Outcomes of repeat kidney transplantation following prior graft failure secondary to BK nephropathy: A single-center retrospective study.

BACKGROUND: BK virus is associated with development of nephropathy (BKVN) that can lead to graft failure after renal transplantation. There are limited data on rates of recurrence and outcomes of repeat renal transplantation after prior graft loss caused by BKVN. METHODS: After IRB approval, data on all patients who underwent a repeat renal transplantation after prior graft failure as a result of BKVN were identified. Data on management of patients prior to retransplantation, induction and maintenance immunosuppression, and key clinical and virologic outcomes were collected. Descriptive statistics were used for analysis. RESULTS: Thirteen patients were identified over a 13-year period, and follow-up of these patients occurred for a median of 4.7 years. Most patients have previous renal transplants removed prior to (7/13, 53.8%) or at the time of retransplantation (3/13, 23.1%). Close virologic monitoring of serum and urine, coupled with early immunosuppression minimization, was associated with few patients developing BK viruria above 1 × 107 c/mL (4/13, 30.8%), BK viremia above 10,000 c/mL (2/13, 15.4%), and biopsy-proven BKVN (1/12, 8.3%); most (8/13, 61.5%) developed BK viruria at any level. Renal function at 1 year post-retransplantation was generally excellent and only 1 patient developed graft failure caused by recurrent focal segmental glomerulosclerosis. In our review of the literature, 2 large observational studies of the UNOS database as well as our analysis of case reports showed excellent graft survival and very low rates of recurrent BKVN leading to graft loss. CONCLUSIONS: Retransplantation after prior graft failure caused by BKVN generally has low rates of recurrence when coupled with close monitoring and early immunosuppression minimization. Removal of failed renal transplant may allow easier monitoring for recurrence.

A novel profibrotic mechanism mediated by TGFß-stimulated collagen prolyl hydroxylase expression in fibrotic lung mesenchymal cells.

Idiopathic pulmonary fibrosis is a severe chronic lung disease with a high mortality rate. Excessive TGFß signalling is recognized as a central player in lung fibrosis. However, the related mechanisms remain unclear. Herein we used a novel Tbx4 lung enhancer-driven Tet-On transgenic system to inhibit TGFß signalling in mouse lung-resident mesenchymal cells at different stages of bleomycin-induced fibrosis, by conditionally knocking out TGFß receptor II or expressing a dominant-negative TGFß receptor II. Abrogation of mesenchymal TGFß signalling markedly attenuated bleomycin-induced fibrotic pathology, which was independent of altered early inflammation. Furthermore, a novel TGFß downstream target gene P4HA3 (an α-subunit of collagen prolyl hydroxylase) was identified, and its expression was significantly increased in fibroblastic foci of both bleomycin-induced fibrotic mouse lungs and idiopathic pulmonary fibrosis patients' lungs. The relationship between activated TGFß signalling, up-regulation of P4HA3 and increased hydroxyproline/collagen production was further verified in cultured lung fibroblasts. Moreover, inhibition of collagen prolyl hydroxylase by pyridine-2,5-dicarboxylate attenuated TGFß-stimulated collagen production in both cultured fibroblasts and bleomycin-induced mouse lung fibrosis. These data indicate that increased expression and activity of collagen prolyl hydroxylase is one of the important mechanisms underlying TGFß-mediated profibrotic effects. Inhibition of collagen prolyl hydroxylase may be a new, promising approach for preventing and treating pulmonary fibrosis.