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Background Islet xenografts have clinical potential, may avoid hyperacute rejection, and therefore are a good place to examine the cellular xenograft immune response. The aim of this study was to examine the cellular, humoral, and cytokine response in islet xenograft rejection and to determine the difference in the immune response with a different donor species. Methods Two islet xenograft models (DA rat islets to B6AF1 mouse and canine islets to B6AF1 mouse) and a mouse syngeneic control model were examined histologically and by a semiquantitative polymerase chain reaction method. Results There was significant up-regulation of all intragraft cytokines tested (interleukin [IL]-2, IL-4, IL-5, IL-10, and interferon-gamma) in both xenograft models compared with the controls. However, the dog islet grafts had higher levels of IL-4 and IL-5 gene expression than the rat islet grafts, which, conversely, had higher levels of interferon-gamma gene expression. These differences correlated with the histological and anti-donor antibody production differences between the two models. The dog to mouse model had an intense eosinophilic infiltrate and an early up-regulation of anti-donor antibody, whereas there was little eosinophilic infiltrate and a delayed anti-donor antibody up-regulation in the rat to mouse model. Conclusions The mouse used different mechanisms to reject the rat and canine islets, suggesting that the immune response in islet xenograft rejection may be dependent on the species combination. It may not be possible to characterize the cellular xenograft rejection response in a bipolar manner as has been the case with humoral rejection response. Caution therefore needs to be taken before extrapolating the cellular immune responses seen in animal models to the clinical setting.

The results of simultaneous pancreas and kidney transplantation (SPK) cannot be matched by pancreas transplantation alone (PTA), in part because an independent diagnosis of pancreas graft rejection remains difficult. The relationship between rejection of the pancreas and rejection of the kidney is poorly understood, and it is not known whether simultaneous transplantation of both organs confers true protection to either graft. To study these questions, reliable canine allotransplant models of kidney transplantation alone (KTA), PTA, and SPK were established. Sixty-seven mongrel dogs received KTA (n=21), PTA (n=23), or SPK (n=23) with either no immunosuppression, low-dose cyclosporine (CsA)-based immunosuppression, or high-dose CsA-based immunosuppression. Needle core biopsy (NCB) and fine needle aspiration biopsy (FNAB) were performed at 0, 2, 4, 7, 9, 11, 14, 21, and 30 days or at the time of graft failure. Pancreas and kidney graft survival after SPK was significantly shorter in dogs given low-dose CsA than in dogs given high-dose CsA (pancreas, P

Background Delayed graft function (DGF) is a common complication after renal transplantation, and may affect graft function. The aim of this analysis was to evaluate risk factors for DGF, as well as parameters and events influencing graft function after DGF. We analyzed data collected in an ongoing international, prospective; observational study, the Neoral-MOST (Multinational Observational Study in renal Transplantation), and included in the analysis all patients with cadaveric kidney transplants for whom renal function at 1 year posttransplantation was documented ( N = 8950). Logistic regression was used to evaluate the risk factors for DGF occurrence, and multifactorial analysis of variance (ANCOVA) to assess the relevance of different factors for GFR at 1 year. Results Higher donor age, longer CIT, male recipients, Caucasian recipients, high recipients body mass index, and PRA were all associated with a higher risk for DGF. Renal function of former DGF kidneys at 1 year was lower in kidneys of elder donors, or which had experienced rejection or CMV infection. Variations of the maintenance regimen at 1 year posttransplantation were not associated with better graft function. Multifactorial analysis showed donor age and acute rejection as significant independent factors. Conclusions Most factors increasing the risk for DGF or having a negative impact on renal function at 1 year in grafts with DGF are predetermined. Additional posttransplant damage by acute rejection was associated with further reductions in GFR. Preventing acute rejection is an important step in achieving optimal function of DGF grafts.

Screening for polyoma BK virus (BK) using nucleic testing (NAT) is recommended for kidney and kidney-pancreas transplant recipients, but the performance characteristics of quantitative BK NAT at different thresholds of plasma BK viral loads are unclear. We aim to evaluate the diagnostic accuracy of quantitative BK NAT as an add-on test to qualitative polyoma NAT for the diagnosis of BK virus-associated nephropathy (BKVAN) in kidney and kidney transplant recipients. We calculated the test sensitivity, specificity, and predictive values at the different thresholds of plasma BK viral load for BKVAN. At the recommended threshold of >1 × 10(3) serum BK copies/mL serum for test positivity, the sensitivity for BKVAN was 92.9% (95% confidence intervals [CI]: 66.1-99.8) and specificity 79.1% (95%: CI 67.4-88.1), with corresponding positive and negative predictive values of 42.0% (95% CI: 24.8-57.7%) and 98.6% (95% CI: 98.3-99.9%), respectively. The overall area under curve for the quantitative BK NAT was 0.92 (95% CI: 0.85-0.97). Quantitative BK NAT displays properties of high sensitivity and specificity that are fit for purpose as an add-on test to qualitative polyomavirus NAT for kidney and kidney-pancreas transplant recipients at risk of BKVAN.

Background The deceased-donor organ shortage has driven widespread adoption of living-donor transplantation. Yet, public views on living donation are not well understood. This study aims to synthesize studies on public awareness and attitudes toward living organ donation. Methods Electronic databases and reference lists were searched to September 2012. Summary estimates from survey data were obtained by random effects meta-analysis. Qualitative descriptive synthesis of each study was performed. Results Forty-seven studies involving 34,610 respondents were included. The proportion of respondents aware of living organ donation was 76.7% (4 studies, n=3248; 95% confidence interval, 46.2%-97.0%; I=99.7%). The majority were in favor of living directed donation (85.5% (11 studies, n=15,836; 95% confidence interval, 81.6%-89.6%; I=98%), with recipient and community benefit as the rationale provided. However, barriers included fear of surgical and health risks, lack of knowledge, respect for cultural norms, financial loss, distrust in hospitals, and avoiding recipient indebtedness. The public voiced concern about possible risks or an obligatory pressure exerted on the donor. Many supported reimbursement for out-of-pocket expenses, paid leave, wait-listing priority, health insurance, and donor acknowledgment. There was strong opposition to financial incentives, which they believed risked exploitation and inequity and diminished voluntary altruistic donation. Conclusions The public is generally supportive of living donation and articulated important equity and ethical considerations for protecting the health and safety of living donors. This supports increased public engagement and strengthening of a shared view among professionals and the public in living donation practice and policy.

Medical products of human origin (MPHO) include blood, organs, bone marrow, cord blood, corneas, tissues, reproductive cells and milk derived from humans for therapeutic use. These materials, obtained from people whose safety, privacy and human rights need to be protected, provide important and often irreplaceable therapies. Obtaining MPHOs from living and deceased donors entails practical, scientific and ethical considerations. Transplantation of vascularized organs and viable tissues carries the same types of risk of disease transmission and incompatibility as blood transfusion, with additional risks and benefits. Donors must be carefully screened through medical history and laboratory tests, yet a thorough history is seldom available for deceased donors. Furthermore, the time from donation to transplantation is often short. Recipients, on the other hand, can die without a transplant. Thus, an MPHO, especially an organ, must be directed to a specific recipient, once the risk of disease transmission and the viability of the MPHO have been weighed against the poor prognosis without transplantation. This individual tailoring, which is critically important in the case of MPHOs, must be conducted reliably and verifiably. For MPHOs to be managed safely, organizational governance must guarantee transparency and traceability. Traceability – the ability to identify the unique origin of an MPHO by tracking the path from donor to recipient – is essential for vigilance, surveillance and activity reporting and to support recall of an MPHO. Because MPHOs can transmit disease,1 the risk of harm can be reduced by rapid notification or recall after disease transmission is identified in one recipient. The medical uses of MPHOs continue to expand. Many MPHOs are transported across national boundaries, but without uniform global standards for identifying their origins, their safety is compromised. Several countries have traceability requirements. However, these often vary for different types of MPHO because there is no global governance framework to ensure international consistency. These important problems have been recognized in global consultations on human cells and tissues for transplantation led by the World Health Organization (WHO). World Health Assembly Resolution WHA63.22 urges Member States “to encourage the implementation of globally consistent coding systems to facilitate national and international traceability”.2 A standard coding system based on globally standardized nomenclature would allow critical information on each MPHO and its origin to be presented in a format conducive to consistent interpretation globally and would overcome language barriers and facilitate electronic data capture and information transfer. An international initiative to ensure the global traceability of MPHOs is already well established. The Information Standard for Blood and Transplant (ISBT 128)3,4 was developed in response to problems in identifying the blood provided by different nations during the First Gulf War. The International Council for Commonality in Blood Bank Automation (ICCBBA) was established in 1995 as a not-for-profit organization to manage ISBT 128, which was introduced in 1996 for blood and extended to cell therapy and tissues in 2000. Today, ISBT 128 is used by more than 4500 facilities in over 60 countries and its use for organ transplantation is being piloted. It is endorsed and strongly supported by many international professional bodies and accreditation organizations and is being expanded to harmonize the nomenclature and coding of all MPHOs to ensure global traceability and biovigilance. To manage ISBT 128, the ICCBBA works closely with professional associations, transfusion and transplantation facilities and individual experts to develop strong expert consensus internationally. Health authorities in many countries accept ISBT 128 as an effective solution for blood and blood products and some mandate its use. A 2012 international transplantation workshop5 convened by WHO considered global traceability and recommended close collaboration between national health authorities and agencies and scientific and professional societies, with the ICCBBA and WHO managing a global governance service for the coding and labelling of MPHOs. ISBT 128 has been highly successful where it has been adopted but global standardization, not yet realized, will depend on international confidence in the long-term sustainability of ISBT 128 and protection of the standard from commercial exploitation, potentially through agreement between the ICCBBA and WHO. The development of an international coding system for MPHOs requires either creating a new system or ensuring a role for the ICCBBA as provider of the global service for nomenclature and coding. Attaining the WHA63.22 objective of globally consistent coding systems will involve the gradual adoption of ISBT 128 by organizations as an element of their development programmes. Implementation of such an international coding system will also require an understanding of the importance of consistent coding and of international traceability and transparency.

Safety of living donors is critical to the success of blood, tissue and organ transplantation. Structured and robust vigilance and surveillance systems exist as part of some national entities, but historically no global systems are in place to ensure conformity, harmonisation and the recognition of rare adverse events (AEs). The World Health Assembly has recently resolved to require AE/reaction (AE/R) reporting both nationally and globally. The World Marrow Donor Association (WMDA) is an international organisation promoting the safety of unrelated donors and progenitor cell products for use in haematopoietic progenitor cell (HPC) transplantation. To address this issue, we established a system for collecting, collating, analysing, distributing and reacting to serious adverse events and reactions (SAE/R) in unrelated HPC donors. The WMDA successfully instituted this reporting system with 203 SAE/R reported in 2011. The committee generated two rapid reports, reacting to specific SAE/R, resulting in practice changing policies. The system has a robust governance structure, formal feedback to the WMDA membership and transparent information flows to other agencies, specialist physicians and transplant programs and the general public.

Although twin-bag disconnect fluid-transfer systems for continuous ambulatory peritoneal dialysis (CAPD) have a lower rate of catheter-related infection than single-bag systems, their greater monetary purchase cost has prevented universal adoption. Therefore, a single-center randomized study was performed in 63 adult patients to compare the efficiency and total cost of Freeline Solo (FS, twin-bag) and Basic Y (BY, single-bag) systems. Patients were new to CAPD (N = 39), or had a new CAPD catheter, or had had no episodes of peritonitis or exit-site infection in the previous 12 months (N = 24). Total follow-up was 631 patient months (pt.mon), and 53 patients were still on the trial at its termination. Patients rated FS as easier to use than BY (P < 0.001). Peritonitis occurred on 23 occasions in 12 out of 30 patients using BY, and on seven occasions in five of 33 patients using FS. Time to first infection was less with BY than FS (hazard ratio, 2.4; 95% confidence interval (CI), 1.0 to 5.3; P < 0.04). Cumulative incidence of peritonitis was 1 per 14.0 pt.mon with BY and 1 per 46.5 pt.mon with FS (odds ratio, 3.6; 95% CI 1.5 to 8.5; P = 0.004). Length of hospitalization for peritonitis or exit-site infection was 98 days in six patients with BY, versus 17 days in two patients with FS. With BY, four catheters were removed because of infection, but none with FS (P < 0.05). With BY, the total cost of infection was $AUD127,079 ($5033 per pt.yr) versus $19,250 ($704 per pt.yr) with FS, which offset the higher purchase cost of FS. The total cost of CAPD was $AUD956 per pt.yr less with FS than BY. In conclusion, the higher purchase cost of the FS twin-bag system is more than offset by savings from its lower incidence of peritonitis.

CTLA4-Fc is a chimeric murine construct consisting of the CD28 homologue CTLA4 and the constant portion of the heavy chain of mouse IgG2a, with a potential to suppress cellular xeno-immune responses. The aim of this study was to determine the degree of binding of CTLA4 to B7 ligands on cells of different species and to use CTLA4-Fc as a tool for the study of cross-species CD28-B7 interactions. As assessed by flow cytometry, CTLA4-Fc bound to mouse L-cells and human Epstein Barr virus (EBV) transformed lymphoblastoid cells and concanavalin A (Con A) or LPS-stimulated peripheral blood mononuclear cells (PBMC) or splenocytes from rat, dog, and pig. CTLA4-Fc inhibited the proliferation of Con A-stimulated PBMC or splenocytes from mouse, rat, dog, and pig, in a dose-dependent fashion with approximately 80% inhibition at a concentration of 10 μg/ml. It did not inhibit the proliferation of Con A-stimulated human PBMC, although it did inhibit the human versus human, and human versus pig primed mixed lymphocyte culture (MLC) in a dose-dependent fashion. At submitogenic concentrations, purified human T-cells did not proliferate after incubation with Con A alone. However, proliferation occurred with the addition of B7 positive L-cells or pig PBMC, but not B7-negative OKT4 cells. Furthermore, CTLA4-Fc inhibited proliferation in a dose-dependent fashion. CTLA4-Fc bound to all species tested and resulted in inhibition of Con A-stimulated proliferation in these species, except for humans. Human T-cells proliferated in response to co-stimulation with xenogeneic B7, and this could be inhibited by CTLA4-Fc, suggesting that xenogeneic B7 was capable of providing a functionally significant co-stimulatory signal necessary for human T cell activation in vitro.

Background Chronic kidney disease is associated with an increased risk of cancer, but whether reduced kidney function also leads to increased cancer mortality is uncertain. The aim of our study was to assess the independent effects of reduced kidney function on the risk of cancer deaths. Study Design Prospective population-based cohort study. Setting & Participants Participants of the Blue Mountains Eye Study (n=4,077; aged 49-97 years). Predictor Estimated glomerular filtration rate (eGFR). Outcomes Overall and site-specific cancer mortality. Results During a median follow-up of 12.8 (IQR, 8.6-15.8) years, 370 cancer deaths were observed in our study cohort. For every 10-mL/min/1.73m 2 reduction in eGFR, there was an increase in cancer-specific mortality of 18% in the fully adjusted model ( P 2 , the adjusted HR for cancer-specific mortality for those with eGFR 2 was 1.27 (95% CI, 1.00-1.60; P =0.05). This excess cancer mortality varied with site, with the greatest risk for breast and urinary tract cancer deaths (adjusted HRs of 1.99 [95% CI, 1.05-3.85; P =0.01] and 2.54 [95% CI, 1.02-6.44; P =0.04], respectively). Limitations Residual confounding, such as from unmeasured socioeconomic factors and the potential effects of erythropoiesis-stimulating agents on cancer deaths, may have occurred. Conclusions eGFR 2 appears to be a significant risk factor for death from cancer. These effects appear to be site specific, with breast and urinary tract cancers incurring the greatest risk of death among those with reduced kidney function.

BACKGROUND The introduction of solid-phase immunoassay (SPI) technology for the detection and characterization of human leukocyte antigen (HLA) antibodies in transplantation while providing greater sensitivity than was obtainable by complement-dependent lymphocytotoxicity (CDC) assays has resulted in a new paradigm with respect to the interpretation of donor-specific antibodies (DSA). Although the SPI assay performed on the Luminex instrument (hereafter referred to as the Luminex assay), in particular, has permitted the detection of antibodies not detectable by CDC, the clinical significance of these antibodies is incompletely understood. Nevertheless, the detection of these antibodies has led to changes in the clinical management of sensitized patients. In addition, SPI testing raises technical issues that require resolution and careful consideration when interpreting antibody results. METHODS With this background, The Transplantation Society convened a group of laboratory and clinical experts in the field of transplantation to prepare a consensus report and make recommendations on the use of this new technology based on both published evidence and expert opinion. Three working groups were formed to address (a) the technical issues with respect to the use of this technology, (b) the interpretation of pretransplantation antibody testing in the context of various clinical settings and organ transplant types (kidney, heart, lung, liver, pancreas, intestinal, and islet cells), and (c) the application of antibody testing in the posttransplantation setting. The three groups were established in November 2011 and convened for a "Consensus Conference on Antibodies in Transplantation" in Rome, Italy, in May 2012. The deliberations of the three groups meeting independently and then together are the bases for this report. RESULTS A comprehensive list of recommendations was prepared by each group. A summary of the key recommendations follows. Technical Group: (a) SPI must be used for the detection of pretransplantation HLA antibodies in solid organ transplant recipients and, in particular, the use of the single-antigen bead assay to detect antibodies to HLA loci, such as Cw, DQA, DPA, and DPB, which are not readily detected by other methods. (b) The use of SPI for antibody detection should be supplemented with cell-based assays to examine the correlations between the two types of assays and to establish the likelihood of a positive crossmatch (XM). (c) There must be an awareness of the technical factors that can influence the results and their clinical interpretation when using the Luminex bead technology, such as variation in antigen density and the presence of denatured antigen on the beads. Pretransplantation Group: (a) Risk categories should be established based on the antibody and the XM results obtained. (b) DSA detected by CDC and a positive XM should be avoided due to their strong association with antibody-mediated rejection and graft loss. (c) A renal transplantation can be performed in the absence of a prospective XM if single-antigen bead screening for antibodies to all class I and II HLA loci is negative. This decision, however, needs to be taken in agreement with local clinical programs and the relevant regulatory bodies. (d) The presence of DSA HLA antibodies should be avoided in heart and lung transplantation and considered a risk factor for liver, intestinal, and islet cell transplantation. Posttransplantation Group: (a) High-risk patients (i.e., desensitized or DSA positive/XM negative) should be monitored by measurement of DSA and protocol biopsies in the first 3 months after transplantation. (b) Intermediate-risk patients (history of DSA but currently negative) should be monitored for DSA within the first month. If DSA is present, a biopsy should be performed. (c) Low-risk patients (nonsensitized first transplantation) should be screened for DSA at least once 3 to 12 months after transplantation. If DSA is detected, a biopsy should be performed. In all three categories, the recommendations for subsequent treatment are based on the biopsy results. CONCLUSIONS A comprehensive list of recommendations is provided covering the technical and pretransplantation and posttransplantation monitoring of HLA antibodies in solid organ transplantation. The recommendations are intended to provide state-of-the-art guidance in the use and clinical application of recently developed methods for HLA antibody detection when used in conjunction with traditional methods.

Background Chronic kidney disease (CKD) poses a financial burden on patients and their households. This descriptive study measures the prevalence of economic hardship and out-of-pocket costs in an Australian CKD population. Methods A cross-sectional study of patients receiving care for CKD (stage III-V) in Western Sydney, Australia using a structured questionnaire. Data collection occurred between November 2010 and April 2011. Multivariate analyses assessed the relationships between economic hardship and individual, household and health system characteristics. Results The study included 247 prevalent CKD patients. A mean of AUD$907 per three months was paid out-of-pocket resulting in 71% (n=153) of participants experiencing financial catastrophe (out-of-pocket costs exceeding 10% of household income). Fifty-seven percent (n=140) of households reported economic hardship. The adjusted risk factors that decreased the likelihood of hardship included: home ownership (OR: 0.32, 95% CI: 0.14-0.71), access to financial resources (OR: 0.24, 95% CI: 0.11-0.50) and quality of life (OR: 0.12, 95% CI: 0.02-0.56). The factors that increased the likelihood of hardship included if income was negatively impacted by CKD (OR: 4.80, 95% CI: 2.17-10.62) and concessional status (i.e. receiving government support) (OR: 3.09, 95% CI: 1.38-6.91). Out-of-pocket costs and financial catastrophe were not found to be significantly associated with hardship in this analysis. Conclusions This study describes the poorer economic circumstances of households affected by CKD and reinforces the inter-relationships between chronic illness, economic well-being and quality of life for this patient population.

Background The role of cytomegalovirus (CMV) in cancer development after transplantation remains uncertain. We aimed to determine the association between donor and recipient CMV serological status and the risk of cancer development after kidney transplantation. Methods Using data from the Australian and New Zealand Dialysis and Transplant (ANZDATA) Registry, we assessed the association between CMV donor/recipient (D/R) serological status and the risk of solid organ cancers in primary adult deceased-donor kidney transplant patients between 1990 and 2012. Results Of 8140 recipients, a total of 895 (11%) recipients developed incident cancers during a follow-up time of 51,555 person-years. Human leukocyte antigen (HLA) mismatches was an effect modifier between CMV serological status and cancer (P =.03 for interaction). In recipients who have received 0–2 HLA-ABDR mismatched kidneys, the adjusted hazard ratios for cancer incidence among those with CMV D–/R–, CMV D–/R+ and CMV D+/R– were 0.47 (95% confidence interval [CI]: 0.24–0.91), 1.42 (95% CI: 0.97–2.07), and 1.02 (95% CI: 0.67–1.57), respectively compared with the reference of CMV D+/R+. A similar association was not observed in those with >2 HLA-ABDR mismatches. Conclusion CMV D–/R– status was associated with a reduced risk of cancer in kidney transplant recipients who have received well-matched renal allografts, suggesting a potential role of HLA-matching in cancer development. This article is protected by copyright. All rights reserved.

Supplemental digital content is available in the text., Background Epitope matching, which evaluates mismatched amino acids within antigen-antibody interaction sites (eplets), may better predict acute rejection than broad antigen matching alone. We aimed to determine the association between eplet mismatches and acute rejection in kidney transplant recipients. Methods The association between eplet mismatches, broad antigen mismatches and acute rejection was assessed using adjusted Cox proportional hazard regression. Model discrimination for acute rejection was evaluated using the area under receiver operating characteristic curves. Results Of the 3,499 kidney transplant recipients from 2006 to 2011, the average (SD) number of broad antigen and eplet mismatches were 3.4 (1.7) and 22.8 (12.2), respectively. Compared with 0 to 2 eplet mismatches, the adjusted hazard ratio (HR) for acute rejection among those with 20 or greater eplet mismatches was 2.16 (95% confidence interval [CI], 1.33-3.52; P = 0.001). The adjusted area under the curve for broad antigen mismatches was 0.58 (95% CI, 0.56-0.61), similar to that for eplet mismatches (HR, 0.59; 95% CI, 0.56-0.61; P = 0.365). In recipients who were considered as low immunological risk (0-2 broad antigen HLA-ABDR mismatch), those with 20 or greater eplet mismatches experienced an increased risk of rejection compared to those with less than 20 mismatches (adjusted HR, 1.85; 95% CI, 1.11-3.08; P = 0.019). Conclusions Increasing number of eplet mismatches is associated with acute rejection in kidney transplant recipients. Consideration of eplet HLA mismatches may improve risk stratification for acute rejection in a selected group of kidney transplant candidates.

Serum creatinine is an important clinical measure of impairment of glomerular filtration rate (GFR) after kidney transplantation. The use of formulas that predict GFR (such as the Cockcroft-Gault) derived from patients with chronic renal failure and standardized against measured creatinine clearance may not be accurate when applied to kidney transplant recipients. The purpose of this study, was to investigate the level of inaccuracy and its causes and then to derive predictive GFR formulas that are appropriate to renal transplantation. Determinants of isotopic GFR, serum creatinine, and muscle mass were evaluated in consecutive kidney recipients (n = 146) using 99mTc DTPA GFR (n = 751) as a reference method. Factors that predicted GFR apart from serum creatinine included sex, height, body weight, serum urea, years on dialysis, numbers of rejections and infective episodes, and prednisolone dose. The relationship between serum creatinine and GFR was highly variable and dependent on factors that alter muscle mass and muscle catabolic rate. The relationship was further altered by ATN and chronic rejection when tubular secretion of creatinine was reduced. Three alternative GFR formulas (which can be applied to renal transplant patients according to the availability of clinical parameters) were derived and tested against six published methods of GFR estimation. Our derived formulas had the highest correlation, no overall bias, least scatter of sum of squares, and least error at low levels of GFR. They represent a better estimation of GFR in kidney transplantation than published formulas, and would allow a standardized approach to the study of long-term renal dysfunction.

Organ donation rates vary markedly around the world. In an attempt to analyse why some patients’ families are not asked about organ donation, the case notes of 6080 patients who died over a twelve-month period from April 1991 to March 1992 in nine hospitals in Sydney, NSW, were studied. Irreversible coma occurred in 515 patients. Of these, 177 were considered to be potentially brain dead donors, 126 of whom had a formal diagnosis of brain death. The clinicians caring for the patients at the time of death were asked at follow-up about the reasons for not considering donation, or the reasons for family refusal. Consent to proceed to organ donation was requested in 112 cases (49 donated and 63 refused) and not requested in 65. Analysis of the proportions asked and consenting in each hospital revealed no correlation. Half of the families refusing gave no reason (24/50) while eleven gave religious or cultural reasons, and six expressed a desire to prevent mutilation of the body as their primary reason for not consenting. There was universal failure to gain consent from families when the patient was not in an Intensive Care Unit. Analysis of those patients of whom consent was not sought showed that they died more quickly after admission, were older and died from causes other than trauma or intracranial haemorrhage. The odds of the family being asked dropped by about half as the age increased from one group to the next. Increases in organ donation may be achieved by ensuring that potential donors reach intensive care units; that criteria for medical suitability for donation are unambiguous and widely known; and that changes occur in public attitudes to consent for donation.

Most Australian transplantation programs are severely restricted in their activities by a limited availability of cadaveric donor organs. To investigate possible reasons for this problem, an audit was undertaken over three 12-month periods of all deaths in 13 hospitals in New South Wales and the Australian Capital Territory. From 7406 deaths, 271 patients were classified as having been realistic, medically suitable potential donors. Of these, only 60 (22%) became actual donors. In the other 211 patients, donation did not occur because of unsuccessful resuscitation (30%), permission refusal by relatives (34%), and failure to identify or support the potential donors (36%). If the impediments to organ donation which were identified in this study could be overcome, allowing a greater number of potential donors to become actual donors, the chronic shortage of cadaveric donor organs for transplantation could be at least partly relieved.

Background Despite the higher risk of colorectal cancer (CRC) in people with chronic kidney disease, it remains uncertain whether early detection through screening is cost-effective in this setting. We aimed to determine the costs and health benefits of CRC screening in people on dialysis or who have received a kidney transplant. Methods Using a government health perspective, three probabilistic Markov models were constructed to compare the cost-effectiveness and cost-utility of annual immunochemical faecal occult blood test (iFOBT) screening against no-screening in a cohort of 1000 patients (age 50–70 years) on dialysis and with kidney transplants. A series of one-way, multi-way and probabilistic sensitivity analyses were conducted to assess the robustness of the model structure and the extent in which the model's assumptions were sensitive to the uncertainties within the input variables. Results The incremental cost-effectiveness ratios (ICERs) of CRC screening compared with no-screening were $138 828 per quality-adjusted life year [QALY; $122 977 per life year saved (LYS)], $121 973 per QALY ($ 85 095 per LYS) and $44 790 per QALY ($25 036 per LYS) for dialysis patients not listed on the transplant waiting list, patients on the transplant waiting list and patients with kidney transplants, respectively. The test specificity of iFOBT, the starting age of screening and cancer prevalence were influential factors that determined the overall cost-effectiveness of screening in this setting. Conclusion Screening for CRC using iFOBT may reduce cancer-specific mortality in patients on dialysis and with kidney transplants. However, the benefits and costs of screening CRCs in patients on dialysis, especially for those deemed not suitable for transplantation, greatly exceeded the typical thresholds for acceptable cost-effectiveness. Refereed/Peer-reviewed

Purpose of review The research undertaken on ‘protocol’ renal transplant biopsies has provided a rich, if not the richest, approach to better understanding of the immune and nonimmune impacts upon the transplant. The purpose of this review is to detail how the direct benefit to the patient also lies in these renamed ‘surveillance’ biopsies. Recent findings Undertaken at fixed time points after transplantation, biopsy provides individual diagnoses with which the clinician can vary immunosuppression both in intensity and in the type of agent used to modify pathological processes early in their course. Initial nonfunction from acute tubular necrosis, subclinical cellular and humoral rejection, calcineurin inhibitor nephrotoxicity, BK virus nephropathy and recurrent glomerulonephritis are all important diagnoses for which early intervention provides better therapeutic outcomes than delaying until they are clinically evident. Summary This review provides the recent evidence that has convinced many transplant units to embark upon surveillance programmes for their patients in order to individualize their immunosuppression and thus gain better outcomes.

Posttransplant lymphoproliferative disorders (PTLDs) are associated with significant morbidity and mortality among solid-organ transplant patients, but approaches to diagnosis and management vary considerably. An international multidisciplinary panel evaluated current understanding of risk factors and classification systems and developed recommendations to aid in PTLD prevention. We considered evidence on PTLD risk factors including Epstein-Barr virus serostatus and immunosuppression and identified knowledge gaps for future research. Recommendations address prophylactic and preemptive strategies to minimize PTLD development, including modulation of immunosuppression and antiviral drug regimens. Finally, new classification criteria were outlined that may help facilitate standardized reporting and improve our understanding of PTLD.

Apparent variability in wait-listing criteria globally has raised concern about inequitable access to kidney transplantation. This study aimed to compare the quality, the scope, and the consistency of international guidelines on wait-listing for kidney transplantation.Electronic databases and guideline registries were searched to December 2011. The Appraisal of Guidelines for Research and Evaluation II instrument and textual synthesis was used to assess and compare recommendations.Fifteen guidelines published from 2001 to 2011 were included. Methodological rigor and scope were variable. We identified 4 major criteria across guidelines: recipient age and life expectancy, medical criteria, social and lifestyle circumstances, and psychosocial considerations. Whereas some recommendations were consistent, there were differences in age cutoffs, estimated life expectancy (2-5 years), and glomerular filtration rate at listing (15-20 mL/min/1.73 m). Cardiovascular contraindications were broadly defined. Recommended cancer-free periods also varied substantially, and whereas uncontrolled infections were universally contraindicated, human immunodeficiency virus thresholds and adherence to highly active antiretroviral therapy were inconsistent. Most guidelines recommended psychological screening but were not augmented with specific clinical assessment tools.Wait-listing recommendations in current guidelines are based on life expectancy, comorbidities, lifestyle, and psychosocial factors. Some recommendations are different across guidelines or broadly defined. There is a case for developing comprehensive, methodologically robust, and regularly updated guidelines on wait-listing for kidney transplantation.

Commercial transplantation has expanded because of the shortage of kidneys for transplantation. This study aims to synthesize qualitative studies on the experiences and perspectives of living commercial kidney donors. We conducted a comprehensive literature search in electronic databases to April 2011 and consulted experts to identify unpublished studies. Thematic synthesis was used to analyze the findings. Seven studies involving over 676 commercial kidney donors were included. Three major themes were identified: desperation (the participants' decision to sell their kidney was forced by poverty, debt, or to fulfill a family obligation); despair (destroyed body integrity, shame and secrecy, dehumanized and dispirited, loss of livelihood, heightened sense of vulnerability, disappointment, and regret); and debasement (deception by brokers and recipients, victimized by the hospital, stigmatized by community, and rejected by family). Commercial kidney transplantation is reported to result in ramifications for the donors' mental, physical, and social well-being. Not only do they remain in poverty, they lose dignity, sense of purpose, respect, relationships, and livelihood. Review of this published literature supports the need for effective implementation of the WHO guiding principles and legislated regulation to deter potential recipients and healthcare providers from pursuing commercial transplantation.

O Dia Mundial do Rim, em 8 de março de 2012, oferece uma chance para refletir sobre o sucesso do transplante renal como um tratamento para a doença renal em estágio terminal, que supera os tratamentos de diálise tanto pela qualidade quanto pela quantidade de vida, fornecida por estes, e devido ao custo-benefício. Qualquer coisa que seja tanto mais barata quanto melhor, mas que não seja realmente o tratamento dominante, deve ter outras desvantagens que previnam a substituição do tratamento da diálise pelo transplante. As barreiras para o transplante universal como a terapia para a doença renal em estágio terminal incluem as limitações econômicas, as quais, em alguns países, classificam o transplante, adequadamente, com prioridade inferior do que os fundamentos da saúde pública, tais como água limpa, saneamento e vacinação. Até mesmo em países de alta renda, os desafios técnicos da cirurgia e as consequências da imunossupressão restringem o número de receptores apropriados, mas as principais restrições limitadas das taxas de transplante renal são: a escassez de órgãos doados e a limitada mão de obra médica, cirúrgica e de enfermeiros com os conhecimentos necessários. Esses problemas têm soluções que envolvem um conjunto total dos ambientes social, profissional, governamental e político. O Dia Mundial do Rim é uma chamada para fornecer a terapia de transplante a um milhão de pessoas por ano, as quais têm o direito de se beneficiarem. World Kidney Day on March 8th 2012 provides a chance to reflect on the success of kidney transplantation as a therapy for end stage kidney disease that surpasses dialysis treatments both for the quality and quantity of life that it provides and for its cost effectiveness. Anything that is both cheaper and better, but is not actually the dominant therapy, must have other drawbacks that prevent replacement of all dialysis treatment by transplantation. The barriers to universal transplantation as the therapy for end stage kidney disease include the economic limitations which, in some countries place transplantation, appropriately, at a lower priority than public health fundamentals such as clean water, sanitation and vaccination. Even in high income countries the technical challenges of surgery and the consequences of immunosuppression restrict the number of suitable recipients, but the major finite restrictions on kidney transplantation rates are the shortage of donated organs and the limited medical, surgical and nursing workforces with the required expertise. These problems have solutions which involve the full range of societal, professional, governmental and political environments. World Kidney Day is a call to deliver transplantation therapy to the one million people a year who have a right to benefit.

Background. BK virus nephropathy (BKVAN) causes about 10% of late kidney graft loss. Cidofovir is widely used to treat BKVAN, but the magnitude of the health benefits and costs are largely unknown. We aimed to evaluate the incremental health benefits and costs of cidofovir and immuno suppression reduction compared with immunosuppression reduction alone in kidney transplant patients with BKVAN. Methods. A probabilistic decision analytic model was developed to simulate a cohort of kidney transplant recipients aged 45 years and above with BKVAN who received cidofovir treatment compared with those who received standard care. The duration of the cycle was 1 year, and the model terminated when all recipients were deceased. Results. Compared with immunosuppression reduction alone, in the base-case, the incremental health benefits of cidofovir were 0.0061 life-years saved (2.2 days), with savings of $20,756 over the lifetime of a transplant recipient.When varying the most influential variables (the probability of response to treatment and graft loss) between best and worst case scenarios, the incremental health outcomes ranged from -0.967 to 1.093 life-years saved, with incremental costs ranging from an extra $27,313 to saving $20,756. Conclusions. Compared with immunosuppression reduction alone, based on best available data, cidofovir treatment and immunosuppression reduction for BKVAN seem to be cost saving and improves health outcomes. However,because of weak clinical data, particularly around comparative effectiveness, there is still moderate uncertainty in the incremental cost effectiveness. Adequately powered trials are still needed to better define optimal treatment strategies for BKVAN before cidofovir can be recommended strongly as routine therapy. Refereed/Peer-reviewed

Whole blood CsA concentrations measured by specific monoclonal RIA (CYCLO-Trac SP whole blood RIA, IncSTAR) were compared with episodes of renal dysfunction (n = 138) and protocol biopsies (n = 52) that occurred within the first 100 days in consecutive renal allograft recipients receiving triple therapy (n = 92). Histological confirmation of events was available in 98% episodes of acute rejection (n = 60/61), 59% of episodes of CsA nephrotoxicity (22/38), and 100% of the diagnoses of acute tubular necrosis (35/35). Mean, minimum, and maximum CsA levels were elevated in CsA nephrotoxicity compared with all other groups (P < 0.001). Interestingly, CsA levels achieved relative to administered dose also increased at the time of CsA nephrotoxicity compared with other groups (P < 0.01). In the context of acute dysfunction, the sensitivity and specificity of mean CsA levels above 400 ng/ml to predict CsA nephrotoxicity were 32% and 89%, respectively. The negative predictive value of a high CsA level to exclude acute rejection was 88% (at 400 ng/ml), 92% (450 ng/ml), and 95% (500 ng/ml). As a marker of effective immunosuppression, CsA levels were not correlated with in vitro proliferation of PHA-stimulated PBL and did not reduce the severity and degree of cellular infiltration in needle core biopsies during rejection. The sensitivity and specificity of a low CsA level (150 ng/ml) in the diagnosis of acute rejection were 31% and 91%, respectively. The majority of episodes of acute dysfunction, including 63% of CsA nephrotoxicity and 59% of acute rejections, occurred with CsA levels between 150 and 400 ng/ml. In summary, when using low dose triple therapy regimens, CsA levels within the range of 150-400 ng/ml were of little diagnostic value in acute allograft dysfunction. In contrast, levels outside this range were useful in the clinical diagnosis of CsA nephrotoxicity and acute allograft rejection.

Despite overall improved graft survival, renal graft thrombosis (RGT) remains an important cause of graft loss. Of 6153 consecutive renal transplants (RTx), 134 index cases of graft loss from RGT were reported to the Australian and New Zealand Dialysis and Transplant Registry between 1980 and 1992.

Summary Organ donation and transplant rates vary widely across the globe, but there remains an almost universal shortage of deceased donors. The unmet need for transplants has resulted in many systematic approaches to increase donor rates, but there have also been practices that have crossed the boundaries of legal and ethical acceptability. Recent years have seen intense interest from international political organizations, led by the World Health Organization, and professional bodies, led by The Transplantation Society. Their efforts have focused on the development of a series of legal and ethical frameworks, designed to encourage all countries to eradicate unacceptable practices while introducing programmes that strive to achieve national or regional self-sufficiency in meeting the need for organ transplants. These programmes should seek to reduce both the need for transplantation and also develop deceased donation to its maximum potential. Living donation remains the mainstay of transplantation in many parts of the world, and many of the controversial—and unacceptable—areas of practice are found in the exploitation of living donors. However, until lessons are learnt, and applied, from countries with highly developed deceased donor programmes, these abuses of human rights will be difficult to eradicate. A clear international framework is now in place to achieve this.

Despite an increased risk of cancer post transplant, little is known about the knowledge, beliefs of and attitudes to cancer and its prevention among kidney transplant recipients. This study aims to explore these beliefs and attitudes, to better understand patient motives and potential barriers to early detection of cancer.Semi-structured interviews were conducted with 14 kidney and eight kidney-pancreas transplant recipients based at a single transplant centre in Sydney, Australia, between October 2009 and February 2010.Thematic data analysis identified four major themes: (1) skin cancer-focused: participants were generally only aware about their increased risk of skin cancer and available prevention strategies for that cancer alone; (2) limited awareness: participants knew little about their excess risk for non-skin cancers and possible preventative and screening strategies; (3) fear of cancer: cancer fears were heightened by prior experiences; some felt vulnerable to cancer and perceived that cancer outcomes were worse than kidney disease; and (4) prioritizing present health issues: participants believed cancer was not imminent and had limited capacity to absorb information about long-term risks, particularly as current health concerns appeared pressing and important.Awareness of increased cancer risk and cancer screening among kidney transplant recipients is focused narrowly on skin cancer, with limited awareness for other cancers. Recipients prioritized current health issues rather than future risks to health such as cancer. Transplant care providers should provide evidence-based information on cancer risk and screening, being sensitive to the timing and needs of the patient. Improved knowledge may empower patients to minimize their risk of cancer by participating in screening and cancer prevention programmes.

To minimize the health risks faced by living kidney donors, multiple clinical practice guidelines have been developed on the assessment and care of potential donors. This study aims to compare the quality, scope, and consistency of these guidelines. We searched for guidelines on living kidney donation in electronic databases, guideline registries, and relevant Web sites to February 21, 2011. Methodological quality was assessed using the Appraisal of Guidelines for Research and Education (AGREE) instrument. Textual synthesis was used to compare guideline recommendations. Ten guidelines, published from 1996 to 2010, were identified. Although generally comprehensive, scope varied considerably and mostly appeared to lack methodological rigor. Many recommendations were consistent, but important differences were evident, particularly for thresholds for comorbidities which precluded donation; obesity/overweight (body mass index, 30-35 kg/m), diabetes/prediabetes (fasting blood glucose level, 6.1-7.0 mmol/L and oral glucose tolerance test, 7.8-11.1 mmol/L), hypertension (130/85 to 140/90 mm Hg), cardiovascular disease, malignancy, and nephrolithiasis. The importance of informed voluntary consent, genuine motivation, support, and psychological health were recognized but difficult to implement as specific tools for conducting psychosocial assessments were not recommended. Multiple major guidelines for living kidney donation have been published recently, resulting in unnecessary duplicative efforts. Most do not meet standard processes for development, and important recommendations about thresholds for exclusion based on comorbidities are contradictory. There is an urgent need for international collaboration and coordination to ensure, where possible, that guidelines for living donation are consistent, evidence based, and comprehensive to promote best outcomes for a precious resource.

The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody-mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions.

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. Methods 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. Results 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). Conclusions 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.

Background Cancer is a major cause of mortality and morbidity in patients with chronic kidney disease (CKD). In patients without kidney disease, screening is a major strategy for reducing the risk of cancer and improving the health outcomes for those who developed cancers by detecting treatable cancers at an early stage. Among those with CKD, the effectiveness, the efficacy and patients' preferences for cancer screening are unknown. Methods/Design This work describes the protocol for the DETECT study examining the effectiveness, efficiency and patient's perspectives of colorectal cancer screening using immunochemical faecal occult blood testing (iFOBT) for people with CKD. The aims of the DETECT study are 1) to determine the test performance characteristics of iFOBT screening in individuals with CKD, 2) to estimate the incremental costs and health benefits of iFOBT screening in CKD compared to no screening and 3) to elicit patients' perspective for colorectal cancer screening in the CKD population. Three different study designs will be used to explore the uncertainties surrounding colorectal cancer screening in CKD. A diagnostic test accuracy study of iFOBT screening will be conducted across all stages of CKD in patients ages 35-70. Using individually collected direct healthcare costs and outcomes from the diagnostic test accuracy study, cost-utility and cost-effective analyses will be performed to estimate the costs and health benefits of iFOBT screening in CKD. Qualitative in-depth interviews will be undertaken in a subset of participants from the diagnostic test accuracy study to investigate the perspectives, experiences, attitudes and beliefs about colorectal cancer screening among individuals with CKD. Discussion The DETECT study will target the three major unknowns about early cancer detection in CKD. Findings from our study will provide accurate and definitive estimates of screening efficacy and efficiency for colorectal cancer, and will allow better service planning and budgeting for early cancer detection in this at-risk population. The DETECT study is also registered with the Australia New Zealand Clinical Trials Registry ACTRN12611000538943

Angioinvasive complications of Scedosporium infections are rare. We report two cases of mycotic aneurysm, following apparent localized infection, due to Scedosporium apiospermum and Pseudallescheria boydii . The thoracoabdominal aorta was affected in one patient, and cerebral vessels were affected in the other. Despite voriconazole therapy and surgical resection, the patients died. Previously reported cases are reviewed.

Calcineurin inhibitor (CNI) nephrotoxicity was recognized in Cambridge in the late 1970s. The vasoconstrictor impact of cyclosporine (CsA) and to a lesser extent tacrolimus, in both acute and chronic settings, results from a decrease in vasodilators and increase in vasconconstrictors while direct tubular toxicity results from blockade of mitochondrial permeability transition pores and inhibition of prolyl isomerase. A biopsy of native kidneys of recipients of CNIs reveals nephrotoxicity as the most common pathological diagnosis with chronic CNI toxicity and hypertension the primary problems. A long-term study of randomized clinical trials with up to 20 years of follow-up shows inferiority of both renal function and graft survival for continuous CsA compared to either CsA withdrawal or continuous azathioprine and prednisolone. Pathological hallmarks of chronic CNI nephrotoxicity include stripped interstitial fibrosis, arteriolar hyalinosis and glomerular sclerosis, but with the exception of nodular arteriolar hyalinosis the findings are non specific. The model for chronic renal allograft loss must be multifactorial with both immune and nonimmune factors operating dependent upon an individual's risk factors for cell and/or antibody-mediated rejection, CNI nephrotoxicity and recurrent disease. Better outcomes will require early diagnosis and individualization of therapy dependent upon the dominant mechanisms impacting each patient. The revisionist view put forward by some senior, experienced and thoughtful individuals, challenges the concept of chronic CNI nephrotoxicity as an important clinical entity. By implication, the view that appears to be promoted is as follows: we need not fear-prolonged exposure to CNIs, and in seeking better long-term solutions for transplant recipients, we have forgotten alloimmunity. It is thus apparent that we must revisit the data and again question the basis for chronic CNI nephrotoxicity in current clinical practice. This contribution to the debate will focus on the evidence that CNIs are nephrotoxic and that their impact needs to be limited if we are to improve long-term outcomes after transplantation, leaving others to promote the contrary perspective and perhaps also to reflect on the largely unproven impact of the steroid avoidance and other minimization strategies so prevalent today.

Recipients (4076) and donors (3325) of kidney transplants performed at 110 transplant centers were typed for HLA-DRB by the DNA RFLP method. The discrepancy rate of replicate samples distributed among 8 participating laboratories was a low 2.6%. The discrepancy rate between RFLP-DRB and serological HLA-DR typings was 25.0% for organ donors and 27.6% for kidney recipients. Discrepancy rates at the different transplant centers ranged from 9.7% to 86.7%. The discrepancies consisted of antigens being incorrectly interpreted by serology (16.8%), and of serological "blanks" turning out to be definable alleles by the DNA method (10.8%). The alleles that were mainly affected by discrepancies were DR1, DR8, DR10, DR12, DR13, DR14, DR16, DR17.2, and DR18.

Today transplant patients have a risk of death a log order higher than someone of the same age but without end-stage renal failure and a prognosis akin to the normal population with a diagnosis of cancer. Graft losses are mostly from chronic allograft nephropathy, and death arises from cardiac disease, malignancy, and infection. Most immunosuppression protocols are designed to minimize acute allograft rejection, through heavy induction strategies, powerful but toxic maintenance therapies, and equally powerful and expensive prophylaxis against resultant infections. However, despite all efforts, the 20-year survival of renal allografts has not improved much over the past 30 years. New metrics and new thinking are needed to change the long-term outcomes. The biological consequences of immunosuppression currently require a balance between controlling the allograft response and reducing toxicity. To improve, we must both control rejection and remove the long-term problems of toxicity and infection. In the early period after transplantation, we need maximum immunosuppressive efficacy with minimal ischemia-reperfusion injury. Later, we need less immunosuppressive efficacy, to avoid risk factors for chronic toxicity, cardiovascular disease, and malignancy. One of the key challenges for the next few years will be to learn how to individualize therapy using surveillance biopsies and then to validate and use noninvasive technologies to guide therapeutic decisions. There is also an urgent need to determine the relevant early indicators for measuring long-term success to help design better management strategies. The multiplicity of alternatives testifies to the absence of a single dominant strategy.

Hematopoietic stem cell transplantation is a curative procedure for life-threatening hematologic diseases. Donation of hematopoietic stem cells (HSCs) from an unrelated donor, frequently residing in another country, may be the only option for 70% of those in need of unrelated hematopoietic stem cell transplantation. To maximize the opportunity to find the best available donor, individual donor registries collaborate internationally. To provide homogeneity of practice among registries, the World Marrow Donor Association (WMDA) sets standards against which registries are accredited and provides guidance and regulations about unrelated donor safety and care. A basic tenet of the donor registries is that unrelated HSC donation is an altruistic act; nonpayment of donors is entrenched in the WMDA standards and in international practice. In the United States, the prohibition against remuneration of donors has recently been challenged. Here, we describe the reasons that the WMDA continues to believe that HSC donors should not be paid because of ethical concerns raised by remuneration, potential to damage the public will to act altruistically, the potential for coercion and exploitation of donors, increased risk to patients, harm to local transplantation programs and international stem cell exchange, and the possibility of benefiting some patients while disadvantaging others.

End-stage kidney disease registries inform outcomes and policy. Data quality is crucial but difficult to measure objectively. We assessed agreement between incident cancer reported to the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) and to the Central Cancer Registry (CCR) in New South Wales.ANZDATA records were linked to CCR using probabilistic matching. We calculated agreement between registries for patients withor =1 cancers, all cancers and site-specific cancer using the kappa statistic (kappa). We investigated cases where records disagreed and compared estimates of cancer risk based either on ANZDATA or on CCR using standardized incidence ratios (indirect standardization by age, sex and calendar year).From 1980 to 2001, 9453 residents had dialysis or transplantation. ANZDATA recorded 867 cancers in 779 (8.2%) registrants; CCR 867 cancers in 788 (8.3%). ANZDATA recorded 170 patients with cancer that CCR did not, CCR recorded 179 patients that ANZDATA did not (kappa = 0.76). ANZDATA had sensitivity 77.3% (confidence interval (CI) 74.2-80.2), specificity 98.1% (CI 97.7-98.3) if CCR records were regarded as the reference standard. Agreement was similar for diagnoses while receiving dialysis (kappa = 0.78) or after transplantation (kappa = 0.79), but varied by cancer type. Agreement was poorest for melanoma (kappa = 0.61) and myeloma (kappa = 0.47) and highest for lymphoma (kappa = 0.80), leukaemia (kappa = 0.86) and breast cancer (kappa = 0.85). Artefact accounted for 20.8% of the non-concordance but error and misclassification did occur in both registries. Estimates of cancer risk based on ANZDATA or CCR records did not differ in any important way.Agreement of cancer records between both registries was high and differences largely explicable. It is likely that both ANZDATA and CCR have some inaccuracies, for reasons that are now more explicit, with themes similar to those likely to be experienced by other registries.

This review highlights the key messages from the KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guidelines for care of kidney transplant recipients, which were written to be global guidelines irrespective of the regulatory, fiscal, cultural, socioeconomic, or geographical environment. The distillation of 3168 randomized control trials, 7543 cohort studies, and 1609 reviews led to recommendations rated by the strength of supporting evidence and the quality of the data from A to D. Despite this, the quality of the evidence is surprisingly low for the majority of decisions that are routinely taken in all transplant units throughout the world, highlighting the needs for properly designed randomized controlled trials. The principle areas covered in the guidelines include immunosuppression, management of acute rejection, monitoring of the patient and graft, chronic allograft injury, kidney biopsy, nonadherence, vaccination, infectious diseases, cardiovascular risk management, malignancy, bone disease, pediatric growth, lifestyle, fertility, and mental health. This review highlights a number of these areas for consideration focusing on the different types of evidence that we use in daily clinical practice.