910 SECTION VII Pediatric Critical Care Renal may alter phospholipase activity and thereby change membrane phospholipids and membrane integrity altered intracellular calcium homeostasis, depletion of[.]
910 S E C T I O N V I I Pediatric Critical Care: Renal may alter phospholipase activity and thereby change membrane phospholipids and membrane integrity: altered intracellular calcium homeostasis, depletion of ATP, and lipid peroxidation Increased phospholipase activity has been associated with an abnormal increase in permeability of the inner mitochondrial membrane, which ultimately results in disruption of mitochondria and loss of the ability to produce adequate energy Cellular Calcium Homeostasis Increased intracellular calcium is commonly found in cell injury However, it is not a consistent finding in all models of renal injury.23 Techniques to study changes in the subcellular distribution of calcium have allowed time-related changes to be assessed In the rat proximal tubule, steady-state hypoxia is accompanied by a prompt increase in cytosolic free calcium that precedes the appearance of membrane damage.24 The increase in calcium is reversed with reoxygenation Increased cellular calcium may activate phospholipases, as previously mentioned; alter the cytoskeleton and cause injury by allowing cell swelling; or affect membrane permeability at the plasma membrane, mitochondrial membrane, or endoplasmic reticulum Alterations in mitochondrial function that occur as a result of calcium loading of this organelle have been extensively studied Excess mitochondrial calcium is associated with changes in the permeability of the inner mitochondrial membrane with loss of the electrochemical gradient and the capacity for oxidative phosphorylation In addition, changes in enzyme activity and mitochondrial levels of nucleotides may exist Production of Free Radicals Renal cell damage induced by inflammation or oxygen deprivation may be mediated, in part, by oxygen free radicals that are generated by several cell processes, including accumulation of long-chain acyl-CoA as a result of mitochondrial dysfunction The net result is increased intracellular calcium and, ultimately, changes in membrane-related functions Tubular Cell Energy Metabolism After exposure to a variety of nephrotoxins or ischemia, renal cortical ATP levels are reduced even before changes in membrane integrity and cell death occur.25 In ischemic injury, alterations in renal perfusion may result in decreased oxygen delivery to tubular epithelium Direct mitochondrial damage has been postulated to be the primary event in many forms of nephrotoxic injury Other nephrotoxins interfere with energy production by the inhibition of enzymes along the citric acid cycle In this way, toxins impair energy production ATP levels decrease immediately after ischemia, with concomitant increases in ATP hydrolysis products Reperfusion is associated with a gradual increase in cell ATP levels Glomerulotubular Dysfunction Hemodynamically Mediated Acute Kidney Injury Renal hypoperfusion with ischemia is a common form of acute renal damage, especially in the ICU This form of renal injury is often accompanied by oliguria and results from alterations in renal perfusion after a period of hypoxia, hypotension, cardiac dysfunction, or any condition that promotes hemodynamic instability, decreased effective plasma volume, or both states This condition is commonly referred to as acute tubular necrosis because it is characterized by necrosis of tubule cells However, this is a nonspecific term that may also define nephrotoxic injury A preferred term is vasomotor nephropathy or hemodynamically mediated renal failure.26 The same physiologic alterations that initiate renal injury in this form of nephropathy may potentiate renal failure in conditions whose primary inciting event may not have been vascular Vasomotor nephropathy commonly follows a period of renal compensatory changes that may be termed prerenal failure, which are discussed in the preceding section on pathophysiology When the kidney has fully used normal compensatory mechanisms, renal oxygen delivery is critically impaired; this impairment results in cell damage or tubular cell necrosis Thus, it is apparent that acute tubular necrosis is the end result of a continuum of renal adaptive mechanisms Acute cortical necrosis is an exaggerated and more advanced form of renal ischemia When vascular or hemodynamic abnormalities persist or are profound, renal compensatory mechanisms are unable to preserve RBF and maintain sufficient oxygen delivery and GFR At a mean renal perfusion pressure of 80 mm Hg, afferent arteriolar dilation is maximal; below these systemic pressures, RBF dramatically declines.26 In addition, loss of the ability to autoregulate as a result of ischemia may cause further damage Renal cell injury develops as the result of deficient oxygen delivery, depletion of cellular energy, loss of membrane integrity, and release of reactive oxygen species Without sufficient oxygen, the kidney cannot support cell functions that maintain architectural integrity and complex transport functions Although total RBF is decreased in vasomotor nephropathy, outer cortical blood flow is preferentially increased The medulla is not spared, however, because of its increased susceptibility to alterations in renal perfusion.27 Oxygen delivery to this segment of the kidney is precarious Medullary partial pressure of oxygen (Po2) is approximately 10 mm Hg in the rat and dog This oxygen level approaches the critical minimum level required to support oxidative phosphorylation and ATP synthesis for cell function In general, the proximal tubule sustains the greatest injury The renal arteriogram of human subjects with vasomotor nephropathy reveals marked narrowing of the arcuate arteries and absence of peripheral vasculature, providing further evidence for the marked vascular resistance enhancement.26 The primary event in vasomotor nephropathy is injury of the renal tubule The initiation of this injury, however, is microvascular in origin Maximal renal compensation with marked efferent and afferent arteriolar vasoconstriction reduces glomerular plasma flow with resulting hypofiltration and compromises postglomerular blood supply to the renal tubule Tubular cell necrosis with sloughing of tubular cells into the lumen results in obstruction of flow and back leakage of filtrate through the injured epithelium Alterations in tubular cell function in cells receiving sublethal or lethal injury increase fluid and salt delivery distally This increase signals the glomerulotubular feedback system to cause vasoconstriction of the afferent arteriole and limit the fraction of plasma filtered at the glomerulus.26 Although the initial reduction in GFR is the result of decreased RBF and tubular factors such as obstruction and back leakage, continued hypofiltration during the maintenance phase is related primarily to continued vasoconstriction and renal hypoperfusion.26 Recovery from post ischemic AKI is biphasic Initially, an increase in GFR occurs with relief of tubular obstruction and, subsequently, improved filtration in association with renal vasodilation Oliguria in the presence of renal hypoperfusion has been referred to as acute renal adaption by investigators who propose that CHAPTER 74 Glomerulotubular Dysfunction and Acute Kidney Injury the response of an intelligent organ to a perceived reduction in blood flow is to reduce fluid and electrolyte losses by vasoconstriction to reduce the fraction of plasma filtered and by maximal reabsorption of fluid and salt to restore the circulation In addition, increased distal delivery of water and solutes because of tubular cell necrosis reflects failure of the renal tubule to absorb what is filtered The appropriate response of an intact nephron is to reduce filtration by release of angiotensin II into the interstitium Angiotensin II mediates arteriolar vasoconstriction, which decreases glomerular plasma flow, and mediates retraction of the glomerular tuft, which reduces Kf, the net effect being decreased glomerular filtration.27 The classic form of hemodynamically mediated AKI was oliguric by definition However, nonoliguric acute vasomotor nephropathy is increasingly recognized.27,28 This form of less severe disease has been referred to as attenuated acute tubular dysfunction and has allowed the recognition of three stages of AKI that actually represent a continuum of worsening disease First, abbreviated renal insufficiency occurs after a single event of renal hypoperfusion, such as aortic cross-clamping, in the face of adequate volume repletion and systolic blood pressure This syndrome is characterized by an acute drop in the GFR with gradual return to normal within a few days The inability to concentrate the urine or to conserve sodium provides evidence of tubular injury The second phase or form is referred to as overt renal failure An example of this is aortic cross-clamping followed by continued renal hypoperfusion because of poor cardiac function A more prolonged period of hypofiltration lasts for several days to weeks with a gradual return of the GFR If recovery of renal perfusion is impaired by repeated episodes of ischemia/hypotension, sepsis, or hypoxia, the third pattern may be observed in which a protracted course may be observed, and chances for recovery may be doubtful.28 One situation in which the last example could exist is aggressive hemodialysis (ultrafiltration) with hypovolemia and, consequently, renal hypoperfusion in the recovering phase of renal failure Clinical experience has supported this theory Patients with multiple renal insults have a more protracted course and increased morbidity.29 Using the updated Schwartz formula for estimate of creatinine clearance (eGFR) in infants and children, a modified RIFLE classification (pRIFLE) has been developed The updated Schwartz formula is as follows30,31: eGFR 0.413 [height(cm)]/[sCr(mg /dL)] The pRIFLE classification is defined by the percentage reduction in estimates of creatinine clearance or the amount of diminishing urine output.2 Treatment of Acute Kidney Injury 911 with animal models of acute renal injury Some of these agents have ultimately been used in clinical situations with variable success In general, methods to reduce renal injury have been aimed at manipulation of RVR or alteration of the metabolic processes of the renal tubular cell Agents that might protect or alter AKI are discussed at ExpertConsult.com Acute Kidney Injury: Clinical Impact Severe deterioration of kidney function can have a profound effect on body fluid homeostasis and on blood pressure The nature of these alterations often requires intensive care management regardless of the precise underlying diagnosis A wide variety of kidney diseases may result in AKI The most urgent aspects of AKI are (1) hyperkalemia, (2) severe hypertension, (3) severe plasma and extracellular volume expansion leading to heart failure and pulmonary edema, (4) unremitting metabolic acidosis, and (5) hypocalcemia/hyperphosphatemia (eTable 74.2) Each of these can be viewed as an indication for intensive care and consideration of dialysis.52 Additionally, the presence and degree of fluid overload has been shown to be a predictor of survival at the initiation of renal replacement therapy (RRT) and is now considered an important indication for intervention.53 Hyperkalemia The major reason for the development of hyperkalemia (serum potassium concentration mEq/L) is the release (or infusion, or both) of potassium into the extracellular space at a rate greater than the kidney’s ability to excrete potassium Further, the intracellular potassium is in the concentration range of 140 to 150 mEq/L, adding to the total source of potassium The fact that AKI and oliguria have developed does not mean that hyperkalemia will develop By the same token, hyperkalemia may develop rapidly in situations of extensive tissue destruction even without oliguria and “full-blown” AKI Thus, in the clinical situation of a crush injury or tumor lysis syndrome, hyperkalemia should be anticipated and careful anticipatory monitoring begun Severe Hypertension Hypertension is frequently associated with kidney disease The two main mechanisms by which kidney disease leads to hypertension, especially accelerated hypertension, are (1) plasma volume expansion caused by the failure to excrete sodium chloride and water and (2) hyperreninemia associated with decreased kidney perfusion Prevention/Attenuation of Acute Kidney Injury Plasma and Extracellular Volume Expansion Prevention or attenuation of AKI has been the subject of numerous studies, as most agree that protection of the kidney from damage or enhancing recovery after damage would be preferable to the currently available supportive therapies Primary prevention of AKI in the ICU is limited to those conditions in which the timing of injury is predictable, such as exposure to radiocontrast dye, cardiopulmonary bypass, nephrotoxic medications, or chemotherapy In contrast to most cases of community-acquired AKI, nearly all cases of ICU-associated AKI result from more than a single insult.32 Protective agents have been studied extensively Plasma and extracellular volume expansion are associated with kidney failure With an abrupt decline in GFR, even “normal” amounts of sodium and water intake expand the extracellular and plasma volumes Depending on the cardiac status of the patient, serum albumin level, and degree of capillary permeability, this extracellular and plasma volume expansion may be manifest as peripheral edema, hypertension, or congestive heart failure and pulmonary edema In situations of hypertension or congestive heart failure, the treatment involves two principles The first is to reduce to as low a level as possible the amount of sodium and 911.e1 Dopamine, when infused in low intravenous doses, increases RBF, GFR, and sodium excretion In the past, clinicians frequently used “renal dose” dopamine in the hopes that such a maneuver might attenuate renal injury and improve survival In addition, clinicians often interpret an increase in urinary output as proof that these two assumptions are valid Dopamine stimulates both dopaminergic and adrenergic receptors As such, dopamine may affect renal blood flow by direct vasodilation (dopamine receptors) by increasing cardiac output (b-receptors) or by increasing perfusion pressure Of particular interest is its action on dopamine (D1) receptors, which are abundantly distributed throughout the renal vasculature.33 Stimulation of D1 receptors results in vasodilation by means of receptor coupling with cyclic adenosine monophosphate and calcium flux generated by protein kinase A In addition, D1 receptors are also found within the brush border and basolateral membranes of the proximal tubule; medullary ascending limb of the loop of Henle; distal tubule; and cortical collecting ducts where agonist induces a decrease in sodium, phosphate, and bicarbonate absorption D1 receptors have also been localized to the macula densa, where they may modify renin production.33 Dopamine inhibits the Na1/K1-ATPase along the nephron Interestingly, this action would be expected to decrease the oxygen consumption of the renal tubule Thus, it would be less susceptible to ischemic or hypoxic injury Dopamine (D2) receptors are present along the renal tubule In the inner medulla, a subclass, D2k, is coupled to prostaglandin E2 and attenuates the action of antidiuretic hormone in this segment Dopamine in the dosage range of 0.5 to 2.0 mg/kg per minute increases RBF by 20% to 40% The GFR increases by 5% to 20%, an effect related to enhanced glomerular ultrafiltration by a preferential vasodilation at the afferent arteriole This is thought to be related to a dopamine-induced increase in local angiotensin production, which attenuates the dopamine-induced vasodilation at the efferent but not the afferent arteriole The increase in medullary blood flow observed with dopamine results in a decrease in the urea concentration within the medullary interstitium and contributes to the limited concentrating ability of the dopaminestimulated renal tubule The observed increase in urinary flow is thought to be related primarily to the tubular actions rather than the vascular actions of dopamine At higher doses, dopamine stimulation of receptors results in decreased sodium and fluid excretion as well as renal vasoconstriction Dopamine clearance is decreased in the presence of renal or liver dysfunction Despite these descriptive studies suggesting the possible benefit of low-dose dopamine infusion in the setting of evolving AKI, the 2012 iteration of the Surviving Sepsis Campaign guidelines state with a GRADE methodology grading of 1A (strong recommendation, strong evidence) that low-dose dopamine should not be used for renal protection.34 A large randomized trial and meta-analysis comparing low-dose dopamine to placebo found no difference in either primary outcomes (peak serum creatinine, need for renal replacement, urine output, time to recovery of normal renal function) or secondary outcomes (survival to either ICU or hospital discharge, ICU stay, hospital stay, arrhythmias) Dopamine may inhibit thyrotropin hormone release from the hypothalamus and have immunosuppressive effects through its inhibition of release of the lymphotropic factor prolactin Dopamine should be used cautiously in neonates because the renal vascular response to dopamine is age dependent,35 although administration of dopamine (0.5 to mg/kg per minute) to premature neonates with respiratory distress syndrome and renal insufficiency was reported to result in improved creatinine clearance without major side effects Diuretics Intravenous diuretics have been frequently used in the UCI to ameliorate fluid overload by increasing urine output.36 This widespread use of loop diuretics in the face of impending renal failure has been ascribed to a combination of animal and human data Loop diuretics decrease RVR and increase RBF.37 In addition, loop diuretics inhibit the sodium/potassium chloride cotransporter system, thereby reducing active oxygen transport and potentially reducing oxygen consumption and thus limiting ischemic injury to the outer medullary tubules Indeed, furosemide has been shown to decrease renal oxygen consumption in critically ill patients Mannitol may attenuate renal failure if it is given before the insult or immediately afterward.37 Loop diuretics, such as furosemide, if given along with a potentially nephrotoxic agent, may increase the renal excretion of the agent and reduce associated nephrotoxicity Mannitol has been shown to ameliorate nephrotoxicity related to gentamicin, amphotericin B, cisplatin, and myoglobin A specific beneficial effect is doubtful, however, because acute saline loading alone provides similar protection When tubular obstruction plays a major role, mannitol may increase tubular flow enough to wash obstructing debris downstream It seems reasonable to use mannitol—and, potentially, furosemide—in the initial phases of oliguria when AKI may not be established However, these agents provide little benefit and may increase toxicity in sustained oliguria as a result of tubular necrosis Mannitol has innate risks of adding to a hyperosmolar situation Using the formula to calculate osmolality (2 Na blood urea nitrogen/2.8 glucose/18), one should calculate the osmolality prior to use of mannitol to ensure that additive (and potentially) risky worsening hyperosmolality does not result Calcium Entry Blockers These agents may prevent renal insufficiency through their vasodilatory action on renal vasculature as well as inhibition of calcium entry The calcium channel blockers verapamil, nitrendipine, diltiazem, and nisoldipine have been administered to various animal models of ischemic injury with some success in the prevention or attenuation of renal failure Minimal protection is observed, however, if they are administered after ischemia.38 Calcium entry blockers had a beneficial effect in endotoxin-mediated AKI This effect was postulated to be a result of an antagonism of platelet-activating factor.39 The perfusion of cadaveric renal grafts before transplantation with diltiazem was associated with improved graft survival compared with control subjects.40 Preoperative administration of calcium channel blockers to adults undergoing cardiac surgical procedures did not provide any obvious protection from the development of AKI.41 Calcium channel blockers are commonly used in the setting of calcineurin inhibitors (CNIs)—for example, tacrolimus, cyclosporine—and are found to be somewhat renal protective when CNIs are used Prostaglandins Vasoconstrictive forces in the renal vasculature may result from the action of vasoconstrictor prostaglandins and are counteracted by vasodilatory substances.42 Infusion or stimulation of the 911.e2 vasodilatory prostaglandins or inhibition of the vasoconstrictor prostaglandins seems to be a reasonable approach Prostacyclin provided protection during ischemia in a rat model Administration of the thromboxane synthetase inhibitor OKY-046 partially ameliorated hypofiltration in a rat model of ischemic renal failure.43 In addition, the administration of the free radical scavenger’s dimethylthiourea and superoxide dismutase attenuated renal insufficiency and reduced thromboxane levels Renin-Angiotensin Antagonists Administration of saralasin, an angiotensin II receptor antagonist, either before or after ischemia was not beneficial in the rat model Blockade of angiotensin production by the conversion of enzyme inhibition with ACE inhibitors was not successful in preventing AKI.44 Whereas ACE inhibitors prevented a fall in RBF, these agents decreased the GFR Adenosine and Adenosine Triphosphate Renal ischemia results in the depletion of cellular adenine nucleotides and increased levels of adenosine, an agent implicated as a mediator of local renal vasoconstriction.45 Adenosine may also have protective tubular effects during ischemia because it inhibits solute reabsorption in the medullary thick ascending limb of the loop of Henle Theophylline, a competitive inhibitor of adenosine receptors, partially prevents the hypofiltration following ischemia in the rat Infusion of ATP-magnesium chloride after renal ischemia promotes more rapid cellular recovery and attenuates renal injury.46 In animal models, exogenous ATP, adenosine diphosphate (ADP), adenosine monophosphate, and adenosine preserve renal tubular cell metabolism during anoxia by protecting the membrane from disruption and providing precursors for rapid synthesis of ATP during reperfusion Atrial Natriuretic Factor Atrial natriuretic factor (ANF) has direct effects on glomerular hemodynamics and GFR.47 ANF dilates arcuate, interlobular, and proximal afferent arterioles, and relaxes mesangial cells In a rat model of rhabdomyolysis, administration of ANF improved GFR and enhanced sodium and water excretion In addition, ANF improved GFR and maintained cell energy levels during ischemic injury.48 ANF preserves glomerular filtration and cellular ATP levels in experimental models of AKI by its effect on glomerular hemodynamics Free Radical Scavengers Reactive oxygen species have been proposed as a cause of cellular injury in many forms of AKI The conversion of xanthine to hypoxanthine during reoxygenation produces reactive oxygen species Antioxidants and xanthine oxidase inhibition (allopurinol) have proved to attenuate renal injury in many models of AKI Thyroxine Thyroxine reduces renal injury in a number of experimental models when given before the injury, immediately after, or 24 hours after ischemia The mechanism by which thyroxine preserves both glomerular and tubular function is not completely understood However, the rate of recovery of cellular ATP levels was much more rapid in animals given thyroxine after ischemic AKI Isolated mitochondria from rats subjected to 45 minutes of ischemia exhibited decreased mitochondrial ADP transport Administration of thyroxine was associated with significantly enhanced ADP transport.49 The investigators speculated that part of the ATP depletion associated with ischemic injury might be the result of decreased mitochondrial uptake of the ATP precursor, ADP The administration of thyroxine at to ng/kg per day for to 10 days in children with AKI resulted in the recovery of renal function in all but one child, who died of the original disease.50 Glycine and Alanine The amino acids glycine and alanine have been shown to have cytoprotective effects against injury in anoxia-hypoxia and chemotherapy-induced renal failure The mechanism of cytoprotection is not understood but does not appear to involve preservation of intracellular ATP levels Studies performed in cultured proximal tubular cells indicate that glycine and alanine may stimulate the expression of HSP genes and increase HSP proteins, which protect cells from injury The cytoprotective effect was not observed with other amino acids and was independent of cellular ATP levels in this model of renal injury Incubation of isolated renal tubules with glycine during hypoxia was associated with increased levels of glutathione as well as increased cell ATP, although these did not appear to account fully for the protective effect of glycine In addition, administration of glycine prevented renal injury in rats treated with nephrotoxic doses of cisplatin.51 911.e3 eTABLE 74.2 Management of Electrolyte Abnormalities Abnormality Management Recommendation Hyperphosphatemia Moderate (2.1 mmol/L) Avoid IV phosphate administration Administration of phosphate binder Severe Dialysis, CAVH, CVVH, CAVHD, or CVVHD Hypocalcemia (#1.75 mmol/L) Asymptomatic No therapy Symptomatic Calcium gluconate 50–100 mg/kg IV administered slowly with ECG monitoring Hyperkalemia Moderate and asymptomatic Avoid IV and oral potassium (6 mmol/L) ECG and cardiac rhythm monitoring Sodium polystyrene sulfonate Severe (.7 mmol/L) or symptomatic Same as above, plus: Calcium gluconate 100–200 mg/kg by slow IV infusion for life-threatening arrhythmias Regular insulin (0.1 U/kg IV) D25 (2 mL/kg) IV Sodium bicarbonate (1-2 mEq/kg IV push) can be given to induce influx of potassium into cells; however, sodium bicarbonate and calcium should not be administered through the same line Dialysis Renal dysfunction (uremia) Fluid and electrolyte management Uric acid and phosphate management Adjust renally excreted drug doses Dialysis (hemodialysis or peritoneal) Hemofiltration (CAVH, CVVH, CAVHD, or CVVHD) CAVH, Continuous arteriovenous hemofiltration; CAVHD, continuous arteriovenous hemodialysis; CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; ECG, electrocardiography; IV, intravenous ... injury in many forms of AKI The conversion of xanthine to hypoxanthine during reoxygenation produces reactive oxygen species Antioxidants and xanthine oxidase inhibition (allopurinol) have proved... adequate volume repletion and systolic blood pressure This syndrome is characterized by an acute drop in the GFR with gradual return to normal within a few days The inability to concentrate the urine... independent of cellular ATP levels in this model of renal injury Incubation of isolated renal tubules with glycine during hypoxia was associated with increased levels of glutathione as well as increased