The role of renal hypoperfusion in development of renal microcirculatory dysfunction in endotoxemic rats

Abstract

PurposeTo study the role of renal hypoperfusion in development of renal microcirculatory dysfunction in endotoxemic rats.MethodsRats were randomized into four groups: a sham group (n = 6), a lipopolysaccharide (LPS) group (n = 6), a group in which LPS administration was followed by immediate fluid resuscitation which prevented the drop of renal blood flow (EARLY group) (n = 6), and a group in which LPS administration was followed by delayed (i.e., a 2-h delay) fluid resuscitation (LATE group) (n = 6). Renal blood flow was measured using a transit-time ultrasound flow probe. Microvascular perfusion and oxygenation distributions in the renal cortex were assessed using laser speckle imaging and phosphorimetry, respectively. Interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α were measured as markers of systemic inflammation. Furthermore, renal tissue samples were stained for leukocyte infiltration and inducible nitric oxide synthase (iNOS) expression in the kidney.ResultsLPS infusion worsened both microvascular perfusion and oxygenation distributions. Fluid resuscitation improved perfusion histograms but not oxygenation histograms. Improvement of microvascular perfusion was more pronounced in the EARLY group compared with the LATE group. Serum cytokine levels decreased in the resuscitated groups, with no difference between the EARLY and LATE groups. However, iNOS expression and leukocyte infiltration in glomeruli were lower in the EARLY group compared with the LATE group.ConclusionsIn our model, prevention of endotoxemia-induced systemic hypotension by immediate fluid resuscitation (EARLY group) did not prevent systemic inflammatory activation (IL-6, IL-10, TNF-α) but did reduce renal inflammation (iNOS expression and glomerular leukocyte infiltration). However, it could not prevent reduced renal microvascular oxygenation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00134-011-2267-4) contains supplementary material, which is available to authorized users.

Renal Hemodynamics in AKI

“…Persistent perfusion deficits and diminished tissue oxygenation have been shown to be of greater magnitude in the highly vulnerable outer medulla compared with the cortex in a variety of experimental models, including total ischemia, radiocontrast nephropathy, and nonsteroidal anti-inflammatory drugand other drug-induced AKI etiologies, including fluid therapy. 23,39 The renal cortex microcirculation is significantly compromised in sepsis models 3,40 and humans, 41 where inhomogeneous patchy areas of microischemia can occur (Figure 2). These heterogeneous areas of hypoxia and normal oxygenation define the nature of hemodynamic alterations leading to inflammation, because it is expected that there is increased reactive oxygen species production associated with hypoxia-normoxia interactions.…”

“…For example, the exact mechanisms by which different fluid compositions (such as normal saline and colloid or buffered solutions) affect renal microcirculation are not well understood, and emerging experimental and clinical data suggest that use of inappropriate fluids or fluid replacement strategies may exert deleterious effects on the microcirculation and renal outcomes. 40,59 Strategies allowing real-time evaluation of microcirculatory fluid and vasopressors responsiveness might be expected to optimize resuscitation effectiveness while limiting the potential to cause harm.…”

Reduction of Tubular Flow Rate as a Mechanism of Oliguria in the Early Phase of Endotoxemia Revealed by Intravital Imaging

“…The biologic mechanisms underlying septic AKI have been found to include irregular peritubular capillary flow, 29,30 disturbances in oxygen supply, 9 and mitochondrial dysfunction. 31,32 Less is known, however, about the mechanisms underlying oliguria, despite it being a diagnostic criterion of AKI in several guidelines (e.g., AKIN, RIFLE, and KDIGO).…”

“…1,2 The incidence of AKI has steadily increased over the last decade, 3 and its mortality rate has remained high. 4,5 Although basic research has identified several pathways involved in the mechanism of AKI, including inflammation 6,7 and alterations in microcirculation, 8,9 thus enabling the development of new therapeutic strategies, specific treatments that can improve AKI outcome are not yet clinically available. [10][11][12] Notably, only modest histologic changes in the kidney gave been observed in patients with sepsis and in animal models of sepsis, 13,14 whereas septic AKI has a high mortality rate.…”

Determinantes precoces en el desarrollo de injuria renal aguda durante la sepsis abdominal experimental

“…Clásicamente, la reducción en el flujo sanguíneo renal (FSR) se ha propuesto como el mecanismo más importante en la patogenia de la IRA 5 , sin embargo, la escasa presencia de necrosis reportada en tejido renal de pacientes que fallecen en sepsis con IRA hacen que la pérdida de flujo renal sea un proceso probablemente poco relevante 7,8 . Trabajos clínicos y experimentales recientes enfatizan la importancia de otros mecanismos en la génesis de la IRA en la sepsis, entre estos destaca la intensidad del cuadro inflamatorio y las alteraciones en la determinantes precoces de injuria renal en la sepsis abdominal -t. regueira et al rev Med chile 2014; 142: 551-558 microcirculación más que los cambios globales en el FSR [9][10][11] . El objetivo de este trabajo es evaluar el impacto de los cambios macro-hemodinámicos y del flujo sanguíneo y plasmático renal sobre la función e histología renal en un modelo experimental de sepsis intra-abdominal.…”