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      An Update on the Current State of Management and Clinical Trials for IgA Nephropathy

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          Abstract

          IgA nephropathy remains the most common primary glomerular disease worldwide. It affects children and adults of all ages, and is a leading cause of end-stage kidney disease, making it a considerable public health issue in many countries. Despite being initially described over 50 years ago, there are still no disease specific treatments, with current management for most patients being focused on lifestyle measures and renin-angiotensin-aldosterone system blockade. However, significant advances in the understanding of its pathogenesis have been made particularly over the past decade, leading to great interest in developing new therapeutic strategies, and a significant rise in the number of interventional clinical trials being performed. In this review, we will summarise the current state of management of IgAN, and then describe major areas of interest where new therapies are at their most advanced stages of development, that include the gut mucosal immune system, B cell signalling, the complement system and non-immune modulators. Finally, we describe clinical trials that are taking place in each area and explore future directions for translational research.

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          Most cited references112

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          Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes

          Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).
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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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              Dapagliflozin in Patients with Chronic Kidney Disease

              Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                04 June 2021
                June 2021
                : 10
                : 11
                : 2493
                Affiliations
                [1 ]Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK; ckc15@ 123456le.ac.uk (C.K.C.); jb81@ 123456le.ac.uk (J.B.)
                [2 ]John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester LE5 4PW, UK
                [3 ]Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, ZRB 614, 1720 2nd Avenue South, Birmingham, AL 35294, USA; arajasekaran@ 123456uabmc.edu
                Author notes
                [* ]Correspondence: drizk@ 123456uabmc.edu
                [†]

                Both authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0001-8593-7625
                https://orcid.org/0000-0002-7564-6362
                https://orcid.org/0000-0002-9063-7229
                Article
                jcm-10-02493
                10.3390/jcm10112493
                8200196
                34200024
                d56c374b-d683-462e-b9f3-bef5af3d81c6
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 29 April 2021
                : 02 June 2021
                Categories
                Review

                iga,iga nephropathy,clinical trials
                iga, iga nephropathy, clinical trials

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