Combining an antiproteinuric approach with mycophenolate mofetil fully suppresses progressive nephropathy of experimental animals.
Chronic renal diseases progress to organ insufficiency, which may require replacement therapy within one to three decades even independently of the type of initial insults. In the majority of cases, the degrees of proteinuria and interstitial leukocyte infiltration and scarring are strictly correlated with the rate of disease progression. This study tests the hypothesis that excess intrarenal protein traffic may cause lymphocyte-dependent interstitial injury that, while not fully controlled by antiproteinuric therapy, can be further inhibited by concomitant immunosuppression. A primarily nonimmune model was used to reproduce progressive renal disease due to a critical loss of nephron mass. Angiotensin-converting enzyme (ACE) inhibitor limited proteinuria, interstitial inflammation, MHC class II antigen expression, and severe lesions. Combined treatment with ACE inhibitor and a specific antilymphocyte agent, mycophenolate mofetil, dramatically attenuated macrophage and T cell infiltration, MHC-class II overexpression, dendritic cells, and all manifestations of the disease. Evidence of lymphocyte-mediated renal injury in the setting of excess protein traffic provides the basis for combining ACE inhibition and immunosuppression to halt progression of proteinuric kidney disease and minimize the need for dialysis or transplantation.
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
G
G
Remuzzi
C
C
Zoja
E
E
Gagliardini
D
D
Corna
M
M
Abbate
A
A
Benigni
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D017706:Lisinopril / Q000008:administration & dosage; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008297:Male; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D011507:Proteinuria / Q000209:etiology / Q000276:immunology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000806:Angiotensin-Converting Enzyme Inhibitors; D007166:Immunosuppressive Agents; D017706:Lisinopril; D009173:Mycophenolic Acid