**3.1 Histopathological features**

*Perioperative Care for Organ Transplant Recipient*

(DSAs) [6].

DSAs against class I HLA [10].

attack complex (C5b-C9) (**Figure 1**) [14, 15].

*donor-specific antibody; HLA-human leukocyte antigen.*

occurred in solid organ transplantation. Nowadays, it is believed that immunologic reactions associated with ABMR can be triggered by circulating antibodies against donor HLA, non-HLA or ABO antigens, i.e. donor specific antibodies

DSAs are most commonly directed against human leukocyte antigen (HLA)/ major-histocompatibility-complex (MHC) class I and II antigens [7]. HLA class I antigens are expressed on all nucleated cells, whereas HLA class II antigens are restricted to antigen-presenting cells (B lymphocytes, dendritic cells) and endothelial cells [8]. In addition to DSAs existing prior to transplant due to recipient sensitization (pregnancy, blood transfusions, and previous transplantation), it has been realized that they can emerge at any time after transplant, thus mediating allograft injury [9, 10]. These *de novo* DSAs are different in their pathogenicity. Those directed against class II HLA are associated with a worse prognosis than

However, the antibodies can also be directed against other donor specific antigens such as MHC-class I-related chain A (MICA) antigens, MHC-class I-related chain B (MICB) antigens, platelet-specific antigens, molecules of the renin-angiotensin pathway, and polymorphisms involving chemokines and their receptors [11–13]. MICA antigens are expressed on endothelial cells, dendritic cells, fibroblasts, epithe-

The major mechanism involved in antibody-mediated kidney injury is activation of the classical complement pathway by the binding of DSA to HLA and subsequent binding of the C1 complex, which ultimately leads to formation of the membrane

This leads to activation of polymorphonuclear inflammatory cells, NK cell and monocyte recruitment and inflammation, as well as activation of the coagulation cascade, which in turn leads to widespread microvascular injury evident as peritubular capillaritis, glomerulitis and microvascular thrombosis. B-cell responses against MHC antigens are T-cell dependent and require the involvement of antigen-presenting cells and costimulatory molecules such as CD40 ligand or soluble interleukins. These responses take 2–3 weeks to develop and lead to immunologic memory, allowing a more efficient antibody response upon repeat stimulation. Eventually transplant glomerulopathy develops (chronic phase) due to recurrent injury and repair with glomerular basement

*Activation of classical complement pathway in ABMR in renal transplant recipients. Following binding of DSA to the vascular endothelium of kidney allograft, the C1 complex activates the serine esterases C1s and C1r, resulting in the cleavage of C4, deposition of C4d, and the assembly of the classical pathway C3 convertase. C3 convertase cleaves C3 into C3a, a potent pro-inflammatory mediator, and C3b, which propagates the complement cascade and leads to the formation of the pro-inflammatory mediator C5a and the membrane attack complex (C5b-C9). For more details, see Stegall et al. [15] ABMR-antibody-mediated rejection; DSA-*

lial cells, and many tumors, but not on peripheral-blood lymphocytes [12].

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**Figure 1.**

By light microscopy, active antibody mediated rejection is characterized by 3 types of tissue injury: acute tubular injury, microcirculation inflammation with neutrophils and mononuclear cells in glomeruli and peritubular capillaries, and fibrinoid necrosis of arteries (**Figure 2**) [14].

Acute tubular injury includes loss of brush borders, thinning of tubular epithelial cells cytoplasm, shedding of tubular epithelium, and focal loss of nuclei (**Figure 3**). Focal necrosis of tubules can be found in minority of cases. In addition to oedema without significant interstitial infiltrate, proximal tubules express HLA-DR (**Figure 4**). Microcirculation inflammation with neutrophils and mononuclear cells in glomeruli and peritubular capillaries appears as glomerulitis and peritubular capillaritis. Glomerular capillaries are dilated and filled with swollen endothelial cells and inflammatory cells (**Figure 5**). In severe cases, glomerular capillary thrombosis can be detected (**Figure 6**). In glomerular injury due to ABMR usually predominates macrophages which express CD68 and neutrophils.

#### **Figure 2.**

*Features of active antibody mediated rejection: Acute tubular injury [(A) hematoxylin-eosin stain (HE), 200×], microcirculation inflammation with neutrophils and mononuclear cells in glomeruli-glomerulitis [(B) HE, 400×] and peritubular capillaries-peritubular capillaritis [(C) HE, 200×], and fibrinoid necrosis of artery [(D) HE, 200×].*

#### **Figure 3.**

*Acute tubular injury/necrosis accompanied by interstitial edema in active antibody mediated rejection [(A) periodic-acid Schiff (PAS), 100×]. Acute tubular injury/necrosis and glomerular capillary necrosis [(B) HE, 100×].*

#### **Figure 4.** *Diffuse HLA-DR positivity in proximal tubules in active antibody mediated rejection (immunohistochemistry, HLA-DR, 100×).*

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**Figure 6.**

*stain, 200×)] in severe active antibody mediated rejection.*

**Figure 5.**

*Antibody Mediated Rejection in Kidney Transplant Recipients*

*filled with swollen endothelial cells and inflammatory cells (PAS, 200×).*

*Focal glomerulitis in active antibody mediated rejection-Banff score g3. Dilated glomerular capillaries are* 

*Glomerular capillary thrombosis [(A) HE, 400×)] and fibrinoid necrosis of hilar arteriole [(B) trichrome* 

*DOI: http://dx.doi.org/10.5772/intechopen.85886*

*Antibody Mediated Rejection in Kidney Transplant Recipients DOI: http://dx.doi.org/10.5772/intechopen.85886*

#### **Figure 5.**

*Perioperative Care for Organ Transplant Recipient*

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**Figure 4.**

*HLA-DR, 100×).*

**Figure 3.**

*Acute tubular injury/necrosis accompanied by interstitial edema in active antibody mediated rejection [(A) periodic-acid Schiff (PAS), 100×]. Acute tubular injury/necrosis and glomerular capillary necrosis [(B) HE, 100×].*

*Diffuse HLA-DR positivity in proximal tubules in active antibody mediated rejection (immunohistochemistry,* 

*Focal glomerulitis in active antibody mediated rejection-Banff score g3. Dilated glomerular capillaries are filled with swollen endothelial cells and inflammatory cells (PAS, 200×).*

#### **Figure 6.**

*Glomerular capillary thrombosis [(A) HE, 400×)] and fibrinoid necrosis of hilar arteriole [(B) trichrome stain, 200×)] in severe active antibody mediated rejection.*

#### *Perioperative Care for Organ Transplant Recipient*

Cortical peritubular capillaries are dilated and filled with numerous inflammatory cells and sometimes focal interstitial hemorrhages are found (**Figure 7**). Presence of neutrophils in dilated peritubular capillaries may be associated with class I DSA and hyperacute rejection. Immunohistochemistry and immunofluorescence revealed diffuse linear positivity of C4d along peritubular capillaries in the

#### **Figure 7.**

*Diffuse peritubular capillaritis in active antibody mediated rejection-Banff score ptc3 [(A and B) HE and immunohistochemistry, C4d, 200×)]. Neutrophils in peritubular capillaries in severe active antibody mediated rejection [(C) HE, 400×].*

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**Figure 9.**

**Figure 8.**

*200×] and immunohistochemistry [(B) 200×].*

*Antibody Mediated Rejection in Kidney Transplant Recipients*

cortex and medulla (**Figure 8**). Dilated vascular spaces in the area between cortex and medulla should not be assessed as peritubular capillaritis, since those vascular spaces represent increased turnover between cortex and medulla not related to

*Diffuse C4d positivity in active antibody mediated rejection (Banff score C4d 3) by immunofluorescence [(A)* 

*Fibrinoid necrosis in small interlobular artery-Banff score v3 in severe active antibody mediated rejection (arrow). Glomerular capillary thrombosis and acute tubular necrosis are also seen (HE, 200×).*

*DOI: http://dx.doi.org/10.5772/intechopen.85886*

cortex and medulla (**Figure 8**). Dilated vascular spaces in the area between cortex and medulla should not be assessed as peritubular capillaritis, since those vascular spaces represent increased turnover between cortex and medulla not related to

#### **Figure 8.**

*Perioperative Care for Organ Transplant Recipient*

Cortical peritubular capillaries are dilated and filled with numerous inflammatory cells and sometimes focal interstitial hemorrhages are found (**Figure 7**). Presence of neutrophils in dilated peritubular capillaries may be associated with class I DSA and hyperacute rejection. Immunohistochemistry and immunofluorescence revealed diffuse linear positivity of C4d along peritubular capillaries in the

*Diffuse peritubular capillaritis in active antibody mediated rejection-Banff score ptc3 [(A and B) HE and immunohistochemistry, C4d, 200×)]. Neutrophils in peritubular capillaries in severe active antibody mediated* 

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**Figure 7.**

*rejection [(C) HE, 400×].*

*Diffuse C4d positivity in active antibody mediated rejection (Banff score C4d 3) by immunofluorescence [(A) 200×] and immunohistochemistry [(B) 200×].*

#### **Figure 9.**

*Fibrinoid necrosis in small interlobular artery-Banff score v3 in severe active antibody mediated rejection (arrow). Glomerular capillary thrombosis and acute tubular necrosis are also seen (HE, 200×).*

rejection. Interstitial oedema and hemorrhage may be prominent. B cells can be found in aggregates, and plasma cells can be detected, but interstitial infiltrate does not fulfill criteria for T-cell mediated rejection.

#### **Figure 10.**

*Chronic active vascular rejection with intimal endarteritis and intimal fibrosis. HE, 200×.*

#### **Figure 11.**

*Acute vascular thrombotic microangiopathy in active antibody mediated rejection [(A) HE, 200×]. Chronic glomerular and vascular thrombotic microangiopathy in chronic active antibody mediated rejection [(B) Weigert stain (W), 100×].*

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**Figure 12.**

*rejection [(C) W, 100×].*

*Antibody Mediated Rejection in Kidney Transplant Recipients*

In about 25% of cases with ABMR, small interlobular arteries show myocyte necrosis, fragmentation of elastica, and accumulation of eosinophilic material termed fibrinoid necrosis (**Figure 9**). There is usually only scant mononuclear infiltrate in the intima and adventitia. Some arteries may show transmural arterial inflammation without fibrinoid necrosis reminiscent of T-cell mediated vascular rejection (**Figure 10**). Whether the cellular component of

*Chronic burn out vascular rejection without intimal infiltrate in arcuate artery-Banff score cv3 [(A) HE, 100×]. Intimal fibrosis due to chronic rejection is superimposed on fibroelastic lamelation associated with arterial hypertension [(B) W, 100×]. Artery with elastic duplication due to arterial hypertension without* 

*DOI: http://dx.doi.org/10.5772/intechopen.85886*

*Antibody Mediated Rejection in Kidney Transplant Recipients DOI: http://dx.doi.org/10.5772/intechopen.85886*

*Perioperative Care for Organ Transplant Recipient*

not fulfill criteria for T-cell mediated rejection.

rejection. Interstitial oedema and hemorrhage may be prominent. B cells can be found in aggregates, and plasma cells can be detected, but interstitial infiltrate does

*Chronic active vascular rejection with intimal endarteritis and intimal fibrosis. HE, 200×.*

*Acute vascular thrombotic microangiopathy in active antibody mediated rejection [(A) HE, 200×]. Chronic glomerular and vascular thrombotic microangiopathy in chronic active antibody mediated rejection* 

**74**

**Figure 11.**

**Figure 10.**

*[(B) Weigert stain (W), 100×].*

In about 25% of cases with ABMR, small interlobular arteries show myocyte necrosis, fragmentation of elastica, and accumulation of eosinophilic material termed fibrinoid necrosis (**Figure 9**). There is usually only scant mononuclear infiltrate in the intima and adventitia. Some arteries may show transmural arterial inflammation without fibrinoid necrosis reminiscent of T-cell mediated vascular rejection (**Figure 10**). Whether the cellular component of

#### **Figure 12.**

*Chronic burn out vascular rejection without intimal infiltrate in arcuate artery-Banff score cv3 [(A) HE, 100×]. Intimal fibrosis due to chronic rejection is superimposed on fibroelastic lamelation associated with arterial hypertension [(B) W, 100×]. Artery with elastic duplication due to arterial hypertension without rejection [(C) W, 100×].*

transplant endarteritis in ABMR is different from that due to T-cell mediated rejection is not apparent. Arterial thrombosis is uncommon. However, acute ABMR may also manifest as TMA affecting glomerular and vascular endothelium (**Figure 11**). TMA is characterized by bloodless glomeruli with swollen endothelium and mucoid intimal thickening and trapped red cells in the vessel walls.

Over time, active ABMR usually transform to chronic ABMR with different levels of activity. Arterial lesions progress to intimal fibrosis with neomedia formation and progressive narrowing of vascular lumen (**Figure 12**) leading to chronic transplant changes—widespread interstitial fibrosis and tubular atrophy. In addition, chronic microvasculature changes appeared, including glomerular and peritubular capillaries. At the beginning, chronic glomerular lesions are visible only by EM as neolamina in glomerular capillary loops (**Figure 13**), which may progress to double contour formation and mesangial interposition seen by light microscopy (**Figure 14**). Peritubular capillaries electron micrograph revealed basement membrane multilamelation consistent with chronic ABMR (**Figure 15**) [14].

#### **Figure 13.**

*Swollen endothelial cells in early glomerular thrombotic microangiopathy due to severe active antibody mediated rejection. Glomerular basement membrane appears normal (A). Subendothelial widening with oedema and neolamina formation in early chronic active antibody mediated rejection seen only by electron microscopy-Banff score cg1a [(B), all electron micrographs].*

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**Figure 14.**

*Antibody Mediated Rejection in Kidney Transplant Recipients*

**3.2 Classification of antibody mediated rejection**

*macrophages predominate (CD68 and PAS, ×400).*

According to Banff 2017 two types of ABMR were proposed-active ABMR

*Double contour formation in glomerulus with chronic glomerulitis in chronic active antibody mediated rejection-Banff score cg3 [(A) Jones, 400×] and normal glomerulus [(B) Jones, 400×]. Glomerulitis in chronic active antibody mediated rejection (Banff score g3, cg3) with diffuse double contour formation (glomerular capillaries with double contours are filled with swollen endothelial cells and inflammatory cells, among them* 

The 2017 Banff meeting report noted the confusion generated by reports on acute and chronic ABMR, and emphasized the importance of correctly defining ABMR, including additional characteristics, like the nature of the antibody; the significance of C4d; the severity of microcapillary injury, gene transcripts, molecular and cellular signatures. As the previously used term acute ABMR was found to be misleading by the majority of the working group, the term active was elected to simply refer to lesions of ABMR with microvascular injury and evidence of current or recent antibody interaction with graft endothelium but without morphologic evidence of chronic vascular injury (transplant glomerulopathy, peritubular capillary

Two principal phenotypes defined in association of previously termed acute ABMR((1) ABMR phenotype 1 in the presensitized patient, occurring early posttransplant; and (2) ABMR phenotype 2, which develops from the emergence of

(previously referred as acute ABMR) and chronic active ABMR [16].

basement membrane multilayering, new-onset arterial intimal fibrosis).

*DOI: http://dx.doi.org/10.5772/intechopen.85886*

*Antibody Mediated Rejection in Kidney Transplant Recipients DOI: http://dx.doi.org/10.5772/intechopen.85886*

#### **Figure 14.**

*Perioperative Care for Organ Transplant Recipient*

vessel walls.

(**Figure 15**) [14].

transplant endarteritis in ABMR is different from that due to T-cell mediated rejection is not apparent. Arterial thrombosis is uncommon. However, acute ABMR may also manifest as TMA affecting glomerular and vascular endothelium (**Figure 11**). TMA is characterized by bloodless glomeruli with swollen endothelium and mucoid intimal thickening and trapped red cells in the

Over time, active ABMR usually transform to chronic ABMR with different levels of activity. Arterial lesions progress to intimal fibrosis with neomedia formation and progressive narrowing of vascular lumen (**Figure 12**) leading to chronic transplant changes—widespread interstitial fibrosis and tubular atrophy. In addition, chronic microvasculature changes appeared, including glomerular and peritubular capillaries. At the beginning, chronic glomerular lesions are visible only by EM as neolamina in glomerular capillary loops (**Figure 13**), which may progress to double contour formation and mesangial interposition seen by light microscopy (**Figure 14**). Peritubular capillaries electron micrograph revealed basement membrane multilamelation consistent with chronic ABMR

*Swollen endothelial cells in early glomerular thrombotic microangiopathy due to severe active antibody mediated rejection. Glomerular basement membrane appears normal (A). Subendothelial widening with oedema and neolamina formation in early chronic active antibody mediated rejection seen only by electron* 

*microscopy-Banff score cg1a [(B), all electron micrographs].*

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**Figure 13.**

*Double contour formation in glomerulus with chronic glomerulitis in chronic active antibody mediated rejection-Banff score cg3 [(A) Jones, 400×] and normal glomerulus [(B) Jones, 400×]. Glomerulitis in chronic active antibody mediated rejection (Banff score g3, cg3) with diffuse double contour formation (glomerular capillaries with double contours are filled with swollen endothelial cells and inflammatory cells, among them macrophages predominate (CD68 and PAS, ×400).*

#### **3.2 Classification of antibody mediated rejection**

According to Banff 2017 two types of ABMR were proposed-active ABMR (previously referred as acute ABMR) and chronic active ABMR [16].

The 2017 Banff meeting report noted the confusion generated by reports on acute and chronic ABMR, and emphasized the importance of correctly defining ABMR, including additional characteristics, like the nature of the antibody; the significance of C4d; the severity of microcapillary injury, gene transcripts, molecular and cellular signatures. As the previously used term acute ABMR was found to be misleading by the majority of the working group, the term active was elected to simply refer to lesions of ABMR with microvascular injury and evidence of current or recent antibody interaction with graft endothelium but without morphologic evidence of chronic vascular injury (transplant glomerulopathy, peritubular capillary basement membrane multilayering, new-onset arterial intimal fibrosis).

Two principal phenotypes defined in association of previously termed acute ABMR((1) ABMR phenotype 1 in the presensitized patient, occurring early posttransplant; and (2) ABMR phenotype 2, which develops from the emergence of

#### **Figure 15.**

*Chronic active antibody mediated rejection: mild basement membrane multilamelation with swollen endothelium (A) and significant basement membrane multilamelation (B, D). Normal peritubular capillary (C, all electron micrographs).*

According to revised Banff 2017 classification of antibody-mediated rejection (ABMR) in renal allografts *antibody-mediated changes* are classified in *Category 2, consisting of:*

Active ABMR; all 3 criteria must be met for diagnosis

1.Histologic evidence of acute tissue injury, including 1 or more of the following:

	- Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by IHC on paraffin sections)
	- At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥1
	- Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with ABMR, if thoroughly validated

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present

classification.

**Table 1.**

see **Table 2**.

*Antibody Mediated Rejection in Kidney Transplant Recipients*

Chronic active ABMR; all 3 criteria must be met for diagnosis

4.Morphologic evidence of chronic tissue injury, including 1 or more of the following:

• Severe peritubular capillary basement membrane multilayering (requires EM)

favor chronic ABMR if there is no prior history of TCMR, but are not required

C4d staining without evidence of rejection; all 4 features must be present for diagnosis

9.No molecular evidence for ABMR as in criterion 2 for active and chronic, active ABMR

• Transplant glomerulopathy (cg > 0) if no evidence of chronic TMA or chronic recurrent/de novo glomerulonephritis; includes changes evident by electron microscopy (EM) alone (cg1a)

• Arterial intimal fibrosis of new onset, excluding other causes; leukocytes within the sclerotic intima

6.Identical to criterion 3 for active ABMR, above, including strong recommendation for DSA testing

7. Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by

*de novo* DSA in the late posttransplant period and is thought to be mostly related to nonadherence or inadequate immunosuppression) are not positioned in Banff 2017

In accordance with major advances in molecular biology and gene rearrangement, the diagnosis of ABMR is now dependent on histologic, serologic and transcriptomics findings (see **Table 1**) [16]. For detailed scoring explanations of histological lesions for antibody mediated rejection according to Banff 2017, please

v0: no arteritis

in 1+ arteries

global)

infiltrate in vessels

g0: no glomerulitis

ptc0: <3 cells/PTC

(minimum = 1 cell, 1 artery)

v1: intimal arteritis with <25% luminal area lost

v3: transmural arteritis or fibrinoid necrosis (medial smooth muscle necrosis) with lymphocyte

v2: intimal arteritis with ≥25% of luminal area lost

g1: <25% of glomeruli involved (mostly segmental) g2: 25–75% of glomeruli involved (segmental to

g3: >75% of glomeruli involved (mostly global)

ptc1: 1+ inflammatory cells in >10% of cortical PTCs with 3–4 cells in most severely involved PTC ptc2: 1+ inflammatory cells in >10% of cortical PTCs with 5–10 cells in most severely involved PTC ptc3: 1+ inflammatory cells in >10% of cortical PTCs with >10 cells in most severely involved PTC

*DOI: http://dx.doi.org/10.5772/intechopen.85886*

5.Identical to criterion 2 for active ABMR, above

8.Criterion 1 for active or chronic, active ABMR not met

10. No acute or chronic active TCMR, or borderline changes

**Banff scoring for antibody mediated rejection** v—vascular inflammation: the most severely affected artery dictates the score; an asterisk is added to the v score if interstitial hemorrhage or infarct present

g—glomerulitis: percentage of glomerular capillaries partially or completely occluded by inflammatory cells (polymorphonuclear leucocytes and mononuclear cells) and endothelial cell enlargement

ptc—peritubular capillaritis: the most severely affected peritubular capillary (PTC) dictates the score; an asterisk is added to the ptc score if neutrophils are lacking/only mononuclear cells are

*Classification of antibody mediated rejection according to Banff 2017 [16].*

whenever criteria 1 and 2 are met

IHC on paraffin sections)

Chronic active ABMR; all 3 criteria must be met for diagnosis

4.Morphologic evidence of chronic tissue injury, including 1 or more of the following:


C4d staining without evidence of rejection; all 4 features must be present for diagnosis


#### **Table 1.**

*Perioperative Care for Organ Transplant Recipient*

According to revised Banff 2017 classification of antibody-mediated rejection (ABMR) in renal allografts

*Chronic active antibody mediated rejection: mild basement membrane multilamelation with swollen endothelium (A) and significant basement membrane multilamelation (B, D). Normal peritubular capillary* 

• Microvascular inflammation (g > 0 and/or ptc > 0), in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 1 alone

2.Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the

• Linear C4d staining in peritubular capillaries (C4d2 or C4d3 by IF on frozen sections, or C4d > 0 by

• At least moderate microvascular inflammation ([g + ptc] ≥2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection,

• Increased expression of gene transcripts/classifiers in the biopsy tissue strongly associated with

3.Serologic evidence of donor-specific antibodies (DSA to HLA or other antigens). C4d staining or expression of validated transcripts/classifiers as noted above in criterion 2 may substitute for DSA; however thorough DSA testing, including testing for non-HLA antibodies if HLA antibody testing is

*antibody-mediated changes* are classified in *Category 2, consisting of:*

1.Histologic evidence of acute tissue injury, including 1 or more of the following:

• Acute thrombotic microangiopathy, in the absence of any other cause • Acute tubular injury, in the absence of any other apparent cause

Active ABMR; all 3 criteria must be met for diagnosis

is not sufficient and g must be ≥1 • Intimal or transmural arteritis (v > 0)

IHC on paraffin sections)

ABMR, if thoroughly validated

ptc ≥ 2 alone is not sufficient and g must be ≥1

negative, is strongly advised whenever criteria 1 and 2 are met.

following:

**Figure 15.**

*(C, all electron micrographs).*

**78**

*Classification of antibody mediated rejection according to Banff 2017 [16].*

*de novo* DSA in the late posttransplant period and is thought to be mostly related to nonadherence or inadequate immunosuppression) are not positioned in Banff 2017 classification.

In accordance with major advances in molecular biology and gene rearrangement, the diagnosis of ABMR is now dependent on histologic, serologic and transcriptomics findings (see **Table 1**) [16]. For detailed scoring explanations of histological lesions for antibody mediated rejection according to Banff 2017, please see **Table 2**.



#### **Table 2.**

*Detailed scoring explanations of histological lesions for antibody mediated rejection according to Banff 2017 [16].*

#### **3.3 Essential differences in comparison to previous classification**

#### *3.3.1 C4d in antibody mediated rejection*

C4d is a split product of C4 activation and has no known biological action. It may be activated by the classical and lectin complement pathways. C4d staining is a specific marker of ABMR when the stain is deposited in the capillaries of kidney allograft and is now considered an alternative for DSA criterion in cases where DSA testing is not available or potentially false negative [17–19]. However, C4d staining has been shown to have significant limitations for diagnosis of ABMR due to low sensitivity, with negative results in up to 50% of patients with antibody-mediated rejection [4, 20]. Furthermore, C4d positivity has been reported in the absence of other evidence of graft injury as its expression depends on the density of PTCs and also may not be associated with measurable DSA in the case of non-HLA antibodies or antibodies absorbed by the allograft [21]. In studies comparing the risk of allograft loss among patients with consistently C4d negative ABMR vs. patients with C4d positive ABMR at a single center, both phenotypes were associated with statistically comparable increased graft loss compared with ABMR free matched controls. No clinical characteristics that reliably differentiated C4d negative and C4d positive ABMR were identified [22].

#### *3.3.2 Expression of endothelium associated transcripts (ENDATs) in antibody mediated rejection*

In patients with negative C4d staining, the diagnosis of ABMR may be confirmed on the basis of increased expression of gene transcripts or classifiers in the biopsy tissue that are strongly associated with ABMR [16].

Molecular markers associated with endothelial injury were first introduced into criteria of the ABMR classification in Banff 2013 [23]. Since that time, combinations of transcripts have been introduced and ABMR specific sets of transcripts proposed by different authors [16]. Data from Loupy et al. [4] showed that adding

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*Antibody Mediated Rejection in Kidney Transplant Recipients*

ability to diagnose ABMR, independently from C4d and DSA.

the results of the ABMR classifier to histologic findings significantly improved their

In clinical setting ABMR can present as hyperacute (occurring within minutes after the vascular anastomosis), acute (occurring days to weeks after transplantation), late acute (occurring 3 months after transplantation), or chronic (occurring

Acute ABMR almost always presents with an increase in serum creatinine, which

is sometimes severe and accompanied with oligo-/anuria necessitating dialysis treatment. It is usually seen during the first few weeks after transplantation but can occur later, in which case it is usually associated with decreased immunosuppression or noncompliance [29]. The incidence varies with the amount of DSA present at the time of transplantation. In patients with high levels of DSA (i.e. sufficient to cause strongly positive crossmatch) the incidence may be as high as 40% in the first month after transplantation, while the incidence is less than 10% in patients with a negative crossmatch and DSA demonstrated only by solid phase assay [30, 31] According to Banff 2017 scoring system [16], histopathology in these patients is related to charac-

The diagnosis of chronic humoral rejection is usually, but not always, made in patients who are more than 6 months post transplantation [32]. The rise in serum creatinine is usually gradual and often accompanied by stepwise increase of proteinuria. Patients with chronic rejection are often hypertensive, sometimes nephrotic range proteinuria or even nephrotic syndrome can be observed. However, patients often have no clinical symptoms associated with chronic rejection, unless renal function is decreased enough that the patient has signs and symptoms of uremia. Except for proteinuria, urinalysis is usually unremarkable in chronic rejection. Contrary, in rare instances progression can be fairly rapid, especially with ongoing active lesions (chronic active ABMR), resulting in graft failure within months [33]. Chronic allograft injury is characteristically seen as transplant glomerulopathy on kidney biopsies. In addition to chronic features, signs of activity are often present, with prominent mononuclear cells

in capillary loops with endothelial swelling (transplant glomerulitis) [34].

However, it should be noted that at this point no specific Banff recommendations are given regarding which molecular transcript sets should be tested to assess gene expression. This includes the decision whether to perform molecular studies on freshly sampled tissue or FFPE. An advanced molecular approach using machine learning and classifiers has been done in recent years and has provided valuable information for improvement of rejection assessment [24]. The Alberta Transplant Applied Genomics Center team at the University of Alberta developed a "molecular microscope" approach to kidney transplant biopsies and has provided a system for distinguishing ABMR from other allograft pathologies by the expression of activated ENDATs. They proposed new rules to integrate molecular tests and histology into a precise diagnostic system that can reduce errors, ambiguity, and inter-pathologist

*DOI: http://dx.doi.org/10.5772/intechopen.85886*

disagreement [25].

**4. Clinical features**

teristics of *active ABMR*.

months to years after transplantation) [26–28].

**4.1 Acute antibody mediated rejection**

**4.2 Chronic antibody mediated rejection**

#### *Antibody Mediated Rejection in Kidney Transplant Recipients DOI: http://dx.doi.org/10.5772/intechopen.85886*

the results of the ABMR classifier to histologic findings significantly improved their ability to diagnose ABMR, independently from C4d and DSA.

However, it should be noted that at this point no specific Banff recommendations are given regarding which molecular transcript sets should be tested to assess gene expression. This includes the decision whether to perform molecular studies on freshly sampled tissue or FFPE. An advanced molecular approach using machine learning and classifiers has been done in recent years and has provided valuable information for improvement of rejection assessment [24]. The Alberta Transplant Applied Genomics Center team at the University of Alberta developed a "molecular microscope" approach to kidney transplant biopsies and has provided a system for distinguishing ABMR from other allograft pathologies by the expression of activated ENDATs. They proposed new rules to integrate molecular tests and histology into a precise diagnostic system that can reduce errors, ambiguity, and inter-pathologist disagreement [25].
