Proteinuria-lowering effect of heparin therapy in diabetic nephropathy without affecting the renin-angiotensin-aldosterone system.
Angiotensin-converting enzyme inhibitors and angiotensin II (AngII) type 1 receptor blockers lower proteinuria and preserve renal function in diabetic nephropathy (DN). The antiproteinuric effects are greater than their blood pressure reduction, involving the sieving properties of the glomerular filter. In DN, glomerular staining for heparan sulfate proteoglycans is decreased. AngII inhibits heparan sulfate synthesis. Also, heparins modulate AngII signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in DN. Is the antiproteinuric effect of heparins due to its interference with the renin-angiotensin-aldosterone system? Ten volunteers each with DN and glomerulonephritis and control subjects were examined before and after low-dosage enoxaparin. Renal hemodynamics were determined with (99m)Tc-DTPA and (131)I-hippurate clearance. Glomerular filtration rate (GFR), effective renal plasma flow, mean arterial pressure, and heart rate were measured at baseline and during AngII infusion before and after enoxaparin while on normal salt and salt restriction. Enoxaparin did not lower aldosterone levels. GFR remained stable in all groups. AngII caused a significant decrease in effective renal plasma flow, whereas mean arterial pressure and heart rate increased significantly. Enoxaparin did not influence the AngII-induced changes of renal hemodynamics during normal salt intake or salt restriction. All groups showed identical responses to AngII before and after enoxaparin. In patients with diabetes, enoxaparin caused a significant decrease in proteinuria. It is concluded that the antiproteinuric effect of heparins in DN cannot be explained via interaction with the renin-angiotensin-aldosterone system. The absence of hemodynamic changes combined with reduced proteinuria point to intrinsic alterations in the glomerular filter. The effects were seen only in DN, not in glomerulonephritis.
Benck
Urs
U
V. Department of Medicine, University Hospital Mannheim, Mannheim, Germany. urs.benck@med5.ma.uni-heidelberg.de
Haeckel
Sarah
S
Clorius
John H
JH
van der Woude
Fokko J
FJ
D000328:Adult; D000368:Aged; D000450:Aldosterone / Q000097:blood; D001794:Blood Pressure / Q000187:drug effects; D003928:Diabetic Nephropathies / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D017984:Enoxaparin / Q000008:administration & dosage*; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006626:Hippurates / Q000493:pharmacokinetics; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies; D011507:Proteinuria / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology; D011877:Radionuclide Imaging; D012079:Renal Circulation / Q000187:drug effects; D012084:Renin-Angiotensin System / Q000502:physiology*; D016284:Technetium Tc 99m Pentetate; D016896:Treatment Outcome
D017984:Enoxaparin; D005343:Fibrinolytic Agents; D006626:Hippurates; D007457:Iodine Radioisotopes; D000450:Aldosterone; C030514:hippuric acid; D016284:Technetium Tc 99m Pentetate