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      Effect of Angiotensin II Receptor Blocker on Plasma Levels of TGF-β1 and Interstitial Fibrosis in Hypertensive Kidney Transplant Patients

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          Abstract

          Background/Aim: Transforming growth factor-β1 (TGF-β1) is involved in the pathogenesis of chronic allograft nephropathy after kidney transplantation. The aim of the study was to evaluate the effect of the angiotensin receptor blocker losartan on TGF-β1 plasma levels and proteinuria in hypertensive transplant recipients. Methods: A total of 162 transplant recipients were included in the study. The patients were randomized into 3 groups: group 1 received losartan; group II received an angiotensin-converting enzyme inhibitor (captopril), and group III received a calcium channel blocker (amlodipine). All the parameters were recorded at the time of therapy initiation and at 1, 4 and 12 weeks and 12 months thereafter. Graft biopsy before the start and at the end of the study was done to evaluate histopathological progression. Results: Blood pressure was controlled in the 3 groups; however, the need for other antihypertensive agents was significant in groups I and II. Treatment with losartan significantly decreased the plasma level of TGF-β1, 24-hour urinary protein and serum uric acid (p < 0.05). No significant changes were seen in the hemoglobin or serum potassium levels. The rate of histopathological progression was significantly lower in the losartan group. No patient was discharged from the study due to side effects. Conclusions: After transplantation all drugs were able to control blood pressure with good safety and tolerability. The study demonstrates that ARB significantly decreases the plasma levels of TGF-β1, proteinuria and uric acid. These results could play an important and decisive role in the treatment and prevention of chronic allograft nephropathy.

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          Most cited references 7

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          Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease.

          Angiotensin-converting enzyme (ACE) inhibitors reduce urine protein excretion and slow the progression of renal disease. The beneficial effect in slowing the progression of renal disease is greater in patients with higher urine protein excretion at the onset of treatment. We hypothesized that the greater beneficial effect of ACE inhibitors on the progression of renal disease in patients with higher baseline levels of proteinuria is due to their greater antiproteinuric effect in these patients. Data were analyzed from 1860 patients enrolled in 11 randomized controlled trials comparing the effect of antihypertensive regimens, including ACE inhibitors to regimens not including ACE inhibitors on the progression of non-diabetic renal disease. Multivariable linear regression analysis was used to assess the relationship between the level of proteinuria at baseline and changes in urine protein excretion during follow-up. The Cox proportional hazards analysis was used to assess the relationship between changes in urine protein excretion during follow-up and the effect of ACE inhibitors on the time to doubling of baseline serum creatinine values or onset of end-stage renal disease. Mean (median) baseline urine protein excretion was 1.8 (0.94) g/day. Patients with higher baseline urine protein excretion values had a greater reduction in proteinuria during the follow-up in association with treatment with ACE inhibitors and in association with lowering systolic and diastolic blood pressures (interaction P < 0.001 for all). A higher level of urine protein excretion during follow-up (baseline minus change) was associated with a greater risk of progression [relative risk 5.56 (3.87 to 7.98) for each 1.0 g/day higher protein excretion]. After controlling for the current level of urine protein excretion, the beneficial effect of ACE inhibitors remained significant [relative risk for ACE inhibitors vs. control was 0.66 (0.52 to 0.83)], but there was no significant interaction between the beneficial effect of ACE inhibitors and the baseline level of urine protein excretion. The antiproteinuric effects of ACE inhibitors and lowering blood pressure are greater in patients with a higher baseline urine protein excretion. The greater beneficial effect of ACE inhibitors on renal disease progression in patients with higher baseline proteinuria can be explained by their greater antiproteinuric effects in these patients. The current level of urine protein excretion is a modifiable risk factor for the progression of non-diabetic renal disease. ACE inhibitors provide greater beneficial effect at all levels of current urine protein excretion.
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            Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study.

             G Opelz,  E. Ritz,  T Wujciak (1997)
            Immunological rejection is the most important cause of kidney transplant failure. Recently, nonimmunological causes of long-term allograft failure have become more widely appreciated. In primary chronic renal disease, blood pressure is of overriding importance for long-term renal function. The role of blood pressure in determining long-term transplant outcome has not yet been established. We studied the influence of blood pressure post-transplantation on long-term kidney graft outcome in 29,751 patients. Outpatient blood pressure measurements were recorded and reported to the Collaborative Transplant Study. Graft and patient survival rates were analyzed over seven years in relation to blood pressure. Increased levels of systolic and diastolic blood pressure post-transplantation were associated with a graded increase of subsequent graft failure (P < 0.0001). Chronic graft failure was significantly associated with blood pressure even when patient death was censored (P < 0.0001). Cox regression analysis established increased blood pressure as an independent risk factor for graft failure. We conclude that post-transplant blood pressure is a highly significant predictor of long-term kidney graft outcome. Whether aggressive lowering of blood pressure improves long-term transplant outcome will have to be studied prospectively.
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              Losartan decreases plasma levels of TGF-beta1 in transplant patients with chronic allograft nephropathy.

              Chronic allograft nephropathy represents the principal cause of graft loss after the first year of transplantation. Transforming growth factor-beta1 (TGF-beta1) is a key factor in fibrogenesis and has been involved in the pathogenesis of chronic allograft nephropathy and other chronic nephropathies. Experimental studies have demonstrated that the angiotensin II receptor antagonist (losartan) could decrease the synthesis of TGF-beta1. The aim of this study was to determine the plasma levels of TGF-beta1 in transplant patients with chronic allograft nephropathy, and to evaluate the effect of losartan on TGF-beta1 plasma levels and other vasoactive peptides (angiotensin II, plasma renin activity, aldosterone, endothelin-1, and nitrites and nitrates). Angiotensin-converting enzyme genotypes were also determined in all patients. Fourteen transplant patients with chronic allograft nephropathy were included. Treatment with losartan (50 mg) was introduced. Consecutive determinations of TGF-beta1 and other vasoactive peptides were performed during follow-up. Patients with chronic allograft nephropathy presented higher plasma levels of TGF-beta1 than the control groups. The treatment with losartan significantly decreased the plasma levels of TGF-beta1 (P < 0.05) and endothelin (P < 0.05) in all patients. The decrease of TGF-beta1 was statistically correlated with the blockade of the angiotensin II receptor (P < 0.05). No significant correlation could be demonstrated between angiotensin-converting enzyme genotypes and TGF-beta, endothelin-1, and nitrite-nitrate serum levels. This study demonstrates that losartan significantly decreases the plasma levels of TGF-beta1, the most important fibrogenetic factor. These results could play a decisive role in the treatment and prevention of chronic nephropathies, not only graft nephropathy, because the intrinsic pathogenetic mechanism is very similar in all forms, with a crucial roles for the renal renin-angiotensin system and TGF-beta1.
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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
                2003
                October 2003
                08 September 2003
                : 23
                : 5
                : 300-306
                Affiliations
                Urology and Nephrology Center, Mansoura University, Mansoura, Egypt
                Article
                72820 Am J Nephrol 2003;23:300–306
                10.1159/000072820
                12904684
                © 2003 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
                Tables: 4, References: 28, Pages: 7
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/72820
                Categories
                Original Article: Patient-Oriented, Translational Research

                Cardiovascular Medicine, Nephrology

                Transforming growth factor-β1, Transplantation, Nephropathy

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