Effect of immunosuppression on damage, leukocyte infiltration, and regeneration after severe warm ischemia/reperfusion renal injury.
BACKGROUND
Post-ischemia/reperfusion (I/R) damage, accompanied by leukocyte infiltration, is unavoidable in renal transplantation, as is the need for immunosuppressive treatment. Influence of immunosuppressive treatment on post-I/R renal damage, nonalloimmune cellular infiltration, and regeneration is not well studied.


METHODS
Uninephrectomized inbred LEW rats were submitted to warm renal ischemia of 45 minutes/60 minutes, and received different immunosuppressive regimens: cyclosporine (CsA) 10 mg/kg/day subcutaneously in the neck daily, or mycophenolate mofetil (MMF) 20 mg/kg/day by daily oral gavage. Control animals underwent sham operation (unilateral nephrectomy) with immunosuppressive treatment or ischemia with vehicle administration. In addition the effect of MMF/mycophenolic acid (MPA) on renal tubule cell proliferation in culture was studied with bromodeoxyuridine incorporation.


RESULTS
The post-I/R interstitial cellular infiltration/proliferation consisted mainly of mononuclear leukocytes [first monocytes/macrophages (Mo/MPhi) followed by CD4+ cells]. This mononuclear cell infiltration became apparent 24 hours after injury at the time of acute tubular necrosis, and was most prominent during the phase of regeneration. Severe I/R combined with CsA aggravated morphologic damage and dysfunction, without effect on tubular cell proliferation and tubular regeneration. Early leukocyte infiltration was qualitatively and quantitatively comparable to control animals, yet decreased moderately later in time. In contrast, MMF in combination with severe I/R did not influence initial morphologic damage and dysfunction. Although the initial leukocyte infiltration was comparable to control animals, the subsequent mononuclear cell accumulation, especially CD4 T cells decreased dramatically during MMF treatment. This was concomitant with a decrease of tubular cell proliferation and hence tubular regeneration. Increasing MPA concentrations in renal tubular cell culture caused a significant decrease in total cell number, and an almost arrest of bromodeoxyuridine incorporation, as measurement of cell proliferation.


CONCLUSIONS
Immunosuppressive treatment with CsA or MMF affected significantly and in a different manner post-I/R renal morphologic damage, interstitial leukocyte, accumulation and regeneration.
Ysebaert
Dirk K
DK
Department of Experimental Surgery, University of Antwerp, Belgium.
De Greef
Kathleen E
KE
Vercauteren
Sven R
SR
Verhulst
Anja
A
Kockx
Marc
M
Verpooten
Gert A
GA
De Broe
Marc E
ME
D000818:Animals; D002455:Cell Division; D016572:Cyclosporine / Q000494:pharmacology; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D007683:Kidney Tubular Necrosis, Acute / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D007962:Leukocytes / Q000473:pathology*; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D012038:Regeneration; D012079:Renal Circulation; D015427:Reperfusion Injury / Q000150:complications / Q000473:pathology* / Q000503:physiopathology*; D012720:Severity of Illness Index
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid