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Nephrology Dialysis Transplantation 2006 21(7):1966-1973; doi:10.1093/ndt/gfl131
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Steroid-free immunosuppression after renal transplantation—long-term experience from a single centre

Mohamad El-Faramawi1, Nils Rohr2 and Bente Jespersen1

1 Department of Nephrology Y and 2 Department of Surgery T, Odense University Hospital, DK-5000 Odense C, Denmark

Correspondence and offprint requests to: Bente Jespersen, MD, DMSc., Department of Nephrology Y, Odense University Hospital, DK-5000 Odense C. Email: Bente.Jespersen{at}OUH.Fyns-amt.dk



   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. A steroid-free immunosuppressive protocol may improve the general well-being of patients, but long-term renal graft survival has been a concern.

Methods. In a retrospective clinical study, 329 consecutive transplantations with renal grafts at our centre during the period 1995–2004, were followed for up to 9.3 years. Patients mainly received steroid-free immunosuppression with an initial induction with antithymocyte globulin or basiliximab and maintenance therapy with ciclosporin and mycophenolate mofetil (MMF). Steroids were given after rejection, or if the physician judged it necessary, for instance because of primary kidney disease or when calcineurin inhibitor toxicity was suspected.

Results. About 71% of the patients did not take steroids at all. Nevertheless, graft survival rates at 1, 5 and 7 years were 95, 77 and 72% for all grafts, including 27% living donor transplants and 27% second or subsequent grafts. Ten patients (3.2%) died with functioning grafts. Within the first year of transplantation there were 69 acute rejections in 63 patients (19%). Four cases (1.3%) of post-transplant lymphoproliferative disorder (PTLD) occurred with one graft loss and no deaths. Owing to a high PTLD rate in a previous patient cohort, total immunosuppression was lessened after 1998.

Conclusions. Steroid avoidance is possible with good results with respect to acute rejection and long-term graft survival. After introducing MMF, largely avoiding muromonab-CD3 mouse raised monoclonal antibody against CD (OKT3), and reducing doses of calcineurin inhibitor, the rates of PTLD did not differ from what is usually found. For the present, induction and use of MMF, together with a calcineurin inhibitor, is probably to be preferred.

Keywords: long-term; renal transplantation; steroid-free



   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Survival of the patient and graft was the chief indicator of success in the early days of renal transplantation, but now that multiple immunosuppressive regimens are available the well-being of the recipients is rightly the main concern. Although there has been a tendency to use more potent immunosuppressive regimens, the long-term survival of kidney grafts has probably not improved as much as expected [1,2], and it is not known how far this could be attributed to the long-term adverse effects of the immunosuppressive drugs, chronic rejection or a more liberal selection of donors and recipients. Steroid minimization was associated with impaired graft function and survival in some [3,4] randomized long-term trials, but not in another [5], before the introduction of mycophenolate mofetil (MMF) and ciclosporine (CsA) microemulsion. Since the introduction of these drugs increased, rates of acute rejection have still been reported when steroids were withdrawn in renal transplant patients [6,7]. On the other hand, early minimization [8–11] or complete avoidance of steroids may be preferable [12]. With respect to steroid avoidance, small short-time studies are available [13–15] including 3-years data from our centre [16], but data on graft survival after 3 years are not yet available from retrospective or controlled trials. The well-known steroid side effects of body disfigurement, growth retardation in children, mood changes, insulin resistance, hypertension [6], hyperlipidaemia [7–9], infections, healing problems, cataract [5] and osteopaenia [5,17], bone necrosis and fractures could be avoided to some extent, but most centres are worried that this has cost more rejections, shorter graft survival, and probably anaemia and more cancer, because other drugs have to be used more extensively. Now that more drugs, and especially MMF, are available permitting lower doses of the calcineurin inhibitor, together with the possibility of low-risk induction, the chances of long-term graft survival are probably better; it has even been suggested recently that the long-term results may be better without steroids than with them [11,14]. Furthermore, it has been theorized that avoidance of steroids might be preferable to early discontinuation of steroids, because discontinuation may trigger a rebound release of cytokines and thus cause rejection [14,18].

We report here the long-term outcome in all patients undergoing transplantation at our centre where steroid avoidance has been possible in most patients. We describe briefly the results from the period 1990–95, where patients were treated with a polyclonal antilymphocyte induction therapy followed by CsA monotherapy, and in greater detail the results during the period 1 September 1995 to the end of 2004, where a dual maintenance therapy was given—a calcineurin inhibitor and MMF.



   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients
The study comprises all the patients undergoing renal transplantation at Odense University Hospital from 1 January 1990 to 31 December 2004. The period 1990–95, with a total of 212 transplantations in 207 patients is briefly referred to for comparison, whereas the period 1995–2004, with 329 transplantations in 314 patients, is described more fully. This latter period starts on 1 September 1995, when MMF was added to the immunosuppressive regimen [16]. The patient and graft survival data cover all patients.

Treatment and definitions
The dosage described below was given to patients older than 15 years.

Induction therapy was given to all patients except for two, who had had a previous episode of post-transplant lymphoproliferative disorder (PTLD). Before 1999 a polyclonal antithymocyte globulin was used in all patients. Minnesota antilymphocyte globulin (Minnesota, USA), at a dose of 20 mg/kg/day was used until thymoglobuline (Sangstat, Lyon, France) became available and replaced it in 1994. At first, 2.1 mg/kg of thymoglobuline 1.25 mg/kg was given for 10 days, but from September 2002 it was only given for a maximum of 5 days at a dose of 1.5 mg/kg, with the first dose initiated before transplantation. In primary transplants in patients without antibodies and older than 15 years, the humanized monoclonal anti-CD25 antibody, basiliximab (Novartis), replaced thymoglobulin as induction from 1 July 1999 (initiating period 1999–2004). Maintenance immunosuppression consisted of MMF and CsA. MMF was given at a dose of 1 g twice a day, which was reduced to 0.75 g twice a day for patients taken off CsA. The oral dose of CsA was adjusted during this period. First, CsA maintenance doses of 8 mg/kg were used. The CsA microemulsion, Sandimmune Neoral (Novartis, Basel, Switzerland) was used when it appeared on the market in 1994. When monitoring was introduced in 1992, the aim was to measure trough levels of 200–400 nmol/l by a whole-blood monoclonal method (Abbott TDx measured fluorescence-polarization-immune analysis). This was reduced from the start of the period 1999–2004 to 150–250 nmol/l during the first 3 months and 100–200 nmol/l, thereafter. Monitoring of the concentration 2 h after intake (C2) was introduced in November 2001 and from September 2002 the aims for C2 levels were as follows: month 1: 1500 nmol/l; month 2: 1300 nmol/l; month 3: 1100 nmol/l; months 4–6: 1000 nmol/l; months 7–12: 900 nmol/l; months 13–24: 800 nmol/l and thereafter 700 nmol/l [19]. Our analysis is controlled by the International Proficiency Testing Scheme. Individual patients—for example, most receiving a 0–0 mismatched kidney—are kept at lower intervals. After June 2002, CsA was replaced for various reasons by tacrolimus as primary immunosuppression in 29 transplantations, and 79 patients were changed to tacrolimus. Sirolimus was given to 11 patients to wear them off calcineurin inhibitors in cases where toxicity was suspected. Until 1999, rejections were mostly diagnosed by multiple fine needle aspiration biopsied (FNABs) [20], but thereafter a core renal biopsy was required for the diagnosis of acute rejection, except in a few instances where contra-indications were present. Until 1999, rejections were treated with monoclonal muromonab-CD3, mouse-raised monoclonal antibody against CD (OKT3, Cilag) at a does of 5 mg daily for 10 days as first-line therapy; steroids were then given starting with 500 mg of methylprednisolone, which was decreased to 15 mg after 3 weeks, to 10 mg after 2 months and to 7.5 mg after 6 months in a man weighing 70 kg. In the case of early non-severe rejections, the standard procedure was to discontinue steroids slowly over a period of 12–18 months after the rejection.

Cytomegalovirus (CMV) disease was diagnosed in a patient, who tested positive for CMV-DNA in the blood and had a fever that could not be otherwise explained, usually with leucopaenia, thrombocytopaenia or CMV-related organ manifestations such as pneumonia. Until 2002, all patients received acyclovir prophylaxis for 3 months, thereafter gancyclovir/valgancyclovir was given to CMV-negative patients receiving CMV-positive kidneys. During the entire period gancyclovir/valgancyclovir was started pre-emptively and given for 3 months when CMV could be demonstrated in granulocytes or later CMV-DNA could be demonstrated in the blood.

Urinary tract infection was diagnosed in a patient with bacteriuria together with dysuria or fever, which could not be explained by other diseases. Since 1999 a JJ stent has been inserted in the ureter during the operation and removed 2 weeks after transplantation. Cefuroxime prophylaxis is given once during the operation and again before removal of the stent.

Since 2001, 20 mg of eroxaparin is given subcutaneously pre-operatively and once daily for about a week.

Post-transplant diabetes mellitus (PTDM) was registered in patients who were not diabetic at the time of transplantation, but then required antidiabetic treatment for more than a month. Hypertension was registered in patients who had a blood pressure higher than 130/80 mmHg, or who were on antihypertensive therapy. Ischaemic heart disease after transplantation was registered if angina pectoris, acute myocardial infarction or cardiac revascularization was described in the patient record. Cerebral insults were registered in the case of the described aphasia or pareses. Lower extremity ischaemia was registered in cases of the described claudicatio intermittens, wound healing problems or amputation.

Endpoints and statistical analysis
The primary endpoint of this evaluation is graft survival in the entire cohort, where graft loss includes death with a functioning graft. Secondary points of interest are graft loss owing to patient death, proportion of patients staying off steroids during the study, rejection rate during the first year, renal function at 1, 3, 5 and 7 years, and safety parameters including frequency of PTLD, CMV disease, urinary tract infections, development of PTDM, hypertension and cardiovascular disease.

Comparison of graft survival data was performed using Kaplan–Meier product limit estimates with 95% confidence intervals.



   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
In the focus period 1995–2004 follow-up data other than graft loss were unfortunately not available on one patient, and three patients were lost to follow-up 983, 1440 and 2788 days after transplantation. Baseline data is given in Table 1. Towards the end of the period matching primary for HLA-DR was aimed at, resulting in an average mismatch on DR of 1.0 in period 1995–99 and 0.8 in period 1999–2004.


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  		Table 1. Demographics

 
Graft Survival (1990–2004) and death with functioning graft (1995–2004)
In the period 1995–2004, graft survival rates at 1, 5 and 7 years were 95, 77 and 72% for all grafts (Figure 1), a significant improvement compared with the former period 1990–95, where graft survival rates at 1, 5, 7 and 10 years were 85, 48, 33 and 22% (P<0.05 from 1 year after transplantation).


Figure 1
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  		Fig. 1. Kaplan–Meier plots of graft survival for all patients transplanted in the period 1995–2004.

 
Of patients transplanted from 1995 to 2004, 10 died with a functioning graft. One patient died 4 days after transplantation after an initial graft function from loss of blood, since as a Jehovah's Witness he had refused blood transfusions. One patient died of an astrocytoma grade II brain tumour, which was detected a few weeks after transplantation. Other causes of death were: infections in three; three found dead possibly from cardiac disorders; one suicide and one from cancer. The total death rate was thus 3.2% for the entire observational period of an average of 3.6 years. Only one patient died within the first month after graft loss.

Of the 29 children who had 31 transplants during 1995–2004, three lost their graft function, one within the first month owing to venous thrombosis and two because of recurrence of glomerulonephritis 23 and 31 months, respectively, after transplantation.

In Figure 2, graft survival is divided into two periods 1995–99 and 1999–2004, the tendency was towards an improvement, but this was not significant.


Figure 2
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  		Fig. 2. Kaplan–Meier plots of graft survival for all patients transplanted in the period 1995–99 and 1999–2004. 1 July 1999 is the dividing date when basiliximab was introduced as induction.

 
Figure 3 shows the results for 1995–2004 for first transplantations with a cadaver kidney and with a living donor kidney. Graft survival rates at 1, 5 and 7 years were 93, 77 and 69% in first cadaver kidney transplantations, and 97, 81 and 81% in first living donor kidney transplantations.


Figure 3
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  		Fig. 3. Kaplan–Meier plots of graft survival for all patients transplanted for the first time in the period 1995–2004 with a kidney from a living donor or a deceased donor.

 
Non-function was the case in 13 transplants (4.0%), one owing to removal because of anaesthesiological problems. Primary graft function occurred in 253 cases (77%), whereas delayed function, defined as a need of dialysis within the first week of transplantation, occurred in 62 cases (19%). Two patients requiring dialysis after primary function because of a bleeding episode and an antiphospholipid antibody syndrome were counted as primary function.

Use of steroids (1995–2004)
A few patients were given steroids from the start, owing to other diseases [total 18; lupus erythematosus disseminatus: 4; rapidly progressive glomerulonephritis in native kidneys: 4; history of PTLD to avoid induction or reduce doses of calcineurin inhibitor: 3; asthma: 1; heart transplant: 1; kidney transplant with some function: 1; when the physician judged the risk of rejection was high: 3; intolerance to MMF: 1]. Steroids were later given because of intolerance to MMF, in which case azathioprine was given together with low-dose prednisolone: 5; or on suspicion of calcineurin inhibitor side effects: 7, in which case the calcineurin inhibitor dose was reduced or replaced by sirolimus. Prednisolone was given for a short time to three patients because of the recurrence of their disease, but these grafts were lost soon after, and to two patients because haemolytic uraemic syndrome was suspected, but could not be confirmed. One patient was put on prednisolone, owing to a planned pregnancy so as to withdraw MMF. Seven patients were put on steroids because of rejections later than the first year after transplantation.

Fifty-five patients, three of whom were taking steroids for other reasons, were given prednisolone because of rejection during the first year, and most of these patients were taken off prednisolone within 18 months of starting. Patients given prednisolone for less than a month for reasons such as asthma, OKT3 treatment and arthritis urica were not counted as steroid-dependent, as with a patient with astrocytoma who had been taking prednisolone the last 2 months of her life due to cerebral symptoms. Thus, a total of 233 patients (71%) stayed off steroids for the entire observation time.

Acute rejection and renal function after 1, 3, 5 and 7 years (1995–2004)
As shown in Table 2, 69 rejections were treated within the first year in 63 of 328 patients (19%), (six patients had two rejections). About 68% of the rejections occurred within the first 3 months after transplantation. The rejections were borderline (20 cases), Banff grade IA (18 cases), grade IB (19 cases), grade IIA (2 cases), grade IIB (1 case). No severe rejections were found. In three cases rejection was suspected and treated without a biopsy and in six cases before 1999 rejection was diagnosed on the basis of a FNAB. According to the standards, OKT3 was given to nine patients as first-line treatment during the period 1995–99, and one of these patients later received prednisolone for recurrent rejection. Fifty-five of the patients were treated with prednisolone for more than a month because of rejection during the period 1995–2004. Four rejections were steroid-resistant and treated with OKT3/thymoglobulin. One of these patients also received immunoglobulin intravenously after plasmapheresis against an IA rejection where complement C4d had been found in the graft and no response to steroid or OKT3 was seen. Unfortunately, this patient did not regain function and had to stay on dialysis; arteriography and ultrasound revealed no abnormalities. Thirty-one out of 123 patients induced with basiliximab had acute rejections within the first year (25%). During the period 1995–99, 14 of 124 transplantations (11%) were complicated by at least one rejection within the first year, while the corresponding value was 49 of 204 transplantations (24%) for the period 1999–2004. If the period 1999–2004 is separated by the introduction of C2 monitoring, 22 of 76 (29%) before and 27 of 128 (21%) after had rejections within one year after transplantation. At follow-up on 31 December 2004, one-year data on patients transplanted in 2004 were not all available.


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  		Table 2. Rejections in 124 transplants from 1995 to 1999 and 204 transplants thereafter until the end of 2004

 
The median serum concentration of creatinine at 1 year in patients alive and off dialysis was 151 µmol/l in the period 1995–99 and 144 µmol/l in the period 1999–2004. At 3, 5 and 7 years after transplantation the values were 154, 159 and 169 µmol/l, respectively (1995–2004).

PTLD (1990–2004), Table 3
PTLD occurred in 16 out of 212 transplantations (207 patients) from 1990 to 1995 (7.7% of patients and 7.5% of transplants), and in four out of 329 transplantations (314 patients) from 1995 to 2004 (1.3% of patients and 1.2% of transplants). Of note, seven of 20 cases of PTLD were diagnosed more than 5 years after the last transplantation. In the latter period, three of the four PTLD patients had been transplanted twice within the period. Of all the patients with PTLD, six died from widespread fulminant disease 3, 16, 56, 100, 102 and 131 months after transplantation, all transplanted during the period 1990–95 [21,22]. From 1995 to 2004 only one of the four grafts was lost because of discontinuation of immunosuppression. The other three grafts (two in children) are still functioning. One of the four PTLD patients had been taking prednisolone since the transplantation and this was later discontinued.


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  		Table 3. Incidence of PTLD in patients transplanted in different periods, and deaths and graft loss caused by PTLD

 
Infections during the first year, PTDM and cardiovascular problems (1995–2004)
CMV disease was diagnosed in 6.7% of the patients, but only one patient was severely ill and she recovered with preserved kidney function. Thirty percent had at least one urinary tract infection and 16% had pneumonia.

PTDM developed in nine patients, (five of them on steroids) corresponding to 5.6% of transplanted non-diabetics given steroids and 2.4% of those not given steroids; only 25 patients were normotensive 1 year after transplantation using the strict criteria indicated above (six of them on steroids). During the observation time ischaemic heart disease occurred in 25 patients, 11 of whom had an acute myocardial infarction or a revascularization (seven had been on steroids for some time), cerebral insults occurred in 15 patients (three had been given steroids) and symptoms of lower extremity ischaemia were present in 17 patients with no amputations (five had been on steroids).



   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
Steroid avoidance after renal transplantation has been the aim at our centre for many years and we therefore consider it important to report our experiences good and bad, now that this approach is having a revival, and long-term randomized studies on new drug combinations unfortunately are not available. Some changes in our regimen have been made over the years, and we now tend to tailor immunosuppression to the individual patient. Our results show that steroid-free immunosuppression is feasible and allows good graft survival in the long-term and a low rate of rejection. Steroid avoidance was the standard not only in low-risk patients [15], but also in those undergoing their second or more transplantation [11,13], if their native kidney disease was not steroid-dependent. As suggested by Vidhun and Sarwal [14], steroid avoidance is also achievable in children, who benefit most from growing and looking like their friends. The indication that graft function may actually be improved in a steroid-free protocol may be attributable to improved compliance [14], as non-compliance is responsible for both acute and chronic rejection and graft loss—especially in teenagers. It is to be hoped that studies in progress [9,13,14] will clarify whether steroid avoidance can produce results comparable with, or even better than, standard triple therapy.

The previous, somewhat high frequency of PTLD [21,22], has caused concern, and we have found it necessary to report the long-term risk of lymphoma in a patient group treated with both antilymphocyte therapy and a rather high dose of calcineurin inhibitor without MMF over the period of 1990–95, where graft survival was also inferior to the present results. During this time OKT3 was used for all rejections and antilymphocyte therapy was given for 10 full days. We believe that introduction of MMF creates a more balanced immunosuppression, as both B- and T-cells are suppressed, and the introduction of MMF was probably the main factor in the prevention of PTLD [21,22]. We now give calcineurin inhibitor doses comparable with those used in standard regimens, and apparently Vidhun and Sarwal [14] have reduced them even further, except for the during months immediately following the transplantation. The previous high incidence of PTLD and the desire for treatment with the fewest side effects led us to use basiliximab instead of thymoglobuline for most patients, to reduce the total dose of thymoglobulin given, to reduce the levels of CsA aimed at, and only rarely use OKT3. This caused some increase in the rejection rate, but our results seem to be improving and the PTLD rate is now low. We chose to treat and include some borderline rejections (23% of our rejections), which, it seems, most reports fail to do [7,8,10,14].

It may be feasible to replace thymoglobulin by basiliximab for all patients, but thymoglobulin is probably more potent as an inhibitor of rejection [23], as it may inhibit delayed graft function, at least when started pre-operatively, and in theory primary deletion may affect long-term graft survival favourably owing to some tolerance induction. According to Khwaja et al. [11], thymoglobulin in exactly the same doses as ours together with prednisolone for 5 days seems to be associated with low rejection rates (6% during the first year) and a graft survival of 93% at 3 years. At least for higher risk patients, such as recipients of transplants with six mismatches, induction with thymoglobulin rather than basiliximab is probably an advantage. In any case, induction may, in our opinion, be desirable, if steroids are to be avoided.

The initial addition of MMF to a steroid-free regimen may reduce the need for steroids without raising a high risk of infections or gastrointestinal distress. Vanrenterghem et al. [8] randomized 833 patients to three different regimens. After an initial 3 months with tacrolimus, MMF and steroids, one group continued with tacrolimus and MMF, one with tacrolimus and steroids and the control group with all three drugs. Preliminary results from that study suggest that MMF is responsible for some increased tendency to infections as is azathioprine in the work of Ponticelli [5]. Our present data and previous reports [16,21,22] seem to suggest that the risk of PTLD is reduced when MMF is added to CsA as long-term immunosuppression, but bias due to regression towards the mean and observation time are obvious pitfalls, and one short-term [13] and one long-term report [5] indicate good results with only CsA monotherapy in lower doses than those formerly used in our centre.

Replacing CsA by tacrolimus in a steroid-free regimen may be an advantage with regard the rejection rate and graft function [9,14], although this has not been confirmed in a randomized study, except possibly in children [24]. Rostaing et al. [9] studied the side effect of a new onset of insulin-dependent diabetes mellitus (IDDM) within 6 months post-transplant, and it was as low as 0.4% when tacrolimus was used without steroids as compared with a rate of 5.4% when tacrolimus was used together with corticosteroids. Steroid-free regimens reduce post-transplant DM including NIDDM markedly, as also suggested by our results, and this is expected to improve quality of life and long-term patient and graft survival.

Some recent large, double-blind, randomized trials of late steroid withdrawal with concomitant maintenance therapy CsA consisting of [6,7] together with MMF, demonstrated that the physician must be alert to the risk of rejection when withdrawing steroids, and frequent control is called for if steroids are to be withdrawn, which most patients desire, and which is possible in our experience in most cases about a year after a rejection. Recently, most have favoured immunosuppression regimens in which steroids are withdrawn very early after transplantation [10,11] or completely avoided [13–15]. Acute rejection in patients with short-term exposure to or avoidance of steroids occurs early after transplantation, when renal allograft recipients are monitored closely and frequently. The exercise of caution is strongly advocated by most clinicians when steroid-free regimens are directed in clinical practice instead of in trials, where patients are rigorously followed. However, our data analysis from which no patient has been excluded indicates that transplantation without steroids is indeed possible in most patients, although long-term randomized studies will still be needed in light of previous disappointing results in some studies [3,4], but not in all [5,25]. Another issue of significance is whether or not rejections can be treated solely with intravenous pulses of methylprednisolone without steroid maintenance therapy, as used by Rostaing et al. [9], or whether the maintenance we used for a year is preferable. At least during half the study year, Rostaing et al. [9] did not seem to have problems with recurrent rejection or steroid-resistant rejection compared with the findings in the control group given triple therapy as maintenance. Ponticelli et al. [5], whose graft functions in the CsA monotherapy group were as good as those in the groups given steroids after 7 years, used the approach of continuing steroids after a second rejection, but their patients were at low risk.

The mortality during our study was not very high, and it is possible that steroid avoidance and minimization reduced the risk of cardiovascular death, which is believed to be the leading cause of death with a functioning graft [26], although the acceptance of patients for transplantation may also have affected our results. Our transplant patients were not much younger nor did they have less diabetes than corresponding non-American populations—actually we performed more transplants for the second time or more compared with the average.

The definition of CMV disease may differ. As severe CMV disease has not been a problem, we have continued to use acyclovir prophylaxis in most cases as described. This has few side effects and is inexpensive, but with standard immunosuppressive protocols, which include steroids, a greater use of gancyclovir is recommended [27].

Steroids are not as expensive as most other immunosuppressive drugs, but it has been estimated that costs of side effects may be considerable [28]. Moreover, avoidance of steroids reduces the calcineurin inhibitor dose needed to maintain the required drug level, owing to the induction of the calcineurin inhibitor metabolism by corticosteroids [8,9]. In children, growth will accelerate after transplantation if steroids can be avoided, and the distress and the expense of growth hormones could be avoided [18].

Starting patients on a steroid-free regimen and adding steroids only when needed is feasible in most renal transplant patients, and may improve the quality of life and survival, without reducing long-term graft survival in a normal renal transplant population. Observation for late PTLD development is necessary.



   Acknowledgments
 
Some of the data reported were supplied by the Danish Renal Registry. We thank Marian Lund, Jette Hansen, Ann Ø. Hofstedt and Susanne Hansen for their kind assistance in the data collection. Astellas is thanked for a grant supplied for data collection.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant 2004; 4: 1289–1295[CrossRef][ISI][Medline]
  2. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000; 342: 605–612[Abstract/Free Full Text]
  3. Sinclair NR. Low-dose steroid therapy in cyclosporine-treated renal transplant recipients with well-functioning grafts. The Canadian Multicentre Transplant Study Group. CMAJ 1992; 147: 645–657[Abstract]
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Received for publication: 26. 2.06
Accepted in revised form: 28. 2.06


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