Research Highlights

Abstract

Apoptosis Inhibitor of Macrophage Protein Enhances Intraluminal Debris Clearance and Ameliorates Acute Kidney Injury in Mice Arai S, Kitada K, Yamazaki T, Takai R, Zhang X, Tsugawa Y, Sugisawa R, Matsumoto A, Mori M, Yoshihara Y, Doi K, Maehara N, Kusunoki S, Takahata A, Noiri E, Suzuki Y, Yahagi N, Nishiyama A, Gunaratnam L, Takano T, and Miyazaki T Nature Medicine, 2016;2:183–193. Acute kidney injury (AKI) has a high prevalence among hospitalized patients and is thought to be a precipitating factor for chronic kidney disease and subsequent end-stage organ failure. Acute kidney injury in a transplanted kidney may also occur posttransplantation as a result of the ischemia-reperfusion injury, infection and nephrotoxic immunosuppression.1 Acute kidney injury is therefore both a cause and consequence of transplantation. Cell death during early stages of AKI can result in renal tubular obstruction, causing a further insult to kidney function and thus a vicious circle of renal damage. There are currently no clear treatment strategies for AKI, and our comprehension of the complex pathophysiology remains limited. However, harnessing physiological clearance mechanisms is a useful strategy for tackling AKI. Injured epithelial cells within tubules may act to help clear dead cells and debris, through a mechanism which requires the use of Kidney Injury Molecule-1 (KIM-1), inducing the dedifferentiation of epithelial cells into phagocytes.2 In the study by Arai and coinvestigators, apoptosis inhibitor of macrophage (AIM; CD5L) was identified as a KIM-1 ligand, involved in the clearance of debris from renal tubules by epithelial cells. In an AIM-deficient mouse model, AIM was shown to be associated with impaired recovery from AKI in mice due to reduced cell debris clearance. More importantly, the interaction of AIM with KIM-1 was shown to accelerate cell debris removal. This pathway is therefore amenable to therapeutic intervention. Promoting dead cell and debris clearance from transplanted kidneys with the use of a recombinant AIM therapy (for example) may thus ameliorate the consequences of ischemia-reperfusion injury and other immediately traumatic events improving overall long-term graft survival. REFERENCES Nehus EJ, Devarajan P. Acute kidney injury: AKI in kidney transplant recipients—here to stay. Nat Rev Nephrol. 2012;8:198–199. Yang L, Brooks CR, Xiao S, et al. KIM-1-mediated phagocytosis reduces acute injury to the kidney. J Clin Invest. 2015;125:1620–1636. Cell-Free DNA Comprises an In Vivo Nucleosome Footprint That Informs Its Tissues-of-Origin Snyder MW, Kircher M, Hill AJ, Daza RM, and Shendure J Cell, 2016;164:57–68. Biomarkers of immune status and graft function are critical in directing current clinical decision making, particularly after transplantation when the aim is to determine the correct immunosuppressive balance without compromising graft function and survival.1 Similarly, there is an interest in understanding when patients are displaying evidence of immune tolerance that might facilitate complete withdrawal of immunosuppression.2 Currently, graft rejection can only reliably be detected based on biopsies that are invasive and possibly further damaging to an already rejecting organ. Other less invasive biomarkers are therefore likely to be useful. Cell-free DNA (cfDNA) is present in blood plasma and urine and is thought to derive from the apoptosis of normal cells. As cfDNA has a short half-life, its baseline presence ongoing release under physiological conditions. Importantly, cfDNA carries a signature related to its size which may help identify its tissue of origin. In the study by Snyder and colleagues, the cfDNA signature is further refined to be able to identify the tissue of origin with more accuracy while assessing whether the tissue producing the cfDNA is normal. Using deep sequencing of cfDNA, the authors identify that in vivo occupancies of transcription factors are directly footprinted by cfDNA and that nucleosome spacing in regulatory elements and gene bodies correlates with gene expression in hematopoeitic cell types. Previously, it has been shown that allograft rejection may be correlated with cfDNA levels.3 The authors' method in the current study is likely to help identify whether the tissue of origin is of donor or recipient origin. In the future, it will be interesting to investigate whether cfDNA is useful for the identification of graft rejection biomarkers before organ damage occurs, and whether cfDNA may help to identify patients who could be amenable to tapering or even withdrawal of immunosuppression. REFERENCES Heidt S, San Segundo D, Shankar S, et al. Peripheral blood sampling for the detection of allograft rejection: biomarker identification and validation. Transplantation. 2011;92:1–9. Heidt S, Wood KJ. Biomarkers of operational tolerance in solid organ transplantation. Expert Opin Med Diagn. 2012;6:281–93. Snyder TM, Khush KK, Valantine HA, et al. Universal noninvasive detection of solid organ transplant rejection. Proc Natl Acad Sci U S A. 2011;108:6229–34.