Marconi Revisited
Authors: Raymond Vanholder, Peter Paul De Deyn, Wim Van Biesen, Norbert Lameire
Journal: Journal of the American Society of Nephrology (2008)

In this issue of JASN, Liu et al.1 demonstrate in an animal model that acute kidney injury (AKI) is related to anatomic lesions and functional disturbances of the brain. This connection seems linked in part to inflammation. Inflammatory markers are increased after AKI not only in serum and kidneys but also in brain. Such long-distance interorgan cross-talk is observed for heart and lungs2–4 as a result of the release of humoral factors generated in damaged kidneys that seep into blood. In the case of the brain, however, the mechanism might be more complex, because the brain-blood barrier (BBB) normally interferes with trespassing substances. The existence of a link between inflammation and the brain has been suggested previously regarding development of fever and so-called "sick behavior."5 The brain lesions observed after AKI1 seem more severe and more definitive (with pyknosis and cell death) versus what is observed in mere sick behavior. Probably damage to the kidney triggers more profound mechanisms because a vital organ is affected and a larger number of messengers are released. Uremic encephalopathy in AKI usually presents in a dramatic way with a fast progression from mild sensorial clouding to delirium and coma.6 How is it possible that distant inflammation affects the brain? Several different mechanisms are possible5,7: Cytokines may circumvent the BBB, affecting brain zones where the BBB is more penetrable, such as circumventricular structures, and may there bind to innate brain macrophages or other immune cells and activate them; cytokines may activate brain endothelial cells, which can pass the message to inflammatory cells across the BBB; cytokines may activate white blood cells, which adhere to brain endothelia and pass their message through the endothelia to the other side; communication may occur directly through neuronal pathways, such as the vagal nerve; transfer of message may occur through noncytokine messengers, such as prostaglandins, which are smaller than the cytokines, so they more easily penetrate the BBB; and the efficacy of the BBB may be altered during inflammation. A second pathway for distant brain damage in the presence of AKI could be uremic solute retention, which in turn triggers a whole cascade of both neuronal cell damage and proinflammatory reactions. A host of uremic compounds are retained in uremia, and several of them exert a deleterious effect on several organ systems,8 including the central nervous system.9 Several protein-bound compounds change endothelial cell function and permeability10 and in this way may contribute to the modification of the BBB. In addition, other compounds activate white blood cells and because of their molecular weight or other characteristics may cross the BBB more easily than the cytokines. Compounds with low molecular weight, such as several of the guanidines11 and the phenolic compound p-cresylsulfate,12 have immune-stimulating properties that might exert this activity on both sides of the BBB, especially if the permeability of the latter is affected by inflammation or uremia. Of note, the phenolic compound quinolinic acid, which is a retained uremic solute,8 is also linked to neurotoxicity.13,14 Likewise, indoxylsulfate, another protein-bound uremic solute belonging to the group of indoles, is linked to central nervous system toxicity in cis-platinum–induced AKI.15 In a comprehensive analysis of the acute effects of 17 candidate uremic neurotoxins on murine spinal cord neurons in primary, dissociated cell cultures, some compounds (guanidinosuccinate and spermine) display neuroexcitatory effects that are mediated by calcium channels.16 Brain leukocytes might also be primed for further activation in case of concomitant conditions, such as already present disease or inflammation. Because AKI frequently develops after sepsis or together with other comorbidities, brain damage might even be worse in vivo than in the relatively "clean" model of pure ischemia-reperfusion, as in the study by Liu et al.1 Bidirectional cross-talk between kidneys and other organs is also possible—that is, other organs may in turn affect kidney function.17 Brain lesion resulting in renal effects is repeatedly observed with cadaveric kidneys harvested from donors with brain death18,19 and might involve catecholamines and inflammatory messengers. Hence, such bidirectional effects may also play a role in AKI. It would be interesting to discern whether the observed effects are attributable to kidney injury per se or merely to inflammation. As a "control" experiment, a model of acute liver injury was evaluated by Liu et al.,1 resulting in modest brain lesions and less inflammation. No other control model of inflammation (e.g., administration of LPS) was included in the study. Likewise, if the "uremic toxin" hypothesis is correct, then brain damage would be comparable in the ischemic and bilateral nephrectomy models. Unfortunately, separate data on anatomic brain damage in bilateral nephrectomy are not reported by Liu et al.1; therefore, the question of whether the brain lesions are linked to systemic inflammation or to kidney injury per se remains unanswered. Finally, one should be careful in extrapolating animal findings to the human condition.20 Nevertheless, unraveling the mechanisms at play might be helpful in developing preventive measures, such as blocking inflammatory events or other mechanisms, or starting renal replacement strategies earlier. Finding adequate means to cope with brain injury might not only create a benefit for the central nervous system in AKI but also disentangle a vicious loop, if brain lesions in their turn would affect kidney function. DISCLOSURES None.