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      Renal Sodium Transporters Are Increased in Urinary Exosomes of Cyclosporine-Treated Kidney Transplant Patients

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          Abstract

          Background/Aims: Cyclosporine (CsA) is a calcineurin inhibitor widely used as an immunosuppressant in organ transplantation. Previous studies demonstrated the relationship between CsA and renal sodium transporters such as the Na-K-2Cl cotransporter in the loop of Henle (NKCC2). Experimental models of CsA-induced hypertension have shown an increase in renal NKCC2. Methods: Using immunoblotting of urinary exosomes, we investigated in CsA-treated kidney transplant patients (n = 39) the excretion of NKCC2 and Na-Cl cotransporter (NCC) and its association with blood pressure (BP) level. We included 8 non-CsA-treated kidney transplant patients as a control group. Clinical data, immunosuppression and hypertension treatments, blood and 24-hour urine tests, and 24-hour ambulatory BP monitoring were recorded. Results: CsA-treated patients tended to excrete a higher amount of NKCC2 than non-CsA-treated patients (mean ± SD, 175 ± 98 DU and 90 ± 70.3 DU, respectively; p = 0.05) and showed higher BP values (24-hour systolic BP 138 ± 17 mm Hg and 112 ± 12 mm Hg, p = 0.003; 24-hour diastolic BP, 83.8 ± 9.8 mm Hg and 72.4 ± 5.2 mm Hg, p = 0.015, respectively). Within the CsA-treated group, there was no correlation between either NKCC2 or NCC excretion and BP levels. This was confirmed by a further analysis including potential confounding factors. On the other hand, a significant positive correlation was observed between CsA blood levels and the excretion of NKCC2 and NCC. Conclusion: Overall, these results support the hypothesis that CsA induces an increase in NKCC2 and NCC in urinary exosomes of renal transplant patients. The fact that the increase in sodium transporters in urine did not correlate with the BP level suggests that in kidney transplant patients, other mechanisms could be implicated in CsA-induced hypertension.

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          Most cited references 27

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          Large-scale proteomics and phosphoproteomics of urinary exosomes.

          Normal human urine contains large numbers of exosomes, which are 40- to 100-nm vesicles that originate as the internal vesicles in multivesicular bodies from every renal epithelial cell type facing the urinary space. Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. Overall, the analysis identified 1132 proteins unambiguously, including 177 that are represented on the Online Mendelian Inheritance in Man database of disease-related genes, suggesting that exosome analysis is a potential approach to discover urinary biomarkers. We extended the proteomic analysis to phosphoproteomic profiling using neutral loss scanning, and this yielded multiple novel phosphorylation sites, including serine-811 in the thiazide-sensitive Na-Cl co-transporter, NCC. To demonstrate the potential use of exosome analysis to identify a genetic renal disease, we carried out immunoblotting of exosomes from urine samples of patients with a clinical diagnosis of Bartter syndrome type I, showing an absence of the sodium-potassium-chloride co-transporter 2, NKCC2. The proteomic data are publicly accessible at http://dir.nhlbi.nih.gov/papers/lkem/exosome/.
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            Hypertension after kidney transplantation.

            Few studies have examined the possible role of blood pressure (BP), independent of acute rejection and graft function, on outcomes after kidney transplantation. We investigated the prevalence, treatment, control, and clinical correlates of hypertension and its association with outcomes, using multivariate analyses with time-dependent covariates, in a retrospective cohort of 1,666 kidney transplant recipients. Hypertension was common, and its control was poor. For example, at 1 year, only 55.5% had a BP less than 140 mm Hg. Control improved only slightly in 1993-2002 compared to 1976-2002, even as patients administered 2 or more antihypertensive medications at 1 year increased from 43.5% to 54.6%. Independent correlates of higher BP included male sex, age, donor age, diabetes, body mass index, the presence of native kidneys, and delayed graft function. Previous acute rejection was associated with higher BP at virtually all times after transplantation, and these associations were independent of estimated creatinine clearance (C(Cr)). Conversely, an association between BP and subsequent acute rejection was not statistically significant when differences in C(Cr) were taken into account. After adjusting for the effects of acute rejection, C(Cr), and other variables, each 10 mm Hg of systolic BP was associated with an increased relative risk for graft failure (1.12; 95% confidence interval, 1.08 to 1.15; P < 0.0001), death-censored graft failure (1.17; 1.12 to 1.22; P < 0.0001), and death (1.18; 1.12 to 1.23; P < 0.0001). High BP is closely tied to graft function, but nevertheless is an independent risk factor for graft failure and mortality. Better strategies are needed to control BP after kidney transplantation.
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              Urinary excretion of aquaporin-2 in patients with diabetes insipidus.

              Urine-concentrating ability is regulated by vasopressin. Recently, the specific water-channel protein of the renal collecting duct, known as aquaporin-2, was cloned. However, it is not certain whether this molecule is responsive to vasopressin. We measured the urinary excretion of aquaporin-2 and its response to vasopressin in 11 normal subjects and 9 patients with central or nephrogenic diabetes insipidus. The urine samples were collected during periods of dehydration and hydration and after the administration of vasopressin. Urine samples were analyzed for aquaporin-2 by the Western blot assay and immunogold labeling, and the amount of aquaporin-2 was determined by radioimmunoassay. Aquaporin-2 was detectable in the urine in both soluble and membrane-bound forms. In the five normal subjects tested, the mean (+/- SE) urinary excretion of aquaporin-2 was 11.2 +/- 2.2 pmol per milligram of creatinine after a period of dehydration, and it decreased to 3.9 +/- 1.9 pmol per milligram of creatinine (P = 0.03) during the second hour after a period of hydration. In the six other normal subjects, an infusion of desmopressin (1-desamino-8-D-arginine vasopressin) increased the urinary excretion of aquaporin-2 from 0.8 +/- 0.3 to 11.2 +/- 1.6 pmol per milligram of creatinine (P < 0.001). The five patients with central diabetes insipidus also had increases in urinary excretion of aquaporin-2 in response to the administration of vasopressin, but the four patients with X-linked or non-X-linked nephrogenic diabetes insipidus did not. Aquaporin-2 is detectable in the urine, and changes in the urinary excretion of this protein can be used as an index of the action of vasopressin on the kidney.
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                Author and article information

                Journal
                AJN
                Am J Nephrol
                10.1159/issn.0250-8095
                American Journal of Nephrology
                S. Karger AG
                0250-8095
                1421-9670
                2014
                July 2014
                12 June 2014
                : 39
                : 6
                : 528-535
                Affiliations
                aMolecular Biology Laboratory, bRenal Transplant Unit, and cRenal and Hypertension Units, Fundació Puigvert, Barcelona, and dUniversitat Autònoma de Barcelona, Instituto de Investigación Biomédica Sant Pau, Sant Pau, Spain
                Author notes
                *Patricia Fernandez-Llama, Fundació Puigvert, Cartagena 340-350, ES-08025 Barcelona (Spain), E-Mail pfernandezllama@fundacio-puigvert.es
                Article
                362905 Am J Nephrol 2014;39:528-535
                10.1159/000362905
                24942911
                © 2014 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.

                Page count
                Figures: 2, Tables: 2, Pages: 8
                Categories
                Original Report: Patient-Oriented, Translational Research

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