907 74 Glomerulotubular Dysfunction and Acute Kidney Injury TIMOTHY E BUNCHMAN, VU NGUYEN, AND MICHELLE L OLSON • Acute kidney injury (AKI) has replaced the term acute kidney failure There are more th[.]
74 Glomerulotubular Dysfunction and Acute Kidney Injury TIMOTHY E BUNCHMAN, VU NGUYEN, AND MICHELLE L OLSON • Acute kidney injury (AKI) is a frequent problem in the pediatric intensive care unit (PICU), but an accurate incidence is difficult to establish owing to the ongoing evolution of a clear definition of renal failure The classic definition was a 50% reduction of glomerular filtration rate (GFR) accompanied by a 50% increase in creatinine A Risk, Injury, Failure, Loss, End stage renal disease (RIFLE) classification of renal injury to allow earlier appreciation of renal dysfunction is now used in adults and a modification of this system, pediatric RIFLE (pRIFLE), can also be applied to children (Table 74.1)1–3 However, use of serum creatinine level in the diagnostic criteria is problematic for several reasons, including variability of creatinine based on muscle mass and a delay in the rise of creatinine after kidney injury Early detection of renal dysfunction by biomarkers is needed to allow a more timely awareness of injury and thereby allow modifications to alleviate the renal stress Investigations in this area, although early in their development, postulate that a panel approach (plasma panel of neutrophil gelatinase-associated lipocalin [NGAL] and cystatin C or a urine panel of NGAL, interleukin 18 [IL-18], and kidney injury molecule-1) may be of help in the future to provide more sensitive and specific detection of early AKI.4–6 • • • Acute kidney injury (AKI) has replaced the term acute kidney failure There are more than 30 definitions of AKI in children Use of the pediatric Risk, Injury, Failure, Loss, End stage renal disease (pRIFLE), Acute Kidney Injury Network (AKIN), or Kidney Disease Improving Global Outcomes (KDIGO) scores for AKI may help streamline the definition In the future, biomarkers may add clarity to this definition at an earlier time frame than when they are presently used In the critically ill child, AKI is often associated with cardiovascular instability, which, if prolonged, exhausts the normal kidney compensatory responses to maintain kidney blood flow and glomerular filtration • PEARLS Because tubular blood flow—and thus oxygen delivery to this vital epithelium—depends on postglomerular blood flow, prolonged vasoconstriction of glomerular arterioles results in tubular necrosis Nephrotoxic drugs, sepsis, and overzealous use of diuretics are common comorbid conditions that further contribute to AKI Attention to cardiovascular status and the avoidance of unnecessary nephrotoxic agents—such as aminoglycosides, nonsteroidal antiinflammatory drugs, and contrast agents—may avoid further AKI Physiology of Glomerular Filtration Normal renal physiology and response of the kidney during stress are detailed in Chapter 70 and summarized at ExpertConsult.com Pathogenesis of Reduced Glomerular Filtration Rate in Acute Kidney Injury AKI may be viewed as an evolving process through three phases: (1) an initiation phase in which the primary mechanism of injury is operational, (2) a maintenance phase during which renal function remains poor and other factors may contribute to sustained injury, and (3) a recovery phase during which there is regeneration of cells and restoration of function Although the primary initiating event may be hypoperfusion with ischemia, often it involves multiple contributing factors that mediate additional cellular damage, usually through alterations in energy supply From a clinical perspective, it may be most helpful to consider acute renal dysfunction syndromes according to the cause of the inciting event However, it is equally vital to understand the other contributing mechanisms that ultimately affect outcome The mechanisms responsible for GFR reduction in acute renal injury have been studied extensively with experimental models of 907 907.e1 Normal Renal Physiology and Response of the Kidney During Stress The kidneys are responsible for plasma water and electrolyte balance through filtration at the glomerular membrane followed by reabsorption of this filtrate from the renal tubular epithelium The loss of filtration and tubular reabsorption in AKI is the result of renal adaptive changes that initially function to preserve renal perfusion and glomerular filtration However, when these are exhausted, the kidney’s compensatory mechanisms fail and renal dysfunction ensues The GFR is the product of the filtration rate of the individual nephron and the number of functioning nephrons A singlenephron glomerular filtration rate (SNGFR) is defined by the Starling forces of the glomerular capillaries and the properties of the glomerular capillary wall, SNGFR Kf ( P ) KfPuf where Kf is a capillary wall property known as the ultrafiltration coefficient and is the product of the surface area available for filtration and the hydraulic conductivity of the membrane The Starling forces (or pressures) that affect filtration are the hydraulic pressure in the glomerular capillary (Pgc), the hydraulic pressure in the Bowman space (Pbs), the oncotic pressure of the glomerular capillary (πgc), and the oncotic pressure in the Bowman space (πbs), which is usually zero because the ultrafiltrate is essentially protein free Pgc favors filtration; Pbs and πgc are opposing forces to filtration The mean ultrafiltration pressure (Puf ) is the difference between the net change in hydraulic pressure and the net change in the oncotic pressure Thus, SNGFR may be modified by alterations in the glomerular capillary pressures, glomerular membrane characteristics, or the surface area available for filtration The GFR depends on adequate renal perfusion; the kidneys receive approximately 25% of total cardiac output The fraction of cardiac output perfusing the kidneys is related to the ratio of renal vascular resistance (RVR) and systemic vascular resistance Renal blood flow (RBF) is determined by systemic blood pressure (SBP) and RVR, expressed by the formula RBF SBP/RVR.3 Kidney autoregulation, which maintains a constant renal perfusion pressure, occurs through alterations in RVR in response to changes in systemic vascular resistance or intravascular volume When SBP is within the normal physiologic or autoregulatory range, the kidney can maintain constant blood flow and GFR by dilation of the preglomerular or afferent arteriole, which reduces RVR and increases RBF This afferent arteriole dilation is accomplished by two known mechanisms: smooth muscle relaxation of the afferent arteriole in response to sensing a transmural pressure drop (the myogenic reflex) and the tubuloglomerular feedback system The tubuloglomerular feedback system is operational following a reduction of plasma flow When solute and water deliveries to the macula densa are reduced, the juxtaglomerular apparatus responds by relaxing the smooth muscle of the adjacent afferent arteriole Thus, a reduction in cardiac output or effective renal plasma flow is accompanied by vasodilation at the preglomerular arteriole This, in turn, reduces RVR, thereby restoring RBF During states of sustained reduced cardiac output or intravascular volume depletion, the systemic vasoconstrictors, angiotensin II and vasopressin, are released systemically to help preserve vascular tone The kidney counteracts the renal vasoconstrictor activity of angiotensin II and increased sympathetic tone through the intrarenal production of vasodilatory prostaglandins, such as prostaglandin I2.7 These locally produced substances may attenuate renal vasoconstrictive forces and help preserve renal perfusion Animal models of congestive heart failure have provided evidence that enhanced prostaglandin synthesis is required for preservation of renal perfusion and GFR Patients receiving prostaglandin synthetase inhibitors, such as nonsteroidal antiinflammatory drugs, have potentiation of renal ischemia because of an increase in renal vasoconstriction not antagonized by intrarenal prostaglandin synthesis.8 The vasodilatory endothelium-derived relaxation factors, and potent vasoconstrictor endothelin, produced by the endothelium, may also affect regional vascular tone.9 Constriction of the postglomerular capillary sphincter, the efferent arteriole, in the face of reduced RBF increases the filtration fraction and preserves the GFR, although this occurs at the expense of renal plasma flow, which may be further reduced Vasoconstriction at the efferent arteriole is mediated by angiotensin II and, to a lesser extent, by the action of the adrenergic system by epinephrine.10 Elevation in postglomerular arteriolar resistance may be blocked by the angiotensin-converting enzyme (ACE) inhibitors When converting enzyme inhibitors are administered to the patient who requires efferent arteriolar constriction to maintain the GFR, renal decompensation often results.11 As previously noted, reductions in effective intravascular volume and cardiac output are accompanied by increased activity of the sympathetic nervous system and renin-angiotensin-aldosterone system and increased circulating levels of vasopressin (see also Chapter 80).12 Hormonal and neural systems signal the kidneys to increase the reabsorption of sodium and water to help restore the deficient intravascular volume, increase cardiac output, and, consequently, improve RBF These and the kidney’s own homeostatic mechanism of afferent arteriolar vasodilation and efferent arteriolar constriction, maintain the kidney’s glomerular filtration The kidney’s homeostatic mechanisms, however, are not without limitation The autoregulatory ability of the afferent arteriole is maximal once the mean SBP falls below 80 mm Hg in the adult kidney The renal autoregulatory range appears to be age dependent, because younger animals can autoregulate over lower pressure ranges The range of perfusion pressure over which the kidney can autoregulate may be limited in certain conditions so that vasodilation is maximal, with a minor reduction in mean arterial blood pressure Examples include extracellular fluid depletion, renal ischemia, or renal vascular disease (e.g., hypertension, diabetes, and atherosclerosis) As the stimulus for release of vasoconstrictors continues, afferent arteriolar constriction rather than vasodilation may predominate The result is a decrease in renal plasma flow and filtration rate Constriction of the afferent arteriole may be stimulated by increased sympathetic nervous system activity and increased levels of endogenous or exogenous circulating catecholamines, such as dopamine or norepinephrine Thus, the administration of these vasoactive-inotropic agents may actually compromise the kidney’s adaptive mechanisms Excessive vasoconstriction eventually results in diminished filtration rate and oxygen delivery to the kidney Pharmacologic agents may alter renal perfusion by changing SBP through an action on systemic vasculature or by direct effects on renal vasculature (eBox 74.1) Vasodilators, such as hydralazine, lower SBP without changing renal perfusion pressure because the decrease in SBP is accompanied by decreased RVR Conversely, epinephrine increases SBP but decreases RBF by its vasoconstrictor effect on intrarenal blood vessels 907.e2 • eBOX 74.1 Vasoactive Substances in the Kidney Vasculature H Kidney Vascular Resistance/d Kidney Blood Flow • • • • • Epinephrine Norepinephrine Angiotensin II Arachidonic acid Thromboxane A2 d Kidney Vascular Resistance/H Kidney Blood Flow • • • • • • • • Prostaglandin E1 Prostaglandin E2 Dopamine Furosemide Angiotensin-converting enzyme inhibitors Bradykinin Isoproterenol Acetylcholine 908 S E C T I O N V I I Pediatric Critical Care: Renal TABLE pRIFLE Classification 74.1 pRIFLE Estimated Creatinine Clearance Urine Output Risk 25% decrease ,0.5 mL/kg/h for h Injury 50% decrease ,0.5 mL/kg/h for 16 h Failure 75% decrease ,0.3 mL/kg/h for 24 h or anuric for 12 h Loss Persistent failure wk End-stage Persistent failure mo renal disease pRIFLE, Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease score AKI Multiple mechanisms are often operational in mediating hypofiltration Whereas one factor may have greater importance in the initiation of injury and decreased filtration, others are involved in the sustained reduction in GFR during the maintenance phase of AKI Four major mechanisms result in reduced GFR during AKI: reduced blood flow, decreased Kf (ultrafiltration rate), tubular obstruction, and back leakage of tubular fluid Each factor is discussed regarding its role in both the initiation and maintenance phases of AKI A reduction in renal blood flow (RBF) can be demonstrated during the initiation phase of many forms of AKI and seems to play a predominant role in ischemic injury and rhabdomyolysis Proposed theories for the reduction of RBF include (1) a proportional increase in the afferent and efferent arteriolar resistances in response to activation of the renin-angiotensin system; (2) vascular endothelial cell swelling and damage with release of vasoactive peptides, such as endothelin; and (3) hyperemic congestion of the medullary peritubular capillaries Kf may be reduced in both nephrotoxic and ischemic forms of renal failure Endothelial or mesangial cell swelling during the initiation phase reduces the surface area available for filtration Additionally, altered permeability induced by humoral factors such as angiotensin II and vasopressin may also decrease Kf Both hormones have increased circulating levels during AKI This reduction in Kf contributes to the maintenance phase of AKI Renal tubular cell injury contributes to both obstruction of the lumen and destruction of the epithelial integrity contributing to back leakage of fluid The renal tubular cells are the primary site of injury in both ischemia and nephrotoxin-induced renal injury Once this injury occurs, cells will either undergo necrosis or apoptosis, subsequentially detaching from the supporting basement membrane or obstructing the tubule lumen Even sublethal injury can disrupt tight junctions, causing a loss of epithelial integrity and allowing back leakage of ultrafiltrate, which contains creatinine and urea This creates further diminution of excretory function and reduced urine formation, eventually contributing to the filtration failure of the entire nephron unit Intratubular obstruction occurs in most forms of acute renal injury, either as a contributing factor in the initiation phase or during the maintenance phase In the case of nephrotoxic injury, the degree of injury may determine the extent of tubular obstruction In an experimental model of gentamicin nephrotoxicity, the drug dose was positively correlated with the contribution of tubular obstruction to reduced GFR.13 Excretion of solute and fluid is decreased; this decrease possibly signals a further reduction in the GFR by stimulation of the tubuloglomerular feedback mechanism Back leakage of fluid involves tubular factors and is not a result of hypofiltration, although it does impair the excretory function of the kidney Consequently, a falsely low estimation of actual GFR may occur because tubular fluid containing urea and creatinine leaks back into the vascular space and interstitium Prevention of the tubular obstruction may alter the course of renal failure even in those states in which the primary mechanism of injury is not obstruction Endothelial injury and vascular dysfunction have been postulated to occur during the initiation and particularly during the maintenance phases of AKI Although most studies have focused on the tubular cell as the primary site of injury leading to dysfunction, studies have provided insight into the potential role for endothelial injury in continued reduced RBF and altered vascular function.13 Sutton and colleagues proposed that an additional phase be added to the current model for AKI: After the initiation phase, an extension phase occurs that is due to microvascular injury related to ischemic damage to endothelial cells, infiltration of leukocytes, and activation of the coagulation system This process is thought to predominate in the corticomedullary and outer medullary microvessels and may occur in the face of early tubular cell regeneration so that limiting the extension process provides a potential mechanism for aiding recovery Morphologic Changes in Renal Injury Morphologic changes seen in acute renal injury, especially those in the tubules, depend on the duration of injury as well as the eliciting mechanism The kidney’s complex structure—with heterogeneous segments receiving differential regional perfusion and, thereby, oxygenation—predisposes some regions to be at greater risk of injury The tubulointerstitium is at greatest risk for ischemia because of its gradient of regional perfusion and oxygenation In addition, vascular disease, including glomerular disease, often occurs in children and results in AKI, but there are studies suggesting that the extent of damage to the tubulointerstitium has the greatest prognostic implication for the degree of final renal recovery Initial structural changes in tubular cells are seen as apical and basal surface changes of simplification, with microvilli of the brush border shortening and disappearing by either detachment from the apical surface or being internalized within the tubular cells.14 In this scenario, enzymes of the brush border (alkaline phosphatase and g-glutamyl transpeptidase) may be found in the urine and may be used as markers of early tubular injury.15 The loss of microvilli surface area leads to loss of enzymes and transport sites for transcellular absorption and apical uptake Additionally, loss at the basolateral interdigitating infoldings of the tubular cells then results in further reduction of surface area for transport and loss of the sodium-potassium adenosine triphosphatase (Na1/K1ATPase) that is localized to this membrane and involved in many transport processes Morphologic changes in distal tubules and outer medulla also occur and may be found even when proximal tubular injury is not readily identified on biopsy Experimentally, the outer medulla has been identified as sensitive to hypoxia, including that induced by toxins such as radiocontrast agents and cyclosporine CHAPTER 74 Glomerulotubular Dysfunction and Acute Kidney Injury Injury at this outer medulla region may be missed on biopsy since this site often is not sampled Tubular cell detachment with exposed, denuded regions of the basement membrane can be found on biopsies as a result of altered cell-matrix attachments.16 Renal tubular sensitivity to ischemic injury is primarily influenced by the individual renal cell’s energy requirements, its glycolytic capacity, and the extent of hypoxic stress on the cell Glycolysis and oxidative phosphorylation both supply the adenosine triphosphate (ATP) required by the cell to drive its metabolism It follows that cells with a greater capacity for glycolysis (distal tubular cells) are less sensitive to oxygen deprivation than the cells that rely mainly on mitochondrial-derived energy (proximal tubular cells) In vivo and in vitro studies may be discordant in identifying susceptibility to hypoxia Medullary straight portions of the proximal tubule have a higher glycolytic capacity than the cortical segments of the proximal tubule However, due to the regional distribution of perfusion within the kidney, the medullary portions operate in a lower oxygen-tension environment and therefore are more susceptible to hypoxia/ischemic injury.17 The individual cell’s energy requirements to conduct its transport activities further influence its risk to hypoxic injury The outer medullary proximal tubular cell (pars recta), due to the highenergy requirements for its transport functions, has a greater injury risk than the deep inner medullary tubular cell with its low-oxygen and low-energy requirement to maintain its transport function When energy stores are rapidly depleted, the normal Na1/K1ATPase pump begins to fail, and the most basic of cell functions, membrane integrity, is jeopardized, with resultant accumulation of Na1, chloride (Cl2), and water within the cell This cell swelling (oncosis) is a hallmark feature of necrosis.18 Not all cells that fail to maintain their energy requirements die through necrosis Apoptosis, which appears morphologically as cell shrinkage, is also a result of inadequate energy support Apoptosis is an asynchronous cell death triggered over hours to days, with the earliest cellular element involving mitochondrial changes, including loss of transmembrane potential and release of mitochondrial cytochrome C into the cytosol (see also Chapter 83) It is mitochondrial function/dysfunction that primarily determines the fate of the cell for recovery and survival or death and by what form: apoptosis or necrosis.19 Mechanisms of Renal Cell Injury The renal tubular cell expends energy in the form of ATP to maintain a high intracellular concentration of potassium and a low intracellular concentration of sodium This concentration gradient depends on the continuous activity of the Na1/K1-ATPase and is the driving force for the reabsorption of sodium Active reabsorption of sodium is the primary driving force for water reabsorption and the coupled transport of amino acids, carbohydrates, organic acids, and other compounds Thus, all transport functions, as well as many other vital cell functions, depend on normal activity of the Na1/K1 pump, which, in turn, depends on an adequate supply of energy In addition, membrane fluidity, or integrity, is important to transport functions in tubular cells Processes that result in alterations in the membrane or in the supply of energy are common final pathways for renal tubular cell death A decrease in cellular ATP content occurs in many forms of renal injury, possibly as the result of primary alterations in the cell’s ability to perform oxidative phosphorylation or as the end 909 result of other perturbations Heterogeneity exists in the susceptibility of nephron segments to oxygen deprivation with more distal segments being relatively resistant This is related to the greater glycolytic capacity of the distal tubule compared with the proximal tubule, which relies on oxygen-consuming pathways for ATP generation Therefore, the net result of renal injury is usually a depletion of energy in the form of ATP, with the inability of the cell to perform vital functions, including transport and maintenance of cell integrity Cellular injury may be modified by the requirements made on its energy stores If more transport is required of the cell, more energy is consumed and less energy is left for cell maintenance Evidence exists to support this theory If transport requirements are reduced by the administration of diuretics or by the stimulation of the glomerulotubular feedback mechanism, then further injury may be attenuated The feedback mechanism, whereby there is reduction of the GFR in the face of reduced reabsorption by the proximal tubule, is a protective signal that conserves cell energy by reducing metabolic demands made on the cell Heat shock proteins (HSPs) are a family of proteins that appear to protect cells from injury as a result of hyperthermia, ischemia, or toxins HSP induction by sublethal thermal stress has been found to attenuate subsequent injury in the kidney.20 Renal transplants from animals that underwent short-term hyperthermia had better initial function and subsequent survival Furthermore, in cultured inner medullary collecting-duct cells, induction of HSP-1 by preconditioning hyperthermia attenuated the alterations in mitochondrial function and glycolysis that were observed after cells were exposed to high temperatures Investigations into potential mechanisms to use this natural cell defense mechanism are underway The ability of renal tubular epithelial cells to undergo regeneration determines in large part the degree of renal recovery Therefore, much work has been done to study ways that cells regenerate and mechanisms that might enhance recovery Early in ischemic injury, there is induction of early response genes, such as c-fos and Egr-1.21 By days after ischemia, the proliferating cell nuclear antigen is detected, followed by expression of other dedifferentiated cell markers, which seem to be a sign of early recovery Other cells appear to undergo apoptosis or cell death Postischemic regeneration seems to be a recapitulation of early renal tubular cell development Growth factors such as insulinlike growth factor-1 (IGF-1) and epidermal growth factor (EGF-1) have been associated with enhanced recovery as well Renal levels of hepatocyte growth factor (HGF) increase after two models of renal failure, postnephrectomy, and following CCL4 (chemokine [C-C motif ] ligand 4) injection This increase supports a role for HGF in renal repair Exogenous EGF has been shown to enhance renal tubular cell regeneration and to lessen the severity and duration of hypoxia and toxin-induced renal failure EGF receptor levels increase within hours of ischemic injury in the rat Elevation of soluble EGF occurs along with morphologic evidence of tubular injury within 12 hours of ischemia, which is followed by cell proliferation and a decrease in soluble EGF by 24 to 48 hours after ischemia Alterations in Cell Membranes Membrane phospholipids have a structural function and affect membrane permeability as well as the activity of membrane transport systems.22 These compounds are regulated in part by the activity of phospholipases, which release free fatty acids from phospholipids Several mechanisms related to acute cell injury ... disappearing by either detachment from the apical surface or being internalized within the tubular cells.14 In this scenario, enzymes of the brush border (alkaline phosphatase and g-glutamyl transpeptidase)... 74 Glomerulotubular Dysfunction and Acute Kidney Injury Injury at this outer medulla region may be missed on biopsy since this site often is not sampled Tubular cell detachment with exposed,... integrity, is jeopardized, with resultant accumulation of Na1, chloride (Cl2), and water within the cell This cell swelling (oncosis) is a hallmark feature of necrosis.18 Not all cells that fail