Allogeneic hematopoietic cell transplantation from alternative donors in children with myelodysplastic syndrome: is that an alternative?

Allogeneic hematopoietic cell transplantation (HCT) in children with myelodysplastic syndrome (MDS) remains a challenge due to the toxic conditioning regimens administered to minimize the risk of relapse in the HLA-matched or of graft rejection in the HLA-mismatched settings. In the absence of matched sibling donors, alternative donors such as unrelated and/or partially matched family sources remain risky, yet the only available, options. Herein we report the results of HCT from alternative donors in 14 children with different subtypes of MDS (juvenile myelomonocytic leukemia [JMML] n = 9; myelodysplastic syndrome [MDS] refractory anemia n = 3; MDS refractory anemia with excess of blasts in transformation n = 2) transplanted at our institution. The median time from diagnosis to HCT was 9 months (range 4 to 90 months). The variety of HCT types included: unrelated peripheral blood progenitor cell transplantation (PBPCT) (n = 2), partially matched family donor T-cell-repleted BMT/PBPCT (n = 6), and haploidentical T-cell-depleted PBPCT (n = 6). Five of 14 patients remain alive at 7 to 37 months posttransplant (including two patients after partially matched family donor BMT, two patients after haploidentical T-cell-depleted-PBPCT, and one after unrelated-PBPCT, respectively). The major complications were: primary graft failure in the haploidentical T-cell-depleted-setting or graft-versus-host disease (GvHD) in T-cell-repleted partially matched family or unrelated settings, respectively. Despite the high transplant-related mortality rate in this series, allogeneic HCT from alternative donors remains an interesting solution for children with MDS who lack matched sibling donors. Due to improved immune reconstitution, despite an increased risk of GvHD, T-cell-repleted transplants from single HLA-mismatched family donors remain a valuable option for children without matched donors. Splenectomy prior to HCT may positively affect the posttransplant course in patients with overt splenomegaly for example those afflicted with JMML.     

Recurrence of IgA nephropathy among renal allograft recipients from living donors is greater among those with zero HLA mismatches

BACKGROUND: Risk factors contributing to recurrence of IgA nephropathy (IgAN) after transplantation are unclear. Some (but not all) series have suggested greater degrees of human leukocyte antigen (HLA) matching play a role. METHODS: Using registry data including all kidney transplants performed in Australia and New Zealand between 1987 and 2004 we examined IgAN recurrence among living donors with zero HLA-mismatches. RESULTS: Of 1354 grafts performed in recipients with IgAN, live donors (LDs) accounted for 488 including 108 with zero HLA-mismatches. Biopsy-proven IgAN recurrence was reported for 110 (7%) of grafts overall, but 17% of those who received zero HLA-mismatched LD grafts (HR for recurrence free graft survival 2.7 [95% CI 1.5-5.1], P=0.001). There was no significant difference in recurrence rates between zero and >or=1 HLA-mismatched grafts from cadaveric donors (CDs). Recurrence of IgAN was associated with worse graft survival, more so among LD recipients (HR 8.5 [4.8-15.2], P<0.001) than CD recipients (HR 4.5 [2.6-7.5], P<0.001). However, there was no difference in graft survival between zero and >or=1 HLA mismatched LD recipients whose native disease was IgAN. In contrast, zero HLA mismatched recipients of kidneys with other primary renal disease enjoyed a graft survival advantage. No difference in recurrence rates was seen among those with HLA B12, B35 or DR4. CONCLUSIONS: The increased rates of IgAN-related graft loss among zero HLA-mismatched LD recipients counterbalance the advantage normally seen among zero HLA-mismatched recipients. However, since graft survivals are similar, there is no reason to avoid donor-recipient pairs with zero HLA-mismatches in this setting.     

Renal transplantation between living-related sibling pairs matched for zero-HLA haplotypes

The functional survival rates of kidney grafts from zero-HLA haplotype-matched sibling pairs are similar to one-haplotype-matched pairs and superior to cadaver grafts. From January 1980 to March 1988, 318 primary renal transplants from sibling donors (151 matched for two, 130 for one, and 37 for zero HLA haplotypes), and 352 cadaver graft transplants were performed at the University of Minnesota. The renal graft survival rates at two years were 94%, 91%, and 94% for the 2, 1, and 0-haplotype pairs versus 75% for cadaver graft recipients (P less than 0.04). When analyzed across the different immunosuppression protocols the same trends held up, similar graft functional survivals for 1- and 0-haplotype-matched pairs both being superior to cadaver graft recipients. The graft functional survival rates at two years of recipients of 0-haplotype-matched sibling donor grafts (n = 37) was 94% versus 80% for recipients of cadaver donor grafts matched for greater than or equal to 4 HLA antigens. In addition, for recipients of 0-haplotype-matched grafts, hospital stay was shorter, fewer patients required dialysis posttransplant, and, despite a slightly higher incidence of rejection episodes (51% versus 40%, P = ns), the creatinine values one year posttransplant were significantly lower (1.5 mg/dl versus 1.9 mg/dl, P less than 0.02) than those of recipients of cadaver grafts matched for greater than or equal to 4 HLA antigens. These data support the use of cadaver grafts for patients not having a willing sibling donor, and the use of all willing sibling donors, whether or not they are a zero-haplotype match, for patients fortunate to have that family commitment.     

Offspring-to-mother and husband-to-wife renal transplantation: a single-center experience

BACKGROUND: It has been demonstrated that graft survival rates of offspring-to-mother and husband-to-wife renal transplants are equivalent to those of other living donors. Although the vast majority of these transplants proceed without incident, hyperacute rejection can result from an anamnestic reaction subsequent to the in utero exposure of the mother to human leukocyte antigen (HLA) of the fetus with sensitization developing during the pregnancy. PATIENTS AND METHODS: Among 1350 renal transplants performed at our center, 12 corresponded to offspring-to-mother (G1) and 9 were husband-to-wife transplantations (G2). All recipients were multiparous (2 to 5 children). We compared these patients with other multiparous women (n = 150) who received grafts from living unrelated donors (G3). RESULTS: Two subjects in G1 (16.6%), two in G2 (22.2%), and none in G3 developed hyperacute rejection, which led to graft loss. One, 3-, and 5-year patient and graft survival rates were different between the remaining patients. CONCLUSIONS: Our limited experience suggested that, for some women, pregnancy is in fact a sensitizing event. A pretransplantation cross-match testing negative result was by no means an absolute guarantee that an adverse anamnestic immunological event would not occur.     

Successful use of 6 antigen HLA mismatched kidneys for cadaveric renal transplantation

PURPOSE: We retrospectively evaluated the outcome of transplantation with kidneys with 6 antigen HLA mismatches. MATERIALS AND METHODS: From October 1990 to September 2001, 1,270 cadaveric renal transplants were performed at our center, including 33 (2.59%) involving recipients of kidneys with 6 antigen HLA mismatches. Mean recipient age +/- SD was 40.2 +/- 14.4 years. Of the 33 recipients 19 were male, 14 were female, 31 received an initial transplant, 4 had diabetes and 6 had panel-reactive antibodies of greater than 10%. Mean donor age was 30.3 +/- 13.7 years and mean cold ischemia time was 22.9 +/- 7.8 hours. All recipients had negative current and previous B and T-cell lymphocytotoxicity cross-matching and all received a triple immunosuppression regimen consisting of the calcineurin inhibitor cyclosporine or tacrolimus combined with steroids and azathioprine. RESULTS: One-year patient and graft survival was 93.3% and 93.7%, respectively. Of the 33 grafts 31 (94%) functioned immediately. During the mean followup of 3.31 years 10 grafts (30%) were lost, including 6 (60%) due to death with a functioning graft and 4 due to chronic rejection. Acute rejection in 8 patients (24%) was reversed in 7 by steroid pulses. No graft was lost to acute rejection. Technical complications included wound infection in 2 patients (6%), transplant-ureteral obstruction in 1 (3%) and a urinary fistula in 1 (3%). CONCLUSIONS: Kidneys with 6 antigen HLA mismatches can be used effectively.     

Factors affecting rejection of second corneal transplants in rats

BACKGROUND: Second and subsequent corneal transplants in the same eye are more prone to rejection reactions and failure than first grafts. This may be a result of local changes or systemic sensitization to antigen shared by the first and second donors. Because HLA typing is not routine in corneal transplantation, a clear correlation between accelerated rejection and specific sensitization has not been established. METHODS: PVG (RT1), Lewis (LEW; RT1), or AO (RT1) strain corneas were transplanted to PVG strain rats, followed by a LEW strain cornea in the ipsilateral or contralateral eye 6 weeks later. Graft survival was evaluated by slit lamp biomicroscopy. Proliferation of recipient lymph node cells was tested against allogeneic, syngeneic and third-party stimulator cells after the second transplantation. RESULTS: A second allograft in the ipsilateral or contralateral eye was rejected in an accelerated fashion that was not donor MHC specific. Rejection was not significantly accelerated in the ipsilateral eye compared with the contralateral eye. There was a secondary lymphocyte proliferation response to third party (AO strain) in animals previously exposed only to the LEW strain. CONCLUSIONS: Systemic sensitization to donor antigens, rather than local changes induced by first transplantation, contributed to accelerated rejection of a second graft. Accelerated rejection is not dependent on MHC compatibility between the grafts. It could be caused by shared "public" MHC determinants, by minor antigens shared by the first and second donors, or by cross-reactivity of T cells to epitopes on AO and LEW grafts. HLA mismatching of first and second donors may not prolong second graft survival.     

Pancreas transplants from related donors

Of 89 pancreas transplants performed at the University of Minnesota between July 1978, and March 1983, 36 have been segmental grafts from living-related donors (17 HLA-identical siblings, 6 identical twins, 13 HLA-mismatched relatives). All recipients had been diabetic for at least 10 years and all donors were at least 10 years older than the ages of onset of diabetes in the recipients; in the case of sibling donors, no other siblings or family members other than the recipient were diabetic. Changes in plasma glucose and serum insulin levels occurred in most donors postoperatively, but glucose tolerance tests usually remained normal. Of the 36 grafts from related donors, 16 are currently functioning (12 were technical failures), as compared with 10 of 53 from cadaver donors (10 were technical failures). The pancreatic ducts were left open, injected with synthetic polymers, or anastomosed to a Roux-en-Y limb of recipient jejunum. All techniques have been associated with successes and failures, but we currently prefer the enteric-drainage technique. The patient survival rates for recipients of transplants from related versus cadaver donors were 94% versus 78% (P less than .013); the respective graft survival rates were 43% versus 20% (P = .25). When only technically successful grafts were considered, the one-year function rates were 65% for pancreas grafts from related donors (n = 29) versus 25% for those from cadaver donors (n = 43) (P = .005). The highest success rate has been in azathioprine-treated recipients of technically successful pancreas transplants from related donors of a previous kidney (3 of 3 grafts from HLA-identical siblings and 3 of 3 from HLA-mismatched relatives are functioning). However, 7 of 9 technically successful grafts from HLA-identical siblings in nonuremic, non-kidney-transplant recipients treated with cyclosporine are also functioning (one-year graft survival rate of 76%). The results in nonuremic, non-kidney-transplant recipients of mismatched related grafts have not been so good, and only one of 5 technically successful grafts in this category is currently functioning. However, this patient has been treated with cyclosporine, azathioprine, and prednisone (triple therapy)--an immunosuppressive regimen we have recently applied with success in nonuremic, non-kidney-transplant recipients of cadaveric grafts.(ABSTRACT TRUNCATED AT 400 WORDS)     

Lack of impact of human leukocyte antigen matching in living donor kidney transplantation: experience at Akdeniz University

Lack of expansion of the deceased donor supply has resulted in a severe shortage of organs worldwide. Spousal donors are one possible alternative organ source for patients on the kidney transplant waiting list. Despite human lymphocyte antigen (HLA) matching between recipients and unrelated donors being poor, the reported survival rates for these grafts, including spouses, are comparable to those for grafts from living related donors and higher than those for deceased donor kidneys. In 2000, our renal transplantation program began accepting living donor-recipient pairs with one or zero HLA matches. The purpose of this study was to assess this policy for accepting living unrelated donors. The 3-year graft survival rates for the transplants from living unrelated donors were similar to that for transplants from living related donors (log-rank = 0.078). The number of HLA mismatches did not significantly influence the survival rates for either of these groups of living donor transplants. Multivariate analysis revealed that dialysis duration (P = .057) and recipient age (P = .066) negatively influenced patient survival in living donor kidney transplantation. The graft and patient survival rates for the donor transplantations were higher than those for deceased donor transplantations. In light of these findings and considering the increasing problem of organ shortage, we conclude that living unrelated kidney transplantation should be performed, with strict guidelines. Spousal donation is the most favorable form of living unrelated renal transplantation.     

Antithymocyte globulin induction therapy in hepatitis c-positive liver transplant recipients

It is unclear whether antithymocyte globulin (ATG) induction therapy in hepatitis C-positive (HCVpositive) liver transplant recipients influences the risk of developing recurrent HCV disease. Multiple acute rejection episodes and high-dose steroids and/or OKT3 used to treat acute rejection increase the risk of graft loss from HCV. We studied the impact of ATG induction on graft and patient survival in HCVpositive liver transplants performed since 1990. Recipients who died or lost their grafts within 1 month of transplantation were excluded. Second, third, and fourth grafts were excluded, as were patients with stage III or IV hepatocellular carcinoma. There were 443 cadaveric liver transplants in adult recipients, of whom 142 (32%) were HCV positive. The incidence of biopsy-proven acute rejection was less in patients who received ATG induction, 34.2% (ATG induction) versus 66.6% (no ATG induction) (P = .01). ATG induction did not influence the risk of graft loss from HCV-related disease (P ≤ .75). When only HCV-related graft loss was considered, 10-year graft survival for HCV-positive recipients was 74% (ATG induction) versus 68.2% (no ATG induction). Whether ATG induction was given or not had no significant impact on either overall graft survival (P = .39) or patient survival (P = .11) in HCVpositive recipients. Presented at the Fifth Biennial Meeting of the American Hepato-Pancreato-Biliary Association, Fort Lauderdale, Florida, April 14–17, 2005     

Impact of HLA class I and class II DNA high-resolution HLA typing on clinical outcome in adult unrelated stem cell transplantation after in vivo T-cell depletion with alemtuzumab

Survival after volunteer unrelated donor (VUD) stem cell transplantation (SCT) is influenced by matching for human leucocyte antigens (HLA). We analysed the effects of serological and molecular typing at HLA-A, -B, -C and -DRB1 in 100 patient/VUD pairs from a single transplant centre. Patients received SCT for good risk [chronic myeloid leukaemia in first chronic phase (CML-CP1), n=55] or poor risk (n=45) diseases after myeloablative conditioning and T-cell depletion with alemtuzumab. By serological typing, 70 pairs were fully matched, whereas molecular typing revealed 10 pairs with additional mismatches. The day 100 transplant related mortality was 15%. Acute graft versus host disease (GvHD) grades III-IV occurred in 11%, whilst extensive chronic GvHD in 13% of evaluable patients. There was no statistical difference in GvHD rates between patients who received grafts from fully matched or from mismatched donors. In univariate analysis the disease risk group and CMV seronegativity of recipient and donor were the only significant predictors for survival, with 3-year survival probabilities of 71.2% for CML-CP1 and 28% for poor risk diseases. In the poor risk group, HLA mismatches had a negative impact on survival (p=0.003) and progression free survival (p=0.009) contrary to CML-CP1 patients, in whom HLA mismatches at molecular or serological level did not have any impact.     

Longmire Lecture: My 50 Years at the University of California, Los Angeles

The main concept driving my work has been the humoral theory of immunity to allografts. It led to the development of the microlymphocytotoxicity test, which is used to look for the relevant transplant antigens using alloantisera. Using alloantibodies produced by pregnancies, the HLA system was defined through a series of international histocompatibility workshops. It was then shown that the HLA system was important for matching donors and recipients for bone marrow transplants and organ transplants. More than 6000 HLA-matched kidney transplants from cadaver donors have now been shared in the United States. HLA antigens were found to be of importance in anthropologic and disease susceptibility studies. Currently HLA antibodies are being studied intensively to determine their role in chronic rejection. If it is proven that these antibodies trigger intimal proliferation, occluding arterioles, HLA antibodies will become essential to the monitoring of chronic rejection.     

Mixed chimerism and immunosuppressive drug withdrawal after HLA-mismatched kidney and hematopoietic progenitor transplantation

BACKGROUND: Rodents and dogs conditioned with total-lymphoid irradiation (TLI), with or without antithymocyte globulin (ATG), have been shown to develop mixed chimerism and immune tolerance without graft-versus-host disease (GVHD) after the infusion of major histocompatability complex (MHC)-mismatched donor bone marrow cells given alone or in combination with an organ allograft. METHODS: Four human leukocyte antigen (HLA)-mismatched recipients of living donor kidney transplants were conditioned with TLI and ATG posttransplantation and infused with cyropreserved donor granulocyte colony-stimulating factor (G-CSF) "mobilized" hematopoietic progenitor (CD34+) cells (3-5x10(6) cells/kg) thereafter. Maintenance prednisone and cyclosporine dosages were tapered, and recipients were monitored for chimerism, GVHD, graft function, T-cell subsets in the blood, and antidonor reactivity in the mixed leukocyte reaction (MLR). RESULTS: Three of the four patients achieved multilineage macrochimerism, with up to 16% of donor-type cells among blood mononuclear cells without evidence of GVHD. Prolonged depletion of CD4+ T cells was observed in all four patients. Rejection episodes were not observed in the three macrochimeric recipients, and immunosuppressive drugs were withdrawn in the first patient by 12 months. Prednisone was withdrawn from a second patient at 9 months, and cyclosporine was tapered thereafter. CONCLUSIONS: Multilineage macrochimerism can be achieved without GVHD in HLA-mismatched recipients of combined kidney and hematopoietic progenitor transplants. Conditioning of the host with posttransplant TLI and ATG was nonmyeloablative and was not associated with severe infections. Recipients continue to be studied for the development of immune tolerance.     

Sharing cross-reactive groups of MHC class I improves long-term graft survival

BACKGROUND: Renal transplant loss from chronic rejection remains substantial. To increase our understanding of this syndrome, we identified risk factors predicting late graft loss, with a special emphasis on the impact of human lymphocyte antigen (HLA) matching. METHODS: We studied all 654 cadaveric kidney transplants performed in our center between 1983 and 1996 that had survived for more than six months. Eighty-two transplants, lost because of chronic rejection, were used as the outcome variable. The influence of HLA mismatches and shares on long-term graft survival was evaluated at the level of private antigens and cross-reactive groups (CREG) of multiple histocompatibility complex (MHC) class I. HLA and other recipient, donors and transplant parameters were studied using univariate and multivariate Cox regression analysis. RESULTS: The cohort had a mean number of 1.9 HLA mismatches. Because of the homozygosity of HLA antigens, HLA mismatches were not reciprocal to shares. CREG and HLA-A-B mismatches had a relative risk for graft loss of 1.19 (95% CI, 0.97 to 1.45) and 1.05 (0.84 to 1.32) per mismatch. In contrast, the relative risk per shared CREG and broad HLA-A-B antigen was 0.76 (0.63 to 0.92) and 0.79 (0.61 to 1.03). Multivariate analysis revealed that individuals sharing less than four CREGs had a relative risk of 2.13 (1.29 to 3.75) for late graft loss. Other independent predictors were a recipient age of less than 50 years, relative risk 1.95 (1.02 to 3.71); a donor age of more than 50 years, relative risk 1.68 (1.01 to 2.80); acute rejection (vascular vs. no rejection), relative risk 3.52 (1.72 to 7.18); proteinuria (dipstick > 1+ vs. negative), relative risk 2.86 (1.29 to 6.35); and a serum creatinine concentration of more than 150 micromol/liter at six months, relative risk 3.41 (1.96 to 5.94). CONCLUSION: We identified several coexisting recipient-, donor-, and transplant-related risk factors for graft loss from chronic rejection. In this well-matched group of renal transplants, HLA mismatches and shares had a nonreciprocal relationship. Sharing of HLA antigens, especially CREG of MHC class I, was associated with improved long-term survival.     

Kidney transplantation using living donors over age 65

Efforts to increase the donor pool of available organs have resulted in some unconventional kidney transplantation procedures. One of these is the use of elderly donors for both living and cadaver kidney transplantations. The aim of this study was to review our experience with kidney transplants from living elderly donors. During a period of 10 years, 70 living renal transplantations were performed. In 32 transplants the age of the donor was above 65 years (mean 69 +/- 4 years, range: 65 to 81 years) and in 10 of these 32 transplants the age of the donor was over 70 years. The survival rate was compared with that of 38 transplants from younger donors (mean age 51 +/- 6 years, range: 24 to 59 years). The time to cold and warm ischemia, the preservation procedure and time to anastomosis of blood vessels were comparable in both groups of donors. Immunosuppression included a sequential quadruple protocol, using thymoglobulin (ATG), prednisolone (PRED), azathioprin (AZA) and cyclosporin A (CsA), which replaced ATG/PRED after day seven. A triple drug maintenance therapy (AZA, PRED, CsA) was used in all recipients. Kaplan-Meier survival curves at 1, 3 and 5 years showed that graft survival was 88%, 79% and 64% respectively for grafts from the advanced age donor group and 92%, 82% and 68% respectively for grafts from the younger donor group. The difference was slightly statistically significant (p < 0.05). Functioning of the graft was delayed in six patients who had received grafts from elderly donors and in one patient who had received a graft from a young donor. Despite worse results in transplantation with grafts from elderly donors, we consider this population as an important source of kidneys, which might help solve the present organ shortage, especially in our region.     

Alloreactivity against repeated HLA mismatches of sequential islet grafts transplanted in non-uremic type 1 diabetes patients

BACKGROUND: Islet transplantation can restore insulin production in type 1 diabetes patients. However, survival of the islet allografts will face rejection or recurrence of autoimmunity or a combination of both. In a study on islet-after-kidney transplants, we previously reported that islet cell recipients presented low T-cell alloresponses for HLA mismatches that were shared by the islet cell graft and the prior kidney graft, that is, repeated mismatch, while vigorous responses were measured against novel HLA mismatches. METHODS: We now investigated T-cell alloreactivity to repeated HLA-mismatches in three non-uremic type 1 diabetic patients each receiving three sequential islet cell implants. RESULTS: These islet-after-islet recipients patients exhibited low or absent responses to repeated mismatches to the first graft which was accompanied by sustained graft function, and reduced responsiveness towards subsequent grafts. In one patient, T-cell responses towards these mismatches were noticed following new mismatches in subsequent grafts, with loss of graft function. CONCLUSION: These case reports further support the view that subsequent islet implantations can reduce alloreactivity for repeated HLA mismatches. They demonstrate the usefulness of monitoring T-cell reactivity against islet allografts to correlate immune function with graft survival and to identify conditions for preservation of beta-cell function.     

Role of persistence of antigen and indirect recognition in the maintenance of tolerance to renal allografts

BACKGROUND: We have previously shown that a 12-day treatment with cyclosporine A (CyA) facilitates induction of tolerance to class-I disparate kidneys, as demonstrated by acceptance of second, donor-matched kidneys without immunosuppression. In the present study, we have examined 1) the duration of tolerance in the absence of donor antigen and 2) the pathway of antigen recognition determining maintenance or loss of tolerance. METHODS: Seventeen miniature swine received class-I mismatched kidneys with 12 days of CyA, and received second donor-matched kidneys without immunosuppression at 0, 1, 3, or 4 months after nephrectomy of the primary graft. Five were sensitized 6 weeks after nephrectomy of the primary graft, three with donor-matched skin grafts, and two with donor class-I peptides to eliminate direct pathway involvement. In addition, two long-term tolerant animals received class-I peptides. RESULTS: Rejection of second grafts required at least a 3 month absence of donor antigen. Although donor-matched skin grafts in animals tolerant to kidneys induced antidonor cytotoxic T lymphocyte responses, second renal transplants revealed no evidence of sensitization. In contrast, immunization of recipients with donor class-I peptides after nephrectomy of the primary graft led to loss of tolerance at both T-cell and B-cell levels, as evidenced by rejection of the second graft in 5 days and development of antidonor immunoglobulin G. Peptide immunization of long-term tolerant in recipients bearing long-term renal grafts did not break tolerance. CONCLUSIONS: These data indicate that the renal allograft is required for the indefinite maintenance of tolerance, that indirect antigen presentation is capable of breaking tolerance, and that in tolerant animals, direct antigen presentation may suppress rejection, allowing tolerance to persist.     

Renal transplantation in patients with systemic lupus erythematosus: increased risk of early graft loss

The outcome of primary renal transplantation in 31 SLE patients was evaluated in relation to two contemporary controls per patient, matched for age, sex and immunosuppressive therapy. The proportion of living donors was one third in both groups. Patient survival did not differ, but graft survival at 6 and 12 months post transplantation was significantly reduced in SLE patients (p less than 0.001). When divided into groups using either azathioprine and steroids or combinations including cyclosporin A (14 and 17 SLE patients in each group), graft survival was significantly reduced for the azathioprine-treated SLE patients, 36% vs. 82% for their controls at one year. For cyclosporin-treated SLE patients, one-year graft survival was 59% vs. 85% for their controls, and 6 out of 17 grafts in the cyclosporin-treated group were lost within the first month vs. only 4 out of 34 controls. These differences were, however, not statistically different. Most failed grafts were lost from rejection, with a high proportion of acute vascular rejection, isolated or in combination with cellular rejection. There was no apparent association between rejection and HLA-matched or presence of HLA antibodies. Retransplantation was successful in 6 out of 7 cases. We conclude that SLE patients have an increased risk of early graft rejection, but that this may be overcome by more powerful immunosuppressive therapy.     

Bone marrow augmentation in kidney transplantation: a large animal study

Specific immunomodulatory strategies are required to eliminate the need for lifelong dependence on debilitating immunosuppressants. One proposed strategy is to simultaneously transplant the kidney and infuse donor-specific bone marrow cells. We prospectively studied the effect of unmodified donor-specific bone marrow infusion (DSBMI) on rejection, infection, graft-versus-host disease (GvHD), and graft survival. We performed 57 kidney transplants in mixed lymphocyte culture (MLC)-reactive, outbred pigs. The groups of recipient pigs differed according to the use of (1) indefinite versus short-term tacrolimus-based immunosuppression, (2) DSBMI, and (3) recipient preconditioning (RPC: whole body irradiation with 400 rads on day 0 and horse anti-pig thymocyte globulin (ATG) on days –2, –1, and 0). In all, we studied eight groups: group 1, nonimmunosuppressed control pigs (n = 8); group 2, nonimmunosuppressed DSBMI pigs (n = 7); group 3, nonimmunosuppressed RPC + DSBMI pigs (n = 5); group 4, tacrolimus (indefinite) pigs (n = 11); group 5, tacrolimus (10 days only) pigs (n = 5); group 6, DSBMI + tacrolimus (indefinite) pigs (n = 8); group 7, DSBMI + tacrolimus (10 days only) pigs (n = 6); and group 8, RPC + DSBMI + tacrolimus (indefinite) pigs (n = 7). DSBMI alone (group 2) or in combination with RPC (group 3) did not prolong graft survival, as compared with nonimmunosuppressed controls (group 1). In groups 1, 2, and 3, all but one pig died from rejection; in group 3 only, 45 % of the pigs died from concurrent infection or GvHD, indicating that RPC in combination with DSBMI aggravated the risk of generalized infection and GvHD. Post-transplant immunosuppression – irrespective of indefinite or short-term administration – was required for prolonged graft survival. With indefinite use of immunosuppression, graft survival rates and death rates from rejection were not different for pigs with (group 6) versus without (group 4) DSBMI; however, the death rate from infection was higher in group 6, suggesting that the bone marrow inoculum increased the risk of systemic infection. With short-term use of immunosuppression, graft survival rates were higher and death rates from rejection lower for pigs with (group 7) versus without (group 5) DSBMI. But DSBMI and short-term immunosuppression (group 7) failed to prolong survival beyond that achieved with indefinite immunosuppression (groups 4 and 6). Although the combination of DSBMI and short-term immunosuppression (group 7) reduced the risk of infection, it did not avert severe rejection. The addition of RPC to DSBMI and indefinite immunosuppression (group 8) significantly decreased graft survival, as compared with groups 4, 6, and 7. It also increased the incidence of death from rejection, GvHD, and infection, or a combination thereof. Unmodified DSBMI did not prolong graft survival after kidney transplantation, nor did it decrease the incidence of rejection. But it aggravated the risk of GvHD and infection. Short-term immunosuppression with DSBMI reduced the incidence of death from infection or GvHD, but it resulted in a higher incidence of death from rejection (as compared with indefinite use of immunosuppression). RPC, combined with DSBMI and indefinite immunosuppression, increased the death rate from rejection, GvHD, infection, or a combination thereof. In this large animal study, the effect of unmodified DSBMI has been disappointing. The search continues for the optimal way to successfully perform bone marrow augmentation in solid organ transplants. Received: 6 June 2000 Accepted: 28 December 2000     

Successful ABO-incompatible pediatric liver transplantation utilizing standard immunosuppression with selective postoperative plasmapheresis.

Transplanting blood group A, B, or O (ABO)-incompatible (ABO-I) liver grafts has resulted in lower patient and graft survival with an increased incidence of vascular and biliary complications and rejection. We report that, without modification of our standard immunosuppression protocol, crossing blood groups is an acceptable option for children requiring liver transplantation. In our study, ABO-I liver grafts -- regardless of recipient age -- have comparable long-term survival (mean follow-up of 3.25 yr) with ABO-compatible grafts without any difference in rejection, vascular or biliary complications. From January 1, 1999 to October 1, 2005, we studied 138 liver transplants in 121 children: 16 (13.2%) received an ABO incompatible liver allograft. One-year actuarial patient survival for ABO-matched grafts vs. ABO-I grafts was 93.0% and 100%, respectively, whereas graft survival was 83.4% and 92.3%. Additionally, 6 of 16 (37.5%) ABO-I transplanted children had 8 rejection episodes, whereas 47 patients (44.8%) had 121 rejection episodes in the ABO-compatible group. There were no vascular complications and 2 biliary strictures in the ABO-I group. Plasmapheresis was not used for pretransplantation desensitization and was only required in 1 posttransplantation recipient. No child was splenectomized. Six of the 16 children were older than 13 yr of age, suggesting the possibility of successfully expanding this technique to an older population. In conclusion, our outcomes may support the concept of using ABO-I grafts in a more elective setting associated with split and living donor liver transplants.     

Pancreas transplantation in crossmatch-positive recipients

BACKGROUND: Prolonged cold preservation time can unfavorably affect outcome in pancreas transplantation. To reduce this ischemic time, cadaver pancreas grafts, in selected cases, are sometimes transplanted before crossmatch results are known. We report our experience with pancreas transplants in recipients with either current or historically positive T- or B-cell crossmatches. METHODS: Crossmatch-positive pancreas transplants were identified using a computerized database. T-cell crossmatches were performed using an antihuman-globulin-augmented complement-dependent cytotoxicity (CDC) test; B-cell crossmatches were performed using an extended incubation CDC test. All patients received anti-T-cell induction therapy and either cyclosporine (1987-1993) or tacrolimus-based (1994-2001) immunosuppression. More recent recipients (2000-2001) also received intravenous gamma globulin and postoperative plasmapheresis. RESULTS: Between October 1, 1987 and March 31, 2001, of a total of 1076 pancreas transplants performed, 59 (5.48%) were crossmatch-positive. Of these, 8 had a current T-cell-positive crossmatch and 15 had a current B-cell-positive crossmatch. One recipient was both current B- and T-positive, and the rest were past B- and/or T-cell positive. One-year pancreas graft survival for current T- and B-cell crossmatch-positive transplants was 63% and 67%, respectively. T- or B-cell crossmatch-negative transplants had a 1-yr survival of 70%. In the T-cell crossmatch-positive group, four grafts are still functioning (follow-up range, 2-12 yr), one patient died with a functioning graft at 4 months, and four grafts failed (one each from pancreatitis, infection, primary nonfunction, and vascular thrombosis). No grafts were lost to rejection. In the B-cell crossmatch-positive group, six grafts are still functioning (follow-up range, 2-11 yr) and nine have failed (four from chronic rejection, three from vascular thromboses, and two from pancreatitis). Crossmatch-positive cases were significantly more likely to be retransplants (70.8%) than crossmatch-negative cases (14.8%, p < 0.0001). In a multivariate analysis, crossmatch positivity did not affect pancreas graft outcome, whereas retransplants had a significant impact on outcome (relative risk 1.84, p < 0.0001). CONCLUSIONS: (: i) Pancreas transplants performed in the setting of a positive current crossmatch may have long-term function. (ii) With current immunosuppressive protocols, graft loss from hyperacute and acute rejection may be prevented in current crossmatch-positive pancreas transplants. Chronic rejection was only seen in B-cell crossmatch-positive cases. (iii) High rates of technical graft loss in crossmatch-positive cases may reflect a high frequency of retransplants in this group.