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- 2011 USCAP Meeting Abstracts (6)
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Acute Glomerulitis with Neutrophils May Underscore the
Development of Glomerular Basement Membrane Multi-Lamination in
Transplant Glomerulopathy.
Joseph P Gaut, Jeanne Shen, Michelle DeGuire, Christina Klein, Helen Liapis. Washington University School of Medicine, St. Louis, MO
Background: Acute glomerulitis (GL) in allograft biopsies is a distinct form of acute glomerular rejection, often seen in the early post-transplant period in association with antibody mediated rejection. A correlation with worse graft survival was previously reported. GL may also accompany transplant glomerulopathy (TGP) but its role in TGP pathogenesis remains unclear. The aim of this study was to evaluate the significance of GL in TGP.
Design: Renal transplant biopsies with TGP (n=50) and indication transplant biopsies without TGP (n=46, control) were retrospectively reviewed. GL was defined on light microscopy (LM) by the presence of monocytes or neutrophils affecting > 30% of glomeruli. TGP was defined by LM as mesangioproliferative glomerulonephritis and by EM with the following: endothelial fenestrae closure, subendothelial expansion, glomerular basement membrane (GBM) duplication, GBM multi-lamination, and luminal inflammatory cells. These EM features were scored as follows: 0 none; 1 <25% of capillary loops affected; 2 26-50% and 3 >50%. Laboratory data included urine protein. Statistical analysis using a t test was used to correlate GL, TGP and GBM multi-lamination with proteinuria.
Results: 10/50 (20%) cases of TGP showed GL compared with 1/46 (2%) control transplant biopsies. Neutrophils were a significant component of GL in 9/10 cases. EM was available for 43 cases (8 TGP with GL, 17 TGP, and 18 controls). The g score for TGP and TGP with GL was similar (1.8); 5/8 TGP cases with GL showed GBM multi-lamination. However, TGP with GL showed focal multi-lamination (score=1), whereas TGP without GL had a broad range of multi-lamination (score=0-3). There was a trend towards increased proteinuria associated with GL (3.35 g/day vs. 2.08 g/day). There was a stronger correlation of GBM multi-lamination with proteinuria (4.25 g/day vs. 2.35 g/day; p=0.08). 2/10 (20%) cases of TGP with GL showed peritubular capillary C4d staining compared with 12/25 (48%) cases of TGP without GL. The GBM multi-lamination score tended to correlate with C4d staining in PTC (1.2 versus 0.8).
Conclusions: Our results suggest a key role for neutrophils in the pathogenesis of GBM injury in TGP. We propose that neutrophils may mediate development of GBM multi-lamination in established TGP. A correlation of multi-lamination with C4d peritubular capillary immunoreactivity is consistent with the concept that both are features of chronic transplant capillaropathy.
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Evaluation of Endothelial Cell Enlargement in Glomerulitis.
Marialuisa Valente, Lucrezia Furian, Paolo Rigotti, Mila Della Barbera, Francesco Marchini, Stefano Marino, Massimo Cardillo, Francesca B Aiello. University of Padua, Medical School, Padova, Italy; Azienda Ospedaliera Padova, Padova, Italy; Azienda Ospedaliera ULSS 12, Venezia, Iraq; Centre for Organ and Tissue Transplant, IRCCS, Ospedale Maggiore, Milano, Italy; University of Chieti, Italy
Background: Glomerulitis is defined by mononuclear cells in glomeruli and endothelial cell enlargement. In T cell mediated acute rejection, according to the Banff classification, glomerulitis is scored but not utilized to grade T cell mediated acute rejection, in contrast, in antibody mediated acute rejection its prognostic significance has been proposed to be relevant.
Design: Glomerulitis was studied in 90 consecutive acute rejections, time interval 2004-2009, matched as closely as possible for type and grade. CD68 and C4d immunostaining was performed in all cases. Glomerular endothelial cell enlargement (ECE) was measured morphometrically following CD31 immunostaining (ECE = endothelial cell area/total capillary area x 100)
Results: Glomerulitis was present in 36 cases (group 1) and absent in 54 (group 2). ECE was measured in 15 biopsies of group 1, 8 of group 2 and in 8 control biopsies with no evidence of rejection. The ECE mean value of group 1 (69.3 + 6.7%) but not that of group 2 (58.5 ++ 3.56%) (P< 0.05). C4d deposition, observed in 14/36 rejections of group 1 (38.9%) and in 7/54 rejections of group 2 (13.0%) (P< 0.05), was associated with steroid resistance (OR = 4.97 95% CI 1.76-14.02, P< 0.05). In patients with C4d+ rejections the presence of glomerulitis markedly increased the association (OR = 9.17, 95% CI 1.15-73.24, P< 0.05).
Conclusions: Our results indicate a significant endothelial cell enlargement in glomerulitis. In C4d+ acute rejection glomerulitis, associated with steroid resistance, may have an important prognostic significance. 6.6%) was higher than in controls (57.0
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HLA-DR Immunohistochemistry Quantitation in Renal Allograft
Biopsies: Objective Discrimination of Rejection and Other Pathologic
Processes.
Alton B Farris, Jun Kong, Candace Chisolm, Howard M Gebel, Robert A Bray, Cynthia Cohen, Daniel J Brat, Joel H Saltz, Allan D Kirk, Randolph Hennigar. Emory University, Atlanta, GA; Emory University, Atlanta
Background: Histologic renal allograft biopsy (bx) assessment methods (e.g., the Banff criteria), although historically useful, largely rely on semi-quantitative, granular criteria, sometimes making the appreciation of subtle pathologic differences difficult. Human leukocyte antigen (HLA)-DR expression has been shown in renal allografts, particularly bxs with rejection. We investigated the utility of renal allograft bx assessment using HLA-DR immunohistochemistry (IHC) whole slide image (WSI) analysis.
Design: IHC was performed with a commercially-available HLA-DR antibody on bxs containing allograft rejection, polyomavirus nephritis (PVN), a borderline pattern, normal donor tissue, and stable allografts. HLA-DR WSIs obtained using an Olympus Nanozoomer scanner were quantitated with regard to total and cortical renal parenchymal staining using the Aperio Imagescope Positive Pixel Count algorithm, yielding a % of parenchyma with HLA-DR positivity.
Results: Highest HLA-DR positivity was seen in allograft rejection bxs [Table]. Elevated levels were also seen in PVN, followed by borderline cases. A baseline HLA-DR level was present in normal donor bxs, and the lowest levels were in stable allografts. Differences were not significant between rejection and polyomavirus nephritis; however HLA-DR levels in rejection and PVN were significantly higher than stable and normal donor bxs. Rejection but not PVN was significantly higher than borderline. Linear regression showed a direct correlation between total and cortical HLA-DR (R2 = 0.98, P < 0.0001).
| Type | HLA-DR total parenchymal positivity (%) [Mean ± S.D.] | Comparison (T-test) |
| Rejection (n = 15) | 62.2 ± 16.2 | ***, *, • |
| Antibody-mediated rejection (n=3) | 68.6 ± 9.3 | ***, *, • |
| Cellular rejection (n =12) | 60.6 ± 17.4 | ***, *, • |
| PVN (n = 3) | 60.6 ± 8.1 | **, ^ |
| Borderline (n = 2) | 36.1 ± 10.4 | |
| Normal donor (n = 4) | 33.6 ± 18.5 | |
| Stable allograft (n =3) | 15.0 ± 4.4 |
Conclusions: Our data suggest that HLA-DR IHC quantitation has a potential for utility in objectively measuring the immunologic activation of allografts, particularly when combined with emerging WSI segmentation algorithms. Future studies using additional histologic, IHC, and molecular markers may prove useful.
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Microcirculation Inflammation in Kidney Transplant Biopsies: Relationship to Diseases and Transplant Outcomes.
Banu Sis, Gian Jhangri, Julie Riopel, Hakimah Mahsin, Jessica Chang, Michael Mengel, Declan de Freitas, Joana Sellares, Stephen Osasan, Bruce Kaplan, Philip Halloran. University of Alberta, Edmonton, Canada; University of Arizona, Tucson
Background: We studied the significance of microcirculation inflammation – glomerulitis and peritubular capillaritis – in kidney transplants in relationship to diseases and outcomes.
Design: We examined 221 renal allograft biopsies for cause from 169 patients (median follow-up after biopsy 32 months).
Results: Glomerulitis (g) and peritubular capillaritis (ptc) were associated with antibody-mediated rejection (ABMR) (63% and 70%, respectively), but were not specific because they were also seen in other diseases (T cell-mediated rejection, glomerulonephritis, acute tubular necrosis). In univariate analysis, all g>0 grades and ptc2,3 predicted poor survival, but ptc1 did not. In multivariate analysis, the combination of g>0 plus ptc>1 independently predicted poor survival, but either g>0 or ptc>1, C4d, alloantibody, and transplant glomerulopathy did not. Transplant glomerulopathy with g>0 plus ptc>1 showed accelerated graft loss, but transplant glomerulopathy without this combination showed an indolent course. The majority (89%) of biopsies with g>0 plus ptc>1 was antibody-mediated rejection (C4d +/-). In multivariate analysis of ABMR patients, concurrent g>0 plus ptc>1 was the only independent predictor of graft loss.
Conclusions: Thus, the combination of glomerulitis (g>0) plus peritubular capillaritis (ptc>1) in the presence of DSA should be recognized as active antibody-mediated rejection with a high risk for graft failure, without requiring C4d staining.
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Clinical Implications of Polyomavirus-Associated Nephropathy after Renal Transplantation.
Helen P Cathro, Jason C Gardenier, Costi D Sifri, Douglas S Keith, Robert G Sawyer, Kenneth L Brayman, Hugo Bonatti. University of Virginia, Charlottesville; Vanderbilt University, Nashville, TN
Background: BK virus nephropathy (BKVN) develops in ∼5% of renal transplants (RT), causing graft loss in 15-80% of cases within 5 years. Most studies suggest that the majority of BKVN occurs during the first post-transplant (PT) year. We noticed an increasing number of cases of late-onset BKVN and conducted a retrospective study.
Design: All renal specimens from patients with biopsy-proven BKVN from 2000-2009 at a single institution were reviewed.
Results: Of 846 RT recipients, 18 had biopsy-proven BKVN (2.1%), 4 of whom had also received pancreatic transplants. The median age of 12 males and 6 females was 52.2 yr (range 27.9-63.8 yr), and the median time PT was 20.1 mn (range 3.2-80.4 mn), with only 4 or 22%, <1 yr out. Fourteen patients were on standard immunosuppression (IS). Screening for BK virus was erratically administered due to geographical/logistical constraints. Five patients had prior biopsy proven episodes of acute rejection and 13 patients (72%) had received intensive prior IS, usually for acute rejection (n=10) or for subsequent pancreas transplantation. Fourteen patients were treated with antiviral therapy, +/- IVIG, +/- IS taper, and single patients were treated with IVIG or IS taper alone. One patient died after returning to dialysis, and 17 were alive at an average of 3.4 yr follow up. Seven of these had returned to dialysis (41%), and 5 had a serum creatinine >2 mg/dL (29%). Only 5 patients had good graft function (29%).
Conclusions: Retrospective analysis of BKVN at a single institution during the current IS era demonstrated 78% of cases occurring after the first PT year, and 39% after the second PT year. Inconsistent screening and over-IS may be playing a role. The poor outcome of 72% of the BKVN cases is in part due to late diagnosis at a severe stage of disease. Late onset BKVN is an underrecognized cause of graft loss and dysfunction, and rigorous screening followed by tapering of IS on positive testing, should be emphasized beyond the first year post-transplantation.
