1 The relationship between blood cyclosporin concentration (CyAC(b)) and a patient's risk of organ rejection following heart-lung (HL) transplantation was investigated. 2 Longitudinal data were collected for 90 days post-operation for 31 HL transplant recipients. Following exploratory analysis, a multiple logistic regression model with a binary outcome variable representing presence or absence of lung rejection (as defined on biopsy findings and/or intention to treat) in the next 5 days was fitted to the data. 3 A significant interaction between time post-transplant and CyAC(b) was found. During weeks 1-3, the relative risk (RR) of rejection per unit increase in log, (5-day mean CyAC(b)) was reduced: RR = 0.29,95% confidence interval (CI) = (0.12,0.72). After 3 post-operative weeks, this trend was reversed: RR = 1.61, 95% CI = (0.96, 2.70). Increases in cyclosporin dose (CyAD) and in coefficient of variation (CV) for both CyAD and CyAC(b) over the previous 10 days significantly increased the risk of rejection: RR per unit increase in log(e) (5-day mean CyAD) = 2.72, 95% CI = (1.18, 6.25); RR per increase of 10% (i.e. from, say, 20% to 30%) in the CV for CyAD = 1.20, 95% CI = (1.07, 1.36); RR if the CV for CyAC(b) > 40% = 1.51,95% CI = (1.01, 2.27). Administration of high dose steroids in the previous 5 days was found to protect against further rejection: RR if steroid treatment was given = 0.23, 95% CI = (0. 13, 0.38). The model fit was significantly improved by the inclusion of patient-specific effects (F26,1347 = 5.27, P < 0.0001) and an interaction between patient and time post-transplant (F26,1321 = 4.71, P < 0.0001). 4 Plots comparing CyAC(b) below various threshold values during rejection and rejection-free periods provided little support for the concept of a therapeutic threshold for CyAC(b). 5 We conclude that a negative relationship between CyAC(b) and lung rejection exists during the first 3 post-operative weeks. After this, the CyAC(b) maintained in these HL patients may be too high to provide any further increase in protective effect. Between-patient differences were also significantly associated with risk of rejection, as was underlying pharmacokinetic instability (reflected by a high CV for CyAC(b)). The positive CyAD-effect relationship was probably due to a tendency for clinicians to increase CyAD in patients whom they suspected were about to reject.
