Publications by authors named "Bryan Kestenbaum"

252 Publications

Kidney Tubulointerstitial Fibrosis and Tubular Secretion.

Am J Kidney Dis 2021 Sep 24. Epub 2021 Sep 24.

Rationale And Objectives: Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) was associated with lower tubular secretory clearance in persons undergoing kidney biopsy.

Study Design: Cross sectional.

Settings And Participants: The Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications.

Exposures: Semi-quantitive score of IFTA reported by two trained pathologists.

Outcomes: We measured plasma and urine concentrations of nine endogenous secretory solutes using a targeted liquid chromatography mass-spectroscopy assay. We used linear regression to test associations of urine to plasma ratios (UPR) of these solutes with IFTA score after controlling for estimated GFR (eGFR) and albuminuria.

Results: Among 418 persons, the mean age was 53 years, 51% were women, 64% were White and 18% were Black. The mean eGFR was 50 ml/min/1.73m2 and median albumin/creatinine ratio was 819 mg/g. Compared to individuals with <25% IFTA, those with >50% IFTA had 12 to 37% lower UPR for the all 9 secretory solutes. Adjusting for age, sex, race, eGFR and urinary albumin and creatinine attenuated the associations, yet trend of lower secretion across groups remained statistically significant (p for trend <0.05) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (p for trend <0.05).

Limitations: Single time point and spot measures of secretory solutes.

Conclusions: Greater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.
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http://dx.doi.org/10.1053/j.ajkd.2021.08.015DOI Listing
September 2021

Bone mineral density and long-term progression of aortic valve and mitral annular calcification: The Multi-Ethnic Study of Atherosclerosis.

Atherosclerosis 2021 Oct 26;335:126-134. Epub 2021 Aug 26.

Cardiology Section, San Francisco Veterans Affairs Health Care System, and Department of Medicine, University of California San Francisco, San Francisco, CA, USA; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. Electronic address:

Background And Aims: Bone and mineral metabolism has been implicated in the pathophysiology of cardiac valve calcification. Whether bone demineralization, a common aging-related disorder, promotes calcific valve disease remains uncertain. We tested the hypothesis that low bone mineral density (BMD) is associated with greater incidence/progression of cardiac valve calcification in the Multi-Ethnic Study of Atherosclerosis.

Methods: Using linear mixed-effects models, we related baseline measurement of BMD of the thoracic vertebrae by computed tomography (CT) in 6768 participants to serial CT assessments of aortic valve calcification (AVC) and mitral annular calcification (MAC) obtained over a >10-year period.

Results: After multivariable adjustment, lower BMD (per SD decrement) was associated with accelerated increase in AVC over time in women (0.76 [95% CI 0.42,1.09] Agatston -units [AU]/year) and men (1.41 [95% CI 0.48,2.33] AU/year), as well as for MAC in women (3.22 [95% CI 1.16,5.28] AU/year) and men (3.59 [95% CI 2.09,5.09] AU/year). Significant effect modification was observed, with more pronounced BMD-related acceleration of AVC and MAC progression in older or white participants of one or both sexes, as well as by estimated glomerular filtration rate, though the latter differed by sex for AVC and MAC.

Conclusions: In this multi-ethnic cohort, low thoracic BMD was significantly, but modestly, associated with increased AVC and MAC progression. This suggests that altered bone mineral metabolism does not have a major impact on calcific valve disease in the general population, but the possibility of a more meaningful influence in higher-risk individuals with osteoporosis will require further investigation.
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http://dx.doi.org/10.1016/j.atherosclerosis.2021.08.031DOI Listing
October 2021

Randomized, Placebo-Controlled Trial of Rifaximin Therapy for Lowering Gut-Derived Cardiovascular Toxins and Inflammation in CKD.

Kidney360 2020 Nov 25;1(11):1206-1216. Epub 2020 Nov 25.

The Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas.

Background: Recent evidence suggests the systemic accumulation of by-products of gut microbes contributes to cardiovascular morbidity in patients with CKD. Limiting the generation of toxic bacterial by-products by manipulating the intestinal microbiota may be a novel strategy for reducing cardiovascular disease in CKD. Rifaximin is a minimally absorbed, oral antibiotic that targets intestinal pathogens and is commonly used as chronic therapy for the prevention of encephalopathy in patients with cirrhosis.

Methods: We conducted a randomized, double-blinded, placebo-controlled trial to determine the effect of a 10-day course of oral rifaximin 550 mg BID versus placebo on circulating concentrations of gut-derived cardiovascular toxins and proinflammatory cytokines in patients with stage 3-5 CKD (=38). The primary clinical outcome was change in serum trimethylamine -oxide (TMAO) concentrations from baseline to study end. Secondary outcomes included change in serum concentrations of p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines (C-reactive protein, IL-6, IL-1), and change in composition and diversity of fecal microbiota.

Results: A total of 19 patients were randomized to each of the rifaximin and placebo arms, with =17 and =14 completing both study visits in these respective groups. We observed no difference in serum TMAO change (post-therapy minus baseline TMAO) between the rifaximin and placebo groups (mean TMAO change -3.9±15.4 for rifaximin versus 0.5±9.5 for placebo, =0.49). Similarly, we found no significant change in serum concentrations for p-cresol sulfate, indoxyl sulfate, kynurenic acid, deoxycholic acid, and inflammatory cytokines. We did observe differences in colonic bacterial communities, with the rifaximin group exhibiting significant decreases in bacterial richness (Chao1, =0.02) and diversity (Shannon H, =0.05), along with altered abundance of several bacterial genera.

Conclusions: Short-term rifaximin treatment failed to reduce gut-derived cardiovascular toxins and inflammatory cytokines in patients with CKD.

Clinical Trial Registry Name And Registration Number: Rifaximin Therapy in Chronic Kidney Disease, NCT02342639.
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http://dx.doi.org/10.34067/kid.0003942020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8315698PMC
November 2020

Cadherin-11, Sparc-related modular calcium binding protein-2, and Pigment epithelium-derived factor are promising non-invasive biomarkers of kidney fibrosis.

Kidney Int 2021 09 27;100(3):672-683. Epub 2021 May 27.

Section of Nephrology, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, Massachussetts, USA; Renal Division, Brigham & Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachussetts, USA. Electronic address:

Kidney fibrosis constitutes the shared final pathway of nearly all chronic nephropathies, but biomarkers for the non-invasive assessment of kidney fibrosis are currently not available. To address this, we characterize five candidate biomarkers of kidney fibrosis: Cadherin-11 (CDH11), Sparc-related modular calcium binding protein-2 (SMOC2), Pigment epithelium-derived factor (PEDF), Matrix-Gla protein, and Thrombospondin-2. Gene expression profiles in single-cell and single-nucleus RNA-sequencing (sc/snRNA-seq) datasets from rodent models of fibrosis and human chronic kidney disease (CKD) were explored, and Luminex-based assays for each biomarker were developed. Plasma and urine biomarker levels were measured using independent prospective cohorts of CKD: the Boston Kidney Biopsy Cohort, a cohort of individuals with biopsy-confirmed semiquantitative assessment of kidney fibrosis, and the Seattle Kidney Study, a cohort of patients with common forms of CKD. Ordinal logistic regression and Cox proportional hazards regression models were used to test associations of biomarkers with interstitial fibrosis and tubular atrophy and progression to end-stage kidney disease and death, respectively. Sc/snRNA-seq data confirmed cell-specific expression of biomarker genes in fibroblasts. After multivariable adjustment, higher levels of plasma CDH11, SMOC2, and PEDF and urinary CDH11 and PEDF were significantly associated with increasing severity of interstitial fibrosis and tubular atrophy in the Boston Kidney Biopsy Cohort. In both cohorts, higher levels of plasma and urinary SMOC2 and urinary CDH11 were independently associated with progression to end-stage kidney disease. Higher levels of urinary PEDF associated with end-stage kidney disease in the Seattle Kidney Study, with a similar signal in the Boston Kidney Biopsy Cohort, although the latter narrowly missed statistical significance. Thus, we identified CDH11, SMOC2, and PEDF as promising non-invasive biomarkers of kidney fibrosis.
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http://dx.doi.org/10.1016/j.kint.2021.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384690PMC
September 2021

An Introduction to Qualitative Inquiry.

J Am Soc Nephrol 2021 06 26;32(6):1275-1278. Epub 2021 May 26.

Division of Nephrology and Kidney Research InstituteUniversity of WashingtonSeattle, Washington.

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http://dx.doi.org/10.1681/ASN.2021040473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259646PMC
June 2021

Assessment of kidney proximal tubular secretion in critical illness.

JCI Insight 2021 May 24;6(10). Epub 2021 May 24.

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

BACKGROUNDSerum creatinine concentrations (SCrs) are used to determine the presence and severity of acute kidney injury (AKI). SCr is primarily eliminated by glomerular filtration; however, most mechanisms of AKI in critical illness involve kidney proximal tubules, where tubular secretion occurs. Proximal tubular secretory clearance is not currently estimated in the intensive care unit (ICU). Our objective was to estimate the kidney clearance of secretory solutes in critically ill adults.METHODSWe collected matched blood and spot urine samples from 170 ICU patients and from a comparison group of 70 adults with normal kidney function. We measured 7 endogenously produced secretory solutes using liquid chromatography-tandem mass spectrometry. We computed a composite secretion score incorporating all 7 solutes and evaluated associations with 28-day major adverse kidney events (MAKE28), defined as doubling of SCr, dialysis dependence, or death.RESULTSThe urine-to-plasma ratios of 6 of 7 secretory solutes were lower in critically ill patients compared with healthy individuals after adjustment for SCr. The composite secretion score was moderately correlated with SCr and cystatin C (r = -0.51 and r = -0.53, respectively). Each SD higher composite secretion score was associated with a 25% lower risk of MAKE28 (95% CI 9% to 38% lower) independent of severity of illness, SCr, and tubular injury markers. Higher urine-to-plasma ratios of individual secretory solutes isovalerylglycine and tiglylglycine were associated with MAKE28 after accounting for multiple testing.CONCLUSIONAmong critically ill adults, tubular secretory clearance is associated with adverse outcomes, and its measurement could improve assessment of kidney function and dosing of essential ICU medications.FUNDINGGrants from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK/NIH) K23DK116967, the University of Washington Diabetes Research Center P30DK017047, an unrestricted gift to the Kidney Research Institute from the Northwest Kidney Centers, and the Vanderbilt O'Brien Kidney Center (NIDDK 5P30 DK114809-03). The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
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http://dx.doi.org/10.1172/jci.insight.145514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262320PMC
May 2021

Comparison of host endothelial, epithelial and inflammatory response in ICU patients with and without COVID-19: a prospective observational cohort study.

Crit Care 2021 04 19;25(1):148. Epub 2021 Apr 19.

Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Washington, 325 9th Avenue, Seattle, WA, 98104, USA.

Background: Analyses of blood biomarkers involved in the host response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection can reveal distinct biological pathways and inform development and testing of therapeutics for COVID-19. Our objective was to evaluate host endothelial, epithelial and inflammatory biomarkers in COVID-19.

Methods: We prospectively enrolled 171 ICU patients, including 78 (46%) patients positive and 93 (54%) negative for SARS-CoV-2 infection from April to September, 2020. We compared 22 plasma biomarkers in blood collected within 24 h and 3 days after ICU admission.

Results: In critically ill COVID-19 and non-COVID-19 patients, the most common ICU admission diagnoses were respiratory failure or pneumonia, followed by sepsis and other diagnoses. Similar proportions of patients in both groups received invasive mechanical ventilation at the time of study enrollment. COVID-19 and non-COVID-19 patients had similar rates of acute respiratory distress syndrome, severe acute kidney injury, and in-hospital mortality. While concentrations of interleukin 6 and 8 were not different between groups, markers of epithelial cell injury (soluble receptor for advanced glycation end products, sRAGE) and acute phase proteins (serum amyloid A, SAA) were significantly higher in COVID-19 compared to non-COVID-19, adjusting for demographics and APACHE III scores. In contrast, angiopoietin 2:1 (Ang-2:1 ratio) and soluble tumor necrosis factor receptor 1 (sTNFR-1), markers of endothelial dysfunction and inflammation, were significantly lower in COVID-19 (p < 0.002). Ang-2:1 ratio and SAA were associated with mortality only in non-COVID-19 patients.

Conclusions: These studies demonstrate that, unlike other well-studied causes of critical illness, endothelial dysfunction may not be characteristic of severe COVID-19 early after ICU admission. Pathways resulting in elaboration of acute phase proteins and inducing epithelial cell injury may be promising targets for therapeutics in COVID-19.
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http://dx.doi.org/10.1186/s13054-021-03547-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054255PMC
April 2021

The Multi-Ethnic Study of Atherosclerosis individual response to vitamin D trial: Building a randomized clinical trial into an observational cohort study.

Contemp Clin Trials 2021 04 12;103:106318. Epub 2021 Feb 12.

Division of Nephrology and Kidney Research Institute, Department of Medicine, University of Washington, Seattle, WA, United States of America.

The INdividual response to VITamin D (INVITe) trial was a randomized, placebo-controlled, parallel group trial of vitamin D supplementation (2000 IU daily) designed to determine clinical and genetic characteristics that modify the response to vitamin D supplementation. To enhance internal and external validity and reduce cost, the INVITe trial was nested within the Multi-Ethnic Study of Atherosclerosis (MESA), an ongoing prospective observational cohort study. The INVITe trial enrolled a community-based population of 666 racially and ethnically diverse participants from January 2017 to April 2019. This represents 30% of 2210 MESA participants approached for screening, and 96% of those found to be eligible. Barriers to enrollment included delayed initiation of the trial relative to scheduled MESA study visits, a lower number of available MESA participants than expected, and a high prevalence (18%) of high-dose vitamin D supplementation (>1000 IU daily, an exclusion criterion). The final study visit was attended by 611 participants (92%), and median adherence was 98%. Our experience suggests that integration of a randomized trial into an existing observational cohort study may leverage strengths of the source population and enhance enrollment, retention, and adherence, although with limited enrollment capacity. The INVITe trial will use rigorously-collected data to advance understanding of individual determinants of vitamin D response.
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http://dx.doi.org/10.1016/j.cct.2021.106318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089051PMC
April 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 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

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

Fibroblast Growth Factor 23 and Long-Term Cardiac Function: The Multi-Ethnic Study of Atherosclerosis.

Circ Cardiovasc Imaging 2020 11 9;13(11):e011925. Epub 2020 Nov 9.

Division of Cardiology, Department of Medicine (R.B.P., S.J.S., D.L-J.), Northwestern University Feinberg School of Medicine, Chicago, IL.

Background: Although FGF23 (fibroblast growth factor 23) is associated with heart failure and atrial fibrillation, the mechanisms driving these associations are unclear. Sensitive measures of cardiovascular structure and function may provide mechanistic insight behind the associations of FGF23 with various cardiovascular diseases.

Methods: In MESA (the Multi-Ethnic Study of Atherosclerosis), we evaluated the associations of baseline serum FGF23 (2000-2002) with measures of left ventricular (LV) and left atrial mechanical function on cardiac magnetic resonance at 10-year follow-up (2010-2012).

Results: Of 2276 participants with available FGF23 and cardiac magnetic resonance at 10-year follow-up, participants with higher FGF23 levels were more likely White race, taking antihypertensive medications, and had lower kidney function. After covariate adjustment, FGF23 was associated with higher LV mass (β coefficient per 1 SD higher, 1.14 [95% CI, 0.16-2.12], =0.02), worse LV global circumferential strain (β coefficient per 1 SD higher, 0.15 [95% CI, 0.05-0.25], =0.003), worse LV midwall circumferential strain (β coefficient per 1 SD higher, 0.20 [95% CI, 0.08-0.31], =0.001), and lower left atrial total emptying fraction (β coefficient per 1 SD higher, -0.52 [95% CI, -1.02 to -0.02], =0.04). These associations were consistent across racial/ethnic groups and the spectrum of glomerular filtration rates. FGF23 was not associated with the presence of myocardial scar (odds ratio per 1 SD higher, 1.12 [95% CI, 0.86-1.45], =0.42).

Conclusions: In a multiethnic, community-based cohort, baseline FGF23 levels were independently associated with higher LV mass, lower LV systolic function, and reduced left atrial function over long-term follow-up. These findings provide potential mechanistic insight into associations of FGF23 with incident heart failure and atrial fibrillation.
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http://dx.doi.org/10.1161/CIRCIMAGING.120.011925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665116PMC
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

Race, Ancestry, and Vitamin D Metabolism: The Multi-Ethnic Study of Atherosclerosis.

J Clin Endocrinol Metab 2020 12;105(12)

Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Context: A comprehensive characterization of racial/ethnic variations in vitamin D metabolism markers may improve our understanding of differences in bone and mineral homeostasis and the risk of vitamin D-related diseases.

Objective: Describe racial/ethnic differences in vitamin D metabolism markers and their associations with genetic ancestry.

Design, Setting, Participants: In a cross-sectional study within the Multi-Ethnic Study of Atherosclerosis (MESA), we compared a comprehensive panel of vitamin D metabolism markers across self-reported racial/ethnic groups of Black (N = 1759), White (N = 2507), Chinese (N = 788), and Hispanic (N = 1411). We evaluated associations of proportion African and European ancestry with this panel of markers in Black and Hispanic participants using ancestry informative markers. Latent class analysis evaluated associations between patterns of vitamin D measurements with race/ethnicity.

Results: Compared with Black participants, White participants had significantly higher serum concentrations of 25-hydroxyvitamin D and fibroblast growth factor-23; lower concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D; circulating vitamin D metabolite ratios suggesting lower CYP27B1 and higher CYP24A1 activity; higher urinary concentrations of calcium and phosphorus with higher urinary fractional excretion of phosphorus; and differences in vitamin D binding globulin haplotypes. Higher percent European ancestry was associated with higher 25-hydroxyvitamin D and lower parathyroid hormone concentrations among Black and Hispanic participants. Latent classes defined by vitamin D measurements reflected these patterns and differed significantly by race/ethnicity and ancestry.

Conclusions: Markers of vitamin D metabolism vary significantly by race/ethnicity, may serve to maintain bone and mineral homeostasis across ranges of 25-hydroxyvitamin D production, and be attributable, at least partly, to genetic ancestry.
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http://dx.doi.org/10.1210/clinem/dgaa612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526733PMC
December 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

Serum Aldosterone Concentration, Blood Pressure, and Coronary Artery Calcium: The Multi-Ethnic Study of Atherosclerosis.

Hypertension 2020 07 18;76(1):113-120. Epub 2020 May 18.

Division of Cardiology (D.G., K.E.W.), Department of Medicine, UCLA, Los Angeles, CA.

Aldosterone is a steroid hormone regulating fluid and electrolyte homeostasis and is known to increase the risk of atherosclerosis. In this study, we examined the associations of serum aldosterone concentrations with subclinical atherosclerosis and all-cause mortality. This study included 948 adults aged 46 to 88 years from the MESA (Multi-Ethnic Study of Atherosclerosis) with measurements of serum aldosterone and plasma renin activity and not taking antihypertensive medications. Coronary calcification was longitudinally assessed using Agatston coronary artery calcium score from computed tomography scans. All-cause mortality was ascertained from the medical record. The average age (SD) was 62.3 (9.4) years and 53% were male. Among 700 subjects who had follow-up coronary artery calcium score (median follow-up of 6.4 years), higher aldosterone levels (per 100 pg/mL) were associated with higher coronary artery calcium (relative ratio, 1.17 [95% CI, 1.04-1.32]), with the association being stronger in individuals with suppressed plasma renin activity (≤0.5 μg/L/hr). Systolic or diastolic blood pressure mediated around 45% of the total effect of aldosterone on coronary artery calcium. Over a median follow-up of 12.5 years (120 deaths identified among 948 subjects), aldosterone was associated with the increased risk of all-cause mortality when plasma renin activity was suppressed; hazard ratio per 100 pg/mL, 1.70 (95% CI, 1.10-2.63). In this study, we found that higher aldosterone levels were associated with the increased risk of subclinical coronary atherosclerosis and all-cause mortality particularly when renin was suppressed. Our findings indicate the importance of aldosterone levels (even within the reference range) with respect to the cardiovascular system and overall health.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15006DOI Listing
July 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

Impaired skeletal muscle mitochondrial bioenergetics and physical performance in chronic kidney disease.

JCI Insight 2020 03 12;5(5). Epub 2020 Mar 12.

Division of Nephrology, Department of Medicine, School of Medicine, UCD, Sacramento, California, USA.

The maintenance of functional independence is the top priority of patients with chronic kidney disease (CKD). Defects in mitochondrial energetics may compromise physical performance and independence. We investigated associations of the presence and severity of kidney disease with in vivo muscle energetics and the association of muscle energetics with physical performance. We performed measures of in vivo leg and hand muscle mitochondrial capacity (ATPmax) and resting ATP turnover (ATPflux) using 31phosphorus magnetic resonance spectroscopy and oxygen uptake (O2 uptake) by optical spectroscopy in 77 people (53 participants with CKD and 24 controls). We measured physical performance using the 6-minute walk test. Participants with CKD had a median estimated glomerular filtration rate (eGFR) of 33 ml/min per 1.73 m2. Participants with CKD had a -0.19 mM/s lower leg ATPmax compared with controls but no difference in hand ATPmax. Resting O2 uptake was higher in CKD compared with controls, despite no difference in ATPflux. ATPmax correlated with eGFR and serum bicarbonate among participants with GFR <60. ATPmax of the hand and leg correlated with 6-minute walking distance. The presence and severity of CKD associate with muscle mitochondrial capacity. Dysfunction of muscle mitochondrial energetics may contribute to reduced physical performance in CKD.
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http://dx.doi.org/10.1172/jci.insight.133289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141399PMC
March 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

Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney.

J Clin Invest 2020 03;130(3):1513-1526

Nephrology Division and.

Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D3 [1,25(OH)2D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fundamental understanding of what regulates FGF23 production is lacking. Because the kidney is the major end organ of FGF23 action, we hypothesized that it releases a factor that regulates FGF23 synthesis. Using aptamer-based proteomics and liquid chromatography-mass spectrometry-based (LC-MS-based) metabolomics, we profiled more than 1600 molecules in renal venous plasma obtained from human subjects. Renal vein glycerol-3-phosphate (G-3-P) had the strongest correlation with circulating FGF23. In mice, exogenous G-3-P stimulated bone and bone marrow FGF23 production through local G-3-P acyltransferase-mediated (GPAT-mediated) lysophosphatidic acid (LPA) synthesis. Further, the stimulatory effect of G-3-P and LPA on FGF23 required LPA receptor 1 (LPAR1). Acute kidney injury (AKI), which increases FGF23 levels, rapidly increased circulating G-3-P in humans and mice, and the effect of AKI on FGF23 was abrogated by GPAT inhibition or Lpar1 deletion. Together, our findings establish a role for kidney-derived G-3-P in mineral metabolism and outline potential targets to modulate FGF23 production during kidney injury.
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http://dx.doi.org/10.1172/JCI131190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269595PMC
March 2020

Vitamin D Metabolic Ratio and Risks of Death and CKD Progression.

Kidney Int Rep 2019 Nov 30;4(11):1598-1607. Epub 2019 Aug 30.

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

Introduction: Assessment of impaired vitamin D metabolism is limited by lack of functional measures. CYP24A1-mediated vitamin D clearance, calculated as the ratio of serum 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 (the vitamin D metabolic ratio, VDMR), is induced by 1,25-dihydroxyvitamin D and may assess tissue-level activity. We tested associations of the VDMR with risks of death and progression to end-stage renal disease (ESRD) in patients with chronic kidney disease (CKD).

Methods: We studied participants from the Chronic Renal Insufficiency Cohort (CRIC), which included a random subset of 1080 CRIC participants plus additional participants who experienced ESRD or died (case cohort study design). Serum 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 was measured 1 year after enrollment. The primary outcomes included death and progression to ESRD. Using inverse probability weighting, we tested associations of VDMR (24,25[OH]D/25[OH]D) with risks of death and ESRD, adjusting for demographics, comorbidity, and kidney function (estimated glomerular filtration rate [eGFR] and urine protein-to-creatinine ratio [PCR]).

Results: There were a total of 708 ESRD events and 650 deaths events over mean (SD) follow-up periods of 4.9 (2.9) years and 6.5 (2.5) years, respectively. Lower VDMR was associated with increased risk of ESRD prior to adjusting for kidney function (hazard ratio [HR], 1.80 per 20 pg/ng lower VDMR; 95% confidence interval [CI], 1.56-2.08), but not with adjustment for kidney function (HR, 0.94 per 20 pg/ng; 95% CI, 0.81-1.10). Lower VDMR was associated with modestly increased mortality risk, including adjustment for kidney function (HR, 1.18 per 20 pg/ng; 95% CI, 1.02-1.36).

Conclusion: Lower VDMR, a measure of CYP24A1-mediated vitamin D clearance, was significantly associated with all-cause mortality but not with progression to ESRD in patients with CKD.
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http://dx.doi.org/10.1016/j.ekir.2019.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933450PMC
November 2019

Impact of Race on the Association of Mineral Metabolism With Heart Failure: the Multi-Ethnic Study of Atherosclerosis.

J Clin Endocrinol Metab 2020 04;105(4)

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

Background: Alterations in mineral metabolism, such as high phosphorus, high parathyroid hormone (PTH), and high fibroblast growth factor-23 (FGF-23) have been identified as potential risk factors for heart failure (HF). Important differences in the prevalence of mineral metabolism abnormalities and in the risk of HF have been reported across race and/or ethnic groups. In this study, we evaluated whether the associations of mineral metabolism markers with HF differed by race and/or ethnicity.

Methods: We included participants free of cardiovascular disease from the Multi-Ethnic Study of Atherosclerosis to quantify rates of HF overall and across race and/or ethnic groups. Using Cox models, we tested associations of baseline higher phosphorus (>4 mg/dL), PTH greater than 65 pg/mL, and FGF-23 greater than 46.5 pg/mL with incident HF, and for interactions by race and/or ethnicity, adjusting for sociodemographic and cardiovascular risk factors.

Results: Among the 6413 participants, median follow-up time was 14.9 years. The incidence rate for HF was highest for African Americans and lowest for Chinese (4.71 and 2.42 per 1000 person-years, respectively). The prevalence of elevated PTH (18.8% vs 7.4%) but not FGF-23 (23.1% vs 28.8%) was higher in African Americans vs Whites. In multivariable models, the associations of elevated PTH (hazard ratio [HR] 1.50, 95% CI: 1.13-1.99) and FGF-23 (HR 1.37, 95% CI: 1.07-1.75) with incident HF were statistically significant. However, the interactions by race and/or ethnicity were not statistically significant.

Conclusions: In a multiethnic population, higher PTH and FGF-23 were associated with risk of HF in African American and Hispanic individuals. There is no evidence that race and/or ethnicity modifies the association of altered mineral metabolism with risk of HF.
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http://dx.doi.org/10.1210/clinem/dgz218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064305PMC
April 2020

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

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

Effects of Calcium, Magnesium, and Potassium Concentrations on Ventricular Repolarization in Unselected Individuals.

J Am Coll Cardiol 2019 06;73(24):3118-3131

Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California.

Background: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.

Objectives: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.

Methods: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.

Results: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.

Conclusions: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.
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http://dx.doi.org/10.1016/j.jacc.2019.03.519DOI Listing
June 2019

Comparative Safety of Phosphate Binders Without Proven Efficacy-How Did We Get Here?

JAMA Intern Med 2019 06;179(6):749-750

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

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http://dx.doi.org/10.1001/jamainternmed.2019.0043DOI Listing
June 2019

Biomarkers of mineral metabolism and progression of aortic valve and mitral annular calcification: The Multi-Ethnic Study of Atherosclerosis.

Atherosclerosis 2019 06 13;285:79-86. Epub 2019 Apr 13.

Cardiology Section, San Francisco Veterans Affairs Health Care System and Departments of Medicine, Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA. Electronic address:

Background And Aims: Previous research has implicated dysregulation of phosphate metabolism and calcium-phosphate solubilization in cardiovascular calcification, but epidemiologic studies evaluating longitudinal associations with valvular or annular calcification by computed tomography (CT), a highly sensitive imaging modality, are lacking. Our primary aim was to investigate the associations of mineral biomarkers with incidence and progression of aortic valve calcification (AVC) and mitral annular calcification (MAC).

Methods: We evaluated the associations of serum FGF-23 (n = 6547 participants), phosphate (n = 6547), and fetuin-A (n = 2550) measured at baseline in the community-based Multi-Ethnic Study of Atherosclerosis with AVC and MAC on CT performed at baseline and at a median of 2.4 (1.6, 3.1) years later. We used linear mixed-effects models to account simultaneously for prevalence, incidence and progression of AVC and MAC.

Results: After adjustment for demographic and clinical characteristics, a significant association was documented for FGF-23 with accelerated annual progression of MAC (2.83 Agatston units (AU), 95% CI = 0.49, 5.17 AU, per standard deviation (18.46 pg/mL) of FGF-23), but this was not seen for phosphate or fetuin-A. None of these biomarkers was associated with accelerated annual progression of AVC.

Conclusions: This study provides evidence relating serum FGF-23 to accelerated annual MAC progression. Whether this mineral regulator is a risk marker or is involved in pathogenesis merits further investigation.
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http://dx.doi.org/10.1016/j.atherosclerosis.2019.04.215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536341PMC
June 2019

Mineral Metabolism Disturbances and Arteriovenous Fistula Maturation.

Eur J Vasc Endovasc Surg 2019 May 15;57(5):719-728. Epub 2019 Apr 15.

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

Background: The arteriovenous fistula (AVF) is central to haemodialysis treatment, but up to half of surgically created AVF fail to mature. Chronic kidney disease often leads to mineral metabolism disturbances that may interfere with AVF maturation through adverse vascular effects. This study tested associations between mineral metabolism markers and vein histology at AVF creation and unassisted and overall clinical AVF maturation.

Methods: Concentrations of fibroblast growth factor 23, parathyroid hormone, calcium, phosphate, and vitamin D metabolites: 1,25(OH)D, 24,25(OH)D, 25(OH)D, and bioavailable 25(OH)D were measured in pre-operative serum samples from 562 of 602 participants in the Haemodialysis Fistula Maturation Study, a multicentre, prospective cohort study of patients undergoing surgical creation of an autologous upper extremity AVF. Unassisted and overall AVF maturation were ascertained for 540 and 527 participants, respectively, within nine months of surgery or four weeks of dialysis initiation. Study personnel obtained vein segments adjacent to the portion of the vein used for anastomosis, which were processed, embedded, and stained for measurement of neointimal hyperplasia, calcification, and collagen deposition in the medial wall.

Results: Participants in this substudy were 71% male, 43% black, and had a mean age of 55 years. Failure to achieve AVF maturation without assistance occurred in 288 (53%) participants for whom this outcome was determined. In demographic and further adjusted models, mineral metabolism markers were not significantly associated with vein histology characteristics, unassisted AVF maturation failure, or overall maturation failure, other than a biologically unexplained association of higher 24,25(OH)D with overall failure. This exception aside, associations were non-significant for continuous and categorical analyses and relevant subgroups.

Conclusions: Serum concentrations of measured mineral metabolites were not substantially associated with major histological characteristics of veins in patients undergoing AVF creation surgery, or with AVF maturation failure, suggesting that efforts to improve AVF maturation rates should increase attention to other processes such as vein mechanics, anatomy, and cellular metabolism among end stage renal disease patients.
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http://dx.doi.org/10.1016/j.ejvs.2019.01.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259372PMC
May 2019
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