Myasthenia Gravis,Autoantibodies, and HL-A Antigens

The serum of 100 patients with myasthenia gravis and 441 of their first-degree relatives was studied for the presence of autoantibodies against several antigens. Antibodies to skeletal muscle were present in 22% of the patients and in 2% of the relatives. Both these frequencies were significantly higher than those in matched control subjects. Also, antinuclear antibodies were present more often both in the patients and in the relatives. Typing for HL-A antigens had shown a positive correlation between HL-A 8 and myasthenia gravis which was significantly higher in women than in men. Antibodies to skeletal muscle and thymomas were found to be much rarer in HL-A 8-positive patients than in HL-A 8-negative patients; HL-A 8-positive patients acquired the disease at an earlier age.HL-A 2-positive patients more often had thymomas and antibodies to skeletal muscle than HL-A 2-negative patients; HL-A 2-positive patients acquired myasthenia gravis at a later age.The fact that the clinical aspects of the HL-A 8-negative and HL-A 2-positive patients were different from those of the HL-A 8-positive and HL-A 2-negative patients justifies the hypothesis that there are two forms of myasthenia gravis.     

Viral infections in renal allograft recipients treated with long-term immunosuppression.

Thirty-nine renal allograft recipients who had received continuous immunosuppression for six to 13 years were examined clinically and virologically for evidence of past or present viral infection. Twenty-five had common warts, usually on the hands. In most the warts had appeared about one year after transplantation; once present, they never disappeared. Six patients had had a zoster rash from two months to four years after transplantation. None had had jaundice, and there was no change in the frequency of colds or non-specific fibrile illness. Four patients had no cytomegalovirus complement-fixing antibodies throughout the observation period; in the other 35 the antibody titre had risen appreciably during the first three to four months after transplantation. Antibody titres were high (mean 64) at follow-up, being only slightly lower than the highest titres achieved during the immediate postoperative period. None of the patients had had symptomatic cytomegalovirus infection, and in only two was the virus isolated from the urine at follow-up; the titres were extremely low. No changes occurred in the frequency of herpes simplex eruptions. Although all patients had herpes simplex humoral antibody, none excreted the virus. Although cytomegalovirus antibody titres were high, virus excretion was rare, indicating that chronic cytomegalovirus infection in these patients is immunologically well controlled.     

IgA-antigliadin antibodies in IgA mesangial nephropathy (Berger's disease).

Circulating IgA-antigliadin antibodies were detected with enzyme linked immunosorbent assay (ELISA) in four of 121 patients (3%) who had IgA mesangial nephropathy and 14 of 17 children (82%) who had untreated coeliac disease. No positive cases were present in the 54 healthy subjects of the control group. Three patients who had IgA nephropathy and IgA-antigliadin antibodies underwent jejunal biopsy, and two showed mucosal atrophy. In these two patients urinary abnormalities, together with the IgA-antigliadin antibodies, disappeared completely after three months and five months, respectively, of following a gluten free diet. Circulating IgA immune complexes were found in most patients who had coeliac disease and Berger''s disease associated with IgA-antigliadin antibodies, suggesting overactivity of the B cells producing IgA in both conditions. By contrast, a circulating IgA rheumatoid factor was detectable in three of the four patients who had IgA nephropathy and asymptomatic coeliac disease but was always absent in children who had coeliac disease but did not show signs of renal disease. These results suggest that a more complex abnormality in the IgA immune response is necessary for renal disease to become manifest in patients who have gluten enteropathy.     

Value of Prospective Tissue Typing in Kidney Transplantation Between HL-A Identical Siblings

The predictability of leucocyte typing in kidney transplantation was assessed by an analysis of 37 kidney transplants from sibling donors. Recipients who were identical for the HL-A antigens with their donors gave highly predictable results. In comparison with those siblings who were incompatible or compatible but not identical their grafts functioned earlier, they required less immunosuppression, and had never had any rejections. They also appeared to have less postoperative morbidity. These results indicate that less immunosuppression than is current in many transplant centres could well be used with benefit in HL-A identical sibling transplants. This could reduce the risk of infection and possibly minimize the adverse effects of steroids on wound healing in these patients.     

Long-term survival of human skin allografts in patients with immunosuppression

Severe burn patients lack adequate skin donor sites to resurface their burn wounds. Patients with severe burn injuries to areas such as an entire face are presently reconstructed with skin grafts that are inferior to normal facial skin. This study was designed in part to determine whether human skin allografts would survive, repopulate, and persist on patients with immunosuppression and after discontinuation of immunosuppression. Small split-thickness skin grafts were synchronously transplanted at the time of renal transplantation from six renal transplant donors to recipients. All six patients were immunosuppressed with the usual doses of renal transplant immunosuppressants (methylprednisolone, cyclosporine, prednisone, and azathioprine). The skin allografts were biopsied when rejection was suspected and at various intervals. Special histologic studies were performed on skin biopsy specimens. Class II DNA tissue typing was performed on transplanted and autogenous skin biopsy specimens of four patients. Fluorescent in situ hybridization was performed successfully on skin biopsies of four patients' transplanted skin and on two of these four patients' autogenous skin. All six human skin allografts sustained a 100 percent take and long-term clinical survival. DNA tissue typing performed on skin allograft biopsy specimens from patients taking immunosuppressants all revealed donor and recipient cells. DNA tissue typing performed on autogenous skin biopsies from the same patients all revealed only recipient cells. Fluorescent in situ hybridization performed on allograft and autogenous specimens from patients taking immunosuppressants revealed transplanted donor cells with rare recipient cells in the allograft and only recipient cells in the autogenous skin. This study of six patients proves that it is possible for human skin allografts to survive indefinitely on patients taking the usual dosages of immunosuppressants used for renal transplantation. There was minimal repopulation of skin allografts by autogenous keratinocytes and fibroblast while patients were taking immunosuppressants. Immunosuppression was discontinued in two patients after renal transplant rejection after 6 weeks and 5 years. When immunosuppression was discontinued after 5 years in one patient, the skin allograft cells were destroyed and replaced with autogenous cells, but the skin graft did not reject acutely and persisted clinically. It is hypothesized that the acellular portion of the skin allograft was not rejected acutely because of relatively low antigenicity and because it acted as a lattice for autogenous cells to migrate into and replace rejected allograft skin cells. No chimerism was seen in autogenous skin in the skin-renal transplant patients in this study.     

Maternal HL-A Antibodies and Fetal Sex

In a study of 960 pregnancies a significantly higher male to female birth ratio was found among primigravidae who developed HL-A antibodies, which was highest where these were monospecific. In the whole group male births predominated in women with antibodies to HL-A 1 and 11 (first locus) and HL-A 5, 12, and 13 and TYT (second locus).     

Use of donor-specific T-cell lines for monitoring of human allograft recipients. I. Demonstration of IgG binding to autologous TCL

Donor-specific and highly cytotoxic T-cell lines (TCL) as well as lectin-induced TCL were established from pretransplant lymphocytes of 6 cadaveric renal allograft recipients. These TCL were used in the 125I-staphylococcus protein A assay to detect IgG antibodies in pre- and posttransplant sera of these patients preferentially binding to autologous donor-specific TCL. Such antibodies were detected in pretransplant sera from 4 of these 6 allograft recipients. Antibody levels in these 4 patients and in 1 additional case who became positive after transplantation further increased during acute cellular rejection episodes. They disappeared after successful treatment but remained elevated until transplantectomy for treatment of irreversible rejection in 1 case. IgG antibodies binding to autologous lectin-induced TCL were detected in only 1 patient and exhibited a pattern clearly different from those binding to donor-reactive TCL. Although attempts to define the antigenic specificity of the autoantibodies binding to donor-specific TCL by genetical and biochemical means has remained unsuccessful so far, the demonstration of their relationship to in vivo expansion of donor-reactive immune cells deserves further attention.     

Nocturnal polyuria and saluresis in renal allograft recipients.

The evolution of nocturnal polyuria and saluresis in renal allograft recipients was studied by comparing the day to night (D:N) ratios of urine volume and sodium excretion in 15 patients who had undergone transplantation less than one year previously (recent-transplant group) with those in 11 patients who had undergone transplantation at least one year previously. Eleven patients with chronic renal failure and 12 normal subjects served as controls. Patients in the recent-transplant group had significantly lower D:N ratios of urine volume and sodium excretion than the patients who had undergone transplantation at least a year before, while the ratios in this last group did not differ significantly from those in the normal subjects. Nocturnal polyuria and saluresis gradually subsided in five patients studied for three months. Chronic renal failure and uraemic autonomic neuropathy were unlikely causes of the nocturia. The patients in the recent-transplant group had significantly lower D:N ratios of urine volume than the controls with chronic renal failure, and the mean Valsalva ratio in eight of them was not significantly different from that in the normal subjects. An undue sensitivity of renal allografts to postural influences was proposed.     

HLA-DRw6 and renal allograft rejection.

HLA-DRw6-positive patients are "high responders" to certain renal allograft antigens. A study was therefore conducted of the outcome of 247 first renal allografts in 74 DRw6-positive and 173 DRw6-negative recipients. The effectiveness of matching for HLA-DR determinants in both groups was also analysed. The one-year graft survival in DRw6-positive patients was 59% as compared with 75% in DRw6-negative recipients (p = 0.012). A striking difference between the two groups was that HLA-DR matching significantly improved renal allograft survival only in the DRw6-positive patients. In those patients the one-year survival of HLA-DR-identical grafts was 95% as compared with only 38% for 2-DR mismatched grafts (p = 0.009). In DRw6-negative patients only a slight beneficial effect of HLA-DR matching was observed (83% versus 72% at one year for the 0-DR and 2-DR mismatched grafts, respectively) (p greater than 0.05). These findings are clear evidence that DRw6-positive patients (about a quarter of the patients on the waiting list of Eurotransplant) should be given HLA-DR-identical kidney transplants only.     

Histocompatibility Antigens in Active Chronic Hepatitis and Primary Biliary Cirrhosis

The frequency of antigens HL-A 1 (48%) and HL-A 8 (52%) in 54 patients with active chronic hepatitis from south-east England was significantly higher than in 89 control subjects from the same region (22% and 17% respectively). No correlation could be detected with the age and sex of the patients or with the presence of a particular immunological abnormality but the frequency of HL-A 1 and HL-A 8 was much lower in the nine patients who were positive for HBAg than in the 45 HBAg-negative cases. These results provide further evidence of the importance of genetic factors in active chronic hepatitis. In contrast the frequency of HL-A 1 and HL-A 8 in primary biliary cirrhosis, both in 45 patients from south-east England and in 28 patients from western Scotland, was not significantly different from that found in control groups from the same regions.     

Abdominal Bruit after Renal Transplantation

Forty-seven recipients of renal allografts have been studied at varying intervals of up to five years after transplantation. Renal artery bruit occurred in eight of 16 patients observed over the first two post-transplant months and disappeared spontaneously in four of these. The disappearance of the bruit was associated with poor renal function. Renal bruits were audible in 10 patients examined more than two months after transplantation; nine of these were hypertensive and of six in whom arteriography was performed five were shown to have stenosis of the allograft artery. By contrast only eight of 37 patients without abdominal bruit were hypertensive, and arteriography in 10 normotensive patients without bruit showed no stenosis. It is concluded that while a renal artery bruit during the first two months after transplantation may be a marker of good renal blood flow at the time, its presence suggests a poor long-term prognosis since persistence of the murmur indicates that significant stenosis of the allograft artery is likely, while its disappearance is associated with poor renal function.     

Renal transplantation in patients treated with haemodialysis and short term and long term continuous ambulatory peritoneal dialysis.

Forty two adult patients who had been treated with continuous ambulatory peritoneal dialysis for one to 142 weeks (mean (SD) 38 (36)) received a total of 44 allografted kidneys. Twenty one had been treated with continuous ambulatory peritoneal dialysis for less than 26 weeks (mean 11 (8)) and the other 21 for longer than 26 weeks (mean 64 (35)). These two groups were compared with 55 patients who had been treated with haemodialysis and received a total of 63 grafts. In the group of patients treated with continuous ambulatory peritoneal dialysis azathioprine and low dose prednisolone were used as the immunosuppressive regimen for 20 transplantations in 18 patients, and 24 patients receiving 24 grafts were treated with cyclosporin A and low dose prednisolone. In the group of patients treated with haemodialysis 38 patients receiving 43 grafts were treated with azathioprine and low dose prednisolone, and 20 patients receiving 20 grafts were treated with cyclosporin A and low dose prednisolone. Actuarial survival of patients and grafts at two years was 95% and 72%, respectively, in the continuous ambulatory peritoneal dialysis group compared with 89% and 58%, respectively, in the haemodialysis group. No difference was found in graft survival between short term treatment with continuous ambulatory peritoneal dialysis (72% graft survival) and long term treatment (65% graft survival). In conclusion, continuous ambulatory peritoneal dialysis is suitable treatment for patients awaiting renal transplantation.     

Ultrasonographic findings of functioning renal allografts in the cynomolgus monkey (Macaca fascicularis)

PURPOSE: The purpose of this study was to describe the findings of serial ultrasound investigations of functioning and histologically normal renal allografts in the cynomolgus monkey. METHODS: Ten cyclosporine (Neoral) treated cynomolgus monkeys underwent renal allograft transplantation with bilateral nephrectomy, seven of which were examined serially with ultrasound. Ultrasound findings were compared to serum creatinine, and the results of histology from allograft biopsy on day 150 post-transplantation. RESULTS: Allografts increased in volume up to one and a half to twice that of their original volume and appeared morphologically similar to native kidneys. Allograft ureters were dilated postoperatively but decreased in size with time. Other than in two cases of ureter complications, the resistive index (RI) was normal in functioning grafts. CONCLUSIONS: Elevations in RI, as well as graft enlargement and increased cortical thickness, were related to graft pathology, but not necessarily to rejection histologically. The ultrasound findings of functioning grafts and of surgical complications after renal allograft transplantation in the cynomolgus monkey were similar to those in humans.     

High versus "low" dose corticosteroids in recipients of cadaveric kidneys: prospective controlled trial.

Corticosteroids have the major role in the immunosuppressive treatment of patients who have received renal transplants. Despite their extensive use there is still debate about the appropriate dose that will prevent rejection of the renal allograft with the least morbidity. From March 1979 to November 1981 a randomised controlled trial of high (33 patients) v low oral dose (34 patients) of prednisolone along with azathioprine was conducted in recipients of first cadaveric transplants who had received a blood transfusion within six months of transplantation. The main difference in outcome between the two groups was a high incidence of some infections in the high dose group. Patient mortality, graft survival, transplant function, and number of rejection episodes were indistinguishable in the two groups, but rejection episodes tended to occur later in the high dose group. These findings suggest that the use of lower doses of corticosteroids soon after cadaveric renal transplantation does not jeopardise graft survival and results in lower patient morbidity.     

Evidence for HL-A-linked genes in "juvenile" diabetes mellitus.

HL-A typing of 150 patients who had developed diabetes mellitus by the age of 30 years showed a significant association with HL-A 8 and W 15. The HL-A genotypes were determined in 17 families in which two or more siblings had this type of diabetes. The zygotic assortment of HL-A haplotypes was found to be significantly disturbed from the expected random pattern, with a reduction in the number of siblings showing no identical haplotypes and an appreciable increase in the number with both haplotypes identical. This appears to be most consistent with the presence of a gene or genes pre-disposing to this type of diabetes at a locus closely linked to the HL-A chromosomal loci. This locus appears to have a fundamental role in the susceptibility to juvenile diabetes.     

Intérêt pronostique de la scintigraphie au 99mTc-MAG3 pour le succès à un an de la transplantation rénale

Because of the increasing use of marginal grafts, it remains a significant difference in terms of transplants half-life between living donor or cadaver donor. The main objective of this study was to assess the prognostic value of various isotopic parameters available on the same day than surgery for the one-year outcome after kidney transplantation. A retrospective study of 100 patients, who received a renal allograft at the University Hospital of Montpellier between 1999 and 2006, and who performed ^99mTc-MAG3 renal scintigraphy within 72 h after transplantation, was performed. Measurement of various isotopic parameters was performed for angiographic and tubular phases, over three different regions of interest. According to judgment criteria, namely the success or not of transplantation after the first year, previously obtained results were statistically compared. The results of our study confirmed the importance of vascular parameters, especially the Kirchner index, with a good correlation with renal function one year after tranplantation. As expected by the physiological models, a well-perfused graft had the most chances of short-term survival. Kirchner index has a negative predictive value of more than 90% for the one-year success after transplantation (VPP = 75%). Parameters assessing more specifically nephronic functional reserve (such as tubular function slope or uptake on perfusion peaks report) are independent risk factors for the failure during the first three months.     

Characterization of tubular basement membrane antigens in human kidney

Tubular basement membrane (TBM) was prepared from normal human kidneys and solubilized with various enzymes. Collagenase digestion released antigenic moieties from the TBM. All four anti-TBM antibodies we studied, three from patients with idiopathic tubulo-interstitial nephritis (TIN) and one from a renal allograft recipient, distinctively reacted with collagenase-digested (CD) TBM during enzyme-linked immunoassay and could discriminate among sera of normal controls or of other nephritis patients, including anti-glomerular basement membrane (anti-GBM) nephritis. When digested with pronase, trypsin, or pepsin, antigenicity of the TBM decreased. We studied the TBM antigens with immunoprecipitation and immunoblotting. After incubation of radio-iodinated CDTBM with anti-TBM sera, immunoprecipitates were identified by single-dimension SDS polyacrylamide gel electrophoresis or two-dimension gel electrophoresis, followed by autoradiography. All four antibodies had identical results on immunoprecipitation; under nonreducing conditions, they gave two protein bands with m.w. of 54,000 and 48,000 and with pI 7.0 to 8.0 and 6.5 to 7.0. Electrophoresis performed under reducing conditions disclosed only one band at the m.w. of 48,000 and pI of 6.5, suggesting that the 54-kDa component is composed of peptides linked by interchain disulfide bonds. Immunoblot analysis showed that the anti-TBM antibodies were heterogeneous; three antibodies from the idiopathic TIN patients reacted with the 54-kDa band, but the one from the renal allograft recipient reacted with neither band. This finding suggests that there are two antigenic determinants on the 54-kDa component. One such determinant that was resistant to denaturation with SDS was detected by the first three antibodies, and the other that was sensitive to such denaturation bound to the last antibody. The 48-kDa component seemed not to be immunoreactive after incubation with SDS. We studied TBM antigens reactive with anti-GBM antibodies. By immunoblotting, all four sera from patients with anti-GBM nephritis stained TBM proteins of 45 to 50 kDa and 25 to 27 kDa at pH 8.0 to 9.0; this was similar to the staining pattern of CDGBM with the same sera, but the highly cationic (pH greater than 9.0) components were specifically detected in the CDGBM. By inhibition ELISA, the binding of the anti-GBM sera to denatured CDTBM decreased with preincubation of the sera with CDGBM, suggesting that the anti-GBM antibodies recognize the same epitope(s) on the GBM and the TBM.     

IVIg Treatment Reduces Catalytic Antibody Titers of Renal Transplanted Patients

Catalytic antibodies are immunoglobulins endowed with enzymatic activity. Catalytic IgG has been reported in several human autoimmune and inflammatory diseases. In particular, low levels of catalytic IgG have been proposed as a prognostic marker for chronic allograft rejection in patients undergoing kidney transplant. Kidney allograft is a treatment of choice for patients with end-stage renal failure. Intravenous immunoglobulins, a therapeutic pool of human IgG, is used in patients with donor-specific antibodies, alone or in conjunction with other immunosuppressive treatments, to desensitize the patients and prevent the development of acute graft rejection. Here, we followed for a period of 24 months the levels of catalytic IgG towards the synthetic peptide Pro-Phe-Arg-methylcoumarinimide in a large cohort of patients undergoing kidney transplantation. Twenty-four percent of the patients received IVIg at the time of transplantation. Our results demonstrate a marked reduction in levels of catalytic antibodies in all patients three months following kidney transplant. The decrease was significantly pronounced in patients receiving adjunct IVIg therapy. The results suggests that prevention of acute graft rejection using intravenous immunoglobulins induces a transient reduction in the levels of catalytic IgG, thus potentially jeopardizing the use of levels of catalytic antibodies as a prognosis marker for chronic allograft nephropathy.     

Antinuclear antibodies during procainamide treatment and drug acetylation.

Acetylator capacity was determined in two groups of patients who had received procainamide for more than three months. In seven patients antinuclear antibodies (A.N.A.) were detected during treatment, and these changes disappeared (in six patients) or were less pronounced (one patient) after withdrawal of the drug. These patients tended to have faster acetylation rates, and five were phenotypically "rapid" acetylators. Five patients who did not develop A.N.A. during treatment had less rapid (P less than 0.05) rates of acetylation, and four were "slow" acetylators. We suggest that the immunological changes which may occur during procainamide treatment may be associated with the acetylated metabolite of procainamide rather than the parent compound and that it might be possible to identify patients at risk.     

Potentially Serious Side Effects of High-dose Twice-weekly Rifampicin

Daily rifampicin in a single dose of 600 mg, combined with other drugs, usually streptomycin and isoniazid, was given to 49 patients for three months. It was planned to continue for another 15 months with twice-weekly rifampicin 1,200 mg plus isoniazid 900 mg, but the high incidence of side effects led to cessation of the intermittent regimen when only two patients had completed 18 months.Though there was no serious problem with daily treatment 11 patients (22%) were unable to continue rifampicin on the intermittent regimen. In 8 (16%) a pyrexial syndrome occurred. In one of these patients there was also temporary renal failure, and in another precipitous thrombocytopenia led to epistaxis and bleeding into the tongue and lips. Symptomless thrombocytopenia developed in two other patients, making three cases (6%) of thrombocytopenia in all.In 16 (33%) of the 49 patients antibodies to rifampicin were detected in the blood. Side effects occurred in 9 (56%) of these, including the three developing thrombocytopenia, but in only 2 (6%) of the 33 patients with no antibodies detected. This association of toxic reactions with antibodies is highly significant (P<0·001).