LAUSR

Renal transplantation (RTx) is the gold standard treatment for patients with endstage renal disease (ESRD). Numerous improvements have increased shortterm graft survival. However, in the long term, rates of renal allograft loss have not changed. It is being increasingly recognized that B cells play an important role in longterm renal allograft attrition through the development of HLAspecific antibodies. Antibodymediated rejection (ABMR) can occur in patients with preexisting antiHLA donorspecific antibodies (pDSA) or in patients who develop de novo DSA (dnDSA). pDSAassociated ABMR is uncommon, in part because most centers generally avoid transplantation of DSApositive patients across a positive crossmatch. The advantages of transplantation over dialysis, and encouraging results in selected DSApositive transplants, have led, however, to more frequent acceptance of this constellation in adults.1 In this issue of Pediatric Transplantation, Steggerda et al shed light on the role of pDSA compared with dnDSA on ABMR in a small cohort of pediatric renal transplant recipients.2 As their main finding, the authors point out the temporal difference of clinical course in their groups of patients with pDSA and dnDSA. Transplant recipients who developed dnDSA showed ABMR significantly later (1344 versus 63 days after RTx) with predominance of HLA class II antibodies. The authors confirm the concept of type 1 ABMR (early rejection after RTx due to persistence of preformed DSA) versus type 2 ABMR (late rejection associated with dnDSA) in the pediatric population. According to earlier reports, they assume viral infections and underimmunosuppression as a consequence of noncompliance as the main reasons for the development of dnDSA. In their cohort, noncompliance was based on families’ selfreport and not underlaid by measurement of drug exposure or variability in trough levels. Without any doubt, the impact of both underand overimmunosuppression is profound and represents key challenges that have not been satisfactorily resolved at this time. In the current study, no patient with pDNA underwent a defined desensitization protocol, but all of them received a single dose of alemtuzumab on the day of transplantation. Of interest, alemtuzumab is not licensed for this use. The potentially higher burden of intensified immunosuppression in the group of presensitized pediatric renal transplant recipients with respect to infections and new cancer has to be considered. Of note, patients with pDSA displayed worse graft function at the time of biopsyproven ABMR as well as 1 year posttreatment compared to patients with dnDSA. The difference in eGFR did not reach statistical significance, which might be due to low patient numbers. However, this is remarkable as it challenges the finding in adult renal transplant recipients in whom dnDSA formation and not existence of pDSA was an independent determinant of allograft loss.3 Likewise, histopathologic findings in the 2 patient groups must be regarded with caution due to the small patient numbers. Nevertheless, C4d positivity was less pronounced in patients with ABMR due to pDSA. Consequently, clinicians should be aware of C4dnegative ABMR. It is a limitation of this study that there was no control group in terms of treatment. Nevertheless, it is crucial to point out that ABMR with dnDSA seems to be more aggressive and difficult to treat. One obvious implication, also reflected by the high amount of antiHLADQ antibodies in cases of de novo DSA formation in other studies, is the need for evaluating HLADQ compatibility in kidney allocation to minimize posttransplant development of dnDSA. Steggerda et al only did histological studies in patients with strong MFI > 10 000 or renal dysfunction. This is comprehensible in a clinical setting. Due to the potentially slow and indolent process of ABMR, one would wish for future studies that also patients with weak and moderate DSA mean fluorescent intensity are investigated for their clinical course and especially their pathology. It is worth mentioning that no patient with pDSA has developed additional dnDSA in this study. There has been a growing body of knowledge on the meaning of dnDSA over the last couple of years that has demonstrated a clear association of dnDSA with poor graft outcome. This has also led to recommendations to introduce dnDSA screening in renal transplant recipients. The progress of knowledge in pediatric cohorts is very well reflected by the studies of Fabrizio Ginevri’s group in Genova, Italy, who followed a rather large group of nonsensitized pediatric renal transplant recipients over a long period: