|Year : 2017 | Volume
| Issue : 2 | Page : 43-51
Corticosteroid in kidney transplant immunotherapy: rid off the giant
Rotimi Oluyombo1, Bridson M Julie2, Ajay Sharma3, Ahmed Halawa4
1 Renal Unit, Department of Medicine, Federal Teaching Hospital, Ido-Ekiti, Ekiti State; Institute of Medical Sciences, University of Liverpool, Liverpool, Nigeria
2 Institute of Medical Sciences, University of Liverpool, Liverpool, UK
3 Institute of Medical Sciences, University of Liverpool, Liverpool; Royal Liverpool University Hospitals, University of Liverpool, Liverpool, UK
4 Institute of Medical Sciences, University of Liverpool, Liverpool; Renal Unit, Sheffield Teaching Hospitals, University of Sheffield, Sheffield, UK
|Date of Submission||18-Dec-2016|
|Date of Acceptance||13-Aug-2017|
|Date of Web Publication||21-Sep-2017|
Renal Unit, Sheffield Teaching Hospital, University of Sheffield, Sheffield
Source of Support: None, Conflict of Interest: None
Corticosteroid use to prevent rejection is ancient but pivotal in transplant immunotherapy. Its benefits are worrisomely being negated by its numerous side effects that affect the quality of life and add to the cost of treatment among transplant patients. The past three decades has witnessed an important dynamism with the advent of many other immunosuppressive agents in various combination protocols, which has led to reports of reduction in episodes of acute rejection. This, in addition to side effects, has raised the question of the need for chronic use of steroid or its avoidance from outset. The benefits of steroid-sparing are compelling especially in low-risk recipients and, recently, paediatric patients. The burden of cardiovascular diseases, the major cause of death in transplant patients, osteopenia and impaired growth among paediatrics confront both patients and their carers. Of concern, however, has been the variation and quality of study designs, which has made the report not only inconsistent but with weak evidence as well. The question still remains whether corticosteroid is disposable. We review corticosteroid use in transplant immunotherapy in the era of improved immunosuppression.
Keywords: avoidance, renal, steroid, transplantation, withdrawal
|How to cite this article:|
Oluyombo R, Julie BM, Sharma A, Halawa A. Corticosteroid in kidney transplant immunotherapy: rid off the giant. J Egypt Soc Nephrol Transplant 2017;17:43-51
|How to cite this URL:|
Oluyombo R, Julie BM, Sharma A, Halawa A. Corticosteroid in kidney transplant immunotherapy: rid off the giant. J Egypt Soc Nephrol Transplant [serial online] 2017 [cited 2018 Sep 22];17:43-51. Available from: http://www.jesnt.eg.net/text.asp?2017/17/2/43/215225
| Introduction|| |
The history of transplantation in the previous half of a century is one that cannot be told without mentioning the landmark discovery of the successful use of corticosteroid. Although not the first in the series, Benzol was reported as the first chemical immunosuppression to be tried around the latter part of 1920s, and no significant success was noted . Rupert Billingham in 1953 reported a success of the use of cortisone to treat skin homograft in rodents , but 2 years later this was not successful when used in dogs by Dempster .
Hume et al.  in Boston, between 1951 and 1953, reported the longest ‘serving’ human kidney graft, which only survived for 5.5 months with the use of steroid. The naivety of surgery might have contributed to this short life of the graft. Confronted with this frustration, the hope of organ transplant in humans was gloomy but expectedly rekindled following the report of the experience of one of the conference attendees. Much confidence was exhumed when in 1963 during a conference in Washington a relatively unknown Starzl  dazzled the attendees with a report that almost two-thirds of his patients’ grafts were still functioning at the end of 1 year based on a steroid-based immunosuppressive protocol used in the treatment. This was in contrast to the miserable 10% graft survival over 3 months among those treated with total body irradiation and 6-mercaptopurine or azathioprine in the reports of others . Therefore, since over three decades ago, kidney transplantation was recognized as the main and better treatment modality for end-stage kidney failure. This did not happen until the landmark discovery of steroid as an immunosuppressive agent.
Mechanisms of action
Since the time of discovery of corticosteroid as a wonder drug in Starzl protocol, it has become a pivot around which other immunotherapies swing for close to five decades. There has been a considerable development in transplant immunotherapy with many other medications coming on board, but it has most of the time been an addition to steroid therapy. The mechanism of action of corticosteroid, despite being in use for ages, remains incompletely understood. It is, however, an established fact that it influences significantly the movement of lymphocytes towards the site of inflammation, a tenet that was first propounded by the scientists at the Rockfeller Institute around 1920s. Lymphocytes, especially the CD4+ cells, are prevented from leaving the reticuloendothelial system. Corticosteroid also blocks the activation, multiplication and activities of macrophages by preventing the production of cytokines such as interleukin (IL)-1, IL-2, IL-6, tumour necrosis factor and interferon-γ. It disrupts antigen presentation of macrophages, dendritic cells and monocytes and reduces the traffic and vascular endothelial adhesion of leucocytes. These activities are achieved by corticosteroid, as it binds to the cytoplasmic receptors being hydrophobic and then moves into the nucleus where it complexes with DNA to form glucocorticoid response elements that block the transcription of cytokines genes.
The transcription factors (activating protein-1 and nuclear factor-кB) are therefore inhibited and prevented from binding to кB regions on the proinflammatory genes by corticosteroid .
In essence, corticosteroid is able to block both antibody-mediated and cellular immune responses, making its effects multidimensional as in [Figure 1], unlike the other immunosuppressive therapies (calcineurin inhibitors, mammalian target of rapamycin inhibitors and antimetabolites), which have specific roles leaving the others untouched with a risk of rejection. It is therefore not a surprise why corticosteroid has been indispensable in the induction, maintenance and treatment of acute rejection episodes. For instance, it is used by many transplant teams as the first-line medication for acute rejection with a success rate for the first episode of acute cellular rejection as high as 70% .
|Figure 1 Showing multiple blocking sites of corticosteroid (extracted from )|
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Rationale for minimization
Corticosteroid is paramount in transplant immunotherapy, but its benefits are worrisomely being negated by its numerous side effects that affect the quality of life and add to the cost of treatment among transplant patients. Prasad et al.  reported attitudes of kidney recipients towards steroid therapy. Just about 10% would prefer to have steroid as the only medication, whereas almost 70% would like to do away with it. On the Likert scale, side effects associated with steroid were scored as high as 6.1±3. The move to reduce corticosteroid dose started in the early 1980s. Interestingly, development of each new and stronger immunotherapy spurs the need to rationalize the use of corticosteroid driving by the undesirable side effects in both adults and children. Death among kidney transplant recipients with a functioning graft at the time of death is associated with cardiovascular diseases in up to 40% of the cases . In addition, about 60% of deaths after kidney transplant are directly related to cardiovascular deaths ,. In terms of chronic loss of allograft, contributing factors are hypertension, hyperlipidaemia and infection from cytomegalovirus and polyoma virus, which are also associated with steroid use. Other known side effects are weight gain with cushingoid facies, cataracts, myopathy, osteopenia, poor wound healing particularly among obese and among children impaired growth. New-onset diabetes after transplantation (NODAT) has increased risks of morbidity and mortality, which are associated with infections and increased odds of cardiovascular diseases. Its incidence as compared with few decades ago has significantly reduced, but it is not completely eliminated. A major contributor to this condition is the corticosteroid. Higher and longer doses of steroid increase the risk of NODAT. Although it is arguable that corticosteroid is not the only therapy that is associated with occurrence of NODAT, it is very essential and desirable to reduce as much risks as possible, and consideration for steroid minimization or withdrawal would be a positive step. Veenstra et al.  estimated the cost of steroid-related side effects in a cohort of 50 patients to be $5300 in a year for each transplant patient. Hypertension was the most expensive to manage as a complication of steroid. The cost of treatment related to poor compliance or noncompliance as a result of adverse effects of steroid was not included in their estimation. Judging from patients’ undesirable experiences with steroid and the concern of transplant community (surgeons and physicians) ([Table 1] and [Figure 2]), in a preconference survey conducted in 1998 more than two-thirds of practitioners answered ‘yes’ when asked whether steroid-free immunosuppressant is a goal, and a majority of them were ready to accept an incremental risk of acute rejection of around 10% with steroid withdrawal over continued use of steroid .
|Table 1 Side effects and incidence of complications of corticosteroid therapy|
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|Figure 2 Bar charts showing the response of Transplant practitioners to whether steroid-free immunosuppression should be a goal. Extracted from Hricik |
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The other reason why steroid-free or withdrawal is being strongly contemplated is the fact there are now better immunosuppressive therapies for improving patient and graft survival. The belief is that with these myriad of side effects from steroid the combined immunosuppressive effects of these other medications should be sufficient to protect patients from acute rejection and give comparable outcome, such as the use of steroid. The goal of steroid minimization therefore is to completely remove or reduce its side effects without having to compromise graft or patient survival, which could result from acute rejection and/or loss due to chronic allograft nephropathy. In spite of the mixed feelings from the various reports on the avoidance or withdrawal of steroid, there has been a continuous rise in the practice since the late 1990s, with more patients being discharged with steroid withdrawal  or avoidance ([Figure 3]) .
|Figure 3 Showing the incidence of steroid-free therapy at discharge and recommencement of steroid at 6 months and 1 year. Extracted from Schold et al. |
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Challenges in steroid minimization
Of concern has been the variation and quality of study designs, which has made the report not only inconsistent but with weak evidence as well. In addition, of note is the duration and power of most studies, timing of withdrawal of steroid, immunological risk and the end point of the studies. As attractive as steroid-sparing approach appears, the initial attempts were not too impressive . In a Canadian study reported by Sinclair , there was no difference in the short-term outcome, but there was an increased graft loss among those on cyclosporine (CsA) compared with those on a combination of steroid and CsA. The legacy of this study is in it being one of the earliest randomized studies and a long-term follow-up of patients, which has been difficult to attain by many other studies in this era of multiple and better immunosuppressive agents probably because of the cost of executing such a prospective, randomized study. It would be rhetorical to say that the use of CsA monotherapy is responsible for the difference in graft survival. The success in outcomes of transplant today in terms of graft and patient survival is a combination of immunosuppressive agents . However, the study stressed the importance of corticosteroid in transplant immunotherapy.
In a randomized multicentre, open-labelled trial conducted by Vincenti et al. , the goals of achieving noninferior outcomes within 12 months is established within the intention-to-treat group but not among actual case analysis with significantly higher episodes of acute rejection than the control groups (36 vs. 29.6%, P<0.05). The three-arm study of Vitko et al.  similarly showed significantly lower episodes of acute rejections (8.2%) among those with standard therapy than 30.5% in trial drugs without steroid .
Pascual et al. , in a systematic review of 30 randomized trials, reported that there was no benefit in graft preservation and mortality; instead, there was increased odds of acute rejection [odds ratio (OR) 1.23] and graft loss (OR 1.27) among cohorts with any type of steroid-sparing protocol than those who had steroid. A similar report was given by this team in 2012 ([Figure 4]a and [Figure 4]b) with higher odds of acute rejection if CsA (OR 1.57) and not tacrolimus (TAC) (OR 1.06) was used with early withdrawal of steroid . This is in spite of induction therapy with either lymphocyte-depleting (antithymocyte globulin) or nondepleting (IL-2 receptor antibody) agents.
|Figure 4 (a) Forest plot for graft loss and death (extracted from ). (b) Forest plot for acute rejection in the systematic review |
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However, the European multicentre, double-blind randomized controlled trial did not show any significant difference in acute rejection among cohorts who were induced with IL-2 antibodies.
Regarding immunological risk of the patients, a study conducted in the US showed an increased risk of rejection among Blacks (30.8 vs. 9.8%, P<0.05) than among non-Blacks . This study and those of others have supported the notion that inclusion of steroid and its late stoppage should be reserved for high-risk recipients . Interestingly, steroid withdrawal or avoidance has been successfully used in paediatrics with both early and late steroid withdrawal being in protocol and practiced. The other high-risk groups who pose problems with steroid-sparing protocols are those with retransplant and the highly sensitized.
The other important concern in steroid minimization is the timing of withdrawal. There are reports that the initial loading dosages of steroid would have initiated damage, which would be difficult to correct even after it has been stopped . Moreover, the low dose used in maintenance has been shown to be of similar effect. It has also been reported in rodents that steroid blunts immune tolerance as it prevents T-cell signals, which eventually results in apoptosis. It is therefore suggested that for complete benefit of steroid sparing to be achieved total avoidance of steroid therapy is better. This seems a herculean task as it may not be applicable to recipients in the high-risk group . Last, the cost benefit of treatment of cardiovascular diseases has been questioned. Cost analysis of corticosteroid side effects attributed so much to hypertension, diabetes and dyslipidaemia as part of increased risk associated with the use of steroid. Lemieux et al.  and Prascual et al. , however, expressed uncertainty regarding benefits of cardiovascular diseases when steroid is withdrawn or avoided compared with steroid continuation. Many studies have, however, reported the cardiovascular benefits of steroid-sparing immunotherapy as it reduces total and low density lipoprotein cholesterol. However, it also concomitantly reduces high-density lipoprotein cholesterol . This should caution the transplant community not to rush to dispose of steroid at the expense of patient and graft loss owing to increased risk of rejection and smouldering chronic allograft loss.
The benefits of steroid sparing are, however, compelling. Paediatric patients would be relieved of impaired growth, the undesirable and heavily burdened cardiovascular risk factors and diseases; the most common cause of death among transplant recipients would be reduced and the cardiovascular-unrelated complications would positively influence the goal of achieving better compliance with improved graft and patient outcomes. The dynamism in transplant immunotherapy from one era to another and the change in tactics from monotherapy to combination immunotherapy have contributed to the achievement so far in steroid sparing. In 1994, in what seems to be one of the earliest successful reports, Opelz  hinted that steroid-free therapy is a possibility, although, in his study, steroid was withdrawn after 6 months and a higher dose of potent immunosuppressive agents was used.
Pushing this further, in view of reports of increased risk of acute rejections  with late steroid withdrawal, various groups have considered the options of rapid withdrawal or total avoidance of corticosteroid. With the introduction of other induction agents such as calcineurin and mTOR inhibitors, there were some improvements in the acute rejection episodes among those who had steroid withdrawal when compared with those who continued. The incidence of biopsy-proven acute rejections, graft survival and patient survival after 3 years of study were comparable in a multicentre, randomized controlled study from Spain . The group also reported improved cardiovascular profile among those who had TAC and mycophenolatemofetil (MMF) but had steroid withdrawn after 3 months as compared with those who had conventional triple therapy. The evidence is not limited to this particular combination, as CsA-based ,, azathioprine  and mTOR inhibitors (e.g. sirolimus)  have also shown no increased risk of acute rejection but comparable short-term and long-term survival especially among low-risk recipients .
Short-term duration (<7 days) of steroid therapy or total elimination of steroid is a plausible idea. This is to further reduce the side effects and avoid the possible tolerogenic effect of steroid. The use of additional stronger induction agents could also have engendered this attempt. Matas et al.  studied over 1000 patients and reported excellent outcomes in what was termed rapid discontinuation of steroid. Other groups have also reported good outcome. Rizzari et al.  reported that 10-year actuarial survival of patients was 71 and 62% for living and cadaveric donation, respectively, whereas graft survival was 61 and 51%, respectively. These figures were comparable to the conventional group. Worrisome though is the increased risk of acute rejection events, which was reported not to have effects on the outcomes of the patients and grafts in the long term. All the studied patients were first-time kidney recipients and had thymoglobulin as induction agents. Eighty-four kidney recipients stopped steroid on the sixth day after transplant in a study by Jaber et al. . Only 11% had acute rejection episodes and this graft was comparable to the historical group. Patient survival was, however, better than that in the historical group. Basiliximab was used as an induction agent in the study conducted by Kumar et al. . Steroid was withdrawn 2 days after transplant. Episodes of acute rejection (14 vs. 16%), biopsy-proven acute rejection and progression of allograft nephropathy, graft and patient survival were comparable. Gotti et al.  considered which of the immunosuppressants could easily be done without. Interestingly, withdrawal of steroid did not show any severe histological picture, but discontinuation of CsA A led to acute rejection, a condition that was not seen in steroid withdrawal. Another group from France , in a randomized trial, reported that the use of IL-2 antibody receptor with early commencement of CNI combined with MMF resulted in a noninferior outcome. Laftavi et al.  in a randomized trial of steroid-free and conventional therapy with the use of thyroglobulin for induction showed severe fibrosis in the cohort without steroid at all. Whether short-term steroid should be sustained to prevent allograft nephropathy remains to be clarified based on the report of these last two groups. However, further large studies would need to be conducted to confirm this effect.
Birkeland in 1998 challenged the transplant community when he pioneered a steroid-free transplant immunotherapy. The conclusion was that steroid-free immunosuppression offers growth benefits to paediatric patients and that its effect is noninferior in acute rejections and long-term outcomes when compared with rapid stoppage of steroid therapy ,. In the Atlas More Details study, one of the main randomized multicentre trials from Europe, after the work of Birkeland, the importance of combined use of antibody induction therapy in combination with other immunosuppressant in maintenance stage was stressed to be beneficial and that it may allow safe use of steroid-free protocol.
Vanrenterghem et al.  reported similar occurrence of acute rejections among three groups of patients randomized to TAC, steroid and MMF group, no steroid group and no MMF group (17.0 vs. 15.1 vs. 14.8%, P=0.744) Lower total cholesterol and low density lipoprotein cholesterol was also reported. The study was only for 6 months. The INFINITY study recently published from France showed no significant difference in subclinical rejection, renal function, proteinuria and adverse events . The author therefore questioned the necessity for the use of steroid in low-risk kidney transplantation.
High risk groups
Most of the steroid-sparing studies have been conducted among low-risk recipients and less among recipients with moderate risk, with little information in high-risk recipients. In fact, the practice is the use of chronic steroid therapy among this cohort. Kumar et al.  demonstrated that African Americans developed significantly lower kidney function, subclinical acute rejection and chronic allograft nephropathy following discontinuation of steroid; however, the 5-year graft survival is not inferior to non-African-Americans. The question is whether the acute rejection events are different from those on steroid. Other factors to consider as high risk are shown in [Figure 4]. In a large retrospective national registry database conducted in US where about 85 000 solitary kidney transplants were reviewed over 7 years, being an African American, previous transplants and high panel reactive antibodie (PRA) were associated with recommencement of steroid . In another retrospective study of 40 African-American patients, Haririan et al.  reported earlier in a study conducted among African Americans that there is no difference in episodes of acute rejection among those maintained on steroid and those who had steroid withdrawn after the fourth day. It is important to note, however, that those maintained on steroids had higher PRAs and retransplants. In this study, both cohorts had high and comparable graft survival rates (97 vs. 100%) at the end of 12 months. Contrary to these favourable findings, Hricik et al.  reported that African Americans have poor outcomes as a result of increased rejections following withdrawal of steroid therapy. Further in support of steroid sparing in high-risk groups, a recent retrospective study from Organ Procurement and Transplant Network/United Network Organ Sharing database showed that steroid therapy among recipients with low PRA is associated with increased risk of death with graft function, whereas a benefit of steroid therapy is observed among cohorts with intermediate or high PRA .
Among paediatric patients, it has also been shown that steroid avoidance or early withdrawal is a possibility with a benefit of improved and sustained growth, cosmetic advantages without compromising graft and patient survival. In a Stanford study looking at paediatric patients with high PRA (>20%) and almost one-thirds having no match, there were no episodes of biopsy-proven acute rejection up to the 12th month post transplant . In a randomized prospective trial from USA , episodes of biopsy-proven acute rejection at 6 and 12 months were comparable. Clinical acute rejection between steroid maintenance (11.4%) and steroid-free therapy (13.3%) at 12 months and 17.1 and 16.7% at 3 years, respectively, are comparable ([Table 2]).
Current and future direction
The past two decades have witnessed significant activities and remarkable improvement in kidney transplant outcomes with acute rejection drastically reduced, although with not much improvement in chronic allograft nephropathy. With the advent of TAC, mycopholate, mTOR inhibitors and later the use of induction agents classified into lymphocyte-depleting (thymoglobulin, alemtuzimab and OKT3) and nondepleting agents (basilixumab and dacluzimab), more protocols on steroid-sparing immunosuppression have emanated from different centres. The various approaches consist of either steroid withdrawal, which could be early or late, or avoidance. The choice by various centres is guided by experience, skills, cost of treatment and/or medications, and immunological and medical risk of recipients.
The Kidney Disease Improving Global Outcome (KDIGO) recommended the use of a biologic agent in combination with other immunosuppressive therapies for induction . In addition, this is to reduce acute rejection and allow the reduction of other agents such as corticosteroid. KDIGO further suggested that maintenance therapy could be with or without steroid and that steroid could be discontinued 7 days post transplant in those with low immunological risks. Canadian practice is slightly different from USA practice. Canadian Society of Transplantation and Nephrology observed that most studies that reported no difference in either steroid avoidance or rapid withdrawal and long-term steroid therapy excluded induction therapy in steroid maintenance arm and could be responsible for the relative increase in the frequency of acute rejection and comparable outcomes . For instance, Vincenti et al.  and Woodle et al.  included induction therapy in the different arms and they both showed increased rates of acute rejection in both steroid-free and withdrawal groups. They also showed increased chronic allograft nephropathy among those whose steroid was withdrawn early and there was no difference in the risk of NODAT. In view of this, Canadian transplant practitioners use steroid for a longer time. However, the work group suggested that steroid therapy should be individualized as they agreed with KDIGO on the rapid minimization of steroid in low immunological risk patients.
European Renal Association  and National Institute of Clinical Excellence guidelines are expectedly similar and not particularly different from KDIGO. The suggestion was that in case steroid has to be used for more than 1 month, the dose should be minimal as 5 mg or less daily. In Nigeria, our protocol is a fallout from KDIGO as healthcare services are predominantly out-of-pocket. We recently started including IL-2 antibody in our induction therapy and we have no experience with steroid-free immunosuppression regimen . However, in Leicester UK, patients have induction therapy with IL-2 antibody basiliximab in addition to CNI (TAC except in high risk for Diabetes) and MMF. Steroid is then tapered off biweekly until the sixth week when the patient would take 5 mg daily. Patients are usually maintained on 5 mg daily unless there are concerns of excessive weight gain, osteoporosis or poor diabetic control. It would be reasonable to audit our protocol, and this would form a basis for improvement on our practice and until then it would be impossible to make any recommendations.
From the evidence available, there are still many questions begging for answers regarding steroid-free therapy or its rapid discontinuation. As mentioned earlier, the design of studies and sample size has been a great limitation. The noninclusion of high-risk recipients in most studies is another concern. In view of these shortcomings, while the search for more convincing evidence continues, it appears that most recipients would still benefit from low dose of steroid to achieve better immunosuppression and moderate the effects of calcineurin inhibitors and better outcomes.
| Conclusion|| |
The number of patients requiring transplant continues to increase. The few available organs for transplantation should be protected for patients to enjoy the gains of transplantation. Achieving tolerance through immunosuppression without steroid is a welcome idea but not at the expense of graft and/or patient loss. There has been a remarkable progress in steroid-sparing immunosuppressive therapy, but better-designed studies should be conducted among medium-risk and high-risk recipients to come up with robust evidence to prolong the life span of the patients and deliver unto them improved quality of life.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]