Preserve Graft Function Research Articles

Inksto transplantato de novo karcinomos gydymas perkutanine radiodažnine abliacija: klinikinis atvejis

Pastebėta, jog piktybinių navikų dažnis žmonėms, kuriems persodinti inkstai, yra didesnis nei bendrojoje populiacijoje. Inkstų karcinomos sudaro 4,8 % visų navikų, nustatomų recipientams, ir vos 10 % – transplantate. Transplantato navikai gali būti perduoti donoro, metastazės iš kitų recipiento organų arba de novo (naujai) vystytis po transplantacijos. De novo navikai transplantate nustatomi vidutiniškai 10 metų po transplantacijos. Mes aprašome klinikinį atvejį 45 metų vyro, kuriam 16 metų po inksto persodinimo atsitiktinai aptikta besimptomė neišplitusi 15 mm dydžio papilinė inksto karcinoma apatiniame transplantato poliuje. Ligoniui sėkmingai atlikta minimaliai invazyvi procedūra – perkutaninė radiodažninė abliacija, kuri visiškai sunaikino naviką išsaugodama transplantato funkciją. Ankstyvųjų komplikacijų nenustatyta. Praėjus vieneriems metams po procedūros vėžinės ligos atsinaujinimo ar vėlyvųjų komplikacijų požymių nėra, išlieka adekvati transplantato funkcija be hemodializės poreikio.

Using Genetic Variation to Predict and Extend Long-term Kidney Transplant Function.

Renal transplantation has transformed the life of patients with end-stage renal disease and other chronic kidney disorders by returning endogenous kidney function and enabling patients to cease dialysis. Several clinical indicators of graft outcome and long-term function have been established. Although rising creatinine levels and graft biopsy can be used to determine graft loss, identifying early predictors of graft function will not only improve our ability to predict long-term graft outcome but importantly provide a window of opportunity to therapeutically intervene to preserve graft function before graft failure has occurred. Since understanding the importance of matching genetic variation at the HLA region between donors and recipients and translating this into clinical practise to improve transplant outcome, much focus has been placed on trying to identify additional genetic predictors of transplant outcome/function. This review will focus on how candidate gene studies have identified variants within immunosuppression, immune response, fibrotic pathways, and specific ethnic groups, which correlate with graft outcome. We will also discuss the challenges faced by candidate gene studies, such as differences in donor and recipient selection criteria and use of small data sets, which have led to many genes failing to be consistently associated with transplant outcome. This review will also look at how recent advances in our understanding of and ability to screen the genome are starting to provide new insights into the mechanisms behind long-term graft loss and with it the opportunity to target these pathways therapeutically to ultimately increase graft lifespan and the associated benefits to patients.

Presentation, diagnosis, and management of early hepatic venous outflow complications in whole cadaveric liver transplant.

Early hepatic venous outflow obstruction (HVOO) can be a devastating complication leading to graft loss after liver transplantation (LT). A retrospective study on 777 adult LT recipients over a 5-year period (August 2007 to August 2012) was undertaken to determine the incidence of early HVOO presenting within 3 months of transplant, its clinical features and management, and potential technical risk factors related to the implanting technique. Cases of early HVOO were screened for by identifying recipients with problematic ascites within 3 months of transplant. Definitive diagnosis for HVOO was based on a wedge pressure of >12 mm Hg. Considering only whole livers, the incidence of early problematic ascites was 3% (20/695) of which more than one-third (35%, 7/20) were then confirmed to have HVOO. Overall, the incidence of early HVOO was 1% (7/695). Two hepatic veins (HVs) with extension piggybacks (PBs; n = 423) were the dominant implanting technique in the time period of study rather than the 3 HV PB (n = 182) and caval replacement techniques (n = 82). Considering the implantation technique, all cases of HVOO occurred after 2 HVs when extension PBs had been used with an incidence of 1.7% (7/423). Institutionally, early HVOO was mainly managed surgically by either cavoplasty within a month of transplant (n = 4) or retransplant (n = 1), and the remainder (n = 2) were medically managed with diuretics. In conclusion, early HVOO is rare, and there is no evidence from this study that a given implantation technique is at a higher risk of developing HVOO (2 HV with extension versus 3 HV and caval replacement; P = 0.11). However, early revisional surgery for HVOO can preserve graft function with retransplantation being reserved for when surgical cavoplasty or radiological stenting is technically not possible.

Evolution of serum atherogenic risk in liver transplant recipients: Role of lipoproteins and metabolic and inflammatory markers.

Although cardiovascular disease (CVD) is the leading cause of long-term mortality in liver transplant recipients (LTRs), the role of recently identified biomarkers of CVD risk in liver transplantation is unknown. We aimed to evaluate an extensive CVD risk profile in LTRs. Markers of CVD risk in 65 LTRs with no known history of diabetes mellitus (DM), dyslipidemia, or ischemic heart disease were compared to age-, sex-, and body mass index (BMI)-matched controls with no chronic medical disease. LTRs on corticosteroids or those with graft cirrhosis (GC) were excluded. The effect of calcineurin inhibitors on the CVD risk profile was separately analyzed in LTRs receiving either tacrolimus (Tac) or cyclosporine A (CsA). To evaluate the impact of GC, a comparison was made between LTRs with and without GC. Non-DM LTRs were matched to controls with respect to age, sex, and BMI. LTRs had similar serum high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and total cholesterol in comparison with BMI-matched controls. Proatherogenic small-dense (sd) LDL-C (33.6 ± 14 versus 25.9 ± 9.9 mg/dL; P < 0.001) and %sdLDL-C (30% ± 10% versus 26.4% ± 9%; P = 0.02) were significantly higher in LTRs. In comparison with controls, LTRs had higher apolipoprotein B (apoB; 98 ± 37 versus 88 ± 24 mg/dL; P < 0.01), very low density lipoprotein-particle concentration (VLDL-P; 7.7 ± 6.7 nmol/L versus 3.2 ± 9.1 nmol/L; P < 0.001), and VLDL size (51.1 ± 6.6 versus 46.5 ± 6.9 nm; P < 0.001). In LTRs, VLDL size and VLDL-P were directly related to serum CsA levels (r = 0.53, P = 0.09, and r = 0.63, P < 0.01, respectively) but not to Tac levels. In comparison with controls, LTRs had significantly lower total serum high-density lipoprotein-particle concentration. In comparison with those with preserved graft function, LTRs with GC had lower levels of serum atherogenic markers characterized by low sdLDL-C, apoB, triglycerides, LDL-C, and total cholesterol. In conclusion, LTRs have a proatherogenic lipoprotein profile that is not captured with a traditional lipid panel, and this suggests that a detailed serum atherogenic profile is needed to truly assess CVD risk in LTRs.

A Retrospective Comparison of Once-Daily Prolonged-Release Tacrolimus Versus Twice-Daily Tacrolimus in Allogeneic Bone Marrow Transplantation from Unrelated Donors

Background: Oral tacrolimus (Tac) was first developed as a twice-daily formulation (Tac BID) and has been widely used in solid organ and allogeneic hematopoietic stem cell transplantation (allo-SCT). Lifelong immunosuppression is required to preserve graft function after solid organ transplantation, and medical nonadherence of transplant recipients has been identified as a major cause of allograft failure. It has been well documented that frequent drug dosing affects patients’ adherence. In response to this potential nonadherence problem, a once-daily modified release formulation of oral tacrolimus (Tac QD) has been developed. Results of randomized prospective phase III studies have indicated that Tac QD is well tolerated with similar efficacy and safety profiles as those of Tac BID in recipients after organ transplantation. Although Tac BID has been widely used in allo-SCT recipients, there are no available data on the use of Tac QD in this population. In this study, we compared retrospectively the efficacy of Tac QD versus Tac BID administration. The objective of this study was to investigate whether Tac QD is as effective as Tac BID in the setting of allo-SCT from unrelated donors.Methods: The study cohort included 77 consecutive patients who received allogeneic bone marrow transplantation from unrelated donors for treatment of hematologic malignancies between 2000 and 2014: AML (n=35), ALL (n=15), CML (n=8), MDS (n=12), NHL (n=5), and MPN (n=2). Patients received Tac iv from day -1 with short-term methotrexate (MTX) on days 1, 3, 6, and 11; Tac iv was converted to either Tac QD (n=37) or Tac BID (n=40) when the patients were engrafted and could tolerate oral medication. Doses were modified to maintain a whole-blood trough concentration of 8-12 ng/ml. Tac BID was administrated until Oct 2008, and Tac QD was used from Nov 2008. Kaplan-Meier estimates were used for overall survival (OS), and cumulative incidence estimates were used for acute GVHD, chronic GVHD, and non-relapse mortality (NRM).Results: Median age was 53 years (range: 23-66) for Tac QD cohorts and 39 years (range: 17-56) for Tac BID cohorts. Tac QD patients were older (P<0.01) and more likely to receive reduced intensity conditioning regimens (P<0.01) than Tac BID patients. The remaining other characteristics, namely, performance status, gender, disease stage, HLA disparity, and HCT-CI score, were evenly distributed between Tac QD and Tac BID cohorts. Median follow-up for survivors was 22 months in Tac QD cohorts and 111 months in Tac BID cohorts. Cumulative incidence of grade II-IV acute GVHD was 34% (95% CI, 19%-50%) for Tac QD cohorts and 29% (95% CI 16%-44%) for Tac BID cohorts (P=0.75). Incidence of grade III-IV acute GVHD was 6% (95% CI, 1%-17%) for Tac QD cohorts and 8% (95% CI 2%-20%) for Tac BID cohorts (P=0.67). There was no significant difference (P=0.23) in the incidence of chronic GVHD between Tac QD cohorts (33%, 95% CI, 18%-49%) and Tac BID cohorts (22%, 95% CI, 10%-37%). OS at 2 years was 62% (95% CI, 41%-78%) in Tac QD cohorts and 75% (95% CI 59%-86%) in Tac BID cohorts (P=0.58). The probability of developing NRM at 2 years was 15% (95% CI, 4%-32%) for Tac QD cohorts and 6% (95% CI 1%-17%) for Tac BID cohorts (P=0.49).Conclusions: Although Tac QD cohorts included older patients than Tac BID cohorts, there was no difference in the risk of acute GVHD or chronic GVHD between Tac QD cohorts and BID cohorts. As Tac QD possibly contributes to reducing physical and mental stress for patients who need to take several different medications, our findings may indicate that the use of Tac QD for GVHD prophylaxis is beneficial for patients undergoing allo-SCT from unrelated donors. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Surgical Complications Related to Transplanted Pancreas After Simultaneous Pancreas and Kidney Transplantation

ObjectiveSimultaneous pancreas and kidney transplantation (SPTKx) is characterized by the high rate and variability of postoperative complications, which could be a limitation of this treatment. The aim of this study was to evaluate prevalence, types, and severity of postoperative complications due to pancreas graft among the simultaneous pancreas and kidney recipients. MethodsPostoperative complications related to transplanted pancreas among 112 SPTKx recipients were analyzed. The cumulative survival rates for pancreas graft function and cumulative freedom from complication on day 60 after transplantation were assessed. Severity of complications was classified according to a modified Clavien-Dindo scale. ResultsThe 12-month cumulative survival rate for pancreatic graft was 0.74. Cumulative freedom from complication on the 60th day after transplantation was 0.57. The rates for II, IIIA, IIIB, IVA, and IVB severity grades were 10,6%, 4,5%, 19,7%, 44%, and 21,2%, respectively. The most severe (IVB) transplanted pancreas complications were due to graft inflammation, infection, pancreatic abscess, and local or diffuse necrosis. The most frequent reason for graft pancreatectomy was vascular thrombosis 35.9% (14/39). The mortality rate after graft pancreatectomy was significantly lower for vascular thrombosis than for infection (0/14 vs 11/25; P < .05). ConclusionReducing vascular thrombosis could preserve graft function rate. Preventing graft inflammation and infection would reduce mortality.

Management and Outcome of BK Viremia in Renal Transplant Recipients - A Prospective Single Centre Study.

Purpose: BK viremia can lead to BK nephropathy which can progress to graft loss. Our prospective study shows management and outcome of BK viremia in renal transplant recipient. Methods: In this study 34 recipients were diagnosed with BK viremia between 2002 to 2012. They were followed for at least 5 years. Standard immunosuppressive therapy consisted of Steroid, Azathioprine / MMF, Neoral / Tacrolimus was employed. In five patients induction was done with either ATG or IL-2 antagonist. Quantification of BK virus DNA surveillance in plasma / urine was performed at six and twelve months after transplant. Patients with significant viremia (defined as > 10,000 viral copies / ml) underwent graft biopsy and treated with 30-50% reduction in doses of immunosuppression without antiviral therapy. Target CNI level were lowered in the significant viremia group while it was unchanged for all other patients. Results: 2726 renal transplants were carried out between 2002 to 2012. Out of these 34 (8.0%) developed significant BK viremia. Eleven patients (39%) developed BK nephropathy, while 23 (61%) presented with viremia without evidence of BK nephropathy on graft biopsy. Mean plasma level of BK virus DNA declined by 98% at 1 yr after peak viremia. In all 13 patients (26%) developed acute rejection and all of them responded to either Solumedrol or ATG. Conclusion: Reduction in immunosuppression alone resulted in the successful resolution of viremia with preservation of graft function.

Resistance of Spontaneously Diabetic Ins2akita Mice to Allograft Tolerance Induced by Anti-CD154 Therapy

BackgroundDespite ongoing advances in the clinical islet transplant field, progressive decline in graft function continues to reduce the long-term success of islet transplantation for restoring euglycemia in type 1 diabetic recipients. To preserve graft function and avoid the use of chronic immunosuppressive drug therapy, a key goal is to induce donor-specific immune tolerance to islet transplants. Preclinical rodent studies of islet transplantation largely utilize models of diabetes either induced experimentally with beta cell toxins or spontaneously occurring in strains genetically prone to autoimmune diabetes. In this study, we sought to determine if chronic, severe hyperglycemia itself, independent of both beta cell toxins and host autoimmunity, influenced acute allograft rejection and/or the capacity to induce allograft tolerance. MethodTo this end, we studied the response to islet allografts in severely diabetic, non-autoimmune C57Bl/6 Ins2akita recipients. ResultsResults indicate that diabetic Ins2akita mice display higher levels of blood glucose, show more rapid acute islet allograft rejection, and are resistant to allograft prolongation induced with anti-CD154 therapy relative to wild-type littermates rendered diabetic with streptozotocin. As such, results suggest that severe hyperglycemia may be an independent risk factor impacting the capacity to induce tolerance to islet allografts. Thus, Ins2akita mice represent a stringent model for evaluating anti-rejection strategies in the setting of severe metabolic demand on islet transplants.

Ablation of Ventricular Tachycardia Originating From the Papillary Muscle of the Left Ventricle Early After Heart Transplantation

A 46-year-old man 2 months status post heart transplant for cardiac amyloidosis was admitted with recurrent palpitations. There was no reported ventricular dysfunction or history of ventricular arrhythmia in the donor, a 26-year-old man who died in a motorcycle accident. Monomorphic ventricular tachycardia (VT) was observed in the second week after heart transplant. Echocardiogram revealed preserved graft function with left ventricular ejection fraction of 55%, and endomyocardial biopsy revealed no evidence of rejection. The patient was treated with metoprolol with reduction in his VT burden, but he subsequently signed out of the hospital against medical advice. Three weeks later, he presented to the emergency department with recurrent palpitations. Cardiac monitoring showed frequent ventricular premature complexes and VT (as many as 30 beats), with right bundle branch block morphology QRS configuration and rightward frontal axis—identical to the early postoperative arrhythmia (Figure, panel A). An …

Preview of Immunological Reviews for 2014

Preview of <i>Immunological Reviews</i> for 2014

Risk factors and outcome of expanded-criteria donor kidney transplants in patients with low immunological risk

The aim of this study was to evaluate risk factors and outcome of expanded-criteria donor (ECD) kidney transplants in patients with low immunological risk. We evaluated graft survival and graft function in 265 recipients with low immunological risk defined as the absence of pretransplant donor-specific HLA antibodies. A total of 112 (42%) kidneys derived from ECD and 153 (58%) from standard-criteria donors (SCDs). Overall, in a multivariate Cox regression, ECD status was the only significant risk factor for graft failure (hazard ratio [HR] 2.31, 95% confidence interval [CI] 1.22-4.37; p = 0.01). In the SCD group there was an increased risk for graft failure with increasing recipient age (HR 1.06 per year, CI 1.01-1.10; p = 0.02) and in the ECD group a trend for risk reduction for recipients treated with tacrolimus (Tac) (HR 0.46, CI 0.20‒1.06; p = 0.07). One, three and five-year graft survival of ECD kidneys was significantly better when recipients were treated with Tac (95%, 88% and 72%, respectively) than when they were treated without Tac (73%, 65% and 50%, respectively) (p = 0.008). At three years, ECD kidneys had a lower median estimated creatinine clearance (eCrCl) than SCD kidneys (37 vs 58 ml/min, p <0.001). Within the ECD group, recipients treated with Tac had a higher median eCrCl than those treated without Tac (41 ml/min vs 33 ml/min, p = 0.004). Graft function from one to three years was preserved in ECD recipients treated with Tac (median change 0.0 ml/min, p = 0.4) compared with those treated without Tac (median change -3.2 ml/min, p = 0.005). Tac-based immunosuppression seems to improve graft survival and to preserve graft function in ECD kidneys with low immunological risk.

Hydrogen Inhalation during Ex Vivo Lung Perfusion Ameliorates the Quality of Lung Grafts in Rats

Purpose Hydrogen (H 2 ) has a high potential as a safe and multi-potent therapeutic gas. We have recently reported inhaled H 2 could prevent acute lung injury through anti-inflammatory and anti-apoptotic effects in lung injury animal models. We hypothesized that H 2 inhalation during ex-vivo lung perfusion (EVLP) that is a novel strategy for donor lung preservation, optimizes the opportunity and contributes to further refinement in the current EVLP strategy. Methods and Materials Using heart-lung blocks harvested from Lewis rats, our rat EVLP system was established in a stable and reliable fashion where rat lungs after 1hr cold preservation, perfused with acellular Steen solution and ventilated at 37°C on EVLP for 4hrs were evaluated. In the H 2 -treated group, lungs were ventilated with 2% H 2 during EVLP and their results were compared with those from lungs ventilated with air on EVLP as the control group. Results H 2 inhalation was associated with significantly better preserved graft function in terms of oxygenation, lung compliance and reduced pulmonary vascular resistance. In addition, H 2 -treated lungs exhibited significantly reduced proinflammatory cytokine (IL-6, IL-1β, TNF-α) mRNA levels in the allografts. Interestingly, H 2 -treated lungs resulted in significantly reduced elevation of lactate levels as well as hypoxia-inducible factor 1 (HIF-1) levels in lung tissues as compared to the control group, suggesting the contribution of H 2 to improve metabolism in lung grafts during EVLP. [ figure 1 ] Conclusions H 2 inhalation during EVLP may play a pivotal role in preserving better graft function through promotion of anti-inflammatory and cytoprotective effects as well as activation of mitochondrial biogenesis in lungs.

Outcomes of endovascular interventions for salvage of renal transplant allografts

Renal transplantation has been performed with increasing frequency, and interventions to preserve graft function and integrity have been steadily increasing. This study examines the outcomes of endovascular therapy based on indication for renal transplant allograft salvage. A prospective transplant registry was queried for all patients undergoing endovascular interventions for transplant allograft salvage from 2002 to 2011. Demographics, perioperative data, and transplant function outcomes were extracted and analyzed. Among 34 renal transplant recipients (62% men) who underwent endovascular interventions for graft salvage, the mean age was 48.2 years (range, 18-74 years). The indications for intervention included worsening renal function in 15, renovascular hypertension in 11, and structural abnormalities identified on noninvasive imaging in eight. Transluminal angioplasty with and without stenting was done in 26 patients: 14 patients (41.2%) with significant transplant stenosis, 11 (32.4%) with peripheral arterial disease in proximal iliac vessels, and one patient with iliac dissection. Five arteriovenous fistulas and two pseudoaneurysms required embolization. One patient required lysis for deep venous thrombosis causing obstruction of allograft outflow. There were no periprocedural deaths, and 30-day morbidity was 17.6%. Renal function improved or stabilized in 67% of patients with worsening renal function. Better blood pressure control was achieved in patients with renovascular hypertension. Mean follow-up was 4.2 years. There were no significant differences in transplant allograft survival during the duration of follow-up based on primary indication for endovascular intervention, but transplant graft survival at follow-up was significantly better in patients with renovascular hypertension at the initial endovascular intervention. Endovascular salvage of renal allograft transplants can be safely done for various indications. The maximum benefit in renal function as assessed by serum creatinine and control of blood pressure is seen in patients with worsening renal function and in the presence of renovascular hypertension, respectively. Long-term transplant graft function wassignificantly better in patients with renovascular hypertension at the initial endovascular intervention.

Long‐term outcomes after cyclosporine or mycophenolate withdrawal in kidney transplantation – results from an aborted trial

Long-term triple immunosuppressive therapy with cyclosporine (CsA), mycophenolate mofetil (MMF) and prednisolone may be excessively powerful for many transplant recipients. We compared withdrawal of either MMF or CsA in stable kidney transplants on triple immunosuppression. The study was a prospective, randomized, controlled 12-months trial in stable kidney transplants. The patients who withdrew CsA were given MMF 2 g/d, and CsA troughs were between 75 and 125 ng/mL in MMF withdrawal. Planned inclusion was 298 patients. The study was prematurely aborted after inclusion of 39 patients. Acute rejection rates were 6/20 (30%) in the MMF group compared with 0/19 (0%) in the CsA group (p = 0.02). Time to acute rejections was 4.0-28.7 months after withdrawal. Trough concentrations of mycophenolic acid (MPA) and CsA showed therapeutic levels. The subjects have been observed for eight yr, and of the 28 patients remaining on randomized therapy, the MMF patients preserved graft function better than CsA patients. Death-censored graft survival was 75% and 95% (p = 0.18) and patient survival was 70% and 68% (p = 0.99) in the MMF and CsA groups, respectively, at the end of long-term follow-up. CsA withdrawal was associated with a high rate of acute rejections. Initially, the treatment of acute rejections was successful. However, five of six lost their grafts in the long term.

Experience with Post Transplant Parathyroidectomy in Gulf Region and Literature Review

Sustained elevation of parathyroid hormone (PTH) levels is not uncommon post renal transplantation. Though in the majority of patients, it gradually normalizes, on average 5% of transplanted patients require parathyroidectomy (PTX). However, PTX itself has been associated with deterioration in allograft function and even completes graft loss seen with both total and subtotal PTX as well as an increased rate of acute rejection. The aim of this study was to determine the effect of post transplant partial PTX on allograft function in our patients as well as the incidence of acute rejection. Our results show that post transplantation, subtotal PTX, was successful in achieving metabolic control while preserving graft function without an increased incidence of acute rejection. Retention of sufficient residual parathyroid tissue with partial PTX might account for favorable outcome in our study. Despite this, surgery for advanced hyperparathyroidism should optimally take place in the pre-transplant period.

Incidence, Risk Factors, and Preventative Management of Skin Cancers in Organ Transplant Recipients: A Review of Single- and Multicenter Retrospective Studies from 2006 to 2010

Organ transplant recipients (OTRs) taking immunosuppressants are at high risk of skin cancer, which is the most common malignant condition in OTRs, so dermatologic surveillance is important for OTRs. To characterize the most common skin cancers arising from chronic immunosuppression in OTRs. A PubMed search for retrospective single- and multicenter studies reporting skin cancer incidence from 2006 to 2010 was undertaken. Data regarding each study's immunosuppressive regimen, affected skin cancer cohort, and associated risk factors were extracted. Thirty-six articles that met our inclusion criteria reported incidences of nonmelanoma skin cancer (NMSC), Kaposi's sarcoma, melanoma, and Merkel cell carcinoma. NMSC was the most commonly reported cancer of all skin cancers after transplantation. Common risk factors were sex, age, sunlight exposure, and immunosuppressive agent-related (duration, type). Sun education programs and frequent screenings in organ transplant clinics have provided the best preventative strategies after transplantation, although the characteristics of the immunosuppressive regimen also play an important role. Thus, the adjuvant strategy of modifying immunosuppression may be effective when confronting severe transplant-associated skin cancer. Although the decision-making process for curbing levels of immunosuppression is difficult, further long-term, randomized controlled studies should assess the effect of using less immunosuppressant medication while preserving graft function.

Pharmacokinetics for Once-Daily Modified Release Formulation Tacrolimus Hydrate in Unrelated Hematopoietic Stem Cell Transplantation.

Abstract 3048 Background:In solid organ transplantation, lifelong immunosuppression is required to preserve graft function, and medication nonadherence is a major risk factor for graft failure. Tacrolimus (Tac) was first developed as an oral twice-daily formulation (Tac BID) and has been widely used in hematopoietic stem cell and solid transplantation, but long-term adherence remains a concern. In renal transplant patients, morning dosing is associated with significantly higher adherence than evening dosing. In response to this potential adherence problem, a once-daily modified release formulation (Tac QD) has been developed with a morning dosing regimen that maximizes the potential for adherence. However, several investigators have recently reported a sustained decrease in Tac exposure in kidney transplant recipients after conversion from Tac BID to Tac QD. In this study, we measured Tac exposure after switching from Tac intravenous infusion (Tac iv) to Tac QD and analyzed the pharmacokinetics (PK) of Tac QD to investigate the correlation between area-under-curve (AUC) and trough in patients who received allogeneic hematopoietic stem cell transplantation (HSCT). This is the first report of the PK study of Tac QD in patients who received allogeneic HSCT. Methods:Patients who were 15–65 years of age and received HSCT from unrelated donors were eligible. They received Tac iv 0.03mg/kg by continuous infusion beginning one day before transplantation, and administration was converted to Tac QD at a 1:4 ratio when the patients engrafted and could tolerate oral medication. Doses were modified to maintain whole-blood trough concentration of 8–12 ng/ml. To analyze PK of Tac QD, plasma samples were obtained at baseline and at 0, 1, 2, 3, 6, 12, and 24 hours after the once-daily administration. Plasma concentration of Tac was determined by an ELISA method. Results:A total of 10 patients with hematological malignancies (AML 6, ALL 1, MDS 2, NHL 1) were enrolled in the PK study. Median age was 45 (23–65) years. Five patients received myeloablative preparative regimens, and 5 patients received reduced intensity regimens, and stem cell sources were bone marrow (BM) from HLA-matched unrelated donor (n=4), BM from HLA DRB1 mismatched unrelated donor (n=4), or cord blood (n=2). After conversion from Tac iv to Tac QD, six out of 10 patients (60%) showed a sustained decrease in Tac exposure and required an increase in their Tac QD daily dose. One patient experienced a quick decrease of more than 78% in trough level of Tac QD, and he developed grade II acute GVHD after the conversion. No other patients developed grade II-IV acute GVHD. None of the patients had to discontinue the agent because of adverse effects, and none developed treatment-related mortality within 100 days after HSCT. In PK analysis, median area-under-curve (AUC) was 246 ng·h/ml. There was a strong correlation between AUC and trough level (Figure 1). Obtaining over 240 ng•h/ml of AUC required 7.5 ng/ml of whole-blood trough levels of tacrolimus. Conclusions:Despite initial reports showing the bioequivalence of Tac QD with Tac BID, we found that 60% of patients experienced a sustained decrease in Tac exposure. Therefore, the conversion from Tac iv to Tac QD should be performed under close medical supervision. Our study demonstrated that AUC and trough concentration level curves showed a strong correlation in patients who underwent allogeneic HSCT. The whole-blood trough should be maintained above 7.5ng/ml to provide an adequate level of AUC. If the trough level of Tac QD can be maintained above 7.5 ng/ml, Tac QD can be as effective as Tac iv and stable administration can be maintained for the patients with reduced stress because of the easier administration schedule. Our findings indicate that the use of Tac QD instead of Tac BID for GVHD prophylaxis is beneficial for patients undergoing allogeneic HSCT without moderate toxicities. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Increased Plasma Timps Concentrations as the Negative Predictor Associated with Deterioration of Kidney Allograft Function in the Long-Term Observation

Introduction: Chronic allograft injury (CAI) is the most frequent cause of kidney graft loss, and presents with progressive graft impairment. Chemokines, cytokines and MMPs/TIMPs system play the role in fibrosis development. The aim of the study was to assess the importance of MMPs/TIMPs, IL-6 and CCL2 (previously MCP-1) in renal transplant recipients (RTR) with long-term allograft function (over 1 year) with impaired graft function Methods: 150 RTR (male 66%, aged 49,2 ± 11,5 y.), at mean 73,4 ± 41,2 months (range 12-240) after kidney transplantation and 37 healthy volunteers (male 54%, aged 48,4 ± 14,1 y.) as controls, were assessed for plasma and urine MMP-2, MMP-9, TIMP-1, TIMP-2, IL-6 and CCL2. Investigated factors were evaluated by ELISA, and urine concentrations were standardized to urine creatinine. Depending on allograft function 45 RTR had eGFR > 60 ml/min/1,73m2, and 104 RTR had eGFR < 60 ml/min/1,73m2, respectively. The data are presented as mean ± SD or median and 95% Cl for the median. The Mann-Whitney U test (for independent samples) was applied, and differences with p < 0,05 were considered statistically significant. Results: 1. RTR compared with controls had significantly lower eGFR (48 ± 16 and 73 ± 10 ml/min/1,73m2; p = 0,0001) and increased concentrations of plasma and urine IL-6 (p = 1,8e-0,5 and p = 0,0001), MMP-9 (p = 0,0015 and p = 0,003), TIMP-1 (p = 2,2e-16 and p=3,4e-05), TIMP-2 (p = 0,003 and p = 0,02), respectively, as well as lower plasma MMP-2 (p = 7,5e-06) and urine CCL2 (p = 3,3e-05) concentrations. 2. RTR with impaired graft function (eGFR < 60 ml/min/1,73m2) compared with RTR with preserved graft function (eGFR > 60 ml/min/1,73m2) had higher median plasma TIMP-1 (165 ng/ml, 95%Cl 151 - 171 ng/ml vs 124 ng/ml, 95%Cl: 115 - 141 ng/ml; p < 0,0001) and TIMP-2 (93 ng/ml, 95%Cl: 88 - 99 ng/ml vs 79 ng/ml, 95%Cl: 76 - 88 ng/ml; p = 0,0005) concentrations and trend to higher median urine IL-6 concentration (0,9 pg/ml, 95%Cl: 0,6- 1,3 pg/ml vs 0,4 pg/ml, 95%Cl: 0,3 - 0,9 pg/ml; p = 0,054). 3. There were no significant differences in plasma and urine CCL2, MMP-2, MMP-9 and plasma IL-6 concentrations between RTR with preserved and impaired graft function. Conclusion: RTR compared with healthy controls had significantly higher plasma and urine IL-6, urine CCL2 concentrations and unsettled MMPs/TIMPs system RTR with impaired graft function had significantly increased plasma TIMP-1, TIMP-2 and trend to increased urine IL-6 concentrations compared with RTR with preserved graft function.

Sirolimus for the Treatment of Kaposi Sarcoma After Renal Transplantation: A Series of 10 Cases

The incidence of Kaposi sarcoma (KS) has substantially increased among immunocompromised patients, suggesting a role for immunosuppressive drugs. The aim of this study was to evaluate the incidence, features, and outcome of KS among 307 kidney transplantation patients at our center between January 1994 and June 2010. During the study period, the 10 patients who developed KS (3.25%) showed a mean age at transplantation of 35.8 ± 8.7 years (range, 22 to 49 years). The mean interval between transplantation and occurrence of KS was 24.7 ± 21.36 months (range, 6 to 64 months). The mean time of antithymocyte globulin induction was 9.5 days (range, 6 to 13 days). KS was restricted to the skin in 7 cases, among which, one presented with associated Hodgkin lymphoma. Visceral involvement (one lung and one colon) was observed in two cases. One patient presented with a gastric KS without skin lesions. Immunosuppressive treatment was reduced, then withdrawn in three cases, resulting in regression of KS a few weeks later, but with graft loss requiring hemodialysis at 1, 3 and 4 months. Among the remaining 7 cases, we stopped mycophenalate mofetil (MMF) and switched from calcineurin inhibitors to sirolimus. Allograft function remained stable after the switch. Only one patient who already had allograft dysfunction due to biopsy-proven chronic allograft nephropathy. Deteriorated progressively, undergoing hemodialysis at 2 years after KS diagnosis. In conclusion, we observed a relatively high incidence of KS among our cases. The introduction of sirolimus resulted in complete regression of KS lesions with preserved graft function.

Post Operative Monitoring of Donor Specific T Cells Response as a Prognostic Factor in Organ Transplantation by the Assay Using the Indirect Presentation of Autologous Dendritic Cells

In spite of current immunosuppressive regimen, chronic allograft nephropathy remains the crucial clinical barrier for long term survival. The aim of present study is to elucidate whether the study regarding indirect allorecognition predicts the well functioning or ongoing rejection kidney allograft. As an assay for indirect T cell recognition in vitro, we performed indirect MLR in 10 kidney transplantation patients. Five patients are with a well preserved graft function at post operative 8-11 years and others with a poor functioning graft at 2-7 years. Because T cell recognition of alloantigens presented by recipient antigen presenting cells, namely indirect pathway, plays a critical role in the development and progression of chronic allograft nephropathy, we generate the alloantigen presenting autologous dendritic cells (DC) from recipient peripheral blood monocytes. We cultured monocytes with GM-CSF plus IL-4 for 6 days and induced their maturation with TNF-α and PGE2 for additional 2 days in the presence donor cell lysate as an alloantigen. The T cell mediated responses were characterized by the indirect MLR using autologous DCs as well as the direct MLR using donor PBMC. Cytokines or chemokines released from indirect and direct MLR, and cytokines from patient serum were measured by Luminex assay. Patient with poor functioning graft had elevated proinflammatory mediators such as MMP-1 and IP-10 in the sera (p< 0.05) but other cytokines were not significantly different between the 2 groups. In the cytokine assay for indirect MLR, all the patients with functioning graft had significantly elevated cytokine secretion such as IL-4, IL-5 and IL-10 compared with poor functioning group. However, IL-12(p70), IL-23 and IL-1β were increased in the poor functioning group. Interestingly, no significant difference was found in the cytokine levels in direct MLR assay, although IL-10 and IL-5 was increased in some well functioning patients (3 out of 5) compared with poor functioning group. From these results, we can conclude that the assay of cytokine released in indirect MLR might be a favorable predictor for long-term function in renal allograft patient in addition to as a non invasive method. Wee need further study to confirm this result in more patient pool.