Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — Most individuals produce approximately 15,000 mmol (considerably more with exercise) of carbon dioxide and 50 to 100 meq of nonvolatile acid each day. Acid-base balance is maintained by normal elimination of carbon dioxide by the lungs (which affects the partial pressure of carbon dioxide [PCO2]) and normal excretion of nonvolatile acid by the kidneys (which affects the plasma bicarbonate concentration). The hydrogen ion concentration of the blood is determined by the ratio of the PCO2 and plasma bicarbonate concentration. (See "Simple and mixed acid-base disorders", section on 'Introduction'.)
Acidosis associated with chronic kidney disease (CKD) will be discussed in this topic. An overview of simple acid-base disorders and renal tubular acidosis, as well as the approach to patients with metabolic acidosis, are presented elsewhere. (See "Simple and mixed acid-base disorders" and "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance" and "Approach to the adult with metabolic acidosis" and "Approach to the child with metabolic acidosis".)
ACID-BASE BALANCE IN CHRONIC KIDNEY DISEASE — Acid-base balance is normally maintained by the renal excretion of the daily acid load (about 1 meq/kg per day, derived mostly from the generation of sulfuric acid during the metabolism of sulfur-containing amino acids) [1,2]. Elimination of this acid load is achieved by the urinary excretion of hydrogen ions, both as titratable acidity and as ammonium . Near-normal balance can be maintained even if the acid load is modestly increased since net acid excretion rises appropriately, primarily via increased ammonium production and excretion (figure 1) .
Development of metabolic acidosis — Metabolic acidosis can develop as a result of one or more of the following pathophysiologic processes :
●Increased production of nonvolatile acids
●Increased loss of bicarbonate
●Decreased renal excretion of acid
Metabolic acidosis is commonly associated with chronic kidney disease (CKD) [6,7]. As the number of functioning nephrons declines in CKD, acid excretion is initially maintained by an increase in the ammonium excreted per nephron . However, total ammonium excretion begins to fall when the glomerular filtration rate (GFR) is below 40 to 50 mL/min [1,2,8]. At this level of renal function, ammonium excretion per total GFR is three to four times above normal, suggesting that the impairment in ammonium excretion is caused by too few functioning nephrons rather than impaired function in the remaining nephrons [1,9].
As a result, CKD leads to retention of hydrogen ions [1,6,8,10]. In addition to the fall in ammonium excretion, diminished excretion of titratable acid (primarily as phosphoric acid) also may play a role in the pathogenesis of metabolic acidosis in patients with advanced kidney disease. Both dietary phosphate restriction and the use of oral phosphate binders to prevent hyperphosphatemia may contribute to the fall in phosphate excretion.
The retained acid is buffered by bicarbonate in the extracellular fluid, by tissue buffers, and by bone . With worsening renal function, however, progressive metabolic acidosis and acidemia can develop. As a result, metabolic acidosis and acidemia become more common with advancing stages of CKD . The prevalence of a serum bicarbonate concentration of <22 meq/L, for example, is <5 percent in CKD stages 1 and 2 and increases linearly to approximately 25 percent in patients with non-dialysis dependent CKD stage G5 (table 1) . As the patient approaches end-stage renal disease (ESRD), the plasma bicarbonate concentration tends to stabilize between 12 and 20 meq/L [1,8,14]. A level below 10 meq/L is unusual since buffering of the retained hydrogen ions prevents a progressive fall in the plasma bicarbonate concentration. Typically, the anion gap remains normal until late stages of CKD when it begins to widen due to the retention of anions such as phosphate, sulfate, urate, and hippurate [14,15]. (See "Approach to the adult with metabolic acidosis".)
Dialysis patients — Initiation of renal replacement therapy typically results in improvement in metabolic acidosis as a result of the additional base load delivered in the dialysate, although metabolic acidosis can persist in patients who have higher net acid generation, typically those whose diet contains higher amounts of animal proteins [16,17].
Some patients undergoing maintenance dialysis have spuriously low plasma bicarbonate levels. If blood samples are transported from the dialysis clinic to the clinical laboratory by air freight, delayed centrifugation of the specimen may lead to increased lactic acid production by blood cells; this can artifactually reduce the plasma bicarbonate concentration .
In contrast, a small number of patients with ESRD have a normal plasma bicarbonate concentration and anion gap . A reduced daily acid load caused by decreased protein intake (which diminishes both acid and sulfate generation) and/or increased fruit intake (which provides citrate that is converted to bicarbonate) are the most likely explanations. For unclear reasons, most patients with ESRD who have a normal plasma bicarbonate and a normal anion gap also have diabetes mellitus .
A superimposed metabolic alkalosis (as occurs with vomiting or diuretic therapy) is another factor that could normalize the plasma bicarbonate concentration in advanced renal failure. In this setting, the anion gap should still be elevated. (See "Approach to the adult with metabolic acidosis" and "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis".)
Renal transplant recipients — A mild metabolic acidosis is frequently observed among kidney transplant recipients  even though the urinary acidification defects associated with CKD often resolve following allograft implantation . In one of the largest studies, the mean serum bicarbonate concentration was 22 meq/L among 823 unselected kidney transplant patients, with nearly 60 percent having levels less than 24 meq/L . Decreased kidney function, increased parathyroid hormone and phosphate levels, and decreased serum albumin and calcium levels were associated with lower bicarbonate levels.
Potential mechanisms responsible for post-transplant metabolic acidosis include the development of renal tubular acidosis (due, for example, to calcineurin inhibitors such as cyclosporine and tacrolimus), hyperkalemia, hypercalcemia, and disordered citrate metabolism and other tubular dysfunctions [23-27]. (See "Cyclosporine and tacrolimus nephrotoxicity", section on 'Metabolic acidosis' and "Potassium balance in acid-base disorders", section on 'Metabolic acidosis' and "Clinical manifestations of hypercalcemia", section on 'Renal tubular acidosis'.)
CONSEQUENCES OF METABOLIC ACIDOSIS IN CKD — Chronic metabolic acidosis in patients with chronic kidney disease (CKD) may produce a variety of pathophysiologic changes:
●Bone resorption and osteopenia [11,28-30]
●Increased muscle protein catabolism [7,31-35]
●Aggravation of secondary hyperparathyroidism [36,37]
●Reduced respiratory reserve and exhaustion of body buffer systems, resulting in increased severity of acute intercurrent illnesses 
●Endocrine disorders such as resistance to growth hormone and insulin, and hypertriglyceridemia [7,31,42]
●Systemic inflammation [43,44]
●Hypotension and malaise [6,7]
Association with mortality — Most observational studies in patients with non-dialysis dependent CKD [45-48] and end-stage renal disease (ESRD) [49-51] have described a significant association of metabolic acidosis with higher mortality. The following studies are representative:
●In a study of 1240 military veterans with non-dialysis dependent CKD, those whose serum bicarbonate was <22 meq/L had a significantly higher risk of mortality as compared with those whose bicarbonate was 26 to 29 meq/L (adjusted hazard ratio 1.43, 95% CI 1.10-1.87) .
●In 3939 patients from the Chronic Renal Insufficiency Cohort (CRIC) with CKD stages 2-4, the four-year mortality rate was higher among those with a serum bicarbonate less than or equal to 22 as compared with greater than 26 meq/L (approximately 3 versus 2 percent) . However, this association was not significant after controlling for other risk factors.
●In a study of 56,385 patients on maintenance hemodialysis, the two-year mortality rate was lowest among those whose serum bicarbonate was 17 to 19 meq/L . However, as noted above, most dialysis patients have a low serum bicarbonate; normal bicarbonate concentrations usually reflect reduced protein intake and malnutrition. After controlling their analysis for markers of poor nutrition, the authors found that patients who had a serum bicarbonate <22 meq/L had a significantly greater mortality risk as compared with patients who had higher values.
Association with progression of CKD — Observational studies in patients with non-dialysis dependent CKD have found that lower serum bicarbonate concentrations, higher net endogenous acid production, high dietary acid load, and inability to excrete acid are all associated with a higher risk of progressive renal function loss [46,47,52-60]. The following examples illustrate the range of findings:
●Among 1094 patients with CKD participating in the African American Study of Kidney Disease (AASK) trial, renal event rates (defined as ESRD, a 50 percent decline in glomerular filtration rate [GFR], or a 25 mL/min decline in GFR from baseline) were approximately three times higher in patients whose serum bicarbonate was <20 as compared with >25 meq/L . After controlling for other factors, a serum bicarbonate of 28 to 30 meq/L was associated with the lowest risk for renal events.
●Among 5422 patients followed in an urban medical clinic, those whose serum bicarbonate was ≤22 as compared with 25 to 26 meq/L had a significantly increased risk for progression of renal disease (defined as a 50 percent reduction in estimated GFR [eGFR] or reaching an eGFR less than 15 mL/min/1.73 m2; adjusted hazard ratio 1.54, 95% CI 1.13-2.09) .
●Among 3939 patients in the CRIC study mentioned above, lower serum bicarbonate was significantly associated with a higher risk of developing ESRD or having a 50 percent decline in eGFR (adjusted hazard ratio 0.97 for every 1 meq/L lower serum bicarbonate, 95% CI 0.94 to 0.99) .
●Among 632 patients enrolled in the AASK trial, higher net endogenous acid production was associated with a faster annual decline of measured GFR .
Lower serum bicarbonate is also associated with progressive loss of renal function among individuals without CKD [61,62]. As an example, in a multiethnic population of 5810 individuals with a baseline eGFR ≥60 mL/min/1.73 m2, those whose serum bicarbonate was <21 meq/L had a significantly increased risk for having rapid kidney function decline (ie, eGFR loss of more than 5 percent per year) compared with those whose serum bicarbonate was 23 to 24 meq/L (adjusted hazard ratio 1.35, 95% CI 1.05-1.73) .
Potential mechanisms for progression of CKD — The reason for the association between metabolic acidosis and more rapid progression of CKD is not clear and may not be causal. If causal, however, it may be due at least in part to the adaptive response of surviving nephrons to the loss of their neighboring nephrons [63-69]. Metabolic acidosis promotes an adaptive increase in ammonium excreted per nephron, which is associated with activation of the complement system, the renin-angiotensin system, and with increased renal production of endothelin-1, all of which may produce tubulointerstitial inflammation and chronic damage to the kidney . (See 'Development of metabolic acidosis' above and "Secondary factors and progression of chronic kidney disease".)
Endothelin-1 may play an important role in the nephrotoxicity associated with metabolic acidosis. In rats, for example, metabolic acidosis induced through either partial nephrectomy or dietary supplementation increases renal endothelin-1 and promotes progressive renal functional decline in the rat [68,71]. Both endothelin receptor antagonists and bicarbonate supplementation ameliorated the nephrotoxicity of the acidosis. However, the benefit was greater with bicarbonate supplementation, suggesting that other factors in addition to endothelin-1 contribute to the renal injury.
Another potential mechanism involves activation of the renin-angiotensin system, which is important for urinary acidification but which can also result in proteinuria , renal damage, and progressive CKD [64,71].
TREATMENT OF METABOLIC ACIDOSIS IN CKD — Children with acidemia are treated with bicarbonate therapy because acidemia impairs normal growth . Traditionally, however, exogenous alkali has not been used to treat the generally mild acidemia (arterial pH generally above 7.25) in asymptomatic adults with kidney disease. Reluctance to treat adults with sodium bicarbonate may reflect concerns that the increased sodium intake will exacerbate the volume expansion and hypertension that are commonly present in chronic kidney disease (CKD), or that raising the pH can precipitate tetany in patients with hypocalcemia.
However, sodium bicarbonate produces much less sodium retention and blood pressure elevation than comparable doses of sodium chloride . The factors responsible for this difference between bicarbonate and chloride are incompletely understood, although a similar phenomenon can be demonstrated in patients with salt-sensitive hypertension who have normal renal function. (See "Salt intake, salt restriction, and primary (essential) hypertension".)
Therapeutic approach — We broadly agree with 2013 Kidney Disease Improving Global Outcomes (KDIGO) guidelines that, in patients with CKD and metabolic acidosis, alkali therapy (usually with sodium bicarbonate) be used to maintain the serum bicarbonate concentration in the normal range (23 to 29 meq/L) [74-76]. The upper bound of this target range is less clear than the lower bound, especially since the association between serum bicarbonate and mortality appears to be U-shaped . (See 'Association with mortality' above.)
Alkali therapy usually consists of sodium bicarbonate or sodium citrate (citrate is rapidly metabolized to bicarbonate), typically in a dose of 0.5 to 1 meq/kg per day. Sodium citrate should be avoided in patients also taking aluminum-containing antacids.
Evidence supporting bicarbonate therapy — In addition to the adverse physiologic consequences linked to metabolic acidosis in CKD and the observational studies showing an association of metabolic acidosis with mortality and CKD progression, the rationale behind this approach is based upon randomized trials showing benefits of alkali therapy on:
●Progression of CKD
Slowing of CKD progression — Bicarbonate supplementation appears to slow the progression of CKD [77-81]. The best data come from a single-center trial of 134 patients with stage 4 CKD (creatinine clearance, 15 to 30 mL/min/1.73 m2) and metabolic acidosis (baseline serum bicarbonate, 16 to 20 meq/L) randomly assigned to oral sodium bicarbonate, beginning with a dose of 600 mg three times daily and increased as needed to achieve a serum bicarbonate ≥23 meq/L, or to no treatment . At two years of follow-up, the following significant benefits of bicarbonate supplementation were observed:
●A lower mean rate of decline of creatinine clearance compared with the control group (1.88 versus 5.93 mL/min/1.73 m2 per year)
●A lower risk of having an annual decline in creatinine clearance of at least 3 mL/min/1.73 m2 (9 versus 45 percent)
●A lower risk of end-stage renal disease (ESRD) (4 versus 22 patients [6.5 versus 33 percent])
Patients in the bicarbonate group were more likely to develop edema and worsened hypertension requiring intensification of therapy, although this difference was not statistically significant. Other concerns about this trial include its open-label design, lack of a placebo control, and small number of events. In addition, the effect size (an 87 percent reduction in the relative risk for ESRD) is considerably larger than the true effects of most rigorously studied interventions. As an example, treating hypertensive patients with antihypertensive medications reduces the relative risk of cardiovascular events by only 20 to 40 percent . Provided that bicarbonate therapy does not substantially increase the rate of uncontrolled hypertension nor impair compliance with other therapies in patients with CKD, there seems to be little downside to its use while awaiting additional data to confirm the clinical benefit.
Two trials by the same investigators demonstrated a benefit from alkali therapy in patients with mild CKD who did not have metabolic acidosis (serum bicarbonate 22 to 24 meq/L). The first trial randomly assigned 120 patients with a mean estimated glomerular filtration rate (eGFR) of 75 mL/min/1.73 m2 and an albumin-to-creatinine ratio >300 mg/g to sodium bicarbonate, sodium chloride (each at 0.5 meq/kg per day), or to matching placebo . At five years, the annual rate of decline in eGFR was slightly but significantly smaller in the sodium bicarbonate group (-1.5 min/min/1.73 m2) as compared with the sodium chloride and placebo groups (-2.0 and -2.1 mL/min/1.73 m2, respectively). The second trial randomly assigned 108 patients with stage 3 CKD (eGFR 30 to 59 mL/min/1.73 m2) to usual care or to alkali therapy achieved with sodium bicarbonate supplements or base-producing fruits and vegetables. At three years, eGFR decreased less in the high alkali group . These studies, which enrolled patients with early CKD, suggest that alkali therapy may help to prevent the potentially harmful features associated with the kidney's adaptive response to a decreased number of functioning nephrons and therefore a decreased ability to excrete the daily acid load. (See 'Potential mechanisms for progression of CKD' above.)
Prevention of bone buffering — Bone buffering of some of the excess hydrogen ions is associated with the release of calcium and phosphate from bone [11,75,82]. Hypocalciuria is one of the earliest findings in renal failure; therefore, calcium released from bone is probably lost in stool. Preventing this change may minimize the degree of negative calcium balance and prevent or delay the progression both of osteopenia and of hyperparathyroid bone disease [11,83-85]. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
A study of 21 patients on maintenance hemodialysis suggests that correction of metabolic acidosis improves metabolic bone disease. Patients were randomly assigned to therapy with a standard bath or a bicarbonate-supplemented bath . The predialysis plasma bicarbonate concentrations were 15.6 and 24 meq/L, respectively. At 18 months, osteoid and osteoblastic surfaces and the plasma PTH level increased in the control group but were unchanged in patients in whom the acidosis was corrected. A similar benefit in terms of improved PTH control with bicarbonate therapy was observed in a randomized trial of patients with mild to moderate CKD .
Correction of acidosis may act in part by diminishing the stimulus to hyperparathyroidism . This mechanism was suggested in a report of eight patients on maintenance hemodialysis . Enhanced therapy of acidosis with bicarbonate-supplemented dialysate (40 meq/L) resulted in increased sensitivity of the parathyroid glands to ionized calcium.
Improved nutritional status and lean body mass — Uremic acidosis can increase skeletal muscle breakdown and diminish albumin synthesis, leading to muscle wasting and muscle weakness [86-90]. The hypercatabolic state appears to be mediated by acidosis, acting in part by increased release of cortisol and diminished release of insulin-like growth factor-I (IGF-I) [86-88,91] and by inhibition of insulin signaling through phosphoinositide 3-kinase , leading to loss of lean body mass and muscle weakness . The degree of muscle breakdown may be exacerbated by institution of a low-protein diet, which is occasionally used in an attempt to minimize progressive renal injury . (See "Dietary recommendations for patients with nondialysis CKD".)
These abnormalities in muscle function and/or albumin metabolism can be reversed by alkali therapy to correct the acidosis [88,92], including optimal correction of acidosis in patients undergoing chronic dialysis [93,94]. In the previously cited randomized trial, bicarbonate significantly improved dietary protein intake and decreased protein catabolism in parallel with increased serum albumin and lean body mass in predialysis patients with CKD . In a small pilot study, the administration of sodium bicarbonate to 20 patients with an eGFR of 15 to 45 ml/min/1.73 m2 resulted in a dose-dependent improvement in muscle strength .
Alkali therapy may also be beneficial in children in whom acidemia can contribute to the impairment in growth [72,89]. Experimental studies have identified a number of abnormalities in the growth hormone axis that are induced by metabolic acidosis and may contribute to the inhibition of growth. These include impaired pulsatile growth hormone secretion, decreased production and plasma levels of IGF-I due at least in part to an impaired hepatic response to circulating growth hormone, and reduced hepatic mRNA for the growth hormone receptor [91,95-97]. Improvement in growth hormone sensitivity has also been described in adults . (See "Growth hormone treatment in children with chronic kidney disease and postrenal transplantation".)
Choice of therapy — Alkali therapy usually consists of sodium bicarbonate or sodium citrate (citrate is rapidly metabolized to bicarbonate), typically in a dose of 0.5 to 1 meq/kg per day. We generally prefer citrate, which does not produce the bloating associated with bicarbonate therapy. However, sodium citrate should be avoided in patients also taking aluminum-containing antacids, as citrate markedly enhances intestinal aluminum absorption both by keeping aluminum soluble (via the formation of aluminum citrate) and by complexing with calcium in the intestinal lumen; the ensuing fall in the free calcium concentration can increase the permeability of the tight junctions of bowel epithelia, a change that can markedly enhance the passive absorption of aluminum (figure 2) [99,100]. As a result, patients taking aluminum-containing antacids to control hyperphosphatemia are at increased risk of developing aluminum intoxication if they are treated with sodium citrate [100,101]. However, aluminum-based phosphate binders are seldom used.
Metabolic acidosis can also be treated using calcium citrate, calcium acetate, or calcium carbonate. In addition, a small study of normokalemic patients with stage 4 CKD showed that dietary modification to increase consumption of fruits and vegetables (ie, an alkaline-ash diet) increased the serum bicarbonate above baseline levels, but to a lesser degree than sodium bicarbonate supplementation . However, because such diets are high in potassium, this approach to treating CKD patients with metabolic acidosis is associated with greater risk . The specific regimen should be individualized based upon patient tolerance, affordability, and individual comorbidities and biochemical characteristics.
In patients on maintenance dialysis, an alternative method to correct the metabolic acidosis is to increase the bicarbonate concentration of the dialysate [83,101]. Levels as high as 42 meq/L may be required with hemodialysis to prevent predialysis acidosis. When implemented correctly, this regimen is generally well-tolerated and does not induce significant postdialysis alkalosis . However, it is possible that dialysate preparations containing higher amounts of bicarbonate equivalents (such as acetate or citrate) could induce significant metabolic alkalosis .
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders".)
SUMMARY AND RECOMMENDATIONS
●Acid-base balance is normally maintained by the renal excretion of the daily acid load; elimination of this acid load is achieved by the urinary excretion of hydrogen ions, both as titratable acidity and as ammonium. Near-normal balance can be maintained even if the acid load is modestly increased since acid excretion rises appropriately, primarily via increased ammonium production and excretion (figure 1). (See 'Acid-base balance in chronic kidney disease' above.)
●As the number of functioning nephrons declines in chronic kidney disease (CKD), acid excretion is initially maintained by an increase in the ammonium excreted per nephron. However, total ammonium excretion begins to fall when the glomerular filtration rate (GFR) is below 40 to 50 mL/min. As a result, CKD leads to retention of hydrogen ions. The retained acid is buffered by bicarbonate in the extracellular fluid, by tissue buffers, and by bone. With worsening renal function, however, progressive metabolic acidosis can develop. (See 'Development of metabolic acidosis' above.)
●Chronic metabolic acidosis in patients with CKD may produce a variety of pathophysiologic changes (see 'Consequences of metabolic acidosis in CKD' above):
•Bone resorption and osteopenia
•Increased muscle protein catabolism
•Aggravation of secondary hyperparathyroidism
•Reduced respiratory reserve and exhaustion of body buffer systems, resulting in increased severity of acute intercurrent illnesses
•Reduced Na+-K+-ATPase activity in red blood cells and myocardial cells, which could impair myocardial contractility and produce congestive heart failure
•Endocrine disorders such as resistance to growth hormone, insulin resistance, and hypertriglyceridemia
•Hypotension and malaise
●Observational studies in patients with non-dialysis dependent CKD and end-stage renal disease (ESRD) have described a significant association of metabolic acidosis with higher mortality. (See 'Association with mortality' above.)
●Observational studies in patients with non-dialysis dependent CKD have found that lower serum bicarbonate concentrations are associated with a higher risk of progressive renal function loss. The reason for this association is not clear, but several mechanisms have been proposed. (See 'Association with progression of CKD' above and 'Potential mechanisms for progression of CKD' above.)
●Our approach to therapy of metabolic acidosis in patients with CKD (described in the next bullet) is based upon randomized trials showing benefits of alkali therapy on (see 'Evidence supporting bicarbonate therapy' above):
•Progression of CKD (see 'Slowing of CKD progression' above)
•Bone health (see 'Prevention of bone buffering' above)
•Nutritional status (see 'Improved nutritional status and lean body mass' above)
●In patients with CKD who have metabolic acidosis, we suggest alkali therapy (Grade 2B). We aim to maintain the serum bicarbonate concentration in the normal range (23 to 29 meq/L). Alkali therapy in such patients usually consists of sodium bicarbonate or sodium citrate (citrate is rapidly metabolized to bicarbonate), typically in a daily dose of 0.5 to 1 meq/kg per day. Sodium citrate should be avoided in patients also taking aluminum-containing antacids. In patients on maintenance dialysis, an alternative method to correct the metabolic acidosis is to increase the bicarbonate concentration in the dialysate. (See 'Therapeutic approach' above and 'Choice of therapy' above.)
- Warnock DG. Uremic acidosis. Kidney Int 1988; 34:278.
- Bailey JL. Metabolic acidosis: an unrecognized cause of morbidity in the patient with chronic kidney disease. Kidney Int Suppl 2005; :S15.
- Moe OW, Rector FC, Alpern RJ. Renal regulation of acid-base metabolism. In: Maxwell and Kleeman's Clinical Disorders of Fluid and Electrolyte Metabolism, 5th ed, Narins RG (Ed), McGraw-Hill, Inc., New York 1994. p.203.
- Garibotto G, Sofia A, Robaudo C, et al. Kidney protein dynamics and ammoniagenesis in humans with chronic metabolic acidosis. J Am Soc Nephrol 2004; 15:1606.
- GOODMAN AD, LEMANN J Jr, LENNON EJ, RELMAN AS. PRODUCTION, EXCRETION, AND NET BALANCE OF FIXED ACID IN PATIENTS WITH RENAL ACIDOSIS. J Clin Invest 1965; 44:495.
- Kraut JA, Kurtz I. Metabolic acidosis of CKD: diagnosis, clinical characteristics, and treatment. Am J Kidney Dis 2005; 45:978.
- Kopple JD, Kalantar-Zadeh K, Mehrotra R. Risks of chronic metabolic acidosis in patients with chronic kidney disease. Kidney Int Suppl 2005; :S21.
- Widmer B, Gerhardt RE, Harrington JT, Cohen JJ. Serum electrolyte and acid base composition. The influence of graded degrees of chronic renal failure. Arch Intern Med 1979; 139:1099.
- Welbourne T, Weber M, Bank N. The effect of glutamine administration on urinary ammonium excretion in normal subjects and patients with renal disease. J Clin Invest 1972; 51:1852.
- Uribarri J, Douyon H, Oh MS. A re-evaluation of the urinary parameters of acid production and excretion in patients with chronic renal acidosis. Kidney Int 1995; 47:624.
- Lemann J Jr, Litzow JR, Lennon EJ. The effects of chronic acid loads in normal man: further evidence for the participation of bone mineral in the defense against chronic metabolic acidosis. J Clin Invest 1966; 45:1608.
- Eustace JA, Astor B, Muntner PM, et al. Prevalence of acidosis and inflammation and their association with low serum albumin in chronic kidney disease. Kidney Int 2004; 65:1031.
- Kovesdy CP. Metabolic acidosis and kidney disease: does bicarbonate therapy slow the progression of CKD? Nephrol Dial Transplant 2012; 27:3056.
- Wallia R, Greenberg A, Piraino B, et al. Serum electrolyte patterns in end-stage renal disease. Am J Kidney Dis 1986; 8:98.
- Hakim RM, Lazarus JM. Biochemical parameters in chronic renal failure. Am J Kidney Dis 1988; 11:238.
- Kurtz I, Maher T, Hulter HN, et al. Effect of diet on plasma acid-base composition in normal humans. Kidney Int 1983; 24:670.
- Uribarri J, Levin NW, Delmez J, et al. Association of acidosis and nutritional parameters in hemodialysis patients. Am J Kidney Dis 1999; 34:493.
- Kirschbaum B. Spurious metabolic acidosis in hemodialysis patients. Am J Kidney Dis 2000; 35:1068.
- Caravaca F, Arrobas M, Pizarro JL, Espárrago JF. Metabolic acidosis in advanced renal failure: differences between diabetic and nondiabetic patients. Am J Kidney Dis 1999; 33:892.
- Ambühl PM. Posttransplant metabolic acidosis: a neglected factor in renal transplantation? Curr Opin Nephrol Hypertens 2007; 16:379.
- Better OS, Chaimowitz C, Alroy GG, Sisman I. Spontaneous remission of the defect in urinary acidification after cadaver kidney homotransplantation. Lancet 1970; 1:110.
- Yakupoglu HY, Corsenca A, Wahl P, et al. Posttransplant acidosis and associated disorders of mineral metabolism in patients with a renal graft. Transplantation 2007; 84:1151.
- Massry SG, Preuss HG, Maher JF, Schreiner GE. Renal tubular acidosis after cadaver kidney homotransplantation. Studies on mechanism. Am J Med 1967; 42:284.
- Better OS, Chaimowitz C, Naveh Y, et al. Syndrome of incomplete renal tubular acidosis after cadaver kidney transplantation. Ann Intern Med 1969; 71:39.
- Györy AZ, Stewart JH, George CR, et al. Renal tubular acidosis, acidosis due to hyperkalaemia, hypercalcaemia, disordered citrate metabolism and other tubular dysfunctions following human renal transplantation. Q J Med 1969; 38:231.
- Schwarz C, Benesch T, Kodras K, et al. Complete renal tubular acidosis late after kidney transplantation. Nephrol Dial Transplant 2006; 21:2615.
- Better OS. Tubular dysfunction following kidney transplantation. Nephron 1980; 25:209.
- Green J, Kleeman CR. Role of bone in regulation of systemic acid-base balance. Kidney Int 1991; 39:9.
- Krieger NS, Frick KK, Bushinsky DA. Mechanism of acid-induced bone resorption. Curr Opin Nephrol Hypertens 2004; 13:423.
- Bushinsky DA, Ori Y. Effects of metabolic and respiratory acidosis on bone. Curr Opin Nephrol Hypertens 1993; 2:588.
- Franch HA, Raissi S, Wang X, et al. Acidosis impairs insulin receptor substrate-1-associated phosphoinositide 3-kinase signaling in muscle cells: consequences on proteolysis. Am J Physiol Renal Physiol 2004; 287:F700.
- Mitch WE. Influence of metabolic acidosis on nutrition. Am J Kidney Dis 1997; 29:xlvi.
- Franch HA, Mitch WE. Catabolism in uremia: the impact of metabolic acidosis. J Am Soc Nephrol 1998; 9:S78.
- Graham KA, Reaich D, Channon SM, et al. Correction of acidosis in hemodialysis decreases whole-body protein degradation. J Am Soc Nephrol 1997; 8:632.
- May RC, Masud T, Logue B, et al. Metabolic acidosis accelerates whole body protein degradation and leucine oxidation by a glucocorticoid-dependent mechanism. Miner Electrolyte Metab 1992; 18:245.
- Greenberg AJ, McNamara H, McCrory WW. Metabolic balance studies in primary renal tubular acidosis: effects of acidosis on external calcium and phosphorus balances. J Pediatr 1966; 69:610.
- Graham KA, Hoenich NA, Tarbit M, et al. Correction of acidosis in hemodialysis patients increases the sensitivity of the parathyroid glands to calcium. J Am Soc Nephrol 1997; 8:627.
- Tuso PJ, Nissenson AR, Danovitch GM. Electrolyte disorders in chronic renal failure. In: Maxwell and Kleeman's Clinical Disorders of Fluid and Electrolyte Metabolism, 5th ed, Narins RG (Ed), McGraw-Hill, Inc., New York City 1994. p.1195.
- Levin ML, Rector FC Jr, Seldin DW. The effects of chronic hypokalaemia, hyponatraemia, and acid-base alterations on erythrocyte sodium transport. Clin Sci 1972; 43:251.
- Brown RH Jr, Cohen I, Noble D. The interactions of protons, calcium and potassium ions on cardiac Purkinje fibres. J Physiol 1978; 282:345.
- Mitchell JH, Wildenthal K, Johnson RL Jr. The effects of acid-base disturbances on cardiovascular and pulmonary function. Kidney Int 1972; 1:375.
- Ordóñez FA, Santos F, Martínez V, et al. Resistance to growth hormone and insulin-like growth factor-I in acidotic rats. Pediatr Nephrol 2000; 14:720.
- Kalantar-Zadeh K, Mehrotra R, Fouque D, Kopple JD. Metabolic acidosis and malnutrition-inflammation complex syndrome in chronic renal failure. Semin Dial 2004; 17:455.
- Bellocq A, Suberville S, Philippe C, et al. Low environmental pH is responsible for the induction of nitric-oxide synthase in macrophages. Evidence for involvement of nuclear factor-kappaB activation. J Biol Chem 1998; 273:5086.
- Raphael KL, Zhang Y, Wei G, et al. Serum bicarbonate and mortality in adults in NHANES III. Nephrol Dial Transplant 2013; 28:1207.
- Kovesdy CP, Anderson JE, Kalantar-Zadeh K. Association of serum bicarbonate levels with mortality in patients with non-dialysis-dependent CKD. Nephrol Dial Transplant 2009; 24:1232.
- Raphael KL, Wei G, Baird BC, et al. Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans. Kidney Int 2011; 79:356.
- 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. Am J Kidney Dis 2013; 62:670.
- Bommer J, Locatelli F, Satayathum S, et al. Association of predialysis serum bicarbonate levels with risk of mortality and hospitalization in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis 2004; 44:661.
- Lowrie EG, Lew NL. Death risk in hemodialysis patients: the predictive value of commonly measured variables and an evaluation of death rate differences between facilities. Am J Kidney Dis 1990; 15:458.
- Wu DY, Shinaberger CS, Regidor DL, et al. Association between serum bicarbonate and death in hemodialysis patients: is it better to be acidotic or alkalotic? Clin J Am Soc Nephrol 2006; 1:70.
- Shah SN, Abramowitz M, Hostetter TH, Melamed ML. Serum bicarbonate levels and the progression of kidney disease: a cohort study. Am J Kidney Dis 2009; 54:270.
- de Brito-Ashurst I, Varagunam M, Raftery MJ, et al. The effect of metabolic acidosis on the rate of decline of glomerular filtration rate in patients with stage 4 chronic kidney disease. Nephrology 2005; 10 (Suppl):A248 (abstr).
- Kovesdy CP, Kalantar-Zadeh K. Oral bicarbonate: renoprotective in CKD? Nat Rev Nephrol 2010; 6:15.
- Menon V, Tighiouart H, Vaughn NS, et al. Serum bicarbonate and long-term outcomes in CKD. Am J Kidney Dis 2010; 56:907.
- Scialla JJ, Appel LJ, Astor BC, et al. Net endogenous acid production is associated with a faster decline in GFR in African Americans. Kidney Int 2012; 82:106.
- Kanda E, Ai M, Kuriyama R, et al. Dietary acid intake and kidney disease progression in the elderly. Am J Nephrol 2014; 39:145.
- Rebholz CM, Coresh J, Grams ME, et al. Dietary Acid Load and Incident Chronic Kidney Disease: Results from the ARIC Study. Am J Nephrol 2015; 42:427.
- Vallet M, Metzger M, Haymann JP, et al. Urinary ammonia and long-term outcomes in chronic kidney disease. Kidney Int 2015; 88:137.
- Banerjee T, Crews DC, Wesson DE, et al. High Dietary Acid Load Predicts ESRD among Adults with CKD. J Am Soc Nephrol 2015; 26:1693.
- Driver TH, Shlipak MG, Katz R, et al. Low serum bicarbonate and kidney function decline: the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Kidney Dis 2014; 64:534.
- Goldenstein L, Driver TH, Fried LF, et al. Serum bicarbonate concentrations and kidney disease progression in community-living elders: the Health, Aging, and Body Composition (Health ABC) Study. Am J Kidney Dis 2014; 64:542.
- Nath KA, Hostetter MK, Hostetter TH. Pathophysiology of chronic tubulo-interstitial disease in rats. Interactions of dietary acid load, ammonia, and complement component C3. J Clin Invest 1985; 76:667.
- Ng HY, Chen HC, Tsai YC, et al. Activation of intrarenal renin-angiotensin system during metabolic acidosis. Am J Nephrol 2011; 34:55.
- Halperin ML, Ethier JH, Kamel KS. Ammonium excretion in chronic metabolic acidosis: benefits and risks. Am J Kidney Dis 1989; 14:267.
- Torres VE, Mujwid DK, Wilson DM, Holley KH. Renal cystic disease and ammoniagenesis in Han:SPRD rats. J Am Soc Nephrol 1994; 5:1193.
- Wesson DE. Regulation of kidney acid excretion by endothelins. Kidney Int 2006; 70:2066.
- Wesson DE, Nathan T, Rose T, et al. Dietary protein induces endothelin-mediated kidney injury through enhanced intrinsic acid production. Kidney Int 2007; 71:210.
- Wesson DE, 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.
- Frassetto LA, Hsu CY. Metabolic acidosis and progression of chronic kidney disease. J Am Soc Nephrol 2009; 20:1869.
- Wesson DE, Simoni J. Acid retention during kidney failure induces endothelin and aldosterone production which lead to progressive GFR decline, a situation ameliorated by alkali diet. Kidney Int 2010; 78:1128.
- McSherry E, Morris RC Jr. Attainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular acidosis. J Clin Invest 1978; 61:509.
- Husted FC, Nolph KD, Maher JF. NaHCO3 and NaC1 tolerance in chronic renal failure. J Clin Invest 1975; 56:414.
- Chapter 3: Management of progression and complications of CKD. Kidney Int Suppl (2011) 2013; 3:73.
- Alpern RJ, Sakhaee K. The clinical spectrum of chronic metabolic acidosis: homeostatic mechanisms produce significant morbidity. Am J Kidney Dis 1997; 29:291.
- Mitch WE. Dietary protein restriction in patients with chronic renal failure. Kidney Int 1991; 40:326.
- de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol 2009; 20:2075.
- Mahajan A, Simoni J, Sheather SJ, et al. Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy. Kidney Int 2010; 78:303.
- 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. Kidney Int 2010; 77:617.
- Rustom R, Grime JS, Costigan M, et al. Oral sodium bicarbonate reduces proximal renal tubular peptide catabolism, ammoniogenesis, and tubular damage in renal patients. Ren Fail 1998; 20:371.
- Goraya N, Simoni J, Jo CH, Wesson DE. 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.
- Bushinsky DA. The contribution of acidosis to renal osteodystrophy. Kidney Int 1995; 47:1816.
- Lefebvre A, de Vernejoul MC, Gueris J, et al. Optimal correction of acidosis changes progression of dialysis osteodystrophy. Kidney Int 1989; 36:1112.
- Mathur RP, Dash SC, Gupta N, et al. Effects of correction of metabolic acidosis on blood urea and bone metabolism in patients with mild to moderate chronic kidney disease: a prospective randomized single blind controlled trial. Ren Fail 2006; 28:1.
- Starke A, Corsenca A, Kohler T, et al. Correction of metabolic acidosis with potassium citrate in renal transplant patients and its effect on bone quality. Clin J Am Soc Nephrol 2012; 7:1461.
- Williams B, Hattersley J, Layward E, Walls J. Metabolic acidosis and skeletal muscle adaptation to low protein diets in chronic uremia. Kidney Int 1991; 40:779.
- Garibotto G, Russo R, Sofia A, et al. Skeletal muscle protein synthesis and degradation in patients with chronic renal failure. Kidney Int 1994; 45:1432.
- Bailey JL, Wang X, England BK, et al. The acidosis of chronic renal failure activates muscle proteolysis in rats by augmenting transcription of genes encoding proteins of the ATP-dependent ubiquitin-proteasome pathway. J Clin Invest 1996; 97:1447.
- Boirie Y, Broyer M, Gagnadoux MF, et al. Alterations of protein metabolism by metabolic acidosis in children with chronic renal failure. Kidney Int 2000; 58:236.
- Löfberg E, Gutierrez A, Anderstam B, et al. Effect of bicarbonate on muscle protein in patients receiving hemodialysis. Am J Kidney Dis 2006; 48:419.
- Ballmer PE, McNurlan MA, Hulter HN, et al. Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans. J Clin Invest 1995; 95:39.
- Abramowitz MK, Melamed ML, Bauer C, et al. Effects of oral sodium bicarbonate in patients with CKD. Clin J Am Soc Nephrol 2013; 8:714.
- Graham KA, Reaich D, Channon SM, et al. Correction of acidosis in CAPD decreases whole body protein degradation. Kidney Int 1996; 49:1396.
- Movilli E, Zani R, Carli O, et al. Correction of metabolic acidosis increases serum albumin concentrations and decreases kinetically evaluated protein intake in haemodialysis patients: a prospective study. Nephrol Dial Transplant 1998; 13:1719.
- Challa A, Krieg RJ Jr, Thabet MA, et al. Metabolic acidosis inhibits growth hormone secretion in rats: mechanism of growth retardation. Am J Physiol 1993; 265:E547.
- Challa A, Chan W, Krieg RJ Jr, et al. Effect of metabolic acidosis on the expression of insulin-like growth factor and growth hormone receptor. Kidney Int 1993; 44:1224.
- Brüngger M, Hulter HN, Krapf R. Effect of chronic metabolic acidosis on the growth hormone/IGF-1 endocrine axis: new cause of growth hormone insensitivity in humans. Kidney Int 1997; 51:216.
- Wiederkehr MR, Kalogiros J, Krapf R. Correction of metabolic acidosis improves thyroid and growth hormone axes in haemodialysis patients. Nephrol Dial Transplant 2004; 19:1190.
- Molitoris BA, Froment DH, Mackenzie TA, et al. Citrate: a major factor in the toxicity of orally administered aluminum compounds. Kidney Int 1989; 36:949.
- Nolan CR, Califano JR, Butzin CA. Influence of calcium acetate or calcium citrate on intestinal aluminum absorption. Kidney Int 1990; 38:937.
- Walker JA, Sherman RA, Cody RP. The effect of oral bases on enteral aluminum absorption. Arch Intern Med 1990; 150:2037.
- Goraya N, Simoni J, Jo CH, Wesson DE. A comparison of treating metabolic acidosis in CKD stage 4 hypertensive kidney disease with fruits and vegetables or sodium bicarbonate. Clin J Am Soc Nephrol 2013; 8:371.
- Yaqoob MM. Treatment of acidosis in CKD. Clin J Am Soc Nephrol 2013; 8:342.
- Oettinger CW, Oliver JC. Normalization of uremic acidosis in hemodialysis patients with a high bicarbonate dialysate. J Am Soc Nephrol 1993; 3:1804.
- Saikumar JH, Kovesdy CP. Bicarbonate Therapy in End-Stage Renal Disease: Current Practice Trends and Implications. Semin Dial 2015; 28:370.