Renal Bicarbonate Research Articles

Metabolic acidosis stimulates bicarbonate reabsorption in the early proximal tubule.

The early proximal tubule is the major site for renal bicarbonate reabsorption but little is known about the influence of acidosis on transport in this segment. This study examined early proximal bicarbonate reabsorption in rats with chronic metabolic acidosis (MA) (induced by NH4Cl administration). Rats were studied by free-flow micropuncture techniques, after varying degrees of plasma volume expansion to vary the filtered load of bicarbonate (FLHCO3). At FLHCO3 less than 700 pmol/min, both control and acidotic animals reabsorbed greater than 80% of the filtered load by 2 mm from Bowman's space. At higher FLHCO3 (700-1,100 pmol/min), reabsorption in the early proximal tubule was significantly greater in MA rats vs. control (633 +/- 26 vs. 449 +/- 24 pmol/min, between 1 and 2 mm from Bowman's space, P less than 0.001). This MA-induced stimulation of early proximal bicarbonate reabsorption was completely reversed by restoring systemic pH to normal either by acute hypocapnia or alkali infusion. Thus bicarbonate reabsorption in the early proximal tubule correlated closely with changes in systemic pH in rats with MA when bicarbonate delivery was increased by plasma expansion. The mechanism of this effect remains to be determined.

Effect of potassium depletion and protein intake in vivo on renal tubular bicarbonate transport in vitro.

These studies evaluated the effect of decreased dietary potassium and increased dietary protein content in rabbits on systemic acid-base parameters, urine pH, and segmental renal tubular bicarbonate handling in vitro. Animals fed a potassium-deficient high-protein diet (KD) for 2 wk developed metabolic acidosis (arterial blood pH 7.31 vs. 7.43) and excreted a more acid urine than control animals fed a diet with normal amounts of potassium and protein; whereas, animals fed the same potassium deficient diet to which supplemental potassium was added (KD + K+) excreted an even more acid urine and had a blood pH of 7.36. In superficial proximal convoluted and straight tubules, there were no differences in rates of fluid and total CO2 absorption between control and KD tubules. Cortical collecting tubules obtained from KD and KD + K+ animals absorbed, and control tubules secreted total CO2 in vitro. With an ambient potassium concentration of 2.5 mM, collecting tubules obtained from the inner stripe of the outer medulla of KD animals absorbed significantly less total CO2 than control tubules. The same tendency was observed in collecting tubules from the outer stripe of the outer medulla. Plasma aldosterone levels fell with development of potassium depletion. Administration of deoxycorticosterone for 1 day to KD animals was associated with a lower urine pH and higher arterial blood pH than in untreated KD animals and with increased total CO2 absorption by both cortical collecting tubules and tubules from the inner stripe of the outer medulla.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced glomerular filtration rate can maintain a rise in plasma bicarbonate concentration in humans.

In humans, deficiency of chloride and potassium were found to perpetuate the hyperbicarbonatemia that attends metabolic alkalosis induced by gastric aspiration partly by increasing renal bicarbonate reabsorption, commensurate with the attendant increase in filtered bicarbonate load, and partly by decreasing glomerular filtration rate (GFR), which minimizes the degree of which the filtered bicarbonate load increases and thereby minimizes the requisite increase in bicarbonate reabsorption. The relative contribution of stimulated renal bicarbonate reabsorption might increase, however, if the supply of extrarenal bicarbonate is increased, in which case a greater degree of hyperbicarbonatemia would be sustained. To investigate that possibility, we reexamined the mechanism of perpetuation of gastric alkalosis in normal subjects eating a low NaCl diet supplemented with bicarbonate salts. Prior to gastric aspiration, plasma bicarbonate concentration ([HCO3]p) and pH were higher than in similarly studied subjects not receiving bicarbonate: 29.9 +/- 0.6 vs. 25.3 +/- 0.1 and 7.43 +/- 0.008 vs. 7.41 +/- 0.002 mEq/l, respectively. With continued bicarbonate supplementation, gastric aspiration induced a further significant increase (p less than 0.05) in [HCO3]p of 10.8%, to values not significantly different from those in nonbicarbonate-loaded subjects with gastric alkalosis: 33.2 +/- 1.2 mEq/l. GFR decreased significantly by 8.4% (from 98 +/- 4 to 90 +/- 3 ml/min, p less than 0.025), offsetting nearly commensurately the increase in [HCO3]p so that total bicarbonate reabsorption was not significantly increased (2.90 +/- 0.12 vs. 2.97 +/- 0.19 mEq/min, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal acidification during chronic hypercapnia in the conscious dog.

Enhanced renal acidification during chronic hypercapnia (CH) results in transient augmentation in net acid excretion (NAE) (adaptation phase) and persistent acceleration in renal bicarbonate reclamation (adaptation and steady-state phases). The mechanisms responsible for the return of NAE to control values despite persistent acidemia during the steady state phase of CH remain undefined. In addition, it remains unsettled whether the enhancement of renal ammoniagenesis known to occur during the adaptation phase of CH persists during the steady-state phase. Furthermore it is uncertain if the alteration in whole-kidney acidification observed in CH originates from augmentation in the acidification of both proximal and distal nephronal segments. To shed further light on these issues, observations on the profile of the urine acid-base moieties during the adaptive and steady-state phases of CH were carried out in dogs chronically exposed to hypercapnia (10% FiCO2) in an environmental chamber (13 days). Additionally, collecting duct hydrogen ion secretion (CDH+S) was evaluated by employing the U-B PCO2 in alkaline urine in intact unanesthetized dogs with either CH (10% FiCO2) or eucapnia. The balance studies demonstrated that NAE increased in early hypercapnia (4.84 meq/kg body weight, control 3.27 meq/kg body weight, p less than 0.05) and returned to baseline thereafter; by contrast, urine NH+4 which was augmented during the adaptation phase (3.71 meq/kg body weight, control 1.97 meq/kg body weight, p less than 0.05) remained elevated throughout (3.25 meq/kg body weight).(ABSTRACT TRUNCATED AT 250 WORDS)

Dissociation of CO2 hydration and renal acid secretion in the dogfish, Squalus acanthias.

Maximal rates of renal hydrogen ion secretion and bicarbonate reabsorption in the dogfish were stimulated by intravascular infusion of acidic and basic buffers: bicarbonate, phosphate, phenol red, dimethadione (DMO), imidazole, and piperazine-N,N'-bis(2 ethanesulfonic acid) (PIPES). There was no difference in titratable acid secretion or urinary pH after bicarbonate infusion despite a sevenfold increase in plasma bicarbonate. Bicarbonate reabsorption was increased 12-fold and showed no evidence of reaching a maximum. This was not altered by methazolamide, as expected, since there is no renal carbonic anhydrase in seagoing fish. Imidazole resulted in the greatest augmentation of renal titratable acid secretion (33----390 mueq . h-1 . kg-1) and did not alter urinary pH. Inhibition of organic base secretion by Darstine had no effect on the imidazole-induced maximal rate of acid secretion. This rate was compared with that of hydrogen ion generation calculated from the uncatalyzed reactions of CO2 and H2O or OH-, maximizing PCO2 and OH- gradients and reaction volumes in vivo. These calculated chemical rates could only account for 9-14% of the measured maximal acidification rate. Thus the powerful process that maintains constant acid urine pH is not only independent of carbonic anhydrase but can function well in a low CO2 environment in which the reactions CO2 + H2O or CO2 + OH- do not furnish enough protons for H+ secretion or HCO3- reabsorption. We conclude that following the cellular protolysis of water, processes other than those involving CO2 buffering of OH- permit H+ to engage in the formation of urine.

Renal bicarbonate handling in low birth weight infants during metabolic acidosis.

We studied the fractional excretion of bicarbonate (FE HCO-3) in 10 low birth weight infants aged 1-6 days during metabolic acidosis (base excess greater than or equal to -5 mEq/l) and during subsequent sodium HCO-3 infusion. The mean birth weight was 1,095 g; the mean gestational age was 29 weeks. The ability to decrease urine pH to less than 5.5 and FE HCO-3 to less than 1% during metabolic acidosis was not limited by low gestational age or birth weight. After HCO-3 therapy, all infants corrected their negative base excess, and plasma HCO-3 increased significantly. All infants with blood pH less than or equal to 7.22 or PaCO2 greater than or equal to 50 mm Hg had minimal or absent FE HCO-3. Infants with elevated PaCO2 and mild or absent acidosis also had complete HCO-3 tubular reabsorption. These results suggest that the HCO-3 tubular reabsorption is adequate during metabolic and/or respiratory acidosis in low birth weight infants.

Ammonia and bicarbonate transport by rat cortical collecting ducts perfused in vitro.

We measured bicarbonate and ammonia transport by isolated perfused cortical collecting ducts from deoxycorticosterone-treated rats. With no ammonia in the perfusate and bath solutions, the collecting ducts secreted bicarbonate. The bicarbonate secretion was prevented when the rats were given 40 mM NH4Cl to drink. When 4 mM total ammonia was added to the perfusate and bath, the collecting ducts secreted ammonia and the direction of bicarbonate transport reversed toward absorption. Under those conditions the collected total ammonia concentration exceeded the value predicted by the diffusion-trapping model, assuming pH equilibrium. However, when carbonic anhydrase was added to the perfusate (to assure pH equilibrium), the collected total ammonia concentration decreased to the level predicted by the diffusion-trapping model. We conclude that rat cortical collecting ducts can secrete bicarbonate at substantial rates; the rate of bicarbonate secretion is modified by changes in the acid-base intake of the rats; ammonia secretion occurs by simple nonionic diffusion in this segment; the ammonia secretion is enhanced by the presence of acidic pH disequilibrium in the lumen; and ammonia in the perfusion and bath solutions inhibits bicarbonate secretion by rat cortical collecting ducts, a response that may be important for the regulation of renal bicarbonate excretion.

Determination of [formula omitted] ratio in inorganic phosphate as an oncogenic marker and indicator for disturbances in phosphate metabolism

Natural stable isotope fractionation is a potential tool in investigation of metabolic process, since rigid mass balance considerations rule the changes in the isotopic ratio. As the natural changes in 13C 12C ratio of total CO 2 between blood and urine served for studying renal bicarbonate reabsorption, studying changes in 18O 16O ratio of phosphate are suggested to investigate deranged phosphate metabolism. The 18O 16O ratio in serum phosphate is constant, determined by the ratio in the environmental drinking water. Therefore, measurements of this ratio in normal individuals, after modifications in phosphate metabolism and in diseases with high alkaline phosphatase activity are proposed. The main purpose of the proposed study is to assess whether measurements of 18O 16O ratio can detect malignant metastases in bones due to deranged phosphate metabolism. An assumption that these determinations might precede other tests for detecting bone metastases and can serve as an oncogenic marker is made.

Mechanisms of antinatriuresis during low-frequency renal nerve stimulation in anesthetized dogs.

The influence of 1.0 Hz renal nerve stimulation (RNS) on the renal excretion of sodium and bicarbonate was determined in anesthetized dogs before and during inhibition of renal bicarbonate reabsorption. RNS decreased both urinary sodium and bicarbonate excretion without changing arterial pressure, renal blood flow, or glomerular filtration rate. Pharmacological blockade of bicarbonate reabsorption with acetazolamide prevented RNS-induced decreases in bicarbonate excretion and reduced the antinatriuretic response. Physiological blockade of tubular bicarbonate reabsorption with intrarenal sodium bicarbonate infusion (1 M) abolished both the antinatriuretic response to RNS and the decrease in bicarbonate excretion. This physiological blockade of neurogenic antinatriuresis resulted from alkalinization of the urine and/or peritubular blood rather than an increase in filtered sodium load, because during intrarenal infusion of 1 M sodium chloride RNS concomitantly decreased sodium and urinary bicarbonate excretion. Since antinatriuretic responses and the decrease in bicarbonate excretion response to RNS were significantly decreased by blockade of bicarbonate reabsorption (with acetazolamide and intrarenal sodium bicarbonate infusion), antinatriuresis during RNS is partly mediated by a mechanism dependent on intact bicarbonate reabsorption. The data suggest that renal nerve activity may participate in the normal regulation of acid-base balance via changes in bicarbonate excretion.

1645 RENAL BICARBONATE HANDLING IN NEONATAL PIGS DURING NORMOXIC RESPIRATORY ACIDOSIS AND ALKALOSIS

Although the neonatal kidney seems to he able to reabsorb HCO3− during respiratory acidosis. It is not clear whether renal bicarbonate tubular reabsorption (HCO3−TR) occurs in response to changes in blood pH, PaCO2 or plasma HCO3−. In an attempt to evaluate the relative importance of each of these factors, measurements of HCO3−TR, fractional excretion of HCO3− (FEHCO3−), glomerular filtration rate as endogenous creatinine clearance (Ccr) and urine flow (V) were done in 6 neonatal, anesthesized and mechanically ventilated pigs during four study periods: 1. Control, normal ventilation in room air (x pH 7.43, PaCO2 35, HCO3− 22); II. Respiratory alkalosis induced hy hyperventilation (x pH 7.62, PaCO2 22, HCO3− 24); III. Respiratory acidosls induced by adding 10% CO2 to inspired gas (x pH 7.12, PaCO2 71, HCO3−22); and IV. Hypercapnea with normal pH, which was ohtained hy infusion of NaHCO3 (x pH 7.38, PaCO2 74, HCO3− 48). Urine was collected anaerohically hy catheter. Results (x+SEM) were:These data suggest: a) HCO3−TR is clearly influenced by HCO3− filtered load more than by PaCO2 or blood pH changes; b) significant increase in FEHCO3− in period IV, whom pH normalized and PaCO2 remained unchanged, indicates that pH exerts an important effect independent of PaCO2; and c) acute respiratory acidosis significantly affects urine flow Ccr.

Regulation of acid-base equilibrium in chronic hypercapnia

Previous studies from this laboratory have demonstrated that the decreased renal bicarbonate reabsorption prevailing during chronic hypocapnia is not mediated by the alkalemia that normally accompanies this acid-base disturbance but by some direct consequence of the change in PaCO2 itself. Based on the reasonable expectation that the mechanisms underlying the kidney's response to primary respiratory disturbances would be similar over the entire spectrum of physiologic carbon dioxide tensions, the present study was designed to assess whether an acidic change in systemic pH is a critical factor in the renal response to chronic hypercapnia. For this purpose, the plasma and renal responses to chronic respiratory acidosis in normal dogs were compared to those in dogs chronically fed a large hydrochloric acid (HCl) load (7 mmoles/kg/day). Exposure to 6% carbon dioxide for 7 days in a large environmental chamber induced a stable increment in PaCO2 which averaged 17 +/- 0.5 and 22 +/- 1.3 mm Hg in normal and HCl-fed animals, respectively. Steady-state plasma bicarbonate concentration rose from 22.0 +/- 0.4 to 27.1 +/- 0.5 mEq/liter in normals and from 14.7 +/- 0.7 to 24.2 +/- 0.8 mEq/liter in the HCl-fed group. As a result of these changes in PaCO2 and plasma bicarbonate, steady-state plasma hydrogen ion concentration rose in normals from 41 +/- 0.8 to 49 +/- 0.9 nEq/liter (pH 7.39 +/- 0.01 vs. 7.31 +/- 0.01) but did not change significantly in the HCl-fed group (55 +/- 1.4 vs. 56 +/- 1.4 nEq/liter; pH 7.26 +/- 0.01 vs. 7.25 +/- 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced glomerular filtration and enhanced bicarbonate reabsorption maintain metabolic alkalosis in humans

The mechanism that sustains chloride-depletion metabolic alkalosis is presumed to be a stimulation of renal acidification, so that the elevated filtered bicarbonate load that attends hyperbicarbonatemia is completely reabsorbed. However, such enhancement of renal bicarbonate reabsorption is not necessary to maintain hyperbicarbonatemia if the filtered bicarbonate load is not increased owing to a concomitant reduction in glomerular filtration rate (GFR). To assess the relative contributions of enhanced renal bicarbonate reabsorption and reduced GFR in the maintenance of chloride-depletion alkalosis in humans, selective hydrochloric acid depletion was induced in five normal subjects. Plasma bicarbonate concentration increased by 27% (25.3 +/- 0.1 to 32.1 +/- 0.3 mEq/liter, P less than 0.005), whereas the rate of renal bicarbonate reabsorption increased by only 17% (2.7 +/- 0.1 to 3.2 +/- 0.2 mEq/min, P less than 0.05) owing to a 10% reduction in GFR (93.2 +/- 4.4 to 84.3 +/- 4.1 ml/min, P less than 0.01). Thus, in chloride-depletion metabolic alkalosis in humans, the increase in plasma bicarbonate concentration is not attended by a commensurate increase in filtered bicarbonate and rate of renal bicarbonate reabsorption. Both a reduction in GFR and an enhancement of renal bicarbonate reabsorption contribute to maintenance of the alkalotic state.

Renal excretory function in alligators infused with acetazolamide

1. 1. Renal clearance experiments were performed in alligators and the effects of acetazolamide studied. 2. 2. The intravenous administration of acetazolamide caused a 40% decrease in blood lactate with no other major systemic change. Ammonium and bicarbonate excretion fell in an inverse relation to that of sodium and chloride. 3. 3. Net renal secretion of bicarbonate was demonstrated, and the alligators recovered from carbonic anhydrase inhibition within a week. 4. 4. It is concluded that renal bicarbonate secretion is intimately related with intracellular carbonic anhydrase activity and chloride reabsorption. These events occur as if they were mirror images of those that take place across parietal cell membranes of mammalian stomach.

Reduction of renal blood flow and proximal bicarbonate reabsorption in rats by gentamicin

AbstractReduction of renal blood flow and proximal bicarbonate reabsorption in rats by gentamicin. Although aminoglycoside-induced acute renal failure occurs commonly, little is known about the mechanisms which alter renal hemodynamics. In sodium-depleted Sprague-Dawley rats treated with gentamicin, we measured RBF and GFR at the onset of this model of nephrotoxic acute renal failure. After 10 days of sodium chloride depletion, one group of rats received a single injection of gentamicin, 100 mg/kg, while control animals received the gentamicin vehicle. Twenty-four hours later, PCr and UNa/UCr were similar in both groups. CIn was unchanged, but RBF was reduced significantly (12.40 ± 1.33 vs. 16.89 ± 1.24 ml/min). Micropuncture studies revealed that although SNGFR was unchanged, end-proximal and early distal flow rates were increased significantly. End-proximal TFCl was reduced significantly in gentamicin-treated animals when compared to controls (130.7 ± 3.9 vs. 149.5 ± 4.1 mEq/liter). Early distal TFCl was also reduced significantly (32.4 ± 2.0 vs. 44.3 ± 1.4 mEq/liter). In other rats, 24hr after a second injection of gentamicin, PCr and UNa/UCr were increased significantly and both GFR and RBF were reduced significantly. We conclude that the earliest hemodynamic change in gentamicin-induced acute renal failure is a reduction in RBF which precedes any change in GFR. A single dose of gentamicin also impairs proximal bicarbonate and water reabsorption and reduces end-proximal and early distal chloride concentration.Réduction du débit sanguin rénal et de la réabsorption proximale des bicarbonates chez des rats par la gentamicine. Bien qu'une insuffisance rénale aiguë induite par les aminoglycosides se produise fréquemment, on sait peu de choses sur les mécanismes qui altèrent l'hémodynamique rénale. Chez des rats Sprague-Dawley déplétés en sodium traités par de la gentamicine, nous avons mesuré RBF et GFR au début de ce modèle d'insuffisance rénale aiguë néphrotoxique. Après 10 jours de déplétion en chlorure de sodium, un groupe de rats a reçu une injection unique de gentamicine, 100 mg/kg, tandis que les animaux contrôles recevaient le solvant de la gentamicine. Vingt-quatre heures plus tard, PCr et UNa/UCr étaient identiques dans les deux groupes. CIn était inchangé, mais RBF était significativement diminué (12,40 ± 1,33 contre 16,89) ± 1,24 ml/min). Des études en microponction ont révélé que bien que SNGFR soit inchangé, les débits dans l'extrémité du proximal et le début du distal étaient significativement augmentés. TFCl à la fin du proximal était significativement réduit chez les animaux traités par la gentamicine par rapport au contrôle (130,7 ± 3,9 contre 149,5 ± 4,1 mEq/litre). TFCl au début du distal était également significativement réduit (32,4 ± 3,2 contre 44,3 ± 1,4 mEq/litre). Chez d'autres rats, 24 heures après une seconde injection de gentamicine, PCr et UNa/UCr étaient significativement augmentés, et GFR et RBF étaient significativement diminués. Nous concluons que la modification hémodynamique la plus précoce au cours de l'insuffisance rénale aiguë induite par la gentamicine est une diminution de RBF qui précède toute modification de GFR. Une dose unique de gentamicine altère également la réabsorption proximale de bicarbonate et d'eau, et diminue la concentration de chlore à la fin du proximal et au début du distal.

Application of the disequilibrium pH method to investigate the mechanism of urinary acidification.

DuBose, Thomas D., Jr. Application of the disequilibrium pH method to investigate the mechanism of urinary acidification. Am. J. Physiol. 245 (Renal Fluid Electrolyte Physiol. 14): F535-F544, 1983.--The cellular mechanism of renal bicarbonate reabsorption has been debated for four decades. Recent technological advances have allowed distinction between primary bicarbonate reabsorption and a proton secretory mechanism. The disequilibrium pH method has been applied widely for this purpose and has supported the latter hypothesis uniformly. The demonstration of elevated values for PCO2 in tubular and vascular structures of the renal cortex has not altered this view. Indeed, by employing a newly developed method for measurement of equilibrium pH in vivo that permits contact with the environment within the tubule lumen to continue, we demonstrated an acid disequilibrium pH in the proximal tubule after carbonic anhydrase inhibition equal to -0.68 pH units. A spontaneous disequilibrium pH was not present in the distal tubule during control conditions or during metabolic alkalosis but was demonstrated during combined respiratory acidosis-metabolic alkalosis. This finding agrees qualitatively with observed rates of bicarbonate reabsorption in the perfused distal tubule in vivo. With use of similar techniques, an acid disequilibrium pH in conjunction with elevated values for PCO2 was observed in the papillary collecting duct. Thus, proton secretion appears to be the predominant mechanism of bicarbonate reabsorption in superficial nephrons and explains, as well, the means by which the urine-to-blood PCO2 gradient in alkaline urine is established.

Metabolic alkalosis in the rat. Evidence that reduced glomerular filtration rather than enhanced tubular bicarbonate reabsorption is responsible for maintaining the alkalotic state.

Maintenance of chronic metabolic alkalosis might occur by a reduction in glomerular filtration rate (GFR) without increased bicarbonate reabsorption or, alternatively, by augmentation of bicarbonate reabsorption with a normal GFR. To differentiate these possibilities, free-flow micropuncture was performed in alkalotic Munich-Wistar rats with a glomerular ultrafiltrate total CO2 concentration of 46.5 +/- 0.9 mM (vs. 27.7 +/- 0.9 mM in controls). Alkalotic animals had a markedly reduced single nephron GFR compared with controls (27.4 +/- 1.5 vs. 51.6 +/- 1.6 nl/min) and consequently unchanged filtered load of bicarbonate. Absolute proximal bicarbonate reabsorption in alkalotic animals was similar to controls (981 +/- 49 vs. 1,081 +/- 57 pmol/min), despite a higher luminal bicarbonate concentration, contracted extracellular volume, and potassium depletion. When single nephron GFR during alkalosis was increased toward normal by isohydric volume expansion or in another group by isotonic bicarbonate loading, absolute proximal bicarbonate reabsorption was not substantially augmented and bicarbonaturia developed. To confirm that a fall in GFR occurs during metabolic alkalosis, additional clearance studies were performed. Awake rats were studied before and after induction of metabolic alkalosis associated with varying amounts of potassium and chloride depletion. In all cases, the rise in blood bicarbonate concentration was inversely proportional to a reduction in GFR; filtered bicarbonate load remained normal. In conclusion, a reduction in GFR is proposed as being critical for maintaining chronic metabolic alkalosis in the rat. Constancy of the filtered bicarbonate load allows normal rates of renal bicarbonate reabsorption to maintain the alkalotic state.

Renal tubular acidosis

In the past decade major advances in our understanding of renal tubular hydrogen ion secretion and bicarbonate reabsorption have provided new insight into the pathophysiology of renal tubular acidosis. Thus "fragment to fragment clings" and the number of disorders categorized within the syndrome grows, until we have come to know and name four types, with many subtypes. We hope this new perspective provides a basis for the physician to recognize renal tubular acidosis in its several forms so that an informed decision may be arrived at in choosing the best therapy. The physician may also be prepared to reasonably project the prognosis for each patient. We also hope that our detailed examination of renal acidification will provide a reference for delineation of new clinical expressions of acid-base disorders and kidney malfunction certain to be described in the years ahead.

Effect of carbonic anhydrase inhibition on superficial and deep nephron bicarbonate reabsorption in the rat.

The nephron segment responsible for the acetazolamide-insensitive fraction of renal bicarbonate reabsorption has not been clearly delineated. This study compares superficial and deep nephron bicarbonate reabsorption before and after acetazolamide at two dose levels (20 and 50 mg/kg per h) in mutant Munich-Wistar rats employing both cortical and papillary micropuncture and microcalorimetry. Systemic acid-base balance and right whole kidney glomerular filtration rate were similar in all groups examined. The effects of the two doses of acetazolamide were indistinguishable and resulted in a significant increase in whole kidney bicarbonate excretion that compared favorably with the fraction delivered out of the left papillary tip. Acetazolamide inhibited superficial proximal bicarbonate reabsorption by 80.0%, whereas reabsorption up to the deep loop of Henle was decreased by only 52% (P less than 0.001). Bicarbonate reabsorption that was insensitive to acetazolamide occurred in the superficial and deep loop of Henle and between the distal tubule and base collecting duct. Because water reabsorption in these segments could serve to generate transepithelial bicarbonate concentration gradients favorable for reabsorption, we attempted to minimize water abstraction by combined administration of mannitol and acetazolamide. During this condition a significant increase in bicarbonate delivery up to the deep loop of Henle was noted (52 vs. 65%), whereas superficial nephron reabsorption was not altered. Furthermore, an outwardly directed bicarbonate concentration gradient from the deep loop of Henle to vasa recta was demonstrated during acetazolamide (delta tCO2 = 20.9 +/- 3.3 mM), but was abolished during combined mannitol and acetazolamide administration (delta tCO2 = 3.5 +/- 0.9 mM). It is concluded that carbonic anhydrase inhibition results in a disparate effect on nephron bicarbonate reabsorption when juxtamedullary and superficial nephron segments are compared. Our findings suggest that a mechanism for residual bicarbonate reabsorption during acetazolamide administration may be passive reabsorption driven by favorable transepithelial concentration gradients.

Natural history of primary distal renal tubular acidosis treated since infancy

Clinical and pathophysiologic studies were performed in five unrelated children with primary distal renal tubular acidosis who were diagnosed during infancy and followed for 3 to 9 1/2 years. All patients had permanent defects in hydrogen ion secretion, sodium reabsorption, and concentrating capacity. A transient, age-related, proximal tubular defect in sodium and bicarbonate reabsorption was also present. Renal bicarbonate wasting was mainly observed during the first years of life and progressively decreased with advancing age. Glomerular filtration rate remained within normal limits. Following sustained therapy with sodium and potassium bicarbonate, the patients had optimal growth, arrest of progression of nephrocalcinosis, and lack of other characteristic features of the disease with the exception of polyuria. Dosage of alkali was mainly determined by the magnitude of the renal bicarbonate loss and decreased progressively from a maximum of 3.9 to 10.0 mEq/kg/day during the first year of life to about 3 mEq/kg/day at or beyond 6 years of age. The total dosage of alkali required could be derived by the sum of the urinary excretion of bicarbonate plus 2 mEq/kg/day, which represents mean endogenous acid production. Although calciuria was normal when metabolic acidosis was corrected, patients with higher urinary sodium excretion had higher urinary excretion of calcium and thus were at greater risk of developing nephrocalcinosis if therapy was not carefully controlled.

The milk-alkali syndrome: current concepts.

The milk-alkali syndrome was first identified in 1923, and continues to occur in patients ingesting large amounts of calcium and absorbable alkali, particularly as calcium carbonate. Hypercalcemia, alkalosis, and renal impairment remain hallmarks of the syndrome, which may occur in acute, subacute, and chronic forms. Although the pathophysiology of the milk-alkali syndrome has not been completely studied, it appears to involve complex interactions between ingested calcium and alkali resulting in an impairment in renal calcium and bicarbonate excretion. The diagnosis of the milk-alkali syndrome is based on a history of calcium and alkali ingestion, the presence of characteristic clinical and laboratory features, and the exclusion of other causes of hypercalcemia. Conservative treatment, including discontinuing calcium and alkali ingestion and supportive measures, is usually effective.