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Background Thirty percent of chronically transfused patients with sickle cell disease (SCD) become alloimmunized. Antigen-matching reduces alloimmunization. Matching may be prospective (for all patients) or based on history (only for patients with an alloimmunization history). We assessed the clinical and financial value of a potential assay to identify at-risk patients to guide antigen-matching.

Background Sickle cell disease is associated with extensive health care utilization; estimated lifetime costs exceed $460,000 per patient. Approximately 30% of chronically transfused sickle cell patients become alloimmunized to red blood cell antigens, but these patients cannot be identified a priori. Prospective antigen matching can prevent alloimmunization, but is costly and may not benefit most patients. Study design and methods A Markov-based model was constructed to compare the health and financial implications of four alternative antigen-matching strategies for chronically transfused sickle cell patients. The strategies varied by the group of patients receiving matched blood (all patients prophylactically or only patients with a history of alloimmunization [history-based]), and by the extent of antigen matching (limited to C, E, and K, or extended to 11 antigens). Direct medical costs and alloimmunization events were assessed over 10- and 20-year periods, for a hypothetical cohort of initially transfusion-naive patients and for a dynamic population. Results Within a hypothetical cohort of initially transfusion-naive patients, implementing prophylactic limited matching for all chronically transfused patients instead of history-based limited matching is expected to cost an additional $765.56 million over 10 years, but result in 2072 fewer alloimmunization events. Within the same cohort, implementing prospective extensive matching is expected to cost $1.86 billion more than history-based extensive matching, but result in 2424 fewer alloimmunization events. Averting a single alloimmunization event using prospective matching would cost $369,482 to $769,284. Among a dynamic population over 10 years, prospective limited matching is expected to cost $358.34 million more than history-based limited matching. Conclusions While prospective matching for all transfused patients would reduce alloimmunization, this strategy requires considerable expenditure.

BACKGROUND: Thousands of patients with chronic renal failure die yearly without a kidney transplant due to the severe shortage of donors. Therapeutic plasma exchange (TPE) is performed to permit ABO-incompatible (ABO-I) kidney transplants, but little is known about how well TPE reduces ABO antibodies or complications related to TPE in this clinical setting. STUDY DESIGN AND METHODS: This retrospective study evaluated 46 individuals that received TPE to permit ABO-I kidney transplant. The number of TPE treatments was based on a goal ABO titer at the anti-human globulin (AHG) phase of 16 or less before surgery. RESULTS: Before TPE, the median titer of recipient was 32 (range, 2-128) at room temperature (RT) phase and 64 (range, 4-1024) at AHG phase. The first TPE reduced the total agglutination reactivity score at AHG phase by 10.2 percent. Before transplantation, there was a mean of 6.2 ± 2.5 TPE treatments and total agglutination reactivity score at AHG phase was reduced by 53.5 percent. The median titer remained reduced at 3 to 6 months after transplantation at 4 (range, 0-64) at RT phase and 8 (range, 1-64) at AHG phase. TPE complications were minimal. During at least one procedure, 15 (32.6%) individuals had either urticaria or pruritis, 18 (39.1%) individuals experienced mild citrate-induced hypocalcemia, 5 (10.2%) individuals had hypotension, 6 (13.0%) individuals had nausea or vomiting, and 1 (2.2%) individual had West Nile virus encephalitis. CONCLUSIONS: With current infectious disease blood screening protocols, TPE has minimal complications and can reduce ABO antibody titers to permit ABO-I renal transplantation.

ABO incompatibility and human leukocyte antigen (HLA) sensitization remain the two largest barriers to optimal utilization of kidneys from live donors. Here we describe the first successful transplantation of patients who were both ABO incompatible and crossmatch positive with their only available donor. A preconditioning regimen of plasmapheresis (PP) and low-dose CMV hyperimmune globulin (CMVIg) was delivered every other day until donor-specific antibody (DSA) titers were reduced to a safe level and isoagglutinin titers were < or =16. Each patient received quadruple sequential immunosuppression, splenectomy and three protocol post-transplant PP/CMVIg treatments. There was no hyperacute rejection. Two of the three patients had a persistent positive cytotoxic crossmatch on the day of transplant and eliminated their DSA subsequently. Antibody-mediated rejection (AMR) in one patient was reversed by reinitiating PP/CMVIg and anti-CD20. The patients are more than 9 months post-transplant with excellent graft function. Preconditioning with PP/CMVIg results in a durable suppression of DSA and permits accommodation of the allograft to a discordant blood type. The ability to cross these two barriers simultaneously is clinically important as sensitized patients have often exhausted their blood type compatible living donors during previous transplants.

BACKGROUND: Febrile nonhemolytic transfusion reactions (FNHTR) is a relatively common complication associated with allogeneic transfusion. Because WBCs have been implicated in the mechanism of FNHTRs, it has been proposed that the transfusion of leukoreduced RBCs should be associated with a decreased incidence of FNHTRs. These reactions are generally not life threatening, but they are expensive in their management, evaluation, and associated blood-product wastage. Over the past several years, the proportion of leukoreduced RBCs has increased at Johns Hopkins Hospital in an effort to move toward complete leuko-reduction. A retrospective analysis is reported here of FNHTRs in RBC recipients as the inventory increased in percentage of leukoreduced RBC units.

Many blood group antigens, genetically controlled carbohydrate molecules, are found on the surface of uroepithelial cells and may affect bacterial adherence and increase the frequency of urinary tract infection (UTI) in adults. Sixty-two children aged 2 weeks to 17 years (mean, 2.3 years) who were hospitalized with fever in association with UTIs caused by Escherichia coli had complete (n = 50) or partial (n = 12) erythrocyte antigen typing to determine the role of erythrocyte antigens and phenotypes in UTI in children; 62 healthy children undergoing nonurologic elective surgery, matched 1 to 1 for age, sex, and race to the patient group, formed the control group. In univariate tests, patients and control subjects did not differ in ABO, Rh, P, Kell, Duffy, MNSs, and Kidd systems by the McNemar test of symmetry (p0.05). The frequency of the Lewis (Le) (a-b-) phenotype was higher (16/50 vs 5/50; p = 0.0076) and the frequency of the Le(a + b +) phenotype was lower (8/50 vs 16/50; p = 0.0455) in the patient population than in the control subjects. A stepwise logistic regression model to predict UTI with the explanatory variables A, B, O, M, N, S, s, Pl, Lea, and Leb showed that only the Lea and Leb antigens entered the model with p0.1. The Le(a-b-) phenotype was associated with UTI in this pediatric population. The relative risk of UTI in children with the Le(a-b-) phenotype was 3.2 (95% confidence interval, 1.3 to 7.9). Specific blood group phenotypes in pediatric populations may provide a means to identify children at risk of having UTI.

BACKGROUND: Thousands of patients with chronic renal failure die yearly and are unable to have a kidney transplant due to the severe shortage of donors. Therapeutic plasma exchange (TPE) is performed to remove ABO antibodies and permit ABO-incompatible (ABO-I) kidney transplants, but there is only limited research within this area and a lack of standardized protocols for TPE. This article reviews the literature to provide a historical perspective of TPE for ABO-I kidney transplantation and also provides the Johns Hopkins Hospital protocol with a focus on both titers and TPE. STUDY DESIGN AND METHODS: The TPE treatment plan is based on ABO titers with the goal of a titer of 16 or less at the anti-human globulin (AHG) phase before surgery. Pretransplant therapy consists of every-other-day TPE followed immediately by cytomegalovirus hyperimmune globulin. ABO antibody titers are closely monitored before and after transplantation. After transplantation, TPE therapy is performed for all patients to prevent rebound of anti-A and anti-B titers until tolerance or accommodation occurs. TPE is discontinued and reinstituted based on the clinical criteria of creatinine levels, biopsy results, and ABO titer. RESULTS: Fifty-three ABO-I kidney transplants have been completed with no episodes of hyperacute antibody-mediated rejection (AMR) and only three episodes of AMR. One-year death-censored graft survival is 100 percent and patient survival is 97.6 percent. CONCLUSIONS: While randomized clinical trials are needed to evaluate the optimal method and protocol to remove ABO antibodies, the current literature and our results indicate a critical role for TPE in ABO-I renal transplantation.

Objectives To describe a case of a ceftriaxone-induced hemolytic anemia and hepatitis leading to multiple organ failure and death in an adolescent with hemoglobin SC disease and to review the previous cases of this rare and potentially fatal disorder in children. Design Case report and literature review. Setting Intensive care unit. Patient Adolescent with hemoglobin SC. Interventions Emergency treatment. Measurements and main results After 4 days of ceftriaxone therapy, the adolescent experienced an acute hemolytic reaction (hemoglobin decreased to 5 g/dL with hemoglobinuria) and severe hepatitis (all enzymes increasing dramatically including aminoaspartate transferase >20,000 IU/L). Renal failure and ultimately multiple organ failure ensued, and the patient died on hospital day 19. Direct antiglobulin tests on red cells obtained from the patient on hospital day 2 showed microscopic agglutination with polyspecific and anticomplement (C3) antiglobulin reagents. Plasma samples showed macroscopic agglutination reactions when incubated in the presence of ceftriaxone, many days after cessation of ceftriaxone, indicating the continued presence of ceftriaxone-dependent antibodies. Conclusions Drug reactions leading to hemolysis are relatively uncommon, and a total of ten cases of ceftriaxone-induced hemolytic anemia have been reported in children. The present case describes an adolescent who ultimately died on hospital day 19 from multiple organ failure, although the presentation of this case seems atypical in several respects. Children with clinical syndromes that place them at risk for hemolysis and children who frequently require broad spectrum antibiotics present unique diagnostic challenges, and the possibility that hemolytic syndromes may be due to ceftriaxone must be considered.

The majority of preconditioning protocols developed to allow ABO-incompatible (ABOi) renal transplantation include concurrent splenectomy as a prerequisite to successful engraftment. Our center has developed a preconditioning protocol that includes plasmapheresis (PP), low-dose CMV hyperimmune globulin (CMVIg), and anti-CD20 monoclonal antibody (rituximab) to allow ABOi renal transplantation without splenectomy. Our initial experience has included treatment of six recipients and successful transplantation from blood group A(1), A(2), and group B living donors. Mean (+/- SD) serum creatinine was 1.3 +/- 0.1 mg/dL among the six recipients and no episodes of antibody-mediated rejection (AMR) occurred at a median follow-up of 12 months. ABO antibody titers have remained below pretreatment levels. The absence of AMR and stable allograft function in this series show the potential of this preconditioning protocol to increase ABOi renal transplantation. The use of rituximab, allowing avoidance of splenectomy, may further remove one of the significant disincentives to ABOi transplantation, and eliminate the risk of post-splenectomy infections.

A 7-year-old Caribbean-American boy with a 5-month history of hemophagocytic lymphohistocytosis and previous ceftriaxone exposure presented with fever. He was empirically given amikacin and ceftriaxone after 1:00 PM on Day 1 and acutely developed back and abdominal pain, vomiting, hematuria, and hypotension. Both plasma (see figure, top panel) and urine showed hemolysis. The peripheral blood smear showed diffuse agglutination of RBCs without schistocytes (see figure, lower left). Serum LDH was elevated (1787 U/L); urine was negative for myoglobin. The patient's Hb dropped from 11.7 to 4.4 g/dL in 32 hours. The symptoms, hemolysis, and agglutination resolved (see figure, lower right) with discontinuation of ceftriaxone and two double-volume whole blood exchange transfusions. Immunohematology studies demonstrated a positive DAT due to C3 only, and serologic drug studies were positive with ceftriaxone, but not with amikacin. The RBC agglutination seen on peripheral smear was most likely due to drug/antidrug immune complexes, a theory supported by the finding of IgM ceftriaxone-dependent antibodies (titer = 32) at presentation. The titer decreased to 8 on Day 2 and to 0 by Day 5, suggesting that the antibody was consumed by the RBCs and/or removed by treatment. Drug-induced immune hemolytic anemia (DIHA) due to ceftriaxone-dependent antibodies is uncommon, but well described. The majority of documented cases have occurred in children with a history of exposure to ceftriaxone. Autoagglutination may be a feature of DIHA due to ceftriaxone. It is important to recognize and treat DIHA early, since it can be fatal, but is reversible with treatment.