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

  • Anita Vincent-Johnson
    Affiliations
    Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA
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  • Julia J. Scialla
    Correspondence
    Address correspondence to Julia J. Scialla, MD, MHS, Division of Nephrology, PO Box 800133, Charlottesville, VA 22908.
    Affiliations
    Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA

    Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, VA
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      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.

      Keywords

      • 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.
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      • Anderson C.A.
      Dietary acid load: a novel nutritional target in chronic kidney disease?.
      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.
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      • Hahn A.
      • Sebastian A.
      Estimation of the diet-dependent net acid load in 229 worldwide historically studied hunter-gatherer societies.
      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.
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      Emerging Features of ammonia metabolism and Transport in acid-base balance.
      ,
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      • Nakhoul N.
      • Hering-Smith K.S.
      Acid-base homeostasis.
      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.
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      Timing of Onset of CKD-related metabolic complications.
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      Prevalence of acidosis and inflammation and their association with low serum albumin in chronic kidney disease.
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      Estimated GFR, albuminuria, and complications of chronic kidney disease.
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      Relationship of estimated GFR and albuminuria to concurrent laboratory abnormalities: an individual participant data meta-analysis in a Global Consortium.

      Prevalence and Impact of Metabolic Acidosis in CKD

      In the United States, over 26 million Americans have CKD.
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      New creatinine- and cystatin C-based equations to estimate GFR without race.
      Of these, nearly 20%, or close to 5 million Americans, have CKD stages G3b-5.
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      Chronic kidney disease.
      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.
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      • et al.
      Relationship of estimated GFR and albuminuria to concurrent laboratory abnormalities: an individual participant data meta-analysis in a Global Consortium.
      These rates are similar to those reported by other cohorts in the United States and internationally.
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      • Froissart M.
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      • et al.
      Timing of Onset of CKD-related metabolic complications.
      ,
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      Serum bicarbonate levels and the progression of kidney disease: a cohort study.
      ,
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      • Appel L.J.
      • et al.
      Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function.
      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.
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      Estimated GFR, albuminuria, and complications of chronic kidney disease.
      As patients with CKD progress and approach dialysis initiation, over 50% of patients may experience metabolic acidosis.
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      Chronic kidney disease: appropriateness of therapeutic management and associated factors in the AVENIR study.
      Certain conditions can predispose patients to metabolic acidosis earlier in CKD, a phenotype often described as a renal tubular acidosis.
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      • Clegg D.J.
      Renal tubular acidosis and management Strategies: a Narrative review.
      ,
      • Rodríguez Soriano J.
      Renal tubular acidosis: the clinical Entity.
      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).
      • Saraf S.L.
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      • Zhang X.
      • et al.
      Hyperkalemia and metabolic acidosis occur at higher estimated glomerular filtration rates in sickle cell disease.
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      • Emmanuel D.
      • Jain V.K.
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      • Negi V.S.
      Renal involvement in primary Sjogren’s syndrome: a prospective cohort study.
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      Renal involvement in primary Sjögren's syndrome: a Clinicopathologic study.
      • Cazenave M.
      • Audard V.
      • Bertocchio J.P.
      • et al.
      Tubular acidification Defect in adults with sickle cell disease.
      Patients with diabetic nephropathy also typically have a higher risk of metabolic acidosis for a given GFR due to hyporeninemic hypoaldosteronism.
      • Palmer B.F.
      • Kelepouris E.
      • Clegg D.J.
      Renal tubular acidosis and management Strategies: a Narrative review.
      These differences in serum bicarbonate level in patients with diabetes have been widely observed in CKD cohorts and large meta-analyses.
      • Inker 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.
      ,
      • Dobre M.
      • Yang W.
      • Chen J.
      • et al.
      Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) study.

      Potential Consequences of Metabolic Acidosis in CKD

      The potential effects of chronic metabolic acidosis are numerous and include impacts on muscle, bone, and the kidney, among others. Metabolic acidosis directly induces protein catabolism via effects on the ubiquitin-proteolysis pathway.
      • Mitch W.E.
      • Du J.
      Cellular mechanisms causing loss of muscle mass in kidney disease.
      Some small studies have shown that alkali supplements can improve nitrogen balance and muscle volume, measured as an increase in midarm muscle circumference and lean body weight.
      • Abramowitz M.K.
      • Melamed M.L.
      • Bauer C.
      • Raff A.C.
      • Hostetter T.H.
      Effects of oral sodium bicarbonate in patients with CKD.
      • de Brito-Ashurst I.
      • Varagunam M.
      • Raftery M.J.
      • Yaqoob M.M.
      Bicarbonate supplementation slows progression of CKD and improves nutritional status.
      • Dubey A.K.
      • Sahoo J.
      • Vairappan B.
      • Haridasan S.
      • Parameswaran S.
      • Priyamvada P.S.
      Correction of metabolic acidosis improves muscle mass and renal function in chronic kidney disease stages 3 and 4: a randomized controlled trial.
      A study of 20 patients with CKD found that measures of physical functioning, such as sit-to-stand time, improved with alkali supplements.
      • Abramowitz M.K.
      • Melamed M.L.
      • Bauer C.
      • Raff A.C.
      • Hostetter T.H.
      Effects of oral sodium bicarbonate in patients with CKD.
      However, the impact on physical functioning has been less consistent with several larger studies showing no significant difference between alkali therapy and placebo including studies using clinical assessments of functioning, such as patient-reported outcomes.
      • Witham M.D.
      • Band M.
      • Chong H.
      • et al.
      Sodium bicarbonate to improve physical function in patients over 60 years with advanced chronic kidney disease: the BiCARB RCT.
      ,
      • 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.
      Bone mineralization and growth are other important targets of therapy. Patients with chronic metabolic acidosis, particularly with the distal renal tubular acidosis phenotype, demonstrate marked calciuria resulting in nephrolithiasis and nephrocalcinosis.
      • Palmer B.F.
      • Kelepouris E.
      • Clegg D.J.
      Renal tubular acidosis and management Strategies: a Narrative review.
      In children, distal renal tubular acidosis and chronic metabolic acidosis more generally associate with impaired linear growth.
      • Brown D.D.
      • Carroll M.
      • Ng D.K.
      • et al.
      Longitudinal associations between low serum bicarbonate and linear growth in children with chronic kidney disease.
      ,
      • Sharma A.P.
      • Singh R.N.
      • Yang C.
      • Sharma R.K.
      • Kapoor R.
      • Filler G.
      Bicarbonate therapy improves growth in children with incomplete distal renal tubular acidosis.
      Metabolic acidosis promotes a shift in potassium from the intracellular to extracellular space and results in higher serum potassium and increased risk of clinically important hyperkalemia.
      • Aronson P.S.
      • Giebisch G.
      Effects of pH on potassium: new explanations for old observations.
      Several small studies demonstrate small, but statistically significant, reduction in serum potassium with alkali supplements, even when metabolic acidosis is not present or is only mild.
      • Abramowitz M.K.
      • Melamed M.L.
      • Bauer C.
      • Raff A.C.
      • Hostetter T.H.
      Effects of oral sodium bicarbonate in patients with CKD.
      ,
      • de Brito-Ashurst I.
      • Varagunam M.
      • Raftery M.J.
      • Yaqoob M.M.
      Bicarbonate supplementation slows progression of CKD and improves nutritional status.
      ,
      • 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.
      ,
      • 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.
      These impacts may be larger for patients with more significant acidosis.
      • Aronson P.S.
      • Giebisch G.
      Effects of pH on potassium: new explanations for old observations.
      Meta-analyses of clinical trials studying alkali interventions have concluded that these benefits, such as improving potassium balance, body composition or nitrogen balance, and measures of bone disease, are possible, but the overall data are limited.
      • Roderick P.J.
      • Willis N.S.
      • Blakeley S.
      • Jones C.
      • Tomson C.
      Correction of chronic metabolic acidosis for chronic kidney disease patients.
      Metabolic acidosis may also impact the kidney and cardiovascular system, potentially promoting CKD progression. Direct mechanisms, such as excessive activation of pathways that promote acid excretion, have been proposed.
      • Wesson D.E.
      • Buysse J.M.
      • Bushinsky D.A.
      Mechanisms of metabolic acidosis–induced kidney injury in chronic kidney disease.
      For instance, excess ammonium generation and concentration in the renal medullary interstitium has been hypothesized to activate complement and cellular injury.
      • Nath K.A.
      • Hostetter M.K.
      • Hostetter T.H.
      Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3.
      Aldosterone and endothelin, which rise in metabolic acidosis to increase urine acidification in the distal nephron, may promote profibrotic pathways.
      • Wesson D.E.
      • Simoni J.
      • Broglio K.
      • Sheather S.
      Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone.
      Effects on endothelial function have been proposed based on experimental impacts of alkali on flow-mediated dilation.
      • Kendrick J.
      • Shah P.
      • Andrews E.
      • et al.
      Effect of treatment of metabolic acidosis on vascular endothelial function in patients with CKD.
      How these biological changes translate to clinical outcomes is less well understood. A large body of observational data generally support associations between metabolic acidosis and CKD progression.
      • Shah S.N.
      • Abramowitz M.
      • Hostetter T.H.
      • Melamed M.L.
      Serum bicarbonate levels and the progression of kidney disease: a cohort study.
      ,
      • Dobre M.
      • Yang W.
      • Chen J.
      • et al.
      Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) study.
      ,
      • Brown D.D.
      • Roem J.
      • Ng D.K.
      • et al.
      Low serum bicarbonate and CKD progression in children.
      ,
      • 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.
      However, there are a number of major challenges in studying the consequences of metabolic acidosis using observational data in CKD. The first is that most of these studies rely exclusively upon the serum bicarbonate concentration that can also be affected by respiratory acid-base disorders and medications often used in CKD including renin-angiotensin-aldosterone inhibitors and diuretics. A second challenge is the tight coupling of serum bicarbonate with kidney function, and thus the potential for residual confounding. In fact, acidosis itself may be a marker of kidney tubular function that predicts progression independently from GFR.
      • Ix J.H.
      • Shlipak M.G.
      The Promise of tubule Biomarkers in kidney disease: a review.
      Modest amounts of clinical trial data are now available to support or refute some of the experimental and observational data described above. One of the first randomized controlled trials was a small (n = 134) open-label study published in 2009.
      • de Brito-Ashurst I.
      • Varagunam M.
      • Raftery M.J.
      • Yaqoob M.M.
      Bicarbonate supplementation slows progression of CKD and improves nutritional status.
      The authors demonstrated a higher creatinine clearance, an indirect measure of GFR, at 24 months for patients with advanced CKD and metabolic acidosis (mean baseline serum bicarbonate ∼20 mEq/L) than for those treated with sodium bicarbonate to a target serum bicarbonate of 23 mEq/L vs nontreated patients. Fewer patients in the treatment arm required dialysis over follow-up. Unlike later studies, the control group in this study did not have a prespecified serum bicarbonate level at which a “rescue” therapy was advised,
      • Abramowitz M.K.
      • Melamed M.L.
      • Bauer C.
      • Raff A.C.
      • Hostetter T.H.
      Effects of oral sodium bicarbonate in patients with CKD.
      ,
      • 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.
      and thus, clinically meaningful acidosis may have influenced initiation of dialysis. Another trial in which patients had metabolic acidosis at baseline (mean serum bicarbonate approximately 18 mEq/L) showed some improvement in estimated GFR after 6 months of treatment with sodium bicarbonate.
      • Dubey A.K.
      • Sahoo J.
      • Vairappan B.
      • Haridasan S.
      • Parameswaran S.
      • Priyamvada P.S.
      Correction of metabolic acidosis improves muscle mass and renal function in chronic kidney disease stages 3 and 4: a randomized controlled trial.
      These results must be interpreted cautiously because the study was of short duration and could reflect sodium/volume loading, the study was not designed for this outcome, and GFR was estimated from serum creatinine which could be biased by the impact of acidosis on muscle. Additional trials have demonstrated potential benefits of treating metabolic acidosis on CKD progression or dialysis initiation but have been limited by small, single-center and open-label designs, limited reporting of outcome ascertainment, poor reporting of randomized sequence generation or lack of randomization, and lack of sodium or volume expansion control.
      • 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.
      ,
      • 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.
      Dietary interventions that reduce dietary acid load through augmented intake of fruits and vegetables may also improve metabolic acidosis. However, results of these interventions are challenging to interpret purely as treatments of metabolic acidosis because these complex interventions deliver many phytonutrients and alter a broad matrix of nutrients and foods.
      Interpreting delays in dialysis initiation with alkali therapy is challenging because acidosis itself is often an indication for initiation. For instance, in the Sodium Bicarbonate Therapy for Patients with Severe Metabolic Acidaemia in the Intensive Care Unit (BICAR-ICU) study of approximately 400 patients with critical illness and acute metabolic acidosis, initiation of sodium bicarbonate compared to control did not reduce mortality but did strongly prevent or delay the need for a renal replacement therapy.
      • Jaber S.
      • Paugam C.
      • Futier E.
      • et al.
      Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial.
      This impact on renal replacement therapy was not likely related to altering the natural history of disease but to removing an acute indication for dialysis, namely severe acidosis. In the chronic setting, the use of alkali may also improve systemic pH and serum potassium, contributing to a delay in dialysis initiation that is due to its role as a supportive, but not disease-modifying, treatment. This is an important distinction and will require trials to be conducted in the setting of more mild metabolic acidosis in moderate stages of CKD for the purpose of slowing disease progression.
      Meta-analyses including these studies and others have largely concluded that there may be a modest benefit of alkali interventions on kidney function decline but recognize substantial limitations in the meta-analyzed studies.
      • Taylor K.S.
      • Mclellan J.
      • Verbakel J.Y.
      • et al.
      Effects of antihypertensives, lipid-modifying drugs, glycaemic control drugs and sodium bicarbonate on the progression of stages 3 and 4 chronic kidney disease in adults: a systematic review and meta-analysis.
      • Hu M.K.
      • Witham M.D.
      • Soiza R.L.
      Oral bicarbonate therapy in non-haemodialysis dependent chronic kidney disease patients: a systematic review and meta-analysis of randomised controlled trials.
      • Navaneethan S.D.
      • Shao J.
      • Buysse J.
      • Bushinsky D.A.
      Effects of treatment of metabolic acidosis in CKD: a systematic review and meta-analysis.
      • Hultin S.
      • Hood C.
      • Campbell K.L.
      • Toussaint N.D.
      • Johnson D.W.
      • Badve S.V.
      A systematic review and meta-analysis on effects of bicarbonate therapy on kidney outcomes.
      Limitations of some of the key studies include small size, single-center experience, lack of blinding, extensive dropout, evaluation of low-risk populations, and short follow-up intervals. With a dearth of large, high-quality studies, the evidence base is inadequate to clearly recommend treatment of metabolic acidosis to slow CKD progression at this time.
      • Navaneethan S.D.
      • Shao J.
      • Buysse J.
      • Bushinsky D.A.
      Effects of treatment of metabolic acidosis in CKD: a systematic review and meta-analysis.
      ,
      • Hultin S.
      • Hood C.
      • Campbell K.L.
      • Toussaint N.D.
      • Johnson D.W.
      • Badve S.V.
      A systematic review and meta-analysis on effects of bicarbonate therapy on kidney outcomes.

      Clinical Practice Guidelines on Treatment of Metabolic Acidosis in CKD

      US CKD clinical practice guidelines have advocated treating metabolic acidosis in CKD since their inception. The first clinical practice guidelines in the United States focused primarily on patients with kidney failure treated with dialysis. These guidelines recommended maintaining serum bicarbonate concentration at or above 22 mEq/L in order to prevent protein catabolism and bone demineralization.
      National Kidney Foundation
      Clinical practice guidelines for nutrition in chronic renal failure.
      No specific guidelines were provided for patients with CKD not requiring dialysis. In 2002-2003, the Kidney Disease Outcomes Quality Initiative (KDOQI) published guidelines for earlier stages of kidney disease.
      National Kidney Foundation
      K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.
      ,
      National Kidney Foundation
      K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.
      Guidelines for Bone Metabolism and Disease also suggested maintaining serum bicarbonate levels at or above 22 mEq/L (Table 1).
      National Kidney Foundation
      K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease.
      The rationale in these guidelines was based upon impacts on bone demineralization and induction of secondary hyperparathyroidism. Guidelines for children with CKD in 2005 and 2008 emphasized similar targets with the additional concern related to linear growth.
      K/DOQI clinical practice guidelines for bone metabolism and disease in children with chronic kidney disease: Work group Membership.
      ,
      KDOQI Work Group
      KDOQI clinical practice guideline for nutrition in children with CKD: 2008 update. Executive summary.
      Subsequent guideline updates on bone diseases did not specifically comment on metabolic acidosis as a summary recommendation.
      KDOQI Work Group
      KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).
      ,
      Kidney Disease: Improving Global Outcomes CKD-MBD Working Group
      KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD).
      The next major update to US clinical practice guidelines commenting on metabolic acidosis came in 2012 with the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines for the evaluation and management of CKD.
      KDIGO CKD Working Group
      KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.
      KDIGO guidelines again suggested maintaining serum bicarbonate at or above 22 mEq/L but now stressed prevention of CKD progression and mortality, with the evidence rated as 2C (ie, suggestion based on low-quality evidence). The 2012 KDOQI commentary on the guideline generally agreed but supported focusing first on higher priority treatment targets such as hypertension and diabetes management.
      • Inker L.A.
      • Astor B.C.
      • Fox C.H.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
      The most recent major national guideline to comment on treatment of metabolic acidosis in CKD is the new joint guideline of the KDOQI and the Academy of Nutrition and Dietetics on nutrition in CKD. This joint group rated the evidence differently, providing a stronger recommendation. The KDOQI group recommends treatment with alkali supplementation to slow CKD progression without reference to whether metabolic acidosis is present, rating this as based on low-quality evidence (1C). They also suggest higher target serum bicarbonate levels of 24-26 mEq/L based on observational data and opinion (Table 1).
      • Ikizler T.A.
      • Burrowes J.D.
      • Byham-Gray L.D.
      • et al.
      KDOQI clinical practice guideline for nutrition in CKD: 2020 update.
      Table 1Evolution of US Clinical Practice Guidelines Related to Metabolic Acidosis in CKD
      Clinical Practice GuidelineRecommendationsPredominant RationaleRating of Evidence
      KDOQI 2003 Guideline for Bone Metabolism and Disease in CKD
      • (1)
        “Serum levels of total CO2 [serum bicarbonate] should be maintained at >22 mEq/L.”
      • (2)
        “If necessary, supplemental alkali salts should be given to achieve this goal.”
      Reduce bone demineralization

      Prevent/treat secondary hyperparathyroidism
      • (1)
        EVIDENCE
      • (2)
        OPINION
      KDOQI 2005 Guideline for Bone Metabolism and Disease in Children with CKD
      • (1)
        “In patients >2 years of age, serum levels of total CO2 [serum bicarbonate] should be maintained at >22 mEq/L; in neonates and young infants below age 2, serum levels of total CO2 should be maintained at ≥20 mEq/L.”
      • (2)
        “If necessary, supplemental alkali salts should be given to achieve this goal.”
      Reduce bone demineralization

      Prevent/treat secondary hyperparathyroidism

      Preserve linear growth
      • (1)
        EVIDENCE
      • (2)
        OPINION
      KDOQI 2008 Guidelines for Nutrition in Children with CKD“Serum bicarbonate level should be corrected to at least the lower limit of normal (22 mmol/L) in children with CKD stages 2 to 5 and 5D.”Preserve linear growthB (moderate)
      KDIGO 2012 Guidelines for Evaluation and Management of CKD“We suggest that in people with CKD and serum bicarbonate concentrations less than 22 mmol/L treatment with oral bicarbonate supplementation be given to maintain serum bicarbonate within the normal range, unless contraindicated. (2B)”
      • Lash J.P.
      • Go A.S.
      • Appel L.J.
      • et al.
      Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function.
      Prevent CKD progression

      Preserve nutritional status
      2C (Weak suggestion; low-quality evidence)
      KDOQI Guidelines on Nutrition in CKD: Update 2020
      • (1)
        “In adults with CKD 3-5D, we recommend reducing net acid production (NEAP) through increased bicarbonate or a citric acid/sodium citrate solution supplementation (1C) in order to reduce the rate of decline of residual kidney function.”
      • (2)
        “In adults with CKD 3-5D, it is reasonable to maintain serum bicarbonate levels at 24-26 mmol/L (OPINION).”
      Prevent GFR decline

      Improve nutritional status/prevent protein catabolism
      • (1)
        1C (Strong recommendation; low-quality evidence)
      • (2)
        OPINION
      Abbreviations: GFR, glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; KDOQI, Kidney Disease Outcome Quality Initiative.
      Note: Total CO2 approximates serum bicarbonate. For these measurements, 1 mmol/L = 1 mEq/L. CKD stages refer to G stages, with 5D reflecting stage 5 treated with dialysis and 5 reflecting stage 5 not treated with dialysis.
      A careful review of the evolution of these guidelines demonstrates a shifting focus from primarily bone and mineral metabolism and nutritional concerns to CKD progression. Caution is advised based on the generally low-quality evidence base. Most of these treatments have not been tested broadly in multicenter studies for the total balance of risks and benefits in patients with CKD. We highlight some practical challenges and need for additional evidence in the remainder of this perspective.

      Real-world Gaps in Evidence and Future Research Needs

      Case 1

      Tabled 1
      2 wk Prior to AdmissionDay of Admission2 wk After Discharge
      Blood urea nitrogen (mg/dL)516753
      Serum creatinine (mg/dL)2.16.32.5
      Serum bicarbonate (mEq/L)231518
      Anion gap (mEq/L)91210
      eGFR (mL/min/1.73 m2)34927
      Abbreviation: eGFR, estimated glomerular filtration rate.
      There are several factors to consider in the decision about treatment with alkali supplementation for presumed metabolic acidosis. Current guidelines largely assume low serum bicarbonate is synonymous with metabolic acidosis in the setting of CKD. In patients with an acute illness, confirmation of metabolic acidosis typically requires an arterial blood gas although this may not always be performed. Here, both gastrointestinal and renal components may also contribute to a complex acid-base disorder, scenarios not typically encountered in small trials conducted to date.
      • Navaneethan S.D.
      • Shao J.
      • Buysse J.
      • Bushinsky D.A.
      Effects of treatment of metabolic acidosis in CKD: a systematic review and meta-analysis.
      A second dilemma concerns when a provider should consider alkali therapy after and during recovery from acute kidney injury. Treatment of metabolic acidosis during acute kidney injury is currently controversial and the subject of recent,
      • Jaber S.
      • Paugam C.
      • Futier E.
      • et al.
      Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicentre, open-label, randomised controlled, phase 3 trial.
      as well as ongoing, multicenter trials, such as the Multicentre Evaluation of Sodium Bicarbonate in Acute Kidney Injury in Critical Care (https://www.isrctn.com/ISRCTN14027629).

      Case 2

      Tabled 1
      2 years ago1 year agoCurrent
      Blood urea nitrogen (mg/dL)312428
      Serum creatinine (mg/dL)2.01.81.9
      Serum bicarbonate (mEq/L)212121
      Anion gap (mEq/L)101013
      eGFR (mL/min/1.73 m2)445047
      Abbreviation: eGFR, estimated glomerular filtration rate.
      At face value, this appears to be a straightforward example. Blood pressure is well controlled, meeting current targets. Serum bicarbonate has been modestly below guideline-suggested targets on several repeated assessments. At his young age, the opportunity to slow CKD progression will be particularly important to lower his lifetime risk of kidney failure. During real-life decision-making, considerations may include the obligate sodium load of current alkali supplements and their potential to impact blood pressure control. Although many trials have not demonstrated clear evidence of worsened blood pressure with alkali supplementation, some studies have raised caution. The Bicarbonate Administration to Stabilize Estimated Glomerular Filtration Rate (BASE) trial evaluated sodium bicarbonate supplementation at a dose of 0.5-0.8 mEq/kg/d in individuals with CKD stage G3 and G4. Over 28 weeks, they noted a small, but statistically significant, increase in albuminuria measured as urine albumin-to-creatinine ratio in the sodium bicarbonate compared to the placebo group.
      • 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.
      This finding may raise a concern about volume expansion, subtle but important increases in blood pressure, and changes in glomerular permeability induced by the use of alkali supplements. Additionally, alkali supplements are often dosed 2-3 times daily, increasing pill burden that may be unacceptable for some patients with CKD. Gastrointestinal side effects may also be limiting for some patients when clear clinical benefits have not been demonstrated in multicenter, randomized controlled trials.
      • Hu M.K.
      • Witham M.D.
      • Soiza R.L.
      Oral bicarbonate therapy in non-haemodialysis dependent chronic kidney disease patients: a systematic review and meta-analysis of randomised controlled trials.

      Case 3

      Tabled 1
      2 years ago1 year agoCurrent
      Blood urea nitrogen (mg/dL)292227
      Serum creatinine (mg/dL)1.21.21.3
      Serum bicarbonate (mEq/L)252121
      Anion gap (mEq/L)9812
      eGFR (mL/min/1.73 m2)454541
      Abbreviation: eGFR, estimated glomerular filtration rate.
      In this patient, we may consider her history of heart failure and edema requiring chronic diuretic use in developing the treatment plan. Most controlled trials of sodium bicarbonate therapy for metabolic acidosis have excluded patients with uncontrolled hypertension or decompensated heart failure. These restrictions make it challenging to know if treatment of metabolic acidosis with sodium-containing supplements is safe in all patients with CKD. Most reported studies have not noted substantial safety signals in terms of clinically meaningful increases in blood pressure or body weight; however, they were typically not designed to rigorously evaluate these signals.
      BiCARB Clinical 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.
      However, meta-analyses suggest the potential for worsening hypertension and edema with these therapies based on the need to escalate antihypertensive and diuretic therapy.
      • Navaneethan S.D.
      • Shao J.
      • Buysse J.
      • Bushinsky D.A.
      Effects of treatment of metabolic acidosis in CKD: a systematic review and meta-analysis.
      In addition, the overall risk of developing kidney failure in her lifetime is predicted to be low based on the Kidney Failure Risk Equation, with a 0.5% and 1.6% chance of requiring dialysis in 2 years and 5 years, respectively.
      • Tangri N.
      • Stevens L.A.
      • Griffith J.
      • et al.
      A predictive Model for progression of chronic kidney disease to kidney failure.
      Recent studies of physical functioning in older adults with metabolic acidosis have not demonstrated clear benefits of alkali supplementation.
      • Witham M.D.
      • Band M.
      • Chong H.
      • et al.
      Sodium bicarbonate to improve physical function in patients over 60 years with advanced chronic kidney disease.
      Thus, based on current knowledge and therapies, the relative benefits in terms of physical functioning or prevention of worsening CKD may not be large enough to offset the potential risks of adverse effects. If potassium is well controlled and implementation is feasible, reducing acid load through the diet may be a reasonable alternative strategy.
      In summary, decisions about treating metabolic acidosis in patients with CKD in the real world can be complex. Without adequate randomized controlled trials defining the full spectrum of clinical benefits, adverse effects, and potential harms, treatment decisions are still largely individualized.

      Equipoise and Uncertainty in Treatment of Metabolic Acidosis in CKD

      Despite guidelines that largely suggest alkali therapy for the treatment of metabolic acidosis in CKD, there is substantial variation in practice. In the NephroTest Cohort conducted between 2000 and 2006 in France, 22% of patients with chronic metabolic acidosis were treated with alkali supplements. The rates were similarly low within the US cohort, the Chronic Renal Insufficiency Cohort. Recruited between 2003 and 2008, only 2.4% of participants in Chronic Renal Insufficiency Cohort were using alkali supplements at baseline although the mean baseline serum bicarbonate was 24 mEq/L with only 5% having levels <19 mEq/L.
      • Dobre M.
      • Yang W.
      • Chen J.
      • et al.
      Association of serum bicarbonate with risk of renal and cardiovascular outcomes in CKD: a report from the Chronic Renal Insufficiency Cohort (CRIC) study.
      Cohort studies in children in the United States demonstrate that only about one-third of patients with metabolic acidosis are currently treated with alkali.
      • Brown D.D.
      • Roem J.
      • Ng D.K.
      • et al.
      Low serum bicarbonate and CKD progression in children.
      In contrast, cohorts including patients at very advanced stages of CKD demonstrate treatment rates that are much higher, approaching 60%.
      • Thilly N.
      • Boini S.
      • Kessler M.
      • Briançon S.
      • Frimat L.
      Chronic kidney disease: appropriateness of therapeutic management and associated factors in the AVENIR study.
      These relatively low rates of treatment may reflect the limited number of long-term multicenter studies of alkali therapy, demonstrating efficacy and safety of treatment. US commentaries on treatment guidelines emphasize the complexity of CKD management, which involves treatment of the underlying disease process, anemia, mineral and bone disease, electrolyte disorders, blood pressure and extracellular volume, glycemic control, and cardiovascular risk factors.
      • Inker L.A.
      • Astor B.C.
      • Fox C.H.
      • et al.
      KDOQI US commentary on the 2012 KDIGO clinical practice guideline for the evaluation and management of CKD.
      Until stronger evidence emerges, the relative importance of treating chronic metabolic acidosis amid other CKD priorities is unclear and likely limits therapy.

      Conclusions and Need for Evidence on Treatment of Metabolic Acidosis in CKD

      Chronic metabolic acidosis is 1 of the most common and predictable complications of CKD present in approximately 30% of patients with stage G4-5 CKD and can occur earlier, particularly in patients with diabetes and tubulointerstitial kidney diseases. Physiologic studies have demonstrated the role of acidosis in potassium homeostasis, calciuria, bone metabolism, linear growth in children, and nutritional status, prompting guidelines to suggest treatment. Now, nearly 2 decades of observational studies suggest the exciting possibility that correction of metabolic acidosis may also slow progression of CKD. Most trials to date on this subject have been methodologically limited including a small sample size, single center, lack of blinding, extensive dropout, use of low-risk populations, and short follow-up periods. As a result, clinical guidelines and practice patterns themselves demonstrate uncertainty in the field. Most recent KDIGO guidelines suggest treatment, but practical commentaries acknowledge challenges and uncertainties.
      Innovations in the field may soon provide new leads on these critical questions and deliver more definitive results to guide practice. A novel HCl binding resin, veverimer, has been shown to improve serum bicarbonate by an average of approximately 3.5-4.5 mEq/L in patients with CKD and metabolic acidosis when used over 2-12 weeks.
      • Bushinsky D.A.
      • Hostetter T.
      • Klaerner G.
      • et al.
      Randomized, controlled trial of TRC101 to increase serum bicarbonate in patients with CKD.
      ,
      • Wesson D.E.
      • Mathur V.
      • Tangri N.
      • et al.
      Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial.
      Importantly, compared to existing alkali supplements, this agent does not increase sodium or potassium loading and showed some improvement in patient-reported physical functioning. A follow-up extension of the 12-week study suggests safety and potential benefits on CKD progression and physical functioning over 40 weeks
      • 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.
      ; however, the study was not designed for these as primary outcomes, and thus cannot be considered definitive. Results of the phase 3 study designed to assess kidney outcomes with veverimer, The Evaluation of Effect of TRC101 on Progression of Chronic Kidney Disease in Subjects with Metabolic Acidosis (VALOR-CKD), are expected in 2024 (www.clinicaltrials.gov; NCT03710291). These studies and others may soon provide better evidence to determine the health benefits of correcting metabolic acidosis in CKD, allowing more definitive clinical practice guidelines.

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