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Background Donor characteristics help guide donor pancreas acceptance for solid pancreas-kidney transplantation; however, these criteria vary worldwide. Such variation could result in nonuse of potentially transplantable organs. Using a registry cohort, we identified donor characteristics associated with donor pancreas retrieval and subsequent solid pancreas transplantation in Australia and New Zealand. Methods Australia and New Zealand Organ Donor registry donor data from 2007 to 2016 were used to define cohort 1 (all donors authorized for pancreas retrieval) and cohort 2 (all retrieved donor pancreata considered for solid pancreas transplantation). Donor factors significantly associated with donor pancreas retrieval (cohort 1) and solid pancreas transplantation of retrieved donor pancreata (cohort 2) were determined via multivariable logistic regression. Results Nonretrieval and nonuse of solid organ donor pancreas increased throughout the study period, and nonauthorization for pancreas donation remained stable. Donor body mass index, sex, and viral serology were associated with donor pancreas retrieval but not transplantation. Donor age, cause of death, donation after brain death status, terminal serum creatinine, and donor region were associated with both donor pancreas retrieval and acceptance for solid pancreas transplantation with donation after brain death status being the strongest predictor for both outcomes. Conclusions Donor age, cause of death, donation after brain death status, terminal serum creatinine, and donor region were associated with both donor pancreas retrieval and subsequent transplantation in Australia and New Zealand. Subsequent correlation of these factors with post-pancreas transplant outcomes would help guide pancreas transplant decisions and minimize nonuse of potentially usable donor pancreata.

Background End-stage kidney disease secondary to hyperoxaluria presents a major challenge for transplant physicians given concern regarding disease recurrence. Few contemporary studies have reported long-term outcomes following transplantation in this population. Methods This study examined the outcomes of all adult patients with end-stage kidney disease secondary to hyperoxaluria who received a kidney or combined liver-kidney transplant in Australia and New Zealand between 1965 and 2015. Patients with hyperoxaluria were propensity score matched to control patients with reflux nephropathy. The primary outcome was graft survival. Secondary outcomes included graft function, acute rejection, and patient survival. Results Nineteen transplants performed in 16 patients with hyperoxaluria were matched to 57 transplants in patients with reflux nephropathy. Graft survival was inferior in patients with hyperoxaluria receiving a kidney transplant alone (subhazard ratio [SHR] = 3.83, 95% confidence interval [CI], 1.22-12.08, P = .02) but not in those receiving a combined liver-kidney transplant (SHR = 0.63, 95% CI, 0.08-5.21, P = .67). Graft failure risk was particularly high in patients with hyperoxaluria receiving a kidney transplant alone after more than 1 year of renal replacement therapy (SHR = 8.90, 95% CI, 2.35-33.76, P = .001). Posttransplant estimated glomerular filtration rate was lower in patients with hyperoxaluria (10.97 mL/min/1.73 m2, 95% CI, 0.53-21.42, P = .04). There was no difference between groups in the risk of acute rejection or death with a functioning graft. Conclusion Compared to reflux nephropathy, hyperoxaluria was associated with inferior graft survival in patients receiving a kidney transplant alone. Long-term graft function was lower in patients with hyperoxaluria, but the risks of acute rejection and death were not different.

In 2016, Australia began reporting the Kidney Donor Performance Index (KDPI) with all deceased donor kidney transplant offers despite this not being used in organ allocation rules, offering a unique opportunity to explore the "labeling effect" of KDPI reporting. We reviewed all kidneys retrieved for transplant in Australia from 2015 to 2018 and analyzed the association of KDPI reporting with organ nonutilization, number of offer declines, and donor/recipient age and longevity matching. Analyses were stratified by organ failure risk: higher risk (KDPI > 80%), standard risk (KDPI 20% to 79%), and lower risk (KDPI 0% to 20%). There was no significant difference in organ nonutilization post KDPI reporting either overall or for higher-risk kidneys. KDPI reporting was associated with an increase in offer declines for both higher-risk (incidence risk ratio 1.45, P = .007) and standard-risk (incidence risk ratio 1.22, P = .021) kidneys but not for lower-risk organs. There was a significant increase in recipient age and expected posttransplant survival score for higher-risk kidneys but no differences among other groups. We conclude that although KDPI reporting in Australia has been associated with an increased number of offer declines for higher-risk kidneys, this has not resulted in increased nonutilization and may have contributed to more appropriate use of these organs.

The aim of this study was to determine if natural killer cell number (CD3- /CD16± /CD56± ) and cytotoxic killing function predicts severity and frequency of infection in kidney transplant recipients. A cohort of 168 kidney transplant recipients with stable graft function underwent assessment of natural killer cell number and functional killing capacity immediately prior to entry into this prospective study. Participants were followed for 2 years for development of severe infection, defined as hospitalization for infection. Area under receiver operating characteristic (AUROC) curves were used to evaluate the accuracy of natural killer cell number and function for predicting severe infection. Adjusted odds ratios were determined by logistic regression. Fifty-nine kidney transplant recipients (35%) developed severe infection and 7 (4%) died. Natural killer cell function was a better predictor of severe infection than natural killer cell number: AUROC 0.84 and 0.75, respectively (P = .018). Logistic regression demonstrated that after adjustment for age, transplant function, transplant duration, mycophenolate use, and increasing natural killer function (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.90; P

Purpose The aim of this study was to determine if measurement of B cell protective immunity was associated with susceptibility to sinopulmonary infection in kidney transplant recipients. Methods and Materials A prospective cohort of 168 patients with stable graft function (median 4.1 years) underwent assessment of B-lymphocyte antigen CD19 (CD19+) cell number, immunoglobulin G concentration, and seroresponses to influenza vaccination upon study entry. Patients received a single dose of a trivalent, seasonal influenza vaccine. Results After 2 years follow-up, 31 patients (18%) developed sinopulmonary infection. CD19+ cell number was strongly associated with future sinopulmonary infection. A higher proportion of patients with CD19+ cell counts below the fifth percentile for controls developed sinopulmonary infections than those above the fifth percentile, 30% (23 of 77 patients) compared with 9% (7 of 79 patients; P = .001). There was a trend toward a higher proportion of patients with reduced immunoglobulin G concentrations developing infections than in the normal range for controls, 29% (14 of 48 patients) compared with 15% (16 of 108 patients; P = .060). Influenza vaccination seroresponses were poor in patients and controls such that they could not be used to identify a subgroup of patients at high risk for the development of severe pulmonary infection. Conclusions Monitoring B-cell numbers represents a simple, inexpensive means of stratifying transplant recipients' risk of sinopulmonary infection.

Kidney transplant recipients are at a high risk of developing cancers after transplantation. Switching from calcineurin inhibitors to sirolimus has been shown to prevent secondary nonmelanoma skin cancer but whether everolimus with reduced exposure to calcineurin inhibitors has similar anti-cancer effects remains unknown. Therefore, we compared the risk of incident cancer over seven years of follow-up among kidney transplant recipients randomized to everolimus plus reduced exposure cyclosporine versus mycophenolate sodium and standard exposure cyclosporine. Using the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), we assessed the seven-year risk of incident cancer and other graft outcomes among a subgroup of recipients who had participated in the A2309 study using adjusted Cox proportional hazard models. Of 95 recipients, 66 were randomized to everolimus (1.5 mg or 3 mg) with reduced cyclosporine and 29 received mycophenolate sodium and standard exposure cyclosporine. Compared to mycophenolate sodium and standard exposure cyclosporine, everolimus treatment was associated with unadjusted hazard ratios of 0.28 (95% confidence interval 0.11-0.74), 0.39 (0.16-0.98) and 0.41 (0.23-0.71), respectively for nonmelanoma skin cancer, non-skin cancers and any cancers. Interestingly, the adjusted hazard ratios were 0.34 (0.13-0.91), 0.35 (0.09-1.25) and 0.32 (0.15-0.71), respectively. There was no association between treatment groups and rejection, graft loss or death. Compared to standard-exposure cyclosporine, everolimus with reduced exposure to cyclosporine may be associated with a reduced risk of cancer, particularly for non-melanoma skin cancer. Thus, if confirmed in larger patient cohorts, de novo use of everolimus with reduced exposure to calcineurin inhibitors may enable a reduction in cancer burden after transplantation.

Patient outcomes in end-stage kidney disease (ESKD) secondary to lupus nephritis have not been well described. To help define this we compared dialysis and transplant outcomes of patients with ESKD due to lupus nephritis to all other causes. All patients diagnosed with ESKD who commenced renal replacement therapy in Australia and New Zealand (1963-2012) were included. Clinical outcomes were evaluated in both a contemporary cohort (1998-2012) and the entire 50-year cohort. Of 64,160 included patients, 744 had lupus nephritis as the primary renal disease. For the contemporary cohort of 425 patients with lupus nephritis, the 5-year dialysis patient survival rate was 69%. Of 176 contemporary patients with lupus nephritis who received their first renal allograft, the 5-year patient, overall renal allograft, and death-censored renal allograft survival rates were 95%, 88%, and 93%, respectively. Patients with lupus nephritis had worse dialysis patient survival (adjusted hazard ratio 1.33, 95% confidence interval 1.12-1.58) and renal transplant patient survival (adjusted hazard ratio 1.87, 95% confidence interval 1.18-2.98), but comparable overall renal allograft survival (adjusted hazard ratio 1.19, 95% confidence interval 0.84-1.68) and death-censored renal allograft survival (adjusted hazard ratio 1.05, 95% confidence interval 0.68-1.62) compared with ESKD controls. Similar results were found in the entire cohort and when using competing-risks analysis. Thus, the ESKD of lupus nephritis was associated with worse dialysis and transplant patient survival but comparable renal allograft survival compared with other causes of ESKD.

This was a systematic review of randomized controlled trials comparing delayed conversion of mammalian target of rapamycin inhibitors (mTORi) for calcineurin inhibitors (CNIs) versus CNI continuation in kidney transplantation. Databases (2000-2012) and conference abstracts (2009-2012) were searched giving a total of 29 trials. Outcomes analyzed included GFR, graft loss, rejection and adverse events and were expressed as weighted mean differences (WMDs) or as risk ratios (RRs). Patients converted to mTORi up to 1 year posttransplant in intention-to-treat analysis had higher GFR compared with those remaining on CNI (WMD 0.28 mL/min/1.73 m(2) , 95% confidence interval [CI] 0.21-0.36; I(2) = 68%, p 0.001). Stratifying trials by time posttransplant or type of mTORi did not change the overall heterogeneity. For on-treatment population, mTORi was associated with higher GFR (14.21 mL/min/1.73 m(2) , 10.34-18.08; I(2) = 0%, p = 0.970) 2-5 years posttransplant. The risk of rejection at 1 year was higher in mTORi trials (RR 1.72, 1.34-2.22; I(2) = 12%, p = 0.330). Discontinuation secondary to adverse events was more common in patients on mTORi, whereas the incidence of skin cancers and cytomegalovirus infection was lower in patients on mTORi. Conversion from CNI to mTORi is associated with short-term improvements in GFR in a number of studies but longer-term follow-up data of graft and patient survival are required.

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.

A basic conservation of cell migration guidance mechanisms in the nervous and immune systems was proposed when Slit, known for its role in axon guidance, was found to inhibit chemokine-induced leukocyte chemotaxis in vitro. These studies examined the role of Slit2 in modulating inflammation in vivo. In a rat model of glomerulonephritis, endogenous glomerular Slit2 expression fell after disease induction, and its inhibition during the early disease period accelerated inflammation. Ex vivo glomerular leukocytes showed decreased chemokine and chemoattractant-induced chemotaxis in response to Slit2, suggesting an anti-inflammatory role for glomerular Slit2. In contrast to the effect of inhibition, glomerulonephritis was ameliorated by systemic Slit2 administration. Slit2 treatment improved disease histologically and also improved renal function when given early in the disease course. Leukocytes harvested from rats receiving Slit2 showed decreased monocyte chemoattractant protein-1 (MCP)-1-mediated migration, consistent with a peripheral Slit2 effect. In keeping with this functional alteration, Slit2-mediated inhibition of RAW264.7 cell chemotaxis was associated with decreased levels of active cdc42 and Rac1, implicating GTPases in leukocyte Slit2 signaling. These findings suggest a role for endogenous Slit2 in the inhibition of chemoattractant-mediated signals, demonstrate a potentially important anti-inflammatory effect for Slit2 in vivo, and provide further evidence for conserved mechanisms guiding the process of migration in distinct cell types.

Renal ischemia-reperfusion increases endothelial VEGFR-2 without increasing VEGF or VEGFR-1 expression. Background Hypoxia is a potent stimulus to angiogenesis. Expression of the angiogenic growth factor vascular endothelial growth factor (VEGF) and its receptors (VEGFR-1 and VEGFR-2) is up-regulated by hypoxia in a variety of organs and cell lines. We have previously reported that VEGF expression is not increased in renal ischemia-reperfusion injury, although tubular cells concentrate VEGF at their basolateral surface. In this study we assess whether altered VEGF receptor expression compensates for the lack of VEGF regulation during renal ischemia-reperfusion injury. Methods VEGFR-1 mRNA expression was assessed by Northern blotting and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). VEGFR-2 mRNA expression was analyzed by Northern blotting and in situ hybridization (ISH), while VEGFR-2 protein expression was studied using immunohistochemistry. VEGF mRNA expression was assessed by ISH. Results VEGFR-2 mRNA and protein expression were up-regulated without an increase in VEGF or VEGFR-1 expression. Normal kidneys showed low-level VEGFR-2 mRNA and protein expression in glomerular and peritubular endothelium. Following ischemia and ischemia-reperfusion, a marked increase in VEGFR-2 mRNA and protein expression was seen (2- to 4-fold). Most prominent was VEGFR-2 mRNA up-regulation in the glomerulus although, surprisingly, increased protein was not demonstrated here. ISH showed that VEGF mRNA was not up-regulated in this model, confirming our previous findings for VEGF. Conclusion VEGF and VEGFR-1 expression are not increased by renal ischemia and ischemia-reperfusion injury. Instead, endothelial expression of VEGFR-2 is increased. VEGFR-2 up-regulation in renal ischemia-reperfusion may be important in mediating the mitogenic and anti-apoptotic actions of VEGF on endothelial cells, thereby preserving the integrity of the endothelium and the potential for blood supply to ischemic tissues.

Redistribution of cytoplasmic VEGF to the basolateral aspect of renal tubular cells in ischemia-reperfusion injury. Background Vascular endothelial growth factor (VEGF) mRNA and protein expression are increased by hypoxia in a variety of cell types and organs. In the kidney, however, chronic hypoxia does not up-regulate VEGF mRNA. This suggests that VEGF may be regulated by unique mechanisms in the kidney. Methods Unilateral ischemia was induced in rats by vascular cross-clamping (40 min) followed by reperfusion (0, 20, 40, and 80 min). The distribution of VEGF protein was determined by immunohistochemical staining and Western blotting. mRNA was detected by Northern blotting and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Immunohistochemical staining for VEGF was verified using two VEGF antibodies. To further substantiate the immunohistochemical findings, laser scanning confocal fluorescence microscopy was used to demonstrate the distribution of VEGF protein in rat renal tubular epithelial cells (NRK52-E) subjected to hypoxia (40 min) and re-oxygenation (0, 5, 20, 40 and 80 min). Results Normal kidneys showed diffuse immunohistochemical staining for VEGF in all tubules of the renal cortex and medulla. Following ischemia, staining demonstrated a prominent shift of cytoplasmic VEGF to the basolateral aspect of tubular cells with both VEGF antibodies. The distribution of cytoplasmic VEGF returned to normal following 40 and 80 minutes of reperfusion. Western blots of cytoplasmic samples from ischemic kidneys reperfused for 0 and 20 minutes showed decreased levels of VEGF 164 compared with normal ( P 164 and VEGF 188 levels in the membrane fraction showed no change. Northern blots and semiquantitative RT-PCR showed no significant up-regulation of VEGF mRNA or change in the splice pattern. NRK52-E cells subjected to hypoxia and re-oxygenation for 0 and 5 minutes showed increased staining for VEGF compared with normal, with prominent VEGF staining at the periphery of the cell, similar to the appearance in ischemic kidneys. VEGF staining became more diffuse with further re-oxygenation. Conclusion Although synthesis of VEGF mRNA and protein is not increased during ischemia reperfusion injury, pre-existing VEGF in the tubular cell cytoplasm redistributes to the basolateral aspect of the cells. These data suggest that the kidney may have evolved unique patterns of VEGF regulation to cope with acute hypoxia.