Chapter 9. Acute Kidney Injury

• Acute increase in blood urea nitrogen (BUN) and serum creatinine.
• May be associated with oliguria or normal urine output.
• Symptoms and signs depend on cause.

Acute kidney injury (AKI) is a life-threatening disease process occurring in approximately 5% of all hospitalized patients and accounting for up to 30% of the admissions to intensive care units. AKI is preferred to acute renal failure as both kidney and injury are more patient-appropriate terms. Patients with AKI, regardless of their associated comorbid conditions, have a greater than 5-fold increased mortality rate. AKI is characterized by a reduction in the glomerular filtration rate (GFR) resulting in retention of nitrogenous wastes (creatinine, BUN, and other molecules that are not routinely measured). Early in the course of AKI patients are often asymptomatic and the condition is diagnosed only by observed elevations of BUN and serum creatinine levels or oliguria. An initial rise in serum creatinine of 0.5 mg/dL or a 25% increase in serum creatinine is often used to define AKI, although there is no definitive definition.

Oliguria (urine output less than 400 mL per 24 hours or 15 mL per hour) occurs commonly in AKI and may be an important indicator of renal dysfunction. However, urine output cannot be the only measure of kidney function. Patients with nonoliguric AKI usually have a better prognosis primarily due to less severe injury and/or a higher incidence of nephrotoxic-induced AKI in the nonoliguric group. Unfortunately, there has been little improvement in survival from AKI since the advent of hemodialysis and the mortality remains greater than 50% in many studies.

The RIFLE criteria consists of various graded levels of kidney injury based upon percent rise in serum creatinine, urine output and outcome measures.

Risk: 1.5-fold increase in the serum creatinine or GFR decrease by 25 percent or urine output <0.5 mL/kg per hour for six hours

Injury: Twofold increase in the serum creatinine or GFR decrease by 50 percent or urine output <0.5 mL/kg per hour for 12 hours

Failure: Threefold increase in the serum creatinine or GFR decrease by 75 percent or urine output of <0.5 mL/kg per hour for 24 hours, or anuria for 12 hours

Loss: Complete loss of kidney function (eg, need for renal replacement therapy) for more than four weeks

ESRD: Complete loss of kidney function (eg, need for renal replacement therapy) for more than three months

The AKIN (Acute Kidney Injury Network) criteria are a modification of the RIFLE criteria and include both diagnostic and staging system.

Stage 1. Increase in serum creatinine ≥0.3 mg/dl or 1.5 to 2 fold increase from baseline or urine output less than 0.5 mL/kg per hour for more than 6 hours

Stage 2. Increase in serum creatinine >2-3 folds from baseline or urine output less than 0.5 mL/kg per hour for more than 12 hours

Stage 3. Increase in serum creatinine >3 fold from baseline or serum creatinine of ≥4.0 mg/dl with an acute rise of at least 0.5 mg/dl or urine output less than 0.3 mL/kg per hour for 24 hours or anuria for 12 hours.

The etiology of AKI is best divided into prerenal, intrarenal, and postrenal causes.

Prerenal Azotemia

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.

The fractional excretion of sodium is calculated as follows:

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.

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.

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.

Intrarenal Acute Kidney Injury

Intrinsic AKI is subdivided into four categories: tubular disease, glomerular disease, interstitial disease, and vascular disease (Table 9–2).

Acute Tubular Necrosis

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.

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.

Acute Kidney Injury and Sepsis

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.

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.

Nephrotoxins

Nephrotoxins induce tubular cell injury by several primary mechanisms including direct cellular injury, vasoconstriction, and tubular obstruction.

Exogenous Nephrotoxins

Antibiotics

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.

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).

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.

Radiographic Contrast Media

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.

Intratubular Obstruction

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.

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.

Ethylene Glycol

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.

Endogenous Nephrotoxins

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.

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.

Glomerular Disease

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.

Interstitial Nephritis

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.

Vascular Disease

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.

Postrenal Acute Kidney Injury

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.

The underlying principles of identification of high-risk patients, use of preventative measures, and aggressive surveillance are of key importance. Prevention of AKI is of paramount importance. Certain risk factors that have been identified to enhance the likelihood of AKI are listed in Table 9–3. These include volume depletion or hypoperfusion, preexisting renal failure, and exposure to vasoconstricting drugs such as NSAIDs.

Prevention of AKI primarily involves recognition of the high risk patient and correction of volume depletion. Persistent volume depletion leads to a prolonged “extension phase” resulting in worsening ATN. Aggressive restoration of intravascular volume dramatically reduces the incidence of ATN after major surgery or trauma. The mortality of AKI is higher if it develops in the hospital. Therefore, it is imperative to prevent AKI, particularly if it is associated with nephrotoxic drugs and interventional procedures. Correction of hypovolemia (normalizing the effective arterial volume) before radiocontrast administration, surgical procedures, and nephrology consultation in patients with even minimally decreased renal function may decrease the frequency of AKI. For the prevention of contrast-induced nephropathy, prophylactic infusion of saline (1 mL/kg for 12 hours before and after the procedure) appears more effective in preventing AKI than other commonly used agents such as mannitol and furosemide. N-Acetylcysteine and sodium bicarbonate infusion may also be beneficial in the prevention of contrast-induced nephropathy. Finally, since many cases of ischemic or nephrotoxic AKI result from sepsis or use of nephrotoxic antibiotics, respectively, limiting infection and careful monitoring for infections are important strategies.

Symptoms and Signs

Unfortunately, the signs and symptoms are limited, nondiagnostic, and often go unrecognized. The symptoms of AKI include those related to azotemia generally and those due to underlying cause. Suggestive symptoms include a decrease in urine output and dark and cola-colored urine. Azotemic patients often complain of anorexia, nausea, malaise, metallic taste in the mouth, itching, confusion, fluid retention, and hypertension. Physical examination may reveal signs of volume overload, pericardial friction rub, or asterixis. This is why aggressive laboratory surveillance in high-risk patients is necessary.

Laboratory Findings

The diagnosis of AKI is made by documenting elevations of the BUN and serum creatinine. Serum cystatin C is also a useful marker of AKI, and may detect AKI 1–2 days earlier than serum creatinine. Cystatin C is a 13-kDa endogenous cysteine protease inhibitor produced by nucleated cells at a constant rate. It is freely filtered at the glomerulus, reabsorbed, and catabolized, but it is not secreted by tubules.

Classifying intrinsic AKI into one of the histologic sites is in large part dependent upon the urinanalysis. For example, in ischemic or nephrotoxin-induced AKI the urinalysis shows mild proteinuria and often pigmented granular casts. However, in acute glomerulonephritis there is a higher degree of proteinuria, white blood cells, erythrocytes, and cellular casts. In interstitial nephritis, urinalysis shows mild to moderate proteinuria, leukocytes, erythrocytes, and eosinophils. The presence of heme positivity on the urine dipstick in a freshly voided sample and no erythrocytes suggest the presence of myoglobin or free hemoglobin, indicating either rhabdomyolysis or hemolysis. The presence of eosinophils is suggestive of acute interstitial nephritis, but can also be seen in renal atheroembolism or pyelonephritis. Specific urinary crystals can also be indicative of causes of AKI. For example, calcium oxalate crystals are seen in cases of ethylene glycol ingestion, and uric acid crystals are seen in cases of tumor lysis syndrome. Urinary diagnostic indices should be sent in any case in which prerenal azotemia is in the differential diagnosis. Glomerulonephritis and acute interstitial nephritis require kidney biopsy for diagnosis. Table 9–4 lists the urine findings suggestive of specific etiologies of AKI.

It is important to remember that a very high serum creatinine does not preclude the diagnosis of prerenal azotemia. A low FeNa+, less than 1%, is generally indicative of prerenal azotemia as the etiology of AKI. If the patient had existing CKD, prior to developing AKI, a high FeNa+ may not indicate ATN. In CKD patients adaptation to volume depletion may take days, not hours, and FeNa+ may be falsely high. An ultrasound is done to evaluate for obstruction. If the clinical situation dictates evaluation of renal vasculature with isotope scans, Doppler flow studies or angiography should be utilized. Figure 9–2 outlines the clinical approach to the common causes of AKI.

Hyperkalemia

In patients with AKI the serum potassium rises rapidly, especially in the presence of cell lysis such as occurs with muscle injury, hemolysis, gastrointestinal ischemia, tumor lysis syndrome, high fever, or blood transfusions. Hyperkalemia is further aggravated by metabolic acidosis as potassium is shifted from the intracellular to the extracellular compartment. The serum potassium concentration can be temporarily lowered by the administration of glucose and insulin, bicarbonate, inhaled β2-agonists, and potassium-binding resins. However, if renal failure persists hyperkalemia will continue to reoccur and will ultimately respond only to renal replacement therapy (RRT). As AKI patients are more prone to the cardiotoxic side effects of hyperkalemia, the serum potassium level should be lowered to nontoxic levels as soon as possible. Potassium is a small molecule and is easily dialyzable. Even at a blood flow of 200 mL/minute, dialysate potassium concentration of 1 mmol/L, and starting serum potassium concentration of 6 mmol/L, about 60 mmol of potassium is removed per hour.

Metabolic Acidosis

The severity of metabolic acidosis cannot usually be explained by the normal production rate of 1 mEq/kg/day of hydrogen ions. Patients with AKI are often in a hypercatabolic state (fever, trauma, sepsis) and, in addition, lactic acidosis may also occur because of anaerobic metabolism (hypoperfusion). The addition of respiratory acidosis, secondary to CO2 retention, to metabolic acidosis can result in severe acidemia (pH <7.1) that may have severe negative inotropic and metabolic effects. Correction of a metabolic acidosis with administration of intravenous sodium bicarbonate is limited by the risk of hypervolemia and/or hypernatremia. Since bicarbonate is the commonly used buffer in hemodialysis dialysate, dialysis will result in reasonable control of metabolic acidosis and removal of organic acids. Continuous forms of dialysis have also been shown to be effective in the correction of severe acidosis.

Volume Overload

Volume overload is a major problem in oliguric AKI (urine output <400 mL/day). Critically ill patients are at high risk of developing hypervolemia, as fluid restriction is not always feasible because of the need for intravenous administration of drugs, nutrition, blood, and blood products. In addition, patients often receive aggressive fluid resuscitation in the early phase of their illness. This may result in pulmonary and peripheral edema when this fluid is redistributed later during their illness.

The most useful therapy for volume overload is loop diuretics. Furosemide or other loop diuretics can be given intravenously as a bolus or by continuous infusion. If started in the early stages of AKI this intervention, along with fluid restriction, can be very beneficial in preventing or minimizing volume overload. When using diuretics it is important to avoid volume depletion as the lack of renal autoregulation during AKI leaves the kidney vulnerable to additional hypotensive insults.

Hemofiltration, both by hemodialysis or continuous renal replacement therapy (CRRT), removes fluid and small-molecular-weight solute by convection and is the treatment modality of choice for fluid removal in hemodynamically unstable patients. In oliguric patients with a degree of fluid overload, who are about to receive large amounts of fluids for therapeutic purposes, RRT should be initiated early with the aim of preventing clinically important pulmonary edema. Episodes of hypotension should be avoided as renal functional recovery may be retarded because of recurrent ischemia and cell injury.

Hyponatremia

Hyponatremia is usually associated with volume overload. The clinical manifestations of hyponatremia are primarily neurologic in nature. Symptomatic hyponatremia should be treated aggressively but also with caution as rapid correction of low sodium levels can lead to central pontine myelinolysis if the duration of electrolyte imbalance has been longer than 48 hours. The targeted range of change of sodium level should be 1–2 mEq/L/hour until symptoms resolve or until the serum sodium level increases to 120 mEq/L.

Anemia

Anemia is very common in patients with AKI. Several mechanisms are involved. The most common cause of anemia associated with AKI is inadequate production of erythropoietin and decreased responsiveness to erythropoietin plays a role. There is also an increase in the rate of destruction of red blood cells as a result of increased erythrocyte fragility. Furthermore, patients with AKI have an increased tendency to bleed from various sites due to platelet dysfunction secondary to azotemia.

Hyperphosphatemia

Hyperphosphatemia is common in patients with AKI. The main mechanism is a decrease in renal excretion, tissue destruction, and shifts from intracellular to extracellular space. If patients can ingest food, hyperphosphatemia should be treated with phosphate binders such as calcium carbonate, calcium acetate, sevelamer HCl, or lanthanum carbonate. If the calcium × phosphorous product is high (>70) or the phosphate concentration exceeds 5.5 mEq/L a non-calcium-based binder such as sevelamer or lanthanum should be used.

Other Electrolyte Imbalances

Hypocalcemia, although common, rarely requires treatment. The factors responsible for hypocalcemia include hypomagnesemia, hyperphosphatemia, resistance to parathyroid hormone, lack of active vitamin D, calcium sequestration in tissues, use of blood products that have been stored in citrate, and use of sodium bicarbonate infusions. Rarely patients may have hypercalcemia if the underlying disorder is malignancy or multiple myeloma. Hypercalcemia can also occur in AKI due to rhabdomyolysis.

Prerenal Azotemia

By definition, prerenal azotemia is rapidly reversible on restoration of renal perfusion. Hypovolemia caused by hemorrhage is ideally corrected with packed red blood cells if the hematocrit is dangerously low. In the absence of active bleeding isotonic saline may suffice. The routine use of colloids has recently been associated with adverse outcomes and this has been called into question. Serum potassium and acid–base status should be monitored in all subjects. Cardiac failure may require aggressive management with positive inotropes, preload- and or afterload-reducing agents, and mechanical aids such as an intraaortic balloon pump. Fluid management is particularly challenging in patients with cirrhosis, requiring careful monitoring to avoid increased ascites formation.

Acute Tubular Necrosis

Management of ATN is usually supportive. Attempts to convert oliguric to nonoliguric AKI may be attempted by giving a loop diuretic such as furosemide. However, volume depletion as a result of the diuretic must be avoided. Use of mannitol should be avoided as it may precipitate congestive heart failure due to intravascular volume expansion if urine output remains low. In oliguric AKI, management consists of restricting fluids to match measurable insensible losses, potassium restriction, and limitation of phosphorous intake.

There are no prospective clinical data to support the use of low-dose dopamine for the protection or improvement of renal function in patients with ATN or AKI. Dopamine has not found to improve survival or eliminate the need for dialysis in AKI.

Role of Renal Replacement Therapy in Acute Kidney Injury

Dialysis is the only Food and Drug Administration-approved treatment of AKI. Although hemodialysis is the standard modality in hemodynamically stable patients with AKI, both continuous renal replacement therapy (CRRT) and peritoneal dialysis are also used in selected cases. The determining factors of which modality is chosen include the catabolic state, hemodynamic stability, and whether the primary goal is solute removal (uremia, hyperkalemia), fluid removal, or both.

Indications for Dialysis

The indications for RRT in patients with AKI include refractory fluid overload, hyperkalemia, severe metabolic acidosis, azotemia, signs of uremia, such as pericarditis, neuropathy, or an otherwise unexplained decline in mental status, and overdose with a dialyzable drug/toxin.

In an attempt to minimize morbidity, dialysis should generally be started prior to the onset of complications due to renal failure. Nephrologists often initiate RRT even in the absence of the above-mentioned indications when the BUN reaches 60–80 mg/dL to prevent complications from AKI. Currently, peritoneal dialysis (PD) is rarely performed in adults as a treatment modality for AKI. This modality can be used in selective patient populations with access difficulties, contraindication to anticoagulation, or patients who are hemodynamically unstable.

Hemodialysis

Frequent hemodialysis is required to control metabolic abnormalities and volume status in AKI. Hypercatabolic patients require more aggressive dialysis to maintain acceptable or optimal steady-state or time-averaged concentrations of solutes. Daily hemodialysis may result in better control of uremia, fewer hypotensive episodes during hemodialysis, and more rapid resolution of AKI than conventional (every other day) hemodialysis.

Continuous Renal Replacement Therapies

Continuous renal replacement therapies (CRRTs) involve either dialysis (diffusion-based solute removal) or filtration (convection-based solute and water removal) treatments that operate in a continuous mode. The various forms of CRRTs include Continuous venovenous hemofiltration (CVVH), Continuous venovenous hemodialysis (CVVHD), Continuous arteriovenous hemodialysis (CAVHD), Continuous venovenous hemodiafiltration (CVVHDF), Slow continuous ultrafiltration (SCUF) and sustained low efficiency dialysis (SLED).

CRRTs have several theoretical advantages over intermittent hemodialysis in critically ill patients with AKI. These include accurate continuous control of volume, increased delivered dose of dialysis, hemodynamic stability, the ability to provide aggressive nutritional support, gradual and continuous removal of fluid and solutes and a possible antiinflammatory effect. Patients with multi-organ failure or sepsis require large amounts of volume in the form of blood products, vasopressors, and parentral nutrition. In these settings, continuous therapies provide an ability to remove fluid, which in most patients achieves an optimal volume balance. The possible elimination of inflammatory mediators is another advantage of CRRT. Many proposed mediators of sepsis have a molecular weight below the cutoff point of hemofilters and thus are filterable. CRRT may also be more beneficial in patients with increased intracranial pressure and combined fulminant hepatic failure and AKI. However, the superiority of CRRT in terms of patient outcomes is still controversial.

Several studies have attempted to assess the optimal dose of continuous renal replacement therapy in acute kidney injury. In one study, patients were randomized to three doses (assessed as effluent flow rate) of continuous venovenous hemofiltration (CVVH): 20 ml/kg per hr, 35 ml/kg per hr, and 45 ml/kg/hr. Although there was a significant improvement in survival with the intermediate dose (35 ml/kg per hour) as compared to the lower dose (25 ml/kg per hour), in non-septic patients there was no added benefit associated with the highest dose (45 ml/kg per hr) of therapy. In another study, CVVH at an average effluent flow rate of 25 ml/kg per hour was compared to continuous venovenous hemodiafiltration (CVVHDF) at an average total effluent flow rate of 42 ml/kg per hour (25 ml/kg per hr ultrafiltration and 18 ml/kg per hour dialysate flow). The higher dose of therapy, delivered as CVVHDF was associated with improved survival. These results suggest that the benefit associated with increased solute clearance can be achieved by either increasing convection (hemofiltration) or adding a diffusive (hemodialysis) component. Thus, an effluent flow rate during CRRT of at least 35 ml/kg per hour is supported by the current data as associated with improved survival as compared to lower doses of therapy. However, no additional survival benefit has been established with higher doses of therapy.

Intensive renal support in critically ill patients with acute kidney injury did not decrease mortality, improve recovery of kidney function, or reduce the rate of non-renal organ failure as compared with less-intensive therapy involving a defined dose of intermittent hemodialysis three times per week and continuous renal-replacement therapy at 20 ml per kilogram per hour.

CRRT also has some disadvantages. Transport of patients for technical investigations becomes far more complicated and many times a new set of disposable tubing have to be used to restart dialysis. Anticoagulation is needed on a continuous basis during CRRT and thus the risk of bleeding is greater in CRRT than HD.

Nutrition in Acute Kidney Injury

Recent evidence indicates more attention should be paid to the nutritional aspect of patients with both chronic renal failure and AKI. Excessive catabolism caused by shock, sepsis, burns, or rhabdomyolysis is common. During sepsis cytokines, including interleukins and tumor necrosis factor, are stimulated and, in turn, increase skeletal muscle breakdown. Severe net protein catabolism may accelerate the rate of rise in plasma concentrations of potassium, phosphorous, nitrogenous metabolites, and non-nitrogen-containing acids. Acute uremia is associated with increased gluconeogenesis and protein degradation as well as reduced protein synthesis. Insulin resistance, secondary hyperparathyrodism, increased glucagon concentrations, and metabolic acidosis also contribute to the malnutrition in AKI.

Renal replacement therapy (RRT) itself can cause increased metabolism through several mechanisms. Inevitable losses of nutrients during RRT also cause increased catabolism. If high flux membranes are used the losses of amino acids increase by 30% as compared to low-flux membranes. The losses of amino acids may range between 7 and 50 g/day with CRRT. This unavoidable removal of nutrients predisposes the AKI patient to negative nitrogen balance. In addition to increased catabolism, AKI patients also have a diminished utilization of available nutrients. Abnormalities in the growth hormone insulin-like growth factor 1 (IGF-1) axis prevent optimal utilization of available nutrients. Although the plasma concentration of growth hormone increases in renal failure, there is growth hormone resistance at the cellular level. Also, many patients are unable to eat adequately because of anorexia or vomiting. Malnutrition is a predictor of outcome in AKI patients.

Protein intake should be around 1.2–1.4 g/kg and 20–25% of daily calories should be provided by lipids. Glucose is usually administered in a 70% solution. The estimated energy requirements for patients with AKI usually fall between 30 and 40 kcal/kg normal body weight/day. Vitamin and mineral requirements have not been well defined for patients with AKI. However, water-soluble vitamins should be supplemented, as these are lost during RRT. Controlled studies are needed as nutrition requirements for HD versus CRRT may be different.

The outcome of patients with AKI has consistently remained at a 50% survival rate despite improved technology. The prognosis for hospitalized patients with AKI depends largely on the site (ICU or ward). In hospitalized patients with AKI caused by ATN, the oliguric phase of ATN typically lasts for 1–2 weeks, but it can persist for 4–6 weeks. It is followed by a diuretic phase. Although uremia and volume overload can be controlled with dialysis, AKI and its complications worsen patient outcomes. Survival after AKI is dramatically influenced by the severity of the underlying illnesses and number of failed organs. The mortality rate of patients with AKI on a ventilator is about 80% and the mortality dramatically increases with an increasing number of failed nonrespiratory organs. Oliguric AKI, developing in a surgical setting or in older patients, carries a higher mortality than other forms of AKI. It has been noted that after discharge from a hospitalization that included AKI, a substantial fraction of patients required RRT in long-term care facilities.

In summary, AKI remains a medical challenge to clinicians and researchers. Recognition of patients at risk, institution of preventive measures and aggressive surveillance, and early treatment of acute kidney injury will be much more effective than treatment of established AKI with RRT.