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Aim: Renal excretion of excess HCO 3 - depends on renal cystic fibrosis transmembrane conductance regulator (CFTR) and is impaired in people with cystic fibrosis (pwCF). Urine HCO 3 - excretion following oral NaHCO 3 -loading may be a simple in vivo biomarker of CFTR function. In this study, we investigated changes in urine acid/base parameters following oral NaHCO 3 -loading to comprehensively assess the physiological response to the test and evaluate HCO 3 - as the primary test result., Methods: Urine acid/base parameters (titratable acid (TA), NH 4 + , net acid excretion (NAE) and pH) were measured in bio-banked urine samples from controls (n = 10) and pwCF (n = 50) who completed the challenged urine HCO 3 - test. The association between urine acid/base excretion parameters and clinical CF disease characteristics and CFTR modulator therapy-induced changes were assessed., Results: Before treatment, challenged urine acid/base excretion associated with important CF disease characteristics. TA excretion and NAE were lower in pwCF with residual function mutations, 7.9 and 16.6 mmol/3 h, respectively, and lower TA excretion and NAE associated with pancreatic sufficiency. A lower excretion of TA, NH 4 + , and NAE associated with a higher percentage of predicted FEV 1 (1.3%, 2.5% and 0.8% per mmol/3 h higher, respectively). Modulator treatment decreased TA excretion and NAE (-2.9 and -5.3 mmol/3 h, respectively)., Conclusion: Following acute NaHCO 3 -loading, increased base excretion is mirrored by decreased acid excretion. Urine HCO 3 - excretion sufficiently represents the additional urine acid/base parameters as test result. The observed changes in acid excretion support CFTR modulator-induced increase of CFTR-dependent type B intercalated cell HCO 3 - secretion and the use of the challenged urine HCO 3 - test as a possible CFTR-biomarker., (© 2024 The Author(s). Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Background: Urinary acidification with ammonium chloride (AC) for urolith dissolution is a common treatment for goats with urolithiasis. Studies have reported increased fractional excretion of calcium (FECa) following AC administration, which could increase calcium-based urolithiasis. D,L methionine (MET) may result in similar acidification with less calcium excretion., Objective: To compare the effects of orally administered MET and AC on urine and blood pH, FECa, and blood HCO3- concentrations in male goats., Methods: Prospective, randomized, crossover study. 12 healthy, 5-to-6-month-old Boer-cross wethers were administered 200 mg/kg of AC or MET orally for 14 days with a 7-day washout period between trials. Venous blood and urine samples were collected every 2 days. The effects of treatment and treatment day on urine and blood pH, HCO3-, and FECa were assessed using linear mixed models., Results: Ammonium chloride and MET lowered least squares means (LSM) urine pH on day 6 (LSM, 7.49; 95% CI, 6.44 to 8.54), 8 (LSM, 7.78; 95% CI, 6.73 to 8.83), and 10 (LSM, 7.53; 95% CI, 6.49 to 8.58) when compared to day 0 (LSM, 8.23; 95% CI, 7.18 to 9.28). Some goats' urine indicated acidification (pH < 7.0) in the first phase of the trial; however, for the entire trial, a significant treatment effect was not detected on urine pH, blood pH, blood HCO3- or log10 FECa., Clinical Relevance: Ammonium chloride and MET acidified urine of some goats. Dietary cation-anion difference should be considered when treating healthy goats to acidify their urine.

Na + /H + exchanger isoform 3 (NHE3) contributes to Na + /bicarbonate reabsorption and ammonium secretion in early proximal tubules. To determine its role in the diabetic kidney, type 1 diabetic Akita mice with tubular NHE3 knockdown [Pax8-Cre; NHE3-knockout (KO) mice] were generated. NHE3-KO mice had higher urine pH, more bicarbonaturia, and compensating increases in renal mRNA expression for genes associated with generation of ammonium, bicarbonate, and glucose (phosphoenolpyruvate carboxykinase) in proximal tubules and H + and ammonia secretion and glycolysis in distal tubules. This left blood pH and bicarbonate unaffected in nondiabetic and diabetic NHE3-KO versus wild-type mice but was associated with renal upregulation of proinflammatory markers. Higher renal phosphoenolpyruvate carboxykinase expression in NHE3-KO mice was associated with lower Na + -glucose cotransporter (SGLT)2 and higher SGLT1 expression, indicating a downward tubular shift in Na + and glucose reabsorption. NHE3-KO was associated with lesser kidney weight and glomerular filtration rate (GFR) independent of diabetes and prevented diabetes-associated albuminuria. NHE3-KO, however, did not attenuate hyperglycemia or prevent diabetes from increasing kidney weight and GFR. Higher renal gluconeogenesis may explain similar hyperglycemia despite lower SGLT2 expression and higher glucosuria in diabetic NHE3-KO versus wild-type mice; stronger SGLT1 engagement could have affected kidney weight and GFR responses. Chronic kidney disease in humans is associated with reduced urinary excretion of metabolites of branched-chain amino acids and the tricarboxylic acid cycle, a pattern mimicked in diabetic wild-type mice. This pattern was reversed in nondiabetic NHE3-KO mice, possibly reflecting branched-chain amino acids use for ammoniagenesis and tricarboxylic acid cycle upregulation to support formation of ammonia, bicarbonate, and glucose in proximal tubule. NHE3-KO, however, did not prevent the diabetes-induced urinary downregulation in these metabolites.

Metabolic acidosis is the most common acid-base disorder in septic patients and is associated with increased mortality. Previously, we demonstrated that sepsis induced by cecal ligation and puncture (CLP) impairs [Formula: see text] absorption in the medullary thick ascending limb (MTAL) by 1) decreasing the intrinsic [Formula: see text] absorptive capacity and 2) enhancing inhibition of [Formula: see text] absorption by LPS through upregulation of Toll-like receptor (TLR) 4 signaling. Both effects depend on ERK activation. Monophosphoryl lipid A (MPLA) is a detoxified TLR4 agonist that enhances innate antimicrobial immunity and improves survival following sepsis. Pretreatment of MTALs with MPLA in vitro prevents LPS inhibition of [Formula: see text] absorption. Here we examined whether pretreatment with MPLA would protect the MTAL against sepsis. Vehicle or MPLA was administered to mice 48 h before sham or CLP surgery, and MTALs were studied in vitro 18 h postsurgery. Pretreatment with MPLA prevented the effects of sepsis to decrease the basal [Formula: see text] absorption rate and enhance inhibition by LPS. These protective effects were mediated through MPLA stimulation of a Toll/IL-1 receptor domain-containing adaptor-inducing IFN-β-(TRIF)-dependent phosphatidylinositol 3-kinase-Akt pathway that prevents sepsis- and LPS-induced ERK activation. The effects of MPLA to improve MTAL [Formula: see text] absorption were associated with marked improvement in plasma [Formula: see text] concentration, supporting a role for the kidneys in the pathogenesis of sepsis-induced metabolic acidosis. These studies support detoxified TLR4-based immunomodulators, such as MPLA, that enhance antimicrobial responses as a safe and effective approach to prevent or treat sepsis-induced renal tubule dysfunction and identify cell signaling pathways that can be targeted to preserve MTAL [Formula: see text] absorption and attenuate metabolic acidosis during sepsis.

Hyperchloremic metabolic acidosis, particularly renal tubular acidosis, can pose diagnostic challenges. The laboratory phenotype of a low total carbon dioxide content, normal anion gap, and hyperchloremia may be misconstrued as hypobicarbonatemia from renal tubular acidosis. Several disorders can mimic renal tubular acidosis, and these must be appropriately diagnosed to prevent inadvertent and inappropriate application of alkali therapy. Key physiologic principles and limitations in the assessment of renal acid handling that can pose diagnostic challenges are enumerated., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

With aging there is a chronic low-grade metabolic-acidosis that may exacerbate negative protein balance during weight loss. The objective of this randomized pilot study was to assess the impact of 90 mmol∙day -1 potassium bicarbonate (KHCO₃) versus a placebo (PLA) on 24-h urinary net acid excretion (NAE), nitrogen balance (NBAL), and whole-body ammonia and urea turnover following short-term diet-induced weight loss. Sixteen (KHCO₃; n = 8, PLA; n = 8) older (64 ± 4 years) overweight (BMI: 28.5 ± 2.1 kg∙day -1 ) men completed a 35-day controlled feeding study, with a 7-day weight-maintenance phase followed by a 28-day 30% energy-restriction phase. KHCO₃ or PLA supplementation began during energy restriction. NAE, NBAL, and whole-body ammonia and urea turnover ( 15 N-glycine) were measured at the end of the weight-maintenance and energy-restriction phases. Following energy restriction, NAE was -9.8 ± 27.8 mmol∙day -1 in KHCO₃ and 43.9 ± 27.8 mmol∙day -1 in PLA ( p < 0.05). No significant group or time differences were observed in NBAL or ammonia and urea turnover. Ammonia synthesis and breakdown tended ( p = 0.09) to be higher in KHCO₃ vs. PLA following energy restriction, and NAE was inversely associated ( r = -0.522; p < 0.05) with urea synthesis in all subjects. This pilot study suggests some benefit may exist with KHCO₃ supplementation following energy restriction as lower NAE indicated higher urea synthesis.

The purpose of this study is to describe a low-cost and simply made instrument capable of measuring the total CO 2 content of microliter volumes of biological fluids utilizing a commercially available CO 2 sensor based on a NDIR detector. The described instrument is based on transformation of dissolved HCO 3 - to CO 2 by acidification and subsequent measurement of the produced CO 2 . The instrument has a linear response in the range 0.025-10 μmol HCO 3 - , which enables measurements in fresh urine and plasma samples down to 5 μl. The values from plasma were compared to measurements made on 65 μl whole blood in an automatic blood gas analyzer and found not to differ significantly. Compared to currently commercially available instruments applying the same principles to measure total CO 2 , this study provides a simple and robust alternative which even can be used on smaller sample volumes.

The approach to acid-base chemistry in medicine includes several methods. Currently, the two most popular procedures are derived from Stewart's studies and from the bicarbonate/BE-based classical formulation. Another method, unfortunately little known, follows the Kildeberg theory applied to acid-base titration. By using the data produced by Dana Atchley in 1933, regarding electrolytes and blood gas analysis applied to diabetes, we compared the three aforementioned methods, in order to highlight their strengths and their weaknesses. The results obtained, by reprocessing the data of Atchley, have shown that Kildeberg's approach, unlike the other two methods, is consistent, rational and complete for describing the organ-physiological behavior of the hydrogen ion turnover in human organism. In contrast, the data obtained using the Stewart approach and the bicarbonate-based classical formulation are misleading and fail to specify which organs or systems are involved in causing or maintaining the diabetic acidosis. Stewart's approach, despite being considered 'quantitative', does not propose in any way the concept of 'an amount of acid' and becomes even more confusing, because it is not clear how to distinguish between 'strong' and 'weak' ions. As for Stewart's approach, the classical method makes no distinction between hydrogen ions managed by the intermediate metabolism and hydroxyl ions handled by the kidney, but, at least, it is based on the concept of titration (base-excess) and indirectly defines the concept of 'an amount of acid'. In conclusion, only Kildeberg's approach offers a complete understanding of the causes and remedies against any type of acid-base disturbance.

Human stone calcium phosphate (CaP) content correlates with higher urine CaP supersaturation (SS) and urine pH as well as with the number of shock wave lithotripsy (SWL) treatments. SWL does damage medullary collecting ducts and vasa recta, sites for urine pH regulation. We tested the hypothesis that SWL raises urine pH and therefore Cap SS, resulting in CaP nucleation and tubular plugging. The left kidney (T) of nine farm pigs was treated with SWL, and metabolic studies were performed using bilateral ureteral catheters for up to 70 days post-SWL. Some animals were given an NH4Cl load to sort out effects on urine pH of CD injury vs. increased HCO3 (-) delivery. Histopathological studies were performed at the end of the functional studies. The mean pH of the T kidneys exceeded that of the control (C) kidneys by 0.18 units in 14 experiments on 9 pigs. Increased HCO3 (-) delivery to CD is at least partly responsible for the pH difference because NH4Cl acidosis abolished it. The T kidneys excreted more Na, K, HCO3 (-), water, Ca, Mg, and Cl than C kidneys. A single nephron site that could produce losses of all of these is the thick ascending limb. Extensive injury was noted in medullary thick ascending limbs and collecting ducts. Linear bands showing nephron loss and fibrosis were found in the cortex and extended into the medulla. Thus SWL produces tubule cell injury easily observed histopathologically that leads to functional disturbances across a wide range of electrolyte metabolism including higher than control urine pH., (Copyright © 2015 the American Physiological Society.)

Objective: To examine the long-term stability and validity of analyte concentrations of 21 clinical biochemistry parameters in 24-h urine samples stored for 12 or 15 yr at -22°C and preservative free., Design and Methods: Healthy children's 24-h urine samples in which the respective analytes had been measured shortly after sample collection (baseline) were reanalyzed. Second measurement was performed after 12 yr (organic acids) and 15 yr (creatinine, urea, osmolality, iodine, nitrogen, anions, cations, acid-base parameters) with the same analytical methodology. Paired comparisons and correlations between the baseline and repeated measurements were done. Recovery rates were calculated., Results: More than half of the analytes (creatinine, urea, iodine, nitrogen, sodium, potassium, magnesium, calcium, ammonium, bicarbonate, citric & uric acid) showed measurement values after >10 yr of storage not significantly different from baseline. 15 of the 21 parameters were highly correlated (r=0.99) between baseline and second measurement. Poorest correlation was r=0.77 for oxalate. Recovery ranged from 73% (oxalate) to 105% (phosphate)., Conclusion: Our results suggest high long-term stability and measurement validity for numerous clinical chemistry parameters stored at -22°C without addition of any urine preservative. Prospective storage of urine aliquots at -22°C for periods even exceeding 10 yr, appears to be an acceptable and valid tool in epidemiological settings for later quantification of several urine analytes., (Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Na(+)-glucose cotransporter 1 (SGLT1)-mediated glucose uptake leads to activation of Na(+)-H(+) exchanger 3 (NHE3) in the intestine by a process that is not dependent on glucose metabolism. This coactivation may be important for postprandial nutrient uptake. However, it remains to be determined whether SGLT-mediated glucose uptake regulates NHE3-mediated NaHCO3 reabsorption in the renal proximal tubule. Considering that this nephron segment also expresses SGLT2 and that the kidneys and intestine show significant variations in daily glucose availability, the goal of this study was to determine the effect of SGLT-mediated glucose uptake on NHE3 activity in the renal proximal tubule. Stationary in vivo microperfusion experiments showed that luminal perfusion with 5 mM glucose stimulates NHE3-mediated bicarbonate reabsorption. This stimulatory effect was mediated by glycolytic metabolism but not through ATP production. Conversely, luminal perfusion with 40 mM glucose inhibited NHE3 because of cell swelling. Notably, pharmacologic inhibition of SGLT activity by Phlorizin produced a marked inhibition of NHE3, even in the absence of glucose. Furthermore, immunofluorescence experiments showed that NHE3 colocalizes with SGLT2 but not SGLT1 in the rat renal proximal tubule. Collectively, these findings show that glucose exerts a bimodal effect on NHE3. The physiologic metabolism of glucose stimulates NHE3 transport activity, whereas, supraphysiologic glucose concentrations inhibit this exchanger. Additionally, Phlorizin-sensitive SGLT transporters and NHE3 interact functionally in the proximal tubule., (Copyright © 2014 by the American Society of Nephrology.)

Background: The clinical dehydration scale (CDS) is a quick, easy-to-use tool with 4 clinical items and a score of 1-8 that serves to classify dehydration in children with gastroenteritis as no, some or moderate/severe dehydration. Studies validating the CDS (Friedman JN) with a comparison group remain elusive. We hypothesized that the CDS correlates with a wide spectrum of established markers of dehydration, making it an appropriate and easy-to-use clinical tool., Methods: This study was designed as a prospective double-cohort trial in a single tertiary care center. Children with diarrhea and vomiting, who clinically required intravenous fluids for rehydration, were compared with minor trauma patients who required intravenous needling for conscious sedation. We compared the CDS with clinical and urinary markers (urinary electrolytes, proteins, ratios and fractional excretions) for dehydration in both groups using receiver operating characteristic (ROC) curves to determine the area under the curve (AUC)., Results: We enrolled 73 children (male = 36) in the dehydration group and 143 (male = 105) in the comparison group. Median age was 32 months (range 3-214) in the dehydration and 96 months (range 2.6-214 months, p < 0.0001) in the trauma group. Median CDS was 3 (range 0-8) within the dehydration group and 0 in the comparison group (p < 0.0001). The following parameters were statistically significant (p < 0.05) between the comparison group and the dehydrated group: difference in heart rate, diastolic blood pressure, urine sodium/potassium ratio, urine sodium, fractional sodium excretion, serum bicarbonate, and creatinine measurements. The best markers for dehydration were urine Na and serum bicarbonate (ROC AUC = 0.798 and 0.821, respectively). CDS was most closely correlated with serum bicarbonate (Pearson r = -0.3696, p = 0.002)., Conclusion: Although serum bicarbonate is not the gold standard for dehydration, this study provides further evidence for the usefulness of the CDS as a dehydration marker in children., Trial Registration: Registered at ClinicalTrials.gov (NCT00462527) on April 18, 2007.

Background: The exact frequency of distal and proximal renal tubular acidosis (RTA) in Sjögren's syndrome is unknown. Other features of Sjögren's syndrome like polyuria, glomerular manifestations, familial occurrence and pregnancy are not widely reported. The aim was to prospectively study the clinical features and outcome of distal and proximal RTA in Sjögren's syndrome and also report on other renal manifestations of Sjögren's syndrome., Methods: The present study is a prospective consecutive case series of patients who presented with a history suggestive of RTA and Sjögren's syndrome. All patients were followed for 1 year. The diagnosis of RTA was by fractional excretion of bicarbonate. The diagnosis of Sjögren's syndrome was according to the American-European classification system [modified by Tzioufas and Voulgarelis: Best Pract Res Clin Rheumatol 2007;21:989-1010]., Results: The total number of RTA patients diagnosed during this period was 149. Sjögren's syndrome accounted for 34.8% (52 of 149) of RTA patients. The important symptoms and laboratory parameters were oral and ocular symptoms in 23 (44.2%), dental caries in 12 (23%), body pains in 47 (90.3%), mean serum pH 7.202 ± 0.03, mean serum bicarbonate, 14.03 ± 1.66 mmol/l, and mean urine pH, 7.125 ± 0.54. There were 30 (57.6%) patients with distal RTA and 22 (42.3%) patients with proximal RTA., Conclusions: The clinical implication of the present study is that RTA is a common feature of Sjögren's syndrome. It may be missed if the presentation is not due to oral and ocular symptoms. The present study is also the only one with a 1-year follow-up., (© 2014 S. Karger AG, Basel.)

Background and Objectives: For accurate measurement of pH, urine collection under oil to limit the escape of CO(2) on air exposure is recommended. This study aims to test the hypothesis that urine collection under oil is not necessary in acidic urine in which bicarbonate and CO(2) are minor buffers, because loss of CO(2) would have little effect on its pH., Design, Setting, Participants, & Measurements: One hundred consecutive random urine samples were collected under oil and analyzed for pH, pCO(2), and HCO(3)(-) immediately and after 5 minutes of vigorous shaking in uncovered flasks to allow CO(2) escape., Results: The pH values in 97 unshaken samples ranged from 5.03 to 6.83. With shaking, urine pCO(2) decreased by 76%, whereas urine HCO(3)(-) decreased by 60%. Meanwhile, urine baseline median pH (interquartile range) of 5.84 (5.44-6.25) increased to 5.93 (5.50-6.54) after shaking (ΔpH=0.12 [0.07-0.29], P<0.001). ΔpH with pH≤6.0 was significantly lower than the ΔpH with pH>6.0 (0.08 [0.05-0.12] versus 0.36 [0.23-0.51], P<0.001). Overall, the lower the baseline pH, the smaller the ΔpH., Conclusions: The calculation of buffer reactions in a hypothetical acidic urine predicted a negligible effect on urine pH on loss of CO(2) by air exposure, which was empirically proven by the experimental study. Therefore, exposure of urine to air does not substantially alter the results of diagnostic tests for urine acidification, and urine collection under oil is not necessary.

Exposure to lead has been reported to have adverse health implications. An assessment of renal function in people occupationally exposed to lead was carried out using the following biochemical markers urea, creatinine, sodium, potassium, chloride and bicarbonate. A total of 53 test subjects (mean age 30.9 ± 7.7) were randomly selected among some workers occupationally exposed to lead in Osogbo city and 42 apparently healthy subjects (mean age 30.1 ± 1.2) were used as controls. The plasma urea, creatinine, chloride and bicarbonate concentration were determined using modified Berthelot method, Jaffe's reaction, Schales and Schales method and back titration methods, respectively. The plasma sodium and potassium concentrations were determined using flame emission spectrophotometry while blood lead level was also determined using atomic absorption spectrophotometry. The result showed significant increases in mean plasma concentration of creatinine (84.9 ± 13.6-97.4 ± 28.7 μmol/L), sodium (131.9 ± 3.9-134.8 ± 3.7 mmol/L) and chloride (98.2 ± 4.0-100.4 ± 3.9 mmol/L) in test subjects when compared with controls (p < 0.05). Furthermore, significant increases (p < 0.01) were observed in mean plasma concentration of urea (4.7 ± 1.2-5.7 ± 1.3 mmol/L) and blood lead levels (18.5 ± 3.5-69.7 ± 13.2 mg/L) in test subjects in comparison with controls. In contrast, there were no significant differences observed when mean plasma potassium and bicarbonate levels in test subjects were compared with controls (p > 0.05). These results indicate that occupational exposure to lead may compromise renal function.

To determine the clinical profile and progression of renal dysfunction in distal renal tubular acidosis (dRTA), we retrospectively studied 96 consecutive cases of dRTA diagnosed at our center. Patients with unexplained metabolic bone disease, short stature, hypokalemia, re-current renal stones, chronic obstructive uropathy or any primary autoimmune condition known to cause dRTA were screened. Distal RTA was diagnosed on the basis of systemic metabolic acidosis with urine pH >5.5 and positive urine anion gap. In those patients who had fasting urine pH >5.5 with normal baseline systemic pH and bicarbonate levels (incomplete RTA), acid load test with ammonium chloride was done. A cause of dRTA could be established in 53 (54%) patients. Urological defect in children (22/44) and autoimmune disease in adults (11/52) were the commonest causes. Hypokalemic paralysis, proximal muscle weakness and voiding difficulty were the common modes of presentation. Doubling of serum creatinine during the study period was noted in 13 out of 27 patients who had GFR <60 mL/min at presentation whereas in only one of the 70 with initial GFR >60 mL/min (P <0.005). In conclusion, urological disorders were the commonest cause of dRTA in children while autoimmune disorders were the commonest asso-ciation in adults. Worse baseline renal function, longer duration of disease and greater frequency of nephrolithiasis/nephrocalcinosis and urological disorders were noted in those who had wor-sening of renal dysfunction during the study period.

Background: Dietary acid charge enhances bone loss. Bicarbonate or alkali diet decreases bone resorption in humans. We compared the effect of an alkaline mineral water, rich in bicarbonate, with that of an acid one, rich in calcium only, on bone markers, in young women with a normal calcium intake., Methods: This study compared water A (per litre: 520 mg Ca, 291 mg HCO(3)(-), 1160 mg SO(4)(-), Potential Renal Acid load (PRAL) +9.2 mEq) with water B (per litre: 547 mg Ca, 2172 mg HCO(3)(-), 9 mg SO(4)(-), PRAL -11.2 mEq). 30 female dieticians aged 26.3 yrs (SD 7.3) were randomized into two groups, followed an identical weighed, balanced diet (965 mg Ca) and drank 1.5 l/d of the assigned water. Changes in blood and urine electrolytes, C-telopeptides (CTX), urinary pH and bicarbonate, and serum PTH were measured after 2 and 4 weeks., Results: The two groups were not different at baseline, and showed a similar increase in urinary calcium excretion. Urinary pH and bicarbonate excretion increased with water B, but not with water A. PTH (p=0.022) and S-CTX (p=0.023) decreased with water B but not with water A., Conclusion: In calcium sufficiency, the acid calcium-rich water had no effect on bone resorption, while the alkaline water rich in bicarbonate led to a significant decrease of PTH and of S-CTX.

A prospective examination of 103 newborns with hypoxic damage of the central nervous system of moderate severity was conducted on the 4-7, 10-14 and 21-28 days after birth and included clinical examination, neurosonographic study with dopplerography of great brain arteries and biochemical study of venous blood and urine. Children with ventriculomegalia were treated with diacarb. A control group included 15 newborns without signs of survived hypoxia. Ventriculomegalia was found in 29% of children in the main group and remained till the end of neonatal period in 15%, with moderate and large dilatation in 63,5% and mild dilatation of anterior horns of lateral ventriculars in 36,5%. The markers of development and long remaining ventriculomegalia are specified as follows: the morphofunctional immaturity of the brain (RR=1,7; 95%CI 1,16-2,45), absence of compensatory reduction of resistance index (RI) in anterior brain arteries on 4-7 days of life (RR=3,03; 95%CI 2,11-4,31), metabolic acidosis - the bicarbonate level in the venous blood less than 21 mmol/l (RR=2,9; 95% CI 1,66-5,02), carbanhydrase activation - bicarbonate concentration in the urine less than 5 mmol/mcmol of creatinine on 4-7 days of life (RR=3,81; 95%CI 2,87-5,02). Diacarb in ventriculomegalia should be prescribed only in case of disturbance of the organism compensatory reaction because it causes the significant increase of compensatory reduced RI. The drug has a nephrotoxic effect and causes metabolic acidosis.

We aimed to compare the recent practical method of capillary beta-hydroxy butyrate (betaOHB) measurement with the widely used urinary ketone measurement in monitoring metabolic status of the patient during treatment of diabetic ketoacidosis (DKA) and diabetic ketosis (DK). Patients with DKA and DK admitted to the hospital were followed with simultaneous measurements of capillary betaOHB by electrochemical method (Medisense Optium, Abbott), and urinary ketone by semi-quantitative method. Blood gases were measured in 2-4 h intervals. Fourteen patients with DKA/DK (7 males and 7 females, age: 9.2 +/- 4.2 years) were included with 50 simultaneous measurements of capillary and urinary ketone. No correlation was detected between urinary ketone and blood pH (P = 0.06) and HCO3 (P = 0.79), whereas a significant negative correlation was found between capillary betaOHB and blood pH (r = -0.41, P < 0.05) and HCO3 (r = -0.35, P < 0.05). Capillary betaOHB and urinary ketone levels did not correlate at the beginning and 3.3 +/- 1.4 h after treatment, but did correlate in the third samples taken 7.8 +/- 2.0 h after treatment (r = 0.8, P < 0.05). Capillary betaOHB levels show good correlation with the degree of acidosis (pH and HCO3). Capillary betaOHB measurement is more sensitive than urinary ketone measurement in reflecting the patient's metabolic status and improvement during treatment.

Background: Inherited proximal renal tubular acidosis (pRTA) is commonly associated with more generalized proximal tubular dysfunctions and occasionally with other organ system defects. Inherited combined pRTA and distal RTA with osteopetrosis and pure pRTA associated with ocular abnormalities, a rare disease which has been recently described. Only one family with pure isolated pRTA has been reported so far and the genetic cause for this disease is unknown. Objectives. We report a unique family with isolated pRTA. The aim of the project was to define the phenotype and to try to find the gene defect causing the disease., Methods: Clinical and metabolic evaluation of all family members was performed and a family pedigree was constructed. DNA was extracted from blood samples of affected and unaffected family members. We amplified by PCR and sequenced the coding areas and splice-sites of the genes that contribute to HCO(-)(3) reclamation in the proximal tubule. The genes studied were as follows: CA II, CA IV, CA XIV, NCB1, Na(+)/H(+) exchanger (NHE)-3, NHE-8, the regulatory proteins of NHE3, NHRF1 and NHRF2 and the Cl(-)/HCO(-)(3) exchanger, SLC26A6., Results: The father and all four children had RTA with blood HCO(-)(3) levels of 11-14 meq/l and urine pH of 5.3-5.4. Increased HCO(-)(3) fractional excretion after bicarbonate loading to 40-60% confirmed the diagnosis pRTA. No other tubular dysfunction was found, and no organ system dysfunction was detected, besides short stature. No mutation was found in all candidate genes studied., Conclusions: We presented a second family in the literature with familial isolated pure pRTA. The mode of inheritance is compatible with an autosomal dominant disease. Because of the small size of the family, wide genome search was not applicable and the gene candidate approach was chosen. Nine important candidate genes were extensively studied but the molecular basis of the disease was not yet found and genotyping nine important gene candidates were negative.

Forty-two lactating Holstein cows 188 +/- 59 d in milk were used in an 8-wk randomized complete block trial with a 2 x 3 factorial arrangement of treatments. The objective was to determine the effects of high dietary cation-anion difference (DCAD) and K:Na ratio on milk yield and composition and blood acid-base chemistry. Treatments included DCAD concentrations of 45 or 60 mEq (Na + K -Cl)/100 g of feed dry matter and K:Na ratios of 2:1, 3:1, or 4:1. Mean DCAD values were later determined to be 41 and 58. Dry matter intake was similar across treatments. Yield of milk and energy corrected milk were lower for the 3:1 K:Na ratio compared with 2:1 and 4:1 ratios. Blood urea N was lower for the highest DCAD, suggesting that DCAD possibly reduced protein degradation or altered protein metabolism and retention. Mean temperature-humidity index was 75.6 for the duration of the trial, exceeding the critical value of 72 for all weeks during the treatment period. Cows maintained relatively normal body temperature with mean a.m. and p.m. body temperature of 38.5 and 38.7 degrees C, respectively. These body temperatures suggest that cows were not subject to extreme heat stress due to good environmental control. Results of this trial indicate that the greatest effect on milk yield occurs when either Na or K is primarily used to increase DCAD, with the lowest yield of energy-corrected milk at a 3:1 K:Na ratio (27.1 kg/d) compared with ratios of 2:1 (29.3 kg/d) and 4:1 (28.7 kg/d). Results also suggest that greater DCAD improves ruminal N metabolism or N utilization may be more efficient with a high DCAD.

Dietary protein as casein (CAS) augments intrinsic acid production, induces endothelin-mediated kidney acidification, and promotes kidney injury. We tested the hypothesis that dietary CAS induces endothelin-mediated kidney injury through augmented intrinsic acid production. Munich-Wistar rats ate minimum electrolyte diets from age 8 to 96 weeks with 50 or 20% protein as either acid-inducing CAS or non-acid-inducing SOY. Urine net acid excretion and distal nephron net HCO3 reabsorption by in vivo microperfusion (Net J(HCO3)) were higher in 50 than 20% CAS but not 50 and 20% SOY. At 96 weeks, 50% compared the 20% CAS had higher urine endothelin-1 excretion (U(ET-1)V) and a higher index of tubulo-interstitial injury (TII) at pathology (2.25+/-0.21 vs 1.25+/-0.13 U, P<0.03), but each parameter was similar in 50 and 20% SOY. CAS (50%) eating NaHCO3 to reduce intrinsic acid production had lower Net J(HCO3), lower U(ET-1)V, and less TII. By contrast, 50% SOY eating dietary acid as (NH4)2SO4 had higher Net J(HCO3), higher U(ET-1)V, and more TII. Endothelin A/B but not A receptor antagonism reduced Net J(HCO3) in 50% CAS and 50% SOY+(NH4)2SO4 animals. By contrast, endothelin A but not A/B receptor antagonism reduced TII in each group. The data support that increased intake of acid-inducing dietary protein induces endothelin B-receptor-mediated increased Net J(HCO3) and endothelin A-receptor-mediated TII through augmented intrinsic acid production.

Background: Topiramate is a novel neuromodulatory agent commonly prescribed for the treatment of seizure disorders and for migraine headache prophylaxis. Calcium phosphate kidney stones have been observed with topiramate treatment, but a comprehensive elucidation of stone-risk profile was not reported previously. This study explores the relationship between topiramate treatment and propensity for kidney stone formation., Methods: Thirty-two topiramate-treated subjects and 50 healthy volunteers participated in a cross-sectional study in which serum chemistry test and 24-hour urine collection results were evaluated for stone risk. Furthermore, a short-term longitudinal study was conducted in 7 patients to assess stone risk before and 3 months after topiramate treatment., Results: Serum bicarbonate levels were lower with topiramate treatment. Urinary pH, urinary bicarbonate excretion, and fractional excretion of bicarbonate increased, whereas urinary citrate excretion was significantly lower (737 +/- 329 versus 278 +/- 226 mg/d; P < 0.001). Net acid excretion did not change. The relative saturation ratio for brushite increased with topiramate treatment (3.14 +/- 1.69 versus 1.27 +/- 1.26; P < 0.001) because of urinary alkalinization and decreased urinary citrate levels. Urinary saturation of undissociated uric acid decreased (41 +/- 52 versus 76 +/- 60 mg/d; P < 0.001)., Conclusion: Treatment with topiramate causes systemic metabolic acidosis, markedly lower urinary citrate excretion, and increased urinary pH. These changes increase the propensity to form calcium phosphate stones.

Background: Neither the prevalence nor the associated risk factors of late post-transplant renal tubular acidosis (RTA) are known., Methods: We conducted a cross-sectional study with 576 patients for more than 12 months after kidney transplantation, and a glomerular filtration rate (GFR) >40 ml/min. RTA was diagnosed by measurement of the urine anionic gap, urine pH and plasma potassium during acidosis, and fractional bicarbonate excretion after bicarbonate loading. Uni- and multi-variable analysis were used to isolate factors associated with post-transplant RTA, and with the different RTA subtypes., Results: All patients (n = 76) had distal post-transplant RTA. A significant association with the presence of RTA was found for the intake of tacrolimus or renin-angiotensin-aldosterone blockers, the Parathyroid hormone level and the GFR. Type Ia (classic, distal), type Ib (hyperkalaemic, voltage-dependent), rate-limited and type IV RTA were present in 37, 14, 21 and 28% of the patients. Acute transplant rejection was the only significant different parameter between the RTA subtypes and more often present in patients with type Ia or Ib RTA., Conclusions: We conclude that a significant fraction of stable long-term renal transplant recipients with adequate graft function develop post-transplant RTA, with a preponderance for type Ia and type IV, and absence of type II. In addition, acute transplant rejection seems to have an influence on the subtype of RTA present post-transplantation.

Objective: To describe a unique example of renal tubular acidosis type 2 (RTA 2) in conjunction with Fanconi's syndrome and osteomalacia consequent to vitamin D and calcium deficiency in an adult without underlying gastrointestinal disease., Methods: We review the clinical, hormonal, histomorphometric, and micro-computed tomographic findings and the response to therapy with vitamin D and calcium in our patient., Results: On admission, a 33-year-old African American woman had the following laboratory findings: serum ionized calcium 3.8 mg/dL (0.95 mmol/L), venous pH 7.26, bicarbonate 20 mEq/L, chloride 111 mEq/L, alkaline phosphatase 1,192 U/L (20.26 microkat/L) (normal, 40 to 136 U/L), 25-hydroxyvitamin D <5 ng/mL (<12 nmol/L) (normal, 10 to 60 ng/mL), parathyroid hormone 1,620 pg/mL (165.2 pmol/L) (normal, 10 to 60 pg/mL), aldosterone 68.4 ng/dL (1,894.7 pmol/L) (normal, 4.5 to 35.4 ng/dL), supine plasma renin activity 19.8 ng/mL per hour (5.35 ng/L per second) (normal, 0.5 to 1.8 ng/mL per hour), and aminoaciduria. A lumbar spine bone density T-score was -4.6, and a femoral neck T-score was -4.9. An undecalcified tetracycline-labeled bone biopsy specimen showed severe osteomalacia, severe osteoporosis, and peritrabecular fibrosis. A small intestinal biopsy revealed normal findings. Results of an ammonium chloride loading test and a bicarbonate infusion test were consistent with RTA 2. After 24 months of vitamin D and calcium therapy, results of serum and urine chemistry studies and bicarbonate infusion normalized. The lumbar spine T-score improved to -2.0, and the femoral neck T-score improved to -2.7. Bone biopsy specimens demonstrated resolution of the osteomalacia., Conclusion: Nutritional vitamin D and calcium deficiency may cause RTA 2, Fanconi's syndrome, and osteomalacia in adults as well as in children.

Acute hypercapnia may develop during periodic breathing from an imbalance between abnormal ventilatory patterns during apnea and/or hypopnea and compensatory ventilatory response in the interevent periods. However, transition of this acute hypercapnia into chronic sustained hypercapnia during wakefulness remains unexplained. We hypothesized that respiratory-renal interactions would play a critical role in this transition. Because this transition cannot be readily addressed clinically, we modified a previously published model of whole-body CO2 kinetics by adding respiratory control and renal bicarbonate kinetics. We enforced a pattern of 8 h of periodic breathing (sleep) and 16 h of regular ventilation (wakefulness) repeated for 20 days. Interventions included varying the initial awake respiratory CO2 response and varying the rate of renal bicarbonate excretion within the physiological range. The results showed that acute hypercapnia during periodic breathing could transition into chronic sustained hypercapnia during wakefulness. Although acute hypercapnia could be attributed to periodic breathing alone, transition from acute to chronic hypercapnia required either slowing of renal bicarbonate kinetics, reduction of ventilatory CO2 responsiveness, or both. Thus the model showed that the interaction between the time constant for bicarbonate excretion and respiratory control results in both failure of bicarbonate concentration to fully normalize before the next period of sleep and persistence of hypercapnia through blunting of ventilatory drive. These respiratory-renal interactions create a cumulative effect over subsequent periods of sleep that eventually results in a self-perpetuating state of chronic hypercapnia.

Nine multiparous and 12 primiparous cows were fed diets containing an anionic salt supplement and moderate Ca (0.99%) or high Ca (1.50%) concentrations for 21 d prepartum to determine the effects of dietary Ca concentration on serum and urine electrolytes and on postpartum intake and milk yield. Blood samples were collected during 21 to 1 d prepartum, 0 to 2 d postpartum, and 3 to 21 d postpartum. Dietary cation-anion difference (DCAD) for prepartum diets was approximately -6 mEq/100 g of dry matter (Na + K - Cl - S). Immediately postpartum, cows were fed diets with positive DCAD with greater than 1.00% Ca concentration. Mean serum Ca concentrations 21 to 1 d prepartum, 0 to 2 d postpartum, and 3 to 21 d postpartum were 9.62, 8.41, and 9.38 mg/dL. There were no treatment effects on serum Ca concentration. Mean serum Ca concentration was higher for primiparous than multiparous cows (9.34 vs. 8.93 mg/dL) for the trial and at calving (8.77 vs. 8.13 mg/dL). Mean serum HCO(3)(-) and urinary pH, respectively, were 20.32 mEq/L and 5.67 prepartum, 25.82 mEq/L and 7.62 at calving, and 26.08 mEq/L and 8.25 postpartum. No differences due to treatment were observed for serum and urinary concentrations of HCO(3)(-), pH, Mg, Na, K, and Cl. Milk yield was similar for 0.99 and 1.50% Ca treatments (22.8 and 20.7 kg/d). Diets containing 0.99 or 1.5% Ca maintained serum Ca at adequate levels around parturition and resulted in similar dry matter intake and postpartum milk yield.

Background: Alkali-rich diets are often recommended in human medicine to prevent the pathological consequences of nutritional acid load in conditions of impaired renal function., Aim of the Study: This study was undertaken in rabbits as common laboratory animals for basic medical research to explore the impact of high versus low dietary alkali intake on systemic acid-base balance and renal control in a typical herbivore., Methods: Male rabbits (2.3-4.8 kg) were kept in a metabolism cage. The 24h urine and arterial blood samples were analysed for acid-base data. The metabolic CO2 production was measured to calculate alveolar ventilation. Three randomized groups of animals were fed ad libitum with rabbit chow providing sufficient energy but variable alkali load, assessed by the ashes' cation-anion difference., Results: The average daily nutritional alkali load (+/- SEM) was 67.1 +/- 2.2 mEq x kg(-1) (N = 58) in the group on high, 45.4 +/- 2.5 mEq x kg(-1) (N = 31) in the group on normal and 1.7 +/- 0.5 mEq x kg(-1) (N = 11) in the group on low alkali food. Respective mean arterial base excess values (BE) were 1.4 +/- 0.3 mM, 0.3 +/- 0.4 mM and 0.0 +/- 0.3 mM, being significantly higher on high alkali food (P < 0.05) than in the other groups. Arterial PCO2, alveolar ventilation and metabolic CO2 production were not significantly different between groups. On normal and high-alkali chow, an alkaline urine (pH(u) > 8.0) with 18-20 mmol x kg(-1) bicarbonate/carbonate was excreted daily, typically containing an insoluble precipitate of 35-60% carbonate. On low-alkali diet, the mean pH(u) decreased to 6.26 +/- 0.14, due to a strong reduction of daily excreted soluble bicarbonate and precipitated carbonate to 1.2 +/- 0.6 and 0.7 +/- 0.2 mmol x kg(-1), respectively. Thereby, nearly complete fractional base reabsorption of 97.8 +/- 0.7 % was reached., Conclusion: Herbivore nutritional alkali-load elicited large rates of renal base excretion including precipitates, to which the urinary tract of the rabbits appeared to be adapted. Dietary base variations were more accurately reflected in the urine than by the blood acid-base status. A strongly base-deficient diet exerted maximum impact on renal base saving mechanisms, implying a critical precondition for growing susceptibility to metabolic acidosis also in the rabbit.

Low-grade metabolic acidosis, consecutive to excessive catabolism of sulfur amino acids and a high dietary Na:K ratio, is a common feature of Western food habits. This metabolic alteration may exert various adverse physiological effects, especially on bone, muscle and kidneys. To assess the actual effects of various K salts, a model of the Westernised diet has been developed in rats: slight protein excess (20 % casein); cations provided as non-alkalinising salts; high Na:K ratio. This diet resulted in acidic urine (pH 5.5) together with a high rate of divalent cation excretion in urine, especially Mg. Compared with controls, K supplementation as KCl accentuated Ca excretion, whereas potassium bicarbonate or malate reduced Mg and Ca excretion and alkalinised urine pH (up to 8). In parallel, citraturia was strongly increased, together with 2-ketoglutarate excretion, by potassium bicarbonate or malate in the diet. Basal sulfate excretion, in the range of 1 mmol/d, was slightly enhanced in rats fed the potassium malate diet. The present model of low-grade metabolic acidosis indicates that potassium malate may be as effective as KHCO3 to counteract urine acidification, to limit divalent cation excretion and to ensure high citrate concentration in urine.

Background: The purpose of this study was to explore the renal acid-base response to acute protein load in patients with heart failure (HF). It was prompted by the fact that there are no data available regarding the role of renal tubules in maintaining acid-base balance following protein loading in HF patients., Methods and Results: Nine male patients with HF and 12 healthy subjects (controls) were enrolled in this study. In the HF patients, average blood pH was 7.42 (0.03), average pCO2 was 36.6 mmHg (6.3) and average bicarbonate was 24.2 mmol/L (4.3). The acid-base status of patients was unaffected by meat ingestion. The values at peak glomerular filtration rate (GFR) did not differ significantly from baseline levels. An oral protein load did not influence the urinary pH, titratable acidity (TA) and ammonium excretion in the patients with HF, contrary to the findings in the controls. On the other hand, ammonium excretion in patients with HF reduced significantly compared with values from controls at baseline and following oral protein loading. Filtered and reabsorbed bicarbonate increased significantly in HF patients following meat ingestion, whereas there was no change in absolute and fractional bicarbonate excretion and fractional bicarbonate reabsorbed., Conclusions: This study demonstrated that in patients with HF, bicarbonate reabsorption increases following an oral protein load without a significant enhancement in bicarbonate excretion. The difference can be explained by the presence of respiratory alkalosis leading to bicarbonate conservation.

The determination of urinary bicarbonate with the Henderson-Hasselbalch equation was compared using two methods: (1) correcting the pK in every urine sample according to ionic strength and using the solubility constant of CO2 in urine (alpha=0.0309) and (2) using a fixed pK value (6.1) and a CO2 solubility constant of 0.0301, which we use to calculate blood bicarbonate. Nine patients were studied and 29 determinations were performed. A high correlation was found between the methods (r=0.99). Bicarbonate calculated with corrected pK was 24.3+/-6.6 mEq/l (95% confidence interval 11.4-37.2) and bicarbonate calculated with pK fixed at 6.1 was 25.6+/-6.6 mEq/l (95% confidence interval 12.7-38.5). For each urine sample, the delta bicarbonate was calculated as the difference between the bicarbonate obtained with pK at 6.1 minus that obtained with the corrected pK (mean 1.25, standard error 0.83, P=0.15). This indicates that the difference between the methods was not significant. No difference was found whether pK was corrected or fixed (6.1). Therefore, our results suggest that it is valid to take the value shown by the equipment for blood gas determination as the urinary bicarbonate value. This would allow the rapid and accurate determination of urinary bicarbonate in patients with hyperchloremic acidosis, especially those with renal tubular acidosis.

The acid- and volume-sensitive TASK2 K+ channel is strongly expressed in renal proximal tubules and papillary collecting ducts. This study was aimed at investigating the role of TASK2 in renal bicarbonate reabsorption by using the task2 -/- mouse as a model. After backcross to C57BL6, task2 -/- mice showed an increased perinatal mortality and, in adulthood, a reduced body weight and arterial blood pressure. Patch-clamp experiments on proximal tubular cells indicated that TASK2 was activated during HCO3- transport. In control inulin clearance measurements, task2 -/- mice showed normal NaCl and water excretion. During i.v. NaHCO3 perfusion, however, renal Na+ and water reabsorption capacity was reduced in -/- animals. In conscious task2 -/- mice, blood pH, HCO3- concentration, and systemic base excess were reduced but urinary pH and HCO3- were increased. These data suggest that task2 -/- mice exhibit metabolic acidosis caused by renal loss of HCO3-. Both in vitro and in vivo results demonstrate the specific coupling of TASK2 activity to HCO3- transport through external alkalinization. The consequences of the task2 gene inactivation in mice are reminiscent of the clinical manifestations seen in human proximal renal tubular acidosis syndrome.

We studied the changes in urinary bicarbonate, urinary pH and some physical parameters such as minute ventilation (VE), oxygen consumption (VO2), respiratory carbon dioxide (VCO2), heart rate, blood pressure, and blood lactate, before and after the submaximal exercise. Six male subjects aged 28-33 years were involved in the study. They performed the incremental exercise test using a bicycle ergometer until exhaustion. Levels of VE, VO2, VCO2, heart rate, and blood pressure increased continuously with an increase in cycling intensity. These parameters markedly decreased and reached the baseline levels within 5-10 minutes after the termination of exercise. According to an increase in cycling intensity, blood lactate increased continuously during exercise, but after termination of exercise the return of lactate to the baseline level was markedly retarded. Urinary bicarbonate and pH were within the range of those at 0 time (baseline levels) from the beginning until 30 minutes after the exercise. However, they began to increase abruptly about 30 minutes after the exercise, and continued to increase extensively for 2 hours thereafter. Such marked increase in urinary bicarbonate and pH seemed to be correlated with the aerobic metabolism of lactate in the muscles, liver, and kidney, finally producing CO2. It was also suggested that the measurement of urinary bicarbonate and pH may be useful for the estimation of physiological changes in the body after submaximal incremental cycling exercise loading.

Objective: To evaluate the effect of a mineral water rich in magnesium (337 mg/l), calcium (232 mg/l) and bicarbonate (3388 mg/l) on urine composition and the risk of calcium oxalate crystallization., Design: A total of 12 healthy male volunteers participated in the study. During the baseline phase, subjects collected two 24-h urine samples while on their usual diet. Throughout the control and test phases, lasting 5 days each, the subjects received a standardized diet calculated according to the recommendations. During the control phase, subjects consumed 1.4 l/day of a neutral fruit tea, which was replaced by an equal volume of a mineral water during the test phase. On the follow-up phase, subjects continued to drink 1.4 l/day of the mineral water on their usual diet and collected 24-h urine samples weekly., Results: During the intake of mineral water, urinary pH, magnesium and citrate excretion increased significantly on both standardized and normal dietary conditions. The mineral water led to a significant increase in urinary calcium excretion only on the standardized diet, and to a significantly higher urinary volume and decreased supersaturation with calcium oxalate only on the usual diet., Conclusions: The magnesium and bicarbonate content of the mineral water resulted in favorable changes in urinary pH, magnesium and citrate excretion, inhibitors of calcium oxalate stone formation, counterbalancing increased calcium excretion. Since urinary oxalate excretion did not diminish, further studies are necessary to evaluate whether the ingestion of calcium-rich mineral water with, rather than between, meals may complex oxalate in the gut thus limiting intestinal absorption and urinary excretion of calcium and oxalate.

The effects of diet-induced acid-base disturbances were examined in 4-week, 13-week and 18-month toxicity studies, and in a 30-month carcinogenicity study. Rats were fed a natural ingredient diet (controls), supplemented with 2% or 4% KHCO(3) (base-forming diets), or with 1% or 2.1% NH(4)Cl (acid-forming diets). Additional controls were fed 3% KCl (neutral diet providing K(+) and Cl(-) in amounts equimolar to those in the 4% KHCO(3) diet and the 2.1% NH(4)Cl diet, respectively). NH(4)Cl induced the expected metabolic acidosis, as shown by decreased base excess in blood, decreased urinary pH and increased urinary net acid excretion. KHCO(3) induced the opposite effects. KCl did not affect the acid-base balance. Clinical condition and death rate were not affected. The feeding of high levels of each salt resulted in growth retardation and increased water intake and urinary volume. Plasma potassium and urinary potassium excretion were increased with KHCO(3) and KCl. Plasma chloride was increased with NH(4)Cl, but not with KCl. Urinary calcium and phosphate excretion were increased with NH(4)Cl, but there were no indications that bone minerals were involved (weight, calcium content and fat free solid of the femur were not affected). Standard haematological and clinical chemistry parameters were not affected. Kidney weights were increased with 2.1% NH(4)Cl. Hypertrophy of the adrenal zona glomerulosa occurred with KHCO(3), KCl and NH(4)Cl, due to chronic stimulation of the adrenal cortex by either K(+) or by NH(4)Cl-induced acidosis. An early onset (from week 13) of oncocytic tubules was noted in the kidneys of rats fed KHCO(3) and, after 30 months, the incidence of this lesion was much higher than the background incidence in ageing controls. No progression to oncocytomas was noted. KCl showed only slight effects on the early onset of oncocytic tubules (from 18 months). In contrast, the severity of nephrosis and the incidence of oncocytic tubules were decreased with 2.1% NH(4)Cl, suggesting a protective effect of acidosis. The feeding of KHCO(3) resulted in hyperplasia, papillomas and carcinomas of the urinary bladder. With KCl only a slight increase in proliferative urothelial lesions was noted. Apart from these (pre-)neoplastic lesions in the urinary bladder there were no treatment-related differences in tumour response among the groups. We concluded that most of the observed changes represent physiological adaptations to the feeding of acid- or base-forming salts. Remarkable effects noted with KHCO(3), and to a far lesser extent with KCl, consisted of renal oncocytic tubules and (pre-)neoplastic lesions of the urinary bladder epithelium. NH(4)Cl-induced chronic metabolic acidosis was not associated with dissolution of alkaline bone salts in rats. Finally, a protective effect of chronic acidosis on tumour development was not found.

Specimens of the euryhaline elasmobranch, Dasyatis sabina were acclimated to seawater and fresh water, and exposed to normocapnic (air) and hypercapnic (1% CO2 in air) environmental water. Blood pH, PCO2, and [HCO3-], as well as whole-animal net-acid excretion, were measured for up to 24 h of hypercapnia. In a separate experimental series, urine was collected from freshwater acclimated stingrays during 8 h of normocapnia and hypercapnia. Stingrays in both salinities at least partially compensated for the respiratory acidosis by accumulating HCO3- in their extracellular spaces. The degree of compensation for blood pH was 88.5% in seawater, but only 31.0% in fresh water after 24 h of hypercapnia. Whole-animal net-acid excretion was also greater in seawater than in fresh water, as was the increase in extracellular fluid [HCO3-]. Mean urinary net-acid excretion rates were slightly negative, and never increased above normocapnic control rates during hypercapnia. Since whole-animal net-acid excretion rates increased with blood [HCO3-], and urinary excretion was always negative, the gills were probably the primary organ responsible for compensation from environmental hypercapnia. The faster, and more complete, compensation for hypercapnia in seawater than in fresh water for this euryhaline elasmobranch is consistent with data for euryhaline teleosts, and probably reflects Na+-dependent mechanisms of branchial acid excretion.

Background: The bulk of bicarbonate reabsorption along the loop of Henle (LOH) is localized at the level of the thick ascending limb (TAL) and is mainly dependent on the presence of luminal Na+-H+ exchanger (NHE-3). We investigated whether the reduction of renal mass is associated with alterations in LOH bicarbonate transport coupled to changes in NHE-3 gene expression and in vivo activity., Methods: Sham-operated and remnant rats (4/6 nephrectomy) were studied 15 days after the surgery. To measure net bicarbonate reabsorption (JHCO3-) superficial loops were perfused by in vivo micropuncture. Perfusate was an end-like proximal solution containing 3H-methoxy-inulin. NHE-3 gene expression was quantified by competitive PCR using an internal standard of cDNA that differed from the wild-type NHE-3 by a deletion of 76 bp. Western blot experiments were performed on TAL suspension using anti-NHE-3 antibodies., Results: At various LOH bicarbonate loads, JHCO3- was constantly larger in remnant rats as compared to sham-operated animals. NHE-3 mRNA abundance was estimated to be 0.339 +/- 0.031 attomoles (amol)/ng-1 total RNA in sham-operated (N = 5) and it increased to 0.465 +/- 0.023 in remnant rats (N = 5, P < 0.01). Western blot experiments showed a significant increase of NHE-3 protein abundance in TAL of remnant rats as compared to sham-operated animals. Finally, by means of a specific NHE-3 inhibitor, S-3226, in vivo microperfusion experiments demonstrated that NHE-3 in vivo activity along the LOH was substantially increased in remnant rats in addition to the non-NHE-3 bicarbonate transport., Conclusions: These data indicate that the reduction of renal mass increases mRNA, protein abundance and in vivo activity of NHE-3 along the TAL. This may explain, at least in part, the augmented transepithelial bicarbonate transport along the LOH. Such an effect will counterbalance the increased glomerular bicarbonate load, thus preventing urinary bicarbonate loss and mitigating the ensuing metabolic acidosis.

Premature infants often present metabolic acidosis without protein load in the early neonatal period, around days 4-6. In order to elucidate the cause of acidosis, we investigated urinary acidification of infants in the early neonatal period. Urine pH, fractional excretion of HCO(3)(-) (FEHCO(3)), excretion of HCO(3)(-) and NH(4)(+) of the appropriate-for-date infants were measured on days 0-2 and on days 4-6 of life. Extremely low birth weight (ELBW) infants showed higher urine pH than more than 1500 g birth weight infants. FEHCO(3) and HCO(3)(-) excretion were of high values in ELBW infants on days 0-2, but decreased on days 4-6. Urine NH(4)(+) excretion rate was lower in ELBW infants than in birth weight more than 1000 g on days 0-2 of life and still remained at a low rate on days 4-6. These data indicated that insufficiency of NH(4)(+) excretion is the main cause for metabolic acidosis of ELBW infants in the early neonatal period.

In order to estimate the physiological responses to heavy muscular exercise with dynamic knee extension, the levels of urinary variables such as bicarbonate, urinary pH and blood lactate were studied before and after the exercise. Nine male volleyball players aged 19 or 20 years were involved in the present study. They performed 10%, 30% and 80% 1 repetition maximum (RM) knee extension. The levels of urinary bicarbonate and urinary pH did not change for 2.5 hours after cessation of the exercise with 10% 1 RM load, compared with the baseline levels. When 30% 1 RM loading was given, urinary bicarbonate and pH moderately increased for 2.5 hours. When 80% 1 RM loading was given, both urinary bicarbonate and pH increased immediately after cessation of the exercise, for 2.5 hours. Levels of blood lactate increased extensively within 1 minute after cessation of the exercise in the subjects with 80% 1 RM load, but no significant increase was seen in subjects with 10% 1 RM load. The changes in urinary bicarbonate and pH could be explained by the continuous production of CO2 in the muscular tissues involved in the exercise with a submaximal load where excess postexercise oxygen consumption is accelerated. It is also possible that the liver and muscle where blood lactate is aerobically metabolized could be the cause of these changes. It was also suggested that the measurement of urinary bicarbonate and pH may be useful for the estimation of events in the body after submaximal exercise loading.

Acute hypoxia causes hyperventilation and respiratory alkalosis, often combined with increased diuresis and sodium, potassium, and bicarbonate excretion. With a low sodium intake, the excretion of the anion bicarbonate may be limited by the lower excretion rate of the cation sodium through activated sodium-retaining mechanisms. This study investigates whether the short-term renal compensation of hypoxia-induced respiratory alkalosis is impaired by a low sodium intake. Nine conscious, tracheotomized dogs were studied twice either on a low-sodium (LS = 0.5 mmol sodium x kg body wt-1 x day-1) or high-sodium (HS = 7.5 mmol sodium x kg body wt-1 x day-1) diet. The dogs breathed spontaneously via a ventilator circuit during the experiments: first hour, normoxia (inspiratory oxygen fraction = 0.21); second to fourth hour, hypoxia (inspiratory oxygen fraction = 0.1). During hypoxia (arterial PO2 34.4 +/- 2.1 Torr), plasma pH increased from 7.37 +/- 0.01 to 7.48 +/- 0.01 (P < 0.05) because of hyperventilation (arterial PCO2 25.6 +/- 2.4 Torr). Urinary pH and urinary bicarbonate excretion increased irrespective of the sodium intake. Sodium excretion increased more during HS than during LS, whereas the increase in potassium excretion was comparable in both groups. Thus the quick onset of bicarbonate excretion within the first hour of hypoxia-induced respiratory alkalosis was not impaired by a low sodium intake. The increased sodium excretion during hypoxia seems to be combined with a decrease in plasma aldosterone and angiotensin II in LS as well as in HS dogs. Other factors, e.g., increased mean arterial blood pressure, minute ventilation, and renal blood flow, may have contributed.

Bicarbonate and nitric oxide levels are important humoral factors in the blood and are affected by the human body's physical condition. There are few reports, however, on changes in blood bicarbonate and nitric oxide levels during exercise and rest. Since urinary bicarbonate and nitric oxide metabolites reflect the levels of bicarbonate and nitric oxide in the blood, we studied circadian changes in 6 female athletes by monitoring their urinary pH and their levels of urinary bicarbonate and nitric oxide metabolites. Measurements were taken during exercise, rest and sleep. Six female athletes participated in a 3-day team handball training camp where they followed a schedule of exercise, rest and sleep. Urinary samples were collected immediately before and after handball training, at bed-time and upon waking. The urinary pH and levels of urinary bicarbonate and nitric oxide metabolites, including nitrite and nitrate, were examined with a blood gas analyzer and a NOx analyzer. The samples collected after handball training, as compared to the samples taken before exercise, showed a decreased pH, a decrease in levels of bicarbonate and little change in NO metabolites. During rest, urinary bicarbonate, NO metabolites and pH increased markedly in all 6 subjects. The levels of urinary bicarbonate, NO metabolites and pH significantly decreased upon waking. This study took into account the subjects' various physiological conditions when considering the significance of their changes in urinary bicarbonate, NO metabolites and pH during the 3 day handball training program. There were significant circadian changes in the urinary pH, and in the levels of urinary bicarbonate and nitric oxide metabolites, in the athletes involved in the exercise, rest and sleep program at team handball camp.

Congenital lactic acidoses (CLAs) constitute a group of rare inborn errors of mitochondrial metabolism in which cellular energy failure is the defining biochemical abnormality. We report the principal manifestations of renal dysfunction in 35 children with CLA caused by defects in either the pyruvate dehydrogenase multienzyme complex or one or more components of the respiratory chain. The most prominent renal abnormalities included bicarbonaturia, phosphaturia, hypercalciuria, complete Fanconi's syndrome, proteinuria, and decreased glomerular filtration rate. These data were compared with those from 79 previously published cases. Clinical manifestations of renal dysfunction in CLA are common and may be the first presenting sign of the disease. The glomerulus and proximal renal tubule appear to be the anatomic sites most vulnerable to abnormal mitochondrial energy transduction. We propose that the primary defect in mitochondrial energy metabolism, together with the consequent intracellular accumulation of lactate and hydrogen ions, precipitates a state of tissue injury that, unless interrupted, becomes self-perpetuating and ultimately leads to renal cell death., (Copyright 2002 by the National Kidney Foundation, Inc.)

Experimental data show that elevation of intracellular pH leads to severe lesions of brain cells. Acidification of intracellular fluid by accumulation of lactate may compensate the effect of respiratory alkalosis. Increased serum pH, and low PCO2, associated with hyperlactataemia (sometimes incorrectly called 'acidosis') have been reported in children with Leigh syndrome (LS). The aim of the study was to determine whether respiratory alkalosis is characteristic of patients with LS due to SURF1 mutations. All venous blood gas data (88 samples) of 18 spontaneously breathing LS patients with recently established SURF1 mutations, hospitalized during 1986-2000, were retrospectively reviewed. The data of an affected boy who survived on a respirator for more than 3 months (79 daily samples) were analysed separately. In spontaneously breathing patients, the data indicated that the patients had compensated or partially compensated respiratory alkalosis (pH 7.388+/-0.060, Pco2 29.2+/-5.7 mmHg, HCO3- 17.4+/-3.0 mmol/L, BE -6.7+/-3.2 mmol/L). Bicarbonate excretion was detected in urine of two examined LS cases in spite of decreased serum HCO3-. In the affected child maintained on a respirator, simple manipulation of the inspired CO2 tension to establish a normal pressure of 35-45 mmHg automatically caused an increase of serum HCO3- concentration to a normal value of 26.3+/-2.9 mmol/L (and BE to +2.2+/-3.1 mmol/L), in spite of cytochrome oxidase (COX) deficiency due to a confirmed SURF1 mutation. We suggest that respiratory alkalosis (hypocapnia) of Leigh syndrome patients with SURF1 mutations results from compulsory hyperventilation and speculate that hypocapnia may contribute to Leigh-like brain damage in the SURF1-deficient patients as well as in other patients presenting with Leigh-like syndrome. The supposition that accumulation of lactate may protect the brain of LS patients from alkalosis-related damage requires further study. Avoidance of any factors stimulating hyperventilation of LS patients and caution when attempting to correct low plasma bicarbonate are suggested.

Background: In the diabetic patient, hyperkalemia and hyperchloremic metabolic acidosis has been attributed to one or more of the following factors associated with diabetic nephropathy: hypoaldosteronism, altered potassium homeostasis, or a distal tubular (DT) defect in hydrogen ion secretion. To evaluate maximal in vivo DT acidification in streptozotocin (STZ) diabetes, unidirectional bicarbonate reabsorption (JHCO3) was measured in DTs after acid loading and in surviving DT after 2/3 nephrectomy (Nx)., Methods: Acid gavage induced hyperchloremic metabolic acidosis in four groups of rats: diabetic rats with hyperglycemia two (a) and (b) eight weeks after STZ injection, (c) diabetic rats with tight glucose control two weeks after STZ injection and insulin pump implantation; and (d) control nondiabetic rats. Another group of diabetic rats underwent (e) Nx one week after STZ injection; these rats were neither acid loaded nor pump implanted., Results: In the acidotic rats, the plasma potassium concentration, the plasma and urine acid-base parameters in the three STZ diabetic groups was not different from control rats, whereas JHCO3 fluxes were brisk without important differences between groups. In Nx rats, although the plasma potassium concentration and acid-base status were normal, surviving JHCO3 fluxes were still brisk and not different from the acid-loaded rats., Conclusions: These in vivo measurements indicate there is no impairment in DT unidirectional bicarbonate reabsorption in the intact or remnant STZ diabetic kidney.

Acetazolamide was compared with bicarbonate for the treatment of contamination with uranium. Uranium was injected peritoneally in rats, and its distribution was investigated. Acetazolamide was three times more efficient than bicarbonate in reducing the renal content of uranium. On the other hand, it had no effect on hepatic or skeletal content. In this study, renal physiology provides the basis for understanding the mode of action of acetazolamide and bicarbonate. In this context, it is of interest to determine the alkalinity of the urine, with the aim of knowing whether bicarbonate is present to mobilize uranium.

Normal adult humans eating Western diets have chronic, low-grade metabolic acidosis, the severity of which is determined in part by the net rate of endogenous noncarbonic acid production (NEAP), which varies with diet. To prevent or reverse age-related sequelae of such diet-dependent acidosis (eg, bone and muscle loss), methods are needed for estimating and regulating NEAP. Because NEAP is difficult to measure directly, we sought a simple method to estimate it from diet-composition data. We focused on protein and potassium contents because the production of sulfuric acid from protein metabolism and bicarbonate from dietary potassium salts of organic acids are the major variable components of NEAP. Using steady state renal net acid excretion (RNAE) as an index of NEAP in 141 normal subjects eating 20 different diets, we found by multiple linear regression analysis that RNAE [mEq/d x 10460 kJ diet (mEq/d 2500 kcal)] was predictable (R2 = 0.62) from protein [g/d x 10460 kJ diet (g/d 2500 kcal); positive regression coefficient, P < 0.001] and potassium [mEq/d x 10460 kJ diet (mEq/d x 2500 kcal): negative regression coefficient, P = 0.001] contents, which were not themselves correlated. Among diets, 71% of the variation in RNAE could be accounted for by the ratio of protein (Pro) to potassium (K) content: RNAE = 62Pro/K - 17.9 (r = 0.84, R2 = 0.71, P < 0.001). Thus, by considering both the acidifying effect of protein and the alkalinizing effect of potassium (organic anions), NEAP can be predicted with confidence from the readily available contents of only 2 nutrients in foods. Provisionally, these findings allow estimation and regulation of NEAP through diet modification.

Objectives: To test effectiveness of an electrolyte paste in correcting fluid, electrolyte and acid base alterations in response to furosemide administration., Animals: 6 Standardbreds., Procedures: Horses received electrolyte paste or water only (control). The paste was given orally 3 hours after furosemide administration (1 mg/kg of body weight, IM). Water was given ad libitum soon after the paste and 3 hours after furosemide administration to treated and control groups, respectively. Paste Na+, K+, and Cl- composition was approximately 2,220, 620, and 2,840 mmol, respectively. The PCV and plasma concentrations of total protein ([TP]), [Na+], [K+], [Cl-]), and bicarbonate ([HCO3-]) were determined, and urinary fluid and electrolyte excretion, fecal water, and body weight changes were measured., Results: At the end of a 6-hour period, the paste-treated group had higher water consumption, which resulted in lower plasma [TP]; net electrolyte losses also were substantially less. With paste administration, [Na+] was approximately 2 mmol/L above a prefurosemide value of 137.3 mmol/L; control horses had values similar to the prefurosemide value. Plasma [Cl-] remained at the prefurosemide value, but values in control horses decreased by 7 mmol/L with water consumption. Plasma [K+] remained approximately 0.8 mmol/L below prefurosemide values in both groups. Venous [HCO3-] returned to prefurosemide values after paste administration, but alkalosis persisted in control horses after consumption of water only. Body weight loss was less after paste administration., Conclusions: Administration of electrolyte paste is advantageous over water alone in restoring fluid, electrolyte, and acid base balance after fluid and electrolyte loss attributable to furosemide administration.

Responses in dry matter intake (DMI) and acidbase balance to three sources of anionic salts (dietary cation-anion difference = -63 to -40 meq/kg of dry matter), an acidified fermentation by-product, MgSO4.7H2O + NH4Cl, and MgSO4.7H2O + CaCl2.2H2O + CaSO4, were evaluated relative to the responses of cows fed a control diet (dietary cationanion difference = 203 meq/kg of dry matter) that did not contain anionic salts. Diets were fed for 1-wk periods to eight nonlactating Holsteins assigned to two replicated 4 x 4 Latin squares. Daily DMI increased as time of access to the diet increased up to d 5; mean DMI over d 5 to 7 was reduced by dietary anionic salts. Diets containing anionic salts induced a mild metabolic acidosis that was completely compensated by nonrespiratory mechanisms (decreased blood bicarbonate and base excess; pCO2 and pH values were unaffected). Urinary pH values and bicarbonate excretion were reduced, and urinary NH4+ and titratable acidity excretion were increased, for cows fed diets containing anionic salts. Strong ion difference in urine was decreased by dietary anionic salts because of the relatively greater excretions of Cl- and S2- versus Na+ and K+ by cows fed these diets. Dietary anionic salts decreased mean ruminal pH by 0.12 units, possibly because of the reduced strong ion difference of ruminal fluid. Dietary anionic salts increased mean ruminal NH3 concentration by 2.2 mM, probably because of the higher nonprotein N content of these diets. The strong negative relationship (r2 = 0.95) between urinary pH and net acid excretion by cows fed the diets containing anionic salts suggested that urinary pH measurement might be a useful tool to assess the degree of metabolic acidosis that was imposed by dietary anionic salts.

The purpose of this study was to provide a better understanding of the physiological role of endogenous net organic acid production in rats consuming their usual diet. Balance studies were performed over 24 h, and urine was collected in the day and night portions of the diurnal cycle. A supplemented low-electrolyte diet(LED) was fed to determine whether urinary organic anions were identical to those in the diet. A titration procedure was developed to determine the pK of titratable groups in the urine of rats studied with and without an acid load. Although normal rats excreted net acid (NAE), the latter was inversely related to the amount of food consumed. The rates of excretion of bicarbonate (HCO3), citrate, unmeasured organic anions, and NH+4 were higher in the night portion of the diurnal cycle. NAE rose dramatically when alkali intake was decreased by consuming the LED. Dietary and urinary organic anions were not identical because rats fed the LED supplemented with potassium citrate excreted <10% of this alkali load as citrate and <25% as HCO3. In the 24 h after 3,000 ¿mol NH4Cl was given intraperitoneally, H+ did not appear to be retained, yet NAE rose by only close to 2,000 ¿eq. The rate of excretion of titratable groups with a pK in the 3 to 5 pH range fell by close to 1,000 ¿eq; most of these changes occurred in the first 7 h after NH4Cl was given. We conclude that rat chow provides a large net alkali load. There appear to be two types of endogenous acid production, a form associated with a rise in NAE (e.g., sulfuric acid) and dietary alkali-driven endogenous net acid production, which titrates this alkali. Renal excretion of organic anions makes these acids end products of metabolism.

Objectives: To determine the effect of an acute soft tissue inflammatory response on biochemical and haematological indices of hepatic and renal function in the Thoroughbred horse., Procedure: Soft tissue inflammation was induced in four Thoroughbred horses by intramuscular injections of Freund's complete adjuvant. The horses were clinically examined and blood and urine samples were collected before and after the adjuvant injections. Biochemical and haematological indices were measured in samples collected and used to determine the onset of the acute-phase response and to assess hepatic and renal function at this time., Results: After adjuvant injection, significant increases (P < 0.01) in total white (13.1 +/- 1.4 x 10(9)/L) and neutrophil (10.2 +/- 1.2 x 109/L) cell counts, rectal temperature (39.7 +/- 0.5 degrees C) and various plasma protein concentrations, including fibrinogen (6.6 +/- 1.2 g/L), haptoglobin (1.3 +/- 0.1 g/L) and total protein (88.1 +/- 2.7 g/L), indicated the induction of an acute-phase response. This corresponded with significant reductions (P < 0.01) in the plasma elimination half-lives (t1/2 beta) sodium bromosulphthalein (3.13 +/- 0.05 to 2.82 +/- 0.07 min) and sodium sulphanilate (38.29 +/- 4.04 to 19.60 +/- 5.68 min) and reductions in the plasma activities of aspartate aminotransferase, glutamate dehydrogenase, creatine kinase, alkaline phosphatase, gamma glutamyl transferase; the urinary creatinine clearance ratios of sodium, chloride and potassium; and the urinary gamma glutamyl transferase-to-creatinine clearance ratios. (All values mean +/- SD.), Conclusions: The effects of the acute-phase response on indices of hepatic and renal function in the horse suggest that the disposition of pharmacological agents administered at this time may be altered and that indices of acute inflammation should be interpreted cautiously.