Cardiac allograft rejection: do trough cyclosporine levels correlate with the grade of histologic rejection?
BACKGROUND
The introduction of cyclosporine to heart transplantation immunosuppressive protocols has been associated with an improvement in the long- and short-term survival rates. The ideal dose of cyclosporine that maximizes its immunosuppressive properties and minimizes its toxicity has remained an enigma since its introduction. This study was undertaken to evaluate which range of cyclosporine levels provided the most effective protection against graft rejection.


METHODS
We studied the correlation between cyclosporine levels and histologic grade of rejection, cardiac function, and renal function by retrospectively analyzing the results of 1407 individual whole blood cyclosporine trough levels. One hundred seven heart transplant recipients were studied within 2 years of undergoing transplantation. As a historical comparison, we also studied 146 individual trough cyclosporine levels from a subgroup of patients (n = 14) who had acute cellular rejection with graft dysfunction or failure. We correlated trough cyclosporine levels with the histologic severity of cellular rejection, cardiac function (right cardiac catheterization), and serum creatinine in both groups. The correlation was performed within patient's own data rather than between patient groups to avoid interpatient variations.


RESULTS
The mean cyclosporine level was significantly higher (206 ng/ml) when the patients had grade 0 cellular rejection in comparison to grade 3A, with a mean cyclosporine level of 173 ng/ml (p = 0.005). Patients with graft dysfunction or failure had higher mean cyclosporine level (230 ng/ml) when they had no rejection compared with 3A rejection with a mean cyclosporine level of 153 ng/ml (p = 0.001). Furthermore, lower cyclosporine levels were associated with graft dysfunction. There was no correlation between serum creatinine and cyclosporine levels (r = 0.059, r2 = 0.351%).


CONCLUSIONS
We conclude that cyclosporine trough levels above 200 ng/ml in the first 2 years after heart transplantation are associated with reduced cellular rejection without deleterious effects on renal function.
el Gamel
A
A
Cardiothoracic Transplant Unit, Wythenshawe Hospital, Manchester, United Kingdom.
Keevil
B
B
Rahman
A
A
Campbell
C
C
Deiraniya
A
A
Yonan
N
N
D000328:Adult; D001706:Biopsy; D003404:Creatinine / Q000097:blood; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004699:Endocardium / Q000473:pathology; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology* / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008875:Middle Aged; D009206:Myocardium / Q000473:pathology; D012189:Retrospective Studies; D016896:Treatment Outcome
D007166:Immunosuppressive Agents; D016572:Cyclosporine; D003404:Creatinine