Argiris Asderakis

Multidisciplinary insights into optimizing adherence after solid organ transplantation

Background. Nonadherence to medical treatment in transplant recipients is a major risk factor for graft rejection episodes, and it has significant financial implications. Despite its importance, there is a lack of common understanding across the disciplines involved of the key issues driving nonadherence. Methods. A qualitative study, comprising a multidisciplinary workshop, followed by a consultation exercise to validate its outcomes, was initiated to gain further insight into nonadherence behavior and to identify priorities for optimizing adherence to posttransplantation regimens. Results. Eight statements relating to actions necessary to maximize adherence to posttransplantation medication were developed and offered for validation. All but one of these attracted a median score of 9 on an agreement scale of 1 to 10, where 10 was the highest level of agreement. Conclusion. The outcomes generate a structure that will facilitate communication and understanding and informing clinical practice and future research.

The influence of socioeconomic deprivation on outcomes following renal transplantation in the United kingdom.

Socio‐economic deprivation is an important determinant of poor health and is associated with a higher incidence of end‐stage renal disease, higher mortality for dialysis patients and lower chance of being listed for transplantation. The influence of deprivation on outcomes following renal transplantation has not previously been reported in the United Kingdom. The Welsh Index of Multiple Deprivation was used to assess the influence of socio‐economic deprivation on outcomes for 621 consecutive renal transplant recipients from a single centre in the United Kingdom transplanted between 1997 and 2005. Outcomes measured were rate of acute rejection and graft survival. Patients from the most deprived areas were significantly more likely to experience an episode of acute rejection requiring treatment (36% vs. 27%, p=0.01) and increasing overall deprivation correlated with increasing rates of rejection (p=0.03). Income deprivation was significantly and independently associated with graft survival (HR 1.484, p=0.046). Among patients who experienced acute rejection 5‐year graft survival was 79% for those from the most deprived areas compared with 90% for patients from the least deprived areas (p = 0.018). Overall socio‐economic deprivation is associated with higher rate of acute rejection following renal transplantation and income deprivation is a significant and independent predictor of graft survival.

Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol

BackgroundKidney transplantation is the best treatment for patients with end-stage renal failure, but uncertainty remains about the best immunosuppression strategy. Long-term graft survival has not improved substantially, and one possible explanation is calcineurin inhibitor (CNI) nephrotoxicity. CNI exposure could be minimized by using more potent induction therapy or alternative maintenance therapy to remove CNIs completely. However, the safety and efficacy of such strategies are unknown.Methods/DesignThe Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C) Study is a multicentre, open-label, randomized controlled trial with 852 participants which is addressing two important questions in kidney transplantation. The first question is whether a Campath (alemtuzumab)-based induction therapy strategy is superior to basiliximab-based therapy, and the second is whether, from 6 months after transplantation, a sirolimus-based maintenance therapy strategy is superior to tacrolimus-based therapy. Recruitment is complete, and follow-up will continue for around 5 years post-transplant. The primary endpoint for the induction therapy comparison is biopsy-proven acute rejection by 6 months, and the primary endpoint for the maintenance therapy comparison is change in estimated glomerular filtration rate from baseline to 2 years after transplantation. The study is sponsored by the University of Oxford and endorsed by the British Transplantation Society, and 18 centers for adult kidney transplant are participating.DiscussionLate graft failure is a major issue for kidney-transplant recipients. If our hypothesis that minimizing CNI exposure with Campath-based induction therapy and/or an elective conversion to sirolimus-based maintenance therapy can improve long-term graft function and survival is correct, then patients should experience better graft function for longer. A positive outcome could change clinical practice in kidney transplantation.Trial registrationClinicalTrials.gov, NCT01120028 and ISRCTN88894088

Clinical Significance of a Positive Flow Crossmatch on the Outcomes of Cadaveric Renal Transplants

Pretransplantation crossmatching is an integral part of kidney transplantation. Flow cytometric crossmatch (FCXM) is more sensitive than complement-dependent cytotoxic crossmatch (CDC-XM). However, the clinical significance of positive FCXM with negative CDC-XM is controversial. We evaluated FCXM in 455 consecutive deceased donor renal transplants. All had a negative CDC-XM. There were 341 T-cell and B-cell FCXM negative and 38 T-cell and B-cell positive. There was a higher percentage of retransplantations and HLA mismatches (26.3% vs 8.2%, P= .002 and 2.45 vs 1.99, P= .02, respectively) in the FCXM-positive group compared with the FCXM-negative group; 65.8% of the FCXM-positive patients had rejection compared with 49.3% of the FCXM-negative patients (odds ratio [OR]=1.89, P= .06). FCXM-positive patients had a higher incidence of vascular rejection (28.9% vs 12.6%, OR=2.68, P= .008). One- and 5-year graft survivals were 84% and 66% in the FCXM-positive group vs 90% and 75% in the FCXM-negative group. Censoring for patient death, 1- and 5-year graft survivals were 84% and 73% in the FCXM-positive group vs 94% and 82% in the FCXM-negative group. There was no difference in renal function between the 2 groups. In conclusion, a positive T-cell and B-cell FCXM transplant with a negative CDC-XM is associated with a higher incidence of rejection, twice the risk of vascular rejection, and a trend toward poorer graft survival.

Impact of expanded criteria variables on outcomes of kidney transplantation from donors after cardiac death

Introduction To expand the donor pool, kidney transplants are being performed using donors who were previously considered unacceptable. We applied the United Network for Organ Sharing criteria to define expanded criteria donors (ECD) within the donation after cardiac death (DCD) and donation after brain stem death (DBD) cohorts. We compared outcomes of DCD and DBD transplants with and without (standard criteria donor [SCD]) the ECD criteria. Methods This was a single-center retrospective study of all deceased donor transplants from 2004 to 2010 (n=359). Four groups were identified—DBD-SCD (n=154), DBD-ECD (n=93), DCD-SCD (n=78), and DCD-ECD (n=34). Kaplan-Meier analysis of graft and patient survival and multiple regression analysis of 1-year graft function were performed. Results One-year and two-year uncensored graft survivals were similar between DCD-ECD and DCD-SCD cohorts (1 year, 90% and 93%; 2 years, 81% and 93% respectively; log-rank test P=0.2). Median estimated glomerular filtration rate (eGFR) was lower in DCD-ECD recipients at 12 months (41 vs. 53 mL/min, P=0.003) and 24 months (33 vs. 54 mL/min, P<0.001) compared with DCD-SCD recipients. Compared with DBD-ECD recipients also at 24 months, DCD-ECD recipients showed a lower graft function (median, eGFR 33 vs. 47 mL/min; P=0.007) but similar graft survival. Expanded criteria donor status (B=−9.7, P=0.01) was associated with a lower 1-year eGFR within the DCD cohort, with donor age (B=−0.42, P=0.002) being the only significant ECD variable. Conclusion Short-term graft survival in DCD-ECD transplants was comparable to DCD-SCD and DBD-ECD transplants albeit with poorer allograft function at 2 years. Quality-of-life studies are needed to determine the true value of these transplants, particularly when performed to older recipients.

Increased nitric oxide production during acute rejection in kidney transplantation: a useful marker to aid in the diagnosis of rejection.

Background. The diagnosis of acute rejection (AR) relies on biopsy (Bx), with all the noninvasive tests failing to show satisfactory predictive value. Nitric oxide (NO) has been shown to play a role in AR. The aim of this study is to analyze the relationship between NO and (1) biopsy-proven allograft rejection and (2) other reasons of allograft dysfunction. Patients and Methods. Fifty consecutive renal allograft recipients ages 23–72 yrs who were transplanted were prospectively recruited. Blood samples were collected for 3 months. Endogenous serum nitrate (SNO3) levels were measured with Griess reagent in 1178 samples. Biopsies were performed as clinically indicated. Tacrolimus levels, urinary cultures, and renal function tests were done as per unit protocol. Results. Fifty recipients (mean±SD age 45.2±2.18 yrs, 24 men and 6 women) underwent 68 biopsies. Forty-five Bx (66.2%) showed AR in 19 recipients (mean age 47±8) and 23 (33.8%) Bx in 13 recipients (mean age 43±12) showed no AR. SNO3 in AR was (73±8.89 &mgr;mol/L) compared with negative Bx (45±4.5 &mgr;mol/L; P<0.05). There was also a significant difference in SNO3 during AR and other causes of allograft dysfunction; delayed graft function (54±7.8 &mgr;mol/L), urinary tract infection (44±2.9 &mgr;mol/L), tacrolimus toxicity (51±2.86 &mgr;mol/L), and increase in serum creatinine (44±2.36 &mgr;mol/L). Conclusion. There is a significant increase of serum nitrate with episodes of acute rejection compared with other causes of renal dysfunction. SNO3 can therefore aid in the diagnosis of acute rejection.

The influence of socioeconomic deprivation on outcomes in pancreas transplantation

Socioeconomic deprivation is an important factor in determining poor health and is associated with a higher prevalence of many chronic diseases including diabetes and renal failure, with poorer outcomes of their treatments.

The Effect of a Longer Cold Ischemia Time for the Second Transplanted Kidney from the Same Donor - a Paired Kidney Analysis from Donation after Cardiac Death Donors: 1323

Introduction: In paired kidney analyses of donation after brain-stem death (DBD) kidney transplantation, prolonged cold ischemia time (CIT) is a risk factor for delayed graft function (DGF) and possibly poor allograft outcomes. No similar reports exist for donation after cardiac death (DCD) kidney transplantation. Methods: To determine the effect of CIT on DGF and graft outcomes in DCD kidney transplants, we undertook a retrospective paired recipient analysis of our centre‘s 48 DCD donors and the corresponding 96 recipients between 2004 and 2010. The 2 recipients from a single donor were transplanted in our own centre sequentially due to logistic reasons, resulting in a longer CIT for the second transplant. Conventional cold storage was used for all kidneys. We compared the following end-points between the 2 groups (1st transplant=Group 1 & 2nd transplant=Group 2; the only differing donor / process characteristic being CIT ) DGF, duration of DGF, 1-year graft survival and 1& 2-year allograft function by estimated GFR (MDRD). Results: Median warm ischemia time was 17 minutes (range 10-24 minutes) and median donor age was 50 years (range 17-74 years). Median CIT was significantly longer for Group 2 (16.5 hours, range 1024) compared to Group 1 (10.3 hours, range 5-14, p< 0.001). Median follow-up time was 24 months. Recipient characteristics are given in the table. Group 2 recipients were older compared to Group 1 recipients (median 57 vs. 51 years, p=0.02).

RO-101 Nitric oxide post-perfusion levels differ in DCD and DBD donor transplants [Abstract]

RO-194 – Classification at 6 weeks and fibrosis/atrophy at one year Variables at one year Classification of biopsies at 6 weeks p (neg vs. bord) p (neg vs. rej) p (bord vs. rej) Negative (n=100) Borderline (n=43) Rejection (n=14) Interstitial fibrosis 0.80 (0.71) 0.91 (0.43) 0.71 (0.47) 0.36 0.66 0.17 Tubular atrophy 1.03 (0.63) 0.98 (0.34) 0.71 (0.46) 0.60 0.073 0.028 Mean (SD). were placed on MPP (pulsatile perfusion machine, RM3) and all patients received the same immunosuppressive treatment. Estimated MDRD and inuline clearance were analysed until 36 months after transplantation and systematic biopsies were performed at M3 and M12 to evaluate the chronic interstitial fibrosis (IF) by colour image quantification. Our experience with RM3 perfusion machine leads us to perform a SKG when the resistance index (RI) is lower than 0.4 after 6 hours of perfusion and a DKG when the RI is between 0.4 and 0.6. Donor’s and recipient’s characteristic (mean age, gender), mean numbers of HLA mismatch were not significantly different. The mean duration time of MPP and the mean warm ischemic time were higher in the DKG than in the SKG group (1319 vs 689 min, p= 0.05 and 105 vs 121 min, p=0.017). Patient and graft survivals were 100% in both groups. PNF (not observed in our cohort) and DGF rate were not statistically different between the 2 groups (100% vs 78%). Acute rejection rate was not different between the groups. Graft outcomes and IF results are reported table 1. Table 1. Evolution of graft function and histology

DOES ANTITHYMOCYTE GLOBULIN (ATG) INDUCTION REMAIN A RISK FACTOR FOR POSTTRANSPLANT LYMPHOPROLIFERATIVE ?: 1612

Introduction and Aim: Posttransplant Lymphoproliferative Disease (PTLD) is a well recognized complication following transplantation with an incidence of approximately 1% for adult renal transplant recipients. Although the presentation and clinical course is variable, mortality rates can be high. The majority of cases occur within the first year posttransplant and the main risk factors for development of PTLD are recipient pretransplant Epstein-Barr virus (EBV) seronegativity, donor EBV seropostivity and high levels of immunosuppression. The total burden of immunosuppression appears to be a very significant factor in determining risk, and more intense immunosuppression regimes have been associated with an earlier occurrence of the disease. Previous studies have suggested an increased incidence of PTLD (up to 4% at 1 year) in patients who have received induction with lymphocyte depleting agents (antithymocyte globulin ATG) and the number of doses of depleting antibody therapy has also been associated with the incidence of PTLD. This study investigates the incidence of PTLD following ATG use as an induction agent in a single transplant unit performing renal and pancreas transplantation. Methods and results: In this unit ATG is used as induction therapy for all recipients of pancreas transplant and for kidney transplant recipients from donors post cardiac death (DCD). Patients receive daily doses of 1.25mg/ kg over 5 days with the first dose given intra-operatively. Steroids are part of the maintenance regime in DCD kidneys for 3 months whereas they are not used in pancreas recipients. All patients received tacrolimus as oral maintenance therapy to achieve a trough level of 7-10microgram/l and mycophenolate 1 gram twice daily. If not tolerated the dose was reduced to the maximum tolerated dose. During the time period from September 2004 to October 2008 a total of 112 patients received ATG induction; 58 pancreas recipients and 56 DCD kidney recipients. All patients were under the age of 60 years old. All patients were reviewed 1 year post transplant (median follow up of 30 months) however; none of the patients have developed PTLD during the follow up period refuting the notion that induction with lymphocyte depleting agents is a consistent risk factor for PTLD development. Conclusion: In our experience the use of ATG as an induction agent using the above regime for pancreas or renal transplant recipients under the age of 60 years old, is not associated with increased risk of PTLD in the first year post transplant.