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Perkins BA, Bebu I, Gao X, Karger AB, Hirsch IB, Karanchi H, Molitch ME, Zinman B, Lachin JM, de Boer IH. Early Trajectory of Estimated Glomerular Filtration Rate and Long-term Advanced Kidney and Cardiovascular Complications in Type 1 Diabetes. Diabetes Care 2022; 45:585-593. [PMID: 35015817 PMCID: PMC8918200 DOI: 10.2337/dc21-1883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/21/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Rapid loss of estimated glomerular filtration rate (eGFR) within its normal range has been proposed as a strong predictor of future kidney disease. We investigated this association of eGFR slope early in the course of type 1 diabetes with long-term incidence of kidney and cardiovascular complications. RESEARCH DESIGN AND METHODS The annual percentage change in eGFR (slope) was calculated during the Diabetes Control and Complications Trial (DCCT) for each of 1,441 participants over a mean of 6.5 years and dichotomized by the presence or absence of early rapid eGFR loss (slope ≤-3% per year) as the exposure of interest. Outcomes were incident reduced eGFR (eGFR <60 mL/min/1.73 m2), composite cardiovascular events, or major adverse cardiovascular events (MACE) during the subsequent 24 years post-DCCT closeout follow-up. RESULTS At DCCT closeout (the baseline for this analysis), diabetes duration was 12 ± 4.8 years, most participants (85.9%) had normoalbuminuria, mean eGFR was 117.0 ± 13.4 mL/min/1.73 m2, and 149 (10.4%) had experienced early rapid eGFR loss over the preceding trial phase. Over the 24-year subsequent follow-up, there were 187 reduced eGFR (6.3 per 1,000 person-years) and 113 MACE (3.6 per 1,000 person-years) events. Early rapid eGFR loss was associated with risk of reduced eGFR (hazard ratio [HR] 1.81, 95% CI 1.18-2.79, P = 0.0064), but not after adjustment for baseline eGFR level (HR 0.94, 95% CI 0.53-1.66, P = 0.84). There was no association with composite cardiovascular events or MACE. CONCLUSIONS In people with type 1 diabetes primarily with normal eGFR and normoalbuminuria, the preceding slope of eGFR confers no additional association with kidney or cardiovascular outcomes beyond knowledge of an individual's current level.
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Affiliation(s)
- Bruce A. Perkins
- Department of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada
| | - Ionut Bebu
- The Biostatistics Center, Milken Institute School of Public Health, The George Washington University, Washington, DC
| | - Xiaoyu Gao
- The George Washington University, Washington, DC
| | - Amy B. Karger
- University of Minnesota Twin Cities, Twin Cities, MN
| | - Irl B. Hirsch
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA
| | - Harsha Karanchi
- Department of Medicine, Medical University of South Carolina, Charleston, SC
| | - Mark E. Molitch
- Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Bernard Zinman
- Departments of Endocrinology and Metabolism, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - John M. Lachin
- The Biostatistics Center, Milken Institute School of Public Health, The George Washington University, Washington, DC
| | - Ian H. de Boer
- Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA
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Westreich KD, Isom S, Divers J, D'Agostino R, Lawrence JM, Kanakatti Shankar R, Dolan LM, Imperatore G, Dabelea D, Mayer-Davis EJ, Mottl AK. Trajectories in estimated glomerular filtration rate in youth-onset type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Study. J Diabetes Complications 2021; 35:107768. [PMID: 33168393 PMCID: PMC7855388 DOI: 10.1016/j.jdiacomp.2020.107768] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/14/2020] [Accepted: 10/14/2020] [Indexed: 11/29/2022]
Abstract
AIMS We sought to characterize the direction and associated factors of eGFR change following diagnosis of youth-onset type 1 and type 2 diabetes. METHODS We assessed the direction of eGFR change at two visits (mean 6.6 years apart) in SEARCH, a longitudinal cohort study of youth-onset type 1 and type 2 diabetes. We used the CKiDCr-CysC equation to estimate GFR and categorized 'rising' and 'declining' eGFR as an annual change of ≥3 ml/min/1.73 m2 in either direction. Multivariable logistic regression evaluated factors associated with directional change in eGFR. RESULTS Estimated GFR declined in 23.8% and rose in 2.8% of participants with type 1 diabetes (N = 1225; baseline age 11.4 years), and declined in 18.1% and rose in 15.6% of participants with type 2 diabetes (N = 160; baseline age 15.0 years). Factors associated with rising and declining eGFR (versus stable) in both type 1 and type 2 diabetes included sex, age at diagnosis, baseline eGFR and difference in fasting glucose between study visits. Additional factors in type 1 diabetes included time from baseline visit, HbA1c and body mass index. CONCLUSIONS Over the first decade of diabetes, eGFR decline is more common in type 1 diabetes whereas eGFR rise is more common in type 2 diabetes.
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Affiliation(s)
- Katherine D Westreich
- University of North Carolina Kidney Center, UNC School of Medicine, Chapel Hill, NC, United States of America.
| | - Scott Isom
- Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, United States of America.
| | - Jasmin Divers
- Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, United States of America.
| | - Ralph D'Agostino
- Department of Biostatistical Sciences, Wake Forest University School of Medicine, Winston-Salem, NC, United States of America.
| | - Jean M Lawrence
- Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, United States of America.
| | - Roopa Kanakatti Shankar
- Division of Endocrinology, Children's National Medical Center, Washington, DC, United States of America
| | - Lawrence M Dolan
- Division of Endocrinology, Cincinnati Children's Hospital, Cincinnati, OH, United States of America.
| | - Giuseppina Imperatore
- Division of Diabetes Translation, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA, United States of America.
| | - Dana Dabelea
- Department of Epidemiology, School of Public Health, University of Colorado Denver, Aurora, CO, United States of America.
| | - Elizabeth J Mayer-Davis
- Department of Nutrition, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, United States of America; Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, United States of America.
| | - Amy K Mottl
- University of North Carolina Kidney Center, UNC School of Medicine, Chapel Hill, NC, United States of America.
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Stephens JW, Brown KE, Min T. Chronic kidney disease in type 2 diabetes: Implications for managing glycaemic control, cardiovascular and renal risk. Diabetes Obes Metab 2020; 22 Suppl 1:32-45. [PMID: 32267078 DOI: 10.1111/dom.13942] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/06/2019] [Accepted: 12/09/2019] [Indexed: 02/06/2023]
Abstract
This review examines the current literature relating to diabetes related kidney disease (DKD) and the optimal management of cardio-renal risk. DKD develops in approximately 40% of patients with type 2 diabetes mellitus. The mainstay of therapy is to reduce the progression of DKD by optimising hyperglycaemia, blood pressure, lipids and lifestyle. Evidence supports the role for renin-angiotensin system blockade in limiting the progression of DKD. Recent data from diabetes related cardiovascular outcome trials and renal specific trials have provided a novel insight on the additional benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in reducing the progression of DKD as well as cardiovascular risk. Lessons have been learnt from CREDENCE and there are expectations that DAPA-CKD and EMPA-KIDNEY will further support the benefits of SGLT2 inhibition in relation to DKD. As a consequence, international guidelines have been updated to reflect the positive benefits. In addition, novel steroidal mineralocorticoid receptor antagonists offer a potential role in future years. The review examines the current evidence and future approach to optimising outcomes for renal protection in patients with diabetes.
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Affiliation(s)
- Jeffrey W Stephens
- Diabetes Research Group, Swansea University Medical School, Swansea University, Swansea, UK
| | - Karen E Brown
- Diabetes Research Group, Swansea University Medical School, Swansea University, Swansea, UK
| | - Thinzar Min
- Diabetes Research Group, Swansea University Medical School, Swansea University, Swansea, UK
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Scarr D, Bjornstad P, Lovblom LE, Lovshin JA, Boulet G, Lytvyn Y, Farooqi MA, Lai V, Orszag A, Weisman A, Keenan HA, Brent MH, Paul N, Bril V, Cherney DZ, Perkins BA. Estimating GFR by Serum Creatinine, Cystatin C, and β2-Microglobulin in Older Adults: Results From the Canadian Study of Longevity in Type 1 Diabetes. Kidney Int Rep 2019; 4:786-796. [PMID: 31194091 PMCID: PMC6551543 DOI: 10.1016/j.ekir.2019.02.010] [Citation(s) in RCA: 11] [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: 01/25/2019] [Accepted: 02/11/2019] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION Glomerular filtration rate (GFR) is routinely used for clinical assessment of kidney function. However, the accuracy of estimating equations in older adults is uncertain. METHODS In 66 adults with ≥50 years type 1 diabetes (T1D) duration and 73 nondiabetic controls from age/sex-matched subgroups (65 ± 8 years old and 77[55%] were women) we evaluated the performance of estimated GFR (eGFR) by creatinine (Modification of Diet and Renal Disease [MDRD], Chronic Kidney Disease-Epidemiology [CKD-EPI]cr), cystatin C (CKD-EPIcys, CKD-EPIcr-cys), and β2-microglobulin (β2M) compared with measured GFR by inulin clearance (mGFR). Performance was evaluated using metrics of bias (mean difference), precision (SD), and accuracy (proportion of eGFR that differed by >20% of mGFR). RESULTS Mean mGFR was 104 ± 18 ml/min per 1.73 m2 (range: 70-154 ml/min per 1.73 m2) and was not different between T1D and controls (103 ± 17 vs. 105 ± 19 ml/min per 1.73 m2, P = 0.39). All equations significantly underestimated mGFR (bias: -15 to -30 ml/min per 1.73 m2, P < 0.001 for all comparisons) except for β2M, which had bias of 1.9 ml/min per 1.73 m2 (P = 0.61). Bias was greatest in cystatin C-based equations. Precision was lowest for β2M (SD: 43.5 ml/min per 1.73 m2, P < 0.001 for each comparison). Accuracy was lowest for CKD-EPIcysC (69.1%, P < 0.001 for each comparison). Cystatin C-based equations demonstrated greater bias and lower accuracy in older age subgroups (<60, 60-69, ≥70 years). All equations demonstrated greater bias across higher ranges of mGFR (60-89, 90-119, ≥120 ml/min per 1.73 m2). Results were similar between T1D and controls except that β2M had lower performance in T1D. CONCLUSION Better estimates of GFR in older adults are needed for research and clinical practice, as this subgroup of the population has an amplified risk for the development of chronic kidney disease (CKD) that requires accurate GFR estimation methods.
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Affiliation(s)
- Daniel Scarr
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Division of Endocrinology, Department of Pediatrics, University of Colorado, Aurora, Colorado, USA
- Division of Nephrology, Department of Medicine, University of Colorado, Aurora, Colorado, USA
| | - Leif E. Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Julie A. Lovshin
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Genevieve Boulet
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Mohammed A. Farooqi
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Vesta Lai
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Andrej Orszag
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Alanna Weisman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Hillary A. Keenan
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Michael H. Brent
- Department of Ophthalmology and Vision Sciences, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Narinder Paul
- Joint Department of Medical Imaging, Division of Cardiothoracic Radiology, University Health Network, Toronto, Ontario, Canada
| | - Vera Bril
- The Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Krembil Neuroscience Centre, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - David Z.I. Cherney
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Bruce A. Perkins
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Performance of Cystatin C-Based Equations for Estimation of Glomerular Filtration Rate in Diabetes Patients: A Prisma-Compliant Systematic Review and Meta-Analysis. Sci Rep 2019; 9:1418. [PMID: 30723243 PMCID: PMC6363744 DOI: 10.1038/s41598-018-38286-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 12/06/2018] [Indexed: 02/01/2023] Open
Abstract
The accuracy of estimated glomerular filtration rate (eGFR) equations in diabetes mellitus (DM) patients has been extensively questioned. We evaluated the performance of cystatin C-based equations alone or in combination with creatinine to estimate GFR in DM patients. A PRISMA-compliant systematic review was performed in the MEDLINE and Embase databases, with “diabetes mellitus” and “cystatin C” as search terms. Studies comparing cystatin C-based eGFR equations with measured GFR (mGFR) in DM patients were eligible. Accuracies P10, P15, P20, and P30 indicated the proportion of eGFR results within 10, 15, 20, and 30% of mGFR. Single-arm meta-analyses were conducted, and the Quality of Diagnostic Accuracy Studies-II tool (QUADAS-2) was applied. Twenty-three studies comprising 7065 participants were included, and 24 equations were analyzed in a broad range of GFRs. Meta-analyses were completed for 10 equations. The mean P30 accuracies of the equations ranged from 41% to 87%, with the highest values found with both CKD-EPI equations. Mean P10-P15 achieved 35% in the best scenario. A sensitivity analysis to evaluate different mGFR methods did not change results. In conclusion, cystatin C-based eGFR equations represent measured GFR fairly at best in DM patients, with high variability among the several proposed equations.
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Bucca BC, Maahs DM, Snell-Bergeon JK, Hokanson J, Rinella S, Bishop F, Boufard A, Homann J, Cheung CY, Wong TY. Dynamic changes in retinal vessel diameter during acute hyperglycemia in type 1 diabetes. J Diabetes Complications 2018; 32:234-239. [PMID: 29174301 DOI: 10.1016/j.jdiacomp.2017.10.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 09/20/2017] [Accepted: 10/04/2017] [Indexed: 11/21/2022]
Abstract
AIMS To investigate changes in retinal vessel diameter during acute hyperglycemia in patients with type 1 diabetes. METHODS We conducted a study on 11 subjects with type 1 diabetes. Euglycemia was maintained for 3h followed by induction of hyperglycemia and simultaneous bolus of rapid acting insulin. Two fundus photos were captured during euglycemia and five fundus photos, blood glucose and blood pressure were taken every 30min for 2.5h post-prandial. Central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) were measured over the study visit and examined using generalized linear mixed models. RESULTS In a multivariate mixed model, mean CRAE and CRVE were reduced at 90min post-prandial in both zones B and C. In repeated measures analysis, arterioles exhibited a significant association with change in vessel caliber per change in blood glucose. Inconsistent effects of blood pressure on vessel diameter were also measured. CONCLUSIONS We document a change in retinal vessel diameter during acute hyperglycemia in persons with type 1 diabetes. Larger controlled studies are required to further investigate this phenomenon and to more accurately assess if hyperglycemia has direct effects on retinal vessel diameter.
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Affiliation(s)
- Brian C Bucca
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States.
| | - David M Maahs
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States; Department of Medicine, Division of Nephrology, University of Colorado Denver, Aurora, CO 80045, United States; Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, United States; Division of Pediatric Endocrinology, Stanford University, Stanford, CA 94305, United States
| | - Janet K Snell-Bergeon
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States; Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, United States
| | - John Hokanson
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, United States
| | - Sean Rinella
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, United States
| | - Franziska Bishop
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Alexis Boufard
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Joanna Homann
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
| | - Carol Y Cheung
- Singapore Eye Research Institute, The Acedemia, 20 College Road, Discovery Tower Level 6, Singapore 169856; Duke-NUS Graduate Medical School, 8 College Road, 169857, Singapore
| | - Tien Y Wong
- Singapore Eye Research Institute, The Acedemia, 20 College Road, Discovery Tower Level 6, Singapore 169856; Duke-NUS Graduate Medical School, 8 College Road, 169857, Singapore
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Bjornstad P, Karger AB, Maahs DM. Measured GFR in Routine Clinical Practice-The Promise of Dried Blood Spots. Adv Chronic Kidney Dis 2018; 25:76-83. [PMID: 29499891 DOI: 10.1053/j.ackd.2017.09.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2017] [Revised: 09/17/2017] [Accepted: 09/20/2017] [Indexed: 12/31/2022]
Abstract
Accurate determination of glomerular filtration rate (GFR) is crucial for the diagnosis of kidney disease. Estimated GFR (eGFR) calculated by serum creatinine and/or cystatin C is a mainstay in clinical practice and epidemiologic research but lacks precision and accuracy until GFR <60 mL/min/1.73 m2. Furthermore, eGFR may not precisely and accurately represent changes in GFR longitudinally. The lack of precision and accuracy is of concern in populations at high risk for kidney disease, as the dissociation between changes in eGFR and GFR may lead to missed diagnoses of early kidney disease. Therefore, improved methods to quantify GFR are needed. Whereas direct measures of GFR have been too cumbersome for screening and ambulatory care, a practical method of measuring GFR by iohexol clearance using dried capillary blood spots exists. In this review, we examine the current literature and data addressing GFR measurements by dried capillary blood spots and its potential application in high-risk groups.
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8
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Kanakatti Shankar R, Dolan LM, Isom S, Saydah S, Maahs DM, Dabelea D, Reynolds K, Hirsch IB, Rodriguez BL, Mayer-Davis EJ, Marcovina S, D'Agostino R, Mauer M, Mottl AK. Serum cystatin C in youth with diabetes: The SEARCH for diabetes in youth study. Diabetes Res Clin Pract 2017; 130:258-265. [PMID: 28666182 PMCID: PMC5575920 DOI: 10.1016/j.diabres.2017.06.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Revised: 06/02/2017] [Accepted: 06/06/2017] [Indexed: 12/16/2022]
Abstract
AIMS We compared cystatin C in youth with versus without diabetes and determined factors associated with cystatin C in youth with type 1 diabetes (T1D) and type 2 diabetes (T2D). METHODS Youth (ages 12-19years) without diabetes (N=544) were ascertained from the NHANES Study 2000-2002 and those with T1D (N=977) and T2D (N=168) from the SEARCH for Diabetes in Youth Study. Adjusted means of cystatin C concentrations were compared amongst the 3 groups. Next, we performed multivariable analyses within the T1D and T2D SEARCH samples to determine the association between cystatin C and race, sex, age, diabetes duration, HbA1c, fasting glucose, and BMI. RESULTS Adjusted cystatin C concentrations were statistically higher in NHANES (0.85mg/L) than in either the T1D (0.75mg/L) or T2D (0.70mg/L) SEARCH groups (P<0.0001). Fasting glucose was inversely related to cystatin C only in T1D (P<0.001) and BMI positively associated only in T2D (P<0.01) while HbA1c was inversely associated in both groups. CONCLUSIONS Cystatin C concentrations are statistically higher in youth without diabetes compared to T1D or T2D, however the clinical relevance of this difference is quite small, especially in T1D. In youth with diabetes, cystatin C varies with BMI and acute and chronic glycemic control, however their effects may be different according to diabetes type.
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Affiliation(s)
- Roopa Kanakatti Shankar
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
| | - Lawrence M Dolan
- Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Scott Isom
- Department of Biostatistical Sciences, Wake Forest University School of Medicine, NC, United States
| | - Sharon Saydah
- Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, GA, United States
| | - David M Maahs
- Barbara Davis Center for Diabetes, University of Colorado, Denver, CO, United States
| | - Dana Dabelea
- Department of Epidemiology, Colorado School of Public Health, University of Colorado, Denver, CO, United States
| | - Kristi Reynolds
- Department of Research and Evaluation, Kaiser Permanente South California, Pasadena, CA, United States
| | - Irl B Hirsch
- Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, United States
| | | | - Elizabeth J Mayer-Davis
- Departments of Nutrition and Medicine, University of North Carolina at Chapel Hill, NC, United States
| | - Santica Marcovina
- Division of Metabolism, Endocrinology and Nutrition, Northwest Lipid Metabolism and Diabetes Research Laboratories, Seattle, WA, United States
| | - Ralph D'Agostino
- Department of Biostatistical Sciences, Wake Forest University School of Medicine, NC, United States
| | - Michael Mauer
- Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Amy K Mottl
- University of North Carolina Kidney Center, UNC School of Medicine, Chapel Hill, NC, United States
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MacIsaac RJ, Jerums G, Ekinci EI. Effects of glycaemic management on diabetic kidney disease. World J Diabetes 2017; 8:172-186. [PMID: 28572879 PMCID: PMC5437616 DOI: 10.4239/wjd.v8.i5.172] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 11/07/2016] [Accepted: 03/17/2017] [Indexed: 02/05/2023] Open
Abstract
Hyperglycaemia contributes to the onset and progression of diabetic kidney disease (DKD). Observational studies have not consistently demonstrated a glucose threshold, in terms of HbA1c levels, for the onset of DKD. Tight glucose control has clearly been shown to reduce the incidence of micro- or macroalbuminuria. However, evidence is now also emerging to suggest that intensive glucose control can slow glomerular filtration rate loss and possibly progression to end stage kidney disease. Achieving tight glucose control needs to be balanced against the increasing appreciation that glucose targets for the prevention of diabetes related complications need be individualised for each patient. Recently, empagliflozin which is an oral glucose lowering agent of the sodium glucose cotransporter-2 inhibitor class has been shown to have renal protective effects. However, the magnitude of empagliflozin’s reno-protective properties are over and above that expected from its glucose lowering effects and most likely largely result from mechanisms involving alterations in intra-renal haemodynamics. Liraglutide and semaglutide, both injectable glucose lowering agents which are analogues of human glucagon like peptide-1 have also been shown to reduce progression to macroalbuminuria through mechanisms that remain to be fully elucidated. Here we review the evidence from observational and interventional studies that link good glucose control with improved renal outcomes. We also briefly review the potential reno-protective effects of newer glucose lowering agents.
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Tonneijck L, Muskiet MHA, Smits MM, van Bommel EJ, Heerspink HJL, van Raalte DH, Joles JA. Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment. J Am Soc Nephrol 2017; 28:1023-1039. [PMID: 28143897 DOI: 10.1681/asn.2016060666] [Citation(s) in RCA: 542] [Impact Index Per Article: 67.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
An absolute, supraphysiologic elevation in GFR is observed early in the natural history in 10%-67% and 6%-73% of patients with type 1 and type 2 diabetes, respectively. Moreover, at the single-nephron level, diabetes-related renal hemodynamic alterations-as an adaptation to reduction in functional nephron mass and/or in response to prevailing metabolic and (neuro)hormonal stimuli-increase glomerular hydraulic pressure and transcapillary convective flux of ultrafiltrate and macromolecules. This phenomenon, known as glomerular hyperfiltration, classically has been hypothesized to predispose to irreversible nephron damage, thereby contributing to initiation and progression of kidney disease in diabetes. However, dedicated studies with appropriate diagnostic measures and clinically relevant end points are warranted to confirm this assumption. In this review, we summarize the hitherto proposed mechanisms involved in diabetic hyperfiltration, focusing on ultrastructural, vascular, and tubular factors. Furthermore, we review available evidence on the clinical significance of hyperfiltration in diabetes and discuss currently available and emerging interventions that may attenuate this renal hemodynamic abnormality. The revived interest in glomerular hyperfiltration as a prognostic and pathophysiologic factor in diabetes may lead to improved and timely detection of (progressive) kidney disease, and could provide new therapeutic opportunities in alleviating the renal burden in this population.
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Affiliation(s)
- Lennart Tonneijck
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands;
| | - Marcel H A Muskiet
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Mark M Smits
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Erik J van Bommel
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacology, University Medical Center Groningen, Groningen, The Netherlands; and
| | - Daniël H van Raalte
- Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam, The Netherlands
| | - Jaap A Joles
- Department of Nephrology and Hypertension, University Medical Center, Utrecht, The Netherlands
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Radcliffe NJ, Seah JM, Clarke M, MacIsaac RJ, Jerums G, Ekinci EI. Clinical predictive factors in diabetic kidney disease progression. J Diabetes Investig 2016; 8:6-18. [PMID: 27181363 PMCID: PMC5217935 DOI: 10.1111/jdi.12533] [Citation(s) in RCA: 130] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 03/10/2016] [Accepted: 03/14/2016] [Indexed: 12/15/2022] Open
Abstract
Diabetic kidney disease (DKD) represents a major component of the health burden associated with type 1 and type 2 diabetes. Recent advances have produced an explosion of ‘novel’ assay‐based risk markers for DKD, though clinical use remains restricted. Although many patients with progressive DKD follow a classical albuminuria‐based pathway, non‐albuminuric DKD progression is now well recognized. In general, the following clinical and biochemical characteristics have been associated with progressive DKD in both type 1 and type 2 diabetes: increased hemoglobin A1c, systolic blood pressure, albuminuria grade, early glomerular filtration rate decline, duration of diabetes, age (including pubertal onset) and serum uric acid; the presence of concomitant microvascular complications; and positive family history. The same is true in type 2 diabetes for male sex category, in patients following an albuminuric pathway to DKD, and also true for the presence of increased pulse wave velocity. The following baseline clinical characteristics have been proposed as risk factors for DKD progression, but with further research required to assess the nature of any relationship: dyslipidemia (including low‐density lipoprotein, total and high‐density lipoprotein cholesterol); elevated body mass index; smoking status; hyperfiltration; decreases in vitamin D, hemoglobin and uric acid excretion (all known consequences of advanced DKD); and patient test result visit‐to‐visit variability (hemoglobin A1c, blood pressure and high‐density lipoprotein cholesterol). The development of multifactorial ‘renal risk equations’ for type 2 diabetes has the potential to simplify the task of DKD prognostication; however, there are currently none for type 1 diabetes‐specific populations. Significant progress has been made in the prediction of DKD progression using readily available clinical data, though further work is required to elicit the role of several variables, and to consolidate data to facilitate clinical implementation.
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Affiliation(s)
- Nicholas J Radcliffe
- Austin Clinical School, Melbourne, Victoria, Australia.,The University of Melbourne, Melbourne, Victoria, Australia
| | - Jas-Mine Seah
- Austin Health Endocrine Center, Melbourne, Victoria, Australia
| | - Michele Clarke
- The University of Melbourne, Melbourne, Victoria, Australia.,Austin Health Endocrine Center, Melbourne, Victoria, Australia
| | - Richard J MacIsaac
- The University of Melbourne, Melbourne, Victoria, Australia.,Department of Endocrinology & Diabetes, St Vincent's Hospital, Melbourne, Victoria, Australia
| | - George Jerums
- The University of Melbourne, Melbourne, Victoria, Australia.,Austin Health Endocrine Center, Melbourne, Victoria, Australia
| | - Elif I Ekinci
- The University of Melbourne, Melbourne, Victoria, Australia.,Austin Health Endocrine Center, Melbourne, Victoria, Australia.,Menzies School of Health, Darwin, Northern Territory, Australia
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12
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Bjornstad P, Cherney DZ, Maahs DM, Nadeau KJ. Diabetic Kidney Disease in Adolescents With Type 2 Diabetes: New Insights and Potential Therapies. Curr Diab Rep 2016; 16:11. [PMID: 26803647 PMCID: PMC5841446 DOI: 10.1007/s11892-015-0708-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) and dialysis in the Western world. Early DKD, including microalbuminuria and renal hyperfiltration, is common in adolescents with type 2 diabetes (T2D). Furthermore, youth-onset T2D carries a higher risk of progressive DKD than adult-onset T2D of similar diabetes duration. DKD is characterized by a long clinically silent period without signs of disease. Therefore, a major challenge in preventing DKD is the difficulty in identifying high-risk T2D patients at an early stage. The Type 2 Diabetes in Adolescents and Youth (TODAY) study demonstrated a high initial prevalence that increased over time, irrespective of treatment arm. This key observation underscores the importance of discovering new therapeutic targets to supplement conventional management, in order to reduce DKD risk. In this review, we focus on early DKD in T2D and summarize potential novel biomarkers and therapeutic targets.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA.
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 13123 East 16th Ave, Box B265, Aurora, CO, 80045, USA.
| | - David Z Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada
| | - David M Maahs
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 13123 East 16th Ave, Box B265, Aurora, CO, 80045, USA
- Department of Medicine, Division of Nephrology, University of Colorado, Aurora, CO, USA
| | - Kristen J Nadeau
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, 13123 East 16th Ave, Box B265, Aurora, CO, 80045, USA
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13
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MacIsaac RJ, Ekinci EI, Premaratne E, Lu ZX, Seah JM, Li Y, Boston R, Ward GM, Jerums G. The Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation does not improve the underestimation of Glomerular Filtration Rate (GFR) in people with diabetes and preserved renal function. BMC Nephrol 2015. [PMID: 26630928 DOI: 10.186/s12882-015-0196-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Our hypothesis was that both the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations would underestimate directly measured GFR (mGFR) to a similar extent in people with diabetes and preserved renal function. METHODS In a cross-sectional study, bias (eGFR - mGFR) was compared for the CKD-EPI and MDRD equations, after stratification for mGFR levels. We also examined the ability of the CKD-EPI compared with the MDRD equation to correctly classify subjects to various CKD stages. In a longitudinal study of subjects with an early decline in GFR i.e., initial mGFR > 60 ml/min/1.73 m(2) and rate of decline in GFR (ΔmGFR) > 3.3 ml/min/1.73 m(2) per year, ΔmGFR (based on initial and final values) was compared with ΔeGFR by the CKD-EPI and MDRD equations over a mean of 9 years. RESULTS In the cross-sectional study, mGFR for the whole group was 80 ± 2.2 ml/min/1.73 m(2) (n = 199, 75 % type 2 diabetes). For subjects with mGFR >90 ml/min/1.73 m(2) (mGFR: 112 ± 2.0, n = 76), both equations significantly underestimated mGFR to a similar extent: bias for CKD-EPI: -12 ± 1.4 ml/min/1.73 m(2) (p < 0.001) and for MDRD: -11 ± 2.1 ml/min/1.73 m(2) (p < 0.001). Using the CKD-EPI compared with the MDRD equation did not improve the number of subjects that were correctly classified to a CKD-stage. No biochemical or clinical patient characteristics were identified to account for the under estimation of mGFR values in the normal to high range by the CKD-EPI equation. In the longitudinal study (n = 30, 66 % type 1 diabetes), initial and final mGFR values were 102.8 ± 6 and 54.6 ± 6.0 ml/min/1.73 m(2), respectively. Mean ΔGFR (ml/min/1.73 m(2) per year) was 6.0 by mGFR compared with only 3.0 by MDRD and 3.2 by CKD-EPI (both p < 0.05 vs mGFR) CONCLUSIONS: Both the CKD-EPI and MDRD equations underestimate reference GFR values > 90 ml/min/1.73 m(2) as well as an early decline in GFR to a similar extent in people with diabetes. There is scope to improve methods for estimating an early decline in GFR.
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Affiliation(s)
- Richard J MacIsaac
- Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, 4th Floor, Daly Wing, 35 Victoria Parade, PO Box 2900, Fitzroy, VIC, 3065, Australia. .,Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, 3065, Victoria, Australia.
| | - Elif I Ekinci
- Endocrine Centre, Austin Health, West Heidelberg, 3081, Victoria, Australia. .,Menzies School of Health Research, Casuarina, 0811, Northern Territory, Australia. .,Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia.
| | - Erosha Premaratne
- Endocrine Centre, Austin Health, West Heidelberg, 3081, Victoria, Australia.
| | - Zhong X Lu
- Melbourne Pathology, Collingwood, 3066, Victoria, Australia.
| | - Jas-Mine Seah
- Endocrine Centre, Austin Health, West Heidelberg, 3081, Victoria, Australia.
| | - Yue Li
- Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, 4th Floor, Daly Wing, 35 Victoria Parade, PO Box 2900, Fitzroy, VIC, 3065, Australia. .,Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, 3065, Victoria, Australia.
| | - Ray Boston
- Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, 4th Floor, Daly Wing, 35 Victoria Parade, PO Box 2900, Fitzroy, VIC, 3065, Australia. .,Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, 3065, Victoria, Australia.
| | - Glenn M Ward
- Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, 4th Floor, Daly Wing, 35 Victoria Parade, PO Box 2900, Fitzroy, VIC, 3065, Australia. .,Clinical Chemistry, St Vincent's Hospital Melbourne, Fitzroy, 3065, Victoria, Australia. .,Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, 3065, Victoria, Australia.
| | - George Jerums
- Endocrine Centre, Austin Health, West Heidelberg, 3081, Victoria, Australia. .,Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia.
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14
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MacIsaac RJ, Ekinci EI, Premaratne E, Lu ZX, Seah JM, Li Y, Boston R, Ward GM, Jerums G. The Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equation does not improve the underestimation of Glomerular Filtration Rate (GFR) in people with diabetes and preserved renal function. BMC Nephrol 2015; 16:198. [PMID: 26630928 PMCID: PMC4668645 DOI: 10.1186/s12882-015-0196-0] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 11/25/2015] [Indexed: 12/18/2022] Open
Abstract
Background Our hypothesis was that both the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) and Modification of Diet in Renal Disease (MDRD) equations would underestimate directly measured GFR (mGFR) to a similar extent in people with diabetes and preserved renal function. Methods In a cross-sectional study, bias (eGFR – mGFR) was compared for the CKD-EPI and MDRD equations, after stratification for mGFR levels. We also examined the ability of the CKD-EPI compared with the MDRD equation to correctly classify subjects to various CKD stages. In a longitudinal study of subjects with an early decline in GFR i.e., initial mGFR >60 ml/min/1.73 m2 and rate of decline in GFR (ΔmGFR) > 3.3 ml/min/1.73 m2 per year, ΔmGFR (based on initial and final values) was compared with ΔeGFR by the CKD-EPI and MDRD equations over a mean of 9 years. Results In the cross-sectional study, mGFR for the whole group was 80 ± 2.2 ml/min/1.73 m2 (n = 199, 75 % type 2 diabetes). For subjects with mGFR >90 ml/min/1.73 m2 (mGFR: 112 ± 2.0, n = 76), both equations significantly underestimated mGFR to a similar extent: bias for CKD-EPI: -12 ± 1.4 ml/min/1.73 m2 (p < 0.001) and for MDRD: -11 ± 2.1 ml/min/1.73 m2 (p < 0.001). Using the CKD-EPI compared with the MDRD equation did not improve the number of subjects that were correctly classified to a CKD-stage. No biochemical or clinical patient characteristics were identified to account for the under estimation of mGFR values in the normal to high range by the CKD-EPI equation. In the longitudinal study (n = 30, 66 % type 1 diabetes), initial and final mGFR values were 102.8 ± 6 and 54.6 ± 6.0 ml/min/1.73 m2, respectively. Mean ΔGFR (ml/min/1.73 m2 per year) was 6.0 by mGFR compared with only 3.0 by MDRD and 3.2 by CKD-EPI (both p < 0.05 vs mGFR) Conclusions Both the CKD-EPI and MDRD equations underestimate reference GFR values >90 ml/min/1.73 m2 as well as an early decline in GFR to a similar extent in people with diabetes. There is scope to improve methods for estimating an early decline in GFR.
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Affiliation(s)
- Richard J MacIsaac
- Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, 4th Floor, Daly Wing, 35 Victoria Parade, PO Box 2900, Fitzroy, VIC, 3065, Australia. .,Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, 3065, Victoria, Australia.
| | - Elif I Ekinci
- Endocrine Centre, Austin Health, West Heidelberg, 3081, Victoria, Australia. .,Menzies School of Health Research, Casuarina, 0811, Northern Territory, Australia. .,Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia.
| | - Erosha Premaratne
- Endocrine Centre, Austin Health, West Heidelberg, 3081, Victoria, Australia.
| | - Zhong X Lu
- Melbourne Pathology, Collingwood, 3066, Victoria, Australia.
| | - Jas-Mine Seah
- Endocrine Centre, Austin Health, West Heidelberg, 3081, Victoria, Australia.
| | - Yue Li
- Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, 4th Floor, Daly Wing, 35 Victoria Parade, PO Box 2900, Fitzroy, VIC, 3065, Australia. .,Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, 3065, Victoria, Australia.
| | - Ray Boston
- Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, 4th Floor, Daly Wing, 35 Victoria Parade, PO Box 2900, Fitzroy, VIC, 3065, Australia. .,Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, 3065, Victoria, Australia.
| | - Glenn M Ward
- Department of Endocrinology and Diabetes, St Vincent's Hospital Melbourne, 4th Floor, Daly Wing, 35 Victoria Parade, PO Box 2900, Fitzroy, VIC, 3065, Australia. .,Clinical Chemistry, St Vincent's Hospital Melbourne, Fitzroy, 3065, Victoria, Australia. .,Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, 3065, Victoria, Australia.
| | - George Jerums
- Endocrine Centre, Austin Health, West Heidelberg, 3081, Victoria, Australia. .,Department of Medicine, Austin Health, University of Melbourne, Heidelberg, 3084, Victoria, Australia.
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Abstract
The American Diabetes Association recommends annual assessment of glomerular filtration rate (GFR) to screen for diabetic nephropathy. GFR is measured indirectly using markers that, ideally, are eliminated only by glomerular filtration. Measured GFR, although the gold standard, remains cumbersome and expensive. GFR is therefore routinely estimated using creatinine and/or cystatin C and clinical variables. In pediatrics, the Schwartz creatinine-based equation is most frequently used even though combined creatinine and cystatin C-based equations demonstrate stronger agreement with measured GFR. In adults, the CKD Epidemiology Collaboration (CKD-EPI) equations with creatinine and/or cystatin C are the most accurate and precise estimating equations. Despite recent advances, current estimates of GFR lack precision and accuracy before chronic kidney disease stage 3 (GFR < 60 mL/min/1.73 m(2)). There is therefore an urgent need to improve the methods for estimating and measuring GFR. In this review, we examine the current literature and data addressing measurement and estimation of GFR in diabetes.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA,
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16
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Szopa M, Kapusta M, Matejko B, Klupa T, Koblik T, Kiec-Wilk B, Borowiec M, Malecki MT. Comparison of Glomerular Filtration Rate Estimation from Serum Creatinine and Cystatin C in HNF1A-MODY and Other Types of Diabetes. J Diabetes Res 2015; 2015:183094. [PMID: 26347889 PMCID: PMC4546972 DOI: 10.1155/2015/183094] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 07/24/2015] [Accepted: 07/28/2015] [Indexed: 01/15/2023] Open
Abstract
INTRODUCTION We previously showed that in HNF1A-MODY the cystatin C-based glomerular filtration rate (GFR) estimate is higher than the creatinine-based estimate. Currently, we aimed to replicate this finding and verify its clinical significance. METHODS The study included 72 patients with HNF1A-MODY, 72 with GCK-MODY, 53 with type 1 diabetes (T1DM), 70 with type 2 diabetes (T2DM), and 65 controls. Serum creatinine and cystatin C levels were measured. GFR was calculated from creatinine and cystatin C using the CKD-EPI creatinine equation (eGRF-cr) and CKD-EPI cystatin C equation (eGFR-cys), respectively. RESULTS Cystatin C levels were lower (p < 0.001) in the control (0.70 ± 0.13 mg/L), HNF1A (0.75 ± 0.21), and GCK (0.72 ± 0.16 mg/L) groups in comparison to those with either T1DM (0.87 ± 0.15 mg/L) or T2DM (0.9 ± 0.23 mg/L). Moreover, eGFR-cys was higher than eGRF-cr in HNF1A-MODY, GCK-MODY, and the controls (p = 0.004; p = 0.003; p < 0.0001). This corresponded to 8.9 mL/min/1.73 m2, 9.7 mL/min/1.73 m2, and 16.9 mL/min/1.73 m2 of difference. Additionally, T1DM patients had higher eGFR-cr than eGFR-cys (11.6 mL/min/1.73 m(2); p = 0.0004); no difference occurred in T2DM (p = 0.91). CONCLUSIONS We confirmed that eGFR-cys values in HNF1A-MODY patients are higher compared to eGFR-cr. Some other differences were also described in diabetic groups. However, none of them appears to be clinically relevant.
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Affiliation(s)
- Magdalena Szopa
- Department of Metabolic Diseases, Jagiellonian University Medical College, 15 Kopernika Street, 31-501 Krakow, Poland
- University Hospital, Krakow, Poland
| | - Maria Kapusta
- Department of Diagnostics, Jagiellonian University Medical College, Krakow, Poland
| | - Bartlomiej Matejko
- Department of Metabolic Diseases, Jagiellonian University Medical College, 15 Kopernika Street, 31-501 Krakow, Poland
| | - Tomasz Klupa
- Department of Metabolic Diseases, Jagiellonian University Medical College, 15 Kopernika Street, 31-501 Krakow, Poland
- University Hospital, Krakow, Poland
| | | | - Beata Kiec-Wilk
- Department of Metabolic Diseases, Jagiellonian University Medical College, 15 Kopernika Street, 31-501 Krakow, Poland
- University Hospital, Krakow, Poland
| | - Maciej Borowiec
- Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland
| | - Maciej T. Malecki
- Department of Metabolic Diseases, Jagiellonian University Medical College, 15 Kopernika Street, 31-501 Krakow, Poland
- University Hospital, Krakow, Poland
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Lytvyn Y, Perkins BA, Cherney DZI. Uric acid as a biomarker and a therapeutic target in diabetes. Can J Diabetes 2015; 39:239-46. [PMID: 25600084 DOI: 10.1016/j.jcjd.2014.10.013] [Citation(s) in RCA: 93] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2014] [Revised: 08/21/2014] [Accepted: 10/10/2014] [Indexed: 02/07/2023]
Abstract
Diabetic nephropathy is a long-standing microvascular complication of diabetes mellitus and is the leading cause of end stage renal disease in developed countries. Current therapeutic strategies used to prevent or delay diabetic nephropathy exert limited clinical protective effects and can have serious adverse effects. Thus, identification of new pharmacologic agents that protect against the initiation and progression of complications of diabetes is of the utmost importance. Uric acid (UA) recently emerged as an inflammatory factor that increases oxidative stress and promotes activation of the renin angiotensin aldosterone system. As a consequence, higher UA levels are associated with various stages of the onset and progression of diabetic nephropathy, including metabolic, cardiovascular and kidney function abnormalities. If UA-lowering drugs, such as the xanthine oxidase inhibitors, block the mechanisms responsible for micro- and macrovascular injury in diabetes, these agents could represent a critical step toward preventing the progression of diabetes. This review focuses on the evidence that supports serum UA levels as a biomarker of renal and cardiovascular risk and as a potential additional therapeutic target in diabetes.
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Affiliation(s)
- Yuliya Lytvyn
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Bruce A Perkins
- Department of Medicine, Division of Endocrinology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
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18
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The impact of hyperfiltration on the diabetic kidney. DIABETES & METABOLISM 2014; 41:5-17. [PMID: 25457474 DOI: 10.1016/j.diabet.2014.10.003] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 10/02/2014] [Accepted: 10/02/2014] [Indexed: 02/07/2023]
Abstract
More than two decades ago, hyperfiltration (HF) in diabetes was postulated to be a maladaptive response observed early in the course of diabetic kidney disease (DKD), which may eventually predispose to irreversible damage to nephrons and development of progressive renal disease. Despite this, the potential mechanisms leading to renal HF in diabetes are not fully understood, although several hypotheses have been proposed, including alterations in glomerular haemodynamic function and tubulo-glomerular feedback. Furthermore, the role of HF as a causative factor in renal disease progression is still unclear and warrants further prospective longer-term studies. Although HF has been entrenched as the first stage in the classic albuminuric pathway to end-stage renal disease in DKD, and HF has been shown to predict the progression of albuminuria in many, but not all studies, the concept that HF predisposes to the development of chronic kidney disease (CKD) stage 3, that is, glomerular filtration rate (GFR) decline to<60mL/min/1.73m(2), remains to be proved. Further long-term studies of GFR gradients therefore are required to establish whether HF ultimately leads to decreased kidney function, after adjustment for glycaemic control and other confounders. Whether reversal of HF with therapeutic agents is protective against reducing the risk of development of albuminuria and renal impairment is also worth investigating in prospective randomized trials.
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Har RLH, Reich HN, Scholey JW, Daneman D, Dunger DB, Moineddin R, Dalton RN, Motran L, Elia Y, Deda L, Ostrovsky M, Sochett EB, Mahmud FH, Cherney DZI. The urinary cytokine/chemokine signature of renal hyperfiltration in adolescents with type 1 diabetes. PLoS One 2014; 9:e111131. [PMID: 25392936 PMCID: PMC4230911 DOI: 10.1371/journal.pone.0111131] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 09/20/2014] [Indexed: 01/20/2023] Open
Abstract
OBJECTIVE Urinary cytokine/chemokine levels are elevated in adults with type 1 diabetes (T1D) exhibiting renal hyperfiltration. Whether this observation extends to adolescents with T1D remains unknown. Our first objective was to determine the relationship between hyperfiltration and urinary cytokines/chemokines in normotensive, normoalbuminuric adolescents with T1D using GFR(cystatin). Our second aim was to determine the relationship between urine and plasma levels of inflammatory biomarkers, to clarify the origin of these factors. METHODS Urine and serum cytokines/chemokines (Luminex platform) and GFR(cystatin) were measured in normofiltering (n = 111, T1D-N, GFR<135 ml/min/1.73 m(2)) and hyperfiltering (n = 31, T1D-H, GFR ≥ 135 ml/min/1.73 m(2)) adolescents with T1D (ages 10-16), and in age and sex matched healthy control subjects (HC, n = 59). RESULTS We noted significant step-wise increases in urinary cytokine/chemokine excretion according to filtration status with highest levels in T1D-H, with parallel trends in serum analyte concentrations. After adjusting for serum glucose at the time of sampling, differences in urinary cytokine excretion were not statistically significant. Only serum IL-2 significantly differed between HC and T1D (p = 0.0076). CONCLUSIONS Hyperfiltration is associated with increased urinary cytokine/chemokine excretion in T1D adolescents, and parallel trends in serum cytokine concentration. The GFR-associated trends in cytokine excretion may be driven by the effects of ambient hyperglycemia. The relationship between hyperfiltration, glycemia, and variations in serum and urine cytokine expression and their impact on future renal and systemic vascular complications requires further study.
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Affiliation(s)
- Ron L. H. Har
- Division of Nephrology, University Health Network - Toronto General Hospital, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
| | - Heather N. Reich
- Division of Nephrology, University Health Network - Toronto General Hospital, Toronto, Ontario, Canada
| | - James W. Scholey
- Division of Nephrology, University Health Network - Toronto General Hospital, Toronto, Ontario, Canada
| | - Denis Daneman
- Department of Pediatrics, Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - David B. Dunger
- Department of Pediatrics, University of Cambridge, Cambridge, United Kingdom
| | - Rahim Moineddin
- Family and Community Medicine, University of Toronto Toronto, Ontario, Canada
| | - R. Neil Dalton
- WellChild Laboratory, Evelina Children's Hospital, St Thomas' Hospital, London, United Kingdom
| | - Laura Motran
- Department of Pediatrics, Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Yesmino Elia
- Department of Pediatrics, Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Livia Deda
- Department of Pediatrics, Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Masha Ostrovsky
- Department of Pediatrics, Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Etienne B. Sochett
- Department of Pediatrics, Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Farid H. Mahmud
- Department of Pediatrics, Division of Endocrinology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - David Z. I. Cherney
- Division of Nephrology, University Health Network - Toronto General Hospital, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
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20
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Yang GK, Har RLH, Lytvyn Y, Yip P, Cherney DZI. Renal hyperfiltration is associated with glucose-dependent changes in fractional excretion of sodium in patients with uncomplicated type 1 diabetes. Diabetes Care 2014; 37:2774-81. [PMID: 25011944 DOI: 10.2337/dc14-0798] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Renal hyperfiltration is a common abnormality associated with diabetic nephropathy in patients with type 1 diabetes (T1D). In animal models, increased proximal tubular sodium reabsorption results in decreased distal sodium delivery, tubuloglomerular feedback activation, afferent vasodilatation, and hyperfiltration. The role of tubular factors is less well understood in humans. The aim of the current study was therefore to compare the fractional sodium excretion (FENa) in hyperfiltering (T1D-H) versus normofiltering (T1D-N) patients and healthy control (HC) subjects, as well as the role of ambient hyperglycemia on FENa. RESEARCH DESIGN AND METHODS Blood pressure, renal function (inulin for glomerular filtration rate [GFR], and paraaminohippurate for effective renal plasma flow), FENa, and circulating neurohormones were measured in T1D-H (n = 28, GFR ≥135 mL/min/1.73 m(2)), T1D-N (n = 30), and HC (n = 35) subjects during clamped euglycemia. Studies were repeated in a subset of patients during clamped hyperglycemia. RESULTS During clamped euglycemia, T1D-H exhibited lower FENa than T1D-N and HC subjects (0.64 ± 0.06% vs. 0.91 ± 0.12% and 0.90 ± 0.10%, P < 0.05). During clamped hyperglycemia, FENa increased (Δ + 0.88 ± 0.22% vs. Δ + 0.02 ± 0.21%; between-group effect, P = 0.01) significantly in T1D-H, whereas FENa did not change in T1D-N. When treated as continuous variables, elevated GFR values were associated with hyperglycemia-induced increases in FENa (R(2) = 0.20, P = 0.007). CONCLUSIONS Patients with uncomplicated T1D-H exhibit lower FENa under euglycemic conditions, which may help to identify patients with hyperfiltration outside of a controlled laboratory setting. Increased FENa in T1D-H but not T1D-N under clamped hyperglycemic conditions suggests that the mechanisms responsible for increased sodium reabsorption leading to hyperfiltration can be saturated.
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Affiliation(s)
- Gary K Yang
- Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Ronnie L H Har
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Paul Yip
- University Health Network, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
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Maahs DM, Bushman L, Kerr B, Ellis SL, Pyle L, McFann K, Bouffard A, Bishop FK, Nguyen N, Anderson PL. A practical method to measure GFR in people with type 1 diabetes. J Diabetes Complications 2014; 28:667-73. [PMID: 25027389 DOI: 10.1016/j.jdiacomp.2014.06.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 05/31/2014] [Accepted: 06/02/2014] [Indexed: 01/02/2023]
Abstract
AIMS Improved early diagnostic methods are needed to identify risk for kidney disease in people with type 1 diabetes. We hypothesized that glomerular filtration rate (GFR) measured by iohexol clearance in dried blood spots (DBS) on filter paper would be comparable to plasma (gold-standard) and superior to estimated GFR (eGFR) and, second, that adjustment for ambient blood glucose would improve accuracy and precision of GFR measurement. METHODS GFR was measured by iohexol clearance in plasma, DBS, and as estimated by the CKD-Epidemiology Collaboration equations in 15 adults with type 1 diabetes at two visits, one euglycemic and one hyperglycemic. RESULTS GFR measured by DBS was more comparable and less biased than GFR cystatin C, serum creatinine, and both combined. GFR was higher during hyperglycemia. Correction for between visit glycemia statistically significantly reduced bias and mean squared error for GFR measured by DBS as compared to gold-standard during euglycemia. CONCLUSIONS Iohexol clearance measured with DBS performed better than eGFR methods. Correction for ambient blood glucose improved precision and accuracy of GFR measurement. This method is more convenient than the gold-standard GFR method and may improve screening and diagnostic capabilities in people with type 1 diabetes, especially when GFR is >60ml/min/1.73m(2).
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Affiliation(s)
- D M Maahs
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO; Department of Medicine, Division of Nephrology, University of Colorado Denver, Aurora, CO.
| | - L Bushman
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO
| | - B Kerr
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO
| | - S L Ellis
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO
| | - L Pyle
- Department of Pediatrics, School of Medicine, University of Colorado Denver, Aurora, CO
| | - K McFann
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - A Bouffard
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - F K Bishop
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - N Nguyen
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - P L Anderson
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO
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Abstract
PURPOSE OF REVIEW Despite improvements in glycemic and blood pressure control in patients with type 1 diabetes, diabetic nephropathy remains the most common cause of chronic kidney disease worldwide. A major challenge in preventing diabetic nephropathy is the inability to identify high-risk patients at an early stage, emphasizing the importance of discovering new therapeutic targets and implementation of clinical trials to reduce diabetic nephropathy risk. RECENT FINDINGS Limitations of managing patients with diabetic nephropathy with renin-angiotensin-aldosterone system blockade have been identified in recent clinical trials, including the failure of primary prevention studies in T1D and the demonstration of harm with dual renin-angiotensin-aldosterone system blockade. Fortunately, several new targets, including serum uric acid, insulin sensitivity, vasopressin, and sodium-glucose cotransporter-2 inhibition, are promising in the prevention and treatment of diabetic nephropathy. SUMMARY Diabetic nephropathy is characterized by a long clinically silent period without signs or symptoms of disease. There is an urgent need for improved methods of detecting early mediators of renal injury, to ultimately prevent the initiation and progression of diabetic nephropathy. In this review, we will focus on early diabetic nephropathy and summarize potential new therapeutic targets.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - David Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Ontario, Canada
| | - David M. Maahs
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
- Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, Colorado, United States
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Bjornstad P, McQueen RB, Snell-Bergeon JK, Cherney D, Pyle L, Perkins B, Rewers M, Maahs DM. Fasting blood glucose--a missing variable for GFR-estimation in type 1 diabetes? PLoS One 2014; 9:e96264. [PMID: 24781861 PMCID: PMC4004575 DOI: 10.1371/journal.pone.0096264] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 04/06/2014] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE Estimation of glomerular filtration rate (eGFR) is one of the current clinical methods for identifying risk for diabetic nephropathy in subjects with type 1 diabetes (T1D). Hyperglycemia is known to influence GFR in T1D and variability in blood glucose at the time of eGFR measurement could introduce bias in eGFR. We hypothesized that simultaneously measured blood glucose would influence eGFR in adults with T1D. METHODS Longitudinal multivariable mixed-models were employed to investigate the relationships between blood glucose and eGFR by CKD-EPI eGFRCYSTATIN C over 6-years in the Coronary Artery Calcification in Type 1 diabetes (CACTI) study. All subjects with T1D and complete data including blood glucose and cystatin C for at least one of the three visits (n = 616, 554, and 521, respectively) were included in the longitudinal analyses. RESULTS In mixed-models adjusting for sex, HbA1c, ACEi/ARB, protein and sodium intake positive associations were observed between simultaneous blood glucose and eGFRCYSTATIN C (β±SE:0.14±0.04 per 10 mg/dL of blood glucose, p<0.0001), and hyperfiltration as a dichotomous outcome (OR: 1.04, 95% CI: 1.01-1.07 per 10 mg/dL of blood glucose, p = 0.02). CONCLUSIONS In our longitudinal data in subjects with T1D, simultaneous blood glucose has an independent positive effect on eGFRCYSTATIN C. The associations between blood glucose and eGFRCYSTATIN C may bias the accurate detection of early diabetic nephropathy, especially in people with longitudinal variability in blood glucose.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - R. Brett McQueen
- University of Colorado School of Pharmacy, Aurora, Colorado, United States of America
| | - Janet K. Snell-Bergeon
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States of America
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - David Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Ontario, Canada
| | - Laura Pyle
- Department of Biostatistics, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Bruce Perkins
- Department of Medicine, Division of Endocrinology, Mount Sinai Hospital, University of Toronto, Ontario, Canada
| | - Marian Rewers
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States of America
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, United States of America
| | - David M. Maahs
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States of America
- Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, United States of America
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Yang GK, Maahs DM, Perkins BA, Cherney DZI. Renal hyperfiltration and systemic blood pressure in patients with uncomplicated type 1 diabetes mellitus. PLoS One 2013; 8:e68908. [PMID: 23861950 PMCID: PMC3701674 DOI: 10.1371/journal.pone.0068908] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2013] [Accepted: 06/07/2013] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Patients with type 1 diabetes mellitus (DM) and renal hyperfiltration also exhibit systemic microvascular abnormalities, including endothelial dysfunction. The effect of renal hyperfiltration on systemic blood pressure (BP) is less clear. We therefore measured BP, renal hemodynamic function and circulating renin angiotensin aldosterone system (RAAS) mediators in type 1 DM patients with hyperfiltration (n = 36, DM-H, GFR≥135 ml/min/1.73 m(2)) or normofiltration (n = 40, DM-N), and 56 healthy controls (HC). Since renal hyperfiltration represents a state of intrarenal RAAS activation, we hypothesized that hyperfiltration would be associated with higher BP and elevated levels of circulating RAAS mediators. METHODS BP, glomerular filtration rate (GFR - inulin), effective renal plasma flow (paraaminohippurate) and circulating RAAS components were measured in DM-H, DM-N and HC during clamped euglycemia (4-6 mmol/L). Studies were repeated in DM-H and DM-N during clamped hyperglycemia (9-11 mmol/L). RESULTS Baseline GFR was elevated in DM-H vs. DM-N and HC (167±6 vs. 115±2 and 115±2 ml/min/1.73 m(2), p<0.0001). Baseline systolic BP (SBP, 117±2 vs. 111±2 vs. 109±1, p = 0.004) and heart rate (76±1 vs. 67±1 vs. 61±1, p<0.0001) were higher in DM-H vs. DM-N and HC. Despite higher SBP in DM-H, plasma aldosterone was lower in DM-H vs. DM-N and HC (42±5 vs. 86±14 vs. 276±41 ng/dl, p = 0.01). GFR (p<0.0001) and SBP (p<0.0001) increased during hyperglycemia in DM-N but not in DM-H. CONCLUSIONS DM-H was associated with higher heart rate and SBP values and an exaggerated suppression of systemic aldosterone. Future work should focus on the mechanisms that explain this paradox in diabetes of renal hyperfiltration coupled with systemic RAAS suppression.
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Affiliation(s)
- Gary K. Yang
- Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David M. Maahs
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado, United States of America
| | - Bruce A. Perkins
- Department of Medicine, Division of Endocrinology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
| | - David Z. I. Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada
- * E-mail:
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Har R, Scholey JW, Daneman D, Mahmud FH, Dekker R, Lai V, Elia Y, Fritzler ML, Sochett EB, Reich HN, Cherney DZI. The effect of renal hyperfiltration on urinary inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes mellitus. Diabetologia 2013; 56:1166-73. [PMID: 23412605 DOI: 10.1007/s00125-013-2857-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2012] [Accepted: 01/23/2013] [Indexed: 12/21/2022]
Abstract
AIMS/HYPOTHESIS High intraglomerular pressure causes renal inflammation in experimental models of diabetes. Our objective was to determine whether renal hyperfiltration, a surrogate for intraglomerular hypertension, is associated with increased excretion of urinary cytokines/chemokines in patients with type 1 diabetes mellitus. METHODS Blood pressure, renal haemodynamic function (inulin and para-aminohippurate clearances for glomerular filtration rate (GFR) and effective renal plasma flow (ERPF), respectively) and urine samples were obtained during clamped euglycaemia in individuals with type 1 diabetes with either hyperfiltration (GFR determined using inulin [GFRINULIN] ≥ 135 ml min⁻¹ 1.73 m⁻², n = 28) or normofiltration (n = 21) and healthy control individuals (n = 18). RESULTS Baseline clinical characteristics, dietary sodium and protein intake and blood pressure levels were similar in the diabetic and healthy control groups. In addition, HbA1c levels were similar in the two diabetic groups. As expected baseline GFR was higher in hyperfilterers than either normofiltering diabetic patients or healthy control patients (165 ± 9 vs 113 ± 2 and 116 ± 4 ml min⁻¹ 1.73 m⁻², respectively, p < 0.01). ERPF and renal blood flow were also comparatively higher and renal vascular resistance was lower in hyperfiltering patients (p < 0.01). Hyperfiltering diabetic patients had higher excretion rates for eotaxin, IFNα2, macrophage-derived chemokine, platelet-derived growth factor (PDGF)-AA, PDGF-AB/BB and granulocyte-macrophage colony-stimulating factor (p ≤ 0.01). Urinary monocyte chemoattractant protein (MCP)-1 and RANTES (regulated on activation, normal T expressed and secreted) excretion was also higher in hyperfiltering vs normofiltering diabetic individuals (p < 0.01) and fibroblast growth factor-2, MCP-3 and CD40K excretion was elevated in hyperfiltering diabetic individuals vs healthy controls (p < 0.01). CONCLUSIONS/INTERPRETATION Renal hyperfiltration is associated with increased urinary excretion of inflammatory cytokines/chemokines in patients with uncomplicated type 1 diabetes.
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Affiliation(s)
- R Har
- Division of Nephrology, Toronto General Hospital, University Health Network, Banting and Best Diabetes Centre, University of Toronto, 585 University Ave, 8N-845, Toronto, ON, Canada M5G 2N2
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Lassus J, Harjola VP. Cystatin C: a step forward in assessing kidney function and cardiovascular risk. Heart Fail Rev 2013; 17:251-61. [PMID: 21431356 DOI: 10.1007/s10741-011-9242-6] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The cardiorenal syndrome is a clinical manifestation of the bidirectional interaction between the heart and kidneys. Evaluating renal function is an essential part of the assessment of every cardiac patient. It has become clear that serum creatinine is not an accurate enough marker of glomerular filtration rate (GFR) and should not be used to evaluate kidney dysfunction. Creatinine-based estimates of GFR are preferred, but require renal function to be stable and are not suitable when changes in kidney function occur. Cystatin C (CysC) has been the target of much interest in the search for an alternative measure of GFR. As an endogenous biomarker, CysC possesses many of the properties required of a good marker of renal function. Compared with that of creatinine, plasma concentrations of CysC are less influenced by factors other than GFR. Consequently, CysC correlates with true GFR more accurately than creatinine. Equations for estimating GFR from CysC values have also been developed, which makes values easier to interpret and facilitates the clinical use of this new marker. The use of CysC in acute kidney injury has also shown promising results. CysC has been studied as a risk marker for prognosis in cardiovascular disease. This effect is attributed to the strong impact of renal dysfunction on progressive cardiovascular disease and impaired survival. Higher levels of CysC have consistently been predictive of incident or recurrent cardiovascular events and adverse outcomes. CysC is a predictor of the development of heart failure and increased levels of CysC have an independent association with higher mortality in both chronic and acute heart failure. In conclusion, CysC appears to be an interesting marker of renal function and is useful for risk stratification in heart failure.
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Affiliation(s)
- Johan Lassus
- Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland.
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Melsom T, Mathisen UD, Eilertsen BAW, Ingebretsen OC, Jenssen T, Njølstad I, Solbu MD, Toft I, Eriksen BO. Physical exercise, fasting glucose, and renal hyperfiltration in the general population: the Renal Iohexol Clearance Survey in Tromsø 6 (RENIS-T6). Clin J Am Soc Nephrol 2012; 7:1801-10. [PMID: 22917703 PMCID: PMC3488946 DOI: 10.2215/cjn.02980312] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Accepted: 07/13/2012] [Indexed: 01/02/2023]
Abstract
BACKGROUND AND OBJECTIVES Abnormally elevated GFR, or hyperfiltration, is a proposed mechanism for kidney injury in diabetes, prediabetes, and obesity. This study investigated whether lack of physical exercise is associated with hyperfiltration and whether exercise modifies the positive association between fasting glucose and measured GFR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The Renal Iohexol Clearance Survey in Tromsø 6 measured GFR as single-sample plasma iohexol clearance in 1506 members of the general population (age 50-62 years) without diabetes, cardiovascular disease, or kidney disease. Leisure-time physical exercise was assessed by a self-administered questionnaire. Hyperfiltration was defined as GFR above the 90th percentile after adjustment for sex, age, weight, height, and use of renin-angiotensin system inhibitors. RESULTS High-intensity exercise was associated with lower adjusted odds of hyperfiltration in men (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.28-0.80) but not in women (OR, 1.02; 95% CI, 0.60-1.72). In both sexes, high-intensity exercise modified the association between fasting glucose and GFR. A fasting glucose level 1 mmol/L higher was associated with a GFR that was 7.3 (95% CI, 4.0-10.6) and 6.2 (95% CI, 3.4-9.0) ml/min per 1.73 m(2) higher in men and women who never exercised or exercised with low intensity. There was no association between fasting glucose and GFR in men and women who exercised with high intensity (interaction, P<0.001). CONCLUSIONS High-intensity exercise was associated with lower odds of hyperfiltration in men and modified the association between glucose and GFR of both sexes in a population without diabetes.
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Affiliation(s)
- Toralf Melsom
- Section of Nephrology, University Hospital of North Norway, Tromsø, Norway.
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JDRF perspective: bridging the gap-translational research to prevent progression of diabetic nephropathy. Semin Nephrol 2012; 32:512-6. [PMID: 23062993 DOI: 10.1016/j.semnephrol.2012.07.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
For those with type 1 diabetes (T1D), the diagnosis of diabetic nephropathy predicts a significant negative impact on quality of life and mortality risk. Diabetic nephropathy is a huge component of the potential cost of diabetes both to the individual and society. For this reason, JDRF and others have prioritized programs aimed to advance our understanding of diabetic nephropathy and translate findings to benefit patients with T1D. Although the current standard of care has reduced the incidence of diabetic nephropathy, a significant proportion of those with T1D are still at risk for declining renal function and progression to end-stage renal disease. Carefully directed research is needed to discover and translate novel targets and biomarkers for diabetic nephropathy to improve the prognosis and outlook for those with T1D and at risk for end-stage renal disease.
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Oh SJ, Lee JI, Ha WC, Jeong SH, Yim HW, Son HS, Sohn TS. Comparison of cystatin C- and creatinine-based estimation of glomerular filtration rate according to glycaemic status in Type 2 diabetes. Diabet Med 2012; 29:e121-5. [PMID: 22414167 DOI: 10.1111/j.1464-5491.2012.03628.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
AIMS The influence of hyperglycaemia on the performance of glomerular filtration rate (GFR) estimating equations remains to be determined. We compared the performance of creatinine-based GFR with cystatin C-based GFR in patients with Type 2 diabetes according to glycaemic status. METHODS In a cross-sectional study of 210 patients with Type 2 diabetes, we staged glycaemic status by HbA(1c) tertiles [HbA(1c) ≤ 75 mmol/mol (9.0%) (n = 70), HbA(1c) 76-95 mmol/mol (9.1-10.8%) (n = 70), HbA(1c) >95 mmol/mol (10.8%) (n = 70)] and measured GFR. Isotopic GFR was measured using renal dynamic imaging with (99m) Tc-diethylene-triamine-penta-acetic acid. Estimated GFR (eGFR) was measured using creatinine-based formulae (Cockcroft-Gault-eGFR, the Modification of Diet in Renal Disease equation-eGFR and the Chronic Kidney Disease Epidemiology Collaboration formula-eGFR) and a cystatin C-based formula (cystatin C-eGFR). RESULTS The isotopic GFR of all patients was 93.1 ± 34.1 ml min(-1) 1.73 m(-2). All methods for estimating GFR underestimated isotopic GFR [Cockcroft-Gault-eGFR (68.8 ± 38.6 ml min(-1) 1.73 m(-2) ) (P < 0.05), Modification of Diet in Renal Disease-eGFR (74.8 ± 31.3 ml min(-1) 1.73 m(-2) ) (P < 0.05), Chronic Kidney Disease Epidemiology Collaboration-eGFR (72.9 ± 26.6 ml min(-1) 1.73 m(-2)) (P < 0.05) and cystatin C-eGFR (83.5 ± 33.2 ml min(-1) 1.73 m(-2)) (P < 0.05)]. In all patient groups, cystatin C-eGFR was less biased and more accurate than the creatinine-based formulae, especially in the group with HbA(1c) > 95 mmol/mol (10.8%) where there was no difference between cystatin C-eGFR and isotopic GFR. CONCLUSIONS Performance of cystatin C-eGFR was superior to creatinine-based GFR in patients with Type 2 diabetes with HbA(1c) >95 mmol/mol (10.8%).
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Affiliation(s)
- S J Oh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea
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Perkins BA, Sochett EB, Cherney DZ. Ability of Cystatin C to Detect Changes in Glomerular Filtration Rate After ACE Inhibition in Patients with Uncomplicated Type 1 Diabetes. Clin Exp Hypertens 2012; 34:606-11. [DOI: 10.3109/10641963.2012.681732] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
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Cystatin C as a marker of glomerular filtration rate: prospects and limitations. Curr Opin Nephrol Hypertens 2012; 20:631-9. [PMID: 21926620 DOI: 10.1097/mnh.0b013e32834b8850] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW There is much interest in cystatin C to replace or supplement serum creatinine to estimate the glomerular filtration rate (GFR). Here we review the performance of cystatin C and combined creatinine-cystatin C estimating equations compared to creatinine-based estimating equations in chronic and acute kidney disease. RECENT FINDINGS Drift in the cystatin C assay has had a large effect on the results reported using cystatin C, but these issues are not routinely considered in evaluation of GFR-estimating equations. The recently released primary reference material for cystatin C will allow less difference among assays in the future. There does not appear to be a consistent message among published studies as to whether cystatin C-based equations are better than creatinine-based equations in the general population or those with chronic kidney disease (CKD), as well as those with reduced muscle mass or chronic illness, or acute kidney injury. Cystatin C could be used in combination with creatinine as a confirmatory test for estimated GFR from creatinine. SUMMARY Cystatin C may have a role to estimate GFR in selected circumstances, and the next set of studies should be directed at developing implementation strategies for its use.
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Sasson AN, Cherney DZ. Renal hyperfiltration related to diabetes mellitus and obesity in human disease. World J Diabetes 2012; 3:1-6. [PMID: 22253940 PMCID: PMC3258534 DOI: 10.4239/wjd.v3.i1.1] [Citation(s) in RCA: 129] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Revised: 12/19/2011] [Accepted: 01/09/2012] [Indexed: 02/05/2023] Open
Abstract
High intraglomerular pressure is associated with renal hyperfiltration, leading to the initiation and progression of kidney disease in experimental models of diabetes mellitus (DM). In humans, hyperfiltration is observed in patients with type 1 and type 2 DM, and is also seen in patients with pre-diabetic conditions, such as the metabolic syndrome. From a mechanistic perspective, both vascular and tubular factors likely contribute to the pathogenesis of hyperfiltration. Until now, human studies have primarily focused on the use of medications that inhibit the renin angiotensin system to reduce efferent vasoconstriction and thereby improve hyperfiltration. More recent advances in the development of investigational adenosine antagonists and inhibitors of sodium glucose co-transport may help to elucidate tubular factors that contribute to afferent vasodilatation. In this review, we summarize available data from experimental and human studies of type 1 and type 2 DM and obesity to provide an overview of factors that contribute to the hyperfiltration state. We have focused on the renin angiotensin system, cyclooxygenase-2 system, nitric oxide, protein kinase C and endothelin as vascular determinants of hyperfiltration. We also discuss relevant tubular factors, since experimental models have suggested that inhibition of sodium-glucose cotransport may be renoprotective.
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Affiliation(s)
- Alexa N Sasson
- Alexa N Sasson, David ZI Cherney, Division of Nephrology, University Health Network, University of Toronto, Ontario M5G 2N2, Canada
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