Pathophysiology of Diet-Induced Acid Stress.

Diets can influence the body's acid-base status because specific food components yield acids, bases, or neither when metabolized. Animal-sourced foods yield acids and plant-sourced food, particularly fruits and vegetables, generally yield bases when metabolized. Modern diets proportionately contain more animal-sourced than plant-sourced foods, are, thereby, generally net acid-producing, and so constitute an ongoing acid challenge. Acid accumulation severe enough to reduce serum bicarbonate concentration, i.e., manifesting as chronic metabolic acidosis, the most extreme end of the continuum of "acid stress", harms bones and muscles and appears to enhance the progression of chronic kidney disease (CKD). Progressive acid accumulation that does not achieve the threshold amount necessary to cause chronic metabolic acidosis also appears to have deleterious effects. Specifically, identifiable acid retention without reduced serum bicarbonate concentration, which, in this review, we will call "covert acidosis", appears to cause kidney injury and exacerbate CKD progression. Furthermore, the chronic engagement of mechanisms to mitigate the ongoing acid challenge of modern diets also appears to threaten health, including kidney health. This review describes the full continuum of "acid stress" to which modern diets contribute and the mechanisms by which acid stress challenges health. Ongoing research will develop clinically useful tools to identify stages of acid stress earlier than metabolic acidosis and determine if dietary acid reduction lowers or eliminates the threats to health that these diets appear to cause.

VALOR-CKD: A Multicenter, Randomized, Double-Blind Placebo-Controlled Trial Evaluating Veverimer in Slowing Progression of CKD in Patients with Metabolic Acidosis.

SIGNIFICANCE STATEMENT: Metabolic acidosis is a common complication of CKD and is associated with more rapid decline of kidney function, but well-powered controlled randomized trials testing the effect of treating metabolic acidosis on slowing CKD progression have not been conducted. The VALOR-CKD study randomized 1480 individuals with CKD and metabolic acidosis, across 320 sites to placebo or veverimer (a novel hydrochloric acid binder). The findings did not demonstrate the efficacy of veverimer in slowing CKD progression, but the difference in serum bicarbonate between placebo and drug arms was only approximately 1 mEq/L. Veverimer was safe and well tolerated. BACKGROUND: Metabolic acidosis is common in CKD, but whether its treatment slows CKD progression is unknown. Veverimer, a novel hydrochloric acid binder that removes acid from the gastrointestinal tract, leads to an increase in serum bicarbonate. METHODS: In a phase 3, double-blind, placebo-controlled trial, patients with CKD (eGFR of 20-40 ml/min per 1.73 m 2 ) and metabolic acidosis (serum bicarbonate of 12-20 mEq/L) from 35 countries were randomized to veverimer or placebo. The primary outcome was the composite end point of CKD progression, defined as the development of ESKD (kidney transplantation or maintenance dialysis), a sustained decline in eGFR of ≥40% from baseline, or death due to kidney failure. RESULTS: The mean (±SD) baseline eGFR was 29.2±6.3 ml/min per 1.73 m 2 , and serum bicarbonate was 17.5±1.4 mEq/L; this increased to 23.4±2.0 mEq/L after the active treatment run-in. After randomized withdrawal, the mean serum bicarbonate was 22.0±3.0 mEq/L and 20.9±3.3 mEq/L in the veverimer and placebo groups at month 3, and this approximately 1 mEq/L difference remained stable for the first 24 months. A primary end point event occurred in 149/741 and 148/739 patients in the veverimer and placebo groups, respectively (hazard ratio, 0.99; 95% confidence interval, 0.8 to 1.2; P = 0.90). Serious and overall adverse event incidence did not differ between the groups. CONCLUSIONS: Among patients with CKD and metabolic acidosis, treatment with veverimer did not slow CKD progression. The lower than expected bicarbonate separation may have hindered the ability to test the hypothesis. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VALOR-CKD, NCT03710291 .

The Fruit and Veggies for Kidney Health Study: A Prospective Randomized Trial.

Rationale & Objective: Providing fruits and vegetables (F&Vs) to health care system patients with elevated urine albumin-creatinine ratio (ACR) reduced ACR, slowed chronic kidney disease (CKD) progression and reduced cardiovascular disease (CVD) risk factors in previous studies. This study evaluated a community-based strategy in lower-income populations to identify African Americans with elevated ACR before health care system involvement and sustain them in a 6-month F&V protocol with (F&V + Cook) and without (F&V Only) cooking instructions, with the hypothesis that adjuvant cooking instructions with F&Vs would further reduce ACR. Study Design: Prospective, randomized, parallel 2-arm design. Setting & Participants: African American adults with ACR >10 mg/g creatinine randomized to 1 of 2 study arms. Interventions: Two cups/day of F&Vs with or without cooking instructions in participants followed 6 months. Outcomes: Participants sustaining the F&V protocol and between-group indicators of CVD risk, kidney injury, and dietary intake at 6 weeks and 6 months. Results: A total of 142 African American adults (mean age, 57.0 years; ACR, 27.4 mg/g; body mass index, 34.4; 24.9% CKD 1; 24.8% CKD 2; 50.4% CKD 3; 55% female) randomized to F&V Only (n=72) or F&V + Cook (n=70), and 71% were retained at 6 months. Participants received 90% of available F&V pick-ups over 6 weeks and 69% over 6 months. In the adjusted model, 6-month ACR was 31% lower for F&V + Cook than F&V Only (P = 0.02). Net 6-week F&V intake significantly increased and biometric variables improved for participants combined into a single group. Limitations: Small sample size, low-baseline ACR, and potential nonresponse bias for 24-hour dietary recall measure. Conclusions: These data support the feasibility of identifying community-dwelling African Americans with ACR indicating elevated CVD and CKD risk and sustaining a F&V protocol shown to improve kidney outcomes and CVD risk factors and provides preliminary evidence that cooking instructions adjuvant to F&Vs are needed to lower ACR. Funding: National Institute on Diabetes, Digestive, and Kidney Diseases grant "Reducing chronic kidney disease burden in an underserved population" (R21DK113440). Trial Registration: NCT03832166. Plain-Language Summary: African Americans, particularly those in low-income communities, have increased rates of chronic kidney disease (CKD) with worsening outcomes over time. Giving fruits and vegetables to individuals with CKD identified in health care systems was previously shown to reduce kidney damage, measured by urine protein albumin, and slow kidney function decline. We recruited African Americans in low-income communities with increased urine albumin levels. They received fruits and vegetables for 6 months, and we tested whether added cooking instructions further reduced urine albumin levels. Most participants continued to receive fruits and vegetables throughout the 6 months. Those given cooking instructions had lower urine albumin levels after 6 months, indicating decreased kidney damage. Providing cooking instructions with fruits and vegetables appears to lessen kidney damage more than just fruits and vegetables alone.

Association of serum bicarbonate with the development of kidney stones in patients with chronic kidney disease: a retrospective cohort study.

Background: Epidemiological studies demonstrate an association between kidney stones and risk of chronic kidney disease (CKD) and CKD progression. Metabolic acidosis, as a consequence of CKD, results in a reduced urine pH which promotes the formation of some types of kidney stones and inhibits the formation of others. While metabolic acidosis is a risk factor for CKD progression, the association of serum bicarbonate with risk of incident kidney stones is not well understood. Methods: We used an Integrated Claims-Clinical dataset of US patients to generate a cohort of patients with non-dialysis-dependent CKD with two serum bicarbonate values of 12 to <22 mmol/L (metabolic acidosis) or 22 to <30 mmol/L (normal serum bicarbonate). Primary exposure variables were baseline serum bicarbonate and change in serum bicarbonate over time. Cox proportional hazards models evaluated time to first occurrence of kidney stones during a median 3.2-year follow-up. Results: A total of 142 884 patients qualified for the study cohort. Patients with metabolic acidosis experienced post-index date kidney stones at greater frequency than patients with normal serum bicarbonate at the index date (12.0% vs 9.5%, P < .0001). Both lower baseline serum bicarbonate [hazard ratio (HR) 1.047; 95% confidence interval (CI) 1.036-1.057] and decreasing serum bicarbonate over time (HR 1.034; 95% CI 1.026-1.043) were associated with increased risk of kidney stone development. Conclusions: Metabolic acidosis was associated with a higher incidence of kidney stones and shorter time to incident stone formation in patients with CKD. Future studies may investigate the role of correcting metabolic acidosis to prevent stone formation.

The mechanisms of alkali therapy in targeting renal diseases.

Chronic kidney disease (CKD) is characterized by progressive reduction in kidney function and treatments aiming at stabilizing or slowing its progression may avoid or delay the necessity of kidney replacement therapy and the increased mortality associated with reduced kidney function. Metabolic acidosis, and less severe stages of the acid stress continuum, are common consequences of CKD and some interventional studies support that its correction slows the progression to end-stage kidney disease. This correction can be achieved with mineral alkali in the form of bicarbonate or citrate salts, ingestion of diets with fewer acid-producing food components or more base-producing food components, or a pharmacological approach. In this mini-review article, we summarize the potential mechanisms involved in the beneficial effects of alkali therapy. We also discuss the perspectives in the field and challenges that must be overcome to advance our understanding of such mechanisms.

Design and population of the VALOR-CKD study: a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of veverimer in slowing progression of chronic kidney disease in patients with metabolic acidosis.

BACKGROUND: Whether treating metabolic acidosis slows progression of chronic kidney disease (CKD) has not been established. Veverimer is a novel hydrochloric acid binder that removes acid from the gastrointestinal tract leading to an increase in serum bicarbonate; it is being developed to treat metabolic acidosis with the goal of slowing progression of CKD. METHODS: The VALOR-CKD trial is an international, randomized, multicenter, double-blind, placebo-controlled study designed to evaluate the effect of once-daily veverimer on kidney disease progression in patients with metabolic acidosis and CKD. Eligibility criteria include a serum bicarbonate in the range of 12-20 mmol/L and an estimated glomerular filtration rate (eGFR) of 20-40 mL/min/1.73 m2. The primary outcome is kidney disease progression defined as the development of end-stage kidney disease, a sustained decline in eGFR of >40% from baseline or death due to kidney failure. Key secondary endpoints include effects on physical function. RESULTS: Between December 2018 and December 2021, 1480 participants were randomized. The mean age at baseline was 65.1 years and 42% of the patients were female. The mean baseline eGFR was 29.1 mL/min/1.73 m2 and mean serum bicarbonate was 17.5 mmol/L. The median urine albumin-to-creatinine ratio at screening was 201 mg/g and the median 5-year predicted risk of kidney failure was 32%. Diabetes and hypertension were present in 56% and 98% of participants, respectively. CONCLUSIONS: VALOR-CKD has recruited a large population of people with metabolic acidosis at high risk for CKD progression to determine the effects of veverimer on the risk of progressive loss of kidney function.

Factors Affecting the Decision to Initiate Dialysis: A National Survey of United States Nephrologists.

INTRODUCTION: The percentage of patients initiating dialysis at an estimated glomerular filtration rate (eGFR) ≤9 mL/min/1.73 m2 decreased between 2000 and 2018 in the USA. Clinical practice guidelines recommend basing the decision to initiate dialysis primarily on uremic signs and symptoms rather than on a particular level of kidney function. However, what signs and symptoms currently practicing nephrologists consider "uremic," how they weigh eGFR and other factors in the decision to initiate dialysis have not been reported. METHODS: The study was an online survey of 255 US nephrologists, conducted between August and October 2021. RESULTS: Nearly half of respondents (49.8%) had an absolute lower eGFR (8.4 [95% CI: 7.6, 9.2] mL/min/1.73 m2) at which they would initiate dialysis in an asymptomatic patient. The top 5 symptoms that would trigger a recommendation to initiate dialysis were loss of appetite/nausea/vomiting (17%), low eGFR (10%), shortness of breath (10%), declining physical ability/function (9%), and generalized weakness (9%). Poor nutritional status and physical function decline were considered very important in the decision to initiate dialysis by 64% and 55% of respondents, respectively. Nephrologists surveyed significantly shortened the time to dialysis initiation in response to declining physical function in an otherwise asymptomatic (hypothetical) patient. CONCLUSIONS: Nearly half of nephrologists sometimes based their decision to initiate dialysis on eGFR alone. The eGFR threshold at which they did so was lower than has been examined in randomized controlled trials of dialysis initiation. Initiatives designed to safely delay dialysis through aggressive medical management could focus on modifiable factors that are the most important drivers of the decision to initiate dialysis.

Metabolic Basis and Pathogenesis of Skeletal Muscle Dysfunction as Cause of Frailty in Chronic Kidney Disease.

BACKGROUND: Frailty is common in patients with chronic kidney disease (CKD), as is its physical component, phenotypic frailty, and each contributes to CKD-related disability and are associated with increased mortality. Chronic kidney disease has been described as a model of premature aging and its phenotypic frailty shares features with that which has been better characterized for aging. SUMMARY: Decreased skeletal muscle function contributes to the phenotypic frailty of CKD and aging and potentially remediable metabolic derangements appear to mediate both. KEY MESSAGES: Metabolic derangements of skeletal muscle dysfunction shared by CKD-related and aging-related phenotypic frailty offer potential research avenues to help identify additional preventive and treatment strategies. Those derangements distinctive for CKD provide potential treatment targets for the kidney care community to enhance the quality and quantity of life for patients with CKD.

Relationship between Metabolic Acidosis and Chronic Kidney Disease Progression across Racial and Ethnic Groups: An Observational, Retrospective Cohort Study.

INTRODUCTION: Metabolic acidosis is associated with chronic kidney disease (CKD) progression and mortality, but the association of race/ethnicity with incident metabolic acidosis and/or its adverse outcomes in patients with CKD is unknown. METHODS: We used deidentified medical records data (2007-2019) to generate a cohort of 136,067 patients with nondialysis-dependent CKD stages 3-5 and ≥2 years' postindex data or death within 2 years. We grouped participants into those with and without metabolic acidosis (serum bicarbonate 12 to <22 mEq/L vs. 22 to <30 mEq/L) as Asian, Black, Hispanic, non-Hispanic White individuals, or unknown. Cox proportional hazards models examined factors associated with (1) incident metabolic acidosis; and (2) time to the composite outcome of death, dialysis, transplant, or ≥40% decline from baseline eGFR (DD40) within each race/ethnic group. RESULTS: Metabolic acidosis incidence was higher for Asian, Black, and Hispanic versus non-Hispanic White individuals (p values for adjusted hazard ratios [HR] all <0.001), but this higher hazard was mitigated in all groups with increasing community education. During the median follow-up of 4.2 years, 47,032 of 136,607 (34.6%) experienced a DD40 event. There was an independent association of metabolic acidosis with DD40 within each race/ethnic group. Adjusted HRs (95% confidence interval) for DD40 were 1.806 (1.312, 2.486), 1.420 (1.313, 1.536), 1.409 (1.211, 1.641), and 1.561 (1.498, 1.626) in Asian, Black, Hispanic, and non-Hispanic White groups, respectively (all p < 0.0001), for metabolic acidosis versus normal serum bicarbonate. DISCUSSION/CONCLUSION: The higher incidence of metabolic acidosis observed in Asian, Black, and Hispanic individuals was mitigated by residing in higher education zip codes. Once established, metabolic acidosis was independently associated with DD40 in patients with CKD in all racial/ethnic groups examined.

The Importance of Recognizing and Addressing the Spectrum of Acid Stress.

Acid accumulation sufficient to reduce plasma bicarbonate concentration, thereby recognized as chronic metabolic acidosis, harms bones and muscles and appears to enhance progression of CKD. Evolving evidence supports that progressive acid accumulation that is not enough to cause chronic metabolic acidosis nevertheless has deleterious effects. Measurable acid retention without reduced plasma bicarbonate concentration, called eubicarbonatemic acidosis, also appears to cause kidney injury and exacerbate CKD progression. Furthermore, chronic engagement of mechanisms to mitigate the ongoing acid challenge of net acid-producing diets of developed societies also appears to be deleterious, including for kidney health. This review challenges clinicians to consider the growing evidence for a spectrum of acid-accumulation disorders that include lesser degrees of acid accumulation than metabolic acidosis yet are harmful. Further research will develop clinically useful tools to identify individuals suffering from these earlier stages of acid stress and determine if the straightforward and comparatively inexpensive intervention of dietary acid reduction relieves or eliminates the harm they appear to cause.

Management of Metabolic Acidosis in Chronic Kidney Disease: Past, Present, and Future Direction.

Chronic kidney disease (CKD) is a major global epidemic associated with increased morbidity and mortality. Despite the effectiveness of kidney protection strategies of hypertension, diabetes, and lipid control and use of newer hypoglycemic agents and anti-angiotensin II drugs, the nephropathy in CKD continues unabated toward irreversible kidney failure. Thus, interventions targeting modifiable risk factors in CKD such as metabolic acidosis (MA) are needed. Acid reduction with sodium-based alkali has been shown to be an effective kidney-protection strategy for patients with CKD and reduced glomerular filtration rate (GFR). Small-scale studies reveal diets emphasizing ingestion of plant-sourced over animal-sourced protein reduce dietary acid, improve MA, and slow further nephropathy progression in patients with CKD and reduced GFR. Additionally, veverimer, an investigational, nonabsorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as a novel treatment for MA. As further studies define how to best use these interventions for kidney protection, clinicians must become aware of their potential utility in the management of patients with CKD. The aim of the present review is to explore the various intervention strategies that increase or normalize serum [HCO3-] in patients with CKD-associated MA or low normal serum [HCO3-] that may further slow progression of CKD.

Primary Medical Care Integrated with Healthy Eating and Healthy Moving is Essential to Reduce Chronic Kidney Disease Progression.

Increasing adverse outcomes in patients with chronic kidney disease reflect growth of patients with early-stage chronic kidney disease and their increasing per population rates of these outcomes. Progression of chronic kidney disease, more than current level of kidney function, is the primary driver of adverse chronic kidney disease-related outcomes. Racial/ethnic minorities progress faster to end-stage kidney disease with greater risk for adverse outcomes. Diabetes and hypertension cause two-thirds of end-stage kidney disease, for which primary medical care integrated with healthy eating and increased physical activity (healthy moving) slows chronic kidney disease progression. Patients with early-stage chronic kidney disease are appropriately managed by primary care practices but most lack infrastructure to facilitate this integration that reduces adverse chronic kidney disease-related outcomes. Individuals of low socioeconomic status are at greater chronic kidney disease risk, and flexible regulatory options in Medicaid can fund infrastructure to facilitate healthy eating and healthy moving integration with primary medical care. This integration promises to reduce chronic kidney disease-related adverse outcomes, disproportionately in racial/ethnic minorities, and thereby reduce chronic kidney disease-related health disparities.

Effects of veverimer on serum bicarbonate and physical function in women with chronic kidney disease and metabolic acidosis: a subgroup analysis from a randomised, controlled trial.

BACKGROUND: Globally, the prevalence of chronic kidney disease (CKD) is higher in women than in men; however, women have been historically under-represented in nephrology clinical trials. Metabolic acidosis increases risk of progressive loss of kidney function, causes bone demineralization and muscle protein catabolism, and may be more consequential in women given their lower bone and muscle mass. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. METHODS: This was a Phase 3, multicenter, randomised, blinded, placebo-controlled trial in 196 patients with CKD (eGFR: 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. We present the findings from a pre-specified subgroup analysis evaluating the effects of veverimer on metabolic acidosis and physical function among women (N = 77) enrolled in this trial. RESULTS: At week 52, women treated with veverimer had a greater increase in mean (± standard error) serum bicarbonate than the placebo group (5.4 [0.5] vs. 2.2 [0.6] mmol/L; P < 0.0001). Physical Function reported by patients on the Kidney Disease and Quality of Life - Physical Function Domain, a measure that includes items related to walking, stair climbing, carrying groceries and other activities improved significantly in women randomized to veverimer vs placebo (+ 13.2 vs. -5.2, respectively, P < 0.0031). Objectively measured performance time on the repeated chair stand test also improved significantly in the veverimer group vs. placebo (P = 0.0002). CONCLUSIONS: Veverimer was effective in treating metabolic acidosis in women with CKD, and significantly improved how they felt and functioned. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03390842 . Registered on January 4, 2018.

Biomarkers of Covert Acid Stress in Patients with Chronic Kidney Disease: A Cross-Sectional Study.

INTRODUCTION: Like metabolic acidosis, earlier stages of acid (H+) stress, including an ongoing H+ challenge in the form of dietary H+, without or with steady-state H+ accumulation but with normal plasma total CO2 (PTCO2) (the latter state known as eubicarbonatemic acidosis), are associated with augmented progression of chronic kidney disease (CKD), but diagnosis of this covert H+ stress is clinically problematic. Prior published studies to identify clinically practical biomarkers of covert H+ stress did not include assessments of either dietary H+ or H+ retention. METHODS: We tested plasma pH (PpH), 8-h urine excretion of citrate (UcitV) or ammonium (UNH4+V) as biomarkers of dietary H+ assessed as potential renal acid load (PRAL), and of steady-state H+ retention by comparing observed to expected PTCO2 increase 2 h after an oral NaHCO3 bolus. We recruited 313 non-diabetic participants with PTCO2 ≥ 22 mM to exclude participants with metabolic acidosis and with eGFR (mean [SD], mL/min/1.73 m2) stages G1 (n = 62, 99.2 [7.3]), G2 (n = 167, 73.8 [6.3]), and G3 (n = 84, 39.9 [6.7]). We performed linear regressions (LR) between H+ retention or PRAL (dependent variables) and PpH, UcitV, or UNH4+V (independent variables) after adjusting for eGFR. RESULTS: Steady-state H+ retention (mean [SD], mmol) increased with stage (G1 = 3.8 [12.5], G2 = 18.2 [12.4], and G3 = 25.6 [9.0]). PpH was not significantly associated with PRAL in any group, and its association with H+ retention was significant only for G3 (p < 0.01). UcitV association with PRAL was significant only for G1 (p < 0.01) but not for G2 (p = 0.65) or G3 (p = 0.11). UcitV association with H+ retention was negative for both G2 (p < 0.01) and G3 (p < 0.01) but was not significant for G1 (p = 0.50). Adding UNH4+V to UcitV as a regressor for H+ retention increased r2 only marginally for G2 (0.61-0.63) and G3 (0.75-0.79). UNH4+V association with PRAL was positive (p < 0.01) for G1 and G2 but was not significant for G3 (p = 0.46). UNH4+V association with H+ retention was significant for both G2 (p < 0.04) and G3 (p < 0.01) but diverged directionally, being positive for G2 but negative for G3. DISCUSSION: Among patients with CKD at risk for covert H+ stress, lower UcitV better identified eubicarbonatemic acidosis than UNH4+V because the UNH4+V versus H+ retention relationship diverged between G2 and G3. Neither test identified eubicarbonatemic acidosis with certainty, indicating need for further work to establish a clinically useful test. On the other hand, UNH4+V had better utility identifying increased dietary H+ assessed as PRAL in G1 and G2.

Effects of veverimer on serum bicarbonate and physical function in diabetic patients with chronic kidney disease and metabolic acidosis: subgroup analysis from a randomized, controlled trial.

BACKGROUND: Metabolic acidosis is a complication of chronic kidney disease (CKD) that increases risk of CKD progression, and causes bone demineralization and muscle protein catabolism. Patients with diabetes are prone to metabolic acidosis and functional limitations that decrease quality of life. Veverimer, an investigational, non-absorbed polymer that binds and removes gastrointestinal hydrochloric acid, is being developed as treatment for metabolic acidosis. This post hoc subgroup analysis evaluated effects of veverimer on metabolic acidosis and physical function among patients with diabetes. METHODS: This was a Phase 3, multicenter, randomized, blinded, placebo-controlled trial in 196 patients with CKD (estimated glomerular filtration rate 20-40 mL/min/1.73 m2) and metabolic acidosis who were treated for up to 1 year with veverimer or placebo. RESULTS: At Week 52, veverimer-treated patients with diabetes (n = 70), had a significantly greater increase in mean serum bicarbonate than the placebo group (n = 57) (4.4 versus 2.9 mmol/L, P < 0.05). Patient-reported limitations of physical function on the Kidney Disease and Quality of Life-Physical Function Domain (e.g. walking several blocks and climbing a flight of stairs) improved significantly in the veverimer versus placebo group (+12.5 versus +0.3, respectively, P < 0.001) as did objective physical performance on the repeated chair stand test (P < 0.0001). CONCLUSIONS: Few interventions for patients with diabetes and CKD have successfully improved quality of life or physical functioning. Our study demonstrated that veverimer effectively treated metabolic acidosis in patients with diabetes and CKD, and significantly improved how these patients felt and functioned.

The Continuum of Acid Stress.

Acid-related injury from chronic metabolic acidosis is recognized through growing evidence of its deleterious effects, including kidney and other organ injury. Progressive acid accumulation precedes the signature manifestation of chronic metabolic acidosis, decreased plasma bicarbonate concentration. Acid accumulation that is not enough to manifest as metabolic acidosis, known as eubicarbonatemic acidosis, also appears to cause kidney injury, with exacerbated progression of CKD. Chronic engagement of mechanisms to mitigate the acid challenge from Western-type diets also appears to cause kidney injury. Rather than considering chronic metabolic acidosis as the only acid-related condition requiring intervention to reduce kidney injury, this review supports consideration of acid-related injury as a continuum. This "acid stress" continuum has chronic metabolic acidosis at its most extreme end, and high-acid-producing diets at its less extreme, yet detrimental, end.