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Background Chronic kidney disease (CKD) is an established risk factor for cardiovascular disease but the relevance of reduced kidney function to cancer risk is uncertain. Methods Individual patient data were collected from six studies (32,057 participants); including one population-based cohort and five randomized controlled trials. Participants were grouped into one of five CKD categories (estimated glomerular filtration rate [eGFR] ≥75 mL/min/1.73 m2; eGFR ≥60 to

Governmental and private programs that pay next of kin who give permission for the removal of their deceased relative's organs for transplantation exist in a number of countries. Such payments, which may be given to the relatives or paid directly for funeral expenses or hospital bills unrelated to being a donor, aim to increase the rate of donation. The Declaration of Istanbul Custodian Group-in alignment with the World Health Organization Guiding Principles and the Council of Europe Convention Against Trafficking in Human Organs-has adopted a new policy statement opposing such practices. Payment programs are unwise because they produce a lower rate of donations than in countries with voluntary, unpaid programs; associate deceased donation with being poor and marginal in society; undermine public trust in the determination of death; and raise doubts about fair allocation of organs. Most important, allowing families to receive money for donation from a deceased person, who is at no risk of harm, will make it impossible to sustain prohibitions on paying living donors, who are at risk. Payment programs are also unethical. Tying coverage for funeral expenses or healthcare costs to a family allowing organs to be procured is exploitative, not "charitable." Using payment to overcome reluctance to donate based on cultural or religious beliefs especially offends principles of liberty and dignity. Finally, while it is appropriate to make donation "financially neutral"-by reimbursing the added medical costs of evaluating and maintaining a patient as a potential donor-such reimbursement may never be conditioned on a family agreeing to donate.

Background Many donors and recipients report an improved relationship after transplantation; however, tension, neglect, guilt, and proprietorial concern over the recipient can impede donor and recipient well-being and outcomes. We aimed to describe donor and recipient expectations and experiences of their relationship in the context of living kidney donation. Study Design Thematic synthesis of qualitative studies. Setting & Population Living kidney donors and recipients. Search Strategy & Sources Electronic databases were searched to October 2015. Analytical Approach Thematic synthesis. Results From 40 studies involving 1,440 participants (889 donors and 551 recipients) from 13 countries, we identified 6 themes. "Burden of obligation" described the recipient's perpetual sense of duty to demonstrate gratitude to the donor. "Earning acceptance" was the expectation that donation would restore relationships. "Developing a unique connection" reflected the inexplicable bond that donor-recipient dyads developed postdonation. "Desiring attention" was expressed by donors who wanted recognition for the act of donation and were envious and resentful of the attention the recipient received. "Retaining kidney ownership" reflected the donor's inclination to ensure that the recipient protected "their" kidney. "Enhancing social participation" encompassed relieving both the caregiver from the constraints of dialysis and the recipient from increased involvement and contribution in family life. Limitations Non-English articles were excluded. Conclusions Living kidney donation can strengthen donor-recipient relationships but may trigger or exacerbate unresolved angst, tension, jealousy, and resentment. Facilitating access to pre- and posttransplantation psychological support that addresses potential relationship changes may help donors and recipients better adjust to changes in the relationship dynamics, which in turn may contribute to improved psychosocial and transplantation outcomes following living kidney donation.

Inadvertent completely HLA-mismatched allogeneic unrelated bone marrow transplant: lessons learned

Background Simultaneous pancreas and kidney (SPK) transplantation is performed to restore normoglycemia and renal function in patients with type 1 diabetes mellitus and end-stage renal failure. The National Pancreas Transplant Unit (NPTU) in Sydney provides a service to a population spread across 7.4 million km. We aimed to see if SPK transplantation outcomes differed between recipients from metropolitan (M) centers and those from nonmetropolitan (NM) regions. Methods Using a prospectively collected database, patient and graft survival were analyzed. Patients were categorized according to region of residence and by distance from the NPTU. Results Between January 2001 and May 2010, 165 patients underwent first-time SPK transplantation at the NPTU. There were 126 M and 39 NM recipients. Median distance from the NPTU was 732 km for donors (range, 0-3930 km) and 887 km for recipients (range, 1-4114 km). Median follow-up was 5.2 years (range, 1.1-10.3 years). Actuarial 5-year patient survival was 94% in M and 95% in NM groups. At 5 years, non-death-censored pancreas graft survival was 75% and 82% among M and NM patients, respectively, while kidney allograft survival was 88% in M and 92% in NM groups. There was no significant difference in patient and graft survival between groups. Distance of donor and recipient from the NPTU did not influence graft or patient survival. Conclusions SPK transplantation can be performed with excellent outcomes at a national center with a vast catchment area, irrespective of donor or recipient location.

Aim Cyclosporine (CsA), dosed to achieve C2 targets, has been shown to provide safe and efficacious immunosuppression when used with a mycophenolate and steroids for de novo kidney transplant recipients. This study examined whether use of enteric-coated mycophenolate sodium (EC-MPS) together with basiliximab and steroids would enable use of CsA dosed to reduced C2 targets in order to achieve improved graft function. Methods Twelve-month, prospective, randomized, open-label trial in de novo kidney transplant recipients in Australia. Seventy-five patients were randomized to receive either usual exposure (n = 33) or reduced exposure (n = 42) CsA, EC-MPS 720 mg twice daily, basiliximab and corticosteroids. Results There was no significant difference in mean Cockcroft-Gault CrCl (creatinine clearance) (60.2 ± 17.6 mL/min per 1.73 m2 vs 63.2 ± 24.3, P = 0.64 for usual versus reduced exposure respectively) at 6 months. There was no significant difference between treatment groups in the incidence of treatment failure defined as biopsy proven acute rejection, graft loss or death (secondary endpoint: 30.3% full exposure vs 35.7% reduced exposure). At 12 months the incidence of overall adverse events was the same in both groups. Conclusion This exploratory study suggests de novo renal transplant patients can safely receive a treatment regimen of either full or reduced exposure CsA in combination with EC-MPS, corticosteroids and basiliximab, with no apparent difference in efficacy or graft function during the first year after transplant.

In the context of islet transplantation, experimental models show that induction of islet intrinsic NF-κB-dependent proinflammatory genes can contribute to islet graft rejection. Isolation of human islets triggers activation of the NF-κB and mitogen-activated kinase (MAPK) stress response pathways. However, the downstream NF-κB target genes induced in human islets during the isolation process are poorly described. Therefore, in this study, using microarray, bioinformatic, and RTqPCR approaches, we determined the pattern of genes expressed by a set of 14 human islet preparations. We found that isolated human islets express a panel of genes reminiscent of cells undergoing a marked NF-κB-dependent proinflammatory response. Expressed genes included matrix metallopeptidase 1 (MMP1) and fibronectin 1 (FN1), factors involved in tissue remodeling, adhesion, and cell migration; inflammatory cytokines IL-1β and IL-8; genes regulating cell survival including A20 and ATF3; and notably high expression of a set of chemokines that would favor neutrophil and monocyte recruitment including CXCL2, CCL2, CXCL12, CXCL1, CXCL6, and CCL28. Of note, the inflammatory profile of isolated human islets was maintained after transplantation into RAG-/- recipients. Thus, human islets can provide a reservoir of NF-κB-dependent inflammatory factors that have the potential to contribute to the anti-islet-graft immune response. To test this hypothesis, we extracted rodent islets under optimal conditions, forced activation of NF-κB, and transplanted them into allogenic recipients. These NF-κB activated islets not only expressed the same chemokine profile observed in human islets but also struggled to maintain normoglycemia posttransplantation. Further, NF-κB-activated islets were rejected with a faster tempo as compared to non-NF-κB-activated rodent islets. Thus, isolated human islets can make cell autonomous contributions to the ensuing allograft response by elaborating inflammatory factors that contribute to their own demise. These data highlight the potential importance of islet intrinsic proinflammatory responses as targets for therapeutic intervention.

The use of mycophenolate mofetil (MMF) is associated with less acute rejection than azathioprine (AZA) early after kidney transplantation. However, the long-term impact of MMF versus AZA is less well studied.The Tricontinental Mycophenolate Mofetil Renal Transplantation Study was a double-blind randomized placebo-controlled trial of MMF versus AZA, together with cyclosporine and steroids, first reported in 1996. We analyzed the long-term outcomes of the Australian cohort of patients enrolled in this study using follow-up data from the Australia and New Zealand Dialysis and Transplant Registry. Patient and graft survival, cancer incidence, and estimated kidney function were compared on an intention-to-treat basis.A total of 133 Australian patients participated in the study: 45 were randomized to AZA, 44 were randomized to MMF 2 g/d, and 44 were randomized to MMF 3 g/d. Baseline characteristics were similar between the groups. Median follow-up was 13.8 years, during which there were 97 graft failures, 75 deaths, and 1 lost to follow-up. There were no statistically significant differences between the groups in long-term patient or graft survival, cancer incidence, or kidney function. Death-censored graft survival was best in the group with 3 g/d MMF and worst in the group with 2 g/d MMF. By 5 years, 42% of the MMF group had switched permanently to AZA, whereas crossover from AZA to MMF was rare.This long-term examination, although limited by small numbers, found little evidence for the superiority of MMF over AZA.

There remain major challenges to providing optimal treatment for ESRD worldwide and a need, particularly in low-income economies, to mandate more focus on community screening and implementation of simple measures to minimize progression of chronic kidney disease. The recent designation of renal disease as an important noncommunicable disease at the United Nations High Level Meeting on Noncommunicable Diseases is one step in this direction.(32) But early detection and prevention programs will never prevent ESRD in everyone with chronic kidney disease, and kidney transplantation is an essential, viable, cost-effective, and life-saving therapy which should be equally available to all people in need. It may be the only tenable long-term treatment option for ESRD in low-income countries since it is both cheaper and provides a better outcome for patients than other treatment for ESRD. However, the success of transplantation has not been delivered evenly across the world and substantial disparities still exist in access to transplantation.We remain troubled by commercialization of living donor transplantation and exploitation of vulnerable populations for profit. There are solutions available. These include demonstrably successful models of kidney transplant programs in many developing countries; growing availability of less-expensive generic immunosuppressive agents; improved clinical training opportunities; governmental and professional guidelines legislating prohibition of commercialization and defining professional standards of ethical practice; and a framework for each nation to develop self-sufficiency in organ transplantation through focus on both living donation and especially nationally managed deceased organ donation programs. The Transplantation Society and the ISN have pledged to work together in coordinated joint global outreach programs to help establish and grow appropriate kidney transplant programs in low- and middle-income countries utilizing their considerable joint expertise. World Kidney Day 2012 provides a focus to help spread this message to governments, all health authorities and communities across the world.

Aim: 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. Methods: 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. Results: 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. Conclusion: 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.

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. Diabetes and chronic kidney disease (CKD) are both associated with an increased risk of cancer but it is unclear whether diabetes complicated by CKD further augments an individual’s cancer risk. The aim of our study was to determine the association of CKD [defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min] with the overall and site-specific risks of incident cancers among individuals with Type 2 diabetes. Methods. Cox proportional hazard regression models and competing risk analyses were used to examine the univariate and multivariate adjusted associations between reduced kidney function and the overall and site-specific risks of cancer in participants enrolled in the Action in Diabetes and Vascular disease: Preterax and Diamicron MR controlled evaluation (ADVANCE) trial. Results. Over a median follow-up of 5.0 years, 700 malignant neoplasms occurred in the 11 140 (6.4%) participants. There was no increase in overall cancer risk [adjusted hazard ratio: 1.07 (95% confidence interval: 0.89–1.29, P ¼ 0.50)] or site-specific cancer risk for individuals with CKD (defined as eGFR

The interaction between motorized and nonmotorized road users has been an issue of contention for many years. Drivers complain that bicyclist behavior ranges from annoying to dangerous to illegal. Bicyclists complain that driver behavior ranges from annoying to dangerous to illegal. Many studies have observed these interactions on urban roads. However, only anecdotal evidence existed for the interactions on rural roads. When looking at driver and bicyclist behavior, specifically during interactions on rural roads, researchers have not had independent data to review. The study underlying this paper collected real-time interaction data between bicycles and motorized vehicles on rural roads, with Dane County, Wisconsin, as a field laboratory. Researchers collected video and sensor data for 1,151 interactions between bicycles and motorized vehicles. This paper provides initial observations drawn from these interactions. This study found that drivers, in fact, operated in a technically unsafe manner by frequently performing passing maneuvers outside designated areas. This study also found that despite the frequent comment from bicyclists that drivers passed too closely, these actions were actually quite rare and accounted for only 0.5% of all the observed interactions (six of 1,151). Drivers were far more likely to give bicyclists more room than required and risked a centerline violation, even when conditions were not safe to do so. Bicycle lanes (paved shoulders) directly affected the likelihood of a driver committing a moving violation, with violation rates four to six times lower when a paved shoulder was available.

Objectives: To estimate the utility-based quality of life (QOL) of people with chronic kidney disease (CKD) and to estimate the QOL associated with two hypothetical colorectal cancer health states. Methods: A cross-sectional study was conducted in people with CKD (stages 3–5, transplant recipients and those on dialysis) from three centres in Sydney, Australia. We measured participants' own QOL and that of two hypothetical colorectal cancer health states using a rating scale, and a utility-based QOL measure, the time trade-off, with extremes of 0 (death) and 1 (full health). Results: Recipients of kidney transplants (n = 79) had the highest mean QOL weights of 0.79 (standard deviation (SD) = 0.34) compared with participants with CKD 3–5 (n = 53) with mean QOL weights of 0.70 (SD = 0.39), and those on dialysis (n = 89), who had the lowest mean QOL weights of 0.62 (SD = 0.41) (P = 0.02). Having early and advanced stage colorectal cancers were valued at mean QOL weights of 0.44 (SD = 0.41) and 0.12 (SD = 0.25) among people with moderate stage CKD; 0.45 (SD = 0.39) and 0.11 (SD = 0.24) among dialysis patients; 0.62 (SD = 0.36) and 0.18 (SD = 0.29) among kidney transplant recipients. Conclusions: People with CKD have poor QOL. Having coexistent illnesses such as cancer further reduces the overall well-being of individuals with kidney disease. In addition to the development of effective screening and treatment programs to improve cancer outcomes in people with CKD, our study also highlights the need for effective interventions to improve the QOL in people with CKD, particularly those with major comorbidities like cancer.

Protocol renal allograft biopsies at fixed time points from transplantation have aided research and provided insights into the pathogenesis of early and late allograft injury. Their role is evolving from research to a clinical management tool needed to detect subclinical pathology requiring treatment adjustment. They frequently reveal unexpected findings and influence therapy in the majority of patients. Detection of subclinical rejection (SCR) remains important despite declining prevalence with triple therapy, the evidence favors treatment, if found. Surveillance biopsies in steroid avoidance and calcineurin inhibitor (CNI) withdrawal programs provide an important safety net against the increased rates of late acute and SCR. Individualization of therapy in high-risk patients and safe reduction of immunosuppression in standard risk individuals becomes possible. Other potentially reversible chronic pathologies that may be detected, include chronic T-cell or antibody-mediated rejection, recurrent disease, BK virus-associated nephropathy, interstitial fibrosis and tubular atrophy and CNI nephrotoxicity, allowing modifications of therapy to limit ongoing graft injury. Biopsy is safe and inexpensive compared with costs of earlier graft failure and return to dialysis. This review summarizes current evidence on use of surveillance histology for the clinical practice of renal transplantation.

The legal framework in which the users of bicycles and motorized vehicles operate varies widely from state to state. For laws governing vehicles on roads, the National Committee on Uniform Traffic Laws and Ordinances has created the Uniform Vehicle Code (UVC). The UVC was developed as a framework that each state can adopt fully or in part or ignore completely as best serves the state. Most states have adopted the majority of the UVC without alteration, but standards applied by various states to the operation of bicycles tend to deviate from the UVC. Twelve areas of the UVC and how the 50 states have each chosen to treat these areas through their state codes were examined. As the rules of the road are made nearly uniform, especially regarding the operation of and interaction with bicycles, the goals of promoting safety and uniformity are advanced. This consistency also mitigates the potential for confusion, as the expectancy for operators of vehicles and bicycles will likely not be violated. This research showed that not every state had placed the same priority on the safety of all road users. This analysis showed that although much progress was being made to alleviate inadequacies, there was still much work to be done. Without a national focus on the uniformity of traffic laws related to bicycling, the continued patchwork covering the nation would remain and leave serious holes that would ultimately make the roads less safe for everyone.

Should poor-quality kidneys be allocated to elderly recipients? A new study has determined that kidney recipients aged ≥70 years have similar outcomes regardless of donor-organ quality, with the exception of the lowest-quintile quality organs. These data can help physicians advise their elderly patients to decide whether or not to accept a kidney offer.

Cancer is a major cause of morbidity among those with kidney transplants. Farrugia et al. examined the overall and site-specific risk of cancer death among kidney transplant recipients. Cancer outcomes, particularly for those with a history of cancer prior to transplantation, are poor. The overall risk of death attributed to cancer in patients with kidney transplants is increased at least tenfold over that in cancer patients in the general population.

Author Affiliations: Department of Liver Surgery, Peking Union Medical College Hospital; National Organ Transplant Committee, Ministry of Health, Beijing 100000, China (Huang JF); The First Affiliated Hospital of Zhejiang University, Hangzhou 310003, China (Zheng SS); The First Hospital of China Medical University, Shenyang 110001, China (Liu YF); Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong; China Organ Transplant Response System Research Center, Shenzhen 518000, China (Wang HB); Centre for Renal and Transplant Research, Westmead Millenium Institute, Sydney University, Sydney, Australia (Chapman J and O'Connell P); Section of Transplantation, Liver Transplantation and Hepatobiliary Surgery, University of Chicago, Chicago, IL, USA (Millis M); Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA (Fung J) and Department of Surgery, Massachusetts General Hospital, Boston, MA, USA (Delmonico F)

Background. Renal cancer is the most common solid organ cancer in the kidney transplant population with an excess risk ~5-fold greater than the general population. It is uncertain whether routine screening for renal cancer is cost-effective. The aim of our study is to estimate the costs and health benefits of ultrasonographic (US) screening for renal cancer in the kidney transplant population. Methods. A Markov model was developed to compare the costs and benefits in a cohort of kidney transplant recipients (n = 1000, aged 18–69 years), who underwent annual and biennial US screening for renal cancer, compared with a cohort that did not. Results. For recipients of kidney transplants aged 18– 69 years, the incremental cost-effectiveness ratio (ICER) for routine US screening ranged from $252 100/LYS for biennial screening to $320 988/LYS for annual screening. A total of two and one cancer deaths were averted in the annually and biennially screened population, with a relative cancer-specific mortality reduction by 25% and 12.5%, respectively. Using a series of sensitivity analyses, the ICER was most sensitive to the costs and test specificity of ultrasonography, prevalence of disease, and the risk of graft failure in the screened population. Conclusions. Routine screening for renal cancer may reduce the risk of cancer-related deaths in recipients of kidney transplants. Uncertainties, however, exist in the model’s influential variables including the risk of graft failure among those who received contrast-enhanced diagnostic computer tomography. Given the available evidence, routine screening for renal cancers may not be cost-effective for recipients of kidney transplants.

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.

Background. Tubulointerstitial damage (TID) is a key feature of chronic kidney transplant failure; however, the associated gene expression changes are poorly defined. Methods. This pilot study used RNA from 59 protocol kidney transplant biopsies at implantation, 1, 3, and 12 months (n= 18 patients), processed into cDNA and hybridized to 8K human cDNA microarrays. Gene expression was correlated with graft histology categorized by the Banff schema. Results. Gene and pathway expression were differentially activated according to the time after transplantation. Immune pathway activity peaked at 1 month, fibrotic expression at 3 months, wound healing-remodelling and cell proliferation-repair processes were activated between 3 and 12 months, whereas macrophage-related gene expression occurred late by 12 months. Forty percent of genes and 50% pathways initially activated persisted to 3 months. Biopsies with TID displayed 262 differentially expressed genes (P 2 compared with implantation), dominated by upregulated fibrogenic and immune-related genes reflecting unique immune (10% to 15% of genes) and fibrotic (15% vs. 4% in normal) pathway activation. Profibrotic genes were expressed before interstitial fibrosis was observed by sequential microscopic analysis. Kidneys progressing to TID by 3 months demonstrated 30 unique genes (B> 1, P 1, P

Subtype-specific incidence patterns in populations at high risk of lymphoma offer insight into lymphomagenesis. The incidence profiles for the 2 most common non-Hodgkin lymphoma subtypes were compared for 2 immunodeficient populations, adults receiving a kidney transplant 1982-2003 (n = 7,730) or diagnosed with human immunodeficiency virus (HIV) infection 1982-2004 (n = 17,175). National, population-based registries were linked and standardized incidence ratios (SIRs) were computed for each cohort and lymphoma subtype. Risk of diffuse large B-cell lymphoma was significantly increased after transplantation (SIR 17.83, 95% CI: 13.61-22.95) and after HIV infection (SIR 58.81, 95% CI: 52.59-65.56). Rates of follicular lymphoma (FL) were neither significantly increased nor decreased in transplant recipients (SIR 0.82, 95% CI: 0.10-2.96) and in people with HIV (SIR 1.25, 95% CI: 0.41-2.91). The findings argue against an infectious or other immunodeficiency-related etiology for FL and clearly differentiate it from diffuse large B-cell lymphoma.

The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients is intended to assist the practitioner caring for adults and children after kidney transplantation. The guideline development process followed an evidence-based approach, and management recommendations are based on systematic reviews of relevant treatment trials. Critical appraisal of the quality of the evidence and the strength of recommendations followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. The guideline makes recommendations for immunosuppression and graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research. This summary includes a brief description of methodology and the complete guideline recommendations but does not include the rationale and references for each recommendation, which are published elsewhere.

Instant blood mediated inflammatory reaction (IBMIR) occurs when islets are exposed to blood and manifests clinically as portal vein thrombosis and graft failure. The aim of this study was to determine the impact of recombinant human activated protein C (rhAPC) and platelet inhibition on IBMIR in order to develop a better targeted treatment for this condition. Five thousand human islet cell equivalents (IEQ) were mixed in a PVC loop system with 7 mL of ABO compatible human blood and incubated with rhAPC, either alone or in combination with tirofiban. Admixing human islets and blood caused rapid clot formation, consumption of platelets, leukocytes, fibrinogen, coagulation factors and raised d-dimers. Islets were encased in a fibrin and platelet clot heavily infiltrated with neutrophils. Tirofiban monotherapy was ineffective, whereas rhAPC monotherapy prevented IBMIR in a dose-dependent manner, preserving islet integrity while maintaining platelet and leukocyte counts, fibrinogen and coagulation factor levels, and reducing d-dimer formation. The combination of tirofiban and low-dose rhAPC inhibited IBMIR synergistically with an efficacy equal to high dose rhAPC. Tirofiban and rhAPC worked synergistically to preserve islets, suggesting that co-inhibition of the platelet and coagulation pathways' contribution to thrombin generation is required for the optimal anti-IBMIR effect.

Non-Hodgkin lymphoma (NHL) incidence is greatly increased after kidney transplantation. NHL risk was investigated in a nationwide cohort of 8164 kidney transplant recipients registered on the Australia and New Zealand Dialysis and Transplant Registry. NHL diagnoses were ascertained using linkage with national cancer registry records. Multivariate Poisson regression was used to compute incidence rate ratios (IRRs) with 95% confidence intervals (CIs) comparing risk by transplant function, and risk factors for early (< 2 years) and late (≥ 2 years) NHL during the first transplantation. NHL occurred in 133 patients. Incidence was strikingly lower after transplant failure and cessation of immunosuppression than during transplant function (IRR, 0.25; 95% CI, 0.08-0.80; P = .019). Early NHL (n = 27) was associated with Epstein-Barr virus (EBV) seronegativity at transplantation (IRR, 4.66; 95% CI, 2.10-10.36, P < .001) and receipt of T cell–depleting antibodies (IRR, 2.39; 95% CI, 1.08-5.30; P = .031). Late NHL (n = 79) was associated with increasing year of age (IRR, 1.02; 95% CI, 1.01-1.04; P = .006), increasing time since transplantation (P < .001), and current use of calcineurin inhibitors (IRR, 3.13; 95% CI, 1.53-6.39; P = .002). These findings support 2 mechanisms of lymphomagenesis, one predominantly of primary EBV infection in the context of intense immunosuppression, and another of dysregulated lymphoid proliferation in a prolonged immunosuppressed state.

Background. Immunological unresponsiveness of T cells to alloantigen can be induced by intrathymic injection of donor-specific antigen in small-animal models. Intrathymic tolerance to vascularized grafts in large animals has not previously been reported. Methods. Thirty-two dogs were allocated into dog leukocyte antigen DP locus allele (class II)-matched donor-recipient pairs. Female recipients were paired with male donors. Tissue typing was based on restriction fragment length polymorphism. Recipients were given 18 Gy total lymphoid irradiation in 16 fractions (1.125 Gy each) over 4 weeks. Thoracotomy after the 6th fraction permitted perithymic (n=4) or intrathymic (n=4) injection of donor bone marrow (BM) or intrathymic injection of saline (n=5). Another group received intravenous peripheral BM infusion (n=3). Fifty days postthoracotomy recipients underwent bilateral nephrectomy and donor-specific kidney transplantation. Acute rejection, suspected when serum creatinine was more than 600 μmol/L or urea was more than 40 mmol/L, was confirmed histologically. Full-thickness skin grafts followed more than 100 days posttransplantation. Tissue samples were taken for Y-chromosome polymerase chain reaction. Results. One intrathymic (25%) and three perithymic (75%) BM recipients developed tolerance to renal allografts. Three intrathymic BM recipients rejected after 27, 32, and 54 days and one perithymic BM recipient rejected after 42 days. All recipients given peripheral BM or saline had rejected by 29 and 38 days, respectively. All recipients surviving more than 100 days posttransplantation, accepted donor specific and rejected dog leukocyte antigen-DP locus allele (class II) identical third-party skin grafts. Polymerase chain reaction detected intrathymic but not hematopoietic chimerism in sex-mismatched pairs. Conclusions. Fractionated total lymphoid irradiation and perithymic or intrathymic donor-specific BM induced tolerance to renal and skin allografts without inducing hematopoietic chimerism.

PURPOSE OF REVIEW New immunosuppressive agents have decreased the incidence of acute rejection rates without improvement in long-term outcomes. Drug toxicity due to a narrow therapeutic index and individual variations in pharmacokinetics and pharmacodynamics significantly contributes to the inferior outcomes. This review focuses on advances in individualization of immunosuppression therapy using therapeutic drug monitoring and pharmacogenetics/pharmacogenomics as a strategy to minimize toxicity. RECENT FINDINGS Although therapeutic drug monitoring for calcineurin inhibitors and mammalian targets of rapamycin inhibitors is well established, its utility in mycophenolate mofetil dosage adjustments is still the subject of ongoing debate. However, there is potential for optimizing mycophenolate mofetil therapy based on polymorphisms in genes that encode metabolizing and target enzymes. Single-nucleotide polymorphisms in cytochrome P450 genes have an effect on tacrolimus response. Donor genotype could have an effect on drug metabolism. SUMMARY Therapeutic drug monitoring remains the most widely used method for individualizing immunotherapy. Improvements in molecular technology have enabled identification of several polymorphisms in genes that encode for drug-metabolizing enzymes, drug transporters, and their targets, which have an effect on individual response to therapy. Prospective studies are needed to explore this field and improve utility of donor and recipient genotype testing in managing immunosuppression therapy.

Kidney transplant recipients are at higher risk of cancer at most sites, and cancer after transplantation causes considerable morbidity and mortality. To optimize long-term patient outcomes, clinicians balance the prospect of graft failure and dialysis, with competing risks of diabetes, cardiovascular and cerebrovascular disease and the risk of malignancy. In this paper we critically examine the assumptions underpinning primary prevention, immunization, chemoprevention and screening programs, and highlight considerations when applying evidence to the kidney transplant population, and suggest a clinical research agenda that aims to define a rational approach to managing posttransplant cancer risk.

It is unknown whether epithelial-to-mesenchymal transition (EMT) leads to tubulointerstitial fibrosis in renal transplants. In this study, interstitial fibrosis and markers of EMT were followed in protocol transplant biopsies in 24 patients. Tubulointerstitial damage (TID) increased from 34 to 54% between 1 and 3 mo after transplantation. Detection of EMT depended on the marker used; low levels of alpha-smooth muscle actin were found in 61% of biopsies, but the less specific marker S100 calcium binding protein-A4 (also known as Fsp1) suggested a higher incidence of EMT. The presence or development of TID did not correlate with EMT but instead significantly correlated with subclinical immune activity (P0.05). Among biopsies showing TID, microarray analysis revealed differential regulation of 127 genes at 1 mo and 67 genes at 3 mo compared with baseline; these genes were predominantly associated with fibrosis, tissue remodeling, and immune response. Of the 173 EMT-associated genes interrogated, however, only 8.1% showed an expression pattern consistent with EMT at 1 mo and 6.3% at 3 mo. The remainder were not differentially altered, or their changes in expression were opposite those expected to promote EMT. Quantitative reverse transcriptase-PCR revealed that the expression pattern of 12 EMT-associated genes was inconsistent over time, opposite that expected, or consistent with subclinical rejection or inflammation. In conclusion, EMT does not seem to play a significant role in the development of early allograft fibrosis.

Measured glomerular filtration rates (mGFRs) were obtained by (99)mTc-DPTA, (125)I-iothalamate, iohexol, (51)Cr-EDTA, non-radiolabeled iothalamate, or inulin clearance from centers agreeing to perform mGFR in six completed and one ongoing Wyeth Research multicenter trials evaluating sirolimus (SRL) in regimens with or without a calcineurin inhibitor (CNI). Estimated GFRs (eGFRs) were calculated by the Cockcroft-Gault (eGFR(CG)), Nankivell (eGFR(NK)), and simplified Modification of Diet in Renal Disease (eGFR(MDRD)) equations. Bias, precision, and accuracy for each of these equations were estimated by tertiles and by regimen. For the Rapamune Maintenance Regimen (RMR) trial, eGFR outcomes were also compared between treatments {[SRL-cyclosporine (CsA) versus SRL]} using the three eGFR formulas. In the lowest mGFR tertile (6-40 ml/min), eGFR(MDRD) gave the best accuracy with the least bias whereas eGFR(NK) and eGFR(CG) performed better in the highest mGFR tertile (58-139 ml/min). At 24 months in the RMR study, mean differences in eGFR between treatments were 13.6, 14.2, and 13.5 ml/min/1.73 m(2) for eGFR(CG), eGFR(NK), and eGFR(MDRD), respectively, favoring CsA withdrawal (P-values for all

Improvements in reducing acute rejection rates following kidney transplantation in the last decade have not been mirrored by improvements in long-term graft survival rates [1,2]. One of the major causes of late graft loss in renal transplant recipients is chronic allograft nephropathy (CAN) [3–5] (Figure 1). CAN is highly prevalent in renal transplant recipients, with moderate to severe CAN present in 24.7% of recipients at 1 year post-transplant and in 89.8% of recipients by 10 years post-transplant [6]. CAN is defined by the histopathological features of interstitial fibrosis and tubular atrophy, but can also be associated with subclinical rejection, transplant glomerulopathy [6–8] or transplant vasculopathy caused by smooth muscle cell proliferation [4,9]. Therefore, the term CAN is being employed quite widely to describe a clinical syndrome instead of defining the presence of interstitial fibrosis or tubular atrophy. In order to avoid misinterpretations of this term, at the most recent ‘Banff’ meeting, it was proposed that pathologists no longer use this term, and simply refer to interstitial fibrosis and tubular atrophy (IF/TA) [10]. The term ‘chronic rejection’ has also been suggested as a possible replacement for CAN. However, this implies the pathology has an immune aetiology. As a pathological change often precedes any deterioration in function, the alternative term ‘chronic allograft dysfunction’ also has limitations. The revised Banff classification now recognizes chronic antibody-mediated rejection, in addition to IF/TA, broadening the underlying pathological lesions and pathophysiology of patients with

For patients with end-stage kidney failure, kidney transplantation improves both their quality of life and overall life expectancy compared with dialysis, but it is not without adverse effects. Cancer is second to cardiovascular disease as one of the major causes of morbidity and mortality in renal transplant recipients. Prolonged use of modern immunosuppression, which leads to alteration of immune function and immune surveillance, is associated with increased cancer risk. There is now convincing evidence from observational studies and registry data to confirm a 3- to 5-fold increase in overall cancer incidence, with viral-related neoplasia incurring the greatest risk when compare with the general population. Despite the increased risk, little is known about the overall cancer prognosis, screening, treatment strategies, and effectiveness in this population. Cancers can recur, occur de novo, and be transmitted from donor organs posttransplantation. Uncertainties exist as to how modern immunosuppressive agents impact on cancer management and outcomes in these patients, with some agents such as calcineurin inhibitors and azathioprine, being more carcinogenic than others. The newer agents, proliferation signal/mammalian target of rapamycin inhibitors and mycophenolate mofitil, may have some antiproliferative and antitumor activities demonstrated in preclinical and clinical studies, but long-term well-powered trial data are needed to determine whether they are either protective or curative for cancers in renal transplant recipients. In this review, the incidence, etiology, prognosis, and potential approaches to cancer screening and management post-renal transplantation are discussed.

Proliferation signal or mammalian target-of-rapamycin inhibitors (PSI/mTOR inhibitors), everolimus and sirolimus, provide attractive options for use in heart transplantation because they are immunosuppressive and anti-proliferative. PSI/mTOR inhibitors work synergistically with calcineurin inhibitors (CNIs) and thus permit the minimization of CNIs without compromising efficacy. This approach is advantageous for the majority of heart transplant recipients and might provide particular benefit in specific cases, such as patients with cardiac allograft vasculopathy, malignancies and renal dysfunction, or in patients intolerant to other immunosuppressive agents. Drawing on the expertise of transplant cardiologists, cardiac surgeons and nephrologists, we addressed the assessment of renal function; management of adverse events associated with this class of drugs; and clinical guidance, specifically for the use of everolimus, including patient selection, indications for treatment and practicalities of drug initiation and monitoring.

Cytomegalovirus (CMV) is a significant pathogen causing disease in renal transplant patients. The highest incidence of CMV disease occurs during the first 3 months post-transplant and is most problematic in CMV-naïve transplant recipients. In this study, we conducted a retrospective review of two databases, the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) and the National Hospital Morbidity Database, from the Australian Institute of Health and Welfare (AIHW), to examine CMV in renal transplant recipients. The first source looked at CMV serostatus at the time of transplantation and the second recorded hospital admissions for recipients with invasive CMV disease.From the ANZDATA registry, we obtained information from 13,530 renal transplants recipients from 1980 to 2004. Of these recipients, 7808 had a known CMV serostatus, of which 65.7% (5134/7808) had a positive sero antibody status and 34.2% (2674/7808) had a negative sero antibody status. In univariate analysis, factors significantly associated with renal rejection were being male, recipient age Preventative strategies for CMV in renal transplant recipients should be a priority. New vaccines for CMV may soon be available and renal transplant recipients would be a suitable target group for vaccination.

Poor long-term outcomes of commercial transplantation of transplant tourists reinforce the need to prevent this form of human trafficking. The development of an International Convention by the Council of Europe is highlighted and the implications for physicians of the criminalizing of organ trafficking are considered. The causes of poor outcomes from transplant tourism are considered, with the actions needed to provide both equity and sufficiency of access to transplantation as critical deterrent measures.

Background: While advances in treatment have dramatically improved short-term graft survival and acute rejection in kidney transplant recipients, long-term graft outcomes have not substantially improved. Transplant recipients also have a considerably increased risk of cancer, cardiovasculardisease, diabetes, and infection, which all contribute to appreciable morbidity and premature mortality. Many trials in kidney transplantation are short-term, frequently use un-validated surrogate endpoints, outcomes of uncertain relevance to patients and clinicians, and do not consistently measure and report key outcomes like death, graft loss, graft function, and adverse effects of therapy. This diminishes the value of trials in supporting treatment decisions that require individual-level multiple trade-offs between graft survival and the risk of side effects, adverse events, and mortality. The StandardizedOutcomes in Nephrology –Transplantation (SONG-Tx) initiative aims to develop a core outcome set for trials in kidney transplantation that is based on the shared priorities of all stakeholders.Methods: This will include a systematic review to identify outcomes reported in randomized trials, a Delphi survey with an international multi-stakeholder panel (patients, caregivers, clinicians, researchers, policy makers, members from industry) to develop a consensus-based prioritized list of outcome domains, and a consensus workshop to review and finalize the core outcome set for trials in kidney transplantation.Conclusions: Developing and implementing a core outcome set to be reported, at a minimum, in all kidney transplantation trials will improve the transparency, quality and relevance of research; to enable kidney transplant recipients and their clinicians to make better informed treatment decisions for improved patient outcomes.

Transplant glomerulopathy (TXG) presents a distinctive pattern of glomerular abnormalities. The aim of this study was to describe its sequential ultrastructural pathology. A paired cohort study of 228 protocol biopsies, from our longitudinal database (n = 1345), compared TXG (7 patients, 95 biopsies) and controls (8 patients, 133 biopsies). Ultrastructural morphometry and C4d immunoperoxidase were evaluated from implantation to 5 years after transplantation against sequential histology and functional changes. TXG was predated by early glomerular endothelial cell activation; typified by vacuolation, hypertrophy, serration and expansion of lamina rara interna from 39 +/- 23 days after transplantation. Endothelial cells were transformed into an activated phenotype, containing numerous mitochondria, Golgi and ribosomes. Transition from fenestrated to continuous endothelium, mesangial matrix expansion and podocyte fusion occurred late. Endothelial cell activation also occurred in peritubular capillaries (PTC) followed by basement membrane multi-lamination (p < 0.05-0.001). Light microscopy changes of TXG occurred at 2.3 years. PTC C4d deposition was intermittently expressed over time, correlating with endothelial abnormalities, glomerular C4d and donor-specific antibodies (DSA) (p < 0.05-0.001). In summary, endothelial and subendothelial ultrastructural abnormalities in glomerular and peritubular capillaries are sensitive, early markers of TXG, likely due to stimulation of endothelial cells into an activated phenotype by antibody-mediated sub-lytic complement deposition.

Transplant recipients have increased cancer risk, but data on risk variation across different patient groups are sparse. Rates and standardized rate ratios (SRR) of cancer (all sites, excluding nonmelanocytic skin and lip cancer) compared to the general population were calculated, using Australia and New Zealand Dialysis and Transplant Registry data. Within the transplant population, risk factors were identified (hazard ratios: HR; 95% CI) and absolute risk estimated for recipient groups. A total of 1642 (10.8%) of 15 183 recipients developed cancer. Risk was inversely related to age (SRR 15-30 children, 2 if >65 years). Females aged 25-29 had rates equivalent to women aged 55-59 from the general population. Age trend for lymphoma, colorectal and breast risk was similar; melanoma showed less variability across ages, prostate showed no risk increase. Within the transplanted population, risk was affected by age differently for each sex (p = 0.007), elevated by prior malignancy (HR 1.40; 1.03-1.89), white race (HR 1.36; 1.12-1.89), but reduced by diabetic end-stage kidney disease (ESKD) (HR 0.67; 0.50-0.89). Cancer rates in kidney recipients are similar to nontransplanted people 20-30 years older, but absolute risk differs across patient groups. Men aged 45-54 surviving 10 years have cancer risks varying from 1 in 13 (non-white, no prior cancer, diabetic ESKD) to 1 in 5 (white, prior cancer, other ESKD).

Increasing success in renal transplantation and longer patient survival has meant that post-transplant malignancies are having an increasing impact on long-term graft and patient survival. Choice of the immunosuppressive agents provides one of the controllable risk factors for the development of malignancies in this population. Calcineurin inhibitors (CNIs) are associated with an increased incidence of cancers, whereas the proliferation signal inhibitors (PSIs), everolimus and sirolimus have demonstrated anti-oncogenic effects in pre-clinical models and are currently being investigated as anti-cancer agents in clinical trials. There is increasing evidence demonstrating a lower incidence of post-transplant malignancies in renal transplant recipients receiving PSI-based immunosuppression compared with those receiving CNIs. Conversion from CNIs to PSIs has been shown to lead to the regression of Kaposi's sarcoma in renal transplant recipients and is now part of accepted standard care for this tumour in this setting. The anti-cancer properties of PSI-based regimens have the potential to combine the dual benefits of immunosuppression without the use of CNIs and the direct anti-oncogenic effects through their inhibition of the mammalian target of rapamycin (mTOR) signalling pathway. In the absence of formal clinical trial evidence on the best way to use PSIs in this setting, a workshop was held to provide practical guidance on immunosuppressive strategies in the context of malignancy, given the current state of knowledge.

Background and objectives The current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes. Design, setting, participants, & measurements Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models. Results Of the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P 6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94). Conclusions HLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients.

T-cell depleting antibody is associated with an increased risk of cancer after kidney transplantation, but a dose-dependent relationship has not been established. This study aimed to determine the association between cumulative doses of T-cell depleting antibody and the risk of cancer after kidney transplantation. Using data from the Australian and New Zealand Dialysis and Transplant Registry between 1997–2012, we assessed the risk of incident cancer and cumulative doses of T-cell depleting antibody using adjusted Cox regression models. Of the 503 kidney transplant recipients with 2835 person-years of follow-up, 276 (55%), 209 (41%) and 18 (4%) patients received T-cell depleting antibody for induction, rejection or induction and rejection respectively. The overall cancer incidence rate was 1,118 cancers per 100,000 patient-years, with 975, 1093 and 1377 cancers per 100,000 patient-years among those who had received 1–5 doses, 6–10 doses and >10 doses, respectively. There was no association between cumulative doses of T cell depleting antibody and risk of incident cancer (1–5: referent, 6–10: adjusted hazard ratio (HR) 1.19, 95%CI 0.48–2.95, >10: HR 1.42, 95%CI 0.50–4.02, p = 0.801). This lack of association is contradictory to our hypothesis and is likely attributed to the low event rates resulting in insufficient power to detect significant differences.