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Evin F, Kırkgöz T, Atik T, Ak G, Köse T, Kabasakal C, Özkan B, Özen S, Darcan Ş, Gökşen D. "Predicting diabetic kidney disease in youth with type 1 diabetes: Insights from genetic risk assessment". J Diabetes Complications 2024; 38:108833. [PMID: 39293150 DOI: 10.1016/j.jdiacomp.2024.108833] [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: 04/19/2024] [Revised: 08/05/2024] [Accepted: 08/05/2024] [Indexed: 09/20/2024]
Abstract
OBJECTIVE Diabetic kidney disease (DKD) is influenced by multiple factors, yet its precise progression mechanisms remain largely unclear. This study aimed to create a clinical risk-scoring system based on genetic polymorphisms in the AFF3, CARS, CERS2, ERBB4, GLRA3, RAET1L, TMPO, and ZMIZ1 genes. METHODS The study included a DKD group diagnosed with diabetic kidney disease before age 18 and a WDC group matched by age, gender, and age at diabetes diagnosis. Genetic data and clinical data from diabetes diagnosis to moderately increased albuminuria (MIA) detection were compared between the groups. RESULTS Among 43 DKD cases, 22 were girls and 21 were boys. At MIA diagnosis, mean body weight SDS was -0.24 ± 0.94, height SDS was 0.34 ± 1.15, and BMI SDS was -0.26 ± 0.94. Systolic blood pressure was at the 72nd percentile (2-99), and diastolic blood pressure was at the 74th percentile (33-99). Significant differences in rs267734, rs267738, and rs942263 polymorphisms were found between DKD and non-complication diabetic groups (13[30.2 %] vs 5[11.6 %], p = 0.034; 14[32.6 %] vs 5[11.6 %], p = 0.019; 26[60.5 %] vs 40[93 %], p < 0.001). CONCLUSION Several factors were identified as significant in DKD onset, including low follow-up weight SDS, elevated diastolic blood pressure, presence of rs267734, and absence of rs942263 polymorphisms. The model demonstrated a specificity of 81.4 % and a sensitivity of 74.4 %.
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Affiliation(s)
- Ferda Evin
- Division of Pediatric Endocrinology, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey.
| | - Tarık Kırkgöz
- Division of Pediatric Endocrinology, Department of Pediatrics, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
| | - Tahir Atik
- Division of Pediatric Genetics, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey
| | - Güneş Ak
- Department of Biochemistry, School of Medicine, Ege University, Izmir, Turkey
| | - Timur Köse
- Department of Biostatistics and Medical Informatics, School of Medicine, Ege University, Izmir, Turkey
| | - Caner Kabasakal
- Division of Pediatric Nephrology, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey
| | - Behzat Özkan
- Division of Pediatric Endocrinology, Department of Pediatrics, Dr. Behçet Uz Children's Education and Research Hospital, Izmir, Turkey
| | - Samim Özen
- Division of Pediatric Endocrinology, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey
| | - Şükran Darcan
- Division of Pediatric Endocrinology, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey
| | - Damla Gökşen
- Division of Pediatric Endocrinology, Department of Pediatrics, School of Medicine, Ege University, Izmir, Turkey
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Shafqat A, Abdul Rab S, Ammar O, Al Salameh S, Alkhudairi A, Kashir J, Alkattan K, Yaqinuddin A. Emerging role of neutrophil extracellular traps in the complications of diabetes mellitus. Front Med (Lausanne) 2022; 9:995993. [PMID: 36082273 PMCID: PMC9445264 DOI: 10.3389/fmed.2022.995993] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 08/05/2022] [Indexed: 11/13/2022] Open
Abstract
Immune dysfunction is widely regarded as one of the central tenants underpinning the pathophysiology of diabetes mellitus (DM) and its complications. When discussing immunity, the role of neutrophils must be accounted for: neutrophils are the most abundant of the circulating immune cells and are the first to be recruited to sites of inflammation, where they contribute to host defense via phagocytosis, degranulation, and extrusion of neutrophil extracellular traps (NETs). NETs are composed of DNA associated with nuclear and cytosolic neutrophil proteins. Although originally reported as an antimicrobial strategy to prevent microbial dissemination, a growing body of evidence has implicated NETs in the pathophysiology of various autoimmune and metabolic disorders. In these disorders, NETs propagate a pathologic inflammatory response with consequent tissue injury and thrombosis. Many diabetic complications—such as stroke, retinopathy, impaired wound healing, and coronary artery disease—involve these mechanisms. Therefore, in this review, we discuss laboratory and clinical data informing our understanding of the role of NETs in the development of these complications. NET markers, including myeloperoxidase, citrullinated histone H3, neutrophil elastase, and cell-free double-stranded DNA, can easily be measured in serum or be detected via immunohistochemical/immunocytochemical staining of tissue specimens. Therefore, NET constituents potentially constitute reliable biomarkers for use in the management of diabetic patients. However, no NET-targeting drug is currently approved for the treatment of diabetic complications; a candidate drug will require the outcomes of well-designed, robust clinical trials assessing whether NET inhibition can benefit patients in terms of morbidity, quality of life, health expenditures, and mortality. Therefore, much work remains to be done in translating these encouraging pieces of data into clinical trials for NET-targeting medications to be used in the clinic.
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Affiliation(s)
- Areez Shafqat
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- *Correspondence: Areez Shafqat
| | | | - Osama Ammar
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | | | - Anas Alkhudairi
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Junaid Kashir
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- Center of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Khaled Alkattan
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
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Wang Y, Feng F, He W, Sun L, He Q, Jin J. miR-188-3p abolishes germacrone-mediated podocyte protection in a mouse model of diabetic nephropathy in type I diabetes through triggering mitochondrial injury. Bioengineered 2022; 13:774-788. [PMID: 34847832 PMCID: PMC8805940 DOI: 10.1080/21655979.2021.2012919] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 11/27/2021] [Indexed: 12/17/2022] Open
Abstract
Mitochondrial injury-triggered podocyte apoptosis is a major risk factor for diabetic nephropathy (DN). However, the detailed relationship between mitochondrial homeostasis and podocyte apoptosis remains unclear. The present study aimed to explore the role and functional mechanism of germacrone in DN in type I diabetes (type I DN). A mouse model of type I DN was established by injecting streptozocin, and a podocyte injury model was constructed using high glucose (HG) induction. Histopathology was detected by hematoxylin and eosin and periodic acid-Schiff staining. Transmission electron microscopy and flow cytometry were used to evaluate the mitochondrial function. Germacrone simultaneously reduced blood glucose, 24 h proteinuria, and other nephrotic symptoms in a type 1 DN mouse model. Moreover, germacrone protected against mitochondrial damage, limited reactive oxygen species (ROS) accumulation, and restored glutathione peroxidase (GPX) activity and GPX4 protein expression, subsequently preventing podocyte apoptosis. Mechanistically, the increased miR-188-3p expression in type I DN mice was reversed in germacrone-challenged DN mice. HG induced miR-188-3p expression and the miR-188-3p antagonist abolished the HG-mediated increase in ROS. Notably, miR-188-3p was found to have a therapeutic effect against DN by aggravating mitochondrial damage and podocyte apoptosis. Germacrone alleviates DN progression in type I diabetes by limiting podocyte apoptosis, which was partly counteracted by miR-188-3p upregulation. The combination of germacrone and miR-188-3p antagonists is expected to be an effective therapeutic strategy for DN.Abbreviations DN: diabetic nephropathy; Type I DN: DN in Type I diabetes; STZ: streptozocin; ROS: reactive oxygen species; NcRNAs: non-coding RNAs; UTR: untranslated regions; NC: negative control; BUN: blood urea nitrogen; BUA: blood uric acid; Ucr: urine creatinine; Scr: serum creatinine; PAS: Periodic Acid-Schiff; IF: Immunofluorescence; FISH: Fluorescence in situ hybridization; TUG1: taurine upregulated gene 1; GPX: Glutathione Peroxidase; GPX4: glutathione peroxidase 4; EMT: epithelial-mesenchymal transition.
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Affiliation(s)
- Yunguang Wang
- Department of Critical Care Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Fangfang Feng
- Department of Critical Care Medicine, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China
| | - Wenfang He
- Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, P.R China
| | - Lifang Sun
- Department of Tuberculosis, Hangzhou Red Cross Hospital, Hangzhou, P.R China
- Department of Tuberculosis, Affiliated Hangzhou Chest Hospital, Zhejiang University School of Medicine, Hangzhou, P.R China
| | - Qiang He
- Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, P.R China
| | - Juan Jin
- Department of Nephrology, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, P.R China
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Hall R, Keeble L, Sünram-Lea SI, To M. A review of risk factors associated with insulin omission for weight loss in type 1 diabetes. Clin Child Psychol Psychiatry 2021; 26:606-616. [PMID: 34121470 PMCID: PMC8264633 DOI: 10.1177/13591045211026142] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Research suggests that as many as 60% of people with type 1 diabetes (T1D) admit to misusing insulin. Insulin omission (IO) for the purpose of weight loss, often referred to as diabulimia, is a behaviour becoming increasingly recognised, not least since prolonged engagement can lead to serious vascular complications and mortality. Several risk factors appear to be relevant to the development of IO, most notably gender, anxiety and depression and increased weight concerns and body dissatisfaction. Evidence suggests that women, especially young girls, are more likely to omit insulin as a method of weight loss compared to men. Mental health conditions such as anxiety and depression are increasingly prevalent in people with T1D compared to their peers, and appear to contribute to the risk of IO. Increased weight concerns and body dissatisfaction are further prominent risk factors, especially given increases in weight which often occur following diagnosis and the monitoring of weight by diabetes teams. This review presents evidence examining these risk factors which increase the likelihood of a person with T1D engaging in IO and highlights the complications associated with prolongment of the behaviour. Further research looking at the comorbidities of these risk factors, alongside other factors, would provide greater insight into understanding IO in people with T1D.
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Affiliation(s)
- Rebecca Hall
- Department of Psychology, 4396Lancaster University, Lancaster, UK
| | - Leanna Keeble
- Department of Psychology, 4396Lancaster University, Lancaster, UK
| | | | - Michelle To
- Department of Psychology, 4396Lancaster University, Lancaster, UK
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Early Detection of Diabetic Peripheral Neuropathy: A Focus on Small Nerve Fibres. Diagnostics (Basel) 2021; 11:diagnostics11020165. [PMID: 33498918 PMCID: PMC7911433 DOI: 10.3390/diagnostics11020165] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 01/14/2021] [Accepted: 01/20/2021] [Indexed: 02/07/2023] Open
Abstract
Diabetic peripheral neuropathy (DPN) is the most common complication of both type 1 and 2 diabetes. As a result, neuropathic pain, diabetic foot ulcers and lower-limb amputations impact drastically on quality of life, contributing to the individual, societal, financial and healthcare burden of diabetes. DPN is diagnosed at a late, often pre-ulcerative stage due to a lack of early systematic screening and the endorsement of monofilament testing which identifies advanced neuropathy only. Compared to the success of the diabetic eye and kidney screening programmes there is clearly an unmet need for an objective reliable biomarker for the detection of early DPN. This article critically appraises research and clinical methods for the diagnosis or screening of early DPN. In brief, functional measures are subjective and are difficult to implement due to technical complexity. Moreover, skin biopsy is invasive, expensive and lacks diagnostic laboratory capacity. Indeed, point-of-care nerve conduction tests are convenient and easy to implement however questions are raised regarding their suitability for use in screening due to the lack of small nerve fibre evaluation. Corneal confocal microscopy (CCM) is a rapid, non-invasive, and reproducible technique to quantify small nerve fibre damage and repair which can be conducted alongside retinopathy screening. CCM identifies early sub-clinical DPN, predicts the development and allows staging of DPN severity. Automated quantification of CCM with AI has enabled enhanced unbiased quantification of small nerve fibres and potentially early diagnosis of DPN. Improved screening tools will prevent and reduce the burden of foot ulceration and amputations with the primary aim of reducing the prevalence of this common microvascular complication.
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Long B, Wan Y, Zhang S, Lv L. LncRNA XIST protects podocyte from high glucose-induced cell injury in diabetic nephropathy by sponging miR-30 and regulating AVEN expression. Arch Physiol Biochem 2020; 129:610-617. [PMID: 33332155 DOI: 10.1080/13813455.2020.1854307] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Diabetic nephropathy (DN) is one of the most important complications of diabetes mellitus. Thus, it is urgent to develop a novel diagnosis or therapeutic strategy that could suspend DN progression. Moreover, there is increasing evidence demonstrating that long non-coding RNA (lncRNA) acts as critical players in regulating autophagy and are involved in DN. We demonstrated that lncRNA X-inactive specific transcript (XIST) was downregulated in high glucose (HG) treated podocytes, accompanied by increased apoptosis of podocytes. Overexpression of XIST significantly reduced the apoptosis and promoted the number of viable cells of podocyte under HG treatment. Prediction by Targets can and dual-luciferase reporter assay revealed the interaction between miR-30 and XIST and AVEN. Further WB (Western Blot), MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), and flow cytometry confirmed that XIST could reverse the expression of AVEN and ameliorate HG-induced apoptosis. In conclusion, our research revealed that XIST plays a protective effect on podocyte injury induced by HG through miR-30/AVEN axis.
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Affiliation(s)
- Bendan Long
- Department of Endocrinology, People's Hospital, Guiyang, PR China
| | - Yun Wan
- Department of Endocrinology, People's Hospital, Guiyang, PR China
| | - Siqin Zhang
- Department of Endocrinology, People's Hospital, Guiyang, PR China
| | - Lisa Lv
- Department of Endocrinology, People's Hospital, Guiyang, PR China
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Dong W, Zhao Y, Liu D, Liu Y, Li F, Li M. Sex-specific association between type 1 diabetes and the risk of end-stage renal disease: a systematic review and meta-analysis. Endocrine 2020; 69:30-38. [PMID: 32166584 DOI: 10.1007/s12020-020-02255-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 03/03/2020] [Indexed: 12/17/2022]
Abstract
PURPOSE This meta-analysis was conducted given the inconsistent findings of studies regarding the sex discrepancy in the relationship between type 1 diabetes (T1D) and the risk of end-stage renal disease (ESRD). METHODS Articles published on PubMed between January 1, 1966 and March 31, 2019 were systematically retrieved without language restrictions. The included articles all presented sex-specific data of the incidence rate ratio, standardized incidence or mortality ratio, hazard ratio, relative risk, or odds ratio, or provided data to estimate the association between T1D and ESRD or kidney disease-related mortality. The gender-specific effect estimates and pooled ratio (female-to-male) for ESRD and for deaths from T1D-related renal disease were acquired via a random-effects meta-analysis with inverse variance weighting, regardless of heterogeneity evaluated based on the I2 statistic. RESULTS Nineteen studies, including 122,842 individuals, were finally selected for this meta-analysis. Sex differences in effect estimates were found in ESRD (pooled ratio = 0.81 (95% confidence interval 0.69-0.94)) with considerable heterogeneity (I2 = 66.9%), but not in mortality with T1D-associated renal disease. CONCLUSION Women with T1D have a lower risk of ESRD compared with that in men, but this finding may be biased by potential confounding factors and must be verified by other well-planned prospective studies.
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Affiliation(s)
- Wei Dong
- Department of Endocrine and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Yue Zhao
- Department of Endocrine and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Dandan Liu
- Center of Physical Examination, The First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Yandi Liu
- Department of Endocrine and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, PR China
| | - Fei Li
- Department of Endocrine and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, PR China.
| | - Mei Li
- Department of Endocrine and Metabolism, The First Hospital of Jilin University, Changchun, Jilin, PR China.
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Giralt-López A, Molina-Van den Bosch M, Vergara A, García-Carro C, Seron D, Jacobs-Cachá C, Soler MJ. Revisiting Experimental Models of Diabetic Nephropathy. Int J Mol Sci 2020; 21:ijms21103587. [PMID: 32438732 PMCID: PMC7278948 DOI: 10.3390/ijms21103587] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Revised: 05/12/2020] [Accepted: 05/13/2020] [Indexed: 12/12/2022] Open
Abstract
Diabetes prevalence is constantly increasing and, nowadays, it affects more than 350 million people worldwide. Therefore, the prevalence of diabetic nephropathy (DN) has also increased, becoming the main cause of end-stage renal disease (ESRD) in the developed world. DN is characterized by albuminuria, a decline in glomerular filtration rate (GFR), hypertension, mesangial matrix expansion, glomerular basement membrane thickening, and tubulointerstitial fibrosis. The therapeutic advances in the last years have been able to modify and delay the natural course of diabetic kidney disease (DKD). Nevertheless, there is still an urgent need to characterize the pathways that are involved in DN, identify risk biomarkers and prevent kidney failure in diabetic patients. Rodent models provide valuable information regarding how DN is set and its progression through time. Despite the utility of these models, kidney disease progression depends on the diabetes induction method and susceptibility to diabetes of each experimental strain. The classical DN murine models (Streptozotocin-induced, Akita, or obese type 2 models) do not develop all of the typical DN features. For this reason, many models have been crossed to a susceptible genetic background. Knockout and transgenic strains have also been created to generate more robust models. In this review, we will focus on the description of the new DN rodent models and, additionally, we will provide an overview of the available methods for renal phenotyping.
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Affiliation(s)
- Anna Giralt-López
- Nephrology Research Group, Vall d’Hebrón Institut de Recerca, 08035 Barcelona, Spain; (A.G.-L.); (M.M.-V.d.B.); (A.V.); (C.G.-C.); (D.S.)
| | - Mireia Molina-Van den Bosch
- Nephrology Research Group, Vall d’Hebrón Institut de Recerca, 08035 Barcelona, Spain; (A.G.-L.); (M.M.-V.d.B.); (A.V.); (C.G.-C.); (D.S.)
| | - Ander Vergara
- Nephrology Research Group, Vall d’Hebrón Institut de Recerca, 08035 Barcelona, Spain; (A.G.-L.); (M.M.-V.d.B.); (A.V.); (C.G.-C.); (D.S.)
- Nephrology Department, Vall d’Hebrón Hospital, 08035 Barcelona, Spain
| | - Clara García-Carro
- Nephrology Research Group, Vall d’Hebrón Institut de Recerca, 08035 Barcelona, Spain; (A.G.-L.); (M.M.-V.d.B.); (A.V.); (C.G.-C.); (D.S.)
- Nephrology Department, Vall d’Hebrón Hospital, 08035 Barcelona, Spain
| | - Daniel Seron
- Nephrology Research Group, Vall d’Hebrón Institut de Recerca, 08035 Barcelona, Spain; (A.G.-L.); (M.M.-V.d.B.); (A.V.); (C.G.-C.); (D.S.)
- Nephrology Department, Vall d’Hebrón Hospital, 08035 Barcelona, Spain
| | - Conxita Jacobs-Cachá
- Nephrology Research Group, Vall d’Hebrón Institut de Recerca, 08035 Barcelona, Spain; (A.G.-L.); (M.M.-V.d.B.); (A.V.); (C.G.-C.); (D.S.)
- Correspondence: (C.J.-C.); (M.J.S.)
| | - Maria José Soler
- Nephrology Research Group, Vall d’Hebrón Institut de Recerca, 08035 Barcelona, Spain; (A.G.-L.); (M.M.-V.d.B.); (A.V.); (C.G.-C.); (D.S.)
- Nephrology Department, Vall d’Hebrón Hospital, 08035 Barcelona, Spain
- Correspondence: (C.J.-C.); (M.J.S.)
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Sekercioglu N, Lovblom LE, Bjornstad P, Lovshin JA, Lytvyn Y, Boulet G, Farooqi MA, Orszag A, Lai V, Tse J, Cham L, Keenan HA, Brent MH, Paul N, Bril V, Perkins BA, Cherney DZI. Risk factors for diabetic kidney disease in adults with longstanding type 1 diabetes: results from the Canadian Study of Longevity in Diabetes. Ren Fail 2020; 41:427-433. [PMID: 31162987 PMCID: PMC6566893 DOI: 10.1080/0886022x.2019.1614057] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objectives: Diabetic kidney disease (DKD) is an independent predictor of cardiovascular morbidity and mortality in type 1 diabetes (T1D). We aimed to explore clinical and biochemical factors, including the achievement of American Diabetes Association (ADA) recommended targets associated with DKD in people living with T1D for ≥50 years. Methods: This was a post hoc analysis of a cross-sectional study of 75 participants enrolled in the Canadian Study of Longevity in T1D. We explored diabetes-related complications, including neuropathy, retinopathy, cardiovascular disease, and DKD. Study participants were dichotomized based on the achievement of ADA recommended targets as the low-target group (achieving ≤4 targets, n = 31) and high-target group (achieving >4 targets, n = 44). The outcome of interest was DKD defined by estimated glomerular filtration rate (eGFR) values <60/mL/min/1.73 m2 and/or 24-h albumin excretion >30 mg. Multivariable logistic regression models were employed to estimate odds ratios (ORs) for DKD with 95% confidence intervals (CIs). Results: Of the 75 participants with prolonged T1D duration (45% male, mean age 66 years), 25 participants had DKD and 50 did not. There was no statistical difference between the high- and low-target groups in terms of age and body mass index. eGFR was significantly higher and the prevalence of diabetic retinopathy was significantly lower in the high-target group. Older age at diagnosis of T1D and lower frequency component to high-frequency component ratio increased the odds of having DKD. Conclusions: In adults with prolonged T1D duration, older age at diagnosis and lower heart rate variability may be associated with DKD.
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Affiliation(s)
- Nigar Sekercioglu
- a Department of Medicine, Division of Nephrology , University of Toronto , Toronto , Canada.,b Department of Health Research Methods, Evidence, and Impact , McMaster University , Hamilton , Canada
| | - Leif Erik Lovblom
- c Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto , Canada
| | - Petter Bjornstad
- d Department of Pediatrics, Division of Endocrinology and Department of Medicine, Division of Nephrology , University of Colorado School of Medicine , Aurora , CO , USA
| | - Julie A Lovshin
- e Department of Medicine, Division of Endocrinology and Metabolism , Sunnybrook Health Sciences Centre, University of Toronto , Toronto , Canada
| | - Yuliya Lytvyn
- a Department of Medicine, Division of Nephrology , University of Toronto , Toronto , Canada
| | - Geneviève Boulet
- c Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto , Canada
| | - Mohammed A Farooqi
- c Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto , Canada
| | - Andrej Orszag
- c Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto , Canada
| | - Vesta Lai
- a Department of Medicine, Division of Nephrology , University of Toronto , Toronto , Canada
| | - Josephine Tse
- a Department of Medicine, Division of Nephrology , University of Toronto , Toronto , Canada
| | - Leslie Cham
- a Department of Medicine, Division of Nephrology , University of Toronto , Toronto , Canada
| | - Hillary A Keenan
- f Research Division , Joslin Diabetes Center , Boston , MA , USA
| | - Michael H Brent
- g Department of Ophthalmology and Vision Sciences Faculty of Medicine , University of Toronto , Toronto , Canada
| | - Narinder Paul
- h Joint Department of Medical Imaging, University of Toronto, Toronto, Canada and Department of Medical Imaging , Western University , London , Canada
| | - Vera Bril
- i Department of Medicine, Division of Neurology , University Health Network, University of Toronto , Toronto , Canada
| | - Bruce A Perkins
- c Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto , Canada.,j Department of Medicine, Division of Endocrinology and Metabolism , Mount Sinai Hospital, University of Toronto , Toronto , Canada
| | - David Z I Cherney
- a Department of Medicine, Division of Nephrology , University of Toronto , Toronto , Canada.,k Department of Physiology , University of Toronto , Toronto , Canada.,l Department of Physiology and Banting and Best Diabetes Centre , University of Toronto , Toronto , Canada
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Selvarajah D, Kar D, Khunti K, Davies MJ, Scott AR, Walker J, Tesfaye S. Diabetic peripheral neuropathy: advances in diagnosis and strategies for screening and early intervention. Lancet Diabetes Endocrinol 2019; 7:938-948. [PMID: 31624024 DOI: 10.1016/s2213-8587(19)30081-6] [Citation(s) in RCA: 279] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 01/02/2019] [Accepted: 01/03/2019] [Indexed: 12/13/2022]
Abstract
Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 and 2 diabetes. It is a leading cause of lower-limb amputation and disabling neuropathic pain. Amputations in patients with diabetes have a devastating effect on quality of life and are associated with an alarmingly low life expectancy (on average only 2 years from the amputation). Amputation also places a substantial financial burden on health-care systems and society in general. With the introduction of national diabetes eye screening programmes, the prevalence of blindness in working-age adults is falling. This is not the case, however, with diabetes related amputations. In this Review, we appraise innovative point-of-care devices that enable the early diagnosis of DPN and assess the evidence for early risk factor-based management strategies to reduce the incidence and slow the progression of DPN. We also propose a framework for screening and early multifactorial interventions as the best prospect for preventing or halting DPN and its devastating sequelae.
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Affiliation(s)
- Dinesh Selvarajah
- Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
| | - Debasish Kar
- Derbyshire Community Health Services NHS Foundation Trust, Bakewell, UK; Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Melanie J Davies
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Adrian R Scott
- Academic Unit of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Jeremy Walker
- Department of Podiatry Services, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Solomon Tesfaye
- Academic Unit of Diabetes and Endocrinology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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11
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Pilemann-Lyberg S, Rasmussen DGK, Hansen TW, Tofte N, Winther SA, Holm Nielsen S, Theilade S, Karsdal MA, Genovese F, Rossing P. Markers of Collagen Formation and Degradation Reflect Renal Function and Predict Adverse Outcomes in Patients With Type 1 Diabetes. Diabetes Care 2019; 42:1760-1768. [PMID: 31262950 DOI: 10.2337/dc18-2599] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 06/13/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Patients with type 1 diabetes (T1D) have a higher risk of developing chronic kidney disease, cardiovascular events (CVEs), and mortality than the general population. We hypothesized that two previously published biomarkers, namely PRO-C6, a biomarker of collagen type VI formation, and C3M, a biomarker of collagen type III degradation, may be associated with impaired renal function and have prognostic value for adverse renal, CVE, and mortality in patients with T1D. RESEARCH DESIGN AND METHODS PRO-C6 and C3M in serum (sPRO-C6, sC3M) and urine (uPRO-C6, uC3M) were measured by ELISA in 663 patients with T1D ranging from normoalbuminuric to macroalbuminuric. Association of the biomarkers with mortality, CVEs, heart failure, decline in estimated glomerular filtration rate (eGFR) ≥30%, and end-stage renal disease (ESRD) were tested in Cox proportional hazards models after log2 transformation and adjusted for relevant clinical characteristics. Hazard ratios (HRs) were reported per doubling of biomarker levels. RESULTS High levels of sPRO-C6 were independently associated with a higher risk of all-cause mortality (HR 2.26 [95% CI 1.31-3.87], P < 0.0031). There was an association with higher risk of CVEs (n = 94) and heart failure (n = 28) but not after adjustment (P ≥ 0.58). In relation to renal outcomes, adjusted sPRO-C6 was associated with a higher risk of eGFR decline ≥30% in T1D, with eGFR >45 and >30 mL/min/1.73 m2, and with a higher risk of ESRD (all P ≤ 0.03). Higher uPRO-C6 was associated with a lower risk of decline in eGFR. CONCLUSIONS In patients with T1D, higher sPRO-C6 was an independent predictor of both decline in eGFR and development of ESRD and of all-cause mortality. Higher uPRO-C6 was also associated with a lower risk of decline in eGFR.
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Affiliation(s)
| | | | | | - Nete Tofte
- Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | | | - Signe Holm Nielsen
- Nordic Bioscience, Herlev, Denmark.,Technical University of Denmark, Lyngby, Denmark
| | | | | | | | - Peter Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark.,University of Copenhagen, Copenhagen, Denmark
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12
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Nickel NP, de Jesus Perez VA, Zamanian RT, Fessel JP, Cogan JD, Hamid R, West JD, de Caestecker MP, Yang H, Austin ED. Low-grade albuminuria in pulmonary arterial hypertension. Pulm Circ 2019; 9:2045894018824564. [PMID: 30632900 PMCID: PMC6557031 DOI: 10.1177/2045894018824564] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Low-grade albuminuria, determined by the urinary albumin to creatinine ratio, has been linked to systemic vascular dysfunction and is associated with cardiovascular mortality. Pulmonary arterial hypertension is related to mutations in the bone morphogenetic protein receptor type 2, pulmonary vascular dysfunction and is increasingly recognized as a systemic disease. In a total of 283 patients (two independent cohorts) diagnosed with pulmonary arterial hypertension, 18 unaffected BMPR2 mutation carriers and 68 healthy controls, spot urinary albumin to creatinine ratio and its relationship to demographic, functional, hemodynamic and outcome data were analyzed. Pulmonary arterial hypertension patients and unaffected BMPR2 mutation carriers had significantly elevated urinary albumin to creatinine ratios compared with healthy controls ( P < 0.01; P = 0.04). In pulmonary arterial hypertension patients, the urinary albumin to creatinine ratio was associated with older age, lower six-minute walking distance, elevated levels of C-reactive protein and hemoglobin A1c, but there was no correlation between the urinary albumin to creatinine ratio and hemodynamic variables. Pulmonary arterial hypertension patients with a urinary albumin to creatinine ratio above 10 µg/mg had significantly higher rates of poor outcome ( P < 0.001). This study shows that low-grade albuminuria is prevalent in pulmonary arterial hypertension patients and is associated with poor outcome. This study shows that albuminuria in pulmonary arterial hypertension is associated with systemic inflammation and insulin resistance.
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Affiliation(s)
- Nils P Nickel
- 1 Stanford University School of Medicine, Stanford University, USA.,2 Vanderbilt University Medical Center, USA
| | | | - Roham T Zamanian
- 1 Stanford University School of Medicine, Stanford University, USA
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13
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Perkins BA, Bebu I, de Boer IH, Molitch M, Tamborlane W, Lorenzi G, Herman W, White NH, Pop-Busui R, Paterson AD, Orchard T, Cowie C, Lachin JM. Risk Factors for Kidney Disease in Type 1 Diabetes. Diabetes Care 2019; 42:883-890. [PMID: 30833370 PMCID: PMC6489116 DOI: 10.2337/dc18-2062] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 02/03/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE In type 1 diabetes (T1D), the course of microalbuminuria is unpredictable and timing of glomerular filtration rate (GFR) loss is uncertain. Thus, there is a need to identify the risk factors associated with the development of more advanced stages of kidney disease through large, long-term systematic analysis. RESEARCH DESIGN AND METHODS Multivariable Cox proportional hazards models assessed the association of baseline and time-dependent glycemic and nonglycemic risk factors for incident macroalbuminuria and reduced estimated GFR (eGFR; defined as <60 mL/min/1.73 m2) over a mean of 27 years in the Diabetes Control and Complications Trial (DCCT) cohort. RESULTS Higher mean HbA1c (hazard ratio [HR] 1.969 per 1% higher level [95% CI 1.671-2.319]) and male sex (HR 2.767 [95% CI 1.951-3.923]) were the most significant factors independently associated with incident macroalbuminuria, whereas higher mean triglycerides, higher pulse, higher systolic blood pressure (BP), longer diabetes duration, higher current HbA1c, and lower mean weight had lower magnitude associations. For incident reduced eGFR, higher mean HbA1c (HR 1.952 per 1% higher level [95% CI 1.714-2.223]) followed by higher mean triglycerides, older age, and higher systolic BP were the most significant factors. CONCLUSIONS Although several risk factors associated with macroalbuminuria and reduced eGFR were identified, higher mean glycemic exposure was the strongest determinant of kidney disease among the modifiable risk factors. These findings may inform targeted clinical strategies for the frequency of screening, prevention, and treatment of kidney disease in T1D.
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Affiliation(s)
- Bruce A Perkins
- Division of Endocrinology and Metabolism, University of Toronto, Toronto, Canada
| | - Ionut Bebu
- Biostatistics Center, The George Washington University, Rockville, MD
| | - Ian H de Boer
- Division of Nephrology, University of Washington, Seattle, WA
| | - Mark Molitch
- Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University, Chicago, IL
| | | | | | - William Herman
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI
| | - Neil H White
- Department of Pediatrics, Washington University in St. Louis, St. Louis, MO
| | - Rodica Pop-Busui
- Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI
| | - Andrew D Paterson
- Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada
| | - Trevor Orchard
- Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA
| | - Catherine Cowie
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - John M Lachin
- Biostatistics Center, The George Washington University, Rockville, MD
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14
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Zhang YW, Wang X, Ren X, Zhang M. Involvement of glucose-regulated protein 78 and spliced X-box binding protein 1 in the protective effect of gliclazide in diabetic nephropathy. Diabetes Res Clin Pract 2018; 146:41-47. [PMID: 28951332 DOI: 10.1016/j.diabres.2017.04.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Revised: 04/12/2017] [Accepted: 04/26/2017] [Indexed: 12/22/2022]
Abstract
AIMS To testing whether endoplasmic reticulum (ER) stress contributes to the development of diabetic nephropathy. Investigated the effect of gliclazide, an oral antihyperglycemic agent, in a rat model of diabetic nephropathy and the underlying mechanism related to the ER stress response. METHODS Sixty SD rats were divided into six groups. Diabetic nephropathy was induced in 30 rats with a streptozotocin (STZ) injection and high fat diet, which were then treated with saline, gliclazide or 4-PBA. 20 rats were treated with Tunicamycin (TM) one-time intraperitoneal injection, following treated with saline or gliclazide. Blood glucose, kidney index and function were evaluated. Light and transmission electron microscopy (TEM) were used to observe kidney histological changes. Quantitative real-time PCR and western blot were performed to access the mRNA and protein levels of glucose-regulated protein 78 (GRP78) and spliced X-box binding protein 1 (sXBP1) in glomeruli. RESULT STZ-induced diabetic rats evidenced nephropathy by higher serum creatinine (sCr), blood urea nitrogen (BUN), microalbuminuria (MAU), and kidney index. Histological examination and TEM assay showed abnormal renal structures including thick glomerular basement membrane and mesangial cell expansion. The same changes were found in TM-treated rats. Gliclazide-treated had similar kidney index, but lower glucose levels, sCr, BUN, and MAU, compared with both saline and 4-PBA-treated diabetic rats or saline-treated TM rats. Synchronize with significantly lower Grp78 and sXbp1 mRNA and protein levels. CONCLUSION Diabetes-induced nephropathy is associated with ER stress. Gliclazide treatment lessens diabetic nephropathy, probably partially by suppressing the GRP78- and sXBP1-mediated ER response.
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Affiliation(s)
- Ying-Wen Zhang
- Department of Chinese with Western Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
| | - Xiuping Wang
- Department of Chinese with Western Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Xiaodan Ren
- Department of Chinese with Western Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Manling Zhang
- Department of Chinese with Western Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
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15
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Bjornstad P, Donaghue KC, Maahs DM. Macrovascular disease and risk factors in youth with type 1 diabetes: time to be more attentive to treatment? Lancet Diabetes Endocrinol 2018; 6:809-820. [PMID: 29475800 PMCID: PMC6102087 DOI: 10.1016/s2213-8587(18)30035-4] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 12/03/2017] [Accepted: 12/05/2017] [Indexed: 02/08/2023]
Abstract
Cardiovascular disease remains the leading cause of mortality in patients with type 1 diabetes. Although cardiovascular disease complications are rare until adulthood, pathology and early markers can manifest in adolescence. Whereas advances have been made in the management of microvascular complications of type 1 diabetes, similar progress in reducing macrovascular complications has not been made. The reasons for the absence of progress remain incompletely understood, but most likely relate to the long time needed for cardiovascular disease to manifest clinically and hence for risk factor management to show a clinical benefit, thus allowing inertia to prevail for diagnosis and particularly for targeting risk factors. In this Review, we summarise paediatric data on traditional and novel risk factors of cardiovascular disease, provide an overview of data from previous and current clinical trials, discuss future directions in cardiovascular disease research for paediatric patients with type 1 diabetes, and advocate for the early identification and treatment of cardiovascular disease risk factors as recommended in multiple guidelines.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatric Endocrinology, University of Colorado School of Medicine, Aurora, CO, USA; Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO, USA.
| | - Kim C Donaghue
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, University of Sydney, NSW, Australia
| | - David M Maahs
- Department of Pediatric Endocrinology, Stanford University School of Medicine, Palo Alto, CA, USA
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16
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Managing the Course of Kidney Disease in Adults With Type 2 Diabetes: From the Old to the New. Can J Diabetes 2018; 42:325-334. [DOI: 10.1016/j.jcjd.2017.06.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Revised: 06/16/2017] [Accepted: 06/20/2017] [Indexed: 02/06/2023]
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17
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Pilemann-Lyberg S, Lindhardt M, Persson F, Andersen S, Rossing P. Serum uric acid and progression of diabetic nephropathy in type 1 diabetes. J Diabetes Complications 2018. [PMID: 29534864 DOI: 10.1016/j.jdiacomp.2018.02.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
AIMS Uric acid (UA) is a risk factor for CKD. We evaluated UA in relation to change in GFR in patients with type 1 diabetes. METHODS Post hoc analysis of a trial of losartan in diabetic nephropathy, mean follow-up 3 years (IQR 1.5-3.5). UA was measured at baseline. Primary end-point was change in measured GFR. UA was tested in a linear regression model adjusted for known progression factors (gender, HbA1c, systolic blood pressure, cholesterol, baseline GFR and baseline urinary albumin excretion rate (UAER)). RESULTS Baseline UA was 0.339 mmol/l (SD ±0.107), GFR 87 ml/min/1.73 m2 (±23), geometric mean UAER 1023 mg/24 h (IQR, 631 - 1995). Mean rate of decline in GFR was 4.6 (3.7) ml/min/year. In the upper quartile of baseline UA the mean decline in GFR from baseline to the end of the study was 6.2 (4.9) ml/min/1.73 m2 and 4.1 (3.1) ml/min/1.73 m2 in the three lower quartiles of UA, (p = 0.088). In a linear model including baseline covariates (UAER, GFR, total cholesterol, HDL cholesterol) UA was associated with decline in GFR (r2 = 0.45, p < 0.001). CONCLUSION Uric acid was weakly associated with decline in GFR in type 1 diabetic patients with overt nephropathy.
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Affiliation(s)
- S Pilemann-Lyberg
- Department of Endocrinology, MEA, NBG, Institute for Clinical Medicine, Aarhus University Hospital, Denmark; Steno Diabetes Center Copenhagen, Gentofte, Denmark.
| | - M Lindhardt
- Steno Diabetes Center Copenhagen, Gentofte, Denmark.
| | | | - S Andersen
- Nordsjaellands Hospital, Hilleroed, Denmark.
| | - P Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark; Institute of Clinical Medicine, University of Copenhagen, Denmark; Aarhus University, Denmark.
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18
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Lu L, Marcovecchio ML, Dalton RN, Dunger D. Cardiovascular autonomic dysfunction predicts increasing albumin excretion in type 1 diabetes. Pediatr Diabetes 2018; 19:464-469. [PMID: 29171134 DOI: 10.1111/pedi.12614] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 11/01/2017] [Accepted: 11/01/2017] [Indexed: 02/02/2023] Open
Abstract
OBJECTIVE To determine the potential role of cardiovascular autonomic dysfunction in the development of renal complications in young people with type 1 diabetes (T1D). METHODS In this prospective study, 199 children and adolescents recruited to the Oxford Regional Prospective Study underwent assessment of autonomic function ~5 years after diagnosis, and were subsequently followed with longitudinal assessments of HbA1c and urine albumin-creatinine ratio (ACR) over 8.6 ± 3.4 years. Autonomic function was assessed with 4 standardized tests of cardiovascular reflexes: heart rate (HR) response to (1) Valsalva Maneuver, (2) deep breathing, (3) standing, and (4) blood pressure (BP) response to standing. Linear mixed models were used to assess the association between autonomic parameters and future changes in ACR. RESULTS Independent of HbA1c , each SD increase in HR response to Valsalva Maneuver predicted an ACR increase of 2.16% [95% CI: 0.08; 4.28] per year (P = .04), while each SD increase in diastolic BP response to standing predicted an ACR increase of 2.55% [95% CI: 0.37; 4.77] per year (P = .02). The effect of HR response to standing on ACR reached borderline significance (-2.07% [95% CI: -4.11; 0.01] per year per SD increase, P = .051). CONCLUSIONS In this cohort of young people with T1D, enhanced cardiovascular reflexes at baseline predicted future increases in ACR. These results support a potential role for autonomic dysfunction in the pathogenesis of diabetic nephropathy.
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Affiliation(s)
- Liangjian Lu
- Department of Paediatrics, MRL Wellcome Trust-MRC Institute of Metabolic Science, NIHR Cambridge Comprehensive Biomedical Research Centre, University of Cambridge, Cambridge, UK.,Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, National University Health System, Singapore, Singapore
| | - M Loredana Marcovecchio
- Department of Paediatrics, MRL Wellcome Trust-MRC Institute of Metabolic Science, NIHR Cambridge Comprehensive Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - R Neil Dalton
- WellChild Laboratory, Evelina London Children's Hospital, London, UK
| | - David Dunger
- Department of Paediatrics, MRL Wellcome Trust-MRC Institute of Metabolic Science, NIHR Cambridge Comprehensive Biomedical Research Centre, University of Cambridge, Cambridge, UK
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19
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Garner KL, Betin VMS, Pinto V, Graham M, Abgueguen E, Barnes M, Bedford DC, McArdle CA, Coward RJM. Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress. Sci Rep 2018; 8:3902. [PMID: 29500363 PMCID: PMC5834602 DOI: 10.1038/s41598-018-22233-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 02/20/2018] [Indexed: 02/06/2023] Open
Abstract
Disruption of the insulin-PI3K-Akt signalling pathway in kidney podocytes causes endoplasmic reticulum (ER) stress, leading to podocyte apoptosis and proteinuria in diabetic nephropathy. We hypothesised that by improving insulin sensitivity we could protect podocytes from ER stress. Here we use established activating transcription factor 6 (ATF6)- and ER stress element (ERSE)-luciferase assays alongside a novel high throughput imaging-based C/EBP homologous protein (CHOP) assay to examine three models of improved insulin sensitivity. We find that by improving insulin sensitivity at the level of the insulin receptor (IR), either by IR over-expression or by knocking down the negative regulator of IR activity, protein tyrosine-phosphatase 1B (PTP1B), podocytes are protected from ER stress caused by fatty acids or diabetic media containing high glucose, high insulin and inflammatory cytokines TNFα and IL-6. However, contrary to this, knockdown of the negative regulator of PI3K-Akt signalling, phosphatase and tensin homolog deleted from chromosome 10 (PTEN), sensitizes podocytes to ER stress and apoptosis, despite increasing Akt phosphorylation. This indicates that protection from ER stress is conferred through not just the PI3K-Akt pathway, and indeed we find that inhibiting the MEK/ERK signalling pathway rescues PTEN knockdown podocytes from ER stress.
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Affiliation(s)
- Kathryn L Garner
- Bristol Renal, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
| | - Virginie M S Betin
- Bristol Renal, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
| | - Vanda Pinto
- Bristol Renal, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
| | - Mark Graham
- Bristol Renal, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
| | - Emmanuelle Abgueguen
- Takeda Cambridge Ltd., 418 Cambridge Science Park, Milton Road, Cambridge, CB4 0PZ, UK
| | - Matt Barnes
- Takeda Cambridge Ltd., 418 Cambridge Science Park, Milton Road, Cambridge, CB4 0PZ, UK
| | - David C Bedford
- Takeda Cambridge Ltd., 418 Cambridge Science Park, Milton Road, Cambridge, CB4 0PZ, UK
| | - Craig A McArdle
- Laboratories for Integrative Neuroscience and Endocrinology, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK
| | - Richard J M Coward
- Bristol Renal, Bristol Medical School, University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol, BS1 3NY, UK.
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20
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Helve J, Sund R, Arffman M, Harjutsalo V, Groop PH, Grönhagen-Riska C, Finne P. Incidence of End-Stage Renal Disease in Patients With Type 1 Diabetes. Diabetes Care 2018; 41:434-439. [PMID: 29263163 DOI: 10.2337/dc17-2364] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 11/16/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To investigate how risk of end-stage renal disease (ESRD) among patients with type 1 diabetes has changed over time and further how the risk is affected by age, sex, and time period of diagnosis of diabetes. RESEARCH DESIGN AND METHODS A cohort including all patients <30 years old diagnosed with type 1 diabetes in Finland in 1965-2011 was followed until start of renal replacement therapy, death, or end of follow-up at the end of 2013. Altogether, 29,906 patients were included. The main outcome was cumulative risk of ESRD, accounting for death as a competing risk. RESULTS The patients were followed up for a median of 20 years. During 616,403 patient-years, 1,543 ESRD cases and 4,185 deaths were recorded. The cumulative risk of ESRD was 2.2% after 20 years and 7.0% after 30 years from the diabetes diagnosis. The relative risk of ESRD was 0.13 (95% CI 0.08-0.22) among patients diagnosed in 1995-2011 compared with those diagnosed in 1965-1979. Patients <5 years old at the time of diagnosis had the lowest risk of ESRD after diagnosis. With the cumulative risk of ESRD estimated from time of birth, the patients aged 5-9 years at diabetes diagnosis were at highest risk. CONCLUSIONS The cumulative risk of ESRD has decreased markedly during the past five decades. This highlights the importance of modern treatment of diabetes and diabetic nephropathy.
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Affiliation(s)
- Jaakko Helve
- Finnish Registry for Kidney Diseases, Helsinki, Finland .,Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Reijo Sund
- Department of Social Research, Centre for Research Methods, University of Helsinki, Helsinki, Finland.,Insitute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
| | - Martti Arffman
- Insitute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.,National Institute for Health and Welfare, Helsinki, Finland
| | - Valma Harjutsalo
- Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.,Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
| | - Per-Henrik Groop
- Finnish Registry for Kidney Diseases, Helsinki, Finland.,Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Diabetes and Obesity Research Program, Research Programs Unit, University of Helsinki, Helsinki, Finland.,Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.,Baker IDI Heart & Diabetes Institute, Melbourne, Australia
| | | | - Patrik Finne
- Finnish Registry for Kidney Diseases, Helsinki, Finland.,Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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21
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Lovshin JA, Boulet G, Lytvyn Y, Lovblom LE, Bjornstad P, Farooqi MA, Lai V, Cham L, Tse J, Orszag A, Scarr D, Weisman A, Keenan HA, Brent MH, Paul N, Bril V, Perkins BA, Cherney DZ. Renin-angiotensin-aldosterone system activation in long-standing type 1 diabetes. JCI Insight 2018; 3:96968. [PMID: 29321380 PMCID: PMC5821172 DOI: 10.1172/jci.insight.96968] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Accepted: 11/28/2017] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND In type 1 diabetes (T1D), adjuvant treatment with inhibitors of the renin-angiotensin-aldosterone system (RAAS), which dilate the efferent arteriole, is associated with prevention of progressive albuminuria and renal dysfunction. Uncertainty still exists as to why some individuals with long-standing T1D develop diabetic kidney disease (DKD) while others do not (DKD resistors). We hypothesized that those with DKD would be distinguished from DKD resistors by the presence of RAAS activation. METHODS Renal and systemic hemodynamic function was measured before and after exogenous RAAS stimulation by intravenous infusion of angiotensin II (ANGII) in 75 patients with prolonged T1D durations and in equal numbers of nondiabetic controls. The primary outcome was change in renal vascular resistance (RVR) in response to RAAS stimulation, a measure of endogenous RAAS activation. RESULTS Those with DKD had less change in RVR following exogenous RAAS stimulation compared with DKD resistors or controls (19%, 29%, 31%, P = 0.008, DKD vs. DKD resistors), reflecting exaggerated endogenous renal RAAS activation. All T1D participants had similar changes in renal efferent arteroilar resistance (9% vs. 13%, P = 0.37) irrespective of DKD status, which reflected less change versus controls (20%, P = 0.03). In contrast, those with DKD exhibited comparatively less change in afferent arteriolar vascular resistance compared with DKD resistors or controls (33%, 48%, 48%, P = 0.031, DKD vs. DKD resistors), indicating higher endogenous RAAS activity. CONCLUSION In long-standing T1D, the intrarenal RAAS is exaggerated in DKD, which unexpectedly predominates at the afferent rather than the efferent arteriole, stimulating vasoconstriction. FUNDING JDRF operating grant 17-2013-312.
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Affiliation(s)
- Julie A. Lovshin
- Division of Endocrinology and Metabolism and
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Geneviève Boulet
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Leif E. Lovblom
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Petter Bjornstad
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Research Division, Barbara Davis Center for Diabetes, Aurora, Colorado, USA
| | - Mohammed A. Farooqi
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Vesta Lai
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Leslie Cham
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Josephine Tse
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Andrej Orszag
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Daniel Scarr
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Alanna Weisman
- Division of Endocrinology and Metabolism and
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Hillary A. Keenan
- Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA
| | - Michael H. Brent
- Department of Ophthalmology and Vision Sciences, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Narinder Paul
- Joint Department of Medical Imaging, Division of Cardiothoracic Radiology, University Health Network, Toronto, Ontario, Canada
| | - Vera Bril
- Ellen and Martin Prosserman Centre for Neuromuscular Diseases, Krembil Neuroscience Centre, Division of Neurology, Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Bruce A. Perkins
- Division of Endocrinology and Metabolism and
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - David Z.I. Cherney
- Division of Nephrology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Glycemia, Hypoglycemia, and Costs of Simultaneous Islet-Kidney or Islet After Kidney Transplantation Versus Intensive Insulin Therapy and Waiting List for Islet Transplantation. Transplantation 2016; 99:2174-80. [PMID: 25905979 DOI: 10.1097/tp.0000000000000720] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND Long-term data of patients with type 1 diabetes mellitus (T1D) after simultaneous islet-kidney (SIK) or islet-after-kidney transplantation (IAK) are rare and have never been compared to intensified insulin therapy (IIT). METHODS Twenty-two patients with T1D and end-stage renal failure undergoing islet transplantation were compared to 70 patients matched for age and diabetes duration treated with IIT and to 13 patients with kidney transplantation alone or simultaneous pancreas-kidney after loss of pancreas function (waiting list for IAK [WLI]). Glycemic control, severe hypoglycemia, insulin requirement, and direct medical costs were analyzed. RESULTS Glycated hemoglobin decreased significantly from 8.2 ± 1.5 to 6.7 ± 0.9% at the end of follow-up (mean 7.2 ± 2.5 years) in the SIK/IAK and remained constant in IIT (7.8 ± 1.0% and 7.6 ± 1.0) and WLI (7.8 ± 0.8 and 7.9 ± 1.0%). Daily insulin requirement decreased from 0.53 ± 0.15 to 0.29 ± 0.26 U/kg and remained constant in IIT (0.59 ± 0.19 and 0.58 ± 0.23 U/kg) and in WLI (0.76 ± 0.28 and 0.73 ± 0.11 U/kg). Severe hypoglycemia dropped in SIK/IAK from 4.5 ± 9.7 to 0.3 ± 0.7/patient-year and remained constant in IIT (0.1 ± 0.7 and 0.2 ± 0.8/patient-year). Detailed cost analysis revealed US $57,525 of additional cost for islet transplantation 5 years after transplantation. Based on a 5- and 10-year analysis, cost neutrality is assumed to be achieved 15 years after transplantation. CONCLUSIONS This long-term cohort with more than 7 years of follow-up shows that glycemic control in patients with T1D after SIK/IAK transplantation improved, and the rate of severe hypoglycemia decreased significantly as compared to control groups. Cost analysis revealed that islet transplantation is estimated to be cost neutral at 15 years after transplantation.
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Otani T, Yokoyama H, Ohashi Y, Uchigata Y. Improved incidence of end-stage renal disease of type 1 diabetes in Japan, from a hospital-based survey. BMJ Open Diabetes Res Care 2016; 4:e000177. [PMID: 27110369 PMCID: PMC4838665 DOI: 10.1136/bmjdrc-2015-000177] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 01/29/2016] [Accepted: 03/04/2016] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To explore whether the incidence of end-stage renal disease (ESRD) in type 1 diabetes (T1DM) was lowered over time, and how the baseline characteristics and risk factor management during follow-up were associated with the incident ESRD. RESEARCH DESIGN AND METHODS An observational cohort study was performed in 1014 patients with T1DM diagnosed from 1961 to 1999, who were admitted to the diabetes center. The incidence of ESRD up to 2010 and the effect of risk factors, including annual mean glycated haemoglobin (HbA1c) and blood pressure, were investigated. RESULTS During a mean follow-up of 19.3 years, with 88.3% follow-up rate, the incidence of ESRD was significantly lower in T1DM diagnosed in 1985-1999 than in 1961-1984 (0.8 vs 5.0 per 1000 person-years, p<0.0001), which was not precluded by preceding death. Multivariate Cox regression analysis indicated that the former group (vs the latter) was associated with a significantly reduced risk of ESRD independent of baseline variables of age, duration and gender (p<0.01). The continuous variable of year of T1DM diagnosis remained significant after adjustment for the above variables plus baseline proteinuria and retinopathy (p=0.02). Time-dependent Cox regression analysis indicated that ESRD was associated with annual mean HbA1c (p<0.01), systolic blood pressure (p<0.001) and baseline proteinuria (p<0.001), followed by continuous variable of year of T1DM diagnosis (p=0.09). CONCLUSIONS Our data indicate that incidence of ESRD is decreasing over time, coinciding with enhanced glycemic and blood pressure controls. The incidence of ESRD in recently diagnosed T1DM appears to be much lower than previously reported ESRD incidence.
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Affiliation(s)
- Toshika Otani
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
- Saitama Memorial Hospital, Saitama, Japan
| | - Hiroki Yokoyama
- Department of Internal Medicine, Jiyugaoka Medical Clinic, Obihiro, Japan
| | - Yasuo Ohashi
- Integrated Science and Engineering for Sustainable Society, Chuo University, Tokyo, Japan
| | - Yasuko Uchigata
- Diabetes Center, Tokyo Women's Medical University School of Medicine, Tokyo, Japan
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Abstract
The global prevalence of diabetic nephropathy is rising in parallel with the increasing incidence of diabetes in most countries. Unfortunately, up to 40 % of persons diagnosed with diabetes may develop kidney complications. Diabetic nephropathy is associated with substantially increased risks of cardiovascular disease and premature mortality. An inherited susceptibility to diabetic nephropathy exists, and progress is being made unravelling the genetic basis for nephropathy thanks to international research collaborations, shared biological resources and new analytical approaches. Multiple epidemiological studies have highlighted the clinical heterogeneity of nephropathy and the need for better phenotyping to help define important subgroups for analysis and increase the power of genetic studies. Collaborative genome-wide association studies for nephropathy have reported unique genes, highlighted novel biological pathways and suggested new disease mechanisms, but progress towards clinically relevant risk prediction models for diabetic nephropathy has been slow. This review summarises the current status, recent developments and ongoing challenges elucidating the genetics of diabetic nephropathy.
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Affiliation(s)
- Amy Jayne McKnight
- Nephrology Research Group, Centre for Public Health, Queen's University Belfast, c/o Regional Genetics Centre, Level A, Tower Block, Belfast City Hospital, Lisburn Road, Belfast, BT9 7AB, UK,
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Bjornstad P, Maahs DM. Diabetes Complications in Childhood Diabetes-New Biomarkers and Technologies. CURRENT PEDIATRICS REPORTS 2015; 3:177-186. [PMID: 26425403 DOI: 10.1007/s40124-015-0081-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
A major challenge in preventing vascular complications in diabetes is the inability to identify high-risk patients at an early stage, emphasizing the importance of discovering new risk factors, technologies and therapeutic targets to reduce the development and progression of complications. Promising biomarkers which may improve risk stratification and serve as therapeutic targets, include: uric acid, insulin sensitivity, copeptin, SGLT-2 and Klotho/FGF-23. Non-invasive measures of macrovasuclar disease in youth, include: 1) pulse wave velocity to examine arterial stiffness; 2) carotid intima-media thickness to evaluate arterial thickness; 3) cardiac MRI to investigate cardiac function and structure. Novel microvascular measures include: GFR by iohexol clearance using filter paper to directly measure GFR, retinal vascular geometry to predict early retinal changes and corneal confocal microscopy to improve detection of early nerve loss to better predict diabetic neuropathy. Herein we will review technologies, novel biomarkers, and therapeutic targets in relation to vascular complications of diabetes.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States ; Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - David M Maahs
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States ; Barbara Davis Center for Diabetes, University of Colorado School of Medicine, Aurora, Colorado, United States
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Klemetti MM, Laivuori H, Tikkanen M, Nuutila M, Hiilesmaa V, Teramo K. Obstetric and perinatal outcome in type 1 diabetes patients with diabetic nephropathy during 1988-2011. Diabetologia 2015; 58:678-86. [PMID: 25575985 DOI: 10.1007/s00125-014-3488-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 12/16/2014] [Indexed: 12/30/2022]
Abstract
AIMS/HYPOTHESIS Our aim was to analyse possible changes in the glycaemic control, BP, markers of renal function, and obstetric and perinatal outcomes of parturients with diabetic nephropathy during 1988-2011. METHODS The most recent childbirth of 108 consecutive type 1 diabetes patients with diabetic nephropathy and a singleton pregnancy were studied. Two periods, 1988-1999 and 2000-2011, were compared. RESULTS The prepregnancy and the first trimester median HbA1c values persisted at high levels (8.2% [66 mmol/mol] vs 8.5% [69 mmol/mol], p = 0.16 and 8.3% [67 mmol/mol] vs 8.4% [68 mmol/mol], p = 0.67, respectively), but decreased by mid-pregnancy (6.7% [50 mmol/mol] vs 6.9% [52 mmol/mol], p = 0.11). Antihypertensive medication usage increased before pregnancy (34% vs 65%, p = 0.002) and in the second and third trimesters of pregnancy (25% vs 47%, p = 0.02, and 36% vs 60%, p = 0.01, respectively). BP exceeded 130/80 mmHg in 62% and 61% (p = 0.87) of patients in the first trimester, and in 95% and 93% (p = 0.69) in the third trimester, respectively. No changes were observed in the markers of renal function. Pre-eclampsia (52% vs 42%, p = 0.29) and preterm birth rates before 32 and 37 gestational weeks (14% vs 21%, p = 0.33, and 71% vs 77%, p = 0.49, respectively) remained high. The elective and emergency Caesarean section rates were 71% and 45% (p = 0.01) and 29% and 48% (p = 0.05), respectively. Neonatal intensive care unit admissions increased from 26% to 49% (p = 0.02). CONCLUSIONS/INTERPRETATION Early pregnancy glycaemic control and hypertension management were suboptimal in both time periods. Pre-eclampsia and preterm delivery rates remained high in patients with diabetic nephropathy.
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Affiliation(s)
- Miira M Klemetti
- Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Central Hospital, P.O. Box 140, Haartmaninkatu 2, 00029, Helsinki, Finland,
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Lloyd A, Komenda P. Optimizing care for Canadians with diabetic nephropathy in 2015. Can J Diabetes 2015; 39:221-8. [PMID: 25805325 DOI: 10.1016/j.jcjd.2014.11.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Revised: 11/12/2014] [Accepted: 11/13/2014] [Indexed: 12/30/2022]
Abstract
Diabetic chronic kidney disease (CKD) is the cause of kidney failure in approximately 35% of Canadian patients requiring dialysis. Traditionally, only a minority of patients with type 2 diabetes and CKD progress to kidney failure because they die of a cardiovascular event first. However, with contemporary therapies for diabetes and cardiovascular disease, this may no longer be true. The classic description of diabetic CKD is the development of albuminuria followed by progressive kidney dysfunction in a patient with longstanding diabetes. Many exciting candidate agents are under study to halt the progression of diabetic CKD; current therapies center on optimizing glycemic control, renin angiotensin system inhibition, blood pressure control and lipid management. Lifestyle modifications, such as salt and protein restriction as well as smoking cessation, may also be of benefit. Unfortunately, these accepted therapies do not entirely halt the progression of diabetic CKD. Also unfortunately, the presence of CKD in general is under-recognized by primary care providers, which can lead to late referral, missed opportunities for preventive care and inadvertent administration of potentially harmful interventions. Not all patients require referral to nephrology for diagnosis and management, but modern risk-prediction algorithms, such as the kidney failure risk equation, may help to guide referral appropriateness and dialysis modality planning in subspecialty nephrology multidisciplinary care clinics.
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Affiliation(s)
- Alissa Lloyd
- University of Manitoba, Department of Medicine, Section of Nephrology, Winnipeg, Canada
| | - Paul Komenda
- University of Manitoba, Department of Medicine, Section of Nephrology, Winnipeg, Canada; Seven Oaks General Hospital, Department of Nephrology, Winnipeg, Canada.
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Defective podocyte insulin signalling through p85-XBP1 promotes ATF6-dependent maladaptive ER-stress response in diabetic nephropathy. Nat Commun 2015; 6:6496. [PMID: 25754093 PMCID: PMC4366504 DOI: 10.1038/ncomms7496] [Citation(s) in RCA: 134] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 02/03/2015] [Indexed: 02/08/2023] Open
Abstract
Endoplasmic reticulum (ER) stress is associated with diabetic nephropathy (DN), but its pathophysiological relevance and the mechanisms that compromise adaptive ER signalling in podocytes remain unknown. Here we show that nuclear translocation of the transcription factor spliced X-box binding protein-1 (sXBP1) is selectively impaired in DN, inducing activating transcription factor-6 (ATF6) and C/EBP homology protein (CHOP). Podocyte-specific genetic ablation of XBP1 or inducible expression of ATF6 in mice aggravates DN. sXBP1 lies downstream of insulin signalling and attenuating podocyte insulin signalling by genetic ablation of the insulin receptor or the regulatory subunits phosphatidylinositol 3-kinase (PI3K) p85α or p85β impairs sXBP1 nuclear translocation and exacerbates DN. Corroborating our findings from murine DN, the interaction of sXBP1 with p85α and p85β is markedly impaired in the glomerular compartment of human DN. Thus, signalling via the insulin receptor, p85, and XBP1 maintains podocyte homeostasis, while disruption of this pathway impairs podocyte function in DN.
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Bjornstad P, Snell-Bergeon JK, Nadeau KJ, Maahs DM. Insulin sensitivity and complications in type 1 diabetes: New insights. World J Diabetes 2015; 6:8-16. [PMID: 25685274 PMCID: PMC4317319 DOI: 10.4239/wjd.v6.i1.8] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 09/24/2014] [Accepted: 12/01/2014] [Indexed: 02/05/2023] Open
Abstract
Despite improvements in glucose, lipids and blood pressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials.
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Bjornstad P, Maahs DM, Johnson RJ, Rewers M, Snell-Bergeon JK. Estimated insulin sensitivity predicts regression of albuminuria in Type 1 diabetes. Diabet Med 2015; 32:257-61. [PMID: 25303233 PMCID: PMC4301993 DOI: 10.1111/dme.12572] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/22/2014] [Indexed: 12/17/2022]
Abstract
AIM To test the hypothesis that greater baseline insulin sensitivity would predict regression of albuminuria over 6 years in adults with Type 1 diabetes. METHOD We enrolled 81 people aged 30-48 years with albuminuria at baseline in the present study and re-examined them 6 years later. Urinary albumin excretion rate was measured and albuminuria was defined as urinary albumin excretion rate ≥ 20 μg/min. Regression of albuminuria was defined as normoalbuminuria (urinary albumin excretion rate < 20 μg/min) at follow-up. Predictors of regression of albuminuria were examined in stepwise logistic regression. The variables age, diabetes duration, sex, serum uric acid, HbA1c , systolic blood pressure, LDL cholesterol, HDL cholesterol, BMI, baseline albumin excretion rate, estimated insulin sensitivity at baseline, change in estimated insulin sensitivity from baseline to follow-up and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were considered for inclusion in the model. RESULTS Estimated insulin sensitivity was significantly higher at both baseline (4.6 ± 1.2 vs 3.4 ± 1.7; P = 0.002) and follow-up (5.2 ± 1.9 vs. 3.5 ± 1.7; P < 0.0001) in people who had regression of albuminuria vs those who did not. HbA1c (odds ratio 0.4, 95% CI 0.2-0.8; P = 0.006), estimated insulin sensitivity (odds ratio 2.5, 95% CI 1.3-4.9; P = 0.006) at baseline and change in estimated insulin sensitivity from baseline to follow-up (odds ratio 2.7, 95% CI 1.4-5.3; P = 0.003) were independently associated with regression of albuminuria in a multivariable stepwise model. CONCLUSIONS In conclusion, over 6 years, higher baseline estimated insulin sensitivity and change in estimated insulin sensitivity independently predicted regression of albuminuria. Improving insulin sensitivity in people with Type 1 diabetes is a potential therapeutic target to increase rates of regression of albuminuria.
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Affiliation(s)
- P Bjornstad
- Department of Paediatrics, University of Colorado School of Medicine, Aurora, CO, USA
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Maahs DM, Bushman L, Kerr B, Ellis SL, Pyle L, McFann K, Bouffard A, Bishop FK, Nguyen N, Anderson PL. A practical method to measure GFR in people with type 1 diabetes. J Diabetes Complications 2014; 28:667-73. [PMID: 25027389 DOI: 10.1016/j.jdiacomp.2014.06.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Revised: 05/31/2014] [Accepted: 06/02/2014] [Indexed: 01/02/2023]
Abstract
AIMS Improved early diagnostic methods are needed to identify risk for kidney disease in people with type 1 diabetes. We hypothesized that glomerular filtration rate (GFR) measured by iohexol clearance in dried blood spots (DBS) on filter paper would be comparable to plasma (gold-standard) and superior to estimated GFR (eGFR) and, second, that adjustment for ambient blood glucose would improve accuracy and precision of GFR measurement. METHODS GFR was measured by iohexol clearance in plasma, DBS, and as estimated by the CKD-Epidemiology Collaboration equations in 15 adults with type 1 diabetes at two visits, one euglycemic and one hyperglycemic. RESULTS GFR measured by DBS was more comparable and less biased than GFR cystatin C, serum creatinine, and both combined. GFR was higher during hyperglycemia. Correction for between visit glycemia statistically significantly reduced bias and mean squared error for GFR measured by DBS as compared to gold-standard during euglycemia. CONCLUSIONS Iohexol clearance measured with DBS performed better than eGFR methods. Correction for ambient blood glucose improved precision and accuracy of GFR measurement. This method is more convenient than the gold-standard GFR method and may improve screening and diagnostic capabilities in people with type 1 diabetes, especially when GFR is >60ml/min/1.73m(2).
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Affiliation(s)
- D M Maahs
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO; Department of Medicine, Division of Nephrology, University of Colorado Denver, Aurora, CO.
| | - L Bushman
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO
| | - B Kerr
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO
| | - S L Ellis
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO
| | - L Pyle
- Department of Pediatrics, School of Medicine, University of Colorado Denver, Aurora, CO
| | - K McFann
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - A Bouffard
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - F K Bishop
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - N Nguyen
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
| | - P L Anderson
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO
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Abstract
PURPOSE OF REVIEW Despite improvements in glycemic and blood pressure control in patients with type 1 diabetes, diabetic nephropathy remains the most common cause of chronic kidney disease worldwide. A major challenge in preventing diabetic nephropathy is the inability to identify high-risk patients at an early stage, emphasizing the importance of discovering new therapeutic targets and implementation of clinical trials to reduce diabetic nephropathy risk. RECENT FINDINGS Limitations of managing patients with diabetic nephropathy with renin-angiotensin-aldosterone system blockade have been identified in recent clinical trials, including the failure of primary prevention studies in T1D and the demonstration of harm with dual renin-angiotensin-aldosterone system blockade. Fortunately, several new targets, including serum uric acid, insulin sensitivity, vasopressin, and sodium-glucose cotransporter-2 inhibition, are promising in the prevention and treatment of diabetic nephropathy. SUMMARY Diabetic nephropathy is characterized by a long clinically silent period without signs or symptoms of disease. There is an urgent need for improved methods of detecting early mediators of renal injury, to ultimately prevent the initiation and progression of diabetic nephropathy. In this review, we will focus on early diabetic nephropathy and summarize potential new therapeutic targets.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - David Cherney
- Department of Medicine, Division of Nephrology, Toronto General Hospital, University of Toronto, Ontario, Canada
| | - David M. Maahs
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
- Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, Colorado, United States
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Gu T, Falhammar H, Gu HF, Brismar K. Epigenetic analyses of the insulin-like growth factor binding protein 1 gene in type 1 diabetes and diabetic nephropathy. Clin Epigenetics 2014; 6:10. [PMID: 24904693 PMCID: PMC4046502 DOI: 10.1186/1868-7083-6-10] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Accepted: 05/13/2014] [Indexed: 02/07/2023] Open
Abstract
Background Clinical observations have demonstrated that high levels of circulating insulin-like growth factor binding protein-1 (IGFBP-1) are associated with type 1 diabetes (T1D), whereas low serum IGFBP-1 levels are associated with the risk of type 2 diabetes (T2D). Recently, we reported that increased DNA methylation levels in the IGFBP1 gene were associated with T2D. In the present study, we evaluated the epigenetic changes of IGFBP1 in T1D and diabetic nephropathy (DN). Results In total, 778 Swedish individuals, including T1D patients with or without DN and subjects with the normal glucose tolerance (NGT), were involved in the study. IGFBP1 methylation levels in genomic DNA extracted from peripheral blood were analyzed with bisulfite pyrosequencing. Serum IGFBP-1 levels were measured with radioimmunoassay. We found that DNA methylation levels in the IGFBP1 gene were decreased (15.6% versus 16.9%; P < 0.001), whereas serum IGFBP-1 levels were increased (31 versus 24 μg/L, P = 0.003) in T1D patients compared with NGT subjects. Furthermore, T1D patients with DN had increased circulating IGFBP-1 concentration compared with the patients without DN (52 versus 28 μg/L; P = 0.006). However, no difference of the IGFBP1 DNA methylation levels between T1D patients with and without DN was observed. Conclusions This study shows for the first time that T1D patients had decreased DNA methylation levels in the IGFBP1 gene and further implies that increased circulating IGFBP-1 levels are associated with T1D and DN.
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Affiliation(s)
- Tianwei Gu
- Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Henrik Falhammar
- Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden ; Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
| | - Harvest F Gu
- Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden ; Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
| | - Kerstin Brismar
- Rolf Luft Research Center for Diabetes and Endocrinology, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden ; Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
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Ho K, McKnight AJ. The changing landscape of diabetic kidney disease: new reflections on phenotype, classification, and disease progression to influence future investigative studies and therapeutic trials. Adv Chronic Kidney Dis 2014; 21:256-9. [PMID: 24780452 DOI: 10.1053/j.ackd.2014.03.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Accepted: 03/10/2014] [Indexed: 11/11/2022]
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McKnight AJ, McKay GJ, Maxwell AP. Genetic and epigenetic risk factors for diabetic kidney disease. Adv Chronic Kidney Dis 2014; 21:287-96. [PMID: 24780457 DOI: 10.1053/j.ackd.2014.03.010] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 03/10/2014] [Indexed: 12/22/2022]
Abstract
Diabetes is increasing at daunting rates worldwide, and approximately 40% of affected individuals will develop kidney complications. Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease, and there are significant healthcare costs providing appropriate renal replacement therapies to affected individuals. For several decades, investigators have sought to discover inherited risk factors and biomarkers for DKD. In recent years, advances in high-throughput laboratory techniques and computational analyses, coupled with the establishment of multicenter consortia, have helped to identify genetic loci that are replicated across multiple populations. Several genome-wide association studies (GWAS) have been conducted for DKD with further meta-analysis of GWAS and comprehensive "single gene" meta-analyses now published. Despite these efforts, much of the inherited predisposition to DKD remains unexplained. Meta-analyses and integrated-omics pathway studies are being used to help elucidate underlying genetic risks. Epigenetic phenomena are increasingly recognized as important drivers of disease risk, and several epigenome-wide association studies have now been completed. This review describes key findings and ongoing genetic and epigenetic initiatives for DKD.
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Affiliation(s)
- Amy Jayne McKnight
- Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom.
| | - Gareth J McKay
- Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom
| | - Alexander P Maxwell
- Nephrology Research, Centre for Public Health, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom
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Marshall SM. Natural history and clinical characteristics of CKD in type 1 and type 2 diabetes mellitus. Adv Chronic Kidney Dis 2014; 21:267-72. [PMID: 24780454 DOI: 10.1053/j.ackd.2014.03.007] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 03/07/2014] [Accepted: 03/10/2014] [Indexed: 12/13/2022]
Abstract
The nature of CKD in diabetes is changing. Diabetic glomerulosclerosis remains the cause of CKD in most type 1 diabetic individuals. However, the rate of progression of diabetic nephropathy has slowed because of improving glucose and blood pressure control. Most individuals with type 2 diabetes and 5% to 30% of those with type 1 diabetes with progressive CKD have normal urine albumin excretion or low-level microalbuminuria (albumin-to-creatinine ratio approximately <100 mg/g), which does not progress despite the decline in glomerular filtration. People with progressive CKD but normal albuminuria have predominantly interstitial or vascular changes with much less glomerular changes. It seems likely that these histological abnormalities relate to blood pressure, aging, obesity, and intrarenal vascular disease. Initial studies suggested that 85% to 100% of diabetic individuals with microalbuminuria (Kidney Disease Improving Global Outcomes [KDIGO] CKD albuminuria A2) progressed to proteinuria (KDIGO CKD albuminuria A3). Recent data demonstrate that even after 2 to 3 years of persistent microalbuminuria, most will revert to normal albumin excretion (KDIGO CKD albuminuria A1). Regression is more likely at lower levels of microalbuminuria and with improved glucose, blood pressure, and lipid control. Thus, low levels of microalbuminuria cannot be considered as established diabetic nephropathy.
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Lecaire TJ, Klein BEK, Howard KP, Lee KE, Klein R. Risk for end-stage renal disease over 25 years in the population-based WESDR cohort. Diabetes Care 2014; 37:381-8. [PMID: 24026564 PMCID: PMC3898749 DOI: 10.2337/dc13-1287] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE In the population-based Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) cohort, we sought to examine whether a decline in the prevalence and incidence of end-stage renal disease (ESRD) was evident with increasing calendar year of type 1 diabetes diagnosis among people followed for 25 years. Factors associated with the hazard of incident ESRD that may mediate a decline were also investigated. RESEARCH DESIGN AND METHODS Participants were examined at baseline in 1980 (n = 996) and at 4-25 years of follow-up. ESRD was defined by self-reported renal transplant or dialysis. Cumulative incidence with competing risk of death was determined. Incident ESRD was modeled by period of diagnosis, adjusting for other known risk factors using discrete time hazard models. RESULTS When diabetes was diagnosed during 1970-1980, the unadjusted cumulative incidence of ESRD at 25 years was 9.3%. The unadjusted hazard of ESRD was reduced by 70% (P < 0.001), compared with those diagnosed with diabetes in 1922-1969; however, the association was attenuated by glycosylated hemoglobin level (HbA1c), systolic blood pressure, and antihypertensive use (hazard ratio [HR] 0.89 [95% CI 0.55-1.45]). HbA1c, age, and male sex remained associated with ESRD hazard after adjustment for kidney function and proliferative retinopathy. CONCLUSIONS A lower incidence of ESRD among those more recently diagnosed with type 1 diabetes was explained by improvements in glycemic and blood pressure control over the last several decades. Intensive diabetes management, especially for glycemic control, remains important even in long-standing diabetes as it may delay the development of ESRD.
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Daniels M, DuBose SN, Maahs DM, Beck RW, Fox LA, Gubitosi-Klug R, Laffel LM, Miller KM, Speer H, Tamborlane WV, Tansey MJ. Factors associated with microalbuminuria in 7,549 children and adolescents with type 1 diabetes in the T1D Exchange clinic registry. Diabetes Care 2013; 36:2639-45. [PMID: 23610082 PMCID: PMC3747908 DOI: 10.2337/dc12-2192] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To examine factors associated with clinical microalbuminuria (MA) diagnosis in children and adolescents in the T1D Exchange clinic registry. RESEARCH DESIGN AND METHODS T1D Exchange participants <20 years of age with type 1 diabetes ≥ 1 year and urinary albumin-to-creatinine ratio (ACR) measured within the prior 2 years were included in the analysis. MA diagnosis required all of the following: 1) a clinical diagnosis of sustained MA or macroalbuminuria, 2) confirmation of MA diagnosis by either the most recent ACR being ≥ 30 mg/g or current treatment with an ACE inhibitor (ACEI) or angiotensin receptor blocker (ARB), and 3) no known cause for nephropathy other than diabetes. Logistic regression was used to assess factors associated with MA. RESULTS MA was present in 329 of 7,549 (4.4%) participants, with a higher frequency associated with longer diabetes duration, higher mean glycosylated hemoglobin (HbA1c) level, older age, female sex, higher diastolic blood pressure (BP), and lower BMI (P ≤ 0.01 for each in multivariate analysis). Older age was most strongly associated with MA among participants with HbA1c ≥ 9.5% (≥ 80 mmol/mol). MA was uncommon (<2%) among participants with HbA1c <7.5% (<58 mmol/mol). Of those with MA, only 36% were receiving ACEI/ARB treatment. CONCLUSIONS Our results emphasize the importance of good glycemic and BP control, particularly as diabetes duration increases, in order to reduce the risk of nephropathy. Since age and diabetes duration are important nonmodifiable factors associated with MA, the importance of routine screening is underscored to ensure early diagnosis and timely treatment of MA.
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Affiliation(s)
- Mark Daniels
- Children’s Hospital of Orange County, Orange, California, USA
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Maahs DM, Caramori ML, Cherney DZ, Galecki AT, Gao C, Jalal D, Perkins BA, Pop-Busui R, Rossing P, Mauer M, Doria A. Uric acid lowering to prevent kidney function loss in diabetes: the preventing early renal function loss (PERL) allopurinol study. Curr Diab Rep 2013; 13:550-9. [PMID: 23649945 PMCID: PMC3703487 DOI: 10.1007/s11892-013-0381-0] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Diabetic kidney disease causes significant morbidity and mortality among people with type 1 diabetes (T1D). Intensive glucose and blood pressure control have thus far failed to adequately curb this problem and therefore a major need for novel treatment approaches exists. Multiple observations link serum uric acid levels to kidney disease development and progression in diabetes and strongly argue that uric acid lowering should be tested as one such novel intervention. A pilot of such a trial, using allopurinol, is currently being conducted by the Preventing Early Renal Function Loss (PERL) Consortium. Although the PERL trial targets T1D individuals at highest risk of kidney function decline, the use of allopurinol as a renoprotective agent may also be relevant to a larger segment of the population with diabetes. As allopurinol is inexpensive and safe, it could be cost-effective even for relatively low-risk patients, pending the completion of appropriate trials at earlier stages.
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Affiliation(s)
- David M. Maahs
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO
| | - M. Luiza Caramori
- Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN
| | - David Z.I. Cherney
- Department of Medicine and Division of Nephrology, University of Toronto, Toronto, ON
| | - Andrzej T. Galecki
- Division of Geriatrics/Institute of Gerontology, Medical School, and Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI
| | - Chuanyun Gao
- Joslin Clinic, Joslin Diabetes Center, Boston, MA
| | - Diana Jalal
- Division of Renal Diseases and Hypertension, University of Colorado Denver, Aurora, CO
| | - Bruce A. Perkins
- Department of Medicine and Division of Endocrinology, University of Toronto, Toronto, ON
| | - Rodica Pop-Busui
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, MI
| | - Peter Rossing
- Steno Diabetes Center, Gentofte, Denmark
- HEALTH, University of Aarhus, Aarhus, Denmark
- NNF CBMR University of Copenhagen, Copenhagen, Denmark
| | - Michael Mauer
- Departments of Pediatrics and Medicine, University of Minnesota, Minneapolis, MN
| | - Alessandro Doria
- Research Division, Joslin Diabetes Center, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
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Abstract
The increasing prevalence of diabetes has led to DKD becoming the leading cause of ESRD in many regions. The economic cost of DKD will grow to prohibitive amounts unless strategies to prevent its onset or progression are urgently implemented. In type 1 and type 2 diabetes, the presence of microalbuminuria and macroalbuminuria confers increased risk of developing ESRD and of death. Comparison of recent studies with earlier historical studies shows that the incidence of ESRD and death has decreased in DKD. Increased risk of albuminuria has been identified in certain non-European ethnic groups. However, the initial concept of progression of DKD as an albuminuric phenotype involving development of microalbuminuria, macroalbuminuria, and then ESRD has had to be modified. Albumin excretion frequently regresses, and GFR can decline without abnormality in albumin excretion. There is emerging evidence that changes in renal function occurring early in the course of diabetes predict future outcomes. The major challenges are to prevent DKD onset, to detect it early, and to improve DKD outcomes globally.
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MESH Headings
- Albuminuria/epidemiology
- Albuminuria/etiology
- Albuminuria/physiopathology
- Cardiovascular Diseases/epidemiology
- Cardiovascular Diseases/etiology
- Cost of Illness
- Diabetes Mellitus, Type 1/complications
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 1/physiopathology
- Diabetes Mellitus, Type 2/complications
- Diabetes Mellitus, Type 2/epidemiology
- Diabetes Mellitus, Type 2/physiopathology
- Diabetic Nephropathies/epidemiology
- Diabetic Nephropathies/etiology
- Diabetic Nephropathies/physiopathology
- Diabetic Nephropathies/prevention & control
- Diabetic Nephropathies/urine
- Disease Progression
- Early Diagnosis
- Early Medical Intervention
- Epidemiologic Studies
- Ethnicity
- Glomerular Filtration Rate
- Humans
- Incidence
- Kidney Failure, Chronic/epidemiology
- Kidney Failure, Chronic/etiology
- Kidney Failure, Chronic/physiopathology
- Kidney Failure, Chronic/urine
- Outcome Assessment, Health Care
- Risk Factors
- Survival Analysis
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Affiliation(s)
- Anne T Reutens
- Department of Epidemiology and Preventive Medicine, Alfred Centre, Monash University, Melbourne, Victoria 3004, Australia.
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Affiliation(s)
- Werner Waldhäusl
- Department of Medicine III, Medical University of Vienna, Vienna, Austria.
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Gu HF, Ma J, Gu KT, Brismar K. Association of intercellular adhesion molecule 1 (ICAM1) with diabetes and diabetic nephropathy. Front Endocrinol (Lausanne) 2012; 3:179. [PMID: 23346076 PMCID: PMC3551242 DOI: 10.3389/fendo.2012.00179] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2012] [Accepted: 12/17/2012] [Indexed: 12/26/2022] Open
Abstract
Diabetes and diabetic nephropathy are complex diseases affected by genetic and environmental factors. Identification of the susceptibility genes and investigation of their roles may provide useful information for better understanding of the pathogenesis and for developing novel therapeutic approaches. Intercellular adhesion molecule 1 (ICAM1) is a cell surface glycoprotein expressed on endothelial cells and leukocytes in the immune system. The ICAM1 gene is located on chromosome 19p13 within the linkage region of diabetes. In the recent years, accumulating reports have implicated that genetic polymorphisms in the ICAM1 gene are associated with diabetes and diabetic nephropathy. Serum ICAM1 levels in diabetes patients and the icam1 gene expression in kidney tissues of diabetic animals are increased compared to the controls. Therefore, ICAM1 may play a role in the development of diabetes and diabetic nephropathy. In this review, we present genomic structure, variation, and regulation of the ICAM1 gene, summarized genetic and biological studies of this gene in diabetes and diabetic nephropathy and discussed about the potential application using ICAM1 as a biomarker and target for prediction and treatment of diabetes and diabetic nephropathy.
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Affiliation(s)
- Harvest F. Gu
- M1:03 Rolf Luft Center for Diabetes and Endocrinology Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University HospitalStockholm, Sweden
- *Correspondence: Harvest F. Gu, M1:03 Rolf Luft Center for Diabetes and Endocrinology Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-17176, Sweden. e-mail:
| | - Jun Ma
- Department of Anesthesiology, Anzhen Hospital, Capital Medical UniversityBeijing, People’s Republic of China
| | - Karolin T. Gu
- Viktor Rydberg Gymnasium Odenplan SchoolStockholm, Sweden
| | - Kerstin Brismar
- M1:03 Rolf Luft Center for Diabetes and Endocrinology Research, Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University HospitalStockholm, Sweden
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