Arterial stiffness in chronic kidney disease: a modifiable cardiovascular risk factor? Purpose of review There is an inverse, graded relationship between worsening chronic kidney disease (CKD) and increasing cardiovascular risk independent of traditional cardiovascular risk factors. Increasing arterial stiffness is a powerful predictor of cardiovascular outcomes in CKD. Developing novel therapeutic strategies to reverse this process is an attractive concept. This review presents the results of a literature survey of the last 18 months to establish if arterial stiffness can be considered a reversible cardiovascular risk factor in patients with CKD. Recent findings Multiple potential therapeutic approaches to reduce arterial stiffness have been proposed and tested. However, arterial stiffness and blood pressure (BP) have a very close bidirectional relationship. Any change in BP will have an effect on arterial stiffness and vice versa. At present, there is no robust evidence to support the notion that arterial stiffness can be considered reversible other than as a direct consequence of reduction in BP. Summary For now, arterial stiffness should be considered an indirectly modifiable cardiovascular risk factor through optimal control of BP. Measures of arterial stiffness should be regarded as research and risk stratification tools rather than a therapeutic target in itself. Correspondence to Charles J. Ferro, Department of Nephrology, Queen Elizabeth Hospital Birmingham, Birmingham B15 2WB, UK. Tel: +44 121 3715839; fax: +44 121 3715858; e-mail: charles.ferro@uhb.nhs.uk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Acute kidney injury prediction models: current concepts and future strategies Purpose of review Acute kidney injury (AKI) is a critical condition associated with poor patient outcomes. We aimed to review the current concepts and future strategies regarding AKI risk prediction models. Recent findings Recent studies have shown that AKI occurs frequently in patients with common risk factors and certain medical conditions. Prediction models for AKI risk have been reported in medical fields such as critical care medicine, surgery, nephrotoxic agent exposure, and others. However, practical, generalizable, externally validated, and robust AKI prediction models remain relatively rare. Further efforts to develop AKI prediction models based on comprehensive clinical data, artificial intelligence, improved delivery of care, and novel biomarkers may help improve patient outcomes through precise AKI risk prediction. Summary This brief review provides insights for current concepts for AKI prediction model development. In addition, by overviewing the recent AKI prediction models in various medical fields, future strategies to construct advanced AKI prediction models are suggested. Correspondence to Hajeong Lee, MD, Ph.D., Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-ro, Seoul 03080, Jongno-gu, South Korea. Tel.: +82 2 2072 4905;. e-mail: mdhjlee@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Fibroblast growth factor 23 and phosphate homeostasis Purpose of review The current review highlights recent advances in the area of renal tubular phosphate transport and its regulation by fibroblast growth factor 23 (FGF23), a potent regulator of phosphate homeostasis. Recent findings Recent studies demonstrate that FGF23 binds to both membrane and soluble form of α-klotho to activate FGF receptor signaling pathways. Parathyroid hormone and FGF23 equivalently decrease sodium-dependent phosphate cotransport but the effect is not additive, suggesting a shared but not synergistic mechanism of action. Crosstalk occurs downstream of parathyroid hormone-receptor and FGF23-receptor signaling and converge at the level of the scaffolding protein, sodium-hydrogen exchanger regulatory factor-1. A novel mechanism for phosphate efflux through the basolateral membrane of renal proximal tubular epithelia via an atypical G-protein coupled receptor, Xenotropic and polytropic retrovirus receptor 1 (XPR1), was recently identified. Conditional deletion of Xpr1 gene in renal proximal tubules in mice leads to hypophosphatemic rickets and Fanconi syndrome establishing an important role for XPR1 in phosphate homeostasis. A novel anti-FGF23 antibody, burosumab, was recently approved to treat X-linked hypophosphatemia, a human disorder of FGF23 excess. Summary Significant advances in understanding the cellular and molecular aspects of renal tubular phosphate transport and its regulation by FGF23 has led to the discovery of novel therapeutics to treat human disorders of phosphate homeostasis. Correspondence to Farzana Perwad, MD, Division of Nephrology, Department of Pediatrics, University of California, San Francisco, 550 16th Street, San Francisco, CA 94158, USA. Tel: +1 415 476 2423; fax: +1 415 476 9976; e-mail: Farzana.perwad@ucsf.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Cullin-Ring ubiquitin ligases in kidney health and disease Purpose of review Members of the Cullin family act as scaffolds in E3 ubiquitin ligases and play a central role in mediating protein degradation. Interactions with many different substrate-binding adaptors permit Cullin-containing E3 ligases to participate in diverse cellular functions. In the kidney, one well established target of Cullin-mediated degradation is the transcription factor Nrf2, a key player in responses to oxidative stress. The goal of this review is to discuss more recent findings revealing broader roles for Cullins in the kidney. Recent findings Cullin 3 acts as the scaffold in the E3 ligase regulating Nrf2 abundance, but was more recently shown to be mutated in the disease familial hyperkalemic hypertension. Studies seeking to elucidate the molecular mechanisms by which Cullin 3 mutations lead to dysregulation of renal sodium transport will be discussed. Disruption of Cullin 3 in mice unexpectedly causes polyuria and fibrotic injury suggesting it has additional roles in the kidney. We will also review recent transcriptomic data suggesting that other Cullins are also likely to play important roles in renal function. Summary Cullins form a large and diverse family of E3 ubiquitin ligases that are likely to have many important functions in the kidney. Correspondence to James A. McCormick, Oregon Health and Science University, 2730 Moody Avenue CL3NR, Portland, OR 97201, USA. Tel: +1 503 494 3980; e-mail: mccormij@ohsu.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Molecular regulation of NKCC2 in blood pressure control and hypertension Purpose of review The apical cotransporter Na+/K+/2Cl− cotransporter (NKCC2) mediates NaCl reabsorption by the thick ascending limb, contributing to maintenance of blood pressure (BP). Despite effective NKCC2 inhibition by loop diuretics, these agents are not viable for long-term management of BP due to side effects. Novel molecular mechanisms that control NKCC2 activity reveal an increasingly complex picture with interacting layers of NKCC2 regulation. Here, we review the latest developments that shine new light on NKCC2-mediated control of BP and potential new long-term therapies to treat hypertension. Recent findings Emerging molecular NKCC2 regulators, often binding partners, reveal a complex overlay of interacting mechanisms aimed at fine tuning NKCC2 activity. Different factors achieve this by shifting the balance between trafficking steps like exocytosis, endocytosis, recycling and protein turnover, or by balancing phosphorylation vs. dephosphorylation. Further molecular details are also emerging on previously known pathways of NKCC2 regulation, and recent in-vivo data continues to place NKCC2 regulation at the center of BP control. Summary Several layers of emerging molecular mechanisms that control NKCC2 activity may operate simultaneously, but they can also be controlled independently. This provides an opportunity to identify new pharmacological targets to fine-tune NKCC2 activity for BP management. Correspondence to Pablo A. Ortiz, Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, 2799 W Grand Blvd, E&R Building 7038, Detroit, MI 48202, USA. Tel: +1 313 916 7164; e-mail: portiz1@hfhs.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Hyperphosphataemia in 2019: have we made progress? Purpose of review This review describes recent developments in the management of serum phosphate in dialysis patients, with a focus on the development of recent trials which randomize patients to different levels of control. Recent findings We review the uncertainties around clinical benefits of serum phosphate control and alternative approaches to current management, as well as a multinational attempt to conduct randomized controlled trials in this area. We discuss novel methods of limiting oral phosphate absorption. Summary Although numerous guidelines and target ranges for serum phosphate management exist, they are largely based on observational data and there is no definitive evidence that good control improves the length or quality of life of dialysis patients. New phosphate binders continue to appear on the market with increasing financial cost but without additional meaningful outcome data. Two recently published trials have demonstrated the feasibility of a large-scale study of differing phosphate levels to test the hypothesis that reduction of serum phosphate is beneficial to dialysis patients. Restriction of oral phosphate intake should not be overlooked. Correspondence to Alastair J. Hutchison, MBChB, FRCP, MD, Medical Director Trust Headquarters, Dorset County Hospital NHS FT, Williams Avenue, Dorchester DT1 2JY, UK. Tel: +44 1305 254644; e-mail: alastair.hutchison@dchft.nhs.uk Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Renal sympathetic denervation for treatment of hypertension: where are we now in 2019? Purpose of review Although sound physiological principles and surgical precedent underpin renal denervation as a therapy for treatment resistant hypertension, and early clinical studies had produced encouraging results, the first sham-controlled study (SYMPLICITY HTN-3) failed to achieve its primary efficacy endpoint. Lessons learnt from this trial, and the knowledge derived from further animal and autopsy work, have been applied in three recently published sham-controlled trials. Recent findings These trials – SPYRAL OFF-MED, RADIANCE SOLO and SPYRAL ON-MED – using newer technologies, demonstrate a 5–10 mmHg incremental reduction in ambulatory SBP from RDN against sham-control, in patients with mild-to-moderate hypertension taking 0–3 drugs. Summary These results provide proof of principle of the blood pressure-lowering effect of renal denervation. We now require data on long-term safety and durability of the procedure. Research is needed to identify predictive markers of response as about one-third of subjects do not respond to renal denervation. Hard-outcome data would be welcome but might be difficult to acquire. Individuals with treatment resistance are obvious treatment candidates, but RDN may also potentially benefit those with medication nonadherence and/or intolerance and those unwilling to take pills. Correspondence to Indranil Dasgupta, Renal Unit, Heartlands Hospital, Bordesley Green East, Birmingham B9 5SS, UK. Tel: +44 121 424 2158; e-mail: Indranil.dasgupta@uhb.nhs.ukTwitterhandle:@idasgupta7 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The Drosophila Malpighian tubule as a model for mammalian tubule function Purpose of review Studies of the genetic model organism, Drosophila melanogaster, have unraveled molecular pathways relevant to human physiology and disease. The Malpighian tubule, the Drosophila renal epithelium, is described here, including tools available to study transport; conserved transporters, channels, and the signaling pathways regulating them; and fly models of kidney stone disease. Recent findings Tools to measure Malpighian tubule transport continue to advance, including use of a transgenic sensor to quantify intracellular pH and proton fluxes. A recent study generated an RNA-sequencing-based atlas of tissue-specific gene expression, with resulting insights into Malpighian tubule gene expression of transporters and channels. Advances have been made in understanding the molecular physiology of the With No Lysine kinase–Ste20-related proline/alanine rich kinase/oxidative stress response kinase cascade that regulates epithelial ion transport in flies and mammals. New studies in Drosophila kidney stone models have characterized zinc transporters and used Malpighian tubules to study the efficacy of a plant metabolite in decreasing stone burden. Summary Study of the Drosophila Malpighian tubule affords opportunities to better characterize the molecular physiology of epithelial transport mechanisms relevant to mammalian renal physiology. Correspondence to Aylin R. Rodan, MD, PhD, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Utah Molecular Medicine Program, 15 North 2030 East, Bldg. 533, Room 2420A, Salt Lake City, UT 84112, USA. Tel: +1-801-587-7929; fax: +1-801-585-0701; e-mail: aylin.rodan@hsc.utah.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Updates on medical management of hyperkalemia Purpose of review Hyperkalemia is a potentially fatal electrolyte disorder, more commonly present when the potassium excretion capacity is imparied. Hyperkalemia can lead to adverse outcomes, especially due to severe cardiac arrhythmias. It can also impair the cardiovascular effects of renin–angiotensin–aldosterone system inhibitors (RAASis) and potassium rich diets, as hyperkalemia frequently leads to their discontinuation. Recent findings Potassium is a predictor of mortality and should be monitored closely for patients who are at risk for hyperkalemia. Acute hyperkalemia protocols have been revised and updated. Randomized trials have shown that the new potassium binders (patiromer and zirconium cyclosilicate) are effective hyperkalemia treatment options. Potassium-binder use may allow for a less restrictive potassium diet and lower RAASi discontinuation rates. Summary Hyperkalemia should be monitored closely for high-risk patients, as it is associated with adverse outcomes. New therapies have demonstrated effective control, offering hope for potential use in patients that would benefit from diet or medications associated with an increase in serum potassium, indicating that binder use can be associated with better outcomes. Correspondence to Roberto Pecoits-Filho, MD, PhD, FASN, FACP, Senior Research Scientist, Arbor Research Collaborative for Health, 340 East Huron Street, Suite 300, Ann Arbor, MI 48104, USA. Tel: +1 734 665 4108/+1 734 369 9374; e-mail: Roberto.Pecoits@ArborResearch.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Hyponatremia in patients with cancer Purpose of review Hyponatremia is seen commonly in patients with cancer and is associated with increased mortality and morbidity. Understanding the proper diagnosis and therapy of cancer-associated hyponatremia is critical to ensure improved outcomes. Recent findings The most common cancers associated with hyponatremia are the various forms of lung cancer with incidences approaching 25–45%. The most common causes of hyponatremia in cancer patients are the syndrome of inappropriate antidiuretic hormone secretion [syndrome of inappropriate antidiuretic hormone (ADH)] and volume depletion. Proper diagnosis rests on clinical information supplemented by laboratory studies and is critical to ensure appropriate therapy. In recent years, the development of drugs that specifically antagonize the vasopressin type 2 receptor in the distal tubule have offered targeted and highly effective therapies for syndrome of inappropriate ADH. Summary Hyponatremia in cancer patients generally indicates advanced or severe disease but proper therapy that targets the underlying process can improve outcomes. Correspondence to Mitchell H. Rosner, MD, Division of Nephrology, Department of Medicine, University of Virginia Health System, Box 800133, Charlottesville, VA 22908, USA. Tel: +1 434 982 6999; fax: +1 434 924 5848; e-mail: mhr9r@virginia.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.