A Critical Review of Steroid Immunotherapy in Kidney Transplantation

Abstract

Steroid immunosuppression has maintained a long-lasting relevance in renal transplantation. In addition to its role in preserving allograft survival, it is often the first line agent in the rescue treatment of acute rejection events. Its major drawbacks include metabolic adverse effects and long-term cardiovascular morbidities. Motivated by the need to avoid growth impairment, pediatric renal transplant community provided a template for steroid minimization strategy. Steroid sparing regimens are often successful in the context of induction therapy with lymphocyte depleting agents. Because most randomized controlled trials are conducted for duration of 1 to 5 years, it is unclear if steroid-based protocol confers a longer renal allograft life span. By avoiding earlyonset rejection, steroid prevents exposure of immunogenic epitopes and therefore reduces the development of late-onset antibodymediated allograft injury. In contrast to the calcineurin inhibitors, steroid promotes allograft tolerance by enhancing preservation of the regulatory T cells. It suppresses inflammatory response to ischemic reperfusion events as produced by transplant surgery. Its anti-inflammatory effects are most beneficial in patients with high immunologic risk profiles. Finally, future therapeutic approach may embrace careful selection of most suitable drug regimen for an individual by using bio-molecular resources for risk categorization. analysis of the role of other classes of ISA, readers are referred to previous excellent reviews by other authors [1,2]. Steroids: historical context Steroid was a pioneering ISA for the first cohort of kidney transplant recipients (KTR) in the early 1960s [3]. Its combination with azathioprine (AZA) produced a very modest one-year graft survival rate, barely reaching 40 to 50% [3]. Subsequent introduction of calcineurin inhibitors (CNI), mycophenolate mofetil (MMF), rapamycin (RAP) and lymphocyte depleting agents led to one-year graft survival rate in excess of 90% [4,5]. This extraordinary feat was, in part, due to the vast improvement in both surgical and organ preservation technologies. However in the last two decades, the steady increase in life span of renal transplant has been driven principally by the attrition rate in the first year. Due to inadequate immunosuppression and/or drug-induced nephrotoxicity, long-term allograft survival has been less satisfactory [4]. Thus rate of deceased donor graft loss in the first year dropped from 20% in 1989 to 7% in 2008, but it remained steadily constant at 5-7% over the same period for those that survived beyond one year [6]. Steroids Minimization Strategies United States registry data showed that more than 25% of the patients who are discharged from hospital after the transplant surgery have had a successful discontinuation of steroids treatment [6]. Although there is no consensus on the nomenclature for minimization strategies, for simplicity we shall use the following definitions: i) Steroid free: A strict definition of a complete elimination would imply...