OJNeph  Vol.4 No.2 , June 2014
Antiproteinuric Effect of Sulodexide versus Losartan in Primary Glomerulonephritis
Abstract: Introduction: Limited data are available for the use of sulodexide in primary glomerulonephritis (GN). Objective: We studied the efficacy of sulodexide compared to losartan in patients with primary GN. Design and Method: This was a prospective, open labelled, randomized control trial in patients with stable primary GN. Patients were randomized to receive either sulodexide or losartan to maximum tolerated doses for 12 weeks. Blood and urine investigations were measured at baseline and at 4-weekly intervals. Adverse effects were recorded. Results: 18 patients were recruited (10-sulodexide and 8-losartan). Their baseline characteristics were comparable. At end study, patients in both groups showed no significant reduction in proteinuria and there were no differences between groups at each visit. Nonetheless, there was a trend towards lower protein uria in the losartan but not in sulodexide group. There were no changes in the other parameters of renal function or of coagulation over time. No adverse events in particular clinical bleeding occurred. Conclusion: Sulodexide and losartan did not demonstrate any significant anti-proteinuric effect in primary GN. Nevertheless, there was a trend of better proteinuria reduction in losartan group. Furthermore, other renal parameters were not significantly affected by both drugs.
Cite this paper: Gafor, A. , Mohamad, W. , Mohd, R. , Cader, R. , Yen, K. , Shah, S. and Kong, N. (2014) Antiproteinuric Effect of Sulodexide versus Losartan in Primary Glomerulonephritis. Open Journal of Nephrology, 4, 69-78. doi: 10.4236/ojneph.2014.42010.

[1]   Mc Grogan, A.F.C. and de Vries, C.S. (2011) The Incidence of Primary Glomerulonephritis Worldwide: A Systematic Review of the Literature. Nephrol Dial Transplant, 26, 414-430.

[2]   Sunita, B. and Lim, S.K. (2009) 3rd Report of the Malaysian Registry of Renal Biopsy 2009. Primary Glomerulonephritis, 2, 24.

[3]   US Renal Data System, USRDS 2012 Annual Data Report (2012) Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, 226.

[4]   Lim, Y.N., Ong, L.M., Ghazali, A. and Lee, D.G. (2012) Nineteen Report of Malaysian Dialysis and Transplantation Registry 2012: Dialysis in Malaysia. The National Renal Registry, Kuala Lumpur.

[5]   Ruggenenti, P., Perna, A., Mosconi, L., Pisoni, R. and Remuzzi, G. (1998) Urinary Protein Excretion Rate Is the Best Independent Predictor of ESRF in Non-Diabetic Proteinuric Chronic Nephropathies. “Gruppo Italiano di Studi Epidemiologici in Nefrologia” (GISEN). Kidney International, 53, 1209-1216.

[6]   Peterson, J.C., Adler, S., Burkart, J.M., Greene, T., Hebert, L.A., Hunsicker, L.G., et al. (1995) Blood Pressure Control, Proteinuria, and the Progression of Renal Disease. The Modification of Diet in Renal Disease Study. Annals of Internal Medicine, 123, 754-762.

[7]   Lea, J., Greene, T., Hebert, et al. (2005) The Relationship between Magnitude of Proteinuria Reduction and Risk of End Stage Renal Disease: Results of the African American Study of Kidney Disease and Hypertension. Achives of Internal Medicine, 165, 2254-2261.

[8]   So, W.Y.K.K., Iseki, C., et al. (2006) Glomerular Filtration Rate, Cardiorenal End Points, and All Cause Mortality in Type 2 Diabetic Patients. Diabetes Care, 29, 2046-2052.

[9]   Lewis, E.J.H.L., Clarke, W.R., Berl, T., Pohl, M.A., Lewis, J.B., et al. (2001) Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes. New England Journal of Medicine, 345, 851-860.

[10]   Maschio, G.A.D., Janin, G., Locatelli, F., Mann, J.F., Motolese, M., et al. (1996) Effect of the Angiotensin-Converting-Enzyme Inhibitor Benazepril on the Progression of Chronic Renal Insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. New England Journal of Medicine, 334, 939-945.

[11]   Group, T.G. (1997) Randomised Placebo Control Trial of Effect of Ramipril on Decline in Glomerular Filtration Rate and Risk of Terminal Renal Failure in Proteinuric, Non Diabetic Nephropathy. Lancet, 349, 1857-1863.

[12]   Brenner, B.M.C.M., de Zeeuw, D., Keane, W.F., Mitch, W.E., Parving, H.H., et al. (2001) Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy. New England Journal of Medicine, 345, 861-869.

[13]   Jacob Van Den Born, L.W.J.V., Marinka, H.B., Jacquesh, V., Karel, J.M.A., Jan, J.W. and Jo, H.M.B. (1993) Distribution of GBM Heparan Sulfate Proteoglycan Core Protein and Side Chains in Human Glomerular Diseases. Kidney Intenational, 43, 454-463.

[14]   Harenberg, J. (1998) Review of Pharmacodynamics, Pharmacokinetics, and Therapeutic Properties of Sulodexide. Medicinal Research Reviews, 18, 1-20.<1::AID-MED1>3.0.CO;2-4

[15]   Ruggeri, A., Guizzardi, S., Franchi, M., Morocutti, M. and Mastacchi, R. (1985) Pharmacokinetics and Distribution of a Fluoresceinated Glycosaminoglycan, Sulodexide, in Rats. Part II: Organ Distribution in Rats. Arzneimittelforschung, 35, 1517-1519.

[16]   Dedov, I., Shestakova, M., Vorontzov, A. and Palazzini, E. (1997) A Randomized, Controlled Study of Sulodexide Therapy for the Treatment of Diabetic Nephropathy. Nephrology Dialysis Transplantation, 12, 2295-2300.

[17]   Bang, K., Chin, H.J., Chae, D.W., Joo, K.W., Kim, Y.S., Kim, S., et al. (2011) Anti-Proteinuric Effect of Sulodexide in Immunoglobulin A Nephropathy. Yonsei Medical Journal, 52, 588-594.

[18]   Yang, B.Y., Lee, H.S., Song, S.H., Kwak, I.S., Lee, S.B., Lee, D.W., et al. (2012) Use of Low-Dose Sulodexide in IgA Nephropathy Patients on Renin-Angiotensin System Blockades. Kidney Research and Clinical Practice, 31, 163-169.

[19]   Rozita, M., Loo, C.Y., et al. (2008) Glycosaminoglycans (Sulodexide) for Resistant Heavy Proteinuria of Chronic Glomerulonephritides (Abstract). 11th Asian Pacific Congress of Nephrology, Kuala Lumpur, 5-8 May 2008.

[20]   Gambaro, G., Kinalska, I., Oksa, A., Pont’uch, P., Hertlová, M., Olsovsky, J., et al. (2002) Oral Sulodexide Reduces Albuminuria in Microalbuminuric and Macroalbuminuric Type 1 and Type 2 Diabetic Patients: The Di.N.A.S. Randomized Trial. Journal of the American Society of Nephrology, 13, 1615-1625.

[21]   Lewis, E.J., Lewis, J.B., Greene, T., Hunsicker, L.G., Berl, T., Pohl, M.A., et al. (2011) Sulodexide for Kidney Protection in Type 2 Diabetes Patients with Microalbuminuria: A Randomized Controlled Trial. American Journal of Kidney Diseases, 58, 729-736.

[22]   Packham, D.K., Wolfe, R., Reutens, A.T., Berl, T., Heerspink, H.L., Rohde, R., et al. (2012) Sulodexide Fails to Demonstrate Renoprotection in Overt Type 2 Diabetic Nephropathy. Journal of the American Society of Nephrology, 23, 123-130.

[23]   Gambaro, G., Venturini, A.P., Noonan, D.M., Fries, W., Re, G., Garbisa, S., et al. (1994) Treatment with a Glycosaminoglycan Formulation Ameliorates Experimental Diabetic Nephropathy. Kidney International, 46, 797-806.

[24]   Caenazzo, C., Garbisa, S., Ceol, M., Baggio, B., Borsatti, A., Marchi, E., et al. (1995) Heparin Modulates Proliferation and Proteoglycan Biosynthesis in Murine Mesangial Cells: Molecular Clues for Its Activity in Nephropathy. Nephrology Dialysis Transplantation, 10, 175-184.

[25]   Ceol, M., Gambaro, G., Sauer, U., Baggio, B., Anglani, F., Forino, M., et al. (2000) Glycosaminoglycan Therapy Prevents TGF-Beta1 Overexpression and Pathologic Changes in Renal Tissue of Long-Term Diabetic Rats. Journal of the American Society of Nephrology, 11, 2324-2336.

[26]   Lewis, E.J. and Xu, X. (2008) Abnormal Glomerular Permeability Characteristics in Diabetic Nephropathy: Implications for the Therapeutic Use of Low-Molecular Weight Heparin. Diabetes Care, 31, S202-S207.

[27]   Gambaro, G. and Kong, N.C. (2010) Glycosaminoglycan Treatment in Glomerulonephritis? An Interesting Option to Investigate. Journal of Nephrology, 23, 244-252.

[28]   Linhardt, R.J., Al-Hakim, A., Liu, J.A., Hoppensteadt, D., Mascellani, G., Bianchini, P., et al. (1991) Structural Features of Dermatan Sulfates and Their Relationship to Anticoagulant and Antithrombotic Activities. Biochemical Pharmacology, 42, 1609-1619.

[29]   Furie, B. and Furie, B.C. (1992) Molecular and Cellular Biology of Blood Coagulation. The New England Journal of Medicine, 326, 800-806.

[30]   Cirujeda, J.L. and Granado, P.C. (2006) A Study on the Safety, Efficacy, and Efficiency of Sulodexide Compared with Acenocoumarol in Secondary Prophylaxis in Patients with Deep Venous Thrombosis. Angiology, 57, 53-64.

[31]   Errichi, B.M., Cesarone, M.R., Belcaro, G., Marinucci, R., Ricci, A., Ippolito, A., et al. (2004) Prevention of Recurrent Deep Venous Thrombosis with Sulodexide: The SanVal Registry. Angiology, 55, 243-249.

[32]   Coccheri, S., Scondotto, G., Agnelli, G., Aloisi, D., Palazzini, E., Zamboni, V., et al. (2002) Randomised, Double Blind, Multicentre, Placebo Controlled Study of Sulodexide in the Treatment of Venous Leg Ulcers. Thrombosis and Haemostasis, 87, 947-952.

[33]   Coccheri, S., Scondotto, G., Agnelli, G., Palazzini, E. and Zamboni, V. (2002) Sulodexide in the Treatment of Intermittent Claudication. Results of a Randomized, Double-Blind, Multicentre, Placebo-Controlled Study. European Heart Journal, 23, 1057-1065.

[34]   Gluhovschi, G.B.G., Petrica, L., et al. (2006) Nephroprotection, Part of Multi-Organprotection. Temporomandibular Joint Disorders, 56, 2-3.

[35]   Rutkowski, P., Tylicki, L., Renke, M., Korejwo, G., Zdrojewski, Z. and Rutkowski, B. (2004) Low-Dose Dual Blockade of the Renin-Angiotensin System in Patients with Primary Glomerulonephritis. American Journal of Kidney Diseases, 43, 260-268.

[36]   Renke, M., Tylicki, L., Rutkowski, P. and Rutkowski, B. (2004) Low-Dose Angiotensin II Receptor Antagonists and Angiotensin II-Converting Enzyme Inhibitors Alone or in Combination for Treatment of Primary Glomerulonephritis. Scandinavian Journal of Urology and Nephrology, 38, 427-433.

[37]   Praga, M., Andrade, C.F., Luño, J., Arias, M., Poveda, R., Mora, J., et al. (2003) Antiproteinuric Efficacy of Losartan in Comparison with Amlodipine in Non-Diabetic Proteinuric Renal Diseases: A Double-Blind, Randomized Clinical Trial. Nephrology Dialysis Transplantation, 18, 1806-1813.

[38]   Tylicki, L., Rutkowski, P., Renke, M. and Rutkowski, B. (2002) Renoprotective Effect of Small Doses of Losartan and Enalapril in Patients with Primary Glomerulonephritis. Short-Term Observation. American Journal of Nephrology, 22, 356-362.

[39]   Tylicki, L., Renke, M., Rutkowski, P., Rutkowski, B. and Lysiak-Szydlowska, W. (2005) Randomized, Controlled Study of the Effects of Losartan versus Enalapril in Small Doses on Proteinuria and Tubular Injury in Primary Glomerulonephritis. Medical Science Monitor, 11, 131-137.

[40]   Hou, F.F., Xie, D., Zhang, X., Chen, P.Y., Zhang, W.R., Liang, M., Guo, Z.J. and Jiang, J.P. (2007) Renoprotective of Optimal Antiproteinuric Doses (ROAD) Study: A Randomized Controlled Study of Benazepril and Losartan in Chronic Renal Insufficiency. Journal of the American Society of Nephrology, 18, 1889-1898.

[41]   Mogensen, C.E., Neldam, S., Tikkanen, I., Oren, S., Viskoper, R., et al. (2000) Randomised Controlled Trial of Dual Blockade of Renin-Angiotensin System in Patients with Hypertension, Microalbuminuria, and Non-Insulin Dependent Diabetes: The Candesartan and Lisinopril Microalbuminuria (CALM) Study. BMJ, 321, 1440-1444.

[42]   Wright Jr., J.T., Bakris, G., Greene, T., Agodoa, L.Y., Appel, L.J., Charleston, J., et al. (2002) Effect of Blood Pressure Lowering and Antihypertensive Drug Class on Progression of Hypertensive Kidney Disease: Results from the AASK Trial. JAMA, 288, 2421-2431.

[43]   Arguedas, J.A., Perez, M.I. and Wright, J.M. (2009) Treatment Blood Pressure Targets for Hypertension. Cochrane Database of Systematic Reviews, Article ID: CD004349.

[44]   Andersen, S., Rossing, P., Juhl, T.R., Deinum, J. and Parving, H.H. (2002) Optimal Dose of Losartan for Renoprotection in Diabetic Nephropathy. Nephrology Dialysis Transplantation, 17, 1413-1418.

[45]   Gluhovschi, A.S.G., Raica, M., Petrica, L., Trandafirescu, V., Velciov, S., Bozdog, G., Patrascu, C. and Gluhovschi, C. (2001) The Effects of the Therapy with Natural Glycosaminoglycans (Sulodexide) on Proteinuria in Different Types of Glomerulonephritis. Medicine and Biology, 8, 26-30.

[46]   Kang, D.H., Nakagawa, T., Feng, L., Watanabe, S., Han, L., Mazzali, M., et al. (2002) A Role for Uric Acid in the Progression of Renal Disease. Journal of the American Society of Nephrology, 13, 2888-2897.

[47]   Miao, Y., Ottenbros, S.A., Laverman, G.D., Brenner, B.M., Cooper, M.E., Parving, H.H., et al. (2011) Effect of a Reduction in Uric Acid on Renal Outcomes during Losartan Treatment: A Post Hoc Analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan Trial. Hypertension, 58, 2-7.