Graft Rejection Episodes Research Articles

Comparison of Induction Based on Continuous vs Discontinuous Administration of Antithymocyte Globulins in Renal Transplant Patients: Efficacy and Long-Term Safety

This retrospective study sought to compare two modes of administration of antithymocyte globulin (RATG) after renal transplantation. Methods Before 1993, group I patients ( n = 93) received fixed doses of RATG (1 mg/kg per day) for 8 consecutive days. Thereafter, RATG was either continued at the same dose for 15 days, in cases of delayed graft function, or was infused every other day at the same dose until serum creatinine level became <150 μmol/L. After 1993, group II patients ( n = 66) received RATG at full dose (1 mg/kg per day) during the first 3 days and thereafter the doses were adjusted to target a CD2 T-cell count <50/mm 3. Both groups received steroids, azathioprine, and cyclosporine. The mean follow-up after transplantation was 117 ± 31 months in group I and 93 ± 19 months in group II. Results The RATG cumulative dose and consequently cost were significantly higher among group I than group II patients. Long-term patient and graft survival were similar in both groups. The rate of acute graft-rejection episodes was significantly higher among group I than group II patients. At 7 years posttransplantation, the serum creatinine level and creatinine clearance were similar in the two groups. The rate of cytomegalovirus infection, as well as the cumulative incidence of severe infections and cancers were also similar in both groups. Among the cancers, skin neoplasms represented 30% in group I and 26% in group II ( P = ns). Conclusion Adjusting RATG doses according to the CD2 lymphocyte count is safe, and a less expensive than using full doses.

Mucociliary clearance following lung transplantation is impaired and improves with acute albuterol inhalation

complications in lung transplantation (LTx). We investigated prospectively the occurrence of posttransplant NI in patients on the ICU following LTx. From Jan 2002 to Dec 2003, NIs were determined according to modified CDC criteria for NI in 157 consecutive transplant recipients (119 Double-LTx, 16 single-LTx, 15 Heart-LTx, 6 Combined-LTx (liver or kidney)). 11 were redo-LTx (7%). Primary endpoints included NIs and 30-day-mortality. 100 out of 157 patients did not develop any infection (64%). A total of 91 NIs (incidence of NIs 60.5%) were recorded in the remaining 57 pts (37 pneumonia (23.6%), 19 primary sepsis (12.1%), 13 wound infections (8.3%), 17 urinary tract infections (10.8%), 5 other infections (3.1%) . 14 acute graft rejection episodes (AGR) (8.9%) occurred and led to a NI / AGR ratio of 6.5 in total and 2.6 for pneumonia, respectively. Risk factor analysis revealed AGR (OR 4.9, CI95% 1.4–16.9, p 0.01) and postoperative bleeding complications (OR 4.5, CI95% 1.2–16., p 0.02) as significant risk factors for NIs. The risk for 30-day-mortality was increased 7-fold by NIs (OR 7.5, CI95% 1.7–33, p 0.01). Surprisingly, no relevant risk factors for 30-day-mortality were redo LTx, underlying diseases, type of LTx (DLTx, SLTx or HLTx), AGR or bacterial donor organ contamination. Surveillance of NIs and AGRs in LTx recipients revealed that currently the probability for developing a NI is 6 fold higher than for AGR. Although almost two-third of all lung recipients remain free from infection despite immunosuppression after LTx, NI remains a major risk factor for 30-day-mortality. Therefore, further efforts in infection prevention are required for improving survival and life quality in clinical lung transplantation.

Penetrating keratoplasty for macular corneal dystrophy

To determine the prognosis of penetrating keratoplasty (PK) for macular corneal dystrophy (MCD). Single-center, retrospective, interventional, noncomparative case series. One hundred forty-one patients (229 eyes) with MCD. Retrospective review of the medical record of every patient who underwent primary PK for histopathologically confirmed MCD at the King Khaled Eye Specialist Hospital between January 1, 1983 and December 31, 2002 and for whom at least 12 months of follow-up is available. Visual acuity (VA), graft survival, and postoperative complications. After a mean follow-up period of 5.9+/-3.8 years (range, 1-17), the mean best-corrected VA was 20/50. At the most recent visit, 206 (90.0%) grafts were clear, and 23 (10.0%) had failed. Probabilities of graft survival were 98.1% at 1 year, 89.8% at 5 years, 82.1% at 10 years, and 74.1% at 15 years. There was a statistically significant increased likelihood of graft failure if the patient was older than 40 years at the time of surgery (P<0.00003). The differences in graft failure between patients older than 40 and those younger were not attributable to statistically significant differences in duration of follow-up, donor age, or donor endothelial cell counts. Corneal endothelial rejection episodes occurred in 47 (20.0%) grafts, but resulted in irreversible graft failure in only 8 (3.5%) eyes. Eighteen (27.3%) of 66 eyes with a recipient size of > or =7.5 mm developed a graft rejection episode, compared with 27 (16.6%) of 163 eyes with a recipient size of <7.5 mm (P = 0.04). Microbial keratitis occurred in 14 (6.1%) grafts and was more likely to occur in patients over 40 (14.0% vs. 3.0%, P = 0.01). Clinically significant recurrence was observed in 12 (5.2%) grafts, after a mean interval of 84+/-48.2 months, and was directly related to patient age (P = 0.04) and inversely related to donor graft size (P = 0.04). Good visual results and excellent graft survival can be achieved after PK for MCD. The risk of graft failure is higher in patients older than 40 years.

Funktionelle Ergebnisse der perforierenden Keratoplastik bei Pseudoexfoliationssyndrom (PEX)-Keratopathie

Keratopathy in pseudoexfoliation syndrome (PEX-keratopathy) is a particular form of corneal endothelial decompensation, which requires a penetrating keratoplasty (PK) for visual rehabilitation at advanced states. The aim of this study was to evaluate the functional outcome and the development of intraocular pressure (IOP) after PK in patients with PEX-keratopathy depending on the presence of pre-existing glaucoma. This retrospective study included 21 eyes of 21 patients (age 78.6 +/- 7.5 years) with a mean postoperative follow-up of 1.8 +/- 2.2 (median 2) years. The diagnosis of PEX-keratopathy was confirmed clinically as well as by electron microscopy. The recipient and donor trephinations were performed from the epithelial side using an 193 nm excimer laser (n = 11) or mechanically (n = 10). An iridotomy was performed routinely during PK. The postoperative treatment with topical steroid was standardized. Preoperatively, a secondary open-angle glaucoma (SOAG) with optic nerve damage was diagnosed in 11 patients (52 %). Topical antiglaucomatous treatment was needed in 81 % of patients with SOAG. Six weeks postoperatively, patients with SOAG showed a higher prevalence of increased intraocular pressure (IOP) and/or antiglaucomatous treatment compared to patients without SOAG (45 % vs. 20 %). Most of the mild-early intraocular pressure elevations were controlled in both groups during the follow-up. From one year post-PK, there was an increased need for topical antiglaucomatous treatment in both patient groups. In all eyes the IOP was controlled by topical antiglaucomatous treatment. Preoperatively, visual acuity was comparable in patients with and without SOAG (0.06 +/- 0.09 vs. 0.08 +/- 0.1, p = 0.7), but increased significantly more in patients without SOAG (0.38 +/- 0.1, median 0.4) than in patients with SOAG (0.2 +/- 0.1, median 0.2; p = 0.01) after PK. Visual acuity remained stable in both groups throughout the follow-up period. During follow-up only one eye developed an episode of reversible endothelial graft rejection 18 months postoperatively. An irreversible graft failure was seen in none of the patients. The functional outcome after PK in PEX-keratopathy seems to be strongly associated with pre-existing SOAG. Patients without SOAG may expect good visual rehabilitation without persistent postoperative IOP increases. However, patients should be followed-up for a prolonged period of time, because from 1 year following PK the need for topical antiglaucomatous treatment increased significantly.

CALCINEURIN INHIBITOR-FREE AND STEROID-FREE IMMUNOSUPPRESSION IN PANCREAS TRANSPLANTATION

O310* Aims: Chronic use of calcineurin inhibitors (CNI) causes nephrotoxicity of native and transplanted kidneys (kd). In an attempt to eliminate CNI-associated nephrotoxicity, we used a CNI- and steroid-free regimen in pancreas (pa) transplant (tx) recipients (recs), combining a CD 52 antibody (Campath) with either mycophenolate mofetil (MMF) or Rapamycin (RAP). Methods: Between February 15, 2003 and February 15, 2004, 56 pa tx recs were enrolled in a Campath-based, CNI-free immunosuppressive protocol. Of those, 14 underwent a sim. pa and kd tx (SPK), 23 a pa after kd tx (PAK), and 19 a pa tx alone (PTA). For induction, the majority of patients (> 95%) received 3 ± 1 doses of Campath (30 mg IV) and 1 ± 1 dose of thymoglobulin. For maintenance immunosuppression, additional Campath doses (30 mg each) were given whenever the absolute lymphocyte count exceeded 200 mm2 (usually required at 2 to 4 month intervals). The only other immunosuppressants given for induction and maintenance therapy were MMF alone (n = 52; 2 to 3 g/d), adjusted by neutrofil count, or the combination of RAP (target level 5 to 8 ng/ml) and MMF (n = 4). Patient and graft survival and rejection episodes were calculated at 6-month follow-up (Kaplan-Meier). Serum creatinine (CR) levels were measured pretx, at discharge, and at 6 months posttx. Results: At 6 months posttx, the patient survival rate for SPK was 85%; for PAK, 90%; for PTA, 100% (p > 0.3). The causes of death were cardiac arrest (n = 2) and hemorrhage (n = 2). At 6 months posttx, the pa graft survival rate for SPK was 86%; for PAK, 90%; for PTA, 65% (p > 0.3). For SPK recs, the 6 month kd graft survival rate was 84%. Graft loss from rejection at 6 months for SPK and PAK was 0%; for PTA, 27%. The 6-month rate of reversible rejection episodes for SPK was 17%; for PAK, 29%; for PTA, 31% (p > 0.9). Only 2 pts were switched to CNI, 1 for GI side effects, the other for recurrent rejection. Serum CR levels at baseline, discharge, and at 6 months posttx for SPK were 7.1 ± 4.4, 2.1 ± 1.8, 1.2 ± 0.4; for PAK, 1.6 ± 0.4, 1.3 ± 0.5, 1.7 ± 0.9; for PTA, 1.6 ± 1.2, 1.3 ± 0.9, 1.6 ± 0.9 mg/dl. Conclusions: This CNI-free, Campath- and MMF-based protocol in pa tx recs was associated with a low rate of graft losses from rejection. Pa graft survival was > 85% for SPK and PAK recipients. CR levels at (pretx) baseline and 6-month posttx were unchanged, but longer follow-up is warranted. This protocol should be considered an alternative to CNI-based, nephrotoxic regimens.

COMPARISON OF INDUCTION THERAPY BASED ON CONTINUOUS VS. DISCONTINUOUS ADMINISTRATION OF ANTI-THYMOCYTE GLOBULINS IN RENAL-TRANSPLANT PATIENTS: EFFICACY AND LONG-TERM SAFETY

P767 Aims: The aim of our retrospective study was to compare two modes of administration of anti-thymocyte globulins (ATG) after renal transplantation. Methods: Before 1993, patients (group I, n=93) received fixed daily doses of ATG, i.e.,1 mg/kg for 8 consecutive days. Thereafter, ATG was either continued at the same dose for 15 days, in the case of delayed graft function, or was infused every other day at the same dose until serum creatinine level became <150 μmol/L. After 1993, patients (group II, n=66) received ATG at full dose (1 mg/kg/day) during the first 3 days and, thereafter, doses (1 mg/kg) were adapted according to CD2 lymphocyte count (in order to target CD2 T cells <50/mm3). Both groups received steroids, azathioprin, and cyclosporine A. The mean follow-up after transplantation was 116 ± 29 months in group I and 91 ± 17 months in group II. Results: ATG cumulative dose was significantly higher in group I than in group II (9.7 ± 4.5 vs. 7.4 ± 3.2 mg/kg, p=0.0002) and, consequently, ATG cost was higher in group I ($4155 ± 1829) than in group II ($3299 ± 1387, p = 0.01). Long-term patient survival and graft survival were similar in both groups at, respectively, 92.5% and 85% in group I and 93.9% and 94% in group II (p=ns). In contrast, the number of acute graft-rejection episodes was significantly higher in group I than in group II (40.9 vs. 15%, p=0.0005). The number of CMV reactivations was more important in group II (51 vs. 24%, p=0.031), which resulted in a higher proportion of CMV seropositive recipients in this group (29 vs. 3%, p=0.004). At 7 years after transplantation, serum creatinine level and creatinine clearance were similar in the two groups. Finally, the cumulative incidence of severe bacterial infections (48% in group I vs 50% in group II, p=ns) and cancers (36 % in group I vs 39 % in group II, p=ns) in the long term were also similar in both groups. Of all cancers, skin’s ones represented 30% in group I and 26 % in group II (p=ns). The time between the transplantation and the occurrence of a cancer was lower in group I as compared to group II (111 vs 85 months, p=0.03). In contrast, the time between the transplantation and the occurrence of a skin cancer was similar in both groups (115.34 vs 93.6 months, p=ns). Conclusion: In conclusion, adapting ATG doses according to CD2 lymphocyte count is safe and is less expensive than using full doses

P0243 POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE (PTLD) AFTER LIVER TRANSPLANTATION IN CHILDREN ???OWN EXPERIENCE.

Introduction: Posttransplant lymphoproliferative disease (PTLD) in children remains a significant clinical problem. Methods: 156 pediatric liver transplantations were performed between March 1990 and December 2002 in Children’s Memorial Health Institute. Five of the children aged 18–29 months experienced EBV-associated PTLD. Recipients’ age at the time of transplantation ranged from 12 to 17 months. PTLD was diagnosed within 3 to 13 months after transplantation. The immunosuppressive regimen of all patients with PTLD consisted of prednisone and tacrolimus. Four pts had EBV VCA IgG before Ltx. Results: The following signs and symptoms were observed: anemia (5), fever (4), hypoalbuminemia (3), anorexia (2), chronic diarrhea (3), values of EBV PCR genomes/105 lymphocytes ranged 400–5000 /N300 – University of Pittsburgh/ (5), biopsies of the lymph nodes revealed two types of histology: plasmacytic hyperplasia (2) and polymorphic B-cell infiltration (3). Patients were treated with immunosuppression withdrawal (4) or reduction (1) and intravenous antiviral therapy. In one case anti-CD20 monoclonal antibody (rituximab) was given intravenously eight weeks after the onset of the disease. Clinical improvement and EBV-PCR reduction were observed in all patients. All children developed acute liver graft rejection episodes, confirmed by liver histology - tacrolimus therapy was then reintroduced. One patient had reccurence of PTLD 34 months after the first episode. The duration of follow-up after the onset of PTLD is 9–39 months. All children are alive. Conclusion: PTLD is an important complication of immunosuppressive therapy, usually encountered in younger children after LTx. In case of non-specific signs/symptoms further PTLD tests should be considered. Reduction of immunosuppression is an effective therapy but must be administered cautiously regarding the acute rejection risk.

Immune Regulation and Graft Survival in Kidney Transplant Recipients Are Both Enhanced by Human Leukocyte Antigen Matching

We hypothesized that donor/recipient sharing of the human leukocyte antigen (HLA) involved in allopeptide presentation to the T regulatory cell increases the incidence of immune regulation, thus contributing to long-term graft survival. Peripheral blood mononuclear cells (PBMC) were obtained from 40 living related donor (LRD) and 31 cadaver renal transplant recipients. The trans vivo delayed type hypersensitivity (DTH) assay was used to assign patients to regulator, nonregulator, and sensitized categories. In a large cohort (n = 1934 patients), primary graft survival and rejection episodes were analyzed using a log rank test for comparison with the DTH results. The highest incidence of regulated anti-donor DTH was observed in the LRD HLA-identical group (6/6; 100%) followed by the LRD HLA 1 haplotype matched group (18/27; 67%). Within the cadaver population, two DR-matched recipients had a higher frequency of regulated anti-donor DTH (6/11; 55%) than 1 & 0 DR-matched recipients (3/18; 17%). In a multivariate model, matching for HLA-DR alone, or for DR plus DQ was significantly (p = 0.045, p = 0.041) correlated with DTH regulation. The better HLA-matched groups showed the highest incidence of DTH regulation and, in a larger retrospective analysis, displayed better graft survival and freedom from acute rejection (p < 0.0001). HLA matching, and HLA-DR matching in particular, correlates with the incidence of immune regulation after kidney transplantation.

Idiopathic colitis following cardiac transplantation: Three pediatric cases

Colitis can cause significant morbidity in pediatric solid organ transplant recipients. In many cases, despite intensive evaluation, a specific infectious, inflammatory, or immunologic etiology is not identified, and idiopathic colitis may be the ultimate diagnosis. We defined idiopathic colitis as the presence of gastrointestinal symptoms (vomiting, diarrhea, abdominal pain) with inflammatory changes seen on intestinal biopsy in the absence of identifiable bowel disease. We describe three cases of idiopathic colitis following cardiac transplantation. In each case, the post-transplant course was complicated by persistent abdominal pain, diarrhea, and in two cases, vomiting. All three patients' post-transplant courses were marked by multiple graft rejection episodes, and all received intensified immune therapy in addition to usual maintenance immunosuppression. Differential diagnosis of the patients' gastrointestinal symptoms included drug side effect, indolent opportunistic infections, inflammatory bowel disease, post-transplant lymphoproliferative disease, and microvascular ischemic colitis. Continued symptoms led these patients to extensive evaluation including imaging studies, endoscopy and tissue biopsy, and stool, blood and tissue cultures for viral, bacterial and parasitic pathogens. Definitive differentiation presented significant diagnostic challenge, and once identifiable etiologies were excluded, the diagnosis of idiopathic colitis was assigned. We conclude that idiopathic colitis following pediatric cardiac transplantation can be a cause of significant morbidity. Endoscopic evaluation of patients who present with gastrointestinal symptoms after transplant is warranted to identify the presence of idiopathic colitis once common causes are ruled out. Further study is needed to identify its incidence, etiology, therapeutic options and prognosis.

Clinical graft evolution of lymphocytes, polymorphonuclear cells, and antigen expression in tubular renal cells in the urine sediment of 20 renal allograft recipients

Urinary samples from 20 kidney transplant recipients were studied to determine the cellular composition of the sediments using an immunocytological (IC) technique. The expression of HLA class I (A, B, C) and class II (DR, DQ, DP), CD2, CD3, CD4, CD8, and interleukin (IL)-2 receptor (IL-2R) on lymphocytes was assessed using a panel of monoclonal antibodies. The results were correlated with graft function and with the number of episodes of acute renal graft rejection (AR) during a period of 6 months posttransplantation. The cellular infiltration of lymphocytes (LC) and polymorphonuclear cells (PMNC) also was studied using a standard cytology (SC) technique. During this period, 17 of 30 episodes of graft dysfunction due to AR occurred in 12 patients: 8 to acute tubular necrosis (ATN) (n = 8); 4 to cyclosporine (CsA) toxicity (n = 4) and 1 to amphotericin toxicity (n = 1). The diagnosis of AR was made clinically by 3 independent observers, using biopsy in some cases. The immunocytology showed a significantly increased expression of HLA-DR, DO, and DP namely, greater than 20% positivity in 10% of samples on the tubular epithelial cells (TEC) of patients presenting with versus without AR ( P ≤ .001). In addition, a high correlation was observed between the expression of IL-2R and the presence of AR (p ≤ .002). The standard cytology results showed a significantly increased percentage of LC and decreased percentage of PMNCs in samples obtained 2 days prior to the clinical manifestations of patients who developed AR ( P = .001). A greater level of expression of antigen determinants was observed prior to AR. These results suggest that immunocytology of urinary sediments, which is a noninvasive technique, has enormous clinical potential for the differential diagnosis of AR, ATN, and CsA toxicity. In our study, the use of HLA class IL–specific monoclonal antibodies (Abs) gave a 100% specificity, 95% sensitivity, and 95% predictability. Although our results also indicate a potential value in the increased IL-2R expression, these findings must be confirmed by further studies. Furthermore, the combination of both immunologic and SC techniques in urinary sediments allows early detection of AR and is cost effective and simple features that could be used routinely for follow-up of renal transplant recipients.

Pathologic analysis of right-lobe graft failure in adult-to-adult live donor liver transplantation.

Live donor adult liver transplantation (LDALT) utilizing right-lobe grafts is now acceptable as an alternative to cadaveric orthotopic liver transplantation (OLT). However, some LDALTs fail and require urgent OLT or result in recipient death. Our aim was to determine the basis of LDALT failure. Liver specimens from 49 LDALT recipients were evaluated and the findings correlated with clinical outcome. Ten patients (20.4%) had either early (< or = 1 month) or late (> 1 month) graft failure. Eight early failures, 7 of which occurred among our first 25 cases, were due to extensive liver parenchymal necrosis as a result of hepatic artery thrombosis (n=3), portal vein thrombosis (n=1), hyperperfusion syndrome (n=1), complete graft thrombosis (n=1) with Factor V Leiden on a regimen of therapeutic heparin (n=1), sepsis and concomitant graft dysfunction with venous outflow tract injury (n=1), and venous outflow tract thrombosis and parenchymal thermal injury with sepsis (n=1). Preoperative, intraoperative, or postoperative severe vessel wall injury was evident in 6/8 early failures. Two patients had late graft failure, 1 from recurrent hepatitis C and 1 with sepsis/multisystem organ failure. There were no significant differences in graft size, rejection episodes, or operative or ischemic times between patients with and without graft failure. In conclusion, LDALT failed in 10/49 (20%) of our patients, with 8/10 occurring within 1 month post-LDALT owing to vascular/thrombotic complications experienced during the early phase of our institutional experience. Perioperative vessel wall injury appeared to be a major factor in predicting early graft loss.

Evaluation of erythropoiesis and changes in serum erythropoietin concentration in cats after renal transplantation.

To investigate the clinicopathologic patterns of the erythropoietic response after renal transplantation in cats with chronic renal failure (CRF). 14 cats with CRF undergoing renal transplantation. Before and at intervals during a 6-month period after transplantation, serum creatinine and erythropoietin concentrations, Hct, erythrocyte indices, aggregate reticulocyte percentage, and iron variables were measured. Additionally, the number of transfusions administered to and any complications that developed in each cat were recorded. In all cats, preoperative azotemia resolved within 6 days after renal transplantation. Two cats had a temporary increase in serum creatinine concentration secondary to an acute graft rejection episode. Anemia (defined as Hct < 28%) resolved in 10 cats 3 to 49 days after surgery. Resolution of anemia was delayed in 2 cats that had acute rejection episodes. Serum erythropoietin concentration and reticulocyte percentage were low preoperatively; values after surgery were highly variable. Compared with preoperative values, serum erythropoietin concentration increased 1 to 4 days after surgery in 11 cats; between days 5 and 58, another increase was detected in 9 cats. Serum iron concentrations were generally low before and 14 days after transplantation. The erythropoietic response was highly variable in cats after renal transplantation, but anemia typically resolved within 1 month after surgery. A delay in resolution of anemia in cats may indicate poor graft function and inadequate iron stores, suggesting the need for further evaluation for concurrent illness.

Plasmacytic hyperplasia—the early form of posttransplant lymphoproliferative disorder—with atypical morphology and clinical course in patient after liver transplantation: a case report

This case report describes an early lesion of posttransplant lymphoproliferative disorder (PLTD)—plasmacytic hyperplasia with atypical morphology. The 54-year-old patient was 4 months after liver transplantation due to alcoholic cirrhosis. The postoperative course had been uneventful without graft rejection episodes. Primary immunosuppressive therapy included tacrolimus and prednisone. On admission to the hospital the patient showed rapidly increasing jaundice, hepatomegaly, anemia, thrombocytopenia, and significant leukocytosis. A biopsy suggested generalized infection. Acute Epstein-Barr virus (EBV) infection was confirmed using serological methods. Despite treatment the patient died. On autopsy we found features of generalized infection. Histological examination of the enlarged lymph nodes showed plasmacytic hyperplasia despite lymph node atrophy. Plasmacytic hyperplasia, an early lesion of PTLD despite usually a good prognosis with multifactor therapy may display a rapid course that leads to death through intensified immunosuppression. In accordance with other reports we confirmed reactivation of EBV infection as the probable cause of plasmacytic hyperplasia. The lymph node morphology of plasmacytic hyperplasia may be atypical with atrophy of lymphoid components accompanying plasma cell proliferation.

Influence of hypercholesterolemia and acute graft rejection on chronic nephropathy development in renal transplant recipients

Graft endothelial lesions resulting from acute rejection may be sustained by concomitant hypercholesterolemia, thus increasing the risk of chronic graft failure. The present study was undertaken to examine the influence of hypercholesterolemia and acute graft rejection (AGR) episodes on graft function and graft loss due to chronic nephropathy. A cohort of 336 patients transplanted between 1993 and 2000 having graft function at 12 months after transplantation were examined. Immunosuppressive therapy consisted of CsA, azathioprine, and corticosteroids in 90% with 10% of patients receiving mycophenolate mofetil in place of azathioprine. During the first year after transplantation, AGR occurred in 134 (39.8%) and hypercholesterolemia (6.2 mmol/L) in 132 (39.2%) of patients. The population was divided into four groups according to AGR occurrence and cholesterol concentrations during the first year after transplantation for analysis of serum creatinine concentrations and graft loss at 5 years of follow-up. Patients with AGR irrespective of cholesterol levels displayed significantly higher creatinine concentrations. Graft loss in these patients increased over twofold compared to the remaining groups. Patients without hypercholesterolemia and AGR showed normal creatinine concentrations and low graft loss rates during 5 years of follow-up.

Rat corneal allograft survival prolonged by the superantigen staphylococcal enterotoxin B.

The purpose of this study was to determine the optimal conditions for prolonging corneal allograft survival by inducing anergy with the superantigen staphylococcal enterotoxin B (SEB). A rat model of penetrating keratoplasty, whereby Fisher344 donor corneas are implanted into Lewis recipients, was used to evaluate the effects of SEB on inhibiting immune-mediated allograft rejection. To induce anergy, SEB was injected into the peribulbar space of Lewis rats. Furthermore, histopathology and immunofluorescent staining were used to examine the levels of infiltrating CD4(+) and CD8(+) T lymphocytes and NK1.1(+) lymphocytes. By administering SEB, at doses of 90 or 120 micro g/kg 7 days before and after keratoplasty, we suppressed the episode of corneal graft rejection for a median of 12 and 30 days, respectively. In contrast, rejection was observed when 30 or 60 micro g/kg of SEB was administered. After SEB injections, lymphocyte infiltration into the corneal grafts was reduced, and the expression of NK1.1(+) lymphocytes was enhanced, suggesting that anergy may be occurring. Also, there were no differences in the number of infiltrating CD4(+) and CD8(+) T lymphocytes cells between the control group and groups injected with 30 and 120 micro g/kg SEB on postoperative days 10 and 30. Inducing anergy with the superantigen SEB prolonged corneal graft survival in a rat model of penetrating keratoplasty. Therefore, these results support the possibility of prolonging corneal allograft survival in a clinical setting by preventing immune-mediated rejection through the administration of the superantigen SEB.

Neoral-to-gengraf conversion in renal transplant recipients

ObjectiveOur objective was to evaluate the safety, efficacy, and need for dosage adjustments when patients taking the Neoral formulation of cyclosporine are converted to the generic formulation, Gengraf. MethodsFrom September 2001 through January 2002, patients receiving follow-up care in the renal transplant clinic at the VA Tennessee Valley Healthcare System were converted from Neoral to Gengraf based on a 1:1 dosing equivalency. Steady-state cyclosporine trough concentrations were obtained both prior to and following Neoral-to-Gengraf conversions. Patients were also monitored for changes in serum creatinine, hospitalization, cyclosporine toxicity, graft rejection, and need for further adjustment in cyclosporine regimen. ResultsForty-one patients were included in data analysis. There were no differences in cyclosporine concentrations (P = .0853) or serum creatinine (P = .4469) following conversion to Gengraf. There were no reports of cyclosporine toxicity, no episodes of graft rejection, and no need for further dose adjustment related to the generic conversion. ConclusionsNeoral and Gengraf are therapeutically equivalent cyclosporine formulations, such that renal transplant recipients maintained on Neoral can be safely and effectively converted to the Gengraf formulation based on a 1:1 conversion ratio. The use of Gengraf over Neoral within the Veterans Affairs Healthcare System offers a reduced cost alternative but maintains equal efficacy and outcomes.

Peripheral blood stem cell transplantation in children with beta-thalassemia major.

To share the preliminary data on stem cell transplantation in Pakistan. This is a single center retrospective analysis of the outcome of allogeneic peripheral blood stem cell (PBSC) transplantation in b-thalassemia major patients. Bismillah Taqee Blood Diseases Centre, Karachi; a tertiary care hematology center from September 1999 to September 2002. Twelve patients with b-thalassemia major received allogeneic PBSC transplantation from HLA identical sibling donors except in one case where mother was the donor. All patients received busulphan and cyclophosphamide conditioning therapy and cyclosporin A/methotrexate for graft versus host disease (GVHD) prophylaxis. Donors were primed with G-CSF for 4 days and stem cells were harvested using Haemonetics MCS + cell separator on 5th day. All patients received G-CSF starting from day + 4 until their neutrophil count rose to normal. Engraftment was achieved in all patients except one who required a second dose of bone marrow graft on day +21. Median time to achieve absolute neutrophil count of > 0.5 x 10(9)/l was 9.0 days (range 8-31 days) and platelet count of > 20 x 10(9)/l was 14 days (12-35 days). Acute GVHD was seen in 3 patients, one patient had grade IV gut GVHD; another patient had grade III gut GVHD while third patient had grade II skin GVHD. Median hospital stay was 29 days. Six patients were well and transfusion independent 3 to 36 months posttransplant. One episode of primary graft failure required a second dose of bone marrow harvest. Another episode of graft rejection received two doses of donor lymphocytes infusion. There were 4 deaths due to grade IV gut GVHD because of uncontrolled systemic Candida infection and one due to hepatic veno-occlusive (VOD) disease. Allogeneic peripheral blood stem cell transplantation can be safely and economically carried out in Pakistan. Although there had been 4 deaths during 36 months follow-up, with increasing understanding and experience the outcome is expected to improve.

Prevalence and clinical significance of human herpesviruses 6 and 7 active infection in pediatric liver transplant patients.

Recent studies in adult liver transplant patients have suggested that both human herpesvirus (HHV)-6 and HHV-7 infection are important causes of morbidity following liver transplantation. However, the impact of HHV-6 and -7 infection in pediatric liver transplant patients remains largely unknown. The aims were to determine the prevalence of HHV-6 and -7 infection in pediatric liver transplant patients and to determine whether there is an association between HHV-6 and -7 infection with episodes of graft rejection and cytomegalovirus (CMV) infection. A total of 46 pediatric liver transplant patients transplanted at Mayo Clinic between January 1994 and January 2000 were evaluated. Quantitative polymerase chain reaction (PCR) assays for CMV, HHV-6 and HHV-7 were performed on stored sera obtained prior to transplant, weekly for 8 wk and at 4 months and 1 yr post-transplant. Pretransplant sera were tested for HHV-6 antibodies by indirect immunofluorescence assay. A total of 215 blood samples were tested (mean 6.5 +/- 3.1, range 3-18). CMV infection occurred in 11 of 33 (33.3%) patients, while CMV disease occurred in 4 of 33 (12%) patients. Infection with HHV-6 (variant B) was detected in three of 33 (9.1%) patients. HHV-7 infection was not detected. Case 1 and 2 were infants (10- and 11-month old, respectively). Both were seronegative for HHV-6 pretransplant. In both cases, HHV-6 infection was associated with concurrent episodes of moderate to severe acute graft rejection. Case 3 was a 16-yr-old girl who was seropositive for HHV-6 pretransplant. No clinical events were recorded and a liver biopsy performed per protocol showed no evidence of rejection. None of the three patients had concomitant CMV infection or disease. In this study, HHV-6 infection occurred in 9% of pediatric liver transplant patients while HHV-7 was not detected. A potential association between primary HHV-6 infection and allograft rejection warrants further investigation.

The influence of HLA alleles on graft loss and rejection episodes in renal transplantation

The influence of HLA alleles on graft loss and rejection episodes in renal transplantation

Combined analysis of cytokine genotype polymorphism and the level of expression with allograft function in African–American renal transplant patients

Cytokine gene polymorphism and expression levels were evaluated in a group of African–American patients who had undergone renal transplantation. It was hypothesized that possession of specific cytokine alleles might be influential in predisposing the recipient to allograft rejection. Thus, we sought to establish a relationship between cytokine gene polymorphism, the levels of cytokine expression, and the outcome of allograft function. Cytokine genotypes and mRNA transcript levels of IL-2, TNF-α, TGF-β1, IL-10, IL-6 and IFN-γ were determined using peripheral blood cells. Genomic DNA samples from 77 transplant recipients and 77 controls were tested by a multiplex PCR with specific primers for the above cytokines. The frequency distributions of cytokines were analyzed in respect to the clinical characterization, including delayed graft function (DGF), rejection episodes (REs) and stable graft function (SGF). The mRNA transcript level was tested both at pre- and early post-transplantation (day 1 and day 4) with primers for coding regions of the above cytokines in a RT-PCR assay. The majority of recipients with successful graft function were matched with their donors for only three out of the six HLA alleles. We have shown that the TGF-β1 T/C G/G high producer and IFN-γ T/A intermediate producer genotypes were associated with allograft rejection, whereas low IFN-γ producer and high IL-10 producer genotypes were significantly protective of the allograft. There was some correlation between the TGF-β1 high producer genotype and DGF, but it was not statistically significant. Overall, 77% of those who experienced REs carried the TGF-β1 T/C G/G, high producer genotype as compared with 52% who experienced DGF, 39% with SGF ( P<0.01, RR=2.0), and 27.3% of controls ( P<0.003, RR=2.6). The IFN-γ T/A intermediate producer genotype was found in 69.2% of patients with REs as compared with 26.8% of patients with SGF ( P<0.008, RR=2.85). The IL-10, ATA/ATA low producer genotype was found in 38.5% of recipients with REs and 14.6% of recipients without REs ( P<0.04, RR=0.53). Expression levels of mRNA transcript were correlated with genotype data, except for the TGF-β1 high producer genotype where there was no significant difference between the level of mRNA transcript at pre- and post-transplantation. Low DRβ1 and high DPβ1 expression by recipient peripheral blood mononuclear cells before transplantation was associated with more SGF, whereas high DRβ1 and low DPβ1 expression at pretransplantation was associated with more REs (DRβ1, P<0.001 and DPβ1, P<0.05, respectively). We concluded that, dual analysis of cytokine genotype and expression levels by peripheral cells may be an important clue to understanding the contribution of the recipient's immune response to an allograft pre- and post-transplantation. Identification of peripheral markers diagnostic of rejection could allow advance anticipation of clinical outcome, and might reduce the need for tissue biopsy.