Metabolic Acidosis in CKD: Pathogenesis, Adverse Effects, and Treatment Effects.

Metabolic acidosis is a frequent complication of chronic kidney disease and is associated with a number of adverse outcomes, including worsening kidney function, poor musculoskeletal health, cardiovascular events, and death. Mechanisms that prevent metabolic acidosis detrimentally promote further kidney damage, creating a cycle between acid accumulation and acid-mediated kidney injury. Disrupting this cycle through the provision of alkali, most commonly using sodium bicarbonate, is hypothesized to preserve kidney function while also mitigating adverse effects of excess acid on bone and muscle. However, results from clinical trials have been conflicting. There is also significant interest to determine whether sodium bicarbonate might improve patient outcomes for those who do not have overt metabolic acidosis. Such individuals are hypothesized to be experiencing acid-mediated organ damage despite having a normal serum bicarbonate concentration, a state often referred to as subclinical metabolic acidosis. Results from small- to medium-sized trials in individuals with subclinical metabolic acidosis have also been inconclusive. Well-powered clinical trials to determine the efficacy and safety of sodium bicarbonate are necessary to determine if this intervention improves patient outcomes.

Targeting Gut Microbiome With Prebiotic in Patients With CKD: The TarGut-CKD Study.

Introduction: Disruption of gut microbiota underpins some of the metabolic alterations observed in chronic kidney disease (CKD). Methods: In a nonrandomized, open-label, 3-phase pilot trial, with repeated measures within each phase, we examined the efficacy of oligofructose-enriched inulin (p-inulin) in changing the gut microbiome and their metabolic products in 15 patients with CKD. The stability of microbiome and metabolome was studied during the pretreatment phase (8 weeks), a p-inulin treatment phase (12 weeks), and a post treatment phase (8 weeks) of the study. Results: Study participants completed 373 of the 420 expected study visits (88.8%). Adherence to p-inulin was 83.4%. 16S rRNA sequencing was performed in 368 stool samples. A total of 1085 stool, urine, and plasma samples were subjected to untargeted metabolomic studies. p-inulin administration altered the composition of the gut microbiota significantly, with an increase in abundance of Bifidobacterium and Anaerostipes. Intersubject variations in microbiome and metabolome were larger than intrasubject variation, indicating the stability of the gut microbiome within each phase of the study. Overall metabolite compositions assessed by beta diversity in urine and stool metabolic profiles were significantly different across study phases. Several specific metabolites in stool, urine, and plasma were significant at false discovery rate (FDR) ≤ 0.1 over phase. Specifically, there was significant enrichment in microbial metabolites derived from saccharolysis. Conclusion: Results from our study highlight the stability of the gut microbiome and the expansive effect of p-inulin on microbiome and host cometabolism in patients with CKD. Findings from this study will enable rigorous design of microbiome-based intervention trials.

Oral Sodium Bicarbonate and Bone Turnover in CKD: A Secondary Analysis of the BASE Pilot Trial.

SIGNIFICANCE STATEMENT: In CKD, metabolic acidosis is commonly treated with alkali in the hope that it will improve bone health. In a post hoc analysis of the Bicarbonate Administration to Stabilize eGFR Pilot Trial, we investigated whether sodium bicarbonate affects serum levels of bone turnover markers and other hormones related to bone health in individuals with CKD who have normal to slightly reduced total CO2 (20-28 mEq/L). Sodium bicarbonate increased serum levels of α-klotho but had no significant effect on other bone health markers, including intact fibroblast growth factor-23 (iFGF-23), intact parathyroid hormone (iPTH), and bone-specific alkaline phosphatase (B-SAP). Further study is needed to determine the effect of bicarbonate administration on clinical aspects of bone health. BACKGROUND: Treatment with alkali has been hypothesized to improve bone health in CKD by mitigating adverse effects of acid on bone mineral. We investigated the effect of treatment with sodium bicarbonate on bone turnover markers and other factors related to bone metabolism in CKD. METHODS: This is a post hoc analysis of the Bicarbonate Administration to Stabilize eGFR Pilot Trial in which 194 individuals with CKD and serum total CO2 20-28 mEq/L were randomly assigned to placebo or one of two doses of sodium bicarbonate (0.5 or 0.8 mEq/kg lean body weight per day) for 28 weeks. The following serum measurements were performed at baseline, week 12, and week 28: B-SAP, c-telopeptide, procollagen type I intact N-terminal propeptide, iPTH, iFGF-23, soluble klotho, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and tartrate-resistant acid phosphatase 5b. The difference (sodium bicarbonate versus placebo) in mean change of each bone biomarker from baseline was determined using linear mixed models. RESULTS: One hundred sixty-eight participants submitted samples for post hoc investigations. Mean eGFR was 37±10 ml/min per 1.73 m2 and mean total CO2 was 24±3 mEq/L at baseline. Sodium bicarbonate induced a dose-dependent increase in soluble klotho levels compared with placebo. There was no significant effect of treatment with either dose of sodium bicarbonate on any of the other bone biomarkers, including iFGF-23, iPTH, and B-SAP. Effects on bone biomarkers were similar in those with baseline serum total CO2 <24 mEq/L compared with those with total CO2 ≥24 mEq/L. CONCLUSIONS: In this pilot trial of individuals with CKD and total CO2 20-28 mEq/L, sodium bicarbonate treatment increased serum klotho levels but did not affect other bone health markers over 28 weeks. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov, NCT02521181.

Couple-based lifestyle intervention to prevent type 2 diabetes: protocol for a randomised pilot trial.

INTRODUCTION: Type 2 diabetes is prevalent among US adults. Lifestyle interventions that modify health behaviours prevent or delay progression to diabetes among individuals at high risk. Despite the well-documented influence of individuals' social context on their health, evidence-based type 2 diabetes prevention interventions do not systematically incorporate participants' romantic partners. Involving partners of individuals at high risk for type 2 diabetes in primary prevention may improve engagement and outcomes of programmes. The randomised pilot trial protocol described in this manuscript will evaluate a couple-based lifestyle intervention to prevent type 2 diabetes. The objective of the trial is to describe the feasibility of the couple-based intervention and the study protocol to guide planning of a definitive randomised clinical trial (RCT). METHODS AND ANALYSIS: We used community-based participatory research principles to adapt an individual diabetes prevention curriculum for delivery to couples. This parallel two-arm pilot study will include 12 romantic couples in which at least one partner (ie, 'target individual') is at risk for type 2 diabetes. Couples will be randomised to either the 2021 version of the CDC's PreventT2 curriculum designed for delivery to individuals (six couples), or PreventT2 Together, the adapted couple-based curriculum (six couples). Participants and interventionists will be unblinded, but research nurses collecting data will be blinded to treatment allocation. Feasibility of the couple-based intervention and the study protocol will be assessed using both quantitative and qualitative measures. ETHICS AND DISSEMINATION: This study has been approved by the University of Utah IRB (#143079). Findings will be shared with researchers through publications and presentations. We will collaborate with community partners to determine the optimal strategy for communicating findings to community members. Results will inform a subsequent definitive RCT. TRIAL REGISTRATION NUMBER: NCT05695170.

Estimated Kidney Tubular Secretion and Kidney, Cardiovascular, and Mortality Outcomes in CKD: The Systolic Blood Pressure Intervention Trial.

Rational & Objective: Many drugs, metabolites, and toxins are cleared by the kidneys via tubular secretion. Whether novel endogenous measures of tubular secretion provide information about kidney, cardiovascular, and mortality risk is uncertain. Study Design: Longitudinal subgroup analysis of clinical trial participants. Setting & Participants: 2,089 Systolic Blood Pressure Intervention Trial participants with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at baseline. Exposure: Summary score incorporating urine-to-plasma ratios of 10 endogenous secretion markers measured in paired urine and plasma samples at baseline. Outcome: The primary outcome was longitudinal change in eGFR. Secondary outcomes included chronic kidney disease (CKD) progression (≥50% eGFR decline or incident kidney failure requiring dialysis or kidney transplantation), a cardiovascular disease (CVD) composite (myocardial infarction, acute coronary syndrome, stroke, acute decompensated heart failure, or death from cardiovascular causes), and mortality. Analytical Approach: Linear mixed-effect models were used to evaluate the association between the secretion score and change in eGFR, and Cox proportional hazards models were used to evaluate associations with CKD progression, CVD, and mortality. Results: At baseline, mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m2. During a median follow-up of 3.3 years, mean change in eGFR was -1.44% per year, and 72 CKD progression events, 272 CVD events, and 144 deaths occurred. In multivariable analyses, lower secretion score was associated with faster eGFR decline and greater risk of CKD progression, CVD, and mortality. After further adjustment for baseline eGFR and albuminuria, each 1-standard deviation lower secretion score was associated with faster eGFR decline (-0.65% per year; 95% CI, -0.84% to -0.46%), but not CKD progression (HR, 1.23; 95% CI, 0.96-1.58), CVD (HR, 1.02; 95% CI, 0.89-1.18), or mortality (HR, 0.90; 95% CI, 0.74-1.09). The secretion score association with eGFR decline appeared stronger in participants with baseline eGFR <45 mL/min/1.73 m2 (P for interaction < 0.001). Limitations: Persons with diabetes and proteinuria >1 g/d were excluded. Conclusions: Among SPRINT participants with CKD, lower estimated tubular secretion was associated with faster eGFR decline, independent of baseline eGFR and albuminuria, but not with CKD progression, CVD, or mortality.

Acid-Mediated Kidney Injury Across the Spectrum of Metabolic Acidosis.

Metabolic acidosis affects about 15% of patients with chronic kidney disease. As kidney function declines, the kidneys progressively fail to eliminate acid, primarily reflected by a decrease in ammonium and titratable acid excretion. Several studies have shown that the net acid load remains unchanged in patients with reduced kidney function; the ensuing acid accumulation can precede overt metabolic acidosis, and thus, indicators of urinary acid or potential base excretion, such as ammonium and citrate, may serve as early signals of impending metabolic acidosis. Acid retention, with or without overt metabolic acidosis, initiates compensatory responses that can promote tubulointerstitial fibrosis via intrarenal complement activation and upregulation of endothelin-1, angiotensin II, and aldosterone pathways. The net effect is a cycle between acid accumulation and kidney injury. Results from small- to medium-sized interventional trials suggest that interrupting this cycle through base administration can prevent further kidney injury. While these findings inform current clinical practice guidelines, large-scale clinical trials are still necessary to prove that base therapy can limit chronic kidney disease progression or associated adverse events.

Increased Rates of Supplement-Associated Oxalate Nephropathy During COVID-19 Pandemic.

Introduction: Causes of secondary oxalate nephropathy include enteric dysfunction and excessive intake of oxalate or oxalate precursors. During the COVID-19 pandemic, there has been a dramatic rise in sales of supplements and vitamin C, during which time we observed an apparent increase in the proportion of ingestion-associated oxalate nephropathy. Methods: We retrospectively reviewed secondary oxalate nephropathy and compared pre-pandemic (2018-2019) and pandemic (2020-early 2022) time periods. Results: We identified 35 patients with kidney biopsy proven (30 native, 5 allograft) oxalate nephropathy at a single academic institution. Supplement-associated oxalate nephropathy comprised a significantly higher proportion of cases during COVID-19 pandemic compared with the preceding 2 years (44% vs. 0%, P = 0.002), and was associated with use of vitamin C, dietary changes, and supplements. Oxalate nephropathy in the kidney allograft, in contrast, remained associated with enteric hyperoxaluria, antibiotic use, and dehydration. Many patients had diabetes mellitus (57%), hypertension (40%) and/or pre-existing chronic kidney disease (CKD, 49%). Of 9 patients in which the potentially causative ingestion was identified and removed, 8 experienced improvement in kidney function. Conclusion: There was a shift toward supplements rather than enteric hyperoxaluria as a leading cause of secondary oxalate nephropathy during the COVID-19 pandemic. Kidney outcomes are better than those observed for enteric hyperoxaluria, if the offending agent is identified and removed.

Measurement of Urinary Ammonium Using a Commercially Available Plasma Ammonium Assay.

Background: Determination of urinary ammonium excretion is helpful in evaluating patients with acid-base disorders, chronic kidney disease, and nephrolithiasis. However, urinary ammonium levels are only measured by specialized laboratories in the United States, limiting widespread implementation. We evaluated the performance of a plasma ammonium assay to quantify urinary ammonium excretion and also determined ammonium stability under a variety of conditions. Methods: An enzymatic plasma ammonium assay (Randox) was modified to measure urinary ammonium concentration. Urine samples were diluted 40-fold and then assayed on an Abbott Architect ci8200 analyzer. Assay precision, limit of quantitation, and linearity were determined. The method was compared against the formalin titration method, and stability studies were conducted at different temperatures and pH. Results: After dilution, the assay had total precision of 18% at 2.54 mmol/L, 5% at 15.58 mmol/L, and 2% at 29.49 mmol/L, with a limit of quantitation of 2.92 mmol/L. Assay performance was linear in the range of 0.7-45 mmol/L. Method comparison against the formalin method showed a slope of 0.98 and intercept of -0.37 mmol/L. Urinary ammonium was determined to be stable for 48 hours at room temperature and for 9 days at 4°C and -20°C at pH 5.6-6.3. Ammonium was less stable at pH 3.8 and 8.5. When stored at -80°C, urinary ammonium was stable for at least 24 months. Conclusions: The modified enzymatic plasma ammonium assay reliably quantifies urine ammonium at physiologic concentrations. It compares well with the formalin titration method and is suitable for routine clinical use on an automated chemistry analyzer.

Urinary Sulfate, Kidney Failure, and Death in CKD: The African American Study of Kidney Disease and Hypertension.

Background: Sulfur is an important mineral element whose principal source is animal protein. Animal protein contributes to the daily acid load, which is associated with poor outcomes in individuals with chronic kidney disease (CKD). We hypothesized that higher urinary sulfate, as a reflection of the daily acid load, is associated with a greater risk of death and CKD progression. Methods: Urinary sulfate was measured in 1057 African American Study of Kidney Disease and Hypertension (AASK) participants at baseline. Participants were categorized by tertiles of daily sulfate excretion. The longitudinal outcome of interest was the composite of death, dialysis, or 50% reduction in measured glomerular filtration rate (GFR). Multivariable adjusted Cox regression models were fit to relate the composite outcome to daily sulfate excretion using the lowest tertile as the reference. Results: Participants in the highest urinary sulfate tertile were more likely to be men and have a higher body mass index, protein intake, measured GFR, and urinary ammonium and phosphate excretion, and lower urinary protein/creatinine. Compared with those in the lowest tertile of sulfate, those in the highest tertile had a 44% lower hazard (95% CI, 0.37 to 0.84), and those in the middle tertile had a 27% lower hazard (95% CI, 0.55 to 0.96) of death, dialysis, or 50% reduction in measured GFR during follow-up after adjusting for demographics, GFR, protein intake, and other potential confounders. Protein intake was not associated with risk of these events. Conclusions: Higher urinary sulfate excretion is associated with more favorable outcomes in Blacks who have CKD attributed to hypertension.

Markers of Kidney Tubular Secretion and Risk of Adverse Events in SPRINT Participants with CKD.

BACKGROUND: Kidney tubular secretion is an essential mechanism for clearing many common antihypertensive drugs and other metabolites and toxins. It is unknown whether novel measures of tubular secretion are associated with adverse events (AEs) during hypertension treatment. METHODS: Among 2089 SPRINT (Systolic Blood Pressure Intervention Trial) participants with baseline eGFR <60 ml/min per 1.73 m2, we created a summary secretion score by averaging across the standardized spot urine-to-plasma ratios of ten novel endogenous tubular secretion measures, with lower urine-to-plasma ratios reflecting worse tubular secretion. Multivariable Cox proportional hazards models were used to evaluate associations between the secretion score and risk of a composite of prespecified serious AEs (hypotension, syncope, bradycardia, AKI, electrolyte abnormalities, and injurious falls). The follow-up protocol for SPRINT routinely assessed two laboratory monitoring AEs (hyperkalemia and hypokalemia). RESULTS: Overall, 30% of participants experienced at least one AE during a median follow-up of 3.0 years. In multivariable models adjusted for eGFR and albuminuria, lower (worse) secretion scores at baseline were associated with greater risk of the composite AE outcome (hazard ratio per 1-SD lower secretion score, 1.16; 95% confidence interval, 1.04 to 1.27). In analyses of the individual AEs, lower secretion score was associated with significantly greater risk of AKI, serious electrolyte abnormalities, and ambulatory hyperkalemia. Associations were similar across randomized treatment assignment groups. CONCLUSION: Among SPRINT participants with CKD, worse tubular secretion was associated with greater risk of AEs, independent of eGFR and albuminuria.

Beyond the Urine Anion Gap: In Support of the Direct Measurement of Urinary Ammonium.

Ammonium is a major urinary buffer that is necessary for the normal excretion of the daily acid load. Its urinary rate of excretion (UNH4) may be increased several fold in the presence of extrarenal metabolic acidosis. Therefore, measurement of UNH4 can provide important clues about causes of metabolic acidosis. Because UNH4 is not commonly measured in clinical laboratories, the urinary anion gap (UAG) was proposed as its surrogate about 4 decades ago, and it is still frequently used for that purpose. Several published studies strongly suggest that UAG is not a good index of UNH4 and support the concept that direct measurement of UNH4 is an important parameter to define in clinical nephrology. Low UNH4 levels have recently been found to be associated with a higher risk of metabolic acidosis, loss of kidney function, and death in persons with chronic kidney disease, while surrogates like the UAG do not recapitulate this risk. In order to advance the field it is necessary for the medical community to become more familiar with UNH4 levels in a variety of clinical settings. Herein, we review the literature, searching for available data on UNH4 under normal and various pathological conditions, in an attempt to establish reference values to interpret UNH4 results if and when UNH4 measurements become available as a routine clinical test. In addition, we present original data in 2 large populations that provide further evidence that the UAG is not a good predictor of UNH4. Measurement of urine NH4 holds promise to aid clinicians in the care of patients, and we encourage further research to determine its best diagnostic usage.

Abnormalities in Cardiac Structure and Function among Individuals with CKD: The COMBINE Trial.

Background: Individuals with CKD have a high burden of cardiovascular disease (CVD). Abnormalities in cardiac structure and function represent subclinical CVD and can be assessed by cardiac magnetic resonance imaging (cMRI). Methods: We investigated differences in cMRI parameters in 140 individuals with CKD stages 3b-4 who participated in the CKD Optimal Management with BInders and NicotinamidE (COMBINE) trial and in 24 age- and sex-matched healthy volunteers. Among COMBINE participants, we examined the associations of eGFR, urine albumin-creatinine ratio (UACR), phosphate, fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH) with baseline (N=140) and 12-month change (N=112) in cMRI parameters. Results: Mean (SD) ages of the COMBINE participants and healthy volunteers were 64.9 (11.9) and 60.4 (7.3) years, respectively. The mean (SD) baseline eGFR values in COMBINE participants were 32.1 (8.0) and 85.9 (16.0) ml/min per 1.73 m2 in healthy volunteers. The median (interquartile range [IQR]) UACR in COMBINE participants was 154 (20.3-540.0) mg/g. Individuals with CKD had lower mitral valve E/A ratio compared with healthy volunteers (for CKD versus non-CKD, ß estimate, -0.13; 95% CI, -0.24 to -0.012). Among COMBINE participants, multivariable linear regression analyses showed that higher UACR was significantly associated with lower mitral valve E/A ratio (ß estimate per 1 unit increase in natural-log UACR, -0.06; 95% CI, -0.09 to -0.03). This finding was preserved among individuals without baseline CVD. UACR was not associated with 12-month change in any cMRI parameter. eGFR, phosphate, FGF23, and PTH were not associated with any cMRI parameter in cross-sectional or change analyses. Conclusions: Individuals with CKD stages 3b-4 have evidence of cMRI abnormalities. Albuminuria was independently associated with diastolic dysfunction, as assessed by mitral valve E/A ratio, in individuals with CKD with and without clinical CVD. Albuminuria was not associated with change in any cMRI parameter.