Hammersmith Hospital cohort
We initially conducted a retrospective review of a cohort of patients transplanted at Hammersmith Hospital, London, from January 1995 to December 2000 (N = 157). Of these, 46 were Indo-Asian and 90 Caucasian. (Indo-Asian ethnicity was self-reported on direct questioning by patients or their family and was defined on the basis of birth or parental birth in India, Pakistan, Bangladesh or Sri Lanka.). The rest were of other ethnic origins. Mean follow-up was 5.5 (±3.0) years.
Patients received two peri-operative doses of methylprednisolone (500 mg) intravenously (at induction and after the vascular anastomosis was fashioned). Thereafter, all patients were managed with prednisolone 20 mg/day, reducing to 7.5 mg/day over the first 3 months and remaining at that dose until 1 year post-transplantation. After 1 year, patients were selected on the basis of clinically assessed immunological risk to have their prednisolone withdrawn over the course of their second post-transplant year. Criteria used to define high immunological risk (and thus inappropriateness for steroid withdrawal) were three or more rejection episodes during the first year or a rejection episode within the preceding 6 months, retransplantation or plasma creatinine >200 μmol/L. Neither membership of any particular ethnic group nor development of post-transplantation diabetes mellitus (PTDM) was considered a reason for deviating from the protocol just outlined in the era covered by this study. No patient undergoing steroid withdrawal in this study suffered late rejection as a result. Patients were also given azathioprine 1 mg/kg/day and ciclosporin from their first post-operative day. Target ciclosporin (CsA) 12-hour trough levels were as follows: 0–3 months, 250–350 ng/mL; 3–6 months, 200–300 ng/mL; 6–12 months, 150–250 ng/mL; and after 12 months, 100–200 ng/mL. No patients were given tacrolimus.
The following clinical data were collected: age, gender, type of transplantation (live or deceased donor), pre-transplant dialysis modality, co-morbidity (which included hypertension, ischemic heart disease, peripheral vascular disease and diabetes mellitus) and HLA mismatch. We also identified the following post-transplantation parameters: delayed graft function, acute rejection (number of episodes, time to first rejection and steroid-resistance), hyperlipidemia and hypertension, as well as graft and patient survival and graft function.
In order to compare immunosuppression in the two groups, we generated an arbitrary measure of exposure to CsA and prednisolone. CsA levels were measured at each clinic visit (12-hour trough levels). To quantify CsA exposure, we charted all 12-hour trough levels of CsA measured over the first year and calculated the area under the curve (AUC) for this level–time graph. A similar measure for steroid exposure was produced by charting the prednisolone dose prescribed on each occasion on which the patient was seen over the first year and again calculating the AUC for this dose–time graph.
Diabetes mellitus was defined as the need for insulin or oral hypoglycemic therapy. The definition of a normal random glucose pre-transplant was less than 5.5 mmol/L, as indicated by the WHO (9). Only one patient who subsequently developed post-transplant diabetes mellitus had a pre-transplant random blood glucose >5.5 mmol/L. (The single exception had a pre-transplant random blood glucose of 5.7 mmol/L.) No patient was allowed to remain hyperglycemic in the absence of treatment for more than a month, and usually much less. Five patients were hepatitis C-positive, two of whom developed post-transplant diabetes mellitus.
Follow-up policy was the same for all patients. In the first year, no patient was seen less frequently than once every 4 weeks, and usually much more frequently, particularly early in the post-transplant period. On each occasion, glucose, lipids and renal function, as well as standard clinical and other laboratory parameters, were measured.
The diagnosis of acute rejection was based on renal transplant biopsy undertaken on account of an otherwise unexplained rise in serum creatinine. Rejection was treated in the first instance by four consecutive daily doses of methylprednisolone 500 mg intravenously.
Skewed datasets were expressed as the median and interquartile range and analyzed using non-parametric tests. Normally distributed datasets were expressed as mean and standard deviation. Univariate analysis of the influence of ethnicity on patient co-morbidity and transplant outcomes was performed using the Chi-square test or Student's t-test, as appropriate. Multivariate analysis was performed, beginning with an exploratory phase, using a forward conditional sequential stepwise method of binary logistic regression analysis for new PTDM by entering variables that we considered clinically relevant into a computerized model (SAS software package for Windows version 8, SAS Institute Inc.). Those variables were: recipient age (years), recipient race (Caucasian or Indo-Asian), donor source (living or deceased donor), BMI (> or ≤30 kg/m2), recipient gender (female or male) and hepatitis C viral status (infected or not).
The probability of graft failure and patient death over time was analyzed by Kaplan-Meier survival plots using Prism 3.0 software. Survival differences between groups were analyzed using the log rank test. Graft survival curves were censored for graft loss due to patient death. A p-value <0.05 was considered to indicate statistical significance.