Association Between Steroid Dosage and Death With a Functioning Graft After Kidney Transplantation
2013; Elsevier BV; Volume: 13; Issue: 8 Linguagem: Inglês
10.1111/ajt.12313
ISSN1600-6143
Autores Tópico(s)Renal and Vascular Pathologies
ResumoAmerican Journal of TransplantationVolume 13, Issue 8 p. 2096-2105 Original ArticleFree Access Association Between Steroid Dosage and Death With a Functioning Graft After Kidney Transplantation G. Opelz, Corresponding Author G. Opelz Department of Transplantation Immunology, University of Heidelberg, Heidelberg, GermanyCorresponding author: Gerhard Opelz, gerhard.opelz@med.uni-heidelberg.deSearch for more papers by this authorB. Döhler, B. Döhler Department of Transplantation Immunology, University of Heidelberg, Heidelberg, GermanySearch for more papers by this author G. Opelz, Corresponding Author G. Opelz Department of Transplantation Immunology, University of Heidelberg, Heidelberg, GermanyCorresponding author: Gerhard Opelz, gerhard.opelz@med.uni-heidelberg.deSearch for more papers by this authorB. Döhler, B. Döhler Department of Transplantation Immunology, University of Heidelberg, Heidelberg, GermanySearch for more papers by this author First published: 10 June 2013 https://doi.org/10.1111/ajt.12313Citations: 49AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Death with a functioning graft remains a major challenge following kidney transplantation. Steroid dosing may be a modifiable risk factor. Collaborative Transplant Study (CTS) data were analyzed to assess the relationship between long-term steroid dose and death with function during years 2–5 posttransplant in 41 953 adult recipients of a deceased-donor kidney transplant during 1995–2010. Steroid dose at year 1 correlated significantly with death with function overall, and with death due to cardiovascular disease or infection (all p < 0.001). In patients with optimal graft function (serum creatinine <130 µmol/L) and no anti-rejection treatment during (a) year 1 (b) years 1 and 2, these significant associations remained (all p < 0.001). The center-specific incidence of steroid withdrawal during year 2 showed a significant inverse association with death due to cardiovascular disease (p < 0.001) or infection (p < 0.001) overall, and within the subpopulation with good graft function and no rejection during year 1 (p = 0.002 and p < 0.001, respectively). Maintenance steroid dose shows a highly significant association with death with a functioning graft caused by cardiovascular disease or infection during years 2–5 after kidney transplantation, even in patients with good graft outcomes in whom steroid treatment would appear to be unnecessary. Abbreviations AZA azathioprine CI confidence interval CsA cyclosporine CTS Collaborative Transplant Study EC-MPS enteric-coated mycophenolate sodium HR hazard ratio MMF mycophenolate mofetil MPA mycophenolic acid PRA preformed panel reactive antibodies Ref reference TAC tacrolimus. Introduction As the incidence of acute rejection has declined after kidney transplantation 1, attention has transferred to improving long-term outcomes in kidney transplant recipients and, in particular, the high rate of death with a functioning graft. Death with function now occurs in 2–5% of patients each year 1, 2, and is almost as frequent as graft failure after the first year posttransplant 3. The most common reason for death in patients with a functioning graft is cardiovascular disease, followed by infection and malignancy 1, 2, 4, 5, and targeting these causes is a key clinical priority. We have previously demonstrated that HLA mismatch is associated with death with a functioning graft due to cardiovascular disease or infection during the first posttransplant year, an effect that declines in subsequent years 4. Several other factors could be expected to contribute to increased risk of death with function, such as increasing recipient age and the presence of diabetes mellitus, but modifiable variables are potentially of greater interest. One such risk factor may be the extent of exposure to steroids. Long-term administration of steroid therapy in kidney transplant recipients has well-recognized adverse effects that contribute to cardiovascular disease 6, and also places patients at increased risk of bacterial, fungal and viral infections 7. Steroid avoidance or withdrawal results in an improvement in cardiovascular risk factors, notably blood pressure 8, new-onset diabetes 8, dyslipidemia 8 and weight gain 9-13, an effect that appears to be dose-dependent 14. There is also evidence that steroid-sparing regimens may lower the risk of infections following kidney transplantation 15. The impact of steroid-sparing regimens on patient survival has not been adequately assessed. No survival benefit for steroid-free immunosuppression has been reported in individual clinical studies 11-13, 16-19 or in meta-analyses 8, 20 of kidney transplant populations, but population sizes and follow-up times in controlled trials are not adequate to detect differences in mortality. In 2005, an analysis of data from the Collaborative Transplant Study (CTS) data showed significantly higher patient survival over a 7-year follow-up period in more than 1000 patients from whom steroids were withdrawn at a minimum of 6 months posttransplant compared to matched controls 21. To date, however, an association between steroid dose and risk of death from cardiovascular causes or infections has not been examined in a sufficiently large population of kidney transplant patients over an extended follow-up period. The CTS offers the benefit of a large patient population with annual data collection from over 300 centers internationally. We report here an analysis of CTS data that assessed the relationship between steroid dose during long-term maintenance therapy and the risk of death with a functioning graft following kidney transplantation. Methods Details of the CTS methodology are available at www.ctstransplant.org. Data were analyzed from all recipients of a deceased-donor kidney transplant performed during the period 1995 to 2010 if the following criteria were met: (a) recipient was aged at least 18 years, (b) data on immunosuppressive regimen, doses and patient's body weight were available at 1 year posttransplant and (c) follow-up data were available to at least 2 years posttransplant. Recipients of multiorgan transplants, including combined kidney-pancreas transplants, were excluded. The analysis assessed death with a functioning graft during years 2–5 after kidney transplantation, defined as death in a patient for whom there was no previous report of a failed or lost graft. Cumulative incidence rates of graft failure and death with a functioning graft were computed using the Kaplan−Meier method. Information on serum creatinine is recorded at 3, 6 and 12 months posttransplant and annually thereafter for all patients registered with the CTS. Serum creatinine values are stratified as less than 130 µmol/L ( 4.5 mg/dL). Approximately half the centers that participate in CTS provide additional data on a nonmandatory extended follow-up questionnaire. The information requested on this questionnaire includes occurrence of treated acute rejection, serum total cholesterol, systolic and diastolic blood pressure, hospitalization because of infection, and dosages of immunosuppressive drugs. Steroid dose per day and body weight at year 1 posttransplant was divided into categories with the cut-offs 0.05, 0.10, 0.15 and 0.20 mg/kg/day for the purpose of analyzing observed rates of death with a functioning graft during years 2–5. The dose of methylprednisolone was converted to prednisolone equivalents using a multiplication factor of 1.25 22. The dose of mycophenolic acid (MPA) was calculated based on mycophenolate mofetil (MMF) equivalents. For 2929 patients (12% off all MPA patients) the dose of enteric-coated mycophenolate sodium (EC-MPS) was converted to the MMF equivalent by multiplying the EC-MPS dose by 1.4 23. Cox regression analysis was undertaken to account for the possible influence of confounding factors. The following confounders were analyzed for potential inclusion in the model: year of transplant, number of transplant (first or retransplant), recipient age, gender and race, original disease leading to transplantation, time on dialysis, increased cardiovascular risk (yes/no as identified by investigator), HLA-A,-B,-DR mismatches, use of IL-2 receptor or thymoglobulin antibody induction, preformed panel reactive antibodies (PRA), treatment for rejection during the first year posttransplant, serum creatinine at year 1, systolic blood pressure at year 1, treatment for diabetes mellitus at year 1, serum level of total cholesterol at year 1 and hospitalization due to infection during the first year posttransplant. Subanalyses were performed to assess the influence of dose of other immunosuppressive drugs for the three most frequent types of immunosuppressive regimen including the calcineurin inhibitors cyclosporine (CsA) or tacrolimus (TAC) and the antimetabolites azathioprine (AZA) or MPA. CsA, TAC, AZA and MPA doses at year 1 were analyzed in the Cox model based on whether values were above, within or below the interquartile range. All confounders were suitably categorized and missing values were considered as a separate category. Hazard ratios (HRs) for the cumulative incidence of death with a functioning graft due to cardiovascular disease (ICD-10 I00-I99) or infection during posttransplant years 2–5 were calculated. p-Values below 0.05 were considered significant. The software package IBM SPSS Statistics version 20 was used. Results In total, 41 953 patients met the criteria for inclusion in the analysis. The probability for death with a functioning graft during the posttransplant years 2–5 for these patients was 7.53%. This rate was virtually identical with the 7.59% rate in 71 500 patients who did not meet the inclusion criteria (p = 0.29) primarily because the exact doses of immunosuppressive medication or body weight at 1 year were unknown, showing that the study population was representative of transplants reported to the CTS. The data set included 135 943 person years for the 4 years of observation (mean 3.2 years per patient) and incomplete follow-up was noted in 4898 patients (11.7%). The majority of patients had undergone a first kidney transplant (86.6%), were male (61.9%) and were white (85.7%; Table 1). The immunosuppressive medication at year 1 posttransplant included a calcineurin inhibitor (CsA or TAC) in 40 007 patients (95.4%) and antimetabolites (AZA or MPA) in 33 734 patients (80.4%). The three most frequent combination regimens were CsA + MPA + steroids (24.2%), TAC + MPA + steroids (21.5%) and CsA + AZA + steroids (15.9%). At year 1, the type of steroid medication was prednisone, prednisolone, methylprednisolone and other in 43.3%, 40.0%, 16.5% and 0.2% of patients. Table 1. Baseline characteristics and immunosuppression of study population (n = 41 953) Characteristic Unknown (%) Patients, n (%) Geographical region 0.0 Europe 27 564 (65.7) North America 2973 (7.1) Latin America 5612 (13.4) Australia/New Zealand 4797 (11.4) Other 1007 (2.4) Transplant number 0.0 First transplant 36 311 (86.6) Retransplant 5639 (13.4) Recipient gender 0.0 Female 16 000 (38.1) Male 25 949 (61.9) Recipient race11 Certain European countries do not allow registration of race. 6.4 White 33 669 (85.7) Other 5598 (14.3) Recipient age (years) 0.0 18–39 11 786 (28.1) 40–49 10 503 (25.0) 50–59 11 221 (26.7) ≥60 8443 (20.1) Immunosuppression at 1 year Calcineurin inhibitors 0.0 Cyclosporine 24 631 (58.7) Tacrolimus 15 376 (36.7) None 1946 (4.6) Antimetabolites 0.0 Azathioprine 8887 (21.2) Mycophenolate acid 24 847 (59.2) None 8219 (19.6) Type of steroids 4.8 Prednisone 14 930 (43.3) Prednisolone 13 802 (40.0) Methylprednisolone 5702 (16.5) Other 59 (0.2) Steroid dose (mg/kg/day) 0.0 No steroids 5717 (13.6) 0.01–0.04 3317 (7.9) 0.05–0.09 16 532 (39.4) 0.10–0.14 10 260 (24.5) 0.15–0.19 4119 (9.8) 0.20–0.40 2008 (4.8) 1 Certain European countries do not allow registration of race. During years 2–5 posttransplant, 2597 patients died with a functioning graft. The causes of death with a functioning graft were cardiovascular (n = 725, 27.9%), infection (n = 538, 20.7%), malignancy (n = 476, 18.3%), other reasons (n = 336, 12.9%) and unknown (n = 522, 20.1%). The proportion of all graft failures during years 2–5 posttransplant that were caused by death with a functioning graft increased progressively over time: 45.5%, 50.0%, 51.4% and 57.3% during the periods 1995–1998, 1999–2002, 2003–2006 and 2007–2010, respectively. Death with a functioning graft due to cardiovascular causes declined significantly over these periods (log rank for trend p = 0.002) while infection-related deaths became more frequent (p = 0.004). There was a close correlation between dose of steroids administered at posttransplant years 1 and 5, such that the cohort order from low to high dose remained unchanged from year 1 to year 5 (Supplementary Figure S1). In the cohort that received ≥0.10 mg/kg/day at year 1, 48.3% of patients received more than 0.10 mg/kg/day at year 5. Of the patients who did not receive any steroids at year 1, 88.7% were still steroid-free at year 5 (data not shown). The observed rate of death with a functioning graft during years 2–5 posttransplant showed a significant correlation with steroid dose at year 1 (log rank for trend p < 0.001; Figure 1). Of the 5717 patients who were steroid-free at 1 year posttransplant, steroids were initially given to 4470 (78.2%) then discontinued during the first posttransplant year, whereas 1247 (21.8%) were steroid-free from the time of transplant. The 5-year incidence of death with a functioning graft in these two cohorts was virtually identical (Supplementary Figure S2, HR = 1.0; p = 0.79). While there was a gradual decrease in steroid dosages since 1995–1998, even during the most recent 2007–2010 interval 21.0% of the patients received ≥0.10 mg/kg/day of steroids per day and only 17.7% were steroid-free 1 year posttransplant (Figure 2). The data were robust when patients were separated according to the original disease leading to renal failure: a significant association of steroid dose with death with a functioning graft was found in risk-group patients with diabetic or hypertensive nephropathy as well as in patients with polycystic kidney disease (Supplementary Figure S3). When analyzed separately, death with a functioning graft due to cardiovascular causes or to infection both showed a significant relationship with steroid dose at year 1 (both log rank p < 0.001; Figure 3A and B) whereas death due to malignancy in patients with a functioning graft was not associated with higher steroid dose (Figure 3C). Figure 1Open in figure viewerPowerPoint Cumulative incidence of death with a functioning graft during years 2–5 posttransplant in kidney transplant recipients according to dose of maintenance steroids administered at year 1. Steroid dose is indicated as mg/kg/day. Log rank p < 0.001. Figure 2Open in figure viewerPowerPoint Evolution of steroid dosing at 1 year posttransplant from period 1995–1998 to 2007–2010. Steroid dose is indicated as mg/kg/day. Figure 3Open in figure viewerPowerPoint Death due to (A) cardiovascular disease (B) infection and (C) malignant neoplasm during years 2–5 posttransplant in kidney transplant patients with a functioning graft according to steroid dose (mg/kg/day) at year 1 posttransplant. Significant confounders identified by multivariable Cox regression (Supplementary Table S1) were included in the Cox model for analysis of steroid dose categories at year 1. The result showed that HR values for risk of death with a functioning graft increased with higher steroid doses (Table 2). In each of the three most frequently administered immunosuppressive regimens (CsA + AZA + steroids, CsA + MPA + steroids and TAC + MPA + steroids), patients with a steroid dose at 1 year posttransplant that was ≥0.10 mg/kg/day had a significantly increased risk of death with a functioning graft compared to patients who were given a low steroid dose, whereas the other immunosuppressive drugs did not have a significant influence on patient death (Table 3). The robustness of findings in patient subpopulations was supported by performing Cox regression analyses in which all significant confounders were considered (Supplementary Table S2). Table 2. Influence of steroid dosage at year 1 posttransplant on cumulative incidence of death with a functioning graft during posttransplant years 2–5 (n = 41 953) Steroid dose (mg/kg/day) HR 95% CI p-Value No steroids 1.0 – Ref 0.01–0.04 1.1 0.9–1.3 0.32 0.05–0.09 1.2 1.0–1.4 0.018 0.10–0.14 1.7 1.4–1.9 <0.001 0.15–0.19 2.1 1.8–2.5 <0.001 0.20–0.40 2.9 2.4–3.6 <0.001 HR, hazard ratio; CI, confidence interval; Ref, reference. Table 3. Influence of immunosuppressant dosage at year 1 posttransplant on cumulative incidence of death with a functioning graft during posttransplant years 2–5 Dose (mg/kg/day) HR 95% CI p-Value CsA + AZA (n = 7125) CsA dose 0.5–2.1 1.1 0.8–1.3 0.65 2.2–3.7 1.0 – Ref 3.8–10.0 1.0 0.8–1.2 0.84 AZA dose 0.1–0.7 1.0 0.8–1.2 0.99 0.8–1.5 1.0 – Ref 1.6–4.0 1.0 0.8–1.3 0.94 Steroid dose No steroids 1.2 0.8–1.7 0.40 0.01–0.09 1.0 – Ref 0.10–0.40 1.4 1.1–1.7 0.006 CsA + MPA (n = 12 126) CsA dose 0.5–2.1 1.0 0.8–1.2 0.91 2.2–3.7 1.0 – Ref 3.8–10.0 1.0 0.8–1.3 0.69 MPA dose 2–17 1.1 0.9–1.3 0.44 18–28 1.0 – Ref 29–80 1.1 0.9–1.4 0.22 Steroid dose No steroids 0.8 0.6–1.1 0.14 0.01–0.09 1.0 – Ref 0.10–0.40 1.5 1.2–1.8 <0.001 TAC + MPA (n = 10 852) TAC dose 0.01–0.03 1.1 0.9–1.3 0.35 0.04–0.10 1.0 – Ref 0.11–0.40 1.2 0.9–1.5 0.24 MPA dose 2–12 0.9 0.8–1.2 0.61 13–22 1.0 – Ref 23–80 1.2 1.0–1.5 0.081 Steroid dose No steroids 0.7 0.5–0.9 0.016 0.01–0.09 1.0 – Ref 0.10–0.40 1.7 1.4–2.0 <0.001 Significant hazard ratios (HR) are shown in bold text; CI, confidence interval; Ref, reference; CsA, cyclosporine; AZA, azathioprine; MPA, mycophenolic acid; TAC, tacrolimus; Categories of dose are based on interquartile ranges. A further analysis was performed to assess the association between steroid dose and death with a functioning graft in patients in whom graft function could be considered optimal, that is, a cohort in whom it could be assumed that higher steroid doses were not clinically mandated. This subpopulation was defined as patients with serum creatinine <130 µmol/L at 1 year posttransplant who had not been treated for rejection during the first year. The significant association between steroid dose and risk of cardiovascular or infectious death with a functioning graft during years 2–5 was maintained in this subpopulation (log rank p < 0.001; Figure 4A1). In patients who were treated for rejection during the first year or had an increased 1-year serum creatinine, the rates of death were generally higher but the association of death with steroid dose remained significant (p < 0.001; Figure 4A2). The corresponding death-censored graft survival rates in these groups of patients showed significant advantages of low dose or steroid-free therapy at 1 year (Figures 4 B1 and B2). These data are reminiscent of the survival advantage of steroid-free maintenance immunosuppression that was observed in a previous prospective steroid withdrawal study in more than 1000 kidney graft recipients 21 and therefore prompted us to analyze the factor systolic blood pressure. Indeed, we found that 1-year systolic blood pressure, a factor well known to be associated with death-censored kidney graft survival 24 was significantly correlated with steroid dose (Figure 5A1 and A2). In support of the correlation of cardiovascular death during years 2–5 with the dosage of steroids administered at year 1, we found a significant association of serum cholesterol levels with the 1-year steroid dose (Figure 5B1 and B2). The de novo occurrence of various risk indicators during posttransplant years 2–5 in patients with serum creatinine <130 µmol/L at 1 year showed significant associations between steroid dose and the occurrence of hospitalization due to infection, hypercholesterolemia, cataracts and osteoporosis, but not with de novo diabetes or hypertension (Supplementary Table S3). Figure 4Open in figure viewerPowerPoint Death with a functioning graft during years 2–5 (A) and corresponding death-censored graft survival (B) in patients with serum creatinine <130 µmol/L at year 1 and no rejection treatment during year 1 (A1 and B1) or patients with serum creatinine ≥130 µmol/L at year 1 or rejection treatment during year 1 (A2 and B2). Steroid doses at 1 year posttransplant are indicated. Figure 5Open in figure viewerPowerPoint Systolic blood pressure (A) and total serum cholesterol (B) at 1 year posttransplant in patients with serum creatinine <130 µmol/L at year 1 and no rejection treatment during year 1 (A1 and B1) or patients with serum creatinine ≥130 µmol/L at year 1 or rejection treatment during year 1 (A2 and B2). Steroid doses at 1 year posttransplant are indicated. The risk of death with function was also assessed using still more rigorous criteria, whereby patients were included only if they had serum creatinine <130 µmol/L at both 1 and 2 years posttransplant, and no anti-rejection therapy during the first or second year posttransplant. Again, in this population steroid dose at year 2 was significantly associated with death with function due to cardiovascular causes or infection (Figure 6). Figure 6Open in figure viewerPowerPoint Death due to (A) cardiovascular disease and (B) infection during years 3–6 posttransplant in kidney transplant patients with serum creatinine <130 µmol/L and no rejection treatments during first two posttransplant years according to steroid dose (mg/kg/day) at year 2. Lastly, we assessed whether the extent to which centers withdrew steroids during year 2 posttransplant influenced the incidence of death with a functioning graft during years 2–5. One hundred eighteen transplant centers with a minimum of 50 transplants in the study population were stratified according to whether they had a low ( 10%, 34 centers) rate of steroid withdrawal during the second year posttransplant. The three categories of centers reported a similar rate of patients with serum creatinine <130 µmol/L at 1 year posttransplant (52.5%, 55.4% and 50.4%, respectively), suggesting similar graft outcomes. There was, however, a significant inverse association between the proportion of patients in whom steroids were withdrawn during year 2 and the rate of death due to cardiovascular disease (log rank p < 0.001) or infection (p < 0.001) to year 5 (data not shown). When the analysis was repeated based on the same center stratification but including only patients with serum creatinine 10% of patients (log rank p = 0.002 and p < 0.001, respectively; Figure 7). Figure 7Open in figure viewerPowerPoint Death due to (A) cardiovascular disease and (B) infection during years 2–5 posttransplant in kidney transplant patients with a functioning graft at 118 transplant centers with ≥50 kidney transplants in whom 10% (34 centers) patients had steroids withdrawn during second year posttransplant. Only data from patients with serum creatinine <130 µmol/L and no rejection treatment during first posttransplant year are shown. Discussion Identifying predictive factors for death following kidney transplantation can only be achieved if a very large population is available for analysis, with extended follow-up. This effectively restricts such analyses to transplant registries, which offer sufficient power and duration using the same data recording methodology for all participants. In this analysis of 41 953 adult kidney transplant patients, steroid dose showed a highly significant association with death due to cardiovascular disease or infection during years 2–5 in patients with a functioning graft. This association was evident for infectious deaths and death for cardiovascular reasons, whereas we observed no association between steroid dose and death due to malignancy. Overall, death with function accounted for approximately a half of all graft losses. We are aware that in this retrospective analysis study the reason for higher steroid dosing cannot be established. If a high steroid dose was consistently administered only in patients with allograft rejection and poor renal function, the observation that higher doses are associated with greater risk of death with function would be of less interest since patients with poor graft function are known to be at increased risk of death 25. Indeed, our finding that 1-year serum creatinine was significantly predictive of death with function due to either cardiovascular or infectious causes (Supplementary Table S1) is consistent with a recent analysis of data from 4016 kidney transplant patients showing progressively higher rates of cardiovascular events and all-cause mortality as estimated GFR declined below 45 mL/min/1.73 m2 25. If steroid treatment was always clinically mandated, it would simply be a marker of risk rather than a contributor. Therefore, we sought to examine whether the effect of steroid dose was still apparent in patients with very good graft function who had not experienced rejection at 1 year posttransplant. This analysis was extended to include patients who met these criteria up to 2 years posttransplant, a cohort in whom graft function could be regarded as stable. In these groups, it seems reasonable to conclude that steroids were being administered due to physician choice, not clinical necessity. The association between steroid dose and death with function due to cardiovascular disease or infection was still present in these subpopulations with good graft function and no rejection to 1 or even 2 years posttransplant, suggesting that these patients may be exposed to an increased risk of death due to unnecessarily high steroid doses. Evidence to support this comes from the center-specific analysis (Figure 7), which demonstrated that among patients with good graft function and no rejection the risk of death due to either cardiovascular disease or infection fell significantly as the rate of steroid withdrawal increased at a given center. An association between higher dose and risk of death with function from any cause, or due to cardiovascular disease or infection, was not observed for calcineurin inhibitors or antimetabolites even after adjustment for confounding factors. The study is limited by its retrospective nature and the absence of information about the reasons for steroid withdrawal. It is possible that steroids were preferentially withdrawn in low-risk patients, although the subanalyses in patients without a history of acute rejection or impairment of graft function still showed a detrimental effect of steroid continuation. The analysis of center preference, in which centers which withdrew more frequently showed the lowest rates of death with a functioning graft, was intended to help address the issue of bias in patient selection. Future studies may identify high-risk patient subgroups in whom steroids withdrawal should not be considered. We would also like to point out that our study was based primarily on a population of European Caucasian recipients so that it is uncertain whether the results apply to nonCaucasians. In conclusion, higher doses of steroids are associated with a significant increase in the overall risk of death with a functioning graft after the first year following kidney transplantation, arising from an increase of cardiovascular death and infectious death. This association is observed even in patients with stable graft function with no history of rejection, in whom high steroid dosing would appear to be unnecessary. Those centers which achieve steroid-free immunosuppression in a relatively high proportion of patients also have a lower incidence of death with function due to cardiovascular disease or infection. This should be taken into account by physicians when deciding what steroid dose is necessary, or indeed if steroid therapy should be continued, in individual kidney transplant patients. Acknowledgments We thank the following 209 transplant centers and their staff for supporting this project: Aachen, Adelaide, Akron, Ancona, Ankara, Antalya, Atlanta, Auckland, Augsburg, Banska-Bystrica, Baracaldo, Barcelona 2, Bari, Barquisimeto, Basel, Belfast, Belo Horizonte 3, Berlin, Bern, Bochum, Bogota, Botucatu, Bremen, Brisbane, Bristol, Budapest, Buenos-Aires 5, Cali 2, Cape Town 3, Caracas, Carshalton, Christchurch, Cincinnati, Cleveland, Cologne 2, Cordoba 2, Dallas 2, Debrecen, Duesseldorf, Edmonton, Erlangen-Nuernberg, Essen, Exeter, Florence, Fort Wayne, Frankfurt, Freiburg, Fulda, Geneva, Giessen, Glasgow, Goettingen, Grand Rapids, Guadalajara, Haifa, Halle, Hamilton (CDN), Hamilton (NZ), Hann-Muenden, Heidelberg (AUS), Heidelberg (D), Helsinki, Homburg, Hong Kong 8, Innsbruck, Istanbul, Izmir 2, Jena, Jerusalem, Kaiserslautern, Katowice, Kaunas, Kiel, Lausanne, Leicester, Leuven, Lexington, Liege, Lille, Lima, Limoges, Linz, Liverpool, Ljubljana, Luebeck, Lyon, Maastricht, Maceio, Madrid, Mainz, Malaga, Manila, Mannheim, Mar del Plata, Maracaibo, Marburg, Martin, Medellin 3, Melbourne 4, Mexico City, Milan, Modena, Muenster, Nancy, Nantes, Nashville, Neiva, New Delhi, New York, Newark, Newcastle (AUS), Newcastle (GB), Nottingham, Novara, Oklahoma 2, Omaha, Osijek, Oviedo, Pamplona, Panama, Pato Branco, Pavia, Pecs, Perth, Plzen, Poitiers, Porto Alegre, Prague, Quebec, Regensburg, Reims, Rennes, Rijeka, Rio de Janeiro, Rome, Rosario 2, Rostock, Santa Fe, Santander, Santiago 2, Sao Paulo 5, Seattle, Seoul, Shreveport, St. Gallen, Stony Brook, Strasbourg, Stuttgart, Sydney 9, Szeged, Tel Aviv, Toledo, Tours, Tuebingen, Turin, Ulm, Uppsala, Valdivia, Valencia 2, Valhalla, Vilnius, Wellington, Wichita, Winnipeg, Wuerzburg, Zagreb, Zurich. The study received no external funding. Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. Supporting Information Additional Supporting Information may be found in the online version of this article. Filename Description ajt12313-sm-0001-SupFig-S1.eps10.6 KB Figure S1: Steroid dose at posttransplant year 5 according to steroid dose at year 1 and the proportion of patients in whom steroids were withdrawn during posttransplant years 2–5. ajt12313-sm-0001-SupFig-S2.eps13.6 KB Figure S2: Death with a functioning graft during years 2–5 in recipients who were steroid-free at year 1 posttransplant according to whether they initially after transplantation were placed on steroids or not. ajt12313-sm-0001-SupFig-S3.eps21.9 KB Figure S3: Death with a functioning graft during years 2–5 in recipients with original disease (A) diabetic nephropathy, (B) hypertensive nephropathy or (C) polycystic kidney disease according to steroid dose (mg/kg/day) at year 1 posttransplant. ajt12313-sm-0001-SupData.doc78 KB Table S1: Significant confounders (excluding dosage of steroids or other immunosuppressants) included in the Cox regression analysis of cumulative incidence of death with a functioning graft due to cardiovascular disease or infection during posttransplant years 2–5 (n = 41 953). Table S2: Results of Cox regression for death with functioning graft during posttransplant years 2 to 5 according to 1-year steroid dose. Table S3: De novo occurrence during posttransplant years 2–5. Patients with serum creatinine > ASTS Members >> FiguresReferencesRelatedInformation
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