Experience with cyclosporine in 1519 kidney transplantations from living donors in a national transplant programme, 1983-2002.

Following the introduction of cyclosporine as basic immunosuppression in our national transplant programme in 1983, the pool of grafts from living donors (LDs) was expanded 2 years later by also accepting LDs mismatched for 2 HLA haplotypes and living unrelated donors (LURDs), mostly spouses. A policy of approaching family members to promote donation was consistently pursued. During 1983 through 2002, nephrectomy was performed on 1519 LDs without mortality. From 1983 through 1988, our learning phase in managing cyclosporine-immunosuppression, 382 patients received first grafts from LDs. One-year graft survival (GS) rates were 94.4%, 90%, 89%, and 82% in 71 HLA identical, 260 haploidentical, 18 2-haplotypes disparate, and 33 LURD graft recipients, respectively. Corresponding half-lives were 15.8, 10.3, 11, and 9.1 years, respectively. Results improved in 1028 patients receiving first LD grafts from 1989 through 2002. Corresponding 1-year GS rates were 96.6% (n=117), 93.5% (n=650), 90.4% (n=73), and 88.8% (n=188), and half-lives were 30, 13.3, 13.5, and 12.3 years, respectively. Similar GS rates were observed in 109 recipients of repeat grafts from LDs. LDs contributed 44% and 21.6% of all first and repeat grafts transplanted, providing grafts to 11 patients (in 1983) increasing to 23 patients (in 2002) per million population per year (pmp/y). When added to grafts from cadaveric donors, 40 to 48 pmp/y were provided with a first or repeat graft since 1990, thus covering at least 65% of the national need for kidney transplantations.

Fewer relapses and increased chronic GVHD in patients transplanted with blood stem cells: a 5-year follow-up in a single centre study.

A total of 61 consecutive adult patients with haematological malignancies with an HLA-identical or one antigen-mismatched haploidentical family donor were randomised to allogeneic transplantation with blood stem cells (BSC) or bone marrow (BM). The median observation time was 5 years. Apart from engraftment parameters and acute graft-versus-host disease (GVHD), transplant-related mortality (TRM), incidence and severity of chronic GVHD, relapse, leukaemia-free survival (LFS) and overall survival (OS) were recorded. In the BSC and BM group, respectively, TRM was 8/30 and 4/30 (P=0.405), the incidence of chronic GVHD was 15/26 and 11/30 (P=0.138), extensive chronic GVHD was 10/26 and 4/30 (P=0.034), and relapse one and 10 patients (P=0.007). In log-rank test restricted to the cases allografted from HLA-identical donors, the difference remained significant with regard to relapse incidence (P=0.039), but not extensive chronic GVHD (P=0.072). No difference in LFS and OS was observed. In conclusion, our study strongly indicates an enhanced graft-versus-leukaemia effect in BSC recipients, which is not expressed in increased survival. The increased chronic GVHD in these patients may contribute, but the relation is complex and not yet understood.

Donation of stem cells from blood or bone marrow: results of a randomised study of safety and complaints.

Biological consequences and physical complaints were compared for donors randomly assigned either to blood stem cell (BSC) or bone marrow (BM) donation. In the period 1994-1999, 61 consecutive donors were included. The BSC donors were given G-CSF 10 microg/kg s.c., daily during 5 days before the first leukapheresis. Nineteen donors had one leukapheresis, 10 required two and one donor needed three leukaphereses in order to reach the target cell number of 2 x 10(6) CD34(+) cells/kg bw of the recipient. A median platelet nadir of 102 x 10(9)/l was reached shortly after the last leukapheresis. Three weeks post harvest, 17 of 30 BSC donors had a mild leukopenia. Six had a leukopenia lasting more than a year before returning to normal values. Both groups were monitored prospectively through a standardised questionnaire completed by the donors. BSC donation was significantly less burdensome than BM donation and was preferred by the donors. The short-term risks of BSC mobilisation and harvest seem negligible. The potential long-term effects of G-CSF are unresolved and the donors must be followed closely.

A randomised study of allogeneic transplantation with stem cells from blood or bone marrow.

Sixty-one consecutive adult patients with leukaemia, primary myelofibrosis or myelodysplastic syndrome with an HLA-identical or one antigen mismatched family donor were randomised to allogeneic transplantation with PBPC or BM. Progenitor cells were mobilised into the blood by giving the donors 10 microg/kg/day G-CSF subcutaneously for 5-7 days. G-CSF was not given to patients after transplantation. The time to neutrophil counts >0.5 x 109/l was 17 days (95% CI 15.2-18.8 days) in the PBPC group compared to 23 (95% CI 20.3-25.7 days) in the BM group (P = 0.0005). The time to platelet counts >20 x 109/l was 13 days (95% CI 11.7-14.3 days) in the PBPC group and 21 days (95% CI 18.7-23.3 days) in the BM group (P = 0.0005). Acute GVHD of grades II-IV developed in six patients transplanted with PBPC and three patients transplanted with BM. The numbers of patients with chronic GVHD were 15 and 8, respectively. Transplant-related mortality and leukaemia-free survival showed no significant differences. Transplantation with PBPC appears preferable for the recipient due to faster neutrophil and platelet recovery. However, the final conclusion can not be drawn before long-term results on chronic GVHD and relapse incidence in longer randomised trials are available.

[Immunosuppressive agents in organ transplantation]. / Immunsuppressive medikamenter ved organtransplantasjon.

Initial use of intensive immunosuppressive therapy is mandatory after organ transplantation; during the following months treatment is tapered to the lowest effective and tolerable maintenance level. Immunosuppressants with different mechanisms of action are combined in order to obtain additive or synergistic effects, and to reduce the incidence of adverse effects. Traditional immunosuppressive agents like azathioprine, steroids, cyclosporine and polyclonal and monoclonal antibodies against T-cell antigens are challenged by new drugs like mycophenolate mofetil, tacrolimus, sirolimus and interleukin-2 receptor monoclonal antibodies. A combination of the most potent drugs could induce nearly complete immunosuppression. Such treatment, however, is a delicate balance between rejection due to poor immunosuppression on one side and, on the other, infections and malignancies induced by overtreatment. According to current protocols, therapeutic drug monitoring is used to individualize the dosage of immunosuppressants and as a means to control the tapering of these drugs. Validation of new immunosuppressive agents should be based on data from long-term studies including patient survival and graft function and survival as endpoints. Among the most recent achievements, inhibitors of costimulatory signaling in T-cells are of clinical interest since they may induce donorspecific tolerance and thereby alleviate the need for life-long maintenance immunosuppressive therapy.

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.

The national kidney transplant program in Norway still results in unchanged waiting lists.

1. Of 2,670 patients starting renal replacement therapy for end-stage renal disease in Norway from 1989-1997, 76% were candidates for transplantation. The annual need for transplantations increased from 47 to 64 grafts PMP as the number of elderly patients increased. The national waiting list has remained almost stable during the period from 1989-1997 at levels of 25-30 PMP, but the dialysis population has increased from 57-105 PMP. 2. A total of 1,681 transplants was performed at an annual rate varying between 38 and 46 grafts PMP. The grafts were procured from LDs in 41% and CDs in 59% of cases. Totally 69% of all patients in need were transplanted and 54% of all patients requiring replacement therapy for end-stage renal disease received a transplant. 3. Graft survival rates in recipients of first LD grafts (n = 641) were 91% and 77% at one and 5 years, respectively. One-year graft survival was 97% in HLA-identical grafts (n = 71), 92% in haploidentical grafts (n = 419), 88% in 2 haplotype-mismatched related grafts (n = 43), and 87% in spousal donor grafts (n = 108). 4. Graft survival rates in recipients of first CD grafts (n = 801) were 84% and 65% at one and 5 years, respectively. The rates were 86% and 74% in younger (n = 557) versus 78% and 46% in older (> 65 years) (n = 244) patients. Death with a functioning graft caused approximately 45% and 75% of all graft losses in younger and older patients, respectively. Cardiovascular disease was the major cause of death. 5. A significant beneficial effect of HLA-DR matching was observed in CD grafts performed after 1989, in particular in patients older than age 65.

No prevention of cytomegalovirus infection by anti-cytomegalovirus hyperimmune globulin in seronegative bone marrow transplant recipients. The Nordic BMT Group.

A randomized multicentre study was conducted to evaluate the effect of anti-CMV hyperimmune globulin in the prophylaxis of CMV infections in CMV seronegative allogeneic BMT patients who received a transplant from a seropositive donor or who had received blood products unscreened for CMV during the treatment before BMT. Twenty-eight patients were included in the study. Thirteen were randomized to receive and 15 not to receive intravenous CMV hyperimmune globulin. A dose of 0.4 g/kg of immunoglobulin was given on day -8 and 0.2 g/kg on days -1, +7, +14, +21, +28, +35, +42, +56 and +70 in relation to the day of transplantation. Among the 15 patients not given immunoglobulin CMV was isolated in three, and two of them developed clinical CMV disease. In addition, one more patient developed CMV antibodies without virus isolation. In five of the 13 patients given immunoglobulin the virus could be isolated, and four of them developed CMV disease. One additional patient showed seroconversion but no other findings of CMV infection. The incidence of acute and chronic GVHD was similar in the two arms. There was no significant difference in survival. In conclusion, the present results do not indicate a beneficial effect of CMV hyperimmune globulin infusions in the prophylaxis of CMV infection or disease in seronegative allogeneic bone marrow transplant recipients from a seropositive donor.

[Mycophenolate mofetil--a new immunosuppressive agent]. / Mykofenolatmofetil--nytt immunsuppressiv.

Mycophenolate mofetil is a prodrug that is rapidly converted to the active immunosuppressant mycophenolic acid. This substance inhibits the enzyme inosine monophosphate dehydrogenase, leading to a depletion of (deoxy-)guanosine nucleotides and thereby a reduction of de novo purine synthesis. Lymphocytes are relatively dependent on this pathway, particularly for RNA and DNA synthesis, and are thereby more susceptible to the antiproliferative effects of mycophenolate. In three randomised, double-blind, multicentre trials, lower rejection rates have been demonstrated in renal allograft recipients during the first months after transplantation. Side effects were more frequent in the mycophenolate mofetil groups. The most important adverse reactions to mycophenolate mofetil are leucopenia, gastrointestinal effects and the increased risk of infections and malignancies associated with immunosuppression in general. At 12 months, graft survival was similar in all groups. The future role of mycophenolate mofetil in immunosuppressive therapy during transplantation has not yet been established. As a start it may be found to have specific use in subgroups of allograft recipients at high risk of rejection.

Pharmacokinetics and immunodynamics of chimeric IL-2 receptor monoclonal antibody SDZ CHI 621 in renal allograft recipients.

SDZ CHI 621 is a murine-human chimeric monoclonal antibody (mAb) to the interleukin-2 (IL-2) receptor (CD25) intended for prophylactic immunosuppression against acute rejection in the first several weeks following kidney transplantation. A multicentre, prospective, dose-finding study was conducted in 37 primary, mismatched cadaver kidney transplant patients to assess its tolerability, pharmacokinetics and immunodynamics. Successive cohorts of patients were stratified to receive total doses of 20, 30, 40 or 60 mg (n = 4, 4, 14, 15, respectively) administered as 15- or 20-mg intravenous infusions with the first dose given preoperatively and subsequent doses within the first 10 days posttransplant. Daily mAb serum concentrations were analysed by a radioimmunoassay method and the percentage of peripheral T-lymphocytes expressing CD25 from serial blood samples was determined by FACScan. Intravenous administrations were well tolerated. mAb concentration profiles exhibited a biphasic decline with an initial t1/2 of 14.4 +/- 14.2 h, terminal t1/2 of 13.4 +/- 6.0 days, distribution volume (Vss) of 6.9 +/- 3.31 and clearance of 17.4 +/- 7.8 ml/h. The concentration-effect (mAb-CD25) relationship indicated that mAb concentrations exceeding a threshold of about 0.7 microgram/ml corresponded to complete suppression of CD25 (< or = 3% CD25+ T-cells). The threshold mAb concentration was exceeded at all dose levels, whereas the duration above the threshold (and thus of CD25 suppression) rose with increasing dose: 20 mg, 20 +/- 7 days; 30 mg, 32 +/- 6 days; 40 mg, 37 +/- 10 days; and 60 mg, 53 +/- 17 days. As mAb concentrations declined below the threshold following the last dose, CD25 expression returned to baseline (18-44% CD25+ T-cells) within a few days.

Ischemic heart disease--major cause of death and graft loss after renal transplantation in Scandinavia.

Causes of graft loss and death were studied in 1347 recipients of primary renal transplants followed for 5 years after transplantation irrespective of graft function. Immunosuppression consisted of high or medium dose CsA and prednisolone or low dose CsA and prednisolone and azathioprine. In recipients of cadaver grafts, death with a functioning transplant was more common than graft rejection after the first posttransplant year, accounting for 49% and 41% of the graft losses, respectively. Of deaths with a functioning graft, 53% were due to ischemic heart disease (IHD) and 10% were due to other vascular disease. In the 55- to 64-year-old age group, the risk of death from IHD was 6.4 times higher in the transplanted nondiabetic patients, 8.6 times higher in the dialysis patients (European Dialysis and Transplant Association figures), and 20.8 times higher in the transplanted diabetic patients than in the general population (national figures). A multivariate Cox regression analysis showed that old age, diabetes mellitus, occurrence of acute rejection, pretransplant transfusions, delayed onset of graft function, and male gender were significant for death in IHD. We conclude that, in comparison to reports from other regions, Scandinavian renal transplant recipients are at high risk of dying of IHD. Future advances in long-term renal graft survival will depend largely on the success of preventing myocardial infarction and death in this patient population.

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.

[Allogeneic transplantation of stem cells--procedure and biological aspects]. / Allogen transplantasjon av stamceller--prosedyre og biologiske forutsetninger.

The biological challenges to be overcome for allogeneic stem cell transplantation to succeed include: 1, eradication of the patient's malignant tissue by effective, yet tolerable cytoreductive preconditioning; 2, suppression of the patient's immunocompetence to prevent graft rejection; 3, a stem cell graft of adequate haematopoietic capacity must be obtained from a donor of acceptable histocompatibility, and transferred to the patient; and 4, since the graft also contains lymphocytes mediating antirecipient donor alloimmunity, posttransplant immunosuppressive therapy is required to prevent, and sometimes to treat graft-versus-host disease. Basic immunobiological and clinical aspects, and methods used in stem cell transplantation are reviewed in the article.

HLA-A incompatibility associated with enhanced long-term renal graft survival in HLA-B, DR mismatched transplants.

The effect of HLA-A matching on long-term cadaver kidney graft survival was analysed, on average, 6 years after transplantation in a total of 1085 cyclosporine (CyA)-treated patients. A beneficial effect of HLA-A mismatching on graft survival was found by univariate and multivariate analyses (P < 0.05). Enhanced graft survival was associated with HLA-A mismatching in transplants mismatched for HLA-B,DR (P = 0.03), but not in HLA-B,DR compatible transplants. High 6 year graft survival rates, 78% and 66%, were found in transplants mismatched for two or one HLA-A antigens, respectively, among patients without any acute rejection episode. This was significantly higher than the survival rate of 55% found in HLA-A compatible transplants (P = 0.001). In patients who had suffered from acute rejection episodes, a prolonged graft survival was also associated with HLA-A mismatching in HLA-B,DR mismatched transplants (P = 0.04). The beneficial effect on graft survival of HLA-A mismatching was most pronounced in patients treated with high/medium dose CyA and prednisolone (P = 0.004 overall and P = 0.0007 for HLA-B,DR mismatched transplants). In conclusion, HLA-A mismatching was associated with enhanced long-term renal graft survival in CyA-treated recipients of HLA-B,DR mismatched transplants. In clinical situations, the present results might, if confirmed, contribute to the prolongation of long-term graft survival. The results might indicate the existence of tolerance promoting allogeneic markers within the HLA-A class I region.