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Organ Quality Determinates Outcome after Kidney Transplantation
of antigen presentation, which increases the incidence of rejection.
42,43
response after transplantation.
TLRs and downstream mediators are thought to link innate and adaptive Organ-quality-adapted immunosuppressive protocols have recently
immunity. TLRs expressed on APCs may regulate co-stimulatory signals attracted interest. As organs from marginal donors are frequently
and cytokine production, which in turn modulate the strength of the transplanted into older recipients, this concept may also need to consider
adaptive immune response.
44
Mice lacking MyD88, a protein that age-related changes in the recipient’s immune response. Elevated
mediates most TLR signals, demonstrated an impaired Th1 response and amounts of memory T cells and reduced amounts and functional
were unable to reject minor mismatched skin allografts.
45
On the other capacities of native T cells are characteristic of the immune response in
hand, the innate system also depends on the adaptive immune system. It the elderly, while older APCs have been shown to elicit a stronger
has been shown that T-cells are required for macrophage activation,
41
while the adaptive immune response can enhance the innate
inflammatory response.
Marginal grafts are extensively utilised
The activation of DCs seems particularly relevant to the increase in graft
immunogenicity.
46,47
Solid and cellular grafts contain DCs at an immature
for transplantation.
stage.
48
DCs, in turn, are activated by ‘danger signals’, substances
produced by distressed or injured cells.
49
This initial injury provides the
maturation signals that DCs need to migrate and induce T-cell
activation.
50
When DCs mature in the presence of inflammatory signals, immune response. Taken together, these factors – in addition to a
they increase the expression of class I and II MHC antigens and reduced capacity for repair mechanisms in the older graft – may explain
co-stimulatory molecules, thus increasing the production of cytokines a higher risk of chronic graft failure and acute rejection episodes when
and amplifying the immune response. In addition, when donor DCs die transplanting marginal kidneys.
in the recipient’s lymph nodes, they can cross-prime antigens through the
indirect pathway of allorecognition.
51–55
Many centres change their immunosuppression regimens for patients at
a high risk of DGF, such as recipients of marginal kidneys. The ultimate
Improvement of Organ Quality and Immunosuppression aim is to adopt regimens tailored to limiting the possible acute toxicity of
Manipulating the initial anti-inflammatory response by treating the calcineurin inhibitors and to maximising antirejection in the graft
donor, the graft or the recipient may reduce the initial organ damage, environment, which is more susceptible to immune response and
impact graft immunogenicity and modify post-transplant ischaemic injury. A common change is to reduce or delay the introduction
immunosuppression.
56,57
Most recently, the potential of pulsatile of calcineurin inhibitors (CNIs) and switch to a depleting antibody.
perfusion (PP) has been reassessed, while clinical studies on organ- Induction therapy with either antithymocyte globulin or basiliximab were
quality-adapted immunosuppression became available. compared in marginal kidney transplants defined by prolonged
ischaemia, donor age, elevated serum creatinine or NHBD in a recent
PP has been associated with an increased utilisation of ECD kidneys and prospective clinical study. Significantly lower acute rejection episodes
reduced rates of DGF in an evaluation of the Scientific Registry of were observed in the thymoglobulin arm, while DGF function, graft and
Transplant Recipients (SRTR) database.
6
Approximately 20% of all ECD patient survival were not different.
61
reported to the UNOS from 2000 to 2003 were utilised following PP.
Despite a greater number of risk factors for reduced graft viability, the Delaying or avoiding CNI when utilising marginal kidneys has been
graft survival of pulsatile perfused kidneys is similar to that of kidneys that discussed. However, dual kidney transplants from marginal donors
have undergone traditional cold storage perfusion.
58
Overall, PP seems to receiving an induction treatment with thymoglobulin and a CNI-free
be beneficial and cost-effective when utilising marginal kidneys. In immunosuppression based on sirolimus, mycophenolate mofetil and
addition to improving early graft function, PP may also provide additional prednisone demonstrated no advantage compared with a CNI-based
parameters to evaluate graft quality. regimen.
62
Kidneys from non-heart-beating donors showed significantly
reduced DGF after PP, induction therapy with daclizumab and delayed
Recent experimental studies showing a flow-dependent expression of introduction of Tacrolimus.
63
In high-risk kidney transplant recipients,
protective genes on the endothelium are of interest. The transcription induction therapy with basiliximab plus low-dose rabbit antithymocyte
factor Kruppel-like Factor 2 (KLF2) has been identified as a mechano- globulin (RATG) effectively prevented acute rejection and was safer and
activated gene. KLF2 has been shown to be critical for maintaining an more cost-effective than induction with standard-dose RATG.
64
New CNI-
anti-inflammatory and anti-thrombotic state at the level of the vessel free immunosuppression protocols – a combination of basiliximab and
wall while inhibiting interleukin (IL)-∫-transmitted expression of co-stimulatory blockade with the selective blocker of T-cell activation
E-selectin, vascular cell adhesion molecule (VCAM)-1 and tissue factor. belatacept – are attracting interest for use in high-risk patients receiving
Importantly, the expression of KLF2 is triggered by the initiation of flow, renal transplantation.
65
while lack of this stimulus leads to the rapid degradation of this
transcription factor.
59,60
At this point, it can also be speculated that the Data on prospective immunosuppressive clinical trials utilising marginal
lack of flow in the vascular system of organs utilised for transplantation grafts are still limited, while a more in-depth knowledge of donor and
may rapidly degrade the expression of protective genes – such as KLF2 recipient age-specific immune responses seems necessary at this time.
expression – leading to a pro-inflammatory, pro-thrombotic vasculature. The current available data imply that a potent induction therapy and a
PP may protect the endothelium, thus ameliorating the early immune delayed induction of CNI are preferable when utilising marginal kidneys.
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