Mechanism of microthrombosis in HUS.

The mechanism of formation of the microthrombi in hemolytic uremic syndrome (HUS) is not known. Plasma from five adult and six pediatric cases of HUS showed aggregation and release of adenosine triphosphate from normal platelets. When the plasma was absorbed with staphylococcal protein A and again exposed to normal platelets there was no aggregation or release, indicating that an antibody was responsible for the aggregation. The plasma reacted with platelet lysate in a western blot, showing reactivity with CD36. This was confirmed by probing with Mo91, a monoclonal antibody to CD36. When the patient's plasma was used to probe purified verotoxin-2, bands of 32 and 7.7 kDa were obtained. Similar results were obtained using Mo91. The reactions suggest structural homologies between CD36 and verotoxin. Although a direct cause-effect relationship is not yet established, the data support the concept of an immunological pathogenesis for HUS with the formation of cross-reacting antibodies.

A Canadian phase II study evaluating the efficacy of rituximab in the management of patients with relapsed/refractory thrombotic thrombocytopenic purpura.

Rituximab is a chimeric monoclonal antibody that targets the human CD-20 antigen present on malignant and normal B lymphocytes. Recent clinical studies have shown a significant response rate when this drug is given to selected patients with thrombotic thrombocytopenic purpura (TTP). Given that the clinical manifestations of TTP may be the direct result of an auto-antibody against a regulatory Von Willebrand factor enzyme (ADAMTS13), it makes biological sense to consider a therapy that has the ability to diminish or eradicate antibody-producing B cells. Despite initial positive results, there is a need to identify which patients derive durable benefit from this agent. As in other conditions that utilize therapeutic immunosuppression, there is a risk that the addition of rituximab may also lead to serious opportunistic infections.

Plasma exchange when myeloma presents as acute renal failure: a randomized, controlled trial.

BACKGROUND: Two small, randomized trials provide conflicting evidence about the benefits of plasma exchange for patients with acute renal failure at the onset of multiple myeloma. OBJECTIVE: To assess the effect of 5 to 7 plasma exchanges on a composite outcome in patients with acute renal failure at the onset of multiple myeloma. DESIGN: Randomized, open, controlled trial, stratified by chemotherapy and dialysis dependence, conducted from 1998 to 2004. SETTING: Hospital plasma exchange units in 14 Canadian medical centers. PARTICIPANTS: 104 patients between 18 and 81 years of age with acute renal failure at the onset of myeloma. INTERVENTION: Study participants were randomly assigned to conventional therapy plus 5 to 7 plasma exchanges of 50 mL per kg of body weight of 5% human serum albumin for 10 days or conventional therapy alone. Ninety-seven participants completed the 6-month follow-up. MEASUREMENTS: The primary outcome was a composite measure of death, dialysis dependence, or glomerular filtration rate less than 0.29 mL x s(-2) x m(-2) (<30 mL/min per 1.73 m2). RESULTS: At enrollment, the plasma exchange and control groups were similar for dialysis dependence, chemotherapy, sex, age, hypercalcemia, serum albumin level, 24-hour urine protein level, serum creatinine level, and Durie-Salmon staging. The primary composite end point occurred in 33 of 57 (57.9%) patients in the plasma exchange group and in 27 of 39 (69.2%) patients in the control group (difference between groups, 11.3% [95% CI, -8.3% to 29.1%]; P = 0.36). One third of patients in each group died. LIMITATIONS: The study was small, used a composite outcome, and did not use renal biopsy as an inclusion criterion. Recruiting physicians were blinded to treatment allocation but not to treatment thereafter. CONCLUSIONS: In patients with acute renal failure at the onset of multiple myeloma, there is no conclusive evidence that 5 to 7 plasma exchanges substantially reduce a composite outcome of death, dialysis dependence, or glomerular filtration rate less than 0.29 mL.s(-2).m(-2) (<30 mL/min per 1.73 m2) at 6 months.

Effect of awareness of a randomized controlled trial on use of experimental therapy.

CONTEXT: Use of experimental therapies during but outside of randomized controlled trials (RCTs) has not been studied. OBJECTIVE: To determine whether initiation of an RCT leads to increased use of the experimental therapy outside the trial. DESIGN AND SETTING: Data on national apheresis use during 3 Canadian RCTs for multiple sclerosis (1986-1988), thrombotic thrombocytopenic purpura (1982-1988), and myeloma cast nephropathy (1998-2000) were obtained from 19 major medical centers in Canada. The multiple sclerosis and myeloma cast nephropathy trials had data on apheresis use for 3 years prior to and during the trials, which permitted a time-series analysis to determine the impact of the RCTs on the use of apheresis. The ongoing myeloma cast nephropathy trial provided data on the number of patients inside and outside of the RCTs in trial and nontrial centers. Initial and follow-up questionnaires were sent to 24 Canadian physicians in trial and nontrial centers to determine if they had noted an increase in apheresis activity during the trials and, if so, their explanation for it. MAIN OUTCOME MEASURE: Change in number of patients undergoing apheresis for thrombotic thrombocytopenic purpura, multiple sclerosis, and myeloma cast nephropathy prior to and during the respective RCTs compared with all patients undergoing apheresis during the same periods. RESULTS: During all 3 RCTs, there were large increases in use of apheresis. The majority of the increased use of apheresis was outside of the trials: for multiple sclerosis, 30 of 49 patients per year (61% of increase); thrombotic thrombocytopenic purpura, 49 of 56 patients per year (72% of increase); and myeloma cast nephropathy, 60 of 72 patients per year (57% of increase). The myeloma cast nephropathy study noted that this increase occurred in both nontrial and trial centers. Among questionnaire respondents (n = 22; 92% response rate), most physicians noted an increase in apheresis activity during the trials and attributed it to a "jumping-the-gun" phenomenon. CONCLUSIONS: During 3 Canadian RCTs, apheresis increased, but most of the increase occurred outside the trials. This behavior during an RCT, in the absence of clear efficacy, can be termed jumping the gun.

The effect of patient-controlled analgesia on coadministered red blood cells.

BACKGROUND: Patient-controlled analgesia (PCA) provides effective pain control. The possibility of administrating opioids in the same line as red blood cells (RBCs) for patients with poor venous access has been entertained. The literature on this approach is not extensive, but generally cautionary. STUDY DESIGN AND METHODS: Standard concentrations of morphine, hydromorphone (Dilaudid), and meperidine (Demerol) were used to determine the effect on RBCs. Three in vitro approaches were used: 1) continuous low-dose opioid infusion with a single bolus, 2) continuous infusion with multiple boluses, and 3) assessment of RBCs with different concentrations of opioids in test tubes. Samples were assayed for hemoglobin (Hb), mean corpuscular volume (MCV), plasma Hb, potassium, and lactate dehydrogenase, and a peripheral blood smear was made. RESULTS: Addition of each drug as a single or multiple bolus(-es) with continuous infusion showed the same effects as normal saline. In vitro exposure of Demerol at a 1:2 ratio (drug:blood) increased the MCV (110 fL), at 1:1 the MCV was 120 fL, and there was 4.5 percent hemolysis. At 2:1, hemolysis increased to 9.2 percent. Both morphine and Dilaudid had similar effects as normal saline. CONCLUSION: Morphine, Dilaudid, and Demerol, given as a bolus in the intravenous line, have the same effects as those seen with saline. When mixed directly with the blood for more than 1 hour, however, Demerol caused increasing RBC swelling and at high, nontherapeutic concentrations, caused hemolysis. Our study suggests that analgesia delivered via PCA may be safely coadministered with RBCs. Further clinical study is warranted.