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Clinical Science (London, England :... May 2021Preeclampsia is a hypertensive disorder of pregnancy effecting ∼5-8% of pregnancies in the United States, and ∼8 million pregnancies worldwide. Preeclampsia is... (Review)
Review
Preeclampsia is a hypertensive disorder of pregnancy effecting ∼5-8% of pregnancies in the United States, and ∼8 million pregnancies worldwide. Preeclampsia is clinically diagnosed after the 20th week of gestation and is characterized by new onset hypertension accompanied by proteinuria and/or thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral or visual symptoms. This broad definition emphasizes the heterogeneity of the clinical presentation of preeclampsia, but also underscores the role of the microvascular beds, specifically the renal, cerebral, and hepatic circulations, in the pathophysiology of the disease. While the diagnostic criteria for preeclampsia relies on the development of de novo hypertension and accompanying clinical symptoms after 20-week gestation, it is likely that subclinical dysfunction of the maternal microvascular beds occurs in parallel and may even precede the development of overt cardiovascular symptoms in these women. However, little is known about the physiology of the non-reproductive maternal microvascular beds during preeclampsia, and the mechanism(s) mediating microvascular dysfunction during preeclamptic pregnancy are largely unexplored in humans despite their integral role in the pathophysiology of the disease. Therefore, the purpose of this review is to provide a summary of the existing literature on maternal microvascular dysfunction during preeclamptic pregnancy by reviewing the functional evidence in humans, highlighting potential mechanisms, and providing recommendations for future work in this area.
Topics: Cerebrovascular Circulation; Endothelium, Vascular; Female; Glycocalyx; Humans; Microcirculation; Microvessels; Pre-Eclampsia; Pregnancy; Renal Circulation
PubMed: 33960392
DOI: 10.1042/CS20200894 -
Nephron 2017Acute kidney injury (AKI) continues to be a major therapeutic challenge. Despite significant advances made in cellular and molecular pathophysiology of AKI, major gaps... (Review)
Review
Acute kidney injury (AKI) continues to be a major therapeutic challenge. Despite significant advances made in cellular and molecular pathophysiology of AKI, major gaps in knowledge exist regarding the changes in renal hemodynamics and oxygenation in the early stages and through the continuum of AKI. Particular features of renal hemodynamics and oxygenation increase the susceptibility of the kidney to sustain injury due to oxygen demand-supply mismatch and also play an important role in the recovery and repair from AKI as well as the transition of AKI to chronic kidney disease. However, lack of well-established physiological biomarkers and noninvasive imaging techniques limit our understanding of the interactions between renal macro and microcirculation and tissue oxygenation in AKI. Advances in our ability to assess these parameters in preclinical and clinical AKI will enable the development of targeted therapeutics to improve clinical outcomes.
Topics: Acute Kidney Injury; Hemodynamics; Humans; Kidney; Oxygen Consumption; Renal Circulation
PubMed: 28614837
DOI: 10.1159/000477830 -
Journal of the American Society of... Jun 2021To perform their functions, the kidneys maintain stable blood perfusion in the face of fluctuations in systemic BP. This is done through autoregulation of blood flow by... (Review)
Review
To perform their functions, the kidneys maintain stable blood perfusion in the face of fluctuations in systemic BP. This is done through autoregulation of blood flow by the generic myogenic response and the kidney-specific tubuloglomerular feedback (TGF) mechanism. The central theme of this paper is that, to achieve autoregulation, nephrons do not work as single units to manage their individual blood flows, but rather communicate electrically over long distances to other nephrons the vascular tree. Accordingly, we define the nephrovascular unit (NVU) to be a structure consisting of the nephron, glomerulus, afferent arteriole, and efferent arteriole. We discuss features that require and enable distributed autoregulation mediated by TGF across the kidney. These features include the highly variable topology of the renal vasculature which creates variability in circulation and the potential for mismatch between tubular oxygen demand and delivery; the self-sustained oscillations in each NVU arising from the autoregulatory mechanisms; and the presence of extensive gap junctions formed by connexins and their properties that enable long-distance transmission of TGF signals. The existence of TGF synchronization across the renal microvascular network enables an understanding of how NVUs optimize oxygenation-perfusion matching while preventing transmission of high systemic pressure to the glomeruli, which could lead to progressive glomerular and vascular injury.
Topics: Animals; Arterioles; Blood Pressure; Connexins; Feedback, Physiological; Homeostasis; Humans; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Nephrons; Renal Circulation; Signal Transduction
PubMed: 33833078
DOI: 10.1681/ASN.2020040423 -
Current Opinion in Critical Care Dec 2016Sepsis is a common and frequently fatal condition in which mortality has been consistently linked to increasing organ dysfunction. For example, acute kidney injury (AKI)... (Review)
Review
PURPOSE OF REVIEW
Sepsis is a common and frequently fatal condition in which mortality has been consistently linked to increasing organ dysfunction. For example, acute kidney injury (AKI) occurs in 40-50% of septic patients and increases mortality six to eight-fold. However, the mechanisms by which sepsis causes organ dysfunction are not well understood and hence current therapy remains reactive and nonspecific.
RECENT FINDINGS
Recent studies have challenged the previous notion that organ dysfunction is solely secondary to hypoperfusion, by showing, for example, that AKI occurs in the setting of normal or increased renal blood flow; and that it is characterized not by acute tubular necrosis or apoptosis, but rather by heterogeneous areas of colocalized sluggish peritubular blood flow and tubular epithelial cell oxidative stress. Evidence has also shown that microvascular dysfunction, inflammation, and the metabolic response to inflammatory injury are fundamental pathophysiologic mechanisms that may explain the development of sepsis-induced AKI.
SUMMARY
The implications of these findings are significant because in the context of decades of negative clinical trials in the field, the recognition that other mechanisms are at play opens the possibility to better understand the processes of injury and repair, and provides an invaluable opportunity to design mechanism-targeted therapeutic interventions.
Topics: Acute Kidney Injury; Apoptosis; Biomarkers; Humans; Kidney; Renal Circulation; Sepsis
PubMed: 27661757
DOI: 10.1097/MCC.0000000000000356 -
American Journal of Physiology. Renal... Jun 2019Afferent arteriole (Af-Art) diameter regulates pressure and flow into the glomerulus, which are the main determinants of the glomerular filtration rate. Thus, Af-Art... (Review)
Review
Afferent arteriole (Af-Art) diameter regulates pressure and flow into the glomerulus, which are the main determinants of the glomerular filtration rate. Thus, Af-Art resistance is crucial for Na filtration. Af-Arts play a role as integrative centers, where systemic and local systems interact to determine the final degree of resistance. The tubule of a single nephron contacts an Af-Art of the same nephron at two locations: in the transition of the thick ascending limb to the distal tubule (macula densa) and again in the connecting tubule. These two sites are the anatomic basis of two intrinsic feedback mechanisms: tubule-glomerular feedback and connecting tubule-glomerular feedback. The cross communications between the tubules and Af-Arts integrate tubular Na and water processing with the hemodynamic conditions of the kidneys. Tubule-glomerular feedback provides negative feedback that tends to avoid salt loss, and connecting tubule-glomerular feedback provides positive feedback that favors salt excretion by modulating tubule-glomerular feedback (resetting it) and increasing glomerular filtration rate. These feedback mechanisms are also exposed to systemic modulators (hormones and the nervous system); however, they can work in isolated kidneys or nephrons. The exaggerated activation or absence of any of these mechanisms may lead to disequilibrium in salt and water homeostasis, especially in extreme conditions (e.g., high-salt diet/low-salt diet) and may be part of the pathogenesis of some diseases. In this review, we focus on molecular signaling, feedback interactions, and the physiological roles of these two feedback mechanisms.
Topics: Animals; Epithelial Sodium Channels; Feedback, Physiological; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney Glomerulus; Kidney Tubules; Renal Circulation; Sodium; Water-Electrolyte Balance; Water-Electrolyte Imbalance
PubMed: 30838873
DOI: 10.1152/ajprenal.00381.2018 -
Critical Care (London, England) Mar 2018The importance of personalized blood pressure management is well recognized. Because renal pressure-flow relationships may vary among patients, understanding how renal... (Review)
Review
The importance of personalized blood pressure management is well recognized. Because renal pressure-flow relationships may vary among patients, understanding how renal autoregulation may influence blood pressure control is essential. However, much remains uncertain regarding the determinants of renal autoregulation in circulatory shock, including the influence of comorbidities and the effects of vasopressor treatment. We review published studies on renal autoregulation relevant to the management of acutely ill patients with shock. We delineate the main signaling pathways of renal autoregulation, discuss how it can be assessed, and describe the renal autoregulatory alterations associated with chronic disease and with shock.
Topics: Animals; Blood Pressure; Disease Models, Animal; Dogs; Homeostasis; Kidney; Mice; Renal Circulation; Shock; Swine; Vasoconstrictor Agents
PubMed: 29566705
DOI: 10.1186/s13054-018-1962-8 -
Kidney360 May 2021This review outlines the available data from the work of our group on renal hemodynamics, function, and oxygenation in patients who are critically ill with acute renal... (Review)
Review
This review outlines the available data from the work of our group on renal hemodynamics, function, and oxygenation in patients who are critically ill with acute renal dysfunction, such as those with postoperative AKI, those in early clinical septic shock, in patients undergoing cardiac surgery with cardiopulmonary bypass, or in patients undergoing liver transplantation. We also provide information on renal hemodynamics, function, and oxygenation in patients with chronic renal impairment due to congestive heart failure. This review will argue that, for all of these groups of patients, the common denominator is that renal oxygenation is impaired due to a lower renal oxygen delivery or a pronounced increase in renal oxygen consumption.
Topics: Critical Illness; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney; Renal Circulation
PubMed: 35373068
DOI: 10.34067/KID.0007012020 -
British Journal of Anaesthesia Sep 2020
Topics: Betacoronavirus; Brain Diseases; COVID-19; Coronavirus Infections; Humans; Lung Diseases; Myocarditis; Pandemics; Pneumonia, Viral; Renal Circulation; SARS-CoV-2; Thromboembolism
PubMed: 32731958
DOI: 10.1016/j.bja.2020.06.013 -
The American Journal of Cardiology Dec 2019Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given... (Review)
Review
Sodium-glucose co-transporter 2 (SGLT2) inhibitors immediately reduce the glomerular filtration rate (GFR) in patients with type 2 diabetes mellitus. When given chronically, they confer benefit by markedly slowing the rate at which chronic kidney disease progresses and are the first agents to do so since the advent of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). Salutary effects on the kidney were first demonstrated in cardiovascular outcomes trials and have now emerged from trials enriched in subjects with type 2 diabetes mellitus and chronic kidney disease. A simple model that unifies the immediate and long-term effects of SGLT2 inhibitors on kidney function is based on the assumption that diabetic hyperfiltration puts the kidney at long-term risk and evidence that hyperfiltration is an immediate response to a reduced signal for tubuloglomerular feedback, which occurs to the extent that SGLT2 activity mediates a primary increase in sodium and fluid reabsorption by the proximal tubule. This model will likely continue to serve as a useful description accounting for the beneficial effect of SGLT2 inhibitors on the diabetic kidney, similar to the hemodynamic explanation for the benefit of ACEIs and ARBs. A more complex model will be required to incorporate positive interactions between SGLT2 and sodium-hydrogen exchanger 3 in the proximal tubule and between sodium-glucose co-transporter 1 (SGLT1) and nitric oxide synthase in the macula densa. The implication of these latter nuances for day-to-day clinical medicine remains to be determined.
Topics: Diabetes Mellitus, Type 2; Disease Progression; Glomerular Filtration Rate; Humans; Kidney; Kidney Tubules; Kidney Tubules, Distal; Kidney Tubules, Proximal; Nitric Oxide Synthase; Renal Circulation; Renal Insufficiency, Chronic; Sodium-Glucose Transporter 1; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sodium-Hydrogen Exchanger 3
PubMed: 31741437
DOI: 10.1016/j.amjcard.2019.10.027 -
Critical Care (London, England) Sep 2022Reduced renal perfusion has been implicated in the development of septic AKI. However, the relative contributions of macro- and microcirculatory blood flow and the... (Observational Study)
Observational Study
Decreased renal cortical perfusion, independent of changes in renal blood flow and sublingual microcirculatory impairment, is associated with the severity of acute kidney injury in patients with septic shock.
BACKGROUND
Reduced renal perfusion has been implicated in the development of septic AKI. However, the relative contributions of macro- and microcirculatory blood flow and the extent to which impaired perfusion is an intrinsic renal phenomenon or part of a wider systemic shock state remains unclear.
METHODS
Single-centre prospective longitudinal observational study was carried out. Assessments were made at Day 0, 1, 2 and 4 after ICU admission of renal cortical perfusion in 50 patients with septic shock and ten healthy volunteers using contrast-enhanced ultrasound (CEUS). Contemporaneous measurements were made using transthoracic echocardiography of cardiac output. Renal artery blood flow was calculated using velocity time integral and vessel diameter. Assessment of the sublingual microcirculation was made using handheld video microscopy. Patients were classified based on the degree of AKI: severe = KDIGO 3 v non-severe = KDIGO 0-2.
RESULTS
At study enrolment, patients with severe AKI (37/50) had prolonged CEUS mean transit time (mTT) (10.2 vs. 5.5 s, p < 0.05), and reduced wash-in rate (WiR) (409 vs. 1203 au, p < 0.05) and perfusion index (PI) (485 vs. 1758 au, p < 0.05); differences persisted throughout the entire study. Conversely, there were no differences in either cardiac index, renal blood flow or renal resistive index. Sublingual microcirculatory variables were not significantly different between groups at study enrolment or at any subsequent time point. Although lactate was higher in the severe AKI group at study enrolment, these differences did not persist, and there were no differences in either ScvO2 or ScvCO2-SaCO2 between groups. Patients with severe AKI received higher doses of noradrenaline (0.34 vs. 0.21mcg/kg/min, p < 0.05). Linear regression analysis showed no correlation between mTT and cardiac index (R-0.18) or microcirculatory flow index (R-0.16).
CONCLUSION
Renal cortical hypoperfusion is a persistent feature in critically ill septic patients who develop AKI and does not appear to be caused by reductions in macrovascular renal blood flow or cardiac output. Cortical hypoperfusion appears not be associated with changes in the sublingual microcirculation, raising the possibility of a specific renal pathogenesis that may be amenable to therapeutic intervention. Trial Registration Clinical Trials.gov NCT03713307 , 19 Oct 2018.
Topics: Acute Kidney Injury; Humans; Microcirculation; Perfusion; Prospective Studies; Renal Circulation; Shock, Septic
PubMed: 36050737
DOI: 10.1186/s13054-022-04134-6