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Aim: To determine whether Syk activation promotes renal ischaemia/reperfusion (I/R) injury. Background(s): Syk is a non-receptor tyrosine kinase which plays a critical role in Fc-receptor signalling. Syk signalling is required for antibody-dependent glomerular injury involving acute neutrophil and platelet activation. To investigate whether Syk is also important in antibody-independent activation of neutrophils and platelets, we examined renal I/R injury. Method(s): Male C57Bl/6J mice underwent 19 minutes of warm ischaemia and were killed after 24 hr of reperfusion. Groups of mice (n = 8) were treated with the Syk inhibitor CC-482417 (30 mg/kg/BID) or vehicle, beginning 1 hr before surgery. Sham operated mice were used as controls. Result(s): Renal I/R caused severe kidney failure in terms of serum creatinine (206 +/- 7 vs 12 +/- 4 mmol/L in sham; P < 0.001) which was significantly reduced by CC-482417 treatment (124 +/- 25 mmol/L; P < 0.001 vs vehicle). PAS staining showed severe tubular necrosis in the outer medulla in vehicle treated mice with 66 +/- 2% tubules showing severe damage, which was significantly reduced with CC-482417 treatment (53 +/- 3%; P < 0.01). This protection against tubular damage was also evident with a 75% reduction in KIM-1 mRNA levels in CC-482417 treated mice (P < 0.001). The neutrophil infiltrate in vehicle treated I/R (43 +/- 19 vs 4 +/- 2 cells/hpf in sham; P < 0.001), was reduced with CC-482417 treatment (19 +/- 11 cells/hpf; P < 0.05). Drug treatment also substantially reduced platelet accumulation and fibrinogen deposition in the outer medulla. This was associated with inhibition of the inflammatory response (39% CCL2 and 49% TNF-alpha mRNA levels; both P < 0.001 vs vehicle). Conclusion(s): This is the first demonstration that Syk plays a functional role in antibody independent kidney injury. This study identifies an important role for Syk activation in neutrophil and platelet function in acute I/R injury.

Aim: To determine whether spleen tyrosine kinase (Syk) plays a role in acute renal allograft rejection. Background(s): Kidney allografts induce strong antibody responses which contributes to graft rejection. Syk is involved in the antibody response (via B-cell receptor signalling) and antibody-dependent activation of macrophages and neutrophils (via FcgR signalling), whereas Syk is not expressed by T-cells. However, the role of Syk in these responses has not been investigated in allograft rejection. Method(s): Groups of 6 Sprague-Dawley rats underwent bilateral nephrectomy and an orthotopic transplant with a MHC mis-matched Wistar rat kidney. Groups of 6 recipient rats were treated with a Syk inhibitor (CC-482417, 30 mg/ kg/bid) or vehicle from 1 hr before surgery until killed on day 5. Isografts controls were used. Result(s): Vehicle treated recipients developed severe allograft failure (serum creatinine 304 +/- 130 vs 46 +/- 7 umol/L in isograft; P < 0.001). Histologic damage included glomerular and peritubular capillaritis, tubular injury (tubulitis, necrosis, dilation) affecting 90 +/- 9% of tubules, and T-cell, macrophage and neutrophil infiltration. Immunostaining identified Syk activation in infiltrating leukocytes. Allografts showed IgG and C4d deposition and circulating donorspecific antibodies (DSA) were identified by flow cytometry. CC-482417 improved allograft function (serum creatinine 149 +/- 18 umol/L; P < 0.05 vs vehicle), with reduced tubular damage (47 +/- 19%; P < 0.001) and a reduction in capillaritis. CC-482417 treatment did not affect T-cell infiltration or activation (IL-2, granzyme B, IL-2Ra). However, CC-482417 reduced macrophage and neutrophil infiltration by 40 and 45%, respectively (P < 0.05 vs vehicle), and reduced macrophage activation (NOS-2, TNF-alpha, MMP-12). Interestingly, CC-482417 reduced serum DSA levels by 60% (P < 0.01). Conclusion(s): This study establishes the involvement of Syk in antibodymediated, but not T-cell mediated

Introduction: A collaborative group of eight Transplant Units in Australia defined a protocol for ABOi kidney transplants in an attempt to standardise therapy and collect prospective data. Method(s): Forty-two ABOi transplants were performed. Blood group titres were predominantly measured by gelcard (alternative method used in 5 cases) and the protocol allowed for Glycorex columns or plasma-exchange to reduce titres to <1:8. All but 2 recipients received Rituximab pre-transplantation, all commenced Mycophenolate and received IVIG 0.5g/kg pre transplant, with Tacrolimus based maintenance immunosuppression. Result(s): Baseline ABO titres ranged from 1:1024 to 1:1. At median follow-up of 14 months (range 1-36), patient survival was 95%, death censored graft survival was 93% and median creatinine was 121umol/l (range 82-175). There were 4 episodes of cellular rejection plus 4 cases of antibody mediated rejection (AbMR), one of which caused graft loss. One graft was lost to chronic transplant glomerulopathy and one to thrombosis, neither of these were thought to relate to ABOi AbMR. There were two deaths from pulmonary Aspergillosis, in males aged 67 and 73 at month 2 and 3 respectively. Other significant complications included haemorrhage requiring transfusion, BK nephropathy (n=2), Mycobacterium haemophilum cellulitis and pulmonary Cryptococcus and Streptococcus pneumonia. Conclusion(s): Our uncontrolled series of ABOi transplants was associated with an increased incidence of graft loss and serious infections compared to routine kidney transplantation. Components of the protocol may be implicated in some of these outcomes which highlights the need for controlled data.

Aim: Currently mycophenolate mofetil (MMF) and tacrolimus (tac) are the most commonly used combination of maintenance immunosuppressants, yet the optimal dose of MMF is not known. This study aimed to determine if the initial MMF dose influences the risk of biopsy proven acute rejection episodes (BPAR), leukopaenia or poorer renal function in the first 12 months after transplant in kidney transplant recipients (KTR). Method(s): Our unit changed the routine initial MMF dose from 1.5gm to 2gm daily in late 2009 for all de novo KTR commenced on tacrolimus. Consecutive KTRs for 16 months either side of this change were included to form 2 cohorts. Cox regression was used to assess the association of MMF dose with BPARs and leukopaenia. Serum creatinine at 12 months was compared. All KTR received maintenance prednisolone and infection prophylaxis with Trimethoprim- Sulfamethoxazole and Valganciclovir/Valaciclovir. Result(s): There were no significant baseline differences between groups in terms of age, gender, peak or current Complement Dependent Cytotoxicity Panel Reactive Assay, HLA mismatch, transplant number or type nor CMV serology. After adjusting for recipient age, gender, cmvd+/r-, cmv viraemia and rejection, MMF 2gm/day was associated with a doubling of the risk of leukopaenia (HR 1.99, 95%CI 1.1-3.6, p=0.02) relative to 1.5gm/day. A 45% reduction in the risk of BPARs (HR 0.55, 95%CI 0.31-0.99, p=0.047) was also observed in the group on MMF 2g/day after adjustment for recipient age, gender, leukopaenia, transplant number and peak CDC PRA. CMV viraemia and transplant number were also significantly associated with leukopaenia and BPAR respectively in the above models. Despite these associations there were no significant differences in mean serum creatinine levels at 12 months, infections episodes or infection related hospitalisations between the two groups. Conclusion(s): The MMF dose chosen for KTR on tacrolimus maintenance influences the rate of BPARs and leukopae

Aim: To determine whether the detection of proteinuria in deceased donors influences recipient outcomes. Background(s): Proteinuria is common in patients with critical illness. The effect of pre-donation proteinuria in deceased donors on recipient outcomes is unknown. DonateLife Victoria began collecting proteinuria data on most donors after 04/2011. This was driven by a demand for this information from transplanting units due to an increase in marginal donors being offered. Method(s): Victorian deceased kidney donors accepted by our institution from 04/2011-12/2012 and associated recipient outcomes were reviewed. Proteinuria was defined as urine protein/creatinine ratio (UPCR) >=45 mg/mmol based on UK CKD guidelines. DonateLife recorded UPCR in 66/72 cases.We assessed whether donor proteinuria was associated with donor factors (age, diabetes, hypertension, cardiovascular disease) or recipient outcomes including 12mth graft function. Result(s): Two donors and recipients were excluded from analysis because of early graft loss. 26/64 (40.6%) donors had proteinuria. Proteinuria was not associated with donor age, hypertension, diabetes, cardiovascular or cerebrovascular disease, cardiac or brain death, or delayed graft function requiring dialysis. Proteinuria was associated with reduced early graft function (day 7 recipient eGFR with donor proteinuria vs no proteinuria: 23 +/- 19 vs 36 +/- 24 mL/min; P = 0.03). There was no association with function at later time points (12mth recipient eGFR with donor proteinuria vs no proteinuria: 50 +/- 16 vs 57 +/- 21 mL/min; P = 0.16). Conclusion(s): For deceased donor kidneys accepted by our institution, donor proteinuria was associated with reduced graft function at day 7 but did not influence function at later time-points including 12mths. Donor proteinuria in the absence of other significant factors influencing organ acceptance, appears to be of little importance in influencing graft outcome. Larger studies are required to furt

Introduction: Antibody-mediated rejection (AMR) is associated with poor short-term allograft survival whilst longer-term outcomes are not well described. We have previously reported excellent short-term outcomes for 7 patients treated for refractory AMR with a protocol which includes the use of low-dose rituximab. We now present longer-term follow-up data for 18 patients treated using this protocol. Method(s): Our protocol for the treatment of AMR includes 4 weeks of plasma exchange with low-dose IVIg (PE/IVIg) on background maintenance immunosuppression of Tac/MMF/PNL. Patients are designated as refractory if they continue to exhibit ongoing biopsy evidence of AMR after 4 weeks of PE/IVIg. In this group of patients a single, low, fixed-dose of rituximab (500mg) is administered and PE/IVIg is ceased. We prospectively monitored patient and graft survival in patients treated as such since the protocol's introduction. Peripheral B-cell counts, urinary protein creatinine ratios and renal function were also followed. Result(s): Since July 2005, we have 18 patients with greater than 12 months follow-up (median follow-up 23 months (range 13-62)) post treatment with rituximab for refractory AMR. Seventeen patients have an identified donor specific antibody (2 after IgM depletion). Patient and graft survival during this period were 100% and 88.9% respectively (12 month graft survival was 94.4%). GFR and proteinuria data are shown below. Two patients have lost their grafts; patient 17 at day 10 (severe vascular rejection) and patient 4 at 19 months (non-compliance). Peripheral blood B-cells were undetectable for >=6 months post-rituximab in most patients (78.6%). Rituximab did not eliminate the need for further therapy in all patients with 2 patients requiring splenectomy for ongoing AMR. In these patients diminished B-cells were noted in the removed spleens whilst plasma cells were preserved. Patient 1 received a second rituximab dose and 10 patients have received subsequent

Background. Non-randomized studies suggest an association between serum uric acid levels and progression of chronic kidney disease (CKD). The aim of this systematic review is to summarize evidence from randomized controlled trials (RCTs) concerning the benefits and risks of uric acid-lowering therapy on renal outcomes. Methods. Medline, Excerpta Medical Database and Cochrane Central Register of Controlled Trials were searched with English language restriction for RCTs comparing the effect of uric acid-lowering therapy with placebo/no treatment on renal outcomes. Treatment effects were summarized using random-effects meta-analysis. Results. Eight trials (476 participants) evaluating allopurinol treatment were eligible for inclusion. There was substantial heterogeneity in baseline kidney function, cause of CKD and duration of follow-up across these studies. In five trials, there was no significant difference in change in glomerular filtration rate from baseline between the allopurinol and control arms [mean difference (MD) 3.1 mL/min/1.73 m 2, 95% confidence intervals (CI) -0.9, 7.1; heterogeneity chi2 = 1.9, I2 = 0%, P = 0.75]. In three trials, allopurinol treatment abrogated increases in serum creatinine from baseline (MD -0.4 mg/dL, 95% CI -0.8, -0.0 mg/dL; heterogeneity chi2 = 3, I 2 = 34%, P = 0.22). Allopurinol had no effect on proteinuria and blood pressure. Data for effects of allopurinol therapy on progression to end-stage kidney disease and death were scant. Allopurinol had uncertain effects on the risks of adverse events. Conclusions. Uric acid-lowering therapy with allopurinol may retard the progression of CKD. However, adequately powered randomized trials are required to evaluate the benefits and risks of uric acid-lowering therapy in CKD. © The Author 2013. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Kidney transplant recipients receiving calcineurin inhibitor-based immunosuppression incur increased long-term risks of cancer and kidney fibrosis. Switch to mammalian target of rapamycin (mTOR) inhibitors may reduce these risks. Steroid or Cyclosporin Removal After Transplant using Everolimus (SOCRATES), a 36-month, prospective, multinational, open-label, randomized controlled trial for de novo kidney transplant recipients, assessed whether everolimus switch could enable elimination of mycophenolate plus either steroids or CNI without compromising efficacy. Patients received cyclosporin, mycophenolate and steroids for the first 14 days then everolimus with mycophenolate and CNIwithdrawal (CNI-WD); everolimus with mycophenolate and steroid withdrawal (steroid-WD); or cyclosporin, mycophenolate and steroids (control). 126 patients were randomized. The steroid WD arm was terminated prematurely because of excess discontinuations. Mean eGFR at month 12 for CNI-WD versus control was 65.1 ml/min/1.73 m2 vs. 67.1 ml/min/1.73 m 2 by ITT, which met predefined noninferiority criteria (P = 0.026). The CNI-WD group experienced a higher rate of BPAR(31% vs. control 13%, P = 0.048) and showed a trend towards higher composite treatment failure (BPAR, graft loss, death, loss to follow-up). The 12 month results from SOCRATES show noninferiority in eGFR, but a significant excess of acute rejection when everolimus was commenced at week 2 to enable a progressive withdrawal of mycophenolate and cyclosporin in kidney transplant recipients. © 2013 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT.

Background: Syk is essential for immunoglobulin-based signalling via the Fcgreceptor on myeloid cells. Aim(s): To identify Syk signalling (Tyr525/526 phosphorylation) in glomerulonephritis biopsies, and whether conditional Syk gene deletion in neutrophils and macrophages (Sykf/fLysMCre) suppresses mouse anti-GBM disease. Method(s): Immunostaining for p-Syk was performed in 96 patients: MCD (3), TBMD (8), PIGN (5), SLE-IV (19), ANCA vasculitis (13), IgAN (31), MN (7) and FGS (10). Anti-GBM disease was induced in primed Sykf/fLysMCre and control Sykf/f mice. Mice were killed at 3 hrs (n = 4) or Day 9 (n = 13) after anti-GBM serum injection. Result(s): p-Syk was seen in infiltrating glomerular leukocytes, mainly neutrophils and some macrophages, in 36/40 cases of crescentic GN. Glomerular p-Syk staining correlated with neutrophil infiltration (r2 = 0.71, p < 0.0001). However, p-Syk staining was largely absent in other forms of GN. Anti-GBM disease in control Sykf/f mice provoked the glomerular influx of p-Syk+ neutrophils at 3 hrs (6.28 +/- 0.77 vs 0.13 +/- 0.05 GR1+ cells/gcs in normals, p < 0.05); and by D9 exhibited 58 +/- 5% crescents, marked up-regulation of KIM-1, renal impairment (serum cystatin 1462 +/- 90 vs 260 +/- 29 ng/mL in normals, p < 0.0001), and heavy proteinuria. In contrast, Sykf/fLysMCre mice had an 85% reduction in glomerular neutrophils at 3 hrs (p < 0.05). At Day 9 Sykf/fLysMCre mice had a 67% reduction in crescent formation (p < 0.01) and improved serum cystatin levels (808 +/- 89 ng/mL, p < 0.0001). Sykf/fLysMCre mice had reduced tubular injury, KIM-1 mRNA levels and glomerular macrophage infiltration (reduced by 79%, 90% and 71% respectively, all p < 0.01). There was no difference in proteinuria between the groups. Conclusion(s): Syk is activated in infiltrating leukocytes in acute glomerulonephritis and Syk gene deletion is protective in experimental disease. These findings support the therapeutic use of Syk inhibitors in rapidly progressive

The aim of this study was to create a model of antibody mediated rejection (AMR) to allow studies into the pathogenesis and treatment of AMR in the absence of cellular rejection which is generally well controlled by current therapies. Sprague Dawley (SD) rats were immunized with Wistar spleen cells and 7 days later (day 0) underwent bilateral nephrectomy and received an orthotopic Wistar renal allograft. Recipient rats were killed 4 days later. Following induction of the alloantibody response, recipient rats underwent T cell depletion by administration of OX-19 antibody beginning 3 days before transplantation. Flow cytometric analysis of blood cells and immunostaining of allografts and spleen tissue confirmed T cell depletion. High titres of donor specific antibodies were detected in serum by flow cytometry using Wistar thymocytes, while immunostaining showed prominent endothelial deposition of IgG and C4d in renal allografts. Allograft dysfunction was evident on day 4 with elevated serum creatinine and histological damage featuring glomerulopathy, peritubular capillaritis, acute tubular damage, leukocytic infiltrates and thrombosis. Immunostaining identified platelet deposition and infiltrates of macrophages, neutrophils and NK cells in allografts. In conclusion, we have developed a rat model which mimics the main features of acute AMR and is suitable for therapeutic studies.

BACKGROUND: Cells of the monocyte/macrophage lineage have been implicated as effectors in acute allograft rejection based on short-term depletion studies. However, the therapeutic potential of targeting monocyte/macrophages in acute rejection is unknown. We investigated the potential of a c-fms kinase inhibitor (fms-I) in acute renal allograft rejection. METHOD(S): Lewis rats underwent bilateral nephrectomy and received an orthotopic Dark Agouti renal allograft. Recipients received fms-I or vehicle from the time of transplantation until being killed on day 5. RESULT(S): Vehicle-treated rats developed severe allograft rejection with massive macrophage and T-cell infiltration. In contrast, fms-I substantially inhibited renal allograft dysfunction and structural damage with abrogation of macrophage and dendritic cell infiltration but had only a minor effect on the T-cell infiltrate. However, fms-I suppressed T-cell activation within the allograft, whereas systemic T- and B-cell activation was not affected. In a longer-term study to assess therapeutic potential, fms-I-treated rats developed severe antibody-mediated rejection on day 8 after transplantation. These transplants exhibited features of antibody-mediated rejection including capillaritis with thrombosis, acute tubular injury, IgG and C4d deposition, and neutrophil infiltration and activation. Interestingly, T-cell activation within these rejecting allografts remained suppressed, indicating separation of T-cell and antibody-mediated rejection. CONCLUSION(S): This study demonstrates the ability of c-fms kinase blockade to selectively deplete monocyte/macrophages in acute allograft rejection, although this did not result in significant prolongation of allograft survival. Furthermore, we identify contrasting roles for macrophages in cellular and humoral mechanisms of acute renal allograft rejection. © 2013 by Lippincott Williams & Wilkins.

Objectives: To determine factors associated with early pancreatic allograft thrombosis (EPAT). Thrombosis is the leading non-immunological cause of early pancreatic allograft failure. Multiple risk factors have been postulated. We hypothesized that recipient perioperative hypotension was a major risk factor and evaluated the correlation of this and other parameters with EPAT. Method(s): We retrospectively reviewed the records of the 118 patients who received a pancreatic allograft at our center between October 1992 and January 2010. Multiple donor and recipient parameters were analyzed as associates of EPAT by univariate and multivariate analysis. Result(s): There were 12 episodes of EPAT, resulting in an incidence of 10.2%. On univariate analysis, EPAT was associated with perioperative hypotension, vasopressor use, and neuropathy in the recipient (p <= 0.04 for all). On multivariate analysis corrected for age, sex, and peripheral vascular disease, only vasopressor use retained a significant association with EPAT with a hazard ratio of 8.74 (CI 1.11-68.9, p = 0.04). Factors associated with vasopressor use included recipient ischemic heart disease, peripheral vascular disease, retinopathy or neuropathy, and any surgical complication. Conclusion(s): Significant hypotension, measured by the need for perioperative vasopressor use was associated with EPAT, suggesting that maintenance of higher perfusion pressures may avoid this complication. © 2013 John Wiley & Sons A/S.

Background: Living kidney donation is associated with better recipient outcomes compared with deceased kidney donation, but living kidney donors face the risk of physical and psychological complications. The aim of this study was to synthesize published qualitative studies of the experiences and perspectives of living kidney donors. Method(s): We conducted a systematic review and thematic synthesis of qualitative studies of motivations to donate and experiences after donation of living kidney donors. MEDLINE, Embase, PsycINFO, CINAHL, and reference lists of articles were searched to April 2011. Result(s): 26 studies involving 478 donors were included. We identified 6 themes about the decision to donate: compelled altruism, inherent responsibility, accepting risks, family expectation, personal benefit, and spiritual confirmation. Three themes dominated the impact of donation and postdonation: renegotiating identity (including subthemes of fear and vulnerability, sense of loss, depression and guilt, new appreciation of life, and personal growth and self-worth), renegotiating roles (including subthemes of multiplicity of roles, unable to resume previous activities, and hero status), and renegotiating relationships (including subthemes of neglect, proprietorial concern, strengthened family and recipient bonds, and avoidance of recipient indebtedness). Conclusion(s): Kidney donation has a profound and multifaceted impact on the lives of donors and requires them to renegotiate their identity, roles, and relationships. Strategies to safeguard against unwarranted coercion, and to maximize donor resilience, capacity to negotiate their multiple roles as a patient and carer, emotional fortitude, and ability to have balanced expectations and relationships with the recipient and the family are needed to ultimately protect the safety and well-being of living kidney donors. © 2012 National Kidney Foundation, Inc.

In late 2009 transplant organizations recommended that kidney recipients be vaccinated for pandemic H1N1 influenza (pH1N1); however, the vaccine efficacy was unknown. We had offered a monovalent non-adjuvanted pH1N1 vaccine to transplant recipients. Here we compared the pre-and post-vaccination seroresponses of 151 transplant recipients to that of 71 hemodialysis patients and 30 healthy controls. Baseline seroprotection was similar between groups but was significantly different at 1 month (44, 56, and 87%, respectively). Seroconversion was significantly less common for transplant recipients (32%) than dialysis patients (45%) and healthy controls (77%). After adjusting for age and gender, dialysis patients were significantly more likely (2.7-fold) to achieve new seroprotection than transplant recipients. The likelihood of seroprotection in transplant recipients was significantly reduced by mycophenolate use (adjusted odds ratio 0.24), in a dose-dependent manner, and by reduced eGFR (adjusted odds ratio 0.16 for worst to best). Seroprotection and geometric mean antibody titers increased substantially in 49 transplant recipients who subsequently received the 2010 seasonal influenza vaccine. Thus, patients requiring renal replacement therapy had reduced seroresponses to vaccination with the monovalent vaccine compared with healthy controls. Transplant recipient responses were further reduced if they were receiving mycophenolate or had significantly lower graft function. © 2012 International Society of Nephrology.

Recent experimental findings have led to renewed interest in the possible role of uric acid in the pathogenesis of both hypertension and vascular disease. Often considered an antioxidant, biochemical and in vitro data indicate that noncrystalline, soluble uric acid also can react to form radicals, increase lipid oxidation, and induce various pro-oxidant effects in vascular cells. In vitro and in vivo findings suggest that uric acid may contribute to endothelial dysfunction by inducing antiproliferative effects on endothelium and impairing nitric oxide production. Proinflammatory and proliferative effects of soluble uric acid have been described on vascular smooth muscle cells (VSMCs), and in animal models of mild hyperuricemia, hypertension develops in association with intrarenal vascular disease. Possible adverse effects of uric acid on the vasculature have been linked to increased chemokine and cytokine expression, induction of the renin-angiotensin system, and to increased vascular C-reactive protein (CRP) expression. Experimental evidence suggests a complex but potentially direct causal role for uric acid in the pathogenesis of hypertension and atherosclerosis. © 2005 Elsevier Inc. All rights reserved.

Aims: Cytomegalovirus (CMV) and BK virus infections are associated with acute and chronic graft rejections. Everolimus (EVR) in heart and renal transplant patients is known to decrease the incidence of CMV. Method(s): Study A2309 was a 24-month (M), randomized, multicenter, open-label, non-inferiority study. Patients were induced with basiliximab and received EVR (1.5mg/day; C0 3-8 ng/mL or 3mg/ day; C0 6-12 ng/mL) with reduced dose cyclosporine (rdCsA) or (mycophenolic acid) MPA (1.44 g/day) with sdCsA. Steroids were given as per center practice. CMV prophylaxis was used in all high risk patients (donor positive/recipient negative). CMV and BK virus infections were reported as per local center evaluations. Result(s): Donor and recipient characteristics were comparable between the treatment groups. Both EVR groups were statistically non-inferior to the MPA control group for primary composite efficacy and renal endpoints at 12M. Overall, incidence of adverse events (AEs) was comparable between the treatment groups over the 12 M. Selected AEs (%) are listed in the Table. (Table presented) Lower incidence of CMV and BK virus was demonstrated in both the EVR groups as compared with the MPA control group. There was a lower incidence of laboratory hematological abnormalities and a higher incidence of lipid abnormalities in the EVR groups. There was a greater use of lipid-modifying agents in the EVR-treated patients. Conclusion(s): This study confirms there is a decreased incidence of CMV and BK virus infections in de novo renal transplant patients which translates as an additional benefit of EVR versus standard therapy.

Traditionally performed by vascular surgeons or urologists, laparoscopic nephrectomy for live kidney donor transplantation has emerged as a new effective and safe technique. This study examines the implementation of this technique at our centre, as performed by a single general surgeon with expertise in advanced laparoscopic surgery. Patient records for 78 live donor transplants performed between February 2002 and September 2008 were divided into two groups (with 39 patients each) analyzed. A variety of outcome variables were compared. The same individual surgeon performed all laparoscopic donor nephrectomy (LDN) procedures. A significant advantage was noted for LDN with respect to hospital stay (LDN 5.1 +/- 1.1 days vs open donor nephrectomy [ODN] 6.4 +/- 2.6 days, P=0.01) while ODN had a significant advantage with respect to operative time (LDN 241.1 +/- 55.7 min vs ODN 152.0 +/- 27.7 min, P<0.01). Within the LDN group, we noted a significant shortening in the operation time with each case as experience increased (see graph; P<0.01). The total postoperative complication rate was similar in both groups (LDN: 31% vs ODN: 44%, P=0.25). There was a trend towards more respiratory complications in ODN (ODN 11/39 [28%] vs LDN 5/39 [13%], P=0.09). While implementing a new procedure may result in longer operative times initially, these improve with time, and our data demonstrates no compromise in patient safety or outcomes. The LDN procedure proved to be a desirable alternative to ODN, with shorter hospital stay and improved operator skills with each case, and without significant compromise in allograft recovery. © 2011 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Blackwell Publishing Asia Pty Ltd.

Aims: In cyclosporine (CsA) treated renal transplant (RTx) recipients approximately 50% do not reach the proposed therapeutic MPA target exposure in the first weeks (wks) post-Tx. We investigated whether an intensified EC-MPS dosing regimen in the first 6 wks post-RTx may improve efficacy while maintaining good tolerability. Method(s): In two 6-month parallel-run studies (ERLDE12 [n=128]; ERL2419 [n=313]), de novo RTx recipients were randomized (1:1) to either 'Intensified' (2 wks of 2880mg/d; subsequently 4 wks of 2160mg/d; followed by 1440mg/d) or ''Standard'' (1440mg/d) EC-MPS, both with CsA and steroids +/- anti-IL2R induction. The primary endpoint was treatment failure (biopsy-proven acute rejection [BPAR], graft loss or death) at Month 6 (M6) post-Tx, with treatment effect differences assessed using a prospectively planned meta-analysis of both trials. Secondary objectives included components of treatment failure, renal function and overall safety between groups. Result(s): All results are presented as Intensified (n=218) vs Standard (n=223) groups. Demographic and baseline characteristics were comparable. The mean EC-MPS doses showed close adherence to the EC-MPS regimens: 2724.5mg vs 1406.5mg between Days 1-14 and 2157.0mg vs 1406.7mg between Days 15-28. At M6 treatment failure rates were 17.4% and 22.4% (weighted difference: -6.0%, 95% CI -0.133, 0.013; ITT population). The combined death and graft loss rates were 3.7% vs 4.0%. The incidence of BPAR was 13.8% vs 19.3% (weighted difference: -7.1%, 95% CI -0.137, -0.005; P=0.034). Renal function at M6 was similar between both groups, with GFR (MDRD) of 52.5 vs 51.8mL/min/1.73m2. The safety profile was comparable between groups. Overall SAEs were 55.4% vs 49.8%. Selected AEs were anemia 26% vs 25%, leukopenia 13% vs 12%, and CMV 8% vs 13%. Conclusion(s): The initially intensified dosing of EC-MPS with CsA within the first 6 wks post-RTx was associated with a significantly lower rate of BPAR vs the standard reg

Recent studies in both humans and experimental animals have led to renewed interest in uric acid and its association with hypertension, cardiovascular events and renal disease progression. This has also refuelled a longstanding debate regarding the precise role of this ubiquitous breakdown product of purine metabolism in these disease processes. Various lines of evidence suggest that uric acid may have a direct role in the pathogenesis of hypertension and vascular disease. Regardless of this possibility, it is apparent that serum uric acid levels serve as a powerful 'biomarker' or independent predictor of prognosis and outcome in certain renal, cardiovascular and cerebrovascular diseases. Whether these outcomes can be improved by specifically treating asymptomatic hyperuricaemia remains inadequately resolved at this stage. Data from various animal studies suggests that lowering uric acid levels may be of benefit, but the crucial human studies are still lacking. This review will examine some of the recent evidence supporting a causal and contributory role for uric acid in cardiovascular and renal disease. How clarification of the role of uric acid may guide future treatment strategies will also be discussed.

Intravenous immunoglobulin (IVIg) therapy for antibody-mediated rejection (AMR) is increasing and is associated with a small but significant incidence of thrombosis. We determined thrombosis rates in patients treated with high-dose IVIg for AMR before and after alteration of an infusion protocol. The newer protocol introduced routine administration of aspirin 300 mg, enoxaparin 1 mg/kg, intravenous hydration and a maximum infusion rate of 100 mg/kg per hour (previously 200 mg/kg per hour). Nine thromboses in 275 infusions occurred before the protocol alteration (event rate 3.3%). Two were arterial thromboses including an acute myocardial infarct and a renal transplant artery thrombosis, which resulted in infarction of 2/3 of the graft. Seven venous thromboses occurred, six in arteriovenous fistulae and one case with bilateral above knee deep venous thromboses. Significant associations with thromboses were seen with higher IVIg dose and male sex. In the 6 months since the introduction of the new infusion protocol, 74 infusions have been administered with no thrombotic events. There have been no significant bleeding or fluid overload side-effects. Infusion times, however, have been doubled. A slower rate of infusion combined with antiplatelet and anticoagulation has thus far eliminated the small but significant IVIg-related thrombosis rate previously observed in our patients treated for AMR without resulting in significant side-effects. Further study is now required to define which elements of this protocol are essential. © 2011 Asian Pacific Society of Nephrology.

Aims: Early conversion to Everolimus (EVR) in a CNI free regime has demonstrated improved renal function in renal transplant recipients (RTs). ASCERTAIN, a prospective, multicenter, open-label, three-arm study investigated the impact of CNI withdrawal or CNI minimization by addition of EVR in maintenance RTs on renal function at 24 months (M). Method(s): In the core study RTs (N=398) with renal impairment (est. GFR 30-70mL/min) receiving CNIs, with MPA (72.6%) or AZA (28.4%) were randomized to Group (GpA) (N=125): continued treatment with CNIs, GpB (N=128): EVR (8-12 ng/mL+ CNI elimination, or GpC (N=145): EVR 3-8 ng/mL+CNI 70-90% reduction. RTs included were 5.6+/-4.13 years post-transplantation with a mean measured (m) GFR of 46+/-16, 49+/-21 and 47+/- 18mL/min/1.73m2, respectively for Gps A, B and C. mGFR was stable in all groups throughout the study period with a mean of 46+/-20, 48+/-22 and 47+/-21mL/min/1.73m2 at 24M after randomization in the three groups respectively. A post-hoc subpopulation analysis was done using estimated GFR cutoff of less than or greater than 55mL/min (Nankivell). For Gps A, B and C <=55mL/min the n's were 33,30 and 27; and for >=55mL/min n's were 28, 26 and 43. Result(s): Overall there was no difference between groups in mGFR values at 24 M. A post hoc on treatment analysis on per protocol (PP) population on change in the mGRF from baseline to M24 with consistent method by baseline mGFR of >=55mL/min, showed a difference of 8.1mL/min difference in LS means for CNI elimination compared to the control group. Estimated (e) GFR (Nankivell) difference was even higher with 11.76mL/min reaching statistical significance (P=0.019 for patients with mGFR>=55mL/min at Baseline. Conclusion(s): A subpopulation of the ASCERTAIN study patients with mGFR or eGFR (N) >=55mL/min at baseline and converted to EVR with CNI withdrawal averaging 5.6 years after transplantation had significantly better renal function after 24M compared to the groups maintaine

Background: To better define subpopulations in which achieving adequate mycophenolic acid (MPA) concentrations quickly would be important, a post hoc exploratory analysis on the fixed-dose concentration-controlled database was performed, comparing high-versus low-risk renal transplant patients. Method(s): Renal transplant patients were treated with mycophenolate mofetil, corticosteroids, and cyclosporine A or tacrolimus. Patients were defined as "high risk" if they had one or more of the following characteristics: delayed graft function, second or third transplantation, panel reactive antibodies >15%, four or more human leukocyte antigen mismatches, or were of black race. Result(s): A total of 549 patients (61%) were classified as high risk, of whom 284 were on cyclosporine A treatment and 265 on tacrolimus. In high-risk patients, the difference in rejection incidence was 14.3% in the MPA-area under the concentration (AUC) less than 30 mg hr/L vs. 7.8% in the MPA-AUC more than or equal to 30 mg hr/L groups (P=0.025) during the first month after transplantation; whereas, in low-risk patients, there were similar rejection rates (5.7% vs. 4.5%). In the subgroup of high-risk tacrolimus-treated patients, the difference in acute rejection incidence in the first month between patients with MPA-AUC0-12 less than or more than or equal to 30 mg hr/L was most pronounced: 16 of 67 patients (23.9%) vs. 18 of 173 patients (10.4%); P=0.012. Conclusion(s): The incidence of acute rejection is higher in high-risk patients if MPA-AUC0-12 is below 30 mg hr/L. In contrast, a difference in acute rejection incidence in low-risk patients with MPA-AUC0-12 less than or more than or equal to 30 mg hr/L was not observed. This supports the use of a higher mycophenolate mofetil starting dose in selected patient populations early after transplantation. Copyright © 2010 by Lippincott Williams & Wilkins.

Glomerular antibody deposition induces acute neutrophil-mediated glomerular injury via activation of c-Jun amino terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK). However, the link between antibody deposition and activation of JNK/p38 MAPK signalling is unclear. This study tested the postulate that spleen tyrosine kinase (Syk), which is activated via Fcgamma-receptor ligation, is required for activation of JNK and p38 signalling and acute neutrophil-mediated glomerular injury. We used a Syk inhibitor (SYKi) in rat nephrotoxic serum nephritis (NTN) in which neutrophil-mediated glomerular injury is dependent upon JNK and p38 signalling. SYKi or vehicle treatment of Sprague-Dawley rats began 30 min before administration of anti-GBM serum with rats killed 3 or 24 h later. Immunostaining identified de novo glomerular Syk activation (p-Tyr 525/526) in untreated NTN, being most prominent in neutrophils. Vehicle and untreated NTN exhibited heavy proteinuria and glomerular thrombosis at 24 h with P-selectin and fibrin immunostaining within capillaries, glomerular macrophage and T cell infiltration, activation of JNK and p38 MAPK signalling, and upregulation of glomerular mRNA levels of pro-inflammatory molecules (TNF-alpha, NOS2, MMP-12 and CCL2). In contrast, SYKi treatment provided complete protection from proteinuria, with a profound reduction in glomerular thrombosis and immunostaining for P-selectin and fibrin, and a substantial reduction in glomerular mRNA levels of pro-inflammatory molecules. SYKi treatment also reduced the acute glomerular neutrophil influx and pro-inflammatory response at 3 h in NTN. These protective effects were associated with a significant reduction in glomerular JNK and p38 MAPK activation. In addition, activation of Syk, JNK and p38 was identified in human biopsy samples of acute crescentic glomerulonephritis. In conclusion, this study demonstrates that Syk signalling is required for JNK and p38 MAPK signalling and acute ne

Aims: Increased expression of Toll-like receptors (TLR2 and 4) and cytokine responses following TLR activation (IL-6 and TNFa) are associated with allograft rejection. Vitamin D appears to downregulate expression of TLR. This study examined the relationship of TLR expression and activation with renal failure, serum 25-OH vitamin D (25D) and other parameters including age in dialysis patients (most underwent transplantation). Method(s): Peripheral blood monocytes (PBMCs) from 16 healthy controls and 49 dialysis patients were analyzed by flow cytometry for TLR and CD86 expression using anti-human monoclonal-antibodies and isotype control-antibodies. Results were expressed as the ratio of mean fluorescence of test antibodies to isotype control antibodies. PBMCs were stimulated with specific TLR ligands (Pam-3Cys and LPS) and assayed for TNFa and IL-6 by ELISA. Result(s): No differences in TLR expression or response were detected in dialysis patients compared with healthy controls; with a trend to increased TLR4 expression in dialysis patients (P=0.06) (Table). In the dialysis subgroup no differences in TLR expression or responses were seen when analyzed by 25D levels. Older patients demonstrated a trend to increased IL-6 expression after stimulation with LPS (P=0.09) and Pam-3Cys (P=0.12). Conclusion(s): This study supports renal failure and older age being proinflammatory states. The lack of association of 25D levels with TLR expression and is contrary to previous reports but may relate to the patient cohort studied and insufficient numbers. Further analysis is underway to determine associations between TLR expression, 25D levels, and rejection episodes in the subset of patients who underwent transplantation.

Background: Living kidney donation is associated with better recipient outcomes compared with deceased kidney donation but living kidney donors face the risk of physical and psychological complications. The aim of this study was to synthesize published qualitative studies on the experiences and perspectives of living kidney donors. Method(s): We conducted a systematic review and thematic synthesis of qualitative studies on motivations to donate and experiences after donation of living kidney donors. MEDLINE, Embase, PsycINFO, CINAHL, references lists of articles were searched to April 2011. Result(s): Twenty-six studies involving 478 donors were included. We identified six themes about the decision to donate: compelled altruism, inherent responsibility, accepting risks, family expectation, personal benefit, and spiritual confirmation. Three themes dominated the impact of donation and post-donation: renegotiating identity (including sub-themes of fear and vulnerability, sense of loss, depression and guilt, new appreciation of life, personal growth and self-worth), renegotiating roles (including sub-themes of multiplicity of roles, unable to resume previous activities, hero status) and renegotiating relationships (including sub-themes of neglect, proprietorial concern, strengthened family and recipient bonds, and avoidance of recipient indebtedness). Conclusion(s): Kidney donation has a profound and multi-faceted impact on the lives of donors, and requires them to renegotiate their identity, roles and relationships. Strategies to safeguard against unwarranted coercion, and to maximise donor resilience, capacity to negotiate their multiple roles as a patient and carer, emotional fortitude, and ability to have balanced expectations and relationships with their recipient and the family, are needed to ultimately protect the safety and well-being of living kidney donors.

Aims: This prospective, multicentre, open-label, three-arm study investigated whether CNI reduction or elimination by the addition of EVR in maintenance RTs, with existing renal impairment, resulted in improved renal function at 24 months (M). Method(s): RTs with renal impairment (estimated GFR 30-70mL/min) post-6M receiving CNIs, with MPA (72.6%) or AZA were randomized to Group (Gp) A: continued treatment with CNIs, GpB: EVR (8-12 ng/mL)+CNI elimination, or GpC: EVR 3-8 ng/mL+CNI 70-90% reduction. Primary endpoint (change in measured GFR, mGFR), plus efficacy and safety endpoints, were assessed at 24M post baseline (BL). Result(s): 398 RTs receiving CsA or Tac (28.7%) were randomized into GpA (125), GpB (128) and GpC (145). Mean time since Tx for all RTs was 5.55 years and was similar between Gps. Mean EVR C0 levels at 24M were 7.69 and 5.33 ng/mL for GpB and GpC respectively. CNI minimization patients had C0 reductions at 24M of 65% for Tac and 78% for CsA. There was no change in mGFR at 24 months (mean difference was 1.12mL/min/1.73m2 for the GpB vs GpA comparison and 0.59mL/min/1.73m2 for the GpC vs GpA. Mean mGFR values (SD) at BL for ITT Gps were 46.1 (16.4), 49.4 (20.7) and 46.7 (18.0) mL/min/1.73m2 for Gps A, B and C respectively. Values at 24M (SD) were 46.0 (20.4), 48.0 (22.0) and 46.6 (21.1) mL/min/ 1.73m2. Subanalyses showed that patients with the longest time since RT (45 years) had the worst results for EVR groups. In this cohort least square mean differences were GpB-GpA =-2.55 and GpCGpA =-1.56mL/min/1.73m2 at 24 M. Improvement of renal function was better for patients who were enrolled earlier after transplantation. Efficacy failure composite endpoints (BPAR, death, graft loss, LOF) at 24M were 8.9%, 13.4% and 11.8% respectively (NS). Frequent adverse events in both EVR Gps were proteinuria, aphthous stomatitis, diarrhoea, hyperlipidemia and mouth ulceration. There were 6 deaths (3 in each EVR Gp) mainly due to infections. Conclusion(s): RTs with re

Aims: Everolimus is an mTOR inhibitor that has immunosuppressive and anti-proliferative properties. Study A2309 is a registration trial in 833 de novo renal transplant recipients to assess the efficacy and safety of everolimus with cyclosporine (CsA) minimization. Method(s): A2309 is a 24-month, randomized, multicenter, open-label, non-inferiority study comparing 2 targets of everolimus (EVR) (C0 3-8 ng/mL or C0 6-12 ng/mL) with reduced CsA exposure versus a control group receiving enteric-coated mycophenolate sodium (MPA) 1.44 g/day with standard exposure CsA. All patients received basiliximab induction and steroids per center practice. The primary composite endpoint is non-inferiority of efficacy (BPAR, graft loss, death, loss to follow-up) between the EVR groups and the MPA control at 12 months. The non-inferiority margin was set at 10%. Result(s): Donor and recipient characteristics were comparable between the groups. Around a 60% reduction in CsA exposure for both EVR groups was achieved at 12 months versus MPA control group (mean C0: 55, 49 137 ng/mL for EVR 3-8 ng/ml, 6-12 ng/ml MPA groups, respectively). Both EVR groups were statistically non-inferior to the MPA control group for the primary composite efficacy endpoint. (Table presented) The 24 month results are currently unreleased and the 2 year primary and secondary efficacy data will be presented at the TSANZ congress. Conclusion(s): At 12 months the A2309 study showed that 60% reduction in CSA exposure combined with EVR doses targeting 3-8 ng/ml or 6-12 ng/ml C0 blood concentrations results in similar efficacy compared to standard CsA exposure combined with MPA. Severe rejections (Banff >=IIA) were lowest in the EVR 3-8 ng/mL group. The 24 month relationship between everolimus trough levels and outcomes will also be explored.

Background. Ischaemia/reperfusion (I/R) is an important factor in delayed graft function in renal transplantation and is a determinant of long-term graft outcome. This study examined the role of c-Jun N-terminal kinase (JNK) signalling in human and experimental renal I/R injury.Methods. Biopsies obtained 15-20 min after reperfusion of human renal allografts were examined for JNK signalling by immunostaining for phospho-c-Jun. To examine the pathologic role of JNK signalling, a selective JNK inhibitor (CC-401) was administered to rats before or after the induction of a 30-min period of bilateral renal ischaemia followed by reperfusion. Renal function and tubular damage were analysed.Results. Substantial JNK activation was evident in tubular epithelial cells in kidneys from deceased donors (n = 30) which was less prominent in kidneys from live donors (n = 7) (44.6 +/- 24.8% vs 29.1 +/- 20% p-c-Jun+, respectively; P < 0.05), whereas biopsies of thin basement membrane disease exhibited little, or no, p-c-Jun staining. The degree of p-c-Jun staining correlated with ischaemic time in deceased donor allografts, but not with graft function. Administration of CC-401 to rats prior to bilateral renal I/R prevented acute renal failure and largely prevented tubular damage, leucocyte infiltration and upregulation of pro-inflammatory molecules. However, delaying CC-401 treatment until 1 h after reperfusion (after the peak of JNK activation) had no protective effect.Conclusions. We have identified acute activation of the JNK signalling pathway following I/R in human kidney allografts. Experimental studies indicate that blockade of JNK signalling, commenced prior to this activation, can prevent acute tubular necrosis and renal dysfunction secondary to I/R injury. © The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Crossmatching of potential renal donors against potential renal transplant recipients has been performed for over 40 years and is a mandatory component of the transplant work-up process. However, gone are the days when all that was available was the T-cell complement-dependent cytotoxicity crossmatch. There are now many more options available for determining the likelihood of donor-specific antibody-mediated responses including flow crossmatching and the 'virtual' crossmatch. In addition, assays to determine the extent of sensitization of cell-mediated responses are being examined. This article builds an understanding of modern day crossmatch interpretation using a case-based approach in order to provide a framework for the general nephrologist to determine the likely immune consequences of a particular donor-recipient pairing. © 2010 Asian Pacific Society of Nephrology.

The latest Caring for Australians with Renal Impairment (CARI) guideline detailing renal transplant care, developed as a local modification of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. © 2011 Asian Pacific Society of Nephrology.

Aims: Primary objectives were to determine non-inferiority of the composite efficacy endpoint (BPAR, graft loss, death, loss to followup) and of the primary safety endpoint (renal function as estimated using MDRD formula) between the EVR groups and MPA control at M12. Method(s): A2309 is a 24-month (M), randomized, multicenter, openlabel, non-inferiority study comparing 2 targets for EVR (C0 3-8 ng/ mL or C0 6-12 ng/mL) with CsA minimization versus a control group receiving enteric-coated mycophenolate sodium (MPA) 1.44 g/day with standard exposure CsA. All patients received basiliximab induction and steroids per center practice. Result(s): Donor and recipient characteristics were comparable between the groups. An approximately 60% reduction in CsA exposure for both EVR groups was achieved at M12 vs MPA control group (mean CsA C0: 55, 49 137 ng /mL for EVR 3-8 ng/ml, 6-12 ng/ml MPA groups, respectively). Both EVR groups were statistically non-inferior to the MPA control group for the composite efficacy endpoint and for renal function at M12. (Table presented) In addition, GFR as measured by Cockcroft-Gault formula and by least square means method for repeated measures was better in the EVR groups than the MPA group at M12. The highest proportion of patients who maintained a GFR>=460mL/min from M1 to M12 was seen in the EVR 3-8 ng/ml group. Urinary protein-creatinine ratios were slightly higher in the EVR groups at M12 (35.7, 61.7, and 31.1mg/mmol for EVR 3-8 ng/ml, 6-12 ng/ml and MPA groups, respectively). Conclusion(s): This study demonstrates that EVR targeted to 3-8 ng/ml in combination with reduced CsA exposure allows for benefits in renal function without compromising overall efficacy and safety.

Aims: In addition to its immunosuppressive action, everolimus (EVR) as a mTOR inhibitor has anti-proliferative properties and wound healing events (WHEs) have been observed within this drug class. Method(s): A2309 is a 24-month (M), randomized, multi-center, openlabel, non-inferiority study comparing 2 regimens of EVR (targeting C0 either at 3-8 ng/mL or 6-12 ng/mL) with reduced dose CsA versus a control group receiving enteric-coated mycophenolate sodium (MPA) 1.44 g/day with standard dose CsA. All patients received basiliximab induction and steroids were given according to local practice guidelines. CsA C0 target ranges for the EVR groups were 100-200 ng/ml from Day 5, 75-150 ng/ml from M2, 50-100 ng/mL from M4 and 25-50 ng/mL from M6. CsA target ranges for the MPA group were 200-300 ng/ml from Day 5 and 100-250 ng/mL from M2. Approximately 60% reduction in CsA exposure for both EVR regimens was achieved at 12M versus MPA control group. Result(s): Donor and recipient characteristics were comparable between groups. Both EVR groups were statistically non-inferior to the MPA control group for primary composite efficacy and renal function at 12 M. Safety profiles of each regimen were consistent with findings from previous studies. (Table presented) Onset of WHEs for all 3 groups was within 5-75 days after TX and over 50% of WHEs were less than 45 days in duration. For the EVR 3-8 ng/ml and 6-12 ng/ml groups, WHE reported in patients with a body mass index (BMI) greater than the 75th percentile were 50% and 46% respectively (vs 27% for the MPA group). Overall, no significant difference was observed between the EVR 3-8 ng/ml group and MPA group. Conclusion(s): An EVR C0 concentration-response relationship was observed for the incidence of wound healing events with consistently lower events in the EVR 3-8 ng/ml target range. WHEs occurred (Graph presented) predominantly in the early de novo period. Patients with a higher BMI who receive EVR may be at higher risk for thes

Aim: To assess (i) differences between Toll-like receptor (TLR2 and TLR4) expression in healthy controls and dialysis patients, and (ii) relationships between TLR expression and clinical outcomes (rejection, BK infection and renal function) in the 6-month period post-transplantation. Background(s): Increased expression of TLR has been variably associated with renal allograft rejection and function. Method(s): TLR expression on peripheral blood monocytes from 16 healthy controls and 49 dialysis patients was analysed by flow cytometry, using anti-human monoclonal antibodies and isotype control antibodies (expressed as a ratio of mean fluorescence of antibodies to isotype control antibodies). TLR measurements in 28 incident renal transplant recipients (RTR) from the dialysis cohort were obtained at 0, 3, 7 and 14 days, and 1, 2, 3 and 6 months. Linear regression models fitted to longitudinal data were used to determine associations between TLR expression and clinical outcomes. Result(s): Baseline TLR did not differ by age or 25-OH vitamin D levels; TLR2 was higher in males (2.76 vs. 2.34, p = 0.02). Baseline TLR4 (2.22 vs. 1.80, p = 0.05) but not TLR2 (2.62 vs. 2.39, p = 0.12) was higher in the dialysis group compared to controls. In RTRs, TLR4 was significantly elevated at 6 months compared to baseline (2.78 vs. 2.19, p = 0.02), however there was no significant association between baseline TLR2 and TLR4 and rejection (p = 0.70 and 0.09, respectively) or incident BK infection (p = 0.20 and 0.28, respectively). Longitudinal analysis showed no association between TLR2 and TLR4 and rejection (p = 0.21 and 0.49, respectively) or graft function (p = 0.47 and 0.53, respectively). Conclusion(s): TLR4 expression was significantly higher in dialysis patients, and TLR4 expression was significantly higher at six months in RTRs. There was no association between TLR expression and clinical outcomes.

Aim: To assess the utility of the CKD-EPI estimated GFR (eGFR) equation in assessing GFR in kidney donors compared to measured GFR (mGFR). Background(s): The CKD-EPI eGFR equation is more accurate than MDRD eGFR at higher levels of mGFR and could potentially be used as a replacement of mGFR in the assessment of kidney donors. Method(s): Data on all potential kidney donors between January 2006 and December 2009 was collected. mGFR determined by chromium EDTA was compared to eGFR by the MDRD and CKD-EPI formulae. Donors with DPTA mGFR were excluded (n = 14). A GFR of >80 ml/min was considered adequate for donation. Agreement was assessed using Bland & Altman limits of agreement (LOA) and contingency tables. Result(s): 94 donors, mean age 51 yrs, were assessed. Sixty percent were female and 70% Caucasian. Mean mGFR was 105.5 ml/min (range 61-160 ml/min) while mean eGFR by CKD-EPI and MDRD was 90 (55-126) & 84 ml/min (54-137 ml/min) respectively. The mean difference between mGFR and eGFR by MDRD and CKD-EPI was 21 ml/min (95% LOA -19-62) & 15 ml/min (95% LOA -20-51). Using a mGFR 80 ml/min as a cut off for donation, 17 subjects were incorrectly classified with an GFR < 80 ml/min by CKD-EPI despite a mGFR of >80 m//min, while 2 subjects had a eGFR > 80 ml/min despite a mGFR < 80 ml/min. The ROC AUC for a cut-off for 80 ml/min was 0.86 overall. AUC for those subjects >50 years was poor at 0.78 compared to <50 years 0.97. Conclusion(s): Despite improvements in accuracy at eGFR levels >60 ml/min, the isolated use of the CKD-EPI equation to assess GFR for kidney donation cannot be recommended.

Background and Aims: Consenting renal transplant recipients (RTRs) received the monovalent 'swine flu' vaccine (MV) in late 2009 in line with international recommendations after the WHO's declaration of an H1N1-pandemic. A group of these patients subsequently received the seasonal influenza vaccine (SV) in 2010. This study compares the seroresponses following the SV in patients that either had or had not previously received the MV. Method(s): 151 RTRs received the MV and had pre and post-vaccine serology; 53 received the SV (test group). Seroresponses were determined 1 month post-SV and compared with post-MV vaccination titres. In addition, 18 RTRs (controls) who had not received the MV had the SV with pre and post-vaccination serology measured. Seroprotection was defined as a titre of >=1:40 and seroconversion was defined as a >=4 x increase in titre. Geometric mean titres (GMTs) were calculated. Result(s): Seroprotection rates in test group were 15% pre-MV, 34% post-MV and 52% post-SV. GMTs were 9, 19.2 and 30.7 at these points; seroconversion occurred in 16%. In the control group seroprotection rates were 22% pre-SV and 56% post-SV. GMTs were 13 and 37 at these points; seroconversion occurred in 41%. Seroprotection rates post SV vaccination were not different between the test and control groups (p = 0.58). There were no statistically significant differences in seroprotection rates in the test cohort post-SV by age, transplant duration, eGFR and immunosuppression). No adverse reactions nor H1N1 infection were seen. Conclusion(s): Booster vaccination with the SV after MV resulted in a stepwise increase in seroprotection and geometric mean antibody titres in the test group. The possible increased rate of seroprotection in controls may relate to underlying differences between the two groups.

Aim/Background: Chronic antibody-mediated rejection (cAMR) is a major cause of premature renal allograft failure, with previous reports of 50% graft loss at 3 years post-diagnosis. We examined the allograft outcomes of patients with cAMR treated with specifiC therapy including a single low-fixed dose of rituximab. Method(s): Transplant recipients with cAMR diagnosed between 09/2006- 02/2011 were included and were treated by optimization of immunosuppression to include tacrolimus and mycophenolate, followed by a minimum of 3 x 1 mg/ kg intravenous immunoglobulin (IVIg). Patients with persistent cAMR at followup biopsy received further IVIg, while those with a donor specifiC antibody were then given a single dose of 500 mg rituximab. Outcomes were examined by Kaplan Meier and multivariate analyses. Result(s): Thirty-four patients were diagnosed with cAMR in the study period, while 24 received rituximab. Median time from transplantation to cAMR was 48.8 mths. Graft failure occurred in 11 patients (32%), 6 from the rituximab group (25%). Mean times from diagnosis to failure were 20.5 mths (overall) and 25.3 mths (rituximab). Lower eGFR and higher proteinuria at diagnosis were predictive of graft failure on multivariate analysis (HR 0.91 and 49.8 respectively, p < 0.05) and reflected more advanced histological changes on initial diagnostic biopsy. Of those treated with rituximab, 17/21 patients (81%) had stabilization or improvement of their eGFR at 12 months whilst all patients who lost their grafts from this group had an eGFR of <=36 ml/min at diagnosis. Conclusion(s): The role of rituximab in cAMR treatment remains unclear however in this cohort of patients a possible benefit in terms of graft survival compared with previous reports support further studies in cAMR.

Background: Pancreas-kidney transplantation is currently the most effective method to re-establish euglycaemia in insulin-dependent diabetics with associated renal failure. The standard technique employed has been bladder drainage of exocrine secretions coupled with systemic venous drainage ('systemic-bladder' (SB) drainage). The more physiological technique, enteric exocrine with portal venous drainage ('portal-enteric' (PE) drainage), has been utilized sparingly in the past as a result of fears of technical complications. This paper compares the Monash Medical Centre experience with both techniques. Method(s): A total of 68 simultaneous pancreas-kidney transplantations were performed at Monash Medical Centre from 1991 until 2004. The first 37 received SB drainage. Since March 2001, 27 have received PE drainage. This retrospective study compared the SB group (n= 37) with the PE group (n= 27), with a 2-year follow-up, examining a number of surgical outcomes. Result(s): Two-year patient (94.3 versus 96.0%), kidney (89.2 versus 85.2%), pancreas (77.9 versus 71.4%) and event-free (73.0 versus 67.7%) survivals were all similar between the SB and PE groups, respectively. Although surgery took longer in PE subjects (4 h: 47 min +/- 0:48 versus 5 h: 16 min +/- 1:00; P= 0.045), less intraoperative transfusions were required (1.3 +/- 1.43 versus 0.52 +/- 0.90; P= 0.024). Length of hospital stay and time to insulin independence were similar. Pancreas graft thrombosis rates were similar (10.8% SB versus 7.4% PE, P= 0.497). Conclusion(s): PE drainage is a safe and viable method for pancreas transplantation, which can be performed with excellent outcomes. An increased rate of complications with PE drainage has not been demonstrated in this series. © 2009 The Authors. ANZ Journal of Surgery © 2009 Royal Australasian College of Surgeons.

Aim: To determine factors associated with early pancreatic allograft thrombosis (EPAT). Background(s): Thrombosis is the leading non-immunological cause of early pancreatic allograft failure with an incidence of approximately 10%. Multiple potential risk factors have been reported. We hypothesized that recipient hypotension (intra-operative and postoperative) was a major risk factor and evaluated the correlation of this and other parameters with EPAT. Method(s): We retrospectively reviewed the records of all patients who received a pancreatic allograft at our centre between October 1992 and January 2010. Multiple donor and recipient parameters were analysed as associates of EPAT by univariate and multivariate analysis. All patients routinely received subcutaneous heparins postoperatively. Result(s): 118 pancreas transplants were performed in the study period (117 simultaneous kidney pancreas and 1 pancreas after kidney). There were 12 episodes of EPAT, all occurring within 7 days of transplantation, resulting in an incidence of 10.2%. On univariate analysis, EPAT was associated with intraoperative or peri-operative hypotension, vasopressor use and neuropathy in the recipient (p = 0.04 for all). On multivariate analysis corrected for age, sex and peripheral vascular disease, only vasopressor use retained a significant association with EPAT with a hazard ratio of 8.74 (CI 1.11-68.9, p = 0.04). Factors associated with the need for vasopressor use included recipient ischaemic heart disease, peripheral vascular disease, retinopathy or neuropathy and any surgical complication. Conclusion(s): Because significant hypotension, measured by the need for intraoperative or post-operative vasopressor use was associated with EPAT, pre-emptive vasopressor use for the maintenance of blood pressure could be trialed to determine if the rate of EPAT can be reduced.