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

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.

[1]  R. Bellomo,et al.  Changes in the incidence and outcome for early acute kidney injury in a cohort of Australian intensive care units , 2007, Critical care.

[2]  E. Ivers,et al.  Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock , 2001 .

[3]  Jonathan Himmelfarb,et al.  Fluid accumulation, survival and recovery of kidney function in critically ill patients with acute kidney injury. , 2009, Kidney international.

[4]  Dirk J. Faber,et al.  Evaluation of multi-exponential curve fitting analysis of oxygen-quenched phosphorescence decay traces for recovering microvascular oxygen tension histograms , 2010, Medical & Biological Engineering & Computing.

[5]  C. Ince,et al.  L-NIL prevents renal microvascular hypoxia and increase of renal oxygen consumption after ischemia-reperfusion in rats. , 2009, American journal of physiology. Renal physiology.

[6]  S. Cain,et al.  Critical O2 delivery to skeletal muscle at high and low PO2 in endotoxemic dogs. , 1989, Journal of applied physiology.

[7]  R. Pearse,et al.  The effect of increasing doses of norepinephrine on tissue oxygenation and microvascular flow in patients with septic shock* , 2009, Critical care medicine.

[8]  P. Pelosi,et al.  A trial of goal-oriented hemodynamic therapy in critically ill patients. SvO2 Collaborative Group. , 1996, The New England journal of medicine.

[9]  H. Rabb,et al.  The interaction between ischemia–reperfusion and immune responses in the kidney , 2009, Journal of Molecular Medicine.

[10]  R. Bellomo,et al.  Plasma and urine neutrophil gelatinase-associated lipocalin in septic versus non-septic acute kidney injury in critical illness , 2010, Intensive Care Medicine.

[11]  R. Bellomo,et al.  Renal blood flow in sepsis , 2005, Critical care.

[12]  L. U. G. Attinoni,et al.  A TRIAL OF GOAL-ORIENTED HEMODYNAMIC THERAPY IN CRITICALLY ILL PATIENTS , 2000 .

[13]  P. T. Phang,et al.  Heterogeneity of gut capillary transit times and impaired gut oxygen extraction in endotoxemic pigs. , 1996, Journal of applied physiology.

[14]  P. Schumacker,et al.  Pathological supply dependence of systemic and intestinal O2 uptake during endotoxemia. , 1988, Journal of applied physiology.

[15]  Y. Huang Monitoring oxygen delivery in the critically ill. , 2005, Chest.

[16]  M. Okusa,et al.  Inflammation in Acute Kidney Injury , 2008, Nephron Experimental Nephrology.

[17]  C. Ince,et al.  Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study , 2009, Critical care.

[18]  M. Singer,et al.  Microvascular and Interstitial Oxygen Tension in the Renal Cortex and Medulla Studied in A 4-H Rat Model of LPS-Induced Endotoxemia , 2011, Shock.

[19]  P. Schumacker,et al.  Analysis of oxygen delivery and uptake relationships in the Krogh tissue model. , 1989, Journal of applied physiology.

[20]  C. Ince,et al.  Microcirculatory oxygenation and shunting in sepsis and shock. , 1999, Critical care medicine.

[21]  P. Radermacher,et al.  Renal haemodynamic, microcirculatory, metabolic and histopathological responses to peritonitis-induced septic shock in pigs , 2008, Critical care.

[22]  R. Bellomo,et al.  Intrarenal blood flow distribution in hyperdynamic septic shock: Effect of norepinephrine , 2003, Critical care medicine.

[23]  C. Ince,et al.  NONRESUSCITATED ENDOTOXEMIA INDUCES MICROCIRCULATORY HYPOXIC AREAS IN THE RENAL CORTEX IN THE RAT , 2009, Shock.

[24]  Didier Payen,et al.  A positive fluid balance is associated with a worse outcome in patients with acute renal failure , 2008, Critical care.

[25]  John A Kellum,et al.  Acute renal failure in critically ill patients: a multinational, multicenter study. , 2005, JAMA.

[26]  P. Cabrales,et al.  INCREASE PLASMA VISCOSITY SUSTAINS MICROCIRCULATION AFTER RESUSCITATION FROM HEMORRHAGIC SHOCK AND CONTINUOUS BLEEDING , 2005, Shock.

[27]  K. Walley,et al.  Heterogeneity of oxygen delivery impairs oxygen extraction by peripheral tissues: theory. , 1996, Journal of applied physiology.

[28]  P. Devos,et al.  Resuscitation with low volume hydroxyethylstarch 130 kDa/0.4 is not associated with acute kidney injury , 2010, Critical care.

[29]  R. Bellomo,et al.  Renal blood flow and function during recovery from experimental septic acute kidney injury , 2007, Intensive Care Medicine.

[30]  P. Venge,et al.  Neutrophil gelatinase-associated lipocalin in adult septic patients with and without acute kidney injury , 2010, Intensive Care Medicine.

[31]  S. Vinogradov,et al.  A new, water soluble, phosphor for oxygen measurements in vivo. , 1997, Advances in experimental medicine and biology.

[32]  K. Tyml,et al.  Septic impairment of capillary blood flow requires nicotinamide adenine dinucleotide phosphate oxidase but not nitric oxide synthase and is rapidly reversed by ascorbate through an endothelial nitric oxide synthase-dependent mechanism* , 2008, Critical care medicine.

[33]  Thomas M van Gulik,et al.  Real-time assessment of renal cortical microvascular perfusion heterogeneities using near-infrared laser speckle imaging. , 2010, Optics express.

[34]  K. Klingel,et al.  LOW-DOSE DEXAMETHASONE-SUPPLEMENTED FLUID RESUSCITATION REVERSES ENDOTOXIN-INDUCED ACUTE RENAL FAILURE AND PREVENTS CORTICAL MICROVASCULAR HYPOXIA , 2009, Shock.

[35]  D. Inthorn,et al.  Hydroxyethyl Starch (130 kD), but Not Crystalloid Volume Support, Improves Microcirculation during Normotensive Endotoxemia , 2002, Anesthesiology.

[36]  Benjamin W. Dugan,et al.  Oxygen distributions in tissue measured by phosphorescence quenching. , 2003, Advances in experimental medicine and biology.

[37]  R. Bellomo,et al.  The impact of experimental hypoperfusion on subsequent kidney function , 2010, Intensive Care Medicine.

[38]  S. Iltar,et al.  Effect of hydroxyethyl starch 130/0.4 on ischaemia/reperfusion in rabbit skeletal muscle , 2009, European journal of anaesthesiology.

[39]  C. Ince,et al.  The role of the microcirculation in acute kidney injury , 2009, Current opinion in critical care.

[40]  Christopher G Ellis,et al.  Effect of sepsis on skeletal muscle oxygen consumption and tissue oxygenation: interpreting capillary oxygen transport data using a mathematical model. , 2004, American journal of physiology. Heart and circulatory physiology.