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Danaparoid Sodium Lowers Proteinuria in Diabetic Nephropathy

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Danaparoid Sodium Lowers Proteinuria in Diabetic Nephropathy Danaparoid Sodium Lowers Proteinuria in Diabetic Nephropathy JOHAN W. VAN DER PIJL,* FOKKO J. VAN DER WOUDE,* PETRONELLA H. L. M. GEELHOEDDUIJVESTIJN,t MARIJKE FROLICH, FELIX J. M. VAN DER MEER, HERMAN H. P.J. LEMKES,” and LEENDERT A. VAN ES,* *Department of Nephrology, Leiden University Hospital, P0 Box 9600, 2300 RC Leiden, The Netherlands; tDepartment of Internal Medicine, Den Haag, The Netherlands; *Department of Clinical Chemistry, Leiden University Hospital, Leiden, The Netherlands; Department of Hematology, Leiden University Hospital, Leiden, The Netherlands; ‘Department of Endocrinology, Leiden University Hospital, Leiden, The Netherlands. Abstract. Diabetic nephropathy is a progressive renal disease sodium, the albumin excretion ratio standardized for urinary with thickening of the gbomerular basement membrane and creatinine reduced with 17% in comparison with an increase of mesangial expansion and proliferation as histological hall- 23% after placebo (95% confidence interval of the difference, marks. The presence of the glycosaminoglycan side chains of -75.9-3.9%; P = 0.03). The percentage change of the urinary heparan sulfate proteoglycan, an important constituent of the protein excretion corrected for urinary creatinine differed at 8 glomerular basement membrane, is decreased in diabetic ne- wk significantly between both treatment arms (P 0.001). phropathy proportionally to the degree of proteinuria. Danap- Additional parameters for safety as hematobogical, hemostasis, aroid sodium is a mixture of sulfated glycosaminoglycans biochemical parameters, and fundusphotography did not show consisting mainly of heparan sulfate. The study presented here any clinically significant difference for both groups. Only two involved performing a randomized placebo-controlled cross- patients had minor skin hematomas at the injection site while over study with danaparoid sodium in diabetic patients with using danaparoid sodium. overt proteinuria. The aim of the study was to evaluate the In conclusion, the supplementation was found to be feasible effect on proteinuria and safety/tolerability. Nine patients com- and was not associated with side effects. A significant decline pleted the study, without major side effects; the crossover of proteinuria was found. More prospective dose-finding and study consisted of two 6-wk periods of treatment with 750 long-term studies must be performed to see whether danap- anti-Xa units danaparoid sodium subcutaneously once-daily or aroid sodium could not only induce a reduction of proteinuria placebo. Following danaparoid sodium, significant declines of but also halt the progression of renal disease. (J Am Soc both albuminuria and proteinuria were found. After danaparoid Nephrol 8: 456-462, 1997) Diabetic nephropathy occurs in 30%-40% of patients with importance because mesangial expansion and proliferation are insulin-dependent diabetes melbitus (DM I). This type of renal both strongly correlated with decline of renal function (4,1 1). disease progresses over time and is strongly related to a high A reduced synthesis and sulfatation of heparan sulfate proteo- mortality and morbidity rate (1-4). Proteoglycans and espe- glycans by podocytes and mesangial cells, when cultured under cially the glycosaminoglycan (OAO) side chains of heparan high glucose conditions, has been reported (12,13). sulfate (HS) are considered to be involved in the pathogenesis The key role of HS for the normal function of the OBM is of diabetic nephropathy. Heparan sulfate is thought to be illustrated by the following findings: removal of HS by hepa- important for the gbomerular basement membrane (OBM) in rinitase (14) or shielding of HS by a monoclonal antibody (15) terms of structure and function. It prevents clogging of the generates albuminuria in vivo. In type I diabetic patients with membrane and determines the sieving-function (5,6). HS is nephropathy, staining for heparan sulfate OAOs in the OBM is mainly responsible for the negative-charge barrier in the OBM reduced in proportion to the amount of proteinuria (16,17). (7), which is of relevance for preventing the passage of albu- In the context of such a pivotal role of HS in diabetic mm through the capillary wall. HS may also slow down mes- nephropathy, several studies have investigated whether supple- angial expansion and proliferation (8-10). This is of utmost mentation of sulfated glycosaminoglycans could be of any benefit. Indeed, the development of diabetic nephropathy could be prevented by giving glycosaminoglycans to rats with strep- Received September 5, 1996 Accepted November 1 1, 1996 tozotocin-induced diabetes meblitus (18). Several clinical stud- Correspondence to Dr. J.W. van der Pijl, Department of Nephrobogy, C3-P, 1 Leiden University Hospital, P0 Box 9600, 2300 RC Leiden, The Netherlands. ies have reported preliminary results in type I diabetics with micro- and macroalbuminuria. Myrup et a!. found a reduction l046-6673/0803-0456$03.00/0 Journal of the American Society of Nephrology of microalbuminuria after treatment with low molecular weight Copyright (C) 1997 by the American Society of Nephrobogy heparin (LMWH) and with standard heparin (19). In mac- Danaparoid Sodium and Proteinuria 457 roalbuminuric patients treated with enoxaparin (a LMWH), a dialysis. The placebo had the same appearance as the danaparoid significant decline of the urinary albumin excretion rate (AER) sodium containing ampoubes; it contained isotonic sodium chloride was found, but significance was not reached in comparison and sodium sulfite. Danaparoid sodium (0.6 ml, 750 anti-Xa units) with the placebo treated group (20). and the placebo were administered once-daily by subcutaneous (SC) injection for 6 wk, followed by a wash-out period of at least 4 wk. The Danaparoid sodium is a new, commercially available, hep- patients were trained to self-administer the study medication in an armnoid. It is a mixture of sulfated OAOs, consisting mainly of abdominal skinfold. The date and time of each injection was recorded HS with a small subfraction, which is highly sulfated. It is used daily by the patient on a list and checked by the investigator at the end both for the prevention and treatment of venous thromboem- of each treatment period, together with the number of returned unused bolism, where it has been shown to be efficacious and rela- ampoules. Protamine-containing insulin preparations were not al- lively safe. It functions by augmenting the inhibitory action of bowed to be injected at the same site, and study medication was not antithrombin on activated clotting factors Xa and ha. The high allowed to be mixed with insulin. ratio of anti-Xa/anti-IIa activity is thought to be responsible for a good efficacy/safety profile. It is seldom associated with heparin-induced thrombocytopenia. Clearance takes place Efficacy Assessments mainly by the kidneys (21-23). Therefore, and because dan- In diabetic nephropathy, both proteinuria and macroalbuminuria are associated with a steady decline of renal function. Taking the aparoid sodium consists to a large extent of heparan sulfate, we relative short duration of treatment into account, we decided to use decided to study the effect of danaparoid sodium on proteinuna proteinuria and albuminuria as surrogate markers. These parameters in type I diabetic patients. were expressed per mmol of creatinine to correct for incomplete urinary collections. The main parameters for efficacy were urinary Materials and Methods albumin excretion rate (AER) and urinary protein excretion rate Design (PER) corrected for urinary creatinine excretion rate. Therefore, total The study was designed as a phase II, randomized, double-blind, protein, albumin, and creatinine contents in 2 X 24-h urine samples placebo-controlled, crossover study. The medical ethical committee of (collected by the subject at home) were assessed. Baseline measure- the Leiden University Hospital had approved the protocol of the study, ments were taken before both treatment periods. At 0, 4, 6, and 8 wk, and all patients gave informed consent. Eligible patients were ran- AER, PER, and creatinine clearance were measured twice, and the domly allocated to one of the two treatment groups: 750 anti-Xa units means were compared with baseline (0 wk). danaparoid sodium (Orgaran#{174}, NV Organon, Oss, the Netherlands), subcutaneously (SC) administered once daily for 6 wk; a wash-out period of at least 4 wk; placebo (saline with sulfite), SC administered Safety Assessments once-daily for 6 wk, or the same scheme in the opposite direction. A general medical history (including duration of patients’ DM I), Medical and laboratory assessments were performed every 2 wk (0 = height, weight, blood pressure, and heart rate after 3 mm in sitting baseline; 2, 4, 6, and 8 wk after start of the respective treatments). position were taken, and a medical examination was performed. Fundusphotography (including staging of observed retinopathy) was performed before the inclusion and at the end of the study period. Patients Sodium, potassium, urea, creatinine, glucose, total protein, albumin, The study population consisted of nine patients who had nephrop- serum glutamic oxaboacetic transaminase (SOOT), serum glutamic athy due to DBM and fulfilled the following selection criteria: they pyruvic transaminase (SOPT), alkaline phosphatase, yGT, HbA , had to be > 18 years old; they had to have insulin-dependent diabetes hemoglobin, hematocrit, leukocytes, thrombocytes, prothrombin time, mellitus type I (DM I) with macroabbuminuria
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