We thank the authors for this useful commentary¹ on our paper analyzing DSA-negative molecular ABMR,² although we disagree to some extent with the conclusions.

Our data found that in the INTERCOMEX population with molecular ABMR, DSA negativity is very common, particularly in early-stage ABMR but also in late-stage ABMR. On average, DSA-negative ABMR was earlier, less intense (i.e. lower ABMR-associated gene expression), and more often C4d-negative, but was virtually identical to DSA-positive ABMR in the top differentially expressed ABMR-associated transcripts. We could not find distinct molecular differences between DSA-negative and DSA-positive ABMR, other than some small increases in injury-related transcript expression, which may be explained by the earlier mean time posttransplant. We have recently confirmed the main points in the new Trifecta-Kidney analysis, where we show that both molecular and histologic ABMR are approximately 50% DSA-negative.³ In Trifecta-Kidney, DSA-negative ABMR is slightly less molecularly active, but still releases donor-derived cell-free DNA at levels similar to that seen in DSA-positive ABMR.³

The main point is that within all ABMR—DSA-negative or DSA-positive—there is extensive heterogeneity in intensity and stage. Type 1 ABMR (in patients with DSA before transplantation) behaves differently from type 2 ABMR with de novo DSA.⁴ In addition, there is a subtle minor ABMR-related process in many biopsies that we have been calling negative for ABMR because they fall below the arbitrary thresholds for ABMR established both in MMDx and histology.⁵ We must start thinking of ABMR-related molecular and histologic changes as a broad spectrum.

At the moment, it is unlikely that distinct disease mechanisms operate in DSA-negative versus DSA-positive ABMR. These labels can be retained as reminders of one aspect of the heterogeneity within ABMR, as long as the much greater heterogeneity in intensity, stage, and duration is recognized. We are in a new era of appreciating the diversity within the ABMR phenotype and its relationship to pathogenic mechanisms. More importantly, management issues are critical: we do not really know how to manage DSA-positive ABMR or DSA-negative ABMR, or for that matter how to adjust management based on other aspects of heterogeneity in the ABMR spectrum. We should keep an open mind on how we should ultimately classify these common, important, and heterogeneous disease states.

我们感谢作者对我们分析 DSA 阴性分子 ABMR 的论文^{2发表的有用评论1} ，尽管我们在某种程度上不同意这些结论。

我们的数据发现，在具有分子 ABMR 的 INTERCOMEX 人群中，DSA 阴性非常普遍，特别是在早期 ABMR 和晚期 ABMR 中。平均而言，DSA 阴性 ABMR 出现得更早，强度更小（即较低的 ABMR 相关基因表达），更常见的是 C4d 阴性，但在顶部差异表达的 ABMR 相关转录物中几乎与 DSA 阳性 ABMR 相同。我们无法发现 DSA 阴性和 DSA 阳性 ABMR 之间存在明显的分子差异，除了损伤相关转录物表达的一些小幅增加，这可能是由于移植后平均时间较早。我们最近确认了新的 Trifecta-Kidney 分析的要点，其中我们显示分子和组织学 ABMR 均为大约 50% DSA 阴性。^3个在 Trifecta-Kidney 中，DSA 阴性 ABMR 的分子活性略低，但仍以与 DSA 阳性 ABMR 相似的水平释放供体来源的无细胞 DNA。^3个

要点是，在所有 ABMR（DSA 阴性或 DSA 阳性）中，强度和阶段存在广泛的异质性。1 型 ABMR（在移植前患有 DSA 的患者中）与具有新发 DSA 的 2 型 ABMR 表现不同。⁴此外，在许多活检中有一个微妙的 ABMR 相关过程，我们一直将其称为 ABMR 阴性，因为它们低于 MMDx 和组织学中建立的 ABMR 的任意阈值。⁵我们必须开始将 ABMR 相关的分子和组织学变化视为广谱变化。

目前，不同的疾病机制不太可能在 DSA 阴性和 DSA 阳性 ABMR 中起作用。这些标签可以保留下来，作为 ABMR 内部异质性的一个方面的提醒，只要在强度、阶段和持续时间方面更大的异质性得到认可。我们正处于一个了解 ABMR 表型多样性及其与致病机制关系的新时代。更重要的是，管理问题很关键：我们真的不知道如何管理 DSA 阳性 ABMR 或 DSA 阴性 ABMR，或者就此而言如何根据 ABMR 谱中异质性的其他方面调整管理。我们应该对最终如何对这些常见的、重要的和异质的疾病状态进行分类保持开放的态度。