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      Effect of Sulodexide on Albuminuria, NAG Excretion and Glomerular Filtration Response to Dopamine in Diabetic Patients

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          Abstract

          Background: Albuminuria is the best and most readily available marker for glomerular damage and progressive renal function loss in patients with diabetic nephropathy. Recently, administration of the oral glycosaminoglycan sulodexide (a mixture of 80% fast-moving heparin and 20% dermatan sulphate) was shown to effectively decrease albumin excretion rate in diabetics with nephropathy. Aims: To evaluate whether the hypoalbuminuric effect of sulodexide is associated with improvement of the renal vascular or tubule function. Methods: Forty-five type 1 diabetic patients, affected by diabetic nephropathy with albuminuria for at least 5 years, were randomly allocated to sulodexide or untreated. Those allocated to sulodexide were given 100 mg of sulodexide daily for 120 days. Renal vascular function (DIR) and N-acetyl-β- D-glucosaminidase (NAG) excretion were estimated before and at the end of the study, the former in thesulodexide group only. DIR was measured as two Cr<sub>cl</sub> lasting 120 min (before and during 2 µg/kg b.w. i.v. dopamine). Results: The analysis of trends during the study demonstrated a marked reduction of albuminuria in the sulodexide group (from 126.1 ± 15.41 to 93.6 ± 13.7 mg/day). DIR rose from 13.2 ± 2.1% to 15.44 ± 1.9% (relative increase: +16.9%), and NAG excretion showed a decreasing trend decreased in the sulodexide group only (from 5.1 ± 0.62 to 4.7 ± 0.40 U/g<sub>creat</sub>). Conclusion: The findings presented in this study indicate for the first time that orally available sulodexide may favorably affect the renal vascular function in type 1 diabetic patients with nephropathy and microalbuminuria. The effect of sulodexide on NAG is strongly influenced by the baseline NAG values, with a significant NAG reduction in the patients with the highest baseline NAG values.

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          Most cited references 19

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          Proteinuria, a target for renoprotection in patients with type 2 diabetic nephropathy: lessons from RENAAL.

          Proteinuria or albuminuria is an established risk marker for progressive renal function loss. Albuminuria can be effectively lowered with antihypertensive drugs that interrupt the renin-angiotensin system (RAS). We investigated whether albuminuria could not only serve as a marker of renal disease, but also function as a monitor of the renoprotective efficacy of RAS intervention by the angiotensin II (Ang II) antagonist, losartan, in patients with diabetic nephropathy. The data from the RENAAL (Reduction in End Points in Noninsulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan) study, a double-blind, randomized trial, were used to examine the effects of losartan on the renal outcome [i.e., the primary composite end point of doubling of serum creatinine, end-stage renal disease (ESRD) or death] in 1513 type 2 diabetic patients with nephropathy. We examined the effect of the degree of albuminuria at baseline, initial antiproteinuric response to therapy, and the degree of remaining (residual) albuminuria on renal outcome (either the primary composite end point of RENAAL or ESRD). We also evaluated the contribution to renal protection of the antiproteinuric effect of losartan independently of changes in blood pressure. Baseline albuminuria is almost linearly related to renal outcome, and is the strongest predictor among all measured well-known baseline risk parameters. After adjusting for baseline risk markers of age, gender, race, weight, smoking, sitting diastolic blood pressure, sitting systolic blood pressure, total cholesterol, serum creatinine, albuminuria, hemoglobin, and hemoglobin A(1c) (HbA(1c)) patients with high baseline albuminuria (> or =3.0 g/g creatinine) showed a 5.2-fold (95% CI 4.3-6.3) increased risk for reaching a renal end point, and a 8.1-fold (95% CI 6.1-10.8) increased risk for progressing to ESRD, compared to the low albuminuria group (<1.5 g/g). The changes in albuminuria in the first 6 months of therapy are roughly linearly related to the degree of long-term renal protection: every 50% reduction in albuminuria in the first 6 months was associated with a reduction in risk of 36% for renal end point and 45% for ESRD during later follow-up. Albuminuria at month 6, designated residual albuminuria, showed a linear relationship with renal outcome, almost identical to the relationship between baseline albuminuria and renal risk. Losartan reduced albuminuria by 28% (95% CI -25% to -36%), while placebo increased albuminuria by 4% (95% CI +8% to -1%) in the first 6 months of therapy. The specific (beyond blood pressure lowering) renoprotective effect of the Ang II antagonist, losartan, in this study is for the major part explained by its antialbuminuric effect (approximately 100% for the renal end point, and 50% for ESRD end point). Albuminuria is the predominant renal risk marker in patients with type 2 diabetic nephropathy on conventional treatment; the higher the albuminuria, the greater the renal risk. Reduction in albuminuria is associated with a proportional effect on renal protection, the greater the reduction the greater the renal protection. The residual albuminuria on therapy (month 6) is as strong a marker of renal outcome as is baseline albuminuria. The antiproteinuric effect of losartan explains a major component of its specific renoprotective effect. In conclusion, albuminuria should be considered a risk marker for progressive loss of renal function in type 2 diabetes with nephropathy, as well as a target for therapy. Reduction of residual albuminuria to the lowest achievable level should be viewed as a goal for future renoprotective treatments.
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            Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death.

            In 328 type 2 diabetic patients followed for 9.0 years (mean), we investigated whether endothelial dysfunction and chronic inflammation (estimated from plasma markers) can explain the association between (micro)albuminuria and mortality. Of the patients, 113 died. Mortality was increased in patients with baseline microalbuminuria or macroalbuminuria (odds ratios as compared with normoalbuminuria, 1.78 [P < 0.05] and 2.86 [P < 0.01]) and in patients with soluble vascular cell adhesion molecule 1 in the third tertile and C-reactive protein in the second and third tertiles (odds ratios as compared with the first tertile, 2.05 [ P < 0.01], and 1.80 [P < 0.05] and 2.92 [ P < 0.01]). These associations were mutually independent. The mean yearly change in urinary albumin excretion was 9.4%; in von Willebrand factor, 8.1%; in tissue-type plasminogen activator, 2.8%; in soluble vascular cell adhesion molecule 1, 5.2%; in soluble E-selectin, -2.3%; in C-reactive protein, 3.8%; and in fibrinogen, 2.3%. The longitudinal development of urinary albumin excretion was significantly and independently determined by baseline levels of and the longitudinal development of BMI, systolic blood pressure, serum creatinine, glycated hemoglobin and plasma von Willebrand factor (baseline only), soluble E-selectin (baseline only), tissue-type plasminogen activator, C-reactive protein, and fibrinogen. The longitudinal developments of markers of endothelial function and inflammation were interrelated. In type 2 diabetes, increased urinary albumin excretion, endothelial dysfunction, and chronic inflammation are interrelated processes that develop in parallel, progress with time, and are strongly and independently associated with risk of death.
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              Urinary N-acetyl-beta-glucosaminidase excretion is a marker of tubular cell dysfunction and a predictor of outcome in primary glomerulonephritis.

              The urinary excretion of N-acetyl-beta-glucosamynidase (NAG) is increased in subjects exposed to substances toxic for renal tubular cells. In experimental and human glomerular diseases, its increased excretion is probably due to the dysfunction of tubular epithelial cells induced by increased traffic of proteins in the tubular lumen. The first aim of this study was to evaluate whether NAG excretion is correlated not only with the amount of proteinuria but also with some proteinuric components which reflect both glomerular capillary wall damage (IgG) and an impairment of tubular reabsorption of microproteins (alpha(1) microglobulin). The second aim was to assess whether NAG excretion has a predictive value on functional outcome and response to therapy. In 136 patients with primary glomerulonephritis [74 with idiopathic membranous nephropathy (IMN), 44 with primary focal segmental glomerulosclerosis (FSGS) and 18 with minimal change disease (MCD)] urinary NAG excretion was measured by a colorimetric method and expressed in units per gram of urinary creatinine. Using univariate linear regression analysis NAG excretion in all 136 patients was significantly dependent on IgG excretion, 24-h proteinuria, fractional excretion of alpha(1) microglobulin (FE alpha(1)m) and diagnosis. Using multiple linear regression analysis, NAG excretion was significantly dependent only on IgG excretion and 24-h proteinuria. Limiting the analysis to 67 patients with nephrotic syndrome (NS) and baseline normal renal function, by multiple linear regression, NAG excretion was significantly dependent on IgG excretion (P=0.0004), 24-h proteinuria (P=0.0067) and FE alpha(1)-m (P=0.0032) (R(2)=0.63). In 66 patients with NS and normal baseline renal function (MCD 10 patients; FSGS 20 patients; IMN 36 patients), according to values below or above defined cut-offs (IMN, 18 U/g urinary Cr; FSGS and MCD, 24 U/g urinary Cr), NAG excretion predicted remission in 86 vs 27% of IMN patients (P=0.0002) and 77 vs 14% of FSGS patients (P=0.005). Progression to chronic renal failure (CRF) was 0 vs 47% in IMN patients (P=0.001) and 8 vs 57% in FSGS patients (P=0.03). Using Cox model, in IMN patients only NAG excretion (P=0.01, RR 5.8), but not 24-h proteinuria, predicted progression to CRF. All MCD patients had NAG excretion values below the chosen cut-off, and 90% of them developed remission. Response to immunosuppressive therapy was significantly different in patients with NAG excretion values below or above the cut-offs. Urinary NAG excretion can be considered as a reliable marker of the tubulo-toxicity of proteinuria in the early stage of IMN, FSGS and MCD; the excretion values show a significant relationship with 24-h proteinuria, IgG excretion and FE alpha(1)m. Its determination may be a non-invasive, useful test for the early identification of patients who will subsequently develop CRF or clinical remission and responsiveness to therapy.
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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
                2006
                January 2007
                19 January 2007
                : 26
                : 6
                : 621-628
                Affiliations
                aDepartment of Nephrology, Hypertension and Internal Medicine and bClinical Laboratory Department, Nicolaus Copernicus University in Toruń, Collegium Medicum Bydgoszcz, and cDiabetology and Edocrinology Centre, Bydgoszcz, Poland; d‘GC. Descovich’ Atherosclerosis Research Centre, ‘D Campanacci’ Clinical Medicine and Applied Biotechnology Department, Bologna University, Bologna, and eEuropean Commission, DG-Joint Research Centre, IHCP, Biotechnology and GMOs Unit, Ispra, Italy
                Article
                98195 Am J Nephrol 2006;26:621–628
                10.1159/000098195
                17191008
                © 2006 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: 3, References: 32, Pages: 8
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/98195
                Categories
                Original Report: Laboratory Investigation

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