Untitled - Roche Trasplantes

EARLY DIAGNOSIS OF CHRONIC ALLOGRAFT NEPHROPATHY
BY MEANS OF PROTOCOL BIOPSIES
anti-Il2 receptor antibody (51). An alternative strategy has been studied since the early
1980’s, notably early conversion from a calcineurin inhibitor based regimen to one which
eliminates the CNI after three, six or twelve months. It is not in the scope of this chapter
to identify and review these studies which others have accomplished in formal metaanalyses
(52, 53), but it is important to note that one of the more recent studies using
sirolimus and corticosteroids as maintenance therapy was accompanied by protocol
biopsies (54). In this study biopsies at implantation, 12 and 36 months were studied in
a subset of patients that provided biopsy material at each time point. The most interesting
feature of this study was that the group in which the CNI was eliminated had
resolution of tubular atrophy between 12 and 36 months, without increased interstitial
fibrosis. Thus the total CADI index of chronic damage was unchanged in the sirolimus
treated patients, suggesting that the strategy might hold out some hopes for long term
improvement in CAN, if effective and applicable clinical regimens can be developed to
avoid the CNI’s.
Future opportunities
Clearly, very early diagnosis of events that may subsequently damage the graft might
increase the effectiveness of interventions. The possibility that gene events will predict
histology has been borne out in early studies from a number of groups including our
own. Vitalone at the World Transplant Congress in Boston in July 2006 (55), presented
data derived from Gene Microarrays demonstrating that genes associated with both
CAN and rejection “turn on” –i.e., produce mRNA– earlier than the histological changes
were apparent. If this is borne out in other laboratories and in other series of patients,
it may offer a way of predicting the patients in whom intervention would be especially
valuable.
SUMMARY
Chronic Allograft Nephropathy is the syndrome that has come to plague renal transplantation
as the cause of most graft losses. It has been evident for as long as we have been
transplanting the kidney, but in the early days it was overshadowed by acute rejection
and mis-interpreted as an entirely immune related phenomenon termed “chronic rejection”.
It has been the source of most concern to clinical transplant programs for the past
ten years, but the long term nature of the syndrome has meant that it has not been an
easy target for research. Paradoxically, the pharmaceutical industry –which has the most
to gain from long term use of particular agents– is most unlikely to fund the research trials
that we will need to prove which are the best treatment options. Long term investments
in this area are likely to be superseded before they have produced any answers. We are
thus left with the individual transplant centre studies, implied answers from long term
cohort studies using older pharmaceutical agents and new molecular genomic and proteomic
technologies that have yet to deliver on their promise.
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