BACKGROUND

Hypercholesterolemia is common after cardiac transplantation and may contribute to the development of coronary vasculopathy. Pravastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, has been shown to be effective and safe in lowering cholesterol levels after cardiac transplantation. Cell-culture studies using inhibitors of HMG-CoA reductase have suggested an immunosuppressive effect.

METHODS

Early after transplantation, we randomly assigned consecutive patients to receive either pravastatin (47 patients) or no HMG-CoA reductase inhibitor (50 patients).

RESULTS

Twelve months after transplantation, the pravastatin group had lower mean (+/- SD) cholesterol levels than the control group (193 +/- 36 vs. 248 +/- 49 mg per deciliter, P < 0.001), less frequent cardiac rejection accompanied by hemodynamic compromise (3 vs. 14 patients, P = 0.005), better survival (94 percent vs. 78 percent, P = 0.025), and a lower incidence of coronary vasculopathy in the transplant as determined by angiography and at autopsy (3 vs. 10 patients, P = 0.049). There was no difference between the two groups in the incidence of mild or moderate episodes of cardiac rejection. In a subgroup of study patients, intracoronary ultrasound measurements at base line and one year after transplantation showed less progression in the pravastatin group in maximal intimal thickness (0.11 +/- 0.09 mm, vs. 0.23 +/- 0.16 mm in the control group; P = 0.002) and in the intimal index (0.05 +/- 0.03 vs. 0.10 +/- 0.10, P = 0.031). In a subgroup of patients, the cytotoxicity of natural killer cells was lower in the pravastatin group than in the control group (9.8 percent vs. 22.2 percent specific lysis, P = 0.014).

CONCLUSIONS

After cardiac transplantation, pravastatin had beneficial effects on cholesterol levels, the incidence of rejection causing hemodynamic compromise, one-year survival, and the incidence of coronary vasculopathy.

BACKGROUND

In the United States, increasing numbers of persons are donating kidneys to their spouses. Despite greater histoincompatibility, the survival rates of these kidneys are higher than those of cadaveric kidneys. We examined the factors influencing the high survival rates of spousal-donor kidneys.

METHODS

Kidney-transplant data from the United Network for Organ Sharing Renal Transplant Registry were used to calculate graft-survival rates with Kaplan-Meier analysis.

RESULTS

The three-year survival rates were 85 percent for kidneys from 368 spouses, 81 percent for kidneys from 129 living unrelated donors who were not married to the recipients, 82 percent for kidneys from 3368 parents, and 70 percent for 43,341 cadaveric kidneys. The three-year survival rate for wife-to-husband grafts was 87 percent, which was the same as for husband-to-wife grafts if the wife had never been pregnant. If the wife had previously been pregnant, the three-year graft-survival rate was 76 percent (P = 0.40). The three-year graft-survival rate among recipients of spousal grafts who did not receive transfusions preoperatively was 81 percent, as compared with 90 percent for recipients who received 1 to 10 transfusions preoperatively (P = 0.008). The superior survival rate of grafts from unrelated donors could not be attributed to better HLA matching, white race, younger donor age, or shorter cold-ischemia times, but might be explained by damage due to shock before removal in 10 percent of the cadaveric kidneys.

CONCLUSIONS

Spouses are an important source of living-donor kidney grafts because, despite poor HLA matching, the graft-survival rate is similar to that of parental-donor kidneys. This high rate of survival is attributed to the fact that the kidneys were uniformly healthy.

A monoclonal antibody CSLEX1 which reacts with sialosyl Lex but not with sialosyl Lea has been produced. The CSLEX1 antigen has a tissue distribution similar to that of Lex, appearing characteristically in the proximal tubules of the kidney and on granulocytes. It is tumor associated in that 14 of 34 (41%) of tumor lines tested reacted with the CSLEX1 antibody, and 50 of 74 (68%) of tumor tissues tested reacted with the antibody. Loss of immunoperoxidase staining of tissues after neuraminidase treatment showed that the antibody is reacting to sialyl derivatives. The antibody reacted in solid-phase radioimmunoassay to sialosyllactofucopentaosyl(III)ceramide and sialosyldifucosylganglioside (6B). These results indicate that the CSLEX1 epitope has the following structure: (formula: see text) This structure had not previously been known to be tumor associated.

Eighteen patients were treated with primary cadaveric renal transplantation using cyclosporin A therapy, and four more patients undersent cadaveric retransplantation. Eleven of the 22 recipients were conditioned with lymphoid depletion before transplantation, using thoracic duct drainage or lymphapheresis for two to eight and one-half weeks. Cyclosporin A was begun a few hours before grafting. The other 11 patients were pretreated with cyclosporin A for from one day to 18 days. After transplantation, the majority of patients in both subgroups of 11 had rejection develop, but in most, the immunologic process was readily controlled with relatively small dosages of prednisone. After follow-up periods of two to four and one-half months, one patient has died of the complications of a coronary artery reconstruction that was not related to the transplantation. Another graft was lost from rejection, and a third organ was removed because of ureteral necrosis. Nineteen of the original 22 cadaveric kidneys are functioning, including 17 of the 18 kidneys given to patients who were undergoing transplantation for the first time. The only loss in the latter group of 18 patients was in the patient who died after an open heart operation. Results of these studies have shown that cyclosporin A is a superior and safe immunosuppressive drug but that, for optimal use in cadaveric transplantation, it usually should not be given alone. Steroid therapy greatly amplified the value of cyclosporin A. Unless major delayed morbidity develops which is not obvious so far, this drug combination should permit revolutionary advances in the transplantation of all organs. Other adjuncts to the cyclosporin A-steroid combination, including lymphoid depletion techniques, will require further investigation.

The background stimulation universally seen when lymphocytes are cultured in vitro has been shown to be markedly lowered by reducing the proportion of B lymphocytes. B-rich fractions of lymphocytes had extremely high background stimulation. It is concluded that stimulation of T cells, probably by autologous B cells, provides the most probable explanation for the findings described.

BACKGROUND

Liver transplantation for type IV glycogen storage disease (branching-enzyme deficiency) results in the resorption of extrahepatic deposits of amylopectin, but the mechanism of resorption is not known.

METHODS

We studied two patients with type IV glycogen storage disease 37 and 91 months after liver transplantation and a third patient with lysosomal glucocerebrosidase deficiency (type 1 Gaucher's disease), in whom tissue glucocerebroside deposition had decreased 26 months after liver replacement, to determine whether the migration of cells from the allograft (microchimerism) could explain the improved metabolism of enzyme-deficient tissues in the recipient. Samples of blood and biopsy specimens of the skin, lymph nodes, heart, bone marrow, or intestine were examined immunocytochemically with the use of donor-specific monoclonal anti-HLA antibodies and the polymerase chain reaction, with preliminary amplification specific to donor alleles of the gene for the beta chain of HLA-DR molecules, followed by hybridization with allele-specific oligonucleotide probes.

RESULTS

Histopathological examination revealed that the cardiac deposits of amylopectin in the patients with glycogen storage disease and the lymph-node deposits of glucocerebroside in the patient with Gaucher's disease were dramatically reduced after transplantation. Immunocytochemical analysis showed cells containing the HLA phenotypes of the donor in the heart and skin of the patients with glycogen storage disease and in the lymph nodes, but not the skin, of the patient with Gaucher's disease. Polymerase-chain-reaction analysis demonstrated donor HLA-DR DNA in the heart of both patients with glycogen storage disease, in the skin of one of them, and in the skin, intestine, blood, and bone marrow of the patient with Gaucher's disease.

CONCLUSIONS

Systemic microchimerism occurs after liver allotransplantation and can ameliorate pancellular enzyme deficiencies.

In 2002, 1329 patients with functioning transplants were prospectively tested for HLA antibodies in the 13th International Histocompatibility Workshop. Four years after testing, deceased donor graft survival among 806 patients not having antibodies in 2002 was 81% compared to 58% for 158 patients with HLA antibodies (p < 0.0001) and 72% for 69 patients with MICA antibodies (p = 0.02). Hazard ratio (HR) using death-censored graft survival from multivariate analysis of HLA antibodies was 3.3 (p < 0.00001) and 2.04 for MICA (p = 0.01). In the 14th Workshop, at 1 year follow-up, survival for 1319 patients receiving deceased donor grafts and no HLA antibodies was 96% compared to 94% for 344 patients with HLA antibodies (p = 0.0004) and 83% survival for 33 patients with MICA (p = 0.0005). HR from multivariate analysis: HLA antibodies was 3.6 (p < 0.00001) and 6.1 for MICA (p = 0.006). Twelve patients with donor specific antibodies tested by single antigen beads had a 1 year survival of 64% (p = 0.008), and 27 patients with non-donor specific 'strong' antibodies had a 66% survival (p = 0.0003) compared to 92% survival in those with no antibodies. In conclusion, these two prospective trials, after 1 and 4 years, provided strong evidence that HLA and MICA antibodies are associated with graft failure.

In a study of 1360 cadaver-donor kidney transplants we found a striking correlation of increased numbers of pretransplant blood transfusions with improved transplant survival (P less than 0.0001). Graft survival rate in recipients with greater than 20 transfusions was 71 p5 per cent at one year as compared with 42p2 per cent for recipients with no transfusions; at four years the survival rates were 65p5 per cent and 30p3 per cent (P less than 10(-6). Frozen blood was less effective than nonfrozen blood in producing this effect. In contrast to previous reports based on fewer numbers of transplants, a single pretransplant transfusion of transfusions given during transplantation had no statistically significant influence on graft outcome. The beneficial effect of pretransplant transfusions was apparent at transplant centers with high or low overall success rates. Deliberate transfusion trials in prospective transplant recipients should consider this strong dose dependence of graft prolongation by transfusions.

Although certain forms of epilepsy have long been suspected to be inherited, heterogeneity has made it difficult to find the genes responsible for any subtypes. We found that families ascertained through patients with juvenile myoclonic epilepsy show linkage with the BF and HLA loci on human chromosome 6. There is some evidence that the locus may be outside the HLA complex and no evidence as yet of an association with any allele of the HLA complex.

We have cited more than 23 studies showing that de novo development of anti-HLA antibodies is associated with increased acute and chronic rejection and decreased graft survival in kidney, heart, lung, liver, and corneal transplants. Antibodies to both HLA class I and class II antigens seem to be detrimental. Antibodies of the IgG isotype and possibly the IgM isotype were clinically relevant. Most studies showed that donor-specific antibodies were associated with rejection and graft loss. Therefore, HLA antibodies provide a clinical readout for patient alloreactivity that may have the ability to distinguish graft dysfunction due to immunologic and nonimmunologic causes. Antibody may act as a critical trigger for rejection of allografts and may serve as an early indicator of a slowly smoldering chronic rejection that is not manifested at a given time by biochemical measures such as serum creatinine levels. The effectiveness of various drugs on chronic rejection should be evaluable by their effects on HLA antibody production. We predict that recently developed ELISA and flow cytometry techniques using purified HLA antigen will increase the clinical relevance of posttransplantation HLA antibody monitoring by (1) allowing the detection of low levels of donor antibody; (2) easily distinguishing the isotype and target (HLA class I or class II) of the antibodies; and (3) correlating the antibody with specific graft pathology.