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Regulation of Acid-Base Balance in Patients With Chronic Kidney Disease

  • Glenn T. Nagami
    Correspondence
    Address correspondence to Glenn T. Nagami, MD, VA Greater Los Angeles Healthcare System, Nephrology Section 111L, 11301 Wilshire Blvd. Los Angeles, CA 90073.
    Affiliations
    Division of Nephrology, Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA

    David Geffen School of Medicine, UCLA, Los Angeles, CA
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  • Jeffrey A. Kraut
    Affiliations
    Division of Nephrology, VHAGLA Healthcare System, Los Angeles, CA

    UCLA Membrane Biology Laboratory, David Geffen UCLA School of Medicine, Los Angeles, CA
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      Normallly the kidneys handle the daily acid load arising from net endogenous acid production from the metabolism of ingested animal protein (acid) and vegetables (base). With chronic kidney disease, reduced acid excretion by the kidneys is primarily due to reduced ammonium excretion such that when acid excertion falls below acid porduction, acid accumulation occurs. With even mild reductions in glomerular filtration rate (60 to 90 ml/min), net acid excretion may fall below net acid production resulting in acid retention which may be initially sequestered in interstitial compartments in the kidneys, bones, and muscles resulting in no fall in measured systemic bicarbonate levels (eubicarbonatemic metabolic acidosis). With greater reductions in kidney function, the greater quantities of acid retained spillover systemically resulting in low pH (overt metabolic acidosis). The evaluation of acid-base balance in patients with CKD is complicated by the heterogeneity of clinical acid-base disorders and by the eubicarbonatemic nature of the early phase of acid retention. If supported by more extensive studies, blood gas analyses to confirm the acid-base disorder and newer ways for assessing the presence of acidosis such as urinary citrate measurements may become routine tools to evaluate and treat acid-base disorders in individuals with CKD.

      Key Words

      • Net acid production (NEAP) in individuals with normal kidney function and CKD results from metabolism of ingested animal protein (H+) and fruits and vegetables (base) and is similar, approximately 1 mEq/kg/d.
      • Reduction in renal acid excretion with CKD is primarily due to reduction in ammonium excretion which can fall below acid production, with the decrease in ammonium excretion being primarily caused by a reduction in ammonium production and possibly alterations in ammonium transport.
      • With mild reductions in GFR (60 to 80 mL/min), net acid excretion may fall below net endogenous acid production levels resulting in acid retention which is initially sequestered in the interstitial compartments in kidney, bone, and muscle resulting in no apparent systemic acid-base disturbance (eubicarbonatemic metabolic acidosis), while with greater reductions in GFR (<60 mL/min), the greater quantities of acid retained spillover systemically resulting in low blood pH (overt metabolic acidosis).
      • Evaluation of acid-base balance in patients with a decrease in GFR should include measurement of serum blood gases and, in some instances, urinary citrate and urinary ammonium levels.
      One of the major functions of the kidney is the maintenance of normal acid-base balance. Two major processes contribute to the maintenance of normal acid-base balance: (1) reabsorption of the more than 4800 milliequivalents (mEq) of bicarbonate that are normally filtered by the glomerulus daily and (2) generation of sufficient new bicarbonate to match the acid produced by metabolism of ingested food.
      With the development of chronic kidney disease (defined as a glomerular filtration rate [GFR] of <60 mL/min/1.732), generation of new bicarbonate can be compromised, leading to a fall in bicarbonate generation below acid production and acid retention. Although there is a correlation between degree of reduction in GFR and bicarbonate generation, it is the damage to the renal tubules that hampers bicarbonate generation.
      The metabolic acidosis that develops with CKD can have a deleterious effect on several organ systems including bones, muscles, and kidneys. Understanding its pathogenesis is essential for appropriate diagnosis and treatment. In this review, we summarize information about the regulation of acid-base balance by the kidney in both health and disease.

      The Net Endogenous Acid Production

      Hydrogen ions and base (bicarbonate) are produced from the hepatic metabolism of ingested food.
      • Relman A.S.
      • Lennon E.J.
      • Lemann Jr., J.
      Endogenous production of fixed acid and the measurement of the net balance of acid in normal subjects.
      The resulting net endogenous acid production (NEAP) is the sum of more than 200 mEq of protons generated daily from the metabolism of the sulfur-containing amino acids, methionine and cysteine, which are converted to sulfate and H+ ions, and the cationic amino acids, lysine, arginine, and some histidine residues, which are converted into neutral products and H+2. More than 150 mEq/d of base is generated from the metabolism of the amino acids, glutamate and aspartate, and organic anions present in fruits and vegetables such as citrate, gluconate, malate, acetate, and lactate. An additional 25 to 75 mEq of organic anions (half of which are metabolizable and, thus, could yield potential base) are excreted in the urine.
      • Halperin M.L.
      • Jungas R.L.
      Metabolic production and renal disposal of hydrogen ions.
      The measurement of urinary organic acid anions may be difficult to obtain in the typical outpatient clinical laboratory, and other means for estimating NEAP with methods more generally available may have value. NEAP can be estimated from measurements of 24-hour urine urea nitrogen and potassium levels using a validated formula incorporating an estimate of protein intake from the daily urine urea excretion rate
      • Maroni B.J.
      • Steinman T.I.
      • Mitch W.E.
      A method for estimating nitrogen intake of patients with chronic renal failure.
      and daily potassium excretion rate: NEAP in mEq/d = −10.2 + 54.5 × [protein intake in g/d] divided by [potassium intake in mEq/d].
      • Frassetto L.A.
      • Todd K.M.
      • Morris Jr., R.C.
      • et al.
      Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents.
      Such an approach has been applied to study healthy individuals
      • Frassetto L.A.
      • Todd K.M.
      • Morris Jr., R.C.
      • et al.
      Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents.
      and individuals with CKD
      • Scialla J.J.
      • Appel L.J.
      • Astor B.C.
      • et al.
      Estimated net endogenous acid production and serum bicarbonate in African Americans with chronic kidney disease.
      and could identify individuals who may be at the highest risk of acid accumulation from excessive acid loading. Overall, NEAP is approximately 50 to 70 mEq/d. Nevertheless, there can be a great variation in the NEAP (range 20 to 120 mEq/d), depending on the dietary content of primarily animal protein and fruits and vegetables.
      Besides organic components of the diet, sodium chloride may also contribute to dietary acid load.
      • Frassetto L.A.
      • Morris Jr., R.C.
      • Sebastian A.
      Dietary sodium chloride intake independently predicts the degree of hyperchloremic metabolic acidosis in healthy humans consuming a net acid-producing diet.
      In healthy individuals, the larger the sodium chloride intake, the lower the observed serum bicarbonate level. This observation has been attributed to increased extracellular fluid compartment volume leading to dilution of bicarbonate and to reduced reabsorption of bicarbonate by the kidney. Also, differences in an individual's gut microbiome (the bacterial population of the gastrointestinal tract) could affect the NEAP. In CKD, an expansion of urease-producing bacteria in the gut
      • Wong J.
      • Piceno Y.M.
      • DeSantis T.Z.
      • et al.
      Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD.
      can lead to the conversion of urea (which may be present at concentrations similar to the blood
      • Lee Y.T.
      Urea concentration in intestinal fluids in normal and uremic dogs.
      ) to ammonia which is carried via the portal vein to the liver where it is detoxified back to urea, a bicarbonate-consuming process.
      • Eklou-Lawson M.
      • Bernard F.
      • Neveux N.
      • et al.
      Colonic luminal ammonia and portal blood L-glutamine and L-arginine concentrations: a possible link between colon mucosa and liver ureagenesis.
      ,
      • van de Poll M.C.
      • Ligthart-Melis G.C.
      • Olde Damink S.W.
      • et al.
      The gut does not contribute to systemic ammonia release in humans without portosystemic shunting.
      A shift of the gut microbiome to more protein- and amino-acid-fermenting bacteria can also contribute to the production of intestinal ammonia and other uremic toxins.
      • Ramezani A.
      • Massy Z.A.
      • Meijers B.
      • et al.
      Role of the Gut Microbiome in Uremia: A Potential Therapeutic Target.
      Additional studies are required to identify the quantitative contribution of the microbiome to changes in acid-base balance in CKD. NEAP on a constant defined diet is similar in individuals with normal kidney function and in those with CKD with varying GFRs (11 to 60 mL/min). However, the NEAP in individuals with CKD prior to dialysis and not on a fixed diet can vary greatly. In 1 study of individuals with CKD ingesting a freely selected diet, a third of individuals had an NEAP of <39 mEq/d, a third had an NEAP of 39 to 55 mEq/d, and a third had an NEAP of >55 mEq/d.
      • Banerjee T.
      • Crews D.C.
      • Wesson D.E.
      • et al.
      High Dietary Acid Load Predicts ESRD among Adults with CKD.
      Thus, the NEAP among patients with CKD can vary significantly, reflecting differences in the quantity and type of protein and fruits and vegetables ingested. Of note, altering the quantity and type of protein and quantity of fruits and vegetables ingested is also an effective method recommended for treating or preventing hypobicarbonatemia in patients with CKD.
      • Goraya N.
      • Simoni J.
      • Jo C.H.
      • et al.
      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.

      Kidney Bicarbonate Reclamation in CKD

      The kidney needs to reclaim bicarbonate that is filtered at the glomeruli so that it is not lost in the urine. With normal levels of GFR (150 to 180 L/d), the filtered load of bicarbonate (GFR × plasma HCO3 concentration of 25 mEq/L) is about 4800 mEq/d. Each of the segments of the nephron contributes to a varying extent of bicarbonate reabsorption. The proximal tubule is the major site of bicarbonate reabsorption and normally accounts for 70% to 80% of bicarbonate reabsorption, the thick ascending limb of the loop of Henle accounts for 15%, and the collecting duct 5%.
      • Hamm L.L.
      • Nakhoul N.
      • Hering-Smith K.S.
      Acid-Base homeostasis.
      Bicarbonate reabsorption in the proximal tubule is mediated by a series of processes involving H+ secretion into the lumen (mostly via sodium-hydrogen exchange and H+-ATPase–mediated proton secretion), the formation of CO2 in the presence of luminal carbonic anhydrase, diffusion of CO2 into the cell, reconversion of CO2 to bicarbonate by intracellular carbonic anhydrase, and transport of bicarbonate back into the blood via a basolateral sodium bicarbonate cotransport (NBCe1). Several factors can increase bicarbonate reabsorption including metabolic acidosis and an intracellular acid pH, hypokalemia, hypovolemia, increased bicarbonate delivery with euvolemia, and increased secretion of hormones such as angiotensin II, endothelin, and parathyroid hormone.
      • Eiam-Ong S.
      • Hilden S.A.
      • Johns C.A.
      • et al.
      Stimulation of basolateral Na(+)-HCO3- cotransporter by angiotensin II in rabbit renal cortex.
      • Eiam-Ong S.
      • Hilden S.A.
      • King A.J.
      • et al.
      Endothelin-1 stimulates the Na+/H+ and Na+/HCO3- transporters in rabbit renal cortex.
      • Paillard M.
      • Bichara M.
      Peptide hormone effects on urinary acidification and acid-base balance: PTH, ADH, and glucagon.
      In a polycystic model of CKD, protein levels of the sodium-bicarbonate cotransport were reduced with acid-loading even though messenger RNA levels were increased.
      • Burki R.
      • Mohebbi N.
      • Bettoni C.
      • et al.
      Impaired expression of key molecules of ammoniagenesis underlies renal acidosis in a rat model of chronic kidney disease.
      Theoretically, a reduction in sodium-bicarbonate transport should reduce the capacity of the proximal tubule to retain bicarbonate and result in a proximal renal tubular acidosis-like state. Yet, as mentioned below, this does not generally appear to apply in human CKD and in the remnant kidney rat model of CKD.
      Most individuals with CKD ingest a diet leading to acid production so that an acidic urine pH (5.5) is appropriate. However, when subjects with CKD are given base to raise the bicarbonate level toward normal, some of them will spill bicarbonate into the urine
      • Schwartz W.B.
      • Hall 3rd, P.W.
      • Hays R.M.
      • et al.
      On the mechanism of acidosis in chronic renal disease.
      suggesting that some patients have a reduced threshold for wasting bicarbonate as it occurs in proximal renal tubular acidosis. It should be kept in mind, however, that in CKD, the single-nephron GFR is high for each remaining functioning nephron so that the filtered bicarbonate load is higher for any given concentration of filtered bicarbonate with the potential for overwhelming the bicarbonate reabsorptive capacity of the nephron. In micropuncture studies, the increased delivery of bicarbonate out of the proximal tubule and thick ascending limb was much higher than the levels observed in control animals. Nevertheless, even though more bicarbonate was allowed to reach the distal nephron, a higher percentage of the filtered bicarbonate was absorbed proximally but not enough to overcome the increased filtered load per nephron.
      • Buerkert J.
      • Martin D.
      • Trigg D.
      • et al.
      Effect of reduced renal mass on ammonium handling and net acid formation by the superficial and juxtamedullary nephron of the rat. Evidence for impaired reentrapment rather than decreased production of ammonium in the acidosis of uremia.
      ,
      • Lubowitz H.
      • Purkerson M.L.
      • Rolf D.B.
      • et al.
      Effect of nephron loss on proximal tubular bicarbonate reabsorption in the rat.
      The subsequent removal of bicarbonate from the urine by the distal nephron is mediated at least in part by an adaptive increase in cells in both the cortical and medullary collecting ducts displaying an apical H+-ATPase as observed in the remnant kidney model of CKD.
      • Bastani B.
      • Gluck S.
      Adaptational changes in renal vacuolar H(+)-ATPase in the rat remnant kidney.

      Titratable Acid Excretion in CKD

      H+ secretion in the urine by itself would contribute little to acid excretion from the body. Indeed, at a urine pH of 5, the concentration of H+ per liter is only 0.01 mM. Urinary buffers (principally phosphate) are necessary to increase acid excretion at any given urinary pH. Titratable acid is the amount of acid that is excreted with urinary buffers and is measured by determining the amount of base added to bring the urine pH to 7.4. Under physiological and pathophysiological conditions, most of the titratable acids are derived from buffering of H+ with the dibasic of phosphate HPO4= and the monobasic H2PO4. The pKa for this buffer pair is 6.8. Thus, the presence of phosphate in the lumen allows for a greater quantity of acid to be excreted into the urine at any given low urine pH than in the absence of buffer.
      In CKD, titratable acid excretion is remarkably preserved as GFR falls. As already mentioned, the urine pH is usually acidic, and the excretion of phosphate is maintained in CKD. The amount of phosphate filtered by each remaining nephron in CKD is increased both by an increase in single-nephron GFR
      • Bank N.
      • Su W.S.
      • Aynedjian H.S.
      A micropuncture study of renal phosphate transport in rats with chronic renal failure and secondary hyperparathyroidism.
      and the elevation in phosphate concentration which occurs with more severe degrees of kidney impairment. Also, the reabsorption of phosphate by the nephron is affected by different factors which may be present in CKD, including metabolic acidosis and increased concentrations of fibroblast growth factor 23 and parathyroid hormone, all of which are phosphaturic.
      • Bank N.
      • Su W.S.
      • Aynedjian H.S.
      A micropuncture study of renal phosphate transport in rats with chronic renal failure and secondary hyperparathyroidism.
      • Biber J.
      • Hernando N.
      • Forster I.
      • et al.
      Regulation of phosphate transport in proximal tubules.
      • Juppner H.
      Phosphate and FGF-23.
      • Felsenfeld A.J.
      • Levine B.S.
      • Rodriguez M.
      Pathophysiology of calcium, phosphorus, and magnesium dysregulation in Chronic Kidney Disease.
      In the remnant kidney model
      • Kwon T.H.
      • Frokiaer J.
      • Fernandez-Llama P.
      • et al.
      Altered expression of Na transporters NHE-3, NaPi-II, Na-K-ATPase, BSC-1, and TSC in CRF rat kidneys.
      and polycystic kidney disease model, sodium-phosphate cotransporters are reduced, thereby allowing the escape of phosphate to more distal segments where more titratable acid can be generated by the buffering of secreted acid.

      Ammonia Production and Transport with Normal Kidney Function

      The kidneys respond to acid challenges primarily by increasing ammonia production and excretion of ammonium; both processes which result in increased generation of bicarbonate.
      • Hamm L.L.
      • Nakhoul N.
      • Hering-Smith K.S.
      Acid-Base homeostasis.
      ,
      • Weiner I.D.
      • Verlander J.W.
      Renal ammonia metabolism and transport.
      Under normal circumstances, when the body is exposed to increased NEAP, the kidneys greatly augment NH3 production and urinary NH4 excretion. Under normal circumstances, most of the urinary ammonium is generated by the metabolism of glutamine in the proximal tubule, the main site of ammoniagenesis. With metabolic acidosis, both the delivery of glutamine to the kidney
      • Welbourne T.C.
      Interorgan glutamine flow in metabolic acidosis.
      and its uptake by the kidney cells
      • Tizianello A.
      • Deferrari G.
      • Garibotto G.
      • et al.
      Renal ammoniagenesis in an early stage of metabolic acidosis in man.
      are enhanced. The latter effect appears to be mediated by increased amount of the glutamine transport protein (SNAT3/Slc38a3) in the proximal tubule.
      • Moret C.
      • Dave M.H.
      • Schulz N.
      • et al.
      Regulation of renal amino acid transporters during metabolic acidosis.
      The enhanced delivery and uptake of the proximal tubule in metabolic acidosis is coupled with increased ammoniagenic enzymes which catalyze the conversion of glutamine to ammonia and carbon dioxide or glucose
      • Weiner I.D.
      • Verlander J.W.
      Renal ammonia metabolism and transport.
      along with increased secretion of ammonia into the proximal tubule lumen
      • Nagami G.T.
      • Sonu C.M.
      • Kurokawa K.
      Ammonia production by isolated mouse proximal tubules perfused in vitro. Effect of metabolic acidosis.
      ,
      • Nagami G.T.
      Enhanced ammonia secretion by proximal tubules from mice receiving NH(4)Cl: role of angiotensin II.
      so that it is delivered distally to the thick ascending limb where ammonium is concentrated in the medullary interstitium. The interstitial ammonium can serve as a resource pool for ammonia to be secreted into the collecting duct lumen via specific ammonia transporters (eg, Rh Glycoproteins) coupled with H+-ATPase-mediated H+ secretion, processes which are enhanced by metabolic acidosis.

      Ammonia Production and Transport in CKD

      In CKD, the ability to compensate for a given level of NEAP may be constrained by limitations in the generation and excretion of ammonium, thereby resulting in the development of acid retention and hypobicarbonatemia.
      • Schwartz W.B.
      • Relman A.S.
      Acidosis in renal disease.
      ,
      • Relman A.S.
      The acidosis of renal disease.
      Even as kidney function falls, each of the remaining functioning nephrons produce and excrete more ammonia,
      • Buerkert J.
      • Martin D.
      • Trigg D.
      • et al.
      Effect of reduced renal mass on ammonium handling and net acid formation by the superficial and juxtamedullary nephron of the rat. Evidence for impaired reentrapment rather than decreased production of ammonium in the acidosis of uremia.
      ,
      • MacClean A.J.
      • Hayslett J.P.
      Adaptive change in ammonia excretion in renal insufficiency.
      ,
      • Tizianello A.
      • De Ferrari G.
      • Garibotto G.
      • et al.
      Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency.
      but eventually total ammonia production and excretion rates fall below what are needed to maintain acid-base balance. Changes in substrate utilization for ammoniagenesis also occur in CKD such that the adaptive pathways become altered. In humans with CKD, glutamine is not taken up or metabolized as well as in individuals with normal kidney function even though there may be increased release of amino acids from muscle breakdown due to acidosis and other factors associated with CKD.
      • Wang X.H.
      • Mitch W.E.
      Mechanisms of muscle wasting in chronic kidney disease.
      Impaired utilization of delivered substrates occurs such that substrates derived from intrarenal proteolysis appear to have a more prominent role in ammoniagenesis.
      • Tizianello A.
      • De Ferrari G.
      • Garibotto G.
      • et al.
      Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency.
      The mechanisms underlying reduced kidney uptake of glutamine and ammonia production, including a decrease in glutamine transporter SNAT3/Slc38a3 and ammoniagenic enzymes phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase, were revealed in studies using animal models of CKD.
      • Burki R.
      • Mohebbi N.
      • Bettoni C.
      • et al.
      Impaired expression of key molecules of ammoniagenesis underlies renal acidosis in a rat model of chronic kidney disease.
      In addition, as studies have demonstrated a potential role of NBCe1-A in the regulation of ammonia production by the proximal tubule,
      • Lee H.W.
      • Osis G.
      • Harris A.N.
      • et al.
      NBCe1-A Regulates Proximal Tubule Ammonia Metabolism under Basal Conditions and in Response to Metabolic Acidosis.
      the reduction of NBCe1 protein levels in a polycystic model of CKD
      • Burki R.
      • Mohebbi N.
      • Bettoni C.
      • et al.
      Impaired expression of key molecules of ammoniagenesis underlies renal acidosis in a rat model of chronic kidney disease.
      could play a role in the reduction in ammonia production in that segment. Nevertheless, the reduction in ammonia transporter and ammoniagenic enzyme levels does not fully prevent the enhanced production and excretion of ammonia per nephron which could reflect alternative compensatory substrate and metabolic pathways.
      Ammonia transport may also be altered in CKD by a reduction in medullary ammonia levels which may coincide with reductions in urinary concentrating ability with the loss of nephron mass. The reduction in medullary ammonia levels was identified in the remnant kidney model of CKD by collection of luminal fluid at the bend of the loop of Henle which showed lower concentration levels of ammonia in kidneys from rats with CKD than in those from controls.
      • Buerkert J.
      • Martin D.
      • Trigg D.
      • et al.
      Effect of reduced renal mass on ammonium handling and net acid formation by the superficial and juxtamedullary nephron of the rat. Evidence for impaired reentrapment rather than decreased production of ammonium in the acidosis of uremia.
      This reduced medullary interstitial gradient appeared to occur as the result of reduced transport from the lumen into the interstitium along the thick ascending limb which led to a higher delivery of ammonia to the cortical distal nephron where ammonia could return to the systemic circulation via the renal veins. The changes in levels of sulfatides which can act as ammonium traps in the medullary interstitium
      • Stettner P.
      • Bourgeois S.
      • Marsching C.
      • et al.
      Sulfatides are required for renal adaptation to chronic metabolic acidosis.
      could affect the accumulation of ammonium in the medulla, but it is unclear whether medullary sulfatide levels change in CKD. As mentioned above, the transport of ammonia into the collecting duct lumen and final urine may not only be limited by the medullary concentration of ammonia but also by changes in the quantity of Rh transport proteins. In the remnant kidney model of CKD, the apical and basolateral membrane Rh C glycoprotein levels appeared to be increased.
      • Kim H.Y.
      • Baylis C.
      • Verlander J.W.
      • et al.
      Effect of reduced renal mass on renal ammonia transporter family, Rh C glycoprotein and Rh B glycoprotein, expression.
      Such increments in transporter levels could optimize the delivery of available ammonia into the final urine.
      In summary, with CKD, ammonia production and urinary ammonium excretion fall despite the presence of metabolic acidosis (eubicarbonatemic or overt metabolic acidosis) due to both a reduction of nephron mass and fundamental changes in metabolic and transport pathways of the collecting ducts. Urinary acidification is preserved (as reflected by the ability to reduce urinary pH to <.5). Titratable acid excretion may increase above normal levels, but the increment may be insufficient to compensate for impaired ammonia production and ammonium excretion resulting in the net acid excretion rate falling below the acid production rate leading to positive acid balance.

      Stages of Acid Retention in CKD

      Recent studies have demonstrated positive acid balance can be observed with only minor reductions in GFR (60 mL/min – 90 mL/min).
      • Wesson D.E.
      The Continuum of Acid Stress.
      Importantly, the acid appears to be retained in tissues without perturbing systemic blood acid-base parameters (so-called eubicarbonatemic or normobicarbonatemic metabolic acidosis). Further, eubicarbonatemic metabolic acidosis can be associated with progression of kidney dysfunction which can be prevented by administration of base.
      • Wesson D.E.
      • Buysse J.M.
      • Bushinsky D.A.
      Mechanisms of Metabolic Acidosis-Induced Kidney Injury in Chronic Kidney Disease.
      These findings imply that net acid excretion is reduced earlier than previously believed. As GFR falls, net acid excretion falls further leading to greater acid retention and eventually hypobicarbonatemia. The presumed progression of acid retention with progression of CKD is shown in Figure 1.
      Figure thumbnail gr1
      Figure 1Acid retention and metabolic acidosis in chronic kidney disease. An imbalance between net endogenous acid production (NEAP) and the reduced ability of the kidney to generate base as kidney function declines results in acid retention. Initially, the retained acid is sequestered in the interstitial fluid compartments with no observable change in blood pH or bicarbonate concentration (eubicarbonatemic metabolic acidosis), but with more severe degrees of acid retention, reductions in blood pH and bicarbonate levels are then observed (overt metabolic acidosis). NL GFR, normal GFR.

      Acid-Base Parameters and Electrolyte Profile in CKD

      As suggested by Figure 1, acid retention initially leads to accumulation of H+ in tissues including those of the kidneys, bones, and muscles.
      • Raphael K.L.
      • Kraut J.A.
      Assessing Acid-Base Status in Patients With CKD: Does Measurement of Blood pH Matter?.
      At this stage, systemic acid-base parameters can be within the normal range. As CKD progresses, there can be development of hypobicarbonatemia which worsens as kidney function declines further. Until recently, metabolic acidosis was defined as [total CO2] ≤ 22 mEq/L. On this basis, an analysis of Department of Veterans Affairs data revealed only 25% of patients with stage 5 non–dialysis-dependent CKD had metabolic acidosis.
      • Kovesdy C.P.
      Metabolic acidosis and kidney disease: does bicarbonate therapy slow the progression of CKD?.
      Also, in the chronic renal insufficiency cohort study, the percent of patients with metabolic acidosis rose from 8% in stage 2 CKD to 12% in stage 3 CKD and 35% in stage 4 CKD.
      • Raphael K.L.
      • Zhang Y.
      • Ying J.
      • et al.
      Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease.
      Further, in the analysis of the Modified Diet in Renal Disease study,
      • Gennari F.J.
      • Hood V.L.
      • Greene T.
      • et al.
      Effect of dietary protein intake on serum total CO2 concentration in chronic kidney disease: Modification of Diet in Renal Disease study findings.
      the mean serum [total CO2] fell from 25 to 23 mEq/L with a GFR of 26 - 40 mL/min.
      The electrolyte pattern with CKD can vary from a non–anion-gap metabolic acidosis to a mixed non–anion-gap and high-anion-gap metabolic acidosis or to a pure high-anion-gap acidosis. It has been proposed that a non–anion-gap acidosis is seen in early stages of CKD (GFR <60 mL/min), followed by a mixed normal- and high-anion-gap acidosis, and then high-anion-gap acidosis alone at a GFR <20 – 30 mL/min.
      • Kraut J.A.
      • Madias N.E.
      Metabolic Acidosis of CKD: An update.
      Evidence from analyses of 2 large databases
      • Abramowitz M.K.
      • Hostetter T.H.
      • Melamed M.L.
      The serum anion gap is altered in early kidney disease and associates with mortality.
      ,
      • Banerjee T.
      • Crews D.C.
      • Wesson D.E.
      • et al.
      Dietary acid load and chronic kidney disease among adults in the United States.
      revealed an increase in the serum anion gap can be observed in some patients with a GFR of 40 to 60 mL/min. Thus, it is likely any of these electrolyte patterns can be observed in all stages of CKD. The elevation in the serum anion gap with CKD is due to the accumulation of phosphate and sulfate.

      Evaluation of Acid-Base Balance in Chronic Kidney Disease

      Studies in isolated tissues, cell culture, and whole animals have demonstrated that changes in the interstitial and intracellular environments of tissues primarily affect cellular functions and disease outcomes.
      • Wesson D.E.
      • Simoni J.
      Increased tissue acid mediates a progressive decline in the glomerular filtration rate of animals with reduced nephron mass.
      However, methods to examine these compartments require sophisticated techniques which are presently not available. In their absence, acid-base balance is primarily assessed from measurements of acid-base parameters in systemic blood. In this regard, full acid-base parameters are usually not measured, rather the serum [total CO2] is measured in clinical laboratories and used as a surrogate for serum [HCO3]. A low [total CO2] in patients with CKD is considered indicative of the presence of metabolic acidosis, an acid-base disorder associated with progression of CKD.
      Recently, in a retrospective study of 1058 Japanese patients with CKD,
      • Kajimoto S.
      • Sakaguchi Y.
      • Asahina Y.
      • et al.
      Modulation of the Association of Hypobicarbonatemia and Incident Kidney Failure With Replacement Therapy by Venous pH: A Cohort Study.
      blood pH, PCO2, and [HCO3] in venous blood were measured demonstrating that only 59% of patients with a low blood [HCO3] were acidemic, whereas the remaining 41% had a normal (38%) or an alkalemic blood pH (3%). As might be expected, only individuals with a low serum [HCO3] (mean 21.5 mEq/L) and who were acidemic had a higher risk of kidney failure and would benefit from base replacement. These data indicate that blood pH might be an important determinant of CKD progression among those with low blood [HCO3] and suggest that measurements of full acid-base parameters are indicated in the assessment of acid-base balance in patients with CKD. Further studies involving a larger number of subjects are needed to confirm the importance of measurement of full acid-base parameters to justify the additional resources needed to make this radical change in the assessment of patients with CKD especially in nonhospitalized individuals.

      Other Measures of Acid-Base Balance in CKD

      As noted above, acid retention in tissue can occur in early stages of CKD without perturbing systemic acid-base parameters. In this regard, eubicarbonatemic metabolic acidosis might be extremely common as it has been observed in individuals with a GFR of 60- 90 mL/min. Measurements of urinary ammonium and urinary citrate have been identified as potential markers of this state. A reduction in urinary ammonium excretion is observed prior to a fall in [total CO2],
      • Raphael K.L.
      • Carroll D.J.
      • Murray J.
      • et al.
      Urine Ammonium Predicts Clinical Outcomes in Hypertensive Kidney Disease.
      and low urinary ammonium excretion is associated with higher risk of CKD progression.
      The estimation of urinary NH4 excretion has traditionally been derived from measurement of the urine anion gap or urine osmolal gap. However, several studies have demonstrated poor correlation of urine NH4 with the anion or osmolal gap and suggested that direct measurement of urine NH4 is more accurate.
      • Uribarri J.
      • Oh M.S.
      The Urine Anion Gap: Common Misconceptions.
      Measurement of urine NH4 can be easily accomplished using a modification of the blood enzymatic determination of plasma NH4 and should be utilized for this purpose.
      Urinary citrate levels are also reduced in the setting of acid retention, due to reclamation of filtered citrate, and the magnitude of this reduction is greater with later stages of CKD. Also, urinary citrate levels increase in response to base therapy in patients with clinically normal acid-base balance, suggesting that renal acid retention was present. Studies in patients with substantial reductions in estimated GFR (30 to 59 mL/min/1.73 m2) have demonstrated that urine pH, ammonium, and citrate levels were significantly lower than those in individuals without CKD and that bicarbonate supplementation increased urinary citrate levels in patients with CKD but not in non-CKD subjects.
      • Tyson C.C.
      • Luciano A.
      • Modliszewski J.L.
      • et al.
      Effect of Bicarbonate on Net Acid Excretion, Blood Pressure, and Metabolism in Patients With and Without CKD: The Acid Base Compensation in CKD Study.
      Further, a low urinary citrate-creatinine ratio has been proposed as a potential marker of acid retention in CKD.
      • Goraya N.
      • Simoni J.
      • Sager L.N.
      • et al.
      Urine citrate excretion as a marker of acid retention in patients with chronic kidney disease without overt metabolic acidosis.
      Additional studies with larger groups of patients stratified to various stages of CKD with determinations of intraindividual variability are needed to confirm the utility of urinary citrate measurements as a tool for guiding base treatment in CKD.
      In summary, measurements of complete acid-base parameters appear to be valuable in the accurate assessment of acid-base balance of patients with CKD. Further, measurements of urinary ammonium and citrate might be effective in identifying the state in which renal acid excretion is compromised enough to result in acid retention without perturbing systemic acid-base parameters.

      Acknowledgments

      This work was supported in part by the Department of Veterans Affairs , United States of America.

      References

        • Relman A.S.
        • Lennon E.J.
        • Lemann Jr., J.
        Endogenous production of fixed acid and the measurement of the net balance of acid in normal subjects.
        J Clin Invest. 1961; 40: 1621-1630
        • Halperin M.L.
        • Jungas R.L.
        Metabolic production and renal disposal of hydrogen ions.
        Kidney Int. 1983; 24: 709-713
        • Maroni B.J.
        • Steinman T.I.
        • Mitch W.E.
        A method for estimating nitrogen intake of patients with chronic renal failure.
        Kidney Int. 1985; 27: 58-65
        • Frassetto L.A.
        • Todd K.M.
        • Morris Jr., R.C.
        • et al.
        Estimation of net endogenous noncarbonic acid production in humans from diet potassium and protein contents.
        Am J Clin Nutr. 1998; 68: 576-583
        • Scialla J.J.
        • Appel L.J.
        • Astor B.C.
        • et al.
        Estimated net endogenous acid production and serum bicarbonate in African Americans with chronic kidney disease.
        Clin J Am Soc Nephrol. 2011; 6: 1526-1532
        • Frassetto L.A.
        • Morris Jr., R.C.
        • Sebastian A.
        Dietary sodium chloride intake independently predicts the degree of hyperchloremic metabolic acidosis in healthy humans consuming a net acid-producing diet.
        Am J Physiol Renal Physiol. 2007; 293: F521-F525
        • Wong J.
        • Piceno Y.M.
        • DeSantis T.Z.
        • et al.
        Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short-chain fatty acid-producing intestinal microbiota in ESRD.
        Am J Nephrol. 2014; 39: 230-237
        • Lee Y.T.
        Urea concentration in intestinal fluids in normal and uremic dogs.
        J Surg Oncol. 1971; 3: 163-168
        • Eklou-Lawson M.
        • Bernard F.
        • Neveux N.
        • et al.
        Colonic luminal ammonia and portal blood L-glutamine and L-arginine concentrations: a possible link between colon mucosa and liver ureagenesis.
        Amino Acids. 2009; 37: 751-760
        • van de Poll M.C.
        • Ligthart-Melis G.C.
        • Olde Damink S.W.
        • et al.
        The gut does not contribute to systemic ammonia release in humans without portosystemic shunting.
        Am J Physiol Gastrointest Liver Physiol. 2008; 295: G760-G765
        • Ramezani A.
        • Massy Z.A.
        • Meijers B.
        • et al.
        Role of the Gut Microbiome in Uremia: A Potential Therapeutic Target.
        Am J Kidney Dis. 2016; 67: 483-498
        • Banerjee T.
        • Crews D.C.
        • Wesson D.E.
        • et al.
        High Dietary Acid Load Predicts ESRD among Adults with CKD.
        J. Am. Soc. Nephrol. 2015; 26: 1693-1700
        • Goraya N.
        • Simoni J.
        • Jo C.H.
        • et al.
        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.
        Kidney Int. 2014; 86: 1031-1038
        • Hamm L.L.
        • Nakhoul N.
        • Hering-Smith K.S.
        Acid-Base homeostasis.
        Clin J Am Soc Nephrol. 2015; 10: 2232-2242
        • Eiam-Ong S.
        • Hilden S.A.
        • Johns C.A.
        • et al.
        Stimulation of basolateral Na(+)-HCO3- cotransporter by angiotensin II in rabbit renal cortex.
        Am J Physiol. 1993; 265: F195-F203
        • Eiam-Ong S.
        • Hilden S.A.
        • King A.J.
        • et al.
        Endothelin-1 stimulates the Na+/H+ and Na+/HCO3- transporters in rabbit renal cortex.
        Kidney Int. 1992; 42: 18-24
        • Paillard M.
        • Bichara M.
        Peptide hormone effects on urinary acidification and acid-base balance: PTH, ADH, and glucagon.
        Am J Physiol. 1989; 256: F973-F985
        • Burki R.
        • Mohebbi N.
        • Bettoni C.
        • et al.
        Impaired expression of key molecules of ammoniagenesis underlies renal acidosis in a rat model of chronic kidney disease.
        Nephrol Dial Transplant. 2015; 30: 770-781
        • Schwartz W.B.
        • Hall 3rd, P.W.
        • Hays R.M.
        • et al.
        On the mechanism of acidosis in chronic renal disease.
        J Clin Invest. 1959; 38: 39-52
        • Buerkert J.
        • Martin D.
        • Trigg D.
        • et al.
        Effect of reduced renal mass on ammonium handling and net acid formation by the superficial and juxtamedullary nephron of the rat. Evidence for impaired reentrapment rather than decreased production of ammonium in the acidosis of uremia.
        J Clin Invest. 1983; 71: 1661-1675
        • Lubowitz H.
        • Purkerson M.L.
        • Rolf D.B.
        • et al.
        Effect of nephron loss on proximal tubular bicarbonate reabsorption in the rat.
        Am J Physiol. 1971; 220: 457-461
        • Bastani B.
        • Gluck S.
        Adaptational changes in renal vacuolar H(+)-ATPase in the rat remnant kidney.
        J Am Soc Nephrol. 1997; 8: 868-879
        • Bank N.
        • Su W.S.
        • Aynedjian H.S.
        A micropuncture study of renal phosphate transport in rats with chronic renal failure and secondary hyperparathyroidism.
        J Clin Invest. 1978; 61: 884-894
        • Biber J.
        • Hernando N.
        • Forster I.
        • et al.
        Regulation of phosphate transport in proximal tubules.
        Pflugers Arch. 2009; 458: 39-52
        • Juppner H.
        Phosphate and FGF-23.
        Kidney Int Suppl. 2011; 121: S24-S27
        • Felsenfeld A.J.
        • Levine B.S.
        • Rodriguez M.
        Pathophysiology of calcium, phosphorus, and magnesium dysregulation in Chronic Kidney Disease.
        Semin Dial. 2015; 28: 564-577
        • Kwon T.H.
        • Frokiaer J.
        • Fernandez-Llama P.
        • et al.
        Altered expression of Na transporters NHE-3, NaPi-II, Na-K-ATPase, BSC-1, and TSC in CRF rat kidneys.
        Am J Physiol. 1999; 277 (F257-F270)
        • Weiner I.D.
        • Verlander J.W.
        Renal ammonia metabolism and transport.
        Compr Physiol. 2013; 3: 201-220
        • Welbourne T.C.
        Interorgan glutamine flow in metabolic acidosis.
        Am J Physiol. 1987; 253: F1069-F1076
        • Tizianello A.
        • Deferrari G.
        • Garibotto G.
        • et al.
        Renal ammoniagenesis in an early stage of metabolic acidosis in man.
        J Clin Invest. 1982; 69: 240-250
        • Moret C.
        • Dave M.H.
        • Schulz N.
        • et al.
        Regulation of renal amino acid transporters during metabolic acidosis.
        Am J Physiol Renal Physiol. 2007; 292: F555-F566
        • Nagami G.T.
        • Sonu C.M.
        • Kurokawa K.
        Ammonia production by isolated mouse proximal tubules perfused in vitro. Effect of metabolic acidosis.
        J Clin Invest. 1986; 78: 124-129
        • Nagami G.T.
        Enhanced ammonia secretion by proximal tubules from mice receiving NH(4)Cl: role of angiotensin II.
        Am J Physiol Renal Physiol. 2002; 282: F472-F477
        • Schwartz W.B.
        • Relman A.S.
        Acidosis in renal disease.
        N Engl J Med. 1957; 256: 1184-1186
        • Relman A.S.
        The acidosis of renal disease.
        Am J Med. 1968; 44: 706-713
        • MacClean A.J.
        • Hayslett J.P.
        Adaptive change in ammonia excretion in renal insufficiency.
        Kidney Int. 1980; 17: 595-606
        • Tizianello A.
        • De Ferrari G.
        • Garibotto G.
        • et al.
        Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency.
        J Clin Invest. 1980; 65: 1162-1173
        • Wang X.H.
        • Mitch W.E.
        Mechanisms of muscle wasting in chronic kidney disease.
        Nat. Rev. Nephrol. 2014; 10: 504-516
        • Lee H.W.
        • Osis G.
        • Harris A.N.
        • et al.
        NBCe1-A Regulates Proximal Tubule Ammonia Metabolism under Basal Conditions and in Response to Metabolic Acidosis.
        J Am Soc Nephrol. 2018; 29: 1182-1197
        • Stettner P.
        • Bourgeois S.
        • Marsching C.
        • et al.
        Sulfatides are required for renal adaptation to chronic metabolic acidosis.
        Proc Natl Acad Sci U S A. 2013; 110: 9998-10003
        • Kim H.Y.
        • Baylis C.
        • Verlander J.W.
        • et al.
        Effect of reduced renal mass on renal ammonia transporter family, Rh C glycoprotein and Rh B glycoprotein, expression.
        Am J Physiol Renal Physiol. 2007; 293: F1238-F1247
        • Wesson D.E.
        The Continuum of Acid Stress.
        Clin J Am Soc Nephrol. 2021; 16: 1292-1299
        • Wesson D.E.
        • Buysse J.M.
        • Bushinsky D.A.
        Mechanisms of Metabolic Acidosis-Induced Kidney Injury in Chronic Kidney Disease.
        J Am Soc Nephrol. 2020; 31: 469-482
        • Raphael K.L.
        • Kraut J.A.
        Assessing Acid-Base Status in Patients With CKD: Does Measurement of Blood pH Matter?.
        Am J Kidney Dis. 2021; 77: 9-11
        • Kovesdy C.P.
        Metabolic acidosis and kidney disease: does bicarbonate therapy slow the progression of CKD?.
        Nephrol Dial Transplant. 2012; 27: 3056-3062
        • Raphael K.L.
        • Zhang Y.
        • Ying J.
        • et al.
        Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease.
        Nephrology (Carlton). 2014; 19: 648-654
        • Gennari F.J.
        • Hood V.L.
        • Greene T.
        • et al.
        Effect of dietary protein intake on serum total CO2 concentration in chronic kidney disease: Modification of Diet in Renal Disease study findings.
        Clin J Am Soc Nephrol. 2006; 1: 52-57
        • Kraut J.A.
        • Madias N.E.
        Metabolic Acidosis of CKD: An update.
        Am J Kidney Dis. 2016; 67: 307-317
        • Abramowitz M.K.
        • Hostetter T.H.
        • Melamed M.L.
        The serum anion gap is altered in early kidney disease and associates with mortality.
        Kidney Int. 2012; 82: 701-709
        • Banerjee T.
        • Crews D.C.
        • Wesson D.E.
        • et al.
        Dietary acid load and chronic kidney disease among adults in the United States.
        BMC. Nephrol. 2014; 15: 137https://doi.org/10.1186/1471-2369-15-137
        • Wesson D.E.
        • Simoni J.
        Increased tissue acid mediates a progressive decline in the glomerular filtration rate of animals with reduced nephron mass.
        Kidney Int. 2009; 75: 929-935
        • Kajimoto S.
        • Sakaguchi Y.
        • Asahina Y.
        • et al.
        Modulation of the Association of Hypobicarbonatemia and Incident Kidney Failure With Replacement Therapy by Venous pH: A Cohort Study.
        Am J Kidney Dis. 2021; 77: 35-43
        • Raphael K.L.
        • Carroll D.J.
        • Murray J.
        • et al.
        Urine Ammonium Predicts Clinical Outcomes in Hypertensive Kidney Disease.
        J Am Soc Nephrol. 2017; 28: 2483-2490
        • Uribarri J.
        • Oh M.S.
        The Urine Anion Gap: Common Misconceptions.
        J Am Soc Nephrol. 2021; 32: 1025-1028
        • Tyson C.C.
        • Luciano A.
        • Modliszewski J.L.
        • et al.
        Effect of Bicarbonate on Net Acid Excretion, Blood Pressure, and Metabolism in Patients With and Without CKD: The Acid Base Compensation in CKD Study.
        Am J Kidney Dis. 2021; 78: 38-47
        • Goraya N.
        • Simoni J.
        • Sager L.N.
        • et al.
        Urine citrate excretion as a marker of acid retention in patients with chronic kidney disease without overt metabolic acidosis.
        Kidney Int. 2019; 95: 1190-1196