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      Diabetic kidney disease: new clinical and therapeutic issues. Joint position statement of the Italian Diabetes Society and the Italian Society of Nephrology on “The natural history of diabetic kidney disease and treatment of hyperglycemia in patients with type 2 diabetes and impaired renal function”

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          Abstract

          Aims

          This joint document of the Italian Diabetes Society and the Italian Society of Nephrology reviews the natural history of diabetic kidney disease (DKD) in the light of the recent epidemiological literature and provides updated recommendations on anti-hyperglycemic treatment with non-insulin agents.

          Data Synthesis

          Recent epidemiological studies have disclosed a wide heterogeneity of DKD. In addition to the classical albuminuric phenotype, two new albuminuria-independent phenotypes have emerged, i.e., “nonalbuminuric renal impairment” and “progressive renal decline”, suggesting that DKD progression toward end-stage kidney disease (ESKD) may occur through two distinct pathways, albuminuric and nonalbuminuric. Several biomarkers have been associated with decline of estimated glomerular filtration rate (eGFR) independent of albuminuria and other clinical variables, thus possibly improving ESKD prediction. However, the pathogenesis and anatomical correlates of these phenotypes are still unclear. Also the management of hyperglycemia in patients with type 2 diabetes and impaired renal function has profoundly changed during the last two decades. New anti-hyperglycemic drugs, which do not cause hypoglycemia and weight gain and, in some cases, seem to provide cardiorenal protection, have become available for treatment of these individuals. In addition, the lowest eGFR safety thresholds for some of the old agents, particularly metformin and insulin secretagogues, have been reconsidered.

          Conclusions

          The heterogeneity in the clinical presentation and course of DKD has important implications for the diagnosis, prognosis, and possibly treatment of this complication. The therapeutic options for patients with type 2 diabetes and impaired renal function have substantially increased, thus allowing a better management of these individuals.

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          Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

          Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.
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            Diabetic Kidney Disease: Challenges, Progress, and Possibilities.

            Diabetic kidney disease develops in approximately 40% of patients who are diabetic and is the leading cause of CKD worldwide. Although ESRD may be the most recognizable consequence of diabetic kidney disease, the majority of patients actually die from cardiovascular diseases and infections before needing kidney replacement therapy. The natural history of diabetic kidney disease includes glomerular hyperfiltration, progressive albuminuria, declining GFR, and ultimately, ESRD. Metabolic changes associated with diabetes lead to glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Despite current therapies, there is large residual risk of diabetic kidney disease onset and progression. Therefore, widespread innovation is urgently needed to improve health outcomes for patients with diabetic kidney disease. Achieving this goal will require characterization of new biomarkers, designing clinical trials that evaluate clinically pertinent end points, and development of therapeutic agents targeting kidney-specific disease mechanisms (e.g., glomerular hyperfiltration, inflammation, and fibrosis). Additionally, greater attention to dissemination and implementation of best practices is needed in both clinical and community settings.
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              Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis.

              Substantial controversy surrounds the use of estimated glomerular filtration rate (eGFR) and albuminuria to define chronic kidney disease and assign its stages. We undertook a meta-analysis to assess the independent and combined associations of eGFR and albuminuria with mortality. In this collaborative meta-analysis of general population cohorts, we pooled standardised data for all-cause and cardiovascular mortality from studies containing at least 1000 participants and baseline information about eGFR and urine albumin concentrations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for all-cause and cardiovascular mortality associated with eGFR and albuminuria, adjusted for potential confounders. The analysis included 105,872 participants (730,577 person-years) from 14 studies with urine albumin-to-creatinine ratio (ACR) measurements and 1,128,310 participants (4,732,110 person-years) from seven studies with urine protein dipstick measurements. In studies with ACR measurements, risk of mortality was unrelated to eGFR between 75 mL/min/1.73 m(2) and 105 mL/min/1.73 m(2) and increased at lower eGFRs. Compared with eGFR 95 mL/min/1.73 m(2), adjusted HRs for all-cause mortality were 1.18 (95% CI 1.05-1.32) for eGFR 60 mL/min/1.73 m(2), 1.57 (1.39-1.78) for 45 mL/min/1.73 m(2), and 3.14 (2.39-4.13) for 15 mL/min/1.73 m(2). ACR was associated with risk of mortality linearly on the log-log scale without threshold effects. Compared with ACR 0.6 mg/mmol, adjusted HRs for all-cause mortality were 1.20 (1.15-1.26) for ACR 1.1 mg/mmol, 1.63 (1.50-1.77) for 3.4 mg/mmol, and 2.22 (1.97-2.51) for 33.9 mg/mmol. eGFR and ACR were multiplicatively associated with risk of mortality without evidence of interaction. Similar findings were recorded for cardiovascular mortality and in studies with dipstick measurements. eGFR less than 60 mL/min/1.73 m(2) and ACR 1.1 mg/mmol (10 mg/g) or more are independent predictors of mortality risk in the general population. This study provides quantitative data for use of both kidney measures for risk assessment and definition and staging of chronic kidney disease. Kidney Disease: Improving Global Outcomes (KDIGO), US National Kidney Foundation, and Dutch Kidney Foundation. Copyright 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Contributors
                giuseppe.pugliese@uniroma1.it
                Journal
                J Nephrol
                J. Nephrol
                Journal of Nephrology
                Springer International Publishing (Cham )
                1121-8428
                1724-6059
                2 October 2019
                2 October 2019
                2020
                : 33
                : 1
                : 9-35
                Affiliations
                [1 ]GRID grid.7841.a, Department of Clinical and Molecular Medicine, , “La Sapienza” University, ; Rome, Italy
                [2 ]GRID grid.18887.3e, ISNI 0000000417581884, Endocrine and Metabolic Unit, , Sant’Andrea University Hospital, ; Rome, Italy
                [3 ]GRID grid.5395.a, ISNI 0000 0004 1757 3729, Department of Clinical and Experimental Medicine, , University of Pisa, ; Pisa, Italy
                [4 ]GRID grid.144189.1, ISNI 0000 0004 1756 8209, Diabetes Unit, , University Hospital, ; Pisa, Italy
                [5 ]GRID grid.144189.1, ISNI 0000 0004 1756 8209, Unit of Internal Medicine, , University Hospital, ; Pisa, Italy
                [6 ]GRID grid.7605.4, ISNI 0000 0001 2336 6580, Department of Medical Sciences, , University of Turin, ; Turin, Italy
                [7 ]Nephrology Unit, “Mons. Dimiccoli” Hospital, Barletta, Italy
                [8 ]GRID grid.9027.c, ISNI 0000 0004 1757 3630, Department of Medicine, , University of Perugia, ; Perugia, Italy
                [9 ]GRID grid.7644.1, ISNI 0000 0001 0120 3326, Department of Emergency and Organ Transplantation, , “Aldo Moro” University, ; Bari, Italy
                [10 ]Nephrology, Dialysis and Transplantation Unit, “Policlinico” University Hospital, Bari, Italy
                [11 ]GRID grid.9841.4, ISNI 0000 0001 2200 8888, Nephrology and Dialysis Unit, Department of Advanced Medical and Surgical Sciences, , University of Campania “Luigi Vanvitelli”, ; Naples, Italy
                Article
                650
                10.1007/s40620-019-00650-x
                7007429
                31576500
                bcaec294-8c04-464f-b58c-f9932b444959
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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                © Italian Society of Nephrology 2020

                diabetes mellitus,diabetic nephropathy,albuminuria,estimated glomerular filtration rate,end-stage kidney disease,anti-hyperglycemic therapy

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