Proteasome inhibition with bortezomib: an effective therapy for severe antibody mediated rejection after renal transplantation.

Antibody-mediated rejection (AMR) following renal transplantation is less responsive to conventional anti-rejection therapies. Plasmapheresis (PP), intravenous immunoglobulin (IVIg), rabbit antithymocyte globulin (rATG) and rituximab deplete immature B-cells but not mature plasma cells. The proteasome inhibitor bortezomib has activity against mature plasma cell, the source of damaging donor-specific antibody (DSA).We present the successful use of bortezomib in 2 patients who developed AMR following kidney transplantation. The first patient was a 54-year-old white female who received living-unrelated kidney transplantation from her husband. She developed severe AMR early after transplantation with rising DSA titers consistent with an anamnestic immune response by memory cells to the donor antigens. Renal function deteriorated despite treatment with pulse methylprednisolone (MP), PP and IVIg. After initiation of therapy with bortezomib, DSA titers became negative and serum creatinine returned to baseline with histological resolution of AMR. The second patient was a 19-year-old white male who received deceased donor kidney transplantation and developed AMR within 2 weeks, refractory to therapy with pulse MP, PP and IVIg with rising DSA. Bortezomib use resulted in disappearance of DSA and renal function improvement. Both patients tolerated the treatment well with stable renal function at last follow-up. The novel mechanisms of action and preliminary results with bortezomib are encouraging, but require larger studies and longer follow-up.

De Novo Collapsing Glomerulopathy: An Unusual Cause of Early Graft Failure following Kidney Transplantation.

Collapsing glomerulopathy (CG) is a variant of focal segmental glomerulosclerosis (FSGS) characterized histologically by prominent glomerular capillary tuft collapse with hypertrophy and hyperplasia of podocytes and tubulointerstitial damage. Patients usually present with heavy proteinuria and rapidly progressive renal failure. We report a patient who developed de novo CG with severe clinical manifestations including worsening renal failure and nephrotic syndrome within six months of receiving deceased donor kidney transplant. Secondary work-up was negative, and despite therapy with high-dose steroids and plasmapheresis, allograft function rapidly deteriorated with the need for dialysis. Theories about the pathogenesis of this entity as well as treatment modalities are discussed.

Endoglin (CD105) expression in endometrial carcinoma.

Tumor angiogenesis plays an important role in tumor growth and metastasis. We evaluated endoglin (CD105) as an endothelial marker of angiogenesis in endometrial carcinoma (EC) and its prognostic significance. Fifty-five cases of EC, 10 cases of complex endometrial hyperplasia with atypia (CHA), and 10 cases of simple hyperplasia (SH) were immunohistochemically stained for endoglin, CD31, and vascular endothelial growth factor (VEGF). Positively stained microvessels (MV) were counted in densely vascular foci (hot spots) in a 400x field in each specimen. For VEGF, intensity of staining was scored on three-tiered scale. Results were correlated with other prognostic parameters using appropriate statistics. Endoglin staining demonstrated significantly more MV than did CD31 (mean 30.8 +/- 10.95 vs. 13.38 +/- 7.53, p < 0.001). There was a positive correlation of both endoglin and CD31 MV counts with tumor differentiation (p < 0.05) and the depth of invasion (p < 0.01). However, only endoglin counts correlated significantly with the presence of angiolymphatic invasion (p < 0.01), lymph nodes metastases (p < 0.01), and tumor stage (p < 0.001). VEGF expression in EC had a significant correlation with angiolymphatic invasion (p < 0.01) and lymph node status (p < 0.05) but not with other prognostic parameters. Endoglin and VEGF showed significant differences between CHA and SH (p < 0.001). Our study showed that endoglin, by staining the proliferating MV in EC, is a more specific and sensitive marker for tumor angiogenesis than is the commonly used pan-endothelial marker, CD31. Endoglin staining also had prognostic significance, with positive correlation with angiolymphatic invasion, lymph node metastases, and tumor stage.