Transplantation with positive complement-dependent microcytotoxicity crossmatch in contemporary kidney transplantation: Practice patterns and associated outcomes.

We analyzed clinical factors and graft survival associated with complement-dependent microcytotoxicity (CDC) crossmatch (XM) positive (+) kidney transplants in 1995 to 2009 United Network of Sharing (UNOS) registry data. CDCXM negative (-) transplants were selected from centers and years in which at least one CDCXM+ transplant was performed at a given center in a given year. CDCXM+ and CDCXM- results were compared with bivariate and multivariate survival analysis. Our observations are as follows: (1) The risk of graft loss with CDCXM+ vs. CDCXM- results was markedly lower than the risk observed historically, e.g., living donor (LD)-CDCXM+ absolute all-cause graft survival reductions were 0.7% at 24 hours (P=0.007), 2.9% at one year (P <0.0001), 3.7% at five years (P<0.0001); deceased donor (DD)-CDCXM+ absolute graft survival reductions were 0.7% at 24 hours (P=0.02), 3.5% at one year (P <0.0001), 2.7% at five years (P=0.0009). On covariate adjustment, the only significant association of CDCXM+ vs. CDCXM- results was with one-year graft loss risk: LD aHR 1.44 (95% CI 1.05-1.96), DD aHR 1.33 (CI 1.10-1.61). (2) CDCXM+ transplantation was more commonly performed among groups disadvantaged with respect to transplant access, including sensitized, previously transplanted women and black recipients. (3) In CDCXM+ recipients, there was a high percentage of flow cytometry (FC) XM- and autoXM+ results. After removing these groups, outcomes with CDCXM+ results were relatively good. (4) CDCXM+/FCXM+ vs. CDCXM-/FCXM- graft loss risk was observed only in LD recipients transplanted at centers performing fewer than 10 such transplants during the study period: 11.0% reduction (P<0.0001) and aHR of 2.86 (CI 1.18-6.94) at one year; 14.7% reduction (P<0.0001) and aHR of 1.77 (CI 0.88-3.58) at five years. Although using CDCXM+ as a contraindication to transplantation has been associated with virtual elimination of hyperacute rejection, the negative effect of a CDCXM+ in contemporary practice is relatively small, questioning the value of the CDCXM as a standalone test.

The Role of the Crossmatch in Kidney Transplantation: Past, Present and Future.

Immunogenetic characterization of the transplant recipient with crossmatch is used to minimize graft loss by detecting preformed antibodies. Use of increasingly sensitive tests including flow cytometry crossmatch (FCXM) has been accompanied by near elimination of hyperacute rejection. We reviewed associations of crossmatch results with kidney graft outcomes in contemporary practice, and provided updates of our past publications with more recent data in several instances. Recent United States registry data for transplants performed with a reported positive crossmatch demonstrate immediate graft loss rates of ≤1.3% or less in FCXM+ recipients, and ≤3.6% in complement-dependent cytotoxicity crossmatch positive (CDCXM+) recipients. One-year graft survival was reduced by ≤6.4% in FCXM+ versus FCXM- recipients, and by ≤11.5% in CDCXM+ versus CDCXM- recipients. Five-year graft survival was reduced by ≤10.2 % in FCXM+ versus FCXM- recipients, and by ≤8.7% in CDCXM+ versus CDCXM- recipients. A possible explanation for the markedly lower graft loss risk with crossmatch positive transplants in modern practice may be selection of recipients with low anti-HLA titers. Although a good correlation between virtual crossmatch and actual crossmatch has been demonstrated, the outcome significance of positive virtual/negative actual and negative virtual/positive actual crossmatches is not clearly established. Post-transplant demonstration of the persistence or appearance of donor-specific antibody is of value in prognostication, but utility for adjustment of therapy is uncertain. In summary, contemporary data suggest that, among selected transplants performed, the impact of a positive crossmatch may be relatively small compared to other accepted clinical factors. Further study is warranted work to determine, prospectively, under what circumstances crossmatch positive transplants can precede with safety.

Association of IL-4RA single nucleotide polymorphisms, HLA-DR and HLA-DQ in children with Alternaria-sensitive moderate-severe asthma.

BACKGROUND: Asthma afflicts 6% to 8% of the United States population, and severe asthma represents approximately 10% of asthmatic patients. Several epidemiologic studies in the United States and Europe have linked Alternaria sensitivity to both persistence and severity of asthma. In order to begin to understand genetic risk factors underlying Alternaria sensitivity and asthma, in these studies we examined T cell responses to Alternaria antigens, HLA Class II restriction and HLA-DQ protection in children with severe asthma. METHODS: Sixty children with Alternaria-sensitive moderate-severe asthma were compared to 49 children with Alternaria-sensitive mild asthma. We examined HLA-DR and HLA-DQ frequencies in Alternaria-sensitive asthmatic by HLA typing. To determine ratios of Th1/Th2 Alternaria-specific T-cells, cultures were stimulated in media alone, Alternaria alternata extract and Alt a1. Sensitivity to IL-4 stimulation was measured by up-regulation of CD23 on B cells. RESULTS: Children with Alternaria-sensitive moderate-severe asthma trended to have increased sensitivities to Cladosporium (46% versus 35%), to Aspergillus (43% versus 28%), and significantly increased sensitivities to trees (78% versus 57%) and to weeds (68% versus 48%). The IL-4RA ile75val polymorphism was significantly increased in Alternaria-sensitive moderate-severe asthmatics, 83% (0.627 allele frequency) compared to Alternaria-sensitive mild asthmatics, 57% (0.388 allele frequency). This was associated with increased sensitivity to IL-4 stimulation measured by significantly increased IL-4 stimulated CD23 expression on CD19+ and CD86+CD19+ B cells of Alternaria-sensitive moderate-severe asthmatics. IL-5 and IL-13 synthesis was significantly increased in Alternaria-sensitive moderate-severe asthmatics compared to mild asthmatics to Alternaria extract and Alt a1 stimulation. The frequency of HLA-DQB1*03 allele was significantly decreased in Alternaria-sensitive moderate-severe asthmatics compared to mild asthmatics, 39% versus 63%, with significantly decreased allele frequency, 0.220 versus 0.398. SUMMARY: In children with Alternaria-sensitive moderate severe asthma, there was an increased Th2 response to Alternaria stimulation and increased sensitivity to IL-4 stimulation. This skewing towards a Th2 response was associated with an increased frequency of the IL-4RA ile75val polymorphism. In evaluating the HLA association, there was a decreased frequency of HLA-DQB1*03 in Alternaria-sensitive moderate severe asthmatic children consistent with previous studies suggest that HLA-DQB1*03 may be protective against the development of mold-sensitive severe asthma.

Crossmatch testing in kidney transplantation: patterns of practice and associations with rejection and graft survival.

Methods of crossmatch testing prior to kidney transplantation are not standardized and there are limited large-scale data on the use and outcomes implications of crossmatch modality. Data describing the most sensitive crossmatch modality for crossmatch-negative kidney transplants were drawn from the Organ Procurement and Transplant Network Registry. Within the cohort transplanted in 1999-2005, we identified patient and transplant characteristics predictive of each testing modality by multivariate logistic regression. We assessed associations of crossmatch modality with rejection risk by logistic regression and with graft survival by Cox's hazards analysis. Among 230,995 transplants, use of flow cytometry with T-and B-lymphocytes (T&B FC) increased progressively in 1987-2005. Among the recent transplants performed in 1999-2005 (n=64,320), negative T&B FC crossmatch was associated with 15% lower relative risk of first-year acute rejection (adjusted HR 0.85, 95% CI 0.80-0.89) compared to negative T-antihuman-globulin and B-National Institutes of Health/Wash (T AHG &B) crossmatch. Five-year graft survival after transplant with negative T&B FC (82.6%) was modestly better than after negative T AHG &B (81.4%, P= 0.008) or T AHG crossmatch (81.1%, P 0.0001), but on adjusted analysis was significantly different only among recipients from deceased donors and patients aged > 60 years. Many subgroups for whom negative T&B FC crossmatch predicted lower rejection risk (Caucasians, deceased donor recipients, re-transplants) were not more likely to be crossmatched by this method. We conclude that current practice patterns have not aligned utilization of T&B FC crossmatch with associated benefits. Prospective evaluation of the relationship of crossmatch modality with outcomes is warranted.

The role of positive flow cytometry crossmatch in late renal allograft loss.

Many studies relating flow cytometery crossmatch (FCXM) results to kidney transplant outcomes have examined risk in the first 3 to 12 months. We used Organ Procurement and Transplant Network registry data for 66,594 kidney transplants from 1995 to 2007 to investigate associations of T-cell positive (T+) and T-cell negative/B-cell positive (T(-)B+) FCXM with graft failure risk early (years 0-1) and late (years >1-5) after transplant. Compared with transplants with T-cell negative/B-cell negative (T(-)B(-)) FCXM, living-donor transplants performed after T+ FCXM had significantly higher adjusted, relative risks of both early (adjusted hazards ratio [aHR] 1.71, p < 0.0001) and late (aHR 1.36, p = 0.017) graft loss. T(-)B+ FCXM was associated with approximately 40% higher relative risk of graft loss in the late period only. Patterns were similar for deceased-donor transplants. The risks of positive FCXM persist beyond the peritransplant period for years after transplant. Damage by memory effector cells may explain the long-term risks associated with positive FCXM.

Bariatric surgery among kidney transplant candidates and recipients: analysis of the United States renal data system and literature review.

BACKGROUND: Limited data exist on the safety and efficacy of bariatric surgery (BS) in patients with kidney failure. METHODS: We examined Medicare billing claims within USRDS registry data (1991-2004) to identify BS cases among renal allograft candidates and recipients. RESULTS: Of 188 BS cases, 72 were performed pre-listing, 29 on the waitlist, and 87 post-transplant. Roux-en-Y gastric bypass was the most common procedure. Thirty-day mortality after BS performed on the waitlist and post-transplant was 3.5%, and one transplant recipient lost their graft within 30 days after BS. BMI data were available for a subset and suggested median excess body weight loss of 31%-61%. Comparison to published clinical trials of BS in populations without kidney disease indicates comparable weight loss but higher post-BS mortality in the USRDS sample. CONCLUSIONS: Given the substantial contributions of obesity to excess morbidity and mortality, BS warrants prospective study as a strategy for improving outcomes before and after kidney transplantation.

Incremental value of the pancreas allograft to the survival of simultaneous pancreas-kidney transplant recipients.

OBJECTIVE: To quantify the incremental survival benefit of the pancreas allograft in simultaneous pancreas-kidney (SPK) transplant recipients. RESEARCH DESIGN AND METHODS: Data from the national transplant database from 2000 to 2007 were analyzed. SPK recipients who had functioning allografts to 1-year post transplant (n = 3,304) were compared with those who had failure of the renal (n = 233) or pancreatic (n = 112) graft. The main outcome was a projection of 10 life-years of patient survival beyond the first transplant anniversary. RESULTS: Recipients with function of both organs accrued 9.4 life-years following transplantation. Projected survival in patients with kidney failure was reduced to 2.5 life-years. Pancreas failure reduced predicted survival to 8 life-years. Renal allograft failure impacts life expectancy significantly (adjusted hazard ratio [aHR] 12.13). However, pancreas allograft failure was also associated with reduced survival (aHR 2.62). CONCLUSIONS: Although the majority of the survival benefit of SPK transplant is due to the renal transplant, pancreas allograft function does contribute to patient survival.

Flow cytometry crossmatch before kidney transplantation in contemporary practice: target cell utilization, results patterns, and associated long-term graft survival.

The flow cytometry crossmatch (FXCM) is an increasingly common method for pre-transplant crossmatching. We examined FCXM use in a national sample of kidney transplants, characterizing target cell utilization, results patterns, and associated graft outcomes. We queried Organ Procurement and Transplant Network Registry to identify kidney transplants performed in 1995-2007 with prospective FCXM testing for IgG antibodies against T-cells, B-cells or undifferentiated lymphocytes. FCXM was categorized according to target utilization and target-specific results. We modeled associations of FCXM testing-results patterns with risk of five-year graft loss and with projected graft survival by multivariable survival analysis. Sixty-five percent of the deceased donor transplants were performed with negative T-cell and B-cell FCXM, 16% with negative T-cell/unmeasured B-cell FCXM, 9% with negative undifferentiated lymphocyte FCXM, and < 0.5% with negative B-cell/unmeasured T-cell FCXM. Test results for at least one target were positive in 7.6% of transplants, most commonly in the form of B-cell positive/T-cell negative. Allograft survival was most favorable when both T-cell and B-cell FCXM targets were included and yielded negative results. Notably, B-cell positive/T-cell negative FCXM predicted elevated graft loss risk, with approximately 16% and 32% relative risk increases for deceased and living donor grafts, respectively, compared to negative T-cell and B-cell FCXM. Negative FCXM results with undifferentiated targets alone also predicted inferior graft survival. These data support the importance of using differentiated B-cell and T-cell targets for FCXM. Transplants that proceeded with positive FCXM experienced decrements in long-term graft survival - the decision to accept such risk must be individualized.

The impact of human leukocyte antigen matching on transplant complications and immunosuppression dosage.

Administrative claims data facilitate ascertainment of outcomes not collected by the transplant registry and provide the opportunity to examine prescribed doses of immunosuppressive medications. Here, we examine the impact of human leukocyte antigen (HLA) matching on traditional outcomes, rejection and survival, and use novel methods to examine immunosuppresion doses and complication rates. The central hypothesis tested in this analysis is that HLA-matched recipients receive lower doses of immunosuppression and have fewer posttransplant complications. We break from tradition by examining HLA matching in both living and deceased donor kidney transplants. As secondary aims, we compare the relative impact of class I and II mismatches and describe outcomes achieved with older donors. Medicare claims linked to the United States Renal Data System database for 23,443 kidney transplants were included in the study. A total of 15,793 transplants were DR mismatched (DRMM), 5,340 manifested no DR mismatches (NODRMM), and 2,310 manifested no ABDR mismatches (NOABDRMM). Patients with NOABDRMM experienced lower adjusted risk of rejection (0.66, 95% confidence interval 0.59-0.74, P < 0.001) and lower hazard of graft loss (0.69, 0.61-0.77, P < 0.001) and death (0.76, 0.63-0.92, P < 0.001) compared with those with DRMM. The hazard of cardiac and diabetic complications was similar between recipients of NOADRMM and DRMM transplants, but the hazard of diarrhea was significantly lower (0.82, 0.73-0.92, P < 0.001) in patients with NOABDRMM. The 6-month dose of mycophenolate mofetil was lower in patients with NOABDRMM. This study validates previous studies that indicated significantly lower risks of rejection, graft loss, and death among patients with 0 HLA-A,B,DR mismatches. Use of administrative claims revealed similar rates of cardiovascular complications. However, HLA-matched deceased donor recipients received lower dosages of mycophenolate mofetil and manifested a lower risk of developing posttransplant diarrhea.

Use of rituximab to decrease panel-reactive antibodies.

Patients with pre-formed antibodies may be at increased risk of rejection after organ transplantation. In this report, we describe the use of rituximab to decrease the percentage of pre-formed antibodies in a pediatric heart transplant recipient.

HLA-DQB1 *03 in allergic fungal sinusitis and other chronic hypertrophic rhinosinusitis disorders.

BACKGROUND: Many common chronic inflammatory disorders have strong HLA gene associations, particularly with MHC class II. Allergic fungal rhinosinusitis (AFS) and hypertrophic sinus disease (HSD) are chronic sinonasal mucosal inflammatory disorders. Allergic bronchopulmonary aspergillosis, a disorder analogous to AFS, was recently reported to have HLA-MHC class II associations. OBJECTIVE: We sought to determine whether MHC class II is also associated with AFS and HSD. METHODS: HLA DNA genotyping was obtained on 44 patients with AFS and 30 patients with HSD (of which 21 were atopic). RESULTS: Sixty-six percent of patients with AFS carried at least one HLA-DQB1 *03 allele; DQB1 *0301 and DQB1 *0302 were the most frequent allelic variants (odds ratio [OR] vs healthy subjects = 8.22; 95% CI, 4.30-15.73; P < .001; OR vs all patients with HSD = 1.93; 95% CI, 1.09-3.41; P < .01; OR vs atopic patients with HSD = 2.57; 95% CI, 1.46-4.53; P < .001). Of the 31 patients with AFS and positive Bipolaris spicifera cultures, 68% had DQB1 *03, with DQB1 *0301 and DQB1 *0302 being most frequent (OR vs healthy subjects = 8.93; 95% CI, 4.65-17.15; P < .001; OR vs patients with HSD = 2.10; 95% CI, 1.18-3.73; P < .001). Of the 30 patients with HSD, 50% carried DQB1 *03 (OR vs healthy subjects = 4.25; 95% CI, 2.25-8.02; P < .001) but differed in frequencies of DQB1 *03 allelic variants compared with patients with AFS ( P = .0004). For HSD, nonatopic subjects had the highest DQB1 *03 association (OR vs healthy subjects = 8.63; 95% CI, 4.50-16.54; P < .001). DQB1 *03 allelic variants did not correlate with allergy skin test results, atopic status, total serum IgE levels, culture results, asthma, or aspirin-nonsteroidal anti-inflammatory drug hypersensitivity. CONCLUSION: Patients with AFS and HSD have HLA-DQB1 *03 alleles as a risk factor for disease, with AFS having the highest association. However, they differ in DQB1 *03 allelic variant frequencies, suggesting several potential roles for MHC class II in their immunopathogenesis.

Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial.

Reported are the reduction of anti-HLA antibody levels and improvement of transplant rates by intravenous immunoglobulin (IVIG) in a randomized, double-blind, placebo-controlled clinical trial. Between 1997 and 2000, a total of 101 adult patients with ESRD who were highly sensitized to HLA antigens (panel reactive antibody [PRA] > or =50% monthly for 3 mo) enrolled onto an NIH-sponsored trial (IG02). Patients received IVIG or placebo. Subjects received IVIG 2 g/kg monthly for 4 mo or an equivalent volume of placebo with additional infusions at 12 and 24 mo after entry if not transplanted. If transplanted, additional infusions were given monthly for 4 mo. Baseline PRA levels were similar in both groups. However, IVIG significantly reduced PRA levels in study subjects compared with placebo. Sixteen IVIG patients (35%) and eight placebo patients (17%) were transplanted. Rejection episodes occurred in 9 of 17 IVIG and 1 of 10 placebo subjects. Seven graft failures occurred (four IVIG, three placebo) among adherent patients with similar 2-yr graft survival rates (80% IVIG, 75% placebo). With a median follow-up of 2 yr after transplant, the viable transplants functioned normally with a mean +/- SEM serum creatinine of 1.68 +/- 0.28 for IVIG versus 1.28 +/- 0.13 mg/dl for placebo. Adverse events rates were similar in both groups. We conclude that IVIG is better than placebo in reducing anti-HLA antibody levels and improving transplantation rates in highly sensitized patients with ESRD. Transplant rates for highly sensitized patients with ESRD awaiting kidney transplants are improved with IVIG therapy.

Panel-reactive antibody screening practices prior to heart transplantation.

BACKGROUND: Evaluation of humoral sensitization, commonly determined by the panel-reactive antibody (PRA) screen, is accepted as an important part of pre-transplant assessment. A variety of definitions and approaches to sensitization have been described in the literature but no analyses of actual practice have been reported. METHODS: We sent surveys to 108 adult heart transplant program directors and 20 tissue-typing laboratories to obtain information about their approaches to PRA and crossmatch determination and management of sensitized patients. RESULTS: Among 65 responding directors (60%), 63.1% were cardiologists and 36.9% surgeons. The most common threshold to consider PRA as positive is > or = 10%. Fifty-five of the respondents consider reactivity with T or B lymphocytes to be significant, whereas 34% consider only T-lymphocyte reactivity. Timing of PRA determination varies considerably among programs. Conversion to positive PRA results in more frequent PRA assessments and often therapy aimed to decrease the degree of sensitization. The most commonly utilized approaches are administration of immunoglobulin and plasmapheresis. The complement-dependent cytotoxicity (CDC) assay is the most commonly used method for PRA determination, but other techniques including flow cytometry and enzyme-linked immunosorbent assay (ELISA) are also used. Crossmatches are performed utilizing CDC and flow cytometry methods. Many laboratories employ more than one technique. CONCLUSIONS: PRA screening, crossmatch determinations and management of sensitized patients vary considerably from center to center. Uncertainty exists about the importance of PRA values, threshold for treatment and clinical implications of sensitization. Important questions about the impact of sensitization on outcomes following heart transplantation may not be resolved until the measurement and management of sensitization becomes more uniform.