Risk Factor For Rejection Research Articles

Association Between Panel Reactive Antibodies and Acute Small Bowel Rejection: Analysis of a Series of 324 Intestinal Transplants

Introduction Panel reactive antibodies (PRA) to class I and II HLA molecules have been associated with acute kidney graft rejection, but their role in small bowel transplantation has not been characterized. Methods Since 1994, 324 SBT, alone or as multivisceral transplantation (MVT), have been performed in 286 patients. Routine and surveillance biopsies were performed to rule out or confirm acute rejection (AR), and PRA quantification was performed at varying intervals. We obtained data from 110 patients and 651 PRA measurements. While AR grade (mild to severe, grades 1–3) was determined by histopathological analysis, the status of no AR was determined also by clinical data. When biopsy samples or PRA measurements were frequent around an AR episode within periods of 7 days, the highest value was used. Results A comparison could be made between 259 instances in which there was a PRA measurement and simultaneous rejection evaluation. Positive PRA showed association with AR ( P < 0.001). The positive and negative predictive values were 44% and 79%, respectively. No correlation was found in the severity of rejection. Conclusion The presence of increased levels of PRA is a risk factor of rejection in small bowel transplantation. Alloantibody-mediated injury to the graft contributes frequently to acute rejection of small bowel, and it is associated with cell-mediated immunity in variable proportion.

Rejection with hemodynamic compromise in the current era of pediatric heart transplantation: A multi-institutional study

Survival after pediatric heart transplant has improved over time, as has the incidence of overall rejection. We studied the effect of era on the occurrence and outcome of rejection with hemodynamic compromise (HC). Data from 2227 patients who received allografts between 1993 and 2006 at 36 centers in the Pediatric Heart Transplant Study were analyzed to determine incidence, outcome, and risk factors for rejection with HC in early (1993-1999) and recent (2000-2006) eras. Rejection with HC was classified as severe (RSHC) when inotropes were used for circulatory support and mild (RMHC) when inotropes were not used. Of 1217 patients with any episode of rejection, 541 had rejection with HC. Freedom from RMHC improved at 1 year (81% vs 90%, p < 0.001) and at 5 years (74% vs 85%, p < 0.001) in the early vs recent eras, but freedom from RSHC was similar between eras (93% vs 95% at 1 year and 85% vs 87% at 5 years, p = 0.24). Survival after RSHC (63% at 1 year and 49% at 5 years) was worse than after RMHC (87% at 1 year and 72% at 5 years, p < 0.001) and did not change over time. Risk factors for RSHC were non-white race (hazard ratio [HR], 1.73; 95% confidence interval [CI], 1.29-2.32, p < 0.01), older age (HR, 2.85; 95% CI, 1.24-6.53; p = 0.01), and non-A blood type (HR, 1.51;, 95% CI, 1.11-2.04,; p = 0.01), but the only risk factor for RMHC was earlier era of transplant (HR, 1.94; 95% CI, 1.56-2.41; p < 0.001). The incidence of RMHC has declined over time but the same era effect has not occurred with RSHC. Close follow-up after RSHC is crucial because mortality is so high.

Does histocompatibility affect homograft valve function? An update

Objectives: Mismatch of human leukocyte antigens [HLA] between donor and recipient is a risk factor for rejection in organ transplantation. The impact of such mismatches for the fate of cryopreserved valve allografts is not known.

Improved Adherence and Outcomes for Pediatric Liver Transplant Recipients by Using Text Messaging

The goal was to improve immunosuppressant adherence for pediatric patients with orthotopic liver transplants by using text messaging (TM). A prospective study of sending TM reminders to the primary medication administrator (patient or caregiver) for pediatric transplant recipients was performed. Patient records were reviewed, comparing the year before and the year of the study. The SD of serum tacrolimus levels was used as an indicator of adherence. Forty-one patients provided consent. The median age was 15 years (range: 1-27 years), and the median age at the time of transplantation was 2 years (range: 4 months to 23 years). Fourteen patients (34%) were male. In 29 of 41 cases, the medications were self-administered by the patient. The mean duration of study was 13 +/- 1.5 months. Twenty-two patients were receiving 1 immunosuppressant, 14 were receiving 2, and 5 were receiving 3. Thirteen patients (37%) stopped the study after 4 months. The mean tacrolimus level SD decreased from 3.46 microg/L before the study to 1.37 microg/L (P < .005). The number of immunosuppressants taken and patient self/caregiver medication administration did not significantly affect the results. The number of acute cellular rejection episodes decreased from 12 to 2 during the study. Risk factors for rejection were older age (17.67 vs 13.28 years) and administration of >1 immunosuppressant. We observed significant improvement in medication adherence and a reduction in rejection episodes with TM reminders for pediatric recipients of liver transplants.

Graft rejection after hematopoietic cell transplantation with nonmyeloablative conditioning

Graft rejection after hematopoietic cell transplantation (HCT) with nonmyeloablative conditioning is a rare but serious clinical problem. Graft rejection and salvage therapy in eight patients in a retrospective analysis of 124 consecutive patients is reported. The patients were conditioned with low-dose fludarabine and total body irradiation (TBI). The association of pretransplantation risk factors with rejection and the effect of chimerism and graft-versus-host disease on rejection were analyzed. Overall survival (OS) and progression free survival (PFS) were compared between patients with and without rejection. Retransplantation was performed with increased TBI conditioning for all patients, and with increased mycophenolate mofetil doses for recipients with HLA-identical sibling donors. No known pretransplantation risk factors were confirmed in this study. Rejection episodes were unevenly distributed over time. The storage temperature of the apheresis products was identified as a risk factor for rejection. Storage of the apheresis products at 5 degrees C diminished the risk of rejection. Low donor T cell chimerism at Day +14 significantly increased the risk of rejection. Seven patients were retransplanted. All but one engrafted successfully, but with decreased OS and PFS. Two patients received pentostatin infusion prior to donor lymphocyte infusions in unsuccessful attempts at reversing rejection. Storage temperature and donor chimerism had a significant effect on rejection. Following rejection, patients are at greater risk of dying from infections and progression/relapse of their malignancy. Retransplantation is feasible and well tolerated after HCT with nonmyeloablative conditioning and should be performed without delay in patients with imminent and manifest graft rejection.

Risk Factors for Rejection and Infection in Pediatric Liver Transplantation

Rejection and infection are important adverse events after pediatric liver transplantation, not previously subject to concurrent risk analysis. Of 2291 children (<18 years), rejection occurred at least once in 46%, serious bacterial/fungal or viral infections in 52%. Infection caused more deaths than rejection (5.5% vs. 0.6% of patients, p < 0.001). Early rejection (<6 month) did not contribute to mortality or graft failure. Recurrent/chronic rejection was a risk in graft failure, but led to retransplant in only 1.6% of first grafts. Multivariate predictors of bacterial/fungal infection included recipient age (highest in infants), race, donor organ variants, bilirubin, anhepatic time, cyclosporin (vs. tacrolimus) and era of transplant (before 2002 vs. after 2002); serious viral infection predictors included donor organ variants, rejection, Epstein-Barr Virus (EBV) naivety and era; for rejection, predictors included age (lowest in infants), primary diagnosis, donor-recipient blood type mismatch, the use of cyclosporin (vs. tacrolimus), no induction and era. In pediatric liver transplantation, infection risk far exceeds that of rejection, which causes limited harm to the patient or graft, particularly in infants. Aggressive infection control, attention to modifiable factors such as pretransplant nutrition and donor organ options and rigorous age-specific review of the risk/benefit of choice and intensity of immunosuppressive regimes is warranted.

Advances in the allogeneic transplantation for thalassemia

Hematopoietic stem cell transplantation (HSCT) remains the only curative option for patients with thalassemia. Current results of transplantation in patients aged less than 17 years from matched related donors offer 80% to 87% probability of cure according to risk classes. Adult thalassemics treated with myeloablative conditioning continue to have inferior results because of their advanced stage of disease. With the introduction of high-resolution tissue typing techniques transplant centres worldwide are able to offer allogeneic HSCT to a much larger cohort of patients who could not benefit from transplantation because of lack of matched family donor. Although limited number of patients treated, results of transplant from unrelated matched donors are comparable to those obtained using sibling donors. Graft failure or rejection remains a significant cause of transplant failure in patients with thalassemia making difficult to perform reduced intensity conditioning regimens. Mixed chimerism is a common phenomenon after transplantation and is a risk factor for rejection. Ex-thalassemics still carry the clinical complications acquired during years of transfusion and chelation therapy. Longer follow-up and management of these complications in ex-thalassemics are essential.

Epidemiology and Risk Factors for Corneal Graft Rejection

Objective The aim of this study was to evaluate the frequency and main risk factors for corneal graft rejection. Patients and Methods This retrospective study included 285 eyes in 256 patients who underwent a penetrating keratoplasty (KPT) from January 1995 to December 2004. The minimum follow-up was 12 months to evaluate graft evolution. Except for complications, the follow-up was weekly, then monthly for 6 months, and ultimately quarterly during the first year. Thereafter the follow-up was performed semi-annually. Patients were informed about the functional signs for which they have to urgently consult. Results Immunologic rejection of the corneal graft occurred in 128 KPT in 112 patients (rejection frequency = 41%). The identified main risk factors were new vascularization of the recipient cornea over 2 or more quadrants, corneal opacity due to an infectious origin, posttraumatic corneal opacity or congenital glaucoma, graft diameter >8 mm, and therapeutic KPT. Conclusions Rejection of the corneal graft is the primary cause of KPT failure. One out of 2 graft failures was due to rejection. Two criteria are unanimously recognized as risk factors for rejection: neovascularization of recipient cornea and antecedents of corneal rejection. The rejection must be treated early to not endanger graft success, which imposes a close follow-up for grafted patients.

Rejection Under Alpha Interferon Therapy in Liver Transplant Recipients

Interferon alpha (IFN) is the corner stone drug for the treatment of recurrent hepatitis C (HCV) in liver transplant (LT) recipients. One of its serious potential adverse effects is acute and chronic rejection. The aim of this study was to review our experience using IFN-based therapy, in order to examine the incidence and the risk factors for rejection, and the outcome of patients who developed rejection. Between September 1990 and December 2004, 70 LT recipients were treated. Patients started antiviral treatment 16 (1-137) months after LT. Histological follow-up was available in all patients according to protocol biopsies. Rejection was diagnosed and graded according to Banff classification. Twenty-one percent of patients developed acute rejection (5 mild, 9 moderate and 1 severe) during IFN-based therapy. Patients were treated for 8 (1-15) months prior to rejection. Previous history of acute rejection before IFN therapy and treatment with pegylated-IFN was significantly associated with rejection (p = 0.04 and p = 0.02, respectively). The rejection was successfully treated in 87% of patients. No chronic rejection or graft losses were observed. Acute rejection under IFN-based therapy often occurs in LT recipients, but early diagnosis with protocol biopsies and early treatment can lead to a favorable outcome.

Il-10 Polymorphism and TGF-β Haplotypes Are Associated with Rejection of Graft in Children with Beta Thalassemia Major Undergoing Matched Related Bone Marrow Transplantation (BMT).

Th2 cytokines, IL-10 and TGF-β have immunoregulatory functions that can affect allograft acceptance. We have evaluated the correlation between IL-10 (-1082, -819, -592) and TGF-β codon 10C>T and 25G>C polymorphisms {(haplotype: TT/GG, TC/GG, high production); (haplotype: TC/GC, CC/GG, TT/GC, intermediate production); (haplotype: CC/GC, CC/CC, TT/CC, TC/CC, low production)}and graft rejection in 129 patients with β thalassaemia major who underwent matched related alloBMT. Patients who expired before day 15 (n=9) and for whom DNA samples was unavailable (n=18) were excluded from this study. None of these patients had graft rejection. Of the 102 patients who were evaluated, 73 (72%) patients received conditioning with Bu (16 mg/kg) / Cy (200 mg/kg) with ALG while 29 (28%) patients received Bu (600 mg/m2) / Cy (200 mg/kg) without ALG. All patients received unmanipulated bone marrow and standard cyclosporine / short course methotrexate regimen as prophylaxis against GVHD. Patients who died before day 21 after transplant (n=2) without achieving ANC >500/mm3 were not evaluated for engraftment. 9 out of 102 patients rejected their graft. Apart from the immunogenetic markers, the effect of other risk factors for rejection like recipient and donor age, sex mismatch, conditioning regimen, cell dose and Lucarelli class were also analyzed. Of these, only increasing donor age was found to mildly increase the risk of rejection (RR=1.06; p=0.019; 95% CI-1.01–1.1). Donor TGF-β haplotypes associated with intermediate or low production and IL-10 polymorphism accounting for low production were found to very significantly increase the risk of graft rejection (Table). TGF-β and IL-10 are essential for both development and the effector function of CD4 regulatory T cells which are important for tolerance induction. Therefore, it is possible that genotypes associated with lower production of these cytokines might contribute to increased graft rejection. We have previously reported that rejection in children with β thalassemia major is influenced by pharmacokinetics of busulfan and cyclophosphamide and genes implicated in their metabolism (BMT 2005 36, 839–845). We conclude that rejection of graft in this condition appears to be a multifactorial event affected not only by pharmacogenetics of the drugs used for conditioning but also by various immunogenetic factors.Risk factorsRelative riskP-value95% CITGFβ haplotypesLow + intermediate6.970.0151.4 – 33.6HighReferenceIL-10 -819 TT5.340.0181.3 – 21.4-819 TC + CCReferenceIL-10 -592 AA5.340.0181.3 – 21.4-592 AC + CCReference

Treatment of HCV recurrence: Do the pretransplantation rules apply?

Treatment of HCV recurrence: Do the pretransplantation rules apply?

Suboptimal Busulphan Exposure Is Associated with Mixed Hematopoietic Chimerism, a Risk Factor for Rejection in Bone Marrow Transplantation for Homozygous beta Thalassemia.

Bone marrow transplantation is the only curative treatment modality available for patients with homozygous beta thalassemia. Although the transplant outcome for good-risk patients is uniformly excellent, rejection continues to remain a serious complication with reported incidences ranging from 10–40%. Since mixed hematopoietic chimerism (MC) has been shown to be a risk factor for rejection in homozygous beta thalassemia, we investigated the relationship between MC and busulfan pharmacokinetics (Bu PK). Between May 1999 and April 2004, we retrospectively analyzed 24 consecutive patients with homozygous beta thalassemia transplanted in this center, for whom data on Bu PK was available. The median age was 9.5yr (3–15 yr). Sixteen (67%) patients were Class II, six (25%) Class III, one patient (4%) Class I and one patient (4%) Class II or III as per the Lucarelli classification for transplant outcome. The conditioning regimen consisted of busulfan/cyclophosphamide in 21/24 (88%) and busulfan/cyclophosphamide/ATG in 3/24 (12%) patients. All patients received a standard dose of cyclophosphamide (200mg/kg) but had varying doses of busulfan, ranging from 15 to 29mg/kg (mean 21mg/kg). Nine out of the 24 patients (38%) received the intravenous preparation of busulfan. Cyclosporine and short-course methotrexate were used as graft versus host disease (GVHD) prophylaxis. Bu PK was performed by liquid chromatography mass-spectrometry on frozen plasma samples obtained after doses 1, 5 and 13. Chimerism was assessed after BMT by DNA fingerprinting using a panel of informative markers. Acute GVHD was seen in 13/23 (56%) evaluable patients, 9/13 were grade I & II and 3/13 grade III & IV. Veno-occlusive disease of the liver (VOD) as per the Seattle and Baltimore criteria occurred in 14/24 (58%) and 3/24 (12%) respectively. MC was documented in 5/24 (21%) patients while graft rejection occurred in 2/23 (9%) evaluable patients. Non-rejection mortality was 4% (1/24). Thalassemia-free survival was 88% (21/24) with a median follow up of 31 months. MC significantly predicted for rejection (p=0.04). Analysis of Bu PK showed that patients with MC had significantly lower minimum and steady state busulfan concentrations (Cmin and Css) and faster clearance of the drug (CL/F) when compared to patients with complete chimerism.REJECTION [n=2]NO REJECTION [n=21]MIXED CHIMERISM2 [100%]3 [14%]p = 0.04MIXED CHIMERISM [n=5]COMPLETE CHIMERISM [n=19]Dose 1 Bu PKCmin (ng/ml)201.00±44.21298.16±98.08p <0.05Css (ng/ml)616.2±108.4842.83±252.2p <0.05Cl/F (L/h/kg)0.343±0.0870.260±0.058p <0.05Mean Bu PKCmin (ng/ml)207.6±48.3288.4±86.3p <0.05Cl/F (L/h/kg)0.345±0.0910.289±0.045p <0.05Although the number of patients is small, this study confirms MC to be a risk factor for rejection, and further demonstrates the occurrence of MC post BMT to be associated with low busulfan systemic exposure during conditioning. Individualizing busulfan dosage based on Bu PK may therefore be one strategy to minimize rejection in bone marrow transplantation for homozygous thalassemia.

The challenge of rejection and cardiac allograft vasculopathy.

Since the first human heart transplantation was performed in 1967, the field of heart transplantation has advanced to the point where survival and acceptable quality of life are commonplace. Despite remarkable progress in the clinical management of rejection, rejection continues to limit survival and quality of life in the heart transplant population. This review will discuss the biologic processes involved in hyperacute rejection, acute rejection, and humoral (vascular) rejection. The development of endomyocardial biopsy techniques represented a significant advancement in the diagnosis of cardiac rejection, and endomyocardial biopsy remains the 'gold standard' in the diagnosis of cellular rejection. To date, no noninvasive parameters will diagnose rejection with adequate sensitivity and specificity. Biopsy frequency and immunosuppressive therapies may be tailored to the risk of rejection. Immunosuppression for cardiac transplantation can be divided into three major phases: 1) perioperative immunosuppression; 2) maintenance immunosuppression, and; 3) treatment of rejection. The strategy for treating transplant rejection should be influenced by several variables: 1) Histologic grade of rejection; 2) Evidence of hemodynamic compromise by ejection fraction or right heart catheterization; 3) Severity of previous rejection episodes and types of immunosuppressives used; and 4) Risk factors for rejection, including time after transplantation. Future rejection therapy will involve more sophisticated attempts to alter host responses toward the donor organ in a more specific and selective way. Despite considerable advances in the care of the heart transplant recipient, long-term survival is limited by cardiac allograft vasculopathy. The final section of this chapter will review the pathology, immunopathology, nonimmunologic risk factors, diagnosis, prevention and treatment of allograft vasculopathy.

The use of positive B cell flow cytometry crossmatch in predicting rejection among renal transplant recipients.

We performed retrospective flow cytometry crossmatch (FCXM) on 106 renal graft recipients who were transplanted based on current T cell negative serologic crossmatch. T and B cell FCXMs were performed on current and historical peak reactive post-transplant sera using 1024-channel flow cytometer and the shift in median channel fluorescence (SMCF) over the negative control was calculated. Cut-off values for a positive T and B crossmatch, > 40 and > 80 SMCF, respectively, were determined based on previous retrospective analysis of the data in the context of clinical outcome in our center, and were 1.5 times the standard deviation (SD) above the mean median channel fluorescence (MCF) of normal sera controls. The 1-yr graft survival was 95% for the total group of patients studied, and 87% for the recipients who had a positive T cell FCXM. To focus on the influence of a positive B cell FCXM on the incidence of rejection, primary transplant recipients who had a negative T cell FCXM (n = 81) were studied. Fifteen of 30 (50%) recipients with a positive B cell FCXM experienced at least one rejection episode within the first year. By contrast, only 15 of 51 (29.4%) of patients with a negative B cell FCXM experienced rejection (p = 0.05). The mean B cell SMCF in the group of patients who had no rejections was 45 +/- 59, while that of the group of patients who experienced at least one rejection was 97 +/- 97 (p = 0.012). By comparison, the rejection rate among the retransplant patients was 44.4%, and the mean B cell SMCF in the group with rejection was 94 +/- 75 while it was 5 +/- 7 among retransplant patients who did not have rejection (p = 0.031). Eighty-six percent of sensitized (panel reactivity antibodies (PRA) > 10%) patients who had a B positive/T negative FCXM experienced rejection, compared to 33% (n = 6 out of 16) of the B negative/T negative sensitized patients (p = 0.03). Furthermore, 62% (n = 13 out of 21) of donor-recipient mismatched patients with a B positive/T negative FCXM experienced rejection, compared to 38% (n = 13 out of 35) of patients with T negative/B negative FCXM who were similarly mismatched (p = 0.064). These data demonstrate the value of a positive B cell FCXM for predicting post-transplant rejections particularly when evaluated in the context of prior sensitization and/or DR mismatching. Our results suggest that B cell FCXM may have significant clinical implications, justifying its use in post-transplant management of recipients who have other risk factors of rejection.

Pilocarpine-Associated Allograft Rejection in Postkeratoplasty Patients

Corneal allograft rejection is a major cause of graft failure. Identifying possible risk factors for rejection may improve chances for successful outcome. We report three cases of graft rejection associated with the use of post-operative pilocarpine at different concentrations. Pilocarpine was used to treat persistent epithelial defects or raised intraocular pressure. The patients were managed until their rejection episodes resolved. In each case, graft rejection ensued in a quiet eye after initiating treatment with pilocarpine, without other change in medications. Each graft rejection episode resolved with discontinuation of pilocarpine and administration of prednisolone acetate. We propose that if pilocarpine does indeed diminish corneal allograft immune privilege and enhance graft rejection, the mechanisms may include induced intraocular inflammation and altering of anterior chamber associated immune deviation. This is the first report implicating a topical ophthalmic medication with possible corneal allograft rejection.

Cyclophosphamide Combined With Antithymocyte Globulin in Preparation for Allogeneic Marrow Transplants in Patients With Aplastic Anemia

Graft rejection has been a problem after marrow grafts for patients with aplastic anemia who were conditioned with cyclophosphamide (CY). Rejection lessened when patients were given the marrow donor's peripheral blood buffy-coat cells in addition to the marrow, but this result was achieved at the price of more chronic graft-versus-host disease (GVHD). Results with second transplants suggested that CY alternating with antithymocyte globulin (ATG) was more immunosuppressive than CY alone. Therefore, the current study explored CY and ATG without buffy-coat cell transfusions in 39 patients with aplastic anemia given marrow transplants from HLA-identical family members (siblings in 38 cases, father in 1 case). We hoped both to minimize the risks of graft rejection and of chronic GVHD and to improve survival. Patients were 2 to 52 years of age (median, 24.5); 87% had received previous transfusions, and 41% had therapy with immunosuppressive agents before transplant. They were administered four daily doses of CY (total, 200 mg/kg) alternating with three doses of ATG (total, 90 mg/kg) followed by an HLA-identical marrow graft. Methotrexate and cyclosporine were administered to prevent GVHD. Two patients rejected their grafts (5%), and both were successfully retransplanted. Acute (grade 2 or 3) GVHD occurred in 15% and chronic GVHD in 34% of patients. The actuarial survival rate at 3 years was 92%, which compares favorably to the 72% survival rate in 39 historical patients who were matched with current patients for age and risk factors for rejection and GVHD. CY/ATG is a well-tolerated and effective conditioning program for marrow grafting in aplastic anemia that, when combined with GVHD prevention by methotrexate/cyclosporine, results in excellent survival.

Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia

Graft rejection has been a problem after marrow grafts for patients with aplastic anemia who were conditioned with cyclophosphamide (CY). Rejection lessened when patients were given the marrow donor“s peripheral blood buffy-coat cells in addition to the marrow, but this result was achieved at the price of more chronic graft-versus-host disease (GVHD). Results with second transplants suggested that CY alternating with antithymocyte globulin (ATG) was more immunosuppressive than CY alone. Therefore, the current study explored CY and ATG without buffy-coat cell transfusions in 39 patients with aplastic anemia given marrow transplants from HLA-identical family members (siblings in 38 cases, father in 1 case). We hoped both to minimize the risks of graft rejection and of chronic GVHD and to improve survival. Patients were 2 to 52 years of age (median, 24.5); 87% had received previous transfusions, and 41% had therapy with immunosuppressive agents before transplant. They were administered four daily doses of CY (total, 200 mg/kg) alternating with three doses of ATG (total, 90 mg/kg) followed by an HLA-identical marrow graft. Methotrexate and cyclosporine were administered to prevent GVHD. Two patients rejected their grafts (5%), and both were successfully retransplanted. Acute (grade 2 or 3) GVHD occurred in 15% and chronic GVHD in 34% of patients. The actuarial survival rate at 3 years was 92%, which compares favorably to the 72% survival rate in 39 historical patients who were matched with current patients for age and risk factors for rejection and GVHD. CY/ATG is a well-tolerated and effective conditioning program for marrow grafting in aplastic anemia that, when combined with GVHD prevention by methotrexate/cyclosporine, results in excellent survival.

Cytomegalovirus infection--an etiological factor for rejection? A prospective study in 242 renal transplant patients.

The study aimed at analyzing the role of CMV infection as a risk factor for rejection occurring after CMV infection because of the clinical consequences of the prevention of CMV infection that might lead to the decrease in rejection episodes. Two hundred forty-two consecutive renal transplant patients were prospectively checked for the occurrence of CMV infection. CMV infection was defined virologically by a positive viremia or/and a positive viruria or/and a seroconversion or/and a significant rise of the anti-CMV antibody titers. Viremia, viruria, and serology were performed weekly for the first month and then at day 90, day 180, and every 6 months, and moreover if clinical symptoms related to a viral infection occurred. Rejection episode was defined by a creatininemia rise of 25%, after cyclosporine nephrotoxicity and urological complications had been discarded, and by the response to the antirejection therapy, steroids, or OKT3 in case of steroid-resistant rejection. The outcome factor was rejection episode occurring from day 4 after the diagnosis of CMV infection. A patient undergoing "a rejection episode after CMV infection" could also be exposed to other potential confounding factors that can be considered as risk factors of rejection among our patients. Rejection occurring before CMV infection was the main factor because it was linked both to CMV infection itself and to "rejection after." Thus infected and noninfected patients were randomly paired off. To the noninfected patient of the pair was attributed the date of a fictitious CMV infection that was the date of the CMV infection of the infected member of the pair. Therefore, "rejection after" and "rejection before" were defined in infected and noninfected patients of the pair according to the time of onset of CMV infection of the infected member of the pair. The incidence of CMV infection was 65%, 157 of the 242 patients were infected, and 85 not infected. Thus 85 pairs of infected-noninfected patients were studied. The incidence of "rejection after" the diagnosis of CMV infection was significantly higher in the group of patients with CMV infection: 45% among infected (38/85) versus 10.60% among noninfected (9/85) (P < 0.0001). Among the 85 pairs, 48 pairs were concordant in which patient of the pair evinced the same outcome factor: 43 showed no rejection after, and 5 showed one.(ABSTRACT TRUNCATED AT 400 WORDS)

Hematopoietic engraftment and graft failure after bone marrow transplantation.

This article reviews the complex process of establishing functional long-term hematopoiesis required for successful clinical bone marrow transplantation. The failure to establish sustained hematopoiesis, either primary or secondary graft failure, is defined and multiple etiologic factors involved are discussed. Data from published studies of experimental and clinical BMT, as well as in vitro stem cell biology, were used to elucidate the elements required for establishing functional hematopoiesis. These include pleuripotential hematopoietic stem cells; homing of stem cell to the hematopoietic micro-environment; hematopoietic stroma and secreted cytokines acting synergistically to promote expansion and hematopoietic differentiation of the stem cells; and, in the setting of allogeneic transplantation, immunological tolerance between the host and the graft, without which graft rejection or graft-vs.-host disease may occur. The factors influencing the establishment of functional hematopoiesis and the risks for graft failure vary with the type of transplant performed. In an autologous transplant, damage to the stem cells or to the stromal microenvironment can contribute to prolonged time to engraftment or primary graft failure. In contrast, the hematopoietic stem cells are normal in both syngeneic and allogeneic transplantation. However, in the latter, because of immunological disparity between the host and recipient, there can be either primary or secondary graft failure due to a host-vs.-graft phenomenon, graft rejection. Classic graft rejection is an immunologic phenomenon mediated by residual host immunocompetent cells, either T cells or NK cells, depending on the allogeneic disparity between host and donor. T cell depletion and increased HLA disparity are risk factors for rejection. Numerous strategies have attempted to decrease the risk of rejection; most have focused primarily on increased immunosuppression of the host either with additional radiation, chemotherapy or in vivo anti-T cell serotherapy. Recent attempts have explored preventing rejection by manipulating donor cell composition of the infused graft.

Multicentre trial of ABO-incompatible kidney transplantation

A multicentre study of ABO incompatible kidney transplantation using Biosynsorb was started in Japan in November 1989. A total of 51 cases were registered comprising 23 cases of A incompatibility, 26 cases of B incompatibility and two cases of AB incompatibility. The removal of antibodies (IgG and IgM) was carried out using Biosynsorb in 16 cases, plasmapheresis in four cases and use of both combined in 31 cases. The treatment using Biosynsorb was repeated 3.4 times on average. Serum titres of anti-A (IgG and IgM) antibodies decreased to 4.9 ± 5.0 and 2.7 ± 1.7 and for anti-B titres decreased to 2.8 ± 3.5 and 2.4 ± 3.2. Rejection was found in 33 cases: hyperacute one, accelerated acute five, and acute 27. In two cases rejection was developed concomitantly with a steep elevation in antibody titres. Three patients died, two with functioning grafts. Eight grafts were lost. Patient and graft survivals at 2 years were 94.1% and 84.3%, respectively. From these results it is concluded that: 1. Biosynsorb and plasmapheresis are effective in removing anti-A and anti-B antibodies; 2. graft and patient survivals are similar to those in ABO compatible cases; 3. anti-A and anti-B titres less than 16 are recommended at the time of transplantation; 4. anti-A and anti-B titres higher than 128 may be considered as a risk factor for rejection in the early stages after transplantation.