Metabolic Acidosis in CKD: A Review of Recent Findings
2021; Elsevier BV; Volume: 3; Issue: 2 Linguagem: Inglês
10.1016/j.xkme.2020.12.006
ISSN2590-0595
AutoresMichal L. Melamed, Kalani L. Raphael,
Tópico(s)Sepsis Diagnosis and Treatment
ResumoMetabolic acidosis is fairly common in patients with chronic kidney disease (CKD). The prevalence of metabolic acidosis increases with worsening kidney function and is observed in ∼40% of those with stage 4 CKD. For the past 2 decades, clinical practice guidelines have suggested treatment of metabolic acidosis to counterbalance adverse effects of metabolic acidosis on bone and muscle. Studies in animal models of CKD also demonstrated that metabolic acidosis causes kidney fibrosis. During the past decade, results from observational studies identified associations between metabolic acidosis and adverse kidney outcomes, and results from interventional studies support the hypothesis that treating metabolic acidosis with sodium bicarbonate preserves kidney function. However, convincing data from large-scale, double-blinded, placebo-controlled, randomized trials have been lacking. This review discusses findings from recent interventional trials of alkali therapy in CKD and new findings linking metabolic acidosis with cardiovascular disease in adults and CKD progression in children. Finally, a novel agent that treats metabolic acidosis in patients with CKD by binding hydrochloric acid in the gastrointestinal tract is discussed. Metabolic acidosis is fairly common in patients with chronic kidney disease (CKD). The prevalence of metabolic acidosis increases with worsening kidney function and is observed in ∼40% of those with stage 4 CKD. For the past 2 decades, clinical practice guidelines have suggested treatment of metabolic acidosis to counterbalance adverse effects of metabolic acidosis on bone and muscle. Studies in animal models of CKD also demonstrated that metabolic acidosis causes kidney fibrosis. During the past decade, results from observational studies identified associations between metabolic acidosis and adverse kidney outcomes, and results from interventional studies support the hypothesis that treating metabolic acidosis with sodium bicarbonate preserves kidney function. However, convincing data from large-scale, double-blinded, placebo-controlled, randomized trials have been lacking. This review discusses findings from recent interventional trials of alkali therapy in CKD and new findings linking metabolic acidosis with cardiovascular disease in adults and CKD progression in children. Finally, a novel agent that treats metabolic acidosis in patients with CKD by binding hydrochloric acid in the gastrointestinal tract is discussed. Kidney regulation of systemic pH principally involves the excretion of protons as ammonium and dihydrogen phosphate. Proton elimination facilitates bicarbonate reclamation and generation to restore bicarbonate ions consumed to buffer endogenously produced acid. Metabolic acidosis is characterized by proton accumulation resulting from insufficient kidney acid excretion relative to the nonvolatile acid burden. In chronic kidney disease (CKD), the clinical diagnosis of metabolic acidosis is typically made when serum bicarbonate level decreases to <22 mEq/L. However, proton accumulation is present before serum bicarbonate level decreases, a state referred to as eubicarbonatemic acidosis, normobicarbonatemic acidosis, or subclinical acidosis (Fig 11Raphael K.L. Kraut J.A. Assessing acid-base status in patients with CKD: does measurement of blood pH matter?.Am J Kidney Dis. 2021; 77: 9-11Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). Continued proton accumulation and impaired bicarbonate production eventually lead to low serum bicarbonate levels, but a low serum bicarbonate level is not always accompanied by low systemic pH in patients with CKD.2Kajimoto S. Sakaguchi Y. Asahina Y. Kaimori J.Y. Isaka Y. Modulation of the association of hypobicarbonatemia and incident kidney failure with replacement therapy by venous pH: a cohort study.Am J Kidney Dis. 2021; 77: 35-43Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Hence, there is a spectrum of metabolic acidosis in CKD extending from eubicarbonatemic metabolic acidosis to an acid state characterized by low bicarbonate level and acidemia (Fig 1). There is a theoretical direct association between the severity of the acid state and risk for poor clinical outcomes.1Raphael K.L. Kraut J.A. Assessing acid-base status in patients with CKD: does measurement of blood pH matter?.Am J Kidney Dis. 2021; 77: 9-11Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Studying this relationship is challenging because identifying eubicarbonatemic acidosis is not straightforward and systemic pH is not routinely measured in clinical practice or research protocols. Consequently, most research studies define metabolic acidosis as serum bicarbonate level 18 but 60 y, eGFR < 30 mL/min/1.73 m2 30 mg/g22-28746 mo0.5 mEq/kg of lean body weight/d•No statistically significant effect on urinary markers of kidney injuryBASE Pilot Trial12Raphael K.L. Isakova T. Ix J.H. et al.A randomized trial comparing the safety, adherence, and pharmacodynamics profiles of two doses of sodium bicarbonate in CKD: the BASE Pilot Trial.J Am Soc Nephrol. 2020; 31: 161-174Crossref PubMed Scopus (14) Google ScholarCKD stage 3b or 4 or CKD 3a with ACR ≥ 50 mg/g20-2819228 wk0.5 or 0.8 mEq/kg lean body weight/d•No significant effect on blood pressure or weight•Dose-dependent increase in serum bicarbonate•Dose-dependent increase in urinary ACRVeverimer (40-wk extension study)13Wesson D.E. 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: 396-406Abstract Full Text Full Text PDF PubMed Scopus (23) Google ScholareGFR 20-40 mL/min/1.73 m212-2019652 wkVeverimer 6 g/d then titrated to target bicarbonate 22-29 mEq/L•3% in veverimer vs 10% in placebo discontinued treatment•Treatment with veverimer improved physical function•Fewer treated with veverimer died or progressed to ESKDAbbreviations: ACR, albumin-creatinine ratio; BASE, Bicarbonate Administration to Stabilize eGFR; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; RRT, renal replacement therapy; UBI, Use of Bicarbonate in CKD. Open table in a new tab Abbreviations: ACR, albumin-creatinine ratio; BASE, Bicarbonate Administration to Stabilize eGFR; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; RRT, renal replacement therapy; UBI, Use of Bicarbonate in CKD. Adverse effects on bone and muscle were some of the first identified complications of chronic metabolic acidosis in CKD.14Bushinsky D.A. Chabala J.M. Gavrilov K.L. Levi-Setti R. Effects of in vivo metabolic acidosis on midcortical bone ion composition.Am J Physiol. 1999; 277: F813-F819PubMed Google Scholar, 15Krieger N.S. Sessler N.E. Bushinsky D.A. Acidosis inhibits osteoblastic and stimulates osteoclastic activity in vitro.Am J Physiol. 1992; 262: F442-F448PubMed Google Scholar, 16Bailey J.L. Wang X. England B.K. Price S.R. Ding X. Mitch W.E. 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: 1447-1453Crossref PubMed Scopus (342) Google Scholar Evidence that metabolic acidosis caused loss of bone architecture and muscle catabolism prompted the National Kidney Foundation to suggest treating metabolic acidosis with oral alkali in patients with CKD in the early 2000s.17National Kidney FoundationK/DOQI clinical practice guidelines for nutrition in chronic renal failure.Am J Kidney Dis. 2000; 35: S1-S140PubMed Google Scholar,18National Kidney FoundationK/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar However, convincing evidence that treating metabolic acidosis with alkali improved bone and/or muscle health was lacking. In the past decade, associations between metabolic acidosis and CKD progression and death were uncovered, corroborating findings in animal studies.19Kovesdy 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 (170) Google Scholar, 20Nath 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 (377) Google Scholar, 21Navaneethan 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 (105) Google Scholar, 22Raphael K. Wei G. Baird B. Greene T. Beddhu S. Higher serum bicarbonate levels within the normal range are associated with better survival and renal outcomes in African Americans.Kidney Int. 2011; 79: 356-362Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar, 23Raphael K.L. Zhang Y. Wei G. Greene T. Cheung A.K. Beddhu S. Serum bicarbonate and mortality in adults in NHANES III.Nephrol Dial Transplant. 2013; 28: 1207-1213Crossref PubMed Scopus (50) Google Scholar, 24Shah S.N. Abramowitz M. Hostetter T.H. Melamed M.L. Serum bicarbonate levels and the progression of kidney disease: a cohort study.Am J Kidney Dis. 2009; 54: 270-277Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar, 25Wesson D.E. Jo C.H. Simoni J. Angiotensin II-mediated GFR decline in subtotal nephrectomy is due to acid retention associated with reduced GFR.Nephrol Dial Transplant. 2015; 30: 762-770Crossref PubMed Scopus (37) Google Scholar, 26Wesson D.E. 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: 1128-1135Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar Results from early-phase clinical trials also suggested that treatment of metabolic acidosis with either nutritional or pharmacologic alkali preserves kidney function.27de Brito-Ashurst I. Varagunam M. Raftery M.J. Yaqoob M.M. Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (549) Google Scholar, 28Phisitkul 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: 617-623Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 29Goraya N. Simoni J. Jo C. Wesson D.E. 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 (202) Google Scholar, 30Goraya N. Simoni J. Jo C.H. Wesson D.E. 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: 371-381Crossref PubMed Scopus (205) Google Scholar, 31Goraya N. Simoni J. Jo C.H. Wesson D.E. 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: 1031-1038Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 32Mahajan A. Simoni J. Sheather S.J. Broglio K.R. Rajab M.H. Wesson D.E. 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 (254) Google Scholar In 2009, de Brito-Ashurst et al27de Brito-Ashurst I. Varagunam M. Raftery M.J. Yaqoob M.M. Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (549) Google Scholar reported results from a randomized, unblinded, non–placebo-controlled trial testing whether treatment of metabolic acidosis preserved kidney function in 134 individuals with CKD. They found that treatment with sodium bicarbonate reduced the rate of creatinine clearance decline (5.9 vs 1.9 mL/min/1.73 m2), lowered the risk for ESKD by 87%, and improved several nutritional parameters, including midarm muscle circumference.27de Brito-Ashurst I. Varagunam M. Raftery M.J. Yaqoob M.M. Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (549) Google Scholar Shortly thereafter, Phisitkul et al28Phisitkul 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: 617-623Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar reported that hypertensive patients with CKD with metabolic acidosis treated with sodium citrate (n = 30) had an improvement in kidney injury marker levels (such as urinary endothelin-1 and N-acetyl-β-d-glucosaminidase) and better preserved kidney function over 2 years than similar individuals who were not treated with alkali (n = 29). Based on the totality of these findings, treatment of metabolic acidosis with alkali has been suggested by clinical practice guidelines.17National Kidney FoundationK/DOQI clinical practice guidelines for nutrition in chronic renal failure.Am J Kidney Dis. 2000; 35: S1-S140PubMed Google Scholar,18National Kidney FoundationK/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification.Am J Kidney Dis. 2002; 39: S1-S266PubMed Google Scholar,33Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work GroupKDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Int Suppl. 2013; 3: 1-150Abstract Full Text Full Text PDF Scopus (1064) Google Scholar Findings from other early-phase studies challenged the notion that alkali should be reserved for those with metabolic acidosis. Mahajan et al32Mahajan A. Simoni J. Sheather S.J. Broglio K.R. Rajab M.H. Wesson D.E. 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 (254) Google Scholar reported in 2010 that treatment with sodium bicarbonate (n = 40), irrespective of baseline serum bicarbonate concentration, better preserved estimated glomerular filtration rate (eGFR) than treatment with either placebo (n = 40) or equimolar sodium chloride (n = 40) in patients with stage 2 CKD over 5 years. Goraya et al31Goraya N. Simoni J. Jo C.H. Wesson D.E. 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: 1031-1038Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar later reported that treatment with fruits and vegetables (n = 36) or sodium bicarbonate (n = 36) preserved kidney function better and similarly over 3 years compared with a control group (n = 36) in patients with stage 3 CKD and serum bicarbonate levels of 22 to 24 mEq/L. These findings raised the possibility that patients with normal serum bicarbonate levels might also benefit from alkali by mitigating compensatory responses that facilitate kidney acid excretion, but detrimentally promote kidney damage, to maintain serum bicarbonate levels. Although these findings suggested that alkali preserved kidney function and improved nutritional parameters, the studies were single center with limited sample size, and most only enrolled individuals with CKD attributed to hypertension. Nevertheless, the findings led to the design and execution of other trials testing the effect of alkali therapy on kidney parameters in patients with broad causes of CKD and serum bicarbonate concentrations. The Use of Bicarbonate in CKD (UBI) Study, conducted at 10 sites in Italy, randomly assigned 795 individuals with CKD stages 3-5 and serum bicarbonate levels >18 but 150/90 mm Hg. During the follow-up period, serum bicarbonate concentration was ∼26 mEq/L in the active treatment group versus 22 mEq/L in the usual care group. In the usual care group, 17% experienced a doubling of serum creatinine level (primary end point) as compared with 6% in the active treatment group (P < 0.0001; Fig 28Di Iorio B.R. Bellasi A. Raphael K.L. et al.Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study.J Nephrol. 2019; 32: 989-1001Crossref PubMed Scopus (35) Google Scholar). Further, treatment with sodium bicarbonate was associated with 50% lower hazard of initiating renal replacement therapy, lower hospitalization rate, and lower mortality rate (6.8% vs 3.1%; P = 0.016), providing the first evidence in trials in humans that treatment of metabolic acidosis may improve survival. There was no appreciable effect on blood pressure or body weight.8Di Iorio B.R. Bellasi A. Raphael K.L. et al.Treatment of metabolic acidosis with sodium bicarbonate delays progression of chronic kidney disease: the UBI Study.J Nephrol. 2019; 32: 989-1001Crossref PubMed Scopus (35) Google Scholar Although the study was open label and not placebo controlled, the UBI Study is the largest metabolic acidosis treatment trial to date, and its results suggest that alkali therapy in patients with serum bicarbonate levels <24 mEq/L improves kidney and patient survival in CKD. While the primary outcome in UBI was doubling of serum creatinine level, the BiCARB Trial tested the effect of treating metabolic acidosis on physical function.9BiCARB Study GroupClinical and cost-effectiveness of oral sodium bicarbonate therapy for older patients with chronic kidney disease and low-grade acidosis (BiCARB): a pragmatic randomised, double-blind, placebo-controlled trial.BMC Med. 2020; 18: 91Crossref PubMed Scopus (2) Google Scholar Although there is strong evidence that acidosis adversely affects bone and muscle health, whether treating acidosis improves physical function is unclear. Several observational studies have identified links between lower serum bicarbonate levels and poorer physical function.34Abramowitz M.K. Hostetter T.H. Melamed M.L. Lower serum bicarbonate and a higher anion gap are associated with lower cardiorespiratory fitness in young adults.Kidney Int. 2012; 81: 1033-1042Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 35Abramowitz M.K. Hostetter T.H. Melamed M.L. Association of serum bicarbonate levels with gait speed and quadriceps strength in older adults.Am J Kidney Dis. 2011; 58: 29-38Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 36Yenchek R. Ix J.H. Rifkin D.E. et al.Association of serum bicarbonate with incident functional limitation in older adults.Clin J Am Soc Nephrol. 2014; 9: 2111-2116Crossref PubMed Scopus (19) Google Scholar As far as the interventional evidence, some studies have found that treating metabolic acidosis in CKD increases midarm muscle circumference27de Brito-Ashurst I. Varagunam M. Raftery M.J. Yaqoob M.M. Bicarbonate supplementation slows progression of CKD and improves nutritional status.J Am Soc Nephrol. 2009; 20: 2075-2084Crossref PubMed Scopus (549) Google Scholar and improves sit-stand-sit time, although the latter was observed in a single-arm study.37Abramowitz M.K. Melamed M.L. Bauer C. Raff A.C. Hostetter T.H. Effects of oral sodium bicarbonate in patients with CKD.Clin J Am Soc Nephrol. 2013; 8: 714-720Crossref PubMed Scopus (78) Google Scholar The BiCARB Trial was multicenter, double blinded, and placebo controlled.9BiCARB Study GroupClinical and cost-effectiveness of oral sodium bicarbonate therapy for older patients with chronic kidney disease and low-grade acidosis (BiCARB): a pragmatic randomised, double-blind, placebo-controlled trial.BMC Med. 2020; 18: 91Crossref PubMed Scopus (2) Google Scholar Key entry criteria were eGFR < 30 mL/min/1.73 m2, age older than 60 years, and serum bicarbonate level < 22 mEq/L. Participants were randomly assigned to receive sodium bicarbonate or placebo for up to 2 years. However the primary outcome was change in Short Physical Performance Battery (SPPB) score at month 12. Importantly, the starting dose of sodium bicarbonate was 1.5 g/d and was increased to 3.0 g/d at month 3 if serum bicarbonate level was <22 mEq/L. Dose increases after month 3 were not allowed even if serum bicarbonate level remained at <22 mEq/L. Recruitment was challenging and was eventually stopped when 300 individuals were enrolled, instead of the 380 that were planned. In general, the study found that treatment of metabolic acidosis was unfavorable. At 1 year, treatment did not improve physical function, assessed by SPPB score. Those in the experimental arm had slightly, but not statistically significantly, lower SPPB scores at month 12 (−0.4 point; 95% CI, −0.9 to 0.1), indicating worse physical function. Along these lines, 6-minute walk distance (mean, 33 m) and grip strength (mean, 1.5 kg) were statistically significantly lower in the experimental arm. No significant treatment effect on various bone and cardiovascular markers was observed. However, more adverse events were reported in the treatment arm. Based on these findings and the results of a cost-effectiveness analysis, the authors concluded that treatment of metabolic acidosis in patients with stage 4 or 5 CKD was unfavorable, potentially harmful, and not cost-effective. While these findings are concerning, the study had 2 major weaknesses. First, recruitment was challenging, which the authors partly attributed to a lack of equipoise. This led to a smaller sample size than anticipated. There was 87% power to detect a 1-point difference in SPPB score with 300 randomly assigned participants. However, data for the primary outcome (SPPB score at month 12) were available in only 274 participants at baseline and 187 at month 12. Hence, missing data was considerable. A second limitation is that metabolic acidosis was insufficiently treated during the trial. Serum bicarbonate level was 1.1 mEq/L higher in the treatment group during the course of the study; however, the mean baseline bicarbonate level was 20.6 mEq/L, indicating that a substantial proportion in the treatment group still had metabolic acidosis during the study. Hence, the overall conclusion that sodium bicarbonate was potentially harmful should be interpreted with these limitations in mind. Like the BiCARB Trial, the primary outcome in the Alkali Therapy in CKD Trial was not kidney related. Instead, the coprimary outcomes were change in bone mineral density at the femoral neck and sit-to-stand time.10Melamed M.L. Horwitz E.J. Dobre M.A. et al.Effects of sodium bicarbonate in CKD stages 3 and 4: a randomized, placebo-controlled, multicenter clinical trial.Am J Kidney Dis. 2020; 75: 225-234Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar One hundred forty-nine individuals with CKD stage 3 or 4 and serum bicarbonate levels of 20 to 26 mEq/L at 3 United States medical centers were randomly assigned to treatment with sodium bicarbonate, 0.4 mEq/kg of ideal body weight per day or matching placebo. Mean serum bicarbonate levels increased to 26.4 (SD, 2.2) mEq/L in the sodium bicarbonate group at 2 months compared to 23.6 (SD, 2.5) mEq/L in the placebo group (P < 0.001). However, over time, the separation between the groups was not sustained. Bone mineral density and sit-to-stand time decreased in both groups during the 2-year follow-up period, and the differences between the groups were not sig
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