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      Renoprotection Provided by Losartan in Combination with Pioglitazone Is Superior to Renoprotection Provided by Losartan Alone in Patients with Type 2 Diabetic Nephropathy

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          Abstract

          Aim: This study was performed to ascertain whether losartan combined with pioglitazone is superior to losartan alone in delaying the progression of chronic renal failure in patients with type 2 diabetic nephropathy. Methods: Sixty patients with type 2 diabetic nephropathy (stage 3 or 4 chronic kidney disease) were enrolled in a randomized, controlled trial. Thirty patients received losartan (100 mg/day) and pioglitazone (30 mg/day), and 30 patients received losartan only (100 mg/day). The patients were assessed at baseline and at 3-month intervals for 24-hour urinary protein excretion, serum creatinine, creatinine clearance, and fasting blood glucose values. The glomerular filtration rate was measured by means of a <sup>99m</sup>Tc-diethylenetriamine penta-acetic renogram at baseline and after 12 months. Results: As compared with therapy with losartan alone, the losartan-pioglitazone combination therapy resulted in significantly lower serum creatinine and fasting glucose values at 12 months and in significantly lower degrees of proteinuria at 6 and 12 months. The declines in creatinine clearance and glomerular filtration rate below baseline measurements at stages 3 and 4 of chronic kidney disease were significantly slower for the losartan-pioglitazone group as compared with the losartan-only group. Conclusions: Renoprotection conferred by losartan combined with pioglitazone is superior to that conferred by losartan alone in subjects with type 2 diabetic nephropathy. The combination is generally well tolerated.

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          Most cited references 20

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          Angiotensin II: a key factor in the inflammatory and fibrotic response in kidney diseases.

          Angiotensin II (AngII) participates in the pathogenesis of renal diseases, through the regulation of two key processes inflammation and fibrosis. AT1 and AT2 are the main receptors of AngII. AT1 mediates most of the actions of AngII. This receptor regulates the expression of profibrotic factors, such as connective tissue growth factor (CTGF). The Smad signalling pathway and the Rho/Rho kinase system are two novel mechanisms involved in AngII-induced matrix regulation recently described. The role of AT2 receptors in renal pathophysiological processes is not fully elucidated. Experimental data suggest that AT2 receptors through activation of nuclear factor-kappaB participate in renal inflammatory cell recruitment. Studies in animal models of kidney injury have shown that the combined blockade of both AT1 and AT2 receptors, as well as the inhibition of the NF-kappaB pathway are necessary to stop the inflammatory process fully. On the whole, these data highlight the complex signalling systems activated by AngII and suggest novel potential targets to block fibrosis and inflammation in renal diseases.
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            Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications.

            It is no a secret that we are confronted by an alarmingly increasing number of patients with progressive renal disease. There is ample evidence for the notion that angiotensin II (Ang II) is a major culprit in progression. The vasopeptide Ang II turned out to have also multiple nonhemodynamic pathophysiologic actions on the kidney, including proinflammatory and profibrogenic effects. Diverse complex Ang II generating systems have been identified, including specifically local tissue-specific renin-angiotensin systems (RAS). For example, proximal tubular cells have all components required for a functional RAS capable of synthesizing Ang II. On the other hand, Ang II is not the only effector of the RAS and other peptides generated by the RAS influence renal function and structure as well. Moreover, the discoveries that Ang II can be generated by enzymes other than angiotensin-converting enzyme (ACE) and that Ang II and other RAS derived peptides bind to various receptors with different functional consequences have further added to the complexity of this system. Several major clinical trials have clearly shown that ACE inhibitor treatment slows the progression of renal diseases, including in diabetic nephropathy. Well-controlled studies demonstrated that this effect is in part independent of blood pressure control. More recently, with Ang II type 1 receptor (AT(1)) receptor antagonists a similarly protective effect on renal function was seen in patients with type 2 diabetes. Neither ACE inhibitor treatment nor AT(1) receptor blockade completely abrogate progression of renal disease. A recently introduced novel therapeutic approach is combination treatment comprising both ACE inhibitor and AT(1) receptor antagonists. The rationale for this approach is based on several considerations. Small-scale clinical studies, mainly of crossover design, documented that combination therapy is more potent in reducing proteinuria in patients with different chronic renal diseases. Blood pressure as an important confounder was, however, significantly lower in the majority of this studies in the combination treatment arms compared to the respective monotherapies. In a recent prospective study Japanese authors avoided this confounder and demonstrated that combination therapy reduced hard end-points (end stage renal failure or doubling of serum creatinine concentration) by 50% compared to the respective monotherapies. This effect could not be explained by a more pronounced reduction of blood pressure in the combination therapy group. Although these results are encouraging, administration of combination therapy should be reserved currently to special high risk groups. Further studies are necessary to confirm these promising results. It is possible that combination therapy may increase the risk of hyperkalemia, particularly when with coadministered with medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or spironolactone. In our opinion patients with proteinuria >1 g/day despite optimal blood pressure control under RAS-blocking monotherapy are a high-risk group which will presumably benefit from combination therapy.
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              Protection of the kidney by thiazolidinediones: an assessment from bench to bedside.

               P Sarafidis,  G Bakris (2006)
              The global epidemic of diabetes mellitus has led to a continuous increase in the prevalence of diabetic nephropathy over the past years. Thus, diabetic nephropathy is currently the number one cause of end-stage renal disease in the Western world. It represents a major public health problem for which more effective prevention and treatment strategies are needed. Thiazolidinediones (TZDs) are a class of agents that lower blood glucose through reduction of insulin resistance in patients with type 2 diabetes. Growing evidence support the concept that TZDs have several beneficial effects on the cardiovascular system beyond their effects on glycemic control. These benefits include: blood pressure lowering, triglyceride reduction, high-density lipoprotein-cholesterol elevation, and reduction in subclinical vascular inflammation. Moreover, data from several animal and human studies support the notion that TZDs reduce urine albumin excretion and may prevent development of renal injury. The relative lack of evidence, however, demonstrating the effects of TZDs on hard renal outcomes mandates the need for well-designed trials with this particular objective. This paper summarizes all the data from clinical and experimental studies relevant to a possible renoprotective effect of TZDs and discusses actions of these compounds that may contribute toward this effect.
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                Author and article information

                Journal
                KBR
                Kidney Blood Press Res
                10.1159/issn.1420-4096
                Kidney and Blood Pressure Research
                S. Karger AG
                1420-4096
                1423-0143
                2007
                July 2007
                15 June 2007
                : 30
                : 4
                : 203-211
                Affiliations
                Division of Nephrology, No. 3 People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
                Article
                104089 Kidney Blood Press Res 2007;30:203–211
                10.1159/000104089
                17575467
                © 2007 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: 4, References: 33, Pages: 9
                Categories
                Original Paper

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