Intrarenal B Cell Cytokines Promote Transplant Fibrosis and Tubular Atrophy.

Renal transplantation is the optimum treatment for end-stage renal failure. B cells have been identified in chronic allograft damage (CAD) and associated with the development of tertiary lymphoid tissue within the human renal allograft. We performed renal transplantation in mice to model CAD and identified B cells forming tertiary lymphoid tissue with germinal centers. Intra-allograft B220(+) B cells comprised of IgM(high) CD23(-) B cells, IgM(lo) CD23(+) B cells, and IgM(lo) CD23(-) B cells with elevated expression of CD86. Depletion of B cells with anti-CD20 was associated with an improvement in CAD but only when administered after transplantation and not before. Isolated intra-allograft B cells were cultured and shown to synthesize multiple cytokines, the most abundant of these were GRO-α (CXCL1), RANTES (CCL5), IL-6 and MCP-1 (CCL2). Tubular loss was observed with T cell accumulation within the allograft and development of interstitial fibrosis, whilst type III collagen deposition was observed in areas of F4/80(+) macrophages and PDGFR-ß(+) and transgelin(+) fibroblasts, all of which were reduced by B cell depletion. We have shown that intra-allograft B cells are key mediators of CAD. B cells possibly contribute to CAD by intra-allograft secretion of cytokines and chemokines.

Indications for thrombolysis in deep venous thrombosis.

OBJECTIVES: Deep venous thromboses (DVTs) are a significant cause of morbidity and mortality in the general and inpatient population. Current anticoagulation therapy is efficient in reducing thrombus propagation but does not contribute to clot lysis or prevention of post-thrombotic limb syndrome. Catheter directed thrombolysis (CDT) is an alternative method for treating DVTs but there is no consensus regarding indications for its use. DATA SOURCES: PubMed and Cochrane library were searched for all articles on deep vein thrombosis and thrombolysis. REVIEW METHOD: Articles presenting data on DVT thrombolysis, DVT anticoagulation, mechanical thrombectomy, venous stenting and May-Thurner's syndrome were considered for inclusion in the review. RESULTS: CDT reduced clot burden, DVT recurrence and may prevent the formation of post-thrombotic syndrome. Indications for its use include younger individuals with a long life expectancy and few co-morbidities, limb-threatening thromboses and proximal ilio-femoral DVTs. There is a marked lack of randomised controlled trials comparing CDT-related mortality and long term outcomes compared to anticoagulation alone. The effectiveness of combined pharmaco-mechanic thrombectomy, although promising, need to be further investigated, as is the role of caval filters in preventing DVT-associated pulmonary emboli. CONCLUSIONS: These results suggest that the outcome of CDT in DVT management are encouraging in selected patient cohorts, but further evidence is required to establish longer term benefits and cost-effectiveness.

Fracture healing in HIV-positive populations.

Highly active anti-retroviral therapy has transformed HIV into a chronic disease with a long-term asymptomatic phase. As a result, emphasis is shifting to other effects of the virus, aside from immunosuppression and mortality. We have reviewed the current evidence for an association between HIV infection and poor fracture healing. The increased prevalence of osteoporosis and fragility fractures in HIV patients is well recognised. The suggestion that this may be purely as a result of highly active anti-retroviral therapy has been largely rejected. Apart from directly impeding cellular function in bone remodelling, HIV infection is known to cause derangement in the levels of those cytokines involved in fracture healing (particularly tumour necrosis factor-alpha) and appears to impair the blood supply of bone. Many other factors complicate this issue, including a reduced body mass index, suboptimal nutrition, the effects of anti-retroviral drugs and the avoidance of operative intervention because of high rates of wound infection. However, there are sound molecular and biochemical hypotheses for a direct relationship between HIV infection and impaired fracture healing, and the rewards for further knowledge in this area are extensive in terms of optimised fracture management, reduced patient morbidity and educated resource allocation. Further investigation in this area is overdue.