Preventive cytolytic treatment following heart transplantation: ATG versus OKT3]

The postoperative prophylactic cytolytic therapy with rabbit-ATG and OKT3 after heart transplantation are compared. The first 20 recipients were treated with ATG (5 days), the next 20 with OKT3 (14 days). The medium histological rejection grade (Texas classification) was significantly higher after 2 weeks in ATG group and after 4 weeks in OKT3 group. The linearised rejection rate was 7.1 (ATG) vs. 0.7 (OKT3) (p less than 0.005) at 2 weeks, resp. 3.6 vs. 8.6 (p less than 0.05) and 1.3 vs. 2.9 (p less than 0.005) at 4 weeks and 2 months. After 3 months there was no difference in histological rejection grade (3.6 +/- 1.5 vs. 3.3 +/- 1.7) and linearised rejection rate (2.4 vs. 2.6 per 100 days and patient) between the two groups. Severe rejections are more frequent after OKT3 (6 vs. 11) and probability of rejection free survival is higher after ATG (25% vs. 0%, resp. 21% vs. 0% after 2 resp. 3 months; p less than 0.05). In this study we find no short and medium term benefit of a rejection prophylaxis with OKT3 (14 days) compared with ATG (5 days). Acute allograft rejections in OKT3 group tend to be more severe with a higher mortality.     

OKT3 treatment for steroid-resistant acute rejection in kidney transplantation

Orthoclone (OKT3, Ortho Biotech Inc, USA) monoclonal antilymphocyte antibody is a powerful T-cell-specific immunosuppressive agent. OKT3 has been used for induction therapy in kidney and liver transplantation, as well as to treat acute or steroid-resistant acute rejection episodes (ARE). This study was a retrospective analysis of 43 renal transplant recipients who developed steroid-resistant ARE and were treated with OKT3 between September 1994 and June 2004. The recipients were 36 men and 7 women of mean age 32.7 +/- 11.6 years (range, 19 to 48 years). The mean time from transplantation to OKT3 treatment was 7.2 +/- 6.7 months. Thirty-four episodes (79.1%) responded to OKT3 therapy with improved graft function, but the remaining 9 (20.9%) grafts did not respond. Among the 34 OKT3 responders, the mean serum creatinine decreased from 3.96 +/- 2.5 mg/dL to 2.45 +/- 1.77 mg/dL after treatment. Eleven (25.6%) of the 43 patients experienced minor side effects: fever, dyspnea, tachycardia, bradycardia. One patient (2.3%) developed acute pulmonary edema; one (2.3%), cytomegalovirus infection; and eight (18.6%), bacterial infections. The 1-, 3-, and 5-year graft survival rates for the 34 patients who responded to OKT3 therapy were 96%, 93%, and 85%, respectively. All patients are currently alive. The results indicate that OKT3 is a safe, effective treatment choice for steroid-resistant ARE in kidney transplantation.     

Quantitative assessment of the first acute rejection as a predictor of renal transplant outcome

BACKGROUND: Acute rejection (AR) of the transplanted kidney has been identified as the major risk factor for the development of chronic rejection and immunological graft loss. However, the clinical presentation and response to AR therapy can vary considerably between recipients. METHODS: We studied the first AR episode in 201 kidney-only recipients transplanted between January 1987 and June 1998 who were biopsied between April 1993 and June 1998 and were graded using the Banff schema. All patients received cyclosporine-based immunosuppression. There were 134 cadaver donor (66.7%) and 67 live donor (33.3%) recipients followed for a mean of 46.2 (range 4-128) months. All Banff grade 1-3 and 40/78 borderline (BL) cases were treated for rejection after biopsy. These patients were compared with a contemporaneous control population who did not experience AR. Demographic risk factors associated with graft loss were identified in both univariate and multivariate analysis. Daily (0-18) serum creatinine (SCr) values during and after the AR were plotted for each patient to generate curves and calculate area under the serum creatinine versus time curve (mg/dl/day). Four response patterns to treatment were identified according to the velocity of % increase (V1) and decrease (V2) of serum creatinine. These were identified as rapid rise and fall (n=62); rapid rise and slow fall (n=43); slow rise and fall (n=55); and slow rise and rapid fall (n=41). Kaplan-Meier graft survivals were compared between the groups. RESULTS: Any Banff grade was associated with increased risk for graft loss (P=0.0001). However, no significant differences were observed between the Banff BL and B1-3 groups, or among those BL patients who were treated or remained untreated for AR. Multivariate analysis identified a black recipient (P=0.03, risk ratio 2.0) and area under the serum creatinine versus time curve (P=0.0001, risk ratio 3.2) as significant risk factors for graft loss. The AR response pattern RS resulted in a significantly (P=0.0072) diminished 5-year graft survival (45%) compared with the other groups. Serum creatinine pattern, but not Banff grade, was also a significant (P=0.025) predictor of re-rejection. CONCLUSIONS: These data suggest that all Banff grades, including BL, carry a significant risk for graft loss, and the initial response to antirejection therapy can predict long-term graft outcome. They support the practice of treating AR promptly and definitively and suggest that the RS subgroup of rejecting grafts could be targeted for additional antirejection therapy. This subgroup can be identified by 10 days of AR therapy, and should be the subject of further study.     

Impact of the delayed graft function in hypersensitized kidney transplant patients

AIM: The aim was to study the incidence, impact, and association of pretransplantation anti-HLA antibodies and delayed graft function (DGF) on the outcome of cadaver kidney transplants independent of the immunosuppressive therapy. METHODS: Data from 1325 cadaver donor kidneys (February 1975 to December 2002) included the variables of current and peak anti-HLA antibodies, presence of DGF, acute rejection (AR) episodes, patient survival, and graft half-life. RESULTS: DGF (need for dialysis in the first week posttransplantation) ranged between 15% and 40% with a mean of 30% in last 5 years. Eighty-five percent of the candidates on the waiting list for kidney transplants displayed <25% panel reactive antibody (PRA) at transplantation with 4.6% between 26% and 50%, 7.7% between 51% and 75%, and 1.5% >75%. Among the patients who developed DGF, 47% displayed AR compared an incidence of 30% among patients without DGF (P=.0026). The patients displaying >50% PRA (either current or maximum) showed a worse graft survival compared with patients with <50% PRA (log rank, P=.0000). DGF reduced graft survival (P=.04), the difference appearing in the early phase after transplantation. The best outcome was observed in the no DGF-no AR group (half-life, 11.6 years) and the worst results were in the hypersensitized patient groups: peak and current PRA >50% (half-lives of 2.4 and 2.2 years). A multivariate analysis showed that the presence of peak or current PRA >50% is the most important risk factor for graft loss. CONCLUSION: Sensitization is the key factor in graft outcome. Presensitization increases the risk of DGF and DGF increases the incidence of AR and both together produce the worst graft survivals.     

Thymoglobulin dose optimization for induction therapy in high risk kidney transplant recipients

BACKGROUND: Thymoglobulin (rATG) has become the agent of choice for induction therapy in high immunological risk kidney transplant recipients. However, its optimal dosing in this subgroup has not been studied. METHODS: To evaluate the effect of total rATG dosing on graft outcomes in such patients, we conducted a retrospective cohort study of 96 adult patients who received repeat transplants (85%) or had panel reactive antibody more than 40% (19%) and were maintained on tacrolimus, mycophenolate mofetil, and steroid. Group 1 (n=33) received less than or equal to 7.5 and group 2 (n=63) received more than 7.5 mg/kg rATG. Graft and patient survival, incidence of acute rejection (AR), and 12-month serum creatinine (SCr) were examined. RESULTS: The groups were comparable regarding demographics, donor source, retransplantation, panel reactive antibody, and human leukocyte antigen mismatch. Group 2 had more African Americans (44.4% vs. 21.2%, P=0.03). During the 25.4+/-18.0 months follow-up graft survival was 82.5% and 79.4%, respectively (P=0.54). Three in group 1 and four in group 2 died (P=0.65). The incidence of biopsy proven AR during the first 12-months did not differ between the groups (9.5% vs. 8.8%, respectively, P=0.9). SCr at 12 months was 1.6+/-0.7 in group 1 and 1.8+/-1.0 in group 2 (P=0.3). There was no independent association between rATG dose and graft survival (hazard ratio: 0.85, P=0.79, 95% CI: 0.26-2.7 for group 2 vs. 1) or 1-year SCr (regression coefficient=0.02 for ln(SCr), P=0.3; 95%CI: -0.01 to 0.6). CONCLUSION: Our results suggest that in high risk kidney transplant recipients total rATG doses less than or equal to 7.5 mg/kg are safe and effective in achieving a low rate of AR and graft outcomes comparable to higher doses.     

Use of a brief steroid trial before initiating OKT3 therapy for renal allograft rejection

OKT3 (Ortho Pharmaceutical, Raritan, NJ) has been employed in a protocol where all patients received cyclosporine as part of their baseline immunosuppressive regimen and, after the diagnosis of rejection was established, were treated with up to three pulses of methylprednisolone before monoclonal antibody therapy was initiated. Use of this protocol has allowed 46% of rejection episodes encountered to be treated on an outpatient basis without resorting to inpatient use of OKT3, but has avoided delaying OKT3 therapy until after all other methods of rejection treatment were found to be ineffective. Of 83 rejection episodes treated with OKT3 between March 1985 and May 1987, 78 (94%) were reversed. Overall graft survival is 84% and patient survival is 96% in OKT3-treated patients. Of the 17 rejection episodes where OKT3 treatment was a second or third exposure to the drug, rejection was successfully reversed in 15 (88%). In cadaver donor allograft recipients transplanted between March 1985 and May 1986, actual 1-year graft survival is 80% for 30 patients requiring no rejection therapy, 80% for 20 patients with rejection episodes responding quickly to steroids, and 82% for 28 patients with OKT3-treated, steroid-insensitive rejections. Mean serum creatinine at 1 year posttransplant is 1.5 +/- 0.5; 1.9 +/- 0.7; and 2.1 +/- 0.8, respectively, for these groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

The incidence and impact of early rejection episodes on graft outcome in recipients of first cadaver kidney transplants.

The objective of this study was to define the incidence and significance of acute rejection occurring in the first year following transplantation. The influence of contemporary induction immunosuppression on rejection, as well as the effect of rejection on graft and patient loss, renal function, and maintenance immunosuppression during the first year in 110 recipients of first cadaver renal transplants were analyzed. All patients received CsA, Aza, and prednisone for 30 days with withdrawal of Aza at 30 days and then prednisone at 105 days; 57 patients were prospectively randomized to receive ALG (Merieux) until serum creatinine was less than 300 mumol/L. Short-term ALG administration did not influence the incidence, severity, nature, or outcome of rejection episodes. Fifty-five (50%) patients had at least 1 rejection in the first 90 days. All patients with delayed graft function and 7/8 (88%) sensitized patients (current PRA greater than 50%) had at least 1 rejection episode; 71% (n = 35) of all rejection episodes occurred in the first 30 days posttransplant. Patients rejection free at 90 days remained rejection free the entire first year. Graft loss was 18% for rejections in the first month, 13% for rejections occurring later (P = NS); 20% (n = 11) of patients had a second rejection and 1% (n = 2) had a third rejection. The risk of graft loss was 9% with a first rejection, 38% with a second rejection, and 50% with a third rejection. Of 12 (22%) rejections that were steroid resistant, 10 (83%) were reversed with OKT3. One-year graft survival for patients without rejection, with steroid-sensitive rejection, and with steroid-resistant rejection was 96%, 88% (P = ns), and 58% (P less than 0.001), respectively; 1 year SCr was 168 +/- 93, 196 +/- 77 (P = ns), and 268 +/- 96 microMol/L (P less than 0.05), respectively. Patients free of rejection and with stable renal function continued to do well on maintenance CsA monotherapy, and they were more likely to be on CsA monotherapy than those with rejection episodes (P less than 0.01).     

Influence of changes in pretransplant sensitization on patient and graft survival in cadaver renal transplantation

Analysis of 2778 primary and 606 regrafted cadaveric donor renal allograft recipients transplanted between June 1977 and July 1982 as part of the South-Eastern Organ Procurement Foundation (SEOPF) Prospective Study was performed to determine the influence of changes in presensitization on graft and patient outcome. Four mutually exclusive groups of patients were identified based on the relative difference in the percentage of panel-reactive antibody (PRA) from highest ever (peak) to most recent (current) pretransplant levels as follows: group 1 (unsensitized): peak = current PRA = 0; group 2 (rising or stable PRA): (peak = current PRA) greater than 0; group 3 (small decrease): (peak - current PRA) = 1-40%;) and group 4 (large decrease): (peak - current PRA) greater than 40%. First-transplant recipients in group 4 had significantly higher mortality when compared with groups 1-3 (P less than 0.002). This decrease in patient survival was evident at 6 months (81% +/- 4 vs 91% +/- 1) and persisted to three years (68% +/- 8 vs 78% +/- 2), and it was associated with a significant (P less than 0.037) increase in death from infectious causes. This finding was even more striking when only transfused recipients were considered: at three years the difference in patient survival was 63% +/- 11 vs. 77% +/- 2. In addition, transfused patients with a decrease in pretransplant PRA of greater than 40% had significantly lower overall graft survival (P less than 0.02) and a higher incidence of irreversible graft rejection (50% +/- 8 vs 33% +/- 1 at two years). For regrafted recipients, there were no differences in patient survival among groups, but those in group 4 had significantly lower graft survival (P less than 0.0033) than groups 1-3. These findings suggest that a substantial decrease in PRA prior to transplant does not necessarily indicate a decrease in potential donor alloreactivity, and in first-graft recipients it may reflect an increased susceptibility to life-threatening infections following transplantation.     

Conversion from mycophenolate mofetil to azathioprine in high-risk renal allograft recipients on cyclosporine-based immunosuppression

OBJECTIVE: In a randomized control trial of mycophenolate mofetil (MMF) versus azathioprine (AZA) with cyclosporine and steroids, we demonstrated that MMF reduced acute rejection (AR) among renal allograft recipients (RTX) who were of low to moderate risk. However, 10% had AR when converted from MMF to AZA at 6 months, postrenal transplantation (RT). Two clinical markers, abnormal serum creatinine (SCr) and proteinuria at 6 months, post-RT, were associated with AR postconversion. The present study examined the safety of such conversion in selected high-risk RTX at 1 year of MMF therapy. METHODS: Thirteen high-risk RTX receiving MMF for either high panel reactive antibody (n = 9) or following AR (n = 4), with normal SCr and no proteinuria at 1 year, were selected for conversion. The incidence of AR, adverse events, and renal parameters (SCr, creatinine clearance, proteinuria) at 6 months postconversion was evaluated. Eight high-risk RTX who did not meet these selection criteria were retrospectively reviewed and used as controls. RESULTS: Renal parameters (SCr 123 +/- 26 vs 129 +/- 27 mumol/L; pre- vs postconversion) were not significantly different; no episodes of AR or proteinuria were documented. Azathioprine was discontinued in two patients due to leukopenia. In the control group, one patient had graft loss from chronic rejection, whereas one developed posttransplant lymphoproliferative disease necessitating MMF withdrawal. CONCLUSION: These results suggest that selective conversion from MMF to AZA after 1 year is safe, even in high-risk RTX. Normal SCr and absence of proteinuria are good screening parameters to identify patients at low risk for AR following such conversion.     

Combination therapy using prednisolone and cyclophosphamide slows the progression of moderately advanced IgA nephropathy

AIM: We retrospectively examined the effect of combination therapy using prednisolone (PSL) and cyclophosphamide (CPA) on the progression of IgA nephropathy (IgAN) in 45 patients with moderate to severe histological changes. PATIENTS AND METHODS: Patients were recruited from 129 consecutive patients with IgAN seen over 10 years based on semiquantitative histological grading. They were divided into two groups: PSL+CPA group (n = 26, male/female = 11/15, age 40+/-3 years (SEM)) or control group undergone conventional therapy with or without antiplatelet agents (n = 19, male/female = 10/9, age 41+/-3). In PSL+CPA group, PSL and CPA treatment commenced using a dose of 30 and 50 mg/day, respectively. PSL was reduced by 5 mg every month. RESULTS: The clinical parameters at the start of treatment such as age, gender, histological score, blood pressure, urinary protein excretion and serum creatinine concentration (SCr) were not different between the groups. The mean observation period in PSL+CPA group (3.3+/-0.3 years) was not different from the control group (4.0+/-0.7 years). In PSL+CPA group, urinary protein excretion, defined as the ratio of urinary protein to creatinine concentration (UP/UCr), significantly decreased from 3.9+/-0.4 to 1.3 +/-0.2 (p<0.01), whereas it remained high in the control group (3.8+/-0.7 to 2.7+/-0.8). The progression rate (PR), which was determined by the slope of the correlation between time after renal biopsy and reciprocal SCr, was significantly lower in PSL+CPA (0.054+/-0.014) than in the control group (0.172+/-0.032 dl/mg/year, p<0.001). Our results indicated that PSL+CPA combination therapy was effective in slowing the progression of moderately advanced IgAN. CONCLUSION: We suggest that the immunosuppressive treatment with CPA is sometimes necessary to preserve renal function in patients with histologically advanced IgAN.     

Protocol core needle biopsy and histological chronic allograft damage index as surrogate endpoint for Long-Term graft survival

Following encouraging results from several single-center studies showing that early histological manifestations of chronic rejection are seen in the graft before a decline in transplant function, we tested this concept in a multicenter study and investigated whether protocol needle biopsy may be used as a surrogate to late graft survival in multicenter renal transplantation trials. During two mycophenolate mofetil trials, 621 representative protocol biopsies were obtained at baseline, 1 year, and 3 years. The samples were coded and evaluated blindly by two pathologists and a Chronic Allograft Damage Index (CADI) score was constructed. At 1 year only 20% of patients had elevated (>1.5 mg/100 mL) serum creatinine, whereas 60% of the biopsies demonstrated an elevated (>2.0) CADI score. The mean CADI score at baseline, 1.3 +/- 1.1, increased to 3.3 +/- 1.8 at 1 year and to 4.1 +/- 2.2 at 3 years. The patients at 1 year were divided into 3 groups, those with CADI <2, between 2 and 3.9, and >4.0, the first two groups having normal (1.4 +/- 0.3 and 1.5 +/- 0.6 mg/dL) and the third group pathological (1.9 +/- 0.8 mg/dL) levels of serum creatinine. At 3 years there were no lost grafts in the "low" CADI group, six lost grafts (4.6%) in the "elevated" CADI group, and 17 lost grafts (16.7%) in the "high" CADI group (P <.001). One-year histological CADI score predicts graft survival even when the graft function is still normal. This observation makes it possible to use CADI as a surrogate endpoint in prevention trials and to identify the patients at risk for intervention trials.     

Posterior urethral valves: preliminary observations on the significance of plasma Renin activity as a prognostic marker

PURPOSE: A significant number of children with posterior urethral valves (PUVs) have chronic renal failure due to tubulointerstitial damage. Activation of the renin-angiotensin system is known to inflict this injury. We investigated the role of plasma renin activity (PRA) in patients with PUVs and sought to establish a relationship between renal damage and PRA. MATERIALS AND METHODS: The records of patients with PUVs were reviewed regarding the time of valve ablation, serum creatinine, scars, grade of reflux and glomerular filtration rate (GFR). PRA was measured before and after valve ablation. RESULTS: A total of 25 patients had PUVs (mean age 3.2 +/- 2.4 years, mean period of observation 4.5 +/- 1.2 years). Mean PRA was increased before valve ablation in all patients irrespective of age, and decreased after ablation. Of 25 patients 14 (56%) had renal damage, with a mean PRA of 36 +/- 4.5 ng/ml per hour compared to 26 +/- 8.2 ng/ml per hour in patients with normal renal function (chi-square 4.2 p = 0.01). Of the 14 patients with renal damage 9 (64%) had normal GFR at age 1 year but increased PRA. Of these 14 patients the accepted criteria for renal damage of increased serum creatinine, high grade reflux, scars and decreasing GFR were present in only 6 (43%), 3 (21%), 2 (14%) and 4 (29%), respectively. PRA was increased in all 14 cases. CONCLUSIONS: PRA was increased before valve ablation and decreased after ablation. It is increased in patients with early renal damage. Our preliminary observations indicate that PRA may be helpful in identifying patients with early renal damage.     

Induction versus noninduction therapy in kidney transplantation: considering different PRA levels and different induction therapies

To evaluate the rate of acute cellular rejection (ACR) and long-term results in different levels of anti-HLA sensitization, using noninduction or different induction therapies, 763 patients who underwent transplantation from January 1995 to December 2001 were evaluated: 213 patients received induction therapy, 71 received Thymoglobulin (Thymo), 66 Simulect, and 44 OKT3. Follow-up time was at least 1 year for all groups. The Simulect group included older recipients and the OKT3 group had more female patients. Simulect and OKT3 groups had more black patients; Thymo and OKT3 groups had more retransplantations. PRA was low in the noninduction group (mean, 7%) and about the same in the Simulect and Thymo groups (mean, 30%). OKT3 was the most sensitized group (mean = 59%). Dialysis during the first posttransplantation week was more frequent among the induction groups (43% vs 65%; P <.005). Fewer patients experienced rejection episodes in the Thymo group (20% vs 50%; P =.02). Patients were classified according to their level of sensitization, and the Thymo group showed the lower rejection rates in all levels (mean, 20%; P =.001). When analyzing PRA >50%, the Thymo group showed lower rejection rates (12% vs 50%; P =.02). At this level of sensitization, there was no significant difference on graft loss and death with a functioning graft. There was a trend to more cytomegalovirus (CMV) disease in the Thymo group (33% vs 23%; P =.08). Two PTLD were diagnosed, both in the noninduction group. Renal function was better in the Thymo group (1.3 mg/dL). In conclusion, Thymo showed lower ACR rates in all PRA groups. No significant differences in CMV infection, tumors, and patient survival were observed.     

Mycophenolatemofetil for immunosuppression after liver transplantation: a follow-up study of 191 patients

BACKGROUND: Mycophenolatemofetil (MMF) combined with calcineurin inhibitors (CNIs) as immunosuppression after orthotopic liver transplantation (OLT) is still under discussion. We retrospectively investigated the immunosuppressive potency of MMF for treatment of steroid-resistant acute rejection (AR) or chronic rejection (CR), chronic graft dysfunction, and CNI-induced toxicity in patients after OLT. METHODS: Between 1988 and 2001 we performed 1386 OLTs in 1258 patients. Since 1995, 191 patients have received MMF after OLT for steroid-resistant AR or CR, chronic graft dysfunction (115 patients), and CNI-induced toxicity (76 patients). The mean follow-up time was 56 months. RESULTS: Of 47 patients with steroid-resistant AR, 12 had been treated with OKT3, without resolving the rejection. Overall, bilirubin and transaminases decreased significantly within 2 weeks after the addition of MMF, and liver function normalized in 38 patients. Five of eight patients with CR demonstrated stable liver function after a follow-up of 55+/-8 months; 52 of 60 patients with chronic graft dysfunction improved within 3 months; and 46 of 59 patients with CNI-induced nephrotoxicity improved after MMF treatment and a reduction of CNIs (with a significant decrease in serum creatinine within 2 weeks and an increase of creatinine clearance within 3 months). Clinical symptoms improved in 10 of 12 patients with neurotoxicity and four of five patients with hepatotoxicity. Side effects of MMF, such as gastrointestinal disorders or bone marrow toxicity, occurred in 60 patients (31.4%). The incidence of infections did not increase. Patient survival was 93%, and graft survival was 88.2%. CONCLUSIONS: MMF is a potent and safe immunosuppressive agent in OLT recipients for rescue therapy in AR, CR, or chronic graft dysfunction and helps to reduce the serious toxic side effects of CNIs.     

Subclinical Acute Antibody-Mediated Rejection in Positive Crossmatch Renal Allografts

Subclinical antibody-mediated rejection (AMR) has been described in renal allograft recipients with stable serum creatinine (SCr), however whether this leads to development of chronic allograft nephropathy (CAN) remains unknown. We retrospectively reviewed data from 83 patients who received HLA-incompatible renal allografts following desensitization to remove donor-specific antibodies (DSA). Ten patients had an allograft biopsy showing subclinical AMR [stable SCr, neutrophil margination in peritubular capillaries (PTC), diffuse PTC C4d, positive DSA] during the first year post-transplantation; 3 patients were treated with plasmapheresis and intravenous immunoglobulin. Three patients had a subsequent rise in SCr and an associated biopsy with AMR; 5 others showed diagnostic or possible subclinical AMR on a later protocol biopsy. One graft was lost, while remaining patients have normal or mildly elevated SCr 8-45 months post-transplantation. However, the mean increase in CAN score (cg + ci + ct + cv) from those biopsies showing subclinical AMR to follow-up biopsies 335 +/- 248 (SD) days later was significantly greater (3.5 +/- 2.5 versus 1.0 +/- 2.0, p = 0.01) than that in 24 recipients of HLA-incompatible grafts with no AMR over a similar interval (360 +/- 117 days), suggesting that subclinical AMR may contribute to development of CAN.     

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.     

Pretransplant cellular alloimmunity as assessed by a panel of reactive T cells assay correlates with acute renal graft rejection

BACKGROUND: The panel reactive antibody test (PRA) is an established method for assessing posttransplant risk of immune-mediated graft injury. The panel of reactive T cell assay (PRT) in which transplant candidates' peripheral blood mononuclear cells are tested for reactivity to a panel of allogenic stimulator cells by the IFN-gamma enzyme-linked immunosorbent spot assay analogously assesses the strength of the pretransplant effector-memory alloreactive T cell repertoire. METHODS: PRT assays were performed in 30 kidney transplant candidates and results were correlated with acute rejection (AR). A positive PRT assay was defined as a response to at least 75% of the stimulators tested. RESULTS: A positive pretransplant PRT test was observed in 11 of 30 (37%) patients, and AR within 1 year posttransplantation was seen in 7 of 30 (23%) subjects. Six of the seven (86%) patients with AR were PRT-positive (P=0.01) whereas only one of seven (14%) patients with a PRA greater than 15% had AR. The mean pretransplant PRT percentage was 40% for patients with no AR versus 81% for patients with AR (P=0.01). Estimated glomerular filtration rate (mL/min/1.73 m2) showed a trend towards a lower value in PRT-positive (48+/-15) versus PRT-negative (55+/-13) individuals. CONCLUSIONS: The data suggest that pretransplant PRT screening can identify patients at risk for posttransplant cellular immune mediated graft injury despite the absence of humoral allosensitization. Once confirmed by larger prospective trials, PRT screening could be used to guide clinical decision-making with regard to choosing donor organs and individualizing immunosuppression regimens.     

Influence of induction therapy on rejection and survival in heart transplantation

BACKGROUND AND AIMS: Immunosuppressive therapy has undergone great changes in recent years as a result of the introduction of new drugs, presumed a prior to be more effective and better tolerated. The greatest advance seems to have been the introduction of interleukin-2 (IL-2) receptor antagonists. The objective of this study was to determine whether the use of IL-2 receptor antagonists in induction therapy has implications for the development of rejection and survival. MATERIALS AND METHODS: Three hundred sixty-five consecutive cardiac transplant patients who received induction therapy were included. Heart-lung and transplants in children under 10 years were excluded. Three groups were compared according to the induction therapy (OKT3, 10 days; OKT3, 7 days; and IL-2R antagonists). Each treatment corresponded to a time period: OKT3 10 days from June 1989 to April 1994; OKT3 7 days from May 1994 to October 2002; and IL-2R antagonists from November 2002 to May 2004. Baseline characteristics of recipient and donor, surgical times, postsurgical complications, maintenance immunosuppression, number of rejections, time (days) to first rejection, and probability of survival at 1 year were recorded. We used analysis of variance, chi(2) test, Kaplan-Meier curves, and log-rank test as appropriate. A P-value < .05 was considered significant. RESULTS: There were significant differences in the characteristics of the transplanted patients in the various time periods. Thus, recipients in the OKT3 10 day group had worse status but better donors, whereas recipients in the IL-2R antagonists group had better status but older donors with longer duration of ischemia. The incidence of acute graft failure was similar in the three groups. The number of rejection episodes in the first year was higher among the OKT3 groups (OKT3 10 days, 1.7 +/- 1.3; OKT3 7 days, 1.2 +/- 1.2; IL-2R antagonists, 1.0 +/- 1.2; P = .02) and the probability of survival at 1 year was also lower (OKT3 10 days, 74%; OKT3 7 days, 77%; IL-2R antagonists, 94%; P = .0007). CONCLUSIONS: Induction therapy with IL-2 antagonists offers important advantages over treatment with OKT3 in terms of survival, with absolute and relative risk reductions of 20% and 27%. Furthermore, it did not increase the number of rejections, although this may have been due to the greater use of MMF versus azathioprine.     

Kidney and pancreas transplantation without a crossmatch in select circumstances – it can be done

Given the constant flux in caseload and the number of personnel available in the OR, waiting for a final XM often prolongs organ preservation time (a room available at the time a XM is started is not available when the XM is completed). Longer preservation is associated with increased DGF and decreased graft survival. We have shown in a retrospective analysis that final XMs on 0% PRA recipients were always negative (Transplantation, 1999). We now describe a policy of: a) not doing screening XM and b) proceeding to the OR without a XM, in situations where the recipients's PRA has been documented to be 0% and when there have not been any interim transfusions (and the OR is ready before XM completion). Final XM is completed after the transplant. All patients send sera every 6 weeks for PRA (antiglobulin technique). If > o r=3 consecutive PRAs are 0%, no donor-specific screening XM is done prior to calling the patient in for tx (UNOS allocation algorithm used). If there have not been any interim transfusions, we have proceeded to tx prior to completion of the final XM. Between 1/1/98-12/31/99, we did 109 CAD kidney (K) and 79 simultaneous kidney pancreas (SPK) tx; 67 (61%) K and 56 (71%) SPK had 0% PRA. Of the 0% PRA, 25/67 (37%) K and 28/56 (50%) SPK had no pre-tx XM. For K with no XM, cold ischemia was shorter (13.2+/-0.2 vs. 18+/-0.9 hrs, p=0.01) and DGF less (12% vs. 24%, p=0.3); for SPK with no XM, cold ischemia was shorter (15.2+/-2 vs. 18+/-0.9 hrs, p=0.1); no diff in DGF. All post-XM were negative and there were no hyperacute rejections; there was no diff in acute rejection episodes. Actuarial 1 yr graft survival: no XM-K=87.5%, SKP=82%; Yes XM-K=88%, SKP=86% (NS). Our data suggests it is safe, in select circumstances, to proceed to the OR without a XM. Elimination of the screening XM for 0% PRA candidates saves money. Proceeding of the OR (if available) without a final XM shortens cold ischemia time.