HLA antibodies (HLA-Ab) have well-recognized associations with graft failure in solid organ transplants. However, there are isolated cases of graft loss with histologic features of antibody mediated or vascular damage, which remain unexplained and the immune targets have yet to be reliably identified. Candidate assays proposed to date, though initially met with enthusiasm, have failed to acquire widespread utilization or applicability . Angiotensin II Type 1 receptor antibodies (AT1R-Ab) are proposed as an alternative mechanism for graft injury and rejection [2, 3], and a new commercial ELISA assay for AT1R-Ab has been greeted with the anticipation it will provide answers for these challenging cases.
In this edition, two studies report on the association of AT1R-Ab and kidney transplant outcomes [4, 5]. The study by Giral et al  would have been stronger if detailed testing to rule out donor specific HLA antibodies (DSA) had been performed in all recipients, rather than only those that developed biopsy proven acute rejection, leaving the antibody status of stable patients uncharacterized. In those with rejection, DSA were also detected or not tested in the majority weakening the implied associations of AT1R-Ab. Only two recipients with AT1R-Ab>10 pretransplant had reliable evidence of no DSA and both had only low levels of AT1R-Ab at the time of rejection. In outcome models, DSA was not included despite proven association with graft loss. Using the less sensitive and specific PRA >0% variable as the comparator for evaluating a novel immunologic assay is suboptimal and may erroneously underrepresent the impact of HLA-Ab.
The association of pretransplant AT1R-Ab with 3-year, but not earlier, graft loss would be more convincing if the authors had documented cause of graft failure and/or data addressing the presence of preexisting or de novo DSA . The pathophysiology of such delayed impact is difficult to explain and the clinical characteristics of these rejections are inconsistent with the initial reports of early (median 4 days) vascular rejection, prominent endarteritis, fibrinoid necrosis and malignant hypertension .
The pretransplant prevalence of AT1R-Ab positive individuals was 47% in one study and 17% in the other [4, 5]. Different study populations may account for this but the variance is concerning and one must consider that such large differences could involve assay precision. The positive cut-off differs between studies and conclusions regarding the significance of pretransplant AT1R-Ab do not align [3-6]. If Taganuchi et al had used the same cut-off as the Giral study for posttransplant antibodies, considerably more patients without graft failure would have been positive, weakening the magnitude of their findings.
Taganuchi et al report that pretransplant AT1R-Ab are not predictive of clinical outcomes, but they observed an increased risk of graft loss with de novo AT1R-Ab alone or in combination with DSA. Transplant glomerulopathy as a graft failure cause is unexpectedly low as many had DSA and antibody mediated rejection on biopsy and it is unclear if the cause of failure was attributed to the original biopsy diagnosis despite significant intervals between biopsy and failure. In another series, inferior outcomes were noted where AT1R-Ab and DSA were both present, suggesting that the coexistence of these antibodies resulted in increased injury . Taganuchi et al report similar findings in the abnormal biopsy group. However comparative data were not provided for the control group or the whole study population, limiting conclusions of the validity or mechanism of this additive impact. It remains unclear whether AT1R-Ab initiate, contribute to or are consequent to an existing injury pathway.
In practical terms, only seven (5%) of abnormal biopsies had isolated AT1R-Ab when compared to 35% DSA alone and 10.5% DSA + AT1R-Ab. Overall, 45.5% had DSA ± AT1R-Ab . Similarly in the Giral study, either preexisting or de novo DSA were detected in the majority of the acute rejections. The additive value of the assay as a pretransplant screen or in routine work-up of graft dysfunction remains controversial. Currently, knowing that AT1R-Ab exist at the time of biopsy if DSA are also present is unlikely to change management. Taganuchi et al have identified these grafts as higher risk for failure but without renal function or other clinical data that impact decision making, and in the absence of known effective therapeutic interventions, one cannot presently surmise that the result adds any additional management value. Based upon the current level of evidence, we propose this assay be performed as a supplementary test where atypical pathology or graft dysfunction exists in the absence of DSA.
Rigorous studies are required to determine if the presence of AT1R-Ab truly represents an independent increased graft loss risk and if so, why. In the absence of mechanistic studies determining cause and effect, and clear documentation of known risk factors, it remains unclear how to manage a positive result, or indeed what defines positivity [3-6]. These data are essential before adoption as standard testing practice; in addition to increasing costs, added monitoring is potentially hazardous if it triggers more biopsies and altered immunosuppression without evidence that outcomes are improved.