Current pharmacotherapeutical options for the prevention of kidney transplant rejection.

INTRODUCTION: Advances in immunosuppression and medical care over the past years resulted in better short- and long-term graft survival following kidney transplantation. Novel potent immunosuppressive agents, combinations of proven substances and the steadily expanding knowledge on the pathophysiology of kidney transplant rejection allows the extension of donor and recipient criteria, including the usage of organs from ABO-incompatible and crossmatch-positive donors, to overcome the increasing problem of organ shortage. AREAS COVERED: Immunosuppressive regimens for the prevention of kidney transplant rejections with a focus on regimens aiming at calcineurin inhibitor or steroid minimization, withdrawal or avoidance. Prevention of antibody-mediated rejections in standard-risk and sensitized recipients, as well as newly introduced immunosuppressive substances are covered. EXPERT OPINION: Currently applied immunosuppressive regimens are associated with excellent short-term graft survival. However, the long-term outcomes of different regimens substantially differ with regard to potential side effects, graft function, rejection and sensitization rates. The adverse effects of effective immunosuppression must carefully be balanced against the benefit, e.g., prevention of the development of donor-specific human leukocyte antigen antibodies and chronic (antibody-mediated) rejection. The choice of the appropriate immunosuppressive regimen requires clinical experience and careful consideration of recipient and transplant characteristics to achieve an optimal long-term graft survival.

Computerized image analysis of iron-stained macrophages.

Analysis of iron levels in single cells is critical to understand the consequences of impaired regulation of iron homeostasis. Here we establish a method to analyze intracellular iron deposits by computerized image analysis of Prussian blue-stained alveolar macrophages as a test system. We efficiently detected small differences in macrophage steady-state iron levels in Hfe (-/-) mice as well as inflammation-induced iron sequestration upon lipopolysaccharide instillation. In conclusion, computerized image analysis of single cells is a robust and reproducible tool suitable for iron measurements in small sample sets with limited cell yield.

Hfe deficiency impairs pulmonary neutrophil recruitment in response to inflammation.

Regulation of iron homeostasis and the inflammatory response are tightly linked to protect the host from infection. Here we investigate how imbalanced systemic iron homeostasis in a murine disease model of hereditary hemochromatosis (Hfe(-/-) mice) affects the inflammatory responses of the lung. We induced acute pulmonary inflammation in Hfe(-/-) and wild-type mice by intratracheal instillation of 20 µg of lipopolysaccharide (LPS) and analyzed local and systemic inflammatory responses and iron-related parameters. We show that in Hfe(-/-) mice neutrophil recruitment to the bronchoalveolar space is attenuated compared to wild-type mice although circulating neutrophil numbers in the bloodstream were elevated to similar levels in Hfe(-/-) and wild-type mice. The underlying molecular mechanisms are likely multifactorial and include elevated systemic iron levels, alveolar macrophage iron deficiency and/or hitherto unexplored functions of Hfe in resident pulmonary cell types. As a consequence, pulmonary cytokine expression is out of balance and neutrophils fail to be recruited efficiently to the bronchoalveolar compartment, a process required to protect the host from infections. In conclusion, our findings suggest a novel role for Hfe and/or imbalanced iron homeostasis in the regulation of the inflammatory response in the lung and hereditary hemochromatosis.