**4. Clinical features**

*Perioperative Care for Organ Transplant Recipient*

**Banff scoring for antibody mediated rejection** C4d—percentage of PTC (or vasa recta in the medulla) that has linear circumferential staining, scored in at least 5 high powered fields of cortex or

cg—transplant glomerulopathy: percentage of glomerular capillary loops with duplication of glomerular basement membrane in most affected

cv—transplant arteriopathy: arterial fibrointimal thickening; percentage of narrowing of lumen of

medulla without scarring or infarct

nonsclerotic glomerulus

most severely affected artery

**Table 2.**

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

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

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

C4d0: no staining of PTC and medullary vasa recta C4d1: <10% of PTC and medullary vasa recta C4d2: 10–50% of PTC and medullary vasa recta C4d3: >50% of PTC and medullary vasa recta

cg0: none by light microscopy (LM) and electron

cg1a: only by electron microscopy in 3 glomerular

cg1b: ≤25% by LM (1+ glomerular capillaries with glomerular basement membrane double contours

microscopy

capillaries

by LM)

cv0: none

cg2: 26–50% by LM cg3: >50% by LM

cv1: ≤25% of the luminal area cv2: 26–50% of the luminal area cv3: >50% of the luminal area

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

biopsy tissue that are strongly associated with ABMR [16].

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

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

*3.3.1 C4d in antibody mediated rejection*

C4d positive ABMR were identified [22].

*mediated rejection*

**80**

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

#### **4.1 Acute antibody mediated rejection**

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 characteristics of *active ABMR*.

#### **4.2 Chronic antibody mediated rejection**

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].

#### **4.3 Subclinical antibody mediated rejection**

A certain amount of kidney transplant recipients present with stable kidney graft function, but histological evidence of smoldering active ABMR on protocol biopsies [35]. These patients often have low-level DSAs (de novo or persistent/recurrent). Evidence suggests that untreated subclinical ABMR is an important predictor of poor renal allograft outcomes [36]. However, the lack of long-term follow-up data has prevented the development of strong guidelines for effective therapeutic interventions.

#### **4.4 Hyperacute antibody mediated rejection**

Nowadays, hyperacute rejection is a rare event in kidney transplantation affecting mostly presensitized patients (previous transplantation, blood transfusions, or pregnancy) [37]. It occurs due to preformed DSA present in high titers and presents as graft failure that can occur within minutes (but sometimes may be delayed for a few days) after transplantation [38]. The occurrence of this type of rejection is extremely rare, as preformed antibodies can usually be excluded by CDC crossmatch. However, there is growing evidence that there may exist hyperacute rejections mediated by endothelial, non-HLA antibodies that cannot be detected in standard T and B lymphocyte crossmatch techniques [39].
