Pharmacological targets in the renal peritubular microenvironment: implications for therapy for sepsis-induced acute kidney injury

Abstract

One of the most frequent and serious complications to develop in septic patients is acute kidney injury (AKI), a disorder characterized by a rapid failure of the kidneys to adequately filter the blood, regulate ion and water balance, and generate urine. AKI greatly worsens the already poor prognosis of sepsis and increases cost of care. To date, therapies have been mostly supportive; consequently there has been little change in the mortality rates over the last decade. This is due, at least in part, to the delay in establishing clinical evidence of an infection and the associated presence of the systemic inflammatory response syndrome and thus, a delay in initiating therapy. A second reason is a lack of understanding regarding the mechanisms leading to renal injury, which has hindered the development of more targeted therapies. In this review, we summarize recent studies, which have examined the development of renal injury during sepsis and propose how changes in the peritubular capillary microenvironment lead to and then perpetuate microcirculatory failure and tubular epithelial cell injury. We also discuss a number of potential therapeutic targets in the renal peritubular microenvironment, which may prevent or lessen injury and/or promote recovery.

Figure 1. Anatomy of the renal circulation

The renal microcirculation is depicted illustrating the anatomical relationship between the renal tubules and the peritubular capillaries.

Figure 2

Schematic showing the synthesis of oxidant derived from NO and superoxide.

Figure 3. Imaging of RNS generation in renal tubules with intravital microscopy

Shown are representative images of perfusion (A) and rhodamine fluorescence (B) captured from videos of the same field of view from the kidney of a live 40-week-old mouse 16 hours after CLP. Arrows indicate capillaries with no perfusion. A pseudocolored image of B is shown in C to highlight changes in pixel intensity. Intense regions of rhodamine fluorescence are localized to discrete regions of the tubular epithelium bordered by capillaries with reduced perfusion (from (L. Wu, Gokden, et al., 2007) used with permission).

Figure 4

Depiction of the mitochondrial electron transport chain.

Figure 5. Changes in the peritubular capillary microenvironment during sepsis

Depicted in A is the normal peritubular capillary microenvironment. The early impaired microcirculation with increased capillary permeability and decrease capillary perfusion are depicted in B. Subsequent tubular epithelial damage is depicted in C.

Figure 6. Sepsis-induced cycle of injury in the peritubular microenvironment

Green arrows indicate events, which may occur too rapidly to be clinically relevant therapeutic targets. Red arrows indicate possible targets in the peritubular microenvironment, which could break the cycle of injury and allow recovery of the renal microcirculation and tubular function.