Untitled - Roche Trasplantes

PROTOCOL BIOPSIES AND THE DIAGNOSIS OF HUMORAL REJECTION
ROLE OF PROTOCOL BIOPSIES
FOR THE DETECTION OF SUBCLINICAL
HUMORAL REJECTION
From protocol biopsies studies it is well known that subclinical cellular rejection is present
in 15-30% of all protocol biopsies. Subclinical rejection is defined as the presence of
morphological signs of cellular rejection fulfilling at least Banff grade IA (i.e., >25% interstitial
infiltrate + tubulitis with more than 4 T-cells per tubular cross section) without simultaneous
clinically overt allograft dysfunction (=significant rise in serum creatinine).
This implies that subclinical rejection can only be detected by biopsies taken from clinically
stable or non-functioning allografts, i.e., protocol biopsies.
During the recent renaissance of humoral rejection in renal transplantation, mostly due
to the widespread availability of C4d, data were lacking concerning the incidence or rather
the existence of subclinical humoral rejection. From the early days of renal transplantation
it was dreadfully known that the presence of preformed antibodies in the recipient’s
serum will rapidly lead to hyperacute rejection with overt allograft dysfunction and rapid
allograft loss. Therefore, it was questionable whether episodes of subclinical circulation
of donor-specific antibodies can be that harmless not leading to clinically overt allograft
dysfunction. Furthermore, if such episodes can be detected it can be assumed that they
rather be a signs of accommodation (see below) to the allograft and herewith represent
a positive event. Against this background our group conducted together with two other
European transplant centers, all doing protocol biopsies on a regular basis, a retrospective
multicenter study staining nearly a thousand protocol and indication biopsies for C4d.
Staning results were correlated to morphology of cellular and humoral rejection as well
as to various clinical parameters (sex, age, presence of panel reactive antibodies, immunosuppression,
induction therapy, number of prior transplants) and short term allograft
outcome. We found C4d focally in 8.5% of the indication biopsies and 2.4% of the
protocol biopsies. A diffuse C4d pattern was seen in 12.2% of indication biopsies (i.e., in
allografts with dysfunction) and subclinical in 2.0% of the protocol biopsies (p< 0.05, Table
I). These findings indicate a quite low incidence of C4d in clinically stable allografts.
Compared to other centers even the incidence in indication biopsies was lower in our series.
Furthermore, one center (Table I, center 2) showed a significantly higher incidence
of C4d positive biopsies.
Analyzing potential reasons for such center-specific variances in the incidence of C4d detection
revealed that in the center with higher numbers of C4d positive cases significant
more patients had re-transplants and in average higher levels of panel reactive antibodies
were detected prior to transplantation. This indicated that also subclinical C4d detection
is related to pre-sensitization. This was further confirmed by correlating C4d to various
clinical parameters in the whole collective revealing again prior transplants and high lev-
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