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      Uric Acid Excretion and Dopamine-Induced Glomerular Filtration Response in Patients with IgA Glomerulonephritis

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          Abstract

          Background/Aim: It is unknown to what extent uric acid (UA) may affect vessel function and participate in tubulointerstitial damage. We examined the relationship between intrarenal vessel function and serum UA and its excretion in association with urinary N-acetyl-β- D-glucosaminidase (NAG). Methods: In 50 IgA patients (mean age 34.7 ± 9.3 years) and 15 controls (mean age 33.5 ± 6.9 years) with a creatinine clearance of 99.4 ± 21.6 and 118.1 ± 17.2 ml/min, respectively, the renal vascular function was estimated based on the dopamine-induced glomerular filtration response (DIR; see text). The DIR was measured using two 120-min creatinine clearance values (before and after intravenous administration of 2 g/kg/min dopamine). Serum UA, triglycerides and cholesterol and urinary NAG (24 h) and protein and UA excretion were measured. Results: Patients with IgA nephropathy versus controls: DIR 8.80 ± 6.6 vs. 12.83% (p < 0.01), NAG 7.25 ± 3.30 vs. 4.69 ± 1.12 U/g creatinine (p < 0.01), and fractional UA excretion 7.80 ± 2.20 versus 6.29 ± 1.80% (p < 0.01). A negative correlation between DIR and NAG was found; regression analysis showed a more prominent relationship in the patients (NAG = 9.99 – 0.29x DIR) than in the controls (NAG = 5.50 – 0.06x DIR). UA and urate excretion and NAG in the patients correlated with DIR (r = –0.39, p < 0.02; r = –0.29, p < 0.04, and r = 0.59, p < 0.001, respectively). Multivariate analysis showed an association of DIR (R<sup>2</sup> = 0.39) with NAG but not with proteinuria and UA and UA excretion; the NAG excretion (R<sup>2</sup> = 0.56) correlated significantly with UA and DIR. Conclusion: It is suggested that UA plays a role, associated with tubular dysfunction, in the regulation of intrarenal vessel function.

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          Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure.

          Recent studies emphasize the role of chronic hypoxia in the tubulointerstitium as a final common pathway to end-stage renal failure. When advanced, tubulointerstitial damage is associated with the loss of peritubular capillaries. Associated interstitial fibrosis impairs oxygen diffusion and supply to tubular and interstitial cells. Hypoxia of tubular cells leads to apoptosis or epithelial-mesenchymal transdifferentiation. This in turn exacerbates fibrosis of the kidney and subsequent chronic hypoxia, setting in train a vicious cycle whose end point is ESRD. A number of mechanisms that induce tubulointerstitial hypoxia at an early stage have been identified. Glomerular injury and vasoconstriction of efferent arterioles as a result of imbalances in vasoactive substances decrease postglomerular peritubular capillary blood flow. Angiotensin II not only constricts efferent arterioles but, via its induction of oxidative stress, also hampers the efficient utilization of oxygen in tubular cells. Relative hypoxia in the kidney also results from increased metabolic demand in tubular cells. Furthermore, renal anemia hinders oxygen delivery. These factors can affect the kidney before the appearance of significant pathologic changes in the vasculature and predispose the kidney to tubulointerstitial injury. Therapeutic approaches that target the chronic hypoxia should prove effective against a broad range of renal diseases. Current modalities include the improvement of anemia with erythropoietin, the preservation of peritubular capillary blood flow by blockade of the renin-angiotensin system, and the use of antioxidants. Recent studies have elucidated the mechanism of hypoxia-induced transcription, namely that prolyl hydroxylase regulates hypoxia-inducible factor. This has given hope for the development of novel therapeutic approaches against this final common pathway.
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            A role for uric acid in the progression of renal disease.

            Hyperuricemia is associated with renal disease, but it is usually considered a marker of renal dysfunction rather than a risk factor for progression. Recent studies have reported that mild hyperuricemia in normal rats induced by the uricase inhibitor, oxonic acid (OA), results in hypertension, intrarenal vascular disease, and renal injury. This led to the hypothesis that uric acid may contribute to progressive renal disease. To examine the effect of hyperuricemia on renal disease progression, rats were fed 2% OA for 6 wk after 5/6 remnant kidney (RK) surgery with or without the xanthine oxidase inhibitor, allopurinol, or the uricosuric agent, benziodarone. Renal function and histologic studies were performed at 6 wk. Given observations that uric acid induces vascular disease, the effect of uric acid on vascular smooth muscle cells in culture was also examined. RK rats developed transient hyperuricemia (2.7 mg/dl at week 2), but then levels returned to baseline by week 6 (1.4 mg/dl). In contrast, RK+OA rats developed higher and more persistent hyperuricemia (6 wk, 3.2 mg/dl). Hyperuricemic rats demonstrated higher BP, greater proteinuria, and higher serum creatinine than RK rats. Hyperuricemic RK rats had more renal hypertrophy and greater glomerulosclerosis (24.2 +/- 2.5 versus 17.5 +/- 3.4%; P < 0.05) and interstitial fibrosis (1.89 +/- 0.45 versus 1.52 +/- 0.47; P < 0.05). Hyperuricemic rats developed vascular disease consisting of thickening of the preglomerular arteries with smooth muscle cell proliferation; these changes were significantly more severe than a historical RK group with similar BP. Allopurinol significantly reduced uric acid levels and blocked the renal functional and histologic changes. Benziodarone reduced uric acid levels less effectively and only partially improved BP and renal function, with minimal effect on the vascular changes. To better understand the mechanism for the vascular disease, the expression of COX-2 and renin were examined. Hyperuricemic rats showed increased renal renin and COX-2 expression, the latter especially in preglomerular arterial vessels. In in vitro studies, cultured vascular smooth muscle cells incubated with uric acid also generated COX-2 with time-dependent proliferation, which was prevented by either a COX-2 or TXA-2 receptor inhibitor. Hyperuricemia accelerates renal progression in the RK model via a mechanism linked to high systemic BP and COX-2-mediated, thromboxane-induced vascular disease. These studies provide direct evidence that uric acid may be a true mediator of renal disease and progression.
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              Mild hyperuricemia induces vasoconstriction and maintains glomerular hypertension in normal and remnant kidney rats.

              Hyperuricemia has been associated with renal disease. Because glomerular hemodynamic alterations critically contribute to initiation and progression of renal disease, we evaluated the effect of mild hyperuricemia in glomerular microcirculatory changes in rats under normal conditions and with renal injury induced by subtotal renal ablation (RK). Hyperuricemia was induced in normal and remnant kidney (RK) rats on a normal sodium diet by administration of oxonic acid (OA). To prevent hyperuricemia, allopurinol (AP) was administered concomitantly. Glomerular hemodynamics were evaluated by micropuncture techniques. Systolic blood pressure (SBP), proteinuria, arterial morphology, and serum uric acid were measured. In RK rats, glomerulosclerosis, fibrosis, and inflammatory cell infiltration (CD5+) were also assessed. In normal rats, hyperuricemia resulted in afferent arteriole thickening associated with renal cortical vasoconstriction [single nephron glomerular filtration rate (SNGFR) -35%, P < 0.05) and glomerular hypertension (P < 0.05). Allopurinol treatment prevented structural and functional alterations. In RK rats, hyperuricemia produced more renal vascular damage than control animals coupled with severe cortical vasoconstriction (SNGFR -40%, P < 0.05) and persistent glomerular hypertension. Allopurinol partially prevented cortical vasoconstriction, and fully prevented arteriolopathy and glomerular hypertension associated with significantly less infiltration of CD5+ cells. Hyperuricemia induces arteriolopathy of preglomerular vessels, which impairs the autoregulatory response of afferent arterioles, resulting in glomerular hypertension. Lumen obliteration induced by vascular wall thickening produces severe renal hypoperfusion. The resulting ischemia is a potent stimulus that induces tubulointerstitial inflammation and fibrosis, as well as arterial hypertension. These studies provide a potential mechanism by which hyperuricemia can mediate hypertension and renal disease.
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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
                2008
                April 2008
                07 December 2007
                : 28
                : 3
                : 391-396
                Affiliations
                Departments of aNephrology, Hypertension and Internal Medicine and bClinical Laboratory Medicine, Nicolaus Copernicus University, Toruń, and Collegium Medicum, Bydgoszcz, and Departments of cClinical Nutrition and dTransplantation, Nephrology and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland
                Article
                112271 Am J Nephrol 2008;28:391–396
                10.1159/000112271
                18063857
                827cbeab-8697-429a-b523-ff3f2c575521
                © 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.

                History
                : 03 August 2007
                : 26 October 2007
                Page count
                Figures: 1, Tables: 2, References: 30, Pages: 6
                Categories
                Original Report: Patient-Oriented, Translational Research

                Cardiovascular Medicine,Nephrology
                IgA glomerulonephritis,Uric acid,N-Acetyl-β-<italic>D</italic>-glucosaminidase,Intrarenal vessel function

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