OKT3-induced nephrotoxicity is associated with release of group II secretory phospholipase A2.
Administration of the murine IgG2a CD3 monoclonal antibody OKT3 exerts a transient nephrotoxic effect. Increased levels of group II secretory phospholipase A2 (sPLA2-II) might account for this nephrotoxicity as sPLA2-II induces the biosynthesis of prostaglandins, vasoactive lipid mediators that influence glomerular haemodynamics and renal function. Furthermore, extracellular phospholipases seem to be involved in proximal tubular cell injury. We studied plasma sPLA2-II levels in relation to circulating creatinine, tumour necrosis factor alpha, interleukin 6 and C-reactive protein levels in 15 renal allograft recipients receiving rejection treatment with OKT3. As a control group, we studied 15 renal allograft recipients receiving rejection treatment with methylprednisolone. A maximal fourfold increase in sPLA2-II levels was observed 48 h after the first OKT3 administration, preceded by increased tumour necrosis factor alpha and interleukin 6 levels and accompanied by increased C-reactive protein levels. Creatinine levels reached a maximal increase 72 h after initiation of treatment. During methylprednisolone treatment no increase in any of the studied parameters was observed. Thus, administration of OKT3 induces increased sPLA2-II levels, presumably via generation of cytokines. We hypothesize that sPLA2-II may contribute to the nephrotoxic effect of OKT3 by inducing vasoconstrictive prostaglandins and renal tubular cell injury.
Renal Transplant Unit, University of Amsterdam, The Netherlands.
P C
PC
Wever
R W
RW
Roest
A M
AM
Wolbink-Kamp
G J
GJ
Wolbink
J J
JJ
Weening
C E
CE
Hack
J M
JM
ten Berge
D000293:Adolescent; D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000032:analysis; D002648:Child; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D015850:Interleukin-6 / Q000097:blood; D007527:Isoenzymes / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D016853:Muromonab-CD3 / Q000009:adverse effects*; D010741:Phospholipases A / Q000378:metabolism*; D054467:Phospholipases A2; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D007166:Immunosuppressive Agents; D015850:Interleukin-6; D007527:Isoenzymes; D016853:Muromonab-CD3; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; D010741:Phospholipases A; D054467:Phospholipases A2