Inter-individual differences in anti-proteinuric response to ACEi in established adriamycin nephrotic rats are predicted by pretreatment renal damage.
ACE inhibition (ACEi) reduces proteinuria and provides reno-protection, but not all subjects benefit from ACEi. Individual differences in the reduction in proteinuria at the onset of treatment and in residual proteinuria during therapy predict differences in renal outcome. The present study investigated whether individual differences in the anti-proteinuric efficacy of ACEi are explained by differences in the severity of pretreatment renal structural damage and whether differences in the level of residual proteinuria during therapy are explained by the severity of renal structural damage at that time, in adriamycin nephrosis in the rat. Pretreatment renal structural damage was assessed in biopsies 6 weeks after exposure to adriamycin (2 mg/kg iv). Then ACEi (75 mg/l lisinopril, n = 23) or vehicle (n = 10) was administered; renal biopsies were repeated after stabilization of the anti-proteinuric response (week 8). Early renal damage (interstitial alpha-smooth muscle actin expression and macrophage accumulation) and established lesions [focal glomerulosclerosis (FGS) and interstitial fibrosis] were scored. During ACEi, proteinuria fell from 834 (487-851) mg/24 h pretreatment to 153 (66-265) mg/24 h at week 8 (p < 0.05); FGS stabilized from 27 (4-70) arbitrar units (AU) pretreatment to 26 (4-84) at week 12, whereas the vehicle did not affect proteinuria, resulting in progressive FGS: 18 (10-26) AU pretreatment versus 88 (46-130) at week 12 (p < 0.05). All parameters of pretreatment damage significantly predicted the anti-proteinuric response. Residual proteinuria during ACEi correlated significantly with renal structural damage parameters at that time. Pretreatment renal damage also predicted renal outcome during extended treatment. Thus, in this experimental setting, in rats with the same renal disorder and the same duration of disease, individual differences in pretreatment renal damage, albeit relatively modest, explain individual differences in renal responsiveness to ACEi. This implies that the limits of the efficacy of ACEi are set by prevalent renal damage. Further studies into the mechanisms of individual resistance to the anti-proteinuric action of ACEi are needed to develop additive intervention strategies.
Kramer
Andrea B
AB
Department of Pathology and Laboratory Medicine, University Hospital Groningen, Groningen, The Netherlands. a.b.kramer@path.azg.nl
Laverman
Gozewijn D
GD
van Goor
Harry
H
Navis
Gerjan
G
D000199:Actins / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D005923:Glomerulosclerosis, Focal Segmental / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D009401:Nephrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D011507:Proteinuria / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome
D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin