Importance of Metabolic Acidosis as a Health Risk in Chronic Kidney Disease

Abstract

Human kidneys are well adapted to excrete the daily acid load from diet and metabolism in order to maintain homeostasis. In approximately 30% of patients with more advanced stages of CKD, these homeostatic processes are no longer adequate, resulting in metabolic acidosis. Potential deleterious effects of chronic metabolic acidosis in CKD, including muscle wasting, bone demineralization, hyperkalemia, and more rapid progression of CKD, have been well cataloged. Based primarily upon concerns related to nutrition and bone disease, early Kidney Disease Outcomes Quality Initiative guidelines recommended treating metabolic acidosis with alkali therapy targeting a serum bicarbonate ≥22 mEq/L. More recent guidelines have suggested similar targets based upon potential slowing of CKD progression. However, appropriately powered, long-term, randomized controlled trials to study efficacy and safety of alkali therapy for these outcomes are largely lacking. As a result, practice among physicians varies, underscoring the complexity of treatment of chronic metabolic acidosis in real-world CKD practice. Novel treatment approaches and rigorous phase 3 trials may resolve some of this controversy in the coming years. Metabolic acidosis is an important complication of CKD, and where it “falls” in the priority schema of CKD care will depend upon the generation of strong clinical evidence. Human kidneys are well adapted to excrete the daily acid load from diet and metabolism in order to maintain homeostasis. In approximately 30% of patients with more advanced stages of CKD, these homeostatic processes are no longer adequate, resulting in metabolic acidosis. Potential deleterious effects of chronic metabolic acidosis in CKD, including muscle wasting, bone demineralization, hyperkalemia, and more rapid progression of CKD, have been well cataloged. Based primarily upon concerns related to nutrition and bone disease, early Kidney Disease Outcomes Quality Initiative guidelines recommended treating metabolic acidosis with alkali therapy targeting a serum bicarbonate ≥22 mEq/L. More recent guidelines have suggested similar targets based upon potential slowing of CKD progression. However, appropriately powered, long-term, randomized controlled trials to study efficacy and safety of alkali therapy for these outcomes are largely lacking. As a result, practice among physicians varies, underscoring the complexity of treatment of chronic metabolic acidosis in real-world CKD practice. Novel treatment approaches and rigorous phase 3 trials may resolve some of this controversy in the coming years. Metabolic acidosis is an important complication of CKD, and where it “falls” in the priority schema of CKD care will depend upon the generation of strong clinical evidence. Clinical Summary•Close to 5 million Americans have CKD G3b-5, and studies suggest 12-20% of patients with CKD stage G3b and 27-38% with G4-5 CKD have chronic metabolic acidosis.•Chronic metabolic acidosis in CKD is associated with potential deleterious health effects including bone mineralization and impaired growth in children, muscle loss, hyperkalemia, and progression of CKD, among others.•Although Kidney Disease Outcomes Quality Initiative and Kidney Disease: Improving Global Outcomes guidelines suggest use of alkali to treat chronic metabolic acidosis, published commentaries recognize low-quality evidence and potential risks including worsening hypertension and edema due to sodium loading.•Novel agents to treat metabolic acidosis and the accompanying clinical trials may help resolve controversy about the role of metabolic acidosis treatment in CKD care. •Close to 5 million Americans have CKD G3b-5, and studies suggest 12-20% of patients with CKD stage G3b and 27-38% with G4-5 CKD have chronic metabolic acidosis.•Chronic metabolic acidosis in CKD is associated with potential deleterious health effects including bone mineralization and impaired growth in children, muscle loss, hyperkalemia, and progression of CKD, among others.•Although Kidney Disease Outcomes Quality Initiative and Kidney Disease: Improving Global Outcomes guidelines suggest use of alkali to treat chronic metabolic acidosis, published commentaries recognize low-quality evidence and potential risks including worsening hypertension and edema due to sodium loading.•Novel agents to treat metabolic acidosis and the accompanying clinical trials may help resolve controversy about the role of metabolic acidosis treatment in CKD care. An essential function of the kidneys is to respond to differences in daily acid load and maintain a relatively constant systemic pH. Under normal physiologic conditions, the human kidneys are typically faced with a load of nonvolatile acids that are generated by diet and daily metabolism.1Scialla J.J. Anderson C.A. Dietary acid load: a novel nutritional target in chronic kidney disease?.Adv Chronic Kidney Dis. 2013; 20: 141-149Google Scholar For instance, metabolism of dietary protein typically results in net acids as sulfur-containing amino acids are oxidized and excreted as sulfate. Other foods may produce acid or base loads based on the relative content of noncombustible anions and cations. The most common modern diets typically generate a daily acid load.2Ströhle A. Hahn A. Sebastian A. Estimation of the diet-dependent net acid load in 229 worldwide historically studied hunter-gatherer societies.Am J Clin Nutr. 2009; 91: 406-412Google Scholar For this reason, the human kidney is well adapted to excrete acid. Ammonium (NH4+) is produced from glutamine and glutamate primarily in the proximal tubule, with additional urine acidification (H+ secretion) occurring in the alpha-intercalated cells of the distal tubule.3Weiner I.D. Verlander J.W. Emerging Features of ammonia metabolism and Transport in acid-base balance.Semin Nephrol. 2019; 39: 394-405Google Scholar,4Hamm L.L. Nakhoul N. Hering-Smith K.S. Acid-base homeostasis.Clin J Am Soc Nephrol. 2015; 10: 2232-2242Google Scholar When either of these processes fail to excrete the daily acid load, metabolic acidosis will occur. Failure of these homeostatic mechanisms is common in CKD.5Moranne O. Froissart M. Rossert J. et al.Timing of Onset of CKD-related metabolic complications.J Am Soc Nephrol. 2009; 20: 164-171Google Scholar, 6Eustace J.A. Astor B. Muntner P.M. Ikizler T.A. Coresh J. Prevalence of acidosis and inflammation and their association with low serum albumin in chronic kidney disease.Kidney Int. 2004; 65: 1031-1040Google Scholar, 7Inker L.A. Coresh J. Levey A.S. Tonelli M. Muntner P. Estimated GFR, albuminuria, and complications of chronic kidney disease.J Am Soc Nephrol. 2011; 22: 2322-2331Google Scholar, 8Inker L.A. Grams M.E. Levey A.S. et al.Relationship of estimated GFR and albuminuria to concurrent laboratory abnormalities: an individual participant data meta-analysis in a Global Consortium.Am J Kidney Dis. 2019; 73: 206-217Google Scholar In the United States, over 26 million Americans have CKD.9Inker L.A. Eneanya N.D. Coresh J. et al.New creatinine- and cystatin C-based equations to estimate GFR without race.N Engl J Med. 2021; 385: 1737-1749Google Scholar Of these, nearly 20%, or close to 5 million Americans, have CKD stages G3b-5.10Levey A.S. Coresh J. Chronic kidney disease.Lancet. 2012; 379: 165-180Google Scholar These advanced stages of CKD are frequently complicated by metabolic acidosis. For instance, data from the CKD Prognosis Consortium, an international collaboration conducting large meta-analyses of established cohorts, estimate that 12-20% of patients with CKD stage G3b and 27-38% of patients with stage G4-5 CKD have metabolic acidosis.8Inker L.A. Grams M.E. Levey A.S. et al.Relationship of estimated GFR and albuminuria to concurrent laboratory abnormalities: an individual participant data meta-analysis in a Global Consortium.Am J Kidney Dis. 2019; 73: 206-217Google Scholar These rates are similar to those reported by other cohorts in the United States and internationally.5Moranne O. Froissart M. Rossert J. et al.Timing of Onset of CKD-related metabolic complications.J Am Soc Nephrol. 2009; 20: 164-171Google Scholar,11Shah S.N. Abramowitz M. Hostetter T.H. Melamed M.L. Serum bicarbonate levels and the progression of kidney disease: a cohort study.Am J Kidney Dis. 2009; 54: 270-277Google Scholar,12Lash J.P. Go A.S. Appel L.J. et al.Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function.Clin J Am Soc Nephrol. 2009; 4: 1302-1311Google Scholar However, these types of cohorts are typically focused on selected populations with qualifying health conditions or that are recruited from health care settings. The National Health and Nutrition Examination Survey is a representative survey of the noninstitutionalized US population. Estimates from National Health and Nutrition Examination Survey are similar, suggesting that approximately 18% of Americans with CKD stage G3b and 32% of Americans with CKD stage G4 or G5 have metabolic acidosis defined as serum bicarbonate <22 mEq/L.7Inker L.A. Coresh J. Levey A.S. Tonelli M. Muntner P. Estimated GFR, albuminuria, and complications of chronic kidney disease.J Am Soc Nephrol. 2011; 22: 2322-2331Google Scholar As patients with CKD progress and approach dialysis initiation, over 50% of patients may experience metabolic acidosis.13Thilly N. Boini S. Kessler M. Briançon S. Frimat L. Chronic kidney disease: appropriateness of therapeutic management and associated factors in the AVENIR study.J Eval Clin Pract. 2009; 15: 121-128Google Scholar Certain conditions can predispose patients to metabolic acidosis earlier in CKD, a phenotype often described as a renal tubular acidosis.14Palmer B.F. Kelepouris E. Clegg D.J. Renal tubular acidosis and management Strategies: a Narrative review.Adv Ther. 2021; 38: 949-968Google Scholar,15Rodríguez Soriano J. Renal tubular acidosis: the clinical Entity.J Am Soc Nephrol. 2002; 13: 2160-2170Google Scholar For instance, patients with interstitial kidney diseases, including patients with connective tissue disorders, such as Sjogren's syndrome, or with sickle cell hemoglobinopathy, often exhibit metabolic acidosis at a higher glomerular filtration rate (GFR).16Saraf S.L. Derebail V.K. Zhang X. et al.Hyperkalemia and metabolic acidosis occur at higher estimated glomerular filtration rates in sickle cell disease.Kidney360. 2022; 3: 608-614https://doi.org/10.34067/KID.0006802021Google Scholar, 17Jain A. Srinivas B.H. Emmanuel D. Jain V.K. Parameshwaran S. Negi V.S. Renal involvement in primary Sjogren’s syndrome: a prospective cohort study.Rheumatol Int. 2018; 38: 2251-2262Google Scholar, 18Maripuri S. Grande J.P. Osborn T.G. et al.Renal involvement in primary Sjögren's syndrome: a Clinicopathologic study.Clin J Am Soc Nephrol. 2009; 4: 1423-1431Google Scholar, 19Cazenave M. Audard V. Bertocchio J.P. et al.Tubular acidification Defect in adults with sickle cell disease.Clin J Am Soc Nephrol. 15: Scholar with typically have a higher of metabolic acidosis for a GFR due to B.F. Kelepouris E. Clegg D.J. Renal tubular acidosis and management Strategies: a Narrative review.Adv Ther. 2021; 38: 949-968Google Scholar These differences in serum bicarbonate in patients with have been in CKD cohorts and large L.A. Grams M.E. Levey A.S. et al.Relationship of estimated GFR and albuminuria to concurrent laboratory abnormalities: an individual participant data meta-analysis in a Global Consortium.Am J Kidney Dis. 2019; 73: 206-217Google M. J. et of serum bicarbonate with of renal and outcomes in a from the Chronic Renal Insufficiency Cohort (CRIC) study.Am J Kidney Dis. 2013; Scholar The potential effects of chronic metabolic acidosis are and on and the among Metabolic acidosis protein effects on the J. mechanisms of muscle in kidney Nephrol. 2004; Scholar studies have that alkali can and muscle as an in muscle and Melamed M.L. Hostetter T.H. of sodium bicarbonate in patients with J Am Soc Nephrol. 2013; Scholar, M. progression of CKD and nutritional Am Soc Nephrol. 2009; 20: Scholar, J. B. S. S. of metabolic acidosis muscle and renal function in chronic kidney stages 3 and 4: a randomized controlled Scholar study of patients with CKD that of such as with alkali Melamed M.L. Hostetter T.H. of sodium bicarbonate in patients with J Am Soc Nephrol. 2013; Scholar However, the on been with studies no alkali therapy and including studies clinical of such as M. et bicarbonate to function in patients over with advanced chronic kidney disease: the M.L. et of sodium bicarbonate in CKD stages 3 and 4: a clinical J Kidney Dis. Scholar mineralization and growth are other important targets of with chronic metabolic acidosis, with the distal renal tubular acidosis resulting in and B.F. Kelepouris E. Clegg D.J. Renal tubular acidosis and management Strategies: a Narrative review.Adv Ther. 2021; 38: 949-968Google Scholar In children, distal renal tubular acidosis and chronic metabolic acidosis more with impaired M. et associations low serum bicarbonate and growth in with chronic kidney disease.Kidney360. 2022; 3: therapy growth in with distal renal tubular Nephrol. 2009; Scholar Metabolic acidosis a in from the to and results in higher serum and of important of on for Am Soc Nephrol. 2011; 22: Scholar studies in serum with alkali metabolic acidosis is or is Melamed M.L. Hostetter T.H. of sodium bicarbonate in patients with J Am Soc Nephrol. 2013; M. progression of CKD and nutritional Am Soc Nephrol. 2009; 20: M.L. et of sodium bicarbonate in CKD stages 3 and 4: a clinical J Kidney Dis. et randomized the and of of sodium bicarbonate in the Am Soc Nephrol. Scholar These may for patients with more of on for Am Soc Nephrol. 2011; 22: Scholar of clinical trials alkali have that these such as or and of bone disease, are the data are S. of chronic metabolic acidosis for chronic kidney Scholar Metabolic acidosis may the kidney and CKD progression. such as of that acid have been of metabolic kidney in chronic kidney disease.J Am Soc Nephrol. Scholar For instance, generation and in the renal been to and Hostetter Hostetter T.H. of chronic in of dietary acid load, and Clin Scholar and in metabolic acidosis to urine acidification in the distal may J. S. GFR in and levels of and J Renal 2011; Scholar on function have been based on of alkali on J. P. E. et of treatment of metabolic acidosis on function in patients with 2018; 13: Scholar these to clinical outcomes is well large of data associations metabolic acidosis and CKD S.N. Abramowitz M. Hostetter T.H. Melamed M.L. 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J. et of serum bicarbonate with of renal and outcomes in a from the Chronic Renal Insufficiency Cohort (CRIC) study.Am J Kidney Dis. 2013; J. et serum bicarbonate and CKD progression in J Am Soc Nephrol. 15: S. serum bicarbonate levels the normal are associated with and renal outcomes in Int. 2011; Scholar However, are a of in the of metabolic acidosis data in The is that most of these studies upon the serum bicarbonate that can by acid-base and often in CKD including and is the of serum bicarbonate with kidney and the potential for In acidosis may a of kidney tubular function that progression from The of in kidney disease: a J Kidney Dis. 2021; Scholar of clinical data are to or some of the and data described of the randomized controlled trials a study published in M. progression of CKD and nutritional Am Soc Nephrol. 2009; 20: Scholar The a higher an of GFR, at for patients with advanced CKD and metabolic acidosis baseline serum bicarbonate for those with sodium bicarbonate to a target serum bicarbonate of patients in the treatment dialysis over the in this study have a serum bicarbonate at a therapy Melamed M.L. 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