Renal Net Acid Excretion Research Articles

Renal Tubular Acidosis

The kidney has as one of its major responsibilities the excretion of the daily nonvolatile acid load. On a normal American diet, this amounts to about 1 mEq of nonvolatile acid per kilogram body weight. This acid is excreted in the form of titratable acids (e.g., H2PO4 −) and ammonium (NH4 +). Alkali is usually excreted in much smaller amounts in the form of bicarbonate and organic anions (citrate, etc.). Renal net acid excretion thus equals the sum of the excretion of ammonium plus titratable acid minus bicarbonate and other anions.

Renal net acid excretion in the adrenalectomized rat

Although adrenalectomy is usually associated with an impairment of ammonium and/or titratable acid excretion by the kidney, it is uncertain whether rates of renal net acid excretion are also reduced. Further, it is unclear whether the absence of the adrenal gland itself or other factors of adrenal insufficiency mediate such changes in renal acidification parameters. For example, dramatic increases in ammonium excretion can accompany correction of the hyperkalemia seen in adrenal insufficiency. There is also evidence that reduced rates of acid excretion can result from changes in food intake, urine flow rate, urine pH or distal sodium delivery rates. With these considerations in mind, we undertook studies to isolate the chronic effects of adrenalectomy on renal net acid excretion rates in the unanaesthetized rat. To avoid supranormal potassium stores, we gave the adrenalectomized animals potassium-restricted diets. In balance studies, urine flow rates, urine pH, food intake, and distal sodium delivery rates were all successfully controlled for 13 days by pair feeding and by appropriately changing the sodium and potassium contents of diets. Adrenalectomized rats excreted less net acid than did control animals with or without ammonium chloride loading. Further, the severe metabolic acidosis associated with ammonium chloride loading was clearly mitigated by steroid replacement. Accordingly, we conclude that the adrenal gland is essential for normal renal net acid excretion.

Renal and systemic acid-base effects of chronic dichloroacetate administration in dogs

Dichloroacetate (DCA) increases metabolic disposal of lactic acid secondary to activation of pyruvate dehydrogenase and consequent acceleration of pyruvate oxidation. DCA has thus been proposed as a therapeutic agent for clinical states of lactic acidosis. Yet, DCA has a potential metabolic acidosis-producing effect by virtue of reported effects of (A) increasing blood ketoacid concentration, (B) decreasing tubular reabsorption of filtered ketoacid anions, and (C) decreasing renal NH 3 production. In the present study chronic administration of DCA, 50 mg/kg p.o. daily for 6–8 days, resulted in a cumulative increase in renal net acid excretion (NAE) (ΣΔNAE, +61 meq, p < 0.05). The increase in NAE was accounted for entirely by increased NH 4 + excretion. Production of ammonia by the kidney appeared to be increased since the increased excretion of NH 4 + was accompanied by an increase in urine pH (ΔUpH, +0.18 ± 0.07, p < 0.05). The increase in NAE was accompanied by a nearly identical increase in urinary anion gap (UAG) (UAG = [NH 4 + + Na + + K +] − [Cl − + HCO 3 − + HPO 4 2− + H 2PO 4 −]). The increase in UAG was caused by increased urinary total organic anions, accounted for at least in part by a significant increase in urinary acetoacetate. No significant increase in urinary potassium or sodium excretion occurred. A change in plasma acid-base composition occurred that was consistent with a mild respiratory acidosis without associated primary metabolic acidosis or alkalosis. These findings indicate that chronic DCA administration results in (1) increased steady state endogenous noncarbonic organic acid production, and (2) retention of carbonic acid. Further investigation of the potential metabolic and respiratory acidosis-producing effects of DCA is required to determine its clinical efficacy in the treatment of clinical lactic acidosis.

THEORETICAL MODEL TO ESTIMATE RENAL NET ACID EXCRETION

Natural food is originated from cell material with constant pH. Patients fed natural food show renal net acid excretion (NAE) far below maximum. During parenteral nutrition or under synthetic diets high NAE was observed. Therefore, a model was developed to calculate NAE under a synthetic diet from the analytical data of this diet. According to Relman (J.Clin. Invest. 40, 1621, 1961) NAE corresponds to the difference of urinary anions [sulfate (SO4) + organic acids (OA) + chloride (Cl) + phosphate (P)] and urinary cations [sodium (Na) + potassium (K) + calcium (Ca) + magnesium (Mg)]. If urinary excretion of each parameter can be estimated from the data of intake, NAE can be predicted. In steady state conditions the urinary excretion of electrolytes correlates with their intestinal absorption, which can be estimated from intake and absorption rate. Absorption from the gut was estimated in the following way: Na + Cl: 100%; K: 90%; Ca: 0.17 × Ca intake (mg) + 60; Mg: 0.39 × Mg intake (mg) −23; P: 0.642 × P intake (mg) − 11. 75% of the ingested organic sulfur (methionine and cystine) is oxidized to SO4 and excreted in the urine. OA excretion is almost independent from the diet (38 meq/d/1.73m2). The usefulness of this theoretical model to estimate NAE was demonstrated in acid-base studies of children with phenylketonuria receiving two synthetic amino acid mixtures (PAM with a high NAE of 4-6 meq/kg/d, PAM74 with a low NAE of 1 meq/kg/d).

Balance of net base in the rat: adaptation to and recovery from sustained hypercapnia

Net base and mineral balances were evaluated in a group of male 350 g Wistar rats exposed to 10% carbon dioxide in air for 10 days with a view to identifying the source of net base subject to retention during renal compensation of sustained respiratory acidosis. In response to hypercapnia, the rate of renal net acid excretion rose but insignificantly. However, a rise in whole body net base concentration from about 215 mmol/kg to about 250 mmol/kg came about by ongoing gastrointestinal absorption in the weight-losing animal, absorbed net base being distributed to extracellular and non-extracellular compartments of the body, presumably including bone. During an 8-day recovery period, a small decrement in whole body net base concentration was observed.

Balance of net base in the rat: adaptation to and recovery from sustained hypercapnia.

Net base and mineral balances were evaluated in a group of male 350 g Wistar rats exposed to 10% carbon dioxide in air for 10 days with a view to identifying the source of net base subject to retention during renal compensation of sustained respiratory acidosis. In response to hypercapnia, the rate of renal net acid excretion rose but insignificantly. However, a rise in whole body net base concentration from about 215 mmol/kg to about 250 mmol/kg came about by ongoing gastrointestinal absorption in the weight-losing animal, absorbed net base being distributed to extracellular and non-extracellular compartments of the body, presumably including bone. During an 8-day recovery period, a small decrement in whole body net base concentration was observed.

Balance of net base in the rat. V. Effects of oral ammonium chloride loading.

The physiology of oral ammonium chloride loading was studied in four groups of male weanling rats weighing about 100 g and fed either standard ground Rostock rat food (containing 317 mmol net base/kg) or ground barley (containing only 20 mmol net base/kg). One group of animals on the Rostock diet received oral supplements of ammonium chloride (approximately 32 mmol . kg-1 . day-1) sufficient to provide a net zero rate of oral net base intake. In this group, ongoing fecal net base excretion caused net acid to be absorbed at an average rate of 15 mmol . kg-1 . day-1. The mean rate of renal net acid excretion rose markedly (by 29.4 mmol . kg-1 . day-1); and over an 8-day balance period the animals were able to maintain near-normal balances of net base. During a subsequent 8-day recovery the pattern of mineral turnover returned to normal. Even in the barley-fed rats, gastrointestinal net acid absorption was observed. These animals suffered a 61% reduction in the rate of body growth, but the overall rate of net base retention, per kilogram of mass gain, was close to the reference value. Finally, the combination of barley and ammonium chloride led to weight loss, positive net acid balances (8.5 mmol . kg-1 . day-1), and a maximal rate of renal net acid excretion (50.8 mmol . kg-1 . day-1). Some implications for the metabolism of organic acids are discussed.

Balance of net base in the rat. IV. Effects of oral calcium and phosphate loading.

Mineral and net base balances were studied in groups of male weanling Wistar rats given oral loads of calcium chloride, monocalcium phosphate plus monosodium phosphate, and disodium phosphate plus monopotassium phosphate, respectively. A group of adult nongrowing rats loaded with calcium chloride was included for comparison. In response to CaCl2 loading, gastrointestinal net base absorption was inhibited due, largely, to luminal precipitation of tertiary phosphates of calcium and magnesium. In the weanling animal, however, a rise in the rate of renal net acid excretion matched the concomitant decrement in the rate of net base absorption, permitting of continued skeletal net base storage. Similarly, in the adult animals augmented renal net acid excretion offset a positive rate of gastrointestinal net acid absorption with a resultant (normal) zero net base balance. Loading with monocalcium phosphate and disodium phosphate at a constant oral net base intake did not influence the overall net base balance, but disodium phosphate loading caused significant sodium retention.

Reduced renal acid excretion in malnutrition: a result of phosphate depletion

Eleven infants recovering from protein-calorie malnutrition secondary to acquired monosaccharide intolerance were found to have reduced plasma bicarbonate concentration associated with inadequate weight gain. Renal net acid excretion (NAE) was decreased to a mean of 34.2 micronEq/1.73m2/min. Titratable acidity (TA) was markedly reduced, accounting for only 16% of NAE. This marked reduction in TA was associated with reduced mean phosphate (PO4) excretion (.074 mg/min) and a reduced mean serum PO4 (3.9 mg/dl), suggesting PO4 depletion. Two patients received intravenous phosphate loads, resulting in an increase in mean NAE from 35.1 to 89.7 microgEq/1.73m2/min. A similar response was seen after oral PO4 supplementation. Three patients were studied after partial correction of their acidosis. At a relatively low plasma bicarbonate concentration (mean = 16.6 mmoles/liter) significant amounts of bicarbonate were detected in the urine (mean = 8.7 micronEq/1.73m2/min), suggesting a defect in bicarbonate reabsorption. Five patients studied after complete recovery from malnutrition had normal NAE in response to ammonium chloride load. The reduction in NAE appears to be secondary to unavailability of urinary buffers and a reduction in bicarbonate reabsorption; both of these defects can be explained by phosphate depletion.

ACID-BASE STATUS IN DIETARY TREATMENT OF PHENYLKETONURIA

Blood acid-base status, serum electrolytes, and urine pH were examined in 64 infants and children with phenylketonuria (PKU) treated with three different low phenylalanine protein hydrolyzates (Aponti, Cymogran, AlbumaidXP) and two synthetic amino acid mixtures (Aminogran, PAM). The formulas caused significant differences in acid-base status, serum potassium, and chloride, and in urine pH. In acid-base balance studies in two patients with PKU, Aponti, PAM, and two modifications of PAM (P2 + P3) were given. We observed a change from mild alkalosis to increasing metabolic acidosis from Aponti (serum bicarbonate 25,8 mval/liter) to P3 (24,0Y, P2 (19, 3) and PAM (17,0). Urine pH decreased and renal net acid excretion increased. In the formulas PAM, P2 and P3 differences in renal net acid excretion correlated with differences in chloride and sulfur contents of the diets and of the urines. New modifications of AlbumaidXP and of PAM, prepared according to our recommendations, showed normal renal net acid excretion (1 mEq/kg/24 hr) in a balance study performed in one patient with PKU and normal acid base status in 20 further patients.

Renal function studies during rejection of kidney transplantation

Renal net acid excretion and fractional solute excretion in response to systemic acidosis induced by ammonium chloride loading were examined in 2 patients, 400 to 500 days post-kidney transplantation during acute rejection episodes and during the quiescent state fifty-four to fifty-nine days afterward. The results demonstrate that the impaired ability to correct the metabolic acidosis during rejection is due to the consequence of marked reduction in glomerular filtration rate rather than a primary defect in the renal tubular acidification mechanisms.

Mechanism of Renal Acid Excretion Following X-Irradiation of the Dog

Alterations in renal net acid excretion were studied in uninephrectomized dogs given 400 R total body irradiation. The early postirradiation (days 1-6) increase in acid excretion was the result of enhanced acid secretion rather than decreased base filtration and was related to a fall in Na+ and K+ excretion. The later postirradiation (days 7-11) decrease in net acid excretion was the result of diminished acid secretion. However, the decrease in acid secretion was not related to an increase in Na+ or K+ excretion, nor could it be attributed to an alteration in carbonic anhydrase activity. Rather the decrease in acid secretion appeared with an elevation in plasma Cl- and fall in plasma HCO3- suggesting an increase in NaCl reabsorption at the expense of the Na+ for H+ exchange.

Net acid balance (NAB) in metabolic acidosis

In previous studies from this laboratory the principles for the determination of the balance (intake minus output) of non-carbonic, non-metabolizable, non-metabolized acid (net acid) have been validated and applied to healthy, growing infants. To determine NAB requires the independent measurement of all components of net acid intake (sulfuric and organic acid production plus net acid generated by skeletal mineralization minus net base intake) and net acid output (renal net acid excretion).In the present study NAB was determined over 3–8 day balance periods in 11 infants developing (n = 3) or recovering from (n = 8) diarrhea, ileostomy, renal or late metabolic acidosis. Four studies on infants having no significant change in acid-base status over the period of study served as controls. MAB was significantly positive during the development of acidosis and negative during recovery. A close (r > 0.9) linear relationship was found between NAB (mEq/kg) and the measured change in blood base excess (Δ BE, mEq/l) over the period of study such that the virtual volume of retained net base or acid approximated 50% of the body weight suggesting considerable involvement of non-ECF buffers. To our knowledge this study represents the first complete quantitative measurement of the total magnitude and the separate components of net base retained (during recovery) or net acid retained (during development) in metabolic acidosis.