Preventing a nonexistent entity: the curious case of contrast and acute kidney injury Purpose of review In recent years, doubt has been cast on the existence of contrast-induced acute kidney injury. The skepticism has stemmed from observational studies from large administrative healthcare databases. Although they correctly call that contrast-induced acute kidney injury is less common than previously thought, they cannot completely exclude selection bias. Recent findings Though less common than previously thought, contrast-induced acute kidney injury still exists. The only prophylactic method that remains valid is that of isotonic volume expansion, which is still deemed beneficial in high-risk patients. N-acetylcysteine and sodium bicarbonate are ineffective and their use should be abandoned. Summary Contrast-induced kidney injury should be defined based on clinical grounds, not merely on biochemical numbers. More research to validate a clinical definition is necessary in order to accurately re-examine its incidence. Correspondence to Swapnil Hiremath, MD, MPH, 1967 Riverside Dr, Ottawa, ON, Canada K1H7W9. Tel: +1 6137388400 x82762; fax: +1 6137388337; e-mail: shiremath@toh.ca Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Intestinal dialysis for conservative management of Uremia Purpose of review Renal replacement therapies, such as hemodialysis are invasive and impose significant financial burden as well as burden on quality of life. Conservative and ‘gentler’ forms of renal replacement therapy for the frail and palliative care patient is an unmet medical need. Recent findings The treatment of uremia using the gut as a substitute for the kidney has been proposed but is not practiced widely because of proven lack of long-term mortality benefit coupled with complications like edema and hyperchloremia. Mounting evidence showed that endotoxins from gastrointestinal tract are a major source of chronic inflammation in chronic kidney disease (CKD). The high load of nitrogenous waste elimination through the bowel could potentially serve as an alternative modality to remove uremic wastes especially in people who opt for conservative management for end-stage renal disease with some recent studies in Iran and China showing promising benefits in uremia. Summary In this review, we will discuss the history, recent evidence and potential of these therapies and their implications in CKD for conservative and easy management of uremia. Correspondence to Subodh J. Saggi, MD, MPH, Renal Division, Department of Medicine, State University of New York Medical Center, 450 Clarkson Avenue, Brooklyn, NY 11203, USA. Tel: +1 718 270 1584/+1 718 270 2848; e-mail: subodh.saggi@downstate.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Charcoal for the management of pruritus and uremic toxins in patients with chronic kidney disease Purpose of review Pruritus is an important, prevalent but often neglected symptom in patients with advanced chronic kidney disease (CKD) or on dialysis. This review addresses the use of activated charcoal and its analogs in the treatment of uremic pruritus, which can be a sign of uremic toxicity. Recent findings When common causes are corrected and dialysis efficiency is optimized, pruritus is mainly ascribed to the retention of middle and protein-bound molecules, of which indoxyl sulfate and p-cresyl sulfate are the best studied. While hemodialysis and hemodiafiltration are of limited use, activated charcoal and its analogs offer interesting alternatives. Oral preparations are associated with symptom improvement and a better metabolic pattern, probably via a combination of absorption and modification of the intestinal microbiota. Large studies, in well phenotyped populations, are needed. Hemoperfusion, commonly used in poisoning and intoxication, could be an interesting alternative in hemodialysis patients. The treatment has proved promising in some preliminary and small studies; more research is now needed to test its validity. Summary Oral activated charcoal and hemoperfusion can be proposed to patients with severe refractory pruritus based on positive, albeit scattered evidence. They also contribute to reducing uremic toxins. Research on their implementation associated with well established treatments is needed to understand whether they can be used as ‘uremic detoxifiers’. Correspondence to Adamasco Cupisti, MD, Professor of Nephrology, Department of Clinical and Experimental Medicine, Università di Pisa, Via Roma 67, 56126 Pisa, Italy. Tel: +00 39 50 997291; e-mail: adamasco.cupisti@med.unipi.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Microbiome modulation to correct uremic toxins and to preserve kidney functions Purpose of review The association between dysbiosis and CKD is well established. This review focuses on the current understanding of microbiome, in normal individuals and CKD patients, in order to hypothesize how to correct uremic toxins levels and preserve the renal function and reduce associated comorbidities. Here we discuss our current opinion on microbiome modulation in order to manage the CKD-associated dysbiosis. Recent findings Emerging evidence confirms the role of gut microbiome in the progression of CKD. In this scenario, the need is felt to set up multifaceted approaches for dysbiosis management. Among many strategies able to improve gut wellness, a crucial approach is represented by the functional nutrition. At the same time, drug-based treatments show significant results in microbiome modulation. Furthermore, we examine here the potentialities of fecal microbiome transplantation (FMT) in CKD, an approach currently applied in Clostridium difficile infection. Summary The gut microbiome plays a pivotal role in the pathophysiology of CKD. The vicious cycle triggered by kidney function decline leads to gut dysbiosis. Considering the gut microbiome as a therapeutic target in CKD, multiple approaches aimed at its modulation should be envisioned to preserve kidney function. Dietary interventions and pharmacological strategies are able to improve microbiome dysbiosis, oxidative stress and fibrosis. Additionally, FMT could represent a promising novel therapy in the management of CKD-associated dysbiosis. Correspondance to Loreto Gesualdo, Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy. Tel: +39 0805594041; e-mail: loreto.gesualdo@uniba.it Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Renoprotective effects of sodium-glucose cotransporter-2 inhibitors and underlying mechanisms Purpose of review Emerging data have demonstrated that sodium-glucose cotransporter-2 (SGLT2) inhibitors prevent cardiovascular events, especially heart failure-associated endpoints. Cardiovascular outcome trials have also suggested their renoprotective effects. One large clinical trial investigated renal primary endpoints and demonstrated that SGLT2 inhibitors slowed the progression of diabetic kidney disease (DKD). This review summarizes clinical trial data on renal outcomes and discusses potential underlying mechanisms. Recent findings The EMPA-REG, CANVAS, and DECLARE-TIMI 58 studies revealed that SGLT2 inhibitors reduce the risk of cardiovascular events and concomitantly suggested that these drugs slow the progression of kidney disease in type 2 diabetes. The CREDENCE trial on patients with high-risk type 2 diabetes and chronic kidney disease demonstrated that canagliflozin treatment reduced the relative risk of a composite outcome, including end-stage kidney disease, serum creatinine doubling, and renal/cardiovascular death, by 30% in these patients. Animal experiments revealed that oxidative stress, inflammation, fibrosis, and tubuloglomerular feedback are underlying renoprotective mechanisms behind SGLT2 inhibitors. Summary Recent clinical trials have established the renoprotective effects of SGLT2 inhibitors. Further investigations on mechanisms of these renoprotective effects will provide deeper insights and understanding of pathogenetic properties of DKD. Correspondence to Naoki Kashihara, MD, PhD, Department of Nephrology and Hypertension, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. Tel: +81 86 462 1111; fax: +81 86 462 1199; e-mail: kashinao@med.kawasaki-m.ac.jp Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Novel dietary and pharmacologic approaches for acid–base modulation to preserve kidney function and manage uremia Purpose of review We review mechanisms for chronic kidney disease (CKD) progression that might be addressed with nonpharmacologic and novel pharmacologic interventions as strategies by which to slow or even prevent CKD progression. Recent findings Evolving data support the contribution of the broad spectrum of disorders of acid (H+) accumulation, which we refer to as ‘H+ stress’, to CKD progression. Recent studies support that amelioration of H+ stress, including spectra of H+ accumulation that are insufficient to cause metabolic acidosis, is kidney-protective. In addition, gut-derived toxins appear to contribute to CKD progression and to the well described increased cardiovascular disease (CVD) risk in patients with CKD. Dietary and novel pharmacologic interventions hold promise as strategies to slow CKD progression through reducing levels of these gut-derived toxins. In addition, oxidative stress appears to mediate CKD progression and contributing factors like diet and cigarette smoking can exacerbate oxidative stress. Dietary changes and smoking cessation hold promise to favorably affect CKD progression by reducing kidney oxidative stress. Summary The urgent need to add to the traditional armamentarium of blood pressure control and antiangiotensin II pharmacologic therapy for kidney protection has led to investigations into additional kidney-protective strategies. Acid stress, a disordered gut microbiome, and oxidative stress each appear to contribute to CKD progression and can be potentially addressed by nonpharmacologic and novel pharmacologic interventions. Correspondence to Donald E. Wesson, MD, Baylor Scott and White Health and Wellness Center, Texas A&M Health Sciences Center College of Medicine, 4500 Spring Avenue, Dallas, TX 75216, USA. Tel: +1 214 865 3064; fax: +1 214 865 3070; e-mail: Donald.wesson@BSWHealth.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Novel therapeutic approaches in chronic kidney disease and uremia management No abstract available

Plant-based diets for prevention and management of chronic kidney disease Purpose of review Plant-based diets have been used with growing popularity for the treatment of a wide range of lifestyle-related diseases, including diabetes, hypertension, and obesity. With the reinvigoration of the conservative and dietary management of chronic kidney disease (CKD) and the use of low protein diets for secondary prevention of CKD to delay or prevent dialysis therapy, there is an increasing interest in the potential role of plant-based diets for these patients. Recent findings Recently, a body of evidence related to the role of plant-based diet in preventing CKD has reemerged. Several observational studies have shown that red and processed meat have been associated with increased risk of CKD as well as faster progressing in those with preexisting CKD. In several substitution analyses, replacement of one serving of red and/or processed meat has been linked with sizable reductions in CKD risk as primary prevention. Although limited, experimental trials for the treatment of metabolic acidosis in CKD with fruits and vegetables show outcomes comparable to oral bicarbonate. The use of plant-based diets in CKD may have other benefits in the areas of hypertension, weight, hyperphosphatemia, reductions in hyperfiltration, and, possibly, mortality. The risk of potassium overload from plant-based diets appears overstated, mostly opinion-based, and not supported the evidence. Plant-based diets are generally well tolerated and provide adequate protein intake, including essential amino acids as long as the is correctly implemented. Summary Plant-based diets should be recommended for both primary and secondary prevention of CKD. Concerns of hyperkalemia and protein inadequacy related to plant-based diets may be outdated and unsupported by the current body of literature. Healthcare providers in general medicine and nephrology can consider plant-based diets as an important tool for prevention and management of CKD. Correspondence to Shivam Joshi, MD, Department of Medicine, NYU School of Medicine, NYC Health and Hospitals/Bellevue, 550 First Avenue, New York, NY 10016, USA. Tel: +1 212 562 1703; e-mail: shivam.joshi@nyulangone.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Pharmacologic epigenetic modulators of alkaline phosphatase in chronic kidney disease Purpose of review In chronic kidney disease (CKD), disturbance of several metabolic regulatory mechanisms cause premature ageing, accelerated cardiovascular disease (CVD), and mortality. Single-target interventions have repeatedly failed to improve the prognosis for CKD patients. Epigenetic interventions have the potential to modulate several pathogenetic processes simultaneously. Alkaline phosphatase (ALP) is a robust predictor of CVD and all-cause mortality and implicated in pathogenic processes associated with CVD in CKD. Recent findings In experimental studies, epigenetic modulation of ALP by microRNAs or bromodomain and extraterminal (BET) protein inhibition has shown promising results for the treatment of CVD and other chronic metabolic diseases. The BET inhibitor apabetalone is currently being evaluated for cardiovascular risk reduction in a phase III clinical study in high-risk CVD patients, including patients with CKD (ClinicalTrials.gov Identifier: NCT02586155). Phase II studies demonstrate an ALP-lowering potential of apabetalone, which was associated with improved cardiovascular and renal outcomes. Summary ALP is a predictor of CVD and mortality in CKD. Epigenetic modulation of ALP has the potential to affect several pathogenetic processes in CKD and thereby improve cardiovascular outcome. Correspondence to Mathias Haarhaus, MD, PhD, Division of Renal Medicine and Baxter Novum, Karolinska Institutet, Karolinska University Hospital, SE-14186 Stockholm, Sweden. Tel: +46 58580000; e-mail: mathias.loberg-haarhaus@sll.se 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.

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.