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ALKALINE pH Metabolic in Chronic Disease: A Clinical Update

> Introduction > Clinical Findings > Pathophysiology > Complications > Management > Conclusion Introduction Pathophysiology is a common hallmark of CKD as a cause of metabolic acidosis advanced chronic (CKD), and in The kidney has the primary role of maintaining this setting it is generally defined as persistently acid-base balance, which is normally low serum levels of < 22 mEq/L.1 accomplished by the renal excretion of the daily Although most non- patients have normal acid load.19 serum bicarbonate levels due to compensatory renal production and bone buffering,2,3,4 However, as kidney function declines, net metabolic acidosis has a prevalence in CKD of functional nephron loss results in net acid approximately 15%-19% overall.5,6,7,8,9 However, retention exceeding net acid excretion. Acid is prevalence increases as kidney function then retained in various tissues and increases declines.7,10 their acidity; when this acid pool reaches a critical saturation point, there is a decrease in serum While possibly slowing kidney function decline, bicarbonate and systemic pH.14 the timely recognition of metabolic acidosis provides an opportunity to prevent metabolic CKD progression due to metabolic acidosis bone disease, muscle wasting, stunted growth Kidney injury due to metabolic acidosis in CKD , hormonal abnormalities, and increased risk of has been attributed to the loss of nephrons, .1,14,15 leading to a compensatory hypertrophy of the remaining nephrons, as well as an increase in Because metabolic acidosis is considered an enzymes that generate ammonia to maintain independent risk factor for CKD progression, there acid-base balance.16,20 (Figure 1) is increased interest in its management. However, managing metabolic acidosis often goes Small studies21,22,23,24 in both animals and humans unrecognized as a treatment strategy.16 In fact, the indicate that metabolic acidosis is associated with prevalence of alkali is estimated at only progression of CKD. These findings are supported 2.4% for adults and only 29% for children.17,18 Alkali by much larger observational studies, including therapy and nutritional interventions have been one with more than 5,000 subjects from a single associated with a decrease in the progression of outpatient clinic over a median follow-up of 3.4 CKD, and should therefore be considered in the years, that determined that a serum bicarbonate CKD plan of care. Novel therapeutics may also < 22 mEq/L is associated with CKD progression, soon be of use. defined as a decrease in estimated glomerular filtration rate (eGFR) by ≥50% of baseline or reaching eGFR < 15 mL/min/1.73 m2.25

Figure 1. Proposed mechanisms for CKD progression with acid retention Acidosis increases aldosterone, angiotensin II, and endothelin, which promote kidney injury and . Metabolic acidosis is also associated with increased renal ammonia production, which activates complement that leads to injury and fibrosis. Finally, an acid environment stimulates pro-inflammatory cytokines, which may also cause kidney injury and fibrosis.26

Glomerular Filtration Rate

H* Retention

pH of Interstitial Intracellular pH of Fluid of Kidney Renal Tubular Cells

Angiotensin II Pro-inflammatory NH3 with Endothelin Cytokines Activation of Aldosterone and Chemokines Complement

Interstitial Fibrosis

Progression of CKD

2 Kalani L. Raphael

with CKD with normal bicarbonate concentrations are bicarbonate concentration remains at ,22 mEq/L. The ongoing (Table 1). rationale for these dose restrictions is that the average Figure 2 presents an approach to the management bicarbonate dose prescribed by de Brito-Ashurst et al7 of metabolic acidosis in CKD. For patients with bi- was 1.82 g daily, and there is less confidence that carbonate concentrations of 19 to 21 mEq/L, a low higher doses are safe over the long term. Because this bicarbonate concentration is confirmed (ie, within 3 patient’s bicarbonate concentration reached the months) before starting alkali treatment. For those KDOQI target of 22 mEq/L while taking 3,900 mg of with bicarbonate concentrations # 18 mEq/L, it is sodium bicarbonate daily, the bicarbonate dosage was reasonable to start alkali treatment without confirming not increased to target a higher bicarbonate concen- a low value provided there is not an acute reason for tration. If her bicarbonate concentration were to the low bicarbonate concentration. Table 2 presents decrease to ,22 mEq/L in the future, the sodium bi- characteristics of commonly prescribed alkalinizing carbonate dosage would be increased until the bicar- agents. In general, -based agents are avoi- bonate concentration reaches 22 mEq/L, while ded unless is also present. Although limiting the total daily dose to 5,850 mg. citrate-based agents enhance aluminum absorption,21 Adherence and intolerance should be considered if they are probably safe as long as aluminum-based the bicarbonate concentration remains at ,22 mEq/L binders are avoided. Sodium bicarbonate is attrac- after several months of treatment with 5,850 mg daily. tive because it avoids these concerns and is less If the number of pills impairs adherence, 1/2 teaspoon expensive than citrate-based . The initial of sodium bicarbonate powder dissolved in water sodium bicarbonate dose should consider the potential provides equimolar bicarbonate to 3.7 tablets of for gastrointestinal intolerance as well as the bicar- 650 mg. If gastrointestinal intolerance occurs, citrate- bonate concentration. Gastrointestinal concerns aside, based agents should be tried. Other strategies to in- 650 mg twice daily is started if bicarbonate concen- crease bicarbonate concentration include increasing tration is 19 to 21 mEq/L, or 1,300 mg twice daily if dietary alkali intake with fruits and vegetables pro- bicarbonate concentration is #18 mEq/L. vided serum potassium level is ,5.0 mEq/L22 and The ideal target bicarbonate concentration seems to reducing dietary, particularly animal, intake.23 be 24 to 26 mEq/L based on the achieved mean bi- In refractory cases, a detailed dietary history may be carbonate concentration in small interventional helpful and an arterial blood gas should be considered studies and the observational data. Therefore, sodium to rule out respiratory , although unlikely. bicarbonate dose is titrated every few months or so Some medications commonly prescribed in CKD to achieve bicarbonate concentrations of 24 to 26 promote low bicarbonate concentrations. For mEq/L. However, the daily dose of sodium bicar- example, bicarbonate concentrations are lower in pa- bonate is limited to 3,900 mg unless bicarbonate tients receiving renin-angiotensin system blockers2; concentration remains at ,22 mEq/L. Daily doses up however, these should not be discontinued in to 5,850 mg of sodium bicarbonate are prescribed if CKD for obvious reasons. By contrast, bicarbonate Table 1. Commonly Prescribed Alkali Supplement Doses and Considerations10 Table 2. Commonly Prescribed Alkalinizing Agents, Doses, and Considerations

2 Agent/Dose [HCO3 ] Considerations Agent/Dose [HCO3] Considerations

NaHCO3 325-mg tablet 3.9 mEq Inexpensive; non–potassium based; conversion of 2 650-mg tablet 7.7 mEq HCO3 to CO2 causes upper GI symptoms 600-mg (1/8 tsp) powdera 7.1 mEq Sodium citrate/citric acid solution

500 mg/334 mg per 5 mL 1 mEq/mL Fewer GI symptoms than NaHCO3; non–potassium 490 mg/640 mg per 5 mL 1 mEq/mL based; enhances aluminum absorption; conversion 2 of citrate to HCO3 may be impaired in liver disease Potassium citrate 6 citric acid 2 540-mg potassium citrate tablet 5 mEq 10- & 15-mEq tablets have more mEq of HCO3 than 1,080-mg potassium citrate tablet 10 mEq NaHCO3 tablets; solution delivers more mEq/mL of 2 1,620-mg potassium citrate tablet 15 mEq HCO3 than sodium citrate solution; rare cause of GI 1,100 mg potassium citrate/334 mg 2 mEq/mL ulceration; enhances aluminum absorption; may 2 citric acid per 5-mL solution cause ; conversion of citrate to HCO3 3,300 mg potassium citrate/1,002 mg 30 mEq per packet may be impaired in liver disease citric acid packeta 2 Abbreviations: CO2, ; GI, gastrointestinal; HCO3 , bicarbonate; NaHCO3, sodium bicarbonate. aShould be dissolved in water.

700 Am J Kidney Dis. 2016;67(4):696-702 Dietary acid reduction Veverimer (formerly TRC101) Diet partly contributes to the daily acid load, Although evidence-based clinical guidelines therefore, the typical Western diet, which is high in recommend alkali therapy, there is currently no animal protein and limited in fruits and vegetables, Food and Drug Administration (FDA) - approved increases net endogenous acid production. treatment indicated for chronic metabolic Conversely, a diet with a predominance of plant acidosis in CKD. Therefore, veverimer, a sodium- proteins over animal proteins, and high amounts free hydrochloric acid (HCl) acid binder, was of fruits and vegetables, may be a reasonable developed for this purpose and is currently under approach to limiting the daily acid load.44 FDA review. As an oral, insoluble, non-absorbed In addition, because fruits and vegetables are polymer, it selectively binds and removes hydrogen base-inducing foods, it has been demonstrated and chloride ions within the gastrointestinal tract. that increasing their daily intake may also The polymer is composed of which are high lower the dietary acid load and produce results molecular weight, cross-linked polyamine beads. comparable to those achieved with alkali It binds HCl without a counterion; therefore, no therapy.45,46,47 Adding 2–4 cups of fruits and mean changes occur in serum sodium, potassium, 49 vegetables to the daily diets of patients with , or magnesium. CKD stage 2 was comparable to giving them The TRC101 study, a multicenter, phase 1/2 0.5 mEq/kg/day of sodium bicarbonate.48 In 76 randomized, double-blind, placebo-controlled patients with CKD stage 4 and serum bicarbonate trial, was the first evaluation of veverimer’s efficacy < 22 mEq/L, increased fruit and vegetable and safety in 135 CKD patients. Patients treated for consumption increased serum bicarbonate, 14 days had a significant increase in mean serum although less than sodium bicarbonate. After bicarbonate that was maintained throughout the 1 year, eGFR was comparable between the 2 treatment period without serious adverse events.49 groups, and increased fruits and vegetables did A 12-week, phase 3 trial then followed, using not cause hyperkalemia in this group, all of whom 217 more patients with CKD; metabolic acidosis had serum potassium levels ≤4.6 mEq/L when was effectively treated without serious adverse they entered the study.46 events.50 A 40-week extension study of 196 Based upon this evidence, adding fruits and patients from the phase 3 trial evaluated safety, 51 vegetables and consuming more plant-based efficacy, and physical functioning. There were protein relative to animal-based protein, may be a fewer serious adverse events in veverimer patients viable approach to decreasing the acid load that than in those on placebo, and more veverimer exacerbates metabolic acidosis in CKD. patients than placebo had an increase in bicarbonate at 52 weeks, and higher levels at all timepoints (Figure 2). Patient responses to the Kidney Disease Quality of Life Instrument revealed subjective improvement in physical function with veverimer.

4 Clinical Findings More recent trials with oral alkali have included patients with CKD co-morbidities. In a 2-year Although and constitutional randomized, placebo-controlled study of 149 symptoms such as and weakness patients with CKD stages 3 and 4, sodium have been reported, most CKD patients are bicarbonate safely and significantly increased asymptomatic. Serum bicarbonate is rarely serum bicarbonate levels, while significantly <14 to 15 mEq/L and is often >20 mEq/L, even decreasing serum potassium. No improvements in 26 with severely low GFRs. An early decrease in muscle function or bone mineral density occurred bicarbonate is compensated for by an increase in both treated and untreated patients. In a 3-year in chloride and does not change the . randomized trial of oral sodium bicarbonate In patients with more advanced CKD, however, in 740 patients with CKD stages 3-5, sodium bicarbonate is more greatly reduced and there is bicarbonate corrected metabolic acidosis, slowed 27,28 an increase in the anion gap. the progression of CKD, and decreased all-cause Complications mortality in the treatment group.40 Major complications associated with metabolic Oral alkali supplementation acidosis in CKD include increased muscle wasting, Due to the variation in serum bicarbonate bone disease, and, possibly measurements, a second measurement should be and increased mortality.26 obtained before starting alkali supplementation. It is also recommended that, in most cases, venous In children, metabolic acidosis impairs growth by blood gas measurement should confirm the acid- inhibiting the secretion of (GH) base disorder, especially if is 29,30 and decreasing its activity in peripheral tissues. suspected.41 A CKD registry at that included more than 41,000 Clinical guidelines suggest using sodium patients revealed increased mortality associated bicarbonate with a starting dose of 650 mg twice with serum bicarbonate levels < 23 mEq/L in daily (15.5 mEq/day of bicarbonate) and escalating patients with moderate kidney disease (stage the dose based upon the response. Recommended 46 G3 CKD). Randomized controlled studies are doses range from 0.5-1.0 mEq bicarbonate or its needed to determine if if correcting metabolic equivalent per kilogram body weight/day. Sodium 26 acidosis decreases mortality. bicarbonate is inexpensive, widely available, and Management generally well tolerated the most common side effects of sodium bicarbonate are bloating and Evidence-based rationale for treatment burping. Sodium citrate may be used for less Studies have demonstrated that oral alkali may bloating, but citrate promotes intestinal aluminum slow CKD progression and improve nutritional absorption and increases the risk of aluminum status.24,32,33,34,35 The Kidney Disease Improving Global toxicity for those on aluminum containing antacids.42 Outcomes (KDIGO) guidelines suggest that serum Sodium salts confer potential risks, including bicarbonate concentrations <22 mEq/L be treated with worsened hypertension, volume overload, and oral bicarbonate to maintain serum bicarbonate within congestive . Although concern has the normal range.1 and the Kidney Disease Outcomes been raised that higher doses in CKD could cause Quality Initiative (KDOQI) guidelines concur.36 volume retention and worsen ,, Several retrospective reviews18,25,37,38 indicate that studies using sodium bicarbonate at much higher outcomes for CKD patients with serum bicarbonate doses than recommended by KDIGO and KDOQI levels below normal are significantly worse than did not reveal an increase in or in patients with normal levels. Additionally, in four .43 Although these results are reassuring, clinical trials, oral alkali increased serum bicarbonate patients were pre-selected and studies often in CKD patients with baseline levels < 22 mEq/L. The excluded those with congestive heart failure and Phisitkul et al. study showed that oral alkali therapy uncontrolled hypertension.41 decreased the number of CKD patients who had Alkali therapy could cause , a ≥ 40% decline in estimated glomerular filtration and in such cases, sodium bicarbonate should rate (eGFR), a surrogate endpoint of kidney disease be temporarily discontinued. Monitoring serum progression to end stage renal disease (ESRD).33 A bicarbonate is important for dose titration, and to limitation of these studies is that subjects did not correct for over-treatment.41 Treatment with oral have the severe comorbidities often found in CKD, alkali should target a normal serum bicarbonate such as edema, heart failure, and poorly controlled level.32,41 Table 1 includes details on commonly hypertension, and sodium-based oral alkali could prescribed alkali supplements and their specific exacerbate these conditions.5,39 dosing considerations. 3 Figure 2. Change in serum bicarbonate Articles (A) The first secondary endpoint, durability of bicarbonate response, defined by the placebo-subtracted proportion of patients achieving a minimum of 4 mmol/L increase from baseline in serum bicarbonate or a serum bicarbonate in the normal range (22–29 mmol/L) at the end of treatment (week 52), is depicted as the top line. The two lower lines depict each component of the endpoint. The individual endpoint component analyses were prespecified but were not adjusted for multiple comparisons. p values are for the difference in proportions between veverimer and placebo groups (Fisher’s exact test). (B) The baseline serum bicarbonate (treatment week 0), the mean of the screening 1, screening 2, and baseline day 1 values, was 17·2 mmol/L in the veverimer group and 17·1 mmol/L in the placebo group. Values depicted are the mean (SE).51

Responders Placebo-subtracted p value A proportion (%, 95% CI) Veverimer (n=110) Placebo (n=74)

Composite primary endpoint 69 (63%) 28 (38%) 0·0015 Component with ≥4 mmol/L increase in serum bicarbonate 67 (61%) 27 (36%) 0·0015 Component with serum bicarbonate in normal range 63 (57%) 20 (27%) 0·0001 (22–29 mmol/L) 0 10–10–20 20 30 40 50 60 70 80

Placebo better Veverimer better B 24 Veverimer Placebo End of treatment

22

20 Serum bicarbonate (mmol/L)

18

17·1 10 2 4 6 8 10 12 14 16 20 24 28 34 40 46 52 54 Time since randomisations (weeks)

Figure 3: Change in serum bicarbonate (A) The first secondary endpoint, durability of bicarbonate response, defined by the placebo-subtracted proportion of patients achieving a minimum of 4 mmol/L increase from baseline in serum bicarbonate or a serum bicarbonate in the normal range (22–29 mmol/L) at the end of treatment (week 52), is depicted as the top line. The two lower lines depict each component of the endpoint. The individualConclusion endpoint component analyses were prespecified but were not adjusted for multiple comparisons. p values are for the difference in proportions between veverimer and placebo groups (Fisher’s exact test). (B) The baseline serum bicarbonate (treatment week 0), the mean of the screening 1, screening 2, and baseline day 1 values, was 17·2 mmol/L in the veverimer group and 17·1 mmol/L in the placebo Chronicgroup. Values metabolic depicted are theacidosis mean (SE). is a potentially modifiable risk factor associated with increased morbidity and mortality in CKD. Evidence suggests that alkali supplementation, dietary modification to reduce acid load, weak to do the test at baseline, eight (73%) of 11 on to mitigate its deleterious consequences.1 In this study, and HClveverimer binding versus in thefour gastrointestinal (44%) of nine on placebo tract can were all able increase we showed serum thatbicarbonate the effect levels. of veverimer Controlling on increasingmetabolic acidosisto do bythe increasingrepeated chair serum stand bicarbonatetest at end of treatment. has been shownserum to slow bicarbonate CKD progression was sustained and over improve 1 year. outcomes. The Long-termThe significant trials that compareimprovements all the in treatments physical functiondiscussed proportion with reproducible of veverimer-treated protocols patients and achievingassessments, at (KDQoL-PFD and repeated chair stand) in the veverimer- least a 4 mmol/L increase or normalisation of serum particularlytreated patients in the versus setting placebo of sodium-sensitive were also evident conditions in age bicarbonate such as thewas advancedsimilar in the stages extension of both study heart (63% failure at (<65 years andand ≥65 CKD, years) will and help sex establish subgroups treatment (appendix guidelinesweek 52) for and metabolic the parent acidosis study (59%in CKD. at week 12).6 p 19). A prespecified sensitivity analysis excluding data Similarly, the least squares mean change from baseline from patients unable to do the repeated chair stand test in serum bicarbonate in veverimer-treated patients was at baseline was consistent with the findings from the similar in the two studies: 4·7 mmol/L (SE 0·3) at primary analyses (appendix p 19). week 52 in the extension study versus 4·4 mmol/L (0·3) at week 12 in the parent study.6 Mean serum bicarbonate Discussion was increased to maximum concentration by 4 weeks In patients with non-dialysis-dependent chronic kidney and remained stable for the remainder of the study. This disease and metabolic acidosis, treatment with veverimer might be an advantage to clinicians (compared with for up to 1 year safely and effectively corrected acidosis titrating alkali therapy). We observed a gradual increase and improved subjective and objective measures of in serum bicarbonate in patients treated with placebo; physical function. Veverimer was well tolerated, with nevertheless, the mean bicarbonate concentration in high adherence to treatment and a safety profile similar placebo-treated patients remained less than 20 mmol/L to placebo. The mechanism of action of this non-absorbed at the end of the study. The reason for the slow increase 5 polymer is novel. Rather than neutralising acid or is not clear but might be related to increased attention reducing acid intake, veverimer selectively binds and to bicarbonate concentrations leading to a reduction in removes hydrochloric acid from the gastrointestinal tract, dietary protein intake. resulting in increased serum bicarbonate concentrations. Metabolic acidosis in non-dialysis-dependent patients Metabolic acidosis in patients with chronic kidney with has been traditionally disease is chronic and thus requires long-term treatment treated with sodium-based alkali supplements, which

www.thelancet.com Vol 394 August 3, 2019 403 References

1  Kidney Disease Improving Global Outcomes. 2012 Clinical Practice Guideline for the 27. Widmer B, Gerhardt RE, Harrington JT, et al. Serum and acid base Evaluation and Management of Chronic Kidney Disease. Kidney Int 2013 (suppl)3:S73-S90. composition: the influence of graded degrees of chronic renal failure. Arch Intern Med 1979;139:1099-1102. 2. Raphael KL. Metabolic acidosis and subclinical metabolic acidosis in CKD. J Am Soc Nephrol. 2018;29:376-382. 28. Hakim RM, Lazarus JM. Biochemical parameters in chronic renal failure. Am J Kidney Dis. 1988;11:238-247. 3. 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 29. Bushinsky DA. The contribution of acidosis to . Kidney Int. metabolic acidosis. J Clin Invest.1966;45:1608–1614. 1995;47:1816.

4. Bushinsky DA, Chabala JM, Gavrilov KL, Levi-Setti R: Effects of in vivo metabolic acidosis 30. Brungger M, Hulter HN, Krapf R. Effect of chronic metabolic acidosis on the growth on midcortical bone ion composition. Am J Physiol.1999;277: F813–F819. hormone/IGF-1 endocrine axis: new cause of growth hormone insensitivity in humans. Kidney Int. 1997;51:216-221. 5. Goraya N, Wesson DE. Clinical evidence that treatment of metabolic acidosis slows the progression of chronic kidney disease. Curr Opin Nephrol Hypertens. 2019;28:1-11. 31. Navaneethan SD. Schold JD, Arrigain S, et al. Serum bicarbonate and mortality in stage and stage 4 chronic kidney disease. Clin J Am Soc Nephrol. 2011;6:2395-2402. 6. 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- 32. Vassalotti JA, Centor R, Turner BJ, et al. Practical approach to detection and management 1040. of chronic kidney disease for the primary care clinician. Am J Med. 2016;129:153-162.

7. Moranne O, Froissart M, Rossert J, et al. NephroTest Study Group: Timing of onset of 33. Phisitkul S, Khanna a, simoni J, et al. Amelioration of metabolic acidosis in patients with CKD-related metabolic complications. J Am Soc Nephrol 2009; 20:164-171. low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR. Kidney Int. 2010;77:617-623. 8. Raphael K, Zhang Y, Ying J, Greene T. Prevalence of and risk factors for reduced serum bicarbonate in chronic kidney disease. 2014; 19:648-654. 34. Susantitaphong P, Sewaralthahab K, Balk EM, et al. Short- and long-term effects of alkali therapy in chronic kidney disease: a systematic review. Am J Nephrol. 2012;35:540-547. 9. Inker LA, Coresh J, Levey AS, et al. Estimated GFR, , and complications of chronic kidney disease. J Am Soc Nephrol 2011; 22:2322-2331. 35. Dubey AK, Sahoo J, Vairappan B, et al. Correction of metabolic acidosis improves muscle mass and renal function in chronic kidney disease stages 3 and 4: a randomized 10. Raphael KL. Approach to the treatment of chronic metabolic acidosis in CKD. controlled trial. Nephrol Dial Transplant. 2018 Jul 24. Doi: 10.1093/ndt/gfy214. [Epub ahead Am J Kidney Dis 2016;67:696-702. of print]

11. United States Renal Data System. 2018 USRDS annual data report: Epidemiology of 36. Kidney Disease Outcomes Quality Initiative. KDOQI US Commentary on the 2012 KDIGO kidney disease in the United States. National Institutes of Health, National Institute of Clinical Practice Guideline for the Evaluation and Management of CKD. Inker LA, Astor and digestive and Kidney Diseases, Bethesda, MD, 2016. BC, Fox CH, et al. Am J Kidney Dis. 2014;63:713-735.

12. Hill NR, Fatoba ST, Oke JL, et al. Global prevalence of chronic kidney disease – 37. Raphael KL, Wei G, Baird BC, et al. Higher serum bicarbonate levels within the normal a systematic review and meta-analysis. PLoS ONE 11(7): e0158765.doi:10.1371/ range are associated with better survival and renal outcomes in African Americans. journal.pone.0158765. Kidney Int. 2011;79:356-362.

13. Kraut JA. Disturbances in acid-base, potassium, and sodium balance in patients with 38. Tangri N, Stevens LA, Griffith J, et al. A predictive model for progression of chronic kidney CKD: new insights and novel therapies. Adv Chronic Kidney Dis 2017;24:272-273. disease to . JAMA. 2011;305:1553-1559.

14. Kraut JA, Madias NE. Adverse effects of the metabolic acidosis of chronic kidney disease. 39. Bushinsky DA. Tolerance to sodium in patients with CKD-induced metabolic acidosis: Adv Chronic Kidney Dis. 2017;24:289-297. does the accompanying anion matter? Am J Kidney Dis 2018: https://doi.org/10.1053/j. ajkd.2018.09.004 15. Greenbaum LA, Warady BA, Furth SL. Current advances in chronic kidney disease in children: growth, cardiovascular, and neurocognitive risk factors. Sem Nephrol. 40. Di lorio BR, Bellasi A, Raphael KL, et al. Treatment of metabolic acidosis with sodium 2009;29:425-434. bicarbonate delays progression of chronic kidney disease: the UBI Study. J Nephrol. 2019 https://doi.org/10.1007/s40620-019-00656-5 16. Ahmed AR, Lappin D. Oral alkali therapy and the management of metabolic acidosis of chronic kidney disease: A narrative literature review. World J Nephrol 2018;10:117-122. 41. Chen W, Abramowitz MK. Treatment of metabolic acidosis in patients with CKD. Am J Kidney Dis. 2014;63:311-317. 17. Chen W, Abramowitz MK. Epidemiology of acid-base derangements in CKD. Adv Chronic Kidney Dis. 2017;24:280-288. 42. Goraya N, Wesson DE. Management of the metabolic acidosis of chronic kidney disease. Adv Chronic Kidney Dis. 2017;24:298-304. 18. 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 43. Husted FC, Nolph KD. NaHCO3 tolerance in chronic renal failure. Clin Nephrol. 1977;7:21-25. (CRIC)study. Am J Kidney Dis 2013;62:670-678. 44. Chauveau P, Koppe L, Combe C, et al. Vegetarian diets and chronic kidney disease. 19. Kovesdy CP. Pathogenesis, consequences, and treatment of metabolic acidosis in Nephrol Dial Transplant. 2019;34:199-207. chronic kidney disease. Sterns RH, Forman JP, eds. UpToDate. Waltham, MA: UpToDate Inc. https://www.uptodate.com (Accessed April 1, 2019) 45. 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 20. Karim Z, Attmane-Elakeb A, Bichara M. Renal handling of NH4+ in relation to the control filtration rate due to hypertensive nephropathy. Kidney Int. 2012;81:86-93. of acid-base balance by the kidney. J Nephrol. 202;15(suppl):S128-S134. 46. Goraya N, Simoni J, Jo C, et al. A comparison of treating metabolic acidosis in CKD stage 21. Goraya N, Wesson DE. Does correction of metabolic acidosis slow chronic kidney disease 4 hypertensive kidney disease with fruits and vegetables of sodium bicarbonate. Clin J progression? Curr Opin Nephrol Hypertens. 2013:22:193-197. Am Soc Nephrol;8:371-381.

22. Kraut JA. Effect of metabolic acidosis on progression of chronic kidney disease.Am J 47. Goraya N, Simoni J, Jo C, et al. Treatment of metabolic acidosis in patients with stage Physiol Renal Physiol. 2011; 300:F828-F829. 3 chronic kidney disease with fruits and vegetables or oral bicarbonate reduces urine angiotensinogen and preserves glomerular filtration rate. Kidney Int. advance online 23. Kovesdy CP. Metabolic acidosis and kidney disease: does bicarbonate therapy slow the publication, 2 April 2014. Doi:10.1038ki.2014.83. progression of CKD? Nephrol Dial Transplant. 2012;27:3056-3062. 48. Rebholz CM, Coresh J, Grams ME, et al. dietary acid load and incident chronic kidney 24. de brito-Ashurst I, Varagunam M, Raftery MJ, et al. Bicarbonate supplementation slows disease: results from the ARIC study. Am J Nephrol. 2015;42:427-435. progression of CKD and improves nutritional status. J Am Soc Nephrol. 2009;20:2075- 2084. 49. Bushinsky DA, Hostetter T, Klaemer G, et al. Randomized, controlled trial of TRC101 to increase serum bicarbonate in patients with CKD. Clin J am Soc Nephrol. 2018;13:26-35. 25. Shah SN, Abramowitz M, Hostetter TH, et al. Serum bicarbonate levels and the progression of kidney disease: a cohort study. Am J Kidney Dis. 2009;54:270-277. 50. Wesson DE, Mathur V, Tangri N, et al. Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicenter, randomized, 26. Kraut JA, Madias NE. Metabolic acidosis in CKD: an update. Am J Kidney Dis. 2016;67: double-blind, controlled, phase 3 trial. Lancet. http://dx.doi.org/10.1016/s0140- 307-317. 6736(18)32562-5 51. Wesson DE, Mathur V, Tangri N, et al. Long-term safety and efficacy of veverimer in patients with metabolic acidosis in chronic kidney disease: a multicentre, randomised, blinded, placebo-controlled, 40-week extension. Lancet. 2019;394:396-406.

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