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Fisiopatologia de la lra
- 1. LESIÓN RENAL AGUDA: FISIOPATOLOGÍA Dra. Laura Sofía García Lee R5 Nefrología Dr. Gerardo Guillermo CorpusJunio 2016
- 2. Agenda Fisiopatología del daño isquémico y tóxico Función normal / Isquémico / Isquémico + AINES Anormalidades hemodinámicas renales y sistémicas Hormonas vasoactivas en la NTA Papel del feedback-túbulo glomerular Adenosina Mecanismos de daño tubular Leucocitos y citocinas inflamatorias Mecanismos de daño mitocondrial
- 3. Agenda Necrosis y apoptosis Rol de las especies reactivas de oxígeno Lesión renal aguda en sepsis Epitelio renal en respuesta a sepsis Integración de mecanismos de daño tubular renal AKI + CKD como síndromes interconectados Conclusiones
- 4. Lesión renal aguda Isquémico Nefrotóxico Endotoxémico Falla orgánica múltiple Vascular Glomerular Tubular
- 5. Fisiopatología del daño isquémico y tóxico Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 6. Función normal del FG Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 7. Depleción de volumen Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 8. Depleción de volumen + AINES Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 9. Mecanismos de falla de filtración en LRA
- 10. Anormalidades hemodinámicas glomerulares y sistémicas Choque séptico Choque cardiogénico LRA establecida
- 11. Resistencias arteriolares, TFG y FPR: normal, choque y LRA
- 12. Causas de reducción del FPR
- 13. Hormonas vasoactivas en NTA Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 14. Sitios de mayor daño por NTA Alta actividad metabólica Mayor consumo de O2
- 15. Feedback tubuloglomerular Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 16. Hipótesis de la adenosina Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 17. Adenosina Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 18. Mecanismos de daño tubular Pérdida de polaridad Pérdida de borde en cepillo Redistribución de integrinas Redistribución de Na+/K+ATPasa apical Especies reactivas de oxígeno (ROS) Obstrucción tubular
- 19. Mecanismos de daño tubular Retrofiltración Pérdida de contacto celular Edema celular Pérdida de estructura de citoesqueleto Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 20. Leucocitos en LRA Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 21. Hypothetical schema of cellular events triggering apoptotic cell death. (FromKroemer et al. [25] Mecanismos de apoptosis celular ROS Ca+ intracelul ar Depleción ATP Depleción NAD/ NADH
- 22. Metabolismo mitocondrial y la cadena respiratoria Mitochondrial dysfunction in inherited renal disease and acute kidney injury, Nature Reviews, Vol 12,
- 23. Lesión mitocondrial y recuperación durante la LRA Mitochondrial dysfunction in inherited renal disease and acute kidney injury, Nature Reviews, Vol 12,
- 25. Necrosis vs Apoptosis Necrosis Toxicidad No requiere energia Edema celular y cariolisis Liberación de contenido celular causa inflamación. Estimulación Requiere energía Célula se encoge, picnosis y cariorrexis No se libera el contenido y los macrófagos fagocitan rápidamente.
- 26. Especies reactivas de oxígeno (ROS) Superoxido Peróxido de hidrógeno Ciclooxigenasas y lipooxigenasas Xantin oxidasa Citocromo p450 Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 27. ROL DE ESPECIES REACTIVAS DE OXIGENO EN LRA Generación de ROS y xantina oxidasa y aumento de la conversión de xantina deshidrogenasa a oxidasa Peroxidación lipídica (prevenida por scavengers de ROS, inhibidores de la xantina oxidasa o quelantes de hierro Tasa redox de glutatión es un parámetro de estrés oxidativo que disminuye durante la isquemia y aumenta con la reperfusión Dieta deficiente en selenio y vitamina E aumenta suceptibilidad de lesión
- 28. Fragmentación de DNA en apoptosis y necrosis Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 30. Organo Efecto Pulmón Infiltración celular (neutrófilos, cels T, macrófagos IL-6, activación TLR4 Corazón Apoptosis celular por TNF-a Fragmentación mitocondrial y apoptosis Infiltración de macrófagos por osteopontina Hipertrofia y fibrosis por actividad de angiotensina I Hígado Infiltración leucocitaria, estrés oxidativo y apoptosis de hepatocitos Alteración del citocromo p450 Intestino Producción de acidos grasos de cadena corta por microbiota Daño a otros órganos por citocinas inflamatorias
- 31. Lesión renal aguda en sepsis
- 32. Epitelio renal en respuesta inflamatoria Sepsis Combinación de activación inmunológica humoral y celular. Nod-like receptor RIG-I-Like receptor Seminars in Nephrology,Vol 35, No 1, January 2015, pp 85–95 Patrones moleculares asociados a da Patrones moleculares asociados a patóge
- 33. Alteración epitelial tubular renal Inhibición de ciclo celular en G1 Ciclina D-CDK4/6 inhibida Seminars in Nephrology,Vol 35, No 1, January 2015, pp 85–95
- 34. Desdiferenciación y rediferenciación en daño epitelial renal inducido por sepsis Seminars in Nephrology,Vol 35, No 1, January 2015, pp 85–95
- 35. Sushrut S. Waikar| Lakshman Gunaratnam| Joseph V. Bonventre. Pathophysiology of Acute Kidney Injury. Chapter 32.
- 37. Robert W. Schrier, Pathophisiology of ischemic renal failure. Atlas of diseases of the kidney.
- 38. N Engl J Med 2014;371:58-66. DOI: 10.1056/NEJMra1214243 AKI + CKD Síndromes interconectados
- 39. N Engl J Med 2014;371:58-66. DOI: 10.1056/NEJMra1214243
- 40. Conclusiones Diversas causas de disminución flujo renal. No siempre hay disminución en TFG. Daño mitocondrial adquirido, representa evento temprano durante la LRA. Daño tubular más importante. En sepsis, los mecanismos de daño activan respuesta inflamatoria: Pérdida de polaridad, daño microcirculatorio, estrés oxidativo, desdiferenciación – rediferenciación, fibrosis, reprioritización de energéticos, mitofagia, detención del ciclo celular y apoptosis.
Notas del editor
- cute renal failure (ARF) is a syndrome characterized by an abrupt and reversible kidney dysfunction. The spectrum of inciting factors is broad: from ischemic and nephrotoxic agents to a variety of endotoxemic states and syndrome of multiple organ failure. The pathophysiology of ARF includes vascular, glomerular and tubular dysfunction which, depending on the actual offending stimulus, vary in the severity and time of appearance. Hemodynamic compromise prevails in cases when noxious stimuli are related to hypotension and septicemia, leading to renal hypoperfusion with secondary tubular changes (described in Chapter 13). Nephrotoxic offenders usually result in primary tubular epithelial cell injury, though endothelial cell dysfunction can also occur, leading to the eventual cessation of glomerular filtration. This latter effect is a consequence of the combined action of tubular obstruction and activation of tubuloglomerular feedback mechanism. In the following pages we shall review the existing concepts on the phenomenology of ARF including the mechanisms of decreased renal perfusion and failure of glomerular filtration, vasoconstriction of renal arterioles, how formed elements gain access to the renal parenchyma, and what the sequelae are of such an invasion by primed leukocytes.
- Pathophysiology of ischemic and toxic acute renal failure (ARF). The severe reduction in glomerular filtration rate (GFR) associated with established ischemic or toxic renal injury is due to the combined effects of alterations in intrarenal hemodynamics and tubular injury. The hemodynamic alterations associated with ARF include afferent arteriolar constriction and mesangial contraction, both of which directly reduce GFR. Tubular injury reduces GFR by causing tubular obstruction and by allowing backleak of glomerular filtrate. Abnormalities in tubular reabsorption of solute may contribute to intrarenal vasoconstriction by activating the tubuloglomerular (TG) feedback system. GPF—glomerular plasmaflow; P—glomerular pressure; K f— glomerular ultrafiltration coefficient
- Prostacyclin is important in maintaining renal blood flow (RBF) and glomerular filtration rate (GFR) in “prerenal” states. A, When intravascular volume is normal, prostacyclin production in the endothelial cells of the kidney is low and prostacyclin plays little or no role in control of vascular tone. B, The reduction in absolute or “effective” arterial blood volume associated with all prerenal states leads to an increase in the circulating levels of a number of of vasoconstrictors, including angiotensin II, catecholamines, and vasopressin. The increase in vasoconstrictors stimulates phospholipase A2 and prostacyclin production in renal endothelial cells. This increase in prostacyclin production partially counteracts the effects of the circulating vasoconstrictors and plays a critical role in maintaining normal or nearly normal RBF and GFR in prerenal states. C, The effect of cycloxygenase inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) in prerenal states. Inhibition of prostacyclin production in the presence of intravascular volume depletion results in unopposed action of prevailing vasoconstrictors and results in severe intrarenal vascasoconstriction. NSAIDs can precipitate severe acute renal failure in these situations.
- Prostacyclin is important in maintaining renal blood flow (RBF) and glomerular filtration rate (GFR) in “prerenal” states. A, When intravascular volume is normal, prostacyclin production in the endothelial cells of the kidney is low and prostacyclin plays little or no role in control of vascular tone. B, The reduction in absolute or “effective” arterial blood volume associated with all prerenal states leads to an increase in the circulating levels of a number of of vasoconstrictors, including angiotensin II, catecholamines, and vasopressin. The increase in vasoconstrictors stimulates phospholipase A2 and prostacyclin production in renal endothelial cells. This increase in prostacyclin production partially counteracts the effects of the circulating vasoconstrictors and plays a critical role in maintaining normal or nearly normal RBF and GFR in prerenal states. C, The effect of cycloxygenase inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) in prerenal states. Inhibition of prostacyclin production in the presence of intravascular volume depletion results in unopposed action of prevailing vasoconstrictors and results in severe intrarenal vascasoconstriction. NSAIDs can precipitate severe acute renal failure in these situations.
- Prostacyclin is important in maintaining renal blood flow (RBF) and glomerular filtration rate (GFR) in “prerenal” states. A, When intravascular volume is normal, prostacyclin production in the endothelial cells of the kidney is low and prostacyclin plays little or no role in control of vascular tone. B, The reduction in absolute or “effective” arterial blood volume associated with all prerenal states leads to an increase in the circulating levels of a number of of vasoconstrictors, including angiotensin II, catecholamines, and vasopressin. The increase in vasoconstrictors stimulates phospholipase A2 and prostacyclin production in renal endothelial cells. This increase in prostacyclin production partially counteracts the effects of the circulating vasoconstrictors and plays a critical role in maintaining normal or nearly normal RBF and GFR in prerenal states. C, The effect of cycloxygenase inhibition with nonsteroidal anti-inflammatory drugs (NSAIDs) in prerenal states. Inhibition of prostacyclin production in the presence of intravascular volume depletion results in unopposed action of prevailing vasoconstrictors and results in severe intrarenal vascasoconstriction. NSAIDs can precipitate severe acute renal failure in these situations.
- Mechanisms of filtration failure in established AKI. Afferent vasoconstriction secondary to TGF activation causes low glomerular hydrostatic pressure whereas tubular and interstitial pressure is increased secondary to inflammatory responses, microvascular dysfunction, tubular obstruction, and failure to resorb filtered salt and water. Increased venous pressure contributes both to reduced renal perfusion and increased renal interstitial pressure
- Causes of reduced generalized or regional renal blood flow (RBF).Various pathophysiologic states and medications can contribute to the reduction of RBF, causing generalized or localized ischemia to the kidney leading to acute kidney injury. A partial list of contributors is shown here, pointing to ischemia as a common pathway in a variety of clinical states affecting the kidney. (Adapted from Bonventre JV, Yang L: Cellular pathophysiology of ischemic acute kidney injury, J Clin Invest121:4210, 2011.)
- Vasoactive hormones that may be responsible for the hemodynamic abnormalities in acute tubule necrosis (ATN). A persistent reduction in renal blood flow has been demonstrated in both animal models of acute renal failure (ARF) and in humans with ATN. The mechanisms responsible for the hemodynamic alterations in ARF involve an increase in the intrarenal activity of vasoconstrictors and a deficiency of important vasodilators. A number of vasoconstrictors have been implicated in the reduction in renal blood flow in ARF. The importance of individual vasoconstrictor hormones in ARF probably varies to some extent with the cause of the renal injury. A deficiency of vasodilators such as endotheliumderived nitric oxide (EDNO) and/or prostaglandin I2 (PGI 2 ) also contributes to the renal hypoperfusion associated with ARF. This imbalance in intrarenal vasoactive hormones favoring vasoconstriction causes persistent intrarenal hypoxia, thereby exacerbating tubular injury and protracting the course of ARF. The mesangium regulates single-nephron glomerular filtration rate (SNGFR) by altering the glomerular ultrafiltration coefficient (K f ). This schematic diagram demonstrates the anatomic relationship between glomerular capillary loops and the mesangium. The mesangium is surrounded by capillary loops. Mesangial cells (M) are specialized pericytes with contractile elements that can respond to vasoactive hormones. Contraction of mesangium can close and prevent perfusion of anatomically associated glomerular capillary loops. This decreases the surface area available for glomerular filtration and reduces the glomerular ultrafiltration coefficient.
- The S3 segment of the proximal tubule and the medullary thick ascending limb are particularly vulnerable to ischemic injury because of the combination of borderline oxygen supply and high metabolic demand
- The tubuloglomerular (TG) feedback mechanism. A, Normal TG feedback. In the normal kidney, the TG feedback mechanism is a sensitive device for the regulation of the single nephron glomerular filtration rate (SNGFR). Step 1: An increase in SNGFR increases the amount of sodium chloride (NaCl) delivered to the juxtaglomerular apparatus (JGA) of the nephron. Step 2: The resultant change in the composition of the filtrate is sensed by the macula densa cells and initiates activation of the JGA. Step 3: The JGA releases renin, which results in the local and systemic generation of angiotensin II. Step 4: Angiotensin II induces vasocontriction of the glomerular arterioles and contraction of the mesangial cells. These events return SNGFR back toward basal levels. B, TG feedback in ARF. Step 1: Ischemic or toxic injury to renal tubules leads to impaired reabsorption of NaCl by injured tubular segments proximal to the JGA. Step 2: The composition of the filtrate passing the macula densa is altered and activates the JGA. Step 3: Angiotensin II is released locally. Step 4: SNGFR is reduced below normal levels. It is likely that vasoconstrictors other than angiotensin II, as well as vasodilator hormones (such as PGI2 and nitric oxide) are also involved in modulating TG feedback. Abnormalities in these vasoactive hormones in ARF may contribute to alterations in TG feedback in ARF.
- Metabolic basis for the adenosine hypothesis. A, Osswald’s hypothesis on the role of adenosine in tubuloglomerular feedback. B, Adenosine metabolism: production and disposal via the salvage and degradation pathways. (A, Modified fromOsswald et al. [2]; with permission.)
- Following ischemia and reperfusion, morphological changes occur in the proximal tubules, including loss of polarity, loss of the brush border, and redistribution of integrins and Na+/K + -ATPase to the apical surface. Calcium and reactive oxygen species may also have a role in these morphological changes, in addition to subsequent cell death resulting from necrosis and apoptosis. Both viable and nonviable cells are shed into the tubular lumen, resulting in the formation of casts and luminal obstruction and contributing to the reduction in the GFR. Figure modified with permission from the New England Journal of Medicine
- Role of adhesion molecules in mediating leukocyte attachment to endothelium. A, The normal inflammatory response is mediated by the release of cytokines that induce leukocyte chemotaxis and activation. The initial interaction of leukocytes with endothelium is mediated by the selectins and their ligands both of which are present on leukocytes and endothelial cells Selectin-mediated leukocyte-endothelial interaction results in the rolling of leukocytes along the endothelium and facilitates the firm adhesion and immobilization of leukocytes. Immobilization of leukocytes to endothelium is mediated by the 2-integrin adhesion molecules on leukocytes and their ICAM ligands on endothelial cells. Immobilization of leukocytes is necessary for diapedesis of leukocytes between endothelial cells into parenchymal tissue. Leukocytes release proteases, elastases, and reactive oxygen radicals that induce tissue injury. Activated leukocytes also elaborate cytokines such as interleukin 1 and tumor necrosis factor which attract additional leukocytes to the site, causing further injury
- Mitochondrial energy metabolism and the respiratory chain Acetyl-coenzyme A (Acetyl-CoA) is the terminal product of carbohydrate and lipid metabolism, and is oxidized through the reactions of the Krebs cycle to produce CO 2 . The high energy electrons (e − ) produced by these reactions enter the respiratory chain and eventually reduce molecular oxygen (0 2) to form water (H 20). The energy released by this process is used to pump protons (H + ) across the mitochondrial inner membrane and generate the electrochemical gradient that enables complex V to synthesize ATP. The red ovals represent mitochondrial DNA-encoded subunits of the respiratory chain complexes. CoQ, coenzyme Q
- Mitochondrial injury and recovery during acute kidney injury (AKI). Tubular epithelial cells in the proximal tubule and outer medulla are heavily invested with mitochondria in order to generate the ATP necessary for solute transport. Diverse aetiologies of AKI injure the mitochondria, leading to organellar swelling and fragmentation. Injured mitochondria, in turn, release an array of proinflammatory and injurious molecules, such as reactive oxygen species (ROS), which, if unchecked, promote cell death. Experimental findings suggest that recovery from AKI might require the clearance of injured mitochondria through mitophagy and the replenishment of mitochondrial mass through mitochondrial biogenesis, a process mediated by the transcriptional co-activator peroxisome proliferator-activated receptor-γco-activator 1-α(PGC-1-α). Examples of potential preventive and therapeutic strategies are highlighted in pink boxes. mtDNA, mitochondrial DNA.
- Apoptosis and necrosis: two distinct morphologic forms of cell death. A, Necrosis. Cells undergoing necrosis become swollen and enlarged. The mitochondria become markedly abnormal. The main morphoplogic features of mitochondrial injury include swelling and flattening of the folds of the inner mitochondrial membrane (the christae). The cell plasma membrane loses its integrity and allows the escape of cytosolic contents including lyzosomal proteases that cause injury and inflammation of the surrounding tissues. B, Apoptosis. In contrast to necrosis, apoptosis is associated with a progressive decrease in cell size and maintenance of a functionally and structurally intact plasma membrane. The decrease in cell size is due to both a loss of cytosolic volume and a decrease in the size of the nucleus. The most characteristic and specific morphologic feature of apoptosis is condensation of nuclear chromatin. Initially the chromatin condenses against the nuclear membrane. Then the nuclear membrane disappears, and the condensed chromatin fragments into many pieces. The plasma membrane undergoes a process of “budding,” which progresses to fragmentation of the cell itself. Multiple plasma membrane–bound fragments of condensed DNA called apoptotic bodies are formed as a result of cell fragmentation. The apoptotic cells and apoptotic bodies are rapidly phagocytosed by neighboring epithelial cells as well as professional phagocytes such as macrophages. The rapid phagocytosis of apoptotic bodies with intact plasma membranes ensures that apoptosis does not cause any surrounding inflammatory reaction.
- Cellular sources of reactive oxygen species (ROS) defense systems from free radicals. Superoxide and hydrogen peroxide are produced during normal cellular metabolism. ROS are constantly being produced by the normal cell during a number of physiologic reactions. Mitochondrial respiration is an important source of superoxide production under normal conditions and can be increased during ischemia-reflow or gentamycininduced renal injury. A number of enzymes generate superoxide and hydrogen peroxide during their catalytic cycling. These include cycloxygenases and lipoxygenes that catalyze prostanoid and leukotriene synthesis. Some cells (such as leukocytes, endothelial cells, and vascular smooth muscle cells) have NADH/ or NADPH oxidase enzymes in the plasma membrane that are capable of generating superoxide. Xanthine oxidase, which converts hypoxathine to xanthine, has been implicated as an important source of ROS after ischemia-reperfusion injury. Cytochrome p450, which is bound to the membrane of the endoplasmic reticulum, can be increased by the presence of high concentrations of metabolites that are oxidized by this cytochrome or by injurious events that uncouple the activity of the p450. Finally, the oxidation of small molecules including free heme, thiols, hydroquinines, catecholamines, flavins, and tetrahydropterins, also contribute to intracellular superoxide production. (Adapted from[22]; with permission.
- DNA fragmentation in apoptosis vs necrosis. DNA is made up of nucleosomal units. Each nucleosome of DNA is about 200 base pairs in size and is surrounded by histones. Between nucleosomes are small stretches of DNA that are not surrounded by histones and are called linker regions. During apoptosis, early activation of endonuclease(s) causes double-strand breaks in DNA between nucleosomes. No fragmentation occurs in nucleosomes because the DNA is “protected” by the histones. Because of the size of nucleosomes, the DNA is fragmented during apoptosis into multiples of 200 base pair pieces (eg, 200, 400, 600, 800). When the DNA of apoptotic cells is electrophoresed, a characteristic ladder pattern is found. In contrast, necrosis is associated with the early release of lyzosomal proteases, which cause proteolysis of nuclear histones, leaving “naked” stretches of DNA not protected by histones. Activation of endonucleases during necrosis therefore cause DNA cleavage at multiple sites into double- and single-stranded DNA fragments of varying size. Electrophoresis of DNA from necrotic cells results in a smear pattern. Potential causes of apoptosis in acute renal failure (ARF). The same cytotoxic stimuli that induce necrosis cause apoptosis. The mechanism of cell death induced by a specific injury depends in large part on the severity of the injury. Because most cells require constant external signals, called survival signals, to remain viable, the loss of these survival signals can trigger apoptosis. In ARF, a deficiency of growth factors and loss of cell-substrate adhesion are potential causes of apoptosis. The death pathways induced by engagement of tumour necrosis factor (TNF) with the TNF receptor or Fas with its receptor (Fas ligand) are well known causes of apoptosis in immune cells. TNF and Fas can also induce apoptosis in epithelial cells and may contribute to cell death in ARF.
- Renal tubule epithelial cells and the inflammatory response. A major effector of sepsis-associated AKI is the RTEC. Sepsis induces an inflammatory response and generates systemic production of DAMPs, PAMPs, and cytokines exogenous to the kidney that can gain access to the tubular space through normal or altered glomerular filtration, or, alternatively, through the peritubular capillary by ill-defined interactions elicited through the endothelial and epithelial layers. These exogenous factors bind to pRRs such as TLRs, Nod-like receptors (NLRs), and RIG-I–like receptors (RLRs) in the RTECs, and endogenous DAMPs and cytokines from these cells are generated that also contribute to damage of downstream tubular epithelial cells. RTECs also can modulate the cellular component of the immune response; RTEC cytokine and chemokine production can attract and/or activate dendritic cells, neutrophils, and T lymphocytes. RTECS can express major histocompatibility complexes (MHCs), and they have been shown to interact directly with neutrophils, monocytes, and T cells, resulting in immune cell infiltration and additional tissue damage. This combination of humoral and cellular immune system activation contributes to RTEC damage directly as well as contributing to the exacerbation of other pathways described in this review. Illustration design was adapted from Gomez et al 8 and Bonventre and Yang.
- Renal tubule epithelial cell-cycle alterations in AKI. (A) In the healthy kidney, RTECs are differentiated, and the rate of cell turnover is very low because the vast majority of cells are in G0. However, during sepsis, DAMPs and PAMPs activate signaling pathways that generate very high rates of proliferation. However, as seen in multiple cell types when exposed to various insults, it also has been shown that during AKI, RTECs also enter a short period of G1cell-cycle arrest, presumably to allow the cell to prepare before dividing. It is hypothesized that injury and repair might be part of the same process, in which appropriate coordination and synchronization result in arrest and repair, and maladaptive repair results in apoptosis, fibrosis, and chronic kidney disease. (B) IGFBP7 and TIMP-2 recently were identified as superior early biomarkers for AKI, and both have been implicated in regulation of G1 cell-cycle arrest, leading to the hypothesis for a role of both in RTEC protection during AKI. Whether or not through increases in exogenous IGFBP7 and TIMP-2, or through up-regulation of IGFBP7 and TIMP-2 in RTECs, the expression/function of p21, p27, and p53 are up-regulated, which inhibits cyclin D–CDK4/6 and cyclin E–CDK2 complexes, leading to the arrest of cells in G1. Cyc, cyclin. Illustration design was adapted from Kashani et al 31 and Bonventre and Yang
- Dedifferentiation and redifferentiation of renal tubule epithelial cells in sepsis-induced AKI. Among the theories of how RTECs repair during and after AKI, the most prominent is the theory that resident surviving differentiated RTECs de-differentiate, proliferate, and re-differentiate back into functioning tubular epithelium. Normal RTECs are polarized and express specific apical and basolateral proteins, as well as tight junctions. During sepsis-induced AKI, RTECs can lose function as a result of loss of polarity and luminal villi/brush border, internalization/relocalization/down-regulation of cell surface proteins, and loss of tight junctions, and, subsequently, cells can die via apoptosis. However, some cells survive, and these cells can dedifferentiate, presumably to repair, and then proliferate, replacing the cells lost to apoptosis. These dedifferentiated cells then can redifferentiate and regain polarity, brush border, expression of cell surface proteins, and RTEC function. Illustration design adapted from Bonventre and Yan
- Bioenergetics and microcirculatory effects in RTECs during sepsis-induced AKI. The origins and processes involved in sepsis-induced AKI are multifaceted, which include the generation of DAMPs and PAMPs, the inflammatory response, humoral and cellular immune responses, perturbation of microvascular flow, oxidative stress, and bioenergetic disturbances and mitochondrial energy re-prioritization. The inflammatory response elicited by DAMPs and PAMPs activates pro- and anti-apoptotic pathways from PRRs such as TLRs that stimulate B-cell lymphoma (BCL) 2 family and caspase cascades, which modulate mitochondria and apoptosis. In addition, microcirculatory perturbations occur through immune cell adhesion and endothelial cell damage, which creates localized sluggish peritubular capillary flow that reduces oxygen and generates oxidative stress. These two separate systems have effects on the mitochondria that alter overall cellular energy balance by increasing reactive oxygen and nitrogen species and uncoupling respiration. As with both the cell-cycle and de-differentiation models mentioned earlier, at least two different outcomes are possible. If the coordination and synchronization of signals or any temporal aspect of the process is maladaptive, mitochondrial fragmentation can occur, resulting in cell death through apoptosis. Alternatively, if the signals are coordinated properly, mitochondria can reprioritize energy use for survival, and damaged mitochondria can enter mitophagy to further conserve energy, which may result in cell survival. Illustration design was adapted from Gomez et al 8 and Bonventre and Yang
- Therapeutic approaches, both experimental and in clinical use, to prevent and manage acute renal failure based on its pathogenetic mechanisms. ETR—ET receptor; GFR— glomerular filtration rate; HGF—hepatocyte growth factor 1; IGF-1—insulin-like growth factor 1; K f —glomerular ultrafiltration coefficient; NOS—nitric oxide synthase; PMN— polymorphonuclear leukocytes; RBF—renal blood flow; T4—thyroxine.
- The architecture of normal kidney tissue is compared with that of injured tissue after an episode of acute kidney injury. Injured tissue shows alteration of tissue architecture and cell structure, including changes in the brush border. A variety of pathologic processes are initiated in injured and regenerating cells, including premature cellcycle arrest, activation of myofibroblasts and fibrocytes, re cruitment of various infiltrating immune and bone mar row cells to the site of injury, vascular dropout, and fi brosis. The change in tissue architecture leads to altered anatomical relationships between structures and a tissue microenvironment that promotes additional fibrosis and vascular dropout. Specific subpopulations of cells such as macrophages and T cells, differentially recruited into injured kidney tissues, may determine whether organ responses are ameliorative or maladaptive. The factors mediating recruitment, the populations of cells in human tissues that will have different responses leading to differ ent longterm outcomes, and the interaction of recruited cells to determine outcomes are still incompletely under stood. The inset shows renal tubular epithelial cells after an episode of acute kidney injury. Representative examples from various experimental studies in animals are listed in the inset. The fate of the cell, as well as the microenvironment and organ, depends on the balance between the results of repair and regenerative pathways, including apoptosis, dedifferentiation, and proinflamma tory and antiinflammatory, epigenetic, and profibrotic changes. These processes may occur differentially in heterogeneous cell sets in the kidney microenvironment. Specific macrophage and Tcell subsets, as well as cer tain cytokines and immunoreactants, may be associated with either injury or repair. The chronic dysregulation of these factors over time and their net interactions are likely to determine the extent of fibrotic responses and organ function. BMP7 denotes bone morphogenetic protein 7, TGFβ transforming growth factor β, and Tregs regulatory T cells
- When sepsis occurs, PAMPS and DAMPS activate the inflammatory response, setting in motion the many processes that damage RTECs, including loss of polarity, microcirculation derangement and oxidative stress, differentiationredifferentiation or fibrosis, reprioritization of bioenergetics and mitophagy, cell-cycle arrest, and apoptosis.