Mechanisms of sodium retention in nephrotic syndrome Purpose of review Proteinuria in nephrotic syndrome is associated with sodium retention and edema. Recent studies from mice, rats and humans have shown that the sodium retention depends on urinary serine proteases and that it can be mitigated by blockers (amiloride, triamterene) of the epithelial sodium channel ENaC. The present review outlines the mechanisms of protease-stimulated sodium retention during proteinuric diseases. Recent findings Inhibition of protease activity in nephrotic mice using aprotinin alleviates sodium retention. From both human and mice studies, an increased proteolytic cleavage of the γENaC subunit plays a role in ENaC activation. In animal models, urokinase-plasmin contributes but not as sole mediators of sodium retention. Across experimental models, human case reports and small intervention trials, amiloride alleviates nephrotic sodium retention and low-renin hypertension with high efficacy. Summary Although the exact mechanisms for proteolytic ENaC activation are not resolved, multiple, redundant proteases are involved. Experimental and clinical evidence indicate that aberrant proteolytic ENaC activation is a primary driver of sodium retention in nephrotic syndrome and contributes to hypertension in conditions with low-grade proteinuria. Thus, we foresee increased and personalized use of amiloride treatment of nephrotic and other proteinuric disease patients with associated sodium retention and hypertension. Correspondence to Per Svenningsen, PhD, Department of Molecular Medicine, Cardiovascular and Renal Research, University of Southern Denmark, J. B. Winsløws vej 21,3., DK-5000 Odense C, Denmark. Tel: +45 6550 7905; e-mail: psvenningsen@health.sdu.dk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Nephrolithiasis in women: how different from men? Purpose of review Men have more kidney stones compared with women; however, the difference is progressively decreasing. The reasons for higher prevalence of stones in men, as well as increasing prevalence in women, is a subject of ongoing speculation. In this review, we summarize the evidence of differences between men and women and expand on the speculative causes. Recent findings Stone incidence is rising in women and adolescent girls. Stone disease is more heritable among men than women, and women demonstrate greater influence of the unique environment. Women under the age of 50 years who have been pregnant, have more than double the odds of kidney stones compared with those who have never been pregnant. Women are more burdened with obesity, bariatric surgery and dieting, all associated with increased stones. Women have higher urinary pH because of greater absorption of dietary organic anions leading to increased urinary citrate, compared with men, and they differ in tubular calcium handling. Summary It is obvious that the cause of stones in men and women is complex and requires further study. Potential clues offered are in the change of the female environment, influencing increasing incidence in stones, particularly of younger women and female adolescents. Correspondence to Lada Beara-Lasic, MD, MS, Nephrology Section, New York Harbor VA Healthcare System, Clinical Assistant Professor of Medicine, New York University School of Medicine, New York Harbor VAMC, 423 E. 23 Street, New York, NY 10010, USA. Tel: +1 212 686 7500 3880; fax: +1 212 951 6842; e-mail: lada.bearalasic@nyulangone.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Conservative vs. preservative management of chronic kidney disease: similarities and distinctions Purpose of review Dialysis has been the prevailing treatment paradigm in advanced chronic kidney disease (CKD) for patients ineligible for or unlikely to receive kidney transplantation. As dialysis may neither offer survival benefit nor improved quality of life in certain groups, there has been increasing interest in conservative management as an alternative approach. Recent findings Experts and workgroups suggest the main goals of conservative management are to optimize quality of life, treat symptoms of end-stage renal disease without dialysis or transplant, and improve survival and cardiovascular health. Given the implications of preserved kidney function on clinical outcomes, preservative management has been proposed as an integral component of conservative management. Growing evidence suggests the survival benefit of dialysis vs. conservative management without dialysis is marginal or even reversed in certain subpopulations (elderly, multimorbid, cardiovascular disease). Limited data suggest that conservative and preservative management is associated with equivalent to more favorable trajectories of health-related quality of life and symptom burden over time as opposed to dialysis. Summary Whereas existing data suggest conservative management is a viable patient-centered treatment strategy, further research is needed to determine the comparative effectiveness of preservative kidney management vs. dialysis or palliative management, as well as which patient subgroups will most benefit from these treatment strategies. Correspondence to Connie M. Rhee, MD, MSc, Harold Simmons Center for Kidney Disease Research and Epidemiology, University of California, Irvine, School of Medicine, 101 The City Drive South, City Tower, Suite 400, Orange, CA 92868, USA. Tel: +1 714 456 5142; fax: +1 714 456 6034; e-mail: crhee1@uci.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Novel options for failing allograft in kidney transplanted patients to avoid or defer dialysis therapy Purpose of review Despite improvement in short-term renal allograft survival in recent years, renal transplant recipients (RTR) have poorer long-term allograft outcomes. Allograft function slowly declines with periods of stable function similar to natural progression of chronic kidney disease in nontransplant population. Nearly all RTR transitions to failing renal allograft (FRG) period and require transition to dialysis. Conservative chronic kidney disease management before transition to end-stage renal disease is an increasingly important topic; however, there is limited data in RTR regarding how to delay dialysis initiation with conservative management. Recent findings Since immunological and nonimmunological factors unique to RTR contribute to decline in allograft function, therapies to slow progression of FRG should take both sets of factors into account. Renal replacement therapy either incremental dialysis or rekidney transplantation should be explored. This required taking benefits and risks of continuing immunosuppressive medications into account when allograft nephrectomy may be necessary. Summary FRG may benefit from various interventions to slow progression of worsening allograft function. Until there are stronger evidence to guide interventions to preserve renal function, extrapolating evidence from nontransplant patients and clinical judgment are necessary. The goal is to provide individualized care for conservative management of RTR with FRG. Correspondence to Kamyar Kalantar-Zadeh, MD, MPH, PhD, Professor and Chief, Division of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, University of California Irvine School of Medicine, Orange, California, USA. Tel: +1 714 456 5142; e-mail: kkz@hs.uci.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Perspiration interventions for conservative management of kidney disease and uremia Purpose of review There has been an increasing interest in developing novel technologies to treat patients with chronic kidney disease as evidenced by KidneyX, the public–private partnership between government and industry. Perhaps a simple technology for treating kidney failure would be to utilize perspiration. It is a physiological process, and when used properly it might not be an unpleasant experience. This review will explore the current state of knowledge regarding perspiration therapy in the setting of far advanced kidney failure. Recent findings A literature review using the PubMed database was conducted between 1 April 2019 and 3 September 2019. Search terms are shown in Table 1. Major themes of the results include diaphoresis therapy for patients with chronic kidney disease, excessive perspiration causing kidney disease, analysis of sweat to diagnose cystic fibrosis, and analysis of sweat to replenish lost electrolytes. This review will focus on intentional perspiration for the treatment of patients with end-stage renal disease (ESRD). Studies have shown that perspiration, or sweat-based therapies, can provide some of the most important currently recognized therapeutic goals in treating ESRD. These goals include decreased interdialytic weight gain, reduced serum potassium levels, and benefits to cardiovascular status. Research has shed light on some of the mechanisms, both molecular and clinical, that may be involved in induced perspiration therapy in ESRD. Summary There is a long history of humans using perspiration for both recreation and therapy. Perspiration therapy for ESRD experienced a surge in the United States in the 1960s but does not have much modern momentum. With the continued growth of the ESRD population worldwide this could be considered an appropriate time to conduct more research into this promising therapy. Correspondence to Raymond W. Keller, DO, Third Kidney, Inc., 546 Pool St, Biddeford, ME 04005, USA. Tel: +1 207 929 0576; e-mail: raykeller@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

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.