Acute Renal Failure and Sepsis

Robert W. Schrier, M.D., and Wei Wang, M.D. Acute renal failure occurs in approximately 19 percent of patients with moderate sepsis, 23 percent with severe sepsis, and 51 percent with septic shock when blood cultures are positive. A progressive increase in the acute respiratory distress syndrome also occurs with moderate and severe sepsis and septic shock. In the United States, an estimated 700,000 cases of sepsis occur each year, resulting in more than 210,000 deaths; this number accounts for 10 percent of all deaths annually and exceeds the number of deaths due to myocardial infarction.3 The combination of acute renal failure and sepsis is associated with a 70 percent mortality, as compared with a 45 percent mortality among patients with acute renal failure alone. Thus, the combination of sepsis and acute renal failure constitutes a particularly serious medical problem in the United States.4 Substantial progress has been made toward understanding the mechanisms whereby sepsis is associated with a high incidence of acute renal failure. Moreover, recently identified clinical interventions may be able to decrease the occurrence of acute renal failure and sepsis and the high associated mortality. The cytokine-mediated induction of nitric oxide synthesis that occurs in sepsis decreases systemic vascular resistance. This arterial vasodilatation predisposes patients with sepsis to acute renal failure, the need for mechanical ventilation, and ultimately, increased mortality. In this article, we review the effects of nitric oxide–mediated arterial vasodilatation on resistance to exogenous pressors and hypotension and we discuss the use of arginine vasopressin in patients with septic shock. We also review the effects of increased plasma concentrations of several endogenous vasoconstrictor hormones, including catecholamines, angiotensin II, and endothelin, which support arterial pressure in patients with sepsis who have vasodilatation but also cause renal vasoconstriction and predispose patients to acute renal failure. Patients who have a combination of sepsis and acute renal failure may have some effects of systemic arterial vasodilatation, such as altered Starling forces in the capillaries, pulmonary edema, and hypoxia, a need for mechanical ventilation, acute respiratory distress syndrome, and multipleorgan dysfunction syndrome, which together may increase mortality to more than 80 percent. We discuss interventions that may prevent this dire sequence of events. Finally, we review several prospective, randomized clinical trials of interventions that have the potential to prevent or attenuate acute renal failure in patients with sepsis and thus decrease mortality. Such trials have addressed anticoagulant therapy, early resuscitation, the treatment of hyperglycemia, the use of corticosteroids, a shortened duration of mechanical ventilation, and various types of renal-replacement therapy. Hemodynamics and Hormones The hemodynamic hallmark of sepsis is generalized arterial vasodilatation with an associated decrease in systemic vascular resistance.

Arterial underfilling due to arterial vasodilatation occurs in several clinical circumstances, including sepsis, and is associated with activation of the neurohumoral axis and an increase in cardiac output secondary to the decreased cardiac afterload. Activation of the sympathetic nervous system and the renin–angiotensin–aldosterone axis, the nonosmotic release of vasopressin, and an increase in cardiac output are essential in maintaining the integrity of the arterial circulation in patients with severe sepsis and septic shock but may lead to acute renal failure. The arterial vasodilatation that accompanies sepsis is mediated, at least in part, by cytokines that up-regulate the expression of inducible nitric oxide synthase in the vasculature. The release of nitric oxide with inducible nitric oxide synthase, as compared with constitutive endothelial nitric oxide synthase, is more profound and prolonged. Moreover, vascular resistance to the pressor response to norepinephrine and angiotensin II5 occurs during sepsis and is attributable in part to the potent vasodilatory effect of nitric oxide. In addition, an increase in plasma concentrations of hydrogen ions and lactate and a decrease in ATP in vascular smooth-muscle cells during septic shock activate the ATP-sensitive potassium channels (KATP channels). The resultant potassium efflux through the KATP channels causes hyperpolarization of the vascular smooth-muscle cells with closure of the voltage-gated calcium channels in the membrane. Since the vasoconstrictor effects of norepinephrine and angiotensin II depend on open calcium channels, vascular resistance to these pressor hormones can occur along with lactic acidosis in patients with sepsis. Furthermore, the high endogenous levels of these vasoactive hormones during sepsis may be associated with down-regulation of their receptors, which would result in a lessening of their effects on the vasculature. The Pressor Effect of Arginine Vasopressin There is evidence that the administration of arginine vasopressin in patients with sepsis-related vasodilatory shock may help maintain blood pressure despite the relative ineffectiveness of other vasopressor hormones such as norepinephrine and angiotensin II.18,19 Specifically, arginine vasopressin may inactivate the KATP channels20 and thereby lessen vascular resistance to norepinephrine12 and angiotensin II. Arginine vasopressin also decreases the synthesis of nitric oxide (as a result of a decrease in the expression of inducible nitric oxide synthase) as well as cyclic guanosine monophosphate (cGMP) signaling by nitric oxide,21 thus attenuating the arterial vasodilatation and pressor resistance during sepsis. The degree of vasoconstriction in response to arginine vasopressin relates to its plasma levels and occupancy of the V1a arginine vasopressin receptors on vascular smooth-muscle cells. Initially, in septic or hemorrhagic shock, the plasma arginine vasopressin concentrations increase to 200 to 300 pg per milliliter, but after approximately an hour, the neurohypophysial stores of vasopressin are depleted and plasma concentrations may fall to approximately 30 pg per milliliter.19 At that time and in the presence of

Another advantage of using arginine vasopressin as a pressor agent in patients with sepsis is that the sites of major arterial vasodilatation in sepsis — the splanchnic circulation. dropping the filtration pressure. thus. including in the lung.27 Furthermore. The decision to use arginine vasopressin as a pressor agent. Norepinephrine profoundly constricts the glomerular afferent arteriole. and the skin — are vascular beds that contain abundant V1a arginine vasopressin receptors. interstitial myocarditis and diastolic dysfunction have also been reported to occur during sepsis. Effects of Systemic Arterial Vasodilatation on Body-Fluid Volume and Starling Forces . during sepsis. and thus may contribute to and prolong the course of acute renal failure in patients with sepsis.26 Increased concentrations of arginine vasopressin constrict the coronary arteries and have been reported to cause myocardial infarction. the muscles. since all three hormones have in common intracellular signaling that involves an increase in the cytosolic calcium concentration. the administration of arginine vasopressin may be effective in patients with septic shock who have vasodilatation and relative resistance to other pressor hormones. consequently. however.28 Since arginine vasopressin is a very potent venoconstrictor that decreases splanchnic compliance. excessive fluid that is administered is distributed more centrally. must involve consideration of several additional physiological properties. Glomerular filtration is determined by the net difference in arterial pressure between the afferent and efferent arterioles across the glomerular capillary bed (termed transcapillary filtration pressure). given the diminished systemic vascular resistance and cardiac afterload. Moreover. the glomerular filtration rate. In contrast. arginine vasopressin has been shown to constrict the glomerular efferent arteriole and therefore can increase the filtration pressure and. the increased cardiac output that generally occurs may be suboptimal for the patient. because circulating cytokines such as tumor necrosis factor that are induced by the septic state have myocardial depressant properties. the increase in cardiac afterload during the infusion of arginine vasopressin can decrease cardiac output.unoccupied V1a receptors. despite the issues mentioned.29 Nevertheless. the administration of exogenous arginine vasopressin can increase blood pressure by 25 to 50 mm Hg by returning the plasma concentrations of antidiuretic hormones to their earlier high levels. In contrast to norepinephrine and angiotensin II. arginine vasopressin does not have a cardiac inotropic effect. and therefore can lead to noncardiogenic pulmonary edema (pseudo–acute respiratory distress syndrome). Arginine vasopressin is also known to be synergistic with the pressor hormones norepinephrine and angiotensin II.6.

to the ability of tumor necrosis factor to release endothelin.35 During endotoxemia. at least in part. albumin distribution. With the use of Guyton's subcutaneous capsule. if endotoxin is infused into a conscious-rat model.36 Endothelial and Inducible Nitric Oxide Synthases The vasodilatory effect of constitutive endothelial nitric oxide synthase within the kidney might be expected to lessen the renal vasoconstriction . these findings would indicate that patients with sepsis who have vasodilatation are susceptible to noncardiogenic pulmonary edema. This latter effect may be due to the increased distribution of albumin within the interstitial space that occurs with arterial vasodilatation. a potent vasoconstrictor.The difference between the oncotic and hydrostatic pressures within the vasculature and interstitium (Starling forces) determines whether plasma water remains within the vasculature or leaks out into the interstitium. If applied to humans. the predominant pathogenetic factor is renal vasoconstriction with intact tubular function. The pulmonary bed is particularly prone to collect interstitial fluid in this situation. and body-fluid volume in normal animals. endothelin may also cause a generalized leakage of fluid from the capillaries and thereby diminish plasma volume. as demonstrated by increased reabsorption of tubular sodium and water.30 The administration of the potent arterial vasodilator minoxidil was shown to cause sodium and water retention with resultant expansion of plasma and interstitial volume. Renal vasoconstriction in sepsis seems to be due. an intrarenal injection of antiserum to endothelin-1 in a rat model was capable of reversing the decrease in the glomerular filtration rate induced by endotoxin. indicating good tubular function. For example. The fall in interstitial pressure that occurred with the intravenous administration of hyperoncotic albumin in the normal animals did not occur in the animals with vasodilatation. intervention at this early stage may prevent progression to acute tubular necrosis. during intravenous saline loading. Experimental Models of Endotoxemia and Sepsis Vasoactive Hormones There is experimental evidence that early in sepsis-related acute renal failure. Experimental studies in rats have examined the effect of arterial vasodilatation on Starling forces.32 Another pressor hormone that has been observed to be elevated in sepsis is endothelin. Thus. arterial vasodilatation in a rat model was shown to reverse the normally negative pressure within the interstitium.34 Indeed. interstitial pressure increased in animals without vasodilatation.30 Moreover. whereas the elevated interstitial pressure in the animals that had vasodilatation did not increase further. There is indeed evidence that this is the case. the early events include a fractional excretion of sodium of less than 1 percent. which is able to measure interstitial pressure.

and the resultant upregulation of adhesion molecules contributes to neutrophil infiltration during endotoxemia. however. has been helpful in elucidating the importance of endothelial damage during sepsis. the results of in vitro studies showed that the increase in the plasma nitric oxide concentration stimulated by inducible nitric oxide synthase during endotoxemia down-regulated endothelial nitric oxide synthase within the kidney. which did not alter the glomerular filtration rate in the control mice. the effect of endotoxin (lipopolysaccharide) was tested in endothelial nitric oxide synthase–knockout mice.46 Several chemokines are also expressed during endotoxemia in association with neutrophil and macrophage infiltration into the glomeruli and interstitium. Chemokines.40 Cytokines. although there is probably an overlap in these processes. angiotensin II.38 In association with this increased expression of inducible nitric oxide synthase. a progressive increase in cGMP in the renal cortex occurred during the initial 16 hours after exposure to endotoxin. The study of knockout mice. which have a significant increase in blood pressure and renal vascular resistance as compared with normal (control) mice. the down-regulation of this enzyme at 24 hours may also contribute to renal vasoconstriction during sepsis. the plasma nitric oxide concentration remained high. not only did the plasma nitric oxide concentration increase. Since there is no specific inhibitor of endothelial nitric oxide synthase. Since cGMP is the secondary messenger for nitric oxide–mediated arterial vasodilatation. caused a profound decrease in the glomerular filtration rate in these knockout mice.37 When cytokines activated inducible nitric oxide synthase. and angiotensin II. At 24 hours. though renal cGMP had decreased. It is known that caspase activates both interleukin-1 and interleukin-18 cytokines. however. a nuclear . and Adhesion Molecules The early vasoconstrictor phase of acute renal failure during endotoxemia may be followed by a proinflammatory phase. and endothelin during sepsis.induced by norepinephrine. The importance of caspase in endotoxemia has been underscored by the observation that caspase-1–knockout mice are protected against renal failure that is induced by either ischemia45 or endotoxemia. which up-regulate nuclear factor-B (NF-B). A small dose of endotoxin. in which the expression of either endothelial nitric oxide synthase or inducible nitric oxide synthase has been ablated. Endothelial damage occurs during sepsis and may be associated with microthrombi and an increased concentration of von Willebrand factor in the circulation. The complex composed of a lipopolysaccharide and the lipopolysaccharide-binding protein activates the membrane-CD14 and tolllike receptors on cells. endothelin. but also the expression of inducible nitric oxide synthase increased in the renal cortex.39 Sepsis-related impairment of the endothelium may also attenuate or abolish the normal effect of endothelial nitric oxide synthase in the kidney to counteract the vasoconstrictor effects of norepinephrine. However.

However. a randomized study of 263 patients . Early Resuscitation Since the early vasoconstrictor phase of sepsis and acute renal failure is potentially reversible. hemorrhage. Also.54 Prospective. Complement pathways are activated during sepsis by bacterial products such as lipopolysaccharide.3 percent. not only were negative56. chemokine. chemokine.57.48 These substances need to be studied both in experimental models and in clinical studies in humans with concurrent sepsis and acute renal failure.51 Although animal models of endotoxemia and sepsis have provided insights into sepsis and acute renal failure.006). in which attempts were made to optimize hemodynamics and monitor the patients with a pulmonary-artery catheter. and ultimately. the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial. Sepsis can be viewed as a procoagulant state that can lead to disseminated intravascular coagulation with consumptive coagulopathy.50. and the fibrinolytic cascade. randomized study. the mouse models in which sepsis was induced by the administration of lipopolysaccharide differed from the models achieved by cecal ligation and puncture.49. thrombosis. and adhesion molecule "storm. In contrast. coagulation. and blocking C5a and C5a receptor in a rodent model of sepsis has been shown to improve survival. and other stimuli. C-reactive protein.47Activation of NF-B may therefore be a critical factor in the proinflammatory phase that involves a cytokine. the translation of these experimental results to patients with sepsis must be made with caution." which leads to acute renal failure and an increased rate of death. clinical studies performed in patients up to 72 hours after admission to the intensive care unit. or adhesion molecule. Blocking agents for NF-B exist that could protect against endotoxemia better than targeting any individual cytokine.58. showed that recombinant human activated protein C (drotrecogin alfa) significantly improved survival in patients with severe sepsis. as compared with those given placebo (75.3 percent vs. and adhesion molecules. chemokines.59 but showed increased mortality among patients with sepsis. A major prospective.53 Disseminated Intravascular Coagulation Sepsis affects the expression of complement.52. Disseminated intravascular coagulation has been associated with glomerular microthrombi and acute renal failure.55 Results of renal-function tests were not reported in this trial. 68.transcription factor for the promoters of multiple cytokines. Complement C5a that is generated during sepsis seems to have procoagulant properties. it should be an optimal time for intervention. randomized trials have been undertaken to evaluate methods of intervening in the procoagulant process associated with sepsis. P=0.

the multiorgan dysfunction score decreased significantly and in-hospital mortality decreased (30.5 percent.009). with the aim of maintaining glucose levels between 180 and 220 mg per deciliter [10. 33 cases. but older studies in which septic shock was treated with large doses of glucocorticoid hormones for a short period of time did not show any benefit.5 percent in the control patients.02). who received standard care.4 and 6. P=0.with a mean serum creatinine concentration of 2.62 Glucocorticoids and Mechanical Ventilation Glucocorticoids have been known to enhance the pressor effects of catecholamines.63.1 mmol per liter]) with conventional treatment (the use of insulin only if the blood glucose levels exceeded 215 mg per deciliter [11.02). a recent study65 in patients with septic shock showed that patients without a response to corticotropin (as defined by a rise in plasma free cortisol of less than 9 µg per deciliter at 30 or 60 minutes) who were treated for 7 days with intravenous boluses of 50 mg of hydrocortisone every 6 hours plus daily oral fludrocortisone (a 50-µg tablet) had a decrease in mortality at 28 days as compared with the placebo group (63 percent vs. If these interventions failed to increase central venous oxygen saturation to greater than 70 percent. and a 41 percent decrease in acute renal failure requiring dialysis or hemofiltration. in patients assigned to such interventions. P=0.6 mg per deciliter (230 µmol per liter) on admission to the emergency department showed that early goal-directed therapy during the first six hours after admission was effective. a 46 percent decrease in positive blood cultures. In this randomized study. as compared with 46.2 mmol per liter]). 53 percent. Hyperglycemia and Insulin Hyperglycemia impairs the function of leukocytes and macrophages.0 mmol per liter) or less.61 The group assigned to tight control of blood glucose levels showed a decrease in mortality in the intensive care unit as compared with the group receiving conventional treatment (4. The goal-directed approach included early volume expansion and administration of vasopressors to maintain mean blood pressure at or above 65 mm Hg and transfusion of red cells to increase the hematocrit to 30 percent or more if central venous oxygen saturation was less than 70 percent.0 and 12. Recent studies further support the importance of controlling blood glucose in critically ill patients but suggest a less stringent goal of maintaining blood glucose at a level of 145 mg per deciliter (8.64 However.9 mmol per liter]. 8 percent.6 percent vs. then therapy with dobutamine was instituted. P<0.60 The central venous oxygen saturation was continuously monitored as goal-directed therapy was instituted.04). A randomized study of 1548 patients compared the use of insulin to control blood glucose levels tightly (maintaining blood glucose levels between 80 and 110 mg per deciliter [4. Multiple-organ failure with a proven focus of sepsis was also decreased (8 cases vs. 229 of the 299 patients with septic shock who were enrolled were classified as not . P=0.

46 percent. For example. P<0. Studies suggesting that increased doses of dialysis improve survival in patients who are hypercatabolic and have acute renal failure are persuasive.71 The benefit of the removal of cytokines by continuous renalreplacement therapy also remains to be proven as a method for improving survival in patients with sepsis and acute renal failure. Withdrawal of vasopressors was also significantly better at 28 days in those without a response (40 percent vs. P=0. P<0. however.68 A recent study showed that daily hemodialysis as compared with alternate-day hemodialysis was associated with less systemic inflammatory response syndrome or sepsis (22 percent vs.001).005). it is known that septic shock is associated with acute renal failure in 38 percent of patients with negative cultures and 51 percent of patients with positive cultures.67 Hemofiltration has been shown to produce better survival rates than peritoneal dialysis in patients with acute renal failure associated with malaria and other infections. and acute renal failure.01) and a shorter duration of acute renal failure (mean [±SD].001). survival was markedly improved with aggressive hemodialysis as compared with peritoneal dialysis in patients who had heatstroke. in patients with sepsisrelated acute renal failure.2 Renal Replacement Patients with sepsis and acute renal failure are hypercatabolic. P=0. 57 percent. lower mortality (28 percent vs. Patients who have sepsis-related acute renal failure have much higher mortality than patients with acute renal failure who do not have sepsis. Recent clinical studies indicate that interventions based on several proposed pathogenetic factors in sepsis-related acute renal failure may have a favorable effect on both the incidence of acute renal failure and the mortality of patients with acute renal failure.70 Moreover. Acute renal failure is a common complication of sepsis and septic shock.001). rhabdomyolysis. .69 Reaction Continuous renal-replacement therapy has increasingly been used to treat acute renal failure. 9±2 vs. A randomized study using continuous venovenous hemofiltration suggested that the ultrafiltration rate of 35 or 45 ml per kilogram per hour as compared with 20 ml per kilogram per hour improves survival in acute renal failure (P<0. better survival was observed with an ultrafiltration rate of 45 ml per kilogram per hour than with a rate of 35 mg per kilogram per hour. but results from such models should be examined stringently before applying them to patients with sepsis. 46 percent.65 Although this study did not report renal function results. 16±6 days. Experimental models of endotoxemia and sepsis have provided insights into the pathogenesis of sepsis-related acute renal failure. Meta-analysis of hemodialysis as compared with continuous renal-replacement therapy in acute renal failure. There was no difference in mortality among the 70 patients with a response to the short corticotropin study.having a response. has not yet shown an advantage for either mode of renal-replacement therapy.

The causes of acute renal failure are classically divided into three categories: prerenal. intrinsic renal azotemia is due to parenchymal injury of the blood vessels. Thus. prerenal azotemia and acute tubular necrosis. Patients with ischemic acute renal failure typically have low systemic perfusion. the clinician may speculate that an unobserved drop in blood pressure must have caused the renal failure. or interstitium. serum concentrations of markers of renal function. such as urea and creatinine. postrenal (or obstructive). Although this scenario cannot be ruled out. A research focus group organized by the American Society of Nephrology recently recommended that the term "acute kidney injury" replace the term "acute renal failure. other causative mechanisms can usually be identified. complete recovery may be seen 1 to 2 days after relief of the offending lesion. Most clinicians still use the term acute renal failure as defined above. whether acute kidney injury refers only to acute tubular necrosis or includes prerenal and postrenal azotemia and parenchymal diseases such as acute glomerulonephritis remains unclear. In contrast. In such cases. rise. Because the rate of production of metabolic waste exceeds the rate of renal excretion in this circumstance. systolic blood pressure >90 to 100 mm Hg). The two forms of ischemic acute renal failure.D. because the patient's blood pressure is — at least temporarily — within the normal range) can occur as a result of several processes. Postrenal azotemia — obstruction of the urinary tract — is initially accompanied by few microscopical changes (early hydronephrosis. the group left the actual definition of acute kidney injury to be determined in the future. most of which involve increased renal susceptibility to modest . Acute renal failure is defined as a rapid decrease in the glomerular filtration rate. glomeruli. This type of ischemic acute renal failure (termed normotensive. Prerenal azotemia is considered a functional response to renal hypoperfusion. Yet in many patients with acute renal failure. occurring over a period of minutes to days. account for more than half the cases of renal failure seen in hospitalized patients and are familiar to most clinicians. M. the contribution of ischemia is initially unrecognized. and intrinsic." However.Normotensive Ischemic Acute Renal Failure J. although their blood pressure may not fall dramatically but instead may remain within the normal range (in an adult. tubules. Gary Abuelo. in the absence of frank hypotension. In prerenal and postrenal azotemia. provided that normal perfusion or urinary outflow is reestablished before structural changes occur. in which renal structure and microstructure are preserved. with enlargement of the pelvic cavity and minimal distention or blunting of the renal papilla) or none. sometimes caused by volume depletion.

but the tubules remain intact. This reduces glomerular capillary pressure and the glomerular filtration rate. Recognition of these factors allows the physician to make an early diagnosis and facilitates the interventions that can help to reestablish normal renal hemodynamics. which perfuses the tubules. Sloughed tubular epithelial cells and brush-border–membrane debris form casts that obstruct tubules. These leukocytes . forming a gel and contributing to cast formation. and discusses the diagnosis of this condition. in turn. with reperfusion. the factors that lead to ischemic renal failure in patients with apparently normal blood pressure are discernible in most instances. which activates a number of critical alterations in metabolism.5 to 35. The importance of addressing even mild renal failure is illustrated by a recent study showing that hospitalized patients with a modest increase in the serum creatinine level (0. especially in the outer medulla. further impairing renal function.reductions in perfusion pressure. initiates leukocyte infiltration. Cytoskeletal disruption leads to loss of brushborder microvilli and cell junctions and to mislocation of integrins and sodium–potassium ATPase from the basal surface to the apical surface. which is marginally oxygenated under normal circumstances. hypoperfusion. impaired sodium reabsorption by injured tubular epithelial cells increases the sodium concentration in the tubular lumen. endogenous vasoconstrictors increase afferent arteriolar resistance. Renal Response to Ischemia As renal perfusion pressure drops below the autoregulatory range.4 mg per deciliter [26. augmented by proinflammatory and chemotactic cytokines generated by ischemic tubular cells. increasing severity and duration of ischemia may cause structural tubular injury. As a result. results in vasoconstriction. The postglomerular capillary bed.4 µmol per liter]) have a 70% greater risk of death than persons without any increase. and experimental data indicate that glomerular filtrate leaks from the tubular lumen across denuded tubular walls into capillaries and the circulation (a phenomenon called back-leak).3 to 0. The expression of adhesion molecules. ATP depletion also activates harmful proteases and phospholipases. However.5 This article reviews the renal response to ischemia. congestion. Fortunately. together with a shift in the balance of vasoactive substances toward vasoconstrictors such as endothelin. has diminished blood flow and pressure. which. This oxidant injury. brush-border membranes and cells slough and may obstruct tubules downstream. and expression of adhesion molecules. The increased intratubular sodium concentration polymerizes Tamm–Horsfall protein. resulting in functional prerenal azotemia. In addition. Similar damage occurs in endothelial cells of the peritubular capillaries. The mechanism whereby ischemia and oxygen depletion injure tubular cells starts with ATP depletion. cause oxidant injury to tubular cells. which is normally secreted by the loop of Henle. notes the risk factors for the development of normotensive ischemic acute renal failure.

when angiotensin II does not raise efferent resistance in patients who are receiving angiotensin-receptor blockers or angiotensin-converting–enzyme (ACE) inhibitors.16. the inability to vasodilate further markedly impairs the kidney's ability to autoregulate the glomerular filtration rate in low-perfusion states..16 Renovascular insufficiency affecting the total renal mass may not . and some are apoptotic (i. afferent arterioles in the functioning glomeruli become dilated. most are viable (either healthy or reversibly injured). The term is misleading. however. sepsis and contrast agents may have direct toxic effects on the tubules. and proteolytic enzymes. which reduce the synthesis of vasodilatory prostaglandins in the kidneys (Figure 2C). normally perfused kidney maintains the glomerular filtration rate. however. Factors Increasing Renal Susceptibility to Ischemia The kidneys are most vulnerable to moderate hypoperfusion when autoregulation is impaired This phenomenon may be seen in elderly patients or in patients with atherosclerosis. which increases their filtration rate (hyperfiltration). and other vasoconstrictors released in low-perfusion states may act on the afferent arterioles unopposed. the contralateral. Although an increased glomerular filtration rate per nephron compensates for the loss of nephrons. reactive oxygen species.20 When this occurs. Increased susceptibility to renal ischemia may also occur in malignant hypertension because of intimal thickening and fibrinoid necrosis of the small arteries and arterioles. hypertension. because only some tubular cells are necrotic. In other situations. angiotensin II. In addition. Failure of afferent resistance to decrease can also occur when a patient is receiving nonsteroidal antiinflammatory drugs (NSAIDs) or cyclooxygenase-2 (COX-2) inhibitors. in chronic kidney disease. in whom hyalinosis and myointimal hyperplasia cause structural narrowing of the arterioles. This tubular damage is commonly known as acute tubular necrosis. Narrowing of the main renal arteries due to atherosclerosis can increase susceptibility to renal ischemia. or chronic renal failure. In the case of unilateral renal-artery stenosis. "Ischemic acute kidney" and "acute tubular injury" have been proposed as better terms14. and radiocontrast agents can act through various vasoconstrictor mediators to increase afferent arteriolar resistance.18. hypercalcemia. renal failure may occur if renal-artery stenosis in a solitary kidney or in both kidneys is greater than 70% of the lumen. which damage the tubular cells. neither of these newer terms is in common use. calcineurin inhibitors. sepsis.19. Decreased renal perfusion may also cause an exaggerated drop in the glomerular filtration rate — for example. further decreasing glomerular capillary pressure. severe liver failure. undergoing an orderly programmed death). norepinephrine.e. In addition.obstruct the microcirculation and release cytotoxic cytokines.

On the first day during which the creatinine concentration . diuretics reduce extracellular volume. Small-vessel disease in malignant hypertension similarly leads to renal ischemia with increased renin secretion. myocardial infarction. Conversely. chronic kidney disease. as described above. In classic ischemic acute renal failure. as well as decreased intake of food. but lowering blood pressure with antihypertensive therapy can worsen ischemia and reduce renal function. which worsens the hypertension. and congestive heart failure. when a patient goes into shock. which may paradoxically maintain or increase blood pressure. infection. all of which are associated with narrowing and blunted vasodilatory capacity of renal vessels.reduce poststenotic perfusion pressure enough to impair glomerular filtration. as mentioned above. in acute myocardial infarction or acute pulmonary edema. for example. Diagnosis of Normotensive Ischemic Acute Renal Failure Common conditions in which normotensive ischemic acute renal failure may develop include hypertension. Low-Perfusion States in Normotensive Renal Failure The cause of classic ischemic acute renal failure is hypovolemic. with systolic blood pressure typically dropping below 90 mm Hg. A less common mechanism for normotensive renal failure is severe hypoperfusion in the presence of increased levels of vasoconstrictive substances that limit the drop in blood pressure but that may occasionally increase the measured blood pressure. Normotensive renal failure usually involves milder degrees of these low-perfusion processes but azotemia occurs because of factors that increase renal susceptibility to ischemia. the poststenotic drop in blood pressure causes intrarenal ischemia but is accompanied by hypertension from hypervolemia or renin release into the circulation. cardiogenic. and old age. In addition. which can reduce renal perfusion. when the urinary output decreases or the creatinine concentration increases. low cardiac output may be accompanied by stable or even elevated blood pressure mediated by sympathetic discharge. the clinician should look for the presence of a low-perfusion state that may not have been readily apparent. or distributive shock. which can compromise cardiac output. Other conditions include cirrhosis. Hypercalcemia may simultaneously cause systemic vasoconstriction. the severe hypoperfusion may be local: in renal-artery stenosis. In the normotensive variant. and may lead to marked hypovolemia because it may increase renal fluid losses. the physician should be vigilant in looking for a decrease in urinary output and an increase in the serum creatinine concentration. Hypercalcemia may increase afferent glomerular arteriolar resistance. Hypoperfusion may be systemic. and medications such as ACE inhibitors and NSAIDs interfere with autoregulation.

g. a patient in stable condition who is receiving diuretics for hypertension or congestive heart failure may have anorexia and stop eating for some reason or may otherwise have decreased salt intake. The following two scenarios are not uncommon. hypercalcemia. and caregivers about recent weight loss or changes in diet. and microbiologic studies. the decrease in blood pressure may be overlooked. or unexplained lactic acidosis. Because normotensive renal failure is multifactorial. In patients with hypovolemia. the clinician needs to question the patient. Frequently the patient's usual blood pressure is not recorded alongside current blood pressures. using physical examination. blood pressure must often be measured in the upright position to confirm the degree and orthostatic nature of the decline in blood pressure. any of these clinical pictures should lead the clinician to search for an occult infection. imaging. a drop in systolic blood pressure from 160 to 118 mm Hg). It is important to ask about the patient's use of over-the-counter NSAIDs that might change renal perfusion and to obtain a measurement of the serum calcium concentration. corrected for any degree of hypoalbuminemia that is present. Patients may not be aware of decreases in oral intake or may not volunteer the information spontaneously. Sepsis. Especially in patients with relative hypotension and acute renal failure. leukocytosis. several low-perfusion states and susceptibility factors may be present. Thus. NSAIDs. Examples are radiocontrast agents given to patients with chronic renal failure and cyclosporine. Such patients usually have one or more of the following signs or symptoms: hypothermia. blood pressure decreases from high to normal (e. In persons who have underlying hypertension. and the hepatorenal syndrome may all cause both low-perfusion states and increased afferent arteriolar resistance. Since patients are normotensive when renal failure occurs. cool extremities. a patient has what turns out to be early sepsis but at the onset does not have fever or any localizing symptoms. tacrolimus. the blood pressure is usually noted to be below its usual level. "bandemia" (an elevated level of band forms of white cells). or COX-2 inhibitors given in high or supratherapeutic doses. In the first. leukopenia.. Alternatively. clinicians should try to identify susceptibility factors for renal ischemia (Table 1). the usual blood pressure must be ascertained from medical records and compared with the blood pressures when the serum creatinine concentration began to rise.increases. the factors result in severe enough renal vasoconstriction to cause a critical reduction in renal perfusion. In these cases. In addition to watching for low-perfusion states. The cause of the decline in blood pressure may not be apparent. Progressive negative sodium balance results in volume depletion and a downward drift in blood pressure. . Susceptibility factors may sometimes result in ischemic acute renal failure in the absence of a low-perfusion state. confusion. family.

by the time glomerular capillary pressure and glomerular filtration rate drop. and urinary sodium and fractional excretion of sodium and urea increase to more than 20 mmol per liter. while the ratio of blood urea nitrogen to creatinine falls back to 10:1. Low-perfusion states and risk factors for renal ischemia are often treatable and thus should be identified and dealt with promptly. the injured tubules are no longer able to increase reabsorption of water. muddy-brown. the renal tubule is reabsorbing more water and sodium.Patients with malignant hypertension. or bilateral renal-artery stenosis have severe hypertension on presentation but also have compromised renal perfusion. the specific gravity of the urine often increases to 1. <1%. Once low-perfusion states and susceptibility factors are recognized. and urea. If further ischemia causes acute tubular necrosis. As high blood pressure is controlled. a tentative diagnosis of normotensive renal failure can be made. suggesting prerenal azotemia. The urinary sediment will show sloughed renal tubular epithelial cells and debrisfilled. There is experimental evidence that this increase in reabsorption is facilitated by increased expression of urea transporters in the collecting duct.015 or higher. white cells. similar to plasma. Thus. Although these elements are easily recognized by the nephrologist examining the urinary sediment. These laboratory findings strongly suggest the presence of renal hypoperfusion. fractional excretion of sodium. Laboratory personnel may not distinguish these pigmented casts from other granular casts and may not examine a sufficient number of fields on the slide to find them. If possible. which also increases passive reabsorption of urea. and greater than 35%. a finding that is consistent with acute tubular necrosis. renal function may worsen because of a critical drop in glomerular capillary pressure.and sodium-conserving mechanisms. mediated by high plasma vasopressin concentrations. supported by laboratory findings and a response to therapy. the dipstick often shows no red cells. a ratio of blood urea nitrogen to creatinine of 25:1 and urinary sodium excretion of 15 mmol per liter. but with renal tubular epithelial cells in the urinary sediment. even with a blood pressure in the normal range. and the ratio of blood urea nitrogen to creatinine rises from the usual value of 10:1 to 20:1 or higher. respectively.37 As a result of these changes. Furthermore. while urinary sodium and urea excretion decrease (urinary sodium. Laboratory Findings Low-perfusion states trigger the body's water. <35%). clinical laboratories may fail to identify them. sodium. or proteinuria. <20 mmol per liter. . The specific gravity of the urine becomes isosthenuric. greater than 1%. so the clinical laboratory may not examine the sediment as part of the urinalysis. renal-artery stenosis in a solitary kidney. and fractional excretion of urea. granular casts. Many patients appear to be "between" prerenal azotemia and acute tubular necrosis because of mixed findings — for example.

and is less expensive. narcotics). fluid. even after the underlying causes have been treated. and electrolyte derangements . malnutrition is associated with increased complications and death in patients with acute renal failure. especially ACE inhibitors or angiotensin-receptor blockers.46 Advice from a dietitian or a nutrition consultant may be helpful. How severe these problems need to be before treatment is initiated is controversial. volume overload. Indications for intermittent or continuous renal-replacement therapy are florid uremic symptoms. diuretics. Adequate nutrition should be provided. Arguments in favor of starting renal-replacement therapy early may be based on the desire to avoid the dangerous metabolic. when possible. especially if they are critically ill or receiving renalreplacement therapy (hemodialysis). hyperkalemia.5 g of protein per kilogram daily. Enteral nutrition with food or formula designed for renal failure is preferred over parenteral nutrition. Such patients frequently have accelerated protein breakdown and increased caloric needs. and antihypertensive agents. However. If the patient does not have frank hypotension. and any such infection should be treated. If the cause of acute renal failure is not apparent or if the patient's condition does not improve. consultation with a nephrologist may help to ensure complete assessment and appropriate management. effective therapy can reverse the increase in the creatinine concentration within 24 to 48 hours. A drop in systolic blood pressure to the low-normal range (100 to 115 mm Hg) must not be overlooked. stopping treatment with NSAIDs may be beneficial in a patient with severe cardiomyopathy. If acute tubular necrosis has not yet occurred.45. and metabolic acidosis that cannot be managed by conservative means.41. or stopping medications such as NSAIDs. catabolic patients should receive up to 1. and supplements may be required. daily intake should include 25 to 30 kcal per kilogram of body weight.g. Although intake of potassium and phosphate is typically restricted because of impaired renal excretion. Improvement may even occur if only one of the causes is reversed — for example. normotensive ischemic acute renal failure must be considered. The patient should be evaluated for occult infection. Reaction An acute increase in the serum creatinine concentration is usually due to renal ischemia.blood pressure that is on the lower end of the normal range should be increased by correction of any hypovolemia and by dose reduction or discontinuation of antihypertensive medication and other medications that may lower blood pressure (e. In general. if acute tubular necrosis has occurred. because it maintains the integrity of the gut. Many cases can be treated quickly by replacing volume. several days are usually required before improvement is seen. treating infection. hypokalemia and hypophosphatemia due to cell uptake or external losses can occur. requires less fluid intake..

such as old age. poor circulation or underlying kidney disease. and possible dialysis-induced recurrent renal injury or delayed renal recovery. ACUTE RENAL FAILURE The sudden interruption of renal function that can be caused by obstruction. sepsis. and heart disease. . many patients with normotensive renal failure have important complicating factors. arguments in favor of withholding renal-replacement therapy until definite indications are present are based on the risk of hemorrhage during vascular access. and progression to frank shock and death is not unusual.49 Unfortunately.of uremia47. hypotension and arrhythmia during dialysis.47.48 Existing data on the timing of renal-replacement therapy are inadequate to provide clear guidance.

heavy metals.Causes 1. so is oxygen delivery. o 3 classifications: nephrotoxic o inflammatory o ischemic  Poorly treated prerenal failure  Nephrotoxins (aminoglycosides.        Cardiac arrhythmias Cardiac tamponade Cardiogenic shock Heart failure Myocardial infarction Burns Dehydration      Diuretic overuse Hemorrhage Hypovolemic shock Trauma Antihypentensive drugs Sepsis   Arterial embolsim Arterial/venous thrombosis   Tumor Disseminated intravascular coagulation (DIC)     Eclampsia Malignant hypertension Vasculitis o When renal blood flow is diminished. analgesics. azotemia and increased tubular reabsorption of sodium and water. 2. radiographic contrast media. Pre-renal: o Conditions that diminishes renal perfusion to kidneys causing hypoperfusion. especially to the tubules. The resulting hypoxemia causes rapid and irreversible damages to the renal system. o The decrease in GFR causes electrolyte imbalances and metabolic acidosis. results from damage to the filtering structures of the kidneys. Renal: o Also called intrinsic or parenchymal renal failure. o Renal hypoperfusion results to decreased glomerular filtration rate. antimicrobials)          Obstetric complications Crush injuries Myopathy Transfusion reaction Acute glumerulonephritis Acute interstitial nephritis Acute pyelonephritis Bilateral renal vein thrombosis Malignant nephrosclerosis   Papillary necrosis Polyarteritis nodosa . organic solvents.

    Renal myeloma Sickle cell disease Systemic lupus erythematosus (SLE) Vasculitis .

o Nephrotoxin damage tends to be limited in the proximal tubules. accidental ligation. coma o Integument: Dryness. necrotic renal papillae. confusion. heart failure. typically leading to chronic renal failure. peripheral neuropathy. 3. o Recovery phase – azotemia gradually disappears. autonomin nerve dysfunction. infection. purpura. o Ischemic tissues generate toxic oxygen-free free radicals. injury and necrosis. tumors/stricture Phases of ARF: Oliguric. then hypertension. irritability. bleeding. seizures. Kussmaul’s respirations (indicates metabolic acidosis) Diagnosis o Hyperkalemia. decreased bicarbonate levels. tumors) o Ureteral obstruction – restricts urine flow from kidneys to bladder (blood clots. uric acid crystals. Recovery o Oliguric phase – urine output may remain at less than 40 mL/hour or 400 mL/day for a few days or weeks o Diuretic phase – marked by increased urine output of more than 400 mL/day. arrhythmias. pallor. the delicate layer under the epithelium (basement membrane) becomes irreversibly damaged. tumors) o Urethral obstruction –by BPH. hematemesis. calculi. while ischemic necrosis tends to distribute along parts of the nephron.o In nephrotoxic damage. anemia. azotemia and/or anuria o GI: anorexia. uremic frost o Cardiovascular: hypotension. uremic breath o CNS: headache. anasarca. causing renal failure that manifests after treatment or other exposures. pruritus. acidemia (low blood pH) . drowsiness. nausea. which cause swelling. Diuretic. as the kidneys become unable to conserve sodium and water. diarrhea-constipation. o Nephrotoxic drugs accumulate in the renal cortex. vomiting. altered clotting mechanisms o Respiratory: pulmonary edema. Post-renal: o Bladder obstruction  (anticholinergic drugs. edema. stomatitis. retroperitoneal fibrosis or hemorrhage. Signs and Symptoms o Early signs: oliguria. this phase causes dehydration and electrolyte imbalances. dry mucous membranes. urine output returns to normal or near-normal renal function over 3-12 months. fluid overload.

retrograde pyelography. disappearing P waves (hyperkalemia) o Ultrasonography: plain abdominal films. Diet/Nutritional Support: 1.5 g/kg/day (to decrease nitrogenous wastes) Carbohydrates: 100 g/day PO4 = 800 mg/day NaCl = < 1 g/day Mg = none 2. Fluid Management: 1. Consider CVP insertion. Indications for initiating hemodialysis o Pulmonary congestion (unresponsive to Lasix) . widened QRS complex. Hyperphosphatemia 5.o Urinalysis: casts. Hypocalcemia 4. proteinuria. urine osmolality close to serum osmolality. maintain euvolemia Total Fluid Intake= Urine output Yesterday + 500 cc insensible water loss In oliguric patients (400 ml/day) limit to < 1L/day B. Push fluid + 200-500 cc NSS to rule out pre-renal azotemia. I&O catheter and check post-void residual to rule out obstruction. decreased urine specific gravity. pulmonary edema 3. renal scan. Avoid Mg-containing antacids. Hyperkalemia 2. NSAIDS and other nephrotoxins D. CT scan Medical Management: A. excretory urography. urine sodium level <20 mEq/L (if resulting in renal hypoperfusion) or > 40 mEq/L (if intrarenal cause) o Creatinine clearance test: o Electrocardiogram: tall. peaked T waves. For weight maintenance: High Caloric Intake Low protein = 0. Metabolic acidosis 3. For weight gain = add 1.000 kcal/day for gain of approx 1 kg/week C. 2. Electrolytes: 1. KUB radiography. Observe for 2 hours for complications: CHF. Hyperuricemia: no treatment unless with gout (Allopurinol 300 mg/day for 2 days then 100 mg/day) 6. Dopamine 1 amp 200 mg + D5W 250 cc x 10 ugtts/min 4. Furosemide (Lasix) 100-200 mg IVP or Mannitol 20% 500 cc x 2 doses. Adjust all drug dosages according to GFR E.

or client will not develop FVE. o Interventions: o Strictly monitor client’s intake and output q shift. o Measure urine specific gravity every shift o Provide oral care PRN. as shown by return to balanced intake and output. o Administer medications with meals. o Provide medications as prescribed by physician (antiemetics) High Risk for Impaired Skin Integrity r/t disease process or poor cellular nutrition o Plan: The client will not develop impaired skin integrity. salt substitutes. provide ice chips or lip balm to patient. o Monitor client’s vital signs q1h with neurochecks. o Present food in small amounts. as shown by intact skin. followed by Fluid Volume Excess r/t inability of kidneys to produce urine secondary to ARF o Plan: Client will not develop FVD and ARF. o Measure client’s weight daily at same time. • Altered Nutrition: Less than Body Requirements r/t anorexia secondary to renal failure or dietary restrictions o Plan: The client will maintain adequate nutrition.o Severe metabolic acidosis o severe hyperkalemia o BUN >100 mg/dl or creatinine > 9 mg/dl Nursing Management: o Weigh daily o Insert Foley catheter o Avoid Mg-containing antacids. call physician if UO <20 cc/hour o Monitor laboratory results. o Interventions: • . as shown by sufficient intake of food. o Interventions: o Strictly monitor client’s fluid intake and output every shift. o Provide pleasant environment at mealtime. NSAIDS and other nephrotoxic agents o Don’t take BP or insert IV line on left (or right) arm Possible Nursing Diagnoses • Fluid Volume Deficit r/t hypovolemia.

reduce complications. patient may take antibiotics to prevent or treat infections. But many experts now feel that they may not be helpful and may actually be . Restricting the amount of protein in the diet may slow the build up of wastes in the blood and control associated symptoms such as nausea and vomiting. as evidenced by normal vital signs and white blood cell count. o Interventions: o Allow client time to ask questions. The medications given are directed on underlying cause of the acute renal failure or to prevent complications. and may take other medicines to get rid of extra fluid and prevent electrolyte imbalances. and slow the progression of the disease. For instance. phosphorus. and other electrolytes may be restricted. Diseases that cause or result from chronic kidney failure must be controlled and treated as appropriate. Blood transfusions or medications such as iron and erythropoietin supplements may be needed to control anemia. o Check client for signs of infection. Salt. often to an amount equal to the volume of urine produced. o Provide frequent turning of client q2h o Encourage range-of-motion (ROM) exercises OD. have traditionally been used to treat acute renal failure because they quickly increase urine output. Fluids may be restricted. • Drug Study The goal of treatment is to control symptoms. o Check Foley catheter for signs of contamination. Anxiety r/t progressive disease process o Plan: The client will be able to cope with present anxiety as shown by calmness and acceptance to present condition.o Monitor client for sign of skin breakdown q shift. Dialysis or kidney transplant may eventually be needed. Diuretic medications. o Interventions: o Monitor laboratory results daily. such as furosemide. • High Risk for Infection r/t lowered resistance o Plan: The client will not develop infection. which can be dangerous. o Give careful explanations for treatment modalities. Health care provider may adjust the dose of medicines so that they work well. potassium.

This medication is also used to treat high blood pressure (hypertension). pain. vomiting. Depending on the cause and severity of your acute renal failure. unusual weakness. • feeling weak. peeling skin rash. • headache. • hearing loss. or • blurred vision . • numbness. or tingly feeling. or light-headed. restless. • fast or uneven heartbeat. drowsy. allowing the salt to instead be passed in your urine. or • nausea. Less serious side effects may include: • diarrhea. stomach pain. claycolored stools. • urinating less than usual or not at all. • a red. Side Effects: • dry mouth.harmful to people who are very ill. dark urine. • muscle pain or weakness. • dizziness. • easy bruising or bleeding. or a kidney disorder such as nephrotic syndrome. jaundice (yellowing of the skin or eyes). loss of appetite. burning. low fever. or stomach pain. blistering. thirst. nausea. Furosemide Furosemide is a loop diuretic (water pill) that prevents your body from absorbing too much salt. your doctor may choose another method to get rid of extra fluids. liver disease.It treats fluid retention (edema) in people with congestive heart failure. constipation.

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