We studied the role of classical phagocytic NADPH oxidase (Nox) in the pathogenesis of kidney allograft tubulointerstitial fibrosis. Immunofluorescence studies showed that Nox-2 and p22phox (electron transfer subunits of Nox) colocalized in the tubulointerstitium of human kidney allografts. Tubular Nox-2 also colocalized with α -SMA in areas of injury, suggestive of epithelial-to-mesenchymal transition (EMT). Interstitial macrophages (CD68+) and myofibroblasts (α -SMA+) expressed Nox-2 while graft infiltrating T cells (CD3+) and mature fibroblasts (S100A4+) were Nox-2−. These results were confirmed in the Fisher-to-Lewis rat kidney transplant model. Areas of tubulitis were associated with Nox-2 and α -SMA, suggestive of EMT. Immunoblot analyses showed that Nox-2 upregulation was associated with oxidative stress (nitrotyrosine) and fibrogenesis (α -SMA and phospho-Smad2) at 3 weeks and 6 months. Allografts treated with Nox inhibitors (DPI or apocynin) for 1 week showed reduced fibronectin and phospho-Smad2 and increased E-cadherin levels. Cyclosporine A, TGF-β1 and angiotensin II increased Nox-2 mRNA levels 2- to 7-fold in vitro (NRK52E cells). Treatment with specific Nox inhibitors (DPI or apocynin) prevented the downregulation of E-cadherin and upregulation of fibronectin transcripts. In aggregate, these studies suggest that Nox-2 is involved in the pathogenesis of allograft tubulointerstitial fibrosis via activation transcription factor Smad2, EMT and myofibroblasts.

Background. Kidney half-life and inter-stage progression rates in native chronic kidney disease (CKD) and CKD-transplant (CKD-T) remain unknown. Methods. We examined stage-to-stage progression/ regression rates in patients with CKD (n ¼ 601) and CKD-T (n ¼ 431) between 1991 and 2001. Kidney function was estimated by Cockcroft-Gault and MDRD eGFR formulae. Kaplan-Meier analyses determined progression and regression half-lives, defined as the time required for 50% of kidneys to advance towards a higher or lower stage of CKD, respectively. Results. Most (67%) of the patients were in stage 3. Patients with native CKD were more likely to progress compared to CKD-T (inter-stage progression rates 12 vs 4 cases per 100 patient-years, P < 0.0001). Accordingly, estimated glomerular filtration rate (eGFR)-based progression half-lives were significantly shorter in CKD compared to CKD-T [6 vs 9.6 years, P < 0.0001, hazard ratio (HR) 3.1, 95% confidence interval (CI) ¼ 2.5-3.7]. Creatinine clearance (CCR)-based stage half-lives were 7.2 months shorter in each group (5.4 and 9 years in CKD and CKD-T, respectively). Despite slower progression rates in patients with transplant kidney disease, adjusted patient survival rates were significantly decreased in CKD-T compared to CKD. Only Scr and CCR-based formulae were significantly associated with patient and allograft outcomes in the CKD-T group. Moreover, death rates were not different in stage 3 compared to stage 2 CKD-T, suggesting that eGFR and the current staging classification have a limited value to predict patient death in this cohort. Conclusion. Kidney half-lives per stage of CKD may be a novel tool to examine disease progression.

The role of stent placement in hemodialysis (HD) access intervention continues to evolve. As more stents are placed, new and unusual complications are coming to light. We describe a case in which an unsuccessful attempt to place a left subclavian dialysis catheter resulted in the inadvertent migration and folding of a previously deployed subclavian stent. Attempts to remove the stent with a snare were unsuccessful. Patency was restored to the access circuit by placing a new stent through the struts of the folded one. Clinical vascular practice guidelines for vascular access on the use of fluoroscopy for temporary HD catheter placement may need to be re-evaluated with the reported increase in stent placement in the US HD population.