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 .

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.

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.

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.

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.

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.

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.

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.

Treatment of Chronic Kidney Disease-Related Metabolic Acidosis With Fruits and Vegetables Compared to NaHCO3 Yields More and Better Overall Health Outcomes and at Comparable Five-Year Cost.

OBJECTIVES: Current guidelines recommend treatment of metabolic acidosis in chronic kidney disease (CKD) with Na+-based alkali but base-producing fruits and vegetables (F + V) might yield more and better health outcomes, making the intervention cost-effective. DESIGN AND METHODS: In this post hoc analysis of a clinical trial we randomized 108 macroalbuminuric, nondiabetic CKD stage 3 participants with metabolic acidosis to receive F + V (n = 36) calculated to reduce dietary acid by half, oral NaHCO3 (HCO3-, n = 36) 0.3 mEq/kg body weight/day, or Usual Care (UC, n = 36) assessed annually for 5 years. We calculated a mean overall health score for the groups as follows: 1 for improved, 0 for no change, and -1 for worsened at 5 years for plasma total CO2, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, change in medication dose (reduction = 1, increased = -1, no change = 0), and 1 for met goal and 0 for not meeting goal for estimated glomerular filtration rate (>30 mL/min/1.73 m2) and systolic blood pressure (<130 mm Hg). We also assessed the number of participants with cardiovascular disease events (myocardial infarctions + strokes) and group medication and hospitalization costs. RESULTS: Net plasma total CO2 increase at 5 years was no different between HCO3- and F + V. Average health scores at 5 years differed among groups (P < .01) with F + V (7.4 [mean] ± 1.6 [standard deviation]) being descriptively larger than HCO3- and UC (2.9 ± 1.6 and 1.2 ± 1.6, respectively). The number of participants suffering cardiovascular disease events differed among groups (P = .009) with none (0) in F + V, 6 in UC, and 2 in HCO3-. Total 5-year household cost per beneficial health outcome differed among groups (P = .005) with UC being highest and that for HCO3- and F + V being comparable. CONCLUSIONS: Metabolic acidosis improved comparably with F + V or standard oral NaHCO3, but F + V yielded ancillary beneficial health outcomes, fewer participants with adverse cardiovascular events, and per-household cost that was comparable to NaHCO3.

Mechanisms of Metabolic Acidosis-Induced Kidney Injury in Chronic Kidney Disease.

Retrospective analyses and single-center prospective studies identify chronic metabolic acidosis as an independent and modifiable risk factor for progression of CKD. In patients with CKD, untreated chronic metabolic acidosis often leads to an accelerated reduction in GFR. Mechanisms responsible for this reduction include adaptive responses that increase acid excretion but lead to a decline in kidney function. Metabolic acidosis in CKD stimulates production of intrakidney paracrine hormones including angiotensin II, aldosterone, and endothelin-1 (ET-1) that mediate the immediate benefit of increased kidney acid excretion, but their chronic upregulation promotes inflammation and fibrosis. Chronic metabolic acidosis also stimulates ammoniagenesis that increases acid excretion but also leads to ammonia-induced complement activation and deposition of C3 and C5b-9 that can cause tubule-interstitial damage, further worsening disease progression. These effects, along with acid accumulation in kidney tissue, combine to accelerate progression of kidney disease. Treatment of chronic metabolic acidosis attenuates these adaptive responses; reduces levels of angiotensin II, aldosterone, and ET-1; reduces ammoniagenesis; and diminishes inflammation and fibrosis that may lead to slowing of CKD progression.

A Randomized Trial Comparing the Safety, Adherence, and Pharmacodynamics Profiles of Two Doses of Sodium Bicarbonate in CKD: the BASE Pilot Trial.

BACKGROUND: Oral sodium bicarbonate (NaHCO3) may preserve kidney function in CKD, even if initiated when serum bicarbonate concentration is normal. Adequately powered trials testing this hypothesis have not been conducted, partly because the best dose for testing is unknown. METHODS: This multicenter pilot trial assessed the safety, tolerability, adherence, and pharmacodynamics of two doses of NaHCO3 over 28 weeks in adults with eGFR 20-44 or 45-59 ml/min per 1.73 m2 with urinary albumin/creatinine (ACR) ≥50 mg/g and serum bicarbonate 20-28 meq/L. We randomly assigned 194 participants from ten clinical sites to receive higher-dose (HD-NaHCO3; 0.8 meq/kg of lean body wt per day; n=90) or lower-dose (LD-NaHCO3; 0.5 meq/kg of lean body wt per day; n=52) NaHCO3 or matching placebo (n=52). The dose was adjusted depending on side effects. The prescribed dose at week 28 was the primary outcome; a dose was considered acceptable for a full-scale trial if ≥67% of participants were on full-dose and ≥80% were on ≥25% of the per-protocol dose. RESULTS: Mean±SD baseline eGFR was 36±9 ml/min per 1.73 m2, serum bicarbonate was 24±2 meq/L, and median (IQR) ACR was 181 (25-745) mg/g. Both doses were well tolerated without significant changes in BP, weight, or serum potassium. The proportions of adverse events and hospitalizations were similar across the groups. Consequently, 87% in HD-NaHCO3, 96% in LD-NaHCO3, and 87% in placebo were on full dose at week 28; and 91% in HD-NaHCO3, 98% in LD-NaHCO3, and 92% in placebo were on ≥25% of the per-protocol dose. Mean urinary ammonium excretion was 25% lower and serum bicarbonate concentration was 1.3 meq/L higher in HD-NaHCO3 compared with LD-NaHCO3 at week 28. However, mean ACR increased by 12% in the lower-dose group and 30% in the higher-dose group. CONCLUSIONS: Both NaHCO3 doses were well tolerated over 28 weeks with no significant difference in adverse events or hospitalization compared with placebo. The higher dose lowered urinary ammonium excretion and increased serum bicarbonate more than the lower dose but was associated with a greater increase in ACR. The higher 0.8 meq/kg of lean body wt per day dose of NaHCO3 may be a reasonable choice for future trials.

Veverimer versus placebo in patients with metabolic acidosis associated with chronic kidney disease: a multicentre, randomised, double-blind, controlled, phase 3 trial.

BACKGROUND: Patients with advanced chronic kidney disease lose the capacity to fully excrete endogenous acid, resulting in chronic metabolic acidosis that increases the risk of disease progression and causes muscle catabolism and bone resorption. Veverimer, a non-absorbed, counterion-free, polymeric drug, selectively binds and removes hydrochloric acid from the gastrointestinal lumen, unlike current oral sodium bicarbonate therapy for metabolic acidosis that only neutralises accumulated acid. We assessed the efficacy and safety of veverimer as a treatment for metabolic acidosis in patients with chronic kidney disease. METHODS: We did a multicentre, parallel, randomised, double-blind, placebo-controlled study at 37 sites (hospitals and specialty clinics) in Bulgaria, Croatia, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA. Eligible participants were patients aged 18-85 years with non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate of 20-40 mL/min per 1·73 m2) and metabolic acidosis (serum bicarbonate concentration of 12-20 mmol/L). Patients were randomly assigned (4:3) to veverimer 6 g/day or placebo for 12 weeks while they consumed their typical diet. Both drugs were taken as oral suspensions in water with lunch. Randomisation was done by study site personnel with a computer-generated randomisation code with balanced permuted blocks (block size of seven) and stratified by baseline bicarbonate (≤18 mmol/L vs >18 mmol/L). Patients and investigators were masked to treatment allocation; however, because the appearance of placebo differed from veverimer, a non-masked site staff member who had no other role in the study dispensed, prepared, and supervised dosing of the study drugs. The composite primary efficacy endpoint was the difference (veverimer-placebo) in the proportion of patients achieving at week 12 either an increase of 4 mmol/L or more from baseline in serum bicarbonate concentration or serum bicarbonate in the normal range of 22-29 mmol/L, assessed in the modified intention-to-treat population (all patients with a baseline and at least one post-baseline serum bicarbonate value). Patients fasted for at least 4 h (consuming only water) before measurements of bicarbonate. Safety was assessed in all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, number NCT03317444. FINDINGS: Between Sept 26, 2017, and Feb 9, 2018, we randomly assigned 124 participants to veverimer and 93 to placebo. The composite primary endpoint was met by 71 (59%) of 120 patients in the veverimer group versus 20 (22%) of 89 patients in the placebo group (a difference of 37%, 95% CI 23-49; p<0·0001). The most common body system in which adverse events in the veverimer group occurred was gastrointestinal; of these, non-treatment limiting diarrhoea was the most common event (11 [9%] vs three [3%] in the veverimer and placebo groups, respectively). The most common treatment-related adverse events were gastrointestinal (diarrhoea, flatulence, nausea, and constipation) occurring in 16 (13%) patients with veverimer and five (5%) patients with placebo. Two deaths occurred during the study, both in the placebo group (unstable angina and pneumonia). INTERPRETATION: Veverimer effectively and safely corrected metabolic acidosis. Longer-term studies are warranted to assess the effects of veverimer on physical functioning and to assess other deleterious consequences of metabolic acidosis including progression of chronic kidney disease and bone health. FUNDING: Tricida.

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.

BACKGROUND: Metabolic acidosis, a complication of chronic kidney disease, causes protein catabolism and bone demineralisation and is associated with adverse kidney outcomes and mortality. Veverimer, a non-absorbed, counterion-free, polymeric drug candidate selectively binds and removes hydrochloric acid from the gastrointestinal lumen. METHODS: We did a multicentre, randomised, blinded, placebo-controlled, 40-week extension of a 12-week parent study at 29 sites (hospitals and specialty clinics) in seven countries (Bulgaria, Georgia, Hungary, Serbia, Slovenia, Ukraine, and the USA). Eligible patients were those with chronic kidney disease (estimated glomerular filtration rate 20-40 mL/min per 1·73 m2) and metabolic acidosis (serum bicarbonate 12-20 mmol/L), who had completed the 12-week parent study, for which they were randomly assigned (4:3) to veverimer (6 g/day) or placebo as oral suspensions in water with food. Participants in the extension continued with the same treatment assignment as in the parent study. The primary endpoint was safety; the four secondary endpoints assessed the long-term effects of veverimer on serum bicarbonate concentration and physical functioning. The safety analysis set was defined as all patients who received any amount of study drug. This trial is registered at ClinicalTrials.gov, number NCT03390842, and has now completed. FINDINGS: Participants entered the study between Dec 20, 2017, and May 4, 2018. Of the 217 patients randomly assigned to treatment in the parent study (124 to veverimer and 93 to placebo), 196 patients (114 veverimer and 82 placebo) continued on their blinded randomised treatment assignment into this 40-week extension study. Compared with placebo, fewer patients on veverimer discontinued treatment prematurely (3% vs 10%, respectively), and no patients on veverimer discontinued because of an adverse event. Serious adverse events occurred in 2% of veverimer-treated patients and in 5% of placebo patients (two of whom died). Renal system adverse events were reported in 8% and 15% in the veverimer and placebo groups, respectively. More patients on veverimer than placebo had an increase in bicarbonate (≥4 mmol/L or normalisation) at week 52 (63% vs 38%, p=0·0015) and higher bicarbonate concentrations were observed with veverimer than placebo at all timepoints starting at week 1 (p<0·001). Veverimer resulted in improved patient-reported physical functioning (Kidney Disease and Quality of Life-Physical Function Domain) versus placebo with a mean placebo-subtracted change at end of treatment of 12·1 points (SE 3·3; p<0·0001). Time to do the repeat chair stand test improved by 4·3 s (1·2) on veverimer versus 1·4 s (1·2) on placebo (p<0·0001). INTERPRETATION: In patients with chronic kidney disease and metabolic acidosis, veverimer safely and effectively corrected metabolic acidosis and improved subjective and objective measures of physical function. FUNDING: Tricida.

Novel dietary and pharmacologic approaches for acid-base modulation to preserve kidney function and manage uremia.

PURPOSE OF REVIEW: We review mechanisms for chronic kidney disease (CKD) progression that might be addressed with nonpharmacologic and novel pharmacologic interventions as strategies by which to slow or even prevent CKD progression. RECENT FINDINGS: Evolving data support the contribution of the broad spectrum of disorders of acid (H) accumulation, which we refer to as 'H stress', to CKD progression. Recent studies support that amelioration of H stress, including spectra of H accumulation that are insufficient to cause metabolic acidosis, is kidney-protective. In addition, gut-derived toxins appear to contribute to CKD progression and to the well described increased cardiovascular disease (CVD) risk in patients with CKD. Dietary and novel pharmacologic interventions hold promise as strategies to slow CKD progression through reducing levels of these gut-derived toxins. In addition, oxidative stress appears to mediate CKD progression and contributing factors like diet and cigarette smoking can exacerbate oxidative stress. Dietary changes and smoking cessation hold promise to favorably affect CKD progression by reducing kidney oxidative stress. SUMMARY: The urgent need to add to the traditional armamentarium of blood pressure control and antiangiotensin II pharmacologic therapy for kidney protection has led to investigations into additional kidney-protective strategies. Acid stress, a disordered gut microbiome, and oxidative stress each appear to contribute to CKD progression and can be potentially addressed by nonpharmacologic and novel pharmacologic interventions.

Urine citrate excretion identifies changes in acid retention as eGFR declines in patients with chronic kidney disease.

Previous studies have shown that acid (H+) retention in patients with chronic kidney disease (CKD) but without metabolic acidosis increases as the estimated glomerular filtration rate (eGFR) decreases over time. The present study examined whether changes in urine excretion of the pH-sensitive metabolite citrate predicted changes in H+ retention over time in similar patients with CKD that were followed for 10 yr. We randomized 120 CKD2 nondiabetic, hypertension-associated nephropathy patients with plasma total CO2 of >24 mM to receive 0.5 meq·kg body wt-1·day-1 NaHCO3 ([Formula: see text]; n = 40), 0.5 meq·kg body wt-1·day-1 NaCl (NaCl; n = 40), or usual care (UC; n = 40). We assessed eGFR (CKD-EPI) and H+ retention by comparing the observed with expected plasma total CO2 increase 2 h after an oral NaHCO3 bolus (0.5 meq/kg body wt). Although 10 yr versus baseline eGFR was lower for each group, 10-yr eGFR was higher (P < 0.01) in [Formula: see text] (59.6 ± 4.8 ml·min-1·1.73 m-2) than NaCl and UC (52.1 ± 5.9 and 52.3 ± 4.1 ml·min-1·1.73 m-2, respectively) groups. Less eGFR preservation was associated with higher 10-yr versus baseline H+ retention in the NaCl group (26.5 ± 13.1 vs. 18.2 ± 15.3 mmol, P < 0.01) and UC group (24.8 ± 11.3 vs. 17.7 ± 10.9 mmol, P < 0.01) and with lower 10-yr versus baseline 8-h urine citrate excretion (UcitrateV) for the NaCl group (162 ± 47 vs. 196 ± 52 mg, respectively, P < 0.01) and UC group (153 ± 41 vs. 186 ± 42 mg, respectively, P < 0.01). Conversely, better eGFR preservation in the [Formula: see text] group was associated with no differences in 10-yr versus baseline H+ retention (14.2 ±13.5 vs. 16.1 ± 15.1 mmol, P = 1.00) or UcitrateV (212 ± 45 vs. 203 ± 49 mg, respectively, P = 0.74). An overall generalized linear model for repeated measures showed that UcitrateV predicted H+ retention (P < 0.01). Less eGFR preservation in patients with CKD2 without metabolic acidosis was associated with increased H+ retention that was predicted by decreased UcitrateV.

Elevated serum anion gap in adults with moderate chronic kidney disease increases risk for progression to end-stage renal disease.

Acid retention associated with reduced glomerular filtration rate (GFR) exacerbates nephropathy progression in partial nephrectomy models of chronic kidney disease (CKD) and might be reflected in patients with CKD with reduced estimated GFR (eGFR) by increased anion gap (AG). We explored the presence of AG and its association with CKD in 14,924 adults aged ≥20 yr with eGFR ≥ 15 ml·min-1·1.73 m-2 enrolled in the National Health and Nutrition Examination Survey III, 1988-1994, using multivariable regression analysis. The model was adjusted for sociodemographic characteristics, diabetes, and hypertension. We further examined the association between AG and incident end-stage renal disease (ESRD) using frailty models, adjusting for demographics, clinical factors, body mass index, serum albumin, bicarbonate, eGFR, and urinary albumin-to-creatinine ratio by following 558 adults with moderate CKD for 12 yr via the United States Renal Data System. Laboratory measures determined AG using the traditional, albumin-corrected, and full AG definitions. Individuals with moderate CKD (eGFR: 30-59 ml·min-1·1.73 m-2) had a greater AG than those with eGFR ≥ 60 ml·min-1·1.73 m-2 in multivariable regression analysis with adjustment for covariates. We found a graded relationship between the adjusted mean for all three definitions of AG and eGFR categories (P trend < 0.0001). During followup, 9.2% of adults with moderate CKD developed ESRD. Those with AG in the highest tertile had a higher risk of ESRD after adjusting for covariates in a frailty model [relative hazard (95% confidence interval) for traditional AG: 1.76 (1.16-2.32)] compared with those in the middle tertile. The data suggest that high AG, even after adjusting for serum bicarbonate, is a contributing acid-base mechanism to CKD progression in adults with moderate chronic kidney disease.

Urine citrate excretion as a marker of acid retention in patients with chronic kidney disease without overt metabolic acidosis.

Acid (H+) retention appears to contribute to progressive decline in glomerular filtration rate (GFR) in patients with chronic kidney disease (CKD), including some patients without metabolic acidosis. Identification of patients with H+ retention but without metabolic acidosis could facilitate targeted alkali therapy; however, current methods to assess H+ retention are invasive and have little clinical utility. We tested the hypothesis that urine excretion of the pH-sensitive metabolite citrate can identify H+ retention in patients with reduced GFR but without overt metabolic acidosis. H+ retention was assessed based on the difference between observed and expected plasma total CO2 after an oral sodium bicarbonate load. The association between H+ retention and urine citrate excretion was evaluated in albuminuric CKD patients with eGFR 60-89 ml/min/1.73m2 (CKD 2, n=40) or >90 ml/min/1.73m2 (CKD 1, n = 26) before and after 30 days of base-producing fruits and vegetables. Baseline H+ retention was higher in CKD 2, while baseline urine citrate excretion was lower in CKD 2 compared to CKD 1. Base-producing fruits and vegetables decreased H+ retention in CKD 2 and increased urine citrate excretion in both groups. Thus, H+ retention is associated with lower urine citrate excretion, and reduction of H+ retention with a base-producing diet is associated with increased urine citrate excretion. These results support further exploration of the utility of urine citrate excretion to identify H+ retention in CKD patients with reduced eGFR but without metabolic acidosis, to determine their candidacy for kidney protection with dietary H+ reduction or alkali therapy.

Clinical evidence that treatment of metabolic acidosis slows the progression of chronic kidney disease.

PURPOSE OF REVIEW: We review the growing clinical evidence that metabolic acidosis mediates chronic kidney disease (CKD) progression and that treatment to increase the associated low serum bicarbonate (HCO3) in CKD is disease-modifying. RECENT FINDINGS: Seven prospective studies of patients with wide ranges of estimated glomerular filtration rates (eGFRs) and serum HCO3 examined the effect on CKD of increasing serum HCO3 using dietary acid reduction with either oral alkali (sodium bicarbonate or sodium citrate), a vegetarian diet very low in acid-producing protein (0.3 g/kg/day) supplemented with ketoanalogues or added base-producing fruits and vegetables. Clinical outcomes included slower kidney function decline (using eGFR measurements) and fewer patients progressing to end-stage kidney disease. Post hoc analyses demonstrated that: treatment of metabolic acidosis for 2 years decreased the number of patients with at least a 40% eGFR decline, a validated surrogate for progression to end-stage kidney disease and across four studies, treatment to increase serum HCO3 by 4-6.8 mEq/l in acidotic patients with CKD was associated with a ∼4 ml/min/1.73 m reduction in the rate of eGFR decline over 6-24 months compared with controls. SUMMARY: Metabolic acidosis appears to enhance CKD progression and its treatment should be studied further as a potential disease-modifying intervention.