Steroid Minimization Protocols: A Nigerian Perspective

Steroids refer to a broad group of endogenous biochemical substances which are produced by the endocrine glands: adrenals, ovaries and testes [1,2]. The steroids of clinical importance in the realm of solid organ transplantation are the glucocorticoids [1]. The utility of steroids in solid organ transplantation dates as far back as the fifties (1950s) when experimental animal studies demonstrated the potential of these compounds to improve skin graft survival [1,3]. Since then, glucocorticoids have been used in various instances in kidney transplantation due to their potent albeit non-specific immune-modifying effects [4] Steroids have pleiotropic effects on the immune system particularly pertaining to transplant immunosuppression, hence their widespread use [2,4] Within target cells, steroids act by binding to the intra-cytoplasmic glucocorticoid receptors which modulate their effects [2]. Dendritic cells play crucial roles in transplant immunology. Within these cells, steroids down-regulate the production of co-stimulatory molecules, and thereby, reduce their ability to stimulate T and B lymphocytes [2]. Furthermore, steroids inhibit the production of pro-inflammatory cytokines by macrophages, T-cells and neutrophils [2,4] (Figure 1) depicts the diverse anti-inflammatory and modulatory effects of steroids on the immune system [2].

Figure 1: Multiple sites of action of steroids.Adapted from: Liberman AC, Budziñski ML, Sokn C, Gobbini RP, Steininger A, Arzt E. Regulatory and mechanistic actions of glucocorticoids on T and inflammatory cells. Front Endocrinol. 2018; 9(235):1-14.IFN, interferon; IL, interleukin; Th, T helper, Treg, regulatory T cell. 

Despite their numerous beneficial effects, steroids use is certainly not without a myriad of adverse effects that limit their efficacy [3,4 ]. These side effects include systemic hypertension, diabetes mellitus, obesity, poor wound healing, dyslipidaemia, susceptibility to infections, cardiovascular disease and skeletal abnormalities (osteoporosis, fractures and avascular necrosis of the long bones), all of which are already prevalent in the kidney transplant recipient [4,5]. These adverse effects are not only deleterious to the patients, they also enhance drug non-adherence, leading to increased rejection episodes and eventual graft dysfunction and/or loss [4,5]. In addition, they exert an economic impact; it was estimated by Veenstra et al. [6] that each transplant recipient spent $5300 (1996 United States dollars) on the management of steroid side effects each year, an estimate which would certainly be higher now, over two decades later [6]. Hence, the advent of steroid withdrawal or minimization protocols to improve patients’ clinical safety [3,4,5,7].

In the late 20^th century, it was possible to achieve steroid minimization or withdrawal following the introduction of calcineurin inhibitors, cyclosporine and tacrolimus. Since then, many protocols or regimens have been introduced with varying results and outcomes [7] Griffin et al.,[8] in one of the earliest reports on steroid minimization, conducted a randomized controlled trial comparing cyclosporine monotherapy (15-17mg/kg/day) with cyclosporine and low dose steroids (0.3mg/kg/day) over a follow-up period of 1-3 years. This study reported comparable patient and graft survival between the two groups, however, over 50% of the monotherapy arm required steroids due to higher acute rejection rates. On the other hand, the patients in the cyclosporine monotherapy group had lesser incidence of infectious and cosmetic complications [8]. In spite of the increased risk of acute rejection, the researchers concluded that there was no added advantage that low-dose steroids conferred to kidney transplant recipients in the combination therapy arm [8]. 

Similar findings were reported in another study evaluating the safety of early steroid withdrawal (within 1-2 weeks of transplant) versus continuous steroid maintenance in a small cohort of 67 kidney transplant recipients [9]. Although, this study had a small sample size, it was conclusively demonstrated that patients who had early steroid withdrawal had more frequent rejections (81.3% vs 54.3%; p value = 0.02) and more severe acute graft rejections (p value <0.01) with earlier onset than those who were maintained on steroids, and these differences were statistically significant [9]. At the turn of the 21^st century, several systematic reviews on the early attempts at steroid minimization in kidney transplant recipients revealed an increased relative risk of graft failure (up to 40%) and a 14% increased risk of rejection with no significant adverse impact on graft or patient survival [10,11]. These discouraging results led to a decline in this particular practice [7]. However, in recent times, there has been a re-emergence of interest in steroid minimization regimens, especially with the advent of newer and more efficacious induction and maintenance immunosuppressive therapies [7,12]. These renewed concerted efforts must, however, strike a balance between minimizing adverse effects of steroid use on one hand, and on the other hand, preventing graft rejection, dysfunction or loss consequent upon steroid withdrawal [13,14]. 

Generally, there appear to be a few unspoken rules when implementing steroid minimization protocols; firstly, selected patients must receive induction therapy usually with interleukin-2 receptor antagonists, alemtuzumab or anti-thymocyte globulin [4,5,12,15]. Although, some studies have reported successes without using induction therapy [16,17]. Secondly, they must be on a maintenance immunosuppression regimen consisting of a calcineurin inhibitor, preferably tacrolimus, mycophenolate mofetil and/or mammalian target of rapamycin inhibitors [5,12,13,15]. In addition, selected recipients should ideally have low immunological risk, that is, unsensitised individuals of non-African descent undergoing a first transplant with negative cross-match and minimal Human Leucocyte Antigen (HLA) mismatches; however, nowadays, steroid minimization has also been conducted in high-risk patients with favourable outcomes [18,19]. Usually, consideration for steroid avoidance and/or withdrawal requires stratification of transplant recipients into: low risk i.e. patients who are more likely to benefit from reduced steroids either due to their low immunological risk or higher likelihood of steroid-associated adverse effects; and high risk i.e. patients who would more likely benefit from continued steroid use. (Table 1) summarizes the risk classification for steroid minimization protocols [4,5,20,21]. 

Table 1: Risk profile for consideration for Steroid minimization. HLA, human leucocyte antigen.*low-risk recipients benefit from steroid minimization protocols^†high risk recipients benefit from steroid maintenance.

There is significant heterogeneity in the definition and practise of steroid minimization protocols globally, especially in regards to the timing of steroid withdrawal, choice of alternative immunosuppressive regimen, patient selection, duration of follow-up and outcomes of interest. Broadly, steroid minimization strategies can be classified into [3-5]: 

1. Steroid-avoidance or steroid-free regimen (also known as rapid discontinuation of prednisolone in some centres): where steroid use is completely avoided or stopped within seven days of transplantation.
2. Early steroid withdrawal regimen: stoppage of steroids after 2 weeks to 3-6 months of transplantation.
3. Delayed or late steroid withdrawal regimen: use of steroids is discontinued from 3-6 months to years after engraftment.
4. Continuous low-dose steroid regimen: rapid tapering of the dose of steroids to the barest minimum, usually 0.05–0.1mg/kg/day, within a few months of kidney transplantation.

A paradigm shift has occurred in the last few years with an increasing rationale for the total avoidance of steroids or its discontinuation within one week of the kidney transplantation and away from later steroid withdrawal [12,15,21].This has the potential of avoiding early drug-related side effects which could occur even after short-term steroid exposure [12,15,21]. The potential benefits of a steroid avoidance protocol was first demonstrated by Birkeland et al. [22] in a mixed cohort of 100 first- and second-time recipients of living and cadaveric kidney grafts over a follow-up period of 54 months. Although, this study was not randomized, it reported a low acute rejection rate of 13% and a high graft survival rate of 82% at 4 years [22] Similarly, Matas et al. [23] reported excellent outcomes of rapid steroid discontinuation (< 7 days) after transplantation in comparison with conventional steroid maintenance therapy [21,23]. In this study, the 4- and 7-year patient survival rates were 92% and 82% respectively, with 4-year acute and chronic rejection-free graft survival rates of 86% and 95% respectively.23 Additionally, graft survival was over 75% after 7 years of follow-up.23 Over 80% of the recipients remained steroid free in the long-term and more significantly, there were notably decreased complication rates compared with historical cohorts on maintenance steroid therapy vis-a-vis post-transplantation diabetes mellitus (p value < 0.001), acute rejection (p value < 0.0004), chronic rejection (p value < 0.02), fractures (p value < 0.04) and cytomegalovirus infection (p value < 0.001) amongst others [21,23]. In another 10-year follow-up study in the United States, 1241 kidney transplant recipients underwent steroid discontinuation on the fifth post-transplant day and were found to have 10-year patient and graft outcomes comparable to United States Scientific Transplant Recipients registry data, with the added benefit of lower risks of cataracts, avascular necrosis of the long bones and post-transplant diabetes mellitus [24]. It should be noted that the reduced rejection rates in these studies were presumably due’ to the higher bioavailability of calcineurin inhibitors and their catabolic products following steroid withdrawal, because steroids induce cytochrome P₄₅₀ [16,25]. 

In the aforementioned studies, the patients received induction therapy as well as calcineurin inhibitor-based maintenance immunosuppressant therapy [21,23,24]. It is, however,  important to highlight that the choice of induction therapy also appears to play a role in the success of steroid avoidance regimens. Woodle et al.[26] reported numerically lower biopsy-proven acute rejection rates with lymphocyte-depleting anti-thymocyte globulin induction compared to interleukin-2 receptor blockers (14.4% vs 24.2%, p value = 0.09) [26]. Steroid avoidance has also been evaluated in some high-risk cohorts such as blacks and recipients of a second transplant with encouraging short- and intermediate-term outcomes [19,26]. Conversely, in a report by Laftavi et al. [27] steroid avoidance (discontinuation at day 7) was associated with significantly higher rates of chronic allograft interstitial fibrosis in surveillance biopsies. However, this study was limited by its small sample size (60 participants) and short follow-up duration (12 months) [27]. Additionally, in the Astellas Corticosteroid Withdrawal study comprising of 386 participants randomised into steroid continuation and early steroid discontinuation (day 7) arms, despite similar kidney function and patient and graft survival rates between the study arms, the steroid discontinuation group had a higher incidence of chronic allograft nephropathy at 5 years and this difference was statistically significant (9.9% vs 4.1%, p value = 0.028), emphasising the need for longer follow-up studies [26]. 

In a recent Cochrane meta-analytical review of 224 reports involving 7803 participants, it was proven that although there were no significant differences in patient and graft outcomes when comparing steroid avoidance with steroid maintenance therapy, transplant recipients who were treated with steroids for less than 2 weeks had significantly elevated risk of acute rejection (RR-1.58, 95% CI 1.08-2.30) [28]. These inferences were, however, blighted  by the small sample sizes, lack of randomization, under-reporting of adverse events and short follow-up periods in some of the individual studies [28]. In light of these contradictory reports, it is therefore difficult to make a conclusive statement on the long-term benefits or harm of this measure.

This protocol can be subdivided into early or late withdrawal [4,5,15]. Whichever the case, there have been conflicting reports on the risks and benefits of this protocol. Many studies have reported an increased risk of acute rejection with late withdrawal of steroids; this is presumably due to the antagonistic effects of steroids on T-lymphocyte structure and function [2,4,12,15]. Long-term use of steroids inhibits the production of pro-inflammatory cytokines by T-cells while simultaneously increasing the expression of said cytokine receptors on other inflammatory cells.2 Hence, delayed steroid withdrawal after initial therapy leads to the release of cytokines into a milieu of up-regulated receptors which could potentially enhance T-cell activation resulting in a rebound of the alloimmune response and graft rejection [4,12,15]. One of the very first major studies to address the feasibility of late steroid withdrawal (greater than 3 months in this case) was the placebo-controlled Canadian Multicentre Transplant trial conducted in the nineties [29]. This study randomized over 500 kidney transplant recipients to receive either cyclosporine with a placebo or cyclosporine in combination with low-dose prednisolone 3 months post-transplantation, and it was found that following initial comparable patient and graft outcomes, at the 5-year mark, the placebo arm had significantly higher incidence of graft loss compared to the steroid arm [29] and while this study has been criticised for its flaws such as the high drop-out rate (at least 50% of the study participants in each group dropped out about 16 months into the study) and suboptimal doses of immunosuppressants, it raised a few concerns regarding the adoptability and long-term safety of delayed steroid withdrawal [29]. 

Likewise, Haller et al. [30] in a retrospective analysis of data from the Austrian Dialysis and Transplant registry spanning a 12-year period, reported that steroid withdrawal within the first 18 months of transplantation was associated with a higher rate of graft loss; patients who had steroid withdrawal within [6,12,18] and 24 months had 1.8, 1.6, 1.3 and 1.2 times increased risk of losing their grafts respectively [30]. Although, discontinuation of steroids after 2 years of transplantation had no impact on graft failure. In this same study, the risk of acute rejection was significantly higher in the steroid withdrawal arm compared to the steroid maintenance arm (17.6% vs 7.2%, p value < 0.001) [30]. Despite its large sample size, this particular study was limited by its retrospective nature and its subjects were predominantly Caucasians; hence its findings may not be generalizable to other populations [30]. In accordance with the above, a recently published meta-analytical review of 10 studies with about 1913 study participants also revealed that steroid withdrawal increased the chances of acute rejection by up to 77% [28]. 

In contrast, a prospective analysis of the Collaborative Transplant Study (CTS) registry indicated that late steroid discontinuation (> 6 months post-transplantation) did not lead to a surge in the incidence of graft rejection; rather, patients who had steroid withdrawal, in comparison with control participants on steroid therapy, had superior outcomes in terms of patient survival (88.8% vs 84.3%, p value = 0.0016), graft survival (81.9% vs 75.3%, p value = 0.0001) and death-censored graft survival (91.8% vs 87.9%, p value = 0.0091) after 7 years of follow-up [31]. In addition, this study also reported improvements in some cardiovascular risk factors; numerically fewer patients in the steroid withdrawal group developed difficult-to-control hypertension (22.1% vs 25.9%, p value = 0.0635), new-onset severe hypercholesterolemia (5.3% vs 8.4%, p value =  0.0078), osteoporosis (13.6% vs 24.3%, p value =  0.002) and cataracts (7.2% vs 13.6%, p value = 0.0092), particularly when steroid withdrawal occurred within the first post-transplant year [31]. The reason for these varying results and outcomes may be the strict patient selection in the CTS trial. Only patients with low immunological risk and stable renal function were considered for steroid withdrawal. In addition, steroids were gradually tapered over a 6-month period, which helped to prevent acute rejection episodes [31]. Of course, like many studies evaluating steroid withdrawal, this study was not randomized and also did not take into account the impact of previous acute rejection episodes on the final results obtained [31]. 

Despite its unrandomized nature, small sample size and short follow-up duration, a study by Hricik et al. [17] demonstrated favourable outcomes with steroid discontinuation at ≥ 3 months post-transplant in African American recipients, a cohort classically described as high-risk [17]. These patients did not receive induction therapy and were maintained on sirolimus-based therapy [17]. The incidence of acute rejection at just over a year was low (6.7%) with the added benefits of better blood pressure and lipid control. Several other studies have reported similar findings [32-34].

This is achieved by rapidly tapering prednisolone to 5mg daily within the first few weeks to 6 months of transplantation [4,26]. This is perhaps the most prevalent practise [4,5]. Many clinicians advocate this protocol, citing studies which have reported reduced acute rejection rates and reduced incidence of chronic allograft nephropathy and graft loss when compared with steroid-free protocols [26,28,29]. In addition, it has been proposed that low-dose prednisolone i.e. ≤ 5mg daily does not result in supra-physiological serum levels of steroids which are responsible for steroid-associated side effects [4].  A number of publications reported no significant differences in the incidence of steroid-related adverse effects such as post-transplantation diabetes mellitus, dyslipidaemia, severe infections, hypertension and cardiovascular mortality amongst patients on steroid minimization versus maintenance prednisolone therapy [26,28,33,35,36]. 

Another argument and rationale for continued low-dose prednisolone therapy is the treatment and prevention of further episodes of acute rejection in patients initially on steroid avoidance regimens. It has been shown that such patients are more likely to develop a second episode of graft rejection if they return to a steroid-free regimen, hence they are best treated and placed on maintenance prednisolone at 5mg daily [37]. Conversely, other studies have reported significantly higher rates of adverse effects and complications with the continued use of steroids [24,26]. In another study, van den Ham et al. [38] demonstrated that long-term use of low-dose steroids (5 mg daily of prednisolone) was significantly associated with weight gain after the first year of transplantation. It was believed that the cumulative dose of steroids was majorly responsible for this effect [38]. Moreover, in a study evaluating the ocular complications of steroid use in transplant patients, it was reported that incremental doses of prednisolone were associated with increasing risk of cataracts. The incidence of cataracts was 55.3%, 28.2% and 6.2% in patients on high-dose steroids, low-dose steroids and steroid-free immunosuppression respectively [39]. 

These differing reports underscore the need for large, long-term studies that compare continued use of low-dose steroids (following a rapid taper) with other steroid minimization strategies to truly evaluate the impact, if any, on patient and/or graft outcomes while taking into account different ethnic groups and immunological risk strata. A summary of the criteria and findings of some of the research conducted on the different steroid minimization strategies is outlined in (tables 2A & 2B). 

Table 2A: Summary of Steroid Minimization Trials. AZA, Azathioprine, CsA, Cyclosporine A; ECMPS, Enteric-coated Mycophenolate Sodium; MMF, Mycophenolate Mofetil; rALG, Rabbit Anti-Lymphocyte Globulin. 

Table 2B: Summary of Steroid Minimization Trials (continuation). RCT, Randomized Controlled Trial. *Paediatric Population.

Nigeria is comprised, predominantly of the black race, which has been categorised as having high immunological risk in the field of kidney transplantation [4,12,15,17]. This is due to a number of factors such as disproportionately high incidence of hypertensive nephropathy, apoliprotein-1 (APOL-1) polymorphisms, higher incidence of delayed graft function, higher degree of HLA polymorphisms and mismatches, increased immune reactivity and higher degree of genetic polymorphisms in the cytochrome P450 enzyme system (CYP3A4/5) leading to differences in immunosuppressant metabolism and requirements [46-49]. For these reasons, steroid minimization protocols are not well adopted. Another limitation to the use of steroid minimization is low resources (Nigeria is a low-middle income country with non-equitable distribution of resources). In addition, steroids are the most readily available and affordable immunosuppressive drugs and the concomitant high cost of alternative immunosuppressants makes steroids one of the most widely utilized medication in our setting. Easily accessible and affordable dialysis facilities are not available to everyone, hence, this limitation plays on the minds of clinicians should an allograft fail.  Lastly, protocol biopsies are not yet routine and the turn-around time on biopsy reports is long; this may make it difficult to monitor the efficacy of steroid minimization regimens as well as detect potential harms if present. 

Moreover,  unpublished guidelines by the Nigerian Association of Nephrology do not include a standardized protocol for steroid avoidance or withdrawal in renal transplantation; rather, it proposes an immunosuppression protocol for all kidney transplant recipients which includes induction therapy with thymoglobulin, basiliximab or alemtuzumab (depending on the immunological risk of the recipient, though thymoglobulin is predominantly used as it is more readily available) and two (2) doses of intravenous methylprednisolone (500mg), the first of which is given preoperatively and the second just after the release of clamps intraoperatively. Subsequently, the patient is commenced on a triple regimen composed of: mycophenolate derivatives, tacrolimus and oral prednisolone. Oral prednisolone is commenced at 40mg daily initially for the first week. This dose is reduced by 10mg weekly until the patient is maintained on 10mg daily which he/she remains on for a year. In subsequent years, the steroid dose is reduced to 5-7.5mg daily and maintained indefinitely. Renal transplantation in Nigeria is largely driven by privately owned health facilities. Two leading transplant centres in the country; Zenith Medical and Kidney Centre and Saint Nicholas Hospital, follow the aforementioned protocol with minimal variations based on the centre experience. Clinicians at both these centres do not routinely adopt either steroid avoidance or withdrawal (Faponle AE, Adelaja A. personal communication, January 2021). Rather, steroid minimization is done on a case-by-case basis in the presence of striking indications. 

We have had a few cases of patients with diabetic nephropathy who developed hyperglycaemic emergencies shortly after transplantation (usually in the first 1-3 weeks of the post-transplant period); these patients had the maintenance oral prednisolone rapidly tapered to 5mg by the end of the third week in addition to insulin therapy to attain glycaemic control. And while tacrolimus has been implicated in post-transplantation hyperglycaemia, the therapeutic levels in the affected patients were within the desired range and it was deemed more important to maintain tacrolimus at therapeutic levels at this point when maximum immunosuppression was required to prevent early acute rejection. This practise of low-dose maintenance steroids is similar to that followed by the East Coast Renal Services in Australia [4,50]. Although, in their centre, steroid minimization is a forethought rather than afterthought, based on careful risk stratification and appropriate patient selection [50]. A centre in the Kingdom of Saudi Arabia also has a similar protocol whereby prednisolone is reduced to 5mg within 2 months of the kidney transplant [4]. In their centre, patients are also stratified based on their immunological risks, they all receive induction therapy and all except those with very minimal risks are maintained on low-dose steroids. Those with low immunological risks such as recipient-donor pairs that are identical twins or those with no HLA mismatches undergo early steroid withdrawal [4]. 

We have also had experience with steroid avoidance in 2 patients who had post-operative organic psychosis which was attributed to the pulsed methyl-prednisolone. These patients developed irrational talk, confusion, agitation and restlessness on the second to third day of transplantation. Steroids were completely withdrawn, and they had parenteral midazolam with subsequent resolution of symptoms. These patients were not recommenced on steroids. One subsequently developed acute cellular rejection within 3 months of the transplant and was successfully managed with anti-thymocyte globulin and lower doses of methylprednisolone. He was subsequently placed on 10 mg daily of oral prednisolone with no recurrence of steroid-induced psychosis. The other patient gradually developed features of graft dysfunction (rising serum creatinine) about 18 months post-transplant with serum creatinine hovering between 180µmol/L and 230µmol/L for the past 6 months. In light of these experiences with steroid usage following transplant, it’s important for other transplant centres to bear in mind that it may be necessary to change their own protocols based on contingencies. It is rational to advocate for the future institution of steroid minimization regimens in select patients in individual centres in Nigeria, but this would require evidential support from well-designed randomized studies. Although some studies have reported favourable outcomes with this protocol in African-American cohorts, these studies have been marred by small sample sizes, lack of randomization and short- to intermediate-term follow-up periods [17,19,23,26]. In addition, it cannot be determined if outcomes in African-Americans may be generalizable or applicable to Blacks resident in Africa; it is quite possible that subtle differences may exist between these two groups that may affect outcomes.

Steroid minimization and withdrawal strategies have potential benefits, however, the evidence so far has been contentious at best, with some studies pointing towards long-term deleterious effects while others have had favourable outcomes. This is perhaps due to variations in study design, immunosuppression protocols, sample sizes and duration of follow-up. In addition, some of these studies were methodologically flawed. Hence, while interpreting the results of these studies blighted by a significant heterogeneity, it is difficult to arrive at compelling conclusions. This is perhaps the reason that globally, there appears to be no standardized protocol for steroid minimization yet. There is certainly a significant paucity of data regarding this protocol in the Nigerian population. It is therefore imperative that larger, longer-term, randomized and prospective studies with uniform protocols are conducted to better evaluate the benefits versus harms inherent in these regimens in our own setting. Till then, steroid minimization practises in Nigeria would need to be individualized according to patients’ profiles.

None

We would like to acknowledge Dr Faponle AE for his contributions towards the manuscript.

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