Kidney graft failure and presensitization against HLA class I and class II antigens

BACKGROUND: It is well known that kidney transplant recipients with preformed lymphocytotoxic antibodies against HLA antigens have an increased graft rejection rate. However, the individual contribution of anti-HLA class I and class II antibodies to this phenomenon is poorly understood. We investigated the clinical relevance of preformed anti-HLA class I and class II antibodies on graft outcome in more than 4000 kidney recipients. METHODS: Pretransplant sera of 4136 cadaver kidney recipients from 28 transplant centers were tested in ELISA for IgG-anti-HLA class I and IgG-anti-HLA class II antibodies. The influence of antibody reactivity on graft survival was analyzed. RESULTS: Four hundred eighty of the anti-HLA class I antibody-positive recipients had a graft survival rate at 2 years of 77+/-2%, compared with an 84+/-1% rate in 3656 anti-HLA class I antibody-negative recipients (P<0.0001), and 770 anti-HLA class II-positive recipients had a graft survival rate of 79+/-2%, compared with an 84+/-1% rate in 3366 anti-HLA class II-negative patients (P<0.0001). Importantly, good 2-year graft survival rates of 85+/-3% and 84+/-2%, respectively, were observed in 206 anti-HLA class I-positive/class II-negative and 496 anti-HLA, class I-negative/class II-positive recipients. In contrast, the 274 recipients positive for both types of antibodies showed a poor graft survival rate of 71+/-3% (P<0.0001). Among 853 patients who received a well-matched kidney (0 or 1 HLA-A+B+DR mismatch), sensitization against either class I or class II, or both, had no deleterious effect. However, in 113 class I and class II antibody-positive patients who received a kidney with > or =3 HLA-A+B+DR mismatches, the 2-year graft survival rate was only 60+/-5%. CONCLUSION: Presensitization of first kidney transplant recipients against either HLA class I or class II is of no clinical consequence, whereas sensitization against both HLA class I and class II results in increased rejection of HLA mismatched grafts.     

Carcinoma of the prostate and HLA antigens

A possible association between HLA antigens and carcinoma of the prostate was searched for in 20 patients and 200 healthy kidney donors. HLA antigens A₂₆, A₂₈, B₁₃, B₁₄, B₄₀, Bw₄ and Cw₄ were more common in patients with carcinoma of the prostate. The relative risk for HLA B₁₄ was 7.78 (95% confidence interval 7.60–8.13). The relative risk for patients carrying the above antigens (except A₂₈) was higher than 2. This study shows that certain HLA antigens may be more frequent in patients with carcinoma of the prostate. Before drawing any conclusions from these findings, they have to be confirmed by other studies.     

Effect of early transplant function as an index of recipient presensitization on long-term function of machine-preserved cadaveric kidneys

The early post-transplantation function of machine-preserved cadaveric kidneys judged to be of good quality from perfusion data appeared to provide a good in vivo clinical index of recipient presensitization to donor transplant antigens. The quality of early function was affected adversely by prolonged pretransplantation hemodialysis, by multiple transplants (second and third), and by the identified presence of antibody-against-the-panel (AbAP) values of 10 per cent or more. The highest pretransplantation AbAP per cent and the per cent nearest the time of transplantation also were factors in the quality of early transplant function (F, F^AR, SF, or NF class early transplant function).The level or “titer” of recipient presensitization appeared to have an effect on long-term transplant survival and the level of function of these kidneys. Long-term (one year) function of cadaveric kidneys in nonsensitized recipients or those with a low titer of sensitization (F class) was 51 per cent. That for recipients with intermediate titers of sensitization (F^AR and SF classes) was 29 per cent and 61 per cent, respectively. Long-term transplant survival for recipients with a presumed high titer of presensitization (NF class) was 40 per cent. The long-term survival of SF class kidneys at risk to the immune response was 79 per cent. That for F^AR and NF class kidneys that recovered function after the initial presumed immunologic assault was 89 and 88 per cent, respectively.Long-term transplant function in “nonsensitized” recipients (F class) was not influenced significantly by the number of HL-A antigens mismatched donor-to-recipient (0, 1, 2, 3, or 4). The long-term transplant survival in a small group (eight patients) of nonsensitized (F class) recipients subjected to splenectomy because of anemia and leukopenia prior to transplantation was 88 per cent, and that for “nonsensitized” (F class) recipients not undergoing splenectomy at the same transplantation center was 44 per cent.     

Purification of HLA antigens from urine.

HLA antigens were purified from urines of kidney transplanted patients, HLA was recovered as a single peak of 45,000 mol wt that was dissociated into beta2-microglobulin and a 33,000 mol wt fraction bearing the allospecificity. The purified fractions contain carbohydrates but no lipids. Electrophoretical mobility and the relative salt concentration of eluting buffers in DEAE-Sephadex chromatography were determined for six antigens of the A locus and seven antigens of the B locus. Isolectric points of antigens A1, A2, A9, and B12 were measured. Physiochemical characteristics of HLA purified from urine appear to be similar to those of papain-solubilized cell membrane HLA. Urinary HLA was shown to originate from serum and not from renal or ureteric tissue.     

HLA antigens and transitional cell carcinoma of the bladder

A possible association between HLA antigens and transitional cell carcinoma of the bladder was searched for in 56 patients and 200 healthy kidney donors. Statistical analysis showed that HLA antigens A23, A25, A28, BW4, BW21, BW22 and CW4 are more common in bladder tumor patients, whereas B27 and BW6 were more common in the control group. The relative risk for HLA CW4 was 2.07 (95% confidence interval 1.51-2.48). Except for CW4, these findings are inconsistent with previous reports. We believe this to be due to various misleading factors, and thus not conclusive. Even if such a statistical association exists, this appears to be clinically not relevant and, therefore, should not alter standard practice.     

Soluble HLA antigens in the circulation of liver graft recipients

Human liver allografts deliver soluble class I (HLA-A and -B) transplantation antigens into the recipients' circulation. These molecules are detectable in recipient serum shortly after transplantation and they persist at high concentration for as long as the liver graft functions. Levels of graft-derived antigens in the recipient serum and self antigens in donor serum are comparable. Kinetic studies of these soluble antigens in donor and recipient show that donor antigens are continuously exported by the transplanted liver, while in the recipient, self antigens are derived from liver and other sources. At least two molecular forms of soluble HLA-A and -B antigens are present in sera from donors, recipients, and normal individuals. One form with m.w. approximately 50 kd seems to be a soluble monomer associated with beta 2-microglobulin, while the other forms of higher m.w. may be aggregates and/or complexes. Monitoring of these antigens in transplant recipients may be a useful indicator of graft pathology and function.     

HLA matching and cadaver kidney transplant survival in North America: influence of center variation and presensitization.

In an analysis of 4,851 first cadaver kidney transplants, we found a statistically highly significant correlation between the number of HLA antigens mismatched and graft survival (P less than 0.0005 at 1 year). The difference in the survival rates of grafts with no HLA mismatch compared with grafts with four mismatches was 11 to 12%, similar to results of previous analyses. HLA-A locus antigens had a slightly stronger effect than B locus antigens. The correlation of HLA matching with graft survival was most significant at centers with poor overall transplant outcome, and there was no correlation at centers with very good overall results. Presensitization also had the strongest effect at centers with poor overall graft survival.     

A highly sensitive,rapid screening method for the detection of antibodies directed against HLA class I and II antigens

Screening of potential transplant recipients for antibodies that can cause graft rejection is an essential part of the pre-transplant monitoring carried out by tissue typing laboratories. This is a time-consuming process and the rapid reporting of results is dependent on the maintenance of frozen cell panels. The usual procedure of screening against a panel of random cells takes up to 6 weeks. In this study we have used flow cytometric analysis of pooled chronic lymphatic leukaemia (CLL) cells to detect antibodies directed against HLA antigens. We show that FACS screening of pooled cells can accurately and rapidly detect these antibodies and that the method is suitable for routine use. An estimate of the degree of patient panel reactivity can be determined within a few hours. In addition, the technique is more sensitive than those conventionally used, an advantage that may be of importance in preventing graft damage.     

Population studies on the association of HLA antigens with duodenal ulcer

HLA-B15 antigen is thought by the authors to occur in 24.4% of patients with duodenal ulcer (in donors--in 6.6%). HLA-A2 antigen is found in 60.3% of cases (in donors--in 48.2%). A conclusion is made of the population immunogenetic (by HLA) heterogeneity of the ulcer disease.     

肝移植术后致敏状态的监测

目的　探讨肝移植受者致敏与移植物功能的关系。方法　采用酶联免疫吸附法(ELISA)对 15例患者肝移植前后的群体反应性抗体 (PRA)进行动态监测。结果　 15例患者肝功能的主要指标 ,包括丙氨酸转氨酶、总胆红素、直接胆红素等大多在术后 1周内恢复正常。 15例中有 1例术前中度致敏 ,术后发生轻度排斥反应 1次 ,经治疗后逆转 ,其PRA在观察期内一直保持阳性。另外 14例受者移植前、后PRA均阴性 (PRA <10 % ) ,其中 1例发生排斥反应 1次 ,但PRA仍保持阴性。结论　肝移植受者的致敏状态与术后的排斥反应密切相关。     

Association of class II antigens of HLA with primary glomerulopathies

HLA antigens of Japanese patients with primary glomerulopathies were determined, and the frequency of each HLA antigen was compared with that of Japanese normal controls. IgA nephropathy with HLA-DR4, idiopathic membraneous glomerulopathy with DR2, lipoid nephrosis with DRw53 and poststreptococcal glomerulonephritis with DR1 were definitely or probably associated. It was suggested that primary glomerulopathies might all be associated with HLA class II and not class I antigens. Japanese patients with HLA-Bw48 and -DRw8 were less susceptible to primary glomerulopathies.     

Evaluation of HLA matching for CREG antigens in Europe.

BACKGROUND: In North America, cross-reactive antigen group (CREG) matching was introduced recently for cadaver kidney allocation. This is expected to result in improved graft outcome and an increased number of transplants for patients with rare HLA antigens. METHODS: We analyzed the impact of CREG matching using the data of the Collaborative Transplant Study for 59,516 first cadaver transplants performed in Western Europe. The 10 HLA class I CREGs described by Takemoto et al. were used for a comparison with the conventional HLA-A+B mismatching scheme. RESULTS: Transplant outcome depends primarily on the number of HLA-A+B mismatches and not on the CREG match grades. In a retrospective analysis, CREG mismatches correlated with the number of HLA-A+B mismatches. However, in computer simulations, we found that prospective CREG matching is not associated with beneficial HLA-A+B matching. CONCLUSION: The positive CREG matching effect observed in retrospective analyses is caused by the underlying effects of conventional HLA-A+B matching. CREG-oriented cadaver kidney allocation in Europe would, therefore, be inferior to the current conventional HLA-A+B+DR allocation.     

Humoral immunity and antigens of HLA system in acute pancreatitis

In the authors investigations patients with acute pancreatitis had antibodies to endogenic antigens: to o-DNA--in 58.5%, to d-DNA--in 53.7%, to n-DNA in 51.2%, to trypsin--in 42.7%, to insulin--in 28.1% and to the tissue antigen of the pancreas--in 19.5%. A rise of serum immunoglobulins' and circulating immune complexes' levels were established. Alterations of humoral immunity in connection with high frequency of antigens HLA A1, B8, B18 associated with disregulation among T- and B-links of immune system detected in patients with acute pancreatitis, represent genetic and humoral mechanisms which mediate the development of autoimmune reactions in this disease.