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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 of renal tubular acidosis" 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 :
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 Δanion gap/ΔHCO3 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:
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:
Association with progression of CKD — 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 [46,47,52-55]. The following examples illustrate the range of findings:
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 [57-63]. 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 (algorithm 1) . (See 'Development of metabolic acidosis' above and "Secondary factors and progression of chronic kidney disease" and "Endothelin and the kidney".)
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 [62,65]. 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 [58,65].
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) [68-70]. 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:
Slowing of CKD progression — Bicarbonate supplementation appears to slow the progression of CKD [71-74]. 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:
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.
A second trial randomly assigned 120 patients without metabolic acidosis who had mild CKD (mean estimated glomerular filtration rate [eGFR], 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). This study, which enrolled patients with early stage CKD, suggests that alkali therapy may help 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 [11,69,75]. 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 [11,76-78]. (See "Overview of chronic kidney disease-metabolic bone disease (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 [79-83]. 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) [79-81,84] 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 "Protein restriction and progression of chronic kidney disease".)
These abnormalities in muscle function and/or albumin metabolism can be reversed by alkali therapy to correct the acidosis , including optimal correction of acidosis in patients undergoing chronic dialysis [85,86]. 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 .
Alkali therapy may also be beneficial in children in whom acidemia can contribute to the impairment in growth [66,82]. 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 [84,87-89]. 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) [91,92]. 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 [92,93]. 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 [76,93]. 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 .
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