Mechanism of Hyperkalemia-Induced Metabolic Acidosis. Harris Autumn N,Grimm P Richard,Lee Hyun-Wook,Delpire Eric,Fang Lijuan,Verlander Jill W,Welling Paul A,Weiner I David Journal of the American Society of Nephrology : JASN Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs. We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)-specific overexpression of constitutively active Ste20/SPS1-related proline-alanine-rich kinase (DCT-CA-SPAK). DCT-CA-SPAK mice developed hyperkalemia in association with metabolic acidosis and suppressed ammonia excretion; however, titratable acid excretion and urine pH were unchanged compared with those in wild-type mice. Abnormal ammonia excretion in DCT-CA-SPAK mice associated with decreased proximal tubule expression of the ammonia-generating enzymes phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and overexpression of the ammonia-recycling enzyme glutamine synthetase. These mice also had decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H-ATPase in the inner stripe of the outer medullary collecting duct. Correcting the hyperkalemia by treatment with hydrochlorothiazide corrected the metabolic acidosis, increased ammonia excretion, and normalized ammoniagenic enzyme and Rhcg expression in DCT-CA-SPAK mice. In wild-type mice, induction of hyperkalemia by administration of the epithelial sodium channel blocker benzamil caused hyperkalemia and suppressed ammonia excretion. Hyperkalemia decreases proximal tubule ammonia generation and collecting duct ammonia transport, leading to impaired ammonia excretion that causes metabolic acidosis. 10.1681/ASN.2017111163
    Metabolic acidosis is common and associates with disease progression in children with chronic kidney disease. Harambat Jérôme,Kunzmann Kevin,Azukaitis Karolis,Bayazit Aysun K,Canpolat Nur,Doyon Anke,Duzova Ali,Niemirska Anna,Sözeri Betul,Thurn-Valsassina Daniela,Anarat Ali,Bessenay Lucie,Candan Cengiz,Peco-Antic Amira,Yilmaz Alev,Tschumi Sibylle,Testa Sara,Jankauskiene Augustina,Erdogan Hakan,Rosales Alejandra,Alpay Harika,Lugani Francesca,Arbeiter Klaus,Mencarelli Francesca,Kiyak Aysel,Dönmez Osman,Drozdz Dorota,Melk Anette,Querfeld Uwe,Schaefer Franz, Kidney international Recent studies in adult chronic kidney disease (CKD) suggest that metabolic acidosis is associated with faster decline in estimated glomerular filtration rate (eGFR). Alkali therapies improve the course of kidney disease. Here we investigated the prevalence and determinants of abnormal serum bicarbonate values and whether metabolic acidosis may be deleterious to children with CKD. Associations between follow-up serum bicarbonate levels categorized as under 18, 18 to under 22, and 22 or more mmol/l and CKD outcomes in 704 children in the Cardiovascular Comorbidity in Children with CKD Study, a prospective cohort of pediatric patients with CKD stages 3-5, were studied. The eGFR and serum bicarbonate were measured every six months. At baseline, the median eGFR was 27 ml/min/1.73m and median serum bicarbonate level 21 mmol/l. During a median follow-up of 3.3 years, the prevalence of metabolic acidosis (serum bicarbonate under 22 mmol/l) was 43%, 60%, and 45% in CKD stages 3, 4, and 5, respectively. In multivariable analysis, the presence of metabolic acidosis as a time-varying covariate was significantly associated with log serum parathyroid hormone through the entire follow-up, but no association with longitudinal growth was found. A total of 211 patients reached the composite endpoint (ESRD or 50% decline in eGFR). In a multivariable Cox model, children with time-varying serum bicarbonate under 18 mmol/l had a significantly higher risk of CKD progression compared to those with a serum bicarbonate of 22 or more mmol/l (adjusted hazard ratio 2.44; 95% confidence interval 1.43-4.15). Thus, metabolic acidosis is a common complication in pediatric patients with CKD and may be a risk factor for secondary hyperparathyroidism and kidney disease progression. 10.1016/j.kint.2017.05.006
    Metabolic Acidosis and Subclinical Metabolic Acidosis in CKD. Raphael Kalani L Journal of the American Society of Nephrology : JASN Metabolic acidosis is not uncommon in CKD and is linked with bone demineralization, muscle catabolism, and higher risks of CKD progression and mortality. Clinical practice guidelines recommend maintaining serum total CO at ≥22 mEq/L to help prevent these complications. Although a definitive trial testing whether correcting metabolic acidosis improves clinical outcomes has not been conducted, results from small, single-center studies support this notion. Furthermore, biologic plausibility supports the notion that a subset of patients with CKD have acid-mediated organ injury despite having a normal serum total CO and might benefit from oral alkali before overt acidosis develops. Identifying these individuals with subclinical metabolic acidosis is challenging, but recent results suggest that urinary acid excretion measurements may be helpful. The dose of alkali to provide in this setting is unknown as well. The review discusses these topics and the prevalence and risk factors of metabolic acidosis, mechanisms of acid-mediated organ injury, results from interventional studies, and potential harms of alkali therapy in CKD. 10.1681/ASN.2017040422
    Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial. Wesson Donald E,Mathur Vandana,Tangri Navdeep,Stasiv Yuri,Parsell Dawn,Li Elizabeth,Klaerner Gerrit,Bushinsky David A Lancet (London, England) BACKGROUND:Patients with advanced chronic kidney disease lose the capacity to fully excrete endogenous acid, resulting in chronic metabolic acidosis that increases the risk of disease progression and causes muscle catabolism and bone resorption. Veverimer, a non-absorbed, counterion-free, polymeric drug, selectively binds and removes hydrochloric acid from the gastrointestinal lumen, unlike current oral sodium bicarbonate therapy for metabolic acidosis that only neutralises accumulated acid. We assessed the efficacy and safety of veverimer as a treatment for metabolic acidosis in patients with chronic kidney disease. METHODS:We did a multicentre, parallel, randomised, double-blind, placebo-controlled study at 37 sites (hospitals and specialty clinics) in Bulgaria, Croatia, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA. Eligible participants were patients aged 18-85 years with non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate of 20-40 mL/min per 1·73 m) and metabolic acidosis (serum bicarbonate concentration of 12-20 mmol/L). Patients were randomly assigned (4:3) to veverimer 6 g/day or placebo for 12 weeks while they consumed their typical diet. Both drugs were taken as oral suspensions in water with lunch. Randomisation was done by study site personnel with a computer-generated randomisation code with balanced permuted blocks (block size of seven) and stratified by baseline bicarbonate (≤18 mmol/L vs >18 mmol/L). Patients and investigators were masked to treatment allocation; however, because the appearance of placebo differed from veverimer, a non-masked site staff member who had no other role in the study dispensed, prepared, and supervised dosing of the study drugs. The composite primary efficacy endpoint was the difference (veverimer-placebo) in the proportion of patients achieving at week 12 either an increase of 4 mmol/L or more from baseline in serum bicarbonate concentration or serum bicarbonate in the normal range of 22-29 mmol/L, assessed in the modified intention-to-treat population (all patients with a baseline and at least one post-baseline serum bicarbonate value). Patients fasted for at least 4 h (consuming only water) before measurements of bicarbonate. Safety was assessed in all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, number NCT03317444. FINDINGS:Between Sept 26, 2017, and Feb 9, 2018, we randomly assigned 124 participants to veverimer and 93 to placebo. The composite primary endpoint was met by 71 (59%) of 120 patients in the veverimer group versus 20 (22%) of 89 patients in the placebo group (a difference of 37%, 95% CI 23-49; p<0·0001). The most common body system in which adverse events in the veverimer group occurred was gastrointestinal; of these, non-treatment limiting diarrhoea was the most common event (11 [9%] vs three [3%] in the veverimer and placebo groups, respectively). The most common treatment-related adverse events were gastrointestinal (diarrhoea, flatulence, nausea, and constipation) occurring in 16 (13%) patients with veverimer and five (5%) patients with placebo. Two deaths occurred during the study, both in the placebo group (unstable angina and pneumonia). INTERPRETATION:Veverimer effectively and safely corrected metabolic acidosis. Longer-term studies are warranted to assess the effects of veverimer on physical functioning and to assess other deleterious consequences of metabolic acidosis including progression of chronic kidney disease and bone health. FUNDING:Tricida. 10.1016/S0140-6736(18)32562-5
    Fruit and Vegetable Treatment of Chronic Kidney Disease-Related Metabolic Acidosis Reduces Cardiovascular Risk Better than Sodium Bicarbonate. Goraya Nimrit,Munoz-Maldonado Yolanda,Simoni Jan,Wesson Donald E American journal of nephrology BACKGROUND:Current guidelines recommend treatment of metabolic acidosis in chronic kidney disease (CKD) with sodium-based alkali. We tested the hypothesis that treatment with base-producing fruits and vegetables (F + V) better improves cardiovascular disease (CVD) risk indicators than oral sodium bicarbonate (NaHCO3). METHODS:We randomized 108 macroalbuminuric, matched, nondiabetic CKD patients with metabolic acidosis to F + V (n = 36) in amounts to reduce dietary acid by half, oral NaHCO3 (HCO3, n = 36) 0.3 mEq/kg bw/day, or to Usual Care (UC, n = 36) to assess the 5-year effect of these interventions on estimated glomerular filtration rate (eGFR) course as the primary analysis and on indicators of CVD risk as the secondary analysis. RESULTS:Five-year plasma total CO2 was higher in HCO3 and F + V than UC but was not different between HCO3 and F + V (difference p value < 0.01). Five-year net eGFR decrease was less in HCO3 (mean -12.3, 95% CI -12.9 to -11.7 mL/min/1.73 m2) and F + V (-10.0, 95% CI -10.6 to -9.4 mL/min/1.73 m2) than UC (-18.8, 95% CI -19.5 to -18.2 mL/min/1.73 m2; p value < 0.01) but was not different between HCO3 and F + V. Five-year systolic blood pressure was lower in F + V than UC and HCO3 (p value < 0.01). Despite similar baseline values, F + V had lower low-density lipoprotein, Lp(a), and higher serum vitamin K1 (low serum K1 is associated with coronary artery calcification) than HCO3 and UC at 5 years. CONCLUSION:Metabolic acidosis improvement and eGFR preservation were comparable in CKD patients treated with F + V or oral NaHCO3 but F + V better improved CVD risk indicators, making it a potentially better treatment option for reducing CVD risk. 10.1159/000500042
    Hyperchloremic normal gap metabolic acidosis. Palmer Biff F,Clegg Deborah J Minerva endocrinologica Metabolic acidosis is defined as a pathologic process that, when unopposed, increases the concentration of hydrogen ions (H+) in the body and reduces the bicarbonate (HCO3-) concentration. Metabolic acidosis can be of a kidney origin or an extrarenal cause. Assessment of urinary ammonium excretion by calculating the urine anion gap or osmolal gap is a useful method to distinguish between these two causes. Extrarenal processes include increased endogenous acid production and accelerated loss of bicarbonate from the body. Metabolic acidosis of renal origin is due to a primary defect in renal acidification with no increase in extrarenal hydrogen ion production. This situation can occur because either the renal input of new bicarbonate is insufficient to regenerate the bicarbonate lost in buffering endogenous acid as with distal renal tubular acidosis (RTA) or the RTA of renal insufficiency, or the filtered bicarbonate is lost by kidney wasting as in proximal RTA. In either condition, because of loss of either NaHCO3 (proximal RTA) or NaA (distal RTA), effective extracellular volume is reduced and as a result the avidity for chloride reabsorption derived from the diet is increased and results in a hyperchloremic normal gap metabolic acidosis. The RTA of renal insufficiency is also characterized by a normal gap acidosis, however, with severe reductions in the glomerular filtration rate an anion gap metabolic acidosis eventually develops. 10.23736/S0391-1977.19.03059-1
    [Dietary control of metabolic acidosis in chronic kidney disease]. Laboux Timothée,Azar Raymond Nephrologie & therapeutique Metabolic acidosis is a frequent complication of chronic kidney disease. Although it is known to appear at advanced stages, many studies suggest a state of "global protonic retention" starting at early stages of the disease, responsible of tissue damage, particularly musculoskeletal, alteration of protidic metabolism and endocrine disorders, promoting malnutrition and chronic inflammation, and finally increasing mortality. The majority of international recommandations suggest of supplementation by alkali, most of the time by sodium bicarbonate, to struggle against this complication. An interesting alternative to correct acidosis would consist on the modulation of the endogenous production of acid by playing with the alimentary incomes. In fact, it has been demonstrated that some different types of food produce or consume protons during their metabolism. Low protein diet and rich fresh fruits and vegetables diet would manage to correct at least as well as the supplementation by sodium bicarbonate the metabolic acidosis, and to struggle against its complications, noteworthy by slowing the decline of glomerular filtration rate by limiting the toxic adaptative fibrotic mechanisms, demonstrated by the decrease of urinary tubulo-interstitial suffering markers. Of the condition of being well led, those diets do not seem to expose patients to an over-risk of malnutrition or hyperkaliemia. They therefore appear to be an attractive alternative, efficiency and safe, to fight against chronic kidney disease metabolic acidosis and its complications. 10.1016/j.nephro.2018.12.001
    Diagnosis and Treatment of Metabolic Acidosis in Patients with Chronic Kidney Disease - Position Statement of the Working Group of the Polish Society of Nephrology. Adamczak Marcin,Masajtis-Zagajewska Anna,Mazanowska Oktawia,Madziarska Katarzyna,Stompór Tomasz,Więcek Andrzej Kidney & blood pressure research Metabolic acidosis is commonly found in patients with chronic kidney disease (CKD), and its causes are: impaired ammonia excretion, reduced tubular bicarbonate reabsorption and insufficient renal bicarbonate production in relation to the amount of acids synthesised by the body and ingested with food. As the consequence, numerous metabolic abnormalities develop, which may lead to dysfunction of several organs. In observational studies, it has been found that CKD patients with metabolic acidosis are characterised by faster progression of kidney disease towards end stage kidney failure, and by increased mortality. Results of interventional studies suggest that alkali therapy in CKD patients slows progression of kidney disease. In view of these facts, the members of "The Working Group of the Polish Society of Nephrology on Metabolic and Endocrine Abnormalities in Kidney Diseases" have prepared the following statement and guidelines for the diagnosis and treatment of metabolic acidosis in CKD patients. Measurement of bicarbonate concentration in venous plasma or venous blood to check for metabolic acidosis should be performed in all CKD patients and metabolic acidosis in these patients should be diagnosed when the venous plasma or venous blood bicarbonate concentration is lower than 22 mmol/l. In patients with metabolic acidosis and CKD, oral sodium bicarbonate administration is recommended. The goal of such a treatment is to achieve a plasma or blood bicarbonate concentration equal to or greater than 22 mmol/l. 10.1159/000490475
    Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study. Di Iorio Biagio R,Bellasi Antonio,Raphael Kalani L,Santoro Domenico,Aucella Filippo,Garofano Luciano,Ceccarelli Michele,Di Lullo Luca,Capolongo Giovanna,Di Iorio Mattia,Guastaferro Pasquale,Capasso Giovambattista, Journal of nephrology BACKGROUND:Metabolic acidosis is associated with accelerated progression of chronic kidney disease (CKD). Whether treatment of metabolic acidosis with sodium bicarbonate improves kidney and patient survival in CKD is unclear. METHODS:We conducted a randomized (ratio 1:1). open-label, controlled trial (NCT number: NCT01640119. www.clinicaltrials.gov ) to determine the effect in patients with CKD stage 3-5 of treatment of metabolic acidosis with sodium bicarbonate (SB) on creatinine doubling (primary endpoint), all-cause mortality and time to renal replacement therapy compared to standard care (SC) over 36-months. Parametric, non-parametric tests and survival analyses were used to assess the effect of SB on these outcomes. RESULTS:A total of 376 and 364 individuals with mean (SD) age 67.8 (14.9) years, creatinine clearance 30 (12) ml/min, and serum bicarbonate 21.5 (2.4) mmol/l were enrolled in SB and SC, respectively. Mean (SD) follow-up was 29.6 (9.8) vs 30.3 (10.7) months in SC and SB. respectively. The mean (SD) daily doses of SB was 1.13 (0.10). 1.12 (0.11). and 1.09 (0.12) mmol/kg*bw/day in the first, second and third year of follow-up, respectively. A total of 87 participants reached the primary endpoint [62 (17.0%) in SC vs 25 (6.6%) in SB, p < 0.001). Similarly, 71 participants [45 (12.3%) in SC and 26 (6.9%) in SB, p = 0.016] started dialysis while 37 participants [25 (6.8%) in SC and 12 (3.1%) in SB, p = 0.004] died. There were no significant effect of SB on blood pressure, total body weight or hospitalizations. CONCLUSION:In persons with CKD 3-5 without advanced stages of chronic heart failure, treatment of metabolic acidosis with sodium bicarbonate is safe and improves kidney and patient survival. 10.1007/s40620-019-00656-5
    Effects of Treatment of Metabolic Acidosis in CKD: A Systematic Review and Meta-Analysis. Navaneethan Sankar D,Shao Jun,Buysse Jerry,Bushinsky David A Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVES:Metabolic acidosis is associated with progression of CKD and has significant adverse effects on muscle and bone. A systematic review and meta-analysis was conducted to evaluate the benefits and risks of metabolic acidosis treatment with oral alkali supplementation or a reduction of dietary acid intake in those with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:MEDLINE, Embase, and Cochrane CENTRAL were searched for relevant trials in patients with stage 3-5 CKD and metabolic acidosis (<22 mEq/L) or low-normal serum bicarbonate (22-24 mEq/L). Data were pooled in a meta-analysis with results expressed as weighted mean difference for continuous outcomes and relative risk for categorical outcomes with 95% confidence intervals (95% CIs), using a random effects model. Study quality and strength of evidence were assessed using Cochrane risk of bias and the Grading of Recommendations Assessment, Development and Evaluation criteria. RESULTS:Fourteen clinical trials were included (=1394 participants). Treatment of metabolic acidosis with oral alkali supplementation or a reduction of dietary acid intake increased serum bicarbonate levels (14 studies, 1378 patients, mean difference 3.33 mEq/L, 95% CI, 2.37 to 4.29) and resulted in a slower decline in eGFR (13 studies, 1329 patients, mean difference -3.28 ml/min per 1.73 m, 95% CI, -4.42 to -2.14; moderate certainty) and a reduction in urinary albumin excretion (very-low certainty), along with a reduction in the risk of progression to ESKD (relative risk, 0.32; 95% CI, 0.18 to 0.56; low certainty). Oral alkali supplementation was associated with worsening hypertension or the requirement for increased antihypertensive therapy (very-low certainty). CONCLUSIONS:Low-to-moderate certainty evidence suggest that oral alkali supplementation or a reduction in dietary acid intake may slow the rate of kidney function decline and potentially reduce the risk of ESKD in patients with CKD and metabolic acidosis. 10.2215/CJN.13091118
    Metabolic Acidosis in CKD: Core Curriculum 2019. Raphael Kalani L American journal of kidney diseases : the official journal of the National Kidney Foundation Maintenance of normal acid-base homeostasis is one of the most important kidney functions. In chronic kidney disease, the capacity of the kidneys to excrete the daily acid load as ammonium and titratable acid is impaired, resulting in acid retention and metabolic acidosis. The prevalence of metabolic acidosis increases with declining glomerular filtration rate. Metabolic acidosis is associated with several clinically important complications, including chronic kidney disease progression, bone demineralization, skeletal muscle catabolism, and mortality. To mitigate these adverse consequences, clinical practice guidelines suggest treating metabolic acidosis with oral alkali in patients with chronic kidney disease. However, large clinical trials to determine the efficacy and safety of correcting metabolic acidosis with oral alkali in patients with chronic kidney disease have yet to be conducted. In this Core Curriculum article, established and emerging concepts regarding kidney acid-base regulation and the pathogenesis, risk factors, diagnosis, and management of metabolic acidosis in chronic kidney disease are discussed. 10.1053/j.ajkd.2019.01.036