T-cell exhaustion: characteristics, causes and conversion

T-cell exhaustion is characterized by the stepwise and progressive loss of T-cell functions and can culminate in the physical deletion of the responding cells. Exhaustion is well-defined during chronic lymphocytic choriomeningitis virus infection and commonly develops under conditions of antigen-persistence, which occur following many chronic infections that are of significant public health concern including hepatitis B virus, hepatitis C virus and human immunodeficiency virus infections, as well as during tumour outgrowth. Exhaustion is not a uniformly disabled setting as a gradation of phenotypic and functional defects can manifest, and these cells are distinct from prototypic effector, memory and also anergic T cells. We are gaining insights into the extrinsic and intrinsic factors that determine the severity of exhaustion. These include the duration and magnitude of antigenic activation, availability of CD4 T-cell help, the levels of stimulatory and suppressive cytokines, as well as the expression of activatory and inhibitory receptors. More information is now becoming available regarding the molecular mechanisms that attenuate the responsiveness of exhausted T cells. As the parameters that dictate exhaustion are more thoroughly defined, this is fostering the development of methods that prevent and rejuvenate functionally inferior responses. In this article we discuss our current understanding of the properties of exhausted T cells and the mechanisms that promote and maintain this state

Reducing the costs of chronic kidney disease while delivering quality health care : a call to action

The treatment of chronic kidney disease (CKD) and of end-stage renal disease (ESRD) imposes substantial societal costs. Expenditure is highest for renal replacement therapy (RRT), especially in-hospital haemodialysis. Redirection towards less expensive forms of RRT (peritoneal dialysis, home haemodialysis) or kidney transplantation should decrease financial pressure. However, costs for CKD are not limited to RRT, but also include nonrenal health-care costs, costs not related to health care, and costs for patients with CKD who are not yet receiving RRT. Even if patients with CKD or ESRD could be given the least expensive therapies, costs would decrease only marginally. We therefore propose a consistent and sustainable approach focusing on prevention. Before a preventive strategy is favoured, however, authorities should carefully analyse the cost to benefit ratio of each strategy. Primary prevention of CKD is more important than secondary prevention, as many other related chronic diseases, such as diabetes mellitus, hypertension, cardiovascular disease, liver disease, cancer, and pulmonary disorders could also be prevented. Primary prevention largely consists of lifestyle changes that will reduce global societal costs and, more importantly, result in a healthy, active, and long-lived population. Nephrologists need to collaborate closely with other sectors and governments, to reach these aims