The most common causes of kidney transplant failure include death with a functioning graft and chronic allograft nephropathy (1, 2). Cardiovascular disease (CVD) causes up to 50% of all deaths among kidney transplant recipients (KTR) with functioning allografts at one-year posttransplant (3). Therefore, understanding the impact of CVD risk factors on posttransplant mortality is vital to the development of effective preventive and interventional strategies. Impairments in posttransplant renal function can affect CVD risk and allograft longevity (4), thus maintaining or improving kidney function may have salubrious effects on both CVD risk and allograft survival.
Due to their efficacy in preventing rejection, calcineurin inhibitors have revolutionized the practice of transplantation. However, they are also associated with both nephrotoxicity and adverse alterations in CVD risk factors. The two major calcineurin inhibitors, cyclosporine-microemulsion (CsA) and tacrolimus (Tac), seem to have different effects on renal function and CVD risk factors. CsA more adversely affects renal function, blood pressure, and lipids, while Tac causes a greater degree of glucose intolerance (5–11).
Recent work on therapeutic drug monitoring strategies for calcineurin inhibitors has shown that the two-hour postingestion level of CsA (C2-CsA), unlike the trough level of CsA, is highly correlated with both the area under the drug exposure curve (AUC) and acute rejection episodes after kidney transplantation (12–14). In light of these findings, C2-CsA has become the standard drug monitoring tool in many centers.
Short-term effects of C2-CsA on renal function and CVD risk factors appear to be comparable to trough-level monitored CsA (15–17) but definitive prospective studies have not been performed. Moreover, there are few data comparing these outcomes in C2-CsA versus trough-level monitored tacrolimus (C0-Tac). The objective of this retrospective cohort study is to evaluate the effect of C2-CsA vs. C0-Tac from the time of transplantation on estimated glomerular filtration rate (eGFR) and CVD risk factors (i.e., mean arterial pressure [MAP], total cholesterol [TC], and new-onset diabetes mellitus [NODM]) in a population of KTR at two Canadian transplant centers.
MATERIALS AND METHODS
Eligible study participants included all KTR who received a primary deceased or living donor kidney transplant in one of two transplant centers at the University of Toronto (the Toronto General Hospital [TGH] and St. Michael’s Hospital [SMH]) from August 1, 2000 to December 31, 2003 (n=587). Since August 1, 2000, physicians at TGH and SMH have employed C2-CsA and C0-Tac (respectively) as the main calcineurin inhibitor in all incident KTR. Typical C2-CsA target levels were 1700 μg/L at one month (lowered by 1/3 if an antilymphocyte product was administered), 1500 μg/L from two to three months, 1200 μg/L from four to six months, 1000 μg/L from 7 to 12 months, and 800 μg/L thereafter. C0-Tac target levels ranged from 10–15 ng/ml for the first month, 8–15 ng/ml at two to three months, 5–12 ng/ml at 4 to 12 months, and 5–8 ng/ml thereafter.
Inclusion and Exclusion Criteria
The main inclusion criteria for this study were adult (>18 years) KTR initiated on a calcineurin inhibitor-based immunosuppressive regimen during their admission for kidney transplantation. Exclusion criteria included: 1) kidney transplant surgery performed at an outside institution (n=45), 2) multi-organ transplant recipient, including double-kidney transplants (n=15), 3) re-transplants (n=53), 4) graft function or follow-up for < one month (n=12), and 5) involvement in a clinical trial of other immunosuppressive agents, including mammalian target of rapamycin inhibitors (n=28). Thirty-five KTR at SMH were initiated on trough-monitored CsA from the time of their transplant and thus were excluded from the study. In order to maintain consistency between treatment comparison groups, 21 TGH patients started on C0-Tac were also excluded.
Study Exposures and Outcomes
The primary exposure was the type of calcineurin inhibitor-drug monitoring strategy employed from the time of kidney transplantation. This effectively translated into a comparison of patients on C2-CsA at TGH vs. C0-Tac at SMH. Potential confounders included recipient age (in years), sex, race (white vs. non-white), cause of end stage renal disease (ESRD; diabetes vs. non-diabetes), time on waitlist (in days), panel reactive antibody (PRA) level >10%, weight at transplant (in kg), donor age (in years), donor source (living vs. deceased), human leukocyte antigen (HLA) mismatches, the occurrence of delayed graft function, and corticosteroid dose at three months posttransplant (in mg/day). Cold ischemia time was available only for deceased donors and thus was not included in the final analysis.
Outcomes of interest included renal function and selected CVD risk factors. Renal function was assessed as the slope of eGFR (ml/min/month) between months one to six posttransplant. The eGFR was calculated using the four-variable Modification of Diet in Renal Disease (MDRD) GFR equation (18). This estimate of GFR has been shown to correlate better with true GFR than the Cockcroft-Gault formula in KTR (19). The one month eGFR was chosen as the baseline in order to minimize the impact of early postoperative events that are associated with acute changes in renal function. Along with absolute changes in eGFR, time to 10% reduction in eGFR was also evaluated.
CVD risk factors of interest included MAP, TC, and the occurrence of NODM, with each outcome determined at six months posttransplant (except for TC [see below]). MAP (in mmHg) was defined as the sum of 2/3 diastolic blood pressure and 1/3 systolic blood pressure. Blood pressure was measured once at each clinic visit with the patient in a seated position and after five min of rest. TC measurements (in mmol/L) were evaluated over a six-month interval. Since most patients had their first TC measured one to six months after transplantation, the second measurement was taken between months 7 to 12. NODM was diagnosed using the Canadian Diabetes Association guidelines: fasting plasma glucose level ≥7.0 mmol/L and/or random plasma glucose level of ≥11.1 mmol/L on at least two occasions in the absence of acute illness (20). Patients not satisfying these criteria but found to have started and remained on oral hypoglycemic agents and/or insulin for ≥30 days were also considered to have NODM.
Univariable comparisons were made using an unpaired Student’s t test or Wilcoxon rank sum test for continuous measures and the chi-square test for proportions. Predictors of slope of eGFR, MAP, and TC were assessed in simple and multiple linear regression models, with model fit evaluated by residual vs. fitted plots and measures of influence. Time-to-event outcomes (i.e., 10% reduction in eGFR and NODM) were graphically examined using Kaplan-Meier survival curves and differences were tested using the log-rank statistic. Time-to-NODM was modeled using univariable and multivariable Cox proportional hazards regression. Violations of the proportionality assumption were assessed using log (-log) survival curves. No important departures were noted. A stepwise backward elimination procedure was employed to obtain the most parsimonious model. Covariates previously shown to be important in predicting the occurrence of NODM were forced into the model (e.g., recipient age, sex, race, and weight at transplant). Further adjustment for confounding variables was achieved by the use of a propensity score analysis that incorporated the probability of being treated with C2-CsA as a covariate in the Cox regression model (21–23). All continuous data are reported as mean ± standard deviation (SD) and regression coefficients are presented with their corresponding 95% confidence intervals. In order to simulate the results of a clinical trial, all analyses were performed using the intention-to-treat principle, i.e., patients were analyzed within the treatment/monitoring groups to which they were initially assigned at the time of transplantation. A two-tailed P value of <0.05 was considered statistically significant. All analyses were performed using Stata 8.2 (StataCorp, College Station, TX). The study received approval by the research ethics boards of both hospitals.
After applying the inclusion and exclusion criteria, 378 KTR comprised the study cohort (202 from TGH and 176 from SMH). Table 1 describes the characteristics of the study population. Patients on C2-CsA were more likely male, had slightly longer cold ischemia times (available only in deceased donor kidney transplants), and were on larger doses of corticosteroids at three months posttransplant. There also appeared to be a trend towards higher rates of delayed graft function and a larger proportion of patients with diabetes mellitus as the cause of ESRD among KTR treated with C2-CsA. C2-CsA patients had a significantly lower baseline eGFR, while MAP and TC levels were higher compared to C0-Tac patients.
Table 2 shows the average daily doses and levels of calcineurin inhibitors in each treatment group at one week, one month, three months, and six months posttransplant. Overall, daily doses and levels of C2-CsA and C0-Tac declined over time. Average drug levels were close to or within target range for most patients on both calcineurin inhibitors at each time point posttransplant.
Mean eGFR at one and six months posttransplant was 59.5 vs. 62.9 ml/min and 50.6 vs. 61.2 ml/min for C2-CsA vs. C0-Tac, respectively. This translated to an eGFR slope of –1.82 ml/min/month and –0.44 ml/min/month for C2-CsA and C0-Tac patients, respectively. The unadjusted difference in eGFR slope of –1.38 ml/min/month was highly statistically significant (P<0.001). Multiple linear regression for the slope of eGFR showed that C2-CsA patients had a rate of decline in eGFR that was, on average, 0.93 ml/min/month faster than C0-Tac patients after accounting for numerous potential confounders (Table 3). This is equivalent to an average eGFR difference of 4.64 ml/min between months one and six posttransplant. Recipient age was independently associated with a more positive eGFR slope whereas male sex, increasing weight at transplantation, older donor age, and higher doses of corticosteroids at three months predicted a more negative slope in C2-CsA patients. In order to rule out the effects of acute rejection on renal function, an analysis of the eGFR slope in patients without acute rejection showed highly comparable results to the entire cohort (data not shown). Of note, a similar proportion of C2-CsA and C0-Tac patients suffered an acute rejection episode (11% vs. 10%, P=0.83).
Figure 1 depicts Kaplan-Meier survival curves for the outcome of time to eGFR reduction ≥ 10% for patients on C2-CsA vs. C0-Tac. Since one of the conditions for entering the study cohort was survival with a functioning allograft for at least 30 days, the survival probability was 100% over the first month posttransplant. Starting on day 43, the curves start to diverge and it is clear that C2-CsA patients were less likely to avoid reductions in eGFR ≥10% as compared to C0-Tac patients (log-rank test, P=0.0002) over the six month follow-up. In total, 112 of 202 C2-CsA patients (55%) and 65 of 176 C0-Tac patients (34%) had at least a 10% reduction in eGFR. A multivariable Cox model (that included the same covariates as the multiple linear regression model) revealed that the risk for an eGFR reduction ≥10% was almost 1.6 times greater in C2-CsA vs. C0-Tac patients (hazard ratio [HR]=1.58 [95% CI 1.02, 2.44]).
Table 3 shows the results of both simple and multiple linear regression models for MAP and TC posttransplant. Differences in baseline MAP and TC values were addressed by incorporating these values as covariates in the regression models. At 6 months, MAP values for C2-CsA and C0-Tac were 94.0 (SD 10.6) and 94.3 (SD 11.0) mmHg, respectively. Unadjusted and adjusted models revealed no statistically significant difference in MAP (Table 4). Of note, the average number of antihypertensive drugs utilized by C2-CsA patients was significantly higher than C0-Tac patients at 6 months posttransplant (1.82 vs. 1.41, P=0.0003). When the number of anti-hypertensive agents used was included in the multiple linear regression model, the results were essentially unchanged (data not shown). None of the remaining covariates were independently predictive of MAP (Table 3).
TC levels at 7 to 12 months for C2-CsA and C0-Tac were 5.24 (SD 1.12) and 4.89 (SD 1.12) mmol/L, respectively. Although this unadjusted comparison reached statistical significance (P=0.02), the adjusted comparison did not (Table 3). Statin use at six months posttransplant was higher in C2-CsA patients than in C0-Tac patients (32% vs. 25%), but the difference was not statistically significant (P=0.12). Including statin use in the regression model had little effect on the regression coefficient for C2-CsA vs. C0-Tac (data not shown). None of the other covariates were independently associated with TC at the 7 to 12 months time interval (Table 3).
Figure 2 depicts Kaplan-Meier survival curves for time-to-NODM as a function of treatment/monitoring strategy in the subgroup of patients who did not have diabetes mellitus at the time of transplantation (162 C2-CsA vs. 152 C0-Tac). C2-CsA patients had a six month NODM rate of 16.7% (27 cases) while C0-Tac had a rate of 13.2% (20 cases). The log rank test confirmed that the unadjusted risk of NODM in the two treatment groups was similar (P=0.36). The stepwise Cox proportional hazards model revealed that patients on C2-CsA were not significantly more likely to develop NODM as compared to patients on C0-Tac (HR=1.77 [95% CI 0.82, 3.85]) (Table 4). Increasing recipient age and weight at transplantation were both independently predictive of a higher risk for NODM at six months posttransplant (HR=1.06 per year of age [95% CI 1.03, 1.09] and HR=1.02 per kg body weight [95% CI 1.00, 1.04], respectively). A peak PRA >10% prior to transplantation was also associated with the occurrence of NODM (HR=2.54 [95% CI 1.07, 6.06]). As previously noted in an earlier cohort from these two centers (24), statin use posttransplant was found to be strongly protective of NODM (HR=0.23 [95% CI 0.09, 0.56]).
Using a propensity score approach, the adjusted HR for the relation between treatment/monitoring strategy (C2-CsA vs. C0-Tac) and time-to-NODM was 1.24 [95% CI 0.55, 2.82]. This estimate was closer to the null value of one (vs. the stepwise Cox model), which likely resulted from more complete adjustment for confounding variables in the presence of a relatively rare outcome (NODM) and a common exposure (C2-CsA) (23).
Using an observational design, this study compared short-term (6 month) outcomes for renal function and CVD risk factors among KTR using different calcineurin inhibitors and therapeutic drug monitoring strategies (C2-CsA vs. C0-Tac). Our results suggest that there was a more marked rate of decline in eGFR in patients on C2-CsA vs. C0-Tac between one to six months posttransplant. MAP and TC were quite comparable using the two approaches, although the use of antihypertensive agents and statins were, on average, higher in the C2-CsA group. The relative hazard of NODM was non-significantly increased in the C2-CsA group based on the stepwise Cox regression model, but it was further attenuated towards the null after more complete adjustment using propensity scores.
It has been shown that impairments in kidney function at one-year posttransplant is a powerful predictor not only of graft loss (25) but also the subsequent risk of CVD events and mortality in KTR (4). In fact, receiving a kidney transplant dramatically reduces an ESRD patient’s risk of future adverse CVD outcomes (26). The association between increased CVD and mortality risk with decrements in kidney function has been replicated in studies of the general population as well (27). Therefore, it is imperative to preserve kidney function posttransplant in order to optimize patient outcomes. Our study revealed that the slope of eGFR from one to six months posttransplant was significantly lower (i.e., more negative) in patients on C2-CsA vs. C0-Tac while the risk of eGFR reduction ≥10% was higher. Several recent studies have found similar associations. A paired-kidney analysis using the Scientific Registry of Transplant Recipients showed that Tac (vs. CsA) was associated with a lower serum creatinine in KTR over a five year follow-up, although the slope of 1/serum creatinine did not differ between the two agents (10). Although differences in kidney function were not apparent at six months in the European randomized trial of Tac vs. CsA (28), the follow-up study suggested that Tac patients enjoyed a significantly lower serum creatinine at two years posttransplant (11). Trough level monitoring was utilized in both treatment arms of this study. Short- and long-term follow-up of a randomized CsA to Tac conversion study have corrobated these findings (8, 9).
No studies to date have compared kidney function outcomes in adult KTR on C2-CsA vs. C0-Tac. The LIS2T study reported similar average serum creatinine values at six months in liver transplant recipients on C2-CsA vs. C0-Tac (29). However, this comparison is likely not very informative in the context of kidney transplantation since the effects of C2-CsA vs. C0-Tac in LIS2T were on the native kidneys of liver transplant recipients as opposed to the denervated kidneys of KTR. Moreover, doses and levels of calcineurin inhibitors generally tend to be higher in kidney vs. liver transplantation. Despite the statistically significant difference in eGFR slope that was observed in our study, the absolute difference was modest (4.64 ml/min) and thus differences in related outcomes, such as MAP, may not have been apparent, especially in the short-term. The long-term impact of these short-term changes in kidney allograft function, and the net effect of heightened anti-rejection efficacy vs. potential long-term nephrotoxicity in patients on C2-CsA, will require further study.
Most studies comparing CsA and Tac have generally suggested that the former is associated with a higher incidence of hypertension (7–9, 28, 30, 31). Both drugs are prone to causing renal vasoconstriction, expression of transforming growth factor-β1, endothelin-1, and renin transcription, while impairing nitric oxide production and endothelial function (32–35). Results from the LIS2T study suggested that the incidence of hypertension at six months was comparable in both C2-CsA and C0-Tac groups (29). The similar level of MAP in our two treatment/monitoring cohorts at six months posttransplant is consistent with this finding. C2 monitoring may allow for more precise dose titration of CsA thus leading to a better balance between optimal immunosuppression vs. drug-related toxicity (12, 16). Alternatively, the six-month time point may not have been long enough to show a difference in MAP. Moreover, the influence of patient selection factors may have masked potential differences. However, the characteristics of the C2-CsA cohort were more compatible with a heightened propensity to elevated MAP (e.g., higher rate of delayed graft function, greater average steroid dose), thus making it more likely that C2-CsA patients would exhibit comparatively higher MAP at six months. This fact, along with the use of multivariable models for covariate adjustment (including the number of antihypertensive agents), lends credence to our finding of no significant difference between the two groups.
Similar to the issue of hypertension, it has been suggested that hyperlipidemia is more prevalent among KTR on trough monitored CsA as compared to Tac therapy (8, 9, 30–32, 36). It is likely that both agents induce a tendency to hyperlipidemia from their effects on bile acid synthesis (from cholesterol), intestinal cholesterol transport, low density lipoprotein binding to its receptor, lipolytic activity, and cholesterol oxidation (5). However, the mechanism by which CsA may have a more adverse effect on lipids is not clear. Among prevalent KTR, Cole et al. showed that conversion from trough monitored CsA to C2-CsA had no significant effect on lipid levels (16). However, the study participants were not incident KTR (the vast majority were >12 months posttransplant) and the before-after methodology left open the possibility of confounding by temporal trends. Median TC at six months was only slightly higher in C2-CsA vs. C0-Tac liver transplant recipients in the LIS2T Study (4.7 vs. 4.3 mmol/L) (29). The unadjusted follow-up comparison suggested that TC was significantly higher in C2-CsA vs. C0-Tac patients in our study, but multivariable adjustment essentially abolished this difference. Akin to MAP, it is possible that differences in lipid profiles were mitigated by more precise dosing of CsA via C2 monitoring (vs. trough monitoring) but was only apparent after adjustment for baseline level of patient risk. The proportion of patients on statins was higher in the C2-CsA group but little difference in TC was noted in patients on C2-CsA vs. C0-Tac both before and after adjustment for statin usage (data not shown).
Our study failed to show a statistically significant difference in the risk of NODM among C2-CsA vs. C0-Tac patients. There have been numerous reports documenting Tac’s greater proclivity to cause NODM in KTR than CsA (28, 37–39), but none have examined the impact of C2 monitoring for CsA. The LIS2T study found that C0-Tac was associated with a six-month NODM rate of 32.5% (vs. 19.0% for C2-CsA) in liver transplant recipients (29). However, the relevance of this finding to KTR is not clear. Although not statistically significant, the increase in the relative hazard for NODM after multivariable adjustment may reflect measurement error in potential confounders, other unmeasured indices of baseline risk that were not captured in our statistical model, inadequate adjustment for measured covariates, or a true increase in the short-term risk (albeit imprecise) of NODM in C2-CsA vs. C0-Tac patients. The propensity score approach provided a means to improve confounder adjustment without overfitting our multivariable Cox model and the results were in support of a true null effect.
There are limitations to our study that deserve mention. First, although this study is the largest comparison of incident KTR treated with C2-CsA vs. C0-Tac to date, the sample size was insufficient to provide optimally precise treatment effect estimates. Increasing the sample size and extending the follow-up will improve the precision of our estimates and allow for the assessment of endpoints such as CVD events, graft failure, and mortality. Second, the observational design increased our study’s susceptibility to selection, information, and confounding biases, as compared to studies with randomized treatment allocation. Apart from the use of C2-CsA vs. C0-Tac, the two kidney transplant centers in Toronto have a common transplant list, use the same HLA laboratory, share similar clinical protocols, and employ comparable management approaches to peri- and posttransplant care. Moreover, C2-CsA and C0-Tac were adopted at roughly the same time at both TGH and SMH, respectively. These facts, along with our efforts to adjust for factors predictive of patient risk, provide some reassurance that the comparisons made in our study are reasonably valid. Third, kidney function was measured by an estimating equation for GFR rather than a gold standard test such as iothalamate clearance. Our decision to use the four-variable MDRD equation was prompted by its superior performance than other GFR equations in KTR (19), its ease of calculation, and the absence of the gold standard in most of our KTR. Fourth, more sensitive measures of glucose intolerance (e.g., oral glucose tolerance test) were not performed in our cohort. Less severe states of abnormal glycemia may predict adverse changes in CVD risk factors as well as CVD events (40). Finally, using an intention-to-treat approach may have narrowed true differences between treatment groups and made it more difficult to distinguish underlying treatment effects. Several before-after studies have shown improvements in metabolic and renal function parameters in stable KTR converted from trough-monitored CsA to Tac (31, 36, 41). However, our goal was to determine the impact of the choice of calcineurin inhibitor therapy/monitoring strategy at baseline on kidney function and CVD risk factors. This was best served with the intention-to-treat approach. In fact, the study findings were unchanged when the data were re-analyzed after excluding or censoring the 35 C2-CsA (17%) and 9 C0-Tac (5%) patients who switched over to the other calcineurin inhibitor within 6 months posttransplant.
In conclusion, this observational study of C2-CsA vs. C0-Tac treated KTR revealed that the rate of change of eGFR from one to six months posttransplant was negative in both groups but the slope was more markedly negative in C2-CsA patients. The risk of developing an eGFR reduction ≥10% was also higher in the C2-CsA group. MAP and TC levels at approximately six months posttransplant were not significantly different. The adjusted relative hazard of NODM was not significantly different from one. A greater appreciation for the potential impact of these findings on long-term allograft survival and the risk of CVD in KTR will require further study.
The authors would like to thank the Trillium Gift of Life Network for providing HLA and donor data on all kidney transplants performed at both Toronto General Hospital and St. Michael’s Hospital.
Dr. Kim was supported by the Dr. Leen Paul Kidney Transplantation Fellowship of the Kidney Foundation of Canada and the Detweiler Traveling Fellowship of the Royal College of Physicians and Surgeons of Canada.
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