Bulent Ergin

The renal microcirculation in sepsis

Despite identification of several cellular mechanisms being thought to underlie the development of septic acute kidney injury (AKI), the pathophysiology of the occurrence of AKI is still poorly understood. It is clear, however, that instead of a single mechanism being responsible for its aetiology, an orchestra of cellular mechanisms failing is associated with AKI. The integrative physiological compartment where these mechanisms come together and exert their integrative deleterious action is the renal microcirculation (MC). This is why it is opportune to review the response of the renal MC to sepsis and discuss the determinants of its (dys)function and how it contributes to the pathogenesis of renal failure. A main determinant of adequate organ function is the adequate supply and utilization of oxygen at the microcirculatory and cellular level to perform organ function. The highly complex architecture of the renal microvasculature, the need to meet a high energy demand and the fact that the kidney is borderline ischaemic makes the kidney a highly vulnerable organ to hypoxaemic injury. Under normal, steady-state conditions, oxygen (O2) supply to the renal tissues is well regulated; however, under septic conditions the delicate balance of oxygen supply versus demand is disturbed due to renal microvasculature dysfunction. This dysfunction is largely due to the interaction of renal oxygen handling, nitric oxide metabolism and radical formation. Renal tissue oxygenation is highly heterogeneous not only between the cortex and medulla but also within these renal compartments. Integrative evaluation of the different determinants of tissue oxygen in sepsis models has identified the deterioration of microcirculatory oxygenation as a key component in the development AKI. It is becoming clear that resuscitation of the failing kidney needs to integratively correct the homeostasis between oxygen, and reactive oxygen and nitrogen species. Several experimental therapeutic modalities have been found to be effective in restoring microcirculatory oxygenation in parallel to improving renal function following septic AKI. However, these have to be verified in clinical studies. The development of clinical physiological biomarkers of AKI specifically aimed at the MC should form a valuable contribution to monitoring such new therapeutic modalities.

Scavenging reactive oxygen species using tempol in the acute phase of renal ischemia/reperfusion and its effects on kidney oxygenation and nitric oxide levels

BackgroundRenal ischemia/reperfusion (I/R) injury is commonly seen in kidney transplantation and affects the allograft survival rates. We aimed to test our hypothesis that scavenging reactive oxygen species (ROS) with tempol would protect renal oxygenation and nitric oxide (NO) levels in the acute phase of renal I/R.MethodsRats were randomly divided: (1) no I/R, no tempol; (2) no I/R, but with tempol; (3) I/R without tempol; and (4) I/R with tempol. I/R was induced by 30-min clamping of the renal artery. Tempol (200xa0μmol/kg/h/i.v) was administered 15xa0min prior to I/R.ResultsI/R without tempol led to a significant decrease in renal oxygen delivery and microvascular oxygenation. Tempol, however, protected renal oxygenation after I/R. At R90, the creatinine clearance rate was lower in the I/R-subjected group that did not receive tempol compared to that in the other groups. I/R injury without tempol treatment led to a significant increase in tissue malondialdehyde levels and a significant decrease in tissue NO levels. Tempol administration before I/R could prevent oxidative stress and altered tissue NO levels.ConclusionsThis underscores that unbalance between oxygen, NO, and ROS forms an important component of the pathogenesis of I/R-induced AKI and should therefore be taken into account when designing a prevention/treatment strategy for renal I/R injury in transplantation.

Effects of a human recombinant alkaline phosphatase on renal hemodynamics, oxygenation and inflammation in two models of acute kidney injury

Two small clinical trials indicated that administration of bovine intestinal alkaline phosphatase (AP) improves renal function in critically ill patients with sepsis-associated acute kidney injury (AKI), for which the mechanism of action is not completely understood. Here, we investigated the effects of a newly developed human recombinant AP (recAP) on renal oxygenation and hemodynamics and prevention of kidney damage and inflammation in two in vivo AKI models. To induce AKI, male Wistar rats (n=18) were subjected to renal ischemia (30min) and reperfusion (I/R), or sham-operated. In a second model, rats (n=18) received a 30min infusion of lipopolysaccharide (LPS; 2.5mg/kg), or saline, and fluid resuscitation. In both models, recAP (1000U/kg) was administered intravenously (15min before reperfusion, or 90min after LPS). Following recAP treatment, I/R-induced changes in renal blood flow, renal vascular resistance and oxygen delivery at early, and cortical microvascular oxygen tension at late reperfusion were no longer significantly affected. RecAP did not influence I/R-induced effects on mean arterial pressure. During endotoxemia, recAP treatment did not modulate the LPS-induced changes in systemic hemodynamics and renal oxygenation. In both models, recAP did exert a clear renal protective anti-inflammatory effect, demonstrated by attenuated immunostaining of inflammatory, tubular injury and pro-apoptosis markers. Whether this renal protective effect is sufficient to improve outcome of patients suffering from sepsis-associated AKI is being investigated in a large clinical trial.

Microbubble Composition and Preparation for High-Frequency Contrast-Enhanced Ultrasound Imaging: In Vitro and In Vivo Evaluation

Although high-frequency ultrasound imaging is gaining attention in various applications, hardly any ultrasound contrast agents (UCAs) dedicated to such frequencies (>15 MHz) are available for contrast-enhanced ultrasound (CEUS) imaging. Moreover, the composition of the limited commercially available UCAs for high-frequency CEUS (hfCEUS) is largely unknown, while shell properties have been shown to be an important factor for their performance. The aim of our study was to produce UCAs in-house for hfCEUS. Twelve different UCA formulations A-L were made by either sonication or mechanical agitation. The gas core consisted of C₄F₁₀ and the main coating lipid was either 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC; A-F formulation) or 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC; G-L formulation). Mechanical agitation resulted in UCAs with smaller microbubbles (number weighted mean diameter ~1 <inline-formula> <tex-math notation=LaTeX>

Mycophenolate mofetil improves renal hemodynamics, microvascular oxygenation, and inflammation in a rat model of supra‐renal aortic clamping‐mediated renal ischemia reperfusion injury

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Effects of N -acetylcysteine (NAC) supplementation in resuscitation fluids on renal microcirculatory oxygenation, inflammation, and function in a rat model of endotoxemia

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Recruitment of sublingual microcirculation using handheld incident dark field imaging as a routine measurement tool during the postoperative de-escalation phase-a pilot study in post ICU cardiac surgery patients.

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Identification and quantification of human microcirculatory leukocytes using handheld video microscopes at the bedside

</tex-math></inline-formula>). UCA formulations with similar size distributions but different main lipid components showed that the DPPC-based UCA formulations had higher nonlinear responses at both the fundamental and subharmonic frequencies in vitro for hfCEUS using the Vevo2100 high-frequency preclinical scanner (FUJIFILM VisualSonics, Inc.). In addition, UCA formulations F (DSPC-based) and L (DPPC-based) that were made by mechanical agitation performed similar in vitro to the commercially available Target-Ready MicroMarker (FUJIFILM VisualSonics, Inc.). UCA formulation F also performed similar to Target-Ready MicroMarker in vivo in pigs with similar mean contrast intensity within the kidney (<inline-formula> <tex-math notation=LaTeX>

Feasibility of in vivo contrast-enhanced imaging of the renal cortex during hemorrhagic shock

n = 7

The measured hepatic function increase after portal vein embolization measured by 99mTc-mebrofenin hepatobiliary scintigraphy is not attributed by an increased microvascular blood flow

</tex-math></inline-formula>), but formulation L did not. This is likely due to the lower stability of formulation L in vivo. Our study shows that DSPC-based microbubbles produced by mechanical agitation resulted in small microbubbles with high nonlinear responses suitable for hfCEUS imaging.