From Banff 1991 to Today: The Changing Landscape of the v-Lesion in Kidney Transplant Rejection

Abstract

Intimal arteritis (v-lesion) has long been considered a hallmark of higher-grade T cell-mediated rejection (TCMR) in kidney transplantation, historically associated with poor graft survival and resistance to therapy. These associations have informed treatment strategies, often prompting intensified immunosuppression, including anti-thymocyte globulins (ATG). However, emerging evidence challenges the assumption that all v-lesions signify TCMR—particularly when they occur in isolation, without significant tubulo-interstitial inflammation. Recent observational studies and molecular analyses suggest that isolated v-lesions may instead reflect non-immune injury mechanisms, such as ischemia-reperfusion injury, particularly in the early post-transplant period. In addition, the shared nature of the v-lesion between TCMR and antibody-mediated rejection (AMR) raises concerns about overdiagnosis and potential overtreatment of “mixed rejection” phenotypes. Following advances in modern immunosuppression and improved donor-recipient matching, the clinical course of v-lesions may have evolved, with severe v3 presentations now rare—rendering historical comparisons less applicable to current practice. These insights highlight the need to revisit traditional paradigms and adopt a more nuanced, context-aware interpretation of v-lesions. This review integrates historical and contemporary perspectives, advocating for a reappraisal of the role of the v-lesion in kidney transplant biopsy evaluation.

Introduction

Despite ongoing advances in transplant medicine, nearly 40% of kidney allografts fail within 10 years [1–3], with rejection remaining the primary cause [4, 5]. Rejection diagnosis relies on histopathological evaluation guided by the Banff classification [6], which primarily distinguishes T cell-mediated rejection (TCMR) from antibody-mediated rejection (AMR). The severity of TCMR is determined by histological findings, with moderate to severe tubular (t2-3) and interstitial inflammation (i2-3) defining grade I, while the presence of intimal arteritis upgrades the diagnosis to grade IIa (v1), IIb (v2), or III (v3), regardless of the extent of tubulo-interstitial inflammation. Intimal arteritis (“v”) is defined by the presence of inflammatory cells in the subendothelial space of one or more arteries [7]. Banff guidelines recommend evaluating at least two arteries for adequate v-lesion scoring. Treatment strategies for TCMR vary, with many U.S. centers favoring corticosteroids for TCMR grade I and a combination of steroids and anti-thymocyte globulin (ATG) for grade II or higher [8, 9], whereas ATG use is less common in Europe [10]. These strategies are largely informed by historical studies associating v-lesions with poorer graft survival and reduced treatment response [11–15].

Recent observational cohort studies [16–19] and molecular biopsy-based analyses [20, 21] have challenged the clinical significance of v-lesions. Emerging evidence suggests that isolated v-lesions—v-lesions occurring without substantial tubulo-interstitial inflammation—may not reflect the severe rejection phenotype traditionally defined by the Banff classification. This review examines the evolving understanding of TCMR and discusses how recent insights could inform and improve future strategies for diagnosing and managing rejection.

Review

Historical Assumptions on Prognostic Significance of the v-Lesion

In the first Banff classification (1991) [22], the v-lesion was introduced as a defining feature of acute rejection. Mild-to-moderate intimal arteritis in at least one artery (v1) was classified as acute rejection grade II, while moderate-to-severe arteritis affecting more than one artery (v2) or severe intimal arteritis involving multiple arterial cross-sections and/or presenting with transmural arteritis, fibrinoid change, and smooth muscle necrosis (v3) was designated as grade III acute rejection. In this 1991 classification, significant interstitial inflammation (t2-3) with moderate tubulitis (t2) was designated as grade I acute rejection, while severe tubulitis (t3) also counted for grade II acute rejection (Table 1; Figure 1).

FIGURE 1

At the Banff 1995 meeting [32], it was proposed to differentiate grade II acute rejection based on tubulitis versus arteritis, as these forms were suggested to have distinct pathogenesis and prognostic implications. It was demonstrated [12, 13] that intimal arteritis was associated with poorer graft survival and reduced response to therapy. This refinement was formally implemented in the 1997 classification [33], where grade II and higher were reserved for cases with intimal arteritis.

Since then, the v-lesion was considered a key marker of severe rejection, with studies from the 1990s and early 2000s consistently demonstrating its negative prognostic impact on kidney allograft survival. Higher v grades were associated with increased rejection severity and worse graft outcomes (Table 2). Kooijmans et al. [11] compared 42 biopsies with acute tubulointerstitial rejection, 18 with acute vascular rejection, and 7 with diffuse thrombosis, reporting that vascular rejection was associated with more frequent rejection episodes and higher allograft loss rates. Colvin et al. [12] found that vascular rejection (N = 24) resulted in worse clinical outcomes than rejection characterized by tubulitis with interstitial infiltration (N = 94). Nickeleit et al. [13] observed that patients with vascular rejection (N = 35) had a significantly lower response to steroid treatment compared to those with tubulitis and interstitial inflammation (N = 20), though both groups responded similarly to ATG and had comparable one-year graft failure rates.

Further supporting these findings, Mueller et al. [14] analyzed 35 biopsies (7 borderline, 11 TCMR grade I, 10 TCMR grade II, 7 TCMR grade III), demonstrating that TCMR grade I-III correlated with treatment unresponsiveness and increased graft failure risk. Minervini et al. (2000) [15] compared 36 cases each of t1, t2, and t3 tubulitis, as well as 36 v1, 18 v2, and 11 v3 cases, irrespective of t scores. These findings confirmed that v2/v3 intimal arteritis had the poorest prognosis, surpassing v1 and all tubulitis grades without concurrent intimal arteritis, while severe tubulitis (t3) had outcomes comparable to v1.

Several limitations of earlier studies warrant consideration. Many did not account for concomitant tubulointerstitial or microvascular inflammation—both of which can independently affect outcomes—and often failed to assess donor-specific antibodies (DSA). Inclusion criteria for acute rejection subtypes were inconsistent, with some studies not adhering to Banff-defined thresholds. Most lacked multivariable analyses to adjust for confounding clinical factors, were limited by small sample sizes, and frequently included repeat biopsies, complicating survival analysis by counting some patients multiple times. Additionally, follow-up durations were often insufficient to capture the long-term impact of rejection phenotypes.

The Concept of “Isolated v” as a Distinct Phenotype

At the Banff 2009 conference [43], a working group on isolated v was established to assess its significance in renal allograft biopsies. This initiative stemmed from growing uncertainty regarding the clinical relevance of isolated arteritis in biopsies that lacked significant tubulointerstitial inflammation and, therefore did not meet the Banff criteria for grade I TCMR. A study by Sellarès et al. [26] found no correlation between v-lesions and graft failure risk, whether analyzed as v0 (N = 88) versus v > 0 (N = 19) or stratified by intimal arteritis severity (v1-2-3). Additionally, microarray analyses [27] revealed minimal inflammatory gene expression, including low levels of T cell activation, IFN-γ, and chemokines, in isolated v biopsies.

These findings led to the initiation of a multicenter retrospective case-control study to further investigate the clinical implications of isolated v. Presented at the 2013 Banff conference [44], the study defined isolated v as intimal arteritis with minimal interstitial inflammation (i ≤ 1) and tubulitis (t ≤ 1) [28]. The results demonstrated that isolated v (N = 103) had comparable treatment response rates and graft survival to v-lesions with significant tubulo-interstitial inflammation (N = 101, v1 with t2-3, i2-3). The Banff 2013 meeting report suggested that “most isolated v-lesions should be reported as type 2 (or 3) acute TCMR.” [44]

However, several limitations should be acknowledged. Some patients had concurrent AMR or microvascular inflammation (MVI), likely confounding the findings. As a case-control study, it was also inherently prone to selection bias. Importantly, the study did not address cases with v1 in combination with either t2–3/i0–1 or t0–1/i2–3, leaving uncertainty about how to classify and manage such presentations. Moreover, the conclusion that “most” isolated v-lesions represent severe TCMR remains vague, as no practical guidance was offered to support its implementation in clinical decision-making.

Recent Data on the Clinical Relevance of Isolated v-Lesions

Over the past decade, accumulating evidence suggests that isolated v may represent a benign phenotype, with multiple studies reporting favorable outcomes. Isolated v has been associated with treatment responses and graft survival rates comparable to—or even better than—those observed in TCMR with significant tubulo-interstitial inflammation (Table 2). Salazar et al. [20] found that the presence of v-lesions (N = 49) did not increase the risk of graft failure compared to v-negative biopsies (N = 654). Novotny et al. [17] concluded that isolated v cases (N = 25) responded well to steroid treatment, showed no persistence of arteritis in follow-up biopsies, and had favorable graft outcomes. Similarly, Nankivell et al. [29] demonstrated that isolated v (N = 34) was associated with better graft survival than vascular rejection cases with concomitant tubulo-interstitial inflammation (N = 66). Also, Lefaucheur et al. [30] found no significant difference in outcomes up to 72 months post-transplant when comparing TCMR with v-lesions (N = 26) to TCMR without v-lesions (N = 139). In a multicenter observational cohort study [19] (707 v-lesion positive biopsies out of a total of 16,774 biopsies, corresponding to 534 transplants) we reported that isolated v-lesions were linked to superior 10-year graft survival compared to biopsies with t and i scores meeting or exceeding the borderline threshold, as well as biopsies fulfilling (probable) AMR/MVI criteria in the absence of significant tubulo-interstitial inflammation. Furthermore, when matching the 534 v-positive cases to v-negative controls, no significant impact of v-lesions on outcomes was observed.

A 2015 study [39] comparing 80 v1 cases to 51 v2 and 17 v3 cases concluded that higher-grade v-lesions (v2 and v3) were associated with significantly poorer response to rejection treatment and lower 8-year death-censored graft survival, with outcomes being more favorable in v1 cases. The study included patients who received kidney transplants between 1996 and 2012. It should be noted that the prevalence of v-lesions in recent observational cohort studies was relatively low, reported at, 2.7% [29], 4% [19, 30], 7% [20] and 9.7% [17], with the majority classified as mild (v1). The rarity of v3 lesions has generally limited the ability to perform meaningful analyses of this severe phenotype in recent studies.

Several factors likely contribute to the low detection rate of v-lesions in kidney allograft biopsies. Most biopsies contain only one to five arterial cross-sections, as arteries represent a small fraction of the total biopsy area compared to tubules and glomeruli. Moreover, rejection-related inflammation is often focal, and arteritis may affect only a segment of the arterial circumference, reflecting a patchy distribution. Together, these factors increase the risk of sampling bias. In addition, reproducibility may also be limited by interobserver variability, as some pathologists rely solely on morphology, while others incorporate immunohistochemical staining.

Nonetheless, the vascular rejection phenotype described in earlier studies may not reflect what is commonly observed today. Historically, vascular rejection was often hyperacute, characterized by severe arteritis, thrombosis, and frequent graft loss. Advances in immunosuppressive therapies [45, 46] and improved donor-recipient matching—particularly the avoidance of recipients with pre-transplant donor-specific HLA antibodies [47]—have significantly reduced the incidence of such severe presentations. Moreover, the current Banff definition of intimal arteritis has a notably low diagnostic threshold, requiring only a single inflammatory cell in the subendothelial space to classify a biopsy as v1 (TCMR grade IIA) [7] This raises the question of whether the v-lesions reported in older studies represent the same pathological process examined in more recent research.

Clinical Factors Related to Isolated v-Lesions

Timing post-transplantation is a key factor in the interpretation of isolated v-lesions. Rabant et al. [16] (N = 33) reported a median of 27 days post-transplantation for biopsies demonstrating isolated v-lesions. Nankivell et al. [29] found that early intimal arteritis (≤1 month, N = 51) was associated with delayed graft function (DGF) and transient elevations in serum creatinine, but generally responded well to therapy. In contrast, late-onset arteritis (>1 month, N = 49) was more frequently associated with chronic fibrosis and graft loss. Buxeda et al. [21] reported that early (≤1 month) isolated v-lesions (N = 10) were associated with the poorest 1-year death-censored graft survival when compared to late isolated v-lesions (N = 13), or to TCMR with v (N = 10), AMR with v (N = 26), and mixed rejection with v (N = 23). In this cohort, 75% of early isolated v cases were associated with DGF, 60% progressed to primary non-function, and all graft losses in this group were due to this early event. However, the study lacked long-term follow-up, and the high proportion of expanded criteria donor kidneys likely increased vulnerability to delayed graft function [48–50]. In contrast, Sellarés et al. [26] (N = 19) compared the prognostic significance of intimal arteritis in biopsies performed within the first year (≤1 year) versus after 1 year (>1 year). Unlike studies focused on the immediate post-transplant period (e.g., ≤1 month), this analysis did not find an association between v-lesions and allograft loss.

In addition, early isolated v-lesions are frequently identified in the absence of donor-specific anti-HLA antibodies (DSA). Several studies [16, 19–21] have reported low DSA positivity rates in early isolated v-lesions, in contrast to higher DSA prevalence in late-onset v-lesions or in cases associated with AMR or mixed rejection.

These findings have led to the hypothesis that early isolated v-lesions may reflect non-immune vascular injury—such as vascular trauma or ischemia-reperfusion injury related to the transplantation procedure—rather than alloimmune rejection [16, 17, 20].

Finally, arteritis is not pathognomonic for rejection. Arterial inflammation may also result from recurrent or de novo vasculitis (e.g., ANCA-associated vasculitis, cryoglobulinemia, IgA vasculitis) or appear adjacent to vascular thrombosis, even in the absence of histological rejection.

v-Lesions in the Context of AMR

While the definitions by the Banff Working Group of “isolated v” were developed in relation to full TCMR [28], another important aspect of intimal arteritis in kidney transplant biopsies, is its non-specificity for TCMR. When AMR was first defined in 2001, v3 was already included among the histological criteria (Table 1; Figure 1). At the 2013 Banff meeting [44], it was further concluded that v1 and v2 should also be considered part of the AMR histologic criteria. This decision was based on findings by Lefaucheur et al. [30], who reported that AMR with v was associated with a worse prognosis than AMR without v. However, only eight out of 64 HLA-DSA-positive cases in their study had v-lesions as the only histologic feature of AMR, making it impossible to assess outcomes specifically in this subgroup. Additionally, AMR with v was associated with a higher incidence of t- and i-lesions, which correlated with graft loss. Since the primary analysis comparing AMR with and without v did not adjust for concomitant tubulointerstitial inflammation, it remains unclear whether the worse outcomes in AMR with v cases were driven by the v-lesion itself or by coexisting tubulointerstitial inflammation.

Since then, the relationship between AMR and intimal arteritis, in the absence of TCMR, has been studied only scarcely (Table 2). Rabant et al. [16] found that graft survival up to eight years after the index biopsy was significantly lower in AMR with v (N = 54) compared to isolated v cases (N = 33). Similarly, Novotny et al. [17] reported that AMR with v (N = 19) was associated with worse three-year graft survival compared to isolated v (N = 25). In addition, the presence of intimal arteritis in AMR was a significant risk factor for progression to transplant glomerulopathy, irrespective of DSA status, but was not associated with an increased risk of graft failure at 36 months [40]. Salazar et al. [20] also concluded that the presence of v-lesions did not increase the risk of graft failure when analyzed in biopsies diagnosed with AMR (N = 17). In a recent multicenter observational cohort study (707 v-lesion positive biopsies, derived from 534 transplants) [19], we observed no difference in 10-year graft survival between cases with a Banff category 2 diagnosis and a v-lesion and those with a category 2 diagnosis without a v-lesion. The study also highlighted the risk of overinterpreting the presence of a v-lesion in (probable)AMR/MVI cases as indicative of mixed rejection when significant tubulo-interstitial inflammation is absent. Notably, cases diagnosed as “mixed rejection” solely due to the presence of a v-lesion had better clinical outcomes than those with both (probable)AMR/MVI and marked tubulo-interstitial inflammation—classified in the study as true “mixed rejection.”

Nevertheless, it is important to note that in studies using biopsies obtained before 2013, v1 and v2 lesions were not included in the diagnostic criteria for AMR. As a result, v-lesions in the context of AMR may have been interpreted and managed as TCMR, in accordance with the Banff classification at that time.

The Pathogenesis of Intimal Arteritis

Since 2017, the Banff classification has recommended biopsy-based transcript analysis to support the differential diagnosis of AMR, TCMR, mixed rejection in isolated v cases that lack MVI and TCMR features, are C4d-negative, and may or may not have DSA [31]. This recommendation underscores the added value of molecular tools to clarify ambiguous cases.

Reeve et al. [37] developed a TCMR score using microarray analysis of 403 kidney transplant biopsies and found that while the score correlated strongly with interstitial inflammation (i) and tubulitis (t), 79% of isolated v-lesions had low TCMR scores. A prospective validation study [38] (N = 300) confirmed that discordance between histology and molecular findings often stemmed from TCMR diagnoses based solely on isolated v-lesions. In a third study, the same team [20] compared 28 isolated v-lesions to 21 biopsies with i-t-v lesions and found that 95% of the latter had positive TCMR scores, whereas only 21% of isolated v-lesions did. Most early (≤1 year post-transplantation) isolated v-lesions lacked molecular rejection signals, whereas those occurring beyond 1 year more frequently exhibited molecular AMR signatures. Logistic regression models trained on molecular diagnoses confirmed that TCMR scores were primarily driven by i and t, but not v [42]. Similarly, studies using the NanoString Banff Human Organ Transplant (B-HOT) panel [51] showed that TCMR-associated gene sets correlated strongly with i and t [41], but not with v [21]. Moreover, early isolated v-lesions (≤1 month post-transplant) demonstrated increased expression of early injury-response genes compared to late-onset cases (>1 month), further supporting a non-immune injury mechanism in the early post-transplant period. While advances in molecular diagnostics have enhanced our understanding of these biopsies, the focal nature of intimal arteritis may still lead to false-negative results due to sampling limitations [52].

Nevertheless, the underlying pathogenesis and cellular composition of intimal arteritis remain poorly characterized. While earlier studies primarily associated intimal arteritis with CD4⁺ and CD8⁺ T cell infiltration, more recent evidence suggests a broader immune response involving both T lymphocytes and macrophages [35, 36]. A recent study [53] using deconvolution of bulk transcriptomic data found that v-lesions were most strongly associated with innate immune cells—such as NK cells and monocytes/macrophages—similar to other vascular lesions like peritubular capillaritis and glomerulitis.

These findings suggest that innate immunity may contribute to the pathogenesis of intimal arteritis. In particular, early isolated v-lesions may reflect endothelial stress and innate immune activation following ischemia-reperfusion injury. This process induces endothelial and parenchymal damage, releasing damage-associated molecular patterns (DAMPs) [54–57] engage pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), on endothelial and immune cells. PRR signaling promotes cytokine release, interferon production, and regulated cell death, amplifying local inflammation and recruiting additional immune cells. Concomitantly, endothelial activation upregulates adhesion molecules (e.g., P-selectin, ICAM-1), promoting platelet adhesion and degranulation. Platelet-derived mediators amplify inflammation and recruit monocytes, neutrophils and T cells [58]. In parallel, stress-induced changes in HLA expression—such as downregulation of classical HLA-I and upregulation of non-classical HLA-I and NKG2D ligands (e.g., MICA, MICB, ULBPs)—can trigger NK cell–mediated cytotoxicity [59, 60]. Persistent injury may also expose cryptic self-antigens (e.g., AT1R, perlecan, collagen V), triggering non-HLA autoantibody responses [61, 62]. These antibodies can form immune complexes that activate Fc receptors or complement pathways, amplifying cytokine release, endothelial damage, and vascular inflammation. However, whether these mechanisms directly contribute to the pathogenesis of intimal arteritis remains uncertain and warrants further investigation.

Given their association with favorable outcomes, early isolated v-lesions are presumed to potentially resolve spontaneously if the inciting insult wanes and immune activation diminishes. However, it remains unclear whether and how this resolution occurs, and whether there is a place for specific therapeutic interventions.

The mechanisms underlying intimal arteritis in TCMR also remain incompletely understood. Donor HLA antigens activate recipient T cells via direct or indirect allorecognition [63], promoting T cell–endothelium interactions through upregulated HLA expression. This may lead to cytokine release and direct cytotoxicity via perforin/granzyme or Fas/FasL pathways [64, 65]. Alternatively, v-lesions—like peritubular capillaritis—may result from increased leukocyte trafficking in areas of interstitial inflammation, without direct endothelial targeting. In contrast, the mechanisms driving arteritis in AMR are better defined: DSAs bind activated endothelium, triggering complement activation and antibody-dependent cellular cytotoxicity (ADCC), primarily mediated by NK cells or monocytes via Fc receptor engagement [66]. In both TCMR and AMR, immune infiltration into the subendothelial space gives rise to intimal arteritis, which can progress to transmural inflammation, smooth muscle necrosis, fibrin deposition, and vascular occlusion in severe cases.

While much remains unknown, v-lesions are clearly a heterogeneous finding whose clinical significance depends on timing post-transplant, immunologic risk (e.g., HLA-DSA status), and coexisting features suggestive of AMR, TCMR, or recurrent disease. Traditional histology offers limited specificity in isolated v-lesions, but emerging tools—such as (spatial) transcriptomics, integrated within multi-omics frameworks—may offer new biological insights. Refining the diagnostic role of v-lesions in the Banff classification will require a context-aware approach that accounts for both immune and non-immune causes of vascular injury.

Discussion

The Banff classification has provided a crucial framework for diagnosing rejection in kidney transplantation, enabling consistency in histopathological assessment across centers worldwide. However, as transplant medicine evolves, so too must our understanding of the clinical significance of specific histological lesions.

Long regarded as a hallmark of moderate-to-severe T cell-mediated rejection (TCMR), the v-lesion is now recognized as a heterogeneous entity. Emerging evidence challenges the assumption that all v-lesions signify TCMR, particularly when they occur in isolation without substantial tubulo-interstitial inflammation. Furthermore, advances in immunosuppressive therapy and improved donor-recipient matching may have fundamentally altered the clinical course of intimal arteritis, raising doubts about whether historical interpretations remain applicable to contemporary transplant populations.

A clear and consistent definition of “isolated v” is essential before its role within the Banff classification can be meaningfully reconsidered. The 2009 Banff isolated v working group [28, 43] proposed defining “isolated v” as intimal arteritis with minimal interstitial inflammation (i ≤ 1) and tubulitis (t ≤ 1). However, cases fulfilling the Banff criteria for borderline TCMR (t1i1), and having v lesions, should likely not be called isolated v, as this would lead to the contradiction that “borderline TCMR” is often treated [9, 10], while the term “isolated v” designates a potentially more benign phenotype. In recent study [19] we proposed a definition more aligned with current Banff thresholds, distinguishing isolated v (v > 0, t0–3i0 or t0i0–3) from borderline TCMR (v0, t1–3i1 or t1i1–3), TCMR I (v0, t2–3i2–3), and TCMR II–III (v > 0, t1–3i1–3). While classifying t2–3i0 or t0i2–3 as isolated v may seem counterintuitive, such cases were rare (2.8% of v-lesion positive biopsies) in our study. In these instances, case-level pathology review is essential to determine whether tubulitis or interstitial inflammation is truly isolated. Tools such as the activity indices by Vaulet et al. [67] or molecular diagnostics such as the B-HOT panel [51] may help refine classification and inform treatment decisions in these exceptional cases.

Second, the prior definitions used by the Banff Working Group [28] did not account for the relationship between intimal arteritis and AMR, leaving it unclear whether v-lesions in AMR represent concurrent TCMR (“mixed rejection”). This is further complicated by the lack of a clear Banff definition for mixed rejection, making shared lesions like v difficult to interpret and potentially leading to overdiagnosis and overtreatment of mixed phenotypes [19]. In such cases, the v-lesion may be more appropriately interpreted as a manifestation of AMR, particularly when other histologic features of TCMR are absent. A more coherent approach would classify these as (probable) AMR/MVI with v, and reserve “isolated v” for biopsies lacking both AMR/MVI and tubulo-interstitial criteria for (borderline) TCMR. Refining the role of the v-lesion within the Banff classification does not mean abandoning its significance but rather integrating new insights to enhance diagnostic precision. Importantly, clinical practice is already evolving, as a recent survey indicated that many European transplant centers no longer treat isolated v-lesions with ATG [10].

The Banff process has always been one of evolution, shaped by emerging data and expert consensus. The challenge now is how best to incorporate these new insights while maintaining a classification system that remains clinically relevant and widely applicable. Over a decade ago, Salazar et al. [20] cautioned that “isolated v-lesions have been seriously misinterpreted for over 20 years, potentially leading to inappropriate treatment decisions.” With accumulating clinical and molecular evidence, the Banff classification may need to adapt and reconsider the specific definition of an “isolated v” phenotype.

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