HDCN Article Review/Hyperlink

Van der Pijl JW, Van Der Woude FJ, Geelhoed-Duijvestijn PHLM, Frohlich M, Van Der Meer FJM, et al

Danaparoid sodium lowers proteinuria in diabetic nephropathy

J Am Soc Nephrol (Mar) 8:456-462 1997

Diabetic nephropathy is characterized by thickening of the glomerular basement membrane (GBM) and mesangial matrix expansion. Heparan sulfate is important in maintaining the negative-charge barrier and prevention of albumin passage through the GBM and proteinuria. Reduced synthesis of heparan sulfate proteoglycans (HSPG) by podocytes and mesangial cells cultured under high glucose conditions and decreased staining for HSPG in clinical diabetic npehropathy have been reported. Therefore, it is reasonable to surmise that administration of HSPG might restore a more normal charge barrier and decrease proteinuria. Danaparoid sodium is a mixture of sulfated glycosaminoglycans consisting mainly of heparan sulfate.

The authors performed a placebo-controlled, randomized crossover study of danaparoid in Type I diabetic patients with overt proteinuria (albumin excretion rate (AER) > 300 mg/24h; creat clearance > 40 ml/min). The design included two 6-wk periods of treatment with 750 anti-Xa units danaparoid sodium subcutaneously once daily or placebo with a 4-wk washout between; the order of treatments was also randomized. Nine patients completed the study without major side effects.

Danaparoid resulted in significant decreases in both albuminuria (AER/creat decreased 17% with danaparoid vs. a 23% increase with placebo, p = 0.03) and proteinuria (PER/creat decreased 18% with danaparoid vs. a 40% increase with placebo, p = 0.001). In conclusion, once daily SC administration of danaparoid sodium resulted in a significant reduction in proteinuria in diabetic patients with overt nephropathy.

Comment: These data support an interesting hypothesis, namely, that administration of HSPG can restore depleted amounts of this proteoglycan in GBM and decrease proteinuria. Previous studies have suggested that both heparin and low-molecular weight heparins can decrease microalbuminuria in diabetic patients but it is not clear whether there is benefit in macroalbuminuric patients. Danaparoid is a heparinoid and as such is associated with a very low incidnece of heparin-induced thrombocytopenia and thrombosis. Thus it may have advantages over heparin therapy especially if long-term use is contemplated.

This is a pilot study and larger and longer-term studies are indicated. A further point to keep in mind: since mesangial expansion is associated with progressive renal failure, it is not clear whether reduction in proteinuria by altering GBM function will prevent this complication. (David J. Leehey, M.D., Loyola University at Chicago)