The measurement of whole blood pre-treatment cyclosporine A: metabolite ratios predicts the onset of renal dysfunction in recipients of allogeneic stem cell transplantation.
BACKGROUND
In the context of post-transplant immunosuppression, cyclosporine A (CSA) is dose adjusted in accordance with whole blood drug monitoring. While currently available immunoassay systems primarily target the parent drug, cross-reactivity results in the detection of the major circulating CSA metabolites, though their contribution to both immunosuppression and toxicity remain unclear. This study examines the relationship of CSA metabolites to hepatic and renal dysfunction and the incidence of graft-versus-host disease (GvHD) through parallel assaying of parent drug and drug/metabolites expressed as a metabolite ratio (Cp:mR).


METHODS
Sequential pre-treatment (trough) whole blood samples (n=527) were collected from 31 allo-stem cell transplantation (SCT) recipients. Both parent drug and drug/metabolite levels were determined using the Abbott fluorescence polarization immunoassay.


RESULTS
The average mean Cp:mR was significantly higher in patients with hepatic (P=0.004) and renal dysfunction (P=0.004) than in those without. Significantly higher Cp:mR were also found in patients with grades II-IV GvHD (P=0.001) than were observed in patients who did not experience significant GvHD. When measured prospectively, an increasing Cp:mR predated the rise in serum creatinine concentration by a median of two weeks.


CONCLUSIONS
This study demonstrates a clinically useful CSA metabolite ratio that shows association with hepatic and renal dysfunction and with GvHD. The measure can be used to predict those patients on CSA therapy who are likely to develop renal dysfunction.
Stephens
E
E
Transplant Immunology Group, Academic Department of Haematology & Oncology, University of Leeds, and Department of Transplant Immunology, St James' University Hospital, Leeds, UK.
Bolderson
I
I
Clark
B
B
Kinsey
S
S
Gooi
H C
HC
Cook
G
G
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D016231:Fluorescence Polarization Immunoassay / Q000379:methods*; D006086:Graft vs Host Disease / Q000097:blood / Q000175:diagnosis; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D007674:Kidney Diseases / Q000097:blood* / Q000175:diagnosis / Q000503:physiopathology; D008107:Liver Diseases / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D015203:Reproducibility of Results; D033581:Stem Cell Transplantation
D007166:Immunosuppressive Agents; D016572:Cyclosporine