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Nephrologist/Head of Renal Transplant Unit
Unidad de Trasplante Renal
Hospital Clinic de Barcelona
Kidney transplantation is the best therapeutic option for the treatment of chronic renal failure. Compared with haemodialysis or peritoneal dialysis, a successful renal transplant offers the uraemic patient lower risk of morbidity and mortality and improvement in health-related quality of life; in addition, it is more cost-efficient.(1)
The introduction of new immunosuppressive drugs in the past few years has contributed to reduce dramatically the one-year incidence of acute rejection, from 20–30% to 5–20%. Today, the standard immunosuppressive regimen consists of a calcineurin inhibitor (CNI), ciclosporin A or tacrolimus, in combination with mycophenolate mofetil (MMF) and low doses of corticosteroids. Despite the reduction of acute rejection, long-term results of renal transplantation remain unchanged.(2) Chronic allograft nephropathy (CAN), acute humoral rejection (AHR) and patient’s death with a functioning graft due to cardiovascular complications, infection and cancer are some of the most important issues to be solved.
In recent years, sirolimus and its analogue everolimus, two potent immunosuppressive drugs with antiproliferative and antitumoural proprieties, have been introduced. The potential efficacy of rituximab, a monoclonal antibody currently used in haematology, is also being tested for the treatment of AHR.
Chronic allograft nephropathy
CAN is a consequence of immunological and nonimmunological injuries (ischaemia-reperfusion injury, donor age, repeated acute rejection, etc). Additionally, a high incidence of unadverted acute rejection is seen despite the increasing number and the potency of new immunosuppressive drugs. Currently, the diagnosis of acute rejection is based on clinical suspicion (eg, elevated serum creatinine) and is confirmed by renal biopsy. Rush et al(3) have reported a 30% prevalence of subclinical acute rejection in ciclosporin A-maintained renal transplant recipients, as detected by routine serial biopsies. Even severe injury can be clinically unapparent in grafts with stable renal function. There is a direct correlation between undiagnosed subclinical acute rejection and chronic rejection.(4) Therefore, protocol biopsies should be part of the management of renal transplant patients. Long-term routine biopsies have also been useful in the study of the natural history of CAN. Later damage in the graft appears to be predominantly associated with the histological pattern of CNI-nephrotoxicity.(5,6) Prevention of chronic CNI- nephrotoxicity may be feasible by reducing or replacing ciclosporin A or tacrolimus. Although the reduction of the dose of CNI or their withdrawal from regimens including ciclosporin A, prednisone and azathioprine (AZA) is usually associated with a high incidence of acute rejection, the use of MMF or sirolimus in place of AZA in ciclosporin A-based, three-drug regimens produces more potent immunosuppression, suggesting that the discontinuation of ciclosporin A after the first year might now be feasible. Furthermore, total avoidance of CNIs has been successfully explored. Recently, a study using a combination of sirolimus, MMF, prednisone and the anti-CD25 lymphocyte-receptor mono‑clonal antibody basiliximab has shown that after two years, in contrast with the group of patients receiving ciclosporin A, sirolimus/MMF patients showed better renal function, a diminished prevalence of CAN and downregulated expression of the genes responsible for progression of CAN.(7)
A second step in the prevention of CAN is the detection and treatment of acute humoral rejection (AHR). Humoral rejection is associated with the development of donor-specific antibodies (DSAs). Typical pathological features of AHR by light microscopy include neutrophils in peritubular capillaries, vasculitis and fibrinoid necrosis in vessel walls.(8) Peritubular capillary staining for C4d is the marker that best identifies AHR in renal allograft biopsies. Antibody-mediated activation of the classical complement pathway leads to the formation of C4d that covalently binds to the endothelial surface, leaving an imprint of antibody activity that persists for days to weeks after complement activation. Therefore, C4d may be an attractive immunohistochemical marker of post-transplant donor-reactive antibody responses.(9) To treat AHR, high-dose corticosteroids, antithymocyte globulin, a switch from ciclosporin A to tacrolimus and MMF, plasmapheresis and polyclonal immunoglobulin have been used with variable success. Recently, a chimeric humanised monoclonal antibody directed against the pan-B-cell surface molecule (CD20), rituximab, has also been used. Several teams have successfully used rituximab as a rescue therapy for AHR (data not published). It is more difficult to assess the role of alloantibody responses in the pathogenesis of CAN. Some data suggest that there is a relationship between late allograft dysfunction and the detection of de-novo anti-HLA-alloantibodies.(10) However, the presence of peritubular capillary C4d staining in the biopsies of patients with stable renal function remains unexplained.
The third issue to be reviewed is the relationship between immunosuppression and cancer. Cancer incidence is enhanced in transplant recipients,(11) due to several factors (disturbances in the immunosurveillance system by the immunosuppressive drugs, chronic viral infections, etc). After renal transplantation, the principal neoplasms and their associated viruses are:
Additionally, a direct oncogenic effect of ciclosporin A has been described by Hojo et al in animal models.(12) Similar results have been obtained with tacrolimus.(13) In such animal models, ciclosporin A and tacrolimus increased cancer dissemination, probably by upregulating the production of growth factors (transforming growth factor β, interleukin-6 and vascular endothelial growth factor) that enhance angiogenesis, tumour growth and metastasis.(12) Conversely, the animals also treated with sirolimus showed a reduction in the tumoural spread. In addition to its immunosuppressive properties, sirolimus (and its analogue, everolimus) have a remarkable antitumoural activity, inhibiting the proliferation of transformed cell lines of lymphoid, central nervous system, hepatic, melanocytic, osteoblastic, myogenic, renal and connective tissue origin, as well as the proliferation of T- and B-cells transformed by human T-cell leukaemia/lymphoma virus type 1 (HTLV-1) and EBV, respectively.(14) The antitumoural activity of sirolimus is closely related to its immunosuppressive mechanism of action. Sirolimus prevents the activation of a cell-cycle- specific kinase (TOR) that results in the blockage of cell-cycle progression. Interestingly, sirolimus is effective in the restraint of the deregulation of the mTOR (mammalian target of rapamycin) activity observed in many human tumours associated with genetic alterations (eg, mutations in PTEN, a protein that downregulates the phosphoinositide 3-kinase/ AKT pathway/mTOR activity). Based on currently available data, patients receiving sirolimus-based therapy without CNI or sirolimus maintenance therapy after early CNI withdrawal have lower rates of malignancy.(15) Importantly, sirolimus is effective in the management of renal transplant recipients with Kaposi’s sarcoma,(16,17) and is probably the best immunosuppressive regimen for transplant patients with a previous history of cancer.
mTOR inhibitors (sirolimus, everolimus) and the anti-CD20 monoclonal antibody rituximab offer new strategies for the improvement of long-term patient and graft survival.