Publications by authors named "Leila R Zelnick"

59 Publications

Upper Reference Limits for High-Sensitivity Cardiac Troponin T and N-Terminal Fragment of the Prohormone Brain Natriuretic Peptide in Patients With CKD.

Am J Kidney Dis 2021 Jul 19. Epub 2021 Jul 19.

Division of Nephrology, School of Medicine, University of Maryland, Baltimore, Maryland.

Rationale & Objective: The utility of conventional upper reference limits (URL) for N-terminal pro-brain natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hsTnT) in chronic kidney disease (CKD) remains debated. We analyzed the distribution of hsTnT and NT-proBNP in people with CKD in ambulatory settings to examine the diagnostic value of conventional URL in this population.

Study Design: Observational study.

Setting & Participants: We studied participants of the Chronic Renal Insufficiency Cohort (CRIC) with CKD and no self-reported history of cardiovascular disease.

Exposure: Estimated glomerular filtration rate (eGFR).

Outcome: NT-proBNP and hsTnT at baseline.

Analytical Approach: We described the proportion of participants above the conventional URL for NT-proBNP (125pg/mL) and hsTnT (14ng/L) overall and by eGFR. We then estimated 99th percentile URL for NT-proBNP and hsTnT. Using quantile regression of the 99th percentile, we modeled the association of eGFR with NT-proBNP and hsTnT.

Results: Among 2,312 CKD participants, 40% and 43% had levels of NT-proBNP and hsTnT above the conventional URL, respectively. In those with eGFR <30mL/min/1.73m, 71% and 68% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, respectively. Among all CKD participants, the 99th percentile for NT-proBNP was 3,592 (95% CI, 2,470-4,849) pg/mL and for hsTnT it was 126 (95% CI, 100-144) ng/L. Each 15mL/min/1.73m decrement in eGFR was associated with a ~40% higher threshold for the 99th percentile of NT-proBNP (1.43 [95% CI, 1.21-1.69]) and hsTnT (1.45 [95% CI, 1.31-1.60]).

Limitations: Study included ambulatory patients, and we could not test the accuracy of the URL of NT-proBNP and hsTnT in the acute care setting.

Conclusions: In this ambulatory CKD population with no self-reported history of cardiovascular disease, a range of 40%-88% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, depending on eGFR strata. Developing eGFR-specific thresholds for these commonly used cardiac biomarkers in the setting of CKD may improve their utility for evaluation of suspected heart failure and myocardial infarction.
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http://dx.doi.org/10.1053/j.ajkd.2021.06.017DOI Listing
July 2021

Body Composition Changes Following Dialysis Initiation and Cardiovascular and Mortality Outcomes in CRIC (Chronic Renal Insufficiency Cohort): A Bioimpedance Analysis Substudy.

Kidney Med 2021 May-Jun;3(3):327-334.e1. Epub 2021 Feb 18.

Kidney Research Institute, Seattle, WA.

Rationale & Objective: Bioelectrical impedance analysis (BIA) provides a noninvasive assessment of body composition. BIA measures of nutritional (phase angle) and hydration (vector length) status are associated with survival among individuals with chronic kidney disease (CKD), including those receiving maintenance dialysis. However, little is known regarding changes in these parameters with CKD following the high-risk transition to maintenance dialysis.

Study Design: Observational study.

Settings & Participants: 427 adults enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study, with BIA measurements performed within 1 year before and after initiation of maintenance dialysis.

Exposures: We calculated the changes in vector length and phase angle for patients with CKD transitioning to maintenance dialysis.

Outcomes: We examined the association of changes in vector length and phase angle during the transition to maintenance dialysis with risk for all-cause mortality or nonfatal myocardial infarction, stroke, or heart failure, adjusting for demographics, comorbid conditions, and nutritional parameters.

Results: Mean age was 58 ± 12 years and mean estimated glomerular filtration rate using the CKD Epidemiology Collaboration equation before dialysis initiation was 17.0 ± 8.7 mL/min/1.73 m. After covariate adjustment, mean changes in vector length and phase angle were 18 (95% CI, 7 to 30) Ω/m and -0.6  (95% CI, -1.3  to 0.1 ), respectively. Changes in both BIA parameters were not associated with risk for heart failure, stroke, myocardial infarction, or all-cause mortality: HR, 1.02 (95% CI, 0.91-1.14) per 1-SD increment in change for vector length and HR, 1.11 (95% CI, 0.88-1.41) per 1-SD increment in change for phase angle.

Limitations: Observational study, relatively small sample size.

Conclusions: In a multicenter cohort of patients with CKD who progressed to kidney failure, the transition to maintenance dialysis was associated with changes in body composition reflecting poorer cellular integrity and improved volume control. However, these longitudinal changes were not associated with adverse clinical events after dialysis initiation.
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http://dx.doi.org/10.1016/j.xkme.2020.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178453PMC
February 2021

Association of the Estimated Glomerular Filtration Rate With vs Without a Coefficient for Race With Time to Eligibility for Kidney Transplant.

JAMA Netw Open 2021 01 4;4(1):e2034004. Epub 2021 Jan 4.

Kidney Research Institute, Division of Nephrology, University of Washington, Seattle.

Importance: Kidney transplant is associated with improved survival and quality of life among patients with kidney failure; however, significant racial disparities have been noted in transplant access. Common equations that estimate glomerular filtration rate (eGFR) include adjustment for Black race; however, how inclusion of the race coefficient in common eGFR equations corresponds with measured GFR and whether it is associated with delayed eligibility for kidney transplant listing are unknown.

Objective: To compare eGFR with measured GFR and evaluate the association between eGFR calculated with vs without a coefficient for race and time to eligibility for kidney transplant.

Design, Setting, And Participants: This prospective cohort study used data from the Chronic Renal Insufficiency Cohort, a multicenter cohort study of participants with chronic kidney disease (CKD). Self-identified Black participants from that study were enrolled between April 2003 and September 2008, with follow-up through December 2018. Statistical analyses were completed on November 11, 2020.

Exposure: Estimated GFR, measured annually and estimated using the creatinine-based Chronic Kidney Disease-Epidemiology (CKD-EPI) equation with and without a race coefficient.

Main Outcomes And Measures: Iothalamate GFR (iGFR) measured in a subset of participants (n = 311) and time to achievement of an eGFR less than 20 mL/min/1.73 m2, an established threshold for kidney transplant referral and listing.

Results: Among 1658 self-identified Black participants, mean (SD) age was 58 (11) years, 848 (51%) were female, and mean (SD) eGFR was 44 (15) mL/min/1.73 m2. The CKD-EPI eGFR with the race coefficient overestimated iGFR by a mean of 3.1 mL/min/1.73 m2 (95% CI, 2.2-3.9 mL/min/1.73 m2; P < .001). The mean difference between CKD-EPI eGFR without the race coefficient and iGFR was of smaller magnitude (-1.7 mL/min/1.73 m2; 95% CI, -2.5 to -0.9 mL/min/1.73 m2). For participants with an iGFR of 20 to 25 mL/min/1.73 m2, the mean difference in eGFR with vs without the race coefficient and iGFR was 5.1 mL/min/1.73 m2 (95% CI, 3.3-6.9 mL/min/1.73 m2) vs 1.3 mL/min/1.73 m2 (95% CI, -0.3 to 2.9 mL/min/1.73 m2). Over a median follow-up time of 4 years (interquartile range, 1-10 years), use of eGFR calculated without vs with the race coefficient was associated with a 35% (95% CI, 29%-41%) higher risk of achieving an eGFR less than 20 mL/min/1.73 m2 and a shorter median time to this end point of 1.9 years.

Conclusions And Relevance: In this cohort study, inclusion of the race coefficient in the estimation of GFR was associated with greater bias in GFR estimation and with delayed achievement of a clinical threshold for kidney transplant referral and eligibility. These findings suggest that nephrologists and transplant programs should be cautious when using current estimating equations to determine kidney transplant eligibility.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.34004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809586PMC
January 2021

Association Between Kidney Clearance of Secretory Solutes and Cardiovascular Events: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Am J Kidney Dis 2021 08 7;78(2):226-235.e1. Epub 2021 Jan 7.

Kidney Research Institute, Seattle, WA; Department of Medicine, Division of Nephrology, University of Washington, Seattle, WA. Electronic address:

Rationale & Objective: The clearance of protein-bound solutes by the proximal tubules is an innate kidney mechanism for removing putative uremic toxins that could exert cardiovascular toxicity in humans. However, potential associations between impaired kidney clearances of secretory solutes and cardiovascular events among patients with chronic kidney disease (CKD) remains uncertain.

Study Design: A multicenter, prospective, cohort study.

Setting & Participants: We evaluated 3,407 participants from the Chronic Renal Insufficiency Cohort (CRIC) study.

Exposures: Baseline kidney clearances of 8 secretory solutes. We measured concentrations of secretory solutes in plasma and paired 24-hour urine specimens using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Outcomes: Incident heart failure, myocardial infarction, and stroke events.

Analytical Approach: We used Cox regression to evaluate associations of baseline secretory solute clearances with incident study outcomes adjusting for estimated GFR (eGFR) and other confounders.

Results: Participants had a mean age of 56 years; 45% were women; 41% were Black; and the median estimated glomerular filtration rate (eGFR) was 43 mL/min/1.73 m. Lower 24-hour kidney clearance of secretory solutes were associated with incident heart failure and myocardial infarction but not incident stroke over long-term follow-up after controlling for demographics and traditional risk factors. However, these associations were attenuated and not statistically significant after adjustment for eGFR.

Limitations: Exclusion of patients with severely reduced eGFR at baseline; measurement variability in secretory solutes clearances.

Conclusions: In a national cohort study of CKD, no clinically or statistically relevant associations were observed between the kidney clearances of endogenous secretory solutes and incident heart failure, myocardial infarction, or stroke after adjustment for eGFR. These findings suggest that tubular secretory clearance provides little additional information about the development of cardiovascular disease events beyond glomerular measures of GFR and albuminuria among patients with mild-to-moderate CKD.
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http://dx.doi.org/10.1053/j.ajkd.2020.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260620PMC
August 2021

Association of circulating cardiac biomarkers with electrocardiographic abnormalities in chronic kidney disease.

Nephrol Dial Transplant 2020 Dec 26. Epub 2020 Dec 26.

Division of Nephrology, Kidney Research Institute, University of Washington, Seattle, WA, USA.

Background: Among patients with chronic kidney disease (CKD), the circulating cardiac biomarkers soluble ST2 (SST2), galectin-3, growth differentiation factor-15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin-T (hsTnT) possibly reflect pathophysiologic processes and are associated with clinical cardiovascular disease. Whether these biomarkers are associated with electrocardiographic findings is not known. The aim of this study was to test the association between serum cardiac biomarkers and the presence of electrocardiographic changes potentially indicative of subclinical myocardial disease in patients with CKD.

Methods: We performed a cross-sectional analysis using 3048 participants from the Chronic Renal Insufficiency Cohort (CRIC) without atrial fibrillation, atrioventricular block, bundle branch block or a pacemaker at the baseline visit. Using logistic regression, we tested the association of each of the five cardiac biomarkers with baseline electrocardiogram (ECG) findings: PR interval >200 ms, QRS interval >100 ms and a prolonged QTc interval. Models were adjusted for demographic variables, measures of kidney function, prevalent cardiovascular disease and cardiovascular risk factors.

Results: In adjusted models, hsTnT levels associated with prolonged PR {odds ratio [OR] 1.23 [95% confidence interval (CI) 1.08-1.40]}, QRS [OR 1.28 (95% CI 1.16-1.42)] and QTc [OR 1.94 (95% CI 1.50-2.51)] intervals. NT-proBNP levels were associated with prolonged QRS [OR 1.11 (95% CI 1.06-1.16)] and QTc [OR 1.82 (95% CI 1.58-2.10)] intervals. SST2, galectin-3 and GDF-15 were not significantly associated with any of the ECG parameters.

Conclusions: hsTnT and NT-proBNP were associated with ECG measures indicative of subclinical myocardial dysfunction. These results may support future research investigating the significance of myocardial ischemia and volume overload in the pathogenesis of dysfunctional myocardial conduction in CKD.
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http://dx.doi.org/10.1093/ndt/gfaa296DOI Listing
December 2020

Association of tubular solute clearances with the glomerular filtration rate and complications of chronic kidney disease: the Chronic Renal Insufficiency Cohort study.

Nephrol Dial Transplant 2020 Nov 17. Epub 2020 Nov 17.

Kidney Research Institute, Seattle, WA, USA.

Background: The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. The degree to which secretory solute clearance corresponds with the glomerular filtration rate (GFR) and potential metabolic implications of net secretory clearance are largely unknown.

Methods: We evaluated 1240 participants with chronic kidney disease (CKD) from the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study. We used targeted mass-spectrometry to quantify candidate secretory solutes in paired 24-h urine and plasma samples. CRIC study personnel measured GFR using 125I-iothalamate clearance (iGFR). We used correlation and linear regression to determine cross-sectional associations of secretory clearances with iGFR and common metabolic complications of CKD.

Results: Correlations between iGFR and secretory solute clearances ranged from ρ  = +0.30 for hippurate to ρ = +0.58 for kynurenic acid. Lower net clearances of most secretory solutes were associated with higher serum concentrations of parathyroid hormone (PTH), triglycerides and uric acid. Each 50% lower kynurenic acid clearance was associated with a 21% higher serum PTH concentration [95% confidence interval (CI) 15-26%] and a 10% higher serum triglyceride concentration (95% CI 5-16%) after adjustment for iGFR, albuminuria and other potential confounders. Secretory solute clearances were not associated with statistically or clinically meaningful differences in serum calcium, phosphate, hemoglobin or bicarbonate concentrations.

Conclusions: Tubular secretory clearances are modestly correlated with measured GFR among adult patients with CKD. Lower net secretory clearances are associated with selected metabolic complications independent of GFR and albuminuria, suggesting potential clinical and biological relevance.
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http://dx.doi.org/10.1093/ndt/gfaa057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237987PMC
November 2020

Change in Cardiac Biomarkers and Risk of Incident Heart Failure and Atrial Fibrillation in CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Am J Kidney Dis 2021 06 9;77(6):907-919. Epub 2020 Dec 9.

Kidney Research Institute, University of Washington, Seattle, WA.

Rationale & Objective: Circulating cardiac biomarkers may signal potential mechanistic pathways involved in heart failure (HF) and atrial fibrillation (AF). Single measures of circulating cardiac biomarkers are strongly associated with incident HF and AF in chronic kidney disease (CKD). We tested the associations of longitudinal changes in the N-terminal fragment of the prohormone brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), galectin-3, growth differentiation factor 15 (GDF-15), and soluble ST-2 (sST-2) with incident HF and AF in patients with CKD.

Study Design: Observational, case-cohort study design.

Setting & Participants: Adults with CKD enrolled in the Chronic Renal Insufficiency Cohort study.

Exposures: Biomarkers were measured at baseline and 2 years later among those without kidney failure. We created 3 categories of absolute change in each biomarker: the lowest quartile, the middle 2 quartiles, and the top quartile.

Outcomes: The primary outcomes were incident HF and AF.

Analytical Approach: Cox proportional hazards regression models were used to test the associations of the change categories of each cardiac biomarker with each outcome (with the middle 2 quartiles of change as the referent group), adjusting for potential confounders and baseline concentrations of each biomarker.

Results: The incident HF analysis included 789 participants (which included 138 incident HF cases), and the incident AF analysis included 774 participants (123 incident AF cases). In multivariable models, the top quartile of NT-proBNP change (>232pg/mL over 2years) was associated with increased risk of incident HF (HR, 1.79 [95% CI, 1.06-3.04]) and AF (HR, 2.32 [95% CI, 1.37-3.93]) compared with the referent group. Participants in the top quartile of sST2 change (>3.37ng/mL over 2years) had significantly greater risk of incident HF (HR, 1.89 [95% CI, 1.13-3.16]), whereas those in the bottom quartile (≤-3.78ng/mL over 2years) had greater risk of incident AF (HR, 2.43 [95% CI, 1.39-4.22]) compared with the 2 middle quartiles. There was no association of changes in hsTnT, galectin-3, or GDF-15 with incident HF or AF.

Limitations: Observational study.

Conclusions: In CKD, increases in NT-proBNP were significantly associated with greater risk of incident HF and AF, and increases in sST2 were associated with HF. Further studies should investigate whether these markers of subclinical cardiovascular disease can be modified to reduce the risk of cardiovascular disease in CKD.
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http://dx.doi.org/10.1053/j.ajkd.2020.09.021DOI Listing
June 2021

Prediction of Kidney Drug Clearance: A Comparison of Tubular Secretory Clearance and Glomerular Filtration Rate.

J Am Soc Nephrol 2021 02 25;32(2):459-468. Epub 2020 Nov 25.

Kidney Research Institute, Seattle, Washington

Background: Although proximal tubular secretion is the primary mechanism of kidney drug elimination, current kidney drug dosing strategies are on the basis of eGFR.

Methods: In a dedicated pharmacokinetic study to compare GFR with tubular secretory clearance for predicting kidney drug elimination, we evaluated stable outpatients with eGFRs ranging from 21 to 140 ml/min per 1.73 m. After administering single doses of furosemide and famciclovir (metabolized to penciclovir), we calculated their kidney clearances on the basis of sequential plasma and timed urine measurements. Concomitantly, we quantified eight endogenous secretory solutes in plasma and urine using liquid chromatography-tandem mass spectrometry and measured GFR by iohexol clearance (iGFR). We computed a summary secretion score as the scaled average of the secretory solute clearances.

Results: Median iGFR of the 54 participants was 73 ml/min per 1.73 m. The kidney furosemide clearance correlated with iGFR (=0.84) and the summary secretion score (=0.86). The mean proportionate error (MPE) between iGFR-predicted and measured furosemide clearance was 30.0%. The lowest MPE was observed for the summary secretion score (24.1%); MPEs for individual secretory solutes ranged from 27.3% to 48.0%. These predictive errors were statistically indistinguishable. Penciclovir kidney clearance was correlated with iGFR (=0.83) and with the summary secretion score (=0.91), with similar predictive accuracy of iGFR and secretory clearances. Combining iGFR with the summary secretion score yielded only modest improvements in the prediction of the kidney clearance of furosemide and penciclovir.

Conclusions: Secretory solute clearance measurements can predict kidney drug clearances. However, tight linkage between GFR and proximal tubular secretory clearance in stable outpatients provides some reassurance that GFR, even when estimated, is a useful surrogate for predicting secretory drug clearances in such patients.
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http://dx.doi.org/10.1681/ASN.2020060833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054886PMC
February 2021

Vitamin D in human serum and adipose tissue after supplementation.

Am J Clin Nutr 2020 Nov 12. Epub 2020 Nov 12.

Department of Laboratory Medicine, University of Washington, Seattle, WA, USA.

Background: Serum 25-hydroxyvitamin D [25(OH)D] concentration is an indicator of vitamin D exposure, but it is also influenced by clinical characteristics that affect 25(OH)D production and clearance. Vitamin D is the precursor to 25(OH)D but is analytically challenging to measure in biological specimens.

Objectives: We aimed to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantification of vitamins D3 and D2 in serum and to explore the potential of circulating vitamin D as a biomarker of exposure in supplementation trials.

Methods: The method was validated using guideline C62-A from the Clinical and Laboratory Standards Institute and was applied in 2 pilot clinical trials of oral vitamin D3 supplementation. Pilot study 1 included 22 adults randomly assigned to placebo or 2000 IU/d. Blood was collected at baseline, 1, 3, 6, and 12 mo. Pilot study 2 included 15 adults randomly assigned to 2000 or 4000 IU/d. Blood and subcutaneous (SUBQ) adipose tissue were collected at baseline and 3 mo.

Results: In study 1, mean change (baseline to 3 mo) in serum vitamin D3 was -0.1 ng/mL in the placebo group and 6.8 ng/mL in the 2000 IU/d group (absolute difference: 6.9; 95% CI: 4.5, 9.3 ng/mL). In study 2, mean change (baseline to 3 mo) in serum vitamin D3 was 10.4 ng/mL in the 2000 IU/d group and 22.2 ng/mL in the 4000 IU/d group (fold difference: 2.15; 95% CI: 1.40, 3.37). Serum and adipose tissue vitamin D3 concentrations were correlated, and the dose-response of vitamin D3 in adipose mirrored that in serum.

Conclusions: We validated a sensitive, robust, and high-throughput LC-MS/MS method to quantify vitamins D3 and D2 in serum. Serum and SUBQ adipose tissue vitamin D3 concentrations increased proportionally to dose with 3 mo of daily supplementation.These trials were registered at clinicaltrials.gov as NCT00552409 (pilot study 1) and NCT01477034 (pilot study 2).
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http://dx.doi.org/10.1093/ajcn/nqaa295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779222PMC
November 2020

Cardiac Biomarkers and Risk of Mortality in CKD (the CRIC Study).

Kidney Int Rep 2020 Nov 10;5(11):2002-2012. Epub 2020 Sep 10.

Kidney Research Institute, Seattle, Washington, USA.

Introduction: Cardiovascular disease (CVD) is the leading cause of mortality among individuals with chronic kidney disease (CKD). Cardiac biomarkers of myocardial distention, injury, and inflammation may signal unique pathways underlying CVD in CKD. In this analysis, we studied the association of baseline levels and changes in 4 traditional and novel cardiac biomarkers with risk of all-cause, CV, and non-CV mortality in a large cohort of patients with CKD.

Methods: Among 3664 adults with CKD enrolled in the Chronic Renal Insufficiency Cohort Study, we conducted a cohort study to examine the associations of baseline levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), cardiac high-sensitivity troponin T (hsTnT), growth differentiation factor-15 (GDF-15), and soluble ST-2 (sST-2) with risks of all-cause and cardiovascular (CV) mortality. Among a subcohort of 842 participants, we further examined the associations between change in biomarker levels over 2 years with risk of all-cause mortality. We used Cox proportional hazards regression models and adjusted for demographics, kidney function measures, cardiovascular risk factors, and medication use.

Results: After adjustment, elevated baseline levels of each cardiac biomarker were associated with increased risk of all-cause mortality: NT-proBNP (hazard ratio [HR] = 1.92, 95% confidence interval [CI] = 1.73-2.12); hsTnT (HR = 1.62, 95% CI = 1.48, 1.78]); GDF-15 (HR = 1.61, 95% CI = 1.46-1.78]); and sST-2 (HR = 1.26, CI = 1.16-1.37). Higher baseline levels of all 4 cardiac biomarkers were also associated with increased risk of CV. Declines in NT-proBNP (adjusted HR = 0.55, 95% CI = 0.36-0.86) and sST2 (HR = 0.55, 95% CI = 0.36-0.86]) over 2 years were associated with lower risk of all-cause mortality.

Conclusion: In a large cohort of CKD participants, elevations of NT-proBNP, hsTnT, GDF-15, and sST-2 were independently associated with greater risks of all-cause and CV mortality.
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http://dx.doi.org/10.1016/j.ekir.2020.08.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609912PMC
November 2020

Differences in 25-Hydroxyvitamin D Clearance by eGFR and Race: A Pharmacokinetic Study.

J Am Soc Nephrol 2021 01 28;32(1):188-198. Epub 2020 Oct 28.

Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington.

Background: Conversion of 25-hydroxyvitamin D (25[OH]D) to the active form of vitamin D occurs primarily in the kidney. Observational studies suggest 25(OH)D clearance from the circulation differs by kidney function and race. However, these potential variations have not been tested using gold-standard methods.

Methods: We administered intravenous, deuterated 25(OH)D (d-25[OH]D) in a pharmacokinetic study of 87 adults, including 43 with normal eGFR (≥60 ml/min per 1.73 m), 24 with nondialysis CKD (eGFR <60 ml/min per 1.73 m), and 20 with ESKD treated with hemodialysis. We measured concentrations of d-25(OH)D and deuterated 24,25-dihydroxyvitamin D at 5 minutes and 4 hours after administration, and at 1, 4, 7, 14, 21, 28, 42, and 56 days postadministration. We calculated 25(OH)D clearance using noncompartmental analysis of d-25(OH)D concentrations over time. We remeasured 25(OH)D clearance in a subset of 18 participants after extended oral vitamin-D supplementation.

Results: The mean age of the study cohort was 64 years; 41% were female, and 30% were Black. Mean 25(OH)D clearances were 360 ml/d, 313 ml/d, and 263 ml/d in participants with normal eGFR, CKD, and kidney failure, respectively (=0.02). After adjustment for age, sex, race, and estimated blood volume, lower eGFR was associated with reduced 25(OH)D clearance (=-17 ml/d per 10 ml/min per 1.73 m lower eGFR; 95% CI, -21 to -12). Black race was associated with higher 25(OH)D clearance in participants with normal eGFR, but not in those with CKD or kidney failure ( for interaction=0.05). Clearance of 25(OH)D before versus after vitamin-D supplementation did not differ.

Conclusions: Using direct pharmacokinetic measurements, we show that 25(OH)D clearance is reduced in CKD and may differ by race.

Clinical Trial Registry Name And Registration Number: Clearance of 25-hydroxyvitamin D in Chronic Kidney Disease (CLEAR), NCT02937350; Clearance of 25-hydroxyvitamin D3 During Vitamin D3 Supplementation (CLEAR-PLUS), NCT03576716.
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http://dx.doi.org/10.1681/ASN.2020050625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894669PMC
January 2021

Effects of long-term vitamin D and n-3 fatty acid supplementation on inflammatory and cardiac biomarkers in patients with type 2 diabetes: secondary analyses from a randomised controlled trial.

Diabetologia 2021 02 24;64(2):437-447. Epub 2020 Oct 24.

Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA, USA.

Aims/hypothesis: Interventions that reduce inflammation may delay progression of microvascular and macrovascular complications in diabetes. We examined the effects of vitamin D and/or n-3 fatty acid supplementation vs placebo on 5 year changes in serum inflammatory and cardiac biomarkers in adults with type 2 diabetes.

Methods: This study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1312 US adults with type 2 diabetes and without known cardiovascular disease, malignancy, or end-stage kidney disease were randomised using computer-generated random numbers in blocks of eight to vitamin D (2000 IU/day) vs placebo and n-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 1 g/day) vs placebo in a 2 × 2 factorial design. Participants, examiners, and researchers assessing outcomes were blinded to intervention assignment. We measured serum IL-6, high-sensitivity C-reactive protein (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after 2 and 5 years.

Results: A total of 333 participants were randomised to vitamin D and placebo n-3 fatty acids, 289 to n-3 fatty acids and placebo vitamin D, 370 to vitamin D and n-3 fatty acids, and 320 to 2 placebos; 989 (75%) and 934 (71%) participants returned blood samples at 2 and 5 years, respectively. Participants had a mean age of 67.6 years (46% women). Overall, baseline geometric means of IL-6, hsCRP and NT-proBNP were 1.2 pg/ml, 1.9 mg/l and 262 ng/l, respectively. After 5 years, mean IL-6 and hsCRP remained within 6% of their baseline values while mean NT-proBNP increased by 55% overall. Compared with placebo, participants assigned to vitamin D had a 1.24-fold greater increase in NT-proBNP over 5 years (95% CI 1.09, 1.41; p = 0.003), while IL-6 and hsCRP did not have a significant difference in change. Comparing n-3 fatty acids with placebo, there was no significant difference in change in IL-6, hsCRP or NT-proBNP. No heterogeneity was observed in subgroup analyses accounting for baseline eGFR, urine albumin to creatinine ratio, initial biomarker concentration, 25-hydroxyvitamin D level or EPA+DHA index.

Conclusions/interpretation: Among adults with type 2 diabetes, supplementation with vitamin D or n-3 fatty acids did not reduce IL-6, hsCRP or NT-proBNP over 5 years.

Trial Registration: ClinicalTrials.gov NCT01684722 FUNDING: The study was funded by grant R01DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05300-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855668PMC
February 2021

Temporal Relationship of Glycemia With Cardiac Arrhythmias in Patients With Type 2 Diabetes and CKD.

Am J Kidney Dis 2021 06 1;77(6):988-990. Epub 2020 Oct 1.

Department of Medicine, University of Washington, Seattle, WA.

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http://dx.doi.org/10.1053/j.ajkd.2020.08.008DOI Listing
June 2021

Continuous Glucose Monitoring and Use of Alternative Markers To Assess Glycemia in Chronic Kidney Disease.

Diabetes Care 2020 10 11;43(10):2379-2387. Epub 2020 Aug 11.

Kidney Research Institute, University of Washington, Seattle, WA.

Objective: In chronic kidney disease, glycated albumin and fructosamine have been postulated to be better biomarkers of glycemic control than HbA. We evaluated the accuracy, variability, and covariate bias of three biomarkers (HbA, glycated albumin, and fructosamine) compared with continuous glucose monitoring (CGM)-derived measurement of glycemia across estimated glomerular filtration rate (eGFR) in type 2 diabetes.

Research Design And Methods: A prospective cohort study was conducted of 104 participants with type 2 diabetes, 80 with eGFR <60 mL/min/1.73 m (not treated with dialysis) and 24 frequency-matched control subjects with eGFR ≥60 mL/min/1.73 m. Participants wore a blinded CGM for two 6-day periods separated by 2 weeks, with blood and urine collected at the end of each CGM period. HbA, glycated albumin, and fructosamine were measured by high-performance liquid chromatographic, enzymatic, and colorimetric nitroblue tetrazolium methods, respectively.

Results: Within-person biomarker values were strongly correlated between the two CGM periods ( = 0.92-0.95), although no marker fully captured the within-person variability of mean CGM glucose. All markers were similarly correlated with mean CGM glucose ( = 0.71-77). Compared with mean CGM glucose, glycated albumin and fructosamine were significantly biased by age, BMI, serum iron concentration, transferrin saturation, and albuminuria; HbA was underestimated in those with albuminuria.

Conclusions: Glycated albumin and fructosamine were not less variable than HbA at a given mean CGM glucose level, with several additional sources of bias. These results support measuring HbA to monitor trends in glycemia among patients with eGFR <60 mL/min/1.73 m. Direct measurements of glucose are necessary to capture short-term variability.
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http://dx.doi.org/10.2337/dc20-0915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510019PMC
October 2020

Tubular Secretory Clearance Is Associated With Whole-Body Insulin Clearance.

J Clin Endocrinol Metab 2020 11;105(11)

Kidney Research Institute, Seattle, Washington.

Context: The kidneys eliminate insulin via glomerular and peritubular mechanisms; consequently, the kidney contribution to insulin clearance may be underestimated by the glomerular filtration rate (GFR) alone.

Objective: To determine associations of tubular secretory clearance with whole-body insulin clearance and sensitivity in a dedicated study of glucose and insulin metabolism.

Design, Setting, And Participants: We performed an ancillary, cross-sectional study of tubular secretion in the Study of Glucose and Insulin in Renal Disease (SUGAR). Hyperinsulinemic-euglycemic clamps were performed in 57 nondiabetic persons with chronic kidney disease and 38 persons without kidney disease.

Intervention: We measured plasma and 24-hour urine concentrations of endogenous solutes primarily eliminated by tubular secretion. Kidney clearances of secretory solutes were calculated as the amount of blood fully cleared of that solute per minute.

Main Outcome Measures: Whole-body insulin clearance, insulin sensitivity.

Results: Mean whole-body insulin clearance was 924 ± 228 mL/min. After adjustment for age, sex, Black race, fat and fat-free mass, each 20% lower estimated GFR was associated with a 13 mL/min lower insulin clearance (95% confidence interval [CI], 2-24 mL/min lower). Each 20% lower clearance of isovalerylglycine and xanthosine were associated with a 16 mL/min lower (95% CI, 5-26 mL/min lower) and 19 mL/min lower (95% CI, 7-31 mL/min lower) insulin clearance, respectively. Neither estimated GFR nor secretory solute clearances were associated with insulin sensitivity after adjustment.

Conclusions: These results highlight the importance of tubular secretory pathways to insulin elimination but suggest that kidney functions in aggregate contribute only modestly to systemic insulin clearance.
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http://dx.doi.org/10.1210/clinem/dgaa522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7500476PMC
November 2020

Relationship Between Chronic Kidney Disease, Glucose Homeostasis, and Plasma Osteocalcin Carboxylation and Fragmentation.

J Ren Nutr 2021 05 18;31(3):248-256. Epub 2020 Jul 18.

Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington; VA Puget Sound Healthcare System, Division of Nephrology, Seattle, Washington.

Objective: Chronic kidney disease (CKD) is associated with reduced insulin sensitivity, through mechanisms that are not well understood. Low vitamin K intake and incomplete carboxylation of the vitamin K-dependent protein osteocalcin may promote insulin resistance. We assessed relationships of osteocalcin concentration, carboxylation, and fragmentation with CKD and glucose homeostasis in a cross-sectional study.

Methods: We included 87 participants without diabetes: 50 (27 female) with moderate to severe CKD (estimated glomerular filtration rate <60 mL/min/1.73 m not treated with dialysis) and 37 (17 female) healthy controls. Total osteocalcin was measured by immunoassay, and osteocalcin carboxylation and fragmentation status by liquid chromatography-electrospray ionization-based mass spectrometric immunoassay. Endpoints included glucose tolerance (based on 2-hour oral glucose tolerance test), insulin sensitivity (hyperinsulinemic-euglycemic clamp), and pancreatic beta-cell function (intravenous glucose tolerance test).

Results: The total plasma osteocalcin concentration was higher in the CKD group (mean [standard deviation] 102.9 [147.5]) than that in the control group (53.6 [51.1] ng/mL, P = .03), and more osteocalcin was circulating as fragments. The extent of osteocalcin carbocylation did not differ between individuals with and without CKD. Osteocalcin concentration, carboxylation, and fragmentation were not associated with any measure of glucose homeostasis in multivariable-adjusted analyses.

Conclusions: In CKD, circulating osteocalcin concentrations are elevated, in part due to larger proportions of fragmented forms. However, osteocalcin carboxylation status is not significantly different between individuals with and without CKD. Our data also do not provide support for the hypothesis that differences in osteocalcin carboxylation may explain reduced insulin sensitivity in individuals with CKD.
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http://dx.doi.org/10.1053/j.jrn.2020.05.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854928PMC
May 2021

Associations Between Cardiac Biomarkers and Cardiac Structure and Function in CKD.

Kidney Int Rep 2020 Jul 7;5(7):1052-1060. Epub 2020 May 7.

Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.

Introduction: Subclinical changes to cardiac structure and function detected with echocardiography precede the development of clinical heart failure (HF) in persons with chronic kidney disease (CKD). Circulating cardiac biomarkers may reflect these pathophysiological changes. This study investigated associations between established biomarkers (N-terminal pro-B-type natriuretic peptide [NT-proBNP] and high-sensitivity troponin T [hsTnT]) and novel biomarkers (growth differentiation factor 15 [GDF-15], galectin-3 [Gal-3], and soluble ST-2 [sST-2]), using echocardiographic measurements in persons with CKD.

Methods: In cross-sectional analyses among 2101 participants with mild to moderate CKD in the Chronic Renal Insufficiency Cohort (CRIC), biomarker levels measured at baseline were evaluated with echocardiographic measurements 1 year later. These included left ventricular mass index (LVMI), left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), left ventricular ejection fraction (LVEF), and left atrial diameter (LAD). Multivariable linear regression analyses tested associations of each biomarker with echocardiographic measurements, adjusting for covariates.

Results: GDF-15 was significantly associated with higher LVMI (1.0 g/m; 95% CI, 0.4-1.7), LVESV (0.4 ml/m; 95% CI, 0.0-0.7), and LVEDV (0.6 ml/m; 95% CI, 0.1-1.1), but not with LVEF or LAD. These findings were not significant when adjusting for NT-proBNP and hsTnT. Gal-3 and sST-2 had no significant associations. Higher levels of NT-proBNP and hsTnT were associated with all echocardiographic measurements.

Conclusion: In patients with CKD, the novel biomarker GDF-15, a marker of inflammation and tissue injury, and clinical biomarkers NT-proBNP and hsTnT, were associated with echocardiographic measurements of subclinical cardiovascular disease. Collectively, these biomarkers may highlight biological pathways that contribute to the development of clinical HF.
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http://dx.doi.org/10.1016/j.ekir.2020.04.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335964PMC
July 2020

Association of Cardiac Biomarkers With the Kansas City Cardiomyopathy Questionnaire in Patients With Chronic Kidney Disease Without Heart Failure.

J Am Heart Assoc 2020 07 24;9(13):e014385. Epub 2020 Jun 24.

Kidney Research Institute University of Washington Seattle WA.

Background The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a measure of heart failure (HF) health status. Worse KCCQ scores are common in patients with chronic kidney disease (CKD), even without diagnosed heart failure (HF). Elevations in the cardiac biomarkers GDF-15 (growth differentiation factor-15), galectin-3, sST2 (soluble suppression of tumorigenesis-2), hsTnT (high-sensitivity troponin T), and NT-proBNP (N-terminal pro-B-type natriuretic peptide) likely reflect subclinical HF in CKD. Whether cardiac biomarkers are associated with low KCCQ scores is not known. Methods and Results We studied participants with CKD without HF in the multicenter prospective CRIC (Chronic Renal Insufficiency Cohort) Study. Outcomes included (1) low KCCQ score <75 at year 1 and (2) incident decline in KCCQ score to <75. We used multivariable logistic regression and Cox regression models to evaluate the associations between baseline cardiac biomarkers and cross-sectional and longitudinal KCCQ scores. Among 2873 participants, GDF-15 (adjusted odds ratio 1.42 per SD; 99% CI, 1.19-1.68) and galectin-3 (1.28; 1.12-1.48) were significantly associated with KCCQ scores <75, whereas sST2, hsTnT, and NT-proBNP were not significantly associated with KCCQ scores <75 after multivariable adjustment. Of the 2132 participants with KCCQ ≥75 at year 1, GDF-15 (adjusted hazard ratio, 1.36 per SD; 99% CI, 1.12-1.65), hsTnT (1.20; 1.01-1.44), and NT-proBNP (1.30; 1.08-1.56) were associated with incident decline in KCCQ to <75 after multivariable adjustment, whereas galectin-3 and sST2 did not have significant associations with KCCQ decline. Conclusions Among participants with CKD without clinical HF GDF-15, galectin-3, NT-proBNP, and hsTnT were associated with low KCCQ either at baseline or during follow-up. Our findings show that elevations in cardiac biomarkers reflect early symptomatic changes in HF health status in CKD patients.
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http://dx.doi.org/10.1161/JAHA.119.014385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670503PMC
July 2020

Kidney Function in Patients With Type 2 Diabetes After Vitamin D Supplementation-Reply.

JAMA 2020 04;323(14):1411-1412

Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

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http://dx.doi.org/10.1001/jama.2020.1400DOI Listing
April 2020

Association Between Early Recovery of Kidney Function After Acute Kidney Injury and Long-term Clinical Outcomes.

JAMA Netw Open 2020 04 1;3(4):e202682. Epub 2020 Apr 1.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle.

Importance: The severity of acute kidney injury (AKI) is usually determined based on the maximum serum creatinine concentration. However, the trajectory of kidney function recovery could be an additional important dimension of AKI severity.

Objective: To assess whether the trajectory of kidney function recovery within 72 hours after AKI is associated with long-term risk of clinical outcomes.

Design, Setting, And Participants: This prospective, multicenter cohort study enrolled 1538 adults with or without AKI 3 months after hospital discharge between December 1, 2009, and February 28, 2015. Statistical analyses were completed November 1, 2018. Participants with or without AKI were matched based on demographic characteristics, site, comorbidities, and prehospitalization estimated glomerular filtration rate. Participants with AKI were classified as having resolving or nonresolving AKI based on previously published definitions. Resolving AKI was defined as a decrease in serum creatinine concentration of 0.3 mg/dL or more or 25% or more from maximum in the first 72 hours after AKI diagnosis. Nonresolving AKI was defined as AKI not meeting the definition for resolving AKI.

Main Outcomes And Measures: The primary outcome was a composite of major adverse kidney events (MAKE), defined as incident or progressive chronic kidney disease, long-term dialysis, or all-cause death during study follow-up.

Results: Among 1538 participants (964 men; mean [SD] age, 64.6 [12.7] years), 769 (50%) had no AKI, 475 (31%) had a resolving AKI pattern, and 294 (19%) had a nonresolving AKI pattern. After a median follow-up of 4.7 years, the outcome of MAKE occurred in 550 (36%) of all participants. The adjusted hazard ratio for MAKE was higher for patients with resolving AKI (adjusted hazard ratio, 1.52; 95% CI, 1.01-2.29; P = .04) and those with nonresolving AKI (adjusted hazard ratio 2.30; 95% CI, 1.52-3.48; P < .001) compared with participants without AKI. Within the population of patients with AKI, nonresolving AKI was associated with a 51% greater risk of MAKE (95% CI, 22%-88%; P < .001) compared with resolving AKI. The higher risk of MAKE among patients with nonresolving AKI was explained by a higher risk of incident and progressive chronic kidney disease.

Conclusions And Relevance: This study suggests that the 72-hour period immediately after AKI distinguishes the risk of clinically important kidney-specific long-term outcomes. The identification of different AKI recovery patterns may improve patient risk stratification, facilitate prognostic enrichment in clinical trials, and enable recognition of patients who may benefit from nephrology consultation.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.2682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7154800PMC
April 2020

Kidney Clearance of Secretory Solutes Is Associated with Progression of CKD: The CRIC Study.

J Am Soc Nephrol 2020 04 23;31(4):817-827. Epub 2020 Mar 23.

Kidney Research Institute, Seattle, Washington;

Background: The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. However, the clinical significance of the kidney's clearance of tubular secretory solutes is uncertain.

Methods: In this prospective cohort study, we evaluated 3416 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured plasma and 24-hour urine concentrations of endogenous candidate secretory solutes at baseline, using targeted liquid chromatography-tandem mass spectrometry. The study defined CKD progression by a ≥50% decline in the eGFR, initiation of maintenance dialysis, or kidney transplantation. We used Cox proportional hazards regression to test associations of secretory-solute clearances with CKD progression and mortality, adjusting for eGFR, albuminuria, and other confounding characteristics.

Results: Participants in this ancillary study had a mean age of 58 years and 41% were black; the median eGFR was 43 ml/min per 1.73 m. After adjustment, lower kidney clearances of six solutes-kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine-were associated with significantly greater risks of CKD progression, with clearance of kynurenic acid, a highly protein-bound solute, having the strongest association. Lower clearances of isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid were significantly associated with all-cause mortality after adjustment.

Conclusions: We found lower kidney clearances of endogenous secretory solutes to be associated with CKD progression and all-cause mortality, independent of eGFR and albuminuria. This suggests that tubular clearance of secretory solutes provides additional information about kidney health beyond measurements of glomerular function alone.
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http://dx.doi.org/10.1681/ASN.2019080811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191931PMC
April 2020

Differential effects of phosphate binders on vitamin D metabolism in chronic kidney disease.

Nephrol Dial Transplant 2020 04;35(4):616-623

Division of Nephrology and Kidney Research Institute, University of Washington, Seattle, WA, USA.

Background: Phosphate binders are commonly used in the treatment of patients with hyperphosphatemia. While phosphate binders are used to lower phosphate, the effects of specific phosphate binder types on vitamin D metabolism are unknown.

Methods: We performed a secondary analysis of the Phosphate Normalization Trial in which patients with moderate to advanced chronic kidney disease were randomized to receive either placebo, sevelamer carbonate, lanthanum carbonate or calcium acetate for 9 months. We evaluated changes in serum concentrations of vitamin D metabolites including 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the ratio of 24,25(OH)2D3 to 25-hydroxyvitamin D [the vitamin D metabolite ratio (VMR)] and the ratio of serum 1,25(OH)2D to 25-hydroxyvitamin D.

Results: Compared with placebo, randomization to the calcium acetate arm was associated with a 0.6 ng/mL (95% CI 0.2, 1) and 13.5 pg/ng (95% CI 5.5, 21.5) increase in 24,25(OH)2D and VMR, respectively, and a 5.2 pg/mL (95% CI 1.1, 9.4) reduction in 1,25(OH)2D. Randomization to sevelamer carbonate was associated with a 0.5 ng/mL (95% CI -0.9, -0.1) and 11.8 pg/ng (95% CI -20, -3.5) reduction in 24,25(OH)2D3 and VMR, respectively. There was no association of the sevelamer arm with the change in 1,25(OH)2D3, and randomization to lanthanum carbonate was not associated with a change in any of the vitamin D metabolites.

Conclusion: Administration of different phosphate binders to patients with moderate to severe CKD results in unique changes in vitamin D metabolism.
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http://dx.doi.org/10.1093/ndt/gfaa010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139206PMC
April 2020

Association of Tubular Solute Clearance with Symptom Burden in Incident Peritoneal Dialysis.

Clin J Am Soc Nephrol 2020 04 9;15(4):530-538. Epub 2020 Mar 9.

Division of Nephrology, Department of Medicine, University of Washington, Seattle Washington.

Background And Objectives: Residual kidney function is important to the health and wellbeing of patients with ESKD. We tested whether the kidney clearances of proximal tubular secretory solutes are associated with burden of uremic and heart failure symptoms among patients on peritoneal dialysis with residual kidney function.

Design, Setting, Participants, & Measurements: We enrolled 29 patients on incident peritoneal dialysis with residual urine output >250 ml daily. We used targeted liquid chromatography-mass spectrometry to quantify plasma, 24-hour urine, and peritoneal dialysate concentrations of ten tubular secretory solutes. We calculated the kidney and peritoneal dialysis clearances of each secretory solute, creatinine, and urea, and we estimated a composite kidney and peritoneal secretion score. We assessed for uremic symptoms using the Dialysis Symptom Index and heart failure-related symptoms using the Kansas City Cardiomyopathy Questionnaire. We used linear regression to determine associations of composite secretory solute clearances and GFR with Dialysis Symptom Index symptom score and Kansas City Cardiomyopathy Questionnaire summary score.

Results: Mean residual kidney clearances of creatinine and urea were 8±5 and 9±6 ml/min per 1.73 m, respectively, and mean GFR was 8±5 ml/min per 1.73 m. The residual kidney clearances of most secretory solutes were considerably higher than creatinine and urea clearance, and also, they were higher than their respective peritoneal dialysis clearances. After adjustments for age and sex, each SD higher composite kidney secretion score was associated with an 11-point lower Dialysis Symptom Index score (95% confidence interval, -20 to -1; =0.03) and a 12-point higher Kansas City Cardiomyopathy Questionnaire score (95% confidence interval, 0.5- to 23-point higher score; =0.04). Composite peritoneal dialysis secretion score was not associated with either symptom assessment.

Conclusions: Residual kidney clearances of secretory solutes are higher than peritoneal dialysis clearances. Kidney clearances of secretory solutes are associated with patient-reported uremic and heart failure-related symptoms.
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http://dx.doi.org/10.2215/CJN.11120919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133131PMC
April 2020

Effect of Vitamin D and Omega-3 Fatty Acid Supplementation on Kidney Function in Patients With Type 2 Diabetes: A Randomized Clinical Trial.

JAMA 2019 11;322(19):1899-1909

Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts.

Importance: Chronic kidney disease (CKD) is a common complication of type 2 diabetes that can lead to end-stage kidney disease and is associated with high cardiovascular risk. Few treatments are available to prevent CKD in type 2 diabetes.

Objective: To test whether supplementation with vitamin D3 or omega-3 fatty acids prevents development or progression of CKD in type 2 diabetes.

Design, Setting, And Participants: Randomized clinical trial with a 2 × 2 factorial design conducted among 1312 adults with type 2 diabetes recruited between November 2011 and March 2014 from all 50 US states as an ancillary study to the Vitamin D and Omega-3 Trial (VITAL), coordinated by a single center in Massachusetts. Follow-up was completed in December 2017.

Interventions: Participants were randomized to receive vitamin D3 (2000 IU/d) and omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid; 1 g/d) (n = 370), vitamin D3 and placebo (n = 333), placebo and omega-3 fatty acids (n = 289), or 2 placebos (n = 320) for 5 years.

Main Outcomes And Measures: The primary outcome was change in glomerular filtration rate estimated from serum creatinine and cystatin C (eGFR) from baseline to year 5.

Results: Among 1312 participants randomized (mean age, 67.6 years; 46% women; 31% of racial or ethnic minority), 934 (71%) completed the study. Baseline mean eGFR was 85.8 (SD, 22.1) mL/min/1.73 m2. Mean change in eGFR from baseline to year 5 was -12.3 (95% CI, -13.4 to -11.2) mL/min/1.73 m2 with vitamin D3 vs -13.1 (95% CI, -14.2 to -11.9) mL/min/1.73 m2 with placebo (difference, 0.9 [95% CI, -0.7 to 2.5] mL/min/1.73 m2). Mean change in eGFR was -12.2 (95% CI, -13.3 to -11.1) mL/min/1.73 m2 with omega-3 fatty acids vs -13.1 (95% CI, -14.2 to -12.0) mL/min/1.73 m2 with placebo (difference, 0.9 [95% CI, -0.7 to 2.6] mL/min/1.73 m2). There was no significant interaction between the 2 interventions. Kidney stones occurred among 58 participants (n = 32 receiving vitamin D3 and n = 26 receiving placebo) and gastrointestinal bleeding among 45 (n = 28 receiving omega-3 fatty acids and n = 17 receiving placebo).

Conclusions And Relevance: Among adults with type 2 diabetes, supplementation with vitamin D3 or omega-3 fatty acids, compared with placebo, resulted in no significant difference in change in eGFR at 5 years. The findings do not support the use of vitamin D or omega-3 fatty acid supplementation for preserving kidney function in patients with type 2 diabetes.

Trial Registration: ClinicalTrials.gov Identifier: NCT01684722.
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http://dx.doi.org/10.1001/jama.2019.17380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865245PMC
November 2019

Alterations of Proximal Tubular Secretion in Autosomal Dominant Polycystic Kidney Disease.

Clin J Am Soc Nephrol 2020 01 18;15(1):80-88. Epub 2019 Oct 18.

Division of Nephrology, Department of Medicine and.

Background And Objectives: In autosomal dominant polycystic kidney disease (ADPKD), the GFR often remains normal despite significant nephron loss. Proximal tubular secretory clearance may be reduced in ADPKD before detectable changes in GFR.

Design, Setting, Participants, & Measurements: We used targeted mass spectrometry to quantify secretory solutes from blood and urine samples from 31 patients with ADPKD and preserved GFR (mean eGFR =111±11 ml/min per 1.73 m) and 25 healthy control individuals as well as from 95 patients with ADPKD and reduced GFR (mean eGFR =53±21 ml/min per 1.73 m) and 92 individuals with non-ADPKD CKD. We used linear regression to compare the fractional excretion of each solute between ADPKD and control groups. Among 112 patients with ADPKD, we used linear regression to determine associations of solute fractional excretion with height-adjusted total kidney volume.

Results: After adjusting for demographics, clinical characteristics, and kidney function measures, the fractional excretions of three secretory solutes were lower in patients with ADPKD and preserved GFR compared with healthy individuals: 52% lower cinnamoylglycine excretion (95% confidence interval, 24% to 70%), 53% lower tiglylglycine excretion (95% confidence interval, 23% to 71%), and 91% lower xanthosine excretion (95% confidence interval, 83% to 95%). In addition to lower excretions of tiglylglycine and xanthosine, patients with ADPKD and reduced GFR also demonstrated 37% lower dimethyluric acid excretion (95% confidence interval, 21% to 50%), 58% lower hippurate excretion (95% confidence interval, 48% to 66%), 48% lower isovalerylglycine excretion (95% confidence interval, 37% to 56%), and 31% lower pyridoxic acid excretion (95% confidence interval, 16% to 42%) compared with patients with non-ADPKD CKD and comparable eGFR. Among patients with ADPKD, solute fractional excretions were not associated with differences in kidney volume.

Conclusions: Patients with ADPKD and preserved and reduced GFR demonstrate lower tubular secretory solute excretion compared with healthy controls and patients with non-ADPKD CKD. Our results suggest that tubular secretion is impaired in ADPKD independent of GFR.
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http://dx.doi.org/10.2215/CJN.05610519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946073PMC
January 2020

Cardiac Biomarkers and Risk of Atrial Fibrillation in Chronic Kidney Disease: The CRIC Study.

J Am Heart Assoc 2019 08 5;8(15):e012200. Epub 2019 Aug 5.

Division of Nephrology Department of Medicine University of Washington Seattle WA.

Background We tested associations of cardiac biomarkers of myocardial stretch, injury, inflammation, and fibrosis with the risk of incident atrial fibrillation (AF) in a prospective study of chronic kidney disease patients. Methods and Results The study sample was 3053 participants with chronic kidney disease in the multicenter CRIC (Chronic Renal Insufficiency Cohort) study who were not identified as having AF at baseline. Cardiac biomarkers, measured at baseline, were NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin T, galectin-3, growth differentiation factor-15, and soluble ST-2. Incident AF ("AF event") was defined as a hospitalization for AF. During a median follow-up of 8 years, 279 (9%) participants developed a new AF event. In adjusted models, higher baseline log-transformed NT-proBNP (N-terminal pro-B-type natriuretic peptide) was associated with incident AF (adjusted hazard ratio [HR] per SD higher concentration: 2.11; 95% CI, 1.75, 2.55), as was log-high-sensitivity troponin T (HR 1.42; 95% CI, 1.20, 1.68). These associations showed a dose-response relationship in categorical analyses. Although log-soluble ST-2 was associated with AF risk in continuous models (HR per SD higher concentration 1.35; 95% CI, 1.16, 1.58), this association was not consistent in categorical analyses. Log-galectin-3 (HR 1.05; 95% CI, 0.91, 1.22) and log-growth differentiation factor-15 (HR 1.16; 95% CI, 0.96, 1.40) were not significantly associated with incident AF. Conclusions We found strong associations between higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity troponin T concentrations, and the risk of incident AF in a large cohort of participants with chronic kidney disease. Increased atrial myocardial stretch and myocardial cell injury may be implicated in the high burden of AF in patients with chronic kidney disease.
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http://dx.doi.org/10.1161/JAHA.119.012200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761652PMC
August 2019

Physician Judgment and Circulating Biomarkers Predict 28-Day Mortality in Emergency Department Patients.

Crit Care Med 2019 11;47(11):1513-1521

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA.

Objectives: To determine whether biomarkers of endothelial activation and inflammation provide added value for prediction of in-hospital mortality within 28 days when combined with physician judgment in critically ill emergency department patients.

Design: Prospective, observational study.

Setting: Two urban, academic emergency departments, with ≈80,000 combined annual visits, between June 2016 and December 2017.

Patients: Admitted patients, greater than 17 years old, with two systemic inflammatory response syndrome criteria and organ dysfunction, systolic blood pressure less than 90 mm Hg, or lactate greater than 4.0 mmol/L. Patients with trauma, intracranial hemorrhage known prior to arrival, or without available blood samples were excluded.

Interventions: Emergency department physicians reported likelihood of in-hospital mortality (0-100%) by survey at hospital admission. Remnant EDTA blood samples, drawn during the emergency department stay, were used to measure angiopoietin-1, angiopoietin-2, tumor necrosis factor receptor-1, interleukin-6, and interleukin-8.

Measurements And Main Results: We screened 421 patients and enrolled 314. The primary outcome of in-hospital mortality within 28 days occurred in 31 (9.9%). When predicting the primary outcome, the best biomarker model included angiopoietin-2 and interleukin-6 and performed moderately well (area under the curve, 0.72; 95% CI, 0.69-0.75), as did physician judgment (area under the curve, 0.78; 95% CI, 0.74-0.82). Combining physician judgment and biomarker models improved performance (area under the curve, 0.85; 95% CI, 0.82-0.87), with area under the curve change of 0.06 (95% CI, 0.04-0.09; p < 0.01) compared with physician judgment alone.

Conclusions: Predicting in-hospital mortality within 28 days among critically ill emergency department patients may be improved by including biomarkers of endothelial activation and inflammation in combination with emergency department physician judgment.
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http://dx.doi.org/10.1097/CCM.0000000000003899DOI Listing
November 2019

Differences in proximal tubular solute clearance across common etiologies of chronic kidney disease.

Nephrol Dial Transplant 2020 11;35(11):1916-1923

Department of Medicine, Division of Nephrology, University of Washington, Seattle, WA, USA.

Background: Laboratory measures of glomerular function such as the glomerular filtration rate (GFR) contribute toward clinical evaluation of chronic kidney disease (CKD). However, diverse CKD etiologies have distinct pathological mechanisms that may differentially impact the kidney tubules. Little is known regarding how tubular function changes with varying kidney disease types.

Methods: We used targeted mass spectrometry to quantify paired serum and urine concentration of 11 solutes of proximal tubular secretion in 223 patients from an outpatient CKD cohort. We reviewed clinic notes to ascertain the primary CKD diagnosis and categorized these as vascular, diabetic, glomerular or tubulointerstitial. We used one-way analysis of variance to compare secretory solute clearance across diagnoses setting a false discovery threshold of ≤5% and used linear regression to compare differences after adjustments for estimated GFR, age, race, sex, body mass index and urine albumin excretion.

Results: After full adjustment, glomerular disease was associated with higher clearances of three tubular secretory solutes compared with vascular disease: 48% higher isovalerylglycine clearance [95% confidence interval (CI) 18-87%], 28% higher kynurenic acid clearance (95% CI 3-59%) and 33% higher tiglylglycine clearance (95% CI 7-67%). Diabetic kidney disease (DKD) was associated with 39% higher isovalerylglycine clearance compared with vascular disease (95% CI 13-72%).

Conclusion: Glomerular disorders and DKD are associated with higher net clearances of several secretory solutes compared with vascular causes of kidney disease. These findings suggest that different underlying etiologies of CKD may differentially impact proximal tubular secretory pathways.
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http://dx.doi.org/10.1093/ndt/gfz144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643672PMC
November 2020

Two-Phase, Generalized Case-Control Designs for the Study of Quantitative Longitudinal Outcomes.

Am J Epidemiol 2020 02;189(2):81-90

Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington.

We propose a general class of 2-phase epidemiologic study designs for quantitative, longitudinal data that are useful when phase 1 longitudinal outcome and covariate data are available but data on the exposure (e.g., a biomarker) can only be collected on a subset of subjects during phase 2. To conduct a study using a design in the class, one first summarizes the longitudinal outcomes by fitting a simple linear regression of the response on a time-varying covariate for each subject. Sampling strata are defined by splitting the estimated regression intercept or slope distributions into distinct (low, medium, and high) regions. Stratified sampling is then conducted from strata defined by the intercepts, by the slopes, or from a mixture. In general, samples selected with extreme intercept values will yield low variances for associations of time-fixed exposures with the outcome and samples enriched with extreme slope values will yield low variances for associations of time-varying exposures with the outcome (including interactions with time-varying exposures). We describe ascertainment-corrected maximum likelihood and multiple-imputation estimation procedures that permit valid and efficient inferences. We embed all methodological developments within the framework of conducting a substudy that seeks to examine genetic associations with lung function among continuous smokers in the Lung Health Study (United States and Canada, 1986-1994).
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http://dx.doi.org/10.1093/aje/kwz127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298772PMC
February 2020
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