Dendritic cells in acute kidney injury
During ischemia, the production of cytokines by resident cells as well as bone marrow-derived cells produces an inflammatory response that is clearly pathogenic. Among these cytokines, tumor necrosis factor (TNF)-
is especially culpable. As they report in this issue, Dong et al. isolated cells to determine the contribution of dendritic cells to the early production of TNF and other inflammatory mediators. They increased secretion of TNF, interleukin-6, monocyte chemoattractant protein-1, and RANTES in cell suspensions taken from ischemic kidneys as compared with control kidneys. When these suspensions were enriched for dendritic cells, the cytokine production further increased, and specifically identified TNF-. When bone marrow-derived dendritic cells were isolated after ischemia to the kidney, they exhibited maturation markers, although their numbers were stable. Dendritic cells were the predominant cells to produce TNF-. When depleted from the kidneys in vivo, dendritic cells substantially attenuated TNF secretion by renal cells in response to ischemic injury. Previous identification of resident dendritic cells in the kidney was a major discovery in kidney research; Dong et al. further expand the domain of these important cells in renal disease. See page 619.
Long-term survival of acute renal failure
What is the long-term outcome of patients with acute tubular necrosis (ATN)? There is a dearth of studies that address this question. In a new article, Liaño et al. studied patients with ATN at a single hospital in Madrid and followed those who were discharged for an average of 7 years. As would be expected, many died — a large number of them because of diseases present when they developed ATN. Detailed analysis did not show many surprises. Those who survived were younger and had survived trauma; hence, they developed ATN without any comorbid events. Many of those who survived had been treated in the intensive care unit of the hospital. Although the long-term mortality in this group of patients was high and related to the original disease, renal function was found to be adequate in most patients. See page 679.
Anti-dsDNA antibodies in lupus nephritis bind to nucleosomes
One of the hallmarks of lupus nephritis is the association of the disease and its severity with anti-double-stranded DNA (anti-dsDNA) antibodies. Antigen–antibody complexes made with these antibodies have been found to be nephritogenic. However, before now, the target of these antibodies was unknown. The major problem in identifying the target is that DNA is a highly negatively charged compound; hence, the antibodies probably bind by electrostatic interactions. This causes a serious issue in identification of
the antigen, as any highly negatively charged protein could bind to these antibodies. Previous studies showed that DNase treatment of glomerular extracts of lupus kidneys did not reduce binding of the antibodies, even though addition of dsDNA did reduce binding. These previous studies show that there may be a crossreacting antigen that resembles DNA, such as heparan sulfate proteoglycan. Located in the glomerular basement membrane, it is highly negatively charged. New research by Kalaaji et al. re-examined this issue. They found that the antibodies were restricted to dense deposits in the basement membrane and colocalized with nucleosome-binding anti-dsDNA/anti-histone/anti-transcription factor antibodies. The authors excluded the possibility that the dense deposits contained dsDNA. The targeting of membrane-associated nucleosomes by anti-dsDNA autoantibodies in human lupus nephritis suggests that nucleosomes are released in the glomerulus — probably from apoptotic cells — and act as antigens. See page 664.
An accompanying Commentary by Berden and colleagues puts this work in its historical context (see page 600).
