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Biomedical subjects

A A Zachary

Publications and source records attributed to A A Zachary.

At least 19 recordsLinked to original sources
PubMed2007

Subclinical acute antibody-mediated rejection in positive crossmatch renal allografts.

Subclinical antibody-mediated rejection (AMR) has been described in renal allograft recipients with stable serum creatinine (SCr), however whether this leads to development of chronic allograft nephropathy (CAN) remains unknown. We retrospectively reviewed data from 83 patients who received HLA-incompatible renal allografts following desensitization to remove donor-specific antibodies (DSA). Ten patients had an allograft biopsy showing subclinical AMR [stable SCr, neutrophil margination in peritubular capillaries (PTC), diffuse PTC C4d, positive DSA] during the first year post-transplantation; 3 patients were treated with plasmapheresis and intravenous immunoglobulin. Three patients had a subsequent rise in SCr and an associated biopsy with AMR; 5 others showed diagnostic or possible subclinical AMR on a later protocol biopsy. One graft was lost, while remaining patients have normal or mildly elevated SCr 8-45 months post-transplantation. However, the mean increase in CAN score (cg + ci + ct + cv) from those biopsies showing subclinical AMR to follow-up biopsies 335 +/- 248 (SD) days later was significantly greater (3.5 +/- 2.5 versus 1.0 +/- 2.0, p = 0.01) than that in 24 recipients of HLA-incompatible grafts with no AMR over a similar interval (360 +/- 117 days), suggesting that subclinical AMR may contribute to development of CAN.

Adult↗
PubMed2006

C4d and C3d staining in biopsies of ABO- and HLA-incompatible renal allografts: correlation with histologic findings.

Biopsies of ABO-incompatible and positive crossmatch (HLA-incompatible) renal allografts were retrospectively examined to compare results of C4d and C3d staining, and the correlation between such staining and histologic findings suggestive of antibody-mediated rejection (AMR). A total of 75 biopsies (55 protocol, 17 for graft dysfunction, 3 for other indications) of 24 ABO-incompatible grafts and 244 biopsies (103 protocol, 129 for graft dysfunction, 12 for other indications) of 66 HLA-incompatible grafts were examined; all were stained for C4d and approximately 40% for C3d. In ABO-incompatible grafts, 80% of protocol biopsies and 59% performed for graft dysfunction showed C4d staining in peritubular capillaries (PTC); this staining was not correlated with neutrophil margination in PTC. In HLA-incompatible grafts, PTC C4d was present in 26% of protocol biopsies and 60% of biopsies for graft dysfunction; 92% of biopsies with >1+ (0-4+ scale), diffuse PTC C4d had > or =1+ margination and/or thrombotic microangiopathy (TMA), compared with 12% of C4d-negative biopsies. C3d was somewhat more predictive of margination than C4d in ABO-incompatible, but not HLA-incompatible, grafts. In summary, while PTC C4d deposition indicates probable AMR in biopsies of HLA-incompatible grafts, including protocol biopsies, there is no histologic evidence that C4d deposition is correlated with injury in most ABO-incompatible grafts.

ABO Blood-Group System↗
PubMed2001

Cohort study of the prognostic significance of acute transplant glomerulitis in acutely rejecting renal allografts.

BACKGROUND: Acute transplant glomerulitis is a unique lesion in renal allografts, the prognostic significance of which is controversial. We conducted this retrospective cohort study to examine the independent prognostic significance of moderate-to-severe transplant glomerulitis in acute rejection. METHODS: Renal allograft survival for patients with acute rejection were studied, comparing one group with significant glomerulitis (G, n=28) with those with no glomerulitis (NG, n=35). Clinical, biopsy, and demographic data and renal graft survival were compared, and the association of G with graft failure was examined. RESULTS: In the G versus NG group, a greater percentage of patients were highly sensitized (peak panel reactive antibody value >80%; P=0.009), had had a previous renal transplant (40% vs. 11%; P=0.02), or had suffered from delayed graft function (P=0.03). The G group had a trend toward earlier rejection episodes (P=0.07), a significantly higher serum creatinine at the time of index biopsy (P=0.01), a higher prevalence of vascular rejection (P=0.02), and less improvement in mean reciprocal serum creatinine at 1-2 weeks after biopsy (P=0.02). Although there was a trend toward shorter allograft survival in the G group (P=0.09), the level of significance of which increased with adjustment for transplantation time period and the duration of the transplant-biopsy interval (P=0.06), the relative risk for graft loss was no longer significant when additionally adjusted for index biopsy Banff score (relative risk, 0.97; P=0.97). CONCLUSION: In this study, G was significantly more common in highly sensitized patients and was strongly associated with vascular rejection biopsies but was not an independent predictor of graft survival.

Acute Disease↗
PubMed2001

Effect of Bw4 and Bw6 epitope mismatches on antibody production, acute and chronic rejection, and graft survival in renal allografts.

BACKGROUND: Highly sensitized patients often have antibodies directed against the HLA Bw4 and Bw6 epitopes. Because of the high frequency of these epitopes, when present, these antibodies result in a high incidence of positive cross-matches. We sought to determine whether antibodies specific for Bw4 or Bw6 affected renal allograft outcome. METHODS: The effect of mismatches for the HLA class I public epitopes, Bw4 and Bw6, was examined in 72 recipients of one haplotype matched recipients of living, related donor renal allografts selected to control for degree of HLA mismatch. Analysis of the production of HLA-specific antibody was performed for 180 recipients of failed cadaveric allografts by complement-dependent cytotoxicity tests and by an enzyme-linked immunoadsorbent assay (ELISA). RESULTS: No significant difference was observed in the incidence of acute rejection, number of rejection episodes or 1-year allograft survival among Bw4/6 matched versus mismatched recipients of one haplotype matched allografts. Additionally, no significant difference in the development of chronic allograft nephropathy was noted among 56 recipients followed long-term (> or =3 years). In the recipients of failed cadaveric transplants, Bw4/6 mismatching was associated with the frequency and magnitude of production of HLA-specific antibody. However, the panel reactive antibodies correlated with the number of HLA-A and -B mismatches, and there was no additional impact of Bw4/6 mismatching. IgG, HLA-specific antibodies were found to be significantly increased among patients homozygous for Bw4 or Bw6, whether or not there was a Bw4/6 mismatch. CONCLUSIONS: Mismatching for Bw4 or Bw6 does not confer any independent, increased risk for humoral sensitization or renal allograft failure.

Acute Disease↗
PubMed2001

Characterization of HLA class I specific antibodies by ELISA using solubilized antigen targets: II. Clinical relevance.

Until recently, the nature of humoral sensitization to HLA has been characterized by data from lymphocyte-based assays, predominantly cytotoxicity tests. We have examined the characteristics, determined by enzyme-linked immunosorbent assay (ELISA), of sera from 191 subjects known to have produced HLA-specific antibody. We found that ELISA detected higher frequencies compared with cytotoxicity of many (74.5%), but not all, HLA-specific antibodies; in many cases (42.6%) the frequencies of these antibodies were higher than predicted from population frequencies whereas some antibodies (23.4%) occurred with lower than expected frequencies. Some of the increase in frequencies can be accounted for by crossreactivity, i.e., sensitization to epitopes shared among two or more allelic products. The presence of epitopes shared between a recipient's antigen and a mismatched antigen in a donor also tended to narrow the specificity of antibody produced. However the data also indicate differences in immunogenicity among different antigens suggesting that crossreactive group matching would be beneficial in some but not all cases. Finally, we present case studies to illustrate the value of ELISA in predicting humoral rejection episodes and in monitoring the efficacy of rejection therapies.

Antibodies↗
PubMed2001

Characterization of HLA class I specific antibodies by ELISA using solubilized antigen targets: I. Evaluation of the GTI QuikID assay and analysis of antibody patterns.

The development of solid phase immunoassays using solubilized HLA molecules as targets has provided a means of detecting HLA-specific antibodies that overcomes many of the shortcomings of lymphocyte based assays. We have evaluated a commercially available assay, the GTI QuikID (QID), that uses solubilized class I molecules from 40 subjects selected for their HLA phenotype, to characterize HLA-specific antibodies. We tested 595 sera from 319 subjects and compared the results obtained with QID to those obtained with cytotoxicity (CYT) and with GTI QuikScreen (QS) as well as to historic data. The correlation of QID with CYT (r = 0.54) was comparable to that between QID and QS (r = 0.60). The majority of disparities between QS and QID were apparent false negatives with QID that could be overcome by analyzing QID data at lower cutoff values. In contrast, most of the disparities between QID and CYT were false negatives in CYT due to the relatively low sensitivity of that assay. As expected, the ELISA was more sensitive (97%) than CYT (78%) but had a somewhat lower specificity (87% vs. 92%) due, most likely, to selection of sera that excluded most sera that were known to be nonspecific by CYT. Determination of antibody specificity could be achieved quickly by manual analysis of the QID data because of the way the data are presented by the manufacturer's software. Interestingly, the frequencies of different antibodies detected by ELISA differed from those detected by CYT with ELISA identifying more sera containing antibodies to both A and B locus antigens.

Antibodies↗
PubMed2001

Sequence-based typing of HLA class I alleles in Alaskan Yupik Eskimo.

In comparison to South America, native North Americans tend to be less diverse in their repertoire of HLA class I alleles. Based upon this observation, we hypothesized that the Yupik Eskimo would exhibit a limited number of previously identified class I HLA alleles. To test this hypothesis, sequence-based typing was performed at the HLA-A, -B and -C loci for 99 Central Yupik individuals from southwestern Alaska. Two new class I alleles, A*2423 and Cw*0806, were identified. While A*2423 was observed in only one sample, Cw*0806 was present in 26 of the 99 individuals and all of the Cw*0806 samples contained B*4801. Allele Cw*0806 differs from Cw*0803 by a single nucleotide substitution such that Cw*0803 may be the progenitor of Cw*0806. Allele Cw*0803 was originally characterized as unique to South America, but detection of Cw*0803 in the Yupik indicates that Cw*0803 was a founding allele of the Americas. The presence of new alleles and previously unrecognized founding alleles in the Yupik population show that natives of North America are more diverse than previously envisioned.

Alaska↗
PubMed2001

Antigen, allele, and haplotype frequencies report of the ASHI minority antigens workshops: part 1, African-Americans.

HLA typing was performed on 977 African Americans residing throughout most of the United States. Class I and class II antigens and class II alleles were defined for all individuals and class I alleles were determined for a subset of individuals. The occurrence of 854 of the individuals in family groups permitted direct counting of allele and haplotype frequencies. The data were analyzed for antigen, allele, and haplotype frequencies; recombination frequencies; segregation distortion; distribution of haplotype frequencies; linkage disequilibria; and geographic distribution of DR antigens. Tables of the antigen, allele, the most common two and three point haplotypes, and 88 extended haplotypes that include class I and class II alleles are presented. Notable findings include a lower than expected frequency of recombination between the B and DR loci (theta= 0.0013), lower than expected frequency of inheritance (44.5% vs 54.5%) of the DRB1*1503; DQB1*0602 haplotype, lower than anticipated linkage disequilibrium values for DR; DQ haplotypes, and a skewed geographic distribution of DR antigens.

Alleles↗
PubMed2001

An unusual case of fatal pulmonary allograft rejection.

This case report describes an atypical form of acute pulmonary allograft rejection that was refractory to conventional therapy. The rejection manifested primarily as interstitial lymphocytic infiltrates with little perivascular involvement. Despite aggressive therapy the patient died within 7 months of transplant. The timely recognition and treatment of unusual forms of allograft rejection is vital in the management of pulmonary transplant patients.

Adolescent↗
PubMed2000

Plasmapheresis and intravenous immune globulin provides effective rescue therapy for refractory humoral rejection and allows kidneys to be successfully transplanted into cross-match-positive recipients.

BACKGROUND: Hyperacute rejection (HAR) and acute humoral rejection (AHR) remain recalcitrant conditions without effective treatments, and usually result in graft loss. Plasmapheresis (PP) has been shown to remove HLA- specific antibody (Ab) in many different clinical settings. Intravenous gamma globulin (IVIG) has been used to suppress alloantibody and modulate immune responses. Our hypothesis was that a combination of PP and IVIG could effectively and durably remove donor-specific, anti-HLA antibody (Ab), rescuing patients with established AHR and preemptively desensitizing recipients who had positive crossmatches with a potential live donor. METHODS: The study patients consisted of seven live donor kidney transplant recipients who experienced AHR and had donor-specific Ab (DSA) for one or more mismatched donor HLA antigens. The patients segregated into two groups: three patients were treated for established AHR (rescue group) and four cross-match-positive patients received therapy before transplantation (preemptive group). RESULTS: Using PP/IVIG we have successfully reversed established AHR in three patients. Four patients who were cross-match-positive (3 by flow cytometry and 1 by cytotoxic assay) and had DSA before treatment underwent successful renal transplantation utilizing their live donor. The overall mean creatinine for both treatment groups is 1.4+/-0.8 with a mean follow up of 58+/-40 weeks (range 17-116 weeks). CONCLUSIONS: In this study, we present seven patients for whom the combined therapies of PP/IVIG were successful in reversing AHR mediated by Ab specific for donor HLA antigens. Furthermore, this protocol shows promise for eliminating DSA preemptively among patients with low-titer positive antihuman globulin-enhanced, complement-dependent cytotoxicity (AHG-CDC) cross-matches, allowing the successful transplantation of these patients using a live donor without any cases of HAR.

Adult↗
PubMed2000

Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome.

Crouzon syndrome and Pfeiffer syndrome are both autosomal dominant craniosynostotic disorders that can be caused by mutations in the fibroblast growth factor receptor 2 (FGFR2) gene. To determine the parental origin of these FGFR2 mutations, the amplification refractory mutation system (ARMS) was used. ARMS PCR primers were developed to recognize polymorphisms that could distinguish maternal and paternal alleles. A total of 4,374 bases between introns IIIa and 11 of the FGFR2 gene were sequenced and were assayed by heteroduplex analysis, to identify polymorphisms. Two polymorphisms (1333TA/TATA and 2710 C/T) were found and were used with two previously described polymorphisms, to screen a total of 41 families. Twenty-two of these families were shown to be informative (11 for Crouzon syndrome and 11 for Pfeiffer syndrome). Eleven different mutations in the 22 families were detected by either restriction digest or allele-specific oligonucleotide hybridization of ARMS PCR products. We molecularly proved the origin of these different mutations to be paternal for all informative cases analyzed (P=2. 4x10-7; 95% confidence limits 87%-100%). Advanced paternal age was noted for the fathers of patients with Crouzon syndrome or Pfeiffer syndrome, compared with the fathers of control individuals (34. 50+/-7.65 years vs. 30.45+/-1.28 years, P<.01). Our data on advanced paternal age corroborates and extends previous clinical evidence based on statistical analyses as well as additional reports of advanced paternal age associated with paternal origin of three sporadic mutations causing Apert syndrome (FGFR2) and achondroplasia (FGFR3). Our results suggest that older men either have accumulated or are more susceptible to a variety of germline mutations.

Acrocephalosyndactylia↗
PubMed1999

Complement deposition in early cardiac transplant biopsies is associated with ischemic injury and subsequent rejection episodes.

BACKGROUND: Prolonged warm or cold ischemia is associated with poor survival of cardiac transplants, and ischemic changes in early posttransplantation endomyocardial biopsies correlate with the later development of chronic rejection. In animal models, tissue ischemia has been shown to activate complement. METHODS: To determine whether ischemic changes in endomyocardial biopsies were associated with complement deposition, biopsies obtained 1-3 weeks after transplantation from 33 patients were evaluated immunohistologically for C4d and C3d deposition as well as for IgM, IgG, and IgA. The histological changes associated with ischemic injury were scored independently, using previously reported criteria without knowledge of the immunohistochemical results. RESULTS: Diffuse capillary and pericapillary deposition of C4d or C3d were detected in endomyocardial biopsies of 14 of the 33 patients. The majority of biopsies (79%) with C4d or C3d deposits had histological evidence of ischemic injury, including eight of the nine biopsies containing both C4d and C3d deposition. In contrast, only 8 of 18 (45%) of the biopsies without C4d or C3d deposition had ischemic injury. Only trace amounts of IgM and no IgG or IgA were demonstrable in the biopsies. Only 2 of the 14 biopsies with C4d or C3d deposition had evidence of moderate acute rejection, whereas 5 of the 18 biopsies without C4d or C3d deposition had moderate acute rejection. However, C4d and C3d deposition did correlate with repeated acute rejection episodes on subsequent biopsies. CONCLUSIONS: Thus, ischemic changes are associated with the activation of complement. Complement activation may in turn promote tissue injury and provide a potential target for future treatment.

Adult↗
PubMed1999

The national impact of the 1995 changes to the UNOS renal allocation system. United Network for Organ Sharing.

In 1995, changes in the United Network for Organ Sharing (UNOS) renal allocation policies expanded the mandatory share (MS) category to include zero antigen mismatches (0 mm), increased points for waiting time and for pediatric status, and eliminated points for certain HLA match grades. Data from the national scientific registry on 11344 and 11652 renal allograft recipients were analyzed for periods prior to and following the policy changes to assess the impact on organ allocation. The overall frequency of transplants going to non-Caucasians increased between the study periods, but the increase was significant only in the MS category. The proportion of MS transplants nearly doubled for African-Americans, increasing from 5.5% to 10.5%, while Hispanic/Latino recipients experienced a smaller increase, from 7.2% to 8.9%. The increased numbers of MS transplants clearly resulted from the inclusion of the 0 mm in the MS category. Among the NMS transplants, the average number of mismatched HLA antigens increased slightly. No effect of the additional points for waiting time was observed among recipients of non-mandatory share (NMS) transplants. The increase in mean waiting time until transplant for NMS recipients was attributable to the growth in the size of the waiting list. In contrast, there was a significant increase in mean waiting time for MS recipients. There were no significant changes in the proportions of sensitized or pediatric recipients between the study periods. In conclusion, only the changes in the MS policies appeared to have any significant effect on renal allocation. Further efforts will be required to address increasing allocation to patients disadvantaged by sensitization and/or prolonged waiting times.

Adolescent↗
PubMed1997

Strategies for determining HLA compatibility in related donor bone marrow transplantation.

BACKGROUND: Although HLA identity between donor and recipient is no longer an absolute requirement for bone marrow transplantation, knowledge of the degree of HLA compatibility is necessary for determining the induction and immunosuppression regimen to be used. In cases of related donor transplantation, HLA compatibility may be assessed by defining the HLA phenotypes at the allele level using high-resolution, DNA-based typing methods or by determining the genotypes of the patient and potential donor from the HLA phenotypes, ascertained by low-resolution typing, of their family members. METHODS: We developed an algorithm that can be used to assess the relative costs of these two approaches. We applied population frequencies for HLA-DR alleles to this algorithm to determine at what cost per test ratio for high-resolution:low-resolution testing the costs of the two approaches are equal. RESULTS: In transplants involving a sibling pair who have the same HLA-A, -B, and -DR antigens, these values are 1.16-1.83 for African-Americans and 1.23-1.97 for Caucasians, depending on the relatives available for testing. With a slight increase in the resolution level achieved with DR antigen testing, the range of values becomes 1.10-1.74. We also estimated that the probability that two antigenically identical siblings have identical HLA-DRB1 alleles is >99% for both African-Americans and Caucasians. A review of 615 cases from our transplant program showed that all of 192 pairs of antigenically identical patients and sibling donors were genotypically or allelically identical, indicating that this estimate is valid. CONCLUSIONS: Transplant programs can apply these algorithms to determine the most cost-effective scheme for histocompatibility testing.

Algorithms↗
PubMed1997

Local impact of 1995 changes in the renal transplant allocation system.

In 1995, changes to the United Network for Organ Sharing renal allocation system eliminated points for certain HLA matches, increased points for waiting time and for pediatric patients, and extended the mandatory share rule to include the zero-antigen mismatch. We analyzed data, from the period December 1993 to August 1996, on 393 donors, 348 kidney-only cadaveric transplants, and 615 patients ranked first or second on the allocation lists generated for each donor, to assess the effect of the changes in the point system. There was an appreciable (46%) but not significant increase in the frequency of transplants occurring under the mandatory share rule, with a greater relative increase seen in African-Americans than in Caucasians. Recipients of transplants not falling under the mandatory share rule had an increased average waiting time but no increase in sensitization or HLA mismatch, whereas patients ranked at the top of the allocation list had higher levels of sensitization but no increase in waiting time. There was an appreciable increase in the percentage of transplants occurring in African-Americans. Of the various changes we observed, only those involving the mandatory share rule could be attributed to changes in the allocation system, whereas others paralleled changes in the composition of our local waiting list.

Black People↗