Elsevier

Transplantation Reviews

Volume 22, Issue 4, October 2008, Pages 241-251
Transplantation Reviews

Immunosuppression in renal transplantation: some aspects for the modern era,☆☆

https://doi.org/10.1016/j.trre.2008.05.003Get rights and content

Abstract

New classes of agents have sequentially increased the specificity of post-transplant immunosuppression, leading to profound improvements in success rates after renal transplantation. The next era will focus on increased long-term survival rates through optimal use of existing agents and the rational development of drugs based on prior identification of specific immunologic targets. Conventionally, long-term outcomes after kidney transplantation have been assessed by surrogate markers, notably acute rejection, but graft-threatening complications such as development of new-onset diabetes mellitus and polyomavirus nephropathy must be addressed if long-term survival rates are to be improved. Mycophenolic acid therapy must be administered optimally to ensure that adequate exposure is achieved in the immediate post-transplant period and, subsequently, by avoiding underdosing due to gastrointestinal events. Chronic allograft nephropathy remains a major concern, and protocol-led, reliable monitoring strategies are essential to enable early intervention, for example, through introduction of proliferation signal inhibitor therapy with concomitant calcineurin inhibitor reduction or withdrawal. The range of immunosuppressive regimens now available and in development, together with improved assessment of patients' risk profiles for immunologic events and comorbid disease, offers the opportunity for further individualization of immunosuppression after renal transplantation.

Introduction

Advances in transplant medicine in recent years have helped to avoid or overcome many clinical challenges in renal transplant recipients, most notably reducing the previous high rates of graft loss to acute rejection, ameliorating the toxicity associated with early immunosuppression regimens, and lowering infection-related mortality. As these areas have been addressed, however, new concerns have become apparent in the quest for higher long-term graft survival rates and quality of life for patients. The clinician is faced with an increasingly diverse range of issues to consider when deciding on the optimal immunosuppressive strategy to adopt based on an individual's specific profile. The relative risk of complications such as diabetes mellitus, the emerging problem of polyomavirus-associated nephropathy, time-dependent adequate dosing of adjunctive therapy, avoidance of chronic nephropathy, and use of novel regimens to achieve balanced calcineurin inhibitor (CNI) exposure are all questions that now need to be taken into account as part of post-transplant management. Remaining up-to-date with the latest findings relating to such a variety of complex areas is a demanding task.

Against this background, an international, multidisciplinary meeting was convened in Berlin in June 2007. The objective was to offer a forum in which transplant clinicians could update themselves on state-of-the-art thinking relating to a wide range of today's challenges in the renal transplant population. This review provides a summary of the data that were presented and discussed at the meeting and seeks to give an insight into how the current knowledge base may influence contemporary clinical practice.

Section snippets

Advances in transplantation medicine—past, present, and future

Development of the surgical expertise to transplant solid organs preceded the immunologic advances necessary to control allograft rejection. Thus, instead of having effective immunosuppressive regimens available from the start of the transplant era, the challenge of organ rejection has stimulated immunologic discoveries that now are beginning to be applied to transplantation. Progress in immunosuppression has focused on the introduction of agents with greater efficacy combined with increasing

Efficacy and glucose metabolism disorders: CNIs in renal transplantation

In recent years, long-term graft survival rates after kidney transplantation have remained largely unchanged despite a concurrent reduction in the incidence of acute rejection [6], [7]. Acute rejection is associated with several disadvantages: treatment with antibody preparations impacts negatively on long-term mortality [8]; steroid treatment increases the risk of complications; more intense maintenance immunosuppression is mandated; and additional health care costs are incurred. The effect of

Polyomavirus infection, replication, and disease in renal transplant recipients

Polyomavirus infection typically occurs during childhood, with seroprevalence rates of 65% to 90% by the age of 10 years, and is usually asymptomatic. Individuals with altered immunity, however, can experience high-level replication and may present with urine cytology (“decoy” cells). In renal transplant recipients, polyomavirus-associated nephropathy (PVAN) develops in 5% of patients and leads to graft loss in approximately 50% of cases. The pathogenesis of PVAN is characterized by persisting

Current issues in MPA therapy

With MPA therapy now routine after renal transplantation, there is a growing need to optimize MPA dosing. One important concern relates to gastrointestinal (GI) symptoms and the consequent need for MMF dose changes or withdrawal, which can have a profound impact on graft outcomes. A series of retrospective analyses has shown a significant increase in the risk of acute rejection [29], [30] or graft loss [31], [32], [33], [34] in renal transplant patients receiving a reduction in or

Chronic allograft nephropathy: a clinical syndrome in renal transplantation

Jeremy Chapman of the Centre for Transplant and Renal Research at the University of Sydney, Australia, discussed strategies for early detection of chronic allograft nephropathy (CAN). Accounting for more than a third of graft losses, CAN is the most frequent cause of graft loss after renal transplantation other than patient death [52], [53]. Using the Banff '97 schema, mild CAN (grade I) is observed in almost all grafts by the end of the first year post-transplant [54], with grade II or III CAN

The potential role of PSIs in de novo and early intervention in maintenance transplant patients

One response to the growing demand for donor kidneys has been the introduction of “old-for-old” transplant programs, in which expanded criteria organs from elderly donors are age-matched to recipients. Increasing donor age, however, is associated with deteriorating renal function, a higher prevalence of risk factors for CAN, and greater susceptibility to CNI nephrotoxicity, all of which contribute to the reduced long-term renal function observed with elderly donors [64]. In addition, older

References (79)

  • KiberdB.A. et al.

    Early adequate mycophenolic acid exposure is associated with less rejection in kidney transplantation

    Am J Transplant

    (2004)
  • SalvadoriM. et al.

    Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients

    Am J Transplant

    (2004)
  • BuddeK. et al.

    Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study

    Am J Transplant

    (2004)
  • NichollsA.J.

    Opportunities for therapeutic monitoring of mycophenolate mofetil dose in renal transplantation suggested by pharmacokinetic/pharmacodynamic relationship for mycophenolic acid and suppression of rejection

    Clin Biochem

    (1998)
  • BestardO. et al.

    Calcineurin-inhibitor–sparing immunosuppressive protocols

    Transplant Proc

    (2005)
  • RuizJ.C. et al.

    Conversion to everolimus in kidney transplant recipients: a safe and simple procedure

    Transplant Proc

    (2006)
  • WaliR.K. et al.

    Early withdrawal of calcineurin inhibitors and rescue immunosuppression with sirolimus-based therapy in renal transplant recipients with moderate to severe renal dysfunction

    Am J Transplant

    (2007)
  • PascualJ. et al.

    Everolimus (Certican) in renal transplantation: a review of clinical data, current usage, and future directions

    Transplant Reviews

    (2006)
  • KahanB.D.

    Cyclosporine

    N Engl J Med

    (1989)
  • CalneR.

    Cyclosporine as a milestone in transplantation

    Transplant Proc

    (2004)
  • OjoA.O. et al.

    Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection

    Transplantation

    (2000)
  • WebsterA.C. et al.

    Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials

    Transplantation

    (2006)
  • JamilB. et al.

    Impact of acute rejection therapy on infections and malignancies in renal transplant recipients

    Transplantation

    (1999)
  • ColeE.H. et al.

    PTDM and acute rejection are associated with a similar risk for graft loss

    Am J Transplant

    (2007)
  • KaplanB. et al.

    Long-term graft survival with Neoral and tacrolimus: a paired kidney analysis

    J Am Soc Nephrol

    (2003)
  • BunnapradistS. et al.

    Renal allograft outcomes according to initial immunosuppressive regimen: a five year follow-up of OPTN database

    Am J Transplant

    (2005)
  • WoodwardR.S. et al.

    Renal graft survival and calcineurin inhibitor

    Transplantation

    (2005)
  • HabibA.N. et al.

    The role of maintenance immunosuppressive regimen in long term kidney transplant outcome

    Am J Transplant

    (2005)
  • IrishW. et al.

    Three year posttransplant graft survival in renal-transplant patients with graft function at 6 months receiving tacrolimus or cyclosporine microemulsion within a triple drug regimen

    Transplantation

    (2003)
  • WebsterA.C. et al.

    Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data

    BMJ

    (2005)
  • HirschH.H. et al.

    Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients

    N Engl J Med

    (2002)
  • HirschH.H. et al.

    Polyomavirus-associated nephropathy in renal transplantation: interdisciplinary analyses and recommendations

    Transplantation

    (2005)
  • HirschH.H. et al.

    BK viremia level strongly correlates with the extent/pattern of viral nephropathy (BKPVN): implications for a diagnostic cut-off value

    Transplantation

    (2006)
  • HirschH.H. et al.

    Prospective study of polyomavirus BK viruria and viremia in de novo renal transplantation

    Am J Transplant

    (2007)
  • WilliamsJ.W. et al.

    Leflunomide for polyomavirus type BV nephropathy

    N Engl J Med

    (2005)
  • RinaldoC.H. et al.

    Antivirals for the treatment of polyomavirus BK replication

    Expert Rev Anti Infect Ther

    (2007)
  • TierceJ.C. et al.

    Impact of mycophenolate mofetil (MMF)–related gastrointestinal complications and MMF dose alterations on transplant outcomes and healthcare costs in renal transplant recipients

    Clin Transplant

    (2005)
  • KnollG.A. et al.

    Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation

    J Am Soc Nephrol

    (2003)
  • PelletierR.P. et al.

    The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation

    Clin Transplant

    (2003)
  • Cited by (18)

    • The Consistency and Reporting of Quality-of-Life Outcomes in Trials of Immunosuppressive Agents in Kidney Transplantation: A Systematic Review and Meta-analysis

      2016, American Journal of Kidney Diseases
      Citation Excerpt :

      However, the risk of bias assessment suggests an improvement in reporting quality (lower risk of bias) with time. Advances in immunosuppression after transplantation have resulted in the incidence of acute rejection being reduced and short-term transplant survival being improved, yet long-term transplant survival rates after kidney transplantation have stayed essentially the same.47 As a consequence, the selection of immunosuppressive drugs best suited to an individual should involve an evaluation of outcomes associated with complications and harms including health outcomes, such as cancer, diabetes, and infections, and QoL.

    • The effect of immunosuppression on manifestations of sepsis in an animal model of cecal ligation and puncture

      2013, Transplantation Proceedings
      Citation Excerpt :

      A variety of immunosuppressive protocols have been used to treat malignancies, autoimmune diseases, and intestinal inflammation, as well as rejection prophylaxis in solid organ and bone marrow transplantations. The immunosuppressive drugs administered during transplantation are targeted either to a single or several sites in the immune system to prevent or treat organ rejection.26,27 The net state of immunosuppression is a dynamic process determined by all of the factors that contribute to risk for infection.

    • Significance of polyomavirus detection in urine cytology: an update

      2012, Diagnostic Histopathology
      Citation Excerpt :

      There are no FDA-approved assays nor a standardized PCR assay for BK virus: each test must be validated within the laboratory.34 Prospective studies using specified assays have determined BK viraemia thresholds shown to be predictive of BKVAN.8,36 In this context a renal biopsy may be avoided if clinical suspicion of BKVAN is confirmed by PCR test.

    • Macrophages and T lymphocytes are the predominant cells in intimal arteritis of resected renal allografts undergoing acute rejection

      2011, Transplant Immunology
      Citation Excerpt :

      The immunocytes in acute rejection have been thought to be predominantly lymphocytes [6]. Consequently, a focus of current immunosuppressive regimens is to prevent T-cell activation and infiltration into the transplanted organ [7]. Nevertheless, recent studies have suggested involvement of other cell types, especially in acute vascular rejection [8,9].

    • Diabetes in organ transplant patients

      2008, Medecine des Maladies Metaboliques
    View all citing articles on Scopus

    H.H.H., S.B., and K.B. have received research grants from Novartis; S.C., H.H.H., S.B., W.A., and K.B. have received honoraria from Novartis. R.M. is an employee of Novartis.

    ☆☆

    The meeting from which this report is derived was supported by an unrestricted educational grant from Novartis Pharma AG, Basel, Switzerland.

    View full text