Clive N. May

The brain renin-angiotensin system: location and physiological roles

Angiotensinogen, the precursor molecule for angiotensins I, II and III, and the enzymes renin, angiotensin-converting enzyme (ACE), and aminopeptidases A and N may all be synthesised within the brain. Angiotensin (Ang) AT(1), AT(2) and AT(4) receptors are also plentiful in the brain. AT(1) receptors are found in several brain regions, such as the hypothalamic paraventricular and supraoptic nuclei, the lamina terminalis, lateral parabrachial nucleus, ventrolateral medulla and nucleus of the solitary tract (NTS), which are known to have roles in the regulation of the cardiovascular system and/or body fluid and electrolyte balance. Immunohistochemical and neuropharmacological studies suggest that angiotensinergic neural pathways utilise Ang II and/or Ang III as a neurotransmitter or neuromodulator in the aforementioned brain regions. Angiotensinogen is synthesised predominantly in astrocytes, but the processes by which Ang II is generated or incorporated in neurons for utilisation as a neurotransmitter is unknown. Centrally administered AT(1) receptor antagonists or angiotensinogen antisense oligonucleotides inhibit sympathetic activity and reduce arterial blood pressure in certain physiological or pathophysiological conditions, as well as disrupting water drinking and sodium appetite, vasopressin secretion, sodium excretion, renin release and thermoregulation. The AT(4) receptor is identical to insulin-regulated aminopeptidase (IRAP) and plays a role in memory mechanisms. In conclusion, angiotensinergic neural pathways and angiotensin peptides are important in neural function and may have important homeostatic roles, particularly related to cardiovascular function, osmoregulation and thermoregulation.

Pathophysiology of septic acute kidney injury: what do we really know?

Septic acute kidney injury accounts for close to 50% of all cases of acute kidney injury in the intensive care unit and, in its various forms, affects between 15% and 20% of intensive care unit patients. However, there is little we really know about its pathophysiology. Although hemodynamic factors might play a role in the loss of glomerular filtration rate, they may not act through the induction of renal ischemia. Septic acute renal failure may, at least in patients with a hyperdynamic circulation, represent a unique form of acute renal failure: hyperemic acute renal failure. Measurements of renal blood flow in septic humans are now needed to resolve this pivotal pathophysiological question. Whatever may happen to renal blood flow during septic acute kidney injury in humans, the evidence available suggests that urinalysis fails to provide useful diagnostic or prognostic information in this setting. In addition, nonhemodynamic mechanisms of cell injury are likely to be at work. These mechanisms are likely due to a combination of immunologic, toxic, and inflammatory factors that may affect the microvasculature and the tubular cells. Among these mechanisms, apoptosis may turn out to be important. It is possible that, as evidence accumulates, the paradigms currently used to explain acute renal failure in sepsis will shift from ischemia and vasoconstriction to hyperemia and vasodilation and from acute tubular necrosis to acute tubular apoptosis or simply tubular cell dysfunction or exfoliation. If this were to happen, our therapeutic approaches would also be profoundly altered.

Renal blood flow in sepsis

IntroductionTo assess changes in renal blood flow (RBF) in human and experimental sepsis, and to identify determinants of RBF.MethodUsing specific search terms we systematically interrogated two electronic reference libraries to identify experimental and human studies of sepsis and septic acute renal failure in which RBF was measured. In the retrieved studies, we assessed the influence of various factors on RBF during sepsis using statistical methods.ResultsWe found no human studies in which RBF was measured with suitably accurate direct methods. Where it was measured in humans with sepsis, however, RBF was increased compared with normal. Of the 159 animal studies identified, 99 reported decreased RBF and 60 reported unchanged or increased RBF. The size of animal, technique of measurement, duration of measurement, method of induction of sepsis, and fluid administration had no effect on RBF. In contrast, on univariate analysis, state of consciousness of animals (P = 0.005), recovery after surgery (P < 0.001), haemodynamic pattern (hypodynamic or hyperdynamic state; P < 0.001) and cardiac output (P < 0.001) influenced RBF. However, multivariate analysis showed that only cardiac output remained an independent determinant of RBF (P < 0.001).ConclusionThe impact of sepsis on RBF in humans is unknown. In experimental sepsis, RBF was reported to be decreased in two-thirds of studies (62 %) and unchanged or increased in one-third (38%). On univariate analysis, several factors not directly related to sepsis appear to influence RBF. However, multivariate analysis suggests that cardiac output has a dominant effect on RBF during sepsis, such that, in the presence of a decreased cardiac output, RBF is typically decreased, whereas in the presence of a preserved or increased cardiac output RBF is typically maintained or increased.

The histopathology of septic acute kidney injury: a systematic review

IntroductionSepsis is the most common trigger of acute kidney injury (AKI) in critically ill patients; understanding the structural changes associated with its occurrence is therefore important. Accordingly, we systematically reviewed the literature to assess current knowledge on the histopathology of septic AKI.MethodsA systematic review of the MEDLINE, EMBASE and CINHAL databases and bibliographies of the retrieved articles was performed for all studies describing kidney histopathology in septic AKI.ResultsWe found six studies reporting the histopathology of septic AKI for a total of only 184 patients. Among these patients, only 26 (22%) had features suggestive of acute tubular necrosis (ATN). We found four primate studies. In these, seven out of 19 (37%) cases showed features of ATN. We also found 13 rodent studies of septic AKI. In total, 23% showed evidence of ATN. In two additional studies performed in a dog model and a sheep model there was no evidence of ATN on histopathologic examination. Overall, when ATN was absent, studies reported a wide variety of kidney morphologic changes in septic AKI – ranging from normal (in most cases) to marked cortical tubular necrosis.ConclusionThere are no consistent renal histopathological changes in human or experimental septic AKI. The majority of studies reported normal histology or only mild, nonspecific changes. ATN was relatively uncommon.

Vital Organ Blood Flow During Hyperdynamic Sepsis

OBJECTIVES To develop a nonlethal model of hyperdynamic sepsis, and to measure vital organ blood flows in this setting. DESIGN Randomized crossover animal study. SETTING Animal laboratory of university-affiliated physiology institute. SUBJECTS Seven Merino cross sheep. INTERVENTIONS Surgical implantation of transit-time flow probes around sagittal sinus and circumflex coronary, superior mesenteric, and left renal arteries, and of an electromagnetic flow probe around the ascending aorta. After recovery, randomization to either 6 h of observation under normal conditions (control) or 6 h of observation after the induction of hyperdynamic nonlethal sepsis (sepsis), with each animal crossing over to the other treatment after a 2-week interval. MEASUREMENTS AND MAIN RESULTS Injection of Escherichia coli induced nonlethal hyperdynamic sepsis within 5 to 6 h with hypotension (mean arterial pressure [+/- SD], 85 +/- 7 mm Hg vs 69 +/- 8 mm Hg), increased cardiac output (4.0 +/- 0.9 L/min vs 7.2 +/- 1.2 L/min), tachycardia (60 +/- 10 beats/min vs 160 +/- 15 beats/min), fever, oliguria, and tachypnea. Compared to control animals, hyperdynamic sepsis increased renal (330 +/- 101 mL/min vs 214 +/- 75 mL/min), mesenteric (773 +/- 370 mL/min vs 516 +/- 221 mL/min), and coronary (54 +/- 24 mL/min vs 23 +/- 10 mL/min) blood flow (p < 0.05). There was no significant change in sagittal sinus flow. Despite increased coronary flow, myocardial contractility decreased (800 +/- 150 L/min/s vs 990 +/- 150 L/min/s). Despite increased mesenteric and renal blood flow, there was hyperlactatemia (0.5 +/- 0.1 mmol/L vs 1.9 +/- 0.3 mmol/L); despite increased renal blood flow, all experimental animals acquired oliguria (160 +/- 75.3 mL/2 h vs 50.2 +/- 13.1 mL/2 h) and increased serum creatinine levels (0.07 +/- 0.02 mmol/L vs 0.11 +/- 0.02 mmol/L). CONCLUSIONS Injection of E coli induced hyperdynamic nonlethal sepsis. During such hyperdynamic sepsis, blood flow to heart, gut, and kidney was markedly increased; however, organ dysfunction developed. We speculate that global ischemia may not be the principal mechanism of vital organ dysfunction in hyperdynamic sepsis.

Haemodynamic influences on kidney oxygenation: clinical implications of integrative physiology

Renal blood flow, local tissue perfusion and blood oxygen content are the major determinants of oxygen delivery to kidney tissue. Arterial pressure and segmental vascular resistance influence kidney oxygen consumption through effects on glomerular filtration rate and sodium reabsorption. Diffusive shunting of oxygen from arteries to veins in the cortex and from descending to ascending vasa recta in the medulla limits oxygen delivery to renal tissue. Oxygen shunting depends on the vascular network, renal haemodynamics and kidney oxygen consumption. Consequently, the impact of changes in renal haemodynamics on tissue oxygenation cannot necessarily be predicted intuitively and, instead, requires the integrative approach offered by computational modelling and multiple measuring modalities. Tissue hypoxia is a hallmark of acute kidney injury (AKI) arising from multiple initiating insults, including ischaemia–reperfusion injury, radiocontrast administration, cardiopulmonary bypass surgery, shock and sepsis. Its pathophysiology is defined by inflammation and/or ischaemia resulting in alterations in renal tissue oxygenation, nitric oxide bioavailability and oxygen radical homeostasis. This sequence of events appears to cause renal microcirculatory dysfunction, which may then be exacerbated by the inappropriate use of therapies common in peri‐operative medicine, such as fluid resuscitation. The development of new ways to prevent and treat AKI requires an integrative approach that considers not just the molecular mechanisms underlying failure of filtration and tissue damage, but also the contribution of haemodynamic factors that determine kidney oxygenation. The development of bedside monitors allowing continuous surveillance of renal haemodynamics, oxygenation and function should facilitate better prevention, detection and treatment of AKI.

Urinary biomarkers in septic acute kidney injury

ObjectiveTo appraise the literature on the value of urinary biomarkers in septic acute kidney injury (AKI).DesignSystematic review.SettingAcademic medical centre.Patients and participantsHuman studies of urinary biomarkers.InterventionsNone.Measurements and resultsFourteen articles fulfilled inclusion criteria. Most studies were small, single-centre, and included mixed medical/surgical adult populations. Few focused solely on septic AKI and all had notable limitations. Retrieved articles included data on low-molecular-weight proteins (β2-microglobulin, α1-microglobulin, adenosine deaminase binding protein, retinol binding protein, cystatin C, renal tubular epithelial antigen-1), enzymes (N-acetyl-β-glucosaminidase, alanine-aminopeptidase, alkaline phosphatase; lactate dehydrogenase, α/π-glutathione-S-transferase, γ-glutamyl transpeptidase), cytokines [platelet activating factor (PAF), interleukin-18 (IL-18)] and other biomarkers [kidney injury molecule-1, Na/H exchanger isoform-3 (NHE3)]. Increased PAF, IL-18, and NHE3 were detected early in septic AKI and preceded overt kidney failure. Several additional biomarkers were evident early in AKI; however, their diagnostic value in sepsis remains unknown. In one study, IL-18 excretion was higher in septic than in non-septic AKI. IL-18 also predicted deterioration in kidney function, with increased values preceding clinically significant kidney failure by 24–48 h. Detection of cystatin C, α1-microglobulin, and IL-18 predicted need for renal replacement therapy (RRT).ConclusionsFew clinical studies of urinary biomarkers in AKI have included septic patients. However, there is promising evidence that selected biomarkers may aid in the early detection of AKI in sepsis and may have value for predicting subsequent deterioration in kidney function. Additional prospective studies are needed to accurately describe their diagnostic and prognostic value in septic AKI.

Vasoactive drugs and acute kidney injury.

The use of norepinephrine, and probably vasopressor therapy in general, in intensive care patients with hypotensive vasodilatation despite fluid resuscitation and evidence of acute kidney injury remains the subject of much debate and controversy. Although there is concern about the use of these drugs, these concerns are unfounded. At this time, the experimental and human data strongly suggest that, in these patients, vasopressor therapy is safe and probably beneficial from a renal, and probably general, point of view. On the basis of currently available evidence, in hypotensive vasodilated patients with acute kidney injury, restoration of blood pressure within autoregulatory values should occur promptly with noradrenaline and be sustained until such vasodilatation dissipates. The additional role of other vasopressors in these situations remains unclear. The addition of vasopressin may be helpful in individual patients, but widespread use is not supported by evidence. &agr;-Dose dopamine has no advantages over noradrenaline and is not as reliably effective in restoring blood pressure and urine output. Its widespread use cannot be supported in patients with vasodilatation and acute kidney injury. Other vasopressor drugs such as epinephrine and phenylephrine may be similar in efficacy to noradrenaline. However, experience and available data with their use is vastly less than with noradrenaline. Adrenaline, in addition, is associated with hyperglycemia, hyperlactatemia, acidosis, and hypokalemia. Terlipressin appears useful in patients with acute kidney injury secondary to hepatorenal syndrome. Whether it is superior to noradrenaline in this setting remains uncertain, and more studies are needed before recommendations can be made.

Intrarenal blood flow distribution in hyperdynamic septic shock: Effect of norepinephrine.

ObjectivesTo measure changes in medullary and cortical renal blood flow during experimental hyperdynamic sepsis and the effect of subsequent norepinephrine infusion on such flows. DesignExperimental animal study. SettingAnimal laboratory of university-affiliated physiology institute. SubjectsEighteen anesthetized merino sheep. InterventionsA transit-time flow probe was placed around the left renal artery. Laser Doppler flow probes were inserted in the left renal medulla and cortex by micromanipulation to measure changes in regional intrarenal blood flow. Measurements and Main ResultsSystemic pressures, cardiac output, renal, and intrarenal blood flows were measured continuously. A bolus of Escherichia coli (7.5 × 10 9 colony forming units) was given intravenously to induce hyperdynamic sepsis. After the onset of hyperdynamic sepsis, all animals were randomly allocated to either norepinephrine (0.4 &mgr;g·kg−1·min−1 for 30 mins) or observation for 30 mins in random order. E. coli injection induced a significant decrease in mean arterial pressure (102.2 ± 15.2 mm Hg to 74.3 ± 16.1 mm Hg, p < .05) and an increase in mean cardiac output (4.60 ± 1.62 L/min to 5.93 ± 1.18 L/min, p < .05). However, renal blood flow did not change significantly (326.4 ± 139.4 mL/min to 293.1 ± 117.5 mL/min, not significant) despite a 30% increase in renal conductance (3.27 ± 1.52 to 4.13 ± 2.01 mL·min−1·mm Hg−1, p < .05). Cortical blood flow decreased by 15% (not significant) and medullary flow by 5% (not significant) during sepsis, but individual changes were unpredictable. On the other hand, norepinephrine infusion caused a significant improvement in mean arterial pressure (74.3 ± 16.1 to 105.7 ± 17.7 mm Hg, p < .05) and a further increase in cardiac output (5.93 ± 1.18 to 7.13 ± 1.52 L/min, p < .05). Mean renal blood flow also increased (293.1 ± 117.5 to 384.5 ± 168.1 mL/min, p < .05) despite decreased renal conductance (4.13 ± 2.01 to 3.73 ± 1.91 mL·min−1·mm Hg−1, p < .05). Infusion of norepinephrine significantly increased medullary blood flow by 35% compared with baseline (p < .05) and by 54% compared with untreated sepsis (p < .05), whereas the increases in cortical blood flow (16 and 53%, respectively) were not significant. ConclusionsHyperdynamic sepsis caused renal vasodilation but had limited effects on regional intrarenal blood flow. Norepinephrine infusion (0.4 &mgr;g·kg−1·min−1) during sepsis significantly increased global and medullary renal blood flow and restored renal vascular tone toward but not above normal.

Cardiovascular actions of CRH and urocortin: an update.

Urocortin is a potent regulator of cardiac function, with actions that are prolonged in experimental animals. These changes are mediated via binding to CRH receptors found in peripheral tissues. The diversity of actions of urocortin on behaviour, appetite, inflammation and the cardiovascular system suggest that this peptide may be an endogenous factor mediating actions previously attributed to CRH. The present review will focus on the recent understanding of mechanisms mediating the cardiovascular actions of urocortin and CRH reported to date.