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Effect of Bicarbonate on Net Acid Excretion, Blood Pressure, and Metabolism in Patients With and Without CKD: The Acid Base Compensation in CKD Study.
Tyson, CC, Luciano, A, Modliszewski, JL, Corcoran, DL, Bain, JR, Muehlbauer, M, Ilkayeva, O, Pourafshar, S, Allen, J, Bowman, C, et al
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2021;(1):38-47
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Abstract
RATIONALE & OBJECTIVE Patients with CKD are at elevated risk of metabolic acidosis due to impaired net acid excretion (NAE). Identifying early markers of acidosis may guide prevention in chronic kidney disease (CKD). This study compared NAE in participants with and without CKD, as well as the NAE, blood pressure (BP), and metabolomic response to bicarbonate supplementation. STUDY DESIGN Randomized order, cross-over study with controlled feeding. SETTING & PARTICIPANTS Participants consisted of 8 patients with CKD (estimated glomerular filtration rate 30-59mL/min/1.73m2 or 60-70mL/min/1.73m2 with albuminuria) and 6 patients without CKD. All participants had baseline serum bicarbonate concentrations between 20 and 28 mEq/L; they did not have diabetes mellitus and did not use alkali supplements at baseline. INTERVENTION Participants were fed a fixed-acid-load diet with bicarbonate supplementation (7 days) and with sodium chloride control (7 days) in a randomized order, cross-over fashion. OUTCOMES Urine NAE, 24-hour ambulatory BP, and 24-hour urine and plasma metabolomic profiles were measured after each period. RESULTS During the control period, mean NAE was 28.3±10.2 mEq/d overall without differences across groups (P=0.5). Urine pH, ammonium, and citrate were significantly lower in CKD than in non-CKD (P<0.05 for each). Bicarbonate supplementation reduced NAE and urine ammonium in the CKD group, increased urine pH in both groups (but more in patients with CKD than in those without), and increased; urine citrate in the CKD group (P< 0.2 for interaction for each). Metabolomic analysis revealed several urine organic anions were increased with bicarbonate in CKD, including 3-indoleacetate, citrate/isocitrate, and glutarate. BP was not significantly changed. LIMITATIONS Small sample size and short feeding duration. CONCLUSIONS Compared to patients without CKD, those with CKD had lower acid excretion in the form of ammonium but also lower base excretion such as citrate and other organic anions, a potential compensation to preserve acid-base homeostasis. In CKD, acid excretion decreased further, but base excretion (eg, citrate) increased in response to alkali. Urine citrate should be evaluated as an early and responsive marker of impaired acid-base homeostasis. FUNDING National Institute of Diabetes and Digestive and Kidney Diseases and the Duke O'Brien Center for Kidney Research. TRIAL REGISTRATION Registered at ClinicalTrials.gov with study number NCT02427594.
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Extracellular buffer choice influences acid-base responses and gastrointestinal symptoms.
Peacock, J, Sparks, SA, Middlebrook, I, Hilton, NP, Tinnion, D, Leach, N, Saunders, B, McNaughton, LR
Research in sports medicine (Print). 2021;(6):505-516
Abstract
To compare the bicarbonate kinetics and gastrointestinal (GI) symptom responses between an equal dose of sodium bicarbonate and sodium citrate using delayed-release capsules. Thirteen active males (age 20.5 ± 2.1 y, height 1.8 ± 0.1 m and body mass [BM] 76.5 ± 9.6 kg) consumed either 0.3 g.kg-1 BM sodium bicarbonate, sodium citrate or a placebo, using a double-blind, randomized crossover design. Blood bicarbonate ion (HCO3-) concentration, pH and GI symptoms were measured pre-consumption and every 10 min for 180 min post-consumption. Blood HCO3- concentration (P < 0.001) and pH (P = 0.040) were significantly higher in the sodium bicarbonate condition compared with sodium citrate condition up to 3 h post-consumption. Peak blood HCO3- concentration was significantly higher with the sodium bicarbonate compared with citrate (P < 0.001). Mean GI symptom scores were lower (P = 0.037) for sodium citrate (1.5 ± 1.8 AU) than bicarbonate (2.6 ± 3.1 AU), with considerable inter-individual variability. No GI symptoms were reported following consumption of the placebo. Both substances increase HCO3- values significantly, with sodium bicarbonate causing significantly higher pH and HCO3- values than the same dose of sodium citrate, but results in slightly more severe GI symptoms.
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Current Management of Hyperkalemia in Non-Dialysis CKD: Longitudinal Study of Patients Receiving Stable Nephrology Care.
Borrelli, S, De Nicola, L, Minutolo, R, Conte, G, Chiodini, P, Cupisti, A, Santoro, D, Calabrese, V, Giannese, D, Garofalo, C, et al
Nutrients. 2021;(3)
Abstract
BACKGROUND No study has explored the limitations of current long-term management of hyperkalemia (HK) in outpatient CKD clinics. METHODS We evaluated the association between current therapeutic options and control of serum K (sK) during 12-month follow up in ND-CKD patients stratified in four groups by HK (sK ≥ 5.0 mEq/L) at baseline and month 12: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). RESULTS We studied 562 patients (age 66.2 ± 14.5 y; 61% males; eGFR 39.8 ± 21.8 mL/min/1.73 m2, RAASI 76.2%). HK was "absent" in 50.7%, "resolving" in 15.6%, "new onset" in 16.6%, and "persistent" in 17.1%. Twenty-four hour urinary measurements testified adherence to nutritional recommendations in the four groups at either visit. We detected increased prescription from baseline to month 12 of bicarbonate supplements (from 5.0 to 14.1%, p < 0.0001), K-binders (from 2.0 to 7.7%, p < 0.0001), and non-K sparing diuretics (from 34.3 to 41.5%, p < 0.001); these changes were consistent across groups. Similar results were obtained when using higher sK level (≥5.5 mEq/L) to stratify patients. Mixed-effects regression analysis showed that higher sK over time was associated with eGFR < 60, diabetes, lower serum bicarbonate, lower use of non-K sparing diuretics, bicarbonate supplementation, and K-binder use. Treatment-by-time interaction showed that sK decreased in HK patients given bicarbonate (p = 0.003) and K-binders (p = 0.005). CONCLUSIONS This observational study discloses that one-third of ND-CKD patients under nephrology care remain with or develop HK during a 12-month period despite low K intake and increased use of sK-lowering drugs.
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Modulation of the Association of Hypobicarbonatemia and Incident Kidney Failure With Replacement Therapy by Venous pH: A Cohort Study.
Kajimoto, S, Sakaguchi, Y, Asahina, Y, Kaimori, JY, Isaka, Y
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2021;(1):35-43
Abstract
RATIONALE & OBJECTIVE Studies showing an association between lower bicarbonate levels and worse kidney disease prognosis have not accounted for the influence of pH. It remains unknown whether this association is consistent across a wide range of blood pH values. This study sought to assess how pH modifies the relationship between hypobicarbonatemia and incident kidney failure requiring kidney replacement therapy (KFRT). STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS 1,058 Japanese patients with estimated glomerular filtration rates<60mL/min/1.73m2. EXPOSURE Baseline venous bicarbonate levels and venous pH. OUTCOME KFRT defined as initiation of kidney replacement therapy (hemodialysis, peritoneal dialysis, and kidney transplantation). ANALYTICAL APPROACH Cox proportional hazards model assessing the interaction between baseline bicarbonate levels and venous pH on incident KFRT. RESULTS In the lowest bicarbonate quartile (≤21.5 mEq/L), 59% of patients had acidemia (pH<7.32), whereas 38% had venous pH within the normal range and 3% had alkalemia (pH>7.42). During a median follow-up of 3.0 years, 374 patients developed KFRT. Venous pH modified the association between bicarbonate level and rate of KFRT (P for interaction=0.04). After adjustment for potential confounders, including capacity for respiratory compensation, the lowest (vs the highest) bicarbonate quartile was associated with a 2.29-fold (95% CI, 1.10-4.77; P=0.03) higher rate of KFRT among patients with acidemia (pH<7.32). In contrast, among patients without acidemia (pH≥7.32), no significant association was found between bicarbonate level and KFRT. In an exploratory analysis, patients with higher respiratory compensation capacity had a lower rate of KFRT (HR per 0.1 increase in respiratory compensation capacity, 0.90; 95% CI, 0.87-0.94; P<0.001). LIMITATIONS Observational study design; blood gas measurements were performed in a select patient population. CONCLUSIONS Venous pH modified the association of hypobicarbonatemia with progression of chronic kidney disease to KFRT. Measurement of venous pH may be valuable for identifying patients with chronic kidney disease and hypobicarbonatemia and may inform treatment.
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Metabolic acidosis is associated with increased risk of adverse kidney outcomes and mortality in patients with non-dialysis dependent chronic kidney disease: an observational cohort study.
Tangri, N, Reaven, NL, Funk, SE, Ferguson, TW, Collister, D, Mathur, V
BMC nephrology. 2021;(1):185
Abstract
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).
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Does varying the ingestion period of sodium citrate influence blood alkalosis and gastrointestinal symptoms?
Urwin, CS, Snow, RJ, Orellana, L, Condo, D, Wadley, GD, Carr, AJ
PloS one. 2021;(5):e0251808
Abstract
OBJECTIVES To compare blood alkalosis, gastrointestinal symptoms and indicators of strong ion difference after ingestion of 500 mg.kg-1 BM sodium citrate over four different periods. METHODS Sixteen healthy and active participants ingested 500 mg.kg-1 BM sodium citrate in gelatine capsules over a 15, 30, 45 or 60 min period using a randomized cross-over experimental design. Gastrointestinal symptoms questionnaires and venous blood samples were collected before ingestion, immediately post-ingestion, and every 30 min for 480 min post-ingestion. Blood samples were analysed for blood pH, [HCO3-], [Na+], [Cl-] and plasma [citrate]. Linear mixed models were used to estimate the effect of the ingestion protocols. RESULTS For all treatments, blood [HCO3-] was significantly elevated above baseline for the entire 480 min post-ingestion period, and peak occurred 180 min post-ingestion. Blood [HCO3-] and pH were significantly elevated above baseline and not significantly below the peak between 150-270 min post-ingestion. Furthermore, blood pH and [HCO3-] were significantly lower for the 60 min ingestion period when compared to the other treatments. Gastrointestinal symptoms were minor for all treatments; the mean total session symptoms ratings (all times summed together) were between 9.8 and 11.6 from a maximum possible rating of 720. CONCLUSION Based on the findings of this investigation, sodium citrate should be ingested over a period of less than 60 min (15, 30 or 45 min), and completed 150-270 min before exercise.
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Serum bicarbonate and cardiovascular events in hypertensive adults: results from the Systolic Blood Pressure Intervention Trial.
Dobre, M, Pajewski, NM, Beddhu, S, Chonchol, M, Hostetter, TH, Li, P, Rahman, M, Servilla, K, Weiner, DE, Wright, JT, et al
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2020;(8):1377-1384
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Abstract
BACKGROUND Low serum bicarbonate level is associated with increased mortality, but its role as a predictor of cardiovascular disease (CVD) is unclear. This study evaluates the association between serum bicarbonate concentration and CVD and whether the effect of intensive blood pressure (BP) lowering on CVD outcomes is modified by serum bicarbonate level. METHODS The Systolic Blood Pressure Intervention Trial (SPRINT) randomized participants to a systolic BP target <120 mmHg (intensive treatment) or <140 mmHg (standard treatment). The primary CVD outcome was a composite of nonfatal myocardial infarction (MI), acute coronary syndrome not resulting in MI, stroke, acute decompensated heart failure and CVD death. Cox proportional hazards models adjusted for demographic, clinical and laboratory characteristics were used to evaluate the association of interest in 9334 SPRINT participants (ClinicalTrials.gov: NCT01206062). RESULTS Over a median follow-up of 3.33 years (interquartile range 2.87-3.87 years), 618 (6.6%) participants experienced a primary CVD outcome. Participants with serum bicarbonate <22 mEq/L had a significantly higher risk of the primary CVD outcome (hazard ratio 1.54; 95% confidence interval 1.11-2.14, P = 0.01), compared with participants with bicarbonate 22-26 mEq/L. The magnitude of the CVD risk reduction with intensive BP lowering was similar across bicarbonate strata (P-value for interaction = 0.97). CONCLUSIONS In hypertensive individuals, serum bicarbonate level <22 mEq/L was associated with an increased CVD risk. The effect of intensive BP lowering on CVD outcomes was not modified by the serum bicarbonate level.
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Hypersensitivity reactions to bicarbonate dialysate containing acetate: a case report with literature review.
Nishiuchi, Y, Shima, H, Fukata, Y, Tao, T, Okamoto, T, Takamatsu, N, Okada, K, Minakuchi, J
CEN case reports. 2020;(3):243-246
Abstract
Although hemodialysis-hypersensitivity reactions have various causes, only a few cases of hypersensitivity to acetate dialysate accompanied by fever have been reported. We present the case of a 69-year-old hemodialysis patient who was admitted due to fever after dialysis. He had undergone online hemodiafiltration using acetate-free citrate-containing dialysate. After admission, we switched to acetate-containing bicarbonate dialysate. He was diagnosed with pneumonia and treated with ceftriaxone. However, fever that occurred post dialysis persisted, displaying a gradual elevation in CRP level and eosinophils (up to 9.7 mg/dL and 3774 cells/μL, respectively). After a series of negative workups for infection and dialysis membrane allergy, we suspected that acetate-containing bicarbonate dialysate to be the cause of the allergic reaction and switched to acetate-free bicarbonate dialysate. Consequently, eosinophil count decreased and the fever abated. The drug-induced lymphocyte stimulation test finding (for acetate dialysate) was positive, and he was diagnosed with acetate dialysate-induced hypersensitivity reactions. The condition was not detected earlier due to the complications associated with pneumonia.
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Clinical and cost-effectiveness of oral sodium bicarbonate therapy for older patients with chronic kidney disease and low-grade acidosis (BiCARB): a pragmatic randomised, double-blind, placebo-controlled trial.
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BMC medicine. 2020;(1):91
Abstract
BACKGROUND Chronic kidney disease with metabolic acidosis is common in older people, but the effectiveness of oral sodium bicarbonate therapy in this group is unclear. We tested whether oral sodium bicarbonate provides net health benefit for older people with advanced chronic kidney disease and serum bicarbonate concentrations < 22 mmol/L. METHODS Pragmatic multicentre, parallel group, double-blind, placebo-controlled randomised trial. We recruited adults aged ≥ 60 years with estimated glomerular filtration rate of < 30 mL/min/1.73 m2, not receiving dialysis, with serum bicarbonate concentration < 22 mmol/L, from 27 nephrology and geriatric medicine departments in the UK. Participants received oral sodium bicarbonate (up to 3 g/day) or matching placebo given for up to 2 years, randomised in a 1:1 ratio. The primary outcome was between-group difference in the Short Physical Performance Battery (SPPB) at 12 months, adjusted for baseline values, analysed by intention to treat. Secondary outcomes included generic and disease-specific quality of life (EQ-5D and KDQoL tools), anthropometry, renal function, walk distance, blood pressure, bone and vascular health markers, and incremental cost per quality-adjusted life year gained. RESULTS We randomised 300 participants between May 2013 and February 2017, mean age 74 years, 86 (29%) female. At 12 months, 116/152 (76%) participants allocated to bicarbonate and 104/148 (70%) allocated to placebo were assessed; primary outcome data were available for 187 participants. We found no significant treatment effect for the SPPB bicarbonate arm 8.3 (SD 2.5) points, placebo arm 8.8 (SD 2.2) and adjusted treatment effect - 0.4 (95% CI - 0.9 to 0.1, p = 0.15). We found no significant treatment effect for glomerular filtration rate (0.6 mL/min/1.73 m2, 95% CI - 0.8 to 2.0, p = 0.39). The bicarbonate arm showed higher costs and lower quality of life as measured by the EQ-5D-3L tool over 1 year (£564 [95% CI £88 to £1154]); placebo dominated bicarbonate under all sensitivity analyses. Adverse events were more frequent in those randomised to bicarbonate (457 versus 400). CONCLUSIONS Oral sodium bicarbonate did not improve physical function or renal function, increased adverse events and is unlikely to be cost-effective for use by the UK NHS for this patient group. TRIAL REGISTRATION European Clinical Trials Database (2011-005271-16) and ISRCTN09486651; registered 17 February 2012.
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Impact of Serum Bicarbonate Levels on Muscle Mass and Kidney Function in Pre-Dialysis Chronic Kidney Disease Patients.
Kittiskulnam, P, Srijaruneruang, S, Chulakadabba, A, Thokanit, NS, Praditpornsilpa, K, Tungsanga, K, Eiam-Ong, S
American journal of nephrology. 2020;(1):24-34
Abstract
BACKGROUND Treatment of metabolic acidosis to target the higher serum bicarbonate level than guideline recommendation may downregulate muscle protein degradation and improve renal function among chronic kidney disease (CKD) patients. We conducted a study to test the effects of increased serum bicarbonate level on muscle parameters, nutrition, and renal function in pre-dialysis CKD patients. METHODS This was a randomized, controlled study. CKD stage 3-4 patients with serum HCO3- <22 mEq/L were randomized to either receive oral sodium bicarbonate with high target bicarbonate level of 25 ± 1 or standard level of 22 ± 1 mEq/L as control group using protocol-based titration of dosage adjustment. The changes of muscle mass measured by bioelectrical impedance analysis (BIA), muscle strength by hand grip dynamometer, estimated glomerular filtration rate (eGFR) using CKD-Epidemiology Collaboration equation, nutritional markers, and muscle-related biomarkers were determined. Data at baseline and after 4 months of sodium bicarbonate supplementation were compared between groups using Student t test or chi-square test as appropriate. RESULTS Forty-two patients completed the study (n = 21 per group). The mean age and eGFR were 61.2 ± 9.8 years and 32.4 ± 14.1 mL/min respectively. Serum bicarbonate levels at baseline were 21.0 ± 2.1 mEq/L. Baseline data including sex, diabetes, serum bicarbonate level, creatinine, and blood pressure were similar. After 4 months of treatment, the average serum bicarbonate levels in both groups were 24.0 ± 1.4 and 20.7 ± 2.3 mEq/L (p < 0.001). Both BIA-derived total-body muscle mass and appendicular lean balance were increased at 4 months in the higher bicarbonate group (26.0 ± 5.3 to 26.7 ± 5.5 kg, p = 0.04 and 19.8 ± 4.1 to 20.7 ± 4.4 kg, p = 0.06, respectively) despite comparable body weight and protein intake. Patients in the high bicarbonate group had a significant reduction of plasma myostatin levels, a surrogate of muscle degradation, at the study exit after adjusting for baseline values (-3,137.8; 95% CI -6,235.3 to -40.4 pg/mL, p= 0.04), but unaltered insulin-like growth factor-1 level, as the mediator of muscle cell growth, (141 [106-156] to 110 [87-144] ng/mL, p = 0.13) compared to the control group. Muscle strength, eGFR as well as serum prealbumin were not significantly different between 2 groups (p > 0.05). Neither worsening hypertension nor congestive heart failure was found throughout the study. CONCLUSION Bicarbonate supplementation to achieve the serum level ∼24 mEq/L demonstrates better muscle mass preservation in patients with pre-dialysis CKD. The impact of alkaline therapy on renal function may require a longer period of study.