Histopathologic Features of Antibody Mediated Rejection: The Banff Classification and Beyond

Antibody mediated rejection (ABMR) in the kidney can show a wide range of clinical presentations and histopathologic patterns. The Banff 2019 classification currently recognizes four diagnostic categories: 1. Active ABMR, 2. Chronic active ABMR, 3. Chronic (inactive) ABMR, and 4. C4d staining without evidence of rejection. This categorization is limited in that it does not adequately represent the spectrum of antibody associated injury in allograft, it is based on biopsy findings without incorporating clinical features (e.g., time post-transplant, de novo versus preformed DSA, protocol versus indication biopsy, complement inhibitor drugs), the scoring is not adequately reproducible, and the terminology is confusing. These limitations are particularly relevant in patients undergoing desensitization or positive crossmatch kidney transplantation. In this article, I discuss Banff criteria for these ABMR categories, with a focus on patients with pre-transplant DSA, and offer a framework for considering the continuum of allograft injury associated with donor specific antibody in these patients.

Clinicopathologic Features and Risk Factors of Proteinuria in Transplant Glomerulopathy

Background: Transplant glomerulopathy (TG) is one of the main causes of post-transplant proteinuria (PU). The features and possible risk factors for proteinuria in TG patients are uncertain.Methods: We investigated all patients who had biopsy-proven TG from 2000 to 2018 in our center. The clinical and histological data were compared between two groups with or without PU (cut-off = 0.3 g/day). Spearman correlation analysis was used to evaluate the relationship between PU and pathological changes. The risk factors for PU in TG patients were determined by multivariable logistic regression analysis.Results: One hundred and twenty-five (75.76%) of all enrolled 165 TG patients had proteinuria ≥0.3 g/day at the time of biopsy. TG patients' PU level was significantly correlated with Banff lesion score cg (ρ = 0.247, P = 0.003), and mm (ρ = 0.257, P = 0.012). Systolic blood pressure ≥140 mmHg (OR 2.72, 95% CI 1.04–7.10, P = 0.041), diastolic blood pressure ≥90 mmHg (OR 4.84, 95% CI 1.39–16.82, P = 0.013), peak PRA ≥5% (OR 6.47, 95% CI 1.67–25.01, P = 0.007), positive C4d staining (OR 4.55, 95% CI 1.29–16.11, 0.019), tacrolimus-based regimen (OR 3.5, 95% CI 1.28–9.54, P = 0.014), and calcium channel blocker usage (OR 4.38, 95% CI 1.59–12.09, P = 0.004) were independent risk factors for PU.Conclusions: Proteinuria is common in TG patients. systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, peak PRA ≥5%, positive C4d staining, tacrolimus-based regimen, and calcium channel blocker usage are associated with proteinuria in TG patients.

The Spectrum of C4d Deposition in Renal Biopsies of Lupus Nephritis Patients

ObjectivesThis study aimed to determine the prevalence and localization of complement factor C4d in renal biopsies from patients with lupus nephritis (LN), as well as its associations with the disease’s clinico-pathological features. The correlation between arteriolar C4d deposition and renal microvascular lesions (RVLs) was further analyzed.MethodsA total of 325 biopsy-proven LN patients were enrolled, and their clinico-pathological data were collected. C4d staining of renal biopsies was performed by immunohistochemistry. The associations between C4d deposition and the clinico-pathological features were further analyzed.ResultsC4d deposition was present in most (98.8%) renal specimens in our cohort. These deposits were localized in the glomeruli (98.2%), tubular basement membrane (TBM) (43.7%), arterioles (31.4%), and peritubular capillary (33.8%). Patients with TBM C4d staining had higher disease activity (measured with the Systemic Lupus Erythematous Disease Activity Index) and higher National Institutes of Health pathological activity and chronicity indices (all P < 0.01). Patients with arteriolar C4d deposition were more likely to develop RVLs (91.2%) compared to those with no arteriolar C4d deposition (78.0%; P = 0.004), especially with two or more types of RVLs (P < 0.001). During the mean follow-up of 55.8 months, arteriolar C4d was related to worse renal outcomes [hazard ration (HR): 2.074, 95% confidence interval (CI) 1.056–4.075, P = 0.034]. Multivariate Cox hazard analysis showed that co-deposition of arteriolar C4d and C3c was an independent risk factor (HR: 3.681, 95% CI 1.519–8.921, P = 0.004) for predicting renal outcomes.ConclusionsC4d deposition was common in renal tissues from LN patients. TBM C4d deposition was related to the disease activity, and arteriolar C4d deposition was associated with RVLs and worse renal outcomes.

Distribution pattern of mesangial C4d deposits as predictor of kidney failure in IgA nephropathy

Mesangial C4d deposits have been associated with worse outcomes in Western patients with IgA nephropathy (IgAN), but there is limited data in Asians. Previously, a high proportion of stained glomeruli was often required for the classification of C4d positive (C4d+ve). Positive staining in lower proportion of staining would be classified as C4d-ve. This retrospective study evaluated the prognostic value of C4d+ve using a less stringent definition (one C4d+ve glomerulus) in Thai patients with IgAN (n = 120). Baseline findings and outcomes were compared between those with more extensive C4d staining patterns and those with more restricted staining. Clinico-pathologic parameters and risk for kidney outcomes (kidney failure or decline GFR50%) were compared between C4d+ve versus C4d-ve, and between different patterns: Focal (< 50%) versus Diffuse (≥ 50% of glomeruli); or Global (≥ 50) versus Segmental (< 50% of mesangial area). The hazard ratios were estimated using Cox proportional hazard models for Model 1 (Oxford score+ C4d) and Model 2 (Model 1+ clinical factors). C4d+ve (n = 81) had lower eGFR, more global sclerosis, and interstitial fibrosis than C4d-ve at baseline. The 5-year kidney survival for C4d+ve was lower (53.7%) than C4d-ve (89.7%); P = 0.0255. By univariate analysis, T1, T2, C4d+ve, eGFR<60, proteinuria were predictors of kidney outcome. By multivariate analysis, proteinuria, T1, T2 and C4d+ve were independent predictors (Model 2 HR (95% CI) C4d+ve: 3.24 (1.09–9.58), p = 0.034). Segmental had lower eGFR, higher tubulointerstitial fibrosis, and segmental sclerosis compared to Global pattern. Clinicopathological parameters were not different between Focal and Diffuse patterns. Outcomes were similar between staining patterns. In conclusion, C4d staining may be a valuable marker of poor prognosis in Asian patients with IgAN. Less stringent criteria for C4d+ve should be considered as no differences in outcomes were observed between more extensive staining with less extensive patterns. More studies are needed to identify the optimum criteria for C4d+ve.

Evaluation of Early Renal Allograft Dysfunction from Living Donors among Egyptian Patients (Histopathological and Immunohistochemical Study)

BACKGROUND: Early renal graft dysfunction is a major problem in the early post-transplantation period and is considered a major cause of graft loss. Clinical diagnosis based on the clinical criteria alone is unreliable; therefore, biopsy remains the gold standard to differentiate between rejection and non-rejection causes. AIM: This study was designed to identify and differentiate between causes of early graft dysfunction during the first post-transplantation month and to correlate between histological lesions and immunohistochemistry (IHC) for accurate diagnosis and a better outcome. MATERIALS AND METHODS: A total of 163 renal allograft biopsies, performed in the first post-transplantation month over 6 years, were included in the study. New sections were prepared from the paraffin blocks and stained with conventional stains. Additional sections were prepared and treated by complement fragment 4d (C4d) and cluster differentiation 3 (CD3) antibodies for IHC evaluation. RESULTS: All the studied cases were from living donors. The mean patient age was 39 years with predominant males. The clinical indication for most biopsies (94.5%) was impaired graft function. Acute rejection (AR) was the main diagnostic category observed in (98/163, 60.1%); out of which, T cell-mediated rejection (TCMR) was observed in (62/98, 63.2%). Drug toxicity was suspected in (53/163, 32.5%), acute tubular injury (ATI) not otherwise specified (nos) in (21/163, 12.9%), and other lesions including thrombotic microangiopathy were observed in the remaining biopsies. The most common cause of graft dysfunction in the 1st and 2nd weeks was AR representing. A significant correlation was seen between mild glomerulitis (g1) and mild peritubular capillaritis (PTC) 1, on the one side, and negative C4d staining, on the other side. No significant correlation was seen between moderate glomerulitis (g2) and moderate ptc2 at one side and positive C4d staining at the other side reflecting the poor association between the microvascular inflammation (“g” and “ptc” scores) and C4d positivity (r = 0.2). Missed mild tubulitis (t1) was found in a single case and missed moderate tubulitis (t2) was found in a single case detected by CD3 IHC. CONCLUSION: AR and drug toxicity account for the majority of early graft dysfunction, however, other pathological lesions, per se or coincide with them may be the cause. The significance of g2 per se as a marker for diagnosis of antibody-mediated rejection requires further study. Considering C4d score 1 (by IHC) positive; also requires further study with follow-up.

MO264COMPLEMENT PATHWAY MIGHT HAVE A ROLE IN FOCAL SEGMENTAL GLOMERULOSCLEROSIS: A RETROSPECTIVE SINGLE CENTER STUDY OF 15 YEARS

Background and Aims The role of complement in focal segmental glomerulosclerosis (FSGS) is an area of interest and C4d staining could indicate complement related renal damage. We investigated detailed C4d staining properties in native kidney biopsies and possible relation to clinical features. Method We retrospectively evaluated the renal biopsies of 114 patients diagnosed with FSGS within last 15 years. C4d expressions examined in glomeruli (mesangial and/or capillary wall, vascular pole, sclerotic areas), tubular region (basement membrane, adsorbtion droplet) and vascular areas (arteriols and arteries) via immunohistochemistry. A novel glomerular C4d score (G-C4d-S) was achieved on the basis of the localization, pattern, extent and intensity of the C4d expression (min-max, 0-13). Results Of the patients (56 females, mean age 43±14 years) with a median follow-up time of 35±3 months, mean proteinuria, eGFR, and albumin level were 4984 mg/day, 72.2 ml/min/1.73m2, 3.56 g/dL, respectively. Median G-C4d-S was 6 (IQR, 4-7) and it was negatively correlated with serum creatinine at diagnosis (r=-0.21, p=0.02). Glomerular staining (both focal and diffuse, higher than moderate in intensity) was positive in 78 (68.4%) of the patients. C4d on glomerular sclerotic area was positive in 43 (37%) patients and it was associated with lower eGFR at diagnosis. Forty five patients achieved remission during the follow-up. Among the pathological features only glomerular C4d staining was associated to remission (p=0.02). There were 20 (18.7%) patients who need renal replacement theraphy (RRT) and 7 deaths (6.1%) at the end of the cohort. Lower rate of C4d staining on tubular adsorption droplets and arteriols/arteries were found to be associated need for RRT (p=0.013, p=0.012, respectively). There were no significant relationship between mortality and C4d staining features. Conclusion In conclusion, we noted that significant number of patients had positivie C4d on glomeruli, arteiroles and tubular area. We indicated that C4d staining at diagnosis could help to distinguish active glomerulonephritis. Additionally, it seems to be essential to examine non-glomerular area of native kidney biopsies, as well.

Predictors of graft outcome in renal transplant recipients with antibody-mediated rejection

Active and chronic antibody-mediated rejection (ABMR) is a common cause of graft failure. Prognostic markers of this complication are not well defined. We aimed to find out the demographic, histopathological and clinical characteristics of transplant recipients who developed ABMR and evaluate the impact of these features, and anti-rejection treatment modalities on graft survival. Methods. Thirty-two patients who developed ABMR (22 male; mean age 40.59±12.52 years) were included in this study. Data were evaluated retrospectively and graft survival was analyzed. All transplant biopsies were evaluated according to Banff's 2013 classification. Results. Among the 32 cases, 26 were transplanted from living donors. Mean serum creatinine at the time of biopsy was 1.99 ±0.09 mg/dL. Proteinuria was 1566.06±353.92 mg/day at the time of biopsy. The need for hemodialysis was significantly related with initial creatinine (p = 0.003); creatinine after three months (p < 0.001) and final creatinine (p < 0.001) as well as initial proteinuria (p = 0.005); proteinuria after three months (p < 0.001) and final proteinuria (p < 0.001). 6 cases showed diffuse C4d positivity, 26 cases showed focal c4d positivity. Five of 6 patients with diffuse C4d staining in renal biopsy were hemodialyzed at first and third months despite anti-rejection therapy (p=0.029 and 0.041, respectively). Mean survival time was 1654.67±220.40 (95% CI 1222.68-2086.66) days for focal staining C4d cases and 366.16±36.44 (95% CI 294.73-437.60) days for diffuse staining C4d cases. The difference was statistically significant (p=0.012). Two of the patients died, 15 experienced graft loss and 17 survived with functioning grafts. Mean survival time between anti-rejection treatment modalities showed no statistical significance (p=0.15) Conclusions. Serum creatinine, proteinuria at the time of biopsy, diffuse peritubular C4d staining were significantly associated with graft survival. Early diagnosis is important to improve success in the treatment of ABMR and graft survival