Nephrology and Hypertension

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.

Recent developments in the management of acute and chronic hyponatremia Purpose of review The aim of the study is to review recent studies on the management of acute and chronic hyponatremia. Recent findings In acute symptomatic hyponatremia, bolus infusion of hypertonic saline improves hyponatremia and neurological status more quickly than continuous infusion. In chronic hyponatremia, newly identified predictors of nonresponse to fluid restriction include a high urine osmolality (>500 mOsm/kg) and high urine sodium (>133 mmol/l). Vasopressin-receptor antagonists effectively raise the serum sodium concentration in patients with euvolemic or hypervolemic hyponatremia but have a risk of overcorrection, even at low doses. Several observational studies now support the use of urea for a more gradual correction of hyponatremia without a risk of overcorrection. Recently identified risk factors for overcorrection include lower serum sodium at presentation, polydipsia, hypovolemia, and early urine output during treatment. Specific treatments with potential efficacy are the use of intravenous albumin for hyponatremia because of liver cirrhosis, and fludrocortisone for hyponatremia in tuberculous meningitis. Summary The recent data will help to further optimize and personalize the management of patients with acute and chronic hyponatremia. However, most data are still observational and retrospective. Therefore, the field is in need of prospective studies comparing interventions for chronic hyponatremia and focusing on patient-relevant outcomes. Correspondence to Goce Spasovski, University Department of Nephrology, Medical Faculty, University of Skopje, Bul. Mother Teresa 17, 1000 Skopje, N. Macedonia. Tel: +389 70 268 232; e-mail: spasovski.goce@gmail.com Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Novel therapeutic options for management of electrolyte disorders No abstract available

Advances in management of chronic metabolic acidosis in chronic kidney disease Purpose of review Chronic metabolic acidosis is a common complication of chronic kidney disease (CKD) and is associated with adverse consequences, such as CKD progression and muscle wasting. We review the findings from recent clinical trials that have examined the effects of sodium bicarbonate therapy and veverimer in patients with CKD and chronic metabolic acidosis. Recent findings There are four recent clinical trials on chronic metabolic acidosis of CKD. In a pilot, cross-over study, 6 weeks of sodium bicarbonate therapy improved vascular endothelial function, measured by brachial artery flow-mediated dilation. In a single-center, randomized, open-label study, 6 months of sodium bicarbonate therapy increased muscle mass and lean body mass, and preserved kidney function. The other two clinical trials (phase 1/2 and phase 3 studies) examined the effects of veverimer, which is a hydrochloric acid binder. The phase 3 study showed that 12-weeks of veverimer increased serum bicarbonate levels and might improve physical function. The effects of veverimer on CKD progression, physical function and cardiovascular endpoints as well as its long-term safety are yet to be determined. Summary Recent studies suggest that sodium bicarbonate therapy may improve vascular endothelial function and muscle mass, and preserve renal function. Veverimer increases serum bicarbonate level and could be a potential new therapeutic option for treating chronic metabolic acidosis. Correspondence to Wei Chen, MD, MS, Assistant Professor of Medicine, Department of Medicine, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Ullmann 615, Bronx, NY 10461, USA. Tel: +1 718 430 3234; e-mail: weichen@montefiore.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.