Publications by authors named "Michael Shlipak"

525 Publications

Urinary EGF and MCP-1 and risk of CKD after cardiac surgery.

JCI Insight 2021 May 11. Epub 2021 May 11.

Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, United States of America.

Background: Assessment of risk for chronic kidney disease (CKD) after acute kidney injury (AKI) is based on a limited set of markers primarily reflecting glomerular function. We evaluated markers of cell integrity (EGF) and inflammation (monocyte chemoattractant protein-1 [MCP-1]) for predicting long-term kidney outcomes after cardiac surgery.

Methods: We measured the urinary biomarkers EGF and MCP-1 in pre- and post-operative urine samples from 865 adult patients who underwent cardiac surgery from 2007-2010 at 2 sites in Canada and the United States and assessed their associations with the composite outcome of CKD incidence or progression. We also used single-cell (Sc) RNAseq of biopsies from patients with AKI to perform a transcriptomic analysis of programs that are coregulated with the genes encoding the 2 biomarkers.

Results: Over a median (IQR) follow-up of 5.8 (4.2-7.1) years, 266 (30.8%) patients developed the composite CKD outcome. Post-operatively, higher levels of urinary EGF were protective and higher levels of MCP-1 were associated with the composite CKD outcome (adjusted HR 0.83, 95% CI 0.73-0.95 and 1.10, 95% CI 1.00-1.21, respectively). Intrarenal scRNAseq transcriptomes in patients with AKI-defined cell populations revealed concordant changes in EGF and MCP-1 levels and identified underlying molecular processes associated with loss of EGF expression and gain of CCL2 (encoding MCP-1) expression.

Conclusion: Urinary EGF and MCP-1 were each independently associated with CKD incidence or progression after cardiac surgery. These markers may serve as noninvasive indicators of tubular damage, supported by tissue transcriptomes and provide opportunity for novel interventions in cardiac surgery.

Trial Registration: ClinicalTrials.gov NCT00774137FUNDING. NIH (R01HL085757 to CRP) funded the TRIBE-AKI Consortium.
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http://dx.doi.org/10.1172/jci.insight.147464DOI Listing
May 2021

The authors reply.

Kidney Int 2021 May;99(5):1241

Diabetes and Vascular Medicine Unit, Monash Health, Clayton, Victoria, Australia; School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2021.02.009DOI Listing
May 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 12. Epub 2021 Apr 12.

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: 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 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/1.73m at baseline.

Exposure(s): 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), alpha-1 microglobulin (α1m) and beta-2 microglobulin (β2m), uromodulin (UMOD), fibroblast growth factor-23 (FGF23), and intact parathyroid hormone (PTH).

Outcome(s): 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 ten biomarkers, EFA generated four factors reflecting tubule injury/repair (NGAL, IL-18 and YKL-40), tubule injury/fibrosis (KIM-1 and MCP-1), tubule reabsorption (α1m and β2m), and tubule reserve/mineral metabolism (UMOD, FGF23, and PTH). Each SD higher tubule reserve/mineral metabolism factor scores were associated with a 0.58% (0.39%, 0.67%) faster eGFR decline independent of baseline eGFR and albuminuria. Both the tubule injury/repair (HR per SD higher 1.18 [1.10, 1.37]) and tubule injury/fibrosis factors (HR 1.23 [1.02, 1.48]) were independently associated with future risk of AKI.

Limitations: The factors require validation in other settings.

Conclusions: EFA allows parsimonious subgrouping of biomarkers into factors which 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

Association of Urine Biomarkers of Kidney Tubular Injury and Dysfunction With Frailty Index and Cognitive Function in Persons with CKD in SPRINT.

Am J Kidney Dis 2021 Feb 26. Epub 2021 Feb 26.

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

Rationale And Objective: The associations of glomerular markers of kidney disease (eGFR and albuminuria) with frailty and cognition are well established. However, the relationship of kidney tubular injury and dysfunction with frailty and cognition are unknown.

Study Design: Observational cross-sectional study; SETTING: & Participants: 2,253 participants with eGFR < 60 ml/min/1.73m in the Systolic Blood Pressure Intervention Trial EXPOSURES: Eight urine biomarkers: Interleukin-18 [IL-18, pg/mL], kidney injury molecule-1 [KIM-1, pg/mL], neutrophil gelatinase-associated lipocalin [NGAL, ng/mL], chitinase-3-like protein-1 [YKL-40, pg/mL], monocyte chemoattractant protein-1 [MCP-1, pg/mL], α-1 microglobulin [α1M mg/g], beta-2 microglobulin [β2M ng/mL], and uromodulin [Umod ng/mL].

Outcomes: Frailty was measured using a previously validated frailty index (FI), categorized as fit (FI < 0.10), less fit (0.10 < FI < 0.21) and frail (FI > 0.21). Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA).

Analytical Approach: Associations between kidney tubule biomarkers with categorical FI were evaluated using multinomial logistic regression with the fit group as the reference. Cognitive function was evaluated using linear regression. Models were adjusted for demographic, behavioral and clinical variables including eGFR and urine albumin.

Results: Three of the 8 urine biomarkers of tubule injury and dysfunction were independently associated with FI. Each two-fold higher level of urine KIM-1, a marker of tubule injury, was associated with a 1.22 [95% CI: 1.01, 1.49) fold greater odds of being in frail group. MCP-1, a marker of tubulo-interstitial fibrosis, was associated with a 1.30 [95% CI 1.04, 1.64] greater odds of being in frail group, and α1M, a marker of tubule re-absorptive capacity, was associated with a 1.48 [95% CI 1.11, 1.96] greater odds. These associations were independent of confounders including eGFR and urine albumin, and were stronger than those of urine albumin with frailty index (1.15 [95% CI 0.99, 1.34]). Higher urine β2M, another marker of tubule reabsorptive capacity, was associated with worse cognitive scores at baseline (β: -0.09; 95% CI -0.17, -0.01). Urine albumin was not associated with cognitive function.

Limitations: Cross-sectional design, FI may not be generalizable in other populations.

Conclusions: Urine biomarkers of tubule injury, fibrosis and proximal tubule reabsorptive capacity are variably associated with FI and worse cognition, independent of glomerular markers of kidney health. Future studies are needed to validate these results among other patient populations.
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http://dx.doi.org/10.1053/j.ajkd.2021.01.009DOI Listing
February 2021

Chronic kidney disease detection, staging and treatment in cardiovascular disease prevention.

Heart 2021 Feb 10. Epub 2021 Feb 10.

Division of Nephrology and Kidney Health Research Collaborative, University of California, San Francisco, California, USA.

Globally, nearly 10% of the population has chronic kidney disease (CKD), defined as a glomerular filtration rate less than 60 mL/min/1.73 m and/or a urinary albumin to creatinine ratio greater than 30 mg/g (3 mg/mmol). Persons with CKD have a substantially high risk of cardiovascular disease. Indeed, most persons with CKD are far more likely to develop a cardiovascular event than to progress to end-stage kidney disease. Although early detection and staging of CKD could help prevent its cardiovascular consequences, current rates of testing for CKD are very low, even among high-risk populations such as persons with diabetes, hypertension and cardiovascular disease. In this review, we first describe the need to test for both estimated glomerular filtration rate and albuminuria among persons at high risk of CKD in order to properly stage CKD and enhance cardiovascular risk stratification. We then discuss how detection and staging for CKD could help prioritise patients at high risk of atherosclerotic cardiovascular disease and heart failure who could derive the largest benefit from cardiovascular preventive interventions. In addition, we discuss the central role of CKD detection and staging in the initiation of cardiorenal preventive therapies, such as the sodium-glucose cotransporter 2 inhibitors, which have shown overwhelming evidence of cardiorenal protection. We conclude by discussing strategies to overcome historical barriers to CKD detection and treatment.
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http://dx.doi.org/10.1136/heartjnl-2020-318004DOI Listing
February 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

Availability and Affordability of Kidney Health Laboratory Tests around the Globe.

Am J Nephrol 2020 17;51(12):959-965. Epub 2020 Dec 17.

Division of Nephrology & Immunology, University of Alberta, Edmonton, Alberta, Canada.

Background: Kidney disease is a major global public health problem, and laboratory testing of kidney health measures is essential for diagnosis and monitoring. The availability and affordability of kidney health laboratory tests across countries has not been systematically described.

Methods: The International Society of Nephrology (ISN), in partnership with leaders of a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference, surveyed a representative subset of ISN-Global Kidney Health Atlas (ISN-GKHA) respondents from April to June 2020. We assessed the association between country gross national income (GNI) per capita and laboratory testing availability and affordability.

Results: Of 33 regional expert nephrologists invited, 24 (73%) responded, representing all 10 ISN regions around the world. Availability of kidney health laboratory tests was as follows: serum Cr (100%), serum cystatin C (67%), urine albumin (96%), urine Cr (100%), and dipstick urinalysis (100%). Median (IQR) reimbursement values in international dollars were as follows: serum Cr Int$ 6.61 (3.42-8.84), serum cystatin C Int$ 31.51 (17.36-46.25), urine albumin Int$ 10.22 (5.90-15.42), urine Cr Int$ 7.50 (1.66-8.84), and dipstick urinalysis Int$ 6.26 (2.56-8.40). Reimbursement values did not differ significantly by World Bank income group or by GNI per capita.

Conclusion: There was widespread availability of kidney health laboratory tests and substantial variation in reimbursement values. To achieve meaningful progress across nations in mitigating the growth of kidney disease, access to affordable diagnostic technology is essential. Our results are highly relevant to policymakers and researchers as countries increasingly consider national strategies for kidney disease detection and management.
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http://dx.doi.org/10.1159/000511848DOI Listing
December 2020

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

Am J Kidney Dis 2020 Dec 14. 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
December 2020

Chronic kidney disease as a risk factor for peripheral nerve impairment in older adults: A longitudinal analysis of Health, Aging and Body Composition (Health ABC) study.

PLoS One 2020 15;15(12):e0242406. Epub 2020 Dec 15.

University of Pittsburgh, Pittsburgh, PA, United States of America.

Introduction: Sensory and motor nerve deficits are prevalent in older adults and are associated with loss of functional independence. We hypothesize that chronic kidney disease predisposes to worsening sensorimotor nerve function over time.

Materials And Methods: Participants were from the Health, Aging and Body Composition Study (N = 1121) with longitudinal data between 2000-01 (initial visit) and 2007-08 (follow-up visit). Only participants with non-impaired nerve function at the initial visit were included. The predictor was presence of CKD (estimated GFR ≤ 60 ml/min/1.73m2) from the 1999-2000 visit. Peripheral nerve function outcomes at 7-year follow-up were 1) Motor: "new" impairments in motor parameters (nerve conduction velocity NCV < 40 m/s or peroneal compound motor action potential < 1 mv) at follow-up, and 2) Sensory: "new" impairment defined as insensitivity to standard 10-g monofilament or light 1.4-g monofilament at the great toe and "worsening" as a change from light to standard touch insensitivity over time. The association between CKD and "new" or "worsening" peripheral nerve impairment was studied using logistic regression.

Results: The study population was 45.9% male, 34.3% Black and median age 75 y. CKD participants (15.6%) were older, more hypertensive, higher in BMI and had 2.37 (95% CI 1.30-4.34) fold higher adjusted odds of developing new motor nerve impairments in NCV. CKD was associated with a 2.02 (95% CI 1.01-4.03) fold higher odds of worsening monofilament insensitivity. CKD was not associated with development of new monofilament insensitivity.

Conclusions: Pre-existing CKD leads to new and worsening sensorimotor nerve impairments over a 7-year time period in community-dwelling older adults.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242406PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737903PMC
January 2021

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

Am J Kidney Dis 2020 Dec 9. Epub 2020 Dec 9.

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

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

Study Design: Observational, case-cohort study design.

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

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

Outcomes: The primary outcomes were incident HF and AF.

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

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

Limitations: Observational study.

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

A New Panel-Estimated GFR, Including β-Microglobulin and β-Trace Protein and Not Including Race, Developed in a Diverse Population.

Am J Kidney Dis 2021 05 7;77(5):673-683.e1. Epub 2020 Dec 7.

Division of Nephrology, Tufts Medical Center; Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA.

Rationale And Objective: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFR) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFR or eGFR, respectively), but the inclusion of creatinine in eGFR requires specification of a person's race. β-Microglobulin (B2M) and β-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is.

Study Design: Study of diagnostic test accuracy.

Setting And Participants: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants.

Tests Compared: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race.

Outcomes: GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of [Cr]EDTA.

Results: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m, and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFR (percentage of estimates greater than 30% different from measured GFR [1 - P] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFR (1 - P of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups.

Limitations: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe.

Conclusions: The 4-marker panel eGFR is as accurate as eGFR without requiring specification of race. A more accurate race-free eGFR could be an important advance.
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http://dx.doi.org/10.1053/j.ajkd.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102017PMC
May 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
March 2021

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

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

Kidney Research Institute, Seattle, Washington, USA.

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

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

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

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

Incorporating kidney disease measures into cardiovascular risk prediction: Development and validation in 9 million adults from 72 datasets.

EClinicalMedicine 2020 Oct 14;27:100552. Epub 2020 Oct 14.

Department of Public Health, Center for Epidemiologic Research in Asia (CERA) Shiga University of Medical Science (SUMS) Seta-Tsukinowa-cho, Shiga, Japan.

Background: Chronic kidney disease (CKD) measures (estimated glomerular filtration rate [eGFR] and albuminuria) are frequently assessed in clinical practice and improve the prediction of incident cardiovascular disease (CVD), yet most major clinical guidelines do not have a standardized approach for incorporating these measures into CVD risk prediction. "CKD Patch" is a validated method to calibrate and improve the predicted risk from established equations according to CKD measures.

Methods: Utilizing data from 4,143,535 adults from 35 datasets, we developed several "CKD Patches" incorporating eGFR and albuminuria, to enhance prediction of risk of atherosclerotic CVD (ASCVD) by the Pooled Cohort Equation (PCE) and CVD mortality by Systematic COronary Risk Evaluation (SCORE). The risk enhancement by CKD Patch was determined by the deviation between individual CKD measures and the values expected from their traditional CVD risk factors and the hazard ratios for eGFR and albuminuria. We then validated this approach among 4,932,824 adults from 37 independent datasets, comparing the original PCE and SCORE equations (recalibrated in each dataset) to those with addition of CKD Patch.

Findings: We confirmed the prediction improvement with the CKD Patch for CVD mortality beyond SCORE and ASCVD beyond PCE in validation datasets (Δc-statistic 0.027 [95% CI 0.018-0.036] and 0.010 [0.007-0.013] and categorical net reclassification improvement 0.080 [0.032-0.127] and 0.056 [0.044-0.067], respectively). The median (IQI) of the ratio of predicted risk for CVD mortality with CKD Patch vs. the original prediction with SCORE was 2.64 (1.89-3.40) in very high-risk CKD (e.g., eGFR 30-44 ml/min/1.73m with albuminuria ≥30 mg/g), 1.86 (1.48-2.44) in high-risk CKD (e.g., eGFR 45-59 ml/min/1.73m with albuminuria 30-299 mg/g), and 1.37 (1.14-1.69) in moderate risk CKD (e.g., eGFR 60-89 ml/min/1.73m with albuminuria 30-299 mg/g), indicating considerable risk underestimation in CKD with SCORE. The corresponding estimates for ASCVD with PCE were 1.55 (1.37-1.81), 1.24 (1.10-1.54), and 1.21 (0.98-1.46).

Interpretation: The "CKD Patch" can be used to quantitatively enhance ASCVD and CVD mortality risk prediction equations recommended in major US and European guidelines according to CKD measures, when available.

Funding: US National Kidney Foundation and the NIDDK.
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http://dx.doi.org/10.1016/j.eclinm.2020.100552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599294PMC
October 2020

The case for early identification and intervention of chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Kidney Int 2021 01 27;99(1):34-47. Epub 2020 Oct 27.

Diabetes and Vascular Medicine Unit, Monash Health, Clayton, Victoria, Australia; School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. Electronic address:

Chronic kidney disease (CKD) causes substantial global morbidity and increases cardiovascular and all-cause mortality. Unlike other chronic diseases with established strategies for screening, there has been no consensus on whether health systems and governments should prioritize early identification and intervention for CKD. Guidelines on evaluating and managing early CKD are available but have not been universally adopted in the absence of incentives or quality measures for prioritizing CKD care. The burden of CKD falls disproportionately upon persons with lower socioeconomic status, who have a higher prevalence of CKD, limited access to treatment, and poorer outcomes. Therefore, identifying and treating CKD at the earliest stages is an equity imperative. In 2019, Kidney Disease: Improving Global Outcomes (KDIGO) held a controversies conference entitled "Early Identification and Intervention in CKD." Participants identified strategies for screening, risk stratification, and treatment for early CKD and the key health system and economic factors for implementing these processes. A consensus emerged that CKD screening coupled with risk stratification and treatment should be implemented immediately for high-risk persons and that this should ideally occur in primary or community care settings with tailoring to the local context.
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http://dx.doi.org/10.1016/j.kint.2020.10.012DOI Listing
January 2021

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

J Am Soc Nephrol 2021 Jan 29;32(1):115-126. Epub 2020 Oct 29.

Division of Nephrology, Department of Internal Medicine, MetroHealth Campus, and Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio.

Background: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals.

Methods: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change.

Results: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline.

Conclusions: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.
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http://dx.doi.org/10.1681/ASN.2020040487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894671PMC
January 2021

Endothelial dysfunction and the risk of heart failure in a community-based study: the Multi-Ethnic Study of Atherosclerosis.

ESC Heart Fail 2020 Oct 20. Epub 2020 Oct 20.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.

Aims: We aimed to investigate the association between endothelial dysfunction, assessed by brachial flow-mediated dilation (FMD), and the incidence of heart failure (HF) in the community-based Multi-Ethnic Study of Atherosclerosis.

Methods And Results: Brachial artery FMD was measured in a nested case-cohort sample including 3496 of 6814 Multi-Ethnic Study of Atherosclerosis participants without prevalent cardiovascular disease (mean age 61 years, 50% women). Multivariable probability-weighted Cox proportional hazards analysis was used to examine the association between FMD and incident HF. We also investigated the association between FMD and HF with reduced vs. preserved ejection fraction [HFrEF (left ventricular ejection fraction <45%) vs. HFpEF (left ventricular ejection fraction ≥45%)]. During follow-up (median 12 years), 149 participants developed incident HF (incidence rate 3.7 events per 1000 person years). There were 56 HFrEF and 69 HFpEF events (incidence rates 1.4 and 1.7 events per 1000 person years, respectively). In multivariable models adjusted for established HF risk factors (age, sex, race/ethnicity, body mass index, systolic blood pressure, antihypertensive treatment, heart rate, diabetes mellitus, history of myocardial infarction, current smoker, and former smoker status), individuals in the highest quartile of FMD (reflecting better endothelial function) had a lower HF risk compared with individuals in the lowest quartile [hazard ratio 0.53, 95% confidence interval (CI) 0.31-0.95]. Lower risk according to higher FMD was particularly evident for HFrEF, but not for HFpEF (hazard ratio per standard deviation increase 0.79, 95% CI 0.64-0.97 vs. 0.99, 95% CI 0.78-1.26, respectively). Results remained similar after adjustment for baseline natriuretic peptide levels. The addition of FMD to established HF risk factors generally rendered no or only modest improvement in C-statistics [C-statistics for model with established HF risk factors: 0.774, and with the addition of FMD: 0.776 (delta C 0.002, 95% confidence interval -0.002 to 0.006)].

Conclusions: Endothelial dysfunction was independently associated with HF in this community cohort, suggesting a pathophysiological contribution of endothelial function to the development of HF, in particular HFrEF. However, the value of FMD measurements for HF risk prediction seems limited.
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http://dx.doi.org/10.1002/ehf2.13054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754733PMC
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

A Comparison of Different Estimates of Albuminuria in Association with Mortality in Epidemiologic Research.

Clin J Am Soc Nephrol 2020 12 14;15(12):1814-1816. Epub 2020 Sep 14.

Division of Renal Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

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http://dx.doi.org/10.2215/CJN.07290520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769031PMC
December 2020

Association of Lower Urinary Tract Symptom Severity with Kidney Function among Community Dwelling Older Men.

J Urol 2020 12 28;204(6):1305-1311. Epub 2020 Jun 28.

Department of Orthopaedics and Rehabilitation, Oregon Health and Science University, Portland, Oregon.

Purpose: Most international practice guidelines recommend screening for chronic kidney disease among older men with lower urinary tract symptoms. However, prior studies supporting these guidelines are insufficient due to incomplete assessments of kidney function and inadequate adjustment for confounding factors.

Materials And Methods: We conducted a cross-sectional study among 5,530 American men older than 65 years in the multicenter Osteoporotic Fractures in Men Study. Chronic kidney disease was defined per international guidelines as estimated glomerular filtration rate less than 60 ml/minute/1.73 m based on serum creatinine or cystatin C, or urinary albumin-to-creatinine ratio 30 mg/gm or greater. Lower urinary tract symptoms were assessed with the American Urological Association Symptom Index. Associations were estimated using multivariable linear and modified Poisson regression models.

Results: Chronic kidney disease prevalence was 16% among 5,530 men with serum creatinine, 24% among 1,504 men with serum cystatin C and 14% among 1,487 men with urinary albumin-to-creatinine measurements. Lower urinary tract symptoms were not associated with lower estimated glomerular filtration rate based on serum creatinine or cystatin C. Although symptom severity was modestly associated with a higher prevalence of chronic kidney disease in age/site adjusted analyses, confidence intervals were wide and associations using all 3 definitions were not statistically significant after adjustment for important confounders, including cardiovascular disease and analgesic use.

Conclusions: Lower urinary tract symptoms are not independently associated with multiple measures of kidney dysfunction or prevalence of chronic kidney disease among older community dwelling men. Our results do not support recommendations for kidney function testing among older men with lower urinary tract symptoms.
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http://dx.doi.org/10.1097/JU.0000000000001310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665901PMC
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

Cystatin C is ready for clinical use.

Curr Opin Nephrol Hypertens 2020 Nov;29(6):591-598

Kidney Health Research Collaborative and Division of General Internal Medicine, San Francisco Veterans Affairs Medical Center, University of California San Francisco, San Francisco, CA, USA.

Purpose Of Review: The goal of this update is to raise awareness of clinical scenarios where cystatin C has clear and immediate benefits as an alternative glomerular filtration rate (GFR) biomarker to supplement creatinine. An additional goal is to focus the estimated GFR (eGFR) controversy onto medication prescribing for agents with narrow therapeutic windows where better GFR estimation will lead to improved medical care.

Recent Findings: Equations that include cystatin C predict GFR more accurately than serum creatinine in children, adults, and older adults with larger effects among persons who are acutely ill. Numerous studies have evaluated medication dosing based on either GFR estimate; vancomycin was the most frequently studied drug and its target level and elimination were better predicted by cystatin C. Overall, approaches to medication dosing and monitoring that include cystatin C concentrations have been shown to result in a better achievement of drug trough levels. Furthermore, cystatin C offers the opportunity to avoid the race coefficient that is required for any current creatinine-based eGFR equation, which has been appropriately criticized for introducing unnecessary imprecision, assumptions and values on GFR estimation.

Summary: Hospital laboratories must make cystatin C available for clinical care to improve the safety and efficacy of medications that have narrow therapeutic windows.
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http://dx.doi.org/10.1097/MNH.0000000000000638DOI Listing
November 2020

A systematic review and participant-level meta-analysis found little association of retinal microvascular caliber with reduced kidney function.

Kidney Int 2021 03 15;99(3):696-706. Epub 2020 Aug 15.

Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, UK. Electronic address:

Previously, variation in retinal vascular caliber has been reported in association with chronic kidney disease (CKD) but findings remain inconsistent. To help clarify this we conducted individual participant data meta-analysis and aggregate data meta-analysis on summary estimates to evaluate cross-sectional associations between retinal vascular caliber and CKD. A systematic review was performed using Medline and EMBASE for articles published until October 2018. The aggregate analysis used a two-stage approach combining summary estimates from eleven studies (44,803 patients) while the individual participant analysis used a one-stage approach combining raw data from nine studies (33,222 patients). CKD stages 3-5 was defined as an estimated glomerular filtration rate under 60 mL/min/1.73m. Retinal arteriolar and venular caliber (central retinal arteriolar and venular equivalent) were assessed from retinal photographs using computer-assisted methods. Logistic regression estimated relative risk of CKD stages 3-5 associated with a 20 μm decrease (approximately one standard deviation) in central retinal arteriolar and venular equivalent. Prevalence of CKD stages 3-5 was 11.2% of 33,222 and 11.3% of 44,803 patients in the individual participant and aggregate data analysis, respectively. No significant associations were detected in adjusted analyses between central retinal arteriolar and venular equivalent and CKD stages 3-5 in the aggregate analysis for central retinal arteriolar relative risk (0.98, 95% confidence interval 0.94-1.03); venular equivalent (0.99, 0.95-1.04) or individual participant central retinal arteriolar (0.99, 0.95-1.04) or venular equivalent (1.01, 0.97-1.05). Thus, meta-analysis provided little evidence to suggest that cross sectional direct measurements of retinal vascular caliber was associated with CKD stages 3-5 in the general population. Hence, meta-analyses of longitudinal studies evaluating the association between retinal parameters and CKD stages 3-5 may be warranted.
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http://dx.doi.org/10.1016/j.kint.2020.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898278PMC
March 2021

Results from the TRIBE-AKI Study found associations between post-operative blood biomarkers and risk of chronic kidney disease after cardiac surgery.

Kidney Int 2021 03 25;99(3):716-724. Epub 2020 Jul 25.

Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address:

Patients undergoing cardiac surgery are placed under intense physiologic stress. Blood and urine biomarkers measured peri-operatively may help identify patients at higher risk for adverse long-term kidney outcomes.We sought to determine independent associations of various biomarkers with development or progression of chronic kidney disease (CKD) following cardiac surgery. In this sub-study of the prospective cohort -TRIBE-AKI Study, we evaluated 613 adult patients undergoing cardiac surgery in Canada in our primary analysis and tested the association of 40 blood and urinary biomarkers with the primary composite outcome of CKD incidence or progression. In those with baseline estimated glomerular filtration rate (eGFR) over 60 mL/min/1.73m, we defined CKD incidence as a 25% reduction in eGFR and an eGFR under 60. In those with baseline eGFR under 60 mL/min/1.73m, we defined CKD progression as a 50% reduction in eGFR or eGFR under 15. Results were evaluated in a replication cohort of 310 patients from one study site in the United States. Over a median follow-up of 5.6 years, 172 patients developed the primary outcome. Each log increase in basic fibroblast growth factor (adjusted hazard ratio 1.52 [95% confidence interval 1.19, 1.93]), Kidney Injury Molecule-1 (1.51 [0.98, 2.32]), N-terminal pro-B-type natriuretic peptide (1.19 [1.01, 1.41]), and tumor necrosis factor receptor 1 (1.75 [1.18, 2.59]) were associated with outcome after adjustment for demographic factors, serum creatinine, and albuminuria. Similar results were noted in the replication cohort. Although there was no interaction by acute kidney injury in continuous analysis, mortality was higher in the no acute kidney injury group by biomarker tertile. Thus, elevated post-operative levels of blood biomarkers following cardiac surgery were independently associated with the development of CKD. These biomarkers can provide additional value in evaluating CKD incidence and progression after cardiac surgery.
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http://dx.doi.org/10.1016/j.kint.2020.06.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077034PMC
March 2021

Validation of a simple equation for glomerular filtration rate measurement based on plasma iohexol disappearance.

Clin Kidney J 2020 Jun 23;13(3):397-401. Epub 2019 Jul 23.

Division of Nephrology, The University of Mississippi Medical Center, Jackson, MS, USA.

Background: A simple equation for glomerular filtration rate (GFR) measurement based on only plasma samples during the slow compartment after injection of iohexol was previously developed among children with chronic kidney disease and adult men with or at risk of HIV infection [Chronic Kidney Disease in Children (CKiD)-Multicenter AIDS Cohort Study (MACS) equation], but has not been externally validated. We aimed to evaluate the performance of the CKiD-MACS equation among elderly participants in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort who underwent directly measured iohexol GFR.

Methods: Using data from 287 participants of the MESA-Kidney study who underwent a five-sample measured iohexol GFR (two and three samples in the fast and slow compartments, respectively), we assessed the performance of the CKiD-MACS equation using only plasma samples in the slow compartment by sex, race and age. Agreement was assessed by bias, correlation, proportion within 5 and 10%, and the root mean square error (RMSE).

Results: The average age and GFR of the participants were 71 years and 70.8 mL/min/1.73 m, respectively, and 46% were black. The equation yielded excellent agreement within stratified groups with high correlation (>0.96), low bias (≤1.2 mL/min/1.73 m) and low RMSE (<4.2 mL/min/1.73 m).

Conclusions: The CKiD-MACS equation demonstrated valid GFR measurement using only samples in the slow compartment in this racially diverse, elderly population. While the equation yielded practically the same results as the original Brochner-Mortensen equation, the CKiD-MACS equation conforms to theoretical principles embedded in the two-compartment model of direct GFR measurement.
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http://dx.doi.org/10.1093/ckj/sfz083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367109PMC
June 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