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Management of Metabolic Acidosis in Chronic Kidney Disease: Past, Present, and Future Direction

      Chronic kidney disease (CKD) is a major global epidemic associated with increased morbidity and mortality. Despite the effectiveness of kidney protection strategies of hypertension, diabetes, and lipid control and use of newer hypoglycemic agents and anti-angiotensin II drugs, the nephropathy in CKD continues unabated toward irreversible kidney failure. Thus, interventions targeting modifiable risk factors in CKD such as metabolic acidosis (MA) are needed. Acid reduction with sodium-based alkali has been shown to be an effective kidney-protection strategy for patients with CKD and reduced glomerular filtration rate (GFR). Small-scale studies reveal diets emphasizing ingestion of plant-sourced over animal-sourced protein reduce dietary acid, improve MA, and slow further nephropathy progression in patients with CKD and reduced GFR. Additionally, veverimer, an investigational, nonabsorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as a novel treatment for MA. As further studies define how to best use these interventions for kidney protection, clinicians must become aware of their potential utility in the management of patients with CKD. The aim of the present review is to explore the various intervention strategies that increase or normalize serum [HCO3-] in patients with CKD-associated MA or low normal serum [HCO3-] that may further slow progression of CKD.

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      References

        • Shlipak M.G.
        • Tummalapalli S.L.
        • Boulware L.E.
        • et al.
        The case for early identification and intervention of chronic kidney disease: conclusions from a Kidney Disease: improving Global Outcomes (KDIGO) Controversies Conference.
        Kidney Int. 2021; 99: 34-47
        • United States Renal Data System
        2013 USRDS Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.
        https://www.usrds.org/
        Date: 2013
        Date accessed: August 10, 2021
        • National Institute of Diabetes and Digestive and Kidney Diseases
        Kidney disease Statistics for the United States.
        • Clase C.M.
        • Kiberd B.A.
        • Garg A.X.
        Relationship between glomerular filtration rate and the prevalence of metabolic abnormalities: results from the Third National Health and Nutrition Examination Survey (NHANES III).
        Nephron Clin Pract. 2007; 105: C178-C184
        • Kovesdy C.P.
        • Anderson J.E.
        • Kalantar-Zadeh K.
        Association of serum bicarbonate levels with mortality in patients with non-dialysis-dependent CKD.
        Nephrol Dial Transpl. 2009; 24: 1232-1237
        • Raphael K.L.
        • Wei G.
        • Baird B.C.
        • Greene T.
        • Beddhu S.
        Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans.
        Kid Int. 2011; 79: 356-362
        • Adeva M.M.
        • Souto G.
        Diet-induced metabolic acidosis.
        Clin Nutr. 2011; 30: 416-421
      1. KDIGO 2012 Clinical Practice Guidelines, Chapter 3: Management of Progression and Complications of CKD.
        Kid Int Suppl. 2013; 3: 73-90
        • Wesson D.E.
        The continuum of acid stress..
        Clin J Am Soc Nephrol. 2021; 16: 1292-1299
        • Goraya N.
        • Simoni J.
        • Sager L.N.
        • Mamun A.
        • Madias N.E.
        • Wesson D.E.
        Urine citrate excretion identifies changes in acid retention as eGFR declines in patients with chronic kidney disease.
        Am J Physiol Ren Physiol. 2019; 317: F502-F511
        • Banerjee T.
        • Crews D.C.
        • Wesson D.E.
        • et al.
        Centers for disease control and prevention chronic kidney disease Surveillance Team. Dietary acid load and chronic kidney disease among adults in the United States.
        BMC Nephrol. 2014; 15: 137-148
        • Goraya N.
        • Wesson D.E.
        Management of the metabolic acidosis of chronic kidney disease.
        Adv Chronic Kidney Dis. 2017; 24: 298-304
        • de Brito-Ashurst I.
        • Varagunum M.
        • Raftery M.J.
        • Yaqoob M.M.
        Bicarbonate supplementation slows progression of CKD and improves nutritional status.
        J Am Soc Nephrol. 2009; 20: 2075-2084
        • Mahajan A.
        • Simoni J.
        • Sheather S.J.
        • et al.
        Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy.
        Kid Int. 2010; 78: 303-309
        • Goraya N.
        • Simoni J.
        • Jo C.H.
        • Wesson D.E.
        A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate.
        Clin J Am Soc Nephrol. 2013; 8: 371-381
        • Goraya N.
        • Simoni J.
        • Jo C.H.
        • Wesson D.E.
        Treatment of metabolic acidosis in patients with stage 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate.
        Kid Int. 2014; 86: 1031-1038
        • Di Iorio B.R.
        • Bellasi A.
        • Raphael K.L.
        • et al.
        Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study.
        J Nephrol. 2019; 32: 989-1001
        • Phisitkul S.
        • Khanna A.
        • Simoni J.
        • et al.
        Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR.
        Kid Int. 2010; 77: 617-623
        • Khanna A.
        • Simoni J.
        • Wesson D.E.
        Endothelin-induced increased aldosterone activity mediates augmented distal nephron acidification as a result of dietary protein.
        J Am Soc Nephrol. 2005; 16: 1929-1935
        • Wesson D.E.
        • Jo C.H.
        • Simoni J.
        Angiotensin II-mediated GFR decline in subtotal nephrectomy is due to acid retention associated with reduced GFR.
        Nephrol Dial Transpl. 2015; 30: 762-770
        • Dubey A.K.
        • Sahoo J.
        • Vairappan B.
        • et al.
        Correction of metabolic acidosis improves muscle mass and renal function in chronic kidney disease stages 3 and 4: a randomized controlled trial.
        Nephrol Dial Transpl. 2020; 35: 121-129
        • Raphael K.L.
        • Isakova T.
        • Ix J.H.
        • et al.
        A randomized trial comparing the safety, Adherence, and Pharmacodynamics profiles of two doses of sodium bicarbonate in CKD: the BASE Pilot trial.
        J Am Soc Nephrol. 2020; 31: 161-174
        • BiCARB Study Group
        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.
        BMC Med. 2020; 18: 91
        • Melamed M.L.
        • Horwitz E.J.
        • Dobre M.A.
        • et al.
        Effects of sodium bicarbonate in CKD stages 3 and 4: a randomized, placebo-controlled, Multicenter clinical trial.
        Am J Kidney Dis. 2020; 75: 225-234
        • Klahr S.
        • Levey A.S.
        • Beck G.J.
        • et al.
        The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease.
        N Engl J Med. 1994; 330: 877-884
        • Aparicio M.
        • Bouchet J.L.
        • Gin H.
        • et al.
        Effect of a low-protein diet on urinary albumin excretion in uremic patients.
        Nephron. 1988; 50: 288-291
        • Remer T.
        Influence of nutrition on acid-base balance - metabolic aspects.
        Eur J Nutr. 2001; 40: 214-220
        • Goraya N.
        • Simoni J.
        • Jo C.H.
        • Wesson D.E.
        Dietary acid reduction with fruits and vegetables or bicarbonate attenuates kidney injury in patients with a moderately reduced glomerular filtration rate due to hypertensive nephropathy.
        Kid Int. 2012; 81: 86-93
        • Barsotti G.
        • Morelli E.
        • Cupisti A.
        • Meola M.
        • Dani L.
        • Giovannetti S.
        A low-nitrogen low- phosphorus Vegan diet for patients with chronic renal failure.
        Nephron. 1996; 74: 390-394
        • Garneata L.
        • Stancu A.
        • Dragomir D.
        • Stefan G.
        • Mircescu G.
        Ketoanalogue-supplemented vegetarian very low-protein diet and CKD progression.
        J Am Soc Nephrol. 2016; 27: 2164-2176
        • Kelly J.T.
        • Guobin S.
        • Zhang L.
        • et al.
        Modifiable Lifestyle factors for primary prevention of CKD: a systematic review and meta-analysis.
        J Am Soc Nephrol. 2021; 32: 239-253
        • Bach K.E.
        • Kelly J.T.
        • Palmer S.C.
        • Khalesi S.
        • Strippoli G.F.M.
        • Campbell K.L.
        • Healthy Dietary Patterns and Incidence of CKD
        A meta-analysis of cohort studies.
        J Am Soc Nephrol. 2019; 14: 1441-1449
        • Goraya N.
        • Munoz-Maldonaldo Y.
        • Simoni J.
        • Wesson D.E.
        Fruit and vegetable treatment of chronic kidney disease-related metabolic acidosis reduces cardiovascular risk better than sodium bicarbonate..
        Am J Nephrol. 2019; 49: 438-448
        • Joshi S.
        • McMacken M.
        • Kalantar-Zadeh K.
        Plant-based diets for kidney disease: a Guide for clinicians..
        Am J Kidney Dis. 2021; 77: 287-296
        • Saglimbene V.M.
        • Wong G.
        • Ruospo M.
        • et al.
        Fruit and vegetable intake and mortality in adults undergoing Maintenance Hemodialysis.
        Clin J Am Soc Nephrol. 2019; 14: 250-260
        • Arnold R.
        • Pianta T.J.
        • Pussell B.A.
        • et al.
        Randomized, controlled trial of the effect of dietary potassium restriction on Nerve function in CKD.
        Clin J Am Soc Nephrol. 2017; 12: 1569-1577
        • Yusbashain W.
        • Asghari G.
        • Mirmiran P.
        • Hosseini F.
        • Azizi F.
        Associations of dietary macronutrients with glomerular filtration rate and kidney dysfunction: Tehran lipid and glucose study.
        J Nephrol. 2015; 28: 173-180
        • Evenepoel P.
        • Meijers B.K.I.
        • Bammens B.R.M.
        • Verbeke K.
        Uremic toxins originating from colonic microbial metabolism.
        Kid Int. 2009; 76: S12-S19
        • Vaziri N.D.
        • Zhao Y.Y.
        • Pahl M.V.
        Altered intestinal microbial flora and impaired epithelial barrier structure and function in CKD: the nature, mechanisms, consequences and potential treatment.
        Nephrol Dial Transpl. 2016; 31: 737-746
        • Sacks F.M.
        • Svetkey L.P.
        • Vollmer W.M.
        • et al.
        Effects on blood pressure of reduced dietary sodium and the dietary approaches to Stop hypertension (DASH) diet. DASH-sodium Collaborative Research group.
        N Engl J Med. 2001; 344: 3-10
        • Estruch R.
        • Ros E.
        • Salas-Salvado J.
        • et al.
        Primary prevention of cardiovascular disease with a Mediterranean diet.
        N Engl J Med. 2013; 368: 1279-1290
        • Bushinsky D.A.
        • Hostetter T.
        • Klaerner G.
        • et al.
        Randomized, controlled trial of TRC101 to increase serum bicarbonate in patients with CKD.
        Clin J Am Soc Nephrol. 2018; 13: 26-35
        • Wesson D.E.
        • Mathur V.
        • Tangri N.
        • et al.
        Veverimer vs placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial.
        Lancet. 2019; 393: 1417-1427
        • Wesson D.E.
        • Mathur V.
        • Tangri N.
        • et al.
        Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension.
        Lancet. 2019; 394: 396-406
        • Tricida, Inc
        Evaluation of effect of TRC101 on progression of chronic kidney disease in subjects with metabolic acidosis (VALOR-CKD). ClinicalTrials.gov: NCT03710291.
        https://clinicaltrials.gov/ct2/show/NCT03710291/
        Date accessed: November 12, 2021
        • Adrogue H.J.
        • Madias N.E.
        Veverimer: an emerging potential treatment option for managing metabolic acidosis of CKD.
        Am J Kidney Dis. 2020; 76: 861-867
        • Melamed M.L.
        • Raphael K.L.
        Metabolic acidosis in CKD: a review of recent findings.
        Kidney Med. 2021; 3: 267-277
        • Ikizler T.A.
        • Burrowes J.D.
        • Byham-Gray L.D.
        • et al.
        KDOQI clinical Practice guideline for nutrition in CKD: 2020 update.
        Am J Kidney Dis. 2020; 76: S1-S107