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Critical Care Clinics Apr 2021Sepsis-associated acute kidney injury (S-AKI) is a common and life-threatening complication in hospitalized and critically ill patients. It is characterized by rapid... (Review)
Review
Sepsis-associated acute kidney injury (S-AKI) is a common and life-threatening complication in hospitalized and critically ill patients. It is characterized by rapid deterioration of renal function associated with sepsis. The pathophysiology of S-AKI remains incompletely understood, so most therapies remain reactive and nonspecific. Possible pathogenic mechanisms to explain S-AKI include microcirculatory dysfunction, a dysregulated inflammatory response, and cellular metabolic reprogramming. In addition, several biomarkers have been developed in an attempt to improve diagnostic sensitivity and specificity of S-AKI. This article discusses the current understanding of S-AKI, recent advances in pathophysiology and biomarker development, and current preventive and therapeutic approaches.
Topics: Acute Kidney Injury; Biomarkers; Humans; Microcirculation; Renal Circulation; Sepsis
PubMed: 33752856
DOI: 10.1016/j.ccc.2020.11.010 -
Physiological Reviews Apr 2015Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) over a defined... (Review)
Review
Intrarenal autoregulatory mechanisms maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) over a defined range (80-180 mmHg). Such autoregulation is mediated largely by the myogenic and the macula densa-tubuloglomerular feedback (MD-TGF) responses that regulate preglomerular vasomotor tone primarily of the afferent arteriole. Differences in response times allow separation of these mechanisms in the time and frequency domains. Mechanotransduction initiating the myogenic response requires a sensing mechanism activated by stretch of vascular smooth muscle cells (VSMCs) and coupled to intracellular signaling pathways eliciting plasma membrane depolarization and a rise in cytosolic free calcium concentration ([Ca(2+)]i). Proposed mechanosensors include epithelial sodium channels (ENaC), integrins, and/or transient receptor potential (TRP) channels. Increased [Ca(2+)]i occurs predominantly by Ca(2+) influx through L-type voltage-operated Ca(2+) channels (VOCC). Increased [Ca(2+)]i activates inositol trisphosphate receptors (IP3R) and ryanodine receptors (RyR) to mobilize Ca(2+) from sarcoplasmic reticular stores. Myogenic vasoconstriction is sustained by increased Ca(2+) sensitivity, mediated by protein kinase C and Rho/Rho-kinase that favors a positive balance between myosin light-chain kinase and phosphatase. Increased RPP activates MD-TGF by transducing a signal of epithelial MD salt reabsorption to adjust afferent arteriolar vasoconstriction. A combination of vascular and tubular mechanisms, novel to the kidney, provides for high autoregulatory efficiency that maintains RBF and GFR, stabilizes sodium excretion, and buffers transmission of RPP to sensitive glomerular capillaries, thereby protecting against hypertensive barotrauma. A unique aspect of the myogenic response in the renal vasculature is modulation of its strength and speed by the MD-TGF and by a connecting tubule glomerular feedback (CT-GF) mechanism. Reactive oxygen species and nitric oxide are modulators of myogenic and MD-TGF mechanisms. Attenuated renal autoregulation contributes to renal damage in many, but not all, models of renal, diabetic, and hypertensive diseases. This review provides a summary of our current knowledge regarding underlying mechanisms enabling renal autoregulation in health and disease and methods used for its study.
Topics: Animals; Calcium Channels; Calcium Signaling; Diabetic Nephropathies; Glomerular Filtration Rate; Homeostasis; Humans; Hypertension; Kidney; Mechanotransduction, Cellular; Muscle, Smooth, Vascular; Renal Artery; Renal Circulation; Vasoconstriction
PubMed: 25834230
DOI: 10.1152/physrev.00042.2012 -
JACC. Cardiovascular Interventions Mar 2019Atherosclerotic renal artery stenosis is the leading cause of secondary hypertension and may lead to resistant (refractory) hypertension, progressive decline in renal... (Review)
Review
Atherosclerotic renal artery stenosis is the leading cause of secondary hypertension and may lead to resistant (refractory) hypertension, progressive decline in renal function, and cardiac destabilization syndromes (pulmonary edema, recurrent heart failure, or acute coronary syndromes) despite guideline-directed medical therapy. Although randomized controlled trials comparing medical therapy with medical therapy and renal artery stenting have failed to show a benefit for renal artery stenting, according to comparative effectiveness reviews by the Agency for Healthcare Research and Quality, the trials may not have enrolled patients with the most severe atherosclerotic renal artery stenosis, who would be more likely to benefit from renal stenting. Because of limitations of conventional angiography, it is critical that the hemodynamic severity of moderately severe (50% to 70%) atherosclerotic renal artery stenosis lesions be confirmed on hemodynamic measurement. The authors review techniques to optimize patient selection, to minimize procedural complications, and to facilitate durable patency of renal stenting. The authors also review the current American College of Cardiology and American Heart Association guidelines and the Society for Cardiovascular Angiography and Interventions appropriate use criteria as they relate to renal stenting.
Topics: Atherosclerosis; Clinical Decision-Making; Endovascular Procedures; Hemodynamics; Humans; Patient Selection; Renal Artery Obstruction; Renal Circulation; Risk Factors; Severity of Illness Index; Stents; Treatment Outcome; Vascular Patency
PubMed: 30898248
DOI: 10.1016/j.jcin.2018.10.023 -
Circulation Research May 2019Acute kidney injury (AKI) has a high prevalence and mortality in critically ill patients. It is also a powerful risk factor for heart failure incidence driven by...
RATIONALE
Acute kidney injury (AKI) has a high prevalence and mortality in critically ill patients. It is also a powerful risk factor for heart failure incidence driven by hemodynamic changes and neurohormonal activation. However, no drugs have been approved by the Food and Drug Administration. Endogenous pGC-A (particulate guanylyl cyclase A receptor) activators were reported to preserve renal function and improve mortality in AKI patients, although hypotension accompanied by pGC-A activators have limited their therapeutic potential.
OBJECTIVE
We investigated the therapeutic potential of a nonhypotensive pGC-A activator/designer natriuretic peptide, CRRL269, in a short-term, large animal model of ischemia-induced AKI and also investigated the potential of uCNP (urinary C-type natriuretic peptide) as a biomarker for AKI.
METHODS AND RESULTS
We first showed that CRRL269 stimulated cGMP generation, suppressed plasma angiotensin II, and reduced cardiac filling pressures without lowering blood pressure in the AKI canine model. We also demonstrated that CRRL269 preserved glomerular filtration rate, increased renal blood flow, and promoted diuresis and natriuresis. Further, CRRL269 reduced kidney injury and apoptosis as evidenced by ex vivo histology and tissue apoptosis analysis. We also showed, compared with native pGC-A activators, that CRRL269 is a more potent inhibitor of apoptosis in renal cells and induced less decreases in intracellular Ca concentration in vascular smooth muscle cells. The renal antiapoptotic effects were at least mediated by cGMP/PKG pathway. Further, CRRL269 inhibited proapoptotic genes expression using a polymerase chain reaction gene array. Additionally, we demonstrated that AKI increased uCNP levels.
CONCLUSIONS
Our study supports developing CRRL269 as a novel renocardiac protective agent for AKI treatment.
Topics: Acute Kidney Injury; Angiotensin II; Animals; Apoptosis; Biomarkers; Blood Pressure; Cyclic GMP; Diuresis; Dogs; Glomerular Filtration Rate; Male; Natriuresis; Natriuretic Peptide, C-Type; Natriuretic Peptides; Receptors, Atrial Natriuretic Factor; Renal Agents; Renal Circulation
PubMed: 30929579
DOI: 10.1161/CIRCRESAHA.118.314164 -
Journal of the American Society of... Aug 2015The transition of AKI to CKD has major clinical significance. As reviewed here, recent studies show that a subpopulation of dedifferentiated, proliferating tubules... (Review)
Review
The transition of AKI to CKD has major clinical significance. As reviewed here, recent studies show that a subpopulation of dedifferentiated, proliferating tubules recovering from AKI undergo pathologic growth arrest, fail to redifferentiate, and become atrophic. These abnormal tubules exhibit persistent, unregulated, and progressively increasing profibrotic signaling along multiple pathways. Paracrine products derived therefrom perturb normal interactions between peritubular capillary endothelium and pericyte-like fibroblasts, leading to myofibroblast transformation, proliferation, and fibrosis as well as capillary disintegration and rarefaction. Although signals from injured endothelium and inflammatory/immune cells also contribute, tubule injury alone is sufficient to produce the interstitial pathology required for fibrosis. Localized hypoxia produced by microvascular pathology may also prevent tubule recovery. However, fibrosis is not intrinsically progressive, and microvascular pathology develops strictly around damaged tubules; thus, additional deterioration of kidney structure after the transition of AKI to CKD requires new acute injury or other mechanisms of progression. Indeed, experiments using an acute-on-chronic injury model suggest that additional loss of parenchyma caused by failed repair of AKI in kidneys with prior renal mass reduction triggers hemodynamically mediated processes that damage glomeruli to cause progression. Continued investigation of these pathologic mechanisms should reveal options for preventing renal disease progression after AKI.
Topics: Acute Kidney Injury; Capillaries; Disease Progression; Humans; Hypoxia; Kidney Tubules; Nephrosclerosis; Renal Circulation; Renal Insufficiency, Chronic; Vasoconstriction
PubMed: 25810494
DOI: 10.1681/ASN.2015010006 -
Pflugers Archiv : European Journal of... Aug 2022Our kidneys receive about one-fifth of the cardiac output at rest and have a low oxygen extraction ratio, but may sustain, under some conditions, hypoxic injuries that... (Review)
Review
Our kidneys receive about one-fifth of the cardiac output at rest and have a low oxygen extraction ratio, but may sustain, under some conditions, hypoxic injuries that might lead to chronic kidney disease. This is due to large regional variations in renal blood flow and oxygenation, which are the prerequisite for some and the consequence of other kidney functions. The concurrent operation of these functions is reliant on a multitude of neuro-hormonal signaling cascades and feedback loops that also include the regulation of renal blood flow and tissue oxygenation. Starting with open questions on regulatory processes and disease mechanisms, we review herein the literature on renal blood flow and oxygenation. We assess the current understanding of renal blood flow regulation, reasons for disparities in oxygen delivery and consumption, and the consequences of disbalance between O delivery, consumption, and removal. We further consider methods for measuring and computing blood velocity, flow rate, oxygen partial pressure, and related parameters and point out how limitations of these methods constitute important hurdles in this area of research. We conclude that to obtain an integrated understanding of the relation between renal function and renal blood flow and oxygenation, combined experimental and computational modeling studies will be needed.
Topics: Humans; Hypoxia; Kidney; Oxygen; Oxygen Consumption; Renal Circulation
PubMed: 35438336
DOI: 10.1007/s00424-022-02690-y -
Physiological Research Jul 2020Proper renal blood flow (RBF) and glomerular filtration rate (GFR) are critical for maintaining normal blood pressure, kidney function and water and electrolyte... (Review)
Review
Proper renal blood flow (RBF) and glomerular filtration rate (GFR) are critical for maintaining normal blood pressure, kidney function and water and electrolyte homeostasis. The renal microvasculature expresses a multitude of receptors mediating vasodilation and vasoconstriction, which can influence glomerular blood flow and capillary pressure. Despite this, RBF and GFR remain quite stable when arterial pressure fluctuates because of the autoregulatory mechanism. ATP and adenosine participate in autoregulatory control of RBF and GFR via activation of two different purinoceptor families (P1 and P2). Purinoceptors are widely expressed in renal microvasculature and tubules. Emerging data show altered purinoceptor signaling in hypertension-associated kidney injury, diabetic nephropathy, sepsis, ischemia-reperfusion induced acute kidney injury and polycystic kidney disease. In this brief review, we highlight recent studies and new insights on purinoceptors regulating renal microvascular function and renal hemodynamics. We also address the mechanisms underlying renal microvascular injury and impaired renal autoregulation, focusing on purinoceptor signaling and hypertension-induced renal microvascular dysfunction. Interested readers are directed to several excellent and comprehensive reviews that recently covered the topics of renal autoregulation, and nucleotides in kidney function under physiological and pathophysiological conditions (Inscho 2009, Navar et al. 2008, Carlstrom et al. 2015, Vallon et al. 2020).
Topics: Animals; Glomerular Filtration Rate; Homeostasis; Humans; Hypertension; Kidney; Receptors, Purinergic; Renal Circulation
PubMed: 32301620
DOI: 10.33549/physiolres.934463 -
Seminars in Nephrology Mar 2015Endothelin (ET) is one of the most potent renal vasoconstrictors. Endothelin plays an essential role in the regulation of renal blood flow, glomerular filtration, sodium... (Review)
Review
Endothelin (ET) is one of the most potent renal vasoconstrictors. Endothelin plays an essential role in the regulation of renal blood flow, glomerular filtration, sodium and water transport, and acid-base balance. ET-1, ET-2, and ET-3 are the three distinct endothelin isoforms comprising the endothelin family. ET-1 is the major physiologically relevant peptide and exerts its biological activity through two G-protein-coupled receptors: ET(A) and ET(B). Both ET(A) and ET(B) are expressed by the renal vasculature. Although ET(A) are expressed mainly by vascular smooth muscle cells, ET(B) are expressed by both renal endothelial and vascular smooth muscle cells. Activation of the endothelin system, or overexpression of downstream endothelin signaling pathways, has been implicated in several pathophysiological conditions including hypertension, acute kidney injury, diabetic nephropathy, and immune nephritis. In this review, we focus on the effects of endothelin on the renal microvasculature, and update recent findings on endothelin in the regulation of renal hemodynamics.
Topics: Endothelins; Glomerular Filtration Rate; Humans; Microcirculation; Renal Circulation
PubMed: 25966346
DOI: 10.1016/j.semnephrol.2015.02.004 -
American Journal of Physiology. Renal... May 2019Tubuloglomerular feedback and the myogenic mechanism form an ensemble in renal afferent arterioles that regulate single-nephron blood flow and glomerular filtration.... (Review)
Review
Tubuloglomerular feedback and the myogenic mechanism form an ensemble in renal afferent arterioles that regulate single-nephron blood flow and glomerular filtration. Each mechanism generates a self-sustained oscillation, the mechanisms interact, and the oscillations synchronize. The synchronization generates a bimodal electrical signal in the arteriolar wall that propagates retrograde to a vascular node, where it meets similar electrical signals from other nephrons. Each signal carries information about the time-dependent behavior of the regulatory ensemble. The converging signals support synchronization of the nephrons participating in the information exchange, and the synchronization can lead to formation of nephron clusters. We review the experimental evidence and the theoretical implications of these interactions and consider additional interactions that can limit the size of nephron clusters. The architecture of the arterial tree figures prominently in these interactions.
Topics: Animals; Arterioles; Blood Flow Velocity; Glomerular Filtration Rate; Homeostasis; Humans; Kidney Glomerulus; Kidney Tubules; Models, Biological; Renal Circulation; Signal Transduction
PubMed: 30759020
DOI: 10.1152/ajprenal.00484.2018 -
Journal of the American Society of... Apr 2019
Topics: Hand Strength; Humans; Kidney Cortex; Magnetic Resonance Imaging; Perfusion; Renal Circulation
PubMed: 30760497
DOI: 10.1681/ASN.2019010049