sepsis and the kidney.pdf - SASSiT

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212 klenzak & himmelfarb Pathophysiology Tubular epithelium and acute tubular necrosis The clinical syndrome of ARF in the setting of critical illness, manifested by rising serum creatinine and decreasing urine output, results from injury to the tubular epithelial cells, or acute tubular necrosis (Fig. 1). Ischemic or toxic injury primarily affects this renal compartment, both because this area is most dependent on downstream blood flow, and these cells are highly metabolically active, engaged in solute and water transport. The tubular epithelial cells most vulnerable to ischemia line the S3 segment of the proximal tubule. Lethal injury to these cells (necrosis or apoptosis) leads to loss of cell adhesion to the tubular basement membrane and subsequent shedding into the lumen. The denuded cells appear in the urine intact as tubular epithelial cell casts, or they may degrade leading to excretion of granular casts, both of which are typically found in the urine of patients with acute tubular necrosis. Such casts may cause micro-obstruction to urine flow. The damaged tubular basement membrane may fill with cast material, cellular debris, and Tamm-Horsfall protein. Sublethal injury results in loss of the brush border, which is the site of much energyconsuming metabolic activity. The mechanisms of injury to tubular epithelial cells in sepsis are difficult to reproduce in the laboratory. Laboratory models of acute tubular necrosis have Pathophysiology of Ischemic Acute Renal Failure MICROVASCULAR Glomerular Medullary Vasoconstriction in response to: endothelin, adenosine, angiotensin II, thromboxane A2, leukotrienes, sympathetic nerve activity Vasodilation in response to: nitric oxide, PGE2, acetylcholine bradykinin Endothelial and vascular smooth muscle cell structural damage Leukocyte-Endothelial adhesion vascular obstruction, leukocyte activation, and inflammation O 2 Inflammatory and vasoactive mediators TUBULAR Cytoskeletal breakdown Loss of polarity Apoptosis and Necrosis Desquamation of viable and necrotic cells Tubular obstruction Backleak Fig. 1. Pathophysiology of ischemic acute renal failure. PGE2, prostaglandin E 2 .
sepsis and the kidney 213 relied on either ischemic or toxic injury to simulate ARF. More than ischemia or toxicity, however, is responsible for the cellular signaling to apoptosis in sepsis. In sepsis the loss of autoregulatory pathways, an imbalance between inflammation and anti-inflammatory cytokines, thrombosis and bleeding, vasodilation and vasoconstriction, oxidation and reduction, catabolic and anabolic activity, and dysregulation of enzyme activity all contribute to organ dysfunction through mechanisms not yet fully elucidated. It is in this pathologic milieu that kidney function deteriorates in sepsis, which further adds the stress of fluid and electrolyte imbalance, waste clearance, and platelet dysfunction. Alterations in renal blood flow Intrarenal hemodynamic changes Systemic hypotension leads to autoregulation of local hemodynamics within the kidney. Afferent arteriolar vasoconstriction decreases capillary hydrostatic pressure and limits the perfusion of capillary beds. Impaired perfusion of capillary beds reduces filtration surface and leads to some reabsorption of interstitial fluid into the capillaries, as long as intravascular oncotic pressure remains constant or increases. Additionally, metabolic activity and waste products increase extracellular osmolality leading to fluid extravasation from cells. For these reasons, intravascular and interstitial volume increase at the expense of intracellular volume. In the kidney, constriction of the afferent arterioles decreases glomerular perfusion. With less glomerular perfusion, less filtrate is generated. Micropuncture studies show that endotoxin decreases filtration rate and glomerular flow with increased renal arteriolar resistance [3]. This compensatory response may be somewhat protective in that it leads to less ATP-requiring work from the highly metabolically active tubular epithelial cells. Downstream of the glomerular capillary bed, decreased blood flow to the efferent arteriole reduces perfusion of the vasa recta. The vasa recta supply nutrients and oxygen, and serve as a conduit for the return of fluid and electrolytes to the systemic circulation from the relatively hypoxic medulla. The S3 segment of the proximal tubule, or pars recta, is highly active and ATP-requiring. This segment is sensitive to alterations in blood flow because it depends on the deoxygenated blood of this microcirculation for its oxygen supply. For this reason, it is usually the first tubular segment to be injured from decreases in renal blood flow (RBF) or hypoxemia [4,5]. Hypoxemia or decreased RBF is likely one of many mechanisms of renal injury in the setting of sepsis. It has also been suggested that renal ischemia related to decreased renal perfusion is not the main mechanism of ARF in sepsis. Animal models have shown increases in renal perfusion in the setting of hyperdynamic shock. ARF can occur in the setting of preserved or increased RBF
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