Renal allograft biopsies in the era of C4d staining: the need for change in the Banff classification system

Abstract

Summary C4d immunostaining in the peritubular capillaries (PTC) is a marker of antibody‐mediated rejection (AMR). We evaluated the histopathologic diagnoses of 388 renal transplant biopsies since the implementation of routine C4d immunostaining at our center. Of these, 155 (40%) biopsies had evidence of acute cellular rejection (ACR), out of which 119 (77%) had pure ACR, 31 (20%) had ACR with concomitant features of AMR, and five (3%) had ACR with focal C4d staining. Sixty‐four (16%) biopsies exhibited features of AMR [33 (52%) pure AMR, and 31(48%) concomitant AMR and ACR]. One hundred and fifty‐five (40%) biopsies had features of interstitial fibrosis and tubular atrophy (IFTA). Of these, 20 (13%) had concomitant AMR [13 (8.5%) had pure AMR and seven (4.5%) had concomitant ACR and AMR]. Creatinine at the time of biopsy was higher in patients with mixed ACR and AMR and the clinical behavior of mixed lesions is more aggressive over time. Despite having a lower serum creatinine at the time of biopsy, patients with IFTA experienced gradual decline in graft function over time. The pathologic findings in renal allograft biopsies are often mixed and mixed lesions appear to have more aggressive clinical behavior. These findings suggest the need for change in the Banff classification system to better capture the complexity of renal allograft pathologies.

An Experimental Model of Acute Humoral Rejection of Renal Allografts Associated with Concomitant Cellular Rejection

“…This also parallels human AHR because in human renal allograft biopsies, taken from patients with AHR, changes of acute cellular rejection are commonly seen. 3,7,21 In our center, 65% of renal allograft biopsies with AHR also show some evidence of acute cellular rejection. However, in these mixed humoral and cellular rejection cases the histological changes of cellular rejection are usually relatively mild and it is believed that in most patients the dominating pathomechanism, responsible for the graft dysfunction is AHR, although this remains a matter of conjecture.…”

The use of C3d and C4d immunohistochemistry on formalin-fixed tissue as a diagnostic adjunct in the assessment of inflammatory skin disease

“…15,19 There is considerable precedent in the literature regarding the significance of both C3d and C4d deposition as a prognostic and diagnostic marker of humoral rejection by IH on paraffin-embedded tissue. [29][30][31] Studies have emphasized the importance of C3d and C4d as a positive correlate to a state of acute rejection and as a predictor of long-term graft survival. Kuypers et al 18 found that C3d deposition in renal allograft biopsy specimens was correlated with poor outcome.…”

Acute Cellular Rejection

“…Mauiyyedi et al (4) found that the outcomes of patients with C4d+ TCMR and also C4d positivity with mixed morphological features of AMR and TCMR correlated closely with pure C4d+ AMR. In more recent studies, Al-Aly et al (5) showed that it is not uncommon for patients to exhibit mixed morphological features of TCMR and AMR, with inferior outcomes to the pure forms of either category. Similarly, Everly et al (7) found that mixed TCMR episodes were associated with an intermediate allograft survival between the pure TCMR and AMR groups, and Kayler et al (14) established that even patients with focal C4d and TCMR might have underlying humoral involvement leading to steroid unresponsiveness.…”