Thrombotic microangiopathy and associated renal disorders

Thrombotic microangiopathy (TMA) is a pathological process involving thrombocytopenia, microangiopathic haemolytic anaemia and microvascular occlusion. TMA is common to haemolytic uraemic syndrome (HUS) associated with shiga toxin or invasive pneumococcal infection, atypical HUS (aHUS), thrombotic thrombocytopenic purpura (TTP) and other disorders including malignant hypertension. HUS complicating infection with shiga toxin-producing Escherichia coli (STEC) is a significant cause of acute renal failure in children worldwide, occurring sporadically or in epidemics. Studies in aHUS have revealed genetic and acquired factors leading to dysregulation of the alternative complement pathway. TTP has been linked to reduced activity of the ADAMTS13 cleaving protease (typically with an autoantibody to ADAMTS13) with consequent disruption of von Willebrand factor multimer processing. However, the convergence of pathogenic pathways and clinical overlap create diagnostic uncertainty, especially at initial presentation. Furthermore, recent developments are challenging established management protocols. This review addresses the current understanding of molecular mechanisms underlying TMA, relating these to clinical presentation with an emphasis on renal manifestations. A diagnostic and therapeutic approach is presented, based on international guidelines, disease registries and published trials. Early treatment remains largely empirical, consisting of plasma replacement/exchange with the exception of childhood STEC-HUS or pneumococcal sepsis. Emerging therapies such as the complement C5 inhibitor eculizumab for aHUS and rituximab for TTP are discussed, as is renal transplantation for those patients who become dialysis-dependent as a result of aHUS

Mammalian innate resistance to highly pathogenic avian influenza H5N1 virus infection is mediated through reduced proinflammation and infectious virus release

Respiratory epithelial cells and macrophages are the key innate immune cells that play an important role in the pathogenesis of influenza A virus infection. We found that these two cell types from both human and pig showed comparable susceptibilities to initial infection with a highly pathogenic avian influenza (HPAI) H5N1 virus (A/turkey/Turkey/1/05) and a moderately pathogenic human influenza H1N1 virus (A/USSR/77), but there were contrasting differences in host innate immune responses. Human cells mounted vigorous cytokine (tumor necrosis factor alpha [TNF-α] and interleukin-6 [IL-6]) and chemokine (CXCL9, CXCL10, and CXCL11) responses to H5N1 virus infection. However, pig epithelial cells and macrophages showed weak or no TNF-α and chemokine induction with the same infections. The apparent lack of a strong proinflammatory response, corroborated by the absence of TNF-α induction in H5N1 virus-challenged pigs, coincided with greater cell death and the reduced release of infectious virus from infected pig epithelial cells. Suppressor of cytokine signaling 3 (SOCS3), a protein suppressor of the JAK-STAT pathway, was constitutively highly expressed and transcriptionally upregulated in H5N1 virus-infected pig epithelial cells and macrophages, in contrast to the corresponding human cells. The overexpression of SOCS3 in infected human macrophages dampened TNF-α induction. In summary, we found that the reported low susceptibility of pigs to contemporary Eurasian HPAI H5N1 virus infections coincides at the level of innate immunity of respiratory epithelial cells and macrophages with a reduced output of viable virus and an attenuated proinflammatory response, possibly mediated in part by SOCS3, which could serve as a target in the treatment or prevention of virus-induced hypercytokinemia, as observed for humans

Outcomes of kidney transplantation from older living donors

BACKGROUND: The disparity between donor kidney availability and demand has increased utilization of kidneys from older living donors (OLD). We compared graft and patient outcomes of patients on maintenance dialysis after transplantation with OLD kidneys to those receiving younger live donor (YLD) kidneys and deceased donor (DD) kidneys. METHODS: Using Australia and New Zealand Dialysis and Transplant Registry, primary live and deceased donor renal transplant recipients aged 18 years or older between 1997 and 2009 were stratified into six groups: standard criteria deceased donor kidneys with total ischemic time of less than 12 hours (SCD, <12), SCD of 12 or greater, expanded criteria donor (ECD) less than 12, ECD of 12 or greater, YLD (LD, <60 years), and OLD kidneys (LD, ≥60 years). Preemptive and multiple-organ transplants were excluded. RESULTS: Of the 6,317 renal transplant recipients, 346 (5.5%) received OLD kidneys. Compared with kidneys from SCD of less than 12 hours, OLD kidneys were associated with a greater risk of death-censored graft failure (DCGF; adjusted HR 2.00; 95% confidence interval, 1.32–3.03) and inferior 5-year graft function (estimated glomerular filtration rate of 45 mL/min vs. 56 mL/min), although no increase in 5-year mortality (HR, 1.18; 95% confidence interval, 0.80–1.76). Outcomes for OLD kidneys were also inferior to YLD recipients, although modestly superior to ECD kidneys. Chronic allograft nephropathy was more commonly reported as the cause of DCGF among recipients of OLD kidneys than other donor types. CONCLUSION: Patient survival was equal, but graft outcomes for recipients of OLD kidneys were inferior to those obtained with YLD and SCD kidneys. This study suggests that OLD kidneys should be utilized cautiously, cognizant of the fact that younger recipients may have a life expectancy in excess of the life of the transplanted kidney.Lim, Wai H., Clayton, Philip, Wong, Germaine, Campbell, Scott B., Cohney, Solomon, Russ, Graeme R., Chadban, Steve J., McDonald, Stephen P

Strengthening Australia’s cybersecurity regulations and incentives: Response to the Department of Home Affairs Discussion Paper

The development of the regulatory and incentives framework is a key opportunity to align Australian enterprises’ cybersecurity practice with latest research, particularly on consumer protections, and emerging cyber threats and security challenges. The Australian Government has an essential role in establishing incentives to encourage best practice and consequences to combat poor practice. It will be increasingly important for government at all levels to act as a role model, by following best practice in the conduct of its public business

Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: recommendations and future directions

A consensus meeting was held in Vienna on September 8–9, 2013, to discuss diagnostic and therapeutic challenges surrounding development of diabetes mellitus after transplantation. The International Expert Panel comprised 24 transplant nephrologists, surgeons, diabetologists and clinical scientists, which met with the aim to review previous guidelines in light of emerging clinical data and research. Recommendations from the consensus discussions are provided in this article. Although the meeting was kidney-centric, reflecting the expertise present, these recommendations are likely to be relevant to other solid organ transplant recipients. Our recommendations include: terminology revision from new-onset diabetes after transplantation to posttransplantation diabetes mellitus (PTDM), exclusion of transient posttransplant hyperglycemia from PTDM diagnosis, expansion of screening strategies (incorporating postprandial glucose and HbA1c) and opinion-based guidance regarding pharmacological therapy in light of recent clinical evidence. Future research in the field was discussed with the aim of establishing collaborative working groups to address unresolved questions. These recommendations are opinion-based and intended to serve as a template for planned guidelines update, based on systematic and graded literature review, on the diagnosis and management of PTDM