Long-term metabolic control in recipients of segmental-pancreas grafts with pancreaticoenterostomy or duct obstruction.

Metabolic control in recipients of segmental-pancreas grafts with pancreaticoenterostomy (performed in Stockholm) or duct obstruction by polymer injection (performed in Oslo) were compared. The recipients were uremic diabetic patients and also received a kidney from the same donor. Because the patient population in the two Scandinavian countries is very similar and the immunosuppressive protocols used are almost identical, such a comparison seemed reasonable. The number of patients available for study at 1, 2, and 3 yr was 22, 10, and 4, respectively, with duct injection and 28, 10, and 3 with pancreaticoenterostomy. The mean age of the patients was somewhat higher in the Oslo series. There were no significant differences regarding immunosuppression or kidney-graft function as estimated by serum creatinine at 1, 2, and 3 yr. No significant differences were found in fasting blood glucose, glycosylated hemoglobin, and intravenous glucose tolerance between the two groups at 1, 2, and 3 yr.

Aluminum metabolism and bone histology after kidney transplantation: a one-year follow-up study.

Parathyroid activity, bone aluminum (Al) metabolism, bone histology, and clinical bone disease were studied in 55 successfully grafted kidney recipients at transplantation (Tx) and after 1 yr of immunosuppression with a low dose corticosteroid and a high dose cyclosporin-A regimen. Symptoms of Al-related bone disease disappeared after Tx. Serum Al and stainable bone Al decreased. The rate of Al removal from the bone surfaces was independent of graft function (creatinine range, 62-415 mumol/L) and bone turnover. Osteoblast activity and bone formation rate increased, while mineralization lag time normalized. Indices of bone resorption remained elevated, indicating persisting hyperparathyroidism. Eighteen percent of the recipients had posttransplant hypercalcemia, most likely caused by incomplete involution of hyperplastic parathyroid glands, while 53% had normocalcemic hyperparathyroidism related to impaired graft function. Cortical thickness decreased, while cancellous bone volume remained stable after Tx; both indices correlated significantly at follow-up with their respective values at Tx. None of 46 radiologically examined recipients had aseptic bone necrosis 1 yr after Tx.

Goodpasture's syndrome. A report of seven patients including long-term follow-up of three who received a kidney transplant.

Seven patients with Goodpasture's syndrome are presented. Bilateral nephrectomy was performed in five patients, and postnephrectomy pulmonary hemorrhage occurred in three. Three nephrectomized patients underwent a successful renal transplant, renal transplantation being postponed until circulating antiglomerular basement membrane antibody had disappeared. The argument is made that pretransplant bilateral nephrectomy in patients with Goodpasture's syndrome is indicated.

Serial complement studies in a patient with Goodpasture's syndrome treated with bilateral nephrectomy and renal transplantation.

A young male patient with Goodpasture's syndrome was treated with bilateral nephrectomy and when antiglomerular basement membrane antibodies could no longer be detected he received a cadaveric renal homograft. Fifteen months later he is in good health and without signs of pulmonary disease. Renal function is satisfactory, and there are no findings indicating recurrence of the nephritis. Serial complement studies during the entire course revealed varying degrees of activity in the sequence in the different phases: a high degree of in vivo activation of complement was found in the period before the nephrectomy, there was a moderate degree of activation in the period between the nephrectomy and transplantation and, finally, there were no signs of activity in the system after transplantation. This investigation strongly suggests that the complement system is of definite pathogenetic significance in this human equivalent to experimental nephrotoxic nephritis.

Cytokine-induced procoagulant activity in monocytes and endothelial cells. Further enhancement by cyclosporine.

IL-1, IL-2, and TNF alpha are important biological response modifiers of inflammatory and immunological reactions. Our experiments show that these cytokines are potent inducers of thromboplastin (TPL) activity but that their effects differ with regard to cell type and kinetics in human umbilical vein endothelial cells (HUVEC), monocytes (M), and mononuclear blood cells (MNC). Recombinant IL-1 alpha, rIL-1 beta and rTNF alpha all induced a dose-dependent increase in endothelial cell TPL activity, whereas rIL-2 had essentially no such effect. In the case of M and MNC cultures, IL-1 and IL-2 each induced TPL synthesis, IL-2 somewhat more slowly than IL-1. Special care was taken to exclude the effect of endotoxin present in the IL-1 preparations. Recombinant TNF alpha had a markedly smaller or no effect. When LPS was used to induce TPL synthesis, addition of rTNF alpha further enhanced HUVEC TPL, whereas no effect or a decrease in TPL was seen in MNC and M, especially in the presence of CsA and TNF alpha. Recombinant IL-1 beta also induced the synthesis of clotting factor VII in monocytes, thus allowing the formation of TPL-factor VII complexes, a most powerful trigger of blood clotting. IL-1 alpha, IL-2, and TNF alpha had no effect on the level of factor VII activity. Cyclosporine significantly augmented the level of TPL activity in HUVEC stimulated with rIL-1 alpha, rIL-1 beta, and rTNF alpha and in MNC and M stimulated with rIL-1 alpha, rIL-1 beta, and rIL-2. These actions of cytokines and cyclosporine may contribute significantly to the development of thrombotic reactions and fibrin deposits in transplanted organs, as well as to other pathophysiological pathways where activated clotting factors are involved.

Renal transplants from HLA-haploidentical living-related donors. The influence of donor-specific transfusions and different immunosuppressive regimens.

A total of 151 potential recipients of kidney grafts from one-HLA-haplotype-mismatched MLC-positive (RR greater than 20%) donors treated during 1980-1984 was investigated. The recipients were divided retrospectively into four groups: (A) 42 patients who received pretransplant donor-specific transfusions (DST) and posttransplant azathioprine/prednisolone (DST-only); (B) 10 patients who received DST with azathioprine before and azathioprine/prednisolone after grafting (DST-aza); (C) 42 patients who received no pretreatment and azathiprione/prednisolone posttransplant (aza group) and (D) 57 patients who also received no pretreatment but cyclosporine/prednisolone posttransplant (CsA group). DST-only led to persistently positive crossmatch in nine (21%) and transient positive crossmatch in two patients, while no sensitization occurred in the DST-aza group. Posttransplant, early acute rejection episodes were frequent in the DST-only group, but no graft was lost to acute rejection during first year; one-year graft survival (GS) = 94%. Similar GS (93%) was obtained in the CsA group, while in the aza group poorer results were obtained; GS = 69%. In the DST-aza group clinical problems including serious infections were observed. As CsA treatment without DST gave as high graft survival as in the DST groups, but avoided the sensitization risk by DST alone and the bone marrow complications of DST-aza, such treatment has become our preferred therapy for haploidentical renal transplants.

Effect of blood transfusions on renal transplantation: study of 191 consecutive first transplants from living related donors.

One hundred ninety-one consecutive living related transplants performed from 1969 to the end of 1978 have been analyzed for the effect of pretransplant blood transfusions. Superior graft survival was observed in transfused patients transplanted with a one HLA haplotype-disparate kidney, whereas no effect of blood transfusions could be observed on the survival of HLA-identical transplants. The frequency of first rejection episodes was significantly reduced in transfused compared to nontransfused one haplotype-mismatched transplants, while no influence of blood transfusions was seen in patients with HLA-identical transplants. The survival of patients was, however, not influenced by previous transfusions. Pretransplant hemodialysis improved graft survival and patient survival; the difference was, however, only significant at 2 years in the one haplotype-mismatched group. When analyzed separately, both blood transfusions and hemodialysis had a beneficial effect on graft survival in one haplotype-mismatched transplants.

A Scandinavian two-center study of BMA 031 in steroid-resistant rejection of renal grafts.

BMA 031 (Behring Monoclonal Antibody) was given to 25 renal graft recipients with biopsy-proven steroid-resistant rejections. A dose of 50 mg of BMA 031 was given i.v. on 7 consecutive days concomitantly with a standard triple-drug regimen. No premedication was administered before the first BMA 031 dose. After the first dose, 7 patients experienced moderate fever (< 39 degrees C), 5 patients had high fever (> 39 degrees C), 4 patients had nausea/vomiting, 3 diarrhea, 1 headache, and 1 hypertension. These reactions were seen only after the first dose except for 1 patient who developed urticaria on days 3-4. All the rejection episodes were reversed or partially reversed. Twenty-one patients experienced re-rejections 3-46 days after the last BMA 031 dose, and were treated with methylprednisolone and/or rabbit antihuman thymocyte globulin. Seven patients lost their grafts within 1 year (28%), including 2 patients who died of infection with a functioning graft. BMA 031 seems to be a safe drug with only few mild side effects, and it effectively reverses steroid-resistant rejections. Re-rejections were frequent, but mostly reversible.

Pretransplant plasma exchange or immunoadsorption facilitates renal transplantation in immunized patients.

Patients with preformed antibodies against HLA molecules accumulate on renal transplant waiting lists and have inferior graft survival compared with nonsensitized patients. One hundred patients were included in a program of pretransplant removal of antibodies by plasma exchange (n = 90) or immunoadsorption (n = 10) in addition to prednisolone and cyclophosphamide medication. After plasma exchange, the panel reactivity and the antibody titer were reduced in about half of the patients, and after immunoadsorption the panel reactivity fell in 6 of 10 patients. Of the 83 patients who received grafts, 17 received a graft from a living donor (LD) and 66 received a graft from a cadaver donor (CD). Patients with a positive crossmatch against their LD were included in the program and were thus grafted with a recent positive, current negative crossmatched organ. Fifteen CD graft recipients had a pretreatment positive crossmatch toward their donor. No episodes of hyperacute rejection were seen. One- and 4-year graft survival rates in LD transplants with a recent positive and current negative crossmatch were 77% and 64%, respectively. At 1 and 4 years, graft survival rates were 70% and 57% in pretreated first CD graft recipients (n = 27) and 61% and 47% in pretreated regrafted patients (n = 39), respectively. In this program, a high rate of transplantation among the sensitized patients was achieved. Graft survival was inferior to that seen in nonsensitized patients, but was comparable to graft survival in sensitized patients at other centers.

Unrelated living donors in 141 kidney transplantations: a one-center study.

BACKGROUND: Kidney transplantation is the optimal treatment for the majority of patients with end-stage renal disease. However, the shortage of kidneys for transplantation is a global problem, and any attempt to improve the donor situation would be of benefit to the growing number of patients on transplant waiting lists. PATIENTS AND METHODS: Since 1984, we have transplanted 141 kidneys from genetically unrelated living donors. Donors were most often spouses and were accepted regardless of HLA match grade. Preemptive transplantation was performed in 39% of the patients. Standard triple-drug immunosuppression with prednisolone, cyclosporine, and azathioprine was used. The patients were followed from 6 months to 13 years. RESULTS: The incidence of acute rejection during the first 3 months after transplantation was higher in recipients of grafts from unrelated donors than in recipients of grafts from related living donors or cadaveric donors. However, unrelated living donor grafts survived significantly better than did cadaveric grafts (P < 0.02) and had a survival rate similar to that of living-related donor grafts mismatched for one or both HLA haplotypes. The perioperative complication rate for the donor was low. CONCLUSION: We consider unrelated living donors an excellent source for alleviating the shortage of donor kidneys.

Alterations in lymphocyte subsets in blood may predict resectability in carcinoma of cardia or oesophagus.

Impaired immune responses in patients with carcinoma of cardia or oesophagus have previously been reported. However, we do not know whether resectability correlates with specific immunological variables. Immunological assessment was performed in 35 such cancer patients including measurement of total T cells (CD3+) and T cell subsets (CD4+ and CD8+), NK cells (CD16+) and B cells (CD19+) in blood. In vitro lymphocyte responses to phytohemagglutinin (PHA) separated from peripheral blood were quantitated. The numbers in peripheral blood of both total T cells (CD3+) and B lymphocytes (CD19+) were significantly lower in the inoperable patients compared to resected patients (P < 0.01). The number of NK cells (CD16+) was, however, not significantly lower in the inoperable patients compared to the patients operated for cure. Lymphocyte responses to PHA in vitro were similar in resectable and non-resectable patients, but significantly lower in inoperable patients compared to the controls (P < 0.01). In conclusion, resectability in carcinoma of cardia or oesophagus is associated with changes in both T (CD3+) and B (CD19+) cell subsets.

Surgical treatment as a principle in patients with advanced abdominal carcinoid tumors.

Seventy-five patients with advanced abdominal carcinoid tumors (65 midgut, 10 others) have been examined retrospectively to evaluate the role of surgical treatment as a principle, irrespective of stage of disease. Eighteen of 52 patients (35%) exhibited the carcinoid syndrome. Two or more primaries were found in 39% of patients with midgut lesion, 81% of these patients had regional metastases, 5% of these patients had distant lymph node metastases, and 74% of the patients had liver secondaries. All patients underwent operation, an additional 34% of the patients had a further reoperation, 9% of the patients had a second reoperation, 3% of the patients had a third reoperation, and one patient (2%) had a fourth reoperation. Intraoperative debulking (liver excluded) was performed in 33% of the patients, and 48% of the patients had treatment (resection, hepatic artery ligation, embolization) directed at the liver. The postoperative mortality rate was 2% after the primary operation for midgut lesions. The median survival for midgut tumors was 92 months, compared to 40 months for other lesions (not significant). A significantly higher survival rate was revealed for those patients with midgut lesion who were undergoing intraabdominal debulking procedures (liver excluded); median survival was 139 months versus 69 months without debulking. For those patients with liver metastases, median survival after intervention was 216 months and 48 months without such treatment (p less than 0.001). It is concluded that resection of intraabdominal carcinoid tumor masses can be performed in a high proportion of patients. Despite the retrospective, uncontrolled nature of this study, the difference in survival probabilities in favor of aggressive surgical therapy is so marked that it is not unreasonable to conclude that surgery has played a role in prolonging life in these patients.

Influence of HLA-A, -B, -C, and -D matching on the outcome of clinical kidney transplantation.

The influence of HLA matching has been studied in the Norwegian material of 142 living related and 311 cadaveric transplants. Graft survival corresponded closely to the degree of HLA haplotype disparity between donors and recipients. Furthermore, graft survival was less in combinations being incompatible for the serologically defined HLA-A and -B antigens as compared to compatible combinations. A weak MLC response, indicating a possible sharing of the HLA-D determinants between donor and recipient, was also associated with superior graft survival, even in the presence of HLA-A and -B disparity. Matching for HLA-C in addition to HLA-A and -B did not seem to improve graft survival.

Influence of HLA-A, B, C, and D matching and pretransplant blood transfusions on kidney graft survival.

A significant influence of matching both for the HLA-A and B and the D/DR antigens on graft survival in patients transplanted with kidneys from living related or cadaveric donors is demonstrated. A generally reduced survival of cadaveric grafts during the last few years may at least in part be explained by the use of more three and four antigen-mismatched donors. The beneficial effect of pretransplant blood transfusions on graft survival in our material is almost nulled when uremic patients, dying while waiting for a transplant, are also considered. In addition, significantly more high-risk patients are included in the nontransfused patient group.

Aluminium accumulation and immunosuppressive effect in recipients of kidney transplants.

Aluminium that has accumulated in the body is thought to have a generalised cytotoxic effect. A prospective study of aluminium accumulation in bone-that is, subclinical aluminium toxicity--was carried out in 94 recipients of kidney allografts, who were followed up for three years. Subclinical aluminium toxicity was found in 66 patients. A significantly smaller proportion of patients with aluminium accumulation experienced a rejection episode: 30 (58%) nu 12 (86%) who received grafts from cadavers and 4 (29%) nu 10 (71%) who received grafts from living donors. On multivariate analysis only the source of the kidney and aluminium accumulation were found to influence the rejection rate. These findings suggest that aluminium accumulation has an immunosuppressive effect.

Hyperparathyroidism in uremia and after kidney transplantation.

From 1969 until the end of 1976, 376 patients have had kidney transplants in our department. Fourteen patients have had subtotal parathyroidectomy done, either in their uremic phase or after a successfull kidney transplantation. All patients, except one, who had an adenoma, had varying degrees of hyperplasia of the glands. The postoperative results were satisfying in 10 patients. 3 patients is medically substituted for hypoparathyroidism while one still is hypercalcemic. There was no operative mortality and no surgical complications.

Simultaneous transplantation of pancreas and kidney in patients with advanced diabetic complications.

From June 1983 to October 1985, 25 uremic diabetic patients aged 24 to 52 (mean 38) years were treated with combined pancreas and kidney transplantation. Mean duration of diabetes was 24 years, and end-stage renal disease was associated with severe extrarenal diabetic complications in all recipients. All transplants were harvested from cadaveric, heart-beating donors aged 5-55 years. The segmental pancreas transplant was duct-occluded with neoprene before it was transplanted to the left iliac fossa. Immunosuppressive treatment was given with cyclosporine and steroids in all cases while azathioprine was added in the last 5 cases. The one year survival of patient, kidney and pancreas was 96, 79 and 60 per cent respectively. Of 17 patients with functioning pancreas transplants, 13 are insulin independent and have normal or near normal glucose homeostasis. Based on the excellent patient survival and the improvement in quality of life experienced by the recipients, it is concluded that simultaneous transplantation of pancreas and kidney should be the treatment of choice for uremic diabetic patients when a living related kidney donor is unavailable.

Kidney transplantation in diabetic nephropathy: four years experience.

Since 1972 65 patients with diabetic nephropathy have been evaluated for renal transplantation. Twenty one were not accepted, 6 died before transplantation and 10 are still under observation. Of 28 transplanted patients 13 are alive with functioning graft, and 3 are treated with hospital dialysis. Patient survival at one year was 65% and graft survival 50%.

Antilymphocyte globulin in cadaveric renal transplantation--a controlled trial.

In a prospective, controlled study, 40 patients receiving a cadaveric renal transplant (first grafts) were randomized into two groups. Twenty patients were given antilymphocyte globulin (Behringwerke AHLG) in a dose of 10 mg/kg body weight for a total no. of 25 times in combination with a standard regimen of prednisone and azathioprine. Graft survival and graft function were similar in the two groups both at 18 and 30 months post transplantation. No serious side effects of the ALG treatment were observed.

The effect of 3-4 HLA-A and -B antigen mis-matched cadaveric kidney transplants on graft and patient survival.

During the period 1969 to 1978 survival of recipients of 1st cadaveric renal grafts improved. This improvement occurred in spite of a sharp increase in high risk patients accepted for transplantation, including patients with high age, diabetic nephropathy and advanced arteriosclerotic disease. In the same period 1st graft survival decreased. The declining graft prognosis was related to the acceptance of 3-4 HLA-A and B incompatible grafts from 1973 onwards. Grafts with 0-2 incompatibilities had a stable survival during the whole 10-years period. The group of patients receiving grafts with 3-4 incompatibilities, however, included significantly more patients with diabetic nephropathy and age above 55 years. Further analysis demonstrated that the inferior graft prognosis was caused by a combined effect of HLA-mismatched grafts and the number of high risk patients. The distribution of antibodies at retransplantation (2nd graft) was similar whether the lost 1st graft was compatible for 0-2 or 3-4 HLA antigens. Also the prognosis of retransplantation was similar in the two groups.