小肠移植术后内镜引导下移植肠黏膜活检的时机及诊断价值

目的 总结小肠移植术后内镜引导下移植肠黏膜活检的时机及该技术对急性排斥反应和感染的诊断价值.方法 根据免疫抑制方案的不同,将15例小肠移植受者分为3个阶段.1994-1995年为第1阶段(3例),2003-2006年为第2阶段(7例),2007年以后为第3阶段(5例).第3阶段进行计划性内镜引导下移植肠黏膜活检的监测,既术后第3天进行首次内镜引导下移植肠黏膜活检,此后活检的频次在术后第1个月为2次/周,术后第2～3个月为1次/周,术后第4～6个月为1次/2周,术后7个月以后为1次/月,在受者出现排斥反应的临床症状和抗排斥反应治疗期间,也进行内镜引导下移植肠黏膜活检.结果 15例共进行内镜引导下移植肠黏膜活检255次,移植肠腹壁造口肉眼直视下取材活检21次.以上276份样本中,诊断排斥反应共51份(18.5%),其中诊断不确定急性排斥反应至轻度排斥反应32份(11.6%)、中度排斥反应9份(3.3%)、重度排斥反应10份(3.6%),巨细胞病毒(CMV)感染2份(0.7%),细菌感染2份(0.7%).15例共发生病理证实并需l临床治疗的排斥反应20次,其中不确定急性排斥反应至轻度排斥反应11次、中度5次、重度4次,发生细菌性和CMV肠炎各1次.结论 内镜引导下移植肠黏膜活检及其病理学检查是小肠移植术后诊断排斥反应和感染的重要手段,有计划的进行该检查对排斥反应有术后监测、早期诊断、鉴别诊断和指导治疗的价值.     

Clinical response and temporal patterns of acute cellular rejection: relationship to chronic transplant nephropathy

Abstract The association between acute cellular rejection (ACR) and the development of chronic rejection has been the subject of much debate. Studies have suggested that the two phenomena may be linked, or, conversely that there may be no association at all. In order to clarify this relationship the outcome of 284 renal allografts were examined. The transplants were all performed at a single institution between April 1989 and December 1991, allowing a minimum follow up of 5 years. ACR was classified into three clinical response groups: (1) fully responsive to therapy (type 1 ACR), (2) partially responsive (type 2) and (3) ACR requiring treatment with ATG or OKT3 (type 3). Acute and chronic rejection were determined by histological (Banff) criteria. Chronic transplant nephropathy (CTN) occurred significantly more frequently in those with late ACR after day 60 than in those who had early rejection (53.5% versus 17.3%, respectively, P < 0.00001). Acute rejection that was fully responsive to therapy (type 1) had no association with CTN, but partially responsive rejection and rejection requiring seconD-line treatment were both significantly associated with CTN ( P < 0.0001 and P < 0.001, respectively). This study suggests that it is the clinical behaviour and response to treatment of ACR that is paramount in determining the onset of chronic rejection, and not the mere presence or absence of the clinical phenomenon.     

Incidence of graft rejection in small bowel transplanted pigs after immunosuppression withdrawal

As intestinal grafts require heavy immunosuppression, there are no reports of immunosuppression withdrawal after clinical small bowel transplantation. In this large-animal study, we investigated the occurrence of graft rejection in intestinal-transplanted pigs after withdrawal. Large-White unrelated piglets were transplanted and divided in three groups: group 1 (n = 5), intestinal transplantation (ITx) with no immunosuppression; group 2 (n = 7), Itx and 60 days of treatment with tacrolimus and mycophenolate mofetil; group 3 (n = 5), Itx and donor bone marrow infusion (DBMi) and 60 days of treatment with tacrolimus and mycophenolate mofetil. Follow-up time after withdrawal was 120 days. Group 1 pigs died of graft acute cellular rejection (ACR) after a median of 11 days. In group 2, two pigs died of ACR-related infection and another two of ACR within 90 days. The remaining three animals (43%) were sacrificed at day 180, and their grafts showed no signs of ACR. In group 3, two pigs died of ACR-related infection and one of graft versus host disease within 80 days; at day 180 the two surviving animals showed signs of chronic rejection in the allograft. This study demonstrates that total withdrawal after ITx is followed by sudden and lethal ACR (or ACR-related infection) in more than 50% of the recipients. When a tolerance-inducing strategy as DBMi is applied, lethal graft versus host disease may also occur. In group 3, the intestinal allograft, to which the recipients were partially tolerant, developed chronic rejection that was probably associated with a decline with time of donor-leukocytes chimerism, as recently demonstrated in rats.     

Incidence, histological pattern, and clinical outcome of rejection episodes occurring in the late posttransplant period

We prospectively monitored clinical data and renal function at minimum monthly intervals in 220 patients who received kidney transplants at our institution between January 1, 1976 and December 31, 1982. All had functioning allografts for a year or longer. During a mean follow-up of 54.7 (14-96) months, 61 patients (28%) developed 74 late rejections, of which 23 (31%) were symptomatic and 51 (69%) were asymptomatic. Twenty-one rejections in 15 patients were diagnosed on clinical grounds (group A) and 53 rejections in 46 patients were diagnosed by renal histology (group B). Of this latter group, 26 biopsy specimens showed histological evidence of acute cellular rejection (ACR), 17 showed acute cellular rejection and chronic rejection (ACR + CR), and 10 showed chronic rejection (CR) only. Of the 26 ACRs, 10 (39%) responded fully to antirejection therapy, 14 (54%) responded partially, and 2 (7%) did not respond. Of the 17 ACR + CRs, the response to therapy was complete in 5 (29%), partial in 8 (47%), and none in 4 (24%). Of the 10 CRs, therapeutic response was none in 7 (70%) and partial in 3 (30%). During the period of our observation, 96% of patients with ACR had preservation of graft function (14% dead, 82% alive) and 4% had returned to dialysis. Among the patients with ACR + CR, 87% had preserved graft function (13% dead, 74% alive) and 13% returned to dialysis. Of the patients with CR, only 33% had preserved renal function (11% dead, 22% alive) and 67% returned to dialysis. Our observations indicate that (1) routine monitoring of renal function at minimum monthly intervals is essential to diagnose and treat these late rejections, which are often asymptomatic; (2) renal histology provides valuable diagnostic and prognostic information in the management of patients with late allograft rejection.     

Subclinical rejection and borderline changes in early protocol biopsy specimens after renal transplantation

BACKGROUND: To determine the significance of early subclinical rejection, we reviewed protocol biopsies performed on days 7 and 28 during a 4-year period. METHODS: The study was confined to patients (n=115) with stable graft function at the time of biopsy; 76 adequate biopsies at day 7 and 79 at day 28 were performed. RESULTS: At day 7, 10 biopsy specimens (13%) showed acute rejection (AR) and 9 (12%) showed borderline changes. Eight of 10 patients with AR received immediate pulsed methylprednisolone (MP) and one untreated patient developed clinical rejection (CR) within 3 days. Four of nine patients whose biopsy specimens showed borderline changes received MP and three untreated patients developed CR within 3 days. At day 28, six biopsy specimens (8%) showed AR and 13 (16%) showed borderline changes. Three of six patients with AR received immediate pulsed MP and one untreated patient developed CR within 6 days. Ten of 13 patients with borderline changes had been treated for AR in the previous 3 weeks. Twelve patients with subclinical rejection or borderline changes at day 28 were never subsequently treated for rejection, and outcome at 6 years did not differ from those patients whose biopsy specimens showed no rejection. CONCLUSIONS: Compared with some units, the incidence of subclinical rejection is low. The majority of untreated subclinical borderline changes and rejection at day 7 behaved as early clinical rejections and at day 28 as resolving clinical rejections. Untreated subclinical rejection or borderline change at day 28 was not an adverse prognostic factor for long-term outcome.     

Acute cellular rejection in liver transplant recipients under cyclosporine immunosuppression: predictive factors of response to antirejection therapy

BACKGROUND: Predictive factors of response to antirejection therapy in acute cellular rejection (ACR) in liver transplantation are not well established. METHODS: To investigate the possible existence of these factors, we reviewed 111 consecutive episodes of ACR fulfilling the following criteria: histologically confirmed ACR; cyclosporine-based immunosuppression; initial antirejection treatment with high-dose steroid boluses; minimum follow-up of 2 weeks after treatment; and no other graft complication interfering with evaluation of therapeutic response. ACR episodes not responding to initial steroid therapy were given additional treatment (OKT3 and/or repeated steroid boluses). We analyzed the association of the response to the antirejection treatment with different clinical, laboratory, histological, and donor-recipient compatibility variables at two times: after the initial antirejection therapy, and after all the antirejection therapy administered. RESULTS: Eighty episodes of ACR (72%) resolved after the initial therapy with high-dose steroid boluses, and another 18 (16%), initially steroid-resistant, resolved with additional antirejection treatment. Thirteen episodes (12%) were refractory to all antirejection treatment administered. Variables with independent predictive value of nonresponse to initial therapy with steroid boluses were late-onset ACR (>2 months after transplantation), high serum bilirubin and alanine aminotransferase, low blood cyclosporine concentration in the week before antirejection treatment, and severe histological endothelialitis. Late-onset ACR and high serum bilirubin were also independent predictors of refractoriness to all the treatment administered. CONCLUSIONS: Response to antirejection treatment in ACR in liver transplantation can be predicted by several clinical and laboratory data. ACR episodes with factors predictive of therapeutic unresponsiveness could benefit from more aggressive antirejection treatment.     

Early outcome of different steroid-free regimens in small bowel transplantation: a large-animal study

The intestine is a highly immunogenic organ that requires heavy immunosuppression (IS); therefore corticosteroid withdrawal after clinical small bowel transplantation (SBT) has not been standardized. In this study, we compared different immunosuppressive regimens (none with steroid or induction treatment) in a SBT pig model. Large White unrelated piglets were transplanted and divided into four groups as follow: group 1 (n = 3): no IS; group 2 (n = 10): IS with tacrolimus only; group 3 (n = 10): IS with tacrolimus and mycophenolate mofetil; group 4 (n = 5): IS with tacrolimus and rapamycin. Follow-up time was 30 days. All IS drugs were given orally; tacrolimus whole blood levels ranged between 5 and 15 ng/mL in all groups except for group 2 whose tacrolimus whole blood levels ranged between 15 and 25 ng/mL. Group 1 pigs died of graft acute rejection (ACR) after a median of 12 days. Overall survival in groups 2, 3, and 4 at day 30 was 40%, 80%, and 60%, respectively. Biochemical parameters, including glycemia and cholesterol, were into the normal range with no significant differences between groups. At the end of the study, one animal in group 2 and another one in group 4 showed histological signs of moderate to severe ACR. The incidence of infection was higher in group 2 (2.1 episodes/pig) compared to group 3 (1.25) and group 4 (1.6). This large-animal study demonstrates that tacrolimus-based IS without corticosteroids allows, in the early postoperative period (30 days) after SBT, good survival rates without an increased risk in the incidence of rejection.     

Lower Platelet Count Following Rabbit Antithymocyte Globulin Induction Is Associated With Less Acute Cellular Rejection in Heart Transplant Recipients

BackgroundUnlike lymphodepletion, a decrease in platelet count following induction immunosuppressive therapy with polyclonal rabbit antithymocyte globulin (rATG) is deemed as an adverse event. However, this phenomenon may represent a particular rATG antirejection mechanism.MethodsThis retrospective single-center study included 156 patients who received a heart transplant (HTx) between 2010 and 2018. All patients received rATG induction therapy for 5 days. Absolute lymphocyte count (ALC) and platelet counts were assessed on days 0, 7, and 14 following HTx. The primary outcome of the study was the first occurrence of acute cellular rejection (ACR) defined as grade ≥ 1B within 24 months after HTx.ResultsBoth ALC and platelet counts decreased rapidly after induction. During the 24-month follow-up period, 17% of patients had ACR. Patients with ACR had significantly higher platelet count on day 7 (145 vs 104, P < .001) and higher ALC on day 14 (162 vs 130, P = .035) than those without rejection. Patients in the highest platelet count quartile showed more ACR (50% in quartile 4 vs 0% in quartile 1, P = .006) as well as a higher cumulative total rejection score. Univariate analysis showed that ACR was associated with platelet count on day 7, recipient age, and pretransplant cytomegalovirus IgG serology. In multivariable regression analysis, platelet count on day 7 was the most accurate predictor of ACR.ConclusionsLower platelet count after induction with rATG is associated with less ACR. This suggests platelet involvement in antirejection mechanisms of rATG and a possible rationale for targeting platelets in future immunosuppressive strategies.     

Prevention of renal allograft rejection in primates by blocking the B7/CD28 pathway.

BACKGROUND: There is accumulating evidence that blockade of the costimulatory pathways offers a valid approach for immune suppression after solid organ transplantation. In this study, the efficacy of anti-CD80 and anti-CD86 monoclonal antibodies (mAbs) in combination with cyclosporine (CsA) to prevent renal allograft rejection was tested in non-human primates. METHODS: Rhesus monkeys were transplanted with a partly major histocompatibility complex-matched kidney on day 0. Anti-CD80 and anti-CD86 mAbs were administered intravenously daily for 14 days starting at day - 1. CsA was given intramuscularly for 35 days starting just after transplantation. The kidney function was monitored by determining serum creatinine levels. RESULTS: The combination of anti-CD80 and anti-CD86 mAbs completely abrogated the mixed lymphocyte reaction. Untreated rhesus monkeys rejected the kidney allograft in 5-7 days. Treatment with anti-CD80 plus anti-CD86 mAbs resulted in a significantly prolonged graft survival of 28+ 7 days (P=0.025). There were no clinical signs of side effects or rejection during treatment. Kidney graft rejection started after the antibody therapy was stopped. The anti-mouse antibody response was delayed from day 10 to 30 after the first injection. No difference in graft survival was observed between animals treated with CsA alone or in combination with anti-CD80 and anti-CD86 mAbs. However, treatment with anti-CD80 and anti-CD86 mAbs reduced development of vascular rejection. CONCLUSIONS: In combination, anti-CD80 and antiCD86 mAbs abrogate T-cell proliferation in vitro, delay the anti-mouse antibody response in vivo, and prevent graft rejection and development of graft vascular disease in a preclinical vascularized transplant model in non-human primates.     

Beneficial effect of plasmapheresis and intravenous immunoglobulin on renal allograft survival of patients with acute humoral rejection

BACKGROUND: Acute humoral rejection (AHR) has been associated with enhanced graft loss. Our study compared the renal allograft survival of patients with AHR treated with plasmapheresis (PP) and intravenous immunoglobulin (IVIG) with allograft survival in patients with acute cellular rejection (ACR). METHODS: We retrospectively analyzed all kidney transplants performed at our institution between January 1999 and August 2001 (n=286). Recipients were classified into three groups according to biopsy reports: AHR, ACR, or no rejection. The ACR group was further divided into early and late rejection (<90 and >90 days posttransplant, respectively). RESULTS: After a mean follow-up of 569+/-19 days, the incidence of AHR was 5.6% (n=16). Recipient presensitization, delayed graft function, early rejection, and higher creatinine at diagnosis were characteristic of AHR. Most AHR patients (14/16) were treated with PP and IVIG. One patient received only IVIG, whereas another received only PP. All AHR patients were given steroid pulses, but only four received antilymphocyte therapy because of concomitant severe ACR. The ACR group comprised 43 patients (15%). One patient with mild rejection received no therapy, 20 improved with steroids alone, and 22 required additional antilymphocyte therapy. One-year graft survival by Kaplan Meier analysis was 81% and 84% in the AHR and ACR groups, respectively (P=NS). Outcomes remained similar when AHR patients were compared with those with early ACR. CONCLUSIONS: We conclude that AHR, when diagnosed early and treated aggressively with PP and IVIG, carries a short-term prognosis that is similar to ACR.     

Anti-TNF-alpha therapy for acute rejection in intestinal transplantation

INTRODUCTION: We present our experience with infliximab rescue therapy for steroid- and OKT3-resistant rejection after intestinal transplantation (ITx). METHODS: Twelve ITx and one multivisceral transplant recipients were immunosuppressed with tacrolimus, rapamycin, daclizumab, steroids (n = 10) or tacrolimus, campath, and steroids (n = 3). RESULTS: In two patients, severe acute rejection did not resolve despite steroid bolus therapy plus 5 to 10 days of OKT3 treatment. Signs of moderate rejection persisted in the distal portions of the grafts. Treatment with infliximab, a chimeric anti-TNF-alpha antibody (four infusions of 3 mg/kg body weight), induced a complete remission of histological and clinical signs of rejection. Two further patients with steroid-resistant rejection received two courses of infliximab (3 mg/kg body weight) as antirejection therapy. All rejection episodes resolved completely. CONCLUSIONS: Infliximab effectively treats steroid and OKT3 resistant acute rejection episodes of intestinal transplantations.     

Renal allograft immunosuppression: II. A randomized trial of withdrawal of one drug in triple drug immunosuppression

Abstract. A prospective randomized study was conducted to evaluate the impact of four different conversion protocols on graft outcome in long-term follow-up. Between January 1986 and May 1987, 128 patients with first cadaveric kidney allografts were randomized at the time of transplantation to four treatment groups of 32 patients each, to be assigned 10 weeks post-transplantation. During the first 10 weeks, all patients received triple therapy with low-dose azathioprine (Aza), cyclosporin (CyA), and methylprednisolone (MP). After 10 weeks, one group continued with triple therapy (group A) while the three other groups received different combinations of two drugs, namely, Aza and CyA (group B), Aza and MP (group C), or CyA and MP (group D). Withdrawal of MP (group B) or especially of CyA (group C) was associated with 4/29 (14%) and 10/28 (36%) acute rejection episodes, respectively, for 60 days after conversion. All rejections were mild and reversible. There were no rejections after Aza withdrawal or in the group that continued on triple therapy during the corresponding time period. The most common reason for dropping out after withdrawal, for those patients who could not continue on the originally randomized medication, was azathioprine intolerance (n= 12). Five patients were switched back to triple therapy after CyA withdrawal due to rejection. Steroid intolerance was rare and CyA in low doses was very well tolerated. At 1 year there were no statistically significant differences in graft survival between groups A, B, C, and D-81 %, 88%, 88%, and 88%, respectively-or in patient survival-88%, 88%, 88%, and 97%, respectively. For those patients continuing with the originally randomized treatment protocol, there were no differences in patient or graft survival either, the means being 91% and 89%, respectively. The most common cause of death after withdrawal was cardiovascular in nature, and there were no more fatal infections under triple drug treatment than with double drug regimens. There were no statistically significant differences in mean serum creatinine values at 1 year. The median serum creatinine values for groups A, B, C, and D were 112, 132, 133, and 133 μmol/l, respectively. At 1 year the mean CyA dose in the groups that continued with CyA was 3. 5–4. 2 mg/kg per day and CyA concentrations were equal.     

Presence of CD163+ macrophages in DCD kidneys with high DGF reduces the risk for acute cellular rejection in 6 months after kidney transplantation

Acute cellular rejection (ACR) occurs in 10% of renal allograft recipients and is characterized by leukocyte infiltration as observed in needle biopsies. ACR onset is subject to several risk factors, including delayed graft function (DGF). As the impact of DGF on the etiology of ACR remains unclear, this study analyzed the association between presence of leukocyte subsets and ACR onset, in DCD kidney biopsies with extensive DGF following transplantation. Immunohistochemical analysis of protocol biopsies taken 10 days after kidney transplantation revealed that patients with high levels of renal CD163⁺ macrophages have a decreased risk (OR = 0.021, P = 0.008) for ACR in the first 6 months after transplantation. In pre-transplant biopsies of a comparable DCD cohort, with >80% DGF, presence of donor CD163+ macrophages showed no effect on ACR risk. Therefore, leukocyte infiltrate present during the inflammatory response at the time of DGF may contain anti-inflammatory macrophages that exert a protective effect against ACR development.     

Diagnosis of tubular injury in renal transplant patients by a urinary assay for a proximal tubular antigen, the adenosine-deaminase-binding protein

Two murine monoclonal antibodies (URO-4 and URO-4a)--which detect different epitopes of a proximal tubular cell glycoprotein antigen, the adenosine-deaminase-binding protein (ABP)--have been formatted into a sandwich enzyme immunoassay for detection of ABP in the urine. Serial urine samples from 34 renal transplant patients during the first six months posttransplant were analyzed to determine the correlation of this test with clinical rejection and cyclosporin (CsA) nephrotoxicity. In 29/29 acute rejection episodes the ABP level was elevated, beginning 1-7 days prior to treatment of rejection. Eighteen patients were treated for rejection with courses of OKT3 or antithymocyte globulin: 0/6 whose ABP level fell to normal during therapy had rerejection; 10/12 whose ABP level remained elevated had rerejection within 7 days of therapy completion. Of 15 patients treated with CsA, 7 had no rejection or drug toxicity; all 7 had normal ABP levels. The remaining 8 had CsA nephrotoxicity, all in association with elevated ABP levels that rapidly fell to normal with decreased CsA dose. An additional 7 patients with creatinine elevations more than 6 months posttransplant were studied: 5 had chronic vascular changes on biopsy, no response to increased immunosuppression, and normal ABP levels; 2 had a cellular infiltrate on biopsy, response to increased immunosuppression, and elevated ABP levels. We conclude that the urinary ABP assay provides information useful in the management of renal transplant patients with acute and chronic rejection and CsA toxicity.     

Randomized prospective trial of OKT3 for early prophylaxis of rejection after liver transplantation

A group of 52 liver transplant patients was prospectively randomized to receive prophylactic immunosuppressive therapy consisting of either Orthoclone OKT3 for 14 days, azathioprine, and steroids (25 patients); or cyclosporine, azathioprine, and steroids (27 patients). The groups were similarly matched for age, diagnosis, and Child's classification. The patients were studied to determine the effect of these two regimens on the incidence of rejection, infection, renal dysfunction, and mortality. Seven rejection episodes, as determined by clinical and histological criteria, occurred in seven of 25 patients (28%) receiving OKT3 compared with 18 episodes in 27 patients (67%) receiving cyclosporine during the first 14 days after transplantation (P less than 0.02). In 20% of the OKT3 patients, CD3+ levels of greater than 10% developed during therapy, and 16% of the patients developed anti-OKT3 antibodies during OKT3 treatment. Five patients were retreated with OKT3 for steroid-resistant acute rejection episodes; all had resolution of the rejection episode. Infectious complications were similar in each group. Renal function, as measured by serum creatinine, was significantly better with OKT3 than with cyclosporine (P less than 0.003) at 14 days. We conclude that prophylactic OKT3 is effective in reducing the number of early rejection episodes after liver transplantation; after 14 days the incidence of rejection is similar; reuse of OKT3 has been successful in liver transplant patients; infectious complications are similar between OKT3 and cyclosporine; and OKT3 preserves renal function better than cyclosporine and is thus indicated in patients with compromised preoperative renal function.     

Severe tubulopathy and kidney graft rupture after coadministration of mannitol and ciclosporin.

Spontaneous allograft rupture after kidney transplantation is a rare complication usually due to an acute rejection of the interstitial type. In a 32-year-old man kidney transplantation was performed under immunosuppression with prednisolone and ciclosporin (CS). The dose of CS was 5 mg/kg body weight intravenously for the first 24 h, on the 2nd day 10 mg/kg/day orally, with gradually decreasing doses thereafter. The patient remained oliguric in the postoperative period and received additionally 600 ml mannitol solution intravenously for osmodiuresis within a period of 6 days. On the 8th postoperative day, 48 h after the last intravenous infusion of mannitol, spontaneous renal rupture occurred. The CS concentrations in the blood during the days before the rupture were within the upper normal range for effective immunosuppression (300-600 ng/ml). Intraoperatively the kidney appeared enlarged due to edematous swelling of the graft, but it showed no signs of rejection. The histological finding was a toxic tubulopathy with extensive isometric vacuolization and peritubular congestion, a known side effect of both of CS and of mannitol. The rupture was successfully repaired. Thirty-four days after the transplantation diuresis increased and hemodialysis therapy could be discontinued. In a second biopsy of the kidney the signs of toxic tubulopathy with isometric vacuolization were reduced. On the following days the serum creatinine dropped below 160 mumol/l. It can be assumed that the combination of CS therapy and administration of massive and continued doses of mannitol in an oliguric patient with allograft kidney may potentiate severe tubulopathy with concomitant edematous swelling of the graft. This can result in an increasing danger of spontaneous renal rupture.     

Predicting factors of long-term results of OKT3 therapy for steroid resistant acute rejection following cadaveric renal transplantation

In this retrospective study, we evaluated the histological and biological predictors of long-term response of renal transplant (RT) patients treated with orthoclone OKT3 for steroid resistant acute rejection (AR). Seventy-three patients, aged 37 +/- 12 years, were included in this study between March 1987 and December 1996. All the patients but one had received sequential quadruple immunosuppression (polyclonal antilymphocyte globulins; steroids; azathioprine, and cyclosporin A). OKT3 (5 mg/day for 10 days) was administered for biopsy-proven steroid resistant AR i.e., after 3 consecutive pulses of methylprednisolone (10 mg/kg each). This was the first AR in 46 cases, the second AR in 22 cases and the third AR in 4 cases. Renal histology (Banff) showed borderline (BL) changes in 18 patients, grade I AR in 28 patients; grade II AR in 22 patients, and grade III AR in 5 patients. When treatment with OKT3 commenced (107 +/- 18 days post-transplantation) the mean serum creatinine (SCr) level was 325 +/- 195 micromol/l; this had decreased to 191 +/- 106 micromol/l by the end of OKT3 therapy. The immediate response to OKT3 therapy i. e., within the first month, was not dependent on the histological score. Twenty-six patients (35%) subsequently experienced at least one more AR episode of whom 4 were retreated with OKT3. The overall patient's survival was 94.5% at last follow-up. The overall cumulative graft survival was 64.5% at 2 years, 52.5% at 5 years, and 40.5% at 8 years. The graft survival (5 years) tended to depend on the initial histological score, i.e. BL 30%; grade I 66%; grades II and III 55.5% (p = 0.08). In a multiple logistic regression analysis we tried to identify independent factors that would predict that a graft would still be functioning at least 2 years after OKT3 therapy. We therefore analyzed the following parameters: donor and recipient's age; gender; cold ischemia time; HLA matching; panel reactive antibodies (PRA) prior to grafting; previous transplantation(s); total number of AR episodes; the time of onset of the AR treated by OKT3 compared to the other AR; the time of onset of the AR treated by OKT3; SCr levels at days 0, 10 and 30 after OKT3 therapy; histological score (Banff) i.e., the magnitude of AR and the presence or absence of chronic lesions. The only independent factors which would predict that a graft was still functioning 2 years after OKT3 therapy were: PRA <25% (Odds ratio (OR) 7.68 (1.15-51.3); p = 0.035); a grade I AR (OR 10.52 (1.18-93. 5); p = 0.035); SCr level 1 month after OKT3 therapy (OR 0.935 (0. 87-1.002); p = 0.05). HLA matching and the presence of histological chronic lesions were nearly significant (p = 0.06 and 0.09 respectively). In conclusion, this retrospective study shows that independent predictors of the long-term response to OKT3 therapy for AR in RT patients are the magnitude of pre-transplant PRA, the histological score, and the SCr level one month after OKT3 therapy. Copyright Copyright 1999 S. Karger AG, Basel     

Hepatocellular MxA protein expression supports the differentiation of recurrent hepatitis C disease from acute cellular rejection after liver transplantation

MacQuillan GC, de Boer WB, Allan JE, Platten MA, Reed WD, Jeffrey GP. Hepatocellular MxA protein expression supports the differentiation of recurrent hepatitis C disease from acute cellular rejection after liver transplantation.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01068.x
© 2009 John Wiley & Sons A/S. Abstract: Differentiation of recurrent hepatitis C virus (HCV) disease from acute cellular rejection (ACR) following liver transplantation can be difficult. Previously, we have found that MxA protein, a specific and sensitive marker for type 1 interferon production, is strongly expressed in chronic HCV disease. Here, we investigate MxA expression as a marker for recurrent HCV disease in the livers of 14 adult HCV patients who underwent liver transplantation. Serial liver biopsies available for 12 of these patients were stained for MxA protein and scored using a semi‐quantitative approach. Hepatocellular MxA protein levels were significantly up‐regulated (p = 0.025) in recurrent HCV disease in comparison to ACR. In biopsies that showed histological changes consistent with recurrent HCV disease, strong hepatocellular MxA staining was present in 14/18 (78%). In the liver biopsies with histological evidence of ACR, strong MxA hepatocellular staining was present in only three of 10 (30%). Thus, assessment of hepatocellular MxA protein expression can contribute to the differential diagnosis of ACR and recurrent HCV disease following liver transplantation. In conclusion, analysis of intrahepatic MxA levels has the potential to reduce the inappropriate use with high‐dose pulsing of steroids post‐operatively.     

Isolated v‐lesion in kidney transplant recipients: Characteristics,association with DSA,and histological follow‐up

Isolated v‐lesion (IvL) represents a rare and challenging situation in renal allograft biopsies because it is unknown whether IvL truly represents rejection, antibody‐ or T cell–mediated, or not. This multicentric retrospective study describes the clinicopathological features of IvL with an emphasis on the donor‐specific antibody (DSA) status, histological follow‐up, and graft survival. Inclusion criteria were the presence of v‐lesion with minimal interstitial (i ≤ 1) and microvascular inflammation (g + ptc≤1). C4d‐positive biopsies were excluded. We retrospectively found 33 IvL biopsies in 33 patients, mainly performed in the early posttransplantation period (median time 27 days) and clinically indicated in 66.7%. A minority of recipients (5/33, 15.2%) had DSA at the time of biopsy. IvL was treated by anti‐rejection therapy in 21 cases (63.6%), whereas 12 (36.4%) were untreated. Seventy percent of untreated patients and 66% of treated patients showed favorable histological evolution on subsequent biopsy. Kidney graft survival in IvL was significantly higher than in a matched cohort of antibody‐mediated rejection with arteritis. In conclusion, IvL is not primarily antibody‐mediated and may show a favorable evolution. The heterogeneity of IvL pathophysiology on early biopsies should prompt DSA testing as well as close clinical and histological follow‐up in all patients with IvL.