Progression of Kidney Fibrosis after Sepsis: The Underestimated Role of Resident Macrophages and Recruited Monocytes

Abstract

Sepsis is a life-threatening condition affecting each year an estimated 49 million people and causing 11 million deaths. Short-term mortality of sepsis was substantially reduced during the past decades and is still improving. Besides its short-term lethality, awareness regarding long-term consequences of sepsis is rising. Among all organs affected during sepsis, the kidney is the most vulnerable. Up to 40% of patients suffering from sepsis develop acute kidney injury (AKI), and sepsis is the leading cause of AKI among critically ills. Half of patients will recover from AKI during their stay; however, several studies have pointed out that those patients were at increased risk for the development of subsequent chronic kidney disease (CKD). In patients suffering from transient AKI, a second injury was found to hasten renal fibrogenesis. Taken together those findings challenge the concept of ad integrum recovery and strongly suggest maladaptive repair AKI, together with profound and durable alterations at intra-organ level. Factors driving AKI to CKD after sepsis are poorly understood and could be of multiple origins. Kidney macrophages have pleiotropic roles in health and disease. Following sepsis, a proportion of kidney macrophages undergoes pyroptosis in an "altruist" maneuver to recruit inflammatory cells. Empty niches are later colonized by circulating monocyte arising from bone marrow in a process called emergency myelopoiesis but also by expansion of resident cells. The role of monocytes and macrophages in the acute phase of sepsis is well described, however, their role in the resolution of inflammation is just beginning to be understood. In the present review, we will discuss the fate of kidney resident macrophages and recruited monocytes in septic AKI. We will review the evidence linking changes in the immune landscape and maladaptive repair after sepsis. Finally, we will consider how targeting macrophage recruitment and polarization might influence sepsis long-term consequences.