Diabetic nephropathy is a progressive renal disease with thickening of the glomerular basement membrane and mesangial expansion and proliferation as histological hallmarks. The presence of the glycosaminoglycan side chains of heparan sulfate proteoglycan, an important constituent of the glomerular basement membrane, is decreased in diabetic nephropathy proportionally to the degree of proteinuria. Danaparoid sodium is a mixture of sulfated glycosaminoglycans consisting mainly of heparan sulfate. The study presented here involved performing a randomized placebo-controlled crossover study with danaparoid sodium in diabetic patients with overt proteinuria. The aim of the study was to evaluate the effect on proteinuria and safety/tolerability. Nine patients completed the study, without major side effects; the crossover study consisted of two 6-wk periods of treatment with 750 anti-Xa units danaparoid sodium subcutaneously once-daily or placebo. Following danaparoid sodium, significant declines of both albuminuria and proteinuria were found. After danaparoid sodium, the albumin excretion ratio standardized for urinary creatinine reduced with 17% in comparison with an increase of 23% after placebo (95% confidence interval of the difference,-75.9-3.9%; P = 0.03). The percentage change of the urinary protein excretion corrected for urinary creatinine differed at 8 wk significantly between both treatment arms (P = 0.001). Additional parameters for safety as hematological, hemostasis, biochemical parameters, and fundusphotography did not show any clinically significant difference for both groups. Only two patients had minor skin hematomas at the injection site while using danaparoid sodium. In conclusion, the supplementation was found to be feasible and was not associated with side effects. A significant decline of proteinuria was found. More prospective dose-finding and long-term studies must be performed to see whether danaparoid sodium could not only induce a reduction of proteinuria but also halt the progression of renal disease.
Reduction of heparan sulphate-associated anionic sites in the glomerular basement membrane of rats with streptozotocin-induced diabetic nephropathy
