsorption at any given glomerular filtration rate is much less than during antidiuresis. Glucose reabsorption divided by glomerular filtration rate varies inversely with fractional sodium excretion. This study demonstrates that glomerular tubular balance for glucose exists in the dog and that this balance is changed when sodium reabsorption changes.

Demonstration of a hormonal inhibitor of proximal tubular reabsorption during expansion of extracellular volume with isotonic saline.

Evidence for the elaboration of a hormonal inhibitor of renal tubular reabsorption in response to expansion of extracellular fluid volume was obtained by examining the effects of plasma from rats and dogs undergoing saline diuresis on the rate of proximal tubular reabsorption measured both directly by micropuncture techniques and indirectly by clearance techniques. Intravenous infusion of plasma from salineloaded rats and dogs, but not plasma from control animals, inhibited the intrinsic reabsorptive capacity of the proximal tubule (as estimated from the shrinking-drop technique) by 35%, and reduced fractional reabsorption (as estimated from the tubular fluid-to-plasma ratio) by 20%. In addition the natriuretic plasma increased urine flow, solute-free water clearance, and potassium excretion in rats with hereditary diabetes insipidus, indicating an increase in the delivery of filtrate out of the proximal tubule to the more distal diluting segments of the nephron. The hormonal inhibition of proximal tubular reabsorption had an extremely rapid onset of action (within seconds after instillation into the tubular lumen) and a short duration of action (less than 30 min after cessation of an intravenous infusion). Inhibitory activity was lost from natriuretic plasma upon dialysis and could be recovered in the dialysate. Dialysates of natriuretic plasma, when injected directly into the tubular lumen, also inhibited proximal reabsorption, indicating an action on the luminal side of the cell.

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.

Metabolic alkalosis.

Metabolic alkalosis is a primary pathophysiologic event characterized by the gain of bicarbonate or the loss of nonvolatile acid from extracellular fluid. The kidney preserves normal acid-base balance by two mechanisms: bicarbonate reclamation mainly in the proximal tubule and bicarbonate generation predominantly in the distal nephron. Bicarbonate reclamation is mediated mainly by a Na-H antiporter and to a smaller extent by the H-ATPase. The principal factors affecting HCO 3 reabsorption include effective arterial blood volume, glomerular filtration rate, chloride, and potassium. Bicarbonate regeneration is primarily affected by distal Na delivery and reabsorption, aldosterone, arterial pH, and arterial pCO2. To generate metabolic alkalosis, either a gain of base or a loss of acid, must occur. The loss of acid may be via the GI tract or by the kidney. Excess base may be gained by oral or parenteral HCO 3 administration or by lactate, acetate, or citrate administration. Factors that help maintain metabolic alkalosis include decreased glomerular filtration rate (GFR), volume contraction, hypokalemia, hypochloremia, and aldosterone excess. Clinical states associated with metabolic alkalosis are vomiting, mineralocorticoid excess, the adrenogenital syndrome, licorice ingestion, diuretic administration, and Bartter's and Gitelma's Syndromes. The effects of metabolic alkalosis on the body are varied and include effects on the central nervous system, myocardium, skeletal muscle, and the liver. Treatment of this disorder is simple, once the pathophysiology of the cause is delineated. Therapy consists of reversing the contributory factors promoting alkalosis and in severe cases, administration of carbonic anhydrase inhibitors, acid infusion, and low bicarbonate dialysis.

Prevalence of renal disease in asymptomatic heroin addicts.

Renal function was studied in 145 asymptomatic male heroin addicts admitted to a methadone detoxification program. The mean duration of addiction was ten years. Three patients had protein excretion greater than 150 mg/24 hr; in one of these, membranous glomerulonephritis was found. All except one had normal creatinine clearance. Hypertension was present in 2.7%. This study does not support the concept that heroin addiction is associated with a high prevalence of renal disease.

Distal renal tubular acidosis with intact capacity to lower urinary pH.

The sine qua non for the diagnosis of distal renal tubular acidosis requires that the urinary pH cannot decrease maximally during systemic acidosis. A defect in distal acidification however, could also result from a decrease in the capacity (or rate) of distal hydrogen ion secretion. In this type of defect, the ability to lower the urinary pH during acidemia could be preserved as long as a certain capacity for hydrogen ion secretion remained. In this report, we describe four patients with deranged distal urinary acidification, in whom urinary pH was able to decrease (4.99 +/- 0.11) during acidemia. One of the patients had hyperchloremic metabolic acidosis whereas the remaining three were not spontaneously acidotic. In these patients, the defect for distal urinary acidification was disclosed by the inability of the urine-blood pCO2 gradient to increase normally (i.e., above 30 mm Hg) during bicarbonate loading. In contrast, a normal increase in the urine-blood pCO2 gradient was observed in each patient in response to neutral sodium phosphate infusion. The reabsorptive capacity of bicarbonate was not depressed in these patients, which indicated that the acidification process in the proximal nephron was intact. We propose that our four patients had a defect in distal urinary acidification caused by a reduction in the rate of distal hydrogen ion secretion rather than an inability to generate a steep pH gradient across the distal nephron. Our data also suggest that the inability to raise urinary pCO2 normally during sodium bicarbonate loading may be the most sensitive index of decreased distal urinary acidification available.

Hyperkalemic hyperchloremic metabolic acidosis in sickle cell hemoglobinopathies.

This report describes the occurrence of hyperkalemic hyperchloremic metabolic acidosis in six patients with sickle cell hemoglobinopathies. Three patients had sickle cell anemia, two had sickle cell trait and one had S-C disease. In all patients, decreased renal potassium excretion was demonstrated by the finding of a fractional potassium excretion lower than that of control subjects with comparable glomerular filtration rates. Two patterns of impaired urinary acidification were discerned. Four patients had a urinary pH above 5.5 in the presence of systemic acidosis and, thus, were classified a having distal renal tubular acidosis. The remaining two patients had very low rates of ammonium excretion despite intact capacity to lower urinary pH below 5.5 during systemic acidosis; this pattern was ascribed to selective aldosterone deficiency. Sickle cell hemoglobinopathies should be included in the differential diagnosis of hyperkalemic hyperchloremic metabolic acidosis.

The pathogenesis of hyperchloremic metabolic acidosis associated with kidney transplantation.

The mechanism of persistent hyperchloremic metabolic acidosis developing after kidney transplantation was investigated in six patients. In five patients in whom acidosis failed to lower the urine pH below 5.5, an infusion of sodium sulfate also failed to lower the urine pH. Neutral phosphate infusion failed to increase the urine minus blood (U-B) carbon dioxide tension (pCO2) difference normally in these patients. This abnormal response to both maneuvers indicates the presence of a tubular defect for distal hydrogen ion secretion. In the remaining patient, spontaneous acidosis lowered the urine pH below 5.5 and increased the U-B pCO2 normally with the administration of phosphate, demonstrating that this patient's distal capacity for hydrogen secretion was intact. The plasma aldosterone level was low in this patient, and thus he had the acidification defect characteristic of aldosterone deficiency. Hyperkalemia developed in two patients; both were aldosterone-deficient, and they had a low fractional potassium excretion ion response to stimulation with sodium sulfate or acetazolamide. In all but one patient, who lost his kidney to accelerated rejection, chronic rejection developed. Homogeneous deposition of complement (C3) along the tubular basement membrane was found in three patients. Our data suggest that a secretory type of distal renal tubular acidosis can be an early sign of the immunologic process that leads to chronic rejection.

Nephritic edema.

Nephritic edema results from the primary retention of salt. Acute glomerulonephritis is the prototypical form of the disorder. The stimulus for the salt retention arises within the kidney by an unknown mechanism. As effective arterial blood volume (EABV) was normal at the start of the disease process, it becomes expanded as salt and water are added to it. The pathophysiological sequelae of this process are compared with those which follow the salt retention of congestive heart failure (CHF). The latter is a syndrome in which salt retention is secondary, driven by the contraction of EABV which is at the heart of CHF. Finally, mechanisms responsible for the salt retention of nephrosis are considered. It is possible, and even likely, that most patients with nephrotic edema have primary salt retention, rather than secondary edema. If this view is correct, salt is retained not because of urinary protein loss and its consequent hypoalbuminemia, but rather because of the glomerulopathy which caused the syndrome in the first place.

Biochemical and genetic advances in distal renal tubular acidosis.

Distal renal tubular acidosis is a constellation of syndromes arising from different derangements of tubular acid transport. Recent advances in the biology of urinary acidification have allowed us to discern various molecular mechanisms responsible for these syndromes. This article relates clinical disorders of distal acidification to the underlying defective mechanisms responsible for them. A clinical classification of these disorders is presented which integrates each disorder with the prevailing serum potassium concentration. That distal renal tubular acidosis can be associated with low, normal, or high serum potassium concentration is now explainable by identifying the specific defect in transport causing each syndrome.

Distal acidification defect induced by phosphate deprivation.

The effect of phosphate deprivation on urinary acidification was investigated in rats fed a phosphate-deficient diet and in control rats fed the same diet supplemented with phosphate. Phosphate-deprived animals developed hypophosphatemia, hypercalcemia, and hypophosphaturia, but failed to develop hyperchloremic metabolic acidosis following 30 or 60 days of phosphate deprivation. Baseline urine pH was significantly higher in phosphate-deprived rats than in controls, but baseline urine HCO3 excretion was not significantly different between the two groups. The pattern of HCO3 reabsorption in phosphate-deprived rats was identical to that of controls at both low and high plasma HCO3 levels. During chronic NH4Cl administration, both 30- and 60-day phosphate-deprived rats had a sigificantly higher minimal urine pH and lower titratable acid and net acid excretion than seen in controls. NH4 excretion was significantly lower than controls in the 60-day phosphate-deprived rats only. During Na2SO4 administration the minimal urine pH was significantly lower in controls than in phosphate-deprived rats, but there was overlap of urine pH values. At comparable levels of urine pH, NH4 excretion was significantly lower in phosphate-deprived rats than in controls. Phosphate-deprived rats were able to raise urine-blood CO2 pressure to the same levels as controls during both HCO3 loading and Tris buffer administration. Phosphate-deprived rats had greater extrarenal buffering capacity than controls as evidenced by a lower decline in blood pH and HCO3 during HCl infusion in phosphate-deprived rats. These data demonstrate that phosphate deprivation is associated with distal acidification defect, impaired NH3 excretion, and increased extrarenal buffering capacity. The increased availability of buffer in phosphate deprivation may play an important role in acid-base homeostasis in this condition.

Humoral hypercalcemia due to squamous cell carcinoma of renal pelvis.

We describe an unusual and rare case of humoral hypercalcemia due to Stage D squamous cell carcinoma of the renal pelvis in a patient with no evidence of bony metastases. The literature on humorally mediated hypercalcemia associated with epithelial tumors of the renal pelvis is reviewed.

Metabolic acidosis and alkalosis.

The factors controlling renal bicarbonate reabsorption and acid excretion under normal conditions and in the presence of metabolic acidosis and alkalosis are reviewed. The methods used to assess distal acidification and its limitations are also discussed. Measurement of urinary pCO2 in maximally alkaline urine (pH greater than 7.8) is a very useful qualitative method to assess distal acidification. The finding of a low urinary pCO2 in maximally alkaline urine indicates a distal acidification defect. We propose that both the secretory and gradient defect types of distal renal tubular acidosis are associated with a low urinary pCO2 when the urine is maximally alkaline. Sodium sulfate and neutral phosphate infusion may allow distinction between a secretory and gradient defect. Sodium sulfate lowers urine pH in the gradient defect but fails to produce the same response in the secretory defect. Neutral phosphate infusion when urine pH (6.8-7.4) is close to the pK of phosphate (6.8) results in an increase in urinary pCO2 in the gradient defect but not in the secretory defect. The mechanisms of generation, maintenance and treatment of metabolic alkalosis are also discussed.

Diseases of renal adenosine triphosphatase.

Most renal transport is a primary or secondary result of the action of one of three membrane bound ion translocating ATPase pumps. The proximal tubule mechanisms for the reabsorption of salt, volume, organic compounds, phosphate, and most bicarbonate reabsorption depend upon the generation and maintenance of a low intracellular sodium concentration by the basolateral membrane Na-K-ATPase pump. The reabsorption of fluid and salt in the loop of Henle is similarly dependent on the energy provided by Na-K-ATPase activity. Some proximal tubule bicarbonate reabsorption and all distal nephron proton excretion is a product of one of two proton translocating ATPase pumps, either an electrogenic H-ATPase or an electroneutral H-K-ATPase. In this article, the authors review the biochemistry and physiology of pump activity and consider the pathophysiology of proximal and distal renal tubular acidosis, the Fanconi syndrome, and Bartter's syndrome as disorders of ATPase pump function.

Metabolic alkalosis.

Metabolic alkalosis is a primary pathophysiologic event characterized by the gain of bicarbonate or the loss of nonvolatile acid from extracellular fluid. The kidney preserves normal acid-base balance by two mechanisms: bicarbonate reclamation, mainly in the proximal tubule, and bicarbonate generation, predominantly in the distal nephron. Bicarbonate reclamation is mediated mainly by a Na(+)-H(+) antiporter and to a smaller extent by the H(+)-ATPase (adenosine triphosphate-ase). The principal factors affecting HCO3(-) reabsorption include effective arterial blood volume, glomerular filtration rate, chloride, and potassium. Bicarbonate regeneration is primarily affected by distal Na(+) delivery and reabsorption, aldosterone, arterial pH, and arterial partial pressure of carbon dioxide. To generate metabolic alkalosis, either a gain of base or a loss of acid must occur. The loss of acid may be via the gastrointestinal tract or via the kidney. Excess base may be gained by oral or parenteral HCO3(-) administration or by lactate, acetate, or citrate administration. Factors that help maintain metabolic alkalosis include decreased glomerular filtration rate, volume contraction, hypokalemia, hypochloremia, and aldosterone excess. Clinical states associated with metabolic alkalosis are vomiting, mineralocorticoid excess, the adrenogenital syndrome, licorice ingestion, diuretic administration, and Bartter's and Gitelman's syndromes. The effects of metabolic alkalosis on the body are variable and include effects on the central nervous system, myocardium, skeletal muscle, and liver. Treatment of this disorder is simple, once the pathophysiology of the cause is delineated. Therapy consists of reversing the contributory factors that are promoting the alkalosis and, in severe cases, administration of carbonic anhydrase inhibitors, acid infusion, and low bicarbonate dialysis.