Publications by authors named "Michael G Shlipak"

454 Publications

Prediction of Incident Atrial Fibrillation in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort Study.

Clin J Am Soc Nephrol 2021 Jul 12;16(7):1015-1024. Epub 2021 Jul 12.

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

Background And Objectives: Atrial fibrillation (AF) is common in CKD and associated with poor kidney and cardiovascular outcomes. Prediction models developed using novel methods may be useful to identify patients with CKD at highest risk of incident AF. We compared a previously published prediction model with models developed using machine learning methods in a CKD population.

Design, Setting, Participants, & Measurements: We studied 2766 participants in the Chronic Renal Insufficiency Cohort study without prior AF with complete cardiac biomarker (N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T) and clinical data. We evaluated the utility of machine learning methods as well as a previously validated clinical prediction model (Cohorts for Heart and Aging Research in Genomic Epidemiology [CHARGE]-AF, which included 11 predictors, using original and re-estimated coefficients) to predict incident AF. Discriminatory ability of each model was assessed using the ten-fold cross-validated -index; calibration was evaluated graphically and with the Grønnesby and Borgan test.

Results: Mean (SD) age of participants was 57 (11) years, 55% were men, 38% were Black, and mean (SD) eGFR was 45 (15) ml/min per 1.73 m; 259 incident AF events occurred during a median of 8 years of follow-up. The CHARGE-AF prediction equation using original and re-estimated coefficients had indices of 0.67 (95% confidence interval, 0.64 to 0.71) and 0.67 (95% confidence interval, 0.64 to 0.70), respectively. A likelihood-based boosting model using clinical variables only had a index of 0.67 (95% confidence interval, 0.64 to 0.70); adding N-terminal pro-B-type natriuretic peptide, high-sensitivity troponin T, or both biomarkers improved the index by 0.04, 0.01, and 0.04, respectively. In addition to N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T, the final model included age, non-Hispanic Black race/ethnicity, Hispanic race/ethnicity, cardiovascular disease, chronic obstructive pulmonary disease, myocardial infarction, peripheral vascular disease, use of angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, calcium channel blockers, diuretics, height, and weight.

Conclusions: Using machine learning algorithms, a model that included 12 standard clinical variables and cardiac-specific biomarkers N-terminal pro-B-type natriuretic peptide and high-sensitivity troponin T had moderate discrimination for incident AF in a CKD population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2215/CJN.01060121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425618PMC
July 2021

Soluble Klotho and Incident Hypertension.

Clin J Am Soc Nephrol 2021 Oct 23;16(10):1502-1511. Epub 2021 Sep 23.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas

Background And Objectives: Hypertension is associated with significant morbidity and mortality despite effective antihypertensive therapies. Soluble klotho is a circulating protein that in preclinical studies is protective against the development of hypertension. There are limited studies of klotho and blood pressure in humans.

Design, Setting, Participants, & Measurements: Within the Health, Aging, and Body Composition Study, a cohort of well-functioning older adults, soluble klotho was measured in serum. We evaluated the cross-sectional and longitudinal association between klotho and blood pressure, prevalent hypertension, incident hypertension, and BP trajectories. Analyses were adjusted for demographics, cardiovascular disease and kidney disease risk factors, and measures of mineral metabolism including calcium, phosphate, parathyroid hormone, 25(OH) vitamin D, and fibroblast growth factor 23.

Results: The median klotho concentration was 630 pg/ml (478-816, 25th to 75th percentile). Within the cohort, 2093 (76%) of 2774 participants had prevalent hypertension and 476 (70%) of the remaining 681 developed incident hypertension. There was no association between klotho and prevalent hypertension or baseline systolic BP, but higher klotho was associated with higher baseline diastolic BP (fully adjusted =0.92 mmHg, 95% confidence interval, 0.24 to 1.60 mmHg, higher per two-fold higher klotho). Higher baseline serum klotho levels were significantly associated with a lower rate of incident hypertension (fully adjusted hazard ratio, 0.80; 95% confidence interval, 0.69 to 0.93 for every two-fold higher klotho). Higher klotho was also associated with lower subsequent systolic BP and diastolic BP (-0.16, 95% confidence interval, -0.31 to -0.01, mmHg lower systolic BP per year and -0.10, 95% confidence interval, -0.18 to -0.02, mmHg lower diastolic BP per year, for each two-fold higher klotho).

Conclusions: Higher klotho is associated with higher baseline diastolic but not systolic BP, a lower risk of incident hypertension, and lower BP trajectories during follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2215/CJN.05020421DOI Listing
October 2021

New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race.

N Engl J Med 2021 Sep 23. Epub 2021 Sep 23.

From the Division of Nephrology (L.A.I., S.J.C., A.S.L.) and the Institute for Clinical Research and Health Policy Studies (H.T.), Tufts Medical Center, Tufts Clinical and Translational Science Institute, Tufts University (H.T.), the Section on Genetics and Epidemiology, Joslin Diabetes Center (A.D.), and the Department of Medicine, Harvard Medical School (A.D.) - all in Boston; the Renal-Electrolyte and Hypertension Division, Perelman School of Medicine (N.D.E.), and the Departments of Biostatistics, Epidemiology, and Informatics, Center for Clinical Epidemiology and Biostatistics (W.Y.), University of Pennsylvania, Philadelphia; the Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health and the Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions (J.C., D.W., Y.S., M.E.G., E.S., S.H.B.), the Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine (D.C.C., M.E.G.), and the Department of Medicine, Division of Nephrology, University of Maryland School of Medicine (R.K.) - all in Baltimore; the Kidney Health Research Collaborative, San Francisco Veterans Affairs (VA) Medical Center and University of California, San Francisco (M.M.E., M.G.S.), the Division of Nephrology, Department of Medicine, San Francisco VA Health Care System and University of California, San Francisco (M.M.E.), and the Department of Medicine, Priscilla Chan and Mark Zuckerberg San Francisco General Hospital and University of California, San Francisco (N.R.P.) - all in San Francisco; the Clinical Trial Unit, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (M.F.); the Division of Biostatistics, Department of Population Health Sciences, University of Utah Health, Salt Lake City (T.G.); the Department of Clinical Chemistry and Pharmacology, Institute of Laboratory Medicine, Lund University, Lund, Sweden (A.G.); the Faculty of Medicine, University of Iceland, Reykjavik, and the Icelandic Heart Association, Kopavogur - both in Iceland (V.G.); the Departments of Medicine and Epidemiology, University of Alabama at Birmingham, Birmingham (O.M.G.); the Departments of Laboratory Medicine and Pathology (A.B.K., J.C.S.), Pediatrics (M.M.), and Medicine (M.M.), University of Minnesota, Minneapolis, and the Division of Nephrology and Hypertension, Mayo Clinic, Rochester (A.D.R., V.E.T.) - all in Minnesota; the Faculty of Medical Sciences, University Medical Center Groningen, Groningen, the Netherlands (G.N.); the Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ (R.G.N.); the Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland (E.D.P.); Rush University Medical Center, Chicago (R.R.); and Steno Diabetes Center Copenhagen and the Department of Clinical Medicine, University of Copenhagen - both in Copenhagen (P.R.).

Background: Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct.

Methods: We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations.

Results: In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks.

Conclusions: New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2102953DOI Listing
September 2021

Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children.

J Am Soc Nephrol 2021 Oct 20;32(10):2664-2677. Epub 2021 Sep 20.

National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.

Background: Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression.

Methods: We investigated the relationship between urine biomarkers of kidney tubular health (EGF and -1 microglobulin), tubular injury (kidney injury molecule-1; KIM-1), and inflammation (monocyte chemoattractant protein-1 [MCP-1] and YKL-40) and CKD progression. The prospective CKD in Children Study enrolled children aged 6 months to 16 years with an eGFR of 30-90ml/min per 1.73m. Urine biomarkers were assayed a median of 5 months [IQR: 4-7] after study enrollment. We indexed the biomarker to urine creatinine by dividing the urine biomarker concentration by the urine creatinine concentration to account for the concentration of the urine. The primary outcome was CKD progression (a composite of a 50% decline in eGFR or kidney failure) during the follow-up period.

Results: Overall, 252 of 665 children (38%) reached the composite outcome over a median follow-up of 6.5 years. After adjustment for covariates, children with urine EGF concentrations in the lowest quartile were at a seven-fold higher risk of CKD progression versus those with concentrations in the highest quartile (fully adjusted hazard ratio [aHR], 7.1; 95% confidence interval [95% CI], 3.9 to 20.0). Children with urine KIM-1, MCP-1, and -1 microglobulin concentrations in the highest quartile were also at significantly higher risk of CKD progression versus those with biomarker concentrations in the lowest quartile. Addition of the five biomarkers to a clinical model increased the discrimination and reclassification for CKD progression.

Conclusions: After multivariable adjustment, a lower urine EGF concentration and higher urine KIM-1, MCP-1, and -1 microglobulin concentrations were each associated with CKD progression in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2021010094DOI Listing
October 2021

The Association between Baseline and 3-Month Albuminuria and 1-Year Prognosis of Ischemic Stroke.

Cerebrovasc Dis 2021 Aug 25:1-8. Epub 2021 Aug 25.

China National Clinical Research Center for Neurological Diseases, Beijing, China.

Introduction: The association between the changes in albuminuria levels and the clinical prognosis of stroke is unknown. The present study aimed to explore the relationships between changes in albuminuria and the risk of adverse stroke outcomes.

Methods: The patients with ischemic stroke or transient ischemic attack from the Third China National Stroke Registry (CNSR-III) who had the urinary albumin-to-creatinine ratio (ACR) detected at baseline and 3-month were recruited. They were classified into 4 groups according to baseline and 3-month ACR and followed up for 1 year.

Results: A total of 5,311 patients were finally included in the study. There were 3,738 (70.4%), 483 (9.1%), 451 (8.5%), and 639 (12.0%) patients with no albuminuria, baseline albuminuria, 3-month albuminuria, and persistent albuminuria, respectively. After adjustment for confounding variables, persistent albuminuria was independently associated with all-cause death (hazard ratio [HR], 2.23; 95% CI, 1.17-4.25; p = 0.02), stroke recurrence (HR, 1.55; 95% CI, 1.02-2.36; p = 0.04), and poor functional outcome (OR, 2.22; 95% CI, 1.66-2.96; p < 0.001). Baseline albuminuria was independently associated with poor functional outcome (OR, 1.65; 95% CI, 1.19-2.28; p = 0.003), while 3-month albuminuria was independently associated with stroke recurrence (HR, 1.68; 95% CI, 1.06-2.65; p = 0.03).

Conclusions: Changes in albuminuria can predict adverse 1-year outcomes in Chinese ischemic stroke patients. In particular, persistent albuminuria was independently associated with 1-year all-cause death, stroke recurrence, and poor functional outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000518180DOI Listing
August 2021

Urine Alpha-1-Microglobulin Levels and Acute Kidney Injury, Mortality, and Cardiovascular Events following Cardiac Surgery.

Am J Nephrol 2021 2;52(8):673-683. Epub 2021 Sep 2.

Kidney Health Research Collaborative, San Francisco VA Health Care System & University of California, San Francisco, San Francisco, California, USA.

Introduction: Urine alpha-1-microglobulin (Uα1m) elevations signal proximal tubule dysfunction. In ambulatory settings, higher Uα1m is associated with acute kidney injury (AKI), progressive chronic kidney disease (CKD), cardiovascular (CV) events, and mortality. We investigated the associations of pre- and postoperative Uα1m concentrations with adverse outcomes after cardiac surgery.

Methods: In 1,464 adults undergoing cardiac surgery in the prospective multicenter Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury (TRIBE-AKI) cohort, we measured the pre-and postoperative Uα1m concentrations and calculated the changes from pre- to postoperative concentrations. Outcomes were postoperative AKI during index hospitalization and longitudinal risks for CKD incidence and progression, CV events, and all-cause mortality after discharge. We analyzed Uα1m continuously and categorically by tertiles using multivariable logistic regression and Cox proportional hazards regression adjusted for demographics, surgery characteristics, comorbidities, baseline estimated glomerular filtration rate, urine albumin, and urine creatinine.

Results: There were 230 AKI events during cardiac surgery hospitalization; during median 6.7 years of follow-up, there were 212 cases of incident CKD, 54 cases of CKD progression, 269 CV events, and 459 deaths. Each 2-fold higher concentration of preoperative Uα1m was independently associated with AKI (adjusted odds ratio [aOR] = 1.36, 95% confidence interval 1.14-1.62), CKD progression (adjusted hazard ratio [aHR] = 1.46, 1.04-2.05), and all-cause mortality (aHR = 1.19, 1.06-1.33) but not with incident CKD (aHR = 1.21, 0.96-1.51) or CV events (aHR = 1.01, 0.86-1.19). Postoperative Uα1m was not associated with AKI (aOR per 2-fold higher = 1.07, 0.93-1.22), CKD incidence (aHR = 0.90, 0.79-1.03) or progression (aHR = 0.79, 0.56-1.11), CV events (aHR = 1.06, 0.94-1.19), and mortality (aHR = 1.01, 0.92-1.11).

Conclusion: Preoperative Uα1m concentrations may identify patients at high risk of AKI and other adverse events after cardiac surgery, but postoperative Uα1m concentrations do not appear to be informative.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000518240DOI Listing
September 2021

Kidney tubule health, mineral metabolism, and adverse events in persons with CKD in SPRINT.

Nephrol Dial Transplant 2021 Sep 2. Epub 2021 Sep 2.

Kidney Health Research Collaborative, Department of Medicine, San Francisco Veterans Affairs Health Care System and University of California San Francisco, San Francisco, CA, USA.

Background: Measures of kidney tubule health are risk markers for acute kidney injury (AKI) in persons with chronic kidney disease (CKD) during hypertension treatment, but their associations with other adverse events (AEs) are unknown.

Methods: Among 2,377 Systolic Blood Pressure Intervention Trial (SPRINT) participants with CKD, we measured at baseline eight urine biomarkers of kidney tubule health and two serum biomarkers of mineral metabolism pathways that act on the kidney tubules. Cox proportional hazards models were used to evaluate biomarker associations with risk of a composite of pre-specified serious AEs (hypotension, syncope, electrolyte abnormalities, AKI, bradycardia, and injurious falls) and outpatient AEs (hyperkalemia and hypokalemia).

Results: At baseline, the mean age was 73 ±9 years and mean eGFR was 46 ±11 ml/min/1.73m2. During a median follow-up of 3.8 years, 716 (30%) participants experienced the composite AE. Higher urine interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL), and monocyte chemoattractant protein-1 (MCP-1), lower urine uromodulin (UMOD), and higher serum fibroblast growth factor-23 were individually associated with higher risk of the composite AE outcome in multivariable-adjusted models including eGFR and albuminuria. When modeling biomarkers in combination, higher NGAL (HR: 1.08 per 2-fold higher biomarker level, 95% CI: 1.03, 1.13), higher MCP-1 (HR: 1.11, 95% CI: 1.03, 1.19), and lower UMOD (HR: 0.91, 95% CI: 0.85, 0.97) were each associated with higher composite AE risk. Biomarker associations did not vary by intervention arm (P >0.10 for all interactions).

Conclusions: Among persons with CKD, several kidney tubule biomarkers are associated with higher risk of AEs during hypertension treatment, independent of eGFR and albuminuria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfab255DOI Listing
September 2021

Associations of CKD risk factors and longitudinal changes in urine biomarkers of kidney tubules among women living with HIV.

BMC Nephrol 2021 Aug 30;22(1):296. Epub 2021 Aug 30.

Kidney Health Research Collaborative, Department of Medicine, San Francisco Veterans Affairs Health Care System and University of California, San Francisco, CA, USA.

Background: Novel urine biomarkers have enabled the characterization of kidney tubular dysfunction and injury among persons living with HIV, a population at an increased risk of kidney disease. Even though several urine biomarkers predict progressive kidney function decline, antiretroviral toxicity, and mortality in the setting of HIV infection, the relationships among the risk factors for chronic kidney disease (CKD) and urine biomarkers are unclear.

Methods: We assessed traditional and infection-related CKD risk factors and measured 14 urine biomarkers at baseline and at follow-up among women living with HIV in the Women's Interagency Health Study (WIHS). We then used simultaneously adjusted multivariable linear regression models to evaluate the associations of CKD risk factors with longitudinal changes in biomarker levels.

Results: Of the 647 women living with HIV in this analysis, the majority (67%) were Black, the median age was 45 years and median follow-up time was 2.5 years. Each traditional and infection-related CKD risk factor was associated with a unique set of changes in urine biomarkers. For example, baseline hemoglobin a1c was associated with worse tubular injury (higher interleukin [IL]-18), proximal tubular reabsorptive dysfunction (higher α1-microglobulin), tubular reserve (lower uromodulin) and immune response to injury (higher chitinase-3-like protein-1 [YKL-40]). Furthermore, increasing hemoglobin a1c at follow-up was associated with further worsening of tubular injury (higher kidney injury molecule-1 [KIM-1] and IL-18), as well as higher YKL-40. HCV co-infection was associated with worsening proximal tubular reabsorptive dysfunction (higher β2-microglobulin [β2m]), and higher YKL-40, whereas HIV viremia was associated with worsening markers of tubular and glomerular injury (higher KIM-1 and albuminuria, respectively).

Conclusions: CKD risk factors are associated with unique patterns of biomarker changes among women living with HIV, suggesting that serial measurements of multiple biomarkers may help in detecting and monitoring kidney disease in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-021-02508-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406753PMC
August 2021

The Vitamin D Metabolite Ratio Is Associated With Changes in Bone Density and Fracture Risk in Older Adults.

J Bone Miner Res 2021 Aug 23. Epub 2021 Aug 23.

Departments of Laboratory Medicine and Medicine and the Kidney Research Institute, University of Washington, Seattle, WA, USA.

Recent studies have suggested that 25-hydroxyvitamin D (25(OH)D) may be a poor biomarker of bone health, in part because measured levels incorporate both protein-bound and free vitamin D. The ratio of its catabolic product (24,25-dihydroxyvitamin D [24,25(OH) D]) to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide more information on sufficient vitamin D stores and is not influenced by vitamin D-binding protein concentrations. We evaluated whether the VMR or 25(OH)D are more strongly associated with bone loss and fracture risk in older adults. We performed a retrospective cohort study of 786 community-dwelling adults aged 70 to 79 years who participated in the Health Aging and Body Composition study. Our primary outcomes were annual changes in bone density and incident fracture. The mean age of these participants was 75 ± 3 years, 49% were female, 42% were Black, and 23% had an estimated glomerular filtration rate (eGFR) <60 mL/mL/1.73m . In fully adjusted models, a 50% lower VMR was associated with 0.3% (0.2%, 0.6%) more rapid decline in total hip bone mineral density (BMD). We found similar relationships with thoracic and lumbar spine BMD. In contrast, 25(OH)D concentrations were not associated with longitudinal change in BMD. There were 178 fractures during a mean follow-up of 10 years. Each 50% lower VMR was associated with a 49% (95% confidence interval [CI] 1.06, 2.08) greater fracture risk, whereas lower 25(OH)D concentrations were not significantly associated with fracture risk (hazard ratio [HR] per 50% lower 1.07 [0.80, 1.43]). In conclusion, among a diverse cohort of community-dwelling older adults, a lower VMR was more strongly associated with both loss of BMD and fracture risk compared with 25(OH)D . Trials are needed to evaluate the VMR as a therapeutic target in persons at risk for worsening BMD and fracture. © 2021 American Society for Bone and Mineral Research (ASBMR).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.4426DOI Listing
August 2021

Patient Awareness of CKD: A Systematic Review and Meta-analysis of Patient-Oriented Questions and Study Setting.

Kidney Med 2021 Jul-Aug;3(4):576-585.e1. Epub 2021 Jun 1.

Department of Medicine, University of California, San Francisco.

Rationale & Objective: Patient awareness of disease is the first step toward effective management and disease control. Awareness of chronic kidney disease (CKD) has consistently been shown to be low, but studies estimating patient awareness of CKD have used different methods. We sought to determine whether the estimated prevalence of CKD awareness differed by the wording used to ascertain awareness or by setting characteristics.

Study Design: Systematic review and meta-analysis.

Setting & Study Populations: Adults with CKD not receiving dialysis.

Selection Criteria For Studies: We included studies that estimated CKD awareness, determined CKD status by laboratory criteria, and provided the exact question wording used to ascertain awareness.

Data Extraction: 2 reviewers independently extracted data for each study; discordance was resolved by a third independent reviewer.

Analytical Approach: Mixed-effects models were used to calculate pooled CKD awareness estimates and 95% CIs.

Results: 32 studies were included. Publication year ranged from 2004 to 2017, with study populations ranging from 107 to 28,923 individuals. CKD awareness in individual studies ranged from 0.9% to 94.0%. Pooled CKD awareness was 19.2% (95% CI, 10.0%-33.6%) overall and was 26.5% (95% CI, 11.9%-48.9%) among individuals with an estimated glomerular filtration rate < 60 mL/min/1.73 m. "Kidney problem" was the most sensitive question for CKD awareness (58.7%; 95% CI, 32.4%-80.8%); "weak or failing kidneys" was the least sensitive (12.3%; 95% CI, 4.5%-29.4%). CKD awareness was highest among patients from nephrology practices (86.2%; 95% CI, 74.9%-93.0%) and lowest in the general population (7.3%; 95% CI, 5.0%-10.5%).

Limitations: Significant heterogeneity across studies overall and among examined subgroups of wording and study setting.

Conclusions: Differently worded questions may lead to widely different estimates of CKD awareness. Consistent terminology is likely needed to most effectively surveil and leverage CKD awareness to improve management and disease control.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xkme.2021.03.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350814PMC
June 2021

Urinary Biomarkers and Kidney Outcomes: Impact of Indexing Versus Adjusting for Urinary Creatinine.

Kidney Med 2021 Jul-Aug;3(4):546-554.e1. Epub 2021 Apr 30.

Kidney Health Research Collaborative, Department of Medicine, San Francisco VA Health Care System, University of California, San Francisco, CA.

Rationale & Objective: Urinary biomarker concentrations are frequently indexed to urinary creatinine (Ucr) concentration in spot samples to account for urine dilution; however, this may introduce biases. We evaluated whether indexing versus adjusting urinary biomarker concentrations for Ucr concentration altered their associations with outcomes.

Study Design: Observational cohort.

Setting & Participants: We analyzed data from 2,360 Systolic Blood Pressure Intervention Trial (SPRINT) participants with estimated glomerular filtration rates < 60 mL/min/1.73 m and urinary albumin (UAlb) and 8 urinary kidney tubule biomarkers measured at baseline.

Outcomes: The primary outcome was a composite of cardiovascular disease events; secondary outcomes were all-cause mortality and a composite of kidney outcomes (50% estimated glomerular filtration rate decline, end-stage kidney disease, or transplantation).

Analytical Approach: We used Cox proportional hazards regression to examine the associations of 1/Ucr with outcomes and compared the associations of UAlb and 8 individual urinary tubule biomarkers with outcomes, analyzed by indexing to Ucr, adjusting for 1/Ucr or the biomarker alone (without Ucr concentration).

Results: During a median follow-up of 3.3 years, 307 composite cardiovascular events, 166 deaths, and 34 composite kidney outcomes occurred. After multivariable adjustment, 1/Ucr was significantly associated with cardiovascular events (HR, 1.27 per 2-fold higher; 95% CI, 1.11-1.45), not associated with either mortality (HR, 1.06; 95% CI, 0.87-1.28) or kidney events (HR, 1.49; 95% CI, 0.95-2.35). For UAlb and urinary tubule biomarker concentrations, most risk estimates were not significantly different when indexed to Ucr concentration versus adjusted for 1/Ucr.

Limitations: Cohort excluded patients with diabetes and overall had low levels of albuminuria.

Conclusions: 1/Ucr is independently associated with cardiovascular events in trial participants with chronic kidney disease. Indexing versus adjusting for 1/Ucr does not significantly change the associations of most urinary biomarkers with clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xkme.2021.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350828PMC
April 2021

Urine creatinine concentration and clinical outcomes in older adults: The Cardiovascular Health Study.

J Am Geriatr Soc 2021 Aug 7. Epub 2021 Aug 7.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Purpose: Loss of muscle mass and strength are associated with long-term adverse health outcomes in older adults. Urine creatinine concentrations (Ucr; mg/dl) are a measure of muscle tissue mass and turnover. This study assessed the associations of a spot Ucr level with muscle mass and with risk of hospitalization, mortality, and diabetes mellitus in older adults.

Methods: We examined 3424 participants from the Cardiovascular Health Study who provided spot urine samples in 1996-1997 and who were followed through June 2015. All participants underwent baseline measurement of grip strength. In a sub-cohort, 1331 participants underwent dual energy X-ray absorptiometry (DEXA) scans, from which lean muscle mass was derived. Participants were followed for a median of 10 years for hospitalizations and mortality, and 9 years for diabetes mellitus.

Results: In linear regression analysis, a one standard deviation higher Ucr concentration (64.6 mg/dl) was associated with greater grip strength (kg force) β = 0.44 [0.16, 0.72]; p = 0.002) and higher lean muscle mass (kg) (β = 0.43 [0.08, 0.78]; p = 0.02). In Cox regression analyses, each standard deviation greater Ucr concentration was associated with lower rates of hospitalizations (0.94 [95% confidence interval, 0.90, 0.98]; p < 0.001) and lower mortality risk (0.92 [0.88, 0.97]; p < 0.001), while a one standard deviation increase in muscle mass derived from DEXA had no such significant association. Ucr levels were not associated with incident diabetes mellitus risk (0.97 [0.85, 1.11]; p = 0.65).

Conclusion: A higher spot Ucr concentration was favorably associated with muscle mass and strength and with health outcomes in older community-living adults. The ease of obtaining a spot Ucr makes it an attractive analyte to use for gauging the health of older adults.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgs.17388DOI Listing
August 2021

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

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

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

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

Study Design: Observational study.

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

Exposure: Estimated glomerular filtration rate (eGFR).

Outcome: NT-proBNP and hsTnT at baseline.

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

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

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

Conclusions: In this ambulatory CKD population with no self-reported history of cardiovascular disease, a range of 40%-88% of participants had concentrations of NT-proBNP and hsTnT above the conventional URL, depending on eGFR strata. Developing eGFR-specific thresholds for these commonly used cardiac biomarkers in the setting of CKD may improve their utility for evaluation of suspected heart failure and myocardial infarction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2021.06.017DOI Listing
July 2021

Urine Biomarkers of Kidney Tubule Health and Incident CKD Stage 3 in Women Living With HIV: A Repeated Measures Study.

Kidney Med 2021 May-Jun;3(3):395-404.e1. Epub 2021 Apr 17.

Kidney Health Research Collaborative, Department of Medicine, San Francisco Veterans Affairs Health Care System and University of California, San Francisco, San Francisco, CA.

Rationale & Objective: Single measurements of urinary biomarkers reflecting kidney tubule health are associated with chronic kidney disease (CKD) risk in HIV infection, but the prognostic value of repeat measurements over time is unknown.

Study Design: Cohort study.

Setting & Participants: 647 women living with HIV infection enrolled in the Women's Interagency Health Study.

Exposures: 14 urinary biomarkers of kidney tubule health measured at 2 visits over a 3-year period.

Outcome: Incident CKD, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m at two 6-month visits and an average eGFR decline ≥ 3% per year.

Analytical Approach: We used multivariable generalized estimating equations adjusting for CKD risk factors to evaluate baseline, time-updated, and change-over-time biomarker associations with incident CKD. We compared CKD discrimination between models with and without a parsimoniously selected set of biomarkers.

Results: During a median 7 years of follow-up, 9.7% (63/647) developed CKD. In multivariable-adjusted analyses, 3 of 14 baseline biomarkers associated with incident CKD. In contrast, 10 of 14 time-updated biomarkers and 9 of 14 biomarkers modeled as change over time associated with incident CKD. Urinary epidermal growth factor (EGF), α-microglobulin (A1M), and albumin were selected using penalized regression methods. In the time-updated model, lower urinary EGF (risk ratio [RR] per 2-fold higher time-updated biomarker levels, 0.69; 95% CI, 0.58-0.81), higher urinary A1M (RR, 1.47; 95% CI, 1.25-1.73), and higher urinary albumin excretion (RR, 1.21; 95% CI, 1.03-1.42) were jointly associated with increased risk for CKD. Compared with a base model (C statistic, 0.75), CKD discrimination improved after adding urinary EGF, A1M, and albumin values across baseline (C = 0.81), time-updated (C = 0.83), and change-over-time (C = 0.83) models ( < 0.01 for all).

Limitations: Observational design, incident CKD definition limited to eGFR.

Conclusions: Repeat urinary biomarker measurements for kidney tubule health have stronger associations with incident CKD compared with baseline measurements and moderately improve CKD discrimination in women living with HIV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.xkme.2021.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178470PMC
April 2021

Time-Updated Changes in Estimated GFR and Proteinuria and Major Adverse Cardiac Events: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study.

Am J Kidney Dis 2021 May 28. Epub 2021 May 28.

Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Rationale & Objective: Evaluating repeated measures of estimated glomerular filtration rate (eGFR) and urinary protein-creatinine ratio (UPCR) over time may enhance our ability to understand the association between changes in kidney parameters and cardiovascular disease risk.

Study Design: Prospective cohort study.

Setting & Participants: Annual visit data from 2,438 participants in the Chronic Renal Insufficiency Cohort (CRIC).

Exposures: Average and slope of eGFR and UPCR in time-updated, 1-year exposure windows.

Outcomes: Incident heart failure, atherosclerotic cardiovascular disease events, death, and a composite of incident heart failure, atherosclerotic cardiovascular disease events, and death.

Analytical Approach: A landmark analysis, a dynamic approach to survival modeling that leverages longitudinal, iterative profiles of laboratory and clinical information to assess the time-updated 3-year risk of adverse cardiovascular outcomes.

Results: Adjusting for baseline and time-updated covariates, every standard deviation lower mean eGFR (19mL/min/1.73m) and declining slope of eGFR (8mL/min/1.73m per year) were independently associated with higher risks of heart failure (hazard ratios [HRs] of 1.82 [95% CI, 1.39-2.44] and 1.28 [95% CI, 1.12-1.45], respectively) and the composite outcome (HRs of 1.32 [95% CI, 1.11-1.54] and 1.11 [95% CI, 1.03-1.20], respectively). Every standard deviation higher mean UPCR (136mg/g) and increasing UPCR (240mg/g per year) were also independently associated with higher risks of heart failure (HRs of 1.58 [95% CI, 1.28-1.97] and 1.20 [95% CI, 1.10-1.29], respectively) and the composite outcome (HRs of 1.33 [95% CI, 1.17-1.50] and 1.12 [95% CI, 1.06-1.18], respectively).

Limitations: Limited generalizability of annual eGFR and UPCR assessments; several biomarkers for cardiovascular disease risk were not available annually.

Conclusions: Using the landmark approach to account for time-updated patterns of kidney function, average and slope of eGFR and proteinuria were independently associated with 3-year cardiovascular risk. Short-term changes in kidney function provide information about cardiovascular risk incremental to level of kidney function, representing possible opportunities for more effective management of patients with chronic kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2021.03.021DOI Listing
May 2021

The Promise of Tubule Biomarkers in Kidney Disease: A Review.

Am J Kidney Dis 2021 May 27. Epub 2021 May 27.

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

For over 70 years, serum creatinine has remained the primary index for detection and monitoring of kidney disease. Tubulointerstitial damage and fibrosis are highly prognostic for subsequent kidney failure in biopsy studies, yet this pathology is invisible to the clinician in the absence of a biopsy. Recent discovery of biomarkers that reflect distinct aspects of kidney tubule disease have led to investigations of whether these markers can provide additional information on risk of chronic kidney disease (CKD) progression and associated adverse clinical end points, above and beyond estimated glomerular filtration rate and albuminuria. These biomarkers can be loosely grouped into those that mark tubule cell injury (eg, kidney injury molecule 1, monocyte chemoattractant protein 1) and those that mark tubule cell dysfunction (eg, α-microglobulin, uromodulin). These kidney tubule biomarkers provide new opportunities to monitor response to therapeutics used to treat CKD patients. In this review, we describe results from some unique contributions in this area and discuss the current challenges and requirements in the field to bring these markers to clinical practice. We advocate for a broader assessment of kidney health that moves beyond a focus on the glomerulus, and we highlight how such tools can improve diagnostic accuracy and earlier assessment of therapeutic efficacy or harm in CKD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2021.03.026DOI Listing
May 2021

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

JCI Insight 2021 Jun 8;6(11). Epub 2021 Jun 8.

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

BACKGROUNDAssessment of chronic kidney disease (CKD) risk after acute kidney injury (AKI) is based on limited 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.METHODSWe measured EGF and MCP-1 in postoperative urine samples from 865 adults who underwent cardiac surgery at 2 sites in Canada and the United States and assessed EGF and MCP-1's associations with the composite outcome of CKD incidence or progression. We used single-cell RNA-Seq (scRNA-Seq) of AKI patient biopsies to perform transcriptomic analysis of programs corregulated with the associated genes.RESULTSOver a median (IQR) follow-up of 5.8 (4.2-7.1) years, 266 (30.8%) patients developed the composite CKD outcome. Postoperatively, 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 scRNA-Seq transcriptomes in patients with AKI-defined cell populations revealed concordant changes in EGF and MCP-1 levels and underlying molecular processes associated with loss of EGF expression and gain of CCL2 (encoding MCP-1) expression.CONCLUSIONUrinary EGF and MCP-1 were each independently associated with CKD after cardiac surgery. These markers may serve as noninvasive indicators of tubular damage, supported by tissue transcriptomes, and provide an opportunity for novel interventions in cardiac surgery.TRIAL REGISTRATIONClinicalTrials.gov NCT00774137.FUNDINGThe NIH funded the TRIBE-AKI Consortium and Kidney Precision Medicine Project. Yale O'Brien Kidney Center, American Heart Association, Patterson Trust Fund, Dr. Adam Linton Chair in Kidney Health Analytics, Canadian Institutes of Health Research, ICES, Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine & Dentistry, Western University, Lawson Health Research Institute, Chan Zuckerberg Initiative Human Cell Atlas Kidney Seed Network.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/jci.insight.147464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262289PMC
June 2021

The authors reply.

Kidney Int 2021 05;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:

View Article and Find Full Text PDF

Download full-text PDF

Source
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 09 20;78(3):361-368.e1. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2021.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384678PMC
September 2021

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

Heart 2021 Aug 10;107(16):1282-1288. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/heartjnl-2020-318004DOI Listing
August 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000511848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482418PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2020.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200370PMC
July 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 2021 06 9;77(6):907-919. Epub 2020 Dec 9.

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

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

Study Design: Observational, case-cohort study design.

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

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

Outcomes: The primary outcomes were incident HF and AF.

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

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

Limitations: Observational study.

Conclusions: In CKD, increases in NT-proBNP were significantly associated with greater risk of incident HF and AF, and increases in sST2 were associated with HF. Further studies should investigate whether these markers of subclinical cardiovascular disease can be modified to reduce the risk of cardiovascular disease in CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2020.09.021DOI Listing
June 2021

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

J Am Geriatr Soc 2021 03 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2020.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8102017PMC
May 2021

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

Clin Chem 2021 01;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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 03 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jgs.16910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175094PMC
March 2021

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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 01 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2020040487DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894671PMC
January 2021
-->