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      Association of Hypo- and Hyperkalemia with Disease Progression and Mortality in Males with Chronic Kidney Disease: The Role of Race

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          Abstract

          Background/Aims: Abnormal serum potassium is associated with higher mortality in dialysis patients, but its impact on outcomes in predialysis chronic kidney disease (CKD) is less clear. Furthermore, blacks with normal kidney function have lower urinary potassium excretion, but it is unclear if such differences have a bearing on race-associated outcomes in CKD. Methods: We studied predialysis mortality and slopes of estimated glomerular filtration rate, eGFR) associated with serum potassium in 1,227 males with CKD. Mortality was examined in time-dependent Cox models, and slopes of eGFR in linear mixed effects models with adjustments for case mix and laboratory values. Results: Both hypo- and hyperkalemia were associated with mortality overall and in 933 white patients, but in 294 blacks hypokalemia was a stronger death predictor. Hypokalemia was associated with loss of kidney function independent of race: a 1 mEq/l lower potassium was associated with an adjusted difference in slopes of eGFR of -0.13 ml/min/1.73 m<sup>2</sup>/year (95% CI: -0.20 to -0.07), p < 0.001. Conclusion: Hypo- and hyperkalemia are associated with higher mortality in CKD patients. Blacks appear to better tolerate higher potassium than whites. Hypokalemia is associated with faster CKD progression independent of race. Hyperkalemia management may warrant race-specific consideration, and hypokalemia correction may slow CKD progression. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel

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          Most cited references26

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          The frequency of hyperkalemia and its significance in chronic kidney disease.

          Hyperkalemia is a potential threat to patient safety in chronic kidney disease (CKD). This study determined the incidence of hyperkalemia in CKD and whether it is associated with excess mortality. This retrospective analysis of a national cohort comprised 2 103 422 records from 245 808 veterans with at least 1 hospitalization and at least 1 inpatient or outpatient serum potassium record during the fiscal year 2005. Chronic kidney disease and treatment with angiotensin-converting enzyme inhibitors and/or angiotensin II receptor blockers (blockers of the renin-angiotensin-aldosterone system [RAAS]) were the key predictors of hyperkalemia. Death within 1 day of a hyperkalemic event was the principal outcome. Of the 66 259 hyperkalemic events (3.2% of records), more occurred as inpatient events (n = 34 937 [52.7%]) than as outpatient events (n = 31 322 [47.3%]). The adjusted rate of hyperkalemia was higher in patients with CKD than in those without CKD among individuals treated with RAAS blockers (7.67 vs 2.30 per 100 patient-months; P or=5.5 and or=6.0 mEq/L) hyperkalemic event was highest with no CKD (OR, 10.32 and 31.64, respectively) vs stage 3 (OR, 5.35 and 19.52, respectively), stage 4 (OR, 5.73 and 11.56, respectively), or stage 5 (OR, 2.31 and 8.02, respectively) CKD, with all P < .001 vs normokalemia and no CKD. The risk of hyperkalemia is increased with CKD, and its occurrence increases the odds of mortality within 1 day of the event. These findings underscore the importance of this metabolic disturbance as a threat to patient safety in CKD.
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            Potassium softens vascular endothelium and increases nitric oxide release.

            In the presence of aldosterone, plasma sodium in the high physiological range stiffens endothelial cells and reduces the release of nitric oxide. We now demonstrate effects of extracellular potassium on stiffness of individual cultured bovine aortic endothelial cells by using the tip of an atomic force microscope as a mechanical nanosensor. An acute increase of potassium in the physiological range swells and softens the endothelial cell and increases the release of nitric oxide. A high physiological sodium concentration, in the presence of aldosterone, prevents these changes. We propose that the potassium effects are caused by submembranous cortical fluidization because cortical actin depolymerization induced by cytochalasin D mimics the effect of high potassium. In contrast, a low dose of trypsin, known to activate sodium influx through epithelial sodium channels, stiffens the submembranous cell cortex. Obviously, the cortical actin cytoskeleton switches from gelation to solation depending on the ambient sodium and potassium concentrations, whereas the center of the cell is not involved. Such a mechanism would control endothelial deformability and nitric oxide release, and thus influence systemic blood pressure.
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              Racial and survival paradoxes in chronic kidney disease.

              Most of the 20 million people in the US with chronic kidney disease (CKD) die before commencing dialysis. One of every five dialysis patients dies each year in the US. Although cardiovascular disease is the most common cause of death among patients with CKD, conventional cardiovascular risk factors such as hypercholesterolemia, hypertension and obesity are paradoxically associated with better survival in hemodialysis populations. Emerging data indicate the existence of this 'reverse epidemiology' in earlier stages of CKD. There are also paradoxical relationships between outcomes and race and ethnicity. For example, the survival rate of African American dialysis patients seems to be superior to that of whites on dialysis. Paradoxes-within-paradoxes have been detected among Hispanic and Asian American CKD patients. These survival paradoxes might evolve and change over the natural course of CKD progression as a result of the time differentials of competing risk factors and the overwhelming impact of malnutrition, inflammation and wasting. Reversal of the reverse epidemiology as a result of successful kidney transplantation underscores the role of nutritional status and kidney function in engendering these paradoxes. The observation of paradoxes and their reversal might lead to the formulation of new paradigms and management strategies to improve the survival of patients with CKD. Such movement away from the use of targets set on the basis of data gathered in general populations (e.g. the Framingham cohort) would be a major paradigm shift in clinical medicine and public health.
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                Author and article information

                Journal
                NEC
                Nephron Clin Pract
                10.1159/issn.1660-2110
                Nephron Clinical Practice
                S. Karger AG
                1660-2110
                2012
                March 2012
                02 December 2011
                : 120
                : 1
                Affiliations
                aDivision of Nephrology, University of Virginia, Charlottesville, Va., bHarold Simmons Center for Chronic Disease Research and Epidemiology, and cDivision of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, Calif., dSalem Research Institute, eDivision of Nephrology, Salem Veterans Affairs Medical Center, Salem, Va., and fDivision of Nephrology, Johns Hopkins University, Baltimore, Md., USA
                Author notes
                *Csaba P. Kovesdy, MD FASN, Division of Nephrology, Salem VA Medical Center, 1970 Roanoke Blvd., Salem, VA 24153 (USA), Tel. +1 540 982 2463, E-Mail csaba.kovesdy@va.gov
                Article
                329511 PMC3267990 Nephron Clin Pract 2012;120:c8-c16
                10.1159/000329511
                PMC3267990
                22156587
                b4fce688-108d-4f93-b96d-cb86f791c854
                This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 18 April 2011
                : 11 May 2011
                Page count
                Figures: 4, Tables: 3, References: 52, Pages: 9
                Categories
                Original Paper

                Cardiovascular Medicine,Nephrology
                Serum potassium,Chronic kidney disease,Mortality,Race,Glomerular filtration rate

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