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Metabolic Acidosis—Is It the Elephant in the Room?

      The study of acid-base equilibrium and its relationship to diet and disease has been a subject of considerable speculation for at least several centuries. Prior to the 19th century, little was known about the concepts of acids and bases, and no means were available to quantify the acid or alkaline load of foods or the pH of physiological processes. As early as 1869, Beale recognized that reduction in meat or protein intake would benefit the patient when he wrote, “A large proportion of excess of meat taken passes off from the body in the form of urea and other urinary constituents, which it is the special work of the kidney to remove from the blood. It is obviously of the utmost importance to relieve the kidneys of at least this unnecessary and useless work in cases in which they are diseased when their working power is seriously impaired”.
      • Beale L.S.
      Kidney diseases, urinary deposits, and calculous disorders; their nature and treatment.
      Sherman in 1912 published data on the effects of an isocaloric exchange of single foods with a different estimated acid intake on urinary excretion of ammonium and titratable acidity in an adult man on a constant basal diet.
      • Sherman H.C.
      • Gettler A.O.
      The balance of acid-forming and base-forming elements in food and its relation to ammonia metabolism.
      However, it was not until the 1960s that input-output acid-base balance studies were performed for the first time in healthy adults and patients with chronic metabolic acidosis due to reduced kidney function.
      • Lennon E.J.
      • Lemann Jr., J.
      • Litzow J.R.
      The effects of diet and stool composition on the net external acid balance of normal subjects.
      ,
      • Goodman A.D.
      • Lemann Jr., J.
      • Lennon E.J.
      • et al.
      Production, excretion, and net balance of fixed acid in patients with renal acidosis.
      These data suggest that in addition to some disease processes that make for a potentially harmful acid body milieu, chronic acid challenges from common diets might also render an acid body milieu whose consequences are still being explored.
      The kidney plays a key role in the regulation of the acid-base balance of an organism.
      • Dhondup T.
      • Qian Q.
      Electrolyte and acid-base disorders in chronic kidney disease and end-stage kidney failure.
      The degree of “fixed” or “nonvolatile” acid load (as opposed to “volatile” acid due to accumulation of carbon dioxide gas) may impair the normal function of the kidney, acutely or chronically, and may promote the decline of kidney function as assessed by estimated glomerular filtration rate.
      • Scialla J.J.
      • Appel L.J.
      • Astor B.C.
      • et al.
      Net endogenous acid production is associated with a faster decline in GFR in African Americans.
      Usual dietary habits of many developed societies contribute an increased proportion of acid equivalents due to the high intake of protein from animal sources. Major determinants of net endogenous acid production are the generation of large amounts of hydrogen ions, mostly by animal-derived protein, which is counterbalanced by the metabolism of base-producing foods like fruits and vegetables.
      In this themed publication of Advances in Chronic Kidney Disease, doyens in the field provide focused reviews on several timely and pertinent topics in the evolving area of metabolic acidosis. In the opening chapter of the issue, Drs Vincent-Johnson and Scialla elucidate the clinical burden, consequences and impact of metabolic acidosis associated with CKD, the evolution of clinical practice guidelines for therapy and highlight the practical challenges and need for additional evidence by illustrative case presentations. Drs Nagami and Kraut in their narrative summarize the regulation of acid-base balance by the kidney in both health and disease diving into the physiological mechanisms as well as measures to evaluate acid-base balance in CKD.
      There is still a great deal of debate on how to define acids and bases. In the 1980s, Peter Stewart challenged traditional thought and mathematically determined that hydrogen ion and bicarbonate concentrations were dependent variables. Dr Madias and colleagues succinctly outline in their treatise the advantages and disadvantages of the physicochemical and Stewart's approaches for assessing acid-base status and diagnosing acid-base disorders utilizing a clinical case for easier understanding.
      Dr Emmett provides a comprehensive review of the diverse etiology and mechanisms for the development of metabolic acidosis with or without anion gap that include increased consumption or generation of organic acids, as well as either insufficient production of bicarbonate or renal and/or gastrointestinal loss of bicarbonate.
      Dr Wesson elaborates on the spectrum of disorders of hydrogen ion accumulation ranging from high net dietary H+ ion production to eubicarbonatemic acidosis to overt metabolic acidosis and speculates on their identification and potential future treatment strategies. Drs Banerjee and Frasetto outline the clinical impact of high dietary acid loads and dietary sources of acids and bases and review the dietary guidelines in the various stages of CKD in adults and children.
      From a clinical standpoint, an important question is whether the pathophysiologic effects of chronic low-grade metabolic acidosis on bone, muscle, or kidney can be mitigated or abolished by reversing the acidosis, thus offering the potential for prevention-based interventions. Dr Moe and colleagues provide an in-depth overview of the effects of acid loads on bone health in preclinical and clinical studies and provide key insights into results of interventional studies utilizing acid neutralization strategies on bone mineral density and bone turnover markers.
      Dr Abramowitz and colleagues in their monograph discuss the specific mechanisms of the various pathways by which metabolic acidosis affects skeletal muscle, the negative impact on physical function, and whether treatment improves functional outcomes.
      Dr Raphael and colleagues expound on the injurious effects of metabolic acidosis on the kidney via adaptive physiologic responses and summarize the results of interventional trials of dietary and pharmacologic alkali administration to slow chronic kidney disease progression.
      In the final chapter, Dr Goraya and colleagues systematically review the therapeutic options providing recommendations for when and how to treat metabolic acidosis and target bicarbonate concentration as well as highlighting the results of clinical trials utilizing dietary fruits and vegetables, sodium-based alkali therapy, and the investigational agent veverimer.
      Observational studies have identified associations between metabolic acidosis and mortality in individuals with and without CKD.
      • Navaneethan S.D.
      • Schold J.D.
      • Arrigain S.
      Serum bicarbonate and mortality in stage 3 and stage 4 chronic kidney disease.
      ,
      • Raphael K.L.
      • Zhang Y.
      • Wei G.
      • et al.
      Serum bicarbonate and mortality in adults in NHANES III.
      In the Systolic Blood Pressure Reduction Intervention Trial, a serum bicarbonate level <22 mEq/L was associated with 54% higher risk for the primary outcome (composite of nonfatal myocardial infarction, acute coronary syndrome not resulting in myocardial infarction, stroke, acute decompensated heart failure, and cardiovascular disease death) as than bicarbonate levels of 22 to 26 mEq/L.
      • Dobre M.
      • Pajewski N.M.
      • Beddhu S.
      Serum bicarbonate and cardiovascular events in hypertensive adults: results from the Systolic Blood Pressure Intervention Trial.
      Correction of metabolic acidosis has been shown to improve vascular function.
      • Kendrick J.
      • Shah P.
      • Andrews E.
      • et al.
      Effect of treatment of metabolic acidosis on vascular endothelial function in patients with CKD.
      A recent study showed waist circumference and metabolic syndrome were associated with a greater risk of anion gap metabolic acidosis.
      • Lambert D.
      • Kane J.
      • Slaton A.
      • Abramowitz M.
      Associations of metabolic syndrome and abdominal obesity with anion gap metabolic acidosis among U.S. Adults.
      Future investigations clarifying the relationship between metabolic acidosis and the likelihood of adverse cardiovascular events will be informative and important to define as many more patients die of cardiovascular disease than progress to end-stage kidney disease.
      The landscape of kidney nutrition is evolving. Metabolic dysfunction may predispose patients without CKD to systemic acidosis from endogenous sources. In a large multicenter metabolomics study of individuals without kidney disease, a higher dietary acid load measured by potential renal acid load or net endogenous acid production was significantly associated with lower serum levels of 11 out of 12 candidate blood biomarkers.
      • Tariq A.
      • Chen J.
      • Yu B.
      • et al.
      Metabolomics of dietary acid load and Incident chronic kidney disease.
      The available research makes a compelling case that diet-induced acidosis is a real phenomenon, has significant clinical relevance, may largely be prevented through dietary changes, and should be recognized and treated for better patient outcomes. With mounting evidence that metabolic acidosis is associated with substantial adverse effects on human health and the positive findings from interventional trials, we hope that this compendium of reviews will provide the clinician adequate information to tackle this multifaceted disorder for the benefit of our patients.

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