During the past two decades, there has developed an increasing awareness of antibody-mediated rejection (ABMR) as an important cause of both short-term and long-term injury to renal allografts [1–3]. Acute rejection in the presence of donor-specific anti-HLA antibodies (DSAs) shows histologic changes very different than those of acute T-cell-mediated rejection (TCMR), and is characterized by microvascular injury and inflammation, including margination of neutrophils and mononuclear leukocytes (later documented to be monocytes/macrophages ) in peritubular and glomerular capillaries, thrombotic microangiopathy (TMA) and, in severe cases, fibrinoid necrosis of arterioles and small arteries . However, antibody usually cannot be detected in the microvasculature by immunofluorescence microscopy , and these morphologic changes are not specific for ABMR, and can be seen with other causes of endothelial injury, including acute calcineurin inhibitor nephrotoxicity and recurrent TMA [6–9].
The utilization of staining for C4d by immunofluorescence or immunohistochemistry has, thus, been an important development in allowing pathologists to more accurately diagnose acute ABMR in allograft biopsies, and in recognizing the contribution of humoral immunity to lesions of chronic renal allograft rejection [10–18]. Although C4d, formed upon cleavage of complement factor C4, a component of the classical complement pathway, is itself biologically inactive, it binds covalently at the site of C4 cleavage, rendering it a relatively long-lived marker for humoral immunity . At the 2001 Banff Conference on Allograft Pathology , consensus diagnostic criteria for acute ABMR in renal allografts were adopted that require immunopathologic evidence in the form of C4d deposition in peritubular capillaries (ptc), as well as morphologic evidence (microvascular lesions as noted above) and the presence of DSA (Table 1). Subsequently, at the 2007 Banff Conference , similar diagnostic criteria for chronic, active ABMR were adopted, also requiring C4d and DSA for diagnosis, in addition to morphologic evidence of chronic tissue injury (Table 2). In each case, if morphologic evidence was present with C4d or DSA but not both, the biopsy findings were designated as suspicious for ABMR.
During the past several years, however, we have come to recognize limitations of these diagnostic criteria. First and foremost, it is now well documented that DSA may cause graft injury in the absence of C4d deposition. Second, there is now evidence that intimal, nonnecrotizing arteritis, previously thought to represent acute TCMR, may in the presence of DSA be (at least in part) humorally mediated. Noting these findings, updated consensus diagnostic criteria for ABMR were developed and agreed on at and during the weeks following the 12th Banff Conference on Allograft Pathology that was held in August 2013 in Comandatuba, Brazil [22▪▪]. In addition, studies of the Banff Working Group (BWG) on glomerular lesions led to revised consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score) with improved interobserver agreement and correlation with clinical, molecular, and serologic data.
FINDINGS OF THE BANFF GLOMERULAR LESIONS WORKING GROUP
A BWG was formed at the 2009 Banff Conference to explore potential revisions to the definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score) that would improve interobserver agreement and correlation with clinical, molecular, and serologic data. Changes made to these definitions and thresholds were based on two independent sets of 30 and 17 biopsies (periodic acid–Schiff and silver methenamine stains), respectively. These cases, selected to represent the full range of g and cg scores (according to existing Banff criteria [20,21,22▪▪,23]), were scanned and scored as virtual slides by 21 and 15 pathologists, respectively, who were blinded to clinical and serologic data and C4d results. The pathologists had a wide range of experience and specialization. For the first slide circulation (30 biopsies), pathologists scored each case according to eight individual sets of definitions and thresholds for the g score and six for the cg score. Only those definitions/thresholds for g (three total) and cg (two total) showing the highest kappa scores were used for the second slide circulation (17 biopsies).
For glomerulitis, the best interobserver agreement and correlation with C4d scores, gene expression profiles of endothelial activation and injury (endothelial activation and injury transcripts, ENDATs) , and DSA-associated gene transcription profiles (DSASTs)  were seen with a definition that includes complete or partial occlusion of at least one glomerular capillary by leukocyte infiltration and endothelial cell enlargement (Fig. 1a). Determination of the numerical g score is still based on the percentage of involved glomeruli as previously [21,23]: 1–25, 26–50, and more than 50% for g1, g2, and g3, respectively. Scoring of glomerulitis based on these fractions of involved glomeruli using the aforementioned definition was superior to scoring based on numbers of leukocytes per glomerulus, even when CD68 staining was added, although the latter was included only in the second set of biopsies and further investigation may be warranted. Addition of CD68 staining did not improve interobserver agreement when glomerulitis was scored using the definition that includes endothelial enlargement/capillary occlusion. Whether such agreement would be improved by addition of a threshold number of leukocytes/glomerulus to the current definition, as suggested by Batal et al., is an issue for future consideration.
For the cg score, interobserver agreement was best with scoring based on the fraction of involved glomeruli and a threshold of glomerular basement membrane (GBM) double contour(s) in at least one capillary loop in a single glomerulus (Fig. 1b), as opposed to the current threshold of at least 10% of capillary loops in the most severely involved glomerulus [21,23]. Furthermore, better correlations with anti-class II DSA and ENDATs were seen with the lower threshold.
Interobserver agreement was fair to moderate for the g score (κ = 0.31 in the second slide circulation) and somewhat better for the cg score (0.47).
Scoring of cg in these trials was based entirely on light microscopy. However, Wavamunno et al. demonstrated that endothelial and GBM lesions detectable within the first 3 months posttransplantation by electron microscopy are highly correlated with later development of overt transplant glomerulopathy (GBM double contours by light microscopy). Subsequent studies [28,29,30▪] have confirmed and extended these findings, demonstrating that endothelial swelling, subendothelial electron-lucent widening, and early GBM duplication by electron microscopy (Fig. 1c) are highly correlated with DSA. Accordingly, at the 2013 Banff Conference [22▪▪], it was determined that electron microscopic findings should be incorporated into the definition of the cg score as follows:
1. cg0 – no GBM double contours by light microscopy or electron microscopy
2. cg1a – no GBM double contours by light microscopy, but GBM double contours (incomplete or circumferential) in at least three glomerular capillaries by electron microscopy with associated endothelial swelling and/or subendothelial electron-lucent widening (Fig. 1c)
3. cg1b – one or more glomerular capillaries with GBM double contours in at least one nonsclerotic glomerulus by light microscopy; electron microscopic confirmation is recommended if electron microscopy is available (Fig. 1b).
There are many transplant centers in different parts of the world without electron microscopy facilities, and as such it should be stressed that the use of electron microscopy is clearly not mandatory in evaluation of renal allograft biopsies. However, for centers with electron microscopy capability, the Banff group now recommends that ultrastructural studies be performed in all biopsies from patients who are sensitized, have documented DSA at any time posttransplantation, and/or who have had a prior biopsy showing C4d staining, glomerulitis, and/or peritubular capillaritis. It is also advised that electron microscopy be considered in all biopsies performed at least 6 months posttransplantation and in for cause biopsies done at least 3 months posttransplantation to determine whether early changes of transplant glomerulopathy are present, prompting testing for DSA.
C4d-NEGATIVE ANTIBODY-MEDIATED REJECTION
As noted above, some studies published since 2009 support the existence of C4d-negative ABMR (reviewed in [31,32▪]); these will only briefly be reviewed here. Sis et al.  used gene expression microarrays done on tissue from 173 indication renal allograft biopsies (performed for acute or persistent graft dysfunction, or proteinuria) to examine ENDAT expression. They found that the combination of DSA and high ENDAT expression (but not DSA alone) was associated with a significantly increased rate of graft loss, even in the absence of C4d, although diffuse ptc C4d staining further increased the rate of graft loss . A second key study came from Loupy et al., who examined pathologic findings in protocol biopsies done at 3 months and at 1 year posttransplantation in 45 recipients of deceased donor renal allografts with known DSA. Based on the 3-month biopsy findings, the patients of Loupy et al. fell into three groups: those with no evidence of ABMR, those with subclinical ABMR characterized by both ptc C4d staining and histologic features of ABMR (glomerulitis, peritubular capillaritis, or both), and those with histologic features of ABMR but no ptc C4d staining. At 1 year posttransplantation, patients whose 3-month biopsy had no evidence of ABMR had good graft function, and interstitial fibrosis/tubular atrophy in only one-third of cases. These 1-year biopsies also showed no evidence of transplant glomerulopathy, a lesion that is most often a manifestation of chronic ABMR [or chronic, active ABMR when present concurrently with active microvascular inflammation (MVI); see below] [34–37]. Patients whose 3-month biopsy showed subclinical ABMR had reduced graft function, interstitial fibrosis/tubular atrophy in all cases, and transplant glomerulopathy in nearly half. Patients whose 3-month biopsy showed glomerulitis and/or peritubular capillaritis, but no C4d had a mean creatinine clearance and frequencies of interstitial fibrosis/tubular atrophy and transplant glomerulopathy intermediate between the no ABMR and C4d-positive subclinical ABMR cohorts . These findings are highly consistent with those of Sis et al. supporting the existence of a C4d-negative form of antibody-mediated graft injury that is less severe than C4d-positive ABMR, but nonetheless associated with the development of chronic changes within the graft, including transplant glomerulopathy.
A number of recent studies have also documented that MVI – glomerulitis and peritubular capillaritis – is a more important prognostic indicator than C4d in patients with both preformed and de-novo DSA. Loupy et al., in a study of protocol biopsies obtained at 3 and 12 months posttransplantation from 80 DSA-positive patients, found that the presence of MVI and anti-class II DSA at 3 months were each associated with a four-fold higher incidence of chronic ABMR (transplant glomerulopathy and/or chronic arteriopathy) at 12 months, independent of C4d staining. In a study of 58 patients with de-novo DSA who underwent an indication renal allograft biopsy at the time of or after initial detection of DSA, de Kort et al.[39▪▪] found that patients whose biopsy showed Banff (g + ptc) scores of at least 3 had a 24-fold higher risk of graft loss than patients with (g + ptc) equal to 0. In contrast, positive ptc C4d staining (diffuse or focal) was not significantly associated with graft loss, although diffuse C4d staining was, with a 4-fold increased risk of graft loss [39▪▪]. Finally, in a study of 128 patients who underwent renal allograft biopsies less than 1 year posttransplantation between 1996 and 2001 that were retrospectively analyzed and stained for C4d, death-censored graft survival was not significantly associated with C4d positivity, but was significantly associated with the presence or absence of MVI, independently of the C4d findings [40▪].
The revised Banff classifications for acute/active and chronic, active ABMR shown in Tables 3 and 4, respectively, are based on drafts circulated during the 2013 Banff Conference to all attendees, and modified during extensive discussions after the meeting. Immunohistologic evidence (typically in the form of C4d staining), previously required for diagnosis of ABMR (Tables 1 and 2), has been replaced by a category of current/recent evidence of antibody interaction with the endothelium. The latter includes C4d positivity, which may be diffuse or focal (i.e., involving at least 10% of ptc) by indirect immunofluorescence or involving any ptc by the less sensitive  method of immunohistochemistry on paraffin sections, but also includes at least moderate MVI or elevated expression in the biopsy tissue of gene transcripts indicative of endothelial injury (Tables 3 and 4). The threshold for moderate MVI (g + ptc ≥2) has been documented to be associated with development of overt transplant glomerulopathy in the presence of DSA, even in C4d-negative cases . The consensus of the Banff meeting attendees was that molecular evidence of active endothelial injury in the biopsy tissue should also be included in this category, provided that thorough validation of the molecular test has been performed. This was mainly done to allow the classification to adapt to emerging data, as at present the only molecular marker so validated is ENDAT expression, shown by Sis et al. to correlate with development of transplant glomerulopathy and graft survival even in the absence of C4d. However, even this validation has been limited to a single center, and the use of ENDAT expression at other centers or other test(s) of gene expression within the biopsy as evidence of ABMR must first undergo independent validation as was done by Sis et al. for ENDATs.
INTIMAL ARTERITIS AS A MANIFESTATION OF ANTIBODY-MEDIATED GRAFT INJURY
Certain arterial lesions in renal allografts are well accepted as having a pathogenesis that often involves humoral immunity. As noted above (Table 1), transmural necrosis in one or more arteries is included among those lesions satisfying the histologic component for diagnosis of acute ABMR in the Banff classification . However, some recent studies provide evidence for expanding the range of arterial lesions associated with antibody-mediated graft injury.
Intimal arteritis has long been classified as a lesion of TCMR, and defines type 2 acute rejection according to the Banff classification of TCMR . However, there is emerging evidence that intimal arteritis may in some cases be, at least in part, humorally mediated. In some cases, lesions of intimal arteritis contain a predominance of CD68-positive macrophages, which are also highly prominent in glomerulitis and peritubular capillaritis [4,25,31], as opposed to CD3-positive T lymphocytes that typically predominate in tubulointerstitial lesions of acute TCMR [42–44]. Most recently, Lefaucheur et al.[45▪▪] reported on 64 cases of intimal arteritis in DSA-positive patients. They found that compared with cases of ABMR without intimal arteritis, those with intimal arteritis had a three-fold higher rate of graft loss. Although the majority of cases of intimal arteritis with DSA also showed interstitial inflammation and tubulitis indicating a combined lesion of ABMR and TCMR, it was also noteworthy that intimal arteritis with DSA was associated with a significantly (and ∼six-fold) higher rate of graft loss than intimal arteritis without DSA, the latter representing pure TCMR [45▪▪]. These findings suggest an association of lesions of intimal arteritis with ABMR when DSAs are present, and may account in part for the frequent lack of a complete response of lesions reported as Banff type 2 acute TCMR to therapy directed at T cells [46,47].
Based on these findings, intimal arteritis is now included among those lesions meeting the updated Banff criteria as histologic evidence of acute ABMR (Table 3). Certainly, the data of Lefaucheur et al.[45▪▪] argue that testing for DSA is indicated in renal allograft recipients with a biopsy showing intimal arteritis, even if C4d staining is negative. Likewise, treatment in these cases should include measures to remove DSA if the latter are present, as persistence of DSA, MVI, and intimal arteritis are all associated with poor graft outcomes in patients with ABMR . Still, the evidence directly linking intimal arteritis to humoral immunity is indirect and still rather preliminary. Of the 64 DSA-positive cases studied by Lefaucheur et al.[45▪▪], only eight showed intimal arteritis as an isolated finding, in the absence of glomerulitis and/or peritubular capillaritis, and isolated intimal arteritis may also be an infrequent manifestation of acute TCMR [22▪▪]. Also, as noted above, 72 and 63% of these 64 cases had interstitial inflammation and tubulitis, respectively, consistent with earlier findings of a strong association between glomerulitis and intimal arteritis  and suggesting the presence of TCMR as well as ABMR. Finally, the link between predominance of CD68-positive cells in lesions of intimal arteritis and ABMR is still hypothetical, and one study found no difference in clinical outcomes in patients having biopsies with intimal arteritis with a predominance of CD68-positive cells as compared with intimal arteritis with primarily CD3-positive T cells . Thus, it is important that additional studies be undertaken to determine whether in fact lesions of intimal arteritis containing mainly CD68-positive cells are significantly associated with the presence of DSA and other histologic lesions of active ABMR, and whether these lesions respond to treatment for ABMR, particularly in those cases in which initial treatment with agents used for the treatment of acute TCMR fails to produce a return of graft function to baseline level.
As with the 2001/2007 Banff schema for ABMR in renal allografts and other Banff schemata, the updated (2013) Banff ABMR schema should be regarded as a working classification subject to revision based on new data. In this regard, it is expected that this schema will be extensively tested for its value in predicting graft outcomes and guiding treatment of patients with morphologic lesions of ABMR. It is also expected that the findings of these studies will be reviewed at future Banff conferences and that the merits and shortcomings of the updated classification will be discussed and revisions to it, if indicated, will be made by consensus as was done in developing the 2013 schema.
Conflicts of interest
The author has no conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
1. Terasaki PI, Cai J. Human leukocyte antigen antibodies and chronic rejection: from association to causation. Transplantation 2008; 86:377–383.
2. Colvin RB. Antibody-mediated renal allograft rejection: diagnosis and pathogenesis. J Am Soc Nephrol 2007; 18:1046–1056.
3. Sis B, Mengel M, Haas M, et al. Banff ’09 meeting report: antibody mediated graft deterioration and implementation of Banff working groups. Am J Transplant 2010; 10:464–471.
4. Magil AB, Tinckam K. Monocytes and peritubular capillary C4d deposition in acute renal allograft rejection. Kidney Int 2003; 63:1888–1893.
5. Trpkov K, Campbell P, Pazderka F, et al. Pathologic features of acute renal allograft rejection associated with donor-specific antibody: analysis using the Banff grading schema. Transplantation 1996; 61:1586–1592.
6. Noris M, Remuzzi G. Thrombotic microangiopathy after kidney transplantation. Am J Transplant 2010; 10:1517–1523.
7. Randhawa PS, Shapiro R, Jordan ML, et al. The histopathological changes associated with allograft rejection and drug toxicity in renal transplant recipients maintained on FK506. Am J Surg Pathol 1993; 17:60–68.
8. Trimarchi HM, Truong LD, Brennan S, et al. FK506-associated thrombotic microangiopathy. Transplantation 1999; 67:539–544.
9. Meehan SM, Baliga R, Poduval R, et al. Platelet CD61 expression in vascular calcineurin inhibitor toxicity of renal allografts. Hum Pathol 2008; 39:550–556.
10. Feucht HE, Felber E, Gokel MJ, et al. Vascular deposition of complement-split products in kidney allografts with cell-mediated rejection. Clin Exp Immunol 1991; 86:464–470.
11. Collins AB, Schneeberger EE, Pascual MA, et al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol 1999; 10:2208–2214.
12. Regele H, Exner M, Watschinger B, et al. Endothelial C4d deposition is associated with inferior kidney allograft outcome independently of cellular rejection. Nephrol Dial Transplant 2001; 16:2058–2066.
13. Mauiyyedi S, Crespo M, Collins AB, et al. Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification. J Am Soc Nephrol 2002; 13:779–787.
14. Bohmig GA, Exner M, Habicht A, et al. Capillary C4d deposition in kidney allografts: a specific marker of alloantibody-dependent graft injury. J Am Soc Nephrol 2002; 13:1091–1099.
15. Herzenberg AM, Gill JS, Djurdjev O, Magil AB. C4d deposition in acute rejection: an independent long-term prognostic factor. J Am Soc Nephrol 2002; 13:234–241.
16. Nickeleit V, Zeiler M, Gudat F, et al. Detection of the complement degradation product C4d in renal allografts: diagnostic and therapeutic implications. J Am Soc Nephrol 2002; 13:242–251.
17. Mauiyyedi S, Pelle PD, Saidman S, et al. Chronic humoral rejection: identification of antibody-mediated chronic allograft rejection by C4d deposits in peritubular capillaries. J Am Soc Nephrol 2001; 12:574–582.
18. Regele H, Bohmig GA, Habicht A, et al. Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to chronic allograft rejection. J Am Soc Nephrol 2002; 13:2371–2380.
19. Zwirner J, Felber E, Herzog V, et al. Classical pathway of complement activation in normal and diseased human glomeruli. Kidney Int 1989; 36:1069–1077.
20. Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria: an addition to the Banff ’97 classification of renal allograft rejection. Am J Transplant 2003; 3:708–714.
21. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant 2008; 8:753–760.
22▪▪. Haas M, Sis B, Racusen LC, et al. Banff 2013 meeting report: inclusion of C4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant 2014; 14:272–283.
This report summarizes the major developments from the 2013 Banff Conference, including the findings of the six current BWGs, the formation of three new BWGs, the updating of the Banff schema for acute/active and chronic, active ABMR in renal allografts, and the specific consensuses reached in the development of this revised classification.
23. Racusen LC, Solez K, Colvin RB, et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55:713–723.
24. Sis B, Jhangri GS, Bunnag S, et al. Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining. Am J Transplant 2009; 9:2312–2323.
25. Hidalgo LG, Sis B, Sellares J, et al. NK cell transcripts and NK cells in kidney biopsies from patients with donor-specific antibodies: evidence for NK cell involvement in antibody-mediated rejection. Am J Transplant 2010; 10:1812–1822.
26. Batal I, Lunz JG III, Aggarwal N, et al. A critical appraisal of methods to grade transplant glomerulitis in renal allograft biopsies. Am J Transplant 2010; 10:2442–2452.
27. Wavamunno MD, O’Connell PJ, Vitalone M, et al. Transplant glomerulopathy: ultrastructural abnormalities occur early in longitudinal analysis of protocol biopsies. Am J Transplant 2007; 7:2757–2768.
28. Haas M, Mirocha J. Early ultrastructural changes in renal allografts: correlation with antibody-mediated rejection and transplant glomerulopathy. Am J Transplant 2011; 11:2123–2131.
29. Stegall M, Diwan T, Raghavaiah S, et al. Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients. Am J Transplant 2011; 11:2405–2413.
30▪. Papadimitriou J, Drachenberg CB, Ramos E, et al. Antibody-mediated allograft rejection: morphologic spectrum and serologic correlations in surveillance and for cause biopsies. Transplantation 2013; 95:128–136.
A comparison of morphologic features of ABMR, including C4d staining and electron microscopic findings, in protocol biopsies versus indication biopsies of renal allografts. Morphologic features of acute and chronic ABMR (Banff g, ptc, and cg scores) were higher in the indication biopsies showing these features, as was the frequency of high titers of donor-specific antibodies. Of 400 protocol biopsies, 34 (8.5%) showed features of ABMR, although only 13 fully met Banff 2001/2007 criteria for acute or chronic, active ABMR. Thirteen (38%) of these cases showed persistence or worsening of ABMR features on a subsequent biopsy; this was independent of whether the initial biopsy was diagnostic of or suspicious for ABMR.
31. Haas M. C4d-negative antibody-mediated rejection in renal allografts: evidence for its existence and effect on graft survival. Clin Nephrol 2011; 75:271–278.
32▪. Haas M. Pathology of C4d-negative antibody-mediated rejection in renal allografts. Curr Opin Organ Transplant 2013; 18:319–326.
A review of the evidence supporting the existence of C4d-negative ABMR in renal allografts and a comparison of morphologic and serologic features of C4d-positive (60 cases) and C4d-negative (34 cases) ABMR on indication biopsies. C4d-negative ABMR was associated with only anti-HLA class II donor-specific antibodies (compared with anti-class I or both anti-class I and anti-class II) significantly more often than C4d-positive ABMR. However, severity of glomerulitis and peritubular capillaritis, presence or absence of transplant glomerulopathy, and severity of arterial intimal fibrosis were not different between the two groups. There was a trend toward more severe tubular atrophy/interstitial fibrosis in C4d-positive cases.
33. Loupy A, Suberbielle-Boissel C, Hill GS, et al. Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies. Am J Transplant 2009; 9:2561–2570.
34. Sis B, Campbell PM, Mueller T, et al. Transplant glomerulopathy, late antibody-mediated rejection and the ABCD tetrad in kidney allograft biopsies for cause. Am J Transplant 2007; 7:1743–1752.
35. Gloor JM, Sethi S, Stegall MD, et al. Transplant glomerulopathy: subclinical incidence and association with alloantibody. Am J Transplant 2007; 7:2124–2132.
36. Baid-Agrawal S, Farris AB III, Pascual M, et al. Overlapping pathways to transplant glomerulopathy: chronic humoral rejection, hepatitis C infection, and thrombotic microangiopathy. Kidney Int 2011; 80:879–885.
37. Cosio FG, Gloor JM, Sethi S, Stegall MD. Transplant glomerulopathy. Am J Transplant 2008; 8:492–496.
38. Loupy A, Hill GS, Suberbielle C, et al. Significance of C4d Banff scores in early protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA). Am J Transplant 2011; 11:56–65.
39▪▪. de Kort H, Willicombe M, Brookes P, et al. Microcirculation inflammation associates with outcome in renal transplant patients with de novo donor-specific antibodies. Am J Transplant 2013; 13:485–492.
A study of 53 standard-risk renal allograft recipients who developed de-novo DSA and had an indication renal allograft biopsy at the time of or after initial detection of DSA. The authors found in a multivariate analysis including the severity of microvascular injury [Banff (g + ptc) score] and peritubular capillary (ptc) C4d staining that grafts with a (g + ptc) score at least 3 had a significantly increased risk of graft loss compared with those with mild [(g + ptc) of 1 or 2] or absent microvascular injury, independent of C4d. Furthermore, ptc C4d staining (focal or diffuse) was not an independent predictor of graft survival.
40▪. Verghese P, Dunn T, Najafian B, et al. The impact of C4d and microvascular inflammation before we knew them. Clin Transplant 2013; 27:388–396.
Indication renal allograft biopsies from 128 patients, performed during the first year posttransplantation between 1996 and 2001, were retrospectively stained for C4d and analyzed for glomerulitis and peritubular capillaritis. The latter findings, but not ptc C4d deposition, were associated with significantly reduced graft survival, and the impact of glomerulitis and/or peritubular capillaritis on graft survival was independent of C4d.
41. Hancock WW, Thomson NM, Atkins RC. Composition of interstitial cellular infiltrate identified by monoclonal antibodies in renal biopsies of rejecting human allografts. Transplantation 1983; 35:458–463.
42. Kolbeck PC, Tatum AH, Sanfilippo F. Relationships among the histologic pattern, intensity, and phenotypes of T cells infiltrating renal allografts. Transplantation 1984; 38:709–713.
43. Einecke G, Melk A, Ramassar V, et al. Expression of CTL associated transcripts precedes the development of tubulitis in T cell mediated kidney graft rejection. Am J Transplant 2005; 5:1827–1836.
44. Seemayer CA, Gaspert A, Nicketeit V, Mihatsch MJ. C4d staining of renal allograft biopsies: a comparative analysis of different staining techniques. Nephrol Dial Transplant 2007; 22:568–576.
45▪▪. Lefaucheur C, Loupy A, Vernerey D, et al. Antibody-mediated vascular rejection of kidney allografts: a population-based study. Lancet 2013; 381:313–319.
A key study supporting an association between DSAs and intimal arteritis in renal allografts. In a study including 64 cases of intimal arteritis in patients with DSA, these investigators found that compared with cases of ABMR without intimal arteritis, those with intimal arteritis had a three-fold higher rate of graft loss. Although the majority of cases of intimal arteritis with DSA also showed interstitial inflammation and tubulitis indicating a combined lesion of ABMR and TCMR, it was also noted that intimal arteritis with DSA was associated with a significantly (and ∼six-fold) higher rate of graft loss than intimal arteritis without DSA, the latter representing pure TCMR. These findings strongly suggest an association of lesions of intimal arteritis with ABMR when DSAs are present.
46. Minervini MI, Torbenson M, Scantlebury V, et al. Acute renal allograft rejection with severe tubulitis (Banff 1997 grade IB). Am J Surg Pathol 2000; 24:553–558.
47. Haas M, Kraus ES, Samaniego-Picota M, et al. Acute renal allograft rejection with intimal arteritis: histologic predictors of response to therapy and graft survival. Kidney Int 2002; 61:1516–1526.
48. Lefaucheur C, Nochy D, Hill GS, et al. Determinants of poor graft outcome in patients with antibody-mediated acute rejection. Am J Transplant 2007; 7:832–841.
49. Messias NC, Eustace JA, Zachary AA, et al. Cohort study of the prognostic significance of acute transplant glomerulitis in acutely rejecting renal allografts. Transplantation 2001; 72:655–660.
50. Kozakowski N, Bohmig GA, Exner M, et al. Monocytes/macrophages in kidney allograft intimal arteritis: no association with markers of humoral rejection or with inferior outcome. Nephrol Dial Transplant 2009; 24:1979–1986.
51▪. Liapis G, Singh HK, Derebail VK, et al. Diagnostic significance of peritubular capillary basement membrane multilaminations in kidney allografts. Old concepts revisited. Transplantation 2012; 94:620–629.
A thorough examination of the diagnostic significance of peritubular capillary basement membrane multilayering (PTCL), particularly as pertains to chronic ABMR. The authors found that severe PTCL was relatively uncommon in biopsies showing mild transplant glomerulopathy, especially C4d-negative cases. They also found a strong correlation between severe PTCL, defined as at least three capillaries with at least five to seven circumferential basement membrane layers, and other morphologic and serologic features of chronic ABMR (or mixed ABMR and TCMR), although lesser degrees of PTCL were far less specific.