Search

Background: Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical trials. Metabolic acidosis increases risk of progressive loss of kidney function, causes bone demineralization and muscle protein catabolism, and may be more consequential in women given their lower bone and muscle mass. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis., Methods: This was a Phase 3, multicenter, randomised, blinded, placebo-controlled trial in 196 patients with CKD (eGFR: 20-40 mL/min/1.73 m 2 ) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. We present the findings from a pre-specified subgroup analysis evaluating the effects of veverimer on metabolic acidosis and physical function among women (N = 77) enrolled in this trial., Results: At week 52, women treated with veverimer had a greater increase in mean (± standard error) serum bicarbonate than the placebo group (5.4 [0.5] vs. 2.2 [0.6] mmol/L; P < 0.0001). Physical Function reported by patients on the Kidney Disease and Quality of Life - Physical Function Domain, a measure that includes items related to walking, stair climbing, carrying groceries and other activities improved significantly in women randomized to veverimer vs placebo (+ 13.2 vs. -5.2, respectively, P < 0.0031). Objectively measured performance time on the repeated chair stand test also improved significantly in the veverimer group vs. placebo (P = 0.0002)., Conclusions: Veverimer was effective in treating metabolic acidosis in women with CKD, and significantly improved how they felt and functioned., Trial Registration: ClinicalTrials.gov Identifier: NCT03390842 . Registered on January 4, 2018., (© 2022. The Author(s).)

Background: Management of chronic kidney disease (CKD) requires the management of risk factors, such as hypertension and albuminuria, that affect CKD progression. Identification of additional modifiable risk factors is necessary to develop new treatment strategies for CKD. We sought to quantify the association of metabolic acidosis with CKD progression and mortality in a large U.S. community-based cohort., Methods: In this longitudinal, retrospective cohort study we identified non-dialysis-dependent patients with stage 3‒5 CKD from Optum's de-identified integrated electronic health records. We selected cohorts of patients with confirmed metabolic acidosis or normal serum bicarbonate levels based on 2 consecutive serum bicarbonate values: 12 to < 22 mEq/L or 22-29 mEq/L, respectively, 28‒365 days apart. The primary composite outcome was ≥ 40 % decline in estimated glomerular filtration rate (eGFR), renal replacement therapy (chronic dialysis or kidney transplant), or all-cause mortality (DD40). Secondary outcomes included each component of the composite outcome. Cox proportional hazards models were used for the DD40 outcome and secondary outcomes, while logistic regression models were used for the DD40 outcome at 2 years., Results: A total of 51,558 patients qualified for the study. The unadjusted 2-year incidence of adverse renal and fatal outcomes was significantly worse among patients in the metabolic acidosis group vs. those who had normal serum bicarbonate levels: 48 % vs. 17 % for DD40, 10 % vs. 4 % for ≥ 40 % decline in eGFR, 20 % vs. 6 % for renal replacement therapy, and 31 % vs. 10 % for all-cause mortality (all P < 0.001). Over a ≤ 10-year period, for each 1-mEq/L increase in serum bicarbonate, the adjusted hazard ratio for DD40 was 0.926 (95 % confidence interval [CI], 0.922-0.930; P < 0.001); over a ≤ 2-year period, the adjusted odds ratio for DD40 was 0.873 (95 % CI, 0.866-0.879; P < 0.001)., Conclusions: In this large community cohort of patients with stage 3‒5 CKD, the presence of metabolic acidosis was a significant, independent risk factor for the composite adverse outcome of CKD progression, renal replacement therapy, and all-cause mortality (DD40).

The objective of this study was to evaluate the levels of plasma bicarbonate levels in narcoleptic children. Clinical, electrophysiological data and bicarbonate levels were evaluated retrospectively in children seen in our paediatric national reference centre for hypersomnia. The cohort included 23 control subjects (11.5 ± 4 years, 43% boys) and 51 patients presenting de-novo narcolepsy (N) (12.7 ± 3.7 years, 47% boys). In narcoleptic children, cataplexy was present in 78% and DQB1*0602 was positive in 96%. The control children were less obese (2 versus 47%, P = 0.001). Compared with control subjects, narcoleptic children had higher bicarbonate levels (P = 0.02) as well as higher PCO2 (P < 0.01) and lower venous pH gas (P < 0.01). Bicarbonate levels higher than 27 mmol L(-1) were found in 41.2% of the narcoleptic children and 4.2% of the controls (P = 0.001). Bicarbonate levels were correlated with the Adapted Epworth Sleepiness Scale (P = 0.01). Narcoleptic patients without obesity often had bicarbonate levels higher than 27 mmol L (-1) (55 versus 25%, P = 0.025). No differences were found between children with and without cataplexy. In conclusion, narcoleptic patients had higher bicarbonate plasma levels compared to control children. This result could be a marker of hypoventilation in this pathology, provoking an increase in PCO2 and therefore a respiratory acidosis, compensated by an increase in plasma bicarbonates. This simple screening tool could be useful for prioritizing children for sleep laboratory evaluation in practice., (© 2015 European Sleep Research Society.)

Background/aims: Bone fracture is often complicated in hemodialysis (HD) patients. Metabolic acidosis is related to bone disease and muscle wasting, but it is not known whether acid-base disturbance is associated with the risk of bone fractures. The aim of this study was to clarify the association of serum bicarbonate level with bone fracture in HD patients., Methods: Using a subcohort of the Mineral and Bone Disorder Outcomes Study for Japanese CKD Stage 5D Patients (MBD-5D), 890 prevalent HD patients (age: 62 years old, male: 62.8%, duration of dialysis: 8.3 years) with secondary hyperparathyroidism were studied. After measuring predialysis serum bicarbonate at a 2-day interdialytic interval, we prospectively followed them every 3 months, and examined the occurrence of any type of bone fracture or hospitalization due to fracture over a 3-year observation period., Results: Seventy-four bone fractures and 47 hospitalizations due to fracture were observed during the follow-up period. HD patients with serum bicarbonate <20 mmol/l had a 1.93 (95% CI 1.01-3.71)-fold higher risk for all-cause fractures than those with serum bicarbonate of 20.0-21.9 mmol/l. A higher bicarbonate level (≥22 mmol/l) was also related to an increased risk of bone fracture. A restricted cubic regression spline disclosed that the higher or the lower than 21.0 mmol/l of serum bicarbonate, the greater the risk for bone fracture., Conclusion: Both a lower level and a higher level of predialysis bicarbonate concentration were associated with risk of bone fracture in HD patients with secondary hyperparathyroidism., (© 2014 S. Karger AG, Basel.)

Background: Normally, end-tidal CO(2) is within 2 mm Hg of arterial PO(2) (PaCO(2)). However, if dead space in the lungs increases owing to shock with poor lung perfusion, the arterial-end tidal PCO(2) difference [P(a-ET)CO(2)] increases. We have found that in severely injured patients, P(a-ET)CO(2) of less than 10 mm Hg is associated with survival and P(a-ET)CO(2) of greater than 16 mm Hg is usually fatal. Our initial studies suggested that intravenously administered bicarbonate increases P(a-ET)CO(2)., Methods: This retrospective therapeutic study evaluated the effects of intravenously administered bicarbonate in a cohort of 225 severely acidotic (arterial pH ≤ 7.10) trauma patients who underwent emergency surgery from 1989 through 2011. Patients were divided into groups: early deaths (<48 hours), deaths in the operating room, deaths within 48 hours, and survivors. Winter's formula was defined as PaCO(2) = (HCO(3)) (1.5) + 8 ± 4., Results: Of the 225 patients, the mean (SD) initial arterial pH was 6.92 (0.16) with HCO(3) of 11.0 (3.5) mEq/L. According to the Winter's formula, PaCO(2) should have been 24 (4) mm Hg but actually was 50 (14) mm Hg. In 73 patients, the effect of an average of two to eight vials of bicarbonate increased HCO(3) from 10.5 (3.1) mEq/L to 16.8 (4.0) mEq/L. In addition, PaCO(2) increased from 44 (9) mm Hg to 51 (11) mm Hg and end-tidal CO(2) stayed relatively constant (26 [6] to 25 [5]). This resulted in a increase in P(a-ET)CO(2) from 17 (9) mm Hg to 24 (13) mm Hg, affecting survival. In the final values after resuscitation, the P(a-ET)CO(2) in the 75 patients who survived was 10 (6) mm Hg, while the 103 patients who died in the operating room or within 48 hours of surgery had a P(a-ET)CO(2) of 23 (10) mm Hg (p < 0.001)., Conclusion: In severely acidotic, critically injured patients, reducing the PaCO(2) to less than 40 mm Hg and decreasing the P(a-ET)CO(2) to 10 (6) mm Hg should be attempted, using as little HCO(3) therapy as possible. Bicarbonate should be given only if severe acidosis persists despite resuscitation and if PaCO(2) levels near those which are appropriate can be obtained., Level of Evidence: Therapeutic study, level IV.

Background: Various cytokines are increased in hemodialysis (HD) patients, and are considered prognostic markers. Metabolic acidosis is common among chronic HD patients and is associated with survival. The relationship between acidosis and cytokines in HD patients has not been fully explored. The study aim was to measure pro- and anti-inflammatory cytokines in HD patients, with relation to bicarbonate levels., Methods: Forty-seven stable HD patients were included (male/female 28/19, mean age 70.4 ± 14.5 years). Blood tests were taken before a midweek dialysis session. Cytokine secretion from peripheral blood mononuclear cells was measured., Results: Acidosis versus no acidosis (serum HCO3 – 21.5 ± 0.2 vs. 24.9 ± 0.3 mEq/l, p < 0.001) was associated with decreased secretion of the anti-inflammatory interleukin-10 (IL-10, 1.16 ± 0.11 vs. 1.71 ± 0.20 ng/ml, p = 0.023). Patients with acidosis had higher parathyroid hormone (PTH), calcium-phosphate product, protein intake and transferrin. Higher IL-10 was associated with increased IL-6 secretion, higher bicarbonate, younger age and lower PTH., Conclusions: In stable chronic HD patients, a possible direct relation exists between metabolic acidosis and IL-10.

Background: Clinical practice guidelines recommend alkali therapy in patients with non-dialysis-dependent chronic kidney disease (CKD) and metabolic acidosis to prevent complications from metabolic acidosis. We systematically reviewed the effect of sodium bicarbonate on benefits and harms in patients with CKD., Methods: We searched for randomized controlled trials in MEDLINE (through July 2011), Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and scientific abstracts. We included trials that compared sodium bicarbonate to standard-of-care therapy or placebo that reported on kidney-related outcomes. We performed random-effects model meta-analyses to compute net changes (for continuous variables) and risk ratios (for binary variables)., Results: Two short-term (≤ 7 days) crossover trials and 4 long-term (≥ 2 months) parallel-design randomized controlled trials met eligibility (312 patients). All 6 trials prescribed sodium bicarbonate in the alkali-treated group. In the long-term studies, alkali therapy was associated with a net decrease in serum creatinine (-0.07 mg/dl, 95% CI -0.09, -0.05; p < 0.001; I(2) = 0), a net improvement in GFR (3.2 ml/min/1.73 m(2), 95% CI 1.6, 4.7; p < 0.001; I(2) = 0), and a lower incidence of dialysis initiation (risk ratio 0.21, 95% CI 0.08, 0.54; p = 0.001; I(2) = 0). No benefit was observed on the serum creatinine or GFR in short-term studies. Alkali therapy was not associated with a higher likelihood of initiating or escalating anti-hypertensive medications., Conclusions: Alkali therapy is associated with an improvement in kidney function, which may afford a long-term benefit in slowing the progression of CKD. However, differences in study protocols and small sample sizes preclude definitive conclusions., (Copyright © 2012 S. Karger AG, Basel.)

Background: As part of our overall interest in the mechanisms and treatment related to the development of the lethal triad of hypothermia, acidosis, and coagulopathy seen in trauma patients, the purpose of this study was to determine whether acidosis, inducible either by HCl infusion or hemorrhage/hypoventilation, leads to coagulopathy, and if correction of the acidosis will alleviate this coagulopathy., Methods: In two separate experiments, acidosis was induced in anesthetized swine by (1) HCl infusion (n = 10) or (2) hemorrhage/hypoventilation (n = 8). Arterial blood samples were taken before HCl infusion or hemorrhage (arterial pH 7.4), after HCl infusion or hemorrhage (pH 7.1), and after bicarbonate infusion to return pH to 7.4. Arterial pH and blood gases were measured every 15 minutes., Results: Acidosis (arterial pH 7.1) led to a hypocoagulation as measured by several coagulation parameters. In both experiments, acidosis was associated with a significant decrease in the maximum strength of the clot and the rate at which the clot formed. There was a significant decrease in endogenous thrombin potential and maximum thrombin concentration after acidosis in both groups (thrombin generation assay). However, the activated clotting time, prothrombin time, and activated partial thromboplastin time were significantly elevated only in the HCl-infused group. Fibrinogen concentration and platelet count were significantly reduced in both groups after acidosis. The hypocoagulation that was induced by either hemorrhage/hypoventilation or HCl infusion was not immediately corrected after returning pH to 7.4 with bicarbonate injection., Conclusions: These data suggest that acidosis induced by HCl infusion or by hemorrhage/hypoventilation leads to hypocoagulation. Simple correction of the arterial pH with bicarbonate is not sufficient to correct this coagulopathy.

Malignant tumours are characterised by a low, acidic extracellular pH (pHe) which facilitates invasion and metastasis. Previous research has proposed the potential benefits of manipulating systemic pHe, and recent experiments have highlighted the potential for buffer therapy to raise tumour pHe, prevent metastases, and prolong survival in laboratory mice. To examine the physiological regulation of tumour buffering and investigate how perturbations of the buffering system (via metabolic/respiratory disorders or changes in parameters) can alter tumour and blood pHe, we develop a simple compartmentalised ordinary differential equation model of pHe regulation by the HCO3-/CO2 buffering system. An approximate analytical solution is constructed and used to carry out a sensitivity analysis, where we identify key parameters that regulate tumour pHe in both humans and mice. From this analysis, we suggest promising alternative and combination therapies, and identify specific patient groups which may show an enhanced response to buffer therapy. In addition, numerical simulations are performed, validating the model against well-known metabolic/respiratory disorders and predicting how these disorders could change tumour pHe., (Copyright © 2010 Elsevier Inc. All rights reserved.)

When a strong acid is added to plasma, one expects a quantitative relationship between excess anion gap (DeltaAG) and bicarbonate deficit (DeltaHCO(3)(-)) with the DeltaAG/DeltaHCO(3)(-) ratio close to unity. If true, then this ratio could be used to diagnose mixed acid-base disorders in patients with metabolic acidosis. Although the mean ratio in selected patients is close to unity, this ratio also has a wide range, making its use in individual patients problematic. The ratio should therefore be used cautiously in making a diagnosis of mixed acid-base disorders.

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: Coagulopathy is an important contributor to morbidity and mortality in trauma patients. Acidosis contributes to coagulopathy. Acidosis can be neutralized with intravascular bicarbonate, but it is unclear if the coagulation defect is rapidly reversed. The effects of acidosis and bicarbonate neutralization on coagulation function were investigated in vivo., Methods: Acidosis was induced in 12 pigs by infusing 0.2 mol/L HCl to pH 7.1. Pigs were then infused with either LR to maintain a pH of 7.1 (A-LR, n = 6) or 0.3 mol/L bicarbonate to a pH of 7.4 (A-Bi, n = 6). Blood samples were taken at baseline, 15 minutes after acidosis induction, and 15 minutes after bicarbonate neutralization. Coagulation function was assessed by prothrombin time (PT), partial thromboplastin time (PTT), thrombin generation, initial clot formation time (R), clotting rapidity (alpha), and clot strength (MA)., Results: Compared with baseline values, acidosis reduced fibrinogen concentration to 66% +/- 2% in A-LR and to 71% +/- 3% in A-Bi, and decreased platelet counts to 49% +/- 4% in A-LR and to 53% +/- 4% in A-Bi. Thrombin generation decreased to 60% +/- 4% in A-LR and to 53% +/- 7% in A-Bi. Acidosis prolonged PT and PTT about 20% and decreased alpha and MA. After pH neutralization, fibrinogen and platelet levels remained depleted and no reversal of acidosis-induced changes in thrombin generation, PT, PTT, alpha, and MA were observed., Conclusion: Acidosis impaired coagulation by depleting fibrinogen and platelets and by inhibiting clotting kinetics. The deficit associated with acidosis was not reversed with bicarbonate pH neutralization.

Metabolic acidosis negatively influences dietary intake, increases protein catabolism, and deteriorates nutritional status. In the present study, we evaluated in peritoneal dialysis (PD) patients whether parameters of blood acid-base equilibrium influence total and subpopulation lymphocyte counts (TLC, SLCs), which are markers of the immunologic and nutritional status of dialyzed patients. Studies were carried out in 55 patients, mean age 50.9 +/- 12.4 years, treated with PD for a mean of 22.2 +/- 11.4 months. Parameters of blood acid-base equilibrium were measured simultaneously with evaluation of TLC and SLCs. (Antigens CD3, CD4, CD5, CD8, CD19, CD16+56 were determined using flow cytometry.) The study patients showed compensated metabolic acidosis (pH: 7.40 +/- 0.04; HCO3-: 22.9 +/- 2.4 mmol/L). Statistical analysis revealed significant (p < 0.05) positive correlations of bicarbonate blood concentration and base excess with TLC and with CD3, CD5, and CD8 cell counts, but not with CD19 and CD16+56 cell counts. The CD4 cell count correlated only with blood bicarbonate level. Patients on PD who show better correction of metabolic acidosis also show higher TLC and CD3, CD4, CD5, and CD8 cell counts. The numbers of B lymphocytes (CD19) and natural killer cells (CD16+56) are not directly related to bicarbonate blood concentration, at least in the examined range.

Background and Purpose: Previous in vitro study has shown that an acidic medium increases osteoclastic and inhibits osteoblastic activity. The present study sought to determine the role of alkali therapy in osteoblast function in patients with chronic renal failure by assessing the serum concentration of procollagen type I carboxyterminal propeptide (PICP), a marker of bone formation, before and after bicarbonate infusion., Patients and Methods: Eighteen patients with chronic renal failure (creatinine clearance 12 +/- 6.6 mL/min) associated with mild to moderate metabolic acidosis were enrolled in this study. None had undergone dialysis. Metabolic acidosis was corrected by continuous bicarbonate infusion while plasma ionized calcium was clamped at the preinfusion level by calcium gluconate infusion throughout the procedure., Results: After bicarbonate infusion, there were significant increases in plasma pH (7.31 +/- 0.04 to 7.40 +/- 0.03, p < 0.001), bicarbonate concentration (18.46 +/- 2.49 to 23.66 +/- 2.72, p < 0.001), serum total calcium concentration (2.01 +/- 0.24 to 2.12 +/- 0.24 mmol/L, p < 0.001), and PICP concentration (137.3 +/- 56.25 to 159.6 +/- 57.30 micrograms/L, p < 0.05), whereas serum parathyroid hormone concentrations assessed by radioimmunoassay decreased significantly (153.7 +/- 88.6 to 111.5 +/- 78.7, p < 0.001). Serum ionized calcium concentrations showed no significant difference before and after bicarbonate infusion., Conclusion: These results suggest that acute correction of metabolic acidosis improves osteoblast function and appear to underline the importance of maintaining normal acid-base homeostasis in chronic renal failure.

Severe acidemia (blood pH < 7.1 to 7.2) suppresses myocardial contractility, predisposes to cardiac arrhythmias, causes venoconstriction, and can decrease total peripheral vascular resistance and blood pressure, reduce hepatic blood flow, and impair oxygen delivery. These alterations in organ function can contribute to increased morbidity and mortality. Although it seemed logical to administer sodium bicarbonate to attenuate acidemia and therefore lessen the impact on cardiac function, the routine use of bicarbonate in the treatment of the most common causes of severe acidemia, diabetic ketoacidosis, lactic acidosis, and cardiac arrest, has been an issue of great controversy. Studies of animals and patients with these disorders have reported conflicting data on the benefits of bicarbonate, showing both beneficial and detrimental effects. Alternative alkalinizing agents, tris-hydroxymethyl aminomethane and Carbicarb, have shown some promise in studies of animals and humans, and reevaluation of these buffers in the treatment of severe acidemic states seems warranted. The potential value of base therapy in the treatment of severe acidemia remains an important issue, and further studies are required to determine which patients should be administered base therapy and what base should be used.

Background: The chronic low-grade metabolic acidosis that occurs in various renal disorders and in normal people, and that is related both to dietary net acid load and age-related renal functional decline, may contribute to osteoporosis by increasing urine calcium excretion. Administration of potassium (K) alkali salts neutralizes acid and lowers urine calcium excretion. Urine calcium excretion also can be reduced by the administration of thiazide diuretics, which are often given with supplemental K to avoid hypokalemia. We determined whether the K alkali salt potassium bicarbonate (KHCO3) and the thiazide diuretic hydrochlorothiazide (HCTZ) combined is more effective in reducing urinary calcium than KHCO3 alone or HCTZ combined with the conventionally coadministered nonalkalinizing K salt potassium chloride (KCl)., Methods: Thirty-one healthy men and women aged 50 or greater were recruited for a four-week, double-blind, randomized study. After a baseline period of 10 days with three 24-hour urine and arterialized blood collections, subjects were randomized to receive either HCTZ (50 mg) plus potassium (60 mmol daily) as either the chloride or bicarbonate salt. Another 19 women received potassium bicarbonate (60 mmol) alone. After two weeks, triplicate collections of 24-hour urines and arterialized bloods were repeated., Results: Urinary calcium excretion decreased significantly in all groups. KHCO3 alone and HCTZ + KCl induced similar decreases (-0.70 +/- 0.60 vs. -0.80 +/- 1. 0 mmol/day, respectively). Compared with those treatments, the combination of HCTZ + KHCO3 induced more than a twofold greater decrease in urinary calcium excretion (-1.8 +/- 1.2 mmol/day, P < 0. 05). Both HCTZ + KHCO3 and KHCO3 alone reduced net acid excretion significantly (P < 0.05) to values of less than zero., Conclusions: KHCO3 was superior to KCl as an adjunct to HCTZ, inducing a twofold greater reduction in urine calcium excretion, and completely neutralizing endogenous acid production so as to correct the pre-existing mild metabolic acidosis that an acid-producing diet usually induces in older people. Accordingly, for reducing urine calcium excretion in stone disease and osteoporosis, the combination of HCTZ + KHCO3 may be preferable to that of HCTZ + KCl.

We report our experience with 11 children treated by continuous veno-venous hemodiafiltration. The median age was 5.0 years (range 3 days to 14 years). Access was via dual-lumen subclavian or femoral vein catheters. Hemofilters were chosen on the basis of patient size and dialysis requirements. Bicarbonate-buffered dialysis solution was prepared shortly before use by supplementation of a specially prepared base solution with commercially available electrolyte solutions. The mean ultrafiltration rate was 37.4 +/- 27 ml/kg body weight per hour. Urea and creatinine clearances were 15.1 +/- 6.4 ml/kg body weight per min and 16.4 +/- 8.4 ml/kg body weight per min, respectively. Metabolic acidosis was readily controlled in all patients. Of the 11 patients, 7 ultimately recovered normal renal function.

Lactic acidosis is characterized by metabolic acidosis due to accumulation of H+ ions from lactic acid with blood lactate of at least 5 mM. The standard treatment is intravenous NaHCO3, with resultant mortality in excess of 50%. Despite the high mortality, the metabolic and systemic effects of NaHCO3 used in the treatment of lactic acidosis have not been extensively studied. The present experiments in diabetic dogs were designed to address these questions. Dogs with phenformin-induced lactic acidosis (blood lactate above 5 mM, arterial pH below 7.20) were treated with equimolar amounts of either NaCl or NaHCO3 or received no therapy. Intravenous NaHCO3 resulted in a decline of cardiac output and intracellular pH (pHi) of liver and erythrocytes, whereas treatment with NaCl did not. With NaHCO3 but not with NaCl infusion gut lactate production increased almost stoichiometrically, with no change in arterial pH or bicarbonate but with a doubling of lactate. Bicarbonate also resulted in a decrease of hepatic portal vein blood flow. The mean survival time and percent mortality were similar in NaCl- vs. NAHCO3(-) treated animals. Although both groups lived longer than did animals receiving no therapy, the differences were not significant. Thus, treatment of experimental lactic acidosis with either NaCl or NaHCO3 or with no therapy results in no change of blood pH and bicarbonate and in a similar mortality. In terms of systemic effects, however, NaHCO3 results in significant decrements of liver and erythrocyte pHi, hepatic portal vein blood flow, and cardiac output and in significant increments of gut lactate production, whereas NaCl does not. The data suggest that the rationale for therapy of lactic acidosis with NaHCO3 should probably be reevaluated.

Sixty-two high-risk acidemic premature newborn infants, given maintenance intravascular infusions of 10% glucose, were assigned to liberal or restricted sodium bicarbonate treatment groups. Those infants in the liberal group received 5 to 15 mEq bicarbonate/dl 10% glucose, depending on the degree of acidosis. Among infants given bicarbonate, correction of pH was not more rapid and mortality was not decreased. Instead, there was a small increase in the number of deaths, but the incidence of intraventricular hemorrhage was similar to that in infants not given bicarbonate.

Nitrogen and potassium balance studies were conducted in six nondialyzed uremic patients. Each patient was investigated before and after supplementation with sodium bicarbonate and sodium chloride. Every period of the study lasted longer than 1 wk. Each patient had the same calorie and protein intake during the whole study. Urea nitrogen appearance was correlated with protein intake for the assessment of the compliance of patients with their diets. There was a significant decrease of blood urea nitrogen (p = 0.014) of 36% during bicarbonate supplementation and both metabolic balance studies improved significantly (p = 0.0005 and 0.0096). However, there was no significant improvement during sodium chloride administration indicating that the effect of bicarbonate was the result of the correction of metabolic acidosis and not of the expansion of the extracellular volume.

To evaluate the extent and cause(s) of dialysis-related hypoxemia, we studied 10 patients, 7 days apart using acetate (AC) and bicarbonate dialysate (HCO3). We measured arterial blood gases, WBC, minute ventilation (VE) and inspired and expired gas concentrations and calculated the respiratory quotient (R) and the alveolar-arterial oxygen difference (A-a)DO2 before and during hemodialysis. 8 patients developed hypoxemia. Arterial PO2 (PaO2) dropped similarly at 30 min from 93 +/- 5 to 78 +/- 6 (p less than 0.05) and 89 +/- 4 to 79 +/- 5 mm Hg (p less than 0.05) with AC and HCO3, respectively. R and VE decreased during AC (p less than 0.05). (A-a)DO2 increased at 30 min and correlated with the drop in PaO2 during both AC (r = 0.68, p less than 0.025) and HCO3 (r = 0.76, p less than 0.025). The fall in PaO2 also correlated with the fall in WBC count for both AC and HCO3 (r = 0.63, p less than 0.005). The increase in arterial pH during HCO3 (up to 7.45 +/- 0.01) was significantly greater than that during AC (up to 7.42 +/- 0.01) (p less than 0.025), and coincided with a relative decrease in VE. We conclude that (1) HCO3 does not prevent hypoxemia, and (2) hypoventilation V/Q abnormalities and increase in arterial pH, contribute variably to dialysis related hypoxemia depending on the type of dialysate and the time during dialysis.

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

Lactic acidosis is a life-threatening disorder in some cases. Treatment should be directed at the primary cause. Sodium bicarbonate should be added if the acidosis is very severe, or if the rate of hydrogen ion production is very rapid and not controlled. In contrast, with moderate degrees of steady state lactic acidosis and poor dietary intake, the risks of therapy with sodium bicarbonate or dichloroacetate may actually outweigh the benefits in a cachectic patient unless a dietary glucose and/or protein load is given.

This study was conducted to determine the effect of a high protein diet on calcium metabolism in rat. Wistar strain male rats (50 days old) were divided into 5 groups (day 0): control diet (18% casein); high protein diet (18% casein +20% lactalbumin); high protein and 0.1% sodium bicarbonate diet; high protein and 0.2% sodium bicarbonate diet; and high protein and 0.4% sodium bicarbonate diet. On days 0, 1, 3, 5, 7, 9, urine samples were collected and, at the same time, feces were collected from half of the animals in each group. Urinary titratable acidity (TA-HCO3-), ammonium ion (NH4+), and net acid excretion (NAE) were measured as an index of acid-base balance in rat body. Urinary volume was rapidly increased and the increase of urinary volume continued throughout the study in rats fed the high protein diet. Urinary excretions of calcium and phosphorus were increased after day 3 and day 1, respectively, in rats fed the high protein diet. The high protein diet depressed calcium absorption and elevated phosphorus absorption from the digestive tract in rats fed the high protein diet. The high protein diet decreased TA-HCO3-, which was closely correlated with the decrease of NAE. Sodium bicarbonate supplementation to the high protein diet had little effect on urinary calcium excretion and NAE. This study suggested that there was no relationship between metabolic acidosis and hypercalciuria in rats fed the high protein diet.

Sixteen patients with medullary sponge kidney (MSK) and renal stones underwent evaluation of calcium metabolism and acid base balance. Six normal subjects and eight patients with non-MSK absorptive hypercalciuria served as control. Nine (56%) were hypercalciuric and seven (44%) were normocalciuric (N-MSK). Hypercalciuria was divided into absorptive (AH-MSK, n = 2) and renal leak hyerpcalciuria (RH-MSK, n = 7). The mean of minimal urine pH of RH-MSK group (5.28 +/- 0.09 (SE] was significantly higher than that of normal control (4.78 +/- 0.12) and of non-MSK AH (4.80 +/- 0.6) during acute acid challenge. The mean of the arterial blood HCO3 concentration of RH-MSK group was significantly lower than that of two control groups. The urine calcium and a frequency of stone passage were decreased significantly after alkali treatment in RH-MSK.

Severe osteomalacia of uncertain etiology was observed in a 44-year-old woman. There was no evidence of chronic renal insufficiency, malabsorption, or of the renal tubular defects classically associated with osteomalacia. However, the dietary history suggested vitamin D deficiency and most of the biochemical findings were compatible with this condition. The unusual feature of the case was a decrease in plasma bicarbonate levels which appeared to be due to a lowered renal tubular threshold for bicarbonate reabsorption. There was no renal tubular defect with respect to hydrogen ion excretion.Rapid symptomatic and radiologic improvement occurred when the dietary intake of vitamin D was increased to approximately 200 I.U. per day and the acidosis was simultaneously corrected with sodium bicarbonate. Although no firm conclusions could be drawn about the relative importance of vitamin D deficiency or chronic acidosis in the production of the osteomalacia, the possibility that the chronic acidosis may have been a major contributing factor is discussed.