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Hill C, McKnight AJ, Smyth LJ. Integrated multiomic analyses: An approach to improve understanding of diabetic kidney disease. Diabet Med 2025; 42:e15447. [PMID: 39460977 PMCID: PMC11733670 DOI: 10.1111/dme.15447] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 10/28/2024]
Abstract
AIM Diabetes is increasing in prevalence worldwide, with a 20% rise in prevalence predicted between 2021 and 2030, bringing an increased burden of complications, such as diabetic kidney disease (DKD). DKD is a leading cause of end-stage kidney disease, with significant impacts on patients, families and healthcare providers. DKD often goes undetected until later stages, due to asymptomatic disease, non-standard presentation or progression, and sub-optimal screening tools and/or provision. Deeper insights are needed to improve DKD diagnosis, facilitating the identification of higher-risk patients. Improved tools to stratify patients based on disease prognosis would facilitate the optimisation of resources and the individualisation of care. This review aimed to identify how multiomic approaches provide an opportunity to understand the complex underlying biology of DKD. METHODS This review explores how multiomic analyses of DKD are improving our understanding of DKD pathology, and aiding in the identification of novel biomarkers to detect disease earlier or predict trajectories. RESULTS Effective multiomic data integration allows novel interactions to be uncovered and empathises the need for harmonised studies and the incorporation of additional data types, such as co-morbidity, environmental and demographic data to understand DKD complexity. This will facilitate a better understanding of kidney health inequalities, such as social-, ethnicity- and sex-related differences in DKD risk, onset and progression. CONCLUSION Multiomics provides opportunities to uncover how lifetime exposures become molecularly embodied to impact kidney health. Such insights would advance DKD diagnosis and treatment, inform preventative strategies and reduce the global impact of this disease.
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Affiliation(s)
- Claire Hill
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
| | - Amy Jayne McKnight
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
| | - Laura J. Smyth
- Centre for Public Health, School of Medicine, Dentistry and Biomedical ScienceQueen's University BelfastBelfastUK
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2
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Jansson Sigfrids F, Lithovius R, Groop P, Thorn LM. Lessons learned from the FinnDiane Study: Epidemiology and metabolic risk factors for diabetic kidney disease in type 1 diabetes. Diabet Med 2025; 42:e15431. [PMID: 39235140 PMCID: PMC11733665 DOI: 10.1111/dme.15431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 08/16/2024] [Accepted: 08/22/2024] [Indexed: 09/06/2024]
Abstract
AIMS Across its operational span of more than 25 years, the observational, nationwide, multicentre Finnish Diabetic Nephropathy (FinnDiane) Study has aimed to unravel mechanisms underlying diabetic kidney disease, with a special focus on its metabolic risk factors. We sought to compile key findings relating to this topic and to offer a current perspective on the natural course of diabetic kidney disease among individuals with type 1 diabetes. METHODS In this narrative review, articles relevant to the subject published by the FinnDiane Study were identified and summarized together with work published by others, when relevant. RESULTS The FinnDiane Study has underscored the significance of dysglycaemia and insulin resistance, increased visceral fat mass, hypertension and dyslipidaemia-particularly high triglycerides and remnant cholesterol-as risk factors for diabetic kidney disease. Factors like abdominal obesity seem to influence the early stages of the disease, while the presence of the metabolic syndrome becomes implicated at later stages. Epidemiological reports have revealed that after an initial decline, the cumulative incidence of albuminuria plateaued post-1980s, with the progression rate to kidney failure remaining high. Fortunately, 23% of the FinnDiane cohort regressed to less advanced stages of albuminuria, improving their overall prognosis. CONCLUSION A substantial burden of albuminuria associated with type 1 diabetes persists, and therefore, novel kidney-protecting therapies are highly awaited. In addition, given that metabolic factors influence the progression of diabetic kidney disease both in its early and advanced stages, emphasis should be placed on ensuring that their treatment targets are met.
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Affiliation(s)
- Fanny Jansson Sigfrids
- Folkhälsan Research CenterHelsinkiFinland
- Research Program for Clinical and Molecular MetabolismUniversity of HelsinkiHelsinkiFinland
- Department of NephrologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - Raija Lithovius
- Folkhälsan Research CenterHelsinkiFinland
- Research Program for Clinical and Molecular MetabolismUniversity of HelsinkiHelsinkiFinland
- Department of NephrologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
| | - Per‐Henrik Groop
- Folkhälsan Research CenterHelsinkiFinland
- Research Program for Clinical and Molecular MetabolismUniversity of HelsinkiHelsinkiFinland
- Department of NephrologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
- Department of Diabetes, Central Clinical SchoolMonash UniversityMelbourneVictoriaAustralia
- Baker Heart and Diabetes InstituteMelbourneVictoriaAustralia
| | - Lena M. Thorn
- Folkhälsan Research CenterHelsinkiFinland
- Research Program for Clinical and Molecular MetabolismUniversity of HelsinkiHelsinkiFinland
- Department of NephrologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
- Department of General Practice and Primary Health CareUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland
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3
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ElSayed NA, McCoy RG, Aleppo G, Balapattabi K, Beverly EA, Briggs Early K, Bruemmer D, Echouffo-Tcheugui JB, Ekhlaspour L, Garg R, Khunti K, Lal R, Lingvay I, Matfin G, Pandya N, Pekas EJ, Pilla SJ, Polsky S, Segal AR, Seley JJ, Stanton RC, Bannuru RR. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2025. Diabetes Care 2025; 48:S239-S251. [PMID: 39651975 PMCID: PMC11635029 DOI: 10.2337/dc25-s011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2024]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Makvandi K, Eliasson B, Carlsen HK, Baid-Agrawal S. Burden and Excess Risk of Adverse Outcomes in Patients With Type 1 Diabetes Using KDIGO Classification: A National Cohort Study. Diabetes Care 2025; 48:106-117. [PMID: 39565836 DOI: 10.2337/dc24-0908] [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: 05/01/2024] [Accepted: 10/18/2024] [Indexed: 11/22/2024]
Abstract
OBJECTIVE The widely adopted Kidney Disease: Improving Global Outcomes (KDIGO) classification system has been underused in assessing the burden and risk of adverse outcomes in type 1 diabetes. This observational study aimed to clarify how each KDIGO category correlates with adverse outcomes in this patient group. RESEARCH DESIGN AND METHODS In a cohort of 40,199 individuals with type 1 diabetes from the Swedish National Diabetes Register, we aimed to investigate the 1) prevalence of different KDIGO categories at baseline; 2) incidence of adverse kidney and cardiovascular (CV) outcomes, including mortality, within each category; and 3) association of baseline category with excess risk of five outcomes: a 40% decline in estimated glomerular filtration rate (eGFR), kidney failure, major adverse kidney/CV events, and all-cause mortality. Cox regression analyses were conducted using three different reference categories: 1) the conventional low-risk "combined G1A1 + G2A1"; 2) "G1A1" alone to assess whether G2A1 had excess risk; and 3) "G1bA1" alone to evaluate whether eGFR ≥105 mL/min/1.73 m2 had increased risk. RESULTS Among 39,067 included patients, with a mean follow-up of 9.1 years, 18.5% presented with chronic kidney disease (CKD), defined as eGFR <60 mL/min/1.73 m2 and/or albuminuria. A progressive increase in the incidence and adjusted hazard ratio for all studied outcomes was found with advancing eGFR and albuminuria categories, including in G2A1 (non-CKD). An eGFR ≥105 mL/min/1.73 m2 without albuminuria was not associated with increased risk. CONCLUSIONS A progressively increasing burden of all studied adverse outcomes was observed with advancing KDIGO categories. Even individuals with preserved eGFR and normoalbuminuria (G2A1), conventionally perceived as non-CKD, had an excess risk for all outcomes.
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Affiliation(s)
- Kianoush Makvandi
- Department of Molecular and Clinical Medicine, The Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Nephrology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Björn Eliasson
- Department of Molecular and Clinical Medicine, The Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- National Diabetes Register, Centre of Registries in Region Western Sweden, Gothenburg, Sweden
| | - Hanne Krage Carlsen
- National Diabetes Register, Centre of Registries in Region Western Sweden, Gothenburg, Sweden
| | - Seema Baid-Agrawal
- Department of Molecular and Clinical Medicine, The Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Transplant Center, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden
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Keum Y, Caramori ML, Cherney DZ, Crandall JP, de Boer IH, Lingvay I, McGill JB, Polsky S, Pop-Busui R, Rossing P, Sigal RJ, Mauer M, Doria A. Albuminuria and Rapid Kidney Function Decline as Selection Criteria for Kidney Clinical Trials in Type 1 Diabetes Mellitus. Clin J Am Soc Nephrol 2025; 20:62-71. [PMID: 39423023 PMCID: PMC11737443 DOI: 10.2215/cjn.0000000000000567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 10/15/2024] [Indexed: 10/21/2024]
Abstract
Key Points Severely increased urinary albumin excretion rate is an effective criterion to select persons with type 1 diabetes at high risk of GFR decline for enrollment in clinical trials. A history of rapid GFR decline is less effective but can be used to extend clinical trials to person with normoalbuminuric diabetic kidney disease. These findings have immediate implications for the design of clinical trials of novel renoprotective interventions in type 1 diabetes. Background The optimal criteria to select individuals with type 1 diabetes mellitus and albuminuric or normoalbuminuric diabetic kidney disease, who are at risk of rapid kidney function decline, for clinical trials are unclear. Methods This study analyzed data from the Preventing Early Renal Loss in Diabetes clinical trial, which investigated whether allopurinol slowed kidney function decline in persons with type 1 diabetes mellitus and early-to-moderate diabetic kidney disease. Rates of iohexol GFR (iGFR) and eGFR decline during the 3-year study were compared by linear mixed effect regression between participants enrolled based on a history of moderately or severely increased albuminuria (n =394) and those enrolled based on a recent history of rapid kidney function decline (≥3 ml/min per 1.73 m2 per year) in the absence of a history of albuminuria (n =124). The association between baseline albuminuria and iGFR/eGFR decline during the trial was also evaluated. Results Rates of eGFR decline during the trial were higher in participants with a history of albuminuria than in those with a history of rapid kidney function decline (−3.56 [95% confidence intervals (CIs), −3.17 to −3.95] versus −2.35 [95% CI, −1.86 to −2.84] ml/min per 1.73 m2 per year, P = 0.001). The results were similar for iGFR decline, although the difference was not significant (P = 0.07). Within the history of albuminuria group, the rate of eGFR decline was −5.30 (95% CI, −4.52 to −6.08) ml/min per 1.73 m2 per year in participants with severely increased albuminuria as compared with −2.97 (95% CI, 2.44 to −3.50) and −2.32 (95% CI, −1.61 to −3.03) ml/min per 1.73 m2 per year in those with moderately increased or normal/mildly increased albuminuria at baseline (P < 0.001). Conclusions Severely increased albuminuria at screening is a powerful criterion for selecting persons with type 1 diabetes mellitus at high risk of kidney function decline. A history of rapid eGFR decline without a history of albuminuria is less effective for this purpose, but it can still identify individuals with type 1 diabetes mellitus who will lose kidney function more rapidly than expected from physiological aging. Clinical Trial registry name and registration number: NCT02017171 .
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Grants
- R01 DK121019 NIDDK NIH HHS
- UL1 TR001105 NCATS NIH HHS
- U01 DK133097 NIDDK NIH HHS
- UL1 TR002494 NCATS NIH HHS
- UC4 DK101108 NIDDK NIH HHS
- R01DK126373 NIDDK NIH HHS
- UL1 TR002319 NCATS NIH HHS
- P30 DK020572 NIDDK NIH HHS
- R01DK121019, UO1DK133097 NIH HHS
- R03 DK094484 NIDDK NIH HHS
- U01 DK119083 NIDDK NIH HHS
- P30AG024824 NIA NIH HHS
- P30DK036836, P30DK020572, P30DK020579 NIDDK NIH HHS
- R01DK107956, R01DK11672, U01DK119083 NIDDK NIH HHS
- R03DK094484, R34DK097808, UC4DK101108 NIDDK NIH HHS
- P30 AG024824 NIA NIH HHS
- UL1TR002494, UL1TR001422, UL1TR002556, UL1TR002319, UL1TR001105 NCATS NIH HHS
- UL1 TR001422 NCATS NIH HHS
- P30 DK036836 NIDDK NIH HHS
- R34 DK097808 NIDDK NIH HHS
- Merit Award University of Toronto
- 17-2012-377 Juvenile Diabetes Research Foundation United States of America
- R01 DK107956 NIDDK NIH HHS
- R01 DK126373 NIDDK NIH HHS
- UL1 TR002556 NCATS NIH HHS
- P30 DK020579 NIDDK NIH HHS
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Affiliation(s)
- Youngshin Keum
- Research Division, Joslin Diabetes Center, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Maria Luiza Caramori
- Endocrinology and Metabolism Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - David Z. Cherney
- Division of Nephrology, Departments of Medicine, Physiology, and Pharmacology and Toxicology, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Jill P. Crandall
- Division of Endocrinology, Fleischer Institute for Diabetes and Metabolism, Albert Einstein College of Medicine, New York, New York
| | - Ian H. de Boer
- Department of Medicine, University of Washington, Seattle, Washington
| | - Ildiko Lingvay
- Departments of Medicine and Population and Data Sciences, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Janet B. McGill
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri
| | - Sarit Polsky
- Barbara Davis Center for Diabetes, University of Colorado, Aurora, Colorado
| | - Rodica Pop-Busui
- Department of Medicine, Oregon Health and Science University, Portland, OR
| | - Peter Rossing
- Steno Diabetes Center and Department of Clinical Medicine, University Copenhagen, Copenhagen, Denmark
| | - Ronald J. Sigal
- Departments of Medicine, Cardiac Sciences, and Community Health Sciences, Faculties of Medicine and Kinesiology, University of Calgary, Alberta, Canada
| | - Michael Mauer
- Departments of Medicine and Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - Alessandro Doria
- Research Division, Joslin Diabetes Center, Boston, Massachusetts
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
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6
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Kim WJ, Oh T, Heo NH, Kwon K, Shin GE, Jeong SH, Lee JH, Park S, Cho NJ, Gil HW, Lee EY. Kidney biopsy can help to predict renal outcomes of patients with type 2 diabetes mellitus. Kidney Res Clin Pract 2025; 44:91-101. [PMID: 38212871 PMCID: PMC11838855 DOI: 10.23876/j.krcp.23.059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 07/17/2023] [Accepted: 07/30/2023] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND In patients with type 2 diabetes mellitus (T2DM), diabetic kidney disease (DKD) is diagnosed based on clinical features. A kidney biopsy is used only in selected cases. This study aimed to reconsider the role of a biopsy in predicting renal outcomes. METHODS Clinical and laboratory parameters and renal biopsy results were obtained from 237 patients with T2DM who underwent renal biopsies at Soonchunhyang University Cheonan Hospital between January 2000 and March 2020 and were analyzed. RESULTS Of 237 diabetic patients, 29.1% had DKD only, 61.6% had non-DKD (NDKD), and 9.3% had DKD with coexisting NDKD (DKD/NDKD). Of the patients with DKD alone, 43.5% progressed to end-stage kidney disease (ESKD), while 15.8% of NDKD patients and 36.4% of DKD/NDKD patients progressed to ESKD (p < 0.001). In the DKD-alone group, pathologic features like ≥50% global sclerosis (p < 0.001), tubular atrophy (p < 0.001), interstitial fibrosis (p < 0.001), interstitial inflammation (p < 0.001), and the presence of hyalinosis (p = 0.03) were related to worse renal outcomes. The Cox regression model showed a higher risk of progression to ESKD in the DKD/NDKD group compared to the DKD-alone group (hazard ratio [HR], 2.73; p = 0.032), ≥50% global sclerosis (HR, 3.88; p < 0.001), and the degree of mesangial expansion (moderate: HR, 2.45; p = 0.045 and severe: HR, 6.22; p < 0.001). CONCLUSION In patients with T2DM, a kidney biopsy can help in identifying patients with NDKD for appropriate treatment, and it has predictive value.
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Affiliation(s)
- Wook-Joon Kim
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
| | - Taehoon Oh
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
| | - Nam Hun Heo
- Department of Biostatistics, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
| | - Kyungsup Kwon
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
| | - Ga-Eun Shin
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
| | - Se-Hwi Jeong
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
| | - Ji Hye Lee
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
- Department of Pathology, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
| | - Samel Park
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
| | - Nam-Jun Cho
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
| | - Hyo-Wook Gil
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
| | - Eun Young Lee
- Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Republic of Korea
- Department of Medicine, College of Medicine, Soonchunhyang University, Cheonan, Republic of Korea
- BK21 Four Project, Soonchunhyang University College of Medicine, Cheonan, Republic of Korea
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7
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Choi YJ, Richard G, Zhang G, Hodgin JB, Demeke DS, Yang Y, Schaub JA, Tamayo IM, Gurung BK, Naik AS, Nair V, Birznieks C, MacDonald A, Narongkiatikhun P, Gross S, Driscoll L, Flynn M, Tommerdahl K, Nadeau KJ, Shah VN, Vigers T, Snell-Bergeon JK, Kendrick J, van Raalte DH, Li LP, Prasad P, Ladd P, Chin BB, Cherney DZ, McCown PJ, Alakwaa F, Otto EA, Brosius FC, Saulnier PJ, Puelles VG, Goodrich JA, Street K, Venkatachalam MA, Ruiz A, de Boer IH, Nelson RG, Pyle L, Blondin DP, Sharma K, Kretzler M, Bjornstad P. Attenuated kidney oxidative metabolism in young adults with type 1 diabetes. J Clin Invest 2024; 134:e183984. [PMID: 39436695 PMCID: PMC11645151 DOI: 10.1172/jci183984] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 10/17/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUNDIn type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism.METHODSYoung adults with T1D (n = 30) and healthy controls (HCs) (n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA-Seq, and spatial metabolomics to assess this relationship.RESULTSParticipants with T1D had significantly higher glomerular basement membrane (GBM) thickness compared with HCs. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HCs, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, and GBM, and lower insulin sensitivity and cortical oxidative metabolism.CONCLUSIONThese early structural and metabolic changes in T1D kidneys may precede clinical DKD.TRIAL REGISTRATIONClinicalTrials.gov NCT04074668.FUNDINGUniversity of Michigan O'Brien Kidney Translational Core Center grant (P30 DK081943); CROCODILE studies by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (P30 DK116073), Juvenile Diabetes Research Foundation (JDRF) (2-SRA-2019-845-S-B), Boettcher Foundation, Intramural Research Program at NIDDK and Centers for Disease Control and Prevention (CKD Initiative) under Inter-Agency Agreement #21FED2100157DPG.
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Affiliation(s)
- Ye Ji Choi
- Department of Biostatistics and Informatics and
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Gabriel Richard
- Department of Medicine, Division of Neurology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Centre de Fecherche du Centre Hospitalier Universitaire de Sherbrooke (CRCHUS), Québec, Canada
| | - Guanshi Zhang
- Center for Renal Precision Medicine, University of Texas Health–San Antonio, San Antonio, Texas, USA
| | - Jeffrey B. Hodgin
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Dawit S. Demeke
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Yingbao Yang
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Jennifer A. Schaub
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Ian M. Tamayo
- Center for Renal Precision Medicine, University of Texas Health–San Antonio, San Antonio, Texas, USA
| | - Bhupendra K. Gurung
- Center for Renal Precision Medicine, University of Texas Health–San Antonio, San Antonio, Texas, USA
| | - Abhijit S. Naik
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Viji Nair
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Carissa Birznieks
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Alexis MacDonald
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Phoom Narongkiatikhun
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Susan Gross
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Lynette Driscoll
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Maureen Flynn
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Kalie Tommerdahl
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Kristen J. Nadeau
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Viral N. Shah
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Tim Vigers
- Department of Biostatistics and Informatics and
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Janet K. Snell-Bergeon
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Jessica Kendrick
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Daniel H. van Raalte
- Diabetes Center, Department of Internal Medicine, Amsterdam University Medical Centers, location VUmc, Amsterdam, Netherlands
| | - Lu-Ping Li
- Radiology Department, Endeavor Health, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Pottumarthi Prasad
- Radiology Department, Endeavor Health, Pritzker School of Medicine, University of Chicago, Chicago, Illinois, USA
| | - Patricia Ladd
- Department of Radiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Bennett B. Chin
- Department of Radiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - David Z. Cherney
- Department of Medicine, Division of Nephrology, University of Toronto School of Medicine, Toronto, Ontario, Canada
| | - Phillip J. McCown
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Fadhl Alakwaa
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Edgar A. Otto
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Frank C. Brosius
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
- Division of Nephrology, The University of Arizona College of Medicine Tucson, Tucson, Arizona, USA
| | - Pierre Jean Saulnier
- University of Poitiers, INSERM, CHU Poitiers, Clinical Investigation Center CIC 1402, Poitiers, France
| | - Victor G. Puelles
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Pathology, Aarhus University Hospital, Aarhus, Denmark
- III. Department of Medicine, University Medical Center Hamburg–Eppendorf, Hamburg, Germany
| | | | - Kelly Street
- Department of Biostatistics, University of Southern California, Los Angeles, California, USA
| | | | - Aaron Ruiz
- Center for Renal Precision Medicine, University of Texas Health–San Antonio, San Antonio, Texas, USA
- SygnaMap, Inc., San Antonio, Texas, USA
| | - Ian H. de Boer
- Kidney Research Institute, University of Washington, Seattle, Washington, USA
| | - Robert G. Nelson
- Chronic Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona, USA
| | - Laura Pyle
- Department of Biostatistics and Informatics and
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Denis P. Blondin
- Department of Medicine, Division of Neurology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Centre de Fecherche du Centre Hospitalier Universitaire de Sherbrooke (CRCHUS), Québec, Canada
| | - Kumar Sharma
- Center for Renal Precision Medicine, University of Texas Health–San Antonio, San Antonio, Texas, USA
| | - Matthias Kretzler
- Department of Internal Medicine, Division of Nephrology, University of Michigan, Ann Arbor, Michigan, USA
| | - Petter Bjornstad
- Department of Pediatrics, Section of Endocrinology, University of Colorado School of Medicine, Aurora, Colorado, USA
- Department of Medicine, Division of Metabolism, Endocrinology and Nutrition, University of Washington School of Medicine, Seattle, Washington, USA
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8
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Dai Q, Huang S, Fang Y, Ding X. Identifying the Potential Diagnostic Gene Biomarkers and Forecasting the Potential Therapeutic Agents for Advanced Diabetic Nephropathy Based on Pyroptosis and Ferroptosis. J Inflamm Res 2024; 17:5763-5779. [PMID: 39224660 PMCID: PMC11368145 DOI: 10.2147/jir.s467388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
Background Diabetic nephropathy (DN) is a prevalent complication of diabetes, often leading to end-stage kidney disease (ESKD). Advanced DN progresses to ESKD rapidly, yet effective diagnostic indicators and treatments are lacking. Methods Two DN-related datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the R packages. Pyroptosis-related genes (PRGs) and ferroptosis-related genes (FRGs) were collected from their respective database. Pyroptosis- and ferroptosis-related differentially expressed genes (PFRDEGs) were identified by overlapping DEGs, PRGs, and FRGs for further analysis, including functional enrichment and immune infiltration. Hub genes were identified using a PPI network via MCODE-plugin in Cytoscape. GeneMANIA was utilized to explore intermolecular interactions among hub genes. Based on these hub genes, a diagnostic model was constructed using the receiver operating characteristic curve and potential therapeutic agents were retrieved. Correlation analysis between hub genes and estimated glomerular filtration rate was performed using Nephroseq v5 database, and expression of hub genes was validated in external GEO database, Nephroseq v5 database and DN mice in vivo. Results Four hub genes (CYBB, LCN2, JUN and ADIPOQ) were identified, and three of the four hub genes (CYBB, LCN2 and ADIPOQ) were found to be potential biomarkers for advanced DN. On this basis, three potential therapeutic agents were screened. More importantly, a series of biological experiments confirmed that CYBB and LCN2 were significantly up-regulated in DN mice. Conclusion This study identifies three hub genes as diagnostic biomarkers and mines three potential therapeutic agents for advanced DN, providing new insights into the role of pyroptosis and ferroptosis in advanced DN and laying the foundation for future research.
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Affiliation(s)
- Qin Dai
- Department of Nephrology, Xuhui District Central Hospital, Shanghai, People’s Republic of China
- Department of Nephrology, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Siyi Huang
- Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China
| | - Yi Fang
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
| | - Xiaoqiang Ding
- Department of Nephrology, Zhongshan Hospital, Fudan University, Shanghai, People’s Republic of China
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9
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Wang Z, Wang F, Liu C, Zhang L. Association of thyroid autoantibodies and diabetic kidney disease in hospitalised patients with type 2 diabetes mellitus: a cross-sectional study from a Chinese university hospital. BMJ Open 2024; 14:e077338. [PMID: 38503411 PMCID: PMC10952948 DOI: 10.1136/bmjopen-2023-077338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 02/27/2024] [Indexed: 03/21/2024] Open
Abstract
OBJECTIVES To analyse and explore the association between thyroid autoantibodies and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). DESIGN A cross-sectional study. SETTING Patients were from the inpatient unit at The Second Endocrinology Department of Shengjing Hospital Affiliated to China Medical University (Shenyang, China) between January 2015 and September 2019. PARTICIPANTS A total of 150 Chinese adults with T2DM were included in the study, including 83 men and 67 women. Their age ranged between 25 and 92 years. METHODOLOGY They grouped by the presence of DKD, urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate, and levels of thyroid peroxidase antibodies (TPOAb) and thyroglobulin antibodies (TgAb). Data on the patients' general characteristics and laboratory measurements (levels of fasting plasma glucose, glycated haemoglobin, and albumin; renal function; and thyroid function) were collected. Binary logistic regression was performed to identify risk factors for DKD. RESULTS The level of TPOAb, the positivity rates of TPOAb (p<0.01) and TgAb (p<0.05) were higher in patients with DKD than in those without DKD. The TPOAb level in patients with a UACR<30 mg/g creatinine was lower than that in patients with a UACR between 30 and 300 mg/g creatinine (p<0.05). The prevalence of DKD was higher in patients with a TPOAb-positive or TgAb-positive status. The result of binary logistic regression analysis showed that a TPOAb-positive status was significantly associated with DKD in patients with T2DM (OR=7.683, 95% CI 1.583 to 37.286, p<0.05). CONCLUSIONS TPOAb-positive status is in association with DKD in patients with T2DM. Large scale, prospective cohort studies are warranted to confirm our findings.
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Affiliation(s)
- Zhi Wang
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Futao Wang
- Department of Endocrinology, Changchun Center Hospital, Changchun, China
| | - Cong Liu
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China
| | - Le Zhang
- Department of Endocrinology, Shengjing Hospital of China Medical University, Shenyang, China
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ElSayed NA, Aleppo G, Bannuru RR, Bruemmer D, Collins BS, Ekhlaspour L, Hilliard ME, Johnson EL, Khunti K, Lingvay I, Matfin G, McCoy RG, Perry ML, Pilla SJ, Polsky S, Prahalad P, Pratley RE, Segal AR, Seley JJ, Stanton RC, Gabbay RA. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care 2024; 47:S219-S230. [PMID: 38078574 PMCID: PMC10725805 DOI: 10.2337/dc24-s011] [Citation(s) in RCA: 97] [Impact Index Per Article: 97.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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11
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Jansson Sigfrids F, Groop PH. Progression and regression of kidney disease in type 1 diabetes. FRONTIERS IN NEPHROLOGY 2023; 3:1282818. [PMID: 38192517 PMCID: PMC10773897 DOI: 10.3389/fneph.2023.1282818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 11/27/2023] [Indexed: 01/10/2024]
Abstract
Diabetic kidney disease is distinguished by the presence of albuminuria, hypertension, declining kidney function, and a markedly elevated cardiovascular disease risk. This constellation of clinical features drives the premature mortality associated with type 1 diabetes. The first epidemiological investigations concerning type 1 diabetes-related albuminuria date back to the 1980s. The early studies found that proteinuria - largely equivalent to severe albuminuria - developed in 35 to 45% of individuals with type 1 diabetes, with the diabetes duration-specific incidence rate pattern portraying one or two peaks. Furthermore, moderate albuminuria, the first detectable sign of diabetic kidney disease, was found to nearly inexorably progress to overt kidney disease within a short span of time. Since the early reports, studies presenting more updated incidence rates have appeared, although significant limitations such as study populations that lack broad generalizability, study designs vulnerable to substantive selection bias, and constrained follow-up times have been encountered by many. Nevertheless, the most recent reports estimate that in modern times, moderate - instead of severe - albuminuria develops in one-third of individuals with type 1 diabetes; yet, a considerable part (up to 40% during the first ten years after the initial albuminuria diagnosis) progresses to more advanced stages of the disease over time. An alternative pathway to albuminuria progression is its regression, which affects up to 60% of the individuals, but notably, the relapse rate to a more advanced disease stage is high. Whether albuminuria regression translates into a decline in cardiovascular disease and premature mortality risk is an area of debate, warranting more detailed research in the future. Another unclear but alarming feature is that although the incidence of severe albuminuria has fallen since the 1930s, the decline seems to have reached a plateau after the 1980s. This stagnation may be due to the lack of kidney-protective medicines since the early 1980s, as the recent breakthroughs in type 2 diabetes have not been applicable to type 1 diabetes. Therefore, novel treatment strategies are at high priority within this patient population.
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Affiliation(s)
- Fanny Jansson Sigfrids
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
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12
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Altıncık SA, Yıldırımçakar D, Avcı E, Özhan B, Girişgen İ, Yüksel S. Plasma leucine-rich α-2-glycoprotein 1 - a novel marker of diabetic kidney disease in children and adolescents with type 1 diabetes mellitus? Pediatr Nephrol 2023; 38:4043-4049. [PMID: 37401956 DOI: 10.1007/s00467-023-06019-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 04/08/2023] [Accepted: 05/02/2023] [Indexed: 07/05/2023]
Abstract
BACKGROUND Glomerular endothelial dysfunction and neoangiogenesis play a significant role in the pathogenesis of diabetic kidney disease (DKD). Leucine-rich α-2 glycoprotein 1 (LRG1) is a recently discovered protein that participates in the molecular pathway of inflammation and angiogenesis. We aimed to investigate efficacy of LRG1 to predict estimated glomerular filtration rate (eGFR) decrease in children and adolescents with type 1 diabetes mellitus (T1DM). METHODS The study comprised 72 participants with diabetes duration for ≥ 2 years. At study initiation, LRG1, urine albumin, eGFR (cystatin C-based, and Schwartz), HbA1c, and lipid values were evaluated and diabetes-related clinical features and anthropometric measurements were collected. These results were compared with final control values after ≥ 1 year. Patients were divided into subgroups according to presence of albuminuria progression, eGFR decrease, and metabolic control parameters. RESULTS There was positive correlation between LRG1 level and Schwartz and cystatin C-based eGFR decline (r = 0.360, p = 0.003; r = 0.447, p = 0.001, respectively), and negative correlation between final cystatin C-based eGFR and LRG1 (p = 0.01, r = -0.345). Patients with cystatin C-based eGFR decrease > 10% had significantly higher LRG1 levels (p = 0.03), however, LRG1 was not different between albuminuria progression subgroups. A 0.282 μg/ml increase in LRG1 correlated with a 1% decrease in eGFR in simple linear regression analysis (β = 0.282, %CI 0.11-0.45, p = 0.001) and LRG1 was an independent predictor of GFR decline even in the presence of covariates. CONCLUSIONS Our study supports the relationship between plasma LRG1 and eGFR decline and suggests LRG1 may be an early marker of DKD progression in children with T1DM. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Selda Ayça Altıncık
- Department of Pediatric Endocrinology, Pamukkale University, Denizli, Turkey
| | - Didem Yıldırımçakar
- Department of Pediatric Endocrinology, Pamukkale University, Denizli, Turkey.
| | - Esin Avcı
- Department of Medical Biochemistry, Pamukkale University, Denizli, Turkey
| | - Bayram Özhan
- Department of Pediatric Endocrinology, Pamukkale University, Denizli, Turkey
| | - İlknur Girişgen
- Department of Pediatric Nephrology, Pamukkale University, Denizli, Turkey
| | - Selçuk Yüksel
- Department of Pediatric Nephrology and Pediatric Rheumatology, Pamukkale University, Denizli, Turkey
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方 晨, 孙 丽, 刘 研, 肖 力, 孙 林. [Non-Classical Clinical Types and Pathological Changes of Diabetic Kidney Disease: A Review]. SICHUAN DA XUE XUE BAO. YI XUE BAN = JOURNAL OF SICHUAN UNIVERSITY. MEDICAL SCIENCE EDITION 2023; 54:1074-1079. [PMID: 38162079 PMCID: PMC10752793 DOI: 10.12182/20231160102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Indexed: 01/03/2024]
Abstract
Diabetic kidney disease (DKD) is a common complication of diabetes mellitus and approximately 1/3 of diabetic patients may progress to DKD. A typical early clinical manifestation of DKD is microalbuminuria and patients may present with macroproteinuria accompanied by a decrease in renal function condition as the disease progresses. It is generally believed that the likelihood of a reversal of the disease is reduced after the development of macroproteinuria in patients with DKD, and that eventually some patients' condition may develop into end-stage renal disease (ESRD). Moreover, the thickening of the glomerular basement membrane, mesangial matrix expansion, Kimmelstiel-Wilson (K-W) nodules, and glomerulosclerosis in end-stage diabetes mellitus are typical pathologic changes of DKD. However, some DKD patients, especially those with type 2 diabetes mellitus (T2DM) combined with DKD, may have diverse clinical manifestations, showing variations in disease progression and regression, and manifesting as non-classical types of DKD, such as normoalbuminuric DKD, proteinuria-reduced DKD, and DKD with rapid decline in renal function. In addition, the formation of crescents, a special pathological change, is observed in renal biopsy. However, this issue is currently under-recognized by clinicians and therefore deserves more attention. In order to improve clinicians' understanding of the presentations and pathological changes of non-classical DKD and the level of DKD prevention and treatment in China, we present a preliminary introduction to the clinical phenotypes and pathological changes of non-classical types of DKD in this paper by summarizing the findings of our prior studies as well as domestic and international literature.
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Affiliation(s)
- 晨茜 方
- 中南大学湘雅二医院 肾内科 （长沙 410011）Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - 丽雅 孙
- 中南大学湘雅二医院 肾内科 （长沙 410011）Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - 研 刘
- 中南大学湘雅二医院 肾内科 （长沙 410011）Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - 力 肖
- 中南大学湘雅二医院 肾内科 （长沙 410011）Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - 林 孙
- 中南大学湘雅二医院 肾内科 （长沙 410011）Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410011, China
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Esposito P, Picciotto D, Cappadona F, Costigliolo F, Russo E, Macciò L, Viazzi F. Multifaceted relationship between diabetes and kidney diseases: Beyond diabetes. World J Diabetes 2023; 14:1450-1462. [PMID: 37970131 PMCID: PMC10642421 DOI: 10.4239/wjd.v14.i10.1450] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/18/2023] [Accepted: 08/28/2023] [Indexed: 10/09/2023] Open
Abstract
Diabetes mellitus is one of the most common causes of chronic kidney disease. Kidney involvement in patients with diabetes has a wide spectrum of clinical presentations ranging from asymptomatic to overt proteinuria and kidney failure. The development of kidney disease in diabetes is associated with structural changes in multiple kidney compartments, such as the vascular system and glomeruli. Glomerular alterations include thickening of the glomerular basement membrane, loss of podocytes, and segmental mesangiolysis, which may lead to microaneurysms and the development of pathognomonic Kimmelstiel-Wilson nodules. Beyond lesions directly related to diabetes, awareness of the possible coexistence of nondiabetic kidney disease in patients with diabetes is increasing. These nondiabetic lesions include focal segmental glomerulosclerosis, IgA nephropathy, and other primary or secondary renal disorders. Differential diagnosis of these conditions is crucial in guiding clinical management and therapeutic approaches. However, the relationship between diabetes and the kidney is bidirectional; thus, new-onset diabetes may also occur as a complication of the treatment in patients with renal diseases. Here, we review the complex and multifaceted correlation between diabetes and kidney diseases and discuss clinical presentation and course, differential diagnosis, and therapeutic oppor-tunities offered by novel drugs.
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Affiliation(s)
- Pasquale Esposito
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa 16132, Italy
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
| | - Daniela Picciotto
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
| | - Francesca Cappadona
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
| | - Francesca Costigliolo
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
| | - Elisa Russo
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa 16132, Italy
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
| | - Lucia Macciò
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa 16132, Italy
| | - Francesca Viazzi
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genoa 16132, Italy
- Unit of Nephrology, Dialysis and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa 16132, Italy
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Sangha S, Yadav RK, Subbiah A, Bagchi S, Mahajan S, Bhowmik D, Agarwal SK. Clinical Profile of Nonproteinuric Kidney Disease in Type 2 Diabetic Patients in India. Indian J Nephrol 2023; 33:283-288. [PMID: 37781550 PMCID: PMC10503571 DOI: 10.4103/ijn.ijn_54_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 09/15/2022] [Accepted: 10/19/2022] [Indexed: 10/03/2023] Open
Abstract
Background Diabetic kidney disease (DKD) is the commonest cause of end-stage renal disease (ESRD) across the world. Development of microalbuminuria is the earliest marker of DKD and predicts progressive decline in estimated glomerular filtration rate (eGFR). However, recent evidence has suggested that a significant proportion of type 2 diabetic patients have chronic kidney disease (CKD) without proteinuria. Methods In this single-center, prospective observational study, 400 consecutive type 2 diabetic patients with either overt proteinuria (>500 mg/day) and/or renal dysfunction eGFR <60 ml/min/1.73 m2) were recruited. Baseline demographic and clinical data were recorded. eGFR and proteinuria were recorded at 6 months and 1 year. Patients with proteinuric (proteinuria >0.5 g/day) and nonproteinuric phenotypes were compared for progression of renal dysfunction in terms of doubling of serum creatinine and need for dialysis. Results In our study cohort, 106 (26.5%) were nonproteinuric. Both the groups were similar in terms of gender, duration of diabetes, comorbidities, body mass index (BMI), blood pressure control, and glycemic control. The nonproteinuric group was older (56.5 ± 2.1 vs. 54.7 ± 11.6 years, P = 0.012), had lesser prevalence of diabetic retinopathy (49 [46.2%] vs. 218 [74.1%], P < 0.001), higher hemoglobin levels (11.3 ± 1.7 vs. 10.5 ± 2.0 g/dl, P < 0.001), and higher cholesterol levels (169.3 ± 43.3 vs 157.1 ± 58.1 mg/dl, P = 0.025). The nonproteinuric phenotype had higher eGFR at baseline, 6 months, and 1 year. However, doubling of serum creatinine (10 [9.4%] vs. 48 [16.3%]) and progression to ESRD (5 [4.7%] vs. 19 [6.5%], P = 0.159) were not different between the two phenotypes. Conclusion Nonproteinuric DKD is common. Patients with nonproteinuric DKD tend to be older with a slower decline in eGFR.
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Affiliation(s)
- Sukhwinder Sangha
- Department of Nephrology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Raj Kanwar Yadav
- Department of Nephrology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Arunkumar Subbiah
- Department of Nephrology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Soumita Bagchi
- Department of Nephrology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Sandeep Mahajan
- Department of Nephrology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Dipankar Bhowmik
- Department of Nephrology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
| | - Sanjay Kumar Agarwal
- Department of Nephrology, All India Institute of Medical Sciences (AIIMS), New Delhi, India
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Swaminathan SM, Rao IR, Shenoy SV, Prabhu AR, Mohan PB, Rangaswamy D, Bhojaraja MV, Nagri SK, Nagaraju SP. Novel biomarkers for prognosticating diabetic kidney disease progression. Int Urol Nephrol 2023; 55:913-928. [PMID: 36271990 PMCID: PMC10030535 DOI: 10.1007/s11255-022-03354-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 08/21/2022] [Indexed: 10/24/2022]
Abstract
The global burden of diabetic kidney disease (DKD) is escalating, and it remains as a predominant cause of the end-stage renal disease (ESRD). DKD is associated with increased cardiovascular disease and morbidity in all types of diabetes. Prediction of progression with albuminuria and eGFR is challenging in DKD, especially in non-proteinuric DKD patients. The pathogenesis of DKD is multifactorial characterized by injury to all components of the nephron, whereas albuminuria is an indicator of only glomerular injury. The limits in the diagnostic and prognostic value of urine albumin demonstrate the need for alternative and clinically significant early biomarkers, allowing more targeted and effective diabetic treatment, to reduce the burden of DKD and ESRD. Identification of biomarkers, based on multifactorial pathogenesis of DKD can be the crucial paradigm in the treatment algorithm of DKD patients. This review focuses on the potential biomarkers linked to DKD pathogenesis, particularly with the hope of broadening the diagnostic window to identify patients with different stages of DKD progression.
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Affiliation(s)
- Shilna Muttickal Swaminathan
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Indu Ramachandra Rao
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Srinivas Vinayak Shenoy
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Attur Ravindra Prabhu
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Pooja Basthi Mohan
- Department of Gastroenterology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Dharshan Rangaswamy
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Mohan V Bhojaraja
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Shivashankara Kaniyoor Nagri
- Department of Medicine, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India
| | - Shankar Prasad Nagaraju
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Manipal, India.
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Heterogeneity in Kidney Histology and Its Clinical Indicators in Type 2 Diabetes Mellitus: A Retrospective Study. J Clin Med 2023; 12:jcm12051778. [PMID: 36902564 PMCID: PMC10003520 DOI: 10.3390/jcm12051778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/26/2023] [Accepted: 02/20/2023] [Indexed: 02/25/2023] Open
Abstract
The heterogeneous spectrum of kidney disease in diabetes ranges from albuminuric or non-albuminuric diabetic kidney disease to non-diabetic kidney diseases. Presumptive clinical diagnosis of diabetic kidney disease may lead to an erroneous diagnosis. MATERIAL AND METHOD We analyzed the clinical profile and kidney biopsy of a total of 66 type 2 diabetes patients. Based on kidney histology, they were divided into-Class I (Diabetic Nephropathy), Class II (Non-diabetic kidney disease), and Class III (Mixed lesion). Demographic data, clinical presentation, and laboratory values were collected and analyzed. This study tried to examine the heterogeneity in kidney disease, its clinical indicator, and the role of kidney biopsy in the diagnosis of kidney disease in diabetes. RESULTS Class I consisted of 36(54.5%), class II 17(25.8%), and class III 13(19.7%) patients. The commonest clinical presentation was nephrotic syndrome 33(50%) followed by chronic kidney disease 16(24.4%) and asymptomatic urinary abnormality 8(12.1%). Diabetic retinopathy (DR) was present in 27(41%) cases. DR was significantly higher in the class I patients (p < 0.05). Specificity and positive predictive values of DR for DN were 0.83 and 0.81, respectively (sensitivity 0.61; negative predictive values 0.64). The Association of the duration of diabetes and the level of proteinuria with DN was statistically not significant (p > 0.05). Idiopathic MN (6) and Amyloidosis (2) were the most common isolated NDKD; whereas diffuse proliferative glomerulonephritis (DPGN) (7) was the commonest NDKD in mixed disease. Another common form of NDKD in mixed disease was Thrombotic Microangiopathy (2) and IgA nephropathy (2). NDKD was observed in 5(18.5%) cases in presence of DR. We noted biopsy-proven DN even in 14(35.9%) cases without DR, in 4(50%) cases with microalbuminuria and 14(38.9%) cases with a short duration of diabetes. CONCLUSION Almost half (45%) of cases with atypical presentation have non-diabetic kidney disease (NDKD), though even among these cases with atypical presentation diabetic nephropathy (either alone or in mixed form) is commonly seen in 74.2% of cases. DN has been seen in a subset of cases without DR, with microalbuminuria, and with a short duration of diabetes. Clinical indicators were insensitive in distinguishing DN Vs NDKD. Hence, a kidney biopsy may be a potential tool for the accurate diagnosis of kidney disease.
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ElSayed NA, Aleppo G, Aroda VR, Bannuru RR, Brown FM, Bruemmer D, Collins BS, Hilliard ME, Isaacs D, Johnson EL, Kahan S, Khunti K, Leon J, Lyons SK, Perry ML, Prahalad P, Pratley RE, Seley JJ, Stanton RC, Gabbay RA, on behalf of the American Diabetes Association. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2023. Diabetes Care 2023; 46:S191-S202. [PMID: 36507634 PMCID: PMC9810467 DOI: 10.2337/dc23-s011] [Citation(s) in RCA: 151] [Impact Index Per Article: 75.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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19
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An N, Wu BT, Yang YW, Huang ZH, Feng JF. Re-understanding and focusing on normoalbuminuric diabetic kidney disease. Front Endocrinol (Lausanne) 2022; 13:1077929. [PMID: 36531487 PMCID: PMC9757068 DOI: 10.3389/fendo.2022.1077929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 11/16/2022] [Indexed: 12/05/2022] Open
Abstract
Diabetes mellitus (DM) has grown up to be an important issue of global public health because of its high incidence rate. About 25% of DM patients can develop diabetic foot/ulcers (DF/DFU). Diabetic kidney disease (DKD) is the main cause of end-stage kidney disease (ESKD). DF/DFU and DKD are serious complications of DM. Therefore, early diagnosis and timely prevention and treatment of DF/DFU and DKD are essential for the progress of DM. The clinical diagnosis and staging of DKD are mostly based on the urinary albumin excretion rate (UAER) and EGFR. However, clinically, DKD patients show normoalbuminuric diabetic kidney disease (NADKD) instead of clinical proteinuria. The old NADKD concept is no longer suitable and should be updated accordingly with the redefinition of normal proteinuria by NKF/FDA. Based on the relevant guidelines of DM and CKD and combined with the current situation of clinical research, the review described NADKD from the aspects of epidemiology, pathological mechanism, clinical characteristics, biomarkers, disease diagnosis, and the relationship with DF/DFU to arouse the new understanding of NADKD in the medical profession and pay attention to it.
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Affiliation(s)
- Na An
- National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Departments of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Bi-tao Wu
- National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Departments of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yu-wei Yang
- National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Departments of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Zheng-hong Huang
- College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jia-fu Feng
- National Health Commission Key Laboratory of Nuclear Technology Medical Transformation (MIANYANG CENTRAL HOSPITAL), Mianyang, China
- Departments of Clinical Laboratory, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
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20
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Jung CY, Yoo TH. Novel biomarkers for diabetic kidney disease. Kidney Res Clin Pract 2022; 41:S46-S62. [DOI: 10.23876/j.krcp.22.084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 06/17/2022] [Indexed: 11/04/2022] Open
Abstract
Although diabetic kidney disease (DKD) remains one of the leading causes of reduced lifespan in patients with diabetes mellitus; its prevalence has failed to decline over the past 30 years. To identify those at high risk of developing DKD and disease progression at an early stage, extensive research has been ongoing in the search for prognostic and surrogate endpoint biomarkers for DKD. Although biomarkers are not used routinely in clinical practice or prospective clinical trials, many biomarkers have been developed to improve the early identification and prognostication of patients with DKD. Novel biomarkers that capture one specific mechanism of the DKD disease process have been developed, and studies have evaluated the prognostic value of assay-based biomarkers either in small sets or in combinations involving multiple biomarkers. More recently, several studies have assessed the prognostic value of omics- based biomarkers that include proteomics, metabolomics, and transcriptomics. This review will first describe the biomarkers used in current practice and their limitations, and then summarize the current status of novel biomarkers for DKD with respect to assay- based protein biomarkers, proteomics, metabolomics, and transcriptomics.
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21
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Nomogram-Based Chronic Kidney Disease Prediction Model for Type 1 Diabetes Mellitus Patients Using Routine Pathological Data. J Pers Med 2022; 12:jpm12091507. [PMID: 36143293 PMCID: PMC9501949 DOI: 10.3390/jpm12091507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/12/2022] [Accepted: 09/13/2022] [Indexed: 11/16/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) patients are a significant threat to chronic kidney disease (CKD) development during their life. However, there is always a high chance of delay in CKD detection because CKD can be asymptomatic, and T1DM patients bypass traditional CKD tests during their routine checkups. This study aims to develop and validate a prediction model and nomogram of CKD in T1DM patients using readily available routine checkup data for early CKD detection. This research utilized 1375 T1DM patients’ sixteen years of longitudinal data from multi-center Epidemiology of Diabetes Interventions and Complications (EDIC) clinical trials conducted at 28 sites in the USA and Canada and considered 17 routinely available features. Three feature ranking algorithms, extreme gradient boosting (XGB), random forest (RF), and extremely randomized trees classifier (ERT), were applied to create three feature ranking lists, and logistic regression analyses were performed to develop CKD prediction models using these ranked feature lists to identify the best performing top-ranked features combination. Finally, the most significant features were selected to develop a multivariate logistic regression-based CKD prediction model for T1DM patients. This model was evaluated using sensitivity, specificity, accuracy, precision, and F1 score on train and test data. A nomogram of the final model was further generated for easy application in clinical practices. Hypertension, duration of diabetes, drinking habit, triglycerides, ACE inhibitors, low-density lipoprotein (LDL) cholesterol, age, and smoking habit were the top-8 features ranked by the XGB model and identified as the most important features for predicting CKD in T1DM patients. These eight features were selected to develop the final prediction model using multivariate logistic regression, which showed 90.04% and 88.59% accuracy in internal and test data validation. The proposed model showed excellent performance and can be used for CKD identification in T1DM patients during routine checkups.
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22
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Nangaku M, Takama H, Ichikawa T, Mukai K, Kojima M, Suzuki Y, Watada H, Wada T, Ueki K, Narita I, Kashihara N, Kadowaki T, Hase H, Akizawa T. Randomized, double-blind, placebo-controlled phase 3 study of bardoxolone methyl in patients with diabetic kidney disease: Design and baseline characteristics of AYAME study. Nephrol Dial Transplant 2022; 38:1204-1216. [PMID: 36002026 PMCID: PMC10157761 DOI: 10.1093/ndt/gfac242] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD), but currently available treatments do not improve kidney function or prevent the initiation of dialysis/kidney replacement therapy. A previous study demonstrated that bardoxolone methyl improves the estimated glomerular filtration rate (eGFR), but the study was prematurely terminated because of an imbalance in heart failure between treatment groups. The subsequent phase 2 TSUBAKI study demonstrated no incidence of heart failure and an improved eGFR and GFR as determined by inulin clearance in DKD patients. METHODS This randomized, double-blind, placebo-controlled multicenter phase 3 study was designed to assess the efficacy and safety of bardoxolone methyl in DKD patients with an eGFR of ≥ 15.0 to < 60.0 mL/min/1.73 m2 and urinary albumin/creatinine ratio of ≤3500 mg/g but without risk factors for heart failure. The primary endpoint is the time to onset of a ≥ 30% decrease in the eGFR or ESKD. Randomized patients (1:1) have been under treatment with once-daily oral bardoxolone methyl (5, 10, or 15 mg by intra-patient dose adjustment) or placebo for at least 3 years. Results The 1013 patients' mean age is 65.9 years, 21.5% are female, the mean eGFR is 37.84 mL/min/1.73 m2, and the median urinary albumin/creatinine ratio is 351.80 mg/g. CONCLUSIONS Appropriate patients are enrolled in this study. This study will investigate the long-term efficacy and safety of bardoxolone methyl in DKD patients covering a wider range of the eGFR (≥15.0 to < 60.0 mL/min/1.73 m2) and albuminuria (≤3500 mg/g) compared with previous studies.
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Affiliation(s)
- Masanomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Takama
- Research & Development Division, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Tomohiro Ichikawa
- Research & Development Division, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Kazuya Mukai
- Research & Development Division, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Masahiro Kojima
- Research & Development Division, Kyowa Kirin Co., Ltd., Tokyo, Japan
| | - Yusuke Suzuki
- Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan
| | - Kohjiro Ueki
- Department of Diabetes, Endocrinology, and Metabolism, Center Hospital, National Center for Global Health and Medicine, Japan.,Department of Molecular Diabetic Medicine, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Japan
| | - Ichiei Narita
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Naoki Kashihara
- Department of Nephrology and Hypertension, Kawasaki Medical School, Okayama, Japan
| | | | | | - Tadao Akizawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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23
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Wang N, Lu Z, Zhang W, Bai Y, Pei D, Li L. Serum Cystatin C Trajectory Is a Marker Associated With Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2022; 13:824279. [PMID: 35634510 PMCID: PMC9130469 DOI: 10.3389/fendo.2022.824279] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 04/04/2022] [Indexed: 11/13/2022] Open
Abstract
Objective To explore the association of the trajectory of serum Cystatin C (Cysc) with diabetic kidney disease (DKD), a retrospective cohort study of Chinese subjects was carried out. Method A review of 2,928 diabetes mellitus (DM) patients admitted to the clinic and ward of the Endocrinology Department, Shengjing Hospital of China Medical University from January 1, 2014 to December 31, 2014 was performed. Subsequent visits to the hospital were followed until December 31, 2020. The primary endpoint was the incidence of DKD as diagnosed by urinary albumin/creatinine ratio ≥30 mg/g and/or estimated glomerular filtration rate <60 ml/min per 1.73 m2. Healthy control subjects were identified from a health checkup database in Shengjing Hospital from 2016 to 2019. The latent class growth mixed modeling (LCGMM) method was used to analyze latent classes of serum Cysc in healthy and DM subjects. Finally, the hazard ratios (HRs) of latent classes of Cysc in DM subjects were analyzed by Cox regression analysis. Results A total of 805 type 2 diabetes mellitus (T2DM) and 349 healthy subjects were included in the trial. The HRs of quartiles of baseline Cysc in T2DM subjects were 7.15 [95% confidence interval (CI), 2.79 to 25.57], 2.30 (95% CI, 1.25 to 4.24), and 2.05 (95% CI, 1.14 to 3.70), respectively, for quartile 4 (Q4), Q3, and Q2 when compared with Q1. Through LCGMM, a 1-class linear model was selected for the Cysc latent class in healthy subjects. In contrast, a 3-class linear model was selected for that in DM subjects. The slopes of the three latent classes in T2DM subjects were larger than the slope in healthy subjects. The HRs of incident DKD were 3.43 (95% CI, 1.93 to 6.11) for the high-increasing class and 1.80 (95% CI, 1.17 to 2.77) for the middle-increasing class after adjusting for confounding variables. Conclusions Patients with T2DM had a higher velocity of increase in Cysc than healthy subjects. Patients with high baseline Cysc values and high latent increasing velocity of Cysc had a higher risk of developing DKD in later life. More attention should be paid to patients with these high-risk factors.
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Affiliation(s)
- Nana Wang
- Endocrinology Department, Shengjing Hospital of China Medical University, Shenyang, China
| | - Zhenyu Lu
- Department of Health Management, Shengjing Hospital of China Medical University, Shenyang, China
| | - Wei Zhang
- Endocrinology Department, Shengjing Hospital of China Medical University, Shenyang, China
| | - Yu Bai
- Endocrinology Department, Shengjing Hospital of China Medical University, Shenyang, China
| | - Dongmei Pei
- Department of Health Management, Shengjing Hospital of China Medical University, Shenyang, China
| | - Ling Li
- Endocrinology Department, Shengjing Hospital of China Medical University, Shenyang, China
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24
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Kim HJ, Kim SS, Song SH. Glomerular filtration rate as a kidney outcome of diabetic kidney disease: a focus on new antidiabetic drugs. Korean J Intern Med 2022; 37:502-519. [PMID: 35368179 PMCID: PMC9082447 DOI: 10.3904/kjim.2021.515] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 02/17/2022] [Indexed: 11/27/2022] Open
Abstract
Diabetes has reached epidemic proportions, both in Korea and worldwide and is associated with an increased risk of chronic kidney disease and kidney failure (KF). The natural course of kidney function among people with diabetes (especially type 2 diabetes) may be complex in real-world situations. Strong evidence from observational data and clinical trials has demonstrated a consistent association between decreased estimated glomerular filtration rate (eGFR) and subsequent development of hard renal endpoints (such as KF or renal death). The disadvantage of hard renal endpoints is that they require a long follow-up duration. In addition, there are many patients with diabetes whose renal function declines without the appearance of albuminuria, measurement of the eGFR is emphasized. Many studies have used GFR-related parameters, such as its change, decline, or slope, as clinical endpoints for kidney disease progression. In this respect, understanding the trends in GFR changes could be crucial for developing clinical management strategies for the prevention of diabetic complications. This review focuses on the clinical implication of the eGFR-related parameters that have been used so far in diabetic kidney disease. We also discuss the use of recently developed new antidiabetic drugs for kidney protection, with a focus on the GFR as clinical endpoints.
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Affiliation(s)
- Hyo Jin Kim
- Division of Nephrology, Department of Internal Medicine, Pusan National University Hospital, Busan,
Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
| | - Sang Soo Kim
- Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Pusan National University Hospital, Busan,
Korea
| | - Sang Heon Song
- Division of Nephrology, Department of Internal Medicine, Pusan National University Hospital, Busan,
Korea
- Biomedical Research Institute, Pusan National University Hospital, Busan,
Korea
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25
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Advancements in nanomedicines for the detection and treatment of diabetic kidney disease. BIOMATERIALS AND BIOSYSTEMS 2022; 6:100047. [PMID: 36824160 PMCID: PMC9934479 DOI: 10.1016/j.bbiosy.2022.100047] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 03/22/2022] [Accepted: 03/27/2022] [Indexed: 12/18/2022] Open
Abstract
In the diabetic kidneys, morbidities such as accelerated ageing, hypertension and hyperglycaemia create a pro-inflammatory microenvironment characterised by extensive fibrogenesis. Radiological techniques are not yet optimised generating inconsistent and non-reproducible data. The gold standard procedure to assess renal fibrosis is kidney biopsy, followed by histopathological assessment. However, this method is risky, invasive, subjective and examines less than 0.01% of kidney tissue resulting in diagnostic errors. As such, less than 10% of patients undergo kidney biopsy, limiting the accuracy of the current diabetic kidney disease (DKD) staging method. Standard treatments suppress the renin-angiotensin system to control hypertension and use of pharmaceuticals aimed at controlling diabetes have shown promise but can cause hypoglycaemia, diuresis and malnutrition as a result of low caloric intake. New approaches to both diagnosis and treatment are required. Nanoparticles (NPs) are an attractive candidate for managing DKD due to their ability to act as theranostic tools that can carry drugs and enhance image contrast. NP-based point-of-care systems can provide physiological information previously considered unattainable and provide control over the rate and location of drug release. Here we discuss the use of nanotechnology in renal disease, its application to both the treatment and diagnosis of DKD. Finally, we propose a new method of NP-based DKD classification that overcomes the current systems limitations.
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26
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Petzuch B, Benardeau A, Hofmeister L, Meyer J, Hartmann E, Pavkovic M, Mathar I, Sandner P, Ellinger-Ziegelbauer H. Urinary miRNA profiles in chronic kidney injury - Benefits of extracellular vesicle enrichment and miRNAs as potential biomarkers for renal fibrosis, glomerular injury and endothelial dysfunction. Toxicol Sci 2022; 187:35-50. [PMID: 35244176 DOI: 10.1093/toxsci/kfac028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Micro-RNAs (miRNAs) are regulators of gene expression and play an important role in physiological homeostasis and disease. In biofluids miRNAs can be found in protein complexes or in extracellular vesicles (EVs). Altered urinary miRNAs are reported as potential biomarkers for chronic kidney disease (CKD). In this context we compared established urinary protein biomarkers for kidney injury with urinary miRNA profiles in obese ZSF1 and hypertensive renin transgenic rats. Additionally, the benefit of urinary EV enrichment was investigated in vivo and the potential association of urinary miRNAs with renal fibrosis in vitro. Kidney damage in both rat models was confirmed by histopathology, proteinuria, and increased levels of urinary protein biomarkers. In total 290 miRNAs were elevated in obese ZSF1 rats compared to lean controls, while 38 miRNAs were altered in obese ZSF1 rats during 14 to 26 weeks of age. These 38 miRNAs correlated better with disease progression than established urinary protein biomarkers. MiRNAs increased in obese ZSF1 rats were associated with renal inflammation, fibrosis, and glomerular injury. Eight miRNAs were also changed in urinary EVs of renin transgenic rats, including one which might play a role in endothelial dysfunction. EV enrichment increased the number and detection level of several miRNAs implicated in renal fibrosis in vitro and in vivo. Our results show the benefit of EV enrichment for miRNA detection and the potential of total urine and urinary EV-associated miRNAs as biomarkers of altered kidney physiology, renal fibrosis and glomerular injury, and disease progression in hypertension and obesity induced CKD.
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Affiliation(s)
- B Petzuch
- Bayer AG, Pharmaceuticals, Investigational Toxicology, 42096 Wuppertal, Germany.,Boehringer Ingelheim Pharma GmbH & Co. KG, Investigative Toxicology, Department of Non-Clinical Drug Safety, 88400 Biberach (Riß), Germany
| | - A Benardeau
- Novo Nordisk A/S,Cardio-Renal Biology, Måløv, Denmark
| | - L Hofmeister
- Bayer AG, Pharmaceuticals, Cardiovascular Research, 42096 Wuppertal, Germany
| | - J Meyer
- Bayer AG, Pharmaceuticals, Cardiovascular Research, 42096 Wuppertal, Germany
| | - E Hartmann
- Bayer AG, Pharmaceuticals, Toxicology, Pathology and Clinical Pathology, 42096 Wuppertal, Germany
| | - M Pavkovic
- Bayer AG, Pharmaceuticals, Investigational Toxicology, 42096 Wuppertal, Germany
| | - I Mathar
- Bayer AG, Pharmaceuticals, Cardiovascular Research, 42096 Wuppertal, Germany
| | - P Sandner
- Bayer AG, Pharmaceuticals, Cardiovascular Research, 42096 Wuppertal, Germany.,Hannover Medical School, Institute of Pharmacology, 30625 Hannover, Germany
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27
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Jaffa MA, Gebregziabher M, Jaffa AA. Shared parameter and copula models for analysis of semicontinuous longitudinal data with nonrandom dropout and informative censoring. Stat Methods Med Res 2022; 31:451-474. [PMID: 34806502 PMCID: PMC8891057 DOI: 10.1177/09622802211060519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Analysis of longitudinal semicontinuous data characterized by subjects' attrition triggered by nonrandom dropout is complex and requires accounting for the within-subject correlation, and modeling of the dropout process. While methods that address the within-subject correlation and missing data are available, approaches that incorporate the nonrandom dropout, also referred to informative right censoring, in the modeling step are scarce due to the computational intensity and possible intractable integration needed for its implementation. Appreciating the complexity of this problem and the need for a new methodology that is feasible for implementation, we propose to extend a framework of likelihood-based marginalized two-part models to account for informative right censoring. The censoring process is modeled using two approaches: (1) Poisson censoring for the count of visits before dropout and (2) survival time to dropout. Novel consideration was given to the proposed joint modeling approaches for the semicontinuous and censoring components of the likelihood function which included (1) shared parameter, and (2) Clayton copula. The cross-part and within-part correlations were accounted for through a complex random effect structure that models correlated random intercepts and slopes. Feasibility of implementation, and accuracy of these approaches were investigated using extensive simulation studies and clinical application.
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Affiliation(s)
- Miran A. Jaffa
- Epidemiology and Population Health Department, Faculty of Health Sciences, American University of Beirut, Beirut, Lebanon, P.O.Box 11-0236 Riad El-Solh / Beirut, Lebanon 1107 2020
| | - Mulugeta Gebregziabher
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC. USA
| | - Ayad A. Jaffa
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, P.O.Box 11-0236 Riad El-Solh / Beirut, Lebanon 1107 2020
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
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28
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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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29
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Low-grade proteinuria and atherosclerotic cardiovascular disease: A transition study of patients with diabetic kidney disease. PLoS One 2022; 17:e0264568. [PMID: 35213636 PMCID: PMC8880428 DOI: 10.1371/journal.pone.0264568] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 02/11/2022] [Indexed: 11/21/2022] Open
Abstract
Diabetic kidney disease (DKD) is heterogeneous in terms of proteinuria. Patients with DKD who present with low-grade proteinuria are more likely to have nephrosclerosis rather than traditional diabetic nephropathy. The amount of proteinuria might reflect the underlying pathology of renal failure and influence the prognosis after dialysis initiation. Clinical implications of proteinuria at the start of dialysis have not been confirmed, while greater proteinuria is associated with higher risk of cardiovascular disease (CVD) in the predialysis stages of chronic kidney disease. We performed a retrospective multicenter cohort study enrolling incident hemodialysis patients with diabetes. Patients were stratified using proteinuria quartiles. We examined the association of proteinuria quartiles with types of subsequent CVD. Among the enrolled 361 patients, the estimated mean glomerular filtration rate and proteinuria was 5.4 mL/min/1.73 m2 and 6.3 g/gCr, respectively. Lower quartile of proteinuria (cut-offs: 3.0, 5.4, and 8.8 g/gCr) was significantly associated with male, older age, and history of atherosclerotic CVD including coronary artery disease, peripheral arterial disease, and cerebral infarction (Ptrend<0.05). Kidney size was smaller in patients with lower levels of proteinuria. Patients with higher levels of proteinuria were more likely to have proliferative diabetic retinopathy (Ptrend<0.05). Multivariate competing risk analysis revealed that the first quartile of proteinuria was associated with a greater risk of atherosclerotic CVD than the third quartile (subhazard ratio [95% confidence interval]: 2.04 [1.00–4.14]). This association was attenuated after additional adjustments for history of atherosclerotic CVD. Furthermore, patients with lower quartiles of proteinuria were more likely to die of atherosclerotic CVD than those with non-atherosclerotic CVD (Ptrend = 0.01). Diabetic patients with lower proteinuria at dialysis initiation were characterized by severer macroangiopathy, as shown by a more atrophic kidney and higher prevalence of past atherosclerotic CVD. Hence, they are at a high risk of developing atherosclerotic CVD.
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Adeva-Andany MM, Fernández-Fernández C, Funcasta-Calderón R, Ameneiros-Rodríguez E, Adeva-Contreras L, Castro-Quintela E. Insulin Resistance is Associated with Clinical Manifestations of Diabetic Kidney Disease (Glomerular Hyperfiltration, Albuminuria, and Kidney Function Decline). Curr Diabetes Rev 2022; 18:e171121197998. [PMID: 34789129 DOI: 10.2174/1573399818666211117122604] [Citation(s) in RCA: 5] [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: 07/06/2021] [Revised: 09/13/2021] [Accepted: 09/15/2021] [Indexed: 11/22/2022]
Abstract
Clinical features of diabetic kidney disease include glomerular hyperfiltration, albuminuria, and kidney function decline towards End-Stage Kidney Disease (ESKD). There are presently neither specific markers of kidney involvement in patients with diabetes nor strong predictors of rapid progression to ESKD. Serum-creatinine-based equations used to estimate glomerular filtration rate are notoriously unreliable in patients with diabetes. Early kidney function decline, reduced glomerular filtration rate, and proteinuria contribute to identifying diabetic patients at higher risk for rapid kidney function decline. Unlike proteinuria, the elevation of urinary albumin excretion in the range of microalbuminuria is frequently transient in patients with diabetes and does not always predict progression towards ESKD. Although the rate of progression of kidney function decline is usually accelerated in the presence of proteinuria, histological lesions of diabetes and ESKD may occur with normal urinary albumin excretion. No substantial reduction in the rate of ESKD associated with diabetes has been observed during the last decades despite intensified glycemic control and reno-protective strategies, indicating that existing therapies do not target underlying pathogenic mechanisms of kidney function decline. Very long-term effects of sodium-glucose transporters- 2 inhibitors and glucagon-like peptide-1 analogs remain to be defined. In patients with diabetes, glucagon secretion is typically elevated and induces insulin resistance. Insulin resistance is consistently and strongly associated with clinical manifestations of diabetic kidney disease, suggesting that reduced insulin sensitivity participates in the pathogenesis of the disease and may represent a therapeutic objective. Amelioration of insulin sensitivity in patients with diabetes is associated with cardioprotective and kidney-protective effects.
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Affiliation(s)
- María M Adeva-Andany
- Nephrology Division, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | | | | | | | | | - Elvira Castro-Quintela
- Nephrology Division, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
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Yamamoto Y, Hanai K, Mori T, Yokoyama Y, Yoshida N, Murata H, Shinozaki T, Babazono T. Kidney outcomes and all-cause mortality in people with type 2 diabetes exhibiting non-albuminuric kidney insufficiency. Diabetologia 2022; 65:234-245. [PMID: 34739552 DOI: 10.1007/s00125-021-05590-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 08/11/2021] [Indexed: 12/19/2022]
Abstract
AIM/HYPOTHESIS It remains unclear whether people with diabetes exhibiting non-albuminuric kidney insufficiency have higher risk of kidney function decline and mortality compared with those exhibiting preserved kidney function without albuminuria. Furthermore, information regarding the incidence of albuminuria in people with this unique phenotype is sparse. Here, we aimed to elucidate the risk of the kidney outcomes and all-cause mortality in people with diabetes exhibiting non-albuminuric kidney insufficiency. METHODS In this retrospective cohort study, 8320 Japanese adults with type 2 diabetes were classified into four groups based on the presence of albuminuria and kidney insufficiency at baseline, defined as urinary albumin/creatinine ratio of equal to or above 30 mg/g and eGFR of less than 60 ml min-1 1.73 m-2, respectively. The primary composite kidney endpoint was a 50% decrease in eGFR from baseline or the initiation of kidney replacement therapy. The annual percentage change in eGFR slope and progression of albuminuria category were evaluated as the secondary and tertiary kidney endpoints, respectively. All-cause death was also set as the endpoint. RESULTS Compared with people exhibiting non-albuminuric preserved kidney function, those with non-albuminuric kidney insufficiency had the higher risk for the primary kidney endpoint (HR 4.1; 95% CI 2.5, 6.7; p < 0.001), steep percentage change in eGFR slope (-1.96%/year vs -1.36%/year, p < 0.001), incidence of albuminuria (HR 2.1; 1.7, 2.6; p < 0.001) and all-cause mortality (HR 1.5; 1.2, 2.0; p = 0.003). In the sensitivity analyses treating the incidence of albuminuria as a competing risk, people with non-albuminuric kidney insufficiency still had higher risk for the primary kidney endpoint and all-cause mortality than those with non-albuminuric preserved kidney function (subdistribution HR 2.8; 1.4, 5.6; p = 0.004; and 1.6; 1.1, 2.2; p = 0.014, respectively). CONCLUSIONS/INTERPRETATION People with type 2 diabetes exhibiting non-albuminuric kidney insufficiency had poorer kidney outcomes and life prognosis than those exhibiting non-albuminuric preserved kidney function.
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Affiliation(s)
- Yui Yamamoto
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Ko Hanai
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
| | - Tomomi Mori
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Yoichi Yokoyama
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Naoshi Yoshida
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Hidekazu Murata
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
| | - Tomohiro Shinozaki
- Department of Information and Computer Technology, Faculty of Engineering, Tokyo University of Science, Tokyo, Japan
| | - Tetsuya Babazono
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
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Lopez LN, Wang W, Loomba L, Afkarian M, Butani L. Diabetic kidney disease in children and adolescents: an update. Pediatr Nephrol 2022; 37:2583-2597. [PMID: 34913986 PMCID: PMC9489564 DOI: 10.1007/s00467-021-05347-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 10/16/2021] [Accepted: 10/18/2021] [Indexed: 12/15/2022]
Abstract
Diabetic kidney disease (DKD), previously encountered predominantly in adult patients, is rapidly gaining center stage as a childhood morbidity and one that pediatric nephrologists are likely to encounter with increasing frequency. This is in large part due to the obesity epidemic and the consequent rise in type 2 diabetes in children and adolescents, as well as the more aggressive diabetes phenotype in today's youth with more rapid β-cell decline and faster development and progression of diabetes-related complications along with lower responsiveness to the treatments used in adults. DKD, an end-organ complication of diabetes, is at the very least a marker of, and more likely a predisposing factor for, the development of adverse cardiovascular outcomes and premature mortality in children with diabetes. On an optimistic note, several new therapeutic approaches are now available for the management of diabetes in adults, such as GLP1 receptor agonists, SGLT2 inhibitors, and DPP4 inhibitors, that have also been shown to have a favorable impact on cardiorenal outcomes. Also promising is the success of very low-energy diets in inducing remission of diabetes in adults. However, the addition of these pharmacological and dietary approaches to the management toolbox of diabetes and DKD in children and adolescents awaits thorough assessment of their safety and efficacy in this population. This review outlines the scope of diabetes and DKD, and new developments that may favorably impact the management of children and young adults with diabetes and DKD.
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Affiliation(s)
- Lauren N. Lopez
- Division of Nephrology, Department of Internal Medicine, University of California, Davis, Sacramento, CA USA
| | - Weijie Wang
- University of California, Berkeley, Berkeley, CA USA
| | - Lindsey Loomba
- Division of Pediatric Endocrinology, Department of Pediatrics, University of California, Davis, Sacramento, CA USA
| | - Maryam Afkarian
- Division of Nephrology, Department of Internal Medicine, University of California, Davis, Sacramento, CA USA
| | - Lavjay Butani
- Division of Pediatric Nephrology, Department of Pediatrics, University of California, Davis, 2516 Stockton Blvd, Room 348, Sacramento, CA, 95817, USA.
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Abstract
The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Sur S, Nguyen M, Boada P, Sigdel TK, Sollinger H, Sarwal MM. FcER1: A Novel Molecule Implicated in the Progression of Human Diabetic Kidney Disease. Front Immunol 2021; 12:769972. [PMID: 34925339 PMCID: PMC8672419 DOI: 10.3389/fimmu.2021.769972] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/08/2021] [Indexed: 01/13/2023] Open
Abstract
Diabetic kidney disease (DKD) is a key microvascular complication of diabetes, with few therapies for targeting renal disease pathogenesis and progression. We performed transcriptional and protein studies on 103 unique blood and kidney tissue samples from patients with and without diabetes to understand the pathophysiology of DKD injury and its progression. The study was based on the use of 3 unique patient cohorts: peripheral blood mononuclear cell (PBMC) transcriptional studies were conducted on 30 patients with DKD with advancing kidney injury; Gene Expression Omnibus (GEO) data was downloaded, containing transcriptional measures from 51 microdissected glomerulous from patients with DKD. Additionally, 12 independent kidney tissue sections from patients with or without DKD were used for validation of target genes in diabetic kidney injury by kidney tissue immunohistochemistry and immunofluorescence. PBMC DKD transcriptional analysis, identified 853 genes (p < 0.05) with increasing expression with progression of albuminuria and kidney injury in patients with diabetes. GEO data was downloaded, normalized, and analyzed for significantly changed genes. Of the 325 significantly up regulated genes in DKD glomerulous (p < 0.05), 28 overlapped in PBMC and diabetic kidney, with perturbed FcER1 signaling as a significantly enriched canonical pathway. FcER1 was validated to be significantly increased in advanced DKD, where it was also seen to be specifically co-expressed in the kidney biopsy with tissue mast cells. In conclusion, we demonstrate how leveraging public and private human transcriptional datasets can discover and validate innate immunity and inflammation as key mechanistic pathways in DKD progression, and uncover FcER1 as a putative new DKD target for rational drug design.
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Affiliation(s)
- Swastika Sur
- Division of Transplant Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Mark Nguyen
- Division of Transplant Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Patrick Boada
- Division of Transplant Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Tara K Sigdel
- Division of Transplant Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Hans Sollinger
- Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
| | - Minnie M Sarwal
- Division of Transplant Surgery, University of California San Francisco, San Francisco, CA, United States
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35
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Deng L, Li W, Xu G. Update on pathogenesis and diagnosis flow of normoalbuminuric diabetes with renal insufficiency. Eur J Med Res 2021; 26:144. [PMID: 34895352 PMCID: PMC8665546 DOI: 10.1186/s40001-021-00612-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/16/2021] [Indexed: 12/11/2022] Open
Abstract
In recent decades, the prevalence of diabetic kidney disease has remained stable and appears to be a wide heterogeneity. Normoalbuminuric diabetes with renal insufficiency, which is characterized by a decline in the glomerular filtration rate in the absence of albuminuria, has been identified as an albuminuria-independent phenotype of diabetic kidney disease. Epidemiological data demonstrate that normoalbuminuric phenotype is prevalent. Compared to albuminuric phenotype, normoalbuminuric phenotype has distinct clinical characteristics and a wide heterogeneity of pathological features. Currently, the pathogenesis of normoalbuminuric phenotype remains unclear. Additionally, the flow of diagnosing normoalbuminuric phenotype is not perfect. In this article, we review the latest studies addressing the epidemiology, clinical characteristics, and pathology of normoalbuminuric phenotype. Based on the studies of clinical features and renal histopathologic changes, we attempt to propose an underlying pathogenesis model and a flow chart for diagnosing normoalbuminuric phenotype.
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Affiliation(s)
- Le Deng
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Wenjie Li
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, Jiangxi, 330006, People's Republic of China
| | - Gaosi Xu
- Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, Jiangxi, 330006, People's Republic of China.
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Chowdhury NH, Reaz MBI, Haque F, Ahmad S, Ali SHM, A Bakar AA, Bhuiyan MAS. Performance Analysis of Conventional Machine Learning Algorithms for Identification of Chronic Kidney Disease in Type 1 Diabetes Mellitus Patients. Diagnostics (Basel) 2021; 11:diagnostics11122267. [PMID: 34943504 PMCID: PMC8700037 DOI: 10.3390/diagnostics11122267] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/12/2021] [Accepted: 12/01/2021] [Indexed: 12/18/2022] Open
Abstract
Chronic kidney disease (CKD) is one of the severe side effects of type 1 diabetes mellitus (T1DM). However, the detection and diagnosis of CKD are often delayed because of its asymptomatic nature. In addition, patients often tend to bypass the traditional urine protein (urinary albumin)-based CKD detection test. Even though disease detection using machine learning (ML) is a well-established field of study, it is rarely used to diagnose CKD in T1DM patients. This research aimed to employ and evaluate several ML algorithms to develop models to quickly predict CKD in patients with T1DM using easily available routine checkup data. This study analyzed 16 years of data of 1375 T1DM patients, obtained from the Epidemiology of Diabetes Interventions and Complications (EDIC) clinical trials directed by the National Institute of Diabetes, Digestive, and Kidney Diseases, USA. Three data imputation techniques (RF, KNN, and MICE) and the SMOTETomek resampling technique were used to preprocess the primary dataset. Ten ML algorithms including logistic regression (LR), k-nearest neighbor (KNN), Gaussian naïve Bayes (GNB), support vector machine (SVM), stochastic gradient descent (SGD), decision tree (DT), gradient boosting (GB), random forest (RF), extreme gradient boosting (XGB), and light gradient-boosted machine (LightGBM) were applied to developed prediction models. Each model included 19 demographic, medical history, behavioral, and biochemical features, and every feature’s effect was ranked using three feature ranking techniques (XGB, RF, and Extra Tree). Lastly, each model’s ROC, sensitivity (recall), specificity, accuracy, precision, and F-1 score were estimated to find the best-performing model. The RF classifier model exhibited the best performance with 0.96 (±0.01) accuracy, 0.98 (±0.01) sensitivity, and 0.93 (±0.02) specificity. LightGBM performed second best and was quite close to RF with 0.95 (±0.06) accuracy. In addition to these two models, KNN, SVM, DT, GB, and XGB models also achieved more than 90% accuracy.
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Affiliation(s)
- Nakib Hayat Chowdhury
- Department of Electrical, Electronic and Systems Engineering, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia; (N.H.C.); (M.B.I.R.); (F.H.); (S.H.M.A.); (A.A.A.B.)
- Department of Computer Science and Engineering, Bangladesh Army University of Science and Technology (BAUST), Saidpur Cantonment, Saidpur 5310, Bangladesh
| | - Mamun Bin Ibne Reaz
- Department of Electrical, Electronic and Systems Engineering, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia; (N.H.C.); (M.B.I.R.); (F.H.); (S.H.M.A.); (A.A.A.B.)
| | - Fahmida Haque
- Department of Electrical, Electronic and Systems Engineering, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia; (N.H.C.); (M.B.I.R.); (F.H.); (S.H.M.A.); (A.A.A.B.)
| | - Shamim Ahmad
- Department of Computer Science and Engineering, University of Rajshahi, Rajshahi 6205, Bangladesh;
| | - Sawal Hamid Md Ali
- Department of Electrical, Electronic and Systems Engineering, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia; (N.H.C.); (M.B.I.R.); (F.H.); (S.H.M.A.); (A.A.A.B.)
| | - Ahmad Ashrif A Bakar
- Department of Electrical, Electronic and Systems Engineering, Universiti Kebangsaan Malaysia, Bangi 43600, Selangor, Malaysia; (N.H.C.); (M.B.I.R.); (F.H.); (S.H.M.A.); (A.A.A.B.)
| | - Mohammad Arif Sobhan Bhuiyan
- Department of Electrical and Electronics Engineering, Xiamen University Malaysia, Bandar Sunsuria, Sepang 43900, Selangor, Malaysia
- Correspondence:
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Bell DSH. Are the Protean Effects of Pentoxifylline in the Therapy of Diabetes and Its Complications Still Relevant? Diabetes Ther 2021; 12:3025-3035. [PMID: 34647189 PMCID: PMC8586317 DOI: 10.1007/s13300-021-01168-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Accepted: 09/29/2021] [Indexed: 12/17/2022] Open
Abstract
Pentoxifylline (Px) has protean effects that can be utilized in the therapy of diabetes and its complications. There have been well-documented but often inconclusive improvements in peripheral arterial disease, foot ulcers, peripheral neuropathy, nephropathy, retinopathy, ischemic heart disease and cerebrovascular disease. In addition, non-alcoholic steatosis and steatohepatitis, which are closely associated with insulin resistance and type 2 diabetes, have been shown to improve with pentoxifylline. Surprisingly, pentoxifylline modestly improves insulin resistance through improvements in capillary blood flow as well as beta cell function and decreased hepatic glucose production. The therapeutic effects of pentoxifylline are complementary to the effects of drugs such as blockers of the renin-angiotensin-aldosterone system when utilized in the therapy of diabetic nephropathy.
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Affiliation(s)
- David S H Bell
- Southside Endocrinology, 1900 Crestwood Blvd, Suite 201, Irondale, AL, 35210, USA.
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38
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Nagasu H, Yano Y, Kanegae H, Heerspink HJL, Nangaku M, Hirakawa Y, Sugawara Y, Nakagawa N, Tani Y, Wada J, Sugiyama H, Tsuruya K, Nakano T, Maruyama S, Wada T, Yamagata K, Narita I, Tamura K, Yanagita M, Terada Y, Shigematsu T, Sofue T, Ito T, Okada H, Nakashima N, Kataoka H, Ohe K, Okada M, Itano S, Nishiyama A, Kanda E, Ueki K, Kashihara N. Kidney Outcomes Associated With SGLT2 Inhibitors Versus Other Glucose-Lowering Drugs in Real-world Clinical Practice: The Japan Chronic Kidney Disease Database. Diabetes Care 2021; 44:2542-2551. [PMID: 34593566 PMCID: PMC8546274 DOI: 10.2337/dc21-1081] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 08/23/2021] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Randomized controlled trials have shown kidney-protective effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors, and clinical practice databases have suggested that these effects translate to clinical practice. However, long-term efficacy, as well as whether the presence or absence of proteinuria and the rate of estimated glomerular filtration rates (eGFR) decline prior to SGLT2 inhibitor initiation modify treatment efficacy among type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) patients, is unknown. RESEARCH DESIGN AND METHODS Using the Japan Chronic Kidney Disease Database (J-CKD-DB), a nationwide multicenter CKD registry, we developed propensity scores for SGLT2 inhibitor initiation, with 1:1 matching with patients who were initiated on other glucose-lowering drugs. The primary outcome included rate of eGFR decline, and the secondary outcomes included a composite outcome of 50% eGFR decline or end-stage kidney disease. RESULTS At baseline, mean age at initiation of the SGLT2 inhibitor (n = 1,033) or other glucose-lowering drug (n = 1,033) was 64.4 years, mean eGFR was 68.1 mL/min per 1.73 m2, and proteinuria was apparent in 578 (28.0%) of included patients. During follow-up, SGLT2 inhibitor initiation was associated with reduced eGFR decline (difference in slope for SGLT2 inhibitors vs. other drugs 0.75 mL/min/1.73 m2 per year [0.51 to 1.00]). During a mean follow-up of 24 months, 103 composite kidney outcomes occurred: 30 (14 events per 1,000 patient-years) among the SGLT2 inhibitors group and 73 (36 events per 1,000 patient-years) among the other drugs group (hazard ratio 0.40, 95% CI 0.26-0.61). The benefit provided by SGLT2 inhibitors was consistent irrespective of proteinuria and rate of eGFR decline before initiation of SGLT2 inhibitors (P heterogeneity ≥ 0.35). CONCLUSIONS The benefits of SGLT2 inhibitors on kidney function as observed in clinical trials translate to patients treated in clinical practice with no evidence that the effects are modified by the underlying rate of kidney function decline or the presence of proteinuria.
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Affiliation(s)
- Hajime Nagasu
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan
| | - Yuichiro Yano
- Center for Novel and Exploratory Clinical Trials, Yokohama City University, Kanagawa, Japan .,Department of Family Medicine and Community Health, Duke University, Durham, NC
| | | | - Hiddo J L Heerspink
- The George Institute for Global Health, University of New South Wales, Sydney, Australia
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Yosuke Hirakawa
- Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Yuka Sugawara
- Division of Nephrology and Endocrinology, University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Naoki Nakagawa
- Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University, Hokkaido, Japan
| | - Yuji Tani
- Department of Medical Informatics and Hospital Management, Asahikawa Medical University, Hokkaido, Japan
| | - Jun Wada
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hitoshi Sugiyama
- Department of Human Resource Development of Dialysis Therapy for Kidney Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | | | - Toshiaki Nakano
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, Aichi, Japan
| | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
| | - Kunihiro Yamagata
- Department of Nephrology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Ichiei Narita
- Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Kouichi Tamura
- Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Motoko Yanagita
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yoshio Terada
- Department of Endocrinology, Metabolism and Nephrology, Kochi Medical School, Kochi University, Kochi, Japan
| | | | - Tadashi Sofue
- Division of Nephrology and Dialysis, Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University, Kagawa, Japan
| | - Takafumi Ito
- Division of Nephrology, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Hirokazu Okada
- Department of Nephrology, Faculty of Medicine, Saitama Medical University, Saitama, Japan
| | - Naoki Nakashima
- Medical Information Center, Kyushu University Hospital, Fukuoka, Japan
| | - Hiromi Kataoka
- Faculty of Health Science and Technology, Kawasaki University of Medical Welfare, Okayama, Japan
| | - Kazuhiko Ohe
- Department of Healthcare Information Management, The University of Tokyo Hospital, Tokyo, Japan
| | - Mihoko Okada
- Institute of Health Data Infrastructure for All, Tokyo, Japan
| | - Seiji Itano
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan
| | - Akira Nishiyama
- Department of Pharmacology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Eiichiro Kanda
- Department of Medical Science, Kawasaki Medical School, Kurashiki, Japan
| | - Kohjiro Ueki
- Diabetes Research Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Naoki Kashihara
- Department of Nephrology and Hypertension, Kawasaki Medical School, Kurashiki, Japan
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Lee JH, Yang FJ, Tsai WY, Lee CT, Liu SY, Yang WS, Tung YC. Serum neutrophil gelatinase-associated lipocalin as a potential biomarker of diabetic kidney disease in patients with childhood-onset type 1 diabetes. J Formos Med Assoc 2021; 121:832-840. [PMID: 34253435 DOI: 10.1016/j.jfma.2021.06.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 06/03/2021] [Accepted: 06/21/2021] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND/PURPOSE Diabetic kidney disease (DKD) is a major complication in patients with type 1 diabetes (T1D). The aim of this study was to evaluate the role of serum neutrophil gelatinase-associated lipocalin (sNGAL) in the early detection of DKD in childhood-onset T1D patients. METHODS A total of 116 patients (mean age, 22.3 ± 6.9 years) with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73 m2 were enrolled in this prospective cross-sectional study. Persistent albuminuria (PA) was defined as a urine albumin-to-creatinine ratio ≥ 30 mg/g for at least two consecutive years; non-albuminuria (NA) was defined otherwise. The patients were divided into the adult (Ad) (≥18 years, n = 91) and pediatric (Ped) (<18 years, n = 25) groups and further into the Ad-PA (n = 8), Ad-NA (n = 83), Ped-PA (n = 2), and Ad-NA (n = 23) subgroups. In all groups, the sNGAL level was determined. RESULTS The mean diabetes duration was 14.2 ± 6.1 years, and 8.6% patients had PA. There was no significant difference in sNGAL levels between the PA and NA groups; notably, in adults, the sNGAL level was significantly higher in the Ad-PA than Ad-NA subgroups (P = 0.039). The sNGAL level was negatively correlated with the eGFR in adults (rho -0.41, P < 0.001). Multiple linear regression models showed that higher sNGAL levels in the adult group were independent and significant determinants of a lower eGFR (P < 0.001). CONCLUSION An elevated sNGAL was significantly correlated with a decreased eGFR even in the range of normal to mildly decreased renal function. Thus, it is a potential biomarker of early deterioration of DKD in childhood-onset T1D.
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Affiliation(s)
- Ju-Hao Lee
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan; Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Pediatrics, Far Eastern Memorial Hospital, New Taipei City, Taiwan
| | - Feng-Jung Yang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital Yun Lin Branch, Douliu, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wen-Yu Tsai
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Cheng-Ting Lee
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Shih-Yao Liu
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wei-Shiung Yang
- Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Ching Tung
- Department of Pediatrics, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan.
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Di Bonito P, Mozzillo E, Rosanio FM, Maltoni G, Piona CA, Franceschi R, Ripoli C, Ricciardi MR, Tornese G, Arnaldi C, Iovane B, Iafusco D, Zanfardino A, Suprani T, Savastio S, Cherubini V, Tiberi V, Piccinno E, Schiaffini R, Delvecchio M, Casertano A, Maffeis C, Franzese A. Albuminuric and non-albuminuric reduced eGFR phenotypes in youth with type 1 diabetes: Factors associated with cardiometabolic risk. Nutr Metab Cardiovasc Dis 2021; 31:2033-2041. [PMID: 34083127 DOI: 10.1016/j.numecd.2021.03.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/21/2021] [Accepted: 03/23/2021] [Indexed: 01/11/2023]
Abstract
BACKGROUND AND AIM Albuminuria and reduced eGFR are hallmarks of Diabetic Kidney Disease in adults. Our aim was to analyze factors associated with albuminuric and non-albuminuric mildly reduced eGFR phenotypes in youths with type 1 diabetes. METHODS AND RESULTS This multicenter cross-sectional study included 1549 youths (age 5-17 years) with type 1 diabetes enrolled at 14 Italian Pediatric Diabetes Centers. Albuminuria, creatinine, glycosylated hemoglobin (HbA1c), lipids, blood pressure (BP), neutrophils (N) and lymphocytes (L) count were analyzed. Uric acid (UA) was available in 848 individuals. Estimated GFR (eGFR) was calculated using bedside Schwartz's equation. The sample was divided in three phenotypes: 1) normoalbuminuria and eGFR ≥90 mL/min/1.73 m2 (reference category, n = 1204), 2) albuminuric and normal GFR phenotype (n = 106), 3) non-albuminuric mildly reduced GFR (MRGFR) phenotype (eGFR 60-89 mL/min/1.73 m2, n = 239). Albuminuric and non-albuminuric reduced eGFR phenotypes were significantly associated with autoimmune thyroiditis (P =0.028 and P=0.044, respectively). Albuminuric phenotype showed high risk of high HbA1c (P=0.029), high BP (P < 0.001), and low HDL-C (P =0.045) vs reference category. Non-albuminuric MRGFR phenotype showed high risk of high BP (P < 0.0001), low HDL-C (P =0.042), high Triglycerides/HDL-C ratio (P =0.019), and high UA (P < 0.0001) vs reference category. CONCLUSION Non albuminuric MRGFR phenotype is more prevalent than albuminuric phenotype and shows a worst cardiometabolic risk (CMR) profile). Both phenotypes are associated with autoimmune thyroiditis. Our data suggest to evaluate both albuminuria and eGFR earlier in type 1 diabetes to timely identify young people with altered CMR profile.
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Affiliation(s)
- Procolo Di Bonito
- Department of Internal Medicine, "S. Maria Delle Grazie", Pozzuoli Hospital, Naples, Italy
| | - Enza Mozzillo
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy.
| | - Francesco M Rosanio
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
| | - Giulio Maltoni
- Department of Woman, Child and Urological Diseases, S. Orsola-Malpighi University Hospital, Bologna, Italy
| | - Claudia A Piona
- Pediatric Diabetes and Metabolic Disorders Unit, University of Verona, Verona, Italy
| | | | - Carlo Ripoli
- Pediatric Diabetology Unit, Pediatric and Microcytemia Department, AO Brotzu, Cagliari, Italy
| | - Maria R Ricciardi
- Pediatric Diabetology Unit, Pediatric and Microcytemia Department, AO Brotzu, Cagliari, Italy
| | - Gianluca Tornese
- Institute for Maternal and Child Health IRCCS 'Burlo Garofolo', Trieste, Italy
| | | | - Brunella Iovane
- Regional Diabetes Center, Children Hospital "Pietro Barilla", University Hospital of Parma, Parma, Italy
| | - Dario Iafusco
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Angela Zanfardino
- Department of Woman, Child and General and Specialized Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | | | - Silvia Savastio
- SCDU of Pediatrics, University Hospital Maggiore Della Carità, Novara, Italy
| | - Valentino Cherubini
- Regional Center for Diabetes in Children and Adolescents, Department of Woman and Child Health, AOU Salesi Hospital, Ancona, Italy
| | - Valentino Tiberi
- Regional Center for Diabetes in Children and Adolescents, Department of Woman and Child Health, AOU Salesi Hospital, Ancona, Italy
| | - Elvira Piccinno
- Metabolic Diseases, Clinical Genetics and Diabetology Unit, Giovanni XXIII Children's Hospital, Bari, Italy
| | | | - Maurizio Delvecchio
- Metabolic Diseases, Clinical Genetics and Diabetology Unit, Giovanni XXIII Children's Hospital, Bari, Italy
| | - Alberto Casertano
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
| | - Claudio Maffeis
- Pediatric Diabetes and Metabolic Disorders Unit, University of Verona, Verona, Italy
| | - Adriana Franzese
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
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Calvo-Hueros JI, Martín-Hidalgo-Barquero MV, Morales-Gabardino JA, Buitrago F. Chronic kidney disease prevalence and cardiovascular risk in a cohort of patients with type 2 diabetes followed for 10 years in Badajoz (Spain). An observational study. Prim Care Diabetes 2021; 15:391-396. [PMID: 33323354 DOI: 10.1016/j.pcd.2020.11.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 11/20/2020] [Accepted: 11/28/2020] [Indexed: 01/10/2023]
Abstract
AIMS To estimate the prevalence of chronic kidney disease (CKD), their risk factors the incidence of cardiovascular and coronary events and total and cardiovascular mortality in a cohort of type 2 diabetes (T2DM) patients observed for 10 years in primary care practices in Badajoz, Spain. METHODS Observational, longitudinal study. A total of 643 patients with T2DM (mean age 64.0 years, 55.7% women), without evidence of cardiovascular disease, were studied. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 at the beginning of the study, by applying the simplified Modification of Diet in Renal Disease (MDRD) Study formula. RESULTS The prevalence rate of CKD was 24.3%. Patients with CKD had higher percentages of coronary, cerebrovascular and cardiovascular events and higher rates of cardiovascular mortality (18.6 vs. 6.0%, p < 0.001) and total mortality (42.3 vs. 23.4%, p < 0.01), compared to patients without CKD. The Cox proportional hazards model, adjusted for age, systolic blood pressure levels, glycated haemoglobin, total cholesterol, obesity and smoking, revealed that patients with CKD had an increased risk of coronary events (HR:2.18; 95% CI:1.13-4.22, p < 0.05). CONCLUSIONS Our study confirms a high prevalence of CKD in patients with T2DM and its relationship with the presence of cardiovascular disease.
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Affiliation(s)
| | | | | | - Francisco Buitrago
- Centro de Salud Universitario "La Paz", Unidad Docente de Medicina Familiar y Comunitaria, Servicio Extremeño de Salud, Badajoz, Facultad de Medicina, Universidad de Extremadura, Spain.
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Bae J, Won YJ, Lee BW. Non-Albumin Proteinuria (NAP) as a Complementary Marker for Diabetic Kidney Disease (DKD). Life (Basel) 2021; 11:life11030224. [PMID: 33802211 PMCID: PMC7998887 DOI: 10.3390/life11030224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/06/2021] [Accepted: 03/06/2021] [Indexed: 11/16/2022] Open
Abstract
Diabetic kidney disease (DKD) is one of the most common forms of chronic kidney disease. Its pathogenic mechanism is complex, and it can affect entire structures of the kidney. However, conventional approaches to early stage DKD have focused on changes to the glomerulus. Current standard screening tools for DKD, albuminuria, and estimated glomerular filtration rate are insufficient to reflect early tubular injury. Therefore, many tubular biomarkers have been suggested. Non-albumin proteinuria (NAP) contains a wide range of tubular biomarkers and is convenient to measure. We reviewed the clinical meanings of NAP and its significance as a marker for early stage DKD.
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Affiliation(s)
- Jaehyun Bae
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary’s Hospital, Incheon KS006, Korea; (J.B.); (Y.J.W.)
| | - Young Jun Won
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary’s Hospital, Incheon KS006, Korea; (J.B.); (Y.J.W.)
| | - Byung-Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul KS013, Korea
- Correspondence:
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Akpınar K, Aslan D, Fenkçi SM. Assessment of estimated glomerular filtration rate based on cystatin C in diabetic nephropathy. J Bras Nefrol 2021; 43:340-348. [PMID: 33599678 PMCID: PMC8428651 DOI: 10.1590/2175-8239-jbn-2020-0145] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 12/07/2020] [Indexed: 01/08/2023] Open
Abstract
Introduction: GFR is estimated by using creatinine and cystatin C to determine renal
dysfunction. Our aim was to evaluate estimated GFR (eGFR) based on cystatin
C in type 2 diabetic patients with diabetic nephropathy (DN). Methods: Study group included 52 controls (46% male, age: 54.5±12.4) and 101 diabetic
patients (46.5% male, age: 58.2±11). The diabetics were divided into three
subgroups according to 24-hour urine albumin: normal to mildly increased
(A1) (n=51), moderately increased (A2) (n=25), severely increased (A3)
(n=25) albuminuria. Creatinine clearance (CrCl) was determined. Correlations
between CrCl and eGFRs estimated according to the CKD-EPI, MDRD, and
Cockcroft-Gault (CG) formulas, and ROC curves were evaluated. Data were
analyzed using SPSS 22.0. Results: Only CKD-EPI-cys eGFR was significantly lower in the A1 group than the
controls (p=0.021). All GFRs were lower in the A3 group than the control
(CKD-EPI-cr, MDRD, CKD-EPI-cys, CKD-EPI-cr-cys: p=0.0001, CG and CrCl:
p=0.001) and A1 (for all GFRs p=0.0001) groups. CKD-EPI-cr (p=0.004), MDRD
(p=0.01), CG (p=0.037), CKD-EPI-cys (p=0.033), and CKD-EPI-cr-cys (p=0.016)
eGFRs in the A2 group were significantly different from the A1 group. All
eGFRs showed a moderate correlation with CrCl in the A1group (CKD-EPI-cr and
CKD-EPI-cr-cys: r=0.49, p=0.0001, MDRD: r=0.44, p=0.001, CG r=0.48,
p=0.0001: CKD-EPI-cys r=0.40, p=0.004). The area under the CKD-EPI-cys ROC
curve was the highest and found to be 0.847 (95%CI 0.763-0.931,
p=0.0001). Conclusions: Our results showed that the CKD-EPI-cys eGFR can be useful in detecting the
early stage of DN and more predictive than the others for prediction of
DN.
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Affiliation(s)
- Kadriye Akpınar
- Pamukkale University, Faculty of Medicine, Department of Medical Biochemistry, Denizli, Turkey
| | - Diler Aslan
- Pamukkale University, Faculty of Medicine, Department of Medical Biochemistry, Denizli, Turkey
| | - Semin Melahat Fenkçi
- Pamukkale University, Faculty of Medicine, Division of Endocrinology and Metabolism, Department of Internal Medicine, Denizli, Turkey
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Abstract
The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Duan S, Lu F, Song D, Zhang C, Zhang B, Xing C, Yuan Y. Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease. Front Endocrinol (Lausanne) 2021; 12:661185. [PMID: 34177803 PMCID: PMC8223745 DOI: 10.3389/fendo.2021.661185] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 05/21/2021] [Indexed: 12/29/2022] Open
Abstract
Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening, diagnosis, and prognosis, as well as novel hypoglycemia agents in clinical trials, thereby rendering more attention focused on the role of renal tubules in DKD. Previous studies have demonstrated that morphological and functional changes in renal tubules are highly involved in the occurrence and development of DKD. Novel tubular biomarkers have shown some clinical importance. However, there are many challenges to transition into personalized diagnosis and guidance for individual therapy in clinical practice. Large-scale clinical trials suggested the clinical relevance of increased proximal reabsorption and hyperfiltration by sodium-glucose cotransporter-2 (SGLT2) to improve renal outcomes in patients with diabetes, further promoting the emergence of renal tubulocentric research. Therefore, this review summarized the recent progress in the pathophysiology associated with involved mechanisms of renal tubules, potential tubular biomarkers with clinical application, and renal tubular factors in DKD management. The mechanism of kidney protection and impressive results from clinical trials of SGLT2 inhibitors were summarized and discussed, offering a comprehensive update on therapeutic strategies targeting renal tubules.
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Chang DY, Li MR, Yu XJ, Wang SX, Chen M, Zhao MH. Clinical and Pathological Characteristics of Patients With Nonproteinuric Diabetic Nephropathy. Front Endocrinol (Lausanne) 2021; 12:761386. [PMID: 34764941 PMCID: PMC8576342 DOI: 10.3389/fendo.2021.761386] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/07/2021] [Indexed: 01/02/2023] Open
Abstract
INTRODUCTION As the most common complication of diabetes mellitus (DM), diabetic nephropathy (DN) was initially considered to begin with proteinuria preceding the progression of renal insufficiency. This clinical paradigm has been questioned in the late decades, as many DM patients without proteinuria have progressive renal insufficiency. However, the characteristics of nonproteinuric DN were not fully clear yet. PATIENTS AND METHODS A total of 390 patients with renal biopsy-proven DN in our center were retrospectively recruited in the current study. Clinical and histopathological data of the patients were analyzed. We used propensity score-matching methods to address the imbalance of age, sex, and diabetes duration for comparative analyses. RESULTS Among all the renal biopsy-proven DN patients with renal biopsy proven DN, 18 patients were classified as nonproteinuric DN. Compared with 36 propensity score-matched proteinuric DN patients, diabetic retinopathy (DR) was less frequent in nonproteinuric DN patients (38.9% vs. 66.4%, p<0.05). During the follow-up of 24.0 (12.0-42.0) months, the probability of developing the end-stage renal disease (ESRD) was significantly lower in nonproteinuric DN patients than in proteinuric ones in both the propensity score-matched cohort and overall cohort (log-rank test, p<0.001 and p<0.001, respectively). CONCLUSIONS Compared with proteinuric DN patients, DR was less frequent in nonproteinuric DN patients. Nonproteinuric DN patients had better renal outcomes than proteinuric DN patients.
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Affiliation(s)
- Dong-Yuan Chang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Meng-Rui Li
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao-Juan Yu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Su-Xia Wang
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Min Chen
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
- *Correspondence: Min Chen,
| | - Ming-Hui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-Mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
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Evans M, Morgan AR, Patel D, Dhatariya K, Greenwood S, Newland-Jones P, Hicks D, Yousef Z, Moore J, Kelly B, Davies S, Dashora U. Risk Prediction of the Diabetes Missing Million: Identifying Individuals at High Risk of Diabetes and Related Complications. Diabetes Ther 2021; 12:87-105. [PMID: 33190216 PMCID: PMC7843706 DOI: 10.1007/s13300-020-00963-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 10/28/2020] [Indexed: 01/08/2023] Open
Abstract
Early diagnosis and effective management of type 2 diabetes (T2D) are crucial in reducing the risk of developing life-changing complications such as heart failure, stroke, kidney disease, blindness and amputation, which are also associated with significant costs for healthcare providers. However, as T2D symptoms often develop slowly it is not uncommon for people to live with T2D for years without being aware of their condition-commonly known as the undiagnosed missing million. By the time a diagnosis is received, many individuals will have already developed serious complications. While the existence of undiagnosed diabetes has long been recognised, wide-reaching awareness among the general public, clinicians and policymakers is lacking, and there is uncertainty in how best to identify high-risk individuals. In this article we have used consensus expert opinion alongside the available evidence, to provide support for the diabetes healthcare community regarding risk prediction of the missing million. Its purpose is to provide awareness of the risk factors for identifying individuals at high, moderate and low risk of T2D and T2D-related complications. The awareness of risk predictors, particularly in primary care, is important, so that appropriate steps can be taken to reduce the clinical and economic burden of T2D and its complications.
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Affiliation(s)
- Marc Evans
- Diabetes Resource Centre, University Hospital Llandough, Cardiff, UK.
| | | | - Dipesh Patel
- Department of Diabetes, Division of Medicine, University College London, Royal Free NHS Trust, London, UK
| | - Ketan Dhatariya
- Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, Norwich, UK
| | - Sharlene Greenwood
- Renal Medicine, King's College Hospital, London, UK
- Renal Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
| | | | | | - Zaheer Yousef
- Wales Heart Research Institute, Cardiff University, Cardiff, UK
| | - Jim Moore
- Stoke Road Surgery, Bishop's Cleeve, Cheltenham, UK
| | | | | | - Umesh Dashora
- East Sussex Healthcare NHS Trust, St Leonards-on-Sea, UK
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Kleinaki Z, Kapnisi S, Theodorelou-Charitou SA, Nikas IP, Paschou SA. Type 2 diabetes mellitus management in patients with chronic kidney disease: an update. Hormones (Athens) 2020; 19:467-476. [PMID: 32500461 DOI: 10.1007/s42000-020-00212-y] [Citation(s) in RCA: 3] [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: 02/23/2020] [Accepted: 05/14/2020] [Indexed: 02/07/2023]
Abstract
Diabetes mellitus (DM) is a chronic multisystem disease. Diabetic nephropathy (DN) is one of its significant microvascular complications, associated with increased morbidity and mortality. The aim of this article is to review the literature regarding the latest advances in the management of type 2 DM (T2DM) in patients with chronic kidney disease (CKD). We initially refer to the screening guidelines, the diagnostic tests used, the need for novel biomarkers in DN, the recent advances in high-risk patient identification, the recommended glycemic targets, and concerns regarding the accuracy of HbA1c in these patients. Then, a detailed explanation of the appropriate medical management based on evidence from recent trials is presented, analyzed, and discussed. All patients with T2DM should be screened for albuminuria at initial diagnosis and annually thereafter. Proteomics and metabolomics today represent promising diagnostic tools. Optimal glycemic control, with individualized HbA1c targets, is fundamental for reduced onset or delayed progression of DN and microvascular complications, in general. This can be enhanced by lifestyle modifications and pharmacological interventions when needed. Metformin represents the first pharmacological step, with, recently, a broadened indication for patients with impaired renal function. If HbA1c remains above the target in patients with established CKD, SGLT2i or GLP-1 RA are the preferred second-line agents, as introduced in all new guidelines. This change was the result of recent landmark trials that highlighted the superiority of the two aforementioned medication categories in terms of both renal and cardiovascular outcomes.
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Affiliation(s)
- Zoi Kleinaki
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Stella Kapnisi
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | | | - Ilias P Nikas
- School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Stavroula A Paschou
- School of Medicine, European University Cyprus, Nicosia, Cyprus.
- Division of Endocrinology and Diabetes, "Aghia Sophia" Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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Xue P, Covassin N, Ran X, Zhou J, Zhang X, Yan D, Li X, Gao Y, Tang X. Association of parameters of nocturnal hypoxemia with diabetic microvascular complications: A cross-sectional study. Diabetes Res Clin Pract 2020; 170:108484. [PMID: 33031843 DOI: 10.1016/j.diabres.2020.108484] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 07/28/2020] [Accepted: 09/25/2020] [Indexed: 02/08/2023]
Abstract
AIMS To examine the association between obstructive sleep apnea (OSA)-related nocturnal hypoxemia parameters and diabetic microvascular complications in patients with type 2 diabetes mellitus (T2DM). METHODS A total of 463 Chinese patients with T2DM underwent overnight polysomnography, followed by diagnosis of diabetic microvascular complications including diabetic peripheral neuropathy (DPN), diabetic retinopathy (DR) and diabetic nephropathy (DN). Parameters of nocturnal hypoxemia, including apnea-hypopnea index (AHI), oxygen desaturation index (ODI), time spent with SpO2 < 90% (T90%) or <85% (T85%), mean SpO2 and lowest SpO2, were recorded. RESULTS AHI was independently associated with higher odds of DPN (OR 1.19; 95% CI, 1.05-1.36; P = 0.008) after adjustment for possible confounders. Moreover, patients with severe OSA (AHI ≥ 30 events/h) had higher likelihood of having DPN than those with mild OSA (OR 2.36; 95% CI, 1.31-4.25; P = 0.004). When combining DPN, DR and DN into an overall diabetic microvascular complication index, AHI was also independently associated with higher odds of having any diabetic microvascular complication (OR 1.21; 95% CI, 1.06-1.38; P = 0.006). CONCLUSIONS The AHI may be the OSA-related index that most strongly reflects the association of OSA and diabetic microvascular complications, compared with other OSA-related hypoxemia parameters.
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Affiliation(s)
- Pei Xue
- Sleep Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Naima Covassin
- Department of Cardiovascular Medicine, Mayo Clinic College of Medicine, Rochester, USA.
| | - Xingwu Ran
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Junying Zhou
- Sleep Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaohan Zhang
- Johns Hopkins University School of Medicine, Baltimore, USA
| | - Donge Yan
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiao Li
- Sleep Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yun Gao
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Xiangdong Tang
- Sleep Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Yu Y, Lin Q, Ye D, Wang Y, He B, Li Y, Huang G, Zhou Z, Xiao Y. Neutrophil count as a reliable marker for diabetic kidney disease in autoimmune diabetes. BMC Endocr Disord 2020; 20:158. [PMID: 33092580 PMCID: PMC7580021 DOI: 10.1186/s12902-020-00597-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 07/15/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND A growing body of evidence supports neutrophils as having an active role in the development of diabetic kidney disease (DKD). However, the clinical relevance of neutrophils and DKD in autoimmune diabetes remains unknown. This study aimed to investigate the relationship between circulating neutrophils and DKD in autoimmune diabetes. METHODS Patients with type 1 diabetes (T1D, n = 226) and latent autoimmune diabetes in adults (LADA, n = 79) were enrolled and stratified according to the urinary albumin to creatinine ratio (ACR). Circulating levels of white blood cells (WBCs), including neutrophils, were measured in a central laboratory, and the neutrophil-to-lymphocyte ratio (NLR) was calculated. The risk factors associated with DKD were analysed by logistic regression. RESULTS In T1D and LADA patients, the peripheral neutrophil counts increased in parallel with DKD advancement. The neutrophil counts in the patients with macroalbuminuria were significantly higher than those in the patients with normoalbuminuria for each type of diabetes. Furthermore, neutrophil counts positively correlated with ACR in T1D. In addition, neutrophils were independently associated with DKD in T1D in the logistic regression analysis, when various well-known risk factors, including age, gender, disease duration, hypertension, dyslipidemia and smoking status, were adjusted. CONCLUSIONS Neutrophil counts are closely associated with DKD in patients with autoimmune diabetes, suggesting that neutrophil-mediated inflammation may be involved in the pathogenesis of DKD in patients with autoimmune diabetes.
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Affiliation(s)
- Yao Yu
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Qiuqiu Lin
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Dewei Ye
- Joint Laboratory between Guangdong and Hong Kong on Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yanfei Wang
- Department of Endocrinology, The First People's Hospital of Foshan, Foshan, Guangdong, China
| | - Binbin He
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Yanhua Li
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Gan Huang
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Yang Xiao
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, 139 Renmin Road, Changsha, 410011, Hunan, China.
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China.
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