R. Pretagostini

Evaluation of pretransplant immunologic status in kidney-transplant recipients by panel reactive antibody and soluble CD30 determinations.

Objectives. To retrospectively compare the accuracy of pretransplant panel of reactivity antibodies (PRA) and serum level of soluble CD30 (sCD30) in predicting early (<6 months) acute rejection (AR) in living-donor and deceased-donor kidney-transplant (KT) patients. Methods. Pretransplant sera of 24 KT recipients were retrospectively tested for sCD30 and compared with PRA. Inclusion criteria were de novo graft patients on calcineurin–inhibitor-based immunosuppression, minimum follow-up of 1 year, alive with a functioning graft, and stable renal function over the last 12 months. Objective measures were incidence of biopsy-proven AR (BPAR) within 6 months of KT and sCD30 and PRA diagnostic indexes. The relative risk (RR) of BPAR for each test was also obtained. Results. Fourteen (58.3%) patients presented at least one episode of BPAR within 6 months of KT. All rejection episodes were responsive to steroid treatment. PRA was positive in six (25%) patients, and four (66.7%) of them presented at least one episode of BPAR. sCD30 tested positive in nine (37.5%) patients, and all these later presented at least one episode of BPAR. sCD30 and PRA diagnostic indexes in predicting early (< 6months) BPAR were sensitivity 64.2% versus 28.5%; specificity 100% versus 80%; accuracy 79.1% versus 50%; positive predictive value 100% versus 66.6%; and negative predictive value 66.6% versus 44.4%. The RR of early AR was 1.4 in PRA-positive patients and extremely higher in the sCD30-positive group. Conclusions. Pretransplant sCD30 is a more accurate predictor of AR when compared with PRA. These results support its use in the pretransplant work-up of kidney-graft recipients.

Tailoring of immunosuppression in renal and liver allograft recipients displaying donor specific T-suppressor cells.

Although transplantation tolerance cannot be yet reliably achieved in humans, there is evidence that active immunosuppression contributes to the maintenance of quiescence. However, the mechanism that underlies quiescence and the precise identity of regulatory cells are not completely understood. We have demonstrated that allograft recipients who remain rejection-free display allospecific T-suppressor cells (Ts). Ts express the CD8(+) CD28(-) phenotype, recognize major histocompatibility complex (MHC) class I antigens, and suppress the up-regulation of costimulatory molecules induced by CD40 ligation of donor antigen presenting cells. The presence of Ts is inversely correlated with T cell alloreactivity to donor MHC peptides, alloantibody production, and rejection. Monitoring of Ts has been successfully used in our studies for tailoring immunosuppression in kidney and liver allograft recipients.

Immunoadsorption with protein A in humoral rejection of kidney transplants

The presence of alloantibodies may play a role in accelerated or acute humoral rejection. Different therapeutic strategies based on a removal of anti donor antibodies and prevention of their resynthesis have been used in the management of transplant rejection episodes. Immunoadsorption with staphylococcal protein A, a method to selectively remove immunoglobulin G, may represent a new treatment to reverse humoral rejection in kidney transplantation. From 1991 to January 1996, such a method was used in 23 patients in whom an acute humoral rejection developed over a mean period of 14.1 +/- 9.5 days after operation. Twenty-two patients had been transplanted from living donors and one from a cadaveric donor. The ages ranged from 23 to 58 years (mean, 34 +/- 10 years). All transplants were performed according to a negative direct crossmatch. Basic immunosuppression included cyclosporine, steroids, azathioprine, and antilymphocyte globulin or monoclonal antibodies (OKT3). Rejection was diagnosed on the basis of hematochemical tests, Doppler ultrasonography, and kidney biopsy. Only steroid and monoclonal and polyclonal antibody resistant rejections with > 165% positive direct crossmatches against the donor were treated with Protein A immunoabsorption. The procedure used is based on the treatment of 2-3 plasma volumes for the first 2 days and then every other day until a negative crossmatch is obtained, together with improvement in clinical status (mean treatments, 7.3 +/- 4.5 [range, 4-23]; mean duration of treatment, 12.3 +/- 10.2 days [range, 3-44]). From the start of treatment, azathioprine is replaced by cyclophosphamide at a dose of 1-2 mg/kg/day. During treatment, a remarkable fall in immunoglobulin G levels is achieved on the first day, whereas immunoglobulin M titers remain constant, with a slight decrease in serum albumin. Immediately after treatment, a negative crossmatch was found in 22 (95.6%) of 23 patients. In six patients (26%), graft function did not recover, and one patient (4.3%) died. Preliminary results show that immunoabsorption with staphylococcal protein A may be an effective support in the treatment of humoral acute rejection, particularly when it is performed as soon as an early diagnosis of humoral rejection is made. In fact, such treatment has a highly selective adsorption, allows treatment of large volumes of plasma, and can achieve a rapid decrease in the titer of circulating immunoglobulins.

Clinical Results of Treatment of Postsurgical Endotoxin-Mediated Sepsis With Polymyxin-B Direct Hemoperfusion

We evaluated the possibility of preventing the evolution of endotoxin-mediated sepsis in severe septic shock using early treatment of critical endotoxemia with polymyxin-B direct hemoperfusion (PMX-DHP). Thirty-eight postsurgical patients who fulfilled at least 2 criteria for systemic inflammatory response syndrome were stratified on the basis of the value of the endotoxin activity assay. Seventeen patients who demonstrated high risk of endotoxin activity (>or=0.6) received standard therapy plus PMX-DHP every 24 hours to lower the endotoxin activity level to less than 0.4, and the remaining 21 patients with endotoxin activity levels less than 0.6 received standard therapy only. Seven patients required 2 courses of PMX-DHP therapy, 8 required 3 courses, and 2 required 4 courses. After treatment, mean arterial pressure increased, from 69.00 mm Hg to 81.35 mm Hg (P < .01); heart rate decreased, from 105.40 bpm to 78.12 bpm (P < .01); white blood cell count decreased, from 20,700 cells/mm(3) to 9740 cells/mm(3) (P < .01); arterial oxygen tension-fraction of inspired oxygen ratio increased, from 273.82 to 305.82 (P < .01); and Sequential Organ Failure Assessment score decreased, from 7 to 4 (P < .01). Length of stay was longer for transplant recipients (16 days) than for other surgical patients (8(1/2) days). All patients survived to 28-day follow-up, and 15 of 16 patients (94%) had survived at 60-day follow-up. Despite the small number of patients included in the study, the encouraging results suggest that PMX-DHP is a useful therapeutic strategy for lowering sepsis-related mortality.

Preharvest donor hyperoxia predicts good early graft function and longer graft survival after liver transplantation

A total of 44 donor/recipient perioperative and intraoperative variables were prospectively analyzed in 89 deceased‐donor liver transplantations classified as initial good graft function (IGGF) or initial poor graft function (IPGF) according to a scoring system based on values obtained during the 1st 72 postoperative hours from the serum alanine aminotransferase (ALT) concentration, bile output, and prothrombin activity. The IGGF compared with the IPGF group showed: 1) longer graft (P = .002) and patient (P = .0004) survival; 2) at univariate analysis, a higher (mean [95% confidence interval]) preharvest donor arterial partial pressure of oxygen (PaO2) (152 [136‐168] and 104 [91‐118] mmHg, respectively; P = .0008) and arterial hemoglobin oxygen saturation (97.9 [97.2‐98.7] and 96.7 [95.4‐98.0]%, respectively; P = .0096), a lower percentage of donors older than 65 years (13 and 33%, respectively; P = .024), a lower percentage of donors treated with noradrenaline (16 and 41%, respectively; P = .012). At multivariate analysis, IGGF was associated positively with donor PaO2 and negatively with donor age greater than 65 years and with donor treatment with noradrenaline. Independently from the grouping according to initial graft function, graft survival was longer when donor PaO2 was >150 mmHg than when donor PaO2 was ≤150 mmHg (P = .045). In conclusion, preharvest donor hyperoxia predicts IGGF and longer graft survival. (Liver Transpl 2005;11:140–151.)

Minimization of immunosuppressive therapy and immunological monitoring of kidney transplant recipients with long-term allograft survival

Incidence of cardiovascular complications, cancers and chronic allograft nephropathy (CAN) suggests reduction of immunosuppressive dosages. Some studies analyzed the effects of minimization of immunosuppression until the avoidance of immunosuppressive drugs. However minimization seems to be related to a higher incidence of acute rejection. Induction of tolerance after transplantation and use of immunological tests that could monitor the immune reactivity are required. The aim of this study is to evaluate immunological state in a group of recipients after deceased and living donor kidney transplantation and to minimize immunosuppressive therapy monitoring simultaneously clinical and immunological parameters. We analyzed 41 patients, 38 from deceased donors and 3 from living donor kidney transplantation. All patients were treated with triple immunosuppressive therapy: cyclosporine or sirolimus or tacrolimus, mycophenolate mofetil and steroids. In all recipients the presence of CD8+CD28- T suppressor cells (Ts) was analyzed. Patients were divided in 2 groups, according to the presence of Ts. In patients with Ts, (Group A, n=19), mycophenolate mofetil (MMF) was progressively reduced and then stopped. Steroids were subsequently reduced and then interrupted, maintaining an immunosuppressive therapy with low doses of calcineurin inhibitors (CNI) or sirolimus (SIR). 22 patients were without presence of Ts: we enrolled for the study only patient acute rejection free, without proteinuria and with creatinine levels stable (Group B, n=19). In these patients, MMF was reduced and then stopped, while steroids were decreased to 5 mg at alternate days, maintaining CNI or SIR at medium therapeutic dosages (minimized therapy). Patient and graft overall survival in Group A and in Group B were respectively at 100% and 94.7%. Incidence of acute rejection was respectively at 0% in group A and 15.7% in Group B. Presence of episodes of acute rejection in Group B confirms risk of later minimization of steroids and the relevance of the analysis of recipient immunological reactivity before modification of immunosuppressive therapy. A careful evaluation of recipient immune reactivity with the presence of T regulatory cells can allow adequate and personalized immunosuppressive regimens, without high risks of acute rejection.

Early Urine Output Predicts Graft Survival After Kidney Transplantation

BACKGROUND In kidney transplantations, the identification of early postoperative parameters with high predictive power for the development of late allograft dysfunction has important implications for clinical practice. This study sought to determine these parameters in a single-center cohort. METHODS We studied 82 deceased donor renal transplantation. We assessed the following measures: dialysis-dependent delayed graft function (ddDGF), extended DGF, serum creatinine level at day 7, creatinine reduction ratio at day 7, urine output at day 1 and at day 7 posttransplantation (UO7). RESULTS Only UO7 showed a significant result upon multivariate analysis (P < .0001). It was less influenced by dialysis with respect to measures based upon serum creatinine. By Receiver Operating characteristic (ROC) analysis, it showed an elevated area under the curve (0.811), with a cut-off value of 500 mL/24 h, showing high sensitivity (98.5%). CONCLUSIONS UO7 may be of clinical utility to assess the risk for subsequent renal dysfunction.

Delayed Graft Function Decreases Early and Intermediate Graft Outcomes After Expanded Criteria Donor Kidney Transplants

Use of expanded criteria donors (ECD) has increased worldwide in previous years because of the donor scarcity. However, ECD are related to a greater risk of complications and shorter graft longevity. Delayed graft function (DGF) which impacts renal graft survival, represents one of the most common complications posttransplantation. The purpose of this study was to analyse DGF incidence among ECD kidneys and its role on early and intermediate recipient and graft survivals. We prospectively analyzed 46 ECD cases divided as group A (absence of DGF; n = 23) and B (DGF; n = 23). Group B was composed of older donors (P = .033) with longer cold ischemia times (P = .017), and greater incidences of acute rejection episodes (ARE) (P < .0001). Comparing group A with group B, we observed 1-year and 3-year overall recipient survivals to be 95.7% and 95.7% versus 91.3% and 91.3%, respectively (P = not significant). Censored 1-year and 3-year overall graft survivals were 100% and 92.9% versus 85.6% and 79.9%, respectively (P = .026). Analyzing the patients with DGF without (n = 9) versus with concomitant ARE (n = 14), no differences were noted in recipient and graft survivals. The incidence of DGF was strictly related to increased donor age, greater cold ischemia time, and presence of an ARE while DGF did not have a role in recipient survival, it reduced, graft survival. Concomitant ARE was not related to an impaired graft function.

Simultaneous pancreas-kidney transplantation: a single-center experience and prospective analysis.

In patients with end-stage chronic kidney disease (CKD) and type 1 diabetes mellitus (DM 1), simultaneous pancreas-kidney (SPK) transplantation is currently considered the gold standard therapy. The aim of this study was to analyze and report the long-term clinical outcomes of the 23 SPK transplantations performed at our institution over an 84-month period (January 1, 2000 to December 31, 2006). A prospective analysis of these patients included donor, recipient, and transplantation characteristics. The only requirements for transplantation were blood group compatibility and a negative cross-match. Bladder drainage via pancreaticoduodenocystostomy was performed in all of the patients. Due to a pulmonary embolus 1 patient (4.3%) died at 2 months. The actuarial patient survival rates at 3 months and 1, 3, and 5 years were 95.6%. Causes for the renal graft loss were chronic allograft nephropathy in 3 cases (13%) and death of the patient in 1 case (4.3%). The actuarial censored renal allograft survival rates at 3 months and at 1 year were 100%, and at 3 and 5 years were 91.3%. Causes for the renal graft loss were chronic rejection in 1 case (4.3%) and patient death in 1 case (4.3%). The actuarial censored pancreatic allograft survival rates at 3 months and at 1 and 3 years were 100%, and at 5 years was 95.6%. The results of this work add further evidence that SPK is the gold standard therapy for selected patients with end-stage CKD due to DM 1.

Living kidney transplantation between spouses: results in 100 cases.

Abstract The use of unrelated living donors in kidney transplantation is still controversial but many transplant centres have accepted this procedure. The main argument against this approach is usually an ethical one. Because of this, at our institution we accept biologically unrelated donors only if they have an emotional closeness to the recipient. From January 1983 to October 1993, out of 654 kidney transplantations we performed at our institution, 364 kidney allografts were from living donors. Of these living donors, 245 were first‐degree relatives of the recipient (LRD) while 119 were unrelated (LURD); 100 cases were spouses‐wife to husband in 76 cases and husband to wife in 24 cases Statistical analysis of the results (chisquare) revealed actuarial patient and graft survival rates of 89.8% and 86.8% at 1 year, 82.9% and 72.3% at 5 years and 12.3% and 60.3% at 9 years, respectively. In our series, the result of living donor kidney transplantation in this group were similar to those obtained in the LRD group, while they were significantly better than those from cadaver donors (P = 0.003). In conclusion, cadaver organs given the shortage of kidney transplantation between spouses may be a good alternative and can be performed successfully, providing a “gift of life” for both the patient and the family.