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The etiology of AKI is best divided into prerenal, intrarenal, and postrenal causes.
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Prerenal azotemia, the most common cause of AKI, accounting for 30–50% of all cases, is characterized by a diminished renal blood flow, primarily due to decreased effective arterial blood flow (Table 9–1). By definition, prerenal azotemia is a rapidly reversible process if recognized early and the underlying cause of reduced renal blood flow is corrected. Prerenal azotemia occurs when there is a reduction in the effective arterial blood flow to the kidney, either from an absolute reduction in the volume of extracellular fluid (eg, hypovolemia) or in conditions in which the effective circulating volume is reduced despite a normal total extracellular fluid volume (eg, congestive heart failure). Effective arterial blood flow is the amount of arterial blood perfusing vital organs. The determinants of effective arterial blood flow include the actual arterial volume, cardiac output, and vascular resistance. It is important to realize that the extracellular fluid (ECF) volume and/or venous volume may have no relationship to effective arterial volume. Although venous and ECF volumes can be accessed by careful physical examination, effective arterial volume cannot. Therefore, in certain circumstances clinicians must rely on additional information beyond the physical examination to ascertain a measure of organ perfusion. Invasive cardiac monitoring and determination of the renal fractional excretion of Na+ (FeNa+) are the useful estimates of effective arterial circulatory volume.
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The fractional excretion of sodium is calculated as follows:
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An FeNa+ of less than 1%, in the setting of an increasing serum creatinine or BUN, is generally indicative of prerenal azotemia as the reduced, renal blood flow results in a sodium avid state. In patients with prerenal azotemia, proximal tubule cells are undamaged and continue to function appropriately to avidly reabsorb Na+ and water. Due to increased proximal reabsorption of Na+ there is decreased distal delivery of Na+ leading to increased renin secretion. This mediates enhanced aldosterone synthesis resulting in increased distal Na+ reabsorption. The end result is a low FeNa+ (<1%). Exceptions to this rule, resulting in a high FeNa+ with prerenal azotemia, include use of diuretics within the previous 24 hours, glucosuria, metabolic alkalosis with high urinary bicarbonate, obligatory loss of Na+, and chronic kidney disease with a high baseline Na+ excretion. A low FeNa+ is also seen in the early stages of acute glomerulonephritis, urinary obstruction, pigment nephropathy, and AKI induced by radiocontrast agents.
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Low effective arterial volume states also stimulate release of antidiuretic hormone (ADH), leading to increased distal urea and water reabsorption. A low fractional excretion of urea nitrogen (<35%) can be especially useful in states of high urinary flow when prerenal azotemia occurs as in cases of high solute administration, such as in burn and trauma patients. The BUN to serum creatinine ratio, which is usually 10:1, also increases (>20:1) as filtered urea is reabsorbed and creatinine is excreted in prerenal azotemia.
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The primary pharmacologic agents causing prerenal azotemia include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and nonsteroidal anti-inflammatory drugs (NSAIDs) including Cox-2 inhibitors. ACE inhibition results in a decreased GFR due to dilation of the efferent arteriole and reduction in glomerular filtration pressure. In certain patients (eg, those with bilateral renal artery stenosis) the GFR is particularly dependent on the effects of angiotensin II. If these patients take an ACE inhibitor, their GFR decreases even though renal blood flow is not reduced. NSAIDs cause prerenal azotemia by blocking the intrarenal vasodilatory effect of prostaglandins. They should be avoided in patients with reduced effective arterial volume including patients with congestive heart failure, liver disease, nephrotic syndrome, and preexisting renal dysfunction.
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Intrarenal Acute Kidney Injury
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Intrinsic AKI is subdivided into four categories: tubular disease, glomerular disease, interstitial disease, and vascular disease (Table 9–2).
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Acute Tubular Necrosis
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Acute tubular cell injury is the most common cause of intrinsic AKI, accounting for approximately 90% of all hospital acquired AKI. Acute tubular necrosis (ATN) is the common term used for this type of AKI, which is usually induced by ischemia, sepsis, or toxins. Acute tubular dysfunction resulting from tubular cell injury is far more common than true cellular necrosis. ATN is usually reversible unless the ischemia was severe enough to cause cortical necrosis, which is associated with severe oliguria or anuria and is rare.
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Tubular cell injury and death are important contributors to alterations in GFR following ischemic injury through several mechanisms. Figure 9–1 outlines the pathophysiology and clinical phases of ischemic AKI. In the initiation phase of AKI there is ATP depletion resulting in proximal tubule, endothelial, and smooth muscle injury and apoptosis. The extension phase of AKI occurs with persistent ischemia, vascular congestion, and ongoing hypoxia. Endothelial damage and activation result in an imbalance in vasoactive mediators and persistent vasoconstriction, particularly in the outer medulla. These mediators and endothelial damage lead to an increase in permeability, which increases interstitial pressure and decreases capillary blood flow. This results in continued hypoxia during reperfusion and enhanced tubular cell injury and death via apoptosis in this area. The end result of these various pathophysiologic processes is further worsening of the GFR. The extension phase is followed by a prolonged maintenance phase in which BUN and creatinine continue to rise. If there is no further injury the recovery phase begins in 1–2 weeks. Apoptosis occurs in all phases leading to remodeling of injured tubules and facilitating their return to a normal structural and functional state. Most cells recover by cellular repair. However, some epithelial cells dedifferentiate, replicate, and migrate to fill the epithelial defect. Thereafter they spread out, become attached to the tubular membrane, and reestablish their polarized differentiated structure.
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Acute Kidney Injury and Sepsis
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AKI occurs in approximately 20-25% of patients with sepsis and 51% with septic shock. The combination of AKI and sepsis is associated with a 70% mortality, as compared with a 45% mortality among patients with AKI alone. Thus, the combination of sepsis and AKI constitutes a particularly serious medical problem. There is experimental evidence that early in sepsis-related AKI the predominant pathogenetic factor is renal vasoconstriction with intact tubular function, as demonstrated by increased reabsorption of tubular sodium and water. Thus, intervention at this early stage may prevent progression to AKI and cell injury. Renal vasoconstriction in sepsis seems to be due, at least in part, to the ability of tumor necrosis factor to release endothelin. Endothelial damage, endotoxemiageneration of oxygen radicals, complement pathway activation, and disseminated intravascular coagulation may all contribute to the pathophysiology of ischemic AKI.
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Since the early vasoconstrictor phase of sepsis and AKI is potentially reversible, it should be an optimal time for intervention. However, clinical studies performed in patients up to 72 hours after admission to the intensive care unit, in which attempts were made to optimize hemodynamics and monitor the patients with a pulmonary artery catheter, not only were negative but showed increased mortality among patients with sepsis. In contrast, a randomized study of over 200 patients showed that early goal-directed therapy during the first 6 hours after admission was effective. In patients treated with this approach, the multiorgan dysfunction score and in-hospital mortality was decreased significantly compared with four patients who received standard care. 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% or more if central venous oxygen saturation was less than 70%. If these interventions failed to increase central venous oxygen saturation to greater than 70%, therapy with dobutamine was instituted.
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Nephrotoxins induce tubular cell injury by several primary mechanisms including direct cellular injury, vasoconstriction, and tubular obstruction.
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Exogenous Nephrotoxins
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Nephrotoxins such as aminoglycosides, amphotericin, heavy metals, foscarnet, pentamidine, and cis-platin cause direct tubular cell injury. The most important manifestation of aminoglycoside nephrotoxicity is AKI secondary to ATN, which occurs in 10–20% of patients receiving aminoglycosides. Maintaining blood levels in the therapeutic range reduces but does not eliminate the risk of nephrotoxicity. Risk factors for developing nephrotoxic nephropathy include use of high or repeated doses or prolonged therapy, advanced age, volume depletion, a reduced effective arterial volume, and the coexistence of renal ischemia or other nephrotoxins. Again, patients with a reduced effective arterial volume are at a markedly increased risk for nephrotoxin-induced AKI. This synergistic interaction may raise the incidence of AKI from a nephrotoxin by as much as a factor of ten.
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AKI caused by aminoglycosides is usually nonoliguric. It is manifested by an increase in BUN and creatinine after about 1 week of therapy, although in patients with concurrent renal hypoperfusion it can occur within 48 hours. Patient may develop polyuria and hypomagnesemia. Once-daily dosing of aminoglycosides is as effective as more frequent dosing and may result in less nephrotoxicity, but should not be used in patients with chronic kidney disease (CKD).
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Cyclosporin and tacrolimus nephrotoxicity is usually dose dependent. High blood levels may help to predict renal failure. In many cases a kidney biopsy may be necessary to distinguish between toxicity and other causes. Renal function usually improves after decreasing the dose or discontinuing the drug.
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Radiographic Contrast Media
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Radiocontrast agents cause both vasoconstriction and direct cellular injury. Contrast nephropathy typically presents as an acute decline in GFR within 24–48 hours following administration. Individuals with reduced baseline kidney function, diabetic nephropathy, severe cardiac failure, volume depletion, and advanced age, as well as those receiving a large dose of contrast and concomitant exposure to other nephrotoxins appear particularly vulnerable and should be volume expanded prior to the study.
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Intratubular Obstruction
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AKI may occur in patients with malignancies with a high rate of tumor cell turnover (tumor lysis syndrome). Such cell turnover may occur either spontaneously or after chemotherapy. There may be an increase in uric acid production and hyperuricosuria, causing uric acid nephropathy. The peak uric acid level is often greater than 20 mg/dL. Prevention of AKI involves establishing a urine output greater than 3–5 L/24 hours and initiating treatment with allopurinol before institution of chemotherapy. Allopurinol blocks uric acid production by inhibiting xanthine oxidase. Urinary alkalization also increases the solubility of xanthine and enhances its excretion. More rapid declines in uric acid levels are seen following the intravenous administration of urate oxidase (uricase, rasburicase), which converts uric acid to allantoin, a much more soluble metabolite.
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Tubular obstruction has been implicated as a central event in the pathophysiology of ATN induced by some therapeutic agents such as acyclovir, sulfonamides, methotrexate, triamterene, ethylene glycol, and myeloma light chains. To minimize possible nephrotoxicity from these agents, hydration and a high urine flow rate should be obtained in these patients.
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Ingestion of ethylene glycol, usually in the form of antifreeze, produces severe metabolic acidosis with an elevated anion gap and osmolar gap. Ethylene glycol is metabolized by alcohol dehydrogenase to glycolic and oxalic acid, which are toxic to the renal tubules. Hypocalcemia is a prominent feature that occurs as a result of the deposition of calcium oxalate in multiple tissues. Calcium oxalate crystals are typically found in the urine sediment. Aggressive intervention with intravenous sodium bicarbonate to increase excretion of glycolate through ion tapping along with intravenous ethanol or fomepizole to block the metabolism of ethylene glycol should be done. In many cases emergent hemodialysis is needed to remove ethylene glycol and glycolate and to correct metabolic acidosis.
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Endogenous Nephrotoxins
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Myoglobinuria as a consequence of rhabdomyolysis is a frequent cause of AKI. The release of large amounts of myoglobin from necrotic muscle tissue in the setting of volume depletion results in ATN. Patients with rhabdomyolysis will frequently complain of muscle pain and have elevated levels of creatine phosphokinase. In addition to trauma, other metabolic derangements that can cause rhabdomyolysis include hypokalemia and hypophosphatemia. Cocaine use, neuroleptic malignant syndrome, and the use of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in the treatment of hypercholesterolemia also contribute or cause rhabdomyolysis. The urine will appear dark brown. The urine dipstick, even in the absence of red blood cells, will be positive for blood because of the presence of myoglobin. Hyperkalemia, hyperphosphatemia, hyperuricemia, and hypocalcemia, followed by hypercalcemia, are other clinical features associated with rhabdomyolysis. The most important aspect of management is rapid volume repletion. Experience from recent disasters has shown that early aggressive hydration and urinary alkalinization are capable of preventing myoglobinuric AKI.
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Massive intravascular hemolysis can be seen in severe transfusion reactions and snake bites and may cause significant hemoglobinuria and ATN. The renal injury in this setting is due to the obstruction by intratubular heme pigment casts and concurrent volume depletion and renal ischemia. In contrast to other forms of acute tubular necrosis, the fractional excretion of sodium is often less than 1%, a finding that may reflect the primacy of tubular obstruction rather than tubular necrosis.
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Glomerulonephritis is characterized by hypertension, proteinuria, and hematuria. Glomerulonephritis that causes AKI is referred to as rapidly progressive glomerulonephritis (RPGN). RPGN can occur in systemic lupus nephritis, Wegener's granulomatosis, polyarteritis nodosa, Goodpasture's syndrome, Henoch–Schönlein purpura, immunologic glomerulonephritis due to infection, and hemolytic uremic syndrome. Together these account for less than 5% of AKI cases.
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Interstitial Nephritis
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Many drugs can induce interstitial nephritis by an idiosyncratic immune-mediated mechanism. This is often associated with fever, maculopapular rash, and eosinophils in the urine. Many drugs can cause acute interstitial nephritis but the most common are NSAIDs, penicillins, cephalosporins, sulfonamides, diuretics, and allopurinol. In the hospital setting AKI is usually multifactorial and it is very important to carefully analyze the hospital course and the medication history of every patient.
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Atheroembolic disease is another important cause of AKI, especially in elderly patients. It may present 1 day to several weeks after undergoing an invasive vascular procedure or major trauma. Patients classically present with lower extremity rash, livedo reticularis, and eosinophils in the urine. Unfortunately, there is no specific treatment. The patient's blood pressure should be controlled and further intra-arterial procedures should be limited.
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Postrenal Acute Kidney Injury
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The primary causes of postrenal AKI include benign prostatic hypertrophy, prostate cancer, cervical cancer, retroperitoneal fibrosis, retroperitoneal lymphoma, metastatic carcinoma, and nephrolithiasis. Blood clots within the urinary tracts can also present with obstruction. Hydronephrosis detected on renal ultrasound examination is the major signal that obstruction is present. False-negative ultrasound examinations can occur if the obstruction is very early or retroperitoneal fibrosis is present.
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