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.

Urinary Biomarkers and Kidney Injury in VA NEPHRON-D: Phenotyping Acute Kidney Injury in Clinical Trials.

RATIONALE & OBJECTIVE: Urinary biomarkers of injury, inflammation, and repair may help phenotype acute kidney injury (AKI) observed in clinical trials. We evaluated the differences in biomarkers between participants randomized to monotherapy or to combination renin-angiotensin-aldosterone system (RAAS) blockade in VA NEPHRON-D, where an increased proportion of observed AKI was acknowledged in the combination arm. STUDY DESIGN: Longitudinal analysis. SETTING & PARTICIPANTS: A substudy of the VA NEPHRON-D trial. PREDICTOR: Primary exposure was the treatment arm (combination [RAAS inhibitor] vs monotherapy). AKI is used as a stratifying variable. OUTCOME: Urinary biomarkers, including albumin, EGF (epidermal growth factor), MCP-1 (monocyte chemoattractant protein-1), YKL-40 (chitinase 3-like protein 1), and KIM-1 (kidney injury molecule-1). ANALYTICAL APPROACH: Biomarkers measured at baseline and at 12 months in trial participants were compared between treatment groups and by AKI. AKI events occurring during hospitalization were predefined safety end points in the original trial. The results were included in a meta-analysis with other large chronic kidney disease trials to assess global trends in biomarker changes. RESULTS: In 707 participants followed for a median of 2.2 years, AKI incidence was higher in the combination (20.7%) versus the monotherapy group (12.7%; relative risk [RR], 1.64 [95% CI, 1.16-2.30]). Compared with the monotherapy arm, in the combination arm the urine biomarkers at 12 months were either unchanged (MCP-1: RR, -3% [95% CI, -13% to 9%], Padj=0.8; KIM-1: RR, -10% [95% CI, -20% to 1%], Padj=0.2; EGF, RR-7% [95% CI, -12% to-1%], Padj=0.08) or lower (albuminuria: RR, -24% [95% CI, -37% to-8%], Padj=0.02; YKL: RR, -40% to-44% [95% CI, -58% to-25%], Padj<0.001). Pooled meta-analysis demonstrated reduced albuminuria in the intervention arm across 3 trials and similar trajectories in other biomarkers. LIMITATIONS: Biomarker measurement was limited to 2 time points independent of AKI events. CONCLUSIONS: Despite the increased risk of serum creatinine-defined AKI, combination RAAS inhibitor therapy was associated with unchanged or decreased urinary biomarkers at 12 months. This suggests a possible role for kidney biomarkers to further characterize kidney injury in clinical trials. PLAIN-LANGUAGE SUMMARY: The VA NEPHRON-D trial investigated inhibition of the renin-angiotensin-aldosterone system (RAAS) hormonal axis on kidney outcomes in a large population of diabetic chronic kidney disease patients. The trial was stopped early due to increased events of serum creatinine-defined acute kidney injury in the combination therapy arm. Urine biomarkers can serve as an adjunct to serum creatinine in identifying kidney injury. We found that urinary biomarkers in the combination therapy group were not associated with a pattern of harm and damage to the kidney, despite the increased number of kidney injury events in that group. This suggests that serum creatinine alone may be insufficient for defining kidney injury and supports further exploration of how other biomarkers might improve identification of kidney injury in clinical trials.

A prespecified exploratory analysis from FIDELITY examined finerenone use and kidney outcomes in patients with chronic kidney disease and type 2 diabetes.

In FIDELITY, a prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD studies, finerenone was found to improve cardiorenal outcomes in patients with type 2 diabetes, a urine albumin-to-creatinine ratio of 30-5000 mg/g, an estimated glomerular filtration rate (eGFR) of 25 ml/min per 1.73 m2 or more and also receiving optimized renin-angiotensin system blockade treatment. This present analysis focused on the efficacy and safety of finerenone on kidney outcomes. Among 13,026 patients with a median follow-up of three years, finerenone significantly reduced the hazard of a kidney composite outcome (time to kidney failure, sustained 57% or more decrease in eGFR from baseline, or kidney death) by 23% versus placebo (hazard ratio, 0.77; 95% confidence interval, 0.67-0.88), with a three-year absolute between-group difference of 1.7% (95% confidence interval, 0.7-2.6). Hazard ratios were directionally consistent for a prespecified baseline eGFR and urine albumin-to-creatinine ratio categories (Pinteraction = 0.62 and Pinteraction = 0.67, respectively), although there was a high degree of uncertainty in the 30-300 mg/g subgroup. Finerenone significantly reduced the hazard of end-stage kidney disease (ESKD) by 20% versus placebo (0.80; 0.64-0.99). Adverse events were similar between treatment arms, although hyperkalemia leading to treatment discontinuation occurred significantly more frequently with finerenone versus placebo (2.4% vs 0.8% and 0.6% vs 0.3% in patients with eGFR less than 60 vs. greater than or equal to 60 ml/min per 1.73 m2, respectively). Thus, finerenone improved kidney outcomes, reduced the hazard of ESKD, and is well tolerated in patients with chronic kidney disease and type 2 diabetes.

High unmet treatment needs in patients with chronic kidney disease and type 2 diabetes: real-world evidence from a US claims database.

BACKGROUND: Chronic kidney disease (CKD), a serious complication of type 2 diabetes (T2D) increases the comorbid risk of cardiovascular disease (CVD) and end-stage kidney disease(ESKD). Treatment guidelines recommend renin-angiotensin blockade and antihyperglycemic treatment with metformin and sodium-glucose cotransporter 2 inhibitors (SGLT2is) as first-line treatment. We evaluated treatment initiation and discontinuation overall and in subgroups of T2D patients with incident CKD (incident cohort) and rates of clinical and economic outcomes in patients with T2D and any CKD (prevalent cohort). METHODS: In this retrospective study of administrative claims in the USA between 1 January 2007 and 31 March 2019, we evaluated the proportion of patients with concomitant, newly initiated and discontinued use of antihypertensive [angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blockers (ARBs), steroidal mineralocorticoid receptor antagonists (sMRAs)] and antidiabetic [SGLT2is, dipeptidyl peptidase-4 inhibitors (DPP4is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), insulin and sulfonylureas] medications, rates of clinical outcomes per 1000 person-years and mean total healthcare costs. RESULTS: We identified 63 127 and 326 763 patients in the incident and prevalent CKD cohorts, respectively. Low initiation and high discontinuation rates were observed with 17.8% and 56.0% for ACEi/ARBs, 1.3% and 66.0% for sMRAs, 2.5% and 65.0% for SGLT2is, 3.7% and 66.8% for DPP4is, 2.31% and 69.0% for GLP-1 RAs, 4% and 75.7% for insulin and 5.5% and 56.9% for sulfonylureas. Similar results were seen by subgroups. Rates of clinical outcomes ranged from 35.07 per 1000 person-years for all-cause mortality to 104.19 for ESKD, with rates of hospitalization ranging from 36.61 for kidney hospitalizations to 283.14 for all-cause hospitalizations. Among patients with comorbidities, higher clinical and economic outcomes were found. CONCLUSION: Our results highlight high unmet needs of CKD and T2D, particularly subgroups of patients with multimorbid CVD, high-risk CKD (low estimated glomerular filtration rate or high urinary albumin:creatinine ratio) or rapidly progressing CKD. Low initiation and high discontinuation of recommended treatments suggest that adherence to guidelines for halting CKD progression is suboptimal. These high-risk patients may benefit from further treatment options to improve morbidity and mortality and reduce the economic burden.

FORWARD: Building a Model to Hold Schools of Public Health Accountable for Antiracism Work.

Schools of public health have increasingly adopted programs, praxis, and competencies for antiracist work. Fighting Oppression, Racism and White Supremacy through Action, Research and Discourse (FORWARD) was founded to accelerate antiracist work at the Columbia University Mailman School of Public Health in New York City. Seven action corps reporting to an accountability cabinet were established with 183 participants. FORWARD achieved progress across five core pillars. We describe how an iterative, dynamic structure and explicit framework for accountability can guide future antiracism work. (Am J Public Health. 2023;113(10):1086-1088. https://doi.org/10.2105/AJPH.2023.307356).

Longitudinal TNFR1 and TNFR2 and Kidney Outcomes: Results from AASK and VA NEPHRON-D.

BACKGROUND: Higher baseline levels of soluble TNF receptors (TNFR1 and TNFR2) have been associated with progressive CKD. Whether longitudinal changes in these biomarkers of inflammation are also associated with worse kidney outcomes has been less studied. METHODS: We evaluated associations of longitudinal changes in TNFR1 and TNFR2 with ESKD in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; 0% diabetes) and kidney function decline (first occurrence of ≥30 ml/min per 1.73 m2 or ≥50% eGFR decline if randomization eGFR ≥60 or <60 ml/min per 1.73 m2, respectively; ESKD) in the Veterans Affairs Nephropathy in Diabetes trial (VA NEPHRON-D; 99% male; 100% diabetes) using Cox models. Biomarkers were measured from samples collected at 0-, 12-, and 24-month visits for AASK (serum) and 0- and 12-month visits for VA NEPHRON-D (plasma). Biomarker slopes (AASK) were estimated using linear mixed-effects models. Covariates included sociodemographic/clinical factors, baseline biomarker level, and kidney function. RESULTS: There were 129 ESKD events over a median of 7.0 years in AASK (n=418) and 118 kidney function decline events over a median of 1.5 years in VA NEPHRON-D (n=754). In AASK, each 1 SD increase in TNFR1 and TNFR2 slope was associated with 2.98- and 1.87-fold higher risks of ESKD, respectively. In VA NEPHRON-D, each 1 SD increase in TNFR1 and TNFR2 was associated with 3.20- and 1.43-fold higher risks of kidney function decline, respectively. CONCLUSIONS: Among individuals with and without diabetes, longitudinal increases in TNFR1 and TNFR2 were each associated with progressive CKD, independent of initial biomarker level and kidney function.

Predictors of cardio-kidney complications and treatment failure in patients with chronic kidney disease and type 2 diabetes treated with SGLT2 inhibitors.

BACKGROUND: Clinical practice guidelines recommend sodium-glucose co-transporter 2 inhibitors (SGLT2is) to mitigate adverse kidney and cardiovascular outcomes in patients with type 2 diabetes (T2D), including patients with comorbid chronic kidney disease (CKD), also referred to as diabetic kidney disease (DKD), who are at even higher risk. In this study, we sought to identify predictors of cardio-kidney events, cardio-kidney complications, and treatment failure (i.e., addition/initiation of a new T2D class, insulin, or discontinuation of SGLT2is) after new initiation of SGLT2is in patients with CKD and T2D (DKD). METHODS: In this retrospective cohort study, we identified adult patients with DKD who initiated SGLT2is between April 1, 2012, and June 30, 2019, in Optum claims data. Outcome rates per 1000 person-years (PY) are reported with 95% confidence intervals (CIs). Cox proportional hazards regression identified patient characteristics associated with each outcome. RESULTS: The study population consisted of 6389 initiators of SGLT2is. The rate of CV hospitalization was 26.0 (95% CI 21.6, 30.4) per 1000 PY. Baseline characteristics associated with higher risk of CV hospitalization included age, atrial fibrillation, peripheral vascular disease (PVD), and cancer. The rate of kidney hospitalization was 12.0 (95% CI 9.0, 15.0) per 1000 PY. The risk increased significantly with baseline evidence of heart failure, hyperkalemia, respiratory failure, depression, and use of loop diuretics. In total, 55.0% of all SGLT2i initiators discontinued treatment during the follow-up period. The rate of treatment failure was 510.5 (95% CI 492.9, 528.1) per 1000 PY. Analysis of key time-dependent SGLT2i-associated adverse events showed that experiencing diabetic ketoacidosis and volume depletion were associated with risk of treatment failure. CONCLUSIONS: Our study demonstrated high rates of residual cardio-kidney outcomes and treatment failure in patients with DKD treated with SGLT2is. Patients with high baseline CV risk and the presence of certain conditions, such as atrial fibrillation, PVD, and heart failure, were at higher risk for cardio-kidney events. Further research is needed to assess the potential relationship between adverse events and SGLT2i treatment failure.

Urinary Biomarkers of Tubular Health and Risk for Kidney Function Decline or Mortality in Diabetes.

INTRODUCTION: Diabetes is a leading cause of end-stage kidney disease (ESKD). Biomarkers of tubular health may prognosticate chronic kidney disease (CKD) progression beyond estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). METHODS: We examined associations of five urinary biomarkers of tubular injury and repair (NGAL, KIM-1, IL-18, MCP-1, YKL-40) with kidney function decline (first occurrence of a decrease in eGFR ≥30 mL/min/1.73 m2 if randomization eGFR ≥60 or ≥50% if randomization eGFR <60; ESKD) and all-cause mortality among 1,135 VA NEPHRON-D trial participants with baseline UACR ≥300 mg/g and available urine samples. Covariates included age, sex, race, BMI, systolic BP, HbA1c, treatment arm, eGFR, and UACR. In a subset of participants with 12-month samples (n = 712), we evaluated associations of KIM-1, MCP-1, and YKL-40 change (from baseline to 12 months) with eGFR decline (from 12 months onward). RESULTS: At baseline, mean age was 65 years, mean eGFR was 56 mL/min/1.73 m2, and median UACR was 840 mg/g. Over a median of 2.2 years, 13% experienced kidney function decline and 9% died. In fully adjusted models, the highest versus lowest quartiles of MCP-1 and YKL-40 were associated with 2.18- and 1.76-fold higher risks of kidney function decline, respectively. One-year changes in KIM-1, MCP-1, and YKL-40 were not associated with subsequent eGFR decline. Higher baseline levels of NGAL, IL-18, MCP-1, and YKL-40 levels (per 2-fold higher) were independently associated with 10-40% higher risk of mortality. CONCLUSION: Among Veterans with diabetes and CKD, urinary biomarkers of tubular health were associated with kidney function decline and mortality.

An objective metric of individual health and aging for population surveys.

BACKGROUND: We have previously developed and validated a biomarker-based metric of overall health status using Mahalanobis distance (DM) to measure how far from the norm of a reference population (RP) an individual's biomarker profile is. DM is not particularly sensitive to the choice of biomarkers; however, this makes comparison across studies difficult. Here we aimed to identify and validate a standard, optimized version of DM that would be highly stable across populations, while using fewer and more commonly measured biomarkers. METHODS: Using three datasets (the Baltimore Longitudinal Study of Aging, Invecchiare in Chianti and the National Health and Nutrition Examination Survey), we selected the most stable sets of biomarkers in all three populations, notably when interchanging RPs across populations. We performed regression models, using a fourth dataset (the Women's Health and Aging Study), to compare the new DM sets to other well-known metrics [allostatic load (AL) and self-assessed health (SAH)] in their association with diverse health outcomes: mortality, frailty, cardiovascular disease (CVD), diabetes, and comorbidity number. RESULTS: A nine- (DM9) and a seventeen-biomarker set (DM17) were identified as highly stable regardless of the chosen RP (e.g.: mean correlation among versions generated by interchanging RPs across dataset of r = 0.94 for both DM9 and DM17). In general, DM17 and DM9 were both competitive compared with AL and SAH in predicting aging correlates, with some exceptions for DM9. For example, DM9, DM17, AL, and SAH all predicted mortality to a similar extent (ranges of hazard ratios of 1.15-1.30, 1.21-1.36, 1.17-1.38, and 1.17-1.49, respectively). On the other hand, DM9 predicted CVD less well than DM17 (ranges of odds ratios of 0.97-1.08, 1.07-1.85, respectively). CONCLUSIONS: The metrics we propose here are easy to measure with data that are already available in a wide array of panel, cohort, and clinical studies. The standardized versions here lose a small amount of predictive power compared to more complete versions, but are nonetheless competitive with existing metrics of overall health. DM17 performs slightly better than DM9 and should be preferred in most cases, but DM9 may still be used when a more limited number of biomarkers is available.

Burden and Cost of Caring for US Veterans With CKD: Initial Findings From the VA Renal Information System (VA-REINS).

Kidney disease is a common, complex, costly, and life-limiting condition. Most kidney disease registries or information systems have been limited to single institutions or regions. A national US Department of Veterans Affairs (VA) Renal Information System (VA-REINS) was recently developed. We describe its creation and present key initial findings related to chronic kidney disease (CKD) without kidney replacement therapy (KRT). Data from the VA's Corporate Data Warehouse were processed and linked with national Medicare data for patients with CKD receiving KRT. Operational definitions for VA user, CKD, acute kidney injury, and kidney failure were developed. Among 7 million VA users in fiscal year 2014, CKD was identified using either a strict or liberal operational definition in 1.1 million (16.4%) and 2.5 million (36.3%) veterans, respectively. Most were identified using an estimated glomerular filtration rate laboratory phenotype, some through proteinuria assessment, and very few through International Classification of Diseases, Ninth Revision coding. The VA spent ∼$18 billion for the care of patients with CKD without KRT, most of which was for CKD stage 3, with higher per-patient costs by CKD stage. VA-REINS can be leveraged for disease surveillance, population health management, and improving the quality and value of care, thereby enhancing VA's capacity as a patient-centered learning health system for US veterans.

Evidence from two cohorts for the frailty syndrome as an emergent state of parallel dysregulation in multiple physiological systems.

Frailty is a clinical syndrome often present in older adults and characterized by a heightened vulnerability to stressors. The biological antecedents and etiology of frailty are unclear despite decades of research: frailty is associated with dysregulation in a wide range of physiological systems, but no specific cause has been identified. Here, we test predictions stemming from the hypothesis that there is no specific cause: that frailty is an emergent property arising from the complex systems dynamics of the broad loss of organismal homeostasis. Specifically, we use dysregulation of six physiological systems using the Mahalanobis distance approach in two cohorts of older adults to test the breadth, diffuseness, and nonlinearity of associations between frailty and system-specific dysregulation. We find clear support for the breadth of associations between frailty and physiological dysregulation: positive associations of all systems with frailty in at least some analyses. We find partial support for diffuseness: the number of systems or total amount of dysregulation is more important than the identity of the systems dysregulated, but results only partially replicate across cohorts. We find partial support for nonlinearity: trends are exponential but not always significantly so, and power is limited for groups with very high levels of dysregulation. Overall, results are consistent with-but not definitive proof of-frailty as an emergent property of complex systems dynamics. Substantial work remains to understand how frailty relates to underlying physiological dynamics across systems.

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.

Frailty: implications for clinical practice and public health.

Frailty is an emerging global health burden, with major implications for clinical practice and public health. The prevalence of frailty is expected to rise alongside rapid growth in the ageing population. The course of frailty is characterised by a decline in functioning across multiple physiological systems, accompanied by an increased vulnerability to stressors. Having frailty places a person at increased risk of adverse outcomes, including falls, hospitalisation, and mortality. Studies have shown a clear pattern of increased health-care costs and use associated with frailty. All older adults are at risk of developing frailty, although risk levels are substantially higher among those with comorbidities, low socioeconomic position, poor diet, and sedentary lifestyles. Lifestyle and clinical risk factors are potentially modifiable by specific interventions and preventive actions. The concept of frailty is increasingly being used in primary, acute, and specialist care. However, despite efforts over the past three decades, agreement on a standard instrument to identify frailty has not yet been achieved. In this Series paper, we provide an overview of the global impact and burden of frailty, the usefulness of the frailty concept in clinical practice, potential targets for frailty prevention, and directions that need to be explored in the future.

A Simple Equation to Estimate Urinary Flow Rate Using Urine Creatinine.

BACKGROUND: Accurate assessment of urine flow remains challenging in both inpatient and outpatient settings. We hypothesized we could derive an equation that would accurately estimate urine flow rate (eV) through derivation from other existing equations commonly used in nephrology clinical practice. METHODS: The eV equation was derived using the Cockcroft-Gault and the measured creatinine clearance (CrCl = UCrV/PCr) equations. Within the African American Study of Kidney Disease and Hypertension (AASK; n = 570) and COMBINE (n = 133) clinical trials, we identified participants with concordant estimated and measured creatinine excretion rates to define a subset with highly accurate 24-h urine collections, to assure a reliable gold standard. We then compared eV to measured 24-h urine flow rates in these trials. RESULTS: In AASK, we found a high correlation between eV and measured urine flow rate (V; r = 0.91, p < 0.001); however, Bland-Altman plots showed that eV was 9.5 mL/h lower than V, on average. Thus, we added a correction factor to the eV equation and externally validated the new equation in COMBINE. eV and V were again highly correlated (r = 0.91, p < 0.001), and bias was improved (mean difference 5.3 mL/h). Overall, 80% of individuals had eV that was within 20% of V. CONCLUSIONS: A simple equation using urine creatinine, demographics, and body weight can accurately predict urine flow rate and may have clinical utility in situations where it is difficult to accurately measure the urine flow rate.

Effects of Nicotinamide and Lanthanum Carbonate on Serum Phosphate and Fibroblast Growth Factor-23 in CKD: The COMBINE Trial.

BACKGROUND: Higher serum phosphate and fibroblast growth factor-23 (FGF23) levels may be modifiable to prevent cardiovascular disease in CKD. Short-term studies have reported modest efficacy in phosphate and FGF23 reduction with intestinal phosphate binders in CKD. METHODS: To investigate effects of lanthanum carbonate (LC; a phosphate binder) and/or nicotinamide (NAM; an inhibitor of active intestinal phosphate transport) on serum phosphate and FGF23 in stage 3b/4 CKD, we conducted a randomized trial among individuals with eGFR 20-45 ml/min per 1.73 m2 to NAM (750 mg twice daily) plus LC (1000 mg thrice daily), NAM plus LC placebo, LC plus NAM placebo, or double placebo for 12 months. Dual primary end points were change from baseline in serum phosphate and intact FGF23 concentrations. RESULTS: Mean eGFR for the 205 participants was 32ml/min per 1.73 m2. At baseline, serum phosphate was 3.7 mg/dl and median FGF23 was 99 pg/ml (10th, 90th percentiles: 59, 205). Mean rates of change in phosphate increased slightly over 12 months in all groups and did not differ significantly across arms. Similarly, percent changes in FGF23 per 12 months increased for all arms except LC plus placebo, and did not differ significantly across arms. Gastrointestinal symptoms limited adherence. Adverse events rates were similar across arms. CONCLUSIONS: LC and/or NAM treatment did not significantly lower serum phosphate or FGF23 in stage 3b/4 CKD over 12 months. Although these agents appeared safe, intestinal symptoms limited adherence. Reducing phosphate and FGF23 in nondialysis CKD will require new approaches.

Chronic kidney disease and peripheral nerve function in the Health, Aging and Body Composition Study.

BACKGROUND: Chronic kidney disease (CKD) is associated with poor mobility. Peripheral nerve function alterations play a significant role in low mobility. We tested the hypothesis that early CKD is associated with altered sensory, motor and autonomic nerve function. METHODS: Participants in the Health, Aging and Body Composition cohort who had kidney function measures in Year 3 (1999-2000) and nerve function measurements at Year 4 (2000-01) were analyzed (n = 2290). Sensory (vibration threshold, monofilament insensitivity to light and standard touch), motor [compound motor action potentials (CMAPs), nerve conduction velocities (NCVs)] and autonomic (heart rate response and recovery after a 400-m walk test) nerve function as well as participant characteristics were compared across cystatin C- and creatinine-based estimated glomerular filtration rate categorized as ≤60 (CKD) or >60 mL/min/1.73 m2 (non-CKD). The association between CKD and nerve function was examined with logistic regression adjusted for covariates. RESULTS: Participants with CKD (n = 476) were older (77 ± 3 versus 75 ± 3 years; P < 0.05) and had a higher prevalence of diabetes (20.6% versus 13.1%; P < 0.001). CKD was associated with higher odds for vibration detection threshold {odds ratio [OR] 1.7 [95% confidence interval (CI) 1.1-2.7]} and light touch insensitivity [OR 1.4 (95% CI 1.1-1.7)]. CMAPs and NCVs were not significantly different between CKD and non-CKD patients. In adjusted analyses, participants with CKD had higher odds of an abnormal heart rate response [OR 1.6 (95% CI 1.1-2.2)] and poor heart rate recovery [OR 1.5 (95% CI 1.1-2.0)]. CONCLUSIONS: CKD is associated with changes in sensory and autonomic nerve function, even after adjustment for demographics and comorbidities, including diabetes. Longitudinal studies in CKD are needed to determine the contribution of nerve impairments to clinically important outcomes.

Low thyroid function is not associated with an accelerated deterioration in renal function.

BACKGROUND: Chronic kidney disease (CKD) is frequently accompanied by thyroid hormone dysfunction. It is currently unclear whether these alterations are the cause or consequence of CKD. This study aimed at studying the effect of thyroid hormone alterations on renal function in cross-sectional and longitudinal analyses in individuals from all adult age groups. METHODS: Individual participant data (IPD) from 16 independent cohorts having measured thyroid stimulating hormone, free thyroxine levels and creatinine levels were included. Thyroid hormone status was defined using clinical cut-off values. Estimated glomerular filtration rates (eGFR) were calculated by means of the four-variable Modification of Diet in Renal Disease (MDRD) formula. For this IPD meta-analysis, eGFR at baseline and eGFR change during follow-up were computed by fitting linear regression models and linear mixed models in each cohort separately. Effect estimates were pooled using random effects models. RESULTS: A total of 72 856 individuals from 16 different cohorts were included. At baseline, individuals with overt hypothyroidism (n = 704) and subclinical hypothyroidism (n = 3356) had a average (95% confidence interval) -4.07 (-6.37 to -1.78) and -2.40 (-3.78 to -1.02) mL/min/1.73 m2 lower eGFR as compared with euthyroid subjects (n = 66 542). In (subclinical) hyperthyroid subjects (n = 2254), average eGFR was 3.01 (1.50-4.52) mL/min/1.73 m2 higher. During 329 713 patient years of follow-up, eGFR did not decline more rapidly in individuals with low thyroid function compared with individuals with normal thyroid function. CONCLUSIONS: Low thyroid function is not associated with a deterioration of renal function. The cross-sectional association may be explained by renal dysfunction causing thyroid hormone alterations.

Alcohol Consumption in Later Life and Mortality in the United States: Results from 9 Waves of the Health and Retirement Study.

BACKGROUND: Alcohol consumption in later life has increased in the past decade, and the relationship between alcohol consumption and mortality is controversial. Recent studies suggest little, if any, health benefit to alcohol. Yet most rely on single-time point consumption assessments and minimal confounder adjustments. METHODS: We report on 16 years of follow-up from the Health and Retirement Study (HRS) cohorts born 1931 to 1941 (N = 7,904, baseline mean age = 61, SD = 3.18). Respondents were queried about drinking frequency/quantity. Mortality was established via exit interviews and confirmed with the national death index. Time-varying confounders included but were not limited to household assets, smoking, body mass index, health/functioning, depression, chronic disease; time-invariant confounders included baseline age, education, sex, and race. RESULTS: After adjustment, current abstainers had the highest risk of subsequent mortality, consistent with sick quitters, and moderate (men: HR = 0.74, 95% CI: 0.60 to 0.91; women: HR = 0.82, 95% CI: 0.63 to 1.07) drinking was associated with a lower mortality rate compared with occasional drinking, though smokers and men evidenced less of an inverse association. Quantitative bias analyses indicated that omitted confounders would need to be associated with ~4-fold increases in mortality rates for men and ~9-fold increases for women to change the results. CONCLUSIONS: There are consistent associations between moderate/occasional drinking and lower mortality, though residual confounding remains a threat to validity. Continued efforts to conduct large-scale observational studies of alcohol consumption and mortality are needed to characterize the changing patterns of consumption in older age.

Automated safety event monitoring using electronic medical records in a clinical trial setting: Validation study using the VA NEPHRON-D trial.

BACKGROUND/AIMS: Electronic medical records are now frequently used for capturing patient-level data in clinical trials. Within the Veterans Affairs health care system, electronic medical record data have been widely used in clinical trials to assess eligibility, facilitate referrals for recruitment, and conduct follow-up and safety monitoring. Despite the potential for increased efficiency in using electronic medical records to capture safety data via a centralized algorithm, it is important to evaluate the integrity and accuracy of electronic medical record-captured data. To this end, this investigation assesses data collection, both for general and study-specific safety endpoints, by comparing electronic medical record-based safety monitoring versus safety data collected during the course of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) clinical trial. METHODS: The VA NEPHRON-D study was a multicenter, double-blind, randomized clinical trial designed to compare the effect of combination therapy (losartan plus lisinopril) versus monotherapy (losartan) on the progression of kidney disease in individuals with diabetes and proteinuria. The trial's safety outcomes included serious adverse events, hyperkalemia, and acute kidney injury. A subset of the participants (~62%, n = 895) enrolled in the trial's long-term follow-up sub-study and consented to electronic medical record data collection. We applied an automated algorithm to search and capture safety data using the VA Corporate Data Warehouse which houses electronic medical record data. Using study safety data reported during the trial as the gold standard, we evaluated the sensitivity and precision of electronic medical record-based safety data and related treatment effects. RESULTS: The sensitivity of the electronic medical record-based safety for hospitalizations was 65.3% without non-VA hospitalization events and 92.3% with the non-VA hospitalization events included. The sensitivity was only 54.3% for acute kidney injury and 87.3% for hyperkalemia. The precision of electronic medical record-based safety data was 89.4%, 38%, and 63.2% for hospitalization, acute kidney injury, and hyperkalemia, respectively. Relative treatment differences under the study and electronic medical record settings were 15% and 3% for hospitalization, 123% and 29% for acute kidney injury, and 238% and 140% for hyperkalemia, respectively. CONCLUSION: The accuracy of using automated electronic medical record safety data depends on the events of interest. Identification of all-cause hospitalizations would be reliable if search methods could, in addition to VA hospitalizations, also capture non-VA hospitalizations. However, hospitalization is different from a cause-specific serious adverse event that could be more sensitive to treatment effects. In addition, some study-specific safety events were not easily identified using the electronic medical records. This limits the effectiveness of the automated central database search for purposes of safety monitoring. Hence, this data captured approach should be carefully considered when implementing endpoint data collection in future pragmatic trials.