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Acute Kidney Injury (AKI)
(Acute Renal Failure)
Acute kidney injury is a rapid decrease in renal function over days to weeks, causing an accumulation of nitrogenous products in the blood (azotemia). It often results from inadequate renal perfusion due to severe trauma, illness, or surgery but is sometimes caused by a rapidly progressive, intrinsic renal disease. Symptoms include anorexia, nausea, and vomiting. Seizures and coma may occur if the condition is untreated. Fluid, electrolyte, and acid-base disorders develop quickly. Diagnosis is based on laboratory tests of renal function, including serum creatinine. Urinary indices, urinary sediment examination, and often imaging and other tests are needed to determine the cause. Treatment is directed at the cause but also includes fluid and electrolyte management and sometimes dialysis.
In all cases of acute kidney injury (AKI), creatinine and urea build up in the blood over several days, and fluid and electrolyte disorders develop. The most serious of these disorders are hyperkalemia and fluid overload (possibly causing pulmonary edema). Phosphate retention leads to hyperphosphatemia. Hypocalcemia is thought to occur because the impaired kidney no longer produces calcitriol and because hyperphosphatemia causes calcium phosphate precipitation in the tissues. Acidosis develops because hydrogen ions cannot be excreted. With significant uremia, coagulation may be impaired, and pericarditis may develop. Urine output varies with the type and cause of AKI.
Causes of AKI (see Table: Major Causes of Acute Kidney Injury) can be classified as
Prerenal azotemia is due to inadequate renal perfusion. The main causes are
Prerenal conditions cause about 50 to 80% of AKI but do not cause permanent kidney damage (and hence are potentially reversible) unless hypoperfusion is severe enough to cause tubular ischemia. Hypoperfusion of an otherwise functioning kidney leads to enhanced reabsorption of sodium and water, resulting in oliguria with high urine osmolality and low urine sodium.
Renal causes of AKI involve intrinsic kidney disease or damage. Renal causes are responsible for about 10 to 40% of cases. Disorders may involve the glomeruli, tubules, or interstitium. Overall, the most common causes are
Prolonged renal ischemia
Nephrotoxins (including IV use of iodinated radiopaque contrast agents).
Glomerular disease reduces glomerular filtration rate (GFR) and increases glomerular capillary permeability to proteins; it may be inflammatory (glomerulonephritis) or the result of vascular damage due to ischemia or vasculitis.
Tubules also may be damaged by ischemia and may become obstructed by cellular debris, protein or crystal deposition, and cellular or interstitial edema. Tubular damage impairs reabsorption of sodium, so urinary sodium tends to be elevated, which is helpful diagnostically.
Interstitial inflammation (nephritis) usually involves an immunologic or allergic phenomenon. These mechanisms of tubular damage are complex and interdependent, rendering the previously popular term acute tubular necrosis an inadequate description.
Postrenalazotemia ( obstructive nephropathy) is due to various types of obstruction in the voiding and collecting parts of the urinary system and is responsible for about 5 to 10% of cases. Obstruction can also occur within the tubules when crystalline or proteinaceous material precipitates and is often grouped with postrenal failure because the mechanism is obstructive.
Obstructed ultrafiltrate, in tubules or more distally, increases pressure in the urinary space of the glomerulus, reducing GFR. Obstruction also affects renal blood flow, initially increasing the flow and pressure in the glomerular capillary by reducing afferent arteriolar resistance. However, within 3 to 4 h, the renal blood flow is reduced, and by 24 h, it has fallen to < 50% of normal because of increased resistance of renal vasculature. Renovascular resistance may take up to a week to return to normal after relief of a 24-h obstruction.
To produce significant azotemia, obstruction at the level of the ureter requires involvement of both ureters unless the patient has only a single functioning kidney.
Bladder outlet obstruction is probably the most common cause of sudden, and often total, cessation of urinary output in men.
Major Causes of Acute Kidney Injury
Initially, weight gain and peripheral edema may be the only findings. Often, predominant symptoms are those of the underlying illness or those caused by the surgical complication that precipitated renal deterioration.
Symptoms of uremia may develop later as nitrogenous products accumulate. Such symptoms include
Asterixis and hyperreflexia may be present on examination. Chest pain (typically worse with inspiration or when recumbent), a pericardial friction rub, and findings of pericardial tamponade may occur if uremic pericarditis is present. Fluid accumulation in the lungs may cause dyspnea and crackles on auscultation.
Other findings depend on the cause. Urine may be cola-colored in glomerulonephritis or myoglobinuria. A palpable bladder may be present with outlet obstruction. The costovertebral angle may be tender if the kidney is acutely enlarged.
Prerenal causes typically manifest with oliguria, not anuria. Anuria usually occurs only in obstructive uropathy or, less commonly, in bilateral renal artery occlusion, acute cortical necrosis, or rapidly progressive glomerulonephritis.
A relatively preserved urine output of 1 to 2.4 L/day is initially present in most renal causes.
In acute tubular injury, output may have 3 phases:
The prodromal phase, with usually normal urine output, varies in duration depending on causative factors (eg, the amount of toxin ingested, the duration and severity of hypotension).
The oliguric phase, with output typically between 50 and 400 mL/day, lasts an average of 10 to 14 days but varies from 1 day to 8 wk. However, many patients are never oliguric. Nonoliguric patients have lower mortality and morbidity and less need for dialysis.
In the postoliguric phase, urine output gradually returns to normal, but serum creatinine and urea levels may not fall for several more days. Tubular dysfunction may persist for a few days or weeks and is manifested by sodium wasting, polyuria (possibly massive) unresponsive to vasopressin , or hyperchloremic metabolic acidosis.
AKI is suspected when urine output falls or serum BUN and creatinine rise. Evaluation should determine the presence and type of AKI and seek a cause. Blood tests generally include CBC, BUN, creatinine, and electrolytes (including calcium and phosphate). Urine tests include sodium and creatinine concentration and microscopic analysis of sediment. Early detection and treatment increase the chances of reversing renal failure and in some cases preventing it.
A progressive daily rise in serum creatinine is diagnostic of AKI. Serum creatinine can increase by as much as 2 mg/dL/day (180 μmol/L/day), depending on the amount of creatinine produced (which varies with lean body mass) and total body water. A rise of > 2 mg/dL/day suggests overproduction due to rhabdomyolysis.
Urea nitrogen may increase by 10 to 20 mg/dL/day (3.6 to 7.1 mmol urea/L/day), but BUN may be misleading because it is frequently elevated in response to increased protein catabolism resulting from surgery, trauma, corticosteroids, burns, transfusion reactions, parenteral nutrition, or GI or internal bleeding.
When creatinine is rising, 24-h urine collection for creatinine clearance and the various formulas used to calculate creatinine clearance from serum creatinine are inaccurate and should not be used in estimating GFR, because the rise in serum creatinine concentration is a delayed function of GFR decline.
Other laboratory findings are progressive acidosis, hyperkalemia, hyponatremia, and anemia. Acidosis is ordinarily moderate, with a plasma bicarbonate content of 15 to 20 mmol/L. Serum potassium concentration increases slowly, but when catabolism is markedly accelerated, it may rise by 1 to 2 mmol/L/day. Hyponatremia usually is moderate (serum sodium, 125 to 135 mmol/L) and correlates with a surplus of water. Normochromic-normocytic anemia with an Hct of 25 to 30% is typical.
Hyperphosphatemia and hypocalcemia are common in AKI and may be profound in patients with rhabdomyolysis or tumor lysis syndrome . Profound hypocalcemia in rhabdomyolysis apparently results from the combined effects of calcium deposition in necrotic muscle, reduced calcitriol production, resistance of bone to parathyroid hormone (PTH), and hyperphosphatemia. During recovery from AKI following rhabdomyolysis-induced acute tubular necrosis, hypercalcemia may supervene as renal calcitriol production increases, the bone becomes responsive to PTH, and calcium deposits are mobilized from damaged tissue. Hypercalcemia during recovery from AKI is otherwise uncommon.
Immediately reversible prerenal or postrenal causes must be excluded first. ECF volume depletion and obstruction are considered in all patients. The drug history must be accurately reviewed and all potentially renal toxic drugs stopped. Urinary diagnostic indices (see Table: Urinary Diagnostic Indices in Prerenal Azotemia and Acute Tubular Injury) are helpful in distinguishing prerenal azotemia from acute tubular injury, which are the most common causes of AKI in hospitalized patients.
Prerenal causes are often apparent clinically. If so, correction of an underlying hemodynamic abnormality should be attempted. For example, in hypovolemia, volume infusion can be tried, in heart failure, diuretics and afterload reducing drugs can be tried, and in liver failure, octreotide can be tried. Abatement of AKI confirms a prerenal cause.
Urinary Diagnostic Indices in Prerenal Azotemia and Acute Tubular Injury
Postrenal causes should be sought in most cases of AKI. Immediately after the patient voids, bedside ultrasonography of the bladder is done (or, alternatively, a urinary catheter is placed) to determine the residual urine in the bladder. A postvoid residual urine volume > 200 mL suggests bladder outlet obstruction, although detrusor muscle weakness and neurogenic bladder may also cause residual volume of this amount. The catheter may be kept in for the first day to monitor hourly output but is removed once oliguria is confirmed (if bladder outlet obstruction is not present) to decrease risk of infection.
Renal ultrasonography is then done to diagnose more proximal obstruction. However, sensitivity for obstruction is only 80 to 85% when ultrasonography is used because the collecting system is not always dilated, especially when the condition is acute, an intrarenal pelvis is present, the ureter is encased (eg, in retroperitoneal fibrosis or neoplasm), or the patient has concomitant hypovolemia. If obstruction is strongly suspected, noncontrast CT can establish the site of obstruction and guide therapy.
The urinary sedimentmay provide etiologic clues. A normal urine sediment occurs in prerenal azotemia and sometimes in obstructive uropathy. With renal tubular injury, the sediment characteristically contains tubular cells, tubular cell casts, and many granular casts (often with brown pigmentation). Urinary eosinophils suggest allergic tubulointerstitial nephritis, but the diagnostic accuracy of this finding is limited. RBC casts indicate glomerulonephritis or vasculitis but rarely may occur in acute tubular necrosis.
Renal causes are sometimes suggested by clinical findings. Patients with glomerulonephritis often have edema, marked proteinuria (nephrotic syndrome), or signs of arteritis in the skin and retina, often without a history of intrinsic renal disease. Hemoptysis suggests granulomatosis with polyangiitis or Goodpasture syndrome. Certain rashes (eg, erythema nodosum, cutaneous vasculitis, discoid lupus) suggest cryoglobulinemia, SLE, or immunoglobulin A-associated vasculitis. Tubulointerstitial nephritis, drug allergy, and possibly microscopic polyangiitis are suggested by a history of drug ingestion and a maculopapular or purpuric rash.
To further differentiate renal causes, antistreptolysin-O and complement titers, antinuclear antibodies, and antineutrophil cytoplasmic antibodies are determined. Renal biopsy may be done if the diagnosis remains elusive (see Table: Causes of Acute Kidney Injury Based on Laboratory Findings).
Causes of Acute Kidney Injury Based on Laboratory Findings
In addition to renal ultrasonography, other imaging tests are occasionally of use. In evaluating for ureteral obstruction, noncontrast CT is preferred over antegrade and retrograde urography. In addition to its ability to delineate soft-tissue structures and calcium-containing calculi, CT can detect nonradiopaque calculi.
Contrast agents should be avoided if possible. However, renal arteriography or venography may sometimes be indicated if vascular causes are suggested clinically. Magnetic resonance angiography was increasingly being used for diagnosing renal artery stenosis as well as thrombosis of both arteries and veins because MRI used gadolinium, which was thought to be safer than the iodinated contrast agents used in angiography and contrast-enhanced CT. However, recent evidence suggests that gadolinium may be involved in the pathogenesis of nephrogenic systemic fibrosis, a serious complication that occurs in patients with AKI as well as chronic kidney disease. Thus, gadolinium should be avoided if possible in patients with reduced renal function.
Kidney size, as determined with imaging tests, is helpful to know, because a normal or enlarged kidney favors reversibility, whereas a small kidney suggests chronic renal insufficiency.
Although many causes are reversible if diagnosed and treated early, the overall survival rate remains about 50% because many patients with AKI have significant underlying disorders (eg, sepsis, respiratory failure). Death is usually the result of these disorders rather than AKI itself. Most survivors have adequate kidney function. About 10% require dialysis or transplantation—half right away and the others as renal function slowly deteriorates.
Immediate treatment of pulmonary edema and hyperkalemia
Dialysis as needed to control hyperkalemia, pulmonary edema, metabolic acidosis, and uremic symptoms
Adjustment of drug regimen
Usually restriction of water, sodium, phosphate, and potassium intake, but provision of adequate protein
Possibly phosphate binders and sodium polystyrene sulfonate
Life-threatening complications are addressed, preferably in a critical care unit. Pulmonary edema is treated with oxygen, IV vasodilators (eg, nitroglycerin), diuretics (often ineffective in AKI), or dialysis.
Hyperkalemia is treated as needed with IV infusion of 10 mL of 10% calcium gluconate, 50 g of dextrose, and 5 to 10 units of insulin. These drugs do not reduce total body potassium, so further (but slower acting) treatment is needed (eg, sodium polystyrene sulfonate, dialysis).
Although correction of an anion gap metabolic acidosis with sodium bicarbonate is controversial, correction of the nonanion gap portion of severe metabolic acidosis (pH < 7.20) is less controversial. The nonanion gap portion may be treated with IV sodium bicarbonate in the form of a slow infusion (≤ 150 mEq sodium bicarbonate in 1 L of 5% D/W at a rate of 50 to 100 mL/h). Using the delta delta gradient calculation,a normal-anion gap metabolic acidosis plus a high anion-gap metabolic acidosis yields a negative delta delta gradient;.,. sodium bicarbonate is given to raise the serum bicarbonate until the delta delta gradient reaches zero. Because variations in body buffer systems and the rate of acid production are hard to predict, calculating the amount of bicarbonate needed to achieve a full correction is usually not recommended. Instead, bicarbonate is given via continuous infusion and the anion gap is monitored serially.
Severe electrolyte abnormalities cannot otherwise be controlled (eg, potassium > 6 mmol/L)
Pulmonary edema persists despite drug treatment
Metabolic acidosis is unresponsive to treatment
Uremic symptoms occur (eg, vomiting thought to be due to uremia, asterixis, encephalopathy, pericarditis, seizures)
BUN and creatinine levels are probably not the best guides for initiating dialysis in AKI. In asymptomatic patients who are not seriously ill, particularly those in whom return of renal function is considered likely, dialysis can be deferred until symptoms occur, thus avoiding placement of a central venous catheter with its attendant complications.
Nephrotoxic drugs are stopped, and all drugs excreted by the kidneys (eg, digoxin, some antibiotics) are adjusted; serum levels are useful.
Daily water intake is restricted to a volume equal to the previous day’s urine output plus measured extrarenal losses (eg, vomitus) plus 500 to 1000 mL/day for insensible loss. Water intake can be further restricted for hyponatremia or increased for hypernatremia. Although weight gain indicates excess fluid, water intake is not decreased if serum sodium remains normal; instead, dietary sodium is restricted.
Sodium and potassium intake is minimized except in patients with prior deficiencies or GI losses. An adequate diet should be provided, including daily protein intake of about 0.8 g/kg. If oral or enteral nutrition is impossible, parenteral nutrition is used; however, in AKI, risks of fluid overload, hyperosmolality, and infection are increased by IV nutrition. Calcium salts (calcium carbonate, calcium acetate) or synthetic non–calcium-containing phosphate binders before meals help maintain serum phosphate at < 5 mg/dL (< 1.78 mmol/L).
If needed to help maintain serum potassium at < 6 mmol/L in the absence of dialysis (eg, if other therapies, such as diuretics, fail to lower potassium), a cation-exchange resin, sodium polystyrene sulfonate, is given 15 to 60 g po or rectally 1 to 4 times/day as a suspension in water or in a syrup (eg, 70% sorbitol).
An indwelling bladder catheter is rarely needed and should be used only when necessary because of an increased risk of UTI and urosepsis.
In many patients, a brisk and even dramatic diuresis after relief of obstruction is a physiologic response to the expansion of ECF during obstruction and does not compromise volume status. However, polyuria accompanied by the excretion of large amounts of sodium, potassium, magnesium, and other solutes may cause hypokalemia, hyponatremia, hypernatremia (if free water is not provided), hypomagnesemia, or marked contraction of ECF volume with peripheral vascular collapse. In this postoliguric phase, close attention to fluid and electrolyte balance is mandatory. Overzealous administration of salt and water after relief of obstruction can prolong diuresis. When postoliguric diuresis occurs, replacement of urine output with 0.45% saline at about 75% of urine output prevents volume depletion and the tendency for excessive free water loss while allowing the body to eliminate excessive volume if this is the cause of the polyuria.
AKI can often be prevented by maintaining normal fluid balance, blood volume, and BP in patients with trauma, burns, or severe hemorrhage and in those undergoing major surgery. Infusion of isotonic saline and blood may be helpful.
Use of contrast agents should be minimized, particularly in at-risk groups (eg, the elderly and patients with preexisting renal insufficiency, volume depletion, diabetes, or heart failure). If contrast agents are necessary, risk can be lowered by minimizing volume of the IV contrast agent, using nonionic and low osmolal or iso-osmolal contrast agents, avoiding NSAIDs, and pretreating with normal saline at 1 mL/kg/h IV for 12 h before the test. Infusion of isotonic sodium bicarbonate before and after contrast administration has also been used successfully instead of normal saline. N-acetylcysteine 600 mg po bid the day before and the day of IV contrast administration has been used to prevent contrast nephropathy, but reports of its efficacy are conflicting.
Before cytolytic therapy is initiated in patients with certain neoplastic diseases (eg, lymphoma, leukemia), treatment with rasburicase or allopurinol should be considered along with increasing urine flow by increasing oral or IV fluids to reduce urate crystalluria. Making the urine more alkaline (by giving oral or IV sodium bicarbonate or acetazolamide) has been recommended by some but is controversial because it may also induce urinary calcium phosphate precipitation and crystalluria, which may worsen AKI.
The renal vasculature is very sensitive to endothelin, a potent vasoconstrictor that reduces renal blood flow and GFR. Endothelin is implicated in progressive renal damage, and endothelin receptor antagonists have successfully slowed or even halted experimental renal disease. Antiendothelin antibodies and endothelin-receptor antagonists are being studied to protect the kidney against ischemic AKI.
Causes of AKI can be prerenal (eg, kidney hypoperfusion), renal (eg, direct effects on the kidney), or postrenal (eg, urinary tract obstruction distal to the kidneys).
With AKI, consider ECF volume depletion and nephrotoxins, obtain urinary diagnostic indices and measure bladder residual volume to identify obstruction.
Avoid using IV contrast in imaging studies.
Initiate hemodialysis or hemofiltration as needed for pulmonary edema, hyperkalemia, metabolic acidosis, or uremic symptoms unresponsive to other treatments.
Minimize risk of AKI in patients at risk by maintaining normal fluid balance, avoiding nephrotoxins (including contrast agents) when possible, and taking precautions such as giving fluids or drugs when contrast or cytolytic therapy is necessary.
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