Bicarbonate therapy for prevention of chronic kidney disease progression
2013; Elsevier BV; Volume: 85; Issue: 3 Linguagem: Inglês
10.1038/ki.2013.401
ISSN1523-1755
AutoresIgor Łoniewski, Donald E. Wesson,
Tópico(s)Electrolyte and hormonal disorders
ResumoKidney injury in chronic kidney disease (CKD) is likely multifactorial, but recent data support that a component is mediated by mechanisms used by the kidney to increase acidification in response to an acid challenge to systemic acid–base status. If so, systemic alkalization might attenuate this acid-induced component of kidney injury. An acid challenge to systemic acid–base status increases nephron acidification through increased production of endothelin, aldosterone, and angiotensin II, each of which can contribute to kidney inflammation and fibrosis that characterizes CKD. Systemic alkalization that ameliorates an acid challenge might attenuate the contributions of angiotensin II, endothelin, and aldosterone to kidney injury. Some small clinical studies support the efficacy of alkalization in attenuating kidney injury and slowing glomerular filtration rate decline in CKD. This review focuses on the potential that orally administered NaHCO3 prevents CKD progression and additionally addresses its mechanism of action, side effects, possible complications, dosage, interaction, galenic form description, and contraindications. Current National Kidney Foundation guidelines recommend oral alkali, including NaHCO3-, in CKD patients with serum HCO3- <22mmol/l. Although oral alkali can be provided by other medications and by base-inducing dietary constituents, oral NaHCO3 will be the focus of this review because of its relative safety and apparent efficacy, and its comparatively low cost. Kidney injury in chronic kidney disease (CKD) is likely multifactorial, but recent data support that a component is mediated by mechanisms used by the kidney to increase acidification in response to an acid challenge to systemic acid–base status. If so, systemic alkalization might attenuate this acid-induced component of kidney injury. An acid challenge to systemic acid–base status increases nephron acidification through increased production of endothelin, aldosterone, and angiotensin II, each of which can contribute to kidney inflammation and fibrosis that characterizes CKD. Systemic alkalization that ameliorates an acid challenge might attenuate the contributions of angiotensin II, endothelin, and aldosterone to kidney injury. Some small clinical studies support the efficacy of alkalization in attenuating kidney injury and slowing glomerular filtration rate decline in CKD. This review focuses on the potential that orally administered NaHCO3 prevents CKD progression and additionally addresses its mechanism of action, side effects, possible complications, dosage, interaction, galenic form description, and contraindications. Current National Kidney Foundation guidelines recommend oral alkali, including NaHCO3-, in CKD patients with serum HCO3- <22mmol/l. Although oral alkali can be provided by other medications and by base-inducing dietary constituents, oral NaHCO3 will be the focus of this review because of its relative safety and apparent efficacy, and its comparatively low cost. Chronic kidney disease (CKD) is a disease of industrialized societies, and it affects approximately 11% of the population in developed countries. Some small-scale studies support that the acid-producing diets typical of industrialized societies contribute to CKD progression. In the USA alone, 11.2 million people are estimated to have Stage 1 and 2 CKD, and continuation of their acid-producing diets without alkali intervention might increase their risk for progression. The social and economic costs of CKD are high, and its prevalence and high treatment costs indicate a need for effective, safe, easily available, and inexpensive prevention. Currently recommended kidney-protective strategies fail to stop CKD in all patients, suggesting a need for complimentary or adjunctive therapies. Important acid–base-related factors that might contribute to the pathology and prevention of CKD include the following:1.Individuals with CKD have a reduced number of functioning nephrons, obligating more acid excretion per remaining nephron in response to the acid-producing diet typical of industrialized societies.2.Kidney mechanisms used to augment nephron acid excretion accomplish the short-term physiological goal of increased acid excretion, but these mechanisms might have pathological long-term consequences, including mediating progressive nephropathy.3.One approach to CKD prevention or progression includes reducing the dietary acid load that must be excreted by the kidney through ingestion of a less-acid-producing diet or adding a base, such as NaHCO3.4.Consequently, in addition to being effective, CKD prevention must be widely available, well tolerated, and inexpensive. Sodium bicarbonate (NaHCO3) is used in the treatment of a wide variety of metabolic acidoses, including renal tubular acidosis, and such treatment has been the topic of many textbooks of nephrology and reviews. It is also used to alkalize urine in patients with cystitis to provide symptomatic relief and prevent the formation of uric acid stones in the kidney. More recently, consideration for the therapeutic use of NaHCO3 has broadened to include its wider use in CKD management and/or prevention. The typical diet of individuals living in industrialized societies is high in acid-producing animal protein and comparatively low in base-producing proteins derived from fruits and vegetables (F+V). This diet produces about 1mEq of hydrogen ions (protons)/kilogram body weight (b.w.)/day.1.Kovesdy C.P. Metabolic acidosis and kidney disease: does bicarbonate therapy slow the progression of CKD?.Nephrol Dial Transplant. 2012; 27: 3056-3062Crossref PubMed Scopus (75) Google Scholar Elimination of protons and regeneration of alkali is done primarily by the kidney, but a detailed description of these processes is beyond the scope of this review. The proposed mechanisms by which acidosis in CKD can worsen the progression of the disease and that are responsible for complications are shown in Figure 1.1.Kovesdy C.P. Metabolic acidosis and kidney disease: does bicarbonate therapy slow the progression of CKD?.Nephrol Dial Transplant. 2012; 27: 3056-3062Crossref PubMed Scopus (75) Google Scholar Metabolic acidosis due to CKD has been associated with progressive deterioration of kidney function in experimental animals2.Phisitkul S. Hacker C. Simoni J. et al.Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors.Kidney Int. 2008; 73: 192-199Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar and patients.3.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; 7: 617-623Abstract Full Text Full Text PDF Scopus (234) Google Scholar On the other hand, a U-shaped association was found between serum bicarbonate concentration ([HCO3]) and all-cause mortality in CKD patients.4.Kovesdy C.P. Anderson J.E. Kalantar-Zadeh K. Association of serum bicarbonate levels with mortality in patients with non-dialysis-dependent CKD.Nephrol Dial Transplant. 2009; 24: 1232-1237Crossref PubMed Scopus (200) Google Scholar Depending on the study, the optimal serum [HCO3] in CKD varies widely, ranging from 22 to 32mEq/l.5.Navaneethan S.D. Schold J.D. Arrigain S. et al.Serum bicarbonate and mortality in stage 3 and stage 4 chronic kidney disease.Clin J Am Soc Nephrol. 2011; 6: 2395-2402Crossref PubMed Scopus (124) Google Scholar Kanda et al.6.Kanda E. Ai M. Yoshida M. et al.High serum bicarbonate level within the normal range prevents the progression of chronic kidney disease in elderly CKD patients.BMC Nephrol. 2013; 14: 4Crossref PubMed Scopus (25) Google Scholar found that low (<25th percentile) serum bicarbonate level is associated with CKD progression, and a 1-mEq/l increase in serum bicarbonate level (in normal range) was associated with low risk of CKD progression Dobre et al.7.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: 670-678Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar showed that low serum bicarbonate was an independent risk factor for CKD progression. On the other hand, the risk of heart failure in CKD patients was increased by 14% per 1-mEq/l increase in serum bicarbonate level over 24mEq/l, i.e., in normal range.7.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: 670-678Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar Other studies showed a direct and positive association between net endogenous acid production and progression of kidney disease.8.Scialla J.J. Appel L.J. Astor B.C. African American Study of Kidney Disease and Hypertension Study Group et al.Net endogenous acid production is associated with a faster decline in GFR in African Americans.Kidney Int. 2012; 82: 106-112Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar Because humans with reduced glomerular filtration rate (GFR),9.Wesson D.E. Simoni J. Broglio K. et al.Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone.Am J Physiol Renal Physiol. 2011; 300: F830-F837Crossref PubMed Scopus (164) Google Scholar similar to experimental animals with reduced GFR,10.Wesson D.E. Simoni J. Increased tissue acid mediates progressive GFR decline in animals with reduced nephron mass.Kidney Int. 2009; 75: 929-935Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar might have acid retention without reduced serum HCO3, reduced GFR without metabolic acidosis might also increase the risk for kidney disease. These observations led to interventional studies to help establish an alkalization strategy in CKD patients. Laboratory studies of CKD have typically used the 5/6 nephrectomy (Nx) model with metabolic acidosis2.Phisitkul S. Hacker C. Simoni J. et al.Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors.Kidney Int. 2008; 73: 192-199Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 10.Wesson D.E. Simoni J. Increased tissue acid mediates progressive GFR decline in animals with reduced nephron mass.Kidney Int. 2009; 75: 929-935Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar and the 2/3 Nx model that has greater GFR preservation but has acid retention (determined by kidney and skeletal muscle microdialysis) and no metabolic acidosis.11.Wesson D.E. Jo C.H. Simoni J. Angiotensin II receptors mediate increased distal nephron acidification caused by acid retention.Kidney Int. 2012; 82: 1184-1194Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar The favorable effect of NaHCO3 and other alkali supplementation in different CKD animal models is shown in Table 1.Table 1Favorable effect of NaHCO3 and alkali supplementation in different CKD animal modelsStudyModelResultNath et al.12.Nath K.A. Hostetter M.K. Hostetter T.H. Pathophysiology of chronic tubulo-interstitial disease in rats: interactions of dietary acid load, ammonia, and complement component C3.J Clin Invest. 1985; 76: 667-675Crossref PubMed Scopus (416) Google Scholar1¾ Nephrectomized rats↓Impairment of tubular function,↓histological evidence of tubulo interstitial damage,↓deposition of the complement components C3 and C5b-9,↓renal vein total ammonia concentrationPhisitkul et al.2.Phisitkul S. Hacker C. Simoni J. et al.Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors.Kidney Int. 2008; 73: 192-199Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar5/6 Nx rats and protein acidificationNaHCO3 in combination with anti-hypertensive therapy ameliorated metabolic acidosis and delayed GFR declineWesson et al.11.Wesson D.E. Jo C.H. Simoni J. Angiotensin II receptors mediate increased distal nephron acidification caused by acid retention.Kidney Int. 2012; 82: 1184-1194Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar2/3 Nx ratsCaHCO3 caused↓H+ retention,↓distal nephron acidification,↓plasma and kidney levels of AII, ET-1, and aldosteroneAbbreviations: AII, angiotensin II; CKD, chronic kidney disease; ET-1, endothelin-1; GFR, glomerular filtration rate. Open table in a new tab Abbreviations: AII, angiotensin II; CKD, chronic kidney disease; ET-1, endothelin-1; GFR, glomerular filtration rate. Small-scale studies that show a beneficial effect of oral NaHCO3 supplementation in CKD patients are presented in Table 2. Nevertheless, nephrologists appropriately await results of larger, long-term clinical studies before altering currently recommended CKD treatment strategies.Table 2Clinical studies of NaHCO3 supplementation in CKD patientsStudyPopulationInterventionResultsde Brito-Ashurst et al.13.de Brito-Ashurst I. Varagunam M. Raftery M.J. et al.Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (634) Google Scholar randomized open labelDuration: 2 yearsn=134, CrCl 15–30ml/min per1.73m2, plasma HCO3-, 16–20mmol/lControl group—standard careTest group—NaHCO3 3 × 600mg/day modified to achieve a serum bicarbonate level ≥23mml/l.The average dose of NaHCO3 was 1.82±0.80g/dayIn the NaHCO3 group:↓extent of decrease in CrCl (1.88±0.38 vs. 5.93±0.39; P<0.0001).↓dialysis requirement 6.5 vs. 33% (P<0.001).↓probability of progression to ESRD within 2 years after the study (8 vs. 33% (Kaplan–Meier analysis), P<0.001).↑dietary protein intake↑muscle massWesson et al.9.Wesson D.E. Simoni J. Broglio K. et al.Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone.Am J Physiol Renal Physiol. 2011; 300: F830-F837Crossref PubMed Scopus (164) Google Scholar placebo-controlled double blindDuration: 30 daysn=106, 26 CKD1 (eGFR 100.8±8.5ml/min per1.73m2), 80 CKD2 (eGFR 75.68±6.2ml/min per1.73m2)Control group: NaClTest group: NaHCO3 0.5 mEq/kg lean b.w.↓ H+ retention in CKD2.↓ plasma ET and aldosterone, but level of these parameters was higher in the CKD2 groupPhisitkul et al3.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; 7: 617-623Abstract Full Text Full Text PDF Scopus (234) Google Scholar open labelDuration: 24 months.n=59, eGFR 20–60ml/minper1.73m2, serum HCO3- 90ml/perminper 1.73m2) and 120 CKD2 (eGFR 60–90ml/minper 1.73m2), TCO2>22mmol/l)Three groups (control, or NaHCO3—0.5 mEq/kg b.w. daily, or fruit+vegetable diet (F+V)).CKD2 patients NaHCO3 and F+V:↓ albuminuria,↓ excretion of ET-1, transforming growth factor β (TGF-β), and N-acetyl-β-D-glucosaminidase.In CKD1 and CKD2 F+V groups: a greater reduction of blood pressure and diminished renal excretion of sodium, increased excretion of potassium. In CKD1 and CKD2 NaHCO3 groups: a greater reduction of serum aldosterone concentrationAbramowitz et al.16.Abramowitz M.K. Melamed M.L. Bauer C. et al.Effects of oral sodium bicarboante in patients with CKD.Clin J Am Soc Nephrol. 2013; 8: 714-720Crossref PubMed Scopus (97) Google Scholar single-blinded, placebo controlledDuration: 8 weeksN=20, eGFR 15-45ml/minper1.73m2, serum NaHCO3 20–24 mEq/lParticipants received during successive 2-week periods placebo and 0.3, 0.6, and 1.0mEq/kg escalating oral NaHCO3 dosesEach 0.1mEq/kg of NaHCO3 per day increase in dose caused an increase of serum bicarbonate level by 0.33mEq/l. NaHCO3: slight↓serum potassium level, small↑weight increase,↑muscle strengthGoraya et al.17.Goraya N. Simoni J. Jo C.H. et al.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: 371-381Crossref PubMed Scopus (253) Google Scholar randomized open labelDuration: 1 yearn=76, eGFR, 15-29ml/min per1.73m2, PTCO2 <22mmol/lOne group (n=35) received during 1 year oral NaHCO3 in a dose of 1.0 meEq/kg/day and the second (n=36) F+V to reduce daily acid by halfSimilar effect of both interventions on eGFR. In NaHCO3 group: higher increased PTCO2 (21.2±1.3 vs. 19.9±1.7mmol/l) and decreased net acid excretion. The same influence on eGFR and transforming growth factor β (TGF-β), and N-acetyl-β-D-glucosaminidase excretion. In NaHCO3 group:↑ urine K+ excretion↓ plasma [K+]↓ urine aldosterone excretion↓ ratio of active to inactive urine cortisol metabolitesSusantitaphong et al.18.Susantitaphong P. Sewaralthahab K. Balk E.M. et al.Short- and long-term effects of alkali therapy in chronic kidney disease: a systematic review.Am J Nephrol. 2012; 35: 540-547Crossref PubMed Scopus (74) Google Scholar meta-analysisShort term (≤7days) two studies, n=17; and long term (≥2 months) four studies, n=29521–180mEq/dayIn long-term studies, mean net changes in GFR, serum creatinine level, and serum urea nitrogen level occurred, that were beneficial for CKD patients. Increased serum bicarbonate and decreased serum potassium and chloride concentrations were also observed. Systolic and diastolic blood pressure were not affected by long-term NaHCO3 administration. The meta-analysis revealed that NaHCO3 therapy produced a net improvement in GFR of 3.2ml/min per1.73m2 and a 79% reduction in the incidence of dialysis requirementAbbreviations: b.w., body weight; CKD, chronic kidney disease; Cr, creatinine; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; ET-1, endothelin-1. Open table in a new tab Abbreviations: b.w., body weight; CKD, chronic kidney disease; Cr, creatinine; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; ET-1, endothelin-1. NaHCO3 given orally supplies bicarbonate ions indirectly (exchange of one HCO3- ion for each H+ ion used in the reaction in the gastric lumen; Figure 2) and directly (absorption from gastrointestinal tract, especially important in case of enteric capsules). There are several hypotheses explaining the apparent benefit of NaHCO3 in CKD patients. The acid environment of metabolic acidosis and/or acid retention might itself induce kidney injury, and alkalinization might reduce this injury directly by ameliorating this acid environment. On the other hand, dietary acid intake might cause kidney injury indirectly. Dietary acid augments kidney acidification through increased production of endothelin, aldosterone, and angiotensin II.11.Wesson D.E. Jo C.H. Simoni J. Angiotensin II receptors mediate increased distal nephron acidification caused by acid retention.Kidney Int. 2012; 82: 1184-1194Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar These agents augment distal nephron acidification in the short term, but might increase kidney inflammation and fibrosis over the longer term if increased dietary acid intake is sustained.2.Phisitkul S. Hacker C. Simoni J. et al.Dietary protein causes a decline in the glomerular filtration rate of the remnant kidney mediated by metabolic acidosis and endothelin receptors.Kidney Int. 2008; 73: 192-199Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar Therefore, alkalization that reduces acid retention9.Wesson D.E. Simoni J. Broglio K. et al.Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone.Am J Physiol Renal Physiol. 2011; 300: F830-F837Crossref PubMed Scopus (164) Google Scholar might be equivalent to drug therapies that reduce kidney levels of and/or effects of angiotensin II, endothelin, and aldosterone11.Wesson D.E. Jo C.H. Simoni J. Angiotensin II receptors mediate increased distal nephron acidification caused by acid retention.Kidney Int. 2012; 82: 1184-1194Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar and might thereby provide kidney protection with a better safety profile than pharmacological antagonists of angiotensin II, endothelin, and aldosterone. Some animal10.Wesson D.E. Simoni J. Increased tissue acid mediates progressive GFR decline in animals with reduced nephron mass.Kidney Int. 2009; 75: 929-935Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 11.Wesson D.E. Jo C.H. Simoni J. Angiotensin II receptors mediate increased distal nephron acidification caused by acid retention.Kidney Int. 2012; 82: 1184-1194Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar and human14.Mahajan A. Simoni J. Sheather S.J. et al.Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy.Kidney Int. 2010; 78: 303-309Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar studies suggest that dietary acid augments progressive nephropathy in the setting of reduced GFR in the absence of metabolic acidosis. Animals10.Wesson D.E. Simoni J. Increased tissue acid mediates progressive GFR decline in animals with reduced nephron mass.Kidney Int. 2009; 75: 929-935Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar and humans9.Wesson D.E. Simoni J. Broglio K. et al.Acid retention accompanies reduced GFR in humans and increases plasma levels of endothelin and aldosterone.Am J Physiol Renal Physiol. 2011; 300: F830-F837Crossref PubMed Scopus (164) Google Scholar with reduced GFR appear to have acid retention that is not reflected by plasma acid–base parameters but is ameliorated by dietary alkali. This proposed acid retention associated with reduced GFR without metabolic acidosis increases kidney levels of endothelin, aldosterone, and angiotensin II in animals11.Wesson D.E. Jo C.H. Simoni J. Angiotensin II receptors mediate increased distal nephron acidification caused by acid retention.Kidney Int. 2012; 82: 1184-1194Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar and plasma endothelin and aldosterone levels in humans.14.Mahajan A. Simoni J. Sheather S.J. et al.Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy.Kidney Int. 2010; 78: 303-309Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar The signal(s) leading to these changes in the absence of frank metabolic acidosis are not known but might include pH 'sensors'19.Sun X. Yang L.V. Tiegs B.C. et al.Deletion of the pH sensor GPR4 decreases renal acid excretion.J Amer Soc Nephrol. 2012; 21: 1745-1755Crossref Scopus (84) Google Scholar located in extra plasma compartments such as the kidney interstitium.10.Wesson D.E. Simoni J. Increased tissue acid mediates progressive GFR decline in animals with reduced nephron mass.Kidney Int. 2009; 75: 929-935Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar Consequently, dietary NaHCO3 might be protective in patients with reduced GFR without metabolic acidosis through the reduction of associated acid retention. The potential kidney-protective effects in patients with reduced GFR but no metabolic acidosis raises consideration as to whether it should be recommended kidney protection earlier in the course of CKD progression. Additional studies are necessary to establish precise criteria for indications concerning such therapy in CKD patients. In clinical studies to date, NaHCO3 has had few notable side effects when given to CKD patients.13.de Brito-Ashurst I. Varagunam M. Raftery M.J. et al.Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (634) Google Scholar, 16.Abramowitz M.K. Melamed M.L. Bauer C. et al.Effects of oral sodium bicarboante in patients with CKD.Clin J Am Soc Nephrol. 2013; 8: 714-720Crossref PubMed Scopus (97) Google Scholar, 18.Susantitaphong P. Sewaralthahab K. Balk E.M. et al.Short- and long-term effects of alkali therapy in chronic kidney disease: a systematic review.Am J Nephrol. 2012; 35: 540-547Crossref PubMed Scopus (74) Google Scholar Most of the common side effects were caused by CO2 released through a reaction in the stomach, as shown in Figure 2, and included belching, gastric distension, and flatulence. Practitioners must be aware that higher alkali doses might cause fluid retention and worse blood pressure control in patients treated with very low GFR. Short-term15.Goraya N. Simoni J. Jo C. et al.Dietary acid reduction with fruits and vegetables or bicarbonate attenuates kidney injury in patients with a moderately reduced glomerular filtration rate due to hypertensive nephropathy.Kidney Int. 2012; 81: 86-93Abstract Full Text Full Text PDF PubMed Scopus (237) Google Scholar and long-term14.Mahajan A. Simoni J. Sheather S.J. et al.Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy.Kidney Int. 2010; 78: 303-309Abstract Full Text Full Text PDF PubMed Scopus (286) Google Scholar studies also show that NaHCO3 therapy can reduce serum potassium, an outcome that can be beneficial in CKD patients who are at increased risk of hyperkalemia, particularly in the later stages of CKD and in such patients taking angiotensin-converting enzyme inhibitors.18.Susantitaphong P. Sewaralthahab K. Balk E.M. et al.Short- and long-term effects of alkali therapy in chronic kidney disease: a systematic review.Am J Nephrol. 2012; 35: 540-547Crossref PubMed Scopus (74) Google Scholar Exogenous NaHCO3 rarely causes metabolic alkalosis in patients with normal GFR and normal extracellular fluid volume,20.Madias N.E. Levey A.S. Metabolic alkalosis due to absorption of "nonabsorbable" antacids.Am J Med. 1983; 74: 155-158Abstract Full Text PDF PubMed Scopus (41) Google Scholar and it did not increase serum [HCO3] above normal when given for 1 year at 1mEq/kg b.w./day (5.9g /day for 70kg b.w.) to CKD stage 4 patients with metabolic acidosis.17.Goraya N. Simoni J. Jo C.H. et al.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: 371-381Crossref PubMed Scopus (253) Google Scholar Therefore, NaHCO3 at doses mostly used in CKD patients (2–3g/day) is unlikely to cause this complication. However, practitioners and patients must be mindful of all circumstances that can cause metabolic alkalosis (e.g., vomiting, diarrhea, and hypokalemia), and in such cases NaHCO3 should be temporarily discontinued. The recent study by Dobre et al.7.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: 670-678Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar revealed that even a slight increase of serum bicarbonate over 24mmol/l is associated with increased heart failure risk. Results of this study should increase vigilance when long-term alkali treatment is being considered. A special situation that can cause metabolic alkalosis is simultaneous ingestion of NaHCO3 and non-absorbable antacids (aluminum and magnesium carbonate) in combination with cation-exchange resins.20.Madias N.E. Levey A.S. Metabolic alkalosis due to absorption of "nonabsorbable" antacids.Am J Med. 1983; 74: 155-158Abstract Full Text PDF PubMed Scopus (41) Google Scholar This situation causes the formation of water-soluble and easily absorbable NaHCO3 in the small intestine.20.Madias N.E. Levey A.S. Metabolic alkalosis due to absorption of "nonabsorbable" antacids.Am J Med. 1983; 74: 155-158Abstract Full Text PDF PubMed Scopus (41) Google Scholar In this case, metabolic alkalosis can occur when base excretion from the extracellular fluid is limited. Another possible complication of NaHCO3 therapy is milk alkali syndrome that occurs only when NaHCO3 is administered with calcium. This syndrome occurs in patients who ingest large quantities of milk and antacids (to treat peptic ulcer disease), or, recently, in patients using calcium alkali salts to treat osteoporosis or individuals habitually chewing betel nuts in Asia.21.Lin S.H. Lin Y.F. Cheema-Dhadli S. et al.Hypercalca
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