Publications by authors named "Ronit Katz"

256 Publications

Triglyceride-Rich Lipoproteins, Apolipoproteins, and Atherosclerotic Cardiovascular Events Among Patients with Diabetes Mellitus and End-Stage Renal Disease on Hemodialysis.

Am J Cardiol 2021 Aug 6;152:63-68. Epub 2021 Jun 6.

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

Hypertriglyceridemia may be implicated in the high atherosclerotic cardiovascular disease (ASCVD) risk experienced by patients with end-stage renal disease (ESRD). In this post-hoc analysis of the "Die Deutsche Diabetes Dialyse Studie (4D)" clinical trial, we examined incident ASCVD events, defined as myocardial infarction, ischemic stroke, or a coronary revascularization procedure, among 1255 participants with type 2 diabetes and ESRD treated with hemodialysis. Cox-regression methods were used to evaluate the association of triglycerides, very-low density lipoprotein cholesterol (VLDL-C), and apolipoproteins B (Apo B) and C-III (Apo C-III) with ASCVD. During a median follow-up time of 2.3 years, 340 (27%) participants experienced an ASCVD event. Higher concentrations of triglycerides were not associated with ASCVD risk: Hazard ratio (HR) 0.95; 95% CI (0.83, 1.10) per doubling concentration. Similarly, VLDL-C HR 1.01; 95% CI (0.90, 1.13); Apo B HR 1.04; 95% CI (0.93, 1.16); and Apo C-III HR 0.97; 95% CI (0.86, 1.09) (per one standard deviation higher concentrations), were not associated with ASCVD events. These associations did not differ by allocation to treatment to atorvastatin or by concentrations of markers of inflammation or malnutrition. In conclusion, we found no evidence that triglycerides, triglyceride-rich lipoproteins, or apolipoproteins B or C-III were associated with risk of ASCVD events among patients with type 2 diabetes and ESRD on hemodialysis. These results suggest that lowering triglycerides may not decrease atherosclerotic cardiovascular risk in this population.
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http://dx.doi.org/10.1016/j.amjcard.2021.04.023DOI Listing
August 2021

Biomarkers of Kidney Tubule Health, CKD Progression, and Acute Kidney Injury in SPRINT (Systolic Blood Pressure Intervention Trial) Participants.

Am J Kidney Dis 2021 Apr 20. Epub 2021 Apr 20.

Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, CA; Division of Nephrology and Hypertension, Department of Medicine, University of California-San Diego, San Diego, CA; Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California-San Diego, San Diego, CA. Electronic address:

Rationale & Objective: The Systolic Blood Pressure Intervention Trial (SPRINT) compared the effect of intensive versus standard systolic blood pressure targets on cardiovascular morbidity and mortality. In this ancillary study, we evaluated the use of exploratory factor analysis (EFA) to combine biomarkers of kidney tubule health in urine and plasma and then study their role in longitudinal estimated glomerular filtration rate (eGFR) change and risk of acute kidney injury (AKI).

Study Design: Observational cohort nested in a clinical trial.

Setting & Participants: 2,351 SPRINT participants with eGFR < 60 mL/min/1.73 m at baseline.

Exposure: Levels of neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), chitinase-3-like protein (YKL-40), kidney injury molecule 1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), α-microglobulin (A1M) and β-microglobulin (B2M), uromodulin (UMOD), fibroblast growth factor 23 (FGF-23), and intact parathyroid hormone (PTH).

Outcome: Longitudinal changes in eGFR and risk of AKI.

Analytical Approach: We performed EFA to capture different tubule pathophysiologic processes. We used linear mixed effects models to evaluate the association of each factor with longitudinal changes in eGFR. We evaluated the association of the tubular factors scores with AKI using Cox proportional hazards regression.

Results: From 10 biomarkers, EFA generated 4 factors reflecting tubule injury/repair (NGAL, IL-18, and YKL-40), tubule injury/fibrosis (KIM-1 and MCP-1), tubule reabsorption (A1M and B2M), and tubule reserve/mineral metabolism (UMOD, FGF-23, and PTH). Each 1-SD higher tubule reserve/mineral metabolism factor score was associated with a 0.58% (95% CI, 0.39%-0.67%) faster eGFR decline independent of baseline eGFR and albuminuria. Both the tubule injury/repair and tubule injury/fibrosis factors were independently associated with future risk of AKI (per 1 SD higher, HRs of 1.18 [95% CI, 1.10-1.37] and 1.23 [95% CI, 1.02-1.48], respectively).

Limitations: The factors require validation in other settings.

Conclusions: EFA allows parsimonious subgrouping of biomarkers into factors that are differentially associated with progressive eGFR decline and AKI. These subgroups may provide insights into the pathological processes driving adverse kidney outcomes.
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http://dx.doi.org/10.1053/j.ajkd.2021.01.021DOI Listing
April 2021

Stroke, Timing of Atrial Fibrillation Diagnosis, and Risk of Death.

Neurology 2021 03 3;96(12):e1655-e1662. Epub 2021 Feb 3.

From the Division of Cardiovascular Medicine, Department of Medicine (A.B., Y.B., M.C.H., J.A., D.J.C., N.C., S.D., A.E.E., D.S.F., F.C.G., R.K., J.J.L., D.L., S.N., M.P.R., P.S., R.D.S., G.E.S., F.M., R.D.), and Department of Neurology (S.R.M., S.E.K.), Perelman School of Medicine at the University of Pennsylvania School of Medicine, Philadelphia; Department of Biostatistics (R.K.), University of Washington, Seattle; and Division of Cardiology (P.J.P.), St. Vincent Medical Group, Indianapolis, IN.

Objective: To evaluate the prognosis of patients with ischemic stroke according to the timing of an atrial fibrillation (AF) diagnosis, we created an inception cohort of incident stroke events and compared the risk of death between patients with stroke with (1) sinus rhythm, (2) known AF (KAF), and (3) AF diagnosed after stroke (AFDAS).

Methods: We used the Penn AF Free study to create an inception cohort of patients with incident stroke. Mortality events were identified after linkage with the National Death Index through June 30, 2017. We also evaluated initiation of anticoagulants and antiplatelets across the study duration. Cox proportional hazards models evaluated associations between stroke subtypes and death.

Results: We identified 1,489 individuals who developed an incident ischemic stroke event: 985 did not develop AF at any point during the study period, 215 had KAF before stroke, 160 had AF detected ≤6 months after stroke, and 129 had AF detected >6 months after stroke. After a median follow-up of 4.9 years (interquartile range 1.9-6.8), 686 deaths occurred. The annualized mortality rate was 8.8% in the stroke, no AF group; 12.2% in the KAF group; 15.8% in the AFDAS ≤6 months group; and 12.7% in the AFDAS >6 months group. Patients in the AFDAS ≤6 months group had the highest independent risk of all-cause mortality even after multivariable adjustment for demographics, clinical risk factors, and the use of antithrombotic therapies (hazard ratio 1.62 [1.22-2.14]). Compared to the stroke, no AF group, those with KAF had a higher mortality risk that was rendered nonsignificant after adjustment.

Conclusions: The AFDAS group had the highest risk of death, which was not explained by comorbidities or use of antithrombotic therapies.
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http://dx.doi.org/10.1212/WNL.0000000000011633DOI Listing
March 2021

Amniotic fluid interleukin 6 and interleukin 8 are superior predictors of fetal lung injury compared with maternal or fetal plasma cytokines or placental histopathology in a nonhuman primate model.

Am J Obstet Gynecol 2021 07 4;225(1):89.e1-89.e16. Epub 2021 Jan 4.

Department of Obstetrics and Gynecology and Global Health, University of Washington, Seattle, WA; Center for Innate Immunity and Immune Disease, University of Washington, Seattle, WA; Center for Emerging and Re-emerging Infectious Diseases, University of Washington, Seattle, WA; Sahlgrenska Academy, University of Gothenburg, Sweden. Electronic address:

Background: Intra-amniotic infection or inflammation is common in early preterm birth and associated with substantial neonatal lung morbidity owing to fetal exposure to proinflammatory cytokines and infectious organisms. Amniotic fluid interleukin 8, a proinflammatory cytokine, was previously correlated with the development of neonatal bronchopulmonary dysplasia, but whether amniotic fluid cytokines or placental pathology more accurately predicts neonatal lung pathology and morbidity is unknown. We have used a pregnant nonhuman primate model of group B Streptococcus infection to study the pathogenesis of intra-amniotic infection, bacterial invasion of the amniotic cavity and fetus, and microbial-host interactions. In this nonhuman primate model, we have studied the pathogenesis of group B Streptococcus strains with differing potential for virulence, which has resulted in a spectrum of intra-amniotic infection and fetal lung injury that affords the opportunity to study the inflammatory predictors of fetal lung pathology and injury.

Objective: This study aimed to determine whether fetal lung injury is best predicted by placental histopathology or the cytokine response in amniotic fluid or maternal plasma.

Study Design: Chronically catheterized pregnant monkeys (Macaca nemestrina, pigtail macaque) at 116 to 125 days gestation (term at 172 days) received a choriodecidual inoculation of saline (n=5), weakly hemolytic group B Streptococcus strain (n=5, low virulence), or hyperhemolytic group B Streptococcus strain (n=5, high virulence). Adverse pregnancy outcomes were defined as either preterm labor, microbial invasion of the amniotic cavity, or development of the fetal inflammatory response syndrome. Amniotic fluid and maternal and fetal plasma samples were collected after inoculation, and proinflammatory cytokines (tumor necrosis factor alpha, interleukin beta, interleukin 6, interleukin 8) were measured by a multiplex assay. Cesarean delivery was performed at the time of preterm labor or within 1 week of inoculation. Fetal necropsy was performed at the time of delivery. Placental pathology was scored in a blinded fashion by a pediatric pathologist, and fetal lung injury was determined by a semiquantitative score from histopathology evaluating inflammatory infiltrate, necrosis, tissue thickening, or collapse scored by a veterinary pathologist.

Results: The principal findings in our study are as follows: (1) adverse pregnancy outcomes occurred more frequently in animals receiving hyperhemolytic group B Streptococcus (80% with preterm labor, 80% with fetal inflammatory response syndrome) than in animals receiving weakly hemolytic group B Streptococcus (40% with preterm labor, 20% with fetal inflammatory response syndrome) and in controls (0% preterm labor, 0% fetal inflammatory response syndrome); (2) despite differences in the rate of adverse pregnancy outcomes and fetal inflammatory response syndrome, fetal lung injury scores were similar between animals receiving the weakly hemolytic group B Streptococcus strains and animals receiving the hyperhemolytic group B Streptococcus strains; (3) fetal lung injury score was significantly correlated with peak amniotic fluid cytokines interleukin 6 and interleukin 8 but not tumor necrosis factor alpha or interleukin 1 beta; and (4) fetal lung scores were poorly correlated with maternal and fetal plasma cytokine levels and placental pathology.

Conclusion: Amniotic fluid interleukin 6 and interleukin 8 levels were superior predictors of fetal lung injury than placental histopathology or maternal plasma cytokines. This evidence supports a role for amniocentesis in the prediction of neonatal lung morbidity owing to intra-amniotic infection, which cannot be provided by cytokine analysis of maternal plasma or placental histopathology.
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http://dx.doi.org/10.1016/j.ajog.2020.12.1214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254735PMC
July 2021

Characterizing TP53 mutations in ovarian carcinomas with and without concurrent BRCA1 or BRCA2 mutations.

Gynecol Oncol 2021 03 26;160(3):786-792. Epub 2020 Dec 26.

Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA.

Objectives: Mutations in the TP53 tumor suppressor gene are common in ovarian carcinoma (OC) but their impact on outcomes is controversial. We sought to define the relationship of TP53 mutations to cancer outcomes and their interactions with co-occurrent BRCA1 or BRCA2 (BRCA) mutations, comparing three different TP53 mutation classification schemes.

Methods: We performed next generation sequencing on 393 cases of OC prospectively followed for survival. TP53 mutations were classified according to three schemes termed Structural, Functional, and Hotspot. Mutation distribution was compared between cases with and without BRCA mutations. In a subset of 281 cases of high grade serous carcinoma (HGSC), overall survival was compared using Kaplan-Meier curves, logrank testing, and multivariate Cox regression analysis, both stratified and adjusted for BRCA mutation status. Multivariate logistic regression was used to analyze the effects of TP53 mutation type on platinum resistance.

Results: TP53 mutations were identified in 76.8% of the total cohort (n = 302/393) and 87.9% of HGSC (n = 247/281). Cases with BRCA mutations demonstrated significantly higher TP53 mutation frequency overall (n = 84/91, 92.3% vs. n = 218/302, 72.2%, p < 0.001). TP53 mutations were not associated with overall survival, even when stratified by BRCA mutation. TP53 mutations were associated with platinum sensitivity, even after adjusting for BRCA mutation status (OR 0.41, p = 0.048). The choice of TP53 mutation classification scheme was not found to alter any significant outcome.

Conclusions: BRCA mutations significantly co-occur with TP53 mutations. After adjusting for BRCA mutations, TP53 mutations are associated with platinum sensitivity, and this effect is not dependent on TP53 mutation type.
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http://dx.doi.org/10.1016/j.ygyno.2020.12.007DOI Listing
March 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

Estimated GFR Variability and Risk of Cardiovascular Events and Mortality in SPRINT (Systolic Blood Pressure Intervention Trial).

Am J Kidney Dis 2021 07 14;78(1):48-56. Epub 2020 Dec 14.

Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA; Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, CA. Electronic address:

Rationale And Objective: Although low estimated glomerular filtration rate (eGFR) is associated with cardiovascular disease (CVD) events and mortality, the clinical significance of variability in eGFR over time is uncertain. This study aimed to evaluate the associations between variability in eGFR and the risk of CVD events and all-cause mortality.

Study Design: Longitudinal analysis of clinical trial participants.

Settings And Participants: 7,520 Systolic Blood Pressure Intervention Trial (SPRINT) participants ≥50 year of age with 1 or more CVD risk factors.

Predictors: eGFR variability, estimated by the coefficient of variation of eGFR assessments at the 6th, 12th, and 18-month study visits.

Outcomes: The SPRINT primary CVD composite outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or CVD death) and all-cause mortality from month 18 to the end of follow-up.

Analytical Approach: Cox models were used to evaluate associations between eGFR variability and CVD outcomes and all-cause mortality. Models were adjusted for demographics, randomization arm, CVD risk factors, albuminuria, and eGFR at month 18.

Results: Mean age was 68 ± 9 years; 65% were men; and 58% were White. The mean eGFR was 73 ± 21 (SD) mL/min/1.73 m at 6 months. There were 370 CVD events and 154 deaths during a median follow-up of 2.4 years. Greater eGFR variability was associated with higher risk for all-cause mortality (hazard ratio [HR] per 1 SD greater variability, 1.29; 95% CI, 1.14-1.45) but not CVD events (HR, 1.05; 95% CI, 0.95-1.16) after adjusting for albuminuria, eGFR, and other CVD risk factors. Associations were similar when stratified by treatment arm and by baseline CKD status, when accounting for concurrent systolic blood pressure changes, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and diuretic medications during follow up.

Limitations: Persons with diabetes and proteinuria > 1 g/d were excluded.

Conclusions: In trial participants at high risk for CVD, greater eGFR variability was independently associated with all-cause mortality but not CVD events.
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http://dx.doi.org/10.1053/j.ajkd.2020.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200370PMC
July 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

Fibroblast growth factor 23 and cognitive impairment: The health, aging, and body composition study.

PLoS One 2020 11;15(12):e0243872. Epub 2020 Dec 11.

Tufts Medical Center, Boston, MA, United States of America.

Background: Concentrations of fibroblast growth factor 23 (FGF-23), a hormone that regulates phosphorus and vitamin D metabolism, increase as kidney function declines. Excess fibroblast growth factor 23 may impact brain function through promotion of vascular disease or through direct effects on neuronal tissue.

Methods: In the Healthy Aging and Body Composition Study, a longitudinal observational cohort of well-functioning older adults, intact serum FGF-23 was assayed in 2,738 individuals. Cognitive function was assessed at baseline and longitudinally at years 3, 5, and 8 by administration of the Modified Mini Mental State Examination (3MSE), a test of global cognitive function, and the Digit Symbol Substitution Test (DSST), a test primarily of executive function. The associations between FGF-23 and baseline cognitive function and incident cognitive impairment were evaluated using logistic and Poisson regression respectively, and were adjusted for demographics, baseline estimated glomerular filtration rate (eGFR), urine albumin/creatinine ratio, comorbidity, and other measures of mineral metabolism including soluble klotho.

Results: The mean (SD) age was 74(3) years, with 51% female, and 39% black. The median (25th, 75th) FGF-23 concentration was 47 pg/mL (37, 60). Three hundred ninety-two individuals had prevalent cognitive impairment by the 3MSE and 461 by the DSST. There was no observed association between FGF-23 and baseline cognitive function for either cognitive test. There were 277 persons with incident cognitive impairment by 3MSE, and 333 persons with incident cognitive impairment by DSST. In fully adjusted models, each two-fold higher concentration of baseline FGF-23 was not associated with incident cognitive impairment by the 3MSE (IRR = 1.02[0.88, 1.19] fully adjusted model) or by the DSST (IRR = 0.98 [0.84, 1.15]. We saw no difference when analyses were stratified by eGFR greater than or less than 60 ml/min/1.73m2.

Conclusion: Intact FGF-23 was not associated with baseline cognitive function or incident cognitive impairment in this cohort well-functioning older adults.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243872PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732072PMC
February 2021

Association of Non-Steroidal Anti-Inflammatory Drugs with Kidney Health in Ambulatory Older Adults.

J Am Geriatr Soc 2021 Mar 10;69(3):726-734. Epub 2020 Dec 10.

Kidney Health Research Collaborative, San Francisco VA Medical Center & University of California, San Francisco, San Francisco, California, USA.

Background/objectives: Non-steroidal anti-inflammatory drugs (NSAIDs) can cause kidney injury, especially in older adults. However, previously reported associations between NSAID use and kidney health outcomes are inconsistent and limited by reliance on serum creatinine-based GFR estimates. This analysis investigated the association of NSAID use with kidney damage in older adults using multiple kidney health measures.

Design: Cross-sectional and longitudinal analyses.

Setting: Multicenter, community-based cohort.

Participants: Two thousand nine hundred and ninty nine older adults in the Health ABC Study. A subcohort (n = 500) was randomly selected for additional biomarker measurements.

Exposure: Prescription and over-the-counter NSAID use ascertained by self-report.

Measurements: Baseline estimated glomerular filtration rate (eGFR) by cystatin C (cysC), urine albumin-to-creatinine ratio (ACR), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18) were measured in 2,999 participants; alpha-1 microglobulin (α1m), neutrophil gelatinase-associated lipocalin (NGAL), propeptide type III procollagen (PIIINP), and uromodulin (UMOD) were measured in 500 participants. GFR was estimated three times over 10 years and expressed as percent change per year.

Results: Participants had a mean age of 74 years, 51% were female, and 41% African-American. No eGFR differences were detected between NSAID users (n = 655) and non-users (n = 2,344) at baseline (72 ml/min/1.73 m in both groups). Compared to non-users, NSAID users had lower adjusted odds of having ACR greater than 30 mg/g (0.67; 95% confidence interval (CI) = 0.51-0.89) and lower mean urine IL-18 concentration at baseline (-11%; 95% CI = -4% to -18%), but similar mean KIM-1 (5%; 95% CI = -5% to 14%). No significant differences in baseline concentrations of the remaining urine biomarkers were detected. NSAID users and non-users did not differ significantly in the rate of eGFR decline (-2.2% vs -2.3% per year).

Conclusion: Self-reported NSAID use was not associated with kidney dysfunction or injury based on multiple measures, raising the possibility of NSAID use without kidney harm in ambulatory older adults. More research is needed to define safe patterns of NSAID consumption.
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http://dx.doi.org/10.1111/jgs.16961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021485PMC
March 2021

FGF23, Frailty, and Falls in SPRINT.

J Am Geriatr Soc 2021 Feb 1;69(2):467-473. Epub 2020 Dec 1.

University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Background/objectives: Chronic kidney disease (CKD) is associated with frailty. Fibroblast growth factor 23 (FGF23) is elevated in CKD and associated with frailty among non-CKD older adults and individuals with human immunodeficiency virus. Whether FGF23 is associated with frailty and falls in CKD is unknown.

Design: Cross-sectional and longitudinal observational study.

Setting: Systolic Blood Pressure Intervention Trial (SPRINT), a randomized trial evaluating standard (systolic blood pressure [SBP] <140 mm Hg) versus intensive (SBP <120 mm Hg) blood pressure lowering on cardiovascular and cognitive outcomes among older adults without diabetes mellitus.

Participants: A total of 2,376 participants with CKD (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m ).

Measurements: The exposure variable was intact FGF23. We used multinomial logistic regression to determine the cross-sectional association of intact FGF23 with frailty and Cox proportional hazards analysis to determine the longitudinal association with incident falls. Models were adjusted for demographics, comorbidities, randomization group, antihypertensives, eGFR, mineral metabolism markers, and frailty.

Results: After adjustment, the odds ratio for prevalent frailty versus non-frailty per twofold higher FGF23 was 1.34 (95% confidence interval [CI] = 1.01-1.77). FGF23 levels in the highest quartile versus the lowest quartile demonstrated more than a twofold increased fall risk (hazard ratio [HR] = 2.32; 95% CI = 1.26-4.26), and the HR per twofold higher FGF23 was 1.99 (95% CI = 1.48-2.68).

Conclusion: Among SPRINT participants with CKD, FGF23 was associated with prevalent frailty and falls.
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http://dx.doi.org/10.1111/jgs.16895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8031468PMC
February 2021

The Vitamin D Metabolite Ratio Is Independent of Vitamin D Binding Protein Concentration.

Clin Chem 2021 Jan;67(2):385-393

Division of Nephrology-Hypertension, University of California, San Diego, San Diego, CA.

Background: 25-Hydroxyvitamin D [25(OH)D] may be a poor marker of vitamin D status as it reflects differences in vitamin D binding protein (VDBP) between individuals. The vitamin D metabolite ratio [VMR, ratio of 24,25(OH)2D3 to 25(OH)D3] is a marker of vitamin D status that has been hypothesized to be independent of variability in VDBP. This hypothesis has not been directly evaluated.

Methods: We measured 25(OH)D3, 24,25(OH)2D3, 1,25(OH)2D3, and VDBP in 377 community-dwelling older adults that participated in the Health Aging and Body Composition Study. 24,25(OH)2D3 and 25(OH)D3 were used to calculate the VMR. We used linear regression to assess the relationship between VDBP with the VMR, 24,25(OH)2D3, 25(OH)D3, and 1,25(OH)2D3.

Results: Participants had mean age 75 ± 3 years, 52% were female, 40% were black, and 24% had chronic kidney disease. VDBP concentrations were associated with sex, serum albumin, and VDBP phenotype in multivariable models. In fully adjusted models, each 1% higher VDBP was associated with a 0.92%[95% CI(0.37,1.49%)], 0.76% (0.39, 1.13%), and 0.57% (0.29, 0.85%), higher 24,25(OH)2D3, 25(OH)D3, and 1,25(OH)2D3. The VMR was independent of VDBP concentration, [0.16%(-0.11, 0.44) higher VMR per 1% higher VDBP, P = .25].

Conclusions: The VMR was independent of VDBP concentration, whereas VDBP was strongly directly associated with the individual vitamin D metabolite concentrations. Prior studies evaluating only 25(OH)D3 may have been confounded by absence of data on VDBP status. The VMR may serve as an important biomarker of vitamin D status and clinical outcomes that can be utilized in populations with a large spectrum of VDBP concentrations.
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http://dx.doi.org/10.1093/clinchem/hvaa238DOI Listing
January 2021

FGF23 and Cause-Specific Mortality in Community-Living Individuals-The Health, Aging, and Body Composition Study.

J Am Geriatr Soc 2021 Mar 10;69(3):711-717. Epub 2020 Nov 10.

Division of Nephrology-Hypertension, University of California San Diego and Veteran Affairs San Diego Healthcare System, San Diego, California, USA.

Objectives: Fibroblast growth factor (FGF)-23 is a key regulator of mineral metabolism and has been linked with left ventricular hypertrophy in animal models. Most existing epidemiologic studies evaluated a C-terminal FGF23 assay which measures both the intact (active) hormone and inactive fragments. The relationship of intact FGF23 with cause-specific mortality is unknown.

Design: Prospective analyses of data from Health, Aging, & Body Composition (HABC) study.

Setting: Community-living adults aged 70 to 79 years with longitudinal follow up.
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http://dx.doi.org/10.1111/jgs.16910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175094PMC
March 2021

Total Cell-Free DNA Predicts Death and Infection Following Pediatric and Adult Heart Transplantation.

Ann Thorac Surg 2020 Oct 8. Epub 2020 Oct 8.

Herma Heart Center, Children's Wisconsin, and Medical College of Wisconsin, Milwaukee, WI. Electronic address:

Background: Elevated total cell-free DNA (TCF) concentration has been associated with critical illness in adults and elevated donor fraction (DF), the ratio of donor specific cell-free DNA to total cell-free DNA present in the recipient's plasma, is associated with rejection following cardiac transplantation. This study investigates relationships between TCF and clinical outcomes after heart transplantation.

Methods: A prospective, blinded, observational study of 87 heart transplantation recipients was performed. Samples were collected at transplantation, prior to endomyocardial biopsy, during treatment for rejection, and at hospital readmissions. Longitudinal clinical data were collected and entered into a RedCAP (Vanderbilt University) database. TCF and DF levels were correlated with endomyocardial biopsy and angiography results, as well as clinical outcomes. Logistic regression for modeling and repeated measures analysis using generalized linear modeling was used. The standard receiver operating characteristic curve, hazard ratios, and odds ratios were calculated.

Results: There were 257 samples from 87 recipients analyzed. TCF greater than 50 ng/mL were associated with increased mortality (P = .01, area under the curve 0.93, sensitivity 0.44, specificity 0.97) and treatment for infection (P < .005, area under the curve 0.68, sensitivity 0.45, specificity 0.96). Increased DF was not correlated with treatment for infection. DF was associated with rejection and cardiac allograft vasculopathy (P < .001), but TCF was not.

Conclusions: TCF elevation predicted death and treatment for infection. DF elevation predicted histopathologic acute rejection and cardiac allograft vasculopathy. Surveillance of TCF and DF levels may inform treatment after heart transplantation.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.006DOI Listing
October 2020

Intact and C-Terminal FGF23 Assays-Do Kidney Function, Inflammation, and Low Iron Influence Relationships With Outcomes?

J Clin Endocrinol Metab 2020 12;105(12)

Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, California.

Context: Higher fibroblast growth factor-23 (FGF23) concentrations are associated with heart failure and mortality in diverse populations, but the strengths of associations differ markedly depending up on which assay is used.

Objective: We sought to evaluate whether iron deficiency, inflammation, or kidney function account for differences in the strengths of associations between these 2 FGF23 assays with clinical outcomes.

Design: Case cohort study from the Cardiovascular Health Study.

Setting: A total of 844 community-dwelling individuals aged 65 years or older with and without chronic kidney disease were followed for 10 years.

Outcomes: Outcomes included death, incident heart failure (HF), and incident myocardial infarction (MI). Exposure was baseline intact and C-terminal FGF23. Using modified Cox models, adjusting sequentially we tested whether observed associations of each assay with outcomes were attenuated by iron status, inflammation, kidney function, or their combinations.

Results: FGF23 measured by either assay was associated with mortality in unadjusted analysis (intact FGF23 hazard ratio [HR] per 2-fold higher 1.45; 95% CI, 1.25-1.68; C-terminal FGF23 HR 1.38; 95% CI, 1.26-1.50). Adjustment for kidney function completely attenuated associations of intact FGF23 with mortality (HR 1.00; 95% CI, 0.85-1.17), but had much less influence on the association of C-terminal FGF23, for which results remained significant after adjustment (HR 1.15; 95% CI, 1.04-1.28). Attenuation was much less with adjustment for iron status or inflammation. Results were similar for the HF end point. Neither C-terminal or intact FGF23 was associated with MI risk.

Conclusions: The relationship of FGF23 with clinical end points is markedly different depending on the type of FGF23 assay used. The associations of biologically active FGF23 with clinical end points may be confounded by kidney disease, and thus much weaker than previously thought.
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http://dx.doi.org/10.1210/clinem/dgaa665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571450PMC
December 2020

Tubular Biomarkers and Chronic Kidney Disease Progression in SPRINT Participants.

Am J Nephrol 2020 9;51(10):797-805. Epub 2020 Sep 9.

Department of Medicine, University of California, San Diego, California, USA.

Background: Kidney tubular atrophy on biopsy is a strong predictor of chronic kidney disease (CKD) progression, but tubular health is poorly quantified by traditional measures including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of impaired tubule function would be associated with faster eGFR declines in persons with CKD.

Methods: We measured baseline urine concentrations of uromodulin, β2-microglobulin (β2m), and α1-microglobulin (α1m) among 2,428 participants of the Systolic Blood Pressure Intervention Trial with an eGFR <60 mL/min/1.73 m2. We used linear mixed models to evaluate biomarker associations with annualized relative change in eGFR, stratified by randomization arm.

Results: At baseline, the mean age was 73 ± 9 years and eGFR was 46 ± 11 mL/min/1.73 m2. In the standard blood pressure treatment arm, each 2-fold higher urinary uromodulin was associated with slower % annual eGFR decline (0.34 [95% CI: 0.08, 0.60]), whereas higher urinary β2m was associated with faster % annual eGFR decline (-0.10 [95% CI: -0.18, -0.02]) in multivariable-adjusted models including baseline eGFR and albuminuria. Associations were weaker and did not reach statistical significance in the intensive blood pressure treatment arm for either uromodulin (0.11 [-0.13, 0.35], p value for interaction by treatment arm = 0.045) or β2m (-0.01 [-0.08, 0.08], p value for interaction = 0.001). Urinary α1m was not independently associated with eGFR decline in the standard (0.01 [-0.22, 0.23]) or intensive (0.03 [-0.20, 0.25]) arm.

Conclusions: Among trial participants with hypertension and CKD, baseline measures of tubular function were associated with subsequent declines in kidney function, although these associations were diminished by intensive blood pressure control.
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http://dx.doi.org/10.1159/000509978DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606644PMC
September 2020

Association of Genotypes With Measures of Microvascular and Endothelial Function, and Blood Pressure in MESA.

J Am Heart Assoc 2020 09 27;9(17):e017039. Epub 2020 Aug 27.

Kidney Health Research Collaborative Department of Medicine University of California San Francisco CA.

Background high-risk genotypes are associated with increased risk for hypertension-attributed kidney disease among Black adults in the United States. Biopsy studies show differences in kidney vasculature by status; less is known about the variants' associations with systemic vascular and endothelial function. Whether risk variants are associated with blood pressure (BP) is also uncertain. Methods and Results Using linear regression, we examined cross-sectional associations of risk genotypes (high=2 risk alleles, low=0 or 1 risk allele) with subclinical measures of vascular function (small arterial elasticity, n=1586; large arterial elasticity, n=1586; ascending aortic distensibility, n=985) and endothelial function (flow-mediated dilation, n=777). Using linear mixed-effects models, we studied longitudinal associations of risk genotypes with BP (n=1619), adjusting for age, sex, and African ancestry. Among 1619 (12% high-risk) Black participants in MESA (Multi-Ethnic Study of Atherosclerosis), mean age was 62 years old, 58% had hypertension, and mean systolic BP was 131 mm Hg at baseline. At examination 1 (2000-2002), there was no significant difference in small arterial elasticity, large arterial elasticity, ascending aortic distensibility, or flow-mediated dilation in participants with high- versus low-risk genotypes (>0.05 for all). Over a mean follow-up of 7.8 years, relative annual changes in systolic and diastolic BP and pulse pressure did not differ significantly by risk status (between-group differences of -0.20, -0.14, and -0.25, respectively; >0.05 for all). Conclusions Among Black participants in MESA, high-risk genotypes were not associated with subclinical vascular and endothelial function or BP trajectories. The relationship of with kidney disease may be intrinsic to the kidney rather than through peripheral effects on systemic vasculature or BP.
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http://dx.doi.org/10.1161/JAHA.120.017039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660790PMC
September 2020

ACE Inhibitor/Angiotensin Receptor Blocker Use Patterns in Advanced CKD and Risk of Kidney Failure and Death.

Kidney Med 2020 May-Jun;2(3):248-257. Epub 2020 Feb 21.

Division of Nephrology, University of Washington, Seattle, WA.

Rationale & Objective: The use of renin-angiotensin system (RAS) inhibitors is standard of care in people with early to moderate chronic kidney disease (CKD). Less is known regarding the efficacy of RAS inhibitors in very advanced CKD. In this study, we describe patterns of use of RAS inhibitors and associations of these patterns of use with risk for CKD progression and mortality in patients with advanced CKD.

Study Design: Propensity-matched cohort study.

Settings & Participants: We identified 678 participants who were enrolled in the multicenter Chronic Renal Insufficiency Cohort (CRIC) Study with estimated glomerular filtration rates (eGFRs) < 30 mL/min/1.73 m at the baseline visit.

Exposure: Use of RAS inhibitors within the first year after the baseline visit, characterized by 4 patterns of use: never users, always users, dynamic users, and new users.

Outcomes: Progression to end-stage renal disease (ESRD) and all-cause mortality.

Analytical Approach: We generated propensity scores and matched participants in the always users group with a 1:1 ratio with a participant from the other 3 groups, matching by age, sex, race, diabetes, hypertension, systolic blood pressure, eGFR, urinary protein-creatinine ratio, and serum potassium level. Cox models were used to test the association of patterns of RAS inhibitor use with risk for kidney failure and death.

Results: Of the 678 participants with eGFRs < 30 mL/min/1.73 m, 57% were identified as always users of RAS inhibitors during the 1 year, 23% as never users, 13% as dynamic users, and 7% as new users. We found no differences in risk for ESRD across patterns of RAS inhibitor use (never users [HR, 1.09; 95% CI, 0.71-1.67], dynamic users [HR, 1.46; 95% CI, 0.83-2.55], new users [HR, 0.78; 95% CI, 0.33-1.84] vs the always users reference group). Similarly, there was no association of patterns of RAS inhibitor use with death (never users [HR, 1.02; CI, 0.74-1.40], dynamic users [HR, 1.23; 95% CI, 0.80-1.90], new users [HR, 1.10; 95% CI, 0.63-1.92] vs always users).

Limitations: Observational study.

Conclusions: Use of RAS inhibitors in patients with eGFRs < 30 mL/min/1.73 m is heterogeneous.We found no difference in risk for progression to ESRD or mortality across patterns of RAS inhibitor use. Further research is required to identify optimal prescribing strategies of RAS inhibitors during advanced stages of CKD.
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http://dx.doi.org/10.1016/j.xkme.2019.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380396PMC
February 2020

The Difference Between Cystatin C- and Creatinine-Based Estimated GFR and Incident Frailty: An Analysis of the Cardiovascular Health Study (CHS).

Am J Kidney Dis 2020 12 16;76(6):896-898. Epub 2020 Jul 16.

Division of Nephrology-Hypertension, University of California San Diego, San Diego, CA; Veterans Affairs San Diego Healthcare System, San Diego, CA.

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http://dx.doi.org/10.1053/j.ajkd.2020.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967899PMC
December 2020

The Difference Between Cystatin C- and Creatinine-Based Estimated GFR and Associations With Frailty and Adverse Outcomes: A Cohort Analysis of the Systolic Blood Pressure Intervention Trial (SPRINT).

Am J Kidney Dis 2020 12 16;76(6):765-774. Epub 2020 Jul 16.

Division of Nephrology-Hypertension, University of California San Diego, San Diego, CA; Veterans Affairs San Diego Healthcare System, San Diego, CA.

Rationale & Objective: In prior research and in practice, the difference between estimated glomerular filtration rate (eGFR) calculated from cystatin C level and eGFR calculated from creatinine level has not been assessed for clinical significance and relevance. We evaluated whether these differences contain important information about frailty.

Study Design: A cohort analysis of the Systolic Blood Pressure Intervention Trial (SPRINT).

Setting & Participants: 9,092 hypertensive SPRINT participants who had baseline measurements of serum creatinine, cystatin C, and frailty.

Exposure: eGFRs calculated using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations (eGFR and eGFR), and eGFR, calculated as eGFR-eGFR.

Outcomes: A validated 35-item frailty index that included questionnaire data for general and physical health, limitations of activities, pain, depression, sleep, energy level, self-care, and smoking status, as well as medical history, cognitive assessment, and laboratory data. We defined frailty as frailty index score>0.21 (range, 0-1). The incidence of injurious falls, hospitalizations, cardiovascular events, and mortality was also recorded.

Analytical Approach: We used logistic regression to model the cross-sectional association of baseline eGFR with frailty among all SPRINT participants. Adjusted proportional hazards regression was used to evaluate the association of eGFR with adverse outcomes and mortality.

Results: Mean age was 68±9 (SD) years, mean eGFR and eGFR were 73±23 and 72±20mL/min/1.73m, and mean eGFR was 0.5±15mL/min/1.73m. In adjusted models, each 1-SD higher eGFR was associated with 24% lower odds of prevalent frailty (OR, 0.76; 95% CI, 0.71-0.81), as well as with lower incidence rate of injurious falls (HR, 0.84; 95% CI, 0.77-0.92), hospitalization (HR, 0.91; 95% CI, 0.88-0.95), cardiovascular events (HR, 0.89; 95% CI, 0.81-0.97), and all-cause mortality (HR, 0.71; 95% CI, 0.63-0.82); P<0.01.

Limitations: Gold-standard measure of kidney function and assessment of muscle mass were not available.

Conclusions: The difference between eGFR and eGFR is associated with frailty and health status. Positive eGFR is strongly associated with lower risks for longitudinal adverse outcomes and mortality, even after adjusting for chronic kidney disease stage and baseline frailty.
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http://dx.doi.org/10.1053/j.ajkd.2020.05.017DOI Listing
December 2020

From Local Explanations to Global Understanding with Explainable AI for Trees.

Nat Mach Intell 2020 Jan 17;2(1):56-67. Epub 2020 Jan 17.

Paul G. Allen School of Computer Science and Engineering, University of Washington.

Tree-based machine learning models such as random forests, decision trees, and gradient boosted trees are popular non-linear predictive models, yet comparatively little attention has been paid to explaining their predictions. Here, we improve the interpretability of tree-based models through three main contributions: 1) The first polynomial time algorithm to compute optimal explanations based on game theory. 2) A new type of explanation that directly measures local feature interaction effects. 3) A new set of tools for understanding global model structure based on combining many local explanations of each prediction. We apply these tools to three medical machine learning problems and show how combining many high-quality local explanations allows us to represent global structure while retaining local faithfulness to the original model. These tools enable us to i) identify high magnitude but low frequency non-linear mortality risk factors in the US population, ii) highlight distinct population sub-groups with shared risk characteristics, iii) identify non-linear interaction effects among risk factors for chronic kidney disease, and iv) monitor a machine learning model deployed in a hospital by identifying which features are degrading the model's performance over time. Given the popularity of tree-based machine learning models, these improvements to their interpretability have implications across a broad set of domains.
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http://dx.doi.org/10.1038/s42256-019-0138-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7326367PMC
January 2020

Biomarkers of Bone Turnover Identify Subsets of Chronic Kidney Disease Patients at Higher Risk for Fracture.

J Clin Endocrinol Metab 2020 08;105(8)

Division of Nephrology-Hypertension, Department of Medicine, School of Medicine, University of California, San Diego, La Jolla, California.

Background: We sought to identify biomarkers that indicate low turnover on bone histomorphometry in chronic kidney disease (CKD) patients, and subsequently determined whether this panel identified differential risk for fractures in community-dwelling older adults.

Methods: Among CKD patients who underwent iliac crest bone biopsies and histomorphometry, we evaluated candidate biomarkers to differentiate low turnover from other bone disease. We applied this biomarker panel to 641 participants in the Health Aging and Body Composition Study (Health ABC) study with estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2 who were followed for fracture. Cox proportional hazards models evaluated the association of bone mineral density (BMD) with fracture risk and determined whether biomarker-defined low bone turnover modified fracture risk at any level of BMD.

Results: In 39 CKD patients age 64 ± 13 years, 85% female, with mean eGFR 37 ± 14 mL/min/1.73 m2 who underwent bone biopsy, lower fibroblast growth factor (FGF)-23, higher ɑ-Klotho, and lower parathyroid hormone (PTH) indicated low bone turnover in accordance with bone histomorphometry parameters (individual area under the curve = 0.62, 0.73, and 0.55 respectively; sensitivity = 22%, specificity = 100%). In Health ABC, 641 participants with CKD were age 75 ± 3 years , 49% female, with mean eGFR 48 ± 10 mL/min/1.73 m2. For every SD lower hip BMD at baseline, there was an 8-fold higher fracture risk in individuals with biomarker-defined low turnover (hazard ratio 8.10 [95% CI, 3.40-19.30]) vs a 2-fold higher risk in the remaining individuals (hazard ratio 2.28 [95% CI, 1.69-3.08]) (Pinteraction = .082).

Conclusions: In CKD patients who underwent bone biopsy, lower FGF-23, higher ɑ-Klotho, and lower PTH together had high specificity for identifying low bone turnover. When applied to older individuals with CKD, BMD was more strongly associated with fracture risk in those with biomarker-defined low turnover.
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http://dx.doi.org/10.1210/clinem/dgaa317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340189PMC
August 2020

Fibroblast Growth Factor 23 and Blood Pressure in Older Adults: The Health, Aging, and Body Composition Study.

Hypertension 2020 07 18;76(1):236-243. Epub 2020 May 18.

University of Alabama at Birmingham (O.M.G.).

FGF-23 (fibroblast growth factor 23) regulates phosphorus and vitamin D. Elevated FGF-23 is associated with incident hypertension in young- and middle-aged adults, but there is limited data in older adults. Serum FGF-23 was measured using an intact ELISA assay in 2496 participants of the Healthy Aging and Body Composition Study. The association between FGF-23 and prevalent hypertension (self-reported and confirmed by use of antihypertensive medications) and number of antihypertensive medications was determined. The associations between FGF-23 and incident hypertension, and diastolic and systolic blood pressure trajectories were evaluated over 10 years. Models were adjusted for demographics, estimated glomerular filtration rate and albuminuria, cardiovascular disease risk factors, and measures of mineral metabolism. The mean (SD) age was 75 (3) years, with 51% women, and 40% black participants. The prevalence of hypertension at baseline was 75% and the mean systolic and diastolic blood pressures were 134 (21) mm Hg and 70 (12) mm Hg, respectively. The majority of participants without hypertension at baseline developed incident hypertension (576 of 1109 or 52%). In adjusted models, each 2-fold higher FGF-23 was associated with prevalent baseline hypertension (odds ratio=1.46 [1.24-1.73]) and greater number of blood pressure medications (IRR=1.14 [1.08-1.21]) but not with baseline diastolic or systolic blood pressure. In fully adjusted longitudinal analyses, a 2-fold higher FGF-23 was associated with incident hypertension (hazard ratio=1.18 [1.03-1.36]) and worsening systolic blood pressures (β=0.24 [0.08-0.40] mm Hg per year increase), but not with diastolic blood pressures (β=0.04 [-0.04 to 0.12] mm Hg per year increase). Higher FGF-23 concentrations are associated with prevalent and incident hypertension as well as rising systolic blood pressures in community-living older adults.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289679PMC
July 2020

Urine Markers of Kidney Tubule Cell Injury and Kidney Function Decline in SPRINT Trial Participants with CKD.

Clin J Am Soc Nephrol 2020 03 28;15(3):349-358. Epub 2020 Feb 28.

Kidney Health Research Collaborative, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, California.

Background And Objectives: eGFR and albuminuria primarily reflect glomerular function and injury, whereas tubule cell atrophy and interstitial fibrosis on kidney biopsy are important risk markers for CKD progression. Kidney tubule injury markers have primarily been studied in hospitalized AKI. Here, we examined the association between urinary kidney tubule injury markers at baseline with subsequent loss of kidney function in persons with nondiabetic CKD who participated in the Systolic Blood Pressure Intervention Trial (SPRINT).

Design, Setting, Participants, & Measurements: Among 2428 SPRINT participants with CKD (eGFR<60 ml/min per 1.73 m) at baseline, we measured urine markers of tubule injury (IL-18, kidney injury molecule-1 [KIM-1], neutrophil gelatinase-associated lipocalin [NGAL]), inflammation (monocyte chemoattractant protein-1 [MCP-1]), and repair (human cartilage glycoprotein-40 [YKL-40]). Cox proportional hazards models evaluated associations of these markers with the kidney composite outcome of 50% eGFR decline or ESKD requiring dialysis or kidney transplantation, and linear mixed models evaluated annualized change in eGFR.

Results: Mean participant age was 73±9 (SD) years, 60% were men, 66% were white, and mean baseline eGFR was 46±11 ml/min per 1.73 m. There were 87 kidney composite outcome events during a median follow-up of 3.8 years. Relative to the respective lowest quartiles, the highest quartiles of urinary KIM-1 (hazard ratio, 2.84; 95% confidence interval [95% CI], 1.31 to 6.17), MCP-1 (hazard ratio, 2.43; 95% CI, 1.13 to 5.23), and YKL-40 (hazard ratio, 1.95; 95% CI, 1.08 to 3.51) were associated with higher risk of the kidney composite outcome in fully adjusted models including baseline eGFR and urine albumin. In linear analysis, urinary IL-18 was the only marker associated with eGFR decline (-0.91 ml/min per 1.73 m per year for highest versus lowest quartile; 95% CI, -1.44 to -0.38), a finding that was stronger in the standard arm of SPRINT.

Conclusions: Urine markers of tubule cell injury provide information about risk of subsequent loss of kidney function, beyond the eGFR and urine albumin.
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http://dx.doi.org/10.2215/CJN.02780319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057300PMC
March 2020

Glucose time in range and peripheral neuropathy in type 2 diabetes mellitus and chronic kidney disease.

BMJ Open Diabetes Res Care 2020 01;8(1)

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

​OBJECTIVE: Compared with hemoglobin A1c (HbA1c), continuous glucose monitoring (CGM) may better capture risk of diabetes complications in patients with chronic kidney disease (CKD), including diabetic peripheral neuropathy (DPN). We hypothesized that glucose time in range (TIR), measured by CGM, is associated with DPN symptoms among participants with type 2 diabetes mellitus (type 2 DM) and moderate-to-severe CKD. ​RESEARCH DESIGN AND METHODS: We enrolled 105 people with type 2 DM treated with insulin or sulfonylurea, 81 participants with CKD (estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m) and 24 matched control participants with eGFR ≥60 mL/min/1.73 m. Each participant wore a CGM for two 6-day periods. Calculated glycemic measures included TIR (glucose 70-180 mg/dL) and glucose management indicator (GMI). DPN symptoms were assessed using the Michigan Neuropathy Screening Instrument (MNSI) questionnaire, with a positive MNSI score defined as ≥2 symptoms. ​RESULTS: Participants with CKD had a mean age of 68 years, diabetes duration 20 years, eGFR 38 mL/min/1.73 m and HbA1c 7.8%, 61 mmol/mol. Sixty-two participants reported ≥2 DPN symptoms, 51 (63%) with CKD and 11 (46%) controls. Less TIR and higher GMI were associated with higher risk of MNSI questionnaire score ≥2 (OR 1.25 (95% CI 1.02 to 1.52) per 10% lower TIR, and OR 1.79 (95% CI 1.05 to 3.04) per 1% higher GMI, adjusting for age, gender and race). Similar results were observed when analyses were restricted to participants with CKD. In contrast, there was no significant association of HbA1c with DPN symptoms. ​CONCLUSIONS: Symptoms of DPN were common among participants with long-standing type 2 DM and CKD. Lower TIR and higher GMI were associated with DPN symptoms.
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http://dx.doi.org/10.1136/bmjdrc-2019-000991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039577PMC
January 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

Military Environmental Exposure Concerns, Posttraumatic Stress Disorder, and Somatic Symptoms: Their Interrelation Among Treatment-Seeking Veterans.

J Occup Environ Med 2020 01;62(1):74-79

War Related Illness and Injury Study Center, Veterans Affairs Palo Alto Health Care System, Palo Alto, California (Dr LaRocca, Dr Ashford, Dr Katz, Dr Furst); Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine (Dr LaRocca, Dr Ashford, Dr Katz, Dr Furst), Palo Alto, California.

Objective: Research suggests military environmental exposure concerns are associated with negative health outcomes. This study investigated the relationship among exposure concerns, Posttraumatic Stress Disorder (PTSD), and somatic symptoms to enhance post-deployment health care programs for veterans.

Methods: We analyzed intake health data from a heterogeneous sample of predominantly Operation Desert Storm/Shield and Operation Enduring Freedom (OEF)/Operation Iraqi Freedom (OIF) veterans (N = 247).

Results: Individual exposure concerns and somatic symptoms were associated with higher PTSD symptom severity. Regression modeling demonstrated total exposure concerns and PTSD symptom severity linked with total somatic symptom severity. Mediation modeling revealed PTSD symptom severity to partially explain the relation between exposure concerns and somatic symptoms.

Conclusions: These findings illustrate the need for integrative treatment approaches incorporating physiological and exposure-related concerns associated with PTSD among veterans.
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http://dx.doi.org/10.1097/JOM.0000000000001767DOI Listing
January 2020