C-reactive protein (CRP) is a phylogenetically conserved protein; in humans, it is present in the plasma and at sites of inflammation. At physiological pH, native pentameric CRP exhibits calcium-dependent binding specificity for phosphocholine. In this study, we determined the binding specificities of CRP at acidic pH, a characteristic of inflammatory sites. We investigated the binding of fluid-phase CRP to six immobilized proteins: complement factor H, oxidized low-density lipoprotein, complement C3b, IgG, amyloid , and BSA immobilized on microtiter plates. At pH 7.0, CRP did not bind to any of these proteins, but, at pH ranging from 5.2 to 4.6, CRP bound to all six proteins. Acidic pH did not monomerize CRP but modified the pentameric structure, as determined by gel filtration, 1-anilinonaphthalene-8-sulfonic acid-binding fluorescence, and phosphocholine-binding assays. Some modifications in CRP were reversible at pH 7.0, for example, the phosphocholine-binding activity of CRP, which was reduced at acidic pH, was restored after pH neutralization. For efficient binding of acidic pHtreated CRP to immobilized proteins, it was necessary that the immobilized proteins, except factor H, were also exposed to acidic pH. Because immobilization of proteins on microtiter plates and exposure of immobilized proteins to acidic pH alter the conformation of immobilized proteins, our findings suggest that conformationally altered proteins form a CRP-ligand in acidic environment, regardless of the identity of the protein. This ligand binding specificity of CRP in its acidic pH-induced pentameric state has implications for toxic conditions involving protein misfolding in acidic environments and favors the conservation of CRP throughout evolution.
BACKGROUNDHyperhemolysis syndrome (HHS) is a posttransfusion complication most frequently seen in sickle cell disease (SCD), characterized by rapid destruction of transfused and autologous red blood cells (RBCs), resulting in reticulocytopenia and a decrease in hemoglobin to below pretransfusion levels. Additional RBC transfusion can be life threatening. Most patients improve with intravenous immune globulin and steroids, but in refractory cases, hyperhemolysis may result in multiorgan failure and death in the absence of salvage therapy. The exact pathophysiology of HHS remains uncertain, yet new insights suggest that RBC destruction is driven by activated macrophages. Therefore, we propose that antimacrophage therapy may represent an effective treatment.CASE REPORTA case of life‐threatening HHS, refractory to intravenous immune globulin and steroids, in a patient with SCD is presented. Marked elevation in ferritin, an indirect marker of macrophage activation, a negative direct antiglobulin test, and the absence of RBC alloantibodies was noted. A hemoglobin nadir of 2.1 g/dL and resultant hypoxemia‐induced organ failure prompted the use of tocilizumab, an interleukin‐6 receptor monoclonal antibody. Hemoglobin‐based oxygen carrier‐201, a cell‐free polymerized bovine hemoglobin, was used to support the patient during critical anemia.RESULTSHemolysis resolved and ferritin dramatically decreased after administration of tocilizumab, which was well tolerated. A full recovery was achieved.CONCLUSIONThis case highlights both a novel and successful approach to managing refractory transfusion‐induced hyperhemolysis with tocilizumab and provides further evidence supporting the role for macrophage activation in the destruction of RBCs in antibody‐negative HHS. We propose that tocilizumab is an effective and rapid salvage therapy for refractory HHS.
242 Background: Cisplatin is a widely used chemotherapeutic in treating malignancies. A common side effects of cisplatin is kidney injury, or nephrotoxicity. This can be a reason for discontinuation of treatment. The majority of the cisplatin is removed from the body by urination. Mannitol is a compound that has been thought to help negate cisplatin-induced nephrotoxicity. Mannitol is a diuretic, causing increased amount of urination, enhancing excretion of cisplatin. Mmultiple studies that indirectly looked into the effect of mannitol in preventing kidney damage in patients receiving cisplatin. However, there are limited prospective data that evaluate the effect of mannitol in preventing cisplatin-induced nephrotoxicity. In this study, we determine the effects of pre-hydration with mannitol on reducing the risk of cisplatin-induced nephrotoxicity, as opposed to normal saline pre-hydration in patients receiving cisplatin. Methods: 50 patients eligible to receive chemotherapy with cisplatin chemotherapy were identified and randomized to receive 1L saline alone (A) or saline plus mannitol (B) before and after chemotherapy. (1) NS 1 Liter pre chemo- > chemo - > NS 1 Liter post chemo; (2) NS + Mannitol pre chemo - > chemo - > NS + Mannitol post chemo. Serum creatinine and BUN were drawn on days 1 (baseline), 5, and 14 Results: Renal function as measured by BUN/Cr ration, GFR, creatinine, and BUN between group (A) and (B) are similar at baseline (BL), day 1, 5, and 14. Cisplatin caused acute decline in renal function as determined by ser Cr, BUN to ser Cr ratio and GFR, however, the addition of mannitol to NS pre-hydration did not change the outcome. The decline in renal function is limited to grade 1 and most patients recover. Conclusions: Mannitol does not prevent acute nephrotoxicity in patients receiving cisplatin. This underscores the importance of adequate hydration in patients treated with cisplatin.[Table: see text]
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