Steroids

Introduction

When the first renal transplants were being performed in the early 1960s the immunosuppressive properties of corticosteroids were already noted, and steroids were successfully used to reverse episodes of acute rejection. In his 1964 book, Starzl described the use of steroids as a “pretreatment” alongside azathioprine as prophylaxis against rejection, based on the premise that rejection was almost inevitable with azathioprine alone. This work was soon followed by groups from Virginia, London, and Cleveland, with the use of steroids in combination with azathioprine from the time of transplantation and increased doses during episodes of acute rejection. This combination of azathioprine and steroids became the mainstay of transplant immunosuppression for almost 20 years.

From the beginning of this so-called azathioprine era, arbitrarily large doses of steroids were given from the time of transplantation with a gradual reduction over 6 to 12 months to maintenance levels. The high doses of steroids used with azathioprine were responsible for most of the morbidity of transplantation (discussed later). It was not until the 1970s that a series of randomized trials as well as observational studies slowly led to the realization that low-dose steroids were as effective as high-dose steroids in preventing rejection and that there was a major reduction in steroid complications of transplantation with low-dose regimens.

With the introduction of newer, more potent induction and maintenance agents, there has been a great deal of interest over recent years in further reducing steroid doses and either withdrawing them from maintenance immunosuppressive regimens or avoiding them altogether.

Mechanism of Action

Steroids are administered as prednisone or prednisolone. These agents are absorbed rapidly from the gut, and peak plasma concentrations occur 1 to 3 hours after administration. The mechanism of action of steroids is extremely complex and is still not understood fully. Steroids are antiinflammatory as well as being immunosuppressive. It was first noted by Billingham et al . that cortisone would produce a modest prolongation of the life of skin allografts in the rabbit. In the treatment of acute rejection, it is probably the antiinflammatory activity that produces the immediate response, whereas when used prophylactically it is the immunosuppressive activity that is predominant. A small randomized trial comparing prednisolone with a nonsteroidal antiinflammatory agent (ibuprofen) showed a higher rate of rejection in the patients receiving the nonsteroidal agent, confirming that the antiinflammatory effect of steroids is not its major role in renal transplantation.

Steroids are metabolized in the liver, where prednisone is converted to prednisolone. Although it has been estimated that the bioavailability of prednisone is approximately 80% of that achieved by prednisolone, no evidence exists in practice that there is a difference in outcome between prednisone (used most commonly in the US) or prednisolone (used most commonly in Europe). The half-life of steroids is short—about 60 minutes for prednisone and 200 minutes for prednisolone. These half-lives are increased substantially in the presence of hepatic dysfunction and are shorter in the presence of drugs such as phenytoin and rifampicin that induce hepatic enzymes. There is no evidence that these interactions have produced significant problems in clinical practice. It has also been shown that the clearance of prednisolone is slower in patients on cyclosporine compared with patients on azathioprine. A later study suggested, however, that cyclosporine did not influence the metabolism of methylprednisolone, but the authors noted a considerable variation of the metabolism of methylprednisolone among patients. The time- and dose-dependent induction of UDP-glucuronosyltransferase activity by steroids may increase the clearance of mycophenolic acid, reducing exposure to mycophenolate. Cattaneo et al . have demonstrated that as steroids are tapered over the postoperative period, the mycophenolic acid area-under-the-curve increases. The pharmacokinetics of prednisolone during sirolimus therapy have also been studied, with some evidence for a minor interaction between sirolimus and prednisolone in some patients.

Steroids do have a significant effect in vitro on T cell proliferation, blocking interleukin-2 production. A variety of other actions may augment their immunosuppressive activity (e.g., preventing the induction of interleukin-1 and interleukin-6 genes in macrophages). Its antiinflammatory activity is perhaps mediated by the inhibition of migration of monocytes to areas of inflammation, and this same antiinflammatory activity has a marked deleterious effect on wound healing.

Steroid Resistance

The sensitivity of individuals to steroid therapy is highly variable. A study in healthy volunteers demonstrated a wide interindividual variation in the inhibition of lymphocyte proliferation by steroids. Steroid resistance is frequently seen in patients with inflammatory conditions and has been shown to correlate well with in vitro measurements of lymphocyte steroid sensitivity in patients suffering with rheumatoid arthritis, ulcerative colitis, asthma, and systemic lupus erythmatosus.

In vitro studies of lymphocyte steroid sensitivity have demonstrated a higher incidence of resistance in patients with chronic renal failure than in healthy volunteers (52.9% vs. 3.8%). In renal transplant recipients, Langhoff and colleagues have demonstrated that pretransplant in vitro measurements of lymphocyte sensitivity are predictive of graft survival at 1 year in patients coadministered azathioprine, but less so in those receiving cyclosporine. These results have been confirmed in vivo, with significantly higher sensitivity to methylprednisolone seen in those patients with graft function at 6 months compared with patients with graft failure. This difference in sensitivity is smaller in cyclosporine-treated patients than those receiving azathioprine, suggesting that this effect may in part be offset by the use of newer, more potent immunosuppressant agents. Dialysis patients demonstrating steroid resistance have an increased risk of acute rejection and chronic allograft nephropathy posttransplant. Interestingly, reduced lymphocyte prednisolone sensitivity correlates with impaired sensitivity to cyclosporine and tacrolimus, which may play a role in the high risk of allograft rejection in these patients.

A number of potential mechanisms for this resistance to steroids have been suggested, including receptor downregulation by glucocorticoid exposure, negative inhibition by the beta-isoform of the glucocorticoid receptor, or inhibition of the alpha isoform of the receptor by the proinflammatory transcription factor NK-κB in inflammatory conditions.

Dosage

When used prophylactically with azathioprine, steroids were used initially in high doses (e.g., 100 mg/day), reducing to a maintenance dose of 20 mg/day over 6 to 9 months. McGeown and coworkers were the first to report consistently excellent graft survival with a low incidence of steroid-related complications using a lower prednisolone dose of 20 mg/day given orally as a single morning dose, with a further reduction occurring at 6 months to a baseline maintenance dose of 10 mg/day. Because most of the Belfast patients had had bilateral nephrectomies and all had had more than 100 blood transfusions before transplantation, it was not clear whether the excellent results were related to the low dosage of steroids or to a transfusion effect, which was recognized widely as an important factor in improving graft outcome in the azathioprine era.

Trials of low-dose steroids versus high-dose steroids were carried out in Oxford, then in many other centers, all of which showed not only that low-dose steroids were as effective as high-dose steroids in preventing rejection but also that there was a significant reduction in steroid-related complications in patients receiving low-dose steroids. The results of these trials led quickly to the wide adoption of low-dose steroid regimens with azathioprine. The results of a large multicenter trial reported by D’Apice et al., demonstrated that low-dose steroids were only equally effective as high-dose steroids in preventing rejection if therapeutic doses of azathioprine were used (i.e., >2 mg/kg/day).

With the introduction of cyclosporine, steroids remained in use with or without azathioprine. In general, low-dose steroid protocols were continued, although there was a tendency, particularly in North America, to go back toward higher steroid dosage regimens in the first few weeks posttransplantation. This was a relatively transient practice and now, with modern immunosuppressive protocols, not only are low-dose steroids the norm but indeed discontinuation of steroids is becoming increasingly possible (see later).

Whether steroids should be given as a single daily dose in the morning or in divided doses has not been resolved. Because of the short half-life of prednisone and prednisolone, divided doses may be more rational, but it could be argued that a single morning daily dose would be more appropriate, taking into account the diurnal rhythm of glucocorticoid metabolism. There is no clinical evidence that one or the other protocol is more effective or less likely to produce side effects.

For many years, maintenance doses of prednisone or prednisolone of 10 mg/day were standard therapy in association with azathioprine. In patients with long-surviving grafts with good function, steroid dosages have been reduced to 5 or 6 mg/day. It is unlikely, however, that many patients who are on long-term azathioprine and steroids would be able to have their steroid dosage reduced to much less than 5 mg/day. Attempts in the past to withdraw steroids have often led to the onset of rejection when doses of less than 5 mg/day are reached. This is important to note as there are many long surviving patients still on azathioprine and steroids. It should also be remembered that when patients have been on steroids for many years, their adrenocortical function may not recover from the long-standing suppression as the steroid dose is reduced (see later).

Alternate-day steroid therapy for maintenance has also been used widely, especially in children, in an attempt to reduce side effects, particularly growth retardation. In children, alternate-day therapy may be associated with a greater incidence of rejection, but this is probably not the case in adults. A small randomized trial of alternate-day therapy failed to show any benefit over daily steroids, however. Alternate-day therapy may lead to greater problems with respect to compliance, in contrast to a daily regimen of steroids.

It has been and still is common practice to administer a bolus of methylprednisolone prophylactically during the transplant operation with the aim of increasing immunosuppression and perhaps preventing delayed graft function, but a randomized prospective trial of bolus methylprednisolone versus placebo at the time of surgery did not show any benefit of the high perioperative intravenous dose of methylprednisolone. Nevertheless it remains standard practice whatever the immunosuppressive regimen is to be.

Treatment of Acute Rejection

Steroids in high doses are the first approach to the treatment of an acute rejection episode. Early experience involved either increasing the oral dosage of steroids to high levels (e.g., 200 mg/day for 3 days), with a rapid reduction over 10 days to the dosage levels of steroids being given before the acute rejection episode, or boluses of intravenous methylprednisolone (e.g., 0.5–1 g/day for 3–5 days). Probably both approaches are equally effective. In an early randomized prospective trial in Oxford, however, high intravenous doses were as effective as high oral doses in reversing rejection, but there was a definite suggestion that steroid-related complications were lower in those who received intravenous therapy. In a randomized study in children, a high intravenous dose of methylprednisolone (600 mg/m ² daily for 3 days) was no more effective than low oral doses of prednisolone, reversing rejection in 70% as opposed to 72% of episodes.

The most common form of high-dose intravenous therapy to treat acute rejection has been 1 g of methylprednisolone given intravenously as a single bolus daily for 3 days. The intravenous bolus should be administered slowly over 5 minutes because the sudden injection of the bolus can lead to cardiac arrhythmias. It is probable that 1 g of methylprednisolone is a much greater dose than required; in Oxford for many years now we have used 0.5 g of methylprednisolone daily intravenously for 3 days, whereas the Stockholm unit has used 0.25 g daily intravenously for 3 days. The lower intravenous doses do not appear to be associated with any greater incidence of steroid-resistant rejection, as originally suggested by a prospective trial of high-dose versus low-dose intravenous steroids to treat rejection. Similarly in a small double-blind, randomized trial, Stromstrad et al . failed to show any therapeutic benefit of a 30 mg/kg bolus over a 3 mg/kg bolus, and similarly Lui et al . failed to show any benefit of a bolus of 15 mg/kg of body weight over a bolus of 3 mg/kg.

Side Effects

The side effects of continuous steroid therapy are numerous ( Table 16.1 ). High-dose steroids were responsible for most complications of renal transplantation in the azathioprine era, which have reduced markedly with the more recent widespread use of low-dose steroids. In a study of the cost of steroid side effects over 10 years in a cohort of 50 patients, the additional cost per patient attributable to a steroid complication was assessed at $5300 (US dollars). Cost analysis in a randomized controlled trial of early steroid withdrawal from Egypt has shown a 2.9-fold increase in management costs for steroid-related morbidities in the steroid maintenance arm.