Banff Working Group Defines Pathological Diagnostic Criteria for Thrombotic Microangiopathy in the Renal Allograft

Thrombotic microangiopathy (TMA) is a clinicopathologic entity characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ injury occurring due to endothelial damage and microthrombi formation in small vessels. Kidney transplantation poses a challenging setting due to multiple potential triggers or mimickers (drugs, infections, and/or immunological factors) of TMA. Prompt recognition and timely treatment are critical to prevent allograft loss.

Post-transplant TMA (Tx-TMA) can be recurrent or de novo. Although recurrent TMA is almost always complement-mediated, de novo Tx-TMA may be complement-mediated or secondary to one of the above triggers. To overcome the challenges of a clinical diagnosis in the presence of multiple triggers, a kidney transplant biopsy is sometimes performed to establish a more definitive diagnosis. Moreover, de novo TMA can often be renal-limited and only identified on a biopsy. Histologically, the hallmark finding of TMA is the presence of thrombi, which can affect glomerular capillaries, arterioles, or arteries, although the absence of thrombi may be due to a sampling issue and should not lead to the exclusion of a TMA diagnosis. Similarly, there are a multitude of other histological parameters that vary in extent and frequency and rely on the interpretation by the pathologist.

To address this issue and standardize the histological diagnostic criteria, the TMA Banff Working Group convened a panel of 23 expert nephropathologists and used a modified Delphi method (1). Delphi is a structured process that involves a series of rounds during which an expert panel shares its opinion on specific questions with controlled feedback from a facilitator. The panelists remain anonymous during surveys to ensure that their interactions remain unbiased. The process continues through multiple iterations until a reliable consensus is reached. This method does not require a physical meeting for the participants, and all interactions are designed to be online (2). Out of the 338 diagnostic criteria initially proposed, following 9 rounds of deliberation, the panelists reached a consensus on 24 diagnostic criteria, including 18 pathologic, 2 clinical, and 4 laboratory criteria (see those with the highest level of agreement among nephropathologists in Table 1).

Table 1

Diagnostic criteria and differential diagnoses with the highest level of agreement among nephropathologists

View Table

The work, undertaken by the TMA Banff Working Group, constitutes a significant step forward in defining the characteristics of Tx-TMA. The authors note the first-time use of Delphi method for Banff classification. Other strengths of the study include use of real-world clinical cases in an attempt to establish differential diagnoses and define acute and chronic features. A major challenge, however, was the lack of consensus on whether antibody-mediated rejection is a trigger or mimicker or falls in the spectrum of TMA differential diagnosis. The authors acknowledge this as an area of controversy and note that a follow-up study that will seek consensus among nephrologists is ongoing to help clarify this conflict and to further refine the laboratory and clinical criteria that may be specific for Tx-TMA.

This study was focused on establishing uniform diagnostic criteria for Tx-TMA, since the authors point out several differences in TMA between native and transplanted kidneys. However, it is important to note that TMA can occur as a manifestation of a systemic disease (such as complement-mediated TMA or lupus) in both the native kidney and after a transplant. Tx-TMA can manifest signs of systemic hemolysis, and TMA in the native kidney is not always a manifestation of a single disease (3). Therefore, the results may also be largely applied to the native kidney. Other minor aspects that need further clarification include the use of terms “acquired HUS [hemolytic uremic syndrome]” and “donor-related TMA,” as acquired HUS may refer to complement-mediated TMA from acquired factors (such as factor H autoantibodies). Personal communication between the authors and panelists (A.J. with M. Afrouzian) helped to clarify that donor-related TMA refers to donor-derived, renal-limited TMA seen in the allograft, particularly when the kidney is procured from donors who died of head trauma or had a history of cocaine or other drug use. Such patients may present with delayed graft function, and biopsy performed in the first 1 to 4 weeks after transplant demonstrates a TMA.

Overall, the TMA Banff Working Group should be applauded for this massive undertaking and its efforts to address critical knowledge gaps in this evolving area. Perhaps the use of newer pathology tools, such as digital and computational pathology, or spatial transcriptomics will be helpful in achieving this goal in the near future. Meanwhile, results from the follow-up study are enthusiastically anticipated.