Late Antibody-Mediated Rejection in Kidney Transplant Recipients: Outcomes after Intravenous Immunoglobulin Therapy.

Development of acute antibody-mediated rejection (AMR) is associated with graft loss and can occur both early (<3 months) and late (>3 months) post-transplant. Treatment and prognosis differ in early and late AMR. Herein, we present a single-center experience using high-dose intravenous immunoglobulin (IVIg) (2g/kg) for the treatment of late AMR. All kidney recipients with negative T- and B-cell flow crossmatch at transplant and biopsy-proven late AMR were included (2009-2013, n=126). All patients were treated with IVIg at 2g/kg over divided doses and high-dose intravenous methylprednisolone. Variables collected included demographics, Banff 2007 renal allograft biopsy scoring criteria, and laboratory values. Multivariable Cox proportional hazard regression was used to identify factors predictive of graft loss. Median age was 46 years, with 60% male and 47.6% African American. Median time from transplant to rejection was 3.8 years. Baseline serum creatinine was 1.6 mg/dl and median serum creatinine at diagnosis was 2.6 mg/dl. Fifty-eight patients (46%) eventually lost their grafts at a median of 12 months (interquartile range: 4-21) from diagnosis. Serum creatinine >5.3 mg/dl at time of diagnosis was associated with a 94% probability of graft loss, and after controlling for multiple recipient and donor factors, only serum creatinine and urine protein creatinine ratio at diagnosis were predictive of graft loss. Late AMR has a poor prognosis, with 46% graft loss at a median follow-up of 12 months. Serum creatinine was a better predictor of subsequent graft failure than histological characteristics in late AMR. These findings help inform treatment plans as well as prognosis.

Loss of Thy-1 inhibits alveolar development in the newborn mouse lung.

Transforming growth factor (TGF)-beta mediates hypoxia-induced inhibition of alveolar development in the newborn lung. TGF-beta is regulated primarily at the level of activation of latent TGF-beta. Fibroblasts expressing Thy-1 (CD90) inhibit TGF-beta activation. We hypothesized that loss of Thy-1 due to hypoxia may be a mechanism by which hypoxia increases TGF-beta activation and that animals deficient in Thy-1 will simulate the effects of hypoxia on lung development. To determine if loss of Thy-1 occurred during hypoxia, non-transgenic (C57BL/6) wild-type (WT) mice exposed to hypoxia were evaluated for Thy-1 mRNA and protein. To determine if Thy-1 deficiency simulated hypoxia, WT and Thy-1 null (Thy-1(-/-)) mice were exposed to air or hypoxia from birth to 2 wk, the critical period of lung development, and lung histology, function, parameters related to TGF-beta signaling, and extracellular matrix protein content were measured. To test if the phenotype in Thy-1(-/-) mice was due to excessive TGF-beta signaling, measurements were also performed in Thy-1(-/-) mice administered TGF-beta neutralizing antibody (1D11). We observed that hypoxia reduced Thy-1 mRNA and Thy-1 staining in WT mice. Thy-1(-/-) mice had impaired alveolarization, increased TGF-beta signaling, reduced lung epithelial and endothelial cell proliferation but increased fibroblast proliferation, and increased collagen and elastin. Lung compliance was lower, and tissue but not airway resistance was higher in Thy-1(-/-) mice at 2 wk. Thy-1(-/-) mice given 1D11 had improved alveolar development and lung function. These data support the hypothesis that hypoxia, by reducing Thy-1, increases TGF-beta activation, and thereby inhibits normal alveolar development.