Increase In Net Acid Excretion Research Articles

A marine teleost, Opsanus beta, compensates acidosis in hypersaline water by H+ excretion or reduced HCO3- excretion rather than HCO3- uptake.

Increases in ambient salinity demand parallel increases in intestinal base secretion for maintenance of osmoregulatory status, which is likely the cause of a transient acidosis following transfer of euryhaline fish from freshwater to seawater. It was predicted that transfer of the marine Gulf toadfish (Opsanus beta) from seawater (35 ppt) to hypersaline (60 ppt) seawater (HSW) would lead to a transient acidosis that would be compensated by increases in branchial acid excretion to offset the acid-base disturbance. Toadfish exposed to HSW showed a significant decrease in blood pH and [HCO3-] but no increase in pCO2, followed by a full recovery after 48-96h. A similar metabolic acidosis and recovery was found when fish were exposed to 60-ppt HCO3--free seawater (HEPES-buffered), which may suggest that compensation for intestinal base loss during hypersaline treatment is from gill H+ excretion rather than gill HCO3- uptake. However, we cannot rule out that reduced branchial HCO3- excretion contributed to an increase in net acid excretion. Since colchicine prevents full compensation, translocation of H+ and/or HCO3- transporters between cytosolic compartments and plasma membrane fractions might be involved in compensating for the hypersalinity-induced acidosis. Translocation of transporters rather than de novo synthesis may represent a faster and less energetically demanding response to rapidly fluctuating and high salinities encountered by toadfish in their natural environment.

Potassium deprivation: a systems approach

Potassium deprivation: a systems approach

Ca2+-driven intestinal HCO(3)(-) secretion and CaCO3 precipitation in the European flounder in vivo: influences on acid-base regulation and blood gas transport.

Marine teleost fish continuously ingest seawater to prevent dehydration and their intestines absorb fluid by mechanisms linked to three separate driving forces: 1) cotransport of NaCl from the gut fluid; 2) bicarbonate (HCO(3)(-)) secretion and Cl(-) absorption via Cl(-)/HCO(3)(-) exchange fueled by metabolic CO(2); and 3) alkaline precipitation of Ca(2+) as insoluble CaCO(3), which aids H(2)O absorption). The latter two processes involve high rates of epithelial HCO(3)(-) secretion stimulated by intestinal Ca(2+) and can drive a major portion of water absorption. At higher salinities and ambient Ca(2+) concentrations the osmoregulatory role of intestinal HCO(3)(-) secretion is amplified, but this has repercussions for other physiological processes, in particular, respiratory gas transport (as it is fueled by metabolic CO(2)) and acid-base regulation (as intestinal cells must export H(+) into the blood to balance apical HCO(3)(-) secretion). The flounder intestine was perfused in vivo with salines containing 10, 40, or 90 mM Ca(2+). Increasing the luminal Ca(2+) concentration caused a large elevation in intestinal HCO(3)(-) production and excretion. Additionally, blood pH decreased (-0.13 pH units) and plasma partial pressure of CO(2) (Pco(2)) levels were elevated (+1.16 mmHg) at the highest Ca perfusate level after 3 days of perfusion. Increasing the perfusate [Ca(2+)] also produced proportional increases in net acid excretion via the gills. When the net intestinal flux of all ions across the intestine was calculated, there was a greater absorption of anions than cations. This missing cation flux was assumed to be protons, which vary with an almost 1:1 relationship with net acid excretion via the gill. This study illustrates the intimate link between intestinal HCO(3)(-) production and osmoregulation with acid-base balance and respiratory gas exchange and the specific controlling role of ingested Ca(2+) independent of any other ion or overall osmolality in marine teleost fish.

Meta-Analysis of the Effect of the Acid-Ash Hypothesis of Osteoporosis on Calcium Balance

The acid-ash hypothesis posits that protein and grain foods, with a low potassium intake, produce a diet acid load, net acid excretion (NAE), increased urine calcium, and release of calcium from the skeleton, leading to osteoporosis. The objectives of this meta-analysis were to assess the effect of changes in NAE, by manipulation of healthy adult subjects' acid-base intakes, on urine calcium, calcium balance, and a marker of bone metabolism, N-telopeptides. This meta-analysis was limited to studies that used superior methodological quality for the study of calcium metabolism. We systematically searched the literature and included studies if subjects were randomized to the interventions and followed the recommendations of the Institute of Medicine's Panel on Calcium and Related Nutrients for calcium studies. Five of 16 studies met the inclusion criteria. The studies altered the amount and/or type of protein. Despite a significant linear relationship between an increase in NAE and urinary calcium (p < 0.0001), there was no relationship between a change of NAE and a change of calcium balance (p = 0.38; power = 94%). There was no relationship between a change of NAE and a change in the marker of bone metabolism, N-telopeptides (p = 0.95). In conclusion, this meta-analysis does not support the concept that the calciuria associated with higher NAE reflects a net loss of whole body calcium. There is no evidence from superior quality balance studies that increasing the diet acid load promotes skeletal bone mineral loss or osteoporosis. Changes of urine calcium do not accurately represent calcium balance. Promotion of the "alkaline diet" to prevent calcium loss is not justified.

Mechanisms of acid–base regulation in the African lungfishProtopterus annectens

African lungfish Protopterus annectens utilized both respiratory and metabolic compensation to restore arterial pH to control levels following the imposition of a metabolic acidosis or alkalosis. Acid infusion (3 mmol kg(-1) NH(4)Cl) to lower arterial pH by 0.24 units increased both pulmonary (by 1.8-fold) and branchial (by 1.7-fold) ventilation frequencies significantly, contributing to 4.8-fold and 1.9-fold increases in, respectively, aerial and aquatic CO(2) excretion. This respiratory compensation appeared to be the main mechanism behind the restoration of arterial pH, because even though net acid excretion (J(net)H(+)) increased following acid infusion in 7 of 11 fish, the mean increase in net acid excretion, 184.5+/-118.5 micromol H(+) kg(-1) h(-1) (mean +/- s.e.m., N=11), was not significantly different from zero. Base infusion (3 mmol kg(-1) NaHCO(3)) to increase arterial pH by 0.29 units halved branchial ventilation frequency, although pulmonary ventilation frequency was unaffected. Correspondingly, aquatic CO(2) excretion also fell significantly (by 3.7-fold) while aerial CO(2) excretion was unaffected. Metabolic compensation consisting of negative net acid excretion (net base excretion) accompanied this respiratory compensation, with J(net)H(+) decreasing from 88.5+/-75.6 to -337.9+/-199.4 micromol H(+) kg(-1) h(-1) (N=8). Partitioning of net acid excretion into renal and extra-renal (assumed to be branchial and/or cutaneous) components revealed that under control conditions, net acid excretion occurred primarily by extra-renal routes. Finally, several genes that are involved in the exchange of acid-base equivalents between the animal and its environment (carbonic anhydrase, V-type H(+)-ATPase and Na(+)/HCO (-)(3) cotransporter) were cloned, and their branchial and renal mRNA expressions were examined prior to and following acid or base infusion. In no case was mRNA expression significantly altered by metabolic acid-base disturbance. These findings suggest that lungfish, like tetrapods, alter ventilation to compensate for metabolic acid-base disturbances, a mechanism that is not employed by water-breathing fish. Like fish and amphibians, however, extra-renal routes play a key role in metabolic compensation.

Renal expression of the ammonia transporters, Rhbg and Rhcg, in response to chronic metabolic acidosis

Chronic metabolic acidosis induces dramatic increases in net acid excretion that are predominantly due to increases in urinary ammonia excretion. The current study examines whether this increase is associated with changes in the expression of the renal ammonia transporter family members, Rh B glycoprotein (Rhbg) and Rh C glycoprotein (Rhcg). Chronic metabolic acidosis was induced in Sprague-Dawley rats by HCl ingestion for 1 wk; control animals were pair-fed. After 1 wk, metabolic acidosis had developed, and urinary ammonia excretion increased significantly. Rhcg protein expression was increased in both the outer medulla and the base of the inner medulla. Intercalated cells in the outer medullary collecting duct (OMCD) and in the inner medullary collecting duct (IMCD) in acid-loaded animals protruded into the tubule lumen and had a sharp, discrete band of apical Rhcg immunoreactivity, compared with a flatter cell profile and a broad band of apical immunolabel in control kidneys. In addition, basolateral Rhcg immunoreactivity was observed in both control and acidotic kidneys. Cortical Rhcg protein expression and immunoreactivity were not detectably altered. Rhcg mRNA expression was not significantly altered in the cortex, outer medulla, or inner medulla by chronic metabolic acidosis. Rhbg protein and mRNA expression were unchanged in the cortex, outer and inner medulla, and no changes in Rhbg immunolabel were evident in these regions. We conclude that chronic metabolic acidosis increases Rhcg protein expression in intercalated cells in the OMCD and in the IMCD, where it is likely to mediate an important role in the increased urinary ammonia excretion.

Acid loading during treatment with sevelamer hydrochloride: Mechanisms and clinical implications

Short-term and long-term studies indicate that patients treated with sevelamer hydrochloride have lower serum bicarbonate levels than patients treated with calcium-containing phosphate binders. This observation has previously been attributed to withdrawal of a source of base with discontinuation of calcium carbonate or calcium acetate. However, understanding of the chemistry of sevelamer hydrochloride suggests at least three potential mechanisms whereby it might induce a dietary acid load. Moreover, preliminary results from an animal model demonstrate that treatment with sevelamer hydrochloride results in a fall in urine pH, as well as an increase in urinary ammonium and calcium excretion consistent with an increase in net acid excretion. Chronic metabolic acidosis in maintenance dialysis patients is associated with major systemic effects. It is independently associated with an increased risk of death in dialysis patients. Metabolic acidosis has both catabolic and antianabolic effects that may lead to a net negative nitrogen balance and total body protein balance. Metabolic acidosis also leads to physiochemical dissolution of bone and promotes cell-mediated bone resorption due to enhanced osteoclast activity and reduced osteoblast activity. It may also exacerbate secondary hyperparathyroidism and renal osteodystrophy. Given the long-term risks of chronic metabolic acidosis in maintenance dialysis patients, Kidney/Dialysis Outcome Quality Initiative (K/DOQI) guidelines have recently recommended maintaining predialysis serum levels of CO2 above 22 mmol/L in order to improve bone histology, and to ameliorate excess protein catabolism.

Introduction

Introduction

A mathematical model of rat collecting duct. I. Flow effects on transport and urinary acidification.

A mathematical model of the rat collecting duct (CD) has been developed by concatenating previously published models of cortical (Weinstein AM. Am J Physiol Renal Physiol 280: F1072-F1092, 2001); outer medullary (Weinstein AM. Am J Physiol Renal Physiol 279: F24-F45, 2000); and inner medullary segments (Weinstein AM. Am J Physiol Renal Physiol 274: F841-F855, 1998). Starting with end-distal tubular flow rate and composition, plus interstitial solute profiles, the model predicts urinary solute flows, including the buffer concentrations required to assess net acid excretion. In the model CD, the interstitial corticomedullary osmotic gradient provides the basis for the flow effect on the transport of several solutes. For substances that have an interstitial accumulation and that can have diffusive secretion (e.g., urea and NH(4)(+)), enhanced luminal flow increases excretion by decreasing luminal accumulation. For substances that are reabsorbed (e.g., K+ and HCO(3)(-)), and for which luminal accumulation can enhance reabsorption, increasing luminal flow again increases excretion by decreasing luminal solute concentration. In model calculations, flow-dependent increases in HCO(3)(-) and NH(4)(+) approximately balance, so net acid excretion is little changed by flow, albeit at a higher urinary pH. The model identifies delivery flow rate to the CD as a potent determinant of urinary pH, with high flows blunting maximal acidification. At even modestly high flows (9 nl x min-1. tubule-1, with 6% of filtered Na+ entering the CD), the model cannot achieve a urinary pH <5.5 unless the delivered HCO(3)(-) concentration is extremely low (<2 mM). Nevertheless, simulation of Na2SO4 diuresis does yield both an increase in net acid excretion and a decrease in urinary HCO(3)(-) (i.e., a decrease in pH) despite the increase in urinary flow. This model should provide a tool for examining hypotheses regarding transport defects underlying distal renal tubular acidosis.

Acid-base and endocrine effects of aldosterone and angiotensin II inhibition in metabolic acidosis in human patients

Chronic metabolic acidosis (CMA) in human beings is characterized by increased renin-angiotensin-aldosterone (RAA) activity and cortisol secretion as well as nitrogen wasting. The purpose of this study was to examine whether and to what extent increased RAA activity (ie, angiotensin II or aldosterone) regulates acid-base equilibrium in CMA and thus might co-determine the severity of acidosis. CMA was induced in 8 normal subjects by oral NH4Cl administration (2.1 mmol/kg body weight per day) for 7 days, followed by a 7-day period of spironolactone (100 mg, 4 times a day by mouth), followed by a 4-day period of spironolactone and losartan (100 mg, every day by mouth). NH4Cl feeding was continued during all study periods. Spironolactone resulted in exacerbation of acidosis ([HCO3]p decreased from 19.8 ± 0.4 mmol/L to 17.7 ± 0.6 mmol/L, P <.005) because of a large increase in endogenous acid production, as evidenced by significant increases in net acid excretion (116 to 185 mmol/day, P <.005), urinary anion gap (+31 mEq/day, P <.05), and sulfate excretion (+32 mEq/day, P <.05). Plasma potassium increased from 4.2 to 4.6 mmol/L (P <.05) because of decreased urinary potassium excretion (from 108 to 92 mmol/day, P <.05). Plasma angiotensin II, cortisol, aldosterone, urinary aldosterone, urinary tetrahydrocortisol, free cortisol, and nitrogen excretion increased significantly. The subsequent addition of losartan to spironolactone administration resulted in further exacerbation of acidosis ([HCO3]p decreased to 15.7 ± 0.4 mmol/L, P <.05) and hyperkalemia (5.0 mmol/L, P <.05) with no change in plasma anion gap. Renal potassium excretion decreased from 92 to 73 mmol/day (P <.05) on day 1. Exacerbation of acidosis was accounted for by a renal mechanism, as evidenced by the significant decrease in net acid excretion and unchanged urinary unmeasured anion and nitrogen excretion. We conclude the following: (1) AT-1 blockade by losartan exacerbates acidosis by inducing a distal-tubular acidification defect. Angiotensin II is an important modulator of the renal acid excretory response to CMA in human beings. (2) Inhibition of aldosterone action by spironolactone in CMA results in an increase in endogenous acid production and exacerbates acidosis by a non-renal mechanism that is mediated, at least in part, by exacerbated hyperglucocorticoidism. (J Lab Clin Med 2000;136:379-89)

On the mechanism of growth hormone-induced stimulation of renal acidification in humans: effect of dietary NaCl

Sustained administration of growth hormone (GH) to human subjects with NH4Cl-induced chronic metabolic acidosis (CMA) results in a large (4.5±0.5 mmol/l) increase in the plasma HCO3- concentration, as mediated by a large increase in renal net acid excretion. The renal mechanism(s) responsible for the potent stimulation of renal hydrogen ion secretion by GH remain to be elucidated. Accordingly, we have assessed the Na+ dependence of prolonged GH-stimulated renal acidification in four normal NaCl-restricted subjects (Na+ intake 0.3 mmol⋅kg-1⋅day-1) during CMA (4.2 mmol of NH4Cl⋅kg-1⋅day-1 for 7 days), CMA plus GH (0.1 unit/kg every 12 h for 5 days) and then CMA plus GH plus NaCl (1.7 mmol⋅kg-1⋅day-1 for 6 days). During CMA, urine Na+ excretion averaged 22.4±4.1 mmol/24 h. In response to GH administration, urinary net acid excretion was essentially unchanged, and the accumulated increment over 5 days of GH treatment was not different from zero (14±12 mmol; not significant). The plasma HCO3- concentration increased only slightly, from 14.2±0.8 to 15.0±1.1 mmol/l (P &lt; 0.05). Despite the constraint on net acid excretion imposed by NaCl restriction, renal ammonia production increased, as suggested by increases in urine pH from 5.58±0.05 to 5.82±0.04 (P &lt; 0.005) and unchanged NH4+ excretion (202±17 to 211±19 mmol/24 h; not significant). In response to dietary NaCl, urine pH decreased to 5.27±0.1 (P &lt; 0.001) and a large increment in net acid excretion accumulated (233±20 mmol; P &lt; 0.05), in association with an increase in plasma HCO3- to 18.7±1.3 mmol/l (P &lt; 0.001), a plasma HCO3- value similar to that reported previously in salt-replete, NH4Cl-fed subjects. These results demonstrate for the first time in any species that the acid excretory effect of GH administration is critically dependent on the availability of a surfeit of Na+ for tubular reabsorption. GH and/or insulin-like growth factor-1 affect renal acid excretion proximally (by stimulation of NH3 production) and by a Na+-transport-dependent mechanism in the collecting duct (voltage-driven acidification) in humans. The present results indicate that an isolated increase in renal NH3 production is insufficient to obligate an increase in net acid excretion.

On the mechanism of growth hormone-induced stimulation of renal acidification in humans: effect of dietary NaCl

Sustained administration of growth hormone (GH) to human subjects with NH(4)Cl-induced chronic metabolic acidosis (CMA) results in a large (4.5+/-0.5 mmol/l) increase in the plasma HCO(3-) concentration, as mediated by a large increase in renal net acid excretion. The renal mechanism(s) responsible for the potent stimulation of renal hydrogen ion secretion by GH remain to be elucidated. Accordingly, we have assessed the Na(+) dependence of prolonged GH-stimulated renal acidification in four normal NaCl-restricted subjects (Na(+) intake 0.3 mmol x kg(-1) x day(-1)) during CMA (4.2 mmol of NH(4)Cl x kg(-1) x day(-1) for 7 days), CMA plus GH (0.1 unit/kg every 12 h for 5 days) and then CMA plus GH plus NaCl (1.7 mmol x kg(-1) x day(-1) for 6 days). During CMA, urine Na(+) excretion averaged 22.4+/-4.1 mmol/24 h. In response to GH administration, urinary net acid excretion was essentially unchanged, and the accumulated increment over 5 days of GH treatment was not different from zero (14+/-12 mmol; not significant). The plasma HCO(3)(-) concentration increased only slightly, from 14.2+/-0.8 to 15.0+/-1.1 mmol/l (P<0.05). Despite the constraint on net acid excretion imposed by NaCl restriction, renal ammonia production increased, as suggested by increases in urine pH from 5.58+/-0.05 to 5.82+/-0.04 (P<0.005) and unchanged NH(4)(+) excretion (202+/-17 to 211+/-19 mmol/24 h; not significant). In response to dietary NaCl, urine pH decreased to 5.27+/-0.1 (P<0.001) and a large increment in net acid excretion accumulated (233+/-20 mmol; P<0.05), in association with an increase in plasma HCO(3-) to 18.7+/-1.3 mmol/l (P<0.001), a plasma HCO(3-) value similar to that reported previously in salt-replete, NH(4)Cl- fed subjects. These results demonstrate for the first time in any species that the acid excretory effect of GH administration is critically dependent on the availability of a surfeit of Na(+) for tubular reabsorption. GH and/or insulin-like growth factor-1 affect renal acid excretion proximally (by stimulation of NH(3) production) and by a Na(+)-transport-dependent mechanism in the collecting duct (voltage-driven acidification) in humans. The present results indicate that an isolated increase in renal NH(3) production is insufficient to obligate an increase in net acid excretion.

Urinary acidification capacity in the elderly

Renal acidification in 18 healthy elderly subjects was studied using furosemide 80 mg orally, as a substance to stimulate H+ and K+ secretion by enhancing Na+ delivery and transport in the cortical collecting duct. In five subjects, group 2 (n=5), the furosemide failed to lower urinary pH below 5.5, but resulted in an increase in potassium excretion and decrease in net acid excretion. These effects were obliterated by amiloride, a drug which decreases transtubular epithelial voltage (lumen-negative) in the cortical collecting tubule (CCT) by blocking Na+ reabsorption. The serum bicarbonate in this group was normal, and they were considered as suffering from incomplete distal renal tubular acidosis (IC-DRTA). In group 1 (n=13), the furosemide resulted in a fall in urinary pH below 5.5, and in an increase in net acid excretion. Our results show that in a subgroup of elderly subjects there is a proton pump defect located in the cortical collecting duct, and that the elderly are susceptible to metabolic acidosis during stress conditions or high protein diet.

Sodium-dependent urinary acidification in patients with aldosterone deficiency and in adrenalectomized rats: Effect of furosemide

Urinary acidification during metabolic acidosis and in response to stimulation of sodium-dependent hydrogen ion secretion using furosemide administration was evaluated in 12 patients with hyperkalemic hyperchloremic metabolic acidosis associated with mild chronic renal insufficiency and aldosterone deficiency. During spontaneous metabolic acidosis, the urine of all patients was acidic (pH less than 5.5), but ammonium excretion was markedly reduced (6.6 ± 1.3 μEq/min) comprising only about 20% of net acid excretion (30.5 ± 5.7 μEq/min). Furosemide (80 mg orally) resulted in a further fall in urine pH (from 5.29 ± 0.06 to 4.97 ± 0.09, P < 0.02) and a significant increase in net acid excretion (from 30 ± 5.8 to 38 ± 5.1 μEq/min, P < 0.02) while plasma aldosterone did not change (from 9.8 ± 1.7 to 9.7 ± 1.6 μg/dL). To investigate whether the acute stimulatory effect of furosemide on distal acidification requires some degree of mineralocorticoid activity, studies were conducted in adrenalectomized rats. The fall in urine pH and the increase in net acid excretion elicited by furosemide in adrenalectomized rats were comparable to those observed in adrenal-intact animals (5.37 ± 0.10 v 5.67 ± 0.11 and 0.43 ± 0.08 v 0.41 ± 0.06 μEq/min, respectively). inhibit sodium transport in the cortical collecting tubule, furosemide failed to lower urine pH (6.44 ± 0.23) and to increase net acid excretion (0.07 ± 0.06 μEq/min). These findings demonstrate that furosemide enhances hydrogen ion secretion in the absence of aldosterone provided that sodium-transport in the cortical collecting tubule is not impaired. The data therefore lends support for the notion that this diuretic stimulates urinary acidification by increasing sodium-dependent hydrogen ion secretion in the cortical collecting tubule and that this effect is mineralocorticoid-independent.

Acid-base homeostasis during chronic PTH excess in humans

The chronic renal and systemic acid-base effects of hyperparathyroidism in humans remain controversial and unresolved. The present studies evaluated the acid-base response of normal human subjects to a 13-day intravenous infusion of synthetic b(1-34) PTH sufficient to result in sustained hypercalcemia and hypophosphatemia. The acid-base response was biphasic: an initial transient renal acidosis developed on the first day of PTH infusion, followed by a prompt increase in net acid excretion and plasma [HCO3-] of sufficient magnitude to result in a steady state of mild metabolic alkalosis. The results indicate that: 1) sustained, continuous, experimentally produced hyperparathyroidism results in a steady state of mild metabolic alkalosis; 2) the alkalosis is both generated and maintained, at least in part, by renal mechanisms; and 3) reported renal acidosis in sustained clinical conditions of primary hyperparathyroidism is not attributable to either direct or indirect effects of PTH excess when present for a 2-week period, an interval sufficient to re-establish a new steady state of renal and systemic acid-base equilibrium.

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.

Effects of glucocorticoid steroids on renal and systemic acid-base metabolism

Clinical states of hyperglucocorticoidism are associated with renal metabolic alkalosis, yet the systemic and renal acid-base response to chronic administration of glucocorticoid steroids (dexamethasone, triamcinolone) possessing little or no mineralocorticoid activity has not been investigated. In balance studies studies in dogs administration of triamcinolone (Tcn), 1.0 mg . kg-1 . day-1 for 6-9 days (group I, n = 5), resulted in a persistent reduction in urine pH and increase in net acid excretion (NAE), and in the excretion of urinary unmeasured anions (C+NH4,Na;K minus A-Cl,HCO3,Pi), which were identified as organic anions and sulfate. A significant degree of metabolic acidosis occurred initially (delta [HCO3-]p, -3.4 meq/liter, P less than 0.05, day 1). As Tcn administration was continued, the cumulative increment in net acid excreted exceeded the cumulative increment in urinary unmeasured anion excreted and [HCO-3]p returned to pre-Tcn control values and remained stable thereafter. In the steady state of Tcn administration plasma potassium concentration and renal potassium clearance were not significantly different from pre-Tcn control, in contrast to the findings of hypokalemia and increased renal potassium clearance during chronic administration of deoxycorticosterone (DOC). Triamcinolone did not result in antinatriuresis or antichloruresis. Chronic administration of a 10-fold smaller dose of Tcn (0.1 mg . kg-1 . day-1) in an additional group (group III) also resulted in a persisting reduction in urine pH and an increase in net acid excretion that exceeded unmeasured anion excretion and resulted in a small increase in steady-state plasma bicarbonate concentration. These results suggest that chronic administration of potent glucocorticoid steroids results in 1) a persisting increase in endogenous acid production, and 2) stimulation of renal hydrogen ion secretion that was of greater degree than accounted for by the increment in endogenous acid production and that was not accompanied by renal mineralocorticoid effects on sodium and potassium transport.

Mechanism by which neutral phosphate infusion elevates urine PCO2.

Currently, the ability to elevate the urine PCO2 above that of the arterial blood is employed as an estimate of distal hydrogen ion secretion. Therefore, it is important to establish the mechanisms by which various factors affect the urine CO2 tension. This paper examines the physiologic process by which phosphate elevates the urine PCO2 in the dog. The rise in urine PCO2 due to phosphate could be the result of either (1) a distal mechanism, by affecting the delayed dehydration of carbonic acid, or (2) an increase in the medullary PCO2. The phosphate-induced elevation of urine PCO2 was abolished by carbonic anhydrase infusion. This indicates that a distal mechanism is a major factor in the phosphate effect. Since acid phosphate infusion did not result in an elevated urine PCO2, it is unlikely that changes in the medullary PCO2 occur as a ry an increase in net acid excretion, indicating an increase in hydrogen ion secretion. The increased hydrogen ion secretion and rise in urine PCO2 were reproduced by infusion of the buffer, Tris-(hydroxymethyl)-aminomethane, but not by sodium sulfate administration. These findings suggest that the phosphate-induced rise in urine PCO2 is due to the buffer properties of phosphate rather than to its nonreabsorable anion characteristics.

Renal response of the lamb fetus to partial occlusion of the umbilical cord

The role of the fetal kidney during impairment of placental exchange was studied in eight fetal lambs, intact in utero; a standard asphyxial insult for a period of 1 hour was produced by occluding the umbilical cord sufficiently to lower the fetal heart rate by 35 +/- 5 beats/min and the pH by 0.15 units. This asphyxial stress caused a fall in urine output from a control of 0.17 to 0.03 ml/kg/min and of glomerular filtration rate from 1.2 to 0.3 ml/min; release of the occlusion was followed by mild diuresis. The fall in urine output was accompanied by a rise in total primary solutes including concentrations of electrolytes; this rise continued for 1 to 2 hours following the release of the occlusion. Because of the low urinary output during the period of occlusion, there was a fall in excretion of electrolyte; an increase in net acid excretion occurred only after the release of the cord. These experiments show that, although the fetal kidney is capable of contributing to elimination of acid following compression of the cord, there may be an associated net loss of water and electrolytes.

Mechanism for the paradoxical aciduria following alkali administration to prolonged-fasted patients

Rapidly induced systemic alkalinization due to either sodium-lactate or sodium-bicarbonate infusion in prolonged-fasted subjects with steady-state ketoacidosis was associated with a decrease in urine pH. This decrease in urine pH from 5.50 to 5.20 was the result of a significant decrease in urinary ammonium excretion from 8.40 to 6.35 mEg/hr and was not accompanied by an increase in net acid excretion (11.3 vs. 10.6 mEg/hr). The decreased ammonium excretion is attributed to the raised pH of the proximal tubular fluid resulting in a less favorable pH gradient for gaseous ammonia entry. This would decrease gaseous ammonia generated in the loop of Henle for collecting duct buffering of secreted hydrogen ions.