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Tumor necrosis factor-alpha (TNF-alpha) is a multifunctional cytokine involved in the expression of many genes integral to the inflammatory response. In addition, it activates both apoptotic and survival pathways, the latter being mediated through the activation of the transcription factor nuclear factor-kappaB (NF-kappaB). Protein kinase CK2, a serine-threonine kinase that is universally upregulated in human malignancies, may be involved at multiple levels in this process. However, its role in mediating a survival response within colon cancer cells remains incompletely understood. Here we report that inhibition of CK2 in HCT-116 and HT-29 cells with the use of two specific CK2 inhibitors, 5,6-dichloro-ribifuranosylbenzimidazole (DRB) and apigenin, effected a synergistic reduction in cell survival when used in conjunction with TNF-alpha. Furthermore, there was a demonstrable synergistic reduction in colony formation in soft agar with the use of the same combinations. Western blot analysis showed that poly-ADP ribose polymerase and procaspase-3 cleavage complemented the fluorescence-activated cell sorter analysis findings of significantly increased subdiploid DNA-containing cell populations using these conditions. Remarkably, these events occurred in the absence of any reduction in the expression of the Bcl-2 family members Bcl-2, Mcl-1, and Bcl-xL or any change in the proapoptotic molecules Bad or Bax. One-hybrid NF-kappaB promoter assays utilizing a Gal4-p65 transactivation domain construct revealed that the TNF-induced transactivation was inhibited by both DRB and apigenin. This was associated with a concomitant reduction in the expression of a recognized anti-apoptotic NF-kappaB target, manganese superoxide dismutase, demonstrated by Q-PCR. Our findings indicate a potentially novel strategy for the treatment of colon cancer, one that targets CK2 simultaneous with TNF-alpha administration.

The findings of iron deposition in affected microvasculature lend support to the potential role of iron in the complex pathophysiologic cascade of CUA. The implications for iron therapy in high-risk patients and the possible rationale for the use of sodium thiosulphate, a metal chelator, in the treatment of CUA are explored.

In this cohort of patients undergoing hemodialysis in 2 Canadian provinces in 2009-2010, the use of e-beam sterilized dialyzers was associated with significant thrombocytopenia following dialysis.

The purpose of this review is to examine the evidence supporting the application of plasma exchange in renal disease. Our review focuses on the following 6 most common renal indications for plasma exchange based on 2014 registry data from the Canadian Apheresis Group: (i) thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome; (ii) renal transplantation, (iii) antineutrophil cytoplasm antibodies-associated vasculitis, (iv) cryoglobulinemia, (v) focal segmental glomerulosclerosis, and (vi) Goodpasture syndrome. The rarity of these diseases and their rapid, often fatal course mean that randomized controlled studies of plasma exchange are rarely conducted. Although evidence from an adequately powered randomized controlled trial supports the use of plasma exchange to treat thrombotic thrombocytopenic purpura, the use of plasma exchange to treat other renal diseases is only supported by observational and mechanistic studies. Larger well-designed trials are needed to clarify the potential role of plasma exchange in renal disease. Growing international collaboration will improve the quality of future studies in this area.

Hemodialysis (HD) and therapeutic plasma exchange (TPE) are extracorporeal treatments that may both be required in the same patient. When provided separately, 7-8 hours of therapy time is required. Simultaneous administration of both therapies can reduce time and personnel requirements. We report our 18-year institutional experience with combination HD and centrifugal TPE therapy. During combination therapy, the TPE circuit is attached to the HD circuit through an extension blood line connected to the HD venous return line, allowing simultaneous operation of both circuits. The HD circuit is anticoagulated with heparin and the TPE circuit with regional citrate. Blood flow rates through the HD circuit can reach 350 mL/min with plasma removal rates in the TPE circuit up to 60 mL/min. Ninety-two patients received a total of 621 treatments between December 1993 and July 2011. All treatments were completed within 4 hours. No major treatment-related adverse events occurred and less than 10% of treatments were complicated by minor events. Main indications for treatment were ANCA (anti-neutrophilic cytoplasmic antibody) vasculitis (n = 25), Goodpasture's/antiglomerular basement membrane disease (n = 24), adult thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (n = 24), and acute antibody-mediated renal transplant rejection (n = 8). Overall rates of renal recovery, in-hospital mortality, and overall mortality at 18-year follow-up were 45% (41/ 92), 2% (2/92), and 21% (19/ 92), respectively, compatible with published literature. Combination HD and TPE is safe, efficient, and requires less human resources and time than conventional sequential therapy. It should be considered in patients whose treatment regimen includes HD and TPE.

BackgroundCalcific uremic arteriolopathy (CUA), also known as calciphylaxis, is a rare but life-threatening condition predominately occurring in patients with end-stage renal disease on dialysis. In the absence of randomized clinical trials to guide management, clinicians must rely on observational data. We have previously reported the outcomes of our multi-intervention management in seven patients and now present a larger series of patients with extended follow-up.MethodsWe performed a retrospective analysis of all patients diagnosed with CUA at a single academic center between 2008 and 2017. We identified 24 patients including 13 hemodialysis, 8 peritoneal dialysis and 3 predialysis Stage 5 chronic kidney disease patients.ResultsMean age at diagnosis was 60.5 years (range 35–83) and mean follow-up 30.5 months (range <1–99). Patients were predominately female (71%) and Caucasian (83%) with diabetes mellitus diagnosed in 16 of 24 patients. Fifteen of 24 patients had ulcerating lesions suggestive of advanced disease and 20 of 24 had extensive involvement (bilateral disease or lesion size >5 cm). Treatment consisted of intensive hemodialysis (>20 h per week), sodium thiosulfate, wound care, analgesics and discontinuation of trigger medications including warfarin. Hyperbaric oxygen, cinacalcet, bisphosphonates and vitamin K were used in some cases. Overall 1 year mortality was 41% (9/22) and overall mortality at the end of follow-up was 64% (14/24). Cause of death was felt to be attributable to CUA in only four cases (16.7%). Complete or partial resolution of lesions occurred in 17 of 24 patients. One patient had recurrence of CUA 20 months after initial diagnosis.ConclusionsAlthough mortality remains high in this group, direct CUA-attributable mortality is lower than historic reports. We conclude that a multi-intervention approach can be successful in treating a group of patients with severe CUA lesions.