Untitled - Roche Trasplantes

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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- 61
BIOPSIA DE PROTOCOLO EN EL TRASPLANTE RENAL Table I Tx-center n Bx C4d (%) C4d (%) C4d (%) Type of biopsy Bx >50% PTC 25-50% PTC negative Center 1 indication Bx 48 5 (10.4) 7 (14.6) 36 (75.0) Center 2 indication Bx 99 15 (15.2) 8 (8.1) 76 (76.7) Center 3 indication Bx 230 26 (11.3) 17 (7.4) 187 (81.3) Total indication Bx 377 46 (12.2) 32 (8.5) 299 (79.3) Center 1 protocol Bx 128 1 (0.8) 2 (1.6) 125 (97.6) Center 2 protocol Bx 94 6 (6.4) 4 (4.3) 84 (89.3) Center 3 protocol Bx 329 4 (1.2) 7 (2.1) 318 (96.7) Total protocol Bx 551 11 (2.0) 13 (2.4) 527 (95.6) Total 928 57 (6.1) 45 (4.8) 826 (89.1) els of panel reactive antibodies as significant risk factors for the detection of C4d in protocol as well indication biopsies. Looking at the morphological features of humoral rejection and C4d showed for indication and protocol biopsies a highly significant correlation with the signs of acute tubular damage, capillaritis, and glomerulitis. Hyaline thrombi or arterial necrosis were very rarely seen at all, in both indication and protocol biopsies. Finding no significant differences in the morphology of C4d positive cases in indication biopsies (with allografts dysfunction) and protocol biopsies (without concomitant dysfunction) suggests that subclinical episodes of acute humoral rejection can be detected, although in a quite low incidence. Analyzing a short-term follow-up of such subclinical episodes of humoral rejection revealed no significant negative prognostic effect, but long term follow-up is still under observation. However, no data concerning circulating donor-specific antibodies at the time point of biopsy was available for our patients, but several groups were able to demonstrate a highly significant correlation (70-95%) between the detection of C4d and circulating allo-specific antibodies. Detecting C4d in clinically stable functioning allografts supports a recently by R. B. Colvin (Boston Massachusetts) introduced scheme of four theoretical stages of antibody-medi- 62
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