Renoprotection in diabetic kidney disease: can incretin-based therapies deliver? Purpose of review Incretin-based therapies mimic or augment the gut-hormone glucagon-like peptide (GLP)-1 and, due to their glucose-lowering potential and beneficial safety profile, as well as their cardiovascular safety and/or protection, are prescribed on a large scale to treat individuals with type 2 diabetes (T2D). However, whether the two drug-classes that belong to this category, respectively GLP-1 receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors, also reduce the risk of diabetic kidney disease (DKD) is at present heavily debated. This review aims to discuss the current evidence. Recent findings Evidence from land-mark cardiovascular safety trials, conducted in people with T2D at high-cardiovascular risk but with normal kidney function, suggest that both drug-classes have excellent renal safety profiles. In contrast to DPP-4 inhibitors, it seems that GLP-1 receptor agonists reduce albuminuria and possibly induce a reduction of estimated glomerular filtration rate decline. However, the trials were not properly designed to test renal outcomes. Summary A dedicated renal trial involving a GLP-1 receptor agonist has recently commenced and will answer the question whether these drugs will be effective to reduce DKD. Moreover, ongoing mechanism-of-action studies are focusing on the renal physiological effects of GLP-1, as the effects on particularly albuminuria reduction remain currently unexplained. Correspondence to Daniël H. van Raalte, MD, PhD, Department of Internal Medicine, Diabetes Center, Amsterdam University Medical Centers, VUMC, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Tel: +31 20 4440534; e-mail: d.vanraalte@amsterdamumc.nl Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The emerging role of activins in renal disease Purpose of review This review highlights recent discoveries and advances that have been made in understanding the role of the TGFβ superfamily members activins, and in particular, activin A (ActA), in renal disease. Recent findings A deleterious role for ActA in renal disease and its complications has begun to emerge. We summarize data supporting an important contribution of ActA to kidney fibrosis and inflammation of varying causes, as well as its role in the development of a particular bone mineral disorder seen in chronic kidney disease (CKD) called mineral bone disorder (MBD), including vascular calcification. Finally, we discuss ActA in the context of anemia associated with chronic kidney disease and review potential approaches to treatment based on ActA blockade. Summary ActA is an important contributor to the pathogenesis of acute and chronic kidney disease of varying causes. Preclinical studies show that ActA inhibition, through various approaches, is protective in rodent models of kidney disease. The potential adverse effects of some of these approaches can be attributed to their targeting of other TGFβ family ligands. Further preclinical and clinical investigations testing the therapeutic efficacy of more selective ActA inhibition on the progression of acute and chronic kidney disease and its impact on bone-mineral disorder would more definitively establish its role in renal disease. Correspondence to Joan C. Krepinsky, St. Joseph's Hospital, 50 Charlton Ave East, Rm T3311, Hamilton, ON L8N 4A6, Canada. Tel: +1 905 522 1155 x34991; fax: +1 905 540 6589; e-mail: krepinj@mcmaster.ca Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Potassium binding for conservative and preservative management of chronic kidney disease Purpose of review Hyperkalemia is a life-threatening complication of chronic kidney disease (CKD). Risk factors include advanced kidney impairment, diabetes, hypertension, heart failure, and consumption of a K+-enriched diet. High-K+ diets provide health benefits to include reductions in blood pressure, stroke risk, and osteoporosis. Individuals at the highest risk for developing hyperkalemia are those who would benefit most from high K+ diets. Inhibitors of the renin--angiotensin--aldosterone system (RAASi) are effective in reducing cardiovascular events and slowing the progression of CKD, yet hyperkalemia is a risk factor. Discussed are new strategies facilitating use of both high-K+ diets and pharmacology to preserve kidney function and reduce cardiovascular events. Recent findings Sodium zirconium cyclosilicate and patiromer are new K+-binding drugs approved for the treatment of hyperkalemia. Both are efficacious in the short-term and long-term treatment of hyperkalemia. These binders are effective in treating hyperkalemia while facilitating RAASi therapy. Summary Hyperkalemia is a life-threatening condition. New K+-binding drugs allow for optimal use of pharmacological therapy, such as RAASi, enhancing their cardiorenal protection. Health benefits from consumption of high K+ foods may also be enhanced by use of these binders. In conclusion, there are new well tolerated and effective K+-binding agents for acutely and chronically managing hyperkalemia. Correspondence to Biff F. Palmer, MD, Professor of Internal Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA. Tel: +1 214 648 7848; fax: +1 214 648 2071; e-mail: biff.palmer@utsouthwestern.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Fluid overload as a therapeutic target for the preservative management of chronic kidney disease Purpose of review There is growing clinical evidence of adverse effects of fluid overload on kidney outcomes in patients with cardiovascular disease who are not yet receiving kidney replacement therapy. In this review, we discuss the patient populations most at risk for fluid overload, the pathophysiology associated with fluid overload, and finally treatment options. Recent findings The severity of fluid overload is an independent risk factor for both an increased risk of rapidly declining kidney function and increased risk for the need of kidney replacement therapy. High venous pressure within the kidney secondarily causes a decrease in kidney perfusion, which in turn signals salt retention and the resulting increase in plasma volume completes a vicious cycle propagating ongoing kidney injury. Fluid overload has also been identified as a risk factor for the combined outcome of all-cause mortality and cardiovascular morbidity. This increased risk in some studies has been identified as more important than hypertension in predicting both the increased risk of kidney disease progression and morbidity and mortality from cardiovascular disease. Once fluid status is accurately assessed, a combination of salt restriction and effective diuretic therapy is the first-line therapy to manage this complication. In those patients who require additional therapy, use of a V2 receptor antagonists can be considered. Finally, some patients may benefit from peritoneal dialysis to bring about volume removal even if they do not yet require dialysis for uremic complications. Summary Excess fluid or fluid overload appears to enhance chronic kidney disease progression and its treatment and resolution is a potential disease-modifying intervention. Correspondence to Biff F. Palmer, MD, Professor of Internal Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA. Tel: +1 214 648 7848; fax: +1 214 648 2071; e-mail: biff.palmer@utsouthwestern.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Mitigating risk of aldosterone in diabetic kidney disease Purpose of review Diabetic kidney disease is a growing problem leading to end-stage kidney disease but also atherosclerotic cardiovascular disease and heart failure. Aldosterone is a key risk factor promoting inflammation and fibrosis causing cardio-renal failure. Current options and challenges with mitigating the risk of aldosterone are reviewed. Recent findings More aggressive renin–angiotensin–aldosterone system (RAAS) blockade can be maintained in individuals with hyperkalemia if new potassium binders are added. Aldosterone synthase inhibitors may lower aldosterone without causing hyperkalemia. Novel nonsteroidal mineralocorticoid receptor antagonists (MRA) are able to lower proteinuria and markers of heart failure, with limited potassium problems and without renal impairment. Ongoing clinical trials are evaluating the safety and potential benefits of nonsteroidal MRAs on progression of renal disease and development of cardiovascular outcomes in type 2 diabetes and kidney disease. Summary Aldosterone is an important driver of inflammation and fibrosis leading to renal and cardiovascular complications. MRA lower albuminuria but data showing prevention of end-stage kidney disease are lacking. Side effects including hyperkalemia have previously prevented long-term studies in diabetic kidney disease but new treatment strategies with potassium binders, aldosterone synthase inhibitors and nonsteroidal MRA have been developed for clinical testing. Correspondence to Peter Rossing, MD, DMSc, Head of Complications Research, Steno Diabetes Center Copenhagen (SDCC), Niels Steensens Vej 2, DK-2820 Gentofte, Denmark. Tel: +45 30 91 33 83; e-mail: Peter.Rossing@RegionH.dk This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Promoting resolution in kidney disease: are we nearly there yet? Purpose of review Nephrology lacks effective therapeutics for many of the presentations and diseases seen in clinical practice. In recent decades, we have come to understand the central place of inflammation in initiating and propagating kidney disease, and, research in more recent years has established that the resolution of inflammation is a highly regulated and active process. With this, has evolved an appreciation that this aspect of the host inflammatory response is defective in kidney disease and led to consideration of a therapeutic paradigm aiming to harness the activity of the molecular drivers of the resolution phase of inflammation. Fatty-acid-derived Specialized pro-resolving mediators (SPMs), partly responsible for resolution of inflammation have gained traction as potential therapeutics. Recent findings We describe our current understanding of SPMs for this purpose in acute and chronic kidney disease. These studies cement the place of inflammation and its defective resolution in the pathogenesis of kidney disease, and highlight new avenues for therapy. Summary Targeting resolution of inflammation is a viable approach to treating kidney disease. We optimistically look forward to translating these experimental advances into tractable therapeutics to treat kidney disease. Correspondence to Eoin Brennan, UCD Diabetes Complications Research Centre, UCD Conway Institute of Biomolecular & Biomedical Research, UCD School of Medicine, University College Dublin, Dublin 4, Ireland. E-mail: eoin.brennan@ucd.ie Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Nuclear factor erythroid 2-related factor 2 as a treatment target of kidney diseases Purpose of review Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor which regulates a wider range of downstream pathways than previously thought. This review focuses on the novel findings about the internal regulatory mechanisms of Nrf2, the expanding understanding of its role in maintaining cellular homeostasis and the attempts to broaden the clinical application of its activators. Recent findings Nrf2 is in charge of the maintenance of cellular homeostasis under stress and there exist the internal regulatory mechanisms for Nrf2 which have recently been elucidated. New downstream pathways of Nrf2 have been discovered, including the defense against ferroptosis, the latest concept of cell death. Several Nrf2 activators are at various stages of clinical development and are being tested in clinical trials for chronic kidney disease (CKD) including diabetic kidney disease, Alport syndrome, autosomal dominant polycystic kidney disease and focal segmental glomerulosclerosis. Summary Nrf2 has been gathering attention as an emerging treatment target of chronic diseases which have oxidative stress and inflammation as their pathogenesis including CKD. Basic and clinical studies are under way to establish its role as a target for treatment of those diseases. Correspondence to Masaomi Nangaku, Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Tel: +81 3 5800 9736; fax: +81 3 5800 9807; e-mail: mnangaku-tky@umin.ac.jp Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Exploring old concepts and new paradigms No abstract available