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D’Antonio M, Arthur TD, Gonzalez Rivera WG, Wu X, Nguyen JP, Gymrek M, Woo-Yeong P, Frazer KA. Genetic analysis of elevated levels of creatinine and cystatin C biomarkers reveals novel genetic loci associated with kidney function. Hum Mol Genet 2025; 34:751-764. [PMID: 39927731 PMCID: PMC12010162 DOI: 10.1093/hmg/ddaf018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 01/22/2025] [Accepted: 01/30/2025] [Indexed: 02/11/2025] Open
Abstract
The rising prevalence of chronic kidney disease (CKD), affecting an estimated 37 million adults in the United States, presents a significant global health challenge. CKD is typically assessed using estimated Glomerular Filtration Rate (eGFR), which incorporates serum levels of biomarkers such as creatinine and cystatin C. However, these biomarkers do not directly measure kidney function; their elevation in CKD results from diminished glomerular filtration. Genome-wide association studies (GWAS) based on eGFR formulas using creatinine (eGFRcre) or cystatin C (eGFRcys) have identified distinct non-overlapping loci, raising questions about whether these loci govern kidney function or biomarker metabolism. In this study, we show that GWAS on creatinine and cystatin C levels in healthy individuals reveal both nonoverlapping genetic loci impacting their metabolism as well as overlapping genetic loci associated with kidney function; whereas GWAS on elevated levels of these biomarkers uncover novel loci primarily associated with kidney function in CKD patients.
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Affiliation(s)
- Matteo D’Antonio
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Timothy D Arthur
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
- Biomedical Sciences Graduate Program, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Wilfredo G Gonzalez Rivera
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
- Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Ximei Wu
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Jennifer P Nguyen
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
- Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Melissa Gymrek
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
- Department of Computer Science and Engineering, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
- Department of Medicine, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093, United States
| | - Park Woo-Yeong
- Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Keimyung University Dongsan Hospital, 1035 Dalgubeol-daero, Daegu, Republic of Korea
| | - Kelly A Frazer
- Department of Pediatrics, University of California San Diego, 9500 Gilman Dr., La Jolla, CA, 92093, United States
- Institute of Genomic Medicine, University of California San Diego, 9500 Gilman Dr, 9500 Gilman Dr., La Jolla, CA 92093, United States
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Oka T, Inker LA, Chaudhari J, Tighiouart H, Flanagin EP, Siggeirsdottir K, Indridason OS, Palsson R, Gudnason VG, Levey AS. Glomerular Filtration of Creatinine: Validation of a Novel Index of Muscle Mass Among Older Adults. Am J Kidney Dis 2025; 85:339-352. [PMID: 39674339 DOI: 10.1053/j.ajkd.2024.09.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 09/06/2024] [Accepted: 09/18/2024] [Indexed: 12/16/2024]
Abstract
RATIONALE & OBJECTIVE Low muscle mass is common among older adults and associated with poor prognosis. Quantifying muscle mass is challenging in routine clinical practice. We hypothesized that glomerular filtration of creatinine (GFcr) reflects muscle mass, and previously proposed estimated GFcr (eGFcr), as a practical index of muscle mass in older adults. This study investigated whether measured GFcr (mGFcr) and eGFcr are similarly associated with the direct measure of muscle mass, the thigh total muscle lean area (TTMLA). STUDY DESIGN Cross-sectional analysis of a community-based prospective cohort. SETTING & PARTICIPANTS A total of 794 older adults with measured glomerular filtration rate (mGFR) and TTMLA in the AGES-Reykjavik Study. EXPOSURE Measured GFcr, the product of serum creatinine (Scr) and mGFR obtained using plasma iohexol clearance and eGFcr, the product of Scr and estimated glomerular filtration rate using serum cystatin C (Scys). OUTCOME TTMLA measured using computed tomography. ANALYTICAL APPROACH Sex-specific Pearson's correlation and linear regression analyses using continuous and categorical mGFcr and eGFcr. Covariates included demographic, behavioral, and clinical variables, and comorbid conditions. RESULTS The mean age and mGFR were 80.3±4.0 (SD) years and 62.3±16.5 (SD) mL/min/1.73m2, respectively. The lowest sex-specific tertile of mGFcr, compared with the highest tertile, was associated with a 14.6 (95% CI, 11.5-17.6) cm2/1.73m2 lower TTMLA in men, and a 7.9 (95% CI, 5.5-10.2) cm2/1.73m2 lower TTMLA in women. Significant associations were observed between eGFcr and TTMLA. Correlations of eGFcr with TTMLA were generally as strong or stronger than correlations of alternative indices derived from Scr and Scys. LIMITATIONS Residual confounding by measured and unmeasured variables. CONCLUSIONS These findings support the validity of GFcr as an index of muscle mass among older adults and the use of eGFcr as a practical alternative to mGFcr in the clinical setting. PLAIN-LANGUAGE SUMMARY Low muscle mass is common among older adults and is associated with poor clinical outcomes. Quantifying muscle mass is challenging in routine clinical practice. We evaluated whether glomerular filtration of creatinine (GFcr) could serve as an index of muscle mass. We performed a cross-sectional study including 794 older adults who underwent computed tomography for thigh muscle lean area as a directly measured indicator of total body muscle mass. Significant positive associations between thigh muscle lean area and both measured GFcr (serum creatinine [Scr] ×measured glomerular filtration rate [GFR]) and estimated GFcr (Scr ×estimated GFR based on serum cystatin C [Scys]), a more practical index, were shown. These findings suggest the value of using eGFcr, a simply obtained novel index in the clinical setting, to assess muscle mass among older adults.
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Affiliation(s)
- Tatsufumi Oka
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts; Department of Nephrology, Osaka University Graduate School of Medicine, Osaka, Japan.
| | - Lesley A Inker
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Juhi Chaudhari
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Hocine Tighiouart
- Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Massachusetts; Tufts Clinical and Translational Science Institute, Tufts University, Boston, Massachusetts
| | - Erin P Flanagin
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Kristin Siggeirsdottir
- Icelandic Heart Association Research Institute, Kopavogur, Iceland; Janus Rehabilitation, Reykjavik, Iceland
| | - Olafur S Indridason
- Section of Nephrology, Internal Medicine Services, Landspitali University Hospital, Reykjavik, Iceland
| | - Runolfur Palsson
- Section of Nephrology, Internal Medicine Services, Landspitali University Hospital, Reykjavik, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Vilmundur G Gudnason
- Icelandic Heart Association Research Institute, Kopavogur, Iceland; Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Andrew S Levey
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
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Dallmeier D, Braisch J, Denkinger M, Koenig W, Rothenbacher D. Three-year changes in high-sensitivity cardiac troponin-T and total mortality in older adults. Sci Rep 2024; 14:28412. [PMID: 39557882 PMCID: PMC11574211 DOI: 10.1038/s41598-024-78641-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Accepted: 11/04/2024] [Indexed: 11/20/2024] Open
Abstract
Elevated high-sensitivity cardiac troponin-T (hs-cTnT) is associated with mortality in older adults. However, little is known about the implications of changes over time. We investigated hs-cTnT 3-year change and its association with subsequent mortality in the Activity and Function in the Elderly Study. Participants with baseline and follow-up hs-cTnT < 5 ng/L built the reference group (G1 = 156). Five groups were defined among those with an increment over time: Undetectable at baseline: follow-up < 14 ng/L (G2 = 295), follow-up ≥ 14 ng/L (G3 = 24). Baseline 5 to <14 ng/L: follow-up < 14 ng/L (G4 = 101), follow-up ≥ 14 ng/L (G5 = 96). G6 included baseline and follow-up > 14 ng/L (n = 74). Cox-proportional hazards models evaluated the association with mortality adjusting for age, sex, education, cardiovascular disease, chronic kidney disease, number of medications, hs-CRP, and NT-proBNP. Among 745 participants (median age 75.9 years, 58.9% male) we observed 98 deaths (median follow-up 4.8 years). G1 had the lowest mortality rate (MR) (5.2 per 1000 person-years). The highest MR were observed by follow-up ≥ 14 ng/L: G3: 95.4 and G6: 100.4 per 1000 person-years, with an adjusted hazard ratio of 5.22 [95% CI 1.46, 18.65] and 3.40 [95% CI 1.02, 11.34], respectively. Hs-cTnT trajectories could help to identify older adults with a high mortality risk even after further adjustment including hs-CRP and NT-proBNP.
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Affiliation(s)
- Dhayana Dallmeier
- Research Unit on Ageing, AGAPLESION Bethesda Clinic Ulm, Ulm, Germany.
- Medical Faculty, Ulm University, Ulm, Germany.
- Department of Epidemiology, Boston University School of Public Health, Boston, USA.
| | - Johanna Braisch
- Research Unit on Ageing, AGAPLESION Bethesda Clinic Ulm, Ulm, Germany
- Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
| | - Michael Denkinger
- Research Unit on Ageing, AGAPLESION Bethesda Clinic Ulm, Ulm, Germany
- Institute for Geriatric Research, Ulm University Medical Center, Ulm, Germany
| | - Wolfgang Koenig
- Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
- School of Medicine and Health, German Heart Centre, Technical University of Munich, TUM University Hospital, Munich, Germany
- Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
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Hanna PE, Ouyang T, Tahir I, Katz‐Agranov N, Wang Q, Mantz L, Strohbehn I, Moreno D, Harden D, Dinulos JE, Cosar D, Seethapathy H, Gainor JF, Shah SJ, Gupta S, Leaf DE, Fintelmann FJ, Sise ME. Sarcopenia, adiposity and large discordance between cystatin C and creatinine-based estimated glomerular filtration rate in patients with cancer. J Cachexia Sarcopenia Muscle 2024; 15:1187-1198. [PMID: 38646842 PMCID: PMC11154767 DOI: 10.1002/jcsm.13469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 12/15/2023] [Accepted: 03/06/2024] [Indexed: 04/23/2024] Open
Abstract
BACKGROUND Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with sarcopenia. While cystatin C-based eGFR (eGFRCYS) is less affected by muscle mass, it may underestimate kidney function in patients with obesity. We sought to evaluate the relationship between body composition defined by computed tomography (CT) scans and discordance between creatinine, eGFRCRE and eGFRCYS in adult patients with cancer. METHODS This study is a cross-sectional study of consecutive adults with cancer with an abdominal CT scan performed within 90 days of simultaneous eGFRCRE and eGFRCYS measurements between May 2010 and January 2022. Muscle and adipose tissue cross-sectional areas were measured at the level of the third lumbar vertebral body using a validated deep-learning pipeline. CT-defined sarcopenia was defined using independent sex-specific cut-offs for skeletal muscle index (<39 cm2/m2 for women and <55 cm2/m2 for men). High adiposity was defined as the highest sex-specific quartile of the total (visceral plus subcutaneous) adiposity index in the cohort. The primary outcome was eGFR discordance, defined by eGFRCYS > 30% lower than eGFRCRE; the secondary outcome was eGFRCYS > 50% lower than eGFRCRE. The odds of eGFR discordance were estimated using multivariable logistic regression modelling. Unadjusted spline regression was used to evaluate the relationship between skeletal muscle index and the difference between eGFRCYS and eGFRCRE. RESULTS Of the 545 included patients (mean age 63 ± 14 years, 300 [55%] females, 440 [80.7%] non-Hispanic white), 320 (58.7%) met the criteria for CT-defined sarcopenia, and 136 (25%) had high adiposity. A total of 259 patients (48%) had >30% eGFR discordance, and 122 (22.4%) had >50% eGFR discordance. After adjustment for potential confounders, CT-defined sarcopenia and high adiposity were both associated with >30% eGFR discordance (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.12-3.24; aOR 2.01, 95% CI 1.15-3.52, respectively) and >50% eGFR discordance (aOR 2.34, 95% CI 1.21-4.51; aOR 2.23, 95% CI 1.19-4.17, respectively). A spline model demonstrated that as skeletal muscle index decreases, the predicted difference between eGFRCRE and eGFRCYS widens considerably. CONCLUSIONS CT-defined sarcopenia and high adiposity are both independently associated with large eGFR discordance. Incorporating valuable information from body composition analysis derived from CT scans performed as a part of routine cancer care can impact the interpretation of GFR estimates.
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Affiliation(s)
- Paul E. Hanna
- Division of Nephrology, Department of MedicineMedical College of WisconsinMilwaukeeWIUSA
| | - Tianqi Ouyang
- Division of Nephrology, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | - Ismail Tahir
- Department of RadiologyMassachusetts General HospitalBostonMAUSA
| | - Nurit Katz‐Agranov
- Division of Nephrology, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | - Qiyu Wang
- Division of Nephrology, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | - Lea Mantz
- Department of RadiologyMassachusetts General HospitalBostonMAUSA
- Department of Diagnostic and Interventional RadiologyUniversity Medical Center of the Johannes Gutenberg University MainzMainzGermany
| | - Ian Strohbehn
- Division of Nephrology, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | - Daiana Moreno
- Division of Nephrology, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | - Destiny Harden
- Division of Nephrology, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | - James E. Dinulos
- Division of Nephrology, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | - Duru Cosar
- Division of Nephrology, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | - Harish Seethapathy
- Division of Nephrology, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | - Justin F. Gainor
- Division of Hematology and Oncology, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | - Sachin J. Shah
- Division of General Internal Medicine, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | - Shruti Gupta
- Division of Renal Medicine, Department of MedicineBrigham and Women's HospitalBostonMAUSA
- Adult Survivorship ProgramDana‐Farber Cancer InstituteBostonMAUSA
| | - David E. Leaf
- Division of General Internal Medicine, Department of MedicineMassachusetts General HospitalBostonMAUSA
| | | | - Meghan E. Sise
- Division of Nephrology, Department of MedicineMassachusetts General HospitalBostonMAUSA
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Tully NW, Chappell MC, Evans JK, Jensen ET, Shaltout HA, Washburn LK, South AM. The role of preterm birth in stress-induced sodium excretion in young adults. J Hypertens 2024; 42:1086-1093. [PMID: 38690907 PMCID: PMC11068094 DOI: 10.1097/hjh.0000000000003705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
BACKGROUND Early-life programming due to prematurity and very low birth weight (VLBW, <1500 g) is believed to contribute to development of hypertension, but the mechanisms remain unclear. Experimental data suggest that altered pressure natriuresis (increased renal perfusion pressure promoting sodium excretion) may be a contributing mechanism. We hypothesize that young adults born preterm will have a blunted pressure natriuresis response to mental stress compared with those born term. METHODS In this prospective cohort study of 190 individuals aged 18-23 years, 156 born preterm with VLBW and 34 controls born term with birth weight at least 2500 g, we measured urine sodium/creatinine before and after a mental stress test and continuous blood pressure before and during the stress test. Participants were stratified into groups by the trajectory at which mean arterial pressure (MAP) increased following the test. The group with the lowest MAP trajectory was the reference group. We used generalized linear models to assess poststress urine sodium/creatinine relative to the change in MAP trajectory and assessed the difference between groups by preterm birth status. RESULTS Participants' mean age was 19.8 years and 57% were women. Change in urine sodium/creatinine per unit increase in MAP when comparing middle trajectory group against the reference group was greater in those born preterm [β 5.4%, 95% confidence interval (95% CI) -11.4 to 5.3] than those born term (β 38.5%, 95% CI -0.04 to 92.0), interaction term P = 0.002. CONCLUSION We observed that, as blood pressure increased following mental stress, young adults born preterm exhibited decreased sodium excretion relative to term-born individuals.
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Affiliation(s)
| | - Mark C. Chappell
- Department of Surgery-Hypertension and Vascular Research, Wake Forest University School of Medicine
| | - Joni K. Evans
- Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest University School of Medicine
| | - Elizabeth T. Jensen
- Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University School of Medicine
| | - Hossam A. Shaltout
- Department of Surgery-Hypertension and Vascular Research, Wake Forest University School of Medicine
- Department of Obstetrics and Gynecology, Wake Forest University School of Medicine
| | - Lisa K. Washburn
- Department of Pediatrics, Wake Forest University School of Medicine
| | - Andrew M. South
- Department of Surgery-Hypertension and Vascular Research, Wake Forest University School of Medicine
- Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest University School of Medicine
- Section of Nephrology, Department of Pediatrics, Wake Forest University School of Medicine, Winston Salem, NC, USA
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Pickett LR, Daukshus NP, Camacho-Bydume C, Mathew S, Mauguen A, Cohen N, Cancio M. Retrospective Evaluation of Cystatin C as a Measure of Renal Function in Pediatric Hematopoietic Stem Cell Transplant Patients Receiving Foscarnet for Cytomegalovirus Reactivation. Pediatr Infect Dis J 2024; 43:457-462. [PMID: 38190640 DOI: 10.1097/inf.0000000000004238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2024]
Abstract
BACKGROUND Cytomegalovirus (CMV) infection following allogeneic hematopoietic cell transplantation has considerable morbidity and mortality, and foscarnet is a treatment option that requires renal dose adjustment. Serum creatinine (SCr)-based estimated glomerular filtration rate (eGFR) equations are used to estimate renal function for patients receiving foscarnet, but cystatin C (cysC) has been shown as a possible alternative. Data examining cysC-based eGFR in this population is sparse. Our primary objective was to evaluate outcomes of patients treated with foscarnet dosed utilizing cysC-based eGFR versus SCr-based eGFR. METHODS We analyzed patients on the transplantation and cellular therapies service at Memorial Sloan Kettering Kids from January 2011 to September 2021 who received allogeneic hematopoietic cell transplantation and ≥14 days of foscarnet for CMV infection. Patients with cysC-based eGFR were compared to a historical cohort of patients who only had SCr-based eGFR. Outcomes included time to CMV clearance, death or change in anti-CMV therapy. Cumulative incidence curves and cause-specific hazards model were used for analysis. RESULTS In 61 analyzed patients, no differences were found between the cohorts in cumulative incidence of change in anti-CMV therapy ( P = 0.17) or death ( P = 0.69). After adjustment for multiple confounders, patients in the SCr cohort seemed to have a higher chance of CMV clearance compared with the cysC cohort, but the difference was not statistically significant (hazard ratio = 2.42, P = 0.089). Patients who received corticosteroids appeared to have lower incidence of CMV clearance ( P = 0.056). CONCLUSIONS We did not find differences in outcomes when dosing foscarnet using cysC versus SCr for treatment of CMV infection.
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Affiliation(s)
- Logan R Pickett
- From the Department of Pharmacy, Children's Healthcare of Atlanta, Atlanta, Georgia
| | - Nicole P Daukshus
- Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Christine Camacho-Bydume
- Department of Pediatric Blood and Marrow Transplant and Cellular Therapy, Joseph M. Sanzari Children's Hospital, Hackensack University Medical Center, Hackensack, New Jersey
| | - Sherry Mathew
- Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York City, New York
| | | | - Nina Cohen
- Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York City, New York
| | - Maria Cancio
- Stem Cell Transplantation and Cellular Therapies, MSK Kids, Memorial Sloan Kettering Cancer Center, New York City, New York
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Hammer T, Braisch U, Rothenbacher D, Denkinger M, Dallmeier D. Relationship between hemoglobin and grip strength in older adults: the ActiFE study. Aging Clin Exp Res 2024; 36:59. [PMID: 38451343 PMCID: PMC10920471 DOI: 10.1007/s40520-024-02698-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 01/05/2024] [Indexed: 03/08/2024]
Abstract
INTRODUCTION Although anemia is associated with low muscle strength, hemoglobin has been rarely studied considering ferritin. AIM To analyze the association between hemoglobin and grip strength in community-dwelling older adults. METHODS We used data from a German cohort of adults ≥ 65 years, excluding those with CRP > 10 mg/L or taking iron supplements. Grip strength (kg) was measured using a Jamar dynamometer. Analysis was performed using multiple linear regression, adjusted for established confounders. Due to interaction, age-stratified (< 80, 80 +), further sex-stratified analysis in those < 80 years old and ferritin-stratified in men < 80 years were performed. RESULTS In total, 1294 participants were included in this analysis (mean age 75.5 years, 549 (42.3%) women, 910 (70.3%) < 80 years). On average, hemoglobin and grip strength were 14.9 g/dL and 41.3 kg for men, 13.9 g/dL and 25.1 kg for women. Hemoglobin was significantly positively associated with grip strength only among women < 80 years (β 0.923 [95% CI 0.196, 1.650]). For men < 80 years, the association was significant when ferritin was ≥ 300 µg/L (β 2.028 [95% CI 0.910, 3.146]). No association was detected among those participants 80 + . DISCUSSION AND CONCLUSIONS Our data show an association between hemoglobin and grip strength only in women < 80 years old. For men < 80 years, the association was only significant with ferritin levels ≥ 300 µg/L. Considering the decreasing levels of hemoglobin and grip strength and the high prevalence of iron deficiency in older adults further analyses investigating this relationship with more iron specific parameters such as transferrin saturation are warranted.
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Affiliation(s)
- Theresa Hammer
- Research Unit on Ageing at Agaplesion Bethesda Clinic Ulm, Ulm, Germany
- Institute for Geriatric Research, Ulm University, Ulm, Germany
| | - Ulrike Braisch
- Research Unit on Ageing at Agaplesion Bethesda Clinic Ulm, Ulm, Germany
- Institute of Epidemiology and Medical Biometry, Ulm University, Ulm, Germany
| | | | - Michael Denkinger
- Research Unit on Ageing at Agaplesion Bethesda Clinic Ulm, Ulm, Germany
- Institute for Geriatric Research, Ulm University, Ulm, Germany
- Medical Faculty, Ulm University, Ulm, Germany
| | - Dhayana Dallmeier
- Research Unit on Ageing at Agaplesion Bethesda Clinic Ulm, Ulm, Germany.
- Medical Faculty, Ulm University, Ulm, Germany.
- Department of Epidemiology, Boston University School of Public Health, Boston, USA.
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Moritz L, Schumann A, Pohl M, Köttgen A, Hannibal L, Spiekerkoetter U. A systematic review of metabolomic findings in adult and pediatric renal disease. Clin Biochem 2024; 123:110703. [PMID: 38097032 DOI: 10.1016/j.clinbiochem.2023.110703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 12/03/2023] [Accepted: 12/07/2023] [Indexed: 12/29/2023]
Abstract
Chronic kidney disease (CKD) affects over 0.5 billion people worldwide across their lifetimes. Despite a growingly ageing world population, an increase in all-age prevalence of kidney disease persists. Adult-onset forms of kidney disease often result from lifestyle-modifiable metabolic illnesses such as type 2 diabetes. Pediatric and adolescent forms of renal disease are primarily caused by morphological abnormalities of the kidney, as well as immunological, infectious and inherited metabolic disorders. Alterations in energy metabolism are observed in CKD of varying causes, albeit the molecular mechanisms underlying pathology are unclear. A systematic indexing of metabolites identified in plasma and urine of patients with kidney disease alongside disease enrichment analysis uncovered inborn errors of metabolism as a framework that links features of adult and pediatric kidney disease. The relationship of genetics and metabolism in kidney disease could be classified into three distinct landscapes: (i) Normal genotypes that develop renal damage because of lifestyle and / or comorbidities; (ii) Heterozygous genetic variants and polymorphisms that result in unique metabotypes that may predispose to the development of kidney disease via synergistic heterozygosity, and (iii) Homozygous genetic variants that cause renal impairment by perturbing metabolism, as found in children with monogenic inborn errors of metabolism. Interest in the identification of early biomarkers of onset and progression of CKD has grown steadily in the last years, though it has not translated into clinical routine yet. This systematic review indexes findings of differential concentration of metabolites and energy pathway dysregulation in kidney disease and appraises their potential use as biomarkers.
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Affiliation(s)
- Lennart Moritz
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Anke Schumann
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany; Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Martin Pohl
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Anna Köttgen
- Institute of Genetic Epidemiology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Luciana Hannibal
- Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany.
| | - Ute Spiekerkoetter
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center, University of Freiburg, 79106 Freiburg, Germany.
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Nagel G, Kurz D, Peter RS, Rosenbohm A, Koenig W, Dupuis L, Bäzner H, Börtlein A, Dempewolf S, Schabet M, Hecht M, Kohler A, Opherk C, Naegele A, Sommer N, Lindner A, Tumani H, Ludolph AC, Rothenbacher D. Cystatin C based estimation of chronic kidney disease and amyotrophic lateral sclerosis in the ALS registry Swabia: associated risk and prognostic value. Sci Rep 2023; 13:19594. [PMID: 37949878 PMCID: PMC10638424 DOI: 10.1038/s41598-023-46179-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 10/28/2023] [Indexed: 11/12/2023] Open
Abstract
Kidney function as part of metabolic changes could be associated with amyotrophic lateral-sclerosis (ALS). We investigated the associations between estimated chronic kidney disease (CKD), based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) cystatin C equation, and the risk at onset and prognostic value of CKD for ALS. Between October 2010 and June 2014, 362 ALS cases (59.4% men, mean age 65.7 years) and 681 controls (59.5% men, means age 66.3 years) were included in a population-based case-control study based on the ALS registry Swabia in Southern Germany. All ALS cases were followed-up (median 89.7 months), 317 died. Serum samples were measured for cystatin C to estimate the glomerular filtration rate (eGFR) according to the CKD-EPI equation. Information on covariates were assessed by an interview-based standardized questionnaire. Conditional logistic regression models were applied to calculate odds ratios (OR) for risk of ALS associated with eGFR/CKD stages. Time-to-death associated with renal parameters at baseline was assessed in ALS cases only. ALS cases were characterized by lower body mass index, slightly lower smoking prevalence, more intense occupational work and lower education than controls. Median serum cystatin-C based eGFR concentrations were lower in ALS cases than in controls (54.0 vs. 59.5 mL/min pro 1.73 m2). The prevalence of CKD stage ≥ 3 was slightly higher in ALS cases than in controls (14.1 vs. 11.0%). In the adjusted models, CKD stage 2 (OR 1.82, 95% CI 1.32, 2.52) and stage 3 (OR 2.34, 95% CI 1.38, 3.96) were associated with increased ALS risk. In this cohort of ALS cases, eGFR and CKD stage ≥ 3 (HR 0.94; 95% CI 0.64, 1.38) were not associated with prognosis. In this case-control study, higher CKD stages were associated with increased ALS risk, while in the prospective cohort of ALS cases, no indication of an association of CysC-based CKD on mortality was seen. In addition, our work strengthens the importance to evaluate renal function using a marker independent of muscle mass in ALS patients.
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Affiliation(s)
- Gabriele Nagel
- Institute of Epidemiology and Medical Biometry, Ulm University, Helmholtzstr. 22, 89081, Ulm, Germany.
| | - Deborah Kurz
- Institute of Epidemiology and Medical Biometry, Ulm University, Helmholtzstr. 22, 89081, Ulm, Germany
| | - Raphael S Peter
- Institute of Epidemiology and Medical Biometry, Ulm University, Helmholtzstr. 22, 89081, Ulm, Germany
| | | | - Wolfgang Koenig
- Institute of Epidemiology and Medical Biometry, Ulm University, Helmholtzstr. 22, 89081, Ulm, Germany
- Deutsches Herzzentrum München, Technische Universität München, Munich, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany
| | - Luc Dupuis
- Université de Strasbourg, Inserm, UMR-S1118, Centre de Recherches en Biomédecine de Strasbourg, Strasbourg, France
| | - Hansjörg Bäzner
- Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany
| | - Axel Börtlein
- Department of Neurology, Klinikum Stuttgart, Stuttgart, Germany
| | - Silke Dempewolf
- Department of Neurology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany
| | - Martin Schabet
- Department of Neurology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany
| | - Martin Hecht
- Department of Neurology, Klinikum Kaufbeuren, Kliniken Ostallgäu Kaufbeuren, Kaufbeuren, Germany
| | - Andreas Kohler
- Department of Neurology, Klinikum am Gesundbrunnen Heilbronn, Heilbronn, Germany
| | - Christian Opherk
- Department of Neurology, Klinikum am Gesundbrunnen Heilbronn, Heilbronn, Germany
| | - Andrea Naegele
- Department of Neurology, Christophsbad Goeppingen, Goeppingen, Germany
| | - Norbert Sommer
- Department of Neurology, Christophsbad Goeppingen, Goeppingen, Germany
| | - Alfred Lindner
- Department of Neurology, Marienhospital Stuttgart, Stuttgart, Germany
| | | | - Albert C Ludolph
- Department of Neurology, Ulm University, Ulm, Germany
- Deutsches Zentrum Für Neurodegenerative Erkrankungen (DZNE), Ulm, Germany
| | - Dietrich Rothenbacher
- Institute of Epidemiology and Medical Biometry, Ulm University, Helmholtzstr. 22, 89081, Ulm, Germany
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10
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Hanna PE, Wang Q, Strohbehn IA, Moreno D, Harden D, Ouyang T, Katz-Agranov N, Seethapathy H, Reynolds KL, Gupta S, Leaf DE, Sise ME. Medication-Related Adverse Events and Discordancies in Cystatin C-Based vs Serum Creatinine-Based Estimated Glomerular Filtration Rate in Patients With Cancer. JAMA Netw Open 2023; 6:e2321715. [PMID: 37405775 PMCID: PMC10323710 DOI: 10.1001/jamanetworkopen.2023.21715] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 05/19/2023] [Indexed: 07/06/2023] Open
Abstract
Importance Serum creatinine-based estimated glomerular filtration rate (eGFRcr) may overestimate the glomerular filtration rate (GFR) in patients with cancer. Cystatin C-based eGFR (eGFRcys) is an alternative marker of GFR. Objective To determine whether the therapeutic drug levels and adverse events (AEs) associated with renally cleared medications were higher in patients with cancer whose eGFRcys was more than 30% lower than their eGFRcr. Design, Setting, and Participants This cohort study analyzed adult patients with cancer at 2 major academic cancer centers in Boston, Massachusetts. These patients had their creatinine and cystatin C measured on the same day between May 2010 and January 2022. The date of the first simultaneous eGFRcr and eGFRcys measurement was considered to be the baseline date. Exposure The primary exposure was eGFR discordance, defined as an eGFRcys that was more than 30% lower than the eGFRcr. Main Outcomes and Measures The primary outcome was risk of the following medication-related AEs within 90 days of the baseline date: (1) supratherapeutic vancomycin trough level greater than 30 μg/mL, (2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5 mEq/L), (3) baclofen toxic effect, and (4) supratherapeutic digoxin level (>2.0 ng/mL). For the secondary outcome, a multivariable Cox proportional hazards regression model was used to compare 30-day survival of those with vs without eGFR discordance. Results A total of 1869 adult patients with cancer (mean [SD] age, 66 [14] years; 948 males [51%]) had simultaneous eGFRcys and eGFRcr measurement. There were 543 patients (29%) with an eGFRcys that was more than 30% lower than their eGFRcr. Patients with an eGFRcys that was more than 30% lower than their eGFRcr were more likely to experience medication-related AEs compared with patients with concordant eGFRs (defined as eGFRcys within 30% of eGFRcr), including vancomycin levels greater than 30 μg/mL (43 of 179 [24%] vs 7 of 77 [9%]; P = .01), trimethoprim-sulfamethoxazole-related hyperkalemia (29 of 129 [22%] vs 11 of 92 [12%]; P = .07), baclofen toxic effects (5 of 19 [26%] vs 0 of 11; P = .19), and supratherapeutic digoxin levels (7 of 24 [29%] vs 0 of 10; P = .08). The adjusted odds ratio for vancomycin levels more than 30 μg/mL was 2.59 (95% CI, 1.08-7.03; P = .04). Patients with an eGFRcys more than 30% lower than their eGFRcr had an increased 30-day mortality (adjusted hazard ratio, 1.98; 95% CI, 1.26-3.11; P = .003). Conclusions and relevance Results of this study suggest that among patients with cancer with simultaneous assessment of eGFRcys and eGFRcr, supratherapeutic drug levels and medication-related AEs occurred more commonly in those with an eGFRcys more than 30% lower than their eGFRcr. Future prospective studies are needed to improve and personalize GFR estimation and medication dosing in patients with cancer.
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Affiliation(s)
- Paul E. Hanna
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Qiyu Wang
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Ian A. Strohbehn
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Daiana Moreno
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Destiny Harden
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Tianqi Ouyang
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Nurit Katz-Agranov
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Harish Seethapathy
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Kerry L. Reynolds
- Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston
| | - Shruti Gupta
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts
- Adult Survivorship Program, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - David E. Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, Massachusetts
| | - Meghan E. Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston
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11
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Mazer CD, Siadati-Fini N, Boehm J, Wirth F, Myjavec A, Brown CD, Koyner JL, Boening A, Engelman DT, Larsson TE, Renfurm R, de Varennes B, Noiseux N, Thielmann M, Lamy A, Laflamme M, von Groote T, Ronco C, Zarbock A. Study protocol of a phase 2, randomised, placebo-controlled, double-blind, adaptive, parallel group clinical study to evaluate the efficacy and safety of recombinant alpha-1-microglobulin in subjects at high risk for acute kidney injury following open-chest cardiac surgery (AKITA trial). BMJ Open 2023; 13:e068363. [PMID: 37024249 PMCID: PMC10410810 DOI: 10.1136/bmjopen-2022-068363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 02/06/2023] [Indexed: 04/08/2023] Open
Abstract
INTRODUCTION Acute kidney injury (AKI) is a common complication after cardiac surgery (CS) and is associated with adverse short-term and long-term outcomes. Alpha-1-microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme binding and mitochondrial-protective mechanisms. RMC-035 is a modified, more soluble, variant of A1M and has been proposed as a novel targeted therapeutic protein to prevent CS-associated AKI (CS-AKI). RMC-035 was considered safe and generally well tolerated when evaluated in four clinical phase 1 studies. METHODS AND ANALYSIS This is a phase 2, randomised, double-blind, adaptive design, parallel group clinical study that evaluates RMC-035 compared with placebo in approximately 268 cardiac surgical patients at high risk for CS-AKI. RMC-035 is administered as an intravenous infusion. In total, five doses will be given. Dosing is based on presurgery estimated glomerular filtration rate (eGFR), and will be either 1.3 or 0.65 mg/kg.The primary study objective is to evaluate whether RMC-035 reduces the incidence of postoperative AKI, and key secondary objectives are to evaluate whether RMC-035 improves postoperative renal function compared with placebo. A blinded interim analysis with potential sample size reassessment is planned once 134 randomised subjects have completed dosing. An independent data monitoring committee will evaluate safety and efficacy data at prespecified intervals throughout the trial. The study is a global multicentre study at approximately 30 sites. ETHICS AND DISSEMINATION The trial was approved by the joint ethics committee of the physician chamber Westfalen-Lippe and the University of Münster (code '2021-778 f-A') and subsequently approved by the responsible ethics committees/relevant institutional review boards for the participating sites. The study is conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER NCT05126303.
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Affiliation(s)
- C David Mazer
- Department of Anesthesia, St. Michael's Hospital, Toronto, Ontario, Canada
- Department of Anesthesiology and Pain Medicine, Physiology and Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | | | - Johannes Boehm
- Department of Cardiovascular Surgery, Technische Universität München, Munchen, Germany
- Insure (Institute for Translational Cardiac Surgery), Department of Cardiovascular Surgery, German Heart Centre Munich, Munchen, Germany
| | - Felix Wirth
- Department of Cardiovascular Surgery, Technische Universität München, Munchen, Germany
- Insure (Institute for Translational Cardiac Surgery), Department of Cardiovascular Surgery, German Heart Centre Munich, Munchen, Germany
| | - Andrej Myjavec
- Department of Cardiac Surgery, University of Hradec Kralove, Hradec Kralove, Czech Republic
| | - Craig D Brown
- Department of Cardiac Surgery, New Brunswick Heart Centre, Saint John, New Brunswick, Canada
| | - Jay L Koyner
- Department of Medicine, Section of Nephrology, University of Chicago Pritzker School of Medicine, Chicago, Illinois, USA
| | - Andreas Boening
- Department of Cardiovascular Surgery, Justus-Liebig-University, Giessen, Germany
| | - Daniel T Engelman
- Heart and Vascular Program, Baystate Medical Center, Springfield, Massachusetts, USA
| | | | - Ronny Renfurm
- Global Drug Development Unit Cardio-Renal-Metabolism, Novartis Pharma AG, Basel, Switzerland
| | - Benoit de Varennes
- Division of Cardiac Surgery, McGill University Faculty of Medicine, Montreal, Québec, Canada
| | - Nicolas Noiseux
- Division of Cardiac Surgery, Universite de Montreal, Montreal, Québec, Canada
| | - Matthias Thielmann
- Department for Thoracic and Cardiovascular Surgery, West-German Heart and Vascular Center Essen, University Duisburg-Essen, Essen, Germany
| | - Andre Lamy
- Department for Thoracic and Cardiovascular Surgery, West-German Heart and Vascular Center Essen, University Duisburg-Essen, Essen, Germany
- Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada
| | - Maxime Laflamme
- Institut universitaire de cardiologie et de pneumologie de Québec, University of Quebec, Quebec, Quebec, Canada
| | - Thilo von Groote
- Department of Anesthesiology, Intensive Care Medicine, University Hospital Münster, Munster, Germany
| | - Claudio Ronco
- International Renal Research Institute of Vicenza, San Bortolo Hospital of Vicenza, Vicenza, Italy
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care Medicine, University Hospital Münster, Munster, Germany
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12
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Yun HG, Smith AJF, DeBacker KC, Pai MP. Estimated glomerular filtration rate with and without race for drug dosing: Cystatin C vs. serum creatinine. Br J Clin Pharmacol 2023; 89:1207-1210. [PMID: 36367379 DOI: 10.1111/bcp.15592] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 10/13/2022] [Accepted: 11/08/2022] [Indexed: 11/13/2022] Open
Abstract
The goal of this study was to use a model kidney function clearance-dependent drug (vancomycin) to understand the gain or loss of precision in dosing with use of serum creatinine (Scr ), serum cystatin C (Scys ) and race and nonrace-based equations of the estimated glomerular filtration rate (eGFR). In this study of hospitalized patients, we compared Scr , Scys and their combination to estimate kidney function and vancomycin clearance. The nonrace-based Scys eGFR model outperformed other clearance models and improved the probability of target attainment by 15%. When Scys is not available, we show that the new 2021 CKD-EPI eGFRcr equation (no race factor) performs as well as the current conventional approach. This improvement in model performance does not negate the need for individualized dosing but exemplifies the need to remove race as a factor of kidney-function dose adjustment.
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Affiliation(s)
- Hyun Gi Yun
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Andrew J F Smith
- Department of Pharmacy Services, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Kenneth C DeBacker
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Manjunath P Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
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13
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Ballew SH, Zhou L, Surapaneni A, Grams ME, Windham BG, Selvin E, Coresh J, Miao S, Inker LA, Levey AS. A Novel Creatinine Muscle Index Based on Creatinine Filtration: Associations with Frailty and Mortality. J Am Soc Nephrol 2023; 34:495-504. [PMID: 36735317 PMCID: PMC10103307 DOI: 10.1681/asn.0000000000000037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 11/09/2022] [Indexed: 01/27/2023] Open
Abstract
SIGNIFICANCE STATEMENT Low muscle mass is related to frailty and increased mortality in older adults. However, muscle mass is not easily assessed in routine clinical practice. This paper describes a novel creatinine muscle index (CMI) on the basis of serum creatinine and cystatin C. CMI was moderately associated with frailty among older adults. A significantly higher proportion of individuals with weak grip strength were in the lowest tertile of CMI. The index was also associated with mortality. These results are consistent with the hypothesis that creatinine filtration may be an index of muscle mass, which may have utility in clinical practice. BACKGROUND Low muscle mass is related to frailty and increased mortality in older adults. However, muscle mass is not easily assessed in routine clinical practice. METHODS This study describes a novel creatinine muscle index (CMI) on the basis of serum creatinine and cystatin C in a community-based sample of older adults from the Atherosclerosis Risk in Communities Study. Analyses included 4639 participants who attended visit 5 (2011-2013) and 12,786 participants who attended visit 2 (1990-1992). CMI was defined as creatinine filtration (the product of serum creatinine times eGFR on the basis of cystatin C) and was analyzed in sex-specific tertiles. Cross-sectional associations of CMI with a frailty trichotomy, defined by the number (robust [0]/prefrail [1-2]/frail [3-5]) of five frailty components (weight loss, slowness, exhaustion, weakness, and low physical activity), were studied using polychotomous logistic regression and binary logistic regression with each frailty component. Cox regression was used to estimate associations of CMI at visit 5 and visit 2 with mortality. Models were adjusted for demographics, clinical variables, and comorbid conditions. RESULTS CMI (tertile 1 versus 3) was moderately associated with frailty (visit 5: adjusted odds ratio 4.23 [95% confidence interval (CI), 2.02 to 8.87] in men and 2.34 [95% CI, 1.41 to 3.89] in women) and with mortality (visit 5: adjusted hazard ratio 1.45 [95% CI, 1.08 to 1.94] in men and 1.55 [95% CI, 1.13 to 2.12] in women; similar results were seen at visit 2). CONCLUSION Lower CMI was associated with frailty and increased mortality, two clinical outcomes known to be associated with decreased muscle mass. Creatinine filtration may be an index of muscle mass and have utility in clinical practice, particularly at low levels.
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Affiliation(s)
- Shoshana H. Ballew
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
| | - Linda Zhou
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
| | - Aditya Surapaneni
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
- Department of Medicine, New York University Grossman School of Medicine, New York, New York
| | - Morgan E. Grams
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
- Department of Medicine, New York University Grossman School of Medicine, New York, New York
| | - B. Gwen Windham
- Division of Geriatrics, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
| | - Elizabeth Selvin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
| | - Shiyuan Miao
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Lesley A. Inker
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Andrew S. Levey
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
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14
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Winger ME, Caserotti P, Cauley JA, Boudreau RM, Piva SR, Cawthon PM, Orwoll ES, Ensrud KE, Kado DM, Strotmeyer ES. Lower Leg Power and Grip Strength Are Associated With Increased Fall Injury Risk in Older Men: The Osteoporotic Fractures in Men Study. J Gerontol A Biol Sci Med Sci 2023; 78:479-485. [PMID: 35662329 PMCID: PMC9977249 DOI: 10.1093/gerona/glac122] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Past research has not investigated both lower-extremity power and upper-extremity strength in the same fall injury study, particularly nonfracture fall injuries. METHODS In the Osteoporotic Fractures in Men Study (baseline: N = 5 994; age 73.7 ± 5.9 years; 10.2% non-White), fall injuries (yes/no) were assessed prospectively with questionnaires approximately every 3 years over 9 years. Maximum leg power (Watts) from Nottingham single leg press and maximum grip strength (kg) from handheld dynamometry were assessed at baseline and standardized to kg body weight. Physical performance included gait speed (6-m usual; narrow walk) and chair stands speed. RESULTS Of men with ≥1/4 follow-ups (N = 5 178; age 73.4 ± 5.7 years), 40.4% (N = 2 090) had ≥1 fall injury. In fully adjusted repeated-measures logistic regressions, lower power/kg and grip strength/kg had higher fall injury risk (trend across quartiles: both p < .0001), with lower quartiles at significantly increased risk versus highest Q4 except for grip strength Q3 versus Q4. Fall injury risk was 19% higher per 1 standard deviation (SD) lower power/kg (95% confidence interval [CI]: 1.12-1.26) and 16% higher per SD lower grip strength/kg (95% CI: 1.10-1.23). In models including both leg power/kg and grip strength/kg, odds ratios (ORs) were similar and independent of each other and physical performance (leg power/kg OR per SD = 1.13, 95% CI: 1.06-1.20; grip strength/kg OR per SD = 1.11, 95% CI: 1.05-1.17). CONCLUSIONS Lower leg power/kg and grip strength/kg predicted future fall injury risk in older men independent of physical performance. Leg power potentially identifies fall injury risk better than grip strength at higher muscle function, though grip strength may be more suitable in clinical/practice settings.
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Affiliation(s)
- Mary E Winger
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Paolo Caserotti
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Jane A Cauley
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Robert M Boudreau
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sara R Piva
- Department of Physical Therapy and Clinical and Translational Science Institute, School of Health and Rehabilitation Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Peggy M Cawthon
- Research Institute, California Pacific Medical Center, San Francisco, California, USA
- Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA
| | - Eric S Orwoll
- Oregon Health and Science University, Portland, Oregon, USA
| | - Kristine E Ensrud
- Department of Medicine and Division of Epidemiology and Community Health, University of Minnesota Center for Care Delivery and Outcomes Research, Minneapolis VA Health Care System, Minneapolis, Minnesota, USA
| | - Deborah M Kado
- Geriatrics Section, Stanford University School of Medicine, Palo Alto, California, USA
- Geriatrics Research Education and Clinical Center, Veterans Health Administration, Palo Alto, California, USA
| | - Elsa S Strotmeyer
- Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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15
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Safdar A, Akram W, Ahmad Khan M, Muhammad S. Optimal Glomerular Filtration Rate Equations for Various Age Groups, Disease Conditions and Ethnicities in Asia: A Systematic Review. J Clin Med 2023; 12:1822. [PMID: 36902609 PMCID: PMC10002889 DOI: 10.3390/jcm12051822] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/12/2023] [Accepted: 02/14/2023] [Indexed: 03/12/2023] Open
Abstract
(1) Background: The performance of estimated glomerular filtration rate (eGFR) equations in the Asian population has been widely questioned. The primary objective of this study was to gather evidence regarding optimal GFR equations in Asia for various age groups, disease conditions, and ethnicities. The secondary objective was to see whether the equations based on the combination of creatinine and cystatin C biomarkers if employed are satisfactory across different age groups and disease conditions in various ethnicities in Asia compared to those based on either of the single biomarkers. (2) Methods: Validation studies that had both creatinine and cystatin C-based equations either alone or in combination, validated in specific disease conditions, and those which compared the performance of these equations with exogenous markers were eligible only. The bias, precision, and 30% accuracy (P30) of each equation were recorded accordingly. (3) Results: Twenty-one studies consisting of 11,371 participants were included and 54 equations were extracted. The bias, precision, and P30 accuracies of the equations ranged from -14.54 to 9.96 mL/min/1.73 m2, 1.61 to 59.85 mL/min/1.73 m2, and 4.7% to 96.10%. The highest values of P30 accuracies were found for the JSN-CKDI equation (96.10%) in Chinese adult renal transplant recipients, for the BIS-2 equation (94.5%) in Chinese elderly CKD patients, and Filler equation (93.70%) also in Chinese adult renal transplant recipients. (4) Conclusions: Optimal equations were identified accordingly and it was proven that combination biomarker equations are more precise and accurate in most of the age groups and disease conditions. These can be considered equations of choice for the specific age groups, disease conditions, and ethnicities within Asia.
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Affiliation(s)
- Aqsa Safdar
- Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore 54000, Pakistan
| | - Waqas Akram
- Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore 54000, Pakistan
| | - Mahtab Ahmad Khan
- Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore 54000, Pakistan
| | - Sajjad Muhammad
- Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, Finland
- Department of Neurosurgery, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-Universität Düsseldorf, 40225 Düsseldorf, Germany
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16
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Hanna PE, Wang Q, Strohbehn I, Moreno D, Harden D, Ouyang T, Katz-Agranov N, Seethapathy H, Reynolds KL, Gupta S, Leaf DE, Sise ME. Medication-related adverse events in patients with cancer and discrepancies in cystatin C- versus creatinine-based eGFR. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.01.18.23284656. [PMID: 36711583 PMCID: PMC9882433 DOI: 10.1101/2023.01.18.23284656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Background Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with cancer. Cystatin C-based eGFR (eGFRCYS) is an alternative marker of kidney function. We investigated whether patients with an eGFR discrepancy, defined as eGFRCYS >30% lower than the concurrent eGFRCRE, had an increased risk of adverse events resulting from renally-cleared medications. Patients and Methods We conducted a cohort study of adult patients with cancer who had serum creatinine and cystatin C measured on the same day between May 2010 and January 2022 at two academic cancer centers in Boston, MA. The primary outcome was the incidence of each of the following medication-related adverse events: 1) supratherapeutic vancomycin levels (>30μg/mL); 2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5mEq/L); 3) baclofen-induced neurotoxicity; and 4) supratherapeutic digoxin levels (>2.0ng/mL). Results 1988 patients with cancer had simultaneous eGFRCYS and eGFRCRE. The mean age was 66 years (SD±14), 965 (49%) were female, and 1555 (78%) were non-Hispanic white. eGFR discrepancy occurred in 579 patients (29%). Patients with eGFR discrepancy were more likely to experience medication-related adverse events compared to those without eGFR discrepancy: vancomycin levels >30μg/mL (24% vs. 10%, p=0.004), trimethoprim- sulfamethoxazole-related hyperkalemia (24% vs. 12%, p=0.013), baclofen-induced neurotoxicity (25% vs. 0%, p=0.13), and supratherapeutic digoxin levels (38% vs. 0%, p=0.03). The adjusted OR for vancomycin levels >30μg/mL was 2.30 (95% CI 1.05 - 5.51, p = 0.047). Conclusion Among patients with cancer with simultaneous assessment of eGFRCYS and eGFRCRE, medication-related adverse events occur more commonly in those with eGFR discrepancy. These findings underscore the importance of accurate assessment of kidney function and appropriate dosing of renally-cleared medications in patients with cancer.
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Affiliation(s)
- Paul E Hanna
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Qiyu Wang
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Ian Strohbehn
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Daiana Moreno
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Destiny Harden
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Tianqi Ouyang
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Nurit Katz-Agranov
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Harish Seethapathy
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Kerry L Reynolds
- Division of Hematology and Oncology, Department of Medicine, Massachusetts General Hospital, Boston, MA
| | - Shruti Gupta
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA
- Adult Survivorship Program, Dana-Farber Cancer Institute, Boston, MA
| | - David E Leaf
- Division of Renal Medicine, Brigham and Women's Hospital, Boston, MA
| | - Meghan E Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA
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17
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Hałka J, Spaleniak S, Kade G, Antosiewicz S, Sigorski D. The Nephrotoxicity of Drugs Used in Causal Oncological Therapies. Curr Oncol 2022; 29:9681-9694. [PMID: 36547174 PMCID: PMC9776938 DOI: 10.3390/curroncol29120760] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/25/2022] [Accepted: 11/29/2022] [Indexed: 12/14/2022] Open
Abstract
In recent years, a dynamic development of oncology has been observed, resulting from the increasingly frequent occurrence of neoplasms and therefore, increasing population of patients. The most effective form of therapy for cancer patients is complex multidisciplinary specialized disease management, including nephro-oncology care. Different forms of renal function impairment are frequently diagnosed in cancer patients. They are caused by different co-morbidities existing before starting the oncologic treatment as well as the direct undesirable effects of this therapy which may cause temporary or irreversible damage of the urinary system-especially kidneys. According to different therapeutic programs, in such cases the degree of renal damage is often crucial for the possibility of further anti-cancer treatment. Medical personnel responsible for delivering care to oncology patients should be properly educated on current methods of prevention and treatment of renal complications resulting from anti-cancer therapy. The development of oncologic medicines design, including especially immuno-oncological agents, obliges us to learn new patomechanisms determining potential adverse effects, including renal complications. This publication is focused on the most important undesirable nephrotoxic effects of the frequently used anti-cancer drugs.
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Affiliation(s)
- Janusz Hałka
- Department of Clinical Hematology, Warmian-Masurian Cancer Center of the Ministry of the Interior and Administration’s Hospital, Wojska Polskiego 37, 10-228 Olsztyn, Poland
| | - Sebastian Spaleniak
- Department of Internal Diseases and Nephrodiabetology, Medical University of Lodz, Żeromskiego 113, 90-549 Lodz, Poland
- Correspondence:
| | - Grzegorz Kade
- Warmian-Masurian Cancer Center of the Ministry of the Interior and Administration’s Hospital, Wojska Polskiego 37, 10-228 Olsztyn, Poland
| | - Stefan Antosiewicz
- Military Institute of Aviation Medicine, Center of Aeromedical Examination and Occupational Medicine, Zygmunta Krasińskiego 54/56, 01-755 Warsaw, Poland
| | - Dawid Sigorski
- Department of Oncology, Collegium Medicum, University of Warmia and Mazury, Aleja Warszawska 30, 11-082 Olsztyn, Poland
- Department of Oncology and Immuno-Oncology, Warmian-Masurian Cancer Center of the Ministry of the Interior and Administration’s Hospital, Wojska Polskiego 37, 10-228 Olsztyn, Poland
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18
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Sills ES, Wood SH, Walsh APH. Covid-19 and adolescent acute kidney injury: Renal recovery with combined enalapril and estrogen therapy. Clin Chim Acta 2022; 535:108-111. [PMID: 35988778 PMCID: PMC9387114 DOI: 10.1016/j.cca.2022.08.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 08/05/2022] [Accepted: 08/08/2022] [Indexed: 11/20/2022]
Abstract
Covid-19 in adolescence with multisystem inflammatory injury (MIS-C) is a newly described condition sharing key features with Kawasaki disease and toxic shock syndrome. A May 2020 United Nations WHO brief covering findings from North America and Europe drew notice to this acute post-viral illness characterized by severe, diffuse hyperinflammation leading to multiorgan failure. While females diagnosed with Covid-19 generally have more favorable outcomes than males, this protection is negated by a low estrogen state. This case reports on acute kidney injury/MIS-C with amenorrhea from ovarian insufficiency in childhood, itself an uncommon presentation of idiopathic hypogonadism. Three exon variants were previously identified in a healthy, phenotypically normal 46,XX adolescent who subsequently underwent whole genome sequencing (WGS). She had only two spontaneous menses with a provisional diagnosis of premature ovarian insufficiency made by age 15. Against this background, Covid-19 infection necessitated hospital admission where progressively reduced renal function was a prime component of MIS-C. Combined angiotensin-converting enzyme inhibitor plus transdermal estrogen replacement therapy resulted in normalized estimated glomerular filtration rate (eGFR) from baseline 43 to 68 ml/min/1.73 m2, post-treatment. Serum cystatin-C also improved during this interval from 1.69 to 1.19 mg/L. Among 7 Covid-19 high risk intron variants identified was rs3131294 (6p21), near NOTCH4. Another finding at rs8068318 (17q23) was associated with creatine level and eGFR. This is the first work to explore Covid-19 and associated kidney injury as a component of MIS-C at the intersection of rare multigene variants and functional ovarian loss. The context of transition from adolescence to adulthood is also considered, where successful recovery of renal function was achieved with combined enalapril and supplemental estrogen.
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Affiliation(s)
- E Scott Sills
- Center for Advanced Genetics/FertiGen, San Clemente, CA 92673, USA; Department of Obstetrics & Gynecology, Palomar Medical Center, Escondido, CA 92029 USA.
| | - Samuel H Wood
- Department of Obstetrics & Gynecology, Palomar Medical Center, Escondido, CA 92029 USA; Gen 5 Fertility Center, San Diego, CA 92121 USA
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19
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Arslan E, Saygili S, Celkan TT, Kurugoglu S, Elicevik M, Camcioglu AE, Konukoglu D, Apak H, Caliskan S, Sever L, Canpolat N. Increased risk for kidney sequelae surrogates in survivors of Wilms tumor. Pediatr Nephrol 2022; 37:2415-2426. [PMID: 35118543 DOI: 10.1007/s00467-022-05460-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 01/14/2022] [Accepted: 01/14/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND There is evidence of increased risk of hypertension, albuminuria, and development of chronic kidney disease (CKD) in long-term follow-up of survivors of Wilms tumor (WT). However, most studies were conducted in heterogeneous groups, including patients with solitary kidney. In addition, little is known about tubular dysfunction. This study aimed to investigate kidney sequelae, including CKD development, hypertension, and glomerular and tubular damage in WT survivors. METHODS This cross-sectional, single-center study included 61 patients treated for WT. Surrogates for kidney sequelae were defined as presence of at least one of the following: decrease in GFR for CKD, hypertension detected by ambulatory blood pressure monitoring, albuminuria (albumin-to-creatinine ratio [ACR] > 30 mg/g), or increase in at least one tubular biomarker (beta-2-microglobulin, neutrophil gelatinase-associated lipocalin, kidney injury marker-1, and liver fatty acid-binding protein) in 24-h urine. RESULTS Median age of patients was 11.7 years, with median follow-up of 8.8 years. Thirty-eight patients (62%) had at least one surrogate for kidney sequelae. Twenty-four patients (39%) had CKD, 14 patients (23%) had albuminuria, 12 patients (21%) had hypertension, and 11 patients (18%) had tubular damage. Urine ACR was significantly higher in patients with advanced tumor stage and patients with nephrotoxic therapy than their counterparts (p < 0.05), but neither eGFR nor tubular biomarkers showed any association with tumor- or treatment-related factors. CONCLUSIONS A considerable number of patients with WT have kidney sequelae, especially early-stage CKD with a high prevalence. Albuminuria emerges as a marker associated with tumor stages and nephrotoxic treatment. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Emrullah Arslan
- Department of Pediatrics, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Seha Saygili
- Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Tülin Tiraje Celkan
- Department of Pediatric Hematology Oncology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Sebuh Kurugoglu
- Department of Radiology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Mehmet Elicevik
- Department of Pediatric Surgery, Division of Pediatric Urology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Abdulhamit Enes Camcioglu
- Department of Public Health, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Dildar Konukoglu
- Department of Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Hilmi Apak
- Department of Pediatric Hematology Oncology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Salim Caliskan
- Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Lale Sever
- Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
| | - Nur Canpolat
- Department of Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey.
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20
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Cai X, Thorand B, Hohenester S, Koenig W, Rathmann W, Peters A, Nano J. Association between the fatty liver index and chronic kidney disease: the population-based KORA study. Nephrol Dial Transplant 2022; 38:1240-1248. [PMID: 36150717 DOI: 10.1093/ndt/gfac266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND We aimed to evaluate the relationship of fatty liver, estimated by fatty liver index (FLI), with kidney function and chronic kidney disease (CKD) in a German cohort study, given the lack of prospective evidence in Europeans. METHODS We included 2920 participants (51.6% women, mean age 56.1 years) from the KORA study, of which 1991 were followed up for an average of 6.4 (± 0.3) years. Kidney function was assessed using the glomerular filtration rate estimated by creatinine (eGFR-cr) or cystatin C (eGFR-cc). We used multiple logistic or linear regressions to evaluate the associations between FLI, kidney function and CKD (eGFR < 60 ml/min per 1.73 m2), and mediation analysis to explore the mediation effects of metabolic factors. RESULTS The prevalence of FLI ≥ 60 and CKD were 40.4% and 5.6% at baseline, and 182 participants developed CKD during the follow-up. Cross-sectionally, FLI was significantly inversely associated with eGFR-cc [β, 95%CI: -1.14 (-1.81, -0.47)] and prevalent CKD based on eGFR-cc [OR, 95%CI: 1.28 (1.01, 1.61)], but not with other markers. After adjusting for lifestyle factors, we found a positive association between FLI and incident CKD defined by eGFR-cc or/eGFR-cr, which was attenuated after controlling for metabolic risk factors. Mediation analysis showed that the association was completely mediated by inflammation, diabetes and hypertension jointly. CONCLUSIONS The positive association between FLI and CKD incidence was fully mediated by the joint effect of metabolic risk factors. Future longitudinal studies need to explore the chronological interplay between fatty liver, cardiometabolic risk factors and kidney function with repeated measurements.
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Affiliation(s)
- Xinting Cai
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.,Institute for Medical Information Processing, Biometry, and Epidemiology - IBE, Ludwig-Maximilians University of Munich, Munich, Germany.,Pettenkofer School of Public Health, Ludwig-Maximilians University of Munich, Munich, Germany
| | - Barbara Thorand
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.,German Center for Diabetes Research (DZD), partner site Munich-Neuherberg, Neuherberg, Germany
| | - Simon Hohenester
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Wolfgang Koenig
- Deutsches Herzzentrum München, Technische Universität München, Munich, Germany.,German Center for Cardiovascular Disease Research (DZHK), partner site Munich Heart Alliance, Munich, Germany.,Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
| | - Wolfgang Rathmann
- Institute for Biometrics and Epidemiology, German Diabetes Center at Heinrich-Heine University, Düsseldorf, Germany.,German Center for Diabetes Research (DZD), partner site Düsseldorf, Neuherberg, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.,Institute for Medical Information Processing, Biometry, and Epidemiology - IBE, Ludwig-Maximilians University of Munich, Munich, Germany.,German Center for Diabetes Research (DZD), partner site Munich-Neuherberg, Neuherberg, Germany.,German Center for Cardiovascular Disease Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
| | - Jana Nano
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.,Department of Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology-IBE, Ludwig-Maximilians-University Munich, Munich, Germany
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21
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Serum Cystatin-C is linked to increased prevalence of diabetes and higher risk of mortality in diverse middle-aged and older adults. PLoS One 2022; 17:e0270289. [PMID: 36094936 PMCID: PMC9467319 DOI: 10.1371/journal.pone.0270289] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 06/06/2022] [Indexed: 01/13/2023] Open
Abstract
Objective Type 2 Diabetes Mellitus (henceforth diabetes) affects roughly 35 million individuals in the US and is a major risk factor for cardiovascular and kidney disease. Serum Cystatin-C is used to monitor renal function and detect kidney damage. Recent research has focused on linking Cystatin-C to cardiovascular risk and disease, but most findings focus on small sample sizes and generalize poorly to diverse populations, thus limiting epidemiological inferences. The aim of this manuscript is to study the association between Cystatin-C, diabetes, and mortality and test for possible sex or racial/ethnic background modifications in these relationships. Methods We analyzed 8-years of biennial panel data from Health and Retirement Study participants 50-years and older who self-identified as White (unweighted N (uN) = 5,595), Black (uN = 867), or Latino (uN = 565) for a total of uN = 7,027 individuals. We modeled diabetes and death over 8-years as function of baseline Cystatin-C (log transformed) adjusting for covariates and tested modifications in associations by race/ethnic background and sex. Results Mean log Cystatin-C at visit 1 was 0.03±0.32 standard deviation. A 10% increase in Cystatin-C levels was associated with 13% increased relative risk of diabetes at baseline (11% and 9% by years 4 and 8). A 10% increase in Cystatin-C was highly associated with increased relative risk of death (28% and 31% by years 4 and 8). These associations were present even after adjusting for possible confounders and were not modified by sex or racial/ethnic background. Conclusion Despite differential risks for diabetes and mortality by racial/ethnic groups, Cystatin-C was equally predictive of these outcomes across groups. Cystatin-C dysregulations could be used as a risk indicator for diabetes and as a warning sign for accelerated risk of mortality.
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22
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Szili-Torok T, Bakker SJL, Tietge UJF. Normal fasting triglyceride levels and incident type 2 diabetes in the general population. Cardiovasc Diabetol 2022; 21:111. [PMID: 35717188 PMCID: PMC9206357 DOI: 10.1186/s12933-022-01530-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 05/20/2022] [Indexed: 12/04/2022] Open
Abstract
Background Type 2 diabetes is increasing worldwide. Traditionally, only hypertriglyceridemia is considered a risk factor. We investigated whether also normal triglycerides prospectively associate with incident type 2 diabetes in healthy subjects. Methods Incident type 2 diabetes was determined in healthy individuals with normal triglyceride levels from a prospective longitudinal cohort study (PREVEND, n = 2085, 11.4-year median follow-up). Results Type 2 diabetes incidence was 3.8%. In linear regression analysis baseline insulin, HOMA-IR, total cholesterol, HDL cholesterol, eGFR, systolic blood pressure (all p < 0.001), glucose, age and creatinine (all p < 0.01) independently associated with triglycerides within the normal range, comparable to what would be expected from associations with increased triglycerides. In Kaplan-Meier analysis sex-stratified tertiles of normal triglycerides prospectively associated with de novo type 2 diabetes (p < 0.001). Cox regression confirmed a significant prospective association independent of HOMA-IR [HR (95% CI), 1.39 (1.12, 1.74), p = 0.002] and several other recognized risk factors. Conclusions Even in healthy subjects without metabolic syndrome increasing triglyceride levels within the normal range confer a continuous increase in type 2 diabetes incidence. These data indicate that virtually everyone could potentially benefit from triglyceride lowering, further encouraging implementation of lifestyle changes in the general population. Supplementary information The online version contains supplementary material available at 10.1186/s12933-022-01530-8.
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Affiliation(s)
- Tamas Szili-Torok
- Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Stephan J L Bakker
- Department of Internal Medicine, University Medical Center Groningen, Groningen, The Netherlands
| | - Uwe J F Tietge
- Division of Clinical Chemistry, Department of Laboratory Medicine (LABMED), Karolinska Institutet, H5, Alfred Nobels Alle 8, S-141 83, Stockholm, Sweden. .,Clinical Chemistry, Karolinska University Laboratory, Karolinska University Hospital, SE-141 86, Stockholm, Sweden.
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23
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Tariq A, Chen J, Yu B, Boerwinkle E, Coresh J, Grams ME, Rebholz CM. Metabolomics of Dietary Acid Load and Incident Chronic Kidney Disease. J Ren Nutr 2022; 32:292-300. [PMID: 34294549 PMCID: PMC8766597 DOI: 10.1053/j.jrn.2021.05.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 04/29/2021] [Accepted: 05/15/2021] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Blood biomarkers of dietary intake are more objective than self-reported dietary intake. Metabolites associated with dietary acid load were previously identified in 2 chronic kidney disease (CKD) populations. We aimed to extend these findings to a general population, replicating their association with dietary acid load, and investigating whether the individual biomarkers were prospectively associated with incident CKD. METHODS Among 15,792 participants in the Atherosclerosis Risk in Communities cohort followed up from 1987 to 1989 (baseline) to 2019, we evaluated 3,844 black and white men and women with dietary and metabolomic data in cross-sectional and prospective analyses. We hypothesized that a higher dietary acid load (using equations for potential renal acid load and net endogenous acid production) was associated with lower serum levels of 12 previously identified metabolites: indolepropionylglycine, indolepropionate, N-methylproline, N-δ-acetylornithine, threonate, oxalate, chiro-inositol, methyl glucopyranoside, stachydrine, catechol sulfate, hippurate, and tartronate. In addition, we hypothesized that lower serum levels of these 12 metabolites were associated with higher risk of incident CKD. RESULTS Eleven out of 12 metabolites were significantly inversely associated with dietary acid load, after adjusting for demographics, socioeconomic status, health behaviors, health status, and estimated glomerular filtration rate: indolepropionylglycine, indolepropionate, N-methylproline, threonate, oxalate, chiro-inositol, catechol sulfate, hippurate, methyl glucopyranoside (α + β), stachydrine, and tartronate. N-methylproline was inversely associated with incident CKD (hazard ratio: 0.95, 95% confidence interval: 0.91, 0.99, P = .01). The metabolomic biomarkers of dietary acid load significantly improved prediction of elevated dietary acid load estimated using dietary data, beyond covariates (difference in C statistics: 0.021-0.077, P ≤ 1.08 × 10-3). CONCLUSION Inverse associations between candidate biomarkers of dietary acid load were replicated in a general population. N-methylproline, representative of citrus fruit consumption, is a promising marker of dietary acid load and could represent an important pathway between dietary acid load and CKD.
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Affiliation(s)
- Anam Tariq
- Division of Nephrology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Jingsha Chen
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Bing Yu
- Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Science Center at Houston, Houston, Texas
| | - Eric Boerwinkle
- Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas Health Science Center at Houston, Houston, Texas
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Morgan E Grams
- Division of Nephrology, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Casey M Rebholz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
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24
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Kim H, Yu B, Li X, Wong KE, Boerwinkle E, Seidelmann SB, Levey AS, Rhee EP, Coresh J, Rebholz CM. Serum metabolomic signatures of plant-based diets and incident chronic kidney disease. Am J Clin Nutr 2022; 116:151-164. [PMID: 35218183 PMCID: PMC9257476 DOI: 10.1093/ajcn/nqac054] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 02/24/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Greater adherence to plant-based diets is associated with a lower risk of incident chronic kidney disease (CKD). Metabolomics can help identify blood biomarkers of plant-based diets and enhance understanding of underlying mechanisms. OBJECTIVES Using untargeted metabolomics, we aimed to identify metabolites associated with 4 plant-based diet indices (PDIs) (overall PDI, provegetarian diet, healthful PDI, and unhealthful PDI) and incident CKD in 2 subgroups within the Atherosclerosis Risk in Communities study. METHODS We calculated 4 PDIs based on participants' responses on an FFQ. We used multivariable linear regression to examine the association between 4 PDIs and 374 individual metabolites, adjusting for confounders. We used Cox proportional hazards regression to evaluate associations between PDI-related metabolites and incident CKD. Estimates were meta-analyzed across 2 subgroups (n1 = 1762; n2 = 1960). We calculated C-statistics to assess whether metabolites improved the prediction of those in the highest quintile compared to the lower 4 quintiles of PDIs, and whether PDI- and CKD-related metabolites predicted incident CKD beyond the CKD prediction model. RESULTS We identified 82 significant PDI-metabolite associations (overall PDI = 27; provegetarian = 17; healthful PDI = 20; unhealthful PDI = 18); 11 metabolites overlapped across the overall PDI, provegetarian diet, and healthful PDI. The addition of metabolites improved prediction of those in the highest quintile as opposed to the lower 4 quintiles of PDIs compared with participant characteristics alone (range of differences in C-statistics = 0.026-0.104; P value ≤ 0.001 for all tests). Six PDI-related metabolites (glycerate, 1,5-anhydroglucitol, γ-glutamylalanine, γ-glutamylglutamate, γ-glutamylleucine, γ-glutamylvaline), involved in glycolysis, gluconeogenesis, pyruvate metabolism, and γ-glutamyl peptide metabolism, were significantly associated with incident CKD and improved prediction of incident CKD beyond the CKD prediction model (difference in C-statistics for 6 metabolites = 0.005; P value = 0.006). CONCLUSIONS In a community-based study of US adults, we identified metabolites that were related to plant-based diets and predicted incident CKD. These metabolites highlight pathways through which plant-based diets are associated with incident CKD.
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Affiliation(s)
- Hyunju Kim
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA,Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA
| | - Bing Yu
- Department of Epidemiology, Human Genetics & Environmental Sciences, University of Texas Health Sciences Center at Houston School of Public Health, Houston, TX, USA
| | - Xin Li
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA
| | | | - Eric Boerwinkle
- Department of Epidemiology, Human Genetics & Environmental Sciences, University of Texas Health Sciences Center at Houston School of Public Health, Houston, TX, USA
| | - Sara B Seidelmann
- College of Physicians & Surgeons, Columbia University, New York, NY, USA
| | - Andrew S Levey
- Division of Nephrology, Tufts Medical Center, Boston, MA, USA
| | - Eugene P Rhee
- Nephrology Division and Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA,Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA,Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Karger AB, Long T, Inker LA, Eckfeldt JH. Improved Performance in Measurement of Serum Cystatin C by Laboratories Participating in the College of American Pathologists' 2019 CYS Survey. Arch Pathol Lab Med 2022; 146:1218-1223. [PMID: 35192685 DOI: 10.5858/arpa.2021-0306-cp] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/23/2021] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Use of cystatin C for glomerular filtration rate estimation (eGFR) has garnered heightened interest as a means to avoid race-based medicine, since eGFRcys equations do not require specification of race. Before considering more widespread use of cystatin C, it is important to confirm that assays provide accurate measurements of cystatin C concentration, to ensure accurate GFR estimates. OBJECTIVE.— To determine if the accuracy of cystatin C measurements in laboratories participating in the College of American Pathologists' (CAP) Cystatin C (CYS) survey has improved since 2014. DESIGN.— Two fresh frozen serum pools, the first from healthy donors without chronic kidney disease (CKD), and the second from patients with CKD, along with a synthetically prepared elevated cystatin C pool, were sent to laboratories participating in the 2019 CYS-A survey. Target values were established by using 2 immunoassays and a bracketed 2-point calibration with diluted ERM-DA471/IFCC reference material. RESULTS.— For the healthy donor fresh frozen pool (ERM-DA471/IFCC-traceable target of 0.725 mg/L), the all-method mean (standard deviation, coefficient of variation) was 0.731 mg/L (0.071, 9.7%). For the CKD pool (ERM-DA471/IFCC-traceable target of 2.136 mg/L), the all-method mean was 2.155 mg/L (0.182, 8.4%). For the synthetically spiked pool (ERM-DA471/IFCC-traceable target of 1.843 mg/L), the all-method mean was 1.886 mg/L (0.152, 8.1%). This represents marked improvement in accuracy and between-method agreement compared to the 2014 CAP survey. CONCLUSIONS.— Manufacturers have markedly improved accuracy and between-method agreement of cystatin C measurement procedures since 2014, which allows for greater confidence in estimated GFR relying on cystatin C.
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Affiliation(s)
- Amy B Karger
- From the Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis (Karger, Eckfeldt)
| | - Thomas Long
- The Department of Biostatistics, College of American Pathologists, Northfield, Illinois (Long)
| | - Lesley A Inker
- William B. Schwartz Division of Nephrology, Tufts Medical Center, Department of Medicine, Tufts University School of Medicine, Boston, Massachusetts (Inker)
| | - John H Eckfeldt
- From the Department of Laboratory Medicine & Pathology, University of Minnesota, Minneapolis (Karger, Eckfeldt)
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Rehm M, Rothenbacher D, Iacoviello L, Costanzo S, Tunstall‐Pedoe H, Fitton CA, Söderberg S, Hultdin J, Salomaa V, Jousilahti P, Palosaari T, Kuulasmaa K, Waldeyer C, Schnabel RB, Zeller T, Blankenberg S, Koenig W, BiomarCaRE Consortium. Chronic kidney disease and risk of atrial fibrillation and heart failure in general population-based cohorts: the BiomarCaRE project. ESC Heart Fail 2022; 9:57-65. [PMID: 34825788 PMCID: PMC8788046 DOI: 10.1002/ehf2.13699] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 09/29/2021] [Accepted: 10/29/2021] [Indexed: 12/28/2022] Open
Abstract
AIMS Chronic kidney disease (CKD) has a complicated relationship with the heart, leading to many adverse outcomes. The aim of this study was to evaluate the relationship between CKD and the incidence of atrial fibrillation (AF) and heart failure (HF) along with mortality as a competing risk in general population cohorts. We also included an assessment of baseline biomarkers of inflammation, myocardial injury, and left ventricular dysfunction with risk of AF and HF, respectively, to shed light on the potential underlying pathophysiology. METHODS AND RESULTS This study was conducted within the BiomarCaRE project using harmonized data from 12 European population-based cohorts (n = 48 518 participants). Renal function was assessed by glomerular filtration rate estimated using the combined Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation with standardized serum creatinine (Cr) and non-standardized serum cystatin C (CysC). Incidence of AF and HF respectively, during a median follow-up of 8 years was recorded. Cox proportional hazards models were used to determine hazard ratios (HRs) for the incidence of AF and HF in CKD and the competing risk of mortality after adjustment for covariates. The mean age at baseline was 51.4 (standard deviation 12.1) years, 49% were men. Overall, 4.3% of subjects had CKD at baseline. The rate for AF was 3.8 per 1000 person-years during follow-up. The HR for AF in patients with CKD compared with patients without CKD was 1.28 (95% confidence interval 1.07-1.54) after adjustment for covariates. The rate for incident HF was 4.1 per 1000 person-years and the HR of CKD for HF was 1.71 (95% confidence interval 1.45-2.01. In subjects with CKD, N-terminal-pro-brain natriuretic peptide (NT-proBNP) showed an association with AF, whereas NT-proBNP and C-reactive protein were associated with HF. CONCLUSIONS Chronic kidney disease is an independent risk factor for subsequent AF and is even more closely associated with HF. In these relatively young participants with CKD, NT-proBNP was strongly associated with subsequent risk of AF. For HF, in addition, elevated levels of hs-C-reactive protein at baseline were related to incident events.
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Affiliation(s)
- Martin Rehm
- Institute of Epidemiology and Medical BiometryUlm UniversityHelmholtzstr. 22UlmD‐89081Germany
| | - Dietrich Rothenbacher
- Institute of Epidemiology and Medical BiometryUlm UniversityHelmholtzstr. 22UlmD‐89081Germany
| | - Licia Iacoviello
- Department of Epidemiology and PreventionIRCCS NeuromedPozzilliItaly
- Research Center in Epidemiology and Preventive Medicine (EPIMED). Department of Medicine and SurgeryUniversity of InsubriaVareseItaly
| | - Simona Costanzo
- Department of Epidemiology and PreventionIRCCS NeuromedPozzilliItaly
| | - Hugh Tunstall‐Pedoe
- Cardiovascular Epidemiology Unit, Institute of Cardiovascular ResearchUniversity of DundeeDundeeUK
| | | | - Stefan Söderberg
- Department of Public Health and Clinical MedicineUmeå UniversityUmeåSweden
| | - Johan Hultdin
- Department of Medical Biosciences, Clinical ChemistryUmeå UniversityUmeåSweden
| | | | | | | | | | - Christoph Waldeyer
- Department of CardiologyUniversity Heart and Vascular Center HamburgHamburgGermany
- German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg/Kiel/LübeckHamburgGermany
| | - Renate B. Schnabel
- Department of CardiologyUniversity Heart and Vascular Center HamburgHamburgGermany
- German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg/Kiel/LübeckHamburgGermany
| | - Tanja Zeller
- Department of CardiologyUniversity Heart and Vascular Center HamburgHamburgGermany
- German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg/Kiel/LübeckHamburgGermany
| | - Stefan Blankenberg
- Department of CardiologyUniversity Heart and Vascular Center HamburgHamburgGermany
- German Center for Cardiovascular Research (DZHK e.V.), partner site Hamburg/Kiel/LübeckHamburgGermany
| | - Wolfgang Koenig
- Institute of Epidemiology and Medical BiometryUlm UniversityHelmholtzstr. 22UlmD‐89081Germany
- Deutsches Herzzentrum MünchenTechnische Universität MünchenMunichGermany
- DZHK (German Centre for Cardiovascular Research), partner site Munich Heart AllianceMunichGermany
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27
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Delgado C, Baweja M, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, Mendu ML, Miller WG, Moxey-Mims MM, Roberts GV, St Peter WL, Warfield C, Powe NR. A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. Am J Kidney Dis 2022; 79:268-288.e1. [PMID: 34563581 DOI: 10.1053/j.ajkd.2021.08.003] [Citation(s) in RCA: 433] [Impact Index Per Article: 144.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND In response to a national call for re-evaluation of the use of race in clinical algorithms, the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) established a Task Force to reassess inclusion of race in the estimation of glomerular filtration rate (GFR) in the United States and its implications for diagnosis and management of patients with, or at risk for, kidney diseases. PROCESS & DELIBERATIONS The Task Force organized its activities over 10 months in phases to (1) clarify the problem and evidence regarding GFR estimating equations in the United States (described previously in an interim report), and, in this final report, (2) evaluate approaches to address use of race in GFR estimation, and (3) provide recommendations. We identified 26 approaches for the estimation of GFR that did or did not consider race and narrowed our focus, by consensus, to 5 of those approaches. We holistically evaluated each approach considering 6 attributes: assay availability and standardization; implementation; population diversity in equation development; performance compared with measured GFR; consequences to clinical care, population tracking, and research; and patient centeredness. To arrive at a unifying approach to estimate GFR, we integrated information and evidence from many sources in assessing strengths and weaknesses in attributes for each approach, recognizing the number of Black and non-Black adults affected. RECOMMENDATIONS (1) For US adults (>85% of whom have normal kidney function), we recommend immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the United States because it does not include race in the calculation and reporting, included diversity in its development, is immediately available to all laboratories in the United States, and has acceptable performance characteristics and potential consequences that do not disproportionately affect any one group of individuals. (2) We recommend national efforts to facilitate increased, routine, and timely use of cystatin C, especially to confirm estimated GFR in adults who are at risk for or have chronic kidney disease, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone. If ongoing evidence supports acceptable performance, the CKD-EPI eGFR-cystatin C (eGFRcys) and eGFR creatinine-cystatin C (eGFRcr-cys_R) refit without the race variables should be adopted to provide another first-line test, in addition to confirmatory testing. (3) Research on GFR estimation with new endogenous filtration markers and on interventions to eliminate race and ethnic disparities should be encouraged and funded. An investment in science is needed for newer approaches that generate accurate, unbiased, and precise GFR measurement and estimation without the inclusion of race, and that promote health equity and do not generate disparate care. IMPLEMENTATION This unified approach, without specification of race, should be adopted across the United States. High-priority and multistakeholder efforts should implement this solution.
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Affiliation(s)
- Cynthia Delgado
- Nephrology Section, San Francisco Veterans Affairs Medical Center and Division of Nephrology, University of California San Francisco, San Francisco, California.
| | - Mukta Baweja
- Nephrology Division, Department of Medicine and Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Deidra C Crews
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nwamaka D Eneanya
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Crystal A Gadegbeku
- Department of Nephrology and Hypertension, Department of Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Lesley A Inker
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Mallika L Mendu
- Division of Renal Medicine and Office of the Chief Medical Officer, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - W Greg Miller
- Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Marva M Moxey-Mims
- Division of Nephrology, Children's National Hospital, Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Glenda V Roberts
- External Relations and Patient Engagement, Kidney Research Institute and Center for Dialysis Innovation, University of Washington, Seattle, Washington
| | - Wendy L St Peter
- College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | | | - Neil R Powe
- Department of Medicine, Priscilla Chan and Mark Zuckerberg San Francisco General Hospital and University of California San Francisco, San Francisco, California.
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Delgado C, Powe NR. Resolving the Debate: The Future of Using Race in Estimating Kidney Function. Adv Chronic Kidney Dis 2022; 29:5-16. [PMID: 35690404 DOI: 10.1053/j.ackd.2022.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 01/27/2022] [Accepted: 02/10/2022] [Indexed: 11/11/2022]
Abstract
Racial and social unrest witnessed during 2020 ignited a national conversation about the appropriateness of the use of race in health care algorithms and in the estimation of kidney function in particular. The growing concerns over the use of race in kidney function-estimating equations prompted the National Kidney Foundation (NKF) and American Society of Nephrology to launch an effort for change by establishing a task force on reassessing the use of race in diagnosing kidney disease. After nearly a year examining the evidence and obtaining testimony from experts and stakeholders, the task force recommended the immediate implementation of the 2020 Chronic Kidney Disease-Epidemiology creatinine equation refit without race in all US laboratories; increased routine use of cystatin C for confirmation of estimated glomerular filtration rate in clinical decision-making and a call for research on glomerular filtration rate estimation with new endogenous filtration markers and on addressing disparities in health and health care. The NKF and American Society of Nephrology strongly encouraged rapid adoption of these new recommendations. Leadership efforts of the NKF have begun to lay the foundation for national implementation through laboratory engagement, clinician awareness, and patient education.
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Affiliation(s)
- Cynthia Delgado
- Nephrology Section, San Francisco VA Medical Center, San Francisco, CA; Department of Medicine, University of California, San Francisco, San Francisco, CA.
| | - Neil R Powe
- Department of Medicine, Priscilla Chan and Mark Zuckerberg San Francisco General Hospital, San Francisco, CA; Department of Medicine, University of California, San Francisco, San Francisco, CA
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29
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Impact of different renal function equations on direct oral anticoagulant concentrations. Sci Rep 2021; 11:23833. [PMID: 34903821 PMCID: PMC8668925 DOI: 10.1038/s41598-021-03318-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Accepted: 11/29/2021] [Indexed: 12/02/2022] Open
Abstract
The purpose of this study is to investigate the correlation between glomerular filtration rate (GFR) estimated by different renal function equations and non-vitamin K antagonist oral anticoagulant concentration. Atrial fibrillation patients who aged ≥ 20 years and used dabigatran, rivaroxaban, or apixaban for thromboembolism prevention were enrolled to collect blood samples and measure drug concentrations using ultra-high-performance liquid chromatography with tandem mass spectrometry. The GFR was estimated using the Cockroft–Gault formula (abbreviated as creatinine clearance, CrCL), Chronic Kidney Disease Epidemiology Collaboration formula (CKD-EPI) featuring both creatinine and cystatin C, and the Modification of Diet in Renal Disease Study equation (MDRD). Multivariate regression was used to investigate the associations of different renal function estimates with drug concentrations. A total of 511 participants were enrolled, including 146 dabigatran users, 164 rivaroxaban users and 201 apixaban users. Compared to clinical trials, 35.4% of dabigatran, 4.9% of rivaroxaban, and 5.5% of apixaban concentrations were higher than the expected range (p < 0.001). CKD-EPI and MDRD estimates classified fewer patients as having GFR < 50 mL/min than CrCL in all 3 groups. Both CrCL and CKD-EPI were associated with higher-than-expected ranges of dabigatran or rivaroxaban concentrations. Nevertheless, none of the renal function equations was associated with higher-than-expected apixaban concentrations. For participants aged ≥ 75 years, CKD-EPI may be associated with higher-than-expected trough concentration of dabigatran. In conclusion, CrCL and CKD-EPI both can be used to identify patients with high trough concentrations of dabigatran or rivaroxaban. Among elderly patients who used dabigatran, CKD-EPI may be associated with increased drug concentration.
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30
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Wong E, Ricardo AC, Rosas SE, Lash JP, Franceschini N. Hepatitis C infection and chronic kidney disease among Hispanics/Latinos. Medicine (Baltimore) 2021; 100:e28089. [PMID: 34889260 PMCID: PMC8663903 DOI: 10.1097/md.0000000000028089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 11/11/2021] [Accepted: 11/15/2021] [Indexed: 01/05/2023] Open
Abstract
ABSTRACT Viral infections, including hepatitis C, can cause secondary glomerular nephropathies. Studies suggest that hepatitis C virus infection (HCV+) is a risk factor for chronic kidney disease (CKD) but evidence of this relationship is lacking among Hispanics/Latinos. We examined the association between HCV+ and incident CKD in a prospective cohort of Hispanics/Latinos enrolled in the Hispanic Community Health Study/Study of Latinos. HCV+ was defined by detectable HCV antibodies with additional confirmation through HCV RNA or recombinant immunoblot assay testing. Incident CKD was defined by an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or sex-specific threshold for albuminuria measured during follow-up. We used Poisson regression to estimate incidence rate ratios (IRR) of CKD and changes in eGFR- or albuminuria-based risk stages, separately. We used linear regression to estimate associations with continuous, annualized changes in eGFR and albuminuria.Over a follow-up period of 5.9 years, 712 incident CKD events occurred among 10,430 participants. After adjustment for demographic characteristics and comorbidities, HCV+ was not associated with incident CKD, defined by eGFR and albuminuria thresholds (IRR 1.29, 95% Confidence Interval 0.61, 2.73). HCV+ was significantly associated with higher eGFR risk stages (IRR 2.39, 95% CI 1.47, 3.61) with most participants transitioning from stage G1 to G2. HCV+ was associated with a continuous, annualized eGFR decline of -0.69 mL/min/m2/year (95% CI -1.23, -0.16). This large, cohort study did not find evidence of a strong association between HCV+ and new-onset CKD among Hispanics/Latinos. HCV infection may not be associated with risk of CKD among Hispanics/Latinos, although treatment with direct-acting antivirals is recommended for all HCV+ individuals, including those with established CKD or end-stage kidney disease.
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Affiliation(s)
- Eugenia Wong
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Ana C. Ricardo
- Department of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Sylvia E. Rosas
- Joslin Diabetes Center and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
| | - James P. Lash
- Department of Medicine, University of Illinois at Chicago, Chicago, IL
| | - Nora Franceschini
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
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31
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Delgado C, Baweja M, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, Mendu ML, Miller WG, Moxey-Mims MM, Roberts GV, St. Peter WL, Warfield C, Powe NR. A Unifying Approach for GFR Estimation: Recommendations of the NKF-ASN Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease. J Am Soc Nephrol 2021; 32:2994-3015. [PMID: 34556489 PMCID: PMC8638402 DOI: 10.1681/asn.2021070988] [Citation(s) in RCA: 205] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 09/05/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND In response to a national call for re-evaluation of the use of race in clinical algorithms, the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) established a Task Force to reassess inclusion of race in the estimation of GFR in the United States and its implications for diagnosis and management of patients with, or at risk for, kidney diseases. PROCESS DELIBERATIONS The Task Force organized its activities over 10 months in phases to ( 1 ) clarify the problem and evidence regarding eGFR equations in the United States (described previously in an interim report), and, in this final report, ( 2 ) evaluate approaches to address use of race in GFR estimation, and ( 3 ) provide recommendations. We identified 26 approaches for the estimation of GFR that did or did not consider race and narrowed our focus, by consensus, to five of those approaches. We holistically evaluated each approach considering six attributes: assay availability and standardization; implementation; population diversity in equation development; performance compared with measured GFR; consequences to clinical care, population tracking, and research; and patient centeredness. To arrive at a unifying approach to estimate GFR, we integrated information and evidence from many sources in assessing strengths and weaknesses in attributes for each approach, recognizing the number of Black and non-Black adults affected. RECOMMENDATIONS ( 1 ) For US adults (>85% of whom have normal kidney function), we recommend immediate implementation of the CKD-EPI creatinine equation refit without the race variable in all laboratories in the United States because it does not include race in the calculation and reporting, included diversity in its development, is immediately available to all laboratories in the United States, and has acceptable performance characteristics and potential consequences that do not disproportionately affect any one group of individuals. ( 2 ) We recommend national efforts to facilitate increased, routine, and timely use of cystatin C, especially to confirm eGFR in adults who are at risk for or have CKD, because combining filtration markers (creatinine and cystatin C) is more accurate and would support better clinical decisions than either marker alone. If ongoing evidence supports acceptable performance, the CKD-EPI eGFR-cystatin C (eGFRcys) and eGFR creatinine-cystatin C (eGFRcr-cys_R) refit without the race variables should be adopted to provide another first-line test, in addition to confirmatory testing. ( 3 ) Research on GFR estimation with new endogenous filtration markers and on interventions to eliminate race and ethnic disparities should be encouraged and funded. An investment in science is needed for newer approaches that generate accurate, unbiased, and precise GFR measurement and estimation without the inclusion of race, and that promote health equity and do not generate disparate care. IMPLEMENTATION This unified approach, without specification of race, should be adopted across the United States. High-priority and multistakeholder efforts should implement this solution.
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Affiliation(s)
- Cynthia Delgado
- Nephrology Section, San Francisco Veterans Affairs Medical Center and Division of Nephrology, University of California San Francisco, San Francisco, California
| | - Mukta Baweja
- Nephrology Division, Department of Medicine and Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Deidra C. Crews
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nwamaka D. Eneanya
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Crystal A. Gadegbeku
- Department of Nephrology and Hypertension, Department of Medicine, Cleveland Clinic, Cleveland, Ohio
| | - Lesley A. Inker
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Mallika L. Mendu
- Division of Renal Medicine and Office of the Chief Medical Officer, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - W. Greg Miller
- Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Marva M. Moxey-Mims
- Division of Nephrology, Children’s National Hospital, Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Glenda V. Roberts
- External Relations and Patient Engagement, Kidney Research Institute and Center for Dialysis Innovation, University of Washington, Seattle, Washington
| | | | | | - Neil R. Powe
- Department of Medicine, Priscilla Chan and Mark Zuckerberg San Francisco General Hospital and University of California San Francisco, San Francisco, California
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Yu Z, Jin J, Tin A, Köttgen A, Yu B, Chen J, Surapaneni A, Zhou L, Ballantyne CM, Hoogeveen RC, Arking DE, Chatterjee N, Grams ME, Coresh J. Polygenic Risk Scores for Kidney Function and Their Associations with Circulating Proteome, and Incident Kidney Diseases. J Am Soc Nephrol 2021; 32:3161-3173. [PMID: 34548389 PMCID: PMC8638405 DOI: 10.1681/asn.2020111599] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 08/29/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) have revealed numerous loci for kidney function (eGFR). The relationship between polygenic predictors of eGFR, risk of incident adverse kidney outcomes, and the plasma proteome is not known. METHODS We developed a genome-wide polygenic risk score (PRS) for eGFR by applying the LDpred algorithm to summary statistics generated from a multiethnic meta-analysis of CKDGen Consortium GWAS ( n =765,348) and UK Biobank GWAS (90% of the cohort; n =451,508), followed by best-parameter selection using the remaining 10% of UK Biobank data ( n =45,158). We then tested the association of the PRS in the Atherosclerosis Risk in Communities (ARIC) study ( n =8866) with incident CKD, ESKD, kidney failure, and AKI. We also examined associations between the PRS and 4877 plasma proteins measured at middle age and older adulthood and evaluated mediation of PRS associations by eGFR. RESULTS The developed PRS showed a significant association with all outcomes. Hazard ratios per 1 SD lower PRS ranged from 1.06 (95% CI, 1.01 to 1.11) to 1.33 (95% CI, 1.28 to 1.37). The PRS was significantly associated with 132 proteins at both time points. The strongest associations were with cystatin C, collagen α -1(XV) chain, and desmocollin-2. Most proteins were higher at lower kidney function, except for five proteins, including testican-2. Most correlations of the genetic PRS with proteins were mediated by eGFR. CONCLUSIONS A PRS for eGFR is now sufficiently strong to capture risk for a spectrum of incident kidney diseases and broadly influences the plasma proteome, primarily mediated by eGFR.
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Affiliation(s)
- Zhi Yu
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts,Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts,Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Jin Jin
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Adrienne Tin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland,Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
| | - Anna Köttgen
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland,Institute of Genetic Epidemiology, Department of Data Driven Medicine, Faculty of Medicine and Medical Centre–University of Freiburg, Freiburg, Germany
| | - Bing Yu
- Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Jingsha Chen
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
| | - Aditya Surapaneni
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
| | - Linda Zhou
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
| | | | - Ron C. Hoogeveen
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Dan E. Arking
- McKusick-Nathans Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Nilanjan Chatterjee
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland,Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Morgan E. Grams
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland,Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland,Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland,Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland,Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
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33
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Kremer KM, Braisch U, Rothenbacher D, Denkinger M, Dallmeier D. Systolic Blood Pressure and Mortality in Community-Dwelling Older Adults: Frailty as an Effect Modifier. Hypertension 2021; 79:24-32. [PMID: 34689594 DOI: 10.1161/hypertensionaha.121.17530] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Current evidence is insufficient to support different hypertension treatment targets in older adults. We evaluated whether frailty modifies the association between systolic blood pressure (SBP) and 8-year all-cause mortality in community-dwelling older adults. Longitudinal data from the ActiFE Ulm study (Activity and Function in the Elderly in Ulm; Germany) was collected. The association between SBP and mortality was analyzed using Cox proportional hazards models adjusted for age, sex, education, smoking, alcohol consumption, sleep disturbance, diastolic blood pressure, and antihypertensive medications, evaluating the presence of effect modification by frailty according to a frailty index based on the accumulation of deficits. Among 1170 participants (median age 73.9 years, 41.6% women), the prevalence of history of hypertension was 53.8% (median SBP, 144.0 mm Hg [interquartile range, 135.0-149.5], median diastolic blood pressure 78.0 mm Hg [interquartile range, 71.0-86.5]). The median follow-up time was 8.1 years, detecting 268 deaths. We identified 251 (21.5%, 114 deaths) frail participants (frailty index ≥0.2). Effect modification by frailty was detected. Among non-frail a J-shaped association was found with hazard ratio, 4.01 (95% CI, 1.13-14.28) for SBP<110 mm Hg, hazard ratio, 0.92 (95% CI, 0.53-1.59) for SBP 140-150 mm Hg, and hazard ratio, 1.98 (95% CI, 0.75-5.27) for SBP≥160 mm Hg. For frail older adults, a tendency toward lower risk among those with SBP≥130 mm Hg was observed. Our results suggest the presence of effect modification by frailty indicating a possible protective effect for elevated SBP in frail older adults with respect to all-cause mortality even after adjusting for diastolic blood pressure and antihypertensive treatment.
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Affiliation(s)
- Kaj-Marko Kremer
- Research Unit on Ageing, Agaplesion Bethesda Clinic Ulm, Germany (K.-M.K., U.B., M.D., D.D.).,Geriatrisches Zentrum Ulm/Alb-Donau, Ulm, Germany (K.-M.K., U.B., M.D., D.D.).,Institute of Geriatric Research, Ulm University, Germany. (K.-M.K., M.D.)
| | - Ulrike Braisch
- Research Unit on Ageing, Agaplesion Bethesda Clinic Ulm, Germany (K.-M.K., U.B., M.D., D.D.).,Geriatrisches Zentrum Ulm/Alb-Donau, Ulm, Germany (K.-M.K., U.B., M.D., D.D.).,Institute of Epidemiology and Medical Biometry, Ulm University, Germany. (U.B., D.R.)
| | - Dietrich Rothenbacher
- Institute of Epidemiology and Medical Biometry, Ulm University, Germany. (U.B., D.R.)
| | - Michael Denkinger
- Research Unit on Ageing, Agaplesion Bethesda Clinic Ulm, Germany (K.-M.K., U.B., M.D., D.D.).,Geriatrisches Zentrum Ulm/Alb-Donau, Ulm, Germany (K.-M.K., U.B., M.D., D.D.).,Institute of Geriatric Research, Ulm University, Germany. (K.-M.K., M.D.)
| | - Dhayana Dallmeier
- Research Unit on Ageing, Agaplesion Bethesda Clinic Ulm, Germany (K.-M.K., U.B., M.D., D.D.).,Geriatrisches Zentrum Ulm/Alb-Donau, Ulm, Germany (K.-M.K., U.B., M.D., D.D.).,Department of Epidemiology, Boston University School of Public Health, Boston, MA (D.D.)
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Said MY, Rodriguez-Niño A, Post A, Schutten JC, Kieneker LM, Gomes-Neto AW, van Londen M, Osté MC, Borgonjen-van den Berg KJ, Nolte IM, van den Berg E, de Blaauw P, van der Krogt J, Heiner-Fokkema MR, Navis G, Yard BA, Bakker SJ. Meat intake and risk of mortality and graft failure in kidney transplant recipients. Am J Clin Nutr 2021; 114:1505-1517. [PMID: 34091671 PMCID: PMC8488867 DOI: 10.1093/ajcn/nqab185] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 05/12/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND It is unknown whether meat intake is beneficial for long-term patient and graft survival in kidney transplant recipients (KTR). OBJECTIVES We first investigated the association of the previously described meat intake biomarkers 1-methylhistidine and 3-methylhistidine with intake of white and red meat as estimated from a validated food frequency questionnaire (FFQ). Second, we investigated the association of the meat intake biomarkers with long-term outcomes in KTR. METHODS We measured 24-h urinary excretion of 1-methylhistidine and 3-methylhistidine by validated assays in a cohort of 678 clinically stable KTR. Cross-sectional associations were assessed by linear regression. We used Cox regression analyses to prospectively study associations of log2-transformed biomarkers with mortality and graft failure. RESULTS Urinary 1-methylhistidine and 3-methylhistidine excretion values were median: 282; interquartile range (IQR): 132-598 µmol/24 h and median: 231; IQR: 175-306 µmol/24 h, respectively. Urinary 1-methylhistidine was associated with white meat intake [standardized β (st β): 0.20; 95% CI: 0.12, 0.28; P < 0.001], whereas urinary 3-methylhistidine was associated with red meat intake (st β: 0.30; 95% CI: 0.23, 0.38; P < 0.001). During median follow-up for 5.4 (IQR: 4.9-6.1) y, 145 (21%) died and 83 (12%) developed graft failure. Urinary 3-methylhistidine was inversely associated with mortality independently of potential confounders (HR per doubling: 0.55; 95% CI: 0.42, 0.72; P < 0.001). Both urinary 1-methylhistidine and urinary 3-methylhistidine were inversely associated with graft failure independent of potential confounders (HR per doubling: 0.84; 95% CI: 0.73, 0.96; P = 0.01; and 0.59; 95% CI: 0.41, 0.85; P = 0.004, respectively). CONCLUSIONS High urinary 3-methylhistidine, reflecting higher red meat intake, is independently associated with lower risk of mortality. High urinary concentrations of both 1- and 3-methylhistidine, of which the former reflects higher white meat intake, are independently associated with lower risk of graft failure in KTR. Future intervention studies are warranted to study the effect of high meat intake on mortality and graft failure in KTR, using these biomarkers.
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Affiliation(s)
- M Yusof Said
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Angelica Rodriguez-Niño
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Adrian Post
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Joelle C Schutten
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Lyanne M Kieneker
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Antonio W Gomes-Neto
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Marco van Londen
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Maryse Cj Osté
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | | | - Ilja M Nolte
- Department of Epidemiology, University of Groningen, Groningen, The Netherlands
| | - Else van den Berg
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Pim de Blaauw
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jennifer van der Krogt
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - M Rebecca Heiner-Fokkema
- Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Gerjan Navis
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Groningen Kidney Center, Groningen, The Netherlands
| | - Benito A Yard
- Vth Department of Medicine (Nephrology/Endocrinology/Rheumatology), University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany
| | - Stephan Jl Bakker
- Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
- Groningen Kidney Center, Groningen, The Netherlands
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Abraham AG, Xu Y, Roem JL, Greenberg JH, Weidemann DK, Sabbisetti VS, Bonventre JV, Denburg M, Warady BA, Furth SL. Variability in CKD Biomarker Studies: Soluble Urokinase Plasminogen Activator Receptor (suPAR) and Kidney Disease Progression in the Chronic Kidney Disease in Children (CKiD) Study. Kidney Med 2021; 3:712-721.e1. [PMID: 34693253 PMCID: PMC8515077 DOI: 10.1016/j.xkme.2021.04.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
RATIONALE & OBJECTIVE Biomarker studies are important for generating mechanistic insight and providing clinically useful predictors of chronic kidney disease (CKD) progression. However, variability across studies can often muddy the evidence waters. Here we evaluated real-world variability in biomarker studies using two published studies, independently conducted, of the novel plasma marker soluble urokinase-type plasminogen activator receptor (suPAR) for predicting CKD progression in children with CKD. STUDY DESIGN A comparison of 2 prospective cohort studies. SETTING & PARTICIPANTS 541 children from the Chronic Kidney Disease in Children (CKiD) study, median age 12 years, median glomerular filtration rate (GFR) of 54 mL/min/1.73m2. OUTCOME The first occurrence of either a 50% decline in GFR from baseline or incident end-stage kidney disease. ANALYTICAL APPROACH The suPAR plasma marker was measured using the Quantikine ELISA immunoassay in the first study and Meso Scale Discovery (MSD) platform in the second. The analytical approaches varied. We used suPAR data from the 2 assays and mimicked each analytical approach in an overlapping subset. RESULTS We found that switching assays had the greatest impact on inferences, resulting in a 38% to 66% change in the magnitude of the effect estimates. Covariate and modeling choices resulted in an additional 8% to 40% variability in the effect estimate. The cumulative variability led to different inferences despite using a similar sample of CKiD participants and addressing the same question. LIMITATIONS The estimated variability does not represent optimal repeatability but instead illustrates real-world variability that may be present in the CKD biomarker literature. CONCLUSIONS Our results highlight the importance of validation, avoiding conclusions based on P value thresholds, and providing comparable metrics. Further transparency of data and equal weighting of negative and positive findings in explorations of novel biomarkers will allow investigators to more quickly weed out less promising biomarkers.
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Affiliation(s)
- Alison G. Abraham
- Department of Epidemiology, School of Public Health, University of Colorado, Aurora, CO
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Yunwen Xu
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Jennifer L. Roem
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Jason H. Greenberg
- Department of Pediatrics, Section of Nephrology, School of Medicine, Yale University, New Haven, CT
- Program of Applied Translational Research, School of Medicine, Yale University, New Haven, CT
| | - Darcy K. Weidemann
- Division of Pediatric Nephrology, Children’s Mercy Kansas City, Kansas City School of Medicine, University of Missouri, Kansas City, MO
| | - Venkata S. Sabbisetti
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Joseph V. Bonventre
- Division of Renal Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
| | - Michelle Denburg
- Department of Pediatrics, Division of Nephrology, Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Bradley A. Warady
- Division of Pediatric Nephrology, Children’s Mercy Kansas City, Kansas City School of Medicine, University of Missouri, Kansas City, MO
| | - Susan L. Furth
- Department of Pediatrics and Department of Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Children’s Hospital of Philadelphia, Philadelphia, PA
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Song QX, He F, Sun X, Liu K, Chen Z, Li M, Lin J, Xu Z, Li Y, Zhang Y, Huang H, Zhang Y, Ye X, Peng Y, Li L, Yin L, Gao X, Song B, Sun Y, Wang J, Xue W, Abrams P. The characteristics and risk factors of healthcare-seeking men with lower urinary tract symptoms in China: Initial report from the POInT group. Neurourol Urodyn 2021; 40:1740-1753. [PMID: 34252243 DOI: 10.1002/nau.24737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 05/18/2021] [Accepted: 06/02/2021] [Indexed: 11/10/2022]
Abstract
AIMS To investigate the clinical characteristics of health care-seeking men presenting with lower urinary tract symptoms (LUTS) in China and to reveal risk factors for symptom severity. METHODS This multicenter, hospital-based, cross-sectional study recruited 1477 eligible male subjects, who were at least 45 years, seeking health care at 9 participating hospitals across the mainland China. The general medical information and subjective symptoms were recorded, followed by the measurement of prostate volume, urodynamic indices, and laboratory tests for kidney function, plus glucose/lipid metabolism. Univariate and multivariate linear regression were employed for the detection of risk factors for symptom severity. RESULTS The proportion of mild, moderate, and severe LUTS was 14.6%, 32.6%, and 52.8%, respectively, with 62.2% reporting the triple combination of storage, voiding, and postmicturition symptoms. Median prostate volume was 44.6 ml, and 71.1% were experiencing comorbidities. Thirteen independent risk factors for LUTS severity were identified, namely, nocturnal voiding episodes and the presence of straining and weak steam; the triple combination of symptom subtypes; general and nocturia quality of life; Qmax and bladder outlet obstruction index; and numbers of comorbidities, hypertension, estimated glomerular filtration rate, and cholesterol and glycosylated hemoglobin. CONCLUSIONS The majority of health care-seeking LUTS men present with moderate-to-severe and overlapping symptoms, with a high prevalence of both lower urinary tract dysfunction and systemic comorbidities. The evidence from both urological and nonurological independent risk factors demonstrate the multifactorial nature of LUTS, for which a multidisciplinary management is essential.
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Affiliation(s)
- Qi-Xiang Song
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Urology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Fan He
- Department of Urology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Xionglin Sun
- Department of Urology, The First Affiliated Hospital of Fujian Medical University, Fujian, China
| | - Ke Liu
- Department of Urology, Peking University Third Hospital, Beijing, China
| | - Zhong Chen
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Mingzhao Li
- Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Jianhai Lin
- Department of Urology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhihui Xu
- Department of Urology, Zhejiang Provincial People's Hospital, Hangzhou, Shanghai, China
| | - Yan Li
- Department of Urology, Qilu Hospital, Shandong University, Shandong, China
| | - Yaoguang Zhang
- Department of Urology, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Hai Huang
- Department of Urology, Sun Yat-Sen Memorial Hospital, Guangzhou, China
| | - Yi Zhang
- Department of Military Health Service, Naval Medical University, Shanghai, China
| | - Xiaofei Ye
- Department of Health Statistics, Naval Medical University, Shanghai, China
| | - Yonghan Peng
- Department of Urology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Longkun Li
- Department of Urology, Changhai Hospital, Naval Medical University, Shanghai, China
| | | | - Xiaofeng Gao
- Department of Urology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Bo Song
- Department of Urology, Southwest Hospital, Army Medical University, Chongqing, China
| | - Yinghao Sun
- Department of Urology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jianye Wang
- Department of Urology, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Wei Xue
- Department of Urology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Paul Abrams
- Bristol Urological Institute, Southmead Hospital, Bristol, UK
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Kremer D, Groothof D, Keyzer CA, Eelderink C, Knobbe TJ, Post A, van Londen M, Eisenga MF, TransplantLines Investigators, Schurgers LJ, Berger SP, de Borst MH, Bakker SJL. Kidney Function-Dependence of Vitamin K-Status Parameters: Results from the TransplantLines Biobank and Cohort Studies. Nutrients 2021; 13:3069. [PMID: 34578950 PMCID: PMC8467091 DOI: 10.3390/nu13093069] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Revised: 08/25/2021] [Accepted: 08/30/2021] [Indexed: 01/07/2023] Open
Abstract
High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend on kidney function. However, many studies with vitamin K-status parameters do not structurally adjust for baseline kidney function, and detailed studies on kidney function-dependence of vitamin K-status markers are lacking. We therefore measured plasma dp-ucMGP using a chemiluminescent assay in 578 kidney transplant recipients (41% females, age 56 ± 13y, 7.5 (3.2 to 13.7)y after transplantation, eGFR 49 ± 17 mL/min/1.73 m2) participating in the prospective TransplantLines Cohort Studies. Additionally, dp-carboxylated MGP, ucOC and carboxylated OC were measured using ELISA in plasma of a subgroup of 60 participants. Finally, dp-ucMGP was measured in a separate cohort of 124 kidney transplant recipients before and three months after kidney transplantation. Dp-ucMGP positively correlated with creatinine, cystatin C, and negatively with eGFR (Spearman's ρ 0.54, 0.60, and -0.54, respectively, p < 0.001 for all), and each 10 mL/min/1.73 m2 increase in eGFR was associated with a 14.0% lower dp-ucMGP. Additionally, dp-ucMGP strongly declined after kidney transplantation (pretransplantation: 1252 (868 to 1744) pmol/L to posttransplantation: 609 (451 to 914) pmol/L, p < 0.001). Proportions of dp-ucMGP over total MGP and ucOC over total OC were not associated with eGFR. This study highlights that dp-ucMGP is strongly associated with kidney function, and that levels strongly decrease after kidney transplantation. We therefore propose adequate adjustment for kidney function, or the use of kidney function-independent parameters such as proportion of uncarboxylated MGP or OC in the assessment of vitamin K-status in clinical practice and research.
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Affiliation(s)
- Daan Kremer
- Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.G.); (C.A.K.); (C.E.); (T.J.K.); (A.P.); (M.v.L.); (M.F.E.); (S.P.B.); (M.H.d.B.); (S.J.L.B.)
| | - Dion Groothof
- Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.G.); (C.A.K.); (C.E.); (T.J.K.); (A.P.); (M.v.L.); (M.F.E.); (S.P.B.); (M.H.d.B.); (S.J.L.B.)
| | - Charlotte A. Keyzer
- Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.G.); (C.A.K.); (C.E.); (T.J.K.); (A.P.); (M.v.L.); (M.F.E.); (S.P.B.); (M.H.d.B.); (S.J.L.B.)
| | - Coby Eelderink
- Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.G.); (C.A.K.); (C.E.); (T.J.K.); (A.P.); (M.v.L.); (M.F.E.); (S.P.B.); (M.H.d.B.); (S.J.L.B.)
| | - Tim J. Knobbe
- Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.G.); (C.A.K.); (C.E.); (T.J.K.); (A.P.); (M.v.L.); (M.F.E.); (S.P.B.); (M.H.d.B.); (S.J.L.B.)
| | - Adrian Post
- Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.G.); (C.A.K.); (C.E.); (T.J.K.); (A.P.); (M.v.L.); (M.F.E.); (S.P.B.); (M.H.d.B.); (S.J.L.B.)
| | - Marco van Londen
- Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.G.); (C.A.K.); (C.E.); (T.J.K.); (A.P.); (M.v.L.); (M.F.E.); (S.P.B.); (M.H.d.B.); (S.J.L.B.)
| | - Michele F. Eisenga
- Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.G.); (C.A.K.); (C.E.); (T.J.K.); (A.P.); (M.v.L.); (M.F.E.); (S.P.B.); (M.H.d.B.); (S.J.L.B.)
| | - TransplantLines Investigators
- University Medical Center Groningen Transplant Center, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands;
| | - Leon J. Schurgers
- Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, 6200 MD Maastricht, The Netherlands;
| | - Stefan P. Berger
- Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.G.); (C.A.K.); (C.E.); (T.J.K.); (A.P.); (M.v.L.); (M.F.E.); (S.P.B.); (M.H.d.B.); (S.J.L.B.)
| | - Martin H. de Borst
- Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.G.); (C.A.K.); (C.E.); (T.J.K.); (A.P.); (M.v.L.); (M.F.E.); (S.P.B.); (M.H.d.B.); (S.J.L.B.)
| | - Stephan J. L. Bakker
- Department of Internal Medicine, Division of Nephrology, University of Groningen and University Medical Center Groningen, 9700 RB Groningen, The Netherlands; (D.G.); (C.A.K.); (C.E.); (T.J.K.); (A.P.); (M.v.L.); (M.F.E.); (S.P.B.); (M.H.d.B.); (S.J.L.B.)
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Ciolino JD, Spino C, Ambrosius WT, Khalatbari S, Cayetano SM, Lapidus JA, Nietert PJ, Oster RA, Perkins SM, Pollock BH, Pomann GM, Price LL, Rice TW, Tosteson TD, Lindsell CJ, Spratt H. Guidance for biostatisticians on their essential contributions to clinical and translational research protocol review. J Clin Transl Sci 2021; 5:e161. [PMID: 34527300 PMCID: PMC8427547 DOI: 10.1017/cts.2021.814] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 06/30/2021] [Accepted: 07/02/2021] [Indexed: 12/23/2022] Open
Abstract
Rigorous scientific review of research protocols is critical to making funding decisions, and to the protection of both human and non-human research participants. Given the increasing complexity of research designs and data analysis methods, quantitative experts, such as biostatisticians, play an essential role in evaluating the rigor and reproducibility of proposed methods. However, there is a common misconception that a statistician's input is relevant only to sample size/power and statistical analysis sections of a protocol. The comprehensive nature of a biostatistical review coupled with limited guidance on key components of protocol review motived this work. Members of the Biostatistics, Epidemiology, and Research Design Special Interest Group of the Association for Clinical and Translational Science used a consensus approach to identify the elements of research protocols that a biostatistician should consider in a review, and provide specific guidance on how each element should be reviewed. We present the resulting review framework as an educational tool and guideline for biostatisticians navigating review boards and panels. We briefly describe the approach to developing the framework, and we provide a comprehensive checklist and guidance on review of each protocol element. We posit that the biostatistical reviewer, through their breadth of engagement across multiple disciplines and experience with a range of research designs, can and should contribute significantly beyond review of the statistical analysis plan and sample size justification. Through careful scientific review, we hope to prevent excess resource expenditure and risk to humans and animals on poorly planned studies.
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Affiliation(s)
- Jody D. Ciolino
- Department of Preventive Medicine, Division of Biostatistics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Cathie Spino
- Department of Biostatistics, University of Michigan, Washington Heights, Ann Arbor, MI, USA
| | - Walter T. Ambrosius
- Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Shokoufeh Khalatbari
- Michigan Institute for Clinical & Health Research (MICHR), University of Michigan, Ann Arbor, MI, USA
| | | | - Jodi A. Lapidus
- School of Public Health, Oregon Health & Sciences University, Portland, OR, USA
| | - Paul J Nietert
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Robert A. Oster
- Department of Medicine, Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, UK
| | - Susan M. Perkins
- Department of Biostatistics, Indiana University, Indianapolis, IN, USA
| | - Brad H. Pollock
- Department of Public Health Sciences, UC Davis School of Medicine, Davis, CA, USA
| | - Gina-Maria Pomann
- Duke Biostatistics, Epidemiology and Research Design (BERD) Methods Core, Duke University, Durham, NC, USA
| | - Lori Lyn Price
- Tufts Clinical and Translational Science Institute, Tufts University, Boston, MA, USA
- Institute of Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA
| | - Todd W. Rice
- Department of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Medical Director, Vanderbilt Human Research Protections Program, Vice-President for Clinical Trials Innovation and Operations, Nashville, TN, USA
| | - Tor D. Tosteson
- Department of Biomedical Data Science, Division of Biostatistics, Geisel School of Medicine at Dartmouth, Hanover, NH, USA
| | | | - Heidi Spratt
- Department of Preventive Medicine and Population Health, University of Texas Medical Branch, Galveston, TX, USA
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Delgado C, Baweja M, Burrows NR, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, Mendu ML, Miller WG, Moxey-Mims MM, Roberts GV, St Peter WL, Warfield C, Powe NR. Reassessing the Inclusion of Race in Diagnosing Kidney Diseases: An Interim Report From the NKF-ASN Task Force. Am J Kidney Dis 2021; 78:103-115. [PMID: 33845065 PMCID: PMC8238889 DOI: 10.1053/j.ajkd.2021.03.008] [Citation(s) in RCA: 103] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
For almost 2 decades, equations that use serum creatinine, age, sex, and race to estimate glomerular filtration rate (GFR) have included "race" as Black or non-Black. Given considerable evidence of disparities in health and health care delivery in African American communities, some regard keeping a race term in GFR equations as a practice that differentially influences access to care and kidney transplantation. Others assert that race captures important non-GFR determinants of serum creatinine and its removal from the calculation may perpetuate other disparities. The National Kidney Foundation (NKF) and American Society of Nephrology (ASN) established a task force in 2020 to reassess the inclusion of race in the estimation of GFR in the United States and its implications for diagnosis and subsequent management of patients with, or at risk for, kidney diseases. This interim report details the process, initial assessment of evidence, and values defined regarding the use of race to estimate GFR. We organized activities in phases: (1) clarify the problem and examine evidence, (2) evaluate different approaches to address use of race in GFR estimation, and (3) make recommendations. In phase 1, we constructed statements about the evidence and defined values regarding equity and disparities; race and racism; GFR measurement, estimation, and equation performance; laboratory standardization; and patient perspectives. We also identified several approaches to estimate GFR and a set of attributes to evaluate these approaches. Building on evidence and values, the attributes of alternative approaches to estimate GFR will be evaluated in the next phases and recommendations will be made.
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Affiliation(s)
- Cynthia Delgado
- Nephrology Section, San Francisco Veterans Affairs Medical Center, Division of Nephrology, University of California San Francisco, San Francisco, CA.
| | - Mukta Baweja
- Nephrology Division, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Nilka Ríos Burrows
- Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, GA
| | - Deidra C Crews
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Nwamaka D Eneanya
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Crystal A Gadegbeku
- Department of Medicine, Section of Nephrology, Hypertension and Kidney Transplantation, Temple University, Philadelphia, PA
| | - Lesley A Inker
- Division of Nephrology, Tufts Medical Center, Boston, MA
| | - Mallika L Mendu
- Division of Renal Medicine and Office of the Chief Medical Officer, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - W Greg Miller
- Department of Pathology, Virginia Commonwealth University, Richmond, VA
| | - Marva M Moxey-Mims
- Division of Nephrology, Children's National Hospital, Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Glenda V Roberts
- External Relations and Patient Engagement, Kidney Research Institute, Center for Dialysis Innovation, University of Washington, Seattle, WA
| | | | | | - Neil R Powe
- Department of Medicine, Priscilla Chan and Mark Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA.
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Chen CW, Tsai CH, Hung CS, Tsai IJ, Chiu YW, Chang CC, Liu KL, Liao SC, Wu VC, Lin YH. Comparison of cystatin C-based and creatinine-based glomerular filtration rate in the prediction of postoperative residual hypertension in aldosterone-producing adenoma patients after adrenalectomy. Clin Chim Acta 2021; 520:147-153. [PMID: 34116005 DOI: 10.1016/j.cca.2021.06.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2020] [Revised: 04/12/2021] [Accepted: 06/03/2021] [Indexed: 12/14/2022]
Abstract
Renal function is associated with postoperative residual hypertension in aldosterone-producing adenoma(APA) patients. Cystatin C-based glomerular filtration rate (GFR) can more accurately estimate renal function than creatinine-based methods. However, which renal function estimation method can more accurately predict postoperative hypertension in APA patients is still unknown. We recruited 180 APA patients who underwent adrenalectomy. Preoperative creatinine and cystatin C-based GFRs were calculated. Residual hypertension was defined as persistent hypertension > 140/90 mmHg or requiring anti-hypertensive medications 1 year after surgery. Sixty-five(36.1%) of the 180 APA patients had residual hypertension. Multivariate logistic regression and receiver operating characteristic (ROC) curve analysis showed a combination of creatinine and cystatin method CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine-cystatin GFR was significantly associated with residual postoperative hypertension and had the largest area under the ROC curve, which was statistically larger than that of Cockcroft-Gault creatinine-based GFR. In both net reclassification index and integrated discrimination index models, CKD-EPI creatinine-cystatin GFR significantly improved the discriminatory power of CG-GFR. Among these renal function estimations used in the presented study, creatinine-cystatin combined GFR was a precise method to predict residual postoperative hypertension in APA patients received adrenalectomy. These finding may help identify those patients with higher risk of residual hypertension after operation.
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Affiliation(s)
- Ching-Way Chen
- Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, Taiwan
| | - Cheng-Hsuan Tsai
- Department of Internal Medicine, National Taiwan University Hospital JinShen Branch, JinShen, Taiwan
| | - Chi-Sheng Hung
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - I-Jung Tsai
- Division of Nephrology, Department of Pediatrics, National Taiwan University Children's Hospital, Taipei, Taiwan
| | - Yu-Wei Chiu
- Cardiology Division of Cardiovascular Medical Center, Far Eastern Memorial Hospital, New Taipei City, Taiwan; Department of Computer Science and Engineering, Yuan Ze University, Taoyuan City, Taiwan
| | - Chin-Cheng Chang
- Department of Medical Imagine, National Taiwan University Hospital, Taipei, Taiwan
| | - Kao-Lang Liu
- Department of Medical Imagine, National Taiwan University Hospital, Taipei, Taiwan
| | - Shih-Cheng Liao
- Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
| | - Vin-Cent Wu
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yen-Hung Lin
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
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Delgado C, Baweja M, Burrows NR, Crews DC, Eneanya ND, Gadegbeku CA, Inker LA, Mendu ML, Miller WG, Moxey-Mims MM, Roberts GV, St. Peter WL, Warfield C, Powe NR. Reassessing the Inclusion of Race in Diagnosing Kidney Diseases: An Interim Report from the NKF-ASN Task Force. J Am Soc Nephrol 2021; 32:1305-1317. [PMID: 33837122 PMCID: PMC8259639 DOI: 10.1681/asn.2021010039] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
For almost two decades, equations that use serum creatinine, age, sex, and race to eGFR have included "race" as Black or non-Black. Given considerable evidence of disparities in health and healthcare delivery in African American communities, some regard keeping a race term in GFR equations as a practice that differentially influences access to care and kidney transplantation. Others assert that race captures important non GFR determinants of serum creatinine and its removal from the calculation may perpetuate other disparities. The National Kidney Foundation (NKF) and American Society of Nephrology (ASN) established a task force in 2020 to reassess the inclusion of race in the estimation of GFR in the United States and its implications for diagnosis and subsequent management of patients with, or at risk for, kidney diseases. This interim report details the process, initial assessment of evidence, and values defined regarding the use of race to estimate GFR. We organized activities in phases: (1) clarify the problem and examine evidence, (2) evaluate different approaches to address use of race in GFR estimation, and (3) make recommendations. In phase one, we constructed statements about the evidence and defined values regarding equity and disparities; race and racism; GFR measurement, estimation, and equation performance; laboratory standardization; and patient perspectives. We also identified several approaches to estimate GFR and a set of attributes to evaluate these approaches. Building on evidence and values, the attributes of alternative approaches to estimate GFR will be evaluated in the next phases and recommendations will be made.
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Affiliation(s)
- Cynthia Delgado
- Nephrology Section, San Francisco Veterans Affairs Medical Center, Division of Nephrology, University of California San Francisco, San Francisco, California
| | - Mukta Baweja
- Nephrology Division, Department of Medicine, Translational Transplant Research Center, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Nilka Ríos Burrows
- Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, Georgia
| | - Deidra C. Crews
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nwamaka D. Eneanya
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Crystal A. Gadegbeku
- Department of Medicine, Section of Nephrology, Hypertension and Kidney Transplantation, Temple University, Philadelphia, Pennsylvania
| | - Lesley A. Inker
- Division of Nephrology, Tufts Medical Center, Boston, Massachusetts
| | - Mallika L. Mendu
- Division of Renal Medicine and Office of the Chief Medical Officer, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
| | - W. Greg Miller
- Department of Pathology, Virginia Commonwealth University, Richmond, Virginia
| | - Marva M. Moxey-Mims
- Division of Nephrology, Children’s National Hospital, Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, DC
| | - Glenda V. Roberts
- External Relations and Patient Engagement, Kidney Research Institute, Center for Dialysis Innovation, University of Washington, Seattle, Washington
| | | | | | - Neil R. Powe
- Department of Medicine, Priscilla Chan and Mark Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, California
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Park WY, Kim Y, Paek JH, Jin K, Han S. Clinical significance of serum galactose-deficient immunoglobulin A1 for detection of recurrent immunoglobulin A nephropathy in kidney transplant recipients. Kidney Res Clin Pract 2021; 40:317-324. [PMID: 33866766 PMCID: PMC8237123 DOI: 10.23876/j.krcp.20.183] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 12/28/2020] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Recurrent glomerulonephritis (GN) is a common cause of allograft loss in kidney transplantation (KT), the most frequent of which is immunoglobulin A (IgA) nephropathy (IgAN). Galactose-deficient IgA1 (Gd-IgA1) plays a major role in the pathophysiology of IgAN, but the association between Gd-IgA1 and recurrent IgAN in kidney transplant recipients (KTRs) is uncertain. We aimed to evaluate the efficacy of Gd-IgA1 for prediction of recurrent IgAN and graft and patient survival according to Gd-IgA1 level. METHODS We enrolled 27 KTRs who underwent allograft biopsy between 2009 and 2016 and measured the serum Gd-IgA1 level of each KTR. We divided the patients into two groups: nonrecurrent IgAN (patients with IgAN prior to KT who were not diagnosed with recurrent IgAN) and recurrent IgAN (patients with IgAN prior to KT who were diagnosed with recurrent IgAN). RESULTS The mean serum Gd-IgA1 level was significantly higher in the recurrent IgAN group than in the nonrecurrent IgAN group (6,419 ± 3,675 ng/mL vs. 3,381 ± 2,844 ng/mL, p = 0.02). The cutoff value of serum Gd-IgA1 in receiver operating characteristic curve analysis was 4,338 ng/mL (area under the curve, 0.76; 95% confidence interval [CI], 0.57-0.95, p = 0.02). Serum Gd-IgA1 level was an independent factor for recurrent IgAN (odds ratio, 17.60; 95% CI, 1.33-233.03, p = 0.03). There was no significant difference in graft or patient survival between the two groups. CONCLUSION Serum Gd-IgA1 can be used as a diagnostic biomarker for recurrent IgAN in KT.
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Affiliation(s)
- Woo Yeong Park
- Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea.,Keimyung University Kidney Institute, Daegu, Republic of Korea.,Institute for Cancer Research, Keimyung University, Daegu, Republic of Korea
| | - Yaerim Kim
- Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea.,Keimyung University Kidney Institute, Daegu, Republic of Korea
| | - Jin Hyuk Paek
- Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea.,Keimyung University Kidney Institute, Daegu, Republic of Korea
| | - Kyubok Jin
- Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea.,Keimyung University Kidney Institute, Daegu, Republic of Korea
| | - Seungyeup Han
- Division of Nephrology, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea.,Keimyung University Kidney Institute, Daegu, Republic of Korea
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Wang Y, Levey AS, Inker LA, Jessani S, Bux R, Samad Z, Khan AR, Karger AB, Allen JC, Jafar TH. Performance and Determinants of Serum Creatinine and Cystatin C-Based GFR Estimating Equations in South Asians. Kidney Int Rep 2021; 6:962-975. [PMID: 33912746 PMCID: PMC8071622 DOI: 10.1016/j.ekir.2021.01.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 01/04/2021] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION The creatinine-based Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) equation was calibrated for the general Pakistan population (eGFRcr-PK) to eliminate bias and improve accuracy. Cystatin C-based CKD-EPI equations (eGFRcys and eGFRcr-cys) have not been assessed in this population, and non-GFR determinants of cystatin C are unknown. METHODS We assessed eGFRcys, eGFRcr-cys, and non-GFR determinants of cystatin C in a cross-sectional study of 557 participants (≥40 years of age) from Pakistan. We compared bias (median difference in measured GFR [mGFR] and eGFR), precision (interquartile range [IQR] of differences), accuracy (percentage of eGFR within 30% of mGFR), root mean square error (RMSE), and classification of mGFR <60 ml/min/1.73 m2 (area under the receiver operating characteristic curve [AUC] and net reclassification index [NRI]) among eGFR equations. RESULTS We found that eGFRcys underestimated mGFR (bias, 12.7 ml/min/1.73 m2 [95% confidence interval {CI} 10.7-15.2]). eGFRcr-cys did not improve performance over eGFRcr-PK in precision (P = 0.52), accuracy (P = 0.58), or RMSE (P = 0.49). Results were consistent among subgroups by age, sex, smoking, body mass index (BMI), and eGFR. NRI was 7.31% (95% CI 1.52%-13.1%; P < 0.001) for eGFRcr-cys versus eGFRcr-PK, but AUC was not improved (0.92 [95% CI 0.87-0.96] vs. 0.90 [95% CI 0.86-0.95]; P = 0.056). Non-GFR determinants of higher cystatin C included male sex, smoking, higher BMI and total body fat, and lower lean body mass. CONCLUSION eGFRcys underestimated mGFR in South Asians and eGFRcr-cys did not offer substantial advantage compared with eGFRcr-PK. Future studies are warranted to better understand the large bias in eGFRcys and non-GFR determinants of cystatin C in South Asians.
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Affiliation(s)
- Yeli Wang
- Program in Health Services and Systems Research, Duke–NUS Medical School, Singapore
| | - Andrew S. Levey
- Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA
| | - Lesley A. Inker
- Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, Massachusetts, USA
| | - Saleem Jessani
- Department of Community Health Sciences, Aga Khan University, Karachi, Pakistan
| | - Rasool Bux
- Department of Pediatrics (Division of Women and Child Health), Aga Khan University, Karachi, Pakistan
| | - Zainab Samad
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Ali Raza Khan
- Department of Medicine, Aga Khan University, Karachi, Pakistan
| | - Amy B. Karger
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota, USA
| | - John C. Allen
- Center for Quantitative Medicine, Office of Clinical Sciences, Duke–NUS Medical School, Singapore
| | - Tazeen H. Jafar
- Program in Health Services and Systems Research, Duke–NUS Medical School, Singapore
- Department of Renal Medicine, Singapore General Hospital, Singapore
- Duke Global Health Institute, Duke University, Durham, North Carolina, USA
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Li N, Huang H, Linsheng L, Lu H, Liu X. Improving glomerular filtration rate estimation by semi-supervised learning: a development and external validation study. Int Urol Nephrol 2021; 53:1649-1658. [PMID: 33710531 DOI: 10.1007/s11255-020-02771-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 12/21/2020] [Indexed: 11/24/2022]
Abstract
BACKGROUND Accurate estimating glomerular filtration rate (GFR) is crucial both in clinical practice and epidemiological survey. We incorporated semi-supervised learning technology to improve GFR estimation performance. METHODS AASK [African American Study of Kidney Disease and Hypertension], CRIC [Chronic Renal Insufficiency Cohort] and DCCT [Diabetes Control and Complications Trial] studies were pooled together for model development, whereas MDRD [Modification of Diet in Renal Disease] and CRISP [Consortium for Radiological Imaging Studies of Polycystic Kidney Disease] studies for model external validation. A total of seven variables (Serum creatinine, Age, Sex, Black race, Diabetes status, Hypertension and Body Mass Index) were included as independent variables, while the outcome variable GFR was measured as the urinary clearance of 125I-iothalamate. The revised CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration] creatinine equations was selected as benchmark for performance comparisons. Head-to-head performance comparisons from four-variable to seven-variable combination were conducted between revised CKD-EPI equations and semi-supervised models. RESULTS In each independent variables combination, the semi-supervised models consistently achieved superior results in all three performance indicators compared with corresponding revised CKD-EPI equations in the external validation data set. Furthermore, compared with revised four-variable CKD-EPI equation, the seven-variable semi-supervised model performed less biased (mean of difference: 0.03 [- 0.28, 0.34] vs 1.53 [1.28, 1.85], P < 0.001), more precise (interquartile range of difference: 7.94 [7.37, 8.50] vs 8.28 [7.76, 8.83], P = 0.1) and accurate (P30: 88.9% [87.4%, 90.2%] vs 86.0% [84.4%, 87.4%], P < 0.001. CONCLUSIONS The superior performance of the semi-supervised models during head-to-head comparisons supported the hypothesis that semi-supervised learning technology could improve GFR estimation performance.
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Affiliation(s)
- Ningshan Li
- SJTU-Yale Joint Center for Biostatistics and Data Science, Department of Bioinformatics and Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Hui Huang
- Cardiovascular Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China
| | - Lv Linsheng
- Operation Room, The Third Affiliated Hospital of Sun Yat-Sen University, Guangdong, China
| | - Hui Lu
- SJTU-Yale Joint Center for Biostatistics and Data Science, Department of Bioinformatics and Biostatistics, School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
- MoE Key Lab of Artificial Intelligence, AI Institute, Shanghai Jiao Tong University, Shanghai, China.
- Shanghai Engineering Research Center for Big Data in Pediatric Precision Medicine, Shanghai, China.
| | - Xun Liu
- Clinical Data Center of the Third Affiliated Hospital of Sun Yat-Sen University, Guangdong, China.
- Division of Nephrology, Department of Internal Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, Guangdong, China.
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Park WY, Chang YK, Kim YS, Jin K, Yang CW, Han S, Chung BH. Impact of acute kidney injury in deceased donors with high Kidney Donor Profile Index on posttransplant clinical outcomes: a multicenter cohort study. Kidney Res Clin Pract 2021; 40:162-174. [PMID: 33663035 PMCID: PMC8041636 DOI: 10.23876/j.krcp.20.083] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 12/07/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND This study evaluated the impact of acute kidney injury (AKI) on posttransplant clinical outcomes for deceased donor (DD) kidney transplantation (KT) using the Kidney Donor Profile Index (KDPI) system. METHODS Overall, 657 kidney transplant recipients (KTRs) receiving kidneys from 526 DDs from four transplant centers were included. We divided them into the high and low KDPI donor groups by 65%, the KDPI score, and both groups were subdivided into the AKI-DDKT and non-AKI-DDKT subgroups according to AKI in DDs. RESULTS There was no significant difference in the incidence of delayed graft function (DGF) between the high and low KDPI-KTR groups; however, the AKI-DDKT subgroup showed significantly higher incidence of DGF than the non-AKI-DDKT subgroup in both groups (p = 0.001, p < 0.001, respectively). The death-censored graft survival rate was significantly lower in the high KDPI-KTR group than in the low KDPI-KTR group (p = 0.005). Only in the high KDPI-KTR group, the death-censored graft survival rate was significantly lower in the KT from DDs with AKI stage 3 than KT from DDs with non-AKI or AKI stage 1 or 2 (p = 0.040). The interaction between AKI stage 3 in DDs and high KDPI on the allograft outcome was significant (p = 0.002). CONCLUSION KTs from DDs with AKI stage 3 showed an adverse impact on the allograft outcome in the high KDPI-KTR group. Therefore, DDs with a high KDPI score should be managed carefully so that severe AKI does not occur prior to KT.
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Affiliation(s)
- Woo Yeong Park
- Division of Nephrology, Department of Internal Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Yoon Kyung Chang
- Division of Nephrology, Department of Internal Medicine, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Republic of Korea
| | - Young Soo Kim
- Division of Nephrology, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Republic of Korea
| | - Kyubok Jin
- Division of Nephrology, Department of Internal Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Chul Woo Yang
- Transplant Research Center, Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seungyeup Han
- Division of Nephrology, Department of Internal Medicine, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Republic of Korea
| | - Byung Ha Chung
- Transplant Research Center, Division of Nephrology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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Fall-Associated Drugs in Community-Dwelling Older Adults: Results from the ActiFE Ulm Study. J Am Med Dir Assoc 2021; 22:2177-2183.e10. [PMID: 33516672 DOI: 10.1016/j.jamda.2020.12.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/18/2020] [Accepted: 12/19/2020] [Indexed: 11/20/2022]
Abstract
OBJECTIVES Many studies describing an association of drugs with falls focus mostly on drugs acting in the central nervous system. We aim to analyze the association of all drugs taken with falls in older adults. DESIGN Prospective population-based study (ActiFE study). SETTING AND PARTICIPANTS A total of 1377 community-dwelling older adults with complete recording of falls and baseline information on drug intake. METHODS Negative binomial regression was used to analyze the association of 34 drug classes with a 12-month incidence rate ratio (IRR) of falls adjusting for age, sex, comorbidities, gait speed, balance, chair rise, kidney function, liver disease, and smoking. RESULTS Participants took a median 3 drugs (interquartile range 1, 5), with 34.5% (n = 469) having ≥5 drugs. The median IRR for a fall per person-year was overall 0.72 [95% confidence interval (CI) 0.60-0.83] and 2.22 (95% CI 1.90-2.53) among those who experienced ≥1 fall. The following drug classes showed significant associations: antiparkinsonian medication [IRR 2.68 (95% CI 1.59-4.51)], thyroid therapy [IRR 1.40 (95% CI 1.08-1.81)], and systemic corticosteroids [IRR 0.33 (95% CI 0.13-0.81)]. Among fall-risk-increasing drugs only antiepileptics [IRR 2.16 (95% CI 1.10-4.24)] and urologicals [IRR 2.47 (95% CI 1.33-4.59)] were associated with falls in those participants without a prior fall history at baseline. CONCLUSION AND IMPLICATIONS Additional drug classes, such as antiparkinsonian medication, thyroid therapy, and systemic corticosteroids, might be associated with falls in older adults, possibly representing pharmacological effects on the musculoskeletal and central nervous systems. Further evaluations in larger study populations are recommended.
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Parvathaneni K, Surapaneni A, Ballew SH, Palta P, Rebholz CM, Selvin E, Coresh J, Grams ME. Association Between Midlife Physical Activity and Incident Kidney Disease: The Atherosclerosis Risk in Communities (ARIC) Study. Am J Kidney Dis 2021; 77:74-81. [PMID: 32971191 PMCID: PMC7752844 DOI: 10.1053/j.ajkd.2020.07.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 07/07/2020] [Indexed: 12/11/2022]
Abstract
RATIONALE & OBJECTIVE Physical activity is associated with lower risk for cardiovascular disease, diabetes, and hypertension, which have shared risk factor profiles with chronic kidney disease (CKD). However, there are conflicting findings regarding the relationship between physical activity and CKD. The objective was to evaluate the association between physical activity and CKD development over long-term follow-up using the Atherosclerosis Risk in Communities (ARIC) Study. STUDY DESIGN Prospective cohort study. SETTING & PARTICIPANTS 14,537 participants aged 45 to 64 years. PREDICTORS Baseline physical activity status was assessed using the modified Baecke Physical Activity Questionnaire at visit 1 (1987-1989) and categorized according to the 2018 Physical Activity Guidelines for Americans to group participants as inactive, insufficiently active, active, and highly active. OUTCOMES Incident CKD defined as estimated glomerular filtration rate (eGFR)<60mL/min/1.73m2 at follow-up and≥25% decline in eGFR relative to baseline, CKD-related hospitalization or death, or initiation of kidney replacement therapy. ANALYTICAL APPROACH Cox proportional hazards regression. RESULTS At baseline, 37.8%, 24.2%, 22.7%, and 15.3% of participants were classified as inactive, insufficiently active, active, and highly active, respectively. During a median follow-up of 24 years, 33.2% of participants developed CKD. After adjusting for age, sex, race-center, education, smoking status, diet quality, diabetes, coronary heart disease, hypertension, antihypertensive medication, body mass index, and baseline eGFR, higher categories of physical activity were associated with lower risk for CKD compared with the inactive group (HRs for insufficiently active, 0.95 [95% CI, 0.88-1.02]; active, 0.93 [95% CI, 0.86-1.01]; highly active, 0.89 [95% CI, 0.81-0.97]; P for trend = 0.007). LIMITATIONS Observational design and self-reported physical activity that was based on leisure time activity only. Due to low numbers, participants who were not Black or White were excluded. CONCLUSIONS Highly active participants had lower risk for developing CKD compared with inactive participants.
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Affiliation(s)
- Kaushik Parvathaneni
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Aditya Surapaneni
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Shoshana H Ballew
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Priya Palta
- Division of General Medicine, Department of Medicine, Columbia University, New York, NY
| | - Casey M Rebholz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Elizabeth Selvin
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD
| | - Morgan E Grams
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, MD.
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48
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Drug dosing in cancer patients with decreased kidney function: A practical approach. Cancer Treat Rev 2020; 93:102139. [PMID: 33370636 DOI: 10.1016/j.ctrv.2020.102139] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 12/06/2020] [Indexed: 10/22/2022]
Abstract
Correct drug dosing of anticancer agents is essential to obtain optimal outcomes. Overdosing will result in increased toxicity, treatment interruption and possible cessation of anticancer treatment. Underdosing may result in suboptimal anti-cancer effects and may increase the risk of cancer-related mortality. As it is practical nor feasible to perform therapeutic drug monitoring for all anti-cancer drugs, kidney function is used to guide drug dosing for those drugs whose primary mode of excretion is through the kidney. However, it is not well-established what method should be utilized to measure or estimate kidney function and the choice of method does influence treatment decisions regarding eligibility for anti-cancer drugs and their dose. In this review, we will provide an overview regarding the importance of drug dosing, the preferred method to determine kidney function and a practical approach to drug dosing of anticancer drugs.
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Selenium and Coenzyme Q10 Supplementation Improves Renal Function in Elderly Deficient in Selenium: Observational Results and Results from a Subgroup Analysis of a Prospective Randomised Double-Blind Placebo-Controlled Trial. Nutrients 2020; 12:nu12123780. [PMID: 33317156 PMCID: PMC7764721 DOI: 10.3390/nu12123780] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Revised: 12/01/2020] [Accepted: 12/06/2020] [Indexed: 12/20/2022] Open
Abstract
A low selenium intake is found in European countries, and is associated with increased cardiovascular mortality. There is an association between selenium level and the severity of kidney disease. An association between inflammation and selenium intake is also reported. The coenzyme Q10 level is decreased in kidney disease. The aim of this study was to examine a possible association between selenium and renal function in an elderly population low in selenium and coenzyme Q10, and the impact of intervention with selenium and coenzyme Q10 on the renal function. The association between selenium status and creatinine was studied in 589 elderly persons. In 215 of these (mean age 71 years) a randomised double-blind placebo-controlled prospective trial with selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/day) (n = 117) or placebo (n = 98) was conducted. Renal function was determined using measures of glomerular function at the start and after 48 months. The follow-up time was 5.1 years. All individuals were low on selenium (mean 67 μg/L (SD 16.8)). The changes in renal function were evaluated by measurement of creatinine, cystatin-C, and the use of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) algorithm, and by the use of T-tests, repeated measures of variance and ANCOVA analyses. An association between low selenium status and impaired renal function was observed. Intervention causes a significantly lower serum creatinine, and cystatin-C concentration in the active treatment group compared with those on placebo (p = 0.0002 and p = 0.001 resp.). The evaluation with CKD-EPI based on both creatinine and cystatin-C showed a corresponding significant difference (p < 0.0001). All validations showed corresponding significant differences. In individuals with a deficiency of selenium and coenzyme Q10, low selenium status is related to impaired renal function, and thus supplementation with selenium and coenzyme Q10 results in significantly improved renal function as seen from creatinine and cystatin-C and through the CKD-EPI algorithm. The explanation could be related to positive effects on inflammation and oxidative stress as a result of the supplementation.
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50
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Benoit SW, Kathman T, Patel J, Stegman M, Cobb C, Hoehn J, Devarajan P, Nehus EJ. GFR Estimation After Cystatin C Reference Material Change. Kidney Int Rep 2020; 6:429-436. [PMID: 33615068 PMCID: PMC7879112 DOI: 10.1016/j.ekir.2020.11.028] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 11/29/2022] Open
Abstract
Introduction Glomerular filtration rate (GFR) is routinely estimated with cystatin C. In June 2010, the International Federation of Clinical Chemistry (IFCC) released a certified cystatin C reference material (ERM-DA471/IFCC), and new cystatin C glomerular filtration rate estimation (eGFR) equations were developed with the IFCC standard. Early in 2018, Siemens discontinued their nonstandardized cystatin C reagent kits and replaced them with IFCC-calibrated kits in the US market. The aim of the current study was to assess the effect of IFCC calibration on cystatin C values and corresponding GFR estimations. Methods Cystatin C concentration was measured in 81 pediatric patients using a plasma sample from their nuclear GFR measurement with 99mTc-diethylenetriaminepentaaccetic acid. Calibration curves were generated using Siemens nonstandardized and IFCC-standardized kits to measure paired cystatin C concentrations in each sample. GFR-estimating equations using pre-IFCC and IFCC cystatin C values were compared using Bland-Altman analyses. Results The IFCC-standardized assay resulted in a mean increase in the measured cystatin C value of 24%. Estimating equations consistently overestimated GFR prior to IFCC standardization. Following incorporation of the IFCC standard, the Full Age Spectrum equation demonstrated the best overall performance, whereas the Chronic Kidney Disease in Children (CKiD) equation was more accurate in children with decreased GFR. Conclusion Incorporation of the IFCC standard significantly increased cystatin C values and affected the performance of GFR estimating equations. Clinical laboratories and providers may need to update the equation used for cystatin C-based estimation of GFR following adoption of the IFCC reference standard.
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Affiliation(s)
- Stefanie W Benoit
- Division of Nephrology & Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA
| | - Thelma Kathman
- Division of Nephrology & Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jay Patel
- Division of Nephrology & Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Melinda Stegman
- Division of Nephrology & Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Cristina Cobb
- Division of Nephrology & Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Jonathan Hoehn
- Department of Emergency Medicine, University of Cincinnati, Cincinnati, Ohio, USA
| | - Prasad Devarajan
- Division of Nephrology & Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA
| | - Edward J Nehus
- Division of Nephrology & Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.,Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, Ohio, USA
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