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Acute Renal Failure and SepsisRobert W. Schrier, M.D., and Wei Wang, M.D.

Acute renal failure occurs in approximately 19 percent of patients withmoderate sepsis, 23 percent with severe sepsis, and 51 percent with septic

shock when blood cultures are positive. A progressive increase in the acuterespiratory distress syndrome also occurs with moderate and severe sepsisand septic shock. In the United States, an estimated 700,000 cases of sepsisoccur each year, resulting in more than 210,000 deaths; this numberaccounts for 10 percent of all deaths annually and exceeds the number ofdeaths due to myocardial infarction.3 The combination of acute renal failureand sepsis is associated with a 70 percent mortality, as compared with a 45percent mortality among patients with acute renal failure alone. Thus, thecombination of sepsis and acute renal failure constitutes a particularlyserious medical problem in the United States.4 Substantial progress hasbeen made toward understanding the mechanisms whereby sepsis is

associated with a high incidence of acute renal failure. Moreover, recentlyidentified clinical interventions may be able to decrease the occurrence ofacute renal failure and sepsis and the high associated mortality.

The cytokine-mediated induction of nitric oxide synthesis that occurs insepsis decreases systemic vascular resistance. This arterial vasodilatationpredisposes patients with sepsis to acute renal failure, the need formechanical ventilation, and ultimately, increased mortality. In this article, wereview the effects of nitric oxidemediated arterial vasodilatation onresistance to exogenous pressors and hypotension and we discuss the use ofarginine vasopressin in patients with septic shock. We also review the effects

of increased plasma concentrations of several endogenous vasoconstrictorhormones, including catecholamines, angiotensin II, and endothelin, whichsupport arterial pressure in patients with sepsis who have vasodilatation butalso cause renal vasoconstriction and predispose patients to acute renalfailure. Patients who have a combination of sepsis and acute renal failuremay have some effects of systemic arterial vasodilatation, such as alteredStarling forces in the capillaries, pulmonary edema, and hypoxia, a need formechanical ventilation, acute respiratory distress syndrome, and multiple-organ dysfunction syndrome, which together may increase mortality to morethan 80 percent. We discuss interventions that may prevent this diresequence of events. Finally, we review several prospective, randomized

clinical trials of interventions that have the potential to prevent or attenuateacute renal failure in patients with sepsis and thus decrease mortality. Suchtrials have addressed anticoagulant therapy, early resuscitation, thetreatment of hyperglycemia, the use of corticosteroids, a shortened durationof mechanical ventilation, and various types of renal-replacement therapy.

Hemodynamics and Hormones

The hemodynamic hallmark of sepsis is generalized arterialvasodilatation with an associated decrease in systemic vascular resistance.


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unoccupied V1a receptors, the administration of exogenous argininevasopressin can increase blood pressure by 25 to 50 mm Hg by returning theplasma concentrations of antidiuretic hormones to their earlier high levels.

Arginine vasopressin is also known to be synergistic with the pressor

hormones norepinephrine and angiotensin II, since all three hormones havein common intracellular signaling that involves an increase in the cytosoliccalcium concentration. Another advantage of using arginine vasopressin as apressor agent in patients with sepsis is that the sites of major arterialvasodilatation in sepsis the splanchnic circulation, the muscles, and theskin are vascular beds that contain abundant V1a arginine vasopressinreceptors.

Glomerular filtration is determined by the net difference in arterialpressure between the afferent and efferent arterioles across the glomerularcapillary bed (termed transcapillary filtration pressure). Norepinephrine

profoundly constricts the glomerular afferent arteriole, dropping the filtrationpressure, and thus may contribute to and prolong the course of acute renalfailure in patients with sepsis. In contrast, arginine vasopressin has beenshown to constrict the glomerular efferent arteriole and therefore canincrease the filtration pressure and, consequently, the glomerular filtrationrate.

The decision to use arginine vasopressin as a pressor agent, however,must involve consideration of several additional physiological properties.26Increased concentrations of arginine vasopressin constrict the coronaryarteries and have been reported to cause myocardial infarction. In contrast

to norepinephrine and angiotensin II, arginine vasopressin does not have acardiac inotropic effect; thus, the increase in cardiac afterload during theinfusion of arginine vasopressin can decrease cardiac output. Moreover,during sepsis, the increased cardiac output that generally occurs may besuboptimal for the patient, given the diminished systemic vascularresistance and cardiac afterload, because circulating cytokines such astumor necrosis factor that are induced by the septic state have myocardialdepressant properties.27 Furthermore, interstitial myocarditis and diastolicdysfunction have also been reported to occur during sepsis.28 Since argininevasopressin is a very potent venoconstrictor that decreases splanchniccompliance, excessive fluid that is administered is distributed more centrally,

including in the lung, and therefore can lead to noncardiogenic pulmonaryedema (pseudoacute respiratory distress syndrome).6,29 Nevertheless,despite the issues mentioned, the administration of arginine vasopressinmay be effective in patients with septic shock who have vasodilatation andrelative resistance to other pressor hormones.

Effects of Systemic Arterial Vasodilatation on Body-Fluid Volume and StarlingForces


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The difference between the oncotic and hydrostatic pressures withinthe vasculature and interstitium (Starling forces) determines whether plasmawater remains within the vasculature or leaks out into the interstitium.Experimental studies in rats have examined the effect of arterialvasodilatation on Starling forces, albumin distribution, and body-fluid volume

in normal animals.30 The administration of the potent arterial vasodilatorminoxidil was shown to cause sodium and water retention with resultantexpansion of plasma and interstitial volume. With the use of Guyton'ssubcutaneous capsule, which is able to measure interstitial pressure, arterialvasodilatation in a rat model was shown to reverse the normally negativepressure within the interstitium.30 Moreover, during intravenous salineloading, interstitial pressure increased in animals without vasodilatation,whereas the elevated interstitial pressure in the animals that hadvasodilatation did not increase further. The fall in interstitial pressure thatoccurred with the intravenous administration of hyperoncotic albumin in thenormal animals did not occur in the animals with vasodilatation. This latter

effect may be due to the increased distribution of albumin within theinterstitial space that occurs with arterial vasodilatation. The pulmonary bedis particularly prone to collect interstitial fluid in this situation. If applied tohumans, these findings would indicate that patients with sepsis who havevasodilatation are susceptible to noncardiogenic pulmonary edema. There isindeed evidence that this is the case.

Experimental Models of Endotoxemia and Sepsis

Vasoactive Hormones

There is experimental evidence that early in sepsis-related acute renalfailure, the predominant pathogenetic factor is renal vasoconstriction withintact tubular function, as demonstrated by increased reabsorption of tubularsodium and water. Thus, intervention at this early stage may preventprogression to acute tubular necrosis. For example, if endotoxin is infusedinto a conscious-rat model, the early events include a fractional excretion ofsodium of less than 1 percent, indicating good tubular function.32

Another pressor hormone that has been observed to be elevated insepsis is endothelin, a potent vasoconstrictor. Renal vasoconstriction insepsis seems to be due, at least in part, to the ability of tumor necrosis

factor to release endothelin.34 Indeed, an intrarenal injection of antiserumto endothelin-1 in a rat model was capable of reversing the decrease in theglomerular filtration rate induced by endotoxin.35 During endotoxemia,endothelin may also cause a generalized leakage of fluid from the capillariesand thereby diminish plasma volume.36

Endothelial and Inducible Nitric Oxide Synthases

The vasodilatory effect of constitutive endothelial nitric oxide synthasewithin the kidney might be expected to lessen the renal vasoconstriction


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induced by norepinephrine, angiotensin II, and endothelin during sepsis.However, the results of in vitro studies showed that the increase in theplasma nitric oxide concentration stimulated by inducible nitric oxidesynthase during endotoxemia down-regulated endothelial nitric oxidesynthase within the kidney.37 When cytokines activated inducible nitric

oxide synthase, however, not only did the plasma nitric oxide concentrationincrease, but also the expression of inducible nitric oxide synthase increasedin the renal cortex.38 In association with this increased expression ofinducible nitric oxide synthase, a progressive increase in cGMP in the renalcortex occurred during the initial 16 hours after exposure to endotoxin. At 24hours, however, the plasma nitric oxide concentration remained high, thoughrenal cGMP had decreased. Since cGMP is the secondary messenger for nitricoxidemediated arterial vasodilatation, the down-regulation of this enzymeat 24 hours may also contribute to renal vasoconstriction during sepsis.

Endothelial damage occurs during sepsis and may be associated with

microthrombi and an increased concentration of von Willebrand factor in thecirculation.39 Sepsis-related impairment of the endothelium may alsoattenuate or abolish the normal effect of endothelial nitric oxide synthase inthe kidney to counteract the vasoconstrictor effects of norepinephrine,endothelin, and angiotensin II. The study of knockout mice, in which theexpression of either endothelial nitric oxide synthase or inducible nitric oxidesynthase has been ablated, has been helpful in elucidating the importance ofendothelial damage during sepsis. Since there is no specific inhibitor ofendothelial nitric oxide synthase, the effect of endotoxin (lipopolysaccharide)was tested in endothelial nitric oxide synthaseknockout mice, which have asignificant increase in blood pressure and renal vascular resistance as

compared with normal (control) mice. A small dose of endotoxin, which didnot alter the glomerular filtration rate in the control mice, caused a profounddecrease in the glomerular filtration rate in these knockout mice.40

Cytokines, Chemokines, and Adhesion Molecules

The early vasoconstrictor phase of acute renal failure duringendotoxemia may be followed by a proinflammatory phase, although there isprobably an overlap in these processes. It is known that caspase activatesboth interleukin-1 and interleukin-18 cytokines, and the resultant up-regulation of adhesion molecules contributes to neutrophil infiltration during

endotoxemia. The importance of caspase in endotoxemia has beenunderscored by the observation that caspase-1knockout mice are protectedagainst renal failure that is induced by either ischemia45 or endotoxemia.46Several chemokines are also expressed during endotoxemia in associationwith neutrophil and macrophage infiltration into the glomeruli andinterstitium.

The complex composed of a lipopolysaccharide and thelipopolysaccharide-binding protein activates the membrane-CD14 and toll-like receptors on cells, which up-regulate nuclear factor-B (NF-B), a nuclear


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transcription factor for the promoters of multiple cytokines, chemokines, andadhesion molecules.47Activation of NF-B may therefore be a critical factor inthe proinflammatory phase that involves a cytokine, chemokine, andadhesion molecule "storm," which leads to acute renal failure and anincreased rate of death. Blocking agents for NF-B exist that could protect

against endotoxemia better than targeting any individual cytokine,chemokine, or adhesion molecule.48 These substances need to be studiedboth in experimental models and in clinical studies in humans withconcurrent sepsis and acute renal failure.

Complement pathways are activated during sepsis by bacterialproducts such as lipopolysaccharide, C-reactive protein, and other stimuli.Complement C5a that is generated during sepsis seems to haveprocoagulant properties, and blocking C5a and C5a receptor in a rodentmodel of sepsis has been shown to improve survival.49,50,51

Although animal models of endotoxemia and sepsis have providedinsights into sepsis and acute renal failure, the translation of theseexperimental results to patients with sepsis must be made with caution. Also,the mouse models in which sepsis was induced by the administration oflipopolysaccharide differed from the models achieved by cecal ligation andpuncture.52,53

Disseminated Intravascular Coagulation

Sepsis affects the expression of complement, coagulation, and thefibrinolytic cascade. Sepsis can be viewed as a procoagulant state that can

lead to disseminated intravascular coagulation with consumptivecoagulopathy, thrombosis, and ultimately, hemorrhage. Disseminatedintravascular coagulation has been associated with glomerular microthrombiand acute renal failure.54 Prospective, randomized trials have beenundertaken to evaluate methods of intervening in the procoagulant processassociated with sepsis. A major prospective, randomized study, thePROWESS (Recombinant Human Activated Protein C Worldwide Evaluation inSevere Sepsis) trial, showed that recombinant human activated protein C(drotrecogin alfa) significantly improved survival in patients with severesepsis, as compared with those given placebo (75.3 percent vs. 68.3 percent,P=0.006).55 Results of renal-function tests were not reported in this trial.

Early Resuscitation

Since the early vasoconstrictor phase of sepsis and acute renal failureis potentially reversible, it should be an optimal time for intervention.However, clinical studies performed in patients up to 72 hours afteradmission to the intensive care unit, in which attempts were made tooptimize hemodynamics and monitor the patients with a pulmonary-arterycatheter, not only were negative56,57,58,59 but showed increased mortalityamong patients with sepsis. In contrast, a randomized study of 263 patients


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with a mean serum creatinine concentration of 2.6 mg per deciliter (230mol per liter) on admission to the emergency department showed that earlygoal-directed therapy during the first six hours after admission waseffective.60 The central venous oxygen saturation was continuouslymonitored as goal-directed therapy was instituted; in patients assigned to

such interventions, the multiorgan dysfunction score decreased significantlyand in-hospital mortality decreased (30.5 percent, as compared with 46.5percent in the control patients, who received standard care; P=0.009). Thegoal-directed approach included early volume expansion and administrationof vasopressors to maintain mean blood pressure at or above 65 mm Hg andtransfusion of red cells to increase the hematocrit to 30 percent or more ifcentral venous oxygen saturation was less than 70 percent. If theseinterventions failed to increase central venous oxygen saturation to greaterthan 70 percent, then therapy with dobutamine was instituted.

Hyperglycemia and Insulin

Hyperglycemia impairs the function of leukocytes and macrophages. Arandomized study of 1548 patients compared the use of insulin to controlblood glucose levels tightly (maintaining blood glucose levels between 80and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) with conventionaltreatment (the use of insulin only if the blood glucose levels exceeded 215mg per deciliter [11.9 mmol per liter], with the aim of maintaining glucoselevels between 180 and 220 mg per deciliter [10.0 and 12.2 mmol perliter]).61 The group assigned to tight control of blood glucose levels showeda decrease in mortality in the intensive care unit as compared with the groupreceiving conventional treatment (4.6 percent vs. 8 percent, P


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having a response. There was no difference in mortality among the 70patients with a response to the short corticotropin study. Withdrawal ofvasopressors was also significantly better at 28 days in those without aresponse (40 percent vs. 57 percent, P


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Normotensive Ischemic Acute Renal FailureJ. Gary Abuelo, M.D.

Acute renal failure is defined as a rapid decrease in the glomerularfiltration rate, occurring over a period of minutes to days. Because the rateof production of metabolic waste exceeds the rate of renal excretion in thiscircumstance, serum concentrations of markers of renal function, such asurea and creatinine, rise. The causes of acute renal failure are classicallydivided into three categories: prerenal, postrenal (or obstructive), andintrinsic. Prerenal azotemia is considered a functional response to renalhypoperfusion, in which renal structure and microstructure are preserved.Postrenal azotemia obstruction of the urinary tract is initially

accompanied by few microscopical changes (early hydronephrosis, withenlargement of the pelvic cavity and minimal distention or blunting of therenal papilla) or none. In contrast, intrinsic renal azotemia is due toparenchymal injury of the blood vessels, glomeruli, tubules, or interstitium.In prerenal and postrenal azotemia, complete recovery may be seen 1 to 2days after relief of the offending lesion, provided that normal perfusion orurinary outflow is reestablished before structural changes occur.

A research focus group organized by the American Society ofNephrology recently recommended that the term "acute kidney injury"replace the term "acute renal failure." However, the group left the actual

definition of acute kidney injury to be determined in the future. Thus,whether acute kidney injury refers only to acute tubular necrosis or includesprerenal and postrenal azotemia and parenchymal diseases such as acuteglomerulonephritis remains unclear. Most clinicians still use the term acuterenal failure as defined above.

The two forms of ischemic acute renal failure, prerenal azotemia andacute tubular necrosis, account for more than half the cases of renal failureseen in hospitalized patients and are familiar to most clinicians. Yet in manypatients with acute renal failure, the contribution of ischemia is initiallyunrecognized. Patients with ischemic acute renal failure typically have low

systemic perfusion, sometimes caused by volume depletion, although theirblood pressure may not fall dramatically but instead may remain within thenormal range (in an adult, systolic blood pressure >90 to 100 mm Hg). Insuch cases, in the absence of frank hypotension, the clinician may speculatethat an unobserved drop in blood pressure must have caused the renalfailure. Although this scenario cannot be ruled out, other causativemechanisms can usually be identified. This type of ischemic acute renalfailure (termed normotensive, because the patient's blood pressure is atleast temporarily within the normal range) can occur as a result of severalprocesses, most of which involve increased renal susceptibility to modest


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reductions in perfusion pressure. Fortunately, the factors that lead toischemic renal failure in patients with apparently normal blood pressure arediscernible in most instances. Recognition of these factors allows thephysician to make an early diagnosis and facilitates the interventions thatcan help to reestablish normal renal hemodynamics.

The importance of addressing even mild renal failure is illustrated by arecent study showing that hospitalized patients with a modest increase inthe serum creatinine level (0.3 to 0.4 mg per deciliter [26.5 to 35.4 mol perliter]) have a 70% greater risk of death than persons without any increase.5This article reviews the renal response to ischemia, notes the risk factors forthe development of normotensive ischemic acute renal failure, and discussesthe diagnosis of this condition.

Renal Response to IschemiaAs renal perfusion pressure drops below the autoregulatory range,

endogenous vasoconstrictors increase afferent arteriolar resistance. Thisreduces glomerular capillary pressure and the glomerular filtration rate,resulting in functional prerenal azotemia. The postglomerular capillary bed,which perfuses the tubules, has diminished blood flow and pressure, but thetubules remain intact. However, increasing severity and duration of ischemiamay cause structural tubular injury, further impairing renal function.Sloughed tubular epithelial cells and brush-bordermembrane debris formcasts that obstruct tubules, and experimental data indicate that glomerularfiltrate leaks from the tubular lumen across denuded tubular walls intocapillaries and the circulation (a phenomenon called back-leak). In addition,impaired sodium reabsorption by injured tubular epithelial cells increases the

sodium concentration in the tubular lumen. The increased intratubularsodium concentration polymerizes TammHorsfall protein, which is normallysecreted by the loop of Henle, forming a gel and contributing to castformation.

The mechanism whereby ischemia and oxygen depletion injure tubularcells starts with ATP depletion, which activates a number of criticalalterations in metabolism. Cytoskeletal disruption leads to loss of brush-border microvilli and cell junctions and to mislocation of integrins andsodiumpotassium ATPase from the basal surface to the apical surface. As aresult, brush-border membranes and cells slough and may obstruct tubules

downstream. ATP depletion also activates harmful proteases andphospholipases, which, with reperfusion, cause oxidant injury to tubular cells.Similar damage occurs in endothelial cells of the peritubular capillaries,especially in the outer medulla, which is marginally oxygenated undernormal circumstances. This oxidant injury, together with a shift in thebalance of vasoactive substances toward vasoconstrictors such asendothelin, results in vasoconstriction, congestion, hypoperfusion, andexpression of adhesion molecules. The expression of adhesion molecules, inturn, initiates leukocyte infiltration, augmented by proinflammatory andchemotactic cytokines generated by ischemic tubular cells. These leukocytes


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obstruct the microcirculation and release cytotoxic cytokines, reactiveoxygen species, and proteolytic enzymes, which damage the tubular cells.

This tubular damage is commonly known as acute tubular necrosis. The term is misleading, however, because only some tubular cells are

necrotic; most are viable (either healthy or reversibly injured), and some areapoptotic (i.e., undergoing an orderly programmed death). "Ischemic acutekidney" and "acute tubular injury" have been proposed as better terms14;neither of these newer terms is in common use.

Factors Increasing Renal Susceptibility to Ischemia

The kidneys are most vulnerable to moderate hypoperfusion whenautoregulation is impaired This phenomenon may be seen in elderly patientsor in patients with atherosclerosis, hypertension, or chronic renal failure, inwhom hyalinosis and myointimal hyperplasia cause structural narrowing of

the arterioles. Increased susceptibility to renal ischemia may also occur inmalignant hypertension because of intimal thickening and fibrinoid necrosisof the small arteries and arterioles. In addition, in chronic kidney disease,afferent arterioles in the functioning glomeruli become dilated, whichincreases their filtration rate (hyperfiltration). Although an increasedglomerular filtration rate per nephron compensates for the loss of nephrons,the inability to vasodilate further markedly impairs the kidney's ability toautoregulate the glomerular filtration rate in low-perfusion states.

Failure of afferent resistance to decrease can also occur when a

patient is receiving nonsteroidal antiinflammatory drugs (NSAIDs) orcyclooxygenase-2 (COX-2) inhibitors, which reduce the synthesis ofvasodilatory prostaglandins in the kidneys (Figure 2C).16,18,19,20 When thisoccurs, angiotensin II, norepinephrine, and other vasoconstrictors released inlow-perfusion states may act on the afferent arterioles unopposed, furtherdecreasing glomerular capillary pressure. In other situations, sepsis,hypercalcemia, severe liver failure, calcineurin inhibitors, and radiocontrastagents can act through various vasoconstrictor mediators to increaseafferent arteriolar resistance. In addition, sepsis and contrast agents mayhave direct toxic effects on the tubules. Decreased renal perfusion may alsocause an exaggerated drop in the glomerular filtration rate for example,

when angiotensin II does not raise efferent resistance in patients who arereceiving angiotensin-receptor blockers or angiotensin-convertingenzyme(ACE) inhibitors.

Narrowing of the main renal arteries due to atherosclerosis canincrease susceptibility to renal ischemia. In the case of unilateral renal-arterystenosis, the contralateral, normally perfused kidney maintains theglomerular filtration rate; however, renal failure may occur if renal-arterystenosis in a solitary kidney or in both kidneys is greater than 70% of thelumen.16 Renovascular insufficiency affecting the total renal mass may not


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reduce poststenotic perfusion pressure enough to impair glomerularfiltration, but lowering blood pressure with antihypertensive therapy canworsen ischemia and reduce renal function.

Low-Perfusion States in Normotensive Renal Failure

The cause of classic ischemic acute renal failure is hypovolemic,cardiogenic, or distributive shock, with systolic blood pressure typicallydropping below 90 mm Hg. Normotensive renal failure usually involvesmilder degrees of these low-perfusion processes but azotemia occursbecause of factors that increase renal susceptibility to ischemia, asdescribed above.

A less common mechanism for normotensive renal failure is severehypoperfusion in the presence of increased levels of vasoconstrictivesubstances that limit the drop in blood pressure but that may occasionally

increase the measured blood pressure. Hypoperfusion may be systemic; forexample, in acute myocardial infarction or acute pulmonary edema, lowcardiac output may be accompanied by stable or even elevated bloodpressure mediated by sympathetic discharge. Hypercalcemia may increaseafferent glomerular arteriolar resistance, as mentioned above, and may leadto marked hypovolemia because it may increase renal fluid losses.Hypercalcemia may simultaneously cause systemic vasoconstriction, whichmay paradoxically maintain or increase blood pressure.

Conversely, the severe hypoperfusion may be local: in renal-arterystenosis, the poststenotic drop in blood pressure causes intrarenal ischemia

but is accompanied by hypertension from hypervolemia or renin release intothe circulation. Small-vessel disease in malignant hypertension similarlyleads to renal ischemia with increased renin secretion, which worsens thehypertension.

Diagnosis of Normotensive Ischemic Acute Renal Failure

Common conditions in which normotensive ischemic acute renal failuremay develop include hypertension, chronic kidney disease, and old age, allof which are associated with narrowing and blunted vasodilatory capacity ofrenal vessels. Other conditions include cirrhosis, infection, myocardial

infarction, and congestive heart failure, as well as decreased intake of food,which can reduce renal perfusion. In addition, diuretics reduce extracellularvolume, which can compromise cardiac output, and medications such as ACEinhibitors and NSAIDs interfere with autoregulation. In classic ischemic acuterenal failure, when a patient goes into shock, the physician should be vigilantin looking for a decrease in urinary output and an increase in the serumcreatinine concentration. In the normotensive variant, when the urinaryoutput decreases or the creatinine concentration increases, the clinicianshould look for the presence of a low-perfusion state that may not have beenreadily apparent. On the first day during which the creatinine concentration


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increases, the blood pressure is usually noted to be below its usual level. Inpersons who have underlying hypertension, blood pressure decreases fromhigh to normal (e.g., a drop in systolic blood pressure from 160 to 118 mmHg). Since patients are normotensive when renal failure occurs, the decreasein blood pressure may be overlooked. Frequently the patient's usual blood

pressure is not recorded alongside current blood pressures; the usual bloodpressure must be ascertained from medical records and compared with theblood pressures when the serum creatinine concentration began to rise. Inpatients with hypovolemia, blood pressure must often be measured in theupright position to confirm the degree and orthostatic nature of the declinein blood pressure.

The cause of the decline in blood pressure may not be apparent. Thefollowing two scenarios are not uncommon. In the first, a patient has whatturns out to be early sepsis but at the onset does not have fever or anylocalizing symptoms. Such patients usually have one or more of the following

signs or symptoms: hypothermia, confusion, cool extremities, leukocytosis,"bandemia" (an elevated level of band forms of white cells), leukopenia, orunexplained lactic acidosis. Especially in patients with relative hypotensionand acute renal failure, any of these clinical pictures should lead the clinicianto search for an occult infection, using physical examination, imaging, andmicrobiologic studies.

Alternatively, a patient in stable condition who is receiving diuretics forhypertension or congestive heart failure may have anorexia and stop eatingfor some reason or may otherwise have decreased salt intake. Progressivenegative sodium balance results in volume depletion and a downward drift in

blood pressure. Patients may not be aware of decreases in oral intake or maynot volunteer the information spontaneously. Thus, the clinician needs toquestion the patient, family, and caregivers about recent weight loss orchanges in diet.

In addition to watching for low-perfusion states, clinicians should try toidentify susceptibility factors for renal ischemia (Table 1). Becausenormotensive renal failure is multifactorial, several low-perfusion states andsusceptibility factors may be present. It is important to ask about thepatient's use of over-the-counter NSAIDs that might change renal perfusionand to obtain a measurement of the serum calcium concentration, corrected

for any degree of hypoalbuminemia that is present. Sepsis, hypercalcemia,and the hepatorenal syndrome may all cause both low-perfusion states andincreased afferent arteriolar resistance.

Susceptibility factors may sometimes result in ischemic acute renalfailure in the absence of a low-perfusion state. In these cases, the factorsresult in severe enough renal vasoconstriction to cause a critical reduction inrenal perfusion. Examples are radiocontrast agents given to patients withchronic renal failure and cyclosporine, tacrolimus, NSAIDs, or COX-2inhibitors given in high or supratherapeutic doses.


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Patients with malignant hypertension, renal-artery stenosis in a solitarykidney, or bilateral renal-artery stenosis have severe hypertension onpresentation but also have compromised renal perfusion. As high bloodpressure is controlled, renal function may worsen because of a critical drop

in glomerular capillary pressure. Once low-perfusion states and susceptibilityfactors are recognized, a tentative diagnosis of normotensive renal failurecan be made, supported by laboratory findings and a response to therapy.

Laboratory Findings

Low-perfusion states trigger the body's water- and sodium-conservingmechanisms. Thus, by the time glomerular capillary pressure and glomerularfiltration rate drop, the renal tubule is reabsorbing more water and sodium,which also increases passive reabsorption of urea. There is experimentalevidence that this increase in reabsorption is facilitated by increased

expression of urea transporters in the collecting duct, mediated by highplasma vasopressin concentrations.37 As a result of these changes, thespecific gravity of the urine often increases to 1.015 or higher, while urinarysodium and urea excretion decrease (urinary sodium,


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blood pressure that is on the lower end of the normal range should beincreased by correction of any hypovolemia and by dose reduction ordiscontinuation of antihypertensive medication and other medications thatmay lower blood pressure (e.g., narcotics). The patient should be evaluatedfor occult infection, and any such infection should be treated. If acute tubular

necrosis has not yet occurred, effective therapy can reverse the increase inthe creatinine concentration within 24 to 48 hours. Improvement may evenoccur if only one of the causes is reversed for example, stoppingtreatment with NSAIDs may be beneficial in a patient with severecardiomyopathy. However, if acute tubular necrosis has occurred, severaldays are usually required before improvement is seen, even after theunderlying causes have been treated. If the cause of acute renal failure isnot apparent or if the patient's condition does not improve, consultation witha nephrologist may help to ensure complete assessment and appropriatemanagement.

Reaction

An acute increase in the serum creatinine concentration is usually dueto renal ischemia. If the patient does not have frank hypotension,normotensive ischemic acute renal failure must be considered. A drop insystolic blood pressure to the low-normal range (100 to 115 mm Hg) mustnot be overlooked. Many cases can be treated quickly by replacing volume,treating infection, or stopping medications such as NSAIDs, diuretics, andantihypertensive agents, especially ACE inhibitors or angiotensin-receptorblockers.

Adequate nutrition should be provided; malnutrition is associated withincreased complications and death in patients with acute renal failure. Suchpatients frequently have accelerated protein breakdown and increasedcaloric needs, especially if they are critically ill or receiving renal-replacement therapy (hemodialysis). In general, daily intake should include25 to 30 kcal per kilogram of body weight; catabolic patients should receiveup to 1.5 g of protein per kilogram daily. Enteral nutrition with food orformula designed for renal failure is preferred over parenteral nutrition, whenpossible, because it maintains the integrity of the gut, requires less fluidintake, and is less expensive.41,45,46 Advice from a dietitian or a nutritionconsultant may be helpful. Although intake of potassium and phosphate is

typically restricted because of impaired renal excretion, hypokalemia andhypophosphatemia due to cell uptake or external losses can occur, andsupplements may be required.

Indications for intermittent or continuous renal-replacement therapyare florid uremic symptoms, volume overload, hyperkalemia, and metabolicacidosis that cannot be managed by conservative means. How severe theseproblems need to be before treatment is initiated is controversial. Argumentsin favor of starting renal-replacement therapy early may be based on thedesire to avoid the dangerous metabolic, fluid, and electrolyte derangements


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of uremia47; arguments in favor of withholding renal-replacement therapyuntil definite indications are present are based on the risk of hemorrhageduring vascular access, hypotension and arrhythmia during dialysis, andpossible dialysis-induced recurrent renal injury or delayed renal recovery.48Existing data on the timing of renal-replacement therapy are inadequate to

provide clear guidance.47,49 Unfortunately, many patients withnormotensive renal failure have important complicating factors, such as oldage, sepsis, and heart disease, and progression to frank shock and death isnot unusual.

ACUTE RENAL FAILURE

The sudden interruption of renal function that can be caused by obstruction,poor circulation or underlying kidney disease.


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Causes1. Pre-renal:o Conditions that diminishes renal perfusion to kidneys causing

hypoperfusion.

Cardiacarrhythmias

Cardiactamponade

Cardiogenicshock

Heart failure

Myocardialinfarction

Burns

Dehydration

Diureticoveruse

Hemorrhage

Hypovolemicshock

Trauma

Anti-hypentensivedrugs

Sepsis

Arterialembolsim

Arterial/venousthrombosis

Tumor Disseminated

intravascularcoagulation (DIC)

Eclampsia

Malignant

hypertension Vasculitis

o When renal blood flow is diminished, so is oxygen delivery. The resulting

hypoxemia causes rapid and irreversible damages to the renal system,especially to the tubules.

o Renal hypoperfusion results to decreased glomerular filtration rate,

azotemia and increased tubular reabsorption of sodium and water.o The decrease in GFR causes electrolyte imbalances and metabolic

acidosis.

2. Renal:o Also called intrinsic or parenchymal renal failure, results from damage to

the filtering structures of the kidneys.o 3 classifications: nephrotoxic

o inflammatory

o ischemic

Poorly treated prerenal failure Nephrotoxins (aminoglycosides, analgesics, heavy metals, radiographic

contrast media, organic solvents, 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


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Renal myeloma

Sickle cell disease

Systemic lupus erythematosus (SLE)

Vasculitis


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o In nephrotoxic damage, the delicate layer under the epithelium

(basement membrane) becomes irreversibly damaged, typically leadingto chronic renal failure.

o Ischemic tissues generate toxic oxygen-free free radicals, which cause

swelling, injury and necrosis.o Nephrotoxic drugs accumulate in the renal cortex, causing renal failure

that manifests after treatment or other exposures.o Nephrotoxin damage tends to be limited in the proximal tubules, while

ischemic necrosis tends to distribute along parts of the nephron.3. Post-renal:o Bladder obstruction

(anticholinergic drugs, autonomin nerve dysfunction,infection, tumors)

o Ureteral obstruction restricts urine flow from kidneys to bladder

(blood clots, calculi, edema, necrotic renal papillae, retroperitoneal

fibrosis or hemorrhage, accidental ligation, uric acid crystals,tumors)

o Urethral obstruction by BPH, tumors/stricture

Phases of ARF: Oliguric, Diuretic, Recoveryo Oliguric phase urine output may remain at less than 40 mL/hour or

400 mL/day for a few days or weekso Diuretic phase marked by increased urine output of more than 400

mL/day, as the kidneys become unable to conserve sodium and water.this phase causes dehydration and electrolyte imbalances.

o Recovery phase azotemia gradually disappears; urine output returns

to normal or near-normal renal function over 3-12 months.

Signs and Symptomso Early signs: oliguria, azotemia and/or anuria

o GI: anorexia, nausea, vomiting, diarrhea-constipation, stomatitis,

bleeding, hematemesis, dry mucous membranes, uremic breatho CNS: headache, drowsiness, irritability, confusion, peripheral

neuropathy, seizures, comao Integument: Dryness, pruritus, pallor, purpura, uremic frost

o Cardiovascular: hypotension, then hypertension, arrhythmias, fluid

overload, heart failure, anasarca, anemia, altered clotting mechanismso Respiratory: pulmonary edema, Kussmauls respirations (indicates

metabolic acidosis)

Diagnosiso Hyperkalemia, decreased bicarbonate levels, acidemia (low blood pH)


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o Urinalysis: casts, decreased urine specific gravity, proteinuria, urine

osmolality close to serum osmolality, urine sodium level 40 mEq/L (if intrarenal cause)

o Creatinine clearance test:

o Electrocardiogram: tall, peaked T waves, widened QRS complex,

disappearing P waves (hyperkalemia)o Ultrasonography: plain abdominal films, KUB radiography, excretory

urography, renal scan, retrograde pyelography, CT scan

Medical Management:

A. Fluid Management:1. Push fluid + 200-500 cc NSS to rule out pre-renal azotemia; I&O catheterand check post-void residual to rule out obstruction.2. Furosemide (Lasix) 100-200 mg IVP or Mannitol 20% 500 cc x 2 doses.

Observe for 2 hours for complications: CHF, pulmonary edema3. Dopamine 1 amp 200 mg + D5W 250 cc x 10 ugtts/min4. Consider CVP insertion, maintain euvolemiaTotal Fluid Intake= Urine output Yesterday + 500 cc insensible water lossIn oliguric patients (400 ml/day) limit to < 1L/day

B. Diet/Nutritional Support:1. For weight maintenance: High Caloric Intake

Low protein = 0.5 g/kg/day (to decrease nitrogenouswastes)

Carbohydrates: 100 g/day PO4 = 800mg/dayNaCl = < 1 g/day Mg = none

2. For weight gain = add 1,000 kcal/day for gain of approx 1 kg/week

C. Electrolytes:1. Hyperkalemia2. Metabolic acidosis3. Hypocalcemia4. Hyperphosphatemia

5. Hyperuricemia: no treatment unless with gout (Allopurinol 300 mg/dayfor 2 days then 100 mg/day)

6. Avoid Mg-containing antacids, NSAIDS and other nephrotoxins

D. Adjust all drug dosages according to GFR

E. Indications for initiating hemodialysiso Pulmonary congestion (unresponsive to Lasix)


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o Severe metabolic acidosis

o severe hyperkalemia

o BUN >100 mg/dl or creatinine > 9 mg/dl

Nursing Management:

o Weigh dailyo Insert Foley catheter

o Avoid Mg-containing antacids, salt substitutes, NSAIDS and other

nephrotoxic agentso Dont take BP or insert IV line on left (or right) arm

Possible Nursing Diagnoses

Fluid Volume Deficit r/t hypovolemia, followed by Fluid VolumeExcess r/t inability of kidneys to produce urine secondary to ARF

o Plan: Client will not develop FVD and ARF, or client will

not develop FVE, as shown by return to balanced intakeand output.

o Interventions:

o Strictly monitor clients fluid intake and output every shift.

o Monitor clients vital signs q1h with neurochecks, call

physician if UO


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o Monitor client for sign of skin breakdown q shift.

o Provide frequent turning of client q2h

o Encourage range-of-motion (ROM) exercises OD.

High Risk for Infection r/t lowered resistance

o Plan: The client will not develop infection, as evidencedby normal vital signs and white blood cell count.

o Interventions:o Monitor laboratory results daily.

o Check client for signs of infection.

o Check Foley catheter for signs of contamination.

Anxiety r/t progressive disease processo Plan:The client will be able to cope with present anxiety

as shown by calmness and acceptance to presentcondition.

o Interventions:

o Allow client time to ask questions.

o Give careful explanations for treatment modalities.

Drug Study

The goal of treatment is to control symptoms, reduce complications,

and slow the progression of the disease. Diseases that cause or result fromchronic kidney failure must be controlled and treated as appropriate.

Blood transfusions or medications such as iron and erythropoietinsupplements may be needed to control anemia.

Fluids may be restricted, often to an amount equal to the volume ofurine produced. Restricting the amount of protein in the diet may slow thebuild up of wastes in the blood and control associated symptoms such asnausea and vomiting.

Salt, potassium, phosphorus, and other electrolytes may be restricted.Dialysis or kidney transplant may eventually be needed.

The medications given are directed on underlying cause of the acute

renal failure or to prevent complications.For instance, patient may take antibiotics to prevent or treat infections,

and may take other medicines to get rid of extra fluid and preventelectrolyte imbalances, which can be dangerous. Health care provider mayadjust the dose of medicines so that they work well.

Diuretic medications, such as furosemide, have traditionally been usedto treat acute renal failure because they quickly increase urine output. Butmany experts now feel that they may not be helpful and may actually be


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harmful to people who are very ill. Depending on the cause and severity ofyour acute renal failure, your doctor may choose another method to get ridof extra fluids.

Furosemide

Furosemide is a loop diuretic (water pill) that prevents your body fromabsorbing too much salt, allowing the salt to instead be passed in yoururine.It treats fluid retention (edema) in people with congestive heart failure,liver disease, or a kidney disorder such as nephrotic syndrome. Thismedication is also used to treat high blood pressure (hypertension).

Side Effects: dry mouth, thirst, nausea, vomiting; feeling weak, drowsy, restless, or light-headed; fast or uneven heartbeat; muscle pain or weakness;

urinating less than usual or not at all; easy bruising or bleeding, unusual weakness; a red, blistering, peeling skin rash; hearing loss; or nausea, stomach pain, low fever, loss of appetite, dark urine, clay-

colored stools, jaundice (yellowing of the skin or eyes).Less serious side effects may include:

diarrhea, constipation, or stomach pain; headache; numbness, burning, pain, or tingly feeling; dizziness; or blurred vision

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