Endothelial Dysfunction of the Kidney in Sepsis


Objectives

This chapter will:

  • 1.

    Describe the role of the endothelium dysfunction during sepsis and its interplay with the local environment.

  • 2.

    Explain how endothelium damage translates into a loss of kidney function: sepsis-induced acute kidney injury.

  • 3.

    Summarize the therapies targeting renal endothelial cells in sepsis-induced acute kidney injury.

Endothelial dysfunction and microcirculation impairment are recognized hallmarks of sepsis-related organ failure. Many experimental and clinical studies have emphasized the central role of endothelial cell (EC) activation and dysfunction in promoting the coagulation cascade, leukocyte adherence, vascular barrier compromise, hemodynamic collapse, and vascular hyporesponsiveness. These processes contribute to organ failure with an increased risk of morbidity and mortality for the patient. Among the organ failures observed in septic patients, acute kidney injury (AKI) is one of the most frequent. Sepsis-induced AKI may be associated with mortality rates above 50%. In fact, the kidney exhibits a high sensitivity to microcirculatory alterations, especially heterogeneity, and to tissue hypoxia, two main phenomena that occur during septic shock.

This chapter provides an overview of sepsis-related endothelial dysfunction with a particular focus on the kidney. We discuss the features of healthy and injured septic vascular endothelium of the kidney, the interplay between ECs and blood cells, and interactions among a wide range of molecules. Moreover, we describe how septic insult to endothelium can lead to a loss of kidney function.

Role of Renal Endothelium in Function

Endothelial Cells

The ECs form the interface between the content of the inner lumen of vessels and the surrounding environment, comprising the vascular smooth muscle cells (VSMCs), the interstitial space and the parenchymal cells that are responsible for organ function. The ECs constitute a monolayer, lining the interior of all blood vessels. This surface is estimated to comprise approximately 10 13 cells, covering 4000 to 7000 m 2 . ECs generally have a thickness of approximately 0.5 µm and are 100 µm long by 10 µm wide.

The endothelium is remarkably heterogeneous in structure and function. The arrangement of ECs may differ significantly from one organ to the next, from juxtaposed arrangements to overlapping arrangements. This heterogeneous distribution also may vary within the same organ; in the kidney, for instance, various EC arrangements grant different permeability properties. The EC lining contains pores and fenestrations to ensure partial permeability and to transport molecules to the underlying cells and basal membrane. The kidney and intestines exhibit the highest permeability. ECs are linked together by transcellular components, including gap junctions for electrical communication for upstream vascular regulation and intercellular tight junctions for maintaining vascular barriers. Previously considered a passive barrier, it is now apparent that ECs play a crucial role in the regulation of vasomotor tone, hemostasis, immunologic functions, and the secretion of molecules by sensing through mechanotransducers, which subsequently initiate transcellular and intracellular signaling and activation.

Glomerular and Peritubular Endothelium

Glomerular endothelial cells are unusually thin; around capillary loops, they have a cell thickness of approximately 50 to 150 nm, whereas in other locations, this thickness is approximately 500 nm. ECs in the glomerulus present large fenestrated areas constituting 20% to 50% of the entire endothelial surface. These fenestrations are typically 60 to 70 nm in diameter but, unlike renal peritubular ECs, do not seem to possess a thin (3–5 nm) diaphragm. In general, these fenestrations act as a sieving barrier to control the production of urine in the glomerulus, filtering plasma because of hydrostatic pressure. The kidney has one of the richest and most diverse EC populations found within any organ. The microcirculation of the kidney presents two specialized capillary beds connected in series: the glomerular capillary bed in the cortex for plasma filtration and the peritubular capillary bed, which forms the vasa recta responsible for electrolyte reabsorption in the outer and inner medulla. Thus the arrangement of ECs and the permeability of the endothelium differ for these two microcirculations. Glomerular microcirculation functions via continuous and fenestrated endothelium with no diaphragm, whereas it is more continuous and nonfenestrated in the descending vasa recta in peritubular microcirculation.

The endothelium must face and resist extreme physiologic conditions, such as large changes in oxygenation and osmolality. Indeed, ECs in the cortex are exposed to almost normal oxygen partial pressure and osmolality, whereas those in medullar microcirculation function in an osmolarity of up to 1200 mosmol/L -1 and a PO 2 as low as 20 mm Hg. The microvascular arrangement has a specialized structure in the medulla. The vasa recta, connected in series with the juxtaglomerular microvasculature, surround the peritubular cells in the outer and inner medulla and are responsible for solute exchange. The ECs of these microvessels are exposed to countercurrent oxygen exchange, resulting in a gradient of decreasing oxygen tension (to approximately 10 mm Hg). Thus their functions differ considerably along the tubule. In addition, ECs are affected and injured by ischemia injury differently.

Interplay of Endothelium and Leukocytes

The inner lumen of ECs is exposed to blood flow, consisting of red blood cells, leukocytes, and plasma. In the physiologic state, endothelium–leukocyte interactions are limited. Five steps generally describe the interactions between ECs and leukocytes during inflammation, beginning with limited contact, then more prolonged contact, leukocyte rolling, strong adhesion, and finally transendothelial migration, a process referred to as diapedesis. ECs regulate leukocyte trafficking between circulating blood and the surrounding tissue. When activated, the endothelium exhibits enhanced endothelium–leukocyte interactions that are secondary to increased expressions of cell adhesion molecules (CAMs), such as intercellular adhesion molecule selectins (E-selectin and L-selectin), ICAM-1, ICAM-2, vascular adhesion molecule (VCAM), and platelet endothelial cell adhesion molecule (PECAM). The upregulation of CAMs promotes increased adhesion, rolling, and transmigration of circulating leukocytes. Many integrins also are involved in the adhesion of polymorphonuclear leukocytes and monocytes in the proximal tubule and serve as transcellular mechanotransducers.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here