Incidence and impact of de novo donor-specific alloantibody in primary renal allografts.

BACKGROUND: To date, limited information is available describing the incidence and impact of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSA) in the primary renal transplant patient. This report details the dnDSA incidence and actual 3-year post-dnDSA graft outcomes. METHODS: The study includes 189 consecutive nonsensitized, non-HLA-identical patients who received a primary kidney transplant between March 1999 and March 2006. Protocol testing for DSA via LABScreen single antigen beads (One Lambda) was done before transplantation and at 1, 3, 6, 9, and 12 months after transplantation then annually and when clinically indicated. RESULTS: Of 189 patients, 47 (25%) developed dnDSA within 10 years. The 5-year posttransplantation cumulative incidence was 20%, with the largest proportion of patients developing dnDSA in the first posttransplantation year (11%). Young patients (18-35 years old at transplantation), deceased-donor transplant recipients, pretransplantation HLA (non-DSA)-positive patients, and patients with a DQ mismatch were the most likely to develop dnDSA. From DSA appearance, 9% of patients lost their graft at 1 year. Actual 3-year death-censored post-dnDSA graft loss was 24%. CONCLUSION: We conclude that 11% of the patients without detectable DSA at transplantation will have detectable DSA at 1 year, and over the next 4 years, the incidence of dnDSA will increase to 20%. After dnDSA development, 24% of the patients will fail within 3 years. Given these findings, future trials are warranted to determine if treatment of dnDSA-positive patients can prevent allograft failure.

A report of the epidemiology of de novo donor-specific anti-HLA antibodies (DSA) in "low-risk" renal transplant recipients.

The donor specific anti-HLA antibody (DSA) has been increasingly recognized as the major cause of allograft loss. Despite this, no published reports exist describing the true epidemiology of de novo DSA.Here we describe the epidemiology of DSA based on the results of one of the longest running antibody study in consecutive renal transplant recipients. The study includes 224 non-sensitized, non-HLA-identical patients who received a primary kidney transplant between 3/1999-3/2006. Protocol testing for DSA was done pre-transplant, at 1, 3, 6, 9, and 12 months, and then annually. DSA was tested using single antigen beads. Data from the East Carolina University transplant cohort indicate that the prevalence of DSA in the first year post-transplant is 12.1 cases per 100. The average annual incidence of DSA is 4.7 per 100 cases, per year. The highest incidence of DSA was in the first year post transplant. Although deceased donors and African-Americans have a higher incidence rate of DSA than the comparator living donors and non-African American groups, respectively, these factors were not associated with DSA onset. The one factor found to be predictive of DSA was DQ mismatch (p = 0.036). Based on these epidemiologic findings in combination with previous reports showing DSA is a cause of allograft failure, it seems reasonable that at least annual testing should be done even in "low-risk" transplant patients, because every year a new 5% of patients will develop DSA.

Beyond histology: lowering human leukocyte antigen antibody to improve renal allograft survival in acute rejection.

BACKGROUND: The common endpoint in the treatment of antibody-mediated rejection (AMR) is functional reversal (creatinine levels). Reduction of human leukocyte antigen (HLA) antibody strength is not commonly considered as an essential endpoint for AMR resolution. The purpose of this study was to determine whether reduction in HLA antibody intensity in patients with histologic AMR reversal influences long-term renal allograft survival. METHODS: Renal allograft recipients were included if he or she had a biopsy diagnosis of AMR (between August 2000 and October 2008) and serial evaluation for HLA antibodies prebiopsy and postbiopsy. Antibody reduction was defined as mean fluorescence intensity decrease more than 50% in highest intensity antibody after AMR therapy and the absence of new antibody formation. Patients were treated with plasmapheresis, thymoglobulin/OKT3, and corticosteroids. Survival analysis was performed using STATA/MP v10 (College Station, TX). RESULTS: Twenty-eight patients were analyzed. Antibody reduction failed to occur in 22 of 28 cases. Baseline characteristics were similar between groups. Antibody nonresponders had significantly shorter allograft survival time (61.4 months) compared with antibody responders (no failures) (P=0.04, log-rank test). CONCLUSIONS: In conclusion, failure to significantly reduce antibody levels and prevent new formation was strongly predictive of allograft loss. This observation suggests that the therapeutic intervention that reduces antibody production may prolong graft survival in transplantation.

Effect of a program to reduce hospital ciprofloxacin use on nosocomial Pseudomonas aeruginosa susceptibility to quinolones and other antimicrobial agents.

OBJECTIVE: We evaluated the effect of an antimicrobial management effort to decrease ciprofloxacin use on the antibiotic susceptibility of nosocomial Pseudomonas aeruginosa isolates. DESIGN: Retrospective, observational study. SETTING: Tertiary care teaching hospital with 731 beds. METHODS: The study was conducted between January 1, 2001, and December 31, 2007. Linear regression analyses and Student t tests were used to determine significant changes in drug use among patients and antimicrobial susceptibility patterns among nosocomial P. aeruginosa isolates during the 84-month period. RESULTS: Following implementation of a program to reduce oral and intravenous use of ciprofloxacin in 2005, there was a 56.6% reduction in ciprofloxacin use (P < .001). Significant reductions in the mean percentage of nosocomial P. aeruginosa isolates that were resistant to ciprofloxacin (from 45.0% to 35.2%; P < .002) and the mean incidence of ciprofloxacin resistance (from 0.77 to 0.67 isolates recovered per 1,000 patient-days; P = .03) were noted after implementation of this program. The total quantity of antipseudomonal antibiotics consumed decreased, but the use of certain antipseudomonal antibiotics (ie, cefepime and imipenem/meropenem) increased. Among nosocomial P. aeruginosa isolates, the prevalence of imipenem/meropenem resistance increased, whereas the prevalence of cefepime resistance did not. During the 84 months of the study, there was a significant association between ciprofloxacin use and the percentage of nosocomial P. aeruginosa isolates that were resistant to ciprofloxacin (rho = 0.47; P = .011), but there was no correlation between ciprofloxacin use and the incidence of ciprofloxacin resistance (rho = 0.21; P = .26). CONCLUSIONS: Major reductions in ciprofloxacin use were associated with small but significant improvements in the rate of ciprofloxacin susceptibility among nosocomial P. aeruginosa isolates. The impact of the program on other antipseudomonal agents was variable.

Clinical and anti-HLA antibody profile of nine renal transplant recipients with failed grafts: donor-specific and non-donor-specific antibody development.

This study applied the single antigen microsphere technology to the retrospective analysis of sequential post-transplant serum samples in the context of the patient's clinical course. Detailed information on nine of the study patients was presented as representative of the larger cohort and illustrative of different patterns of anti-HLA antibody development and different clinical scenarios that culminated in graft failure. Our major observations are summarized as follows: 1. These data confirm the high sensitivity of the single antigen bead method: In some patients, DSA and NDSA that were undetected by standard methods were found pre-transplant and in sequential post-transplant samples. 2. The precise role that anti-HLA antibody plays in a particular rejection are complicated in cases in which humoral rejection is not diagnosed in the biopsy: The possible involvement of ADCC and mechanisms involving an indirect role for antibody in the rejection process should be carefully investigated. 3. Although anti-HLA antibodies are associated with graft rejection, the time interval between detection and rejection can vary dramatically between patients. Both DSA and NDSA can be adsorbed by the graft and erratically detected in the circulation, in some cases remaining undetected until nephrectomy. 4. Anti-HLA antibody strengths often fluctuate widely over a patient's clinical course, with de novo DSA generally of greater strength than de novo NDSA. 5. In addition to DSA, we have observed the consistent induction of diverse, cross-reactive NDSA. This occurs not only during the post-transplant course but also after graft failure, when immunosuppression is tapered prior to nephrectomy. Our data support further studies to evaluate the value of prospective monitoring of anti-HLA antibodies to better understand the place of anti-HLA antibodies in acute rejection. This may improve our ability to reverse some acute rejection episodes. Since acute rejection has been considered a predictor of late graft loss via chronic allograft nephropathy, understanding and modifying the antibody response is critical to extending the longevity of transplanted organs. Finally, since the strong sensitization to NDSA will seriously hamper the ability to identify a compatible donor for a future transplant, these data reinforce the importance of minimizing HLA mismatches between the donor and the recipient.

Longitudinal testing of 266 renal allograft patients for HLA and MICA antibodies: Greenville experience.

1. From the analysis of 266 Greenville kidney recipients, we found that almost every patient who had graft failure had HLA antibodies (93%), while less than half of patients with currently functioning graft had antibodies (46%). 2. The difference between failed grafts and successful grafts was even greater for de novo antibodies (60% vs. 14%) and greatest for donor-specific antibodies (75% vs. 9%). 3. The incidence of HLA-DQ antibodies was surprisingly high, and the majority was donor-specific. Now that the improved detection beads are available, the effect of DQ antibodies on transplants should be further studied. 4. MICA antibodies were found in 12% of total 266 patients, and found to be more frequent (21%) in patients with graft failure than in patients with successful graft (7%). Almost all patients with MICA antibodies also had HLA antibodies. 5. From the sequential sera testing, we were able to see that, in most cases, antibodies are produced long before the failure and before the elevation of serum creatinine. 6. Periodic testing of sera by single antigen beads enable us to distinguish de novo antibodies from preformed antibodies and to determine whether they are donor-specific. This is important since de novo DSA are most detrimental to graft.

Reduction in broad-spectrum antimicrobial use associated with no improvement in hospital antibiogram.

OBJECTIVE: To evaluate the effect of an antimicrobial management programme on broad-spectrum antimicrobial use and antimicrobial susceptibilities of common nosocomial pathogens at a tertiary-care teaching hospital. METHODS: Review of hospital charts of patients who had been prescribed broad-spectrum antimicrobials 48 h earlier. Recommendations to streamline or discontinue antimicrobials were made based on results of available microbiology data, radiography studies, as well as the working diagnosis at the time of review. The charts were reviewed again on the following day to assess acceptance or rejection of the recommendations. Antimicrobial use, measured as defined daily dose per 1000 patient days (DDD/1000 PD), was determined before and after the antimicrobial management programme was started and was assessed as the mean quarterly use in the six quarters preceding implementation of the programme compared to the most recent six quarters that the programme has been in existence. Antibiotic susceptibilities were obtained from the clinical microbiology laboratory. RESULTS: Compared to the six quarters before the programme, broad-spectrum antibiotic use decreased by 28% (693 DDD/1000 PD to 502 DDD/1000 PD, P = 0.003). Total antifungal agent use decreased by a similar amount, i.e. 28% (144 DDD/1000 PD to 103 DDD/1000 PD, P = 0.02). Total antimicrobial use decreased by 27% (1461 DDD/1000 PD to 1069 DDD/1000 PD, P = 0.0007). Susceptibilities of common nosocomial Gram-negative organisms to commonly prescribed antibiotics did not change significantly over the 3 years of the programme. The rate of methicillin-resistant Staphylococcus aureus increased significantly in the non-intensive care areas of the hospital (P = 0.02) and decreased significantly in the intensive care areas of the hospital (P = 0.009) over the 4 year period from 2000 to 2003. CONCLUSION: Implementation of an antibiotic management programme resulted in substantial reductions in both broad-spectrum and total antimicrobial consumption without having a significant impact on antibiotic susceptibilities of common Gram-negative microorganisms within the institution. The changes in MRSA rate in the non-ICU and ICU settings may reflect infection control measures that were in place during the study period.