Nephrology and Hypertension

Cardiovascular autonomic nervous system dysfunction in chronic kidney disease and end-stage kidney disease: disruption of the complementary forces Purpose of review Several nontraditional risk factors have been the focus of research in an attempt to understand the disproportionately high cardiovascular morbidity and mortality in chronic kidney disease (CKD) and end-stage kidney disease (ESKD) populations. One such category of risk factors is cardiovascular autonomic dysfunction. Its true prevalence in the CKD/ESKD population is unknown but existing evidence suggests it is common. Due to lack of standardized diagnostic and treatment options, this condition remains undiagnosed and untreated in many patients. In this review, we discuss current evidence pointing toward the role of autonomic nervous system (ANS) dysfunction in CKD, building off of crucial historical evidence and thereby highlighting the areas in need for future research interest. Recent findings There are several key mediators and pathways leading to cardiovascular autonomic dysfunction in CKD and ESKD. We review studies exploring the mechanisms involved and discuss the current measurement tools and indices to evaluate the ANS and their pitfalls. There is a strong line of evidence establishing the temporal sequence of worsening autonomic function and kidney function and vice versa. Evidence linking ANS dysfunction and arrhythmia, sudden cardiac death, intradialytic hypotension, heart failure and hypertension are discussed. Summary There is a need for early recognition and referral of CKD and ESKD patients suspected of cardiovascular ANS dysfunction to prevent the downstream effects described in this review. There are many unknowns in this area and a clear need for further research. Correspondence to David M. Charytan, MD, MSc, Chief, Nephrology Division, NYU Langone Medical Center, 462 1st Avenue C & D 689, New York, New York 10010, USA. Tel: +646 501 9086; e-mail: David.charytan@nyulangone.org Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Challenges in communication, prognostication and dialysis decision-making in the COVID-19 pandemic: implications for interdisciplinary care during crisis settings Purpose of review Using case vignettes, we highlight challenges in communication, prognostication, and medical decision-making that have been exacerbated by the coronavirus disease-19 (COVID-19) pandemic for patients with kidney disease. We include best practice recommendations to mitigate these issues and conclude with implications for interdisciplinary models of care in crisis settings. Recent findings Certain biomarkers, demographics, and medical comorbidities predict an increased risk for mortality among patients with COVID-19 and kidney disease, but concerns related to physical exposure and conservation of personal protective equipment have exacerbated existing barriers to empathic communication and value clarification for these patients. Variability in patient characteristics and outcomes has made prognostication nuanced and challenging. The pandemic has also highlighted the complexities of dialysis decision-making for older adults at risk for poor outcomes related to COVID-19. Summary The COVID-19 pandemic underscores the need for nephrologists to be competent in serious illness communication skills that include virtual and remote modalities, to be aware of prognostic tools, and to be willing to engage with interdisciplinary teams of palliative care subspecialists, intensivists, and ethicists to facilitate goal-concordant care during crisis settings. Correspondence to Devika Nair, MD, MSCI, Instructor of Medicine, Vanderbilt University Medical Center, Division of Nephrology and Hypertension, Vanderbilt Center for Health Services Research, 2525 West End Avenue, Suite 450, Office 416, Nashville, Tennessee 37203, USA. Tel: +615 322 7285; e-mail: Devika.nair@vumc.org Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Angiotensin-converting enzyme 2: from a vasoactive peptide to the gatekeeper of a global pandemic Purpose of review We provide a comprehensive overview of angiotensin-converting enzyme 2 (ACE2) as a possible candidate for pharmacological approaches to halt inflammatory processes in different pathogenic conditions. Recent findings ACE2 has quickly gained prominence in basic research as it has been identified as the main entry receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This novel pathogen causes Coronavirus Disease 2019 (COVID-19), a pathogenic condition that reached pandemic proportion and is associated with unprecedented morbidity and mortality. Summary The renin–angiotensin system is a complex, coordinated hormonal cascade that plays a pivotal role in controlling individual cell behaviour and multiple organ functions. ACE2 acts as an endogenous counter-regulator to the pro-inflammatory and pro-fibrotic pathways triggered by ACE through the conversion of Ang II into the vasodilatory peptide Ang 1–7. We discuss the structure, function and expression of ACE2 in different tissues. We also briefly describe the role of ACE2 as a pivotal driver across a wide spectrum of pathogenic conditions, such as cardiac and renal diseases. Furthermore, we provide the most recent data concerning the possible role of ACE2 in mediating SARS-CoV-2 infection and dictating COVID-19 severity. Correspondence to Luca Perico, PhD, Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Via Stezzano 87, 24126 Bergamo, Italy. Tel: +39 035 42131; fax: +39 035 319331; e-mail: luca.perico@marionegri.it Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Sodium bicarbonate therapy for acute respiratory acidosis Purpose of review Respiratory acidosis is commonly present in patients with respiratory failure. The usual treatment of hypercapnia is to increase ventilation. During the recent surge of COVID-19, respiratory acidosis unresponsive to increased mechanical ventilatory support was common. Increasing mechanical ventilation comes at the expense of barotrauma and hemodynamic compromise from increasing positive end-expiratory pressures or minute ventilation. Treating acute respiratory acidemia with sodium bicarbonate remains controversial. Recent findings There are no randomized controlled trials of administration of sodium bicarbonate for respiratory acidemia. A recent review concluded that alkali therapy for mixed respiratory and metabolic acidosis might be useful but was based on the conflicting and not conclusive literature regarding metabolic acidosis. This strategy should not be extrapolated to treatment of respiratory acidemia. Low tidal volume ventilation in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) has beneficial effects associated with permissive hypercapnia. Whether the putative benefits will be negated by administration of alkali is not known. Hypercapnic acidosis is well tolerated, with few adverse effects as long as tissue perfusion and oxygenation are maintained. Summary There is a lack of clinical evidence that administration of sodium bicarbonate for respiratory acidosis has a net benefit; in fact, there are potential risks associated with it. Correspondence to David S. Goldfarb, MD, Clinical Chief, Nephrology Division, NYU Langone Health, Professor of Medicine and Physiology, New York University School of Medicine, Nephrology Section 111G, 423 E. 23 Street, New York, NY 10010, USA. Tel: +1 212 686 7500, x3877; fax: +1 212 951 6842; e-mail: david.goldfarb@nyulangone.org Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Controversies in nephrologic covidology No abstract available

Diagnosis of amyloid beyond Congo red Purpose of review Amyloidoses are a group of rare and heterogeneous diseases in which abnormally folded proteins deposit in tissues and lead to organ damage. A brief review of advances in the diagnosis of extracerebral systemic amyloidoses in the context of recent advances in their clinical management is provided. Recent findings Although steady progress in the treatment of AL and AA has evolved over many years, significant advances in the treatment of ATTR, transthyretin-derived amyloidosis, have been achieved only recently. This coincides with the emergence of nontissue diagnosis of cardiac ATTR in both the hereditary and wild-type settings. The latter is emerging as possibly the most prevalent type of systemic amyloidosis. Available treatments are amyloid protein type dependent and, hence, following amyloid detection, amyloid protein typing is necessary. Although mass spectrometry has emerged as the preferred method of amyloid typing, careful application of immune methods is still clinically useful but caution and experience, as well as awareness of the limitations of each method, are necessary in their interpretation. Summary Despite significant advances in the treatment of the systemic amyloidoses, outcomes remain poor, primarily due to delays in diagnosis. Precise diagnosis of the amyloid protein type is critical for treatment selection. Correspondence to Maria M. Picken, MD, PhD, Loyola University Medical Center, Pathology, 2160S. First Avenue, Maywood, IL 60153, USA. Tel: +1 708 327 2607; e-mail: mpicken@lumc.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

WNK4 kinase: role of chloride sensing in the distal convoluted tubule Purpose of review This review focuses on recent efforts in identifying with-no-lysine kinase 4 (WNK4) as a physiological intracellular chloride sensor and exploring regulators of intracellular chloride concentration ([Cl-]i) in the distal convoluted tubule (DCT). Recent findings The discovery of WNK1's chloride-binding site provides the mechanistic details of the chloride-sensing regulation of WNK kinases. The subsequent in-vitro studies reveal that the chloride sensitivities of WNK kinases were variable. Because of its highest chloride sensitivity and dominant expression, WNK4 emerges as the leading candidate of the chloride sensor in DCT. The presentation of hypertension and increased sodium-chloride cotransporter (NCC) activity in chloride-insensitive WNK4 mice proved that WNK4 is inhibitable by physiological [Cl-]i in DCT. The chloride-mediated WNK4 regulation is responsible for hypokalemia-induced NCC activation but unnecessary for hyperkalemia-induced NCC deactivation. This chloride-sensing mechanism requires basolateral potassium and chloride channels or cotransporters, including Kir4.1/5.1, ClC-Kb, and possibly KCCs, to modulate [Cl-]i in response to the changes of plasma potassium. Summary WNK4 is both a master NCC stimulator and an in-vivo chloride sensor in DCT. The understanding of chloride-mediated regulation of WNK4 explains the inverse relationship between dietary potassium intake and NCC activity. Correspondence to Chih-Jen Cheng, MD, PhD, Division of Nephrology, Department of Medicine, Tri-Service General Hospital, No. 325, Section 2, Cheng-Kung Road, Neihu, 114, Taipei, Taiwan. Tel: +886 2 87927213; fax: +886 2 87927322; e-mail: laurence1234kimo@yahoo.com.tw;chih-jen-cheng@uiowa.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Bisphosphonates and management of kidney stones and bone disease Purpose of review Kidney stones are strongly associated with low bone density and bone fracture. Clinical management focuses on prevention of kidney stones and bone fracture. We reviewed literature of kidney stones and bone disease with a special focus on updates in therapeutic strategies. We will review the literature regarding dietary management, supplements, and medications and emphasize the recent studies on bisphosphonates and kidney stone management. Recent findings Bisphosphonate medications are commonly used in management of low bone density. Previous studies showed that they reduce urinary calcium. A recent large prospective study found that bisphosphonates may reduce the risk of kidney stones in individuals who have low bone density. In addition to lowering urinary calcium, a recent study found that bisphosphonates may act as an inhibitor in the urinary space. Summary There are multiple dietary and pharmacologic strategies that can be considered for kidney stones and bone disease, such as low salt and normal calcium diet, as well as thiazides, alkali, and bisphosphonate medications. Bisphosphonates may have an important role in reducing bone resorption and reducing overall risk of kidney stone and bone disease. Correspondence to Megan Prochaska, 5841 S. Maryland Avenue, MC 5100, Chicago, IL 60637, USA. Tel: +1 773 702 1041; e-mail: mprocha2@medicine.bsd.uchicago.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Contribution of Th17 cells to tissue injury in hypertension Purpose of review Hypertension has been demonstrated to be a chief contributor to morbidity and mortality throughout the world. Although the cause of hypertension is multifactorial, emerging evidence, obtained in experimental studies, as well as observational studies in humans, points to the role of inflammation and immunity. Many aspects of immune function have now been implicated in hypertension and end-organ injury; this review will focus upon the recently-described role of Th17 cells in this pathophysiological response. Recent findings Studies in animal models and human genetic studies point to a role in the adaptive immune system as playing a contributory role in hypertension and renal tissue damage. Th17 cells, which produce the cytokine IL17, are strongly pro-inflammatory cells, which may contribute to tissue damage if expressed in chronic disease conditions. The activity of these cells may be enhanced by physiological factors associated with hypertension such as dietary salt or Ang II. This activity may culminate in the increased sodium retaining activity and exacerbation of inflammation and renal fibrosis via multiple cellular mechanisms. Summary Th17 cells are a distinct component of the adaptive immune system that may strongly enhance pathways leading to increased sodium reabsorption, elevated vascular tone and end-organ damage. Moreover, this pathway may lend itself towards specific targeting for treatment of kidney disease and hypertension. Correspondence to David P. Basile, Department of Anatomy, Cell Biology & Physiology, Indiana Univ. School of Medicine, 635 Barnhill Dr MS 2063, Indianapolis, IN 46202, USA. Fax: +1 317 274 3318; e-mail: dpbasile@iupui.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Gut–brain–bone marrow axis in hypertension Purpose of review Rapidly emerging evidence implicates an important role of gut–brain–bone marrow (BM) axis involving gut microbiota (GM), gut epithelial wall permeability, increased production of pro-inflammatory BM cells and neuroinflammation in hypertension (HTN). However, the precise sequence of events involving these organs remains to be established. Furthermore, whether an impaired gut–brain–BM axis is a cause or consequence of HTN is actively under investigation. This will be extremely important for translation of this fundamental knowledge to novel, innovative approaches for the control and management of HTN. Therefore, our objectives are to summarize the latest hypothesis, provide evidence for and against the impaired gut, BM and brain interactions in HTN and discuss perspectives and future directions. Recent findings Hypertensive stimuli activate autonomic neural pathways resulting in increased sympathetic and decreased parasympathetic cardiovascular modulation. This directly affects the functions of cardiovascular-relevant organs to increase blood pressure. Increases in sympathetic drive to the gut and BM also trigger sequences of signaling events that ultimately contribute to altered GM, increased gut permeability, enhanced gut- and brain-targeted pro-inflammatory cells from the BM in perpetuation and establishment of HTN. Summary In this review, we present the mechanisms involving the brain, gut, and BM, whose dysfunctional interactions may be critical in persistent neuroinflammation and key in the development and establishment of HTN. Correspondence to Mohan K. Raizada, PhD, Department of Physiology and Functional Genomics, University of Florida College of Medicine, PO Box 100274, Gainesville, FL 32610, USA. Tel: +352 392 9299; e-mail: mraizada@ufl.edu Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

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