Acute Kidney Injury (AKI)
Acute renal failure, Acute renal insufficiency, Acute kidney impairment
K and Mg Imbalance
AKI–Renal replacement therapy
Acute on chronic kidney failure
Pulmonary renal syndrome
AKI during pregnancy
Abdominal compartment syndrome
Nutritional support in the AKI/CKD patient
Acute kidney injury in the infant/child
1. Description of the problem
What every clinician needs to know
AKI is an abrupt and sustained decrease in kidney function
AKI is defined according to modified RIFLE (Risk, Injury, Failure, Loss, End-stage Renal Disease) criteria (also known as KDIGO criteria).
Acute Kidney "injury" or "impairment"
The term “acute kidney injury” (AKI) has been proposed to encompass the entire spectrum of acute changes in renal function, from minor changes in markers of renal function to need for renal replacement therapy.
AKI is not analogous to acute tubular necrosis, nor to acute renal failure. Instead, it encompasses both and also includes other less severe conditions. Indeed, as a syndrome, it includes patients without actual damage to the kidney but with functional impairment relative to physiologic demand. Including such patients in the classification of AKI is conceptually attractive because these are precisely the patients who may benefit from early intervention. However, it means that AKI includes both injury and/or impairment.
Rather than focusing exclusively on patients with renal failure or on those who receive dialysis or who have a clinical syndrome defined by tubular necrosis or pathology (which is usually absent anyway), the strong association of AKI with hospital mortality demands that we change the way we think about this disorder.
Sustained AKI leads to profound alterations in fluid, electrolyte, acid-base, and hormonal regulation. AKI results in abnormalities in the central nervous, immune, and coagulation systems. Many patients with AKI already have multi-system organ failure.
One study examined outcomes for over 1,000 patients enrolled in the control arms of two large sepsis trials (see Levy et al. PUBMED:16215369). In this study early improvement (within 24 hours) in cardiovascular (p =. 0010), renal (p <. 0001), or respiratory (p =. 0469) function was significantly related to survival. This study suggests that outcomes for patients with severe sepsis in the ICU are closely related to early resolution of AKI. While rapid resolution of AKI may simply be a marker of a good prognosis, it may also indicate a window of therapeutic opportunity to improve outcome in such patients.
Clinical manifestations of AKI include azotemia and oliguria (see chapter).
The concept of AKI has undergone significant reexamination in recent years. Mounting evidence suggests that acute, relatively mild, injury to the kidney or impairment of kidney function manifest by changes in urine output and blood chemistries portends serious clinical consequences.
Traditionally most reviews and textbook chapters emphasize the most severe reduction in kidney function, with severe azotemia and often with oliguria or anuria. It has only been in the past few years that moderate decreases of kidney function have been recognized as potentially important in the critically ill and in studies on contrast-induced nephropathy.
The approach to the patient with presumed AKI can be broken down as follows:
It should be understood that AKI is a medical emergency and should be managed promptly and effectively. As such, step one (verify diagnosis) should not involve a comprehensive work-up (this will be accomplished later) but rather a rapid check to ensure that the necessary information is obtained and is correct.
Verify Diagnosis: History of present illness, past medical history, laboratory and physical examination.
History of present illness: AKI occurs in the setting of acute and often critical illness. Sepsis, shock, major surgery, cancer treatment and vascular imaging studies are typical settings. AKI in isolation is rare. The diagnosis should be questioned when the history is not supportive.
Past medical history: To make the diagnosis of AKI using serum creatinine, a baseline serum creatinine is required. The most accurate baseline creatinine is one obtained recently (within a few weeks) while the patient was healthy (i.e., routine lab testing at an annual physical).
However, it is quite common that such a creatinine does not exist. The clinician must then use all available information to determine the baseline creatinine to the best of his or her ability (see “Choosing a Baseline Creatinine” below for more details). Once this creatinine has been determined, it can be used as the reference creatinine for staging of AKI using modified RIFLE criteria (see Table I).
|Stage*||Serum Creatinine**||Urine Output***|
|1 (Risk)||1.5-1.9x baseline serum creatinine||<0.5 ml/kg/h for at least 6 but less than 12 hrs|
|OR a documented increase in serum creatinine of at least 0.3 mg/dl within a 48-hour period|
|2 (Injury)||2.0 -2.9x baseline serum creatinine||<0.5 ml/kg/h for at least 12 hrs|
|3 (Failure)||3 or more x baseline serum creatinine|
|OR an increase in serum creatinine to at least 4 mg/dl with a documented acute increase of at least 0.3 mg/dl with a 48-hour period||<0.3 ml/kg/h for at least 24 hrs|
|OR patients who fullfil any of the above serum creatinine or urine output criteria who require renal replacement therapy||OR anuria (<10 cc) for 12 hrs or more|
*AKI can be diagnosed when any of the above criteria (either serum creatinine OR urine output) are met (see clinical application below) and the stage is defined on the basis of the worst (creatinine or urine output) criterion fulfilled.
**Changes in serum creatinine should be be abrupt (a change of 50% or more within one week or a change of 0.3 mg/dl or more within 48 hours) and sustained (24 hours or more). Note that the criteria allow one to infer timing for the 50% change, but the 0.3-mg/dl change must be documented. Also AKI occurs within an appropriate clinical context, and without such context, it should not be diagnosed (see clinical application under diagnosis below).
***Urine output criteria assume background treatment including assessment and correction of volume status, and patency of urinary tract. Also, for obese patients, ideal body weight should be used to determine the expected urine output rather than actual weight. Use of diuretics does not appear to significantly affect these criteria.
Laboratory: Consider repeating lab tests (creatinine, but also BUN) if there is doubt about accuracy. In patients presenting with an elevated serum creatinine level the primary differential diagnosis involves distinguishing AKI from chronic kidney disease (CKD), with the understanding that AKI is also common in patients with CKD. An approach to such patients is provided in the “Diagnosis” section below. When in doubt, management should begin under the presumption of AKI. Additional laboratory testing is required to determine the etiology of AKI (see below).
Physical exam: Urine output should be measured. This may require bladder catheterization in some patients, but catheterization is not a strict requirement in spontaneously voiding patients. Physical examination should also be used to determine patency of the urinary tract and abdominal findings suggestive of compartment syndrome, and finally, examination is required to assess volume status (jugular venous pulse, orthostatic arterial pressure, etc.). The presence of oliguria in the setting of clinical signs of volume overload is highly suggestive of kidney failure.
Choosing a baseline creatinine
The baseline creatinine refers to the serum creatinine concentration that is thought to represent a patient’s premorbid renal function. When available from the medical record it will be used as the reference creatinine to judge changes in creatinine as a result of AKI so that the patient can be diagnosed with AKI as well as staged for severity. Often the baseline concentration is not available (see “Approach to the Patient with Increased Serum Creatinine and No Known Baseline Creatinine” below).
When multiple prior creatinine values are available from the medical record, typically the most recent should be used as the baseline. However, when values are obtained during an illness and when the patient is well, generally those taken when the patient is well are more representative of the patient’s baseline, even if they are not the most recent. Clinical judgment should be used in such cases.
2. Emergency Management
The first step in emergency management of AKI is to check for immediately life-threatening fluid-electrolyte abnormalities.
Potassium balance is principally controlled by the kidney, and hyperkalemia (see K and MG Imbalance) is the chief immediately life-threatening complication of AKI. K should be checked immediately on diagnosis of AKI and monitored closely.
Disorders of Na, Mg, Cl, Ca, and Phos balance may also occur with AKI, but they are usually not life-threatening.
Fluid overload is a risk of AKI and volume depletion can precipitate AKI. Therefore, attention to volume status is paramount in the management of AKI. Assessment of volume overload includes a chest radiograph and physical exam looking for evidence of edema. Volume depletion can be hard to determine as patients may maintain systemic arterial pressure until late in the course of fluid loss, and typical signs and symptoms of volume loss (e.g., tachycardia, thirst) can be masked by drugs and comorbid illness.
ICU admission is generally indicated for patients with symptomatic hyperkalemia or pulmonary edema secondary to AKI. Emergent renal replacement therapy may be required (see AKI–Renal Replacement Therapy).
The second step is to determine the stage of AKI.
Morbidity and mortality secondary to AKI are tightly correlated with AKI stage. Therefore, once the diagnosis of AKI is made, it’s important to determine the stage and then to follow the patient closely for any progression to a more severe stage.
Stage-based management has been recommended by international guidelines such as KDIGO (www.kdigo.org). However, stage-based management is largely supportive and nonspecific. These management steps do not take the place of specific therapy based on the underlying cause of AKI (see Table II).
|Stage 1**||Stage 2||Stage 3|
|Medications||Discontinue all potentially nephrotoxic drugs where safer alternative exist||Discontinue all non-essential nephrotoxic drugs||Discontinue all nephrotoxic drugs except life-saving agents|
|Review/adjust drug dosing||Review/adjust drug dosing|
|Hemodynamics||Ensure volume status and perfusion pressure||Ensure volume status and perfusion pressure||Ensure volume status and perfusion pressure|
|Consider invasive functional hemodynamic monitoring||Consider invasive functional hemodynamic monitoring|
|Lab monitoring||Monitor serum creatinine, urine output, electrolytes and glucose||Monitor serum creatinine, urine output, electrolytes and glucose||Monitor serum creatinine, urine output, electrolytes and glucose|
|Consider invasive workup||Consider invasive workup|
|Consider renal replacement therapy|
|Other||Consider renal replacement therapy||Consider ICU admission|
|Consider ICU admission||Avoid subclavian catheters if possible|
*Adapted from the KDIGO AKI guideline www.kdigo.com.
**Stage 1 management can also be initiated for high-risk patients.
The next step is to determine the cause of AKI.
Most causes of AKI are not immediately life threatening. Exceptions include abdominal compartment syndrome, HUS/TTP, and certain pulmonary renal syndromes which can be rapidly fatal. In addition, urinary tract obstruction and vascular occlusive disease should be ruled out rapidly to avoid irreversible damage to the kidneys.
Abdominal exam and bladder pressures should be used to assess for abdominal compartment syndrome. Examination of the peripheral smear for schizocytes, platelet counts, and skin exam can effectively rule out HUS/TTP, though incomplete presentation can occur. Presence of red cell casts in the urine should prompt an extensive work-up for glomerular disease.
Renal ultrasound is reasonably sensitive for obstruction, although it can miss hydronephrosis, particularly if checked early in the course. Serial ultrasounds may be indicated if there is a high index of suspicion.
Sepsis, with or without septic shock, is the most common cause of AKI, and the presence of unexplained AKI should prompt a work-up for undiagnosed infection.
Once life-threatening disease has been excluded, a through diagnostic work-up should be undertaken to determine the cause of AKI (see below).
The cardinal features of AKI (oliguria and azotemia) may occur as a result of a severe injury to the kidneys, or they may be the result of a normal renal response to an abnormal situation (e.g., hypovolemia). Conceptually, this situation is analogous to your car engine suddenly stopping. Is it because the engine is broken, or is the engine fine but the gas tank is empty? Unfortunately, the human body doesn’t have a fuel gauge, but there are several ways to help determine if the kidney has stopped working because it’s injured or because its gas tank is empty.
Hemodynamic assessment: One way to distinguish these two very different causes of decreased renal function is to do the medical equivalent of looking inside the gas tank. Numerous tests, from echocardiography to functional hemodynamic monitoring, can help determine if there is adequate circulating blood volume for the kidney to function. Note, these tests do not confirm that the kidney is not injured (the tank can be empty AND the engine can still be broken). Moreover, running out of gas may harm the kidney (especially if it’s already diseased) if it is not reversed rapidly.
Lab tests: Another way to approach the problem is to look under the hood. By examining the patient for signs of kidney disease, including examining the urine, one can determine if kidney injury is more likely. Furthermore, lab tests can help. The presence of abnormal urine sediment suggests kidney disease and may even point to the cause (as discussed above). Conversely, very concentrated urine argues in favor of intact renal tubular function. Two specific ways to look at renal tubular function are to calculate the BUN:creatinine (BUN:Cr) ratio and fractional excretion of Na (FENa):
FENa = (PCr * UNa ) / (PNa * UCr) x 100.
A FENa less than 1 and a BUN: Creatinine ratio greater than 20 suggests that the kidney is behaving as though it is underperfused. However, there are two notes of caution. First, evidence that the kidney is behaving as though it is underperfused may be a manifestation of kidney disease and thus does not prove that the cause of the problem is not the kidney. This seems to be especially true in sepsis, the most common cause of AKI.
Second, when the kidney is injured it can no longer be counted on to behave normally in the setting of decreased perfusion. Thus, a FENa of 3 and a BUN:Cr ratio of 10 could still occur in a patient with AKI and hypovolemia. Thus, experienced intensivists are cautious in their use and interpretation of these tests.
Application of modified RIFLE criteria
The criteria outlined in Table I should be used to diagnose and stage AKI. However, there are a number of circumstances when this may be difficult. Consider, for example, a patient who presents with pneumonia and an abnormal creatinine level. Assume for this example that the patient’s baseline creatinine is 1.0 mg/dl and he presents with a creatinine of 1.3 mg/dl. Assuming urine output was greater than 0.5 ml/kg/h, we could not make the diagnosis of AKI at this point because the serum creatinine remains less than 1.5x baseline and we have not documented an increase of 0.3 mg/dl over a 48-hour period (or less).
Had the patient presented 48 hours ago with a creatinine of 1.0 mg/dl we would be able to diagnose AKI, but since we do not have that documentation we need to either have his serum creatinine reach 1.5 mg/dl or we need to document a new change of 0.3 mg/dl within a 48-hour period.
A patient with a baseline creatinine of 2.4 mg/dl presents with a GI bleed and a serum creatinine of 3.0 mg/dl. Her urine output is not decreased but her creatinine is 3.3 the next day. Is this AKI? Answer: Yes, when the creatinine is documented to increase by 0.3 or more within 48 hours or less. What if the creatinine increased only 0.1 mg/dl each day? Answer: AKI cannot be diagnosed until the creatinine reaches 3.6 mg/dl (1.5x baseline).
A patient with a baseline creatinine of 1.2 mg/dl presents with a 3-day history of fever and abdominal pain and a serum creatinine of 2.9 mg/dl. Despite volume resuscitation his urine output averages less than 0.3 mg/kg/h for the next 24 hours. Does he have AKI, and if so what stage? Answer: Stage 3 (failure) because of the low urine output.
A patient with a baseline creatinine of 3.7 mg/dl presents with a creatinine of 4.0 mg/dl. Does she have AKI? Answer: Not unless she has a documented change in serum creatinine over 48 hours or less. If she does, is she really in stage 3? Answer: Yes. The logic here is that she has acute on chronic disease and most of the management will be in line with stage 3. Furthermore, there is evidence that her risk of death is just as high as a patient without prior kidney disease and stage 3 AKI. So she should be staged this way.
The framework for the clinical diagnosis of AKI discussed above should not be interpreted to replace or to exclude clinical judgment. While the vast majority of cases will fit both AKI diagnostic criteria as well as clinical judgment, AKI is still a clinical diagnosis – not all cases of AKI will fit within the proposed definition, and not all cases fitting the definition should be diagnosed with AKI. However, exceptions should be very rare.
As with other clinical diagnoses defined by laboratory results (e.g., hyponatremia), the clinician must be cautious to interpret laboratory data in the clinical context. The most obvious example is with laboratory errors or errors in reporting. Erroneous laboratory values should obviously not be used to diagnose disease and suspicious lab results should always be repeated.
Another example is when two creatinine measurements are obtained by different laboratories. While the coefficient of variation for serum creatinine is very small (<5%) by various clinical testing methods, variation (bias) from one laboratory to the next may be considerably higher, although it is unlikely to approach 50%.
Given that the serum creatinine definition of AKI always uses at least two values, the variation and bias between each measure is further magnified – the coefficient of variation for comparison of two lab tests is equal to the square root of the sum of each coefficient squared. Although the international standardization of serum creatinine measurements will largely eliminate inter-laboratory bias in the future, care is needed in interpreting lab values obtained from different labs.
Furthermore, daily variation in creatinine owing to differences in diet and activity may be as great as 10%. The cumulative effect of these various factors influencing precision, bias and biological variation may approach the level at which it could affect the diagnosis of AKI.
A similar problem exists with urine output.
Particularly outside the ICU, urine output is not often reported and urine collections may be inaccurate, especially in non-catheterized patients. Finally, as discussed above, a weight-based criterion for urine output will mean that some very obese patients will fulfill the definition of AKI without any kidney abnormality. Clinical judgment should always be exercised in interpreting such data, and I recommend using ideal body weight in such cases.
A complementary problem is the situation where a case of AKI fails to meet the definition. These cases should be distinguished from conditions in which data are simply missing (see below) and refer to situations in which existing data are unreliable. For example, a patient might receive very large quantities of intravascular fluids such that serum creatinine is falsely lowered.
Similarly, massive blood transfusions will result in the serum creatinine more closely reflecting the renal function of the blood donors than the patient. However, it is unusual for these cases not to result in oliguria, and thus most patients will be diagnosed with AKI even if serum creatinine is not increased. Nevertheless, the clinician should be cognizant of the possibility that serum creatinine values may be falsely lowered by large volume fluid resuscitation or transfusion, and thus a normal value may not rule out AKI.
Approach to the patient with increased serum creatinine and no known baseline creatinine
Many patients will present with AKI without a reliable baseline serum creatinine on record. When a patient presents with an abnormal creatinine, the first question the clinician should ask should be: Does this patient have CKD? If the patient has a history of “kidney disease” it will be clear that his or her baseline creatinine will not be normal, but this does not exclude AKI.
Patients with CKD typically have risk factors for CKD, especially diabetes, and in blacks, hypertension. Patients without a family history of kidney disease, who are neither diabetic nor hypertensive, are at low risk for CKD.
A renal ultrasound showing normal-sized kidneys in a patient with an increased creatinine level also supports the diagnosis of AKI. AKI biomarkers, such as tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), may also be helpful. The NephrocheckTM test measures urinary [TIMP-2] x [IGFBP7] and increasing concentrations are associated with increasing risk for AKI (see the section below: ‘AKI biomarkers’).
Finally, the hallmark of AKI is an unstable (non-steady state) glomerular filtration rate. Thus, serum creatinine values should be changing (up or down) in a patient with AKI. A patient who presents with an increased creatinine level that remains stable is unlikely to have AKI.
In a patient without CKD, the baseline serum creatinine can be estimated using the MDRD Study equation assuming that baseline eGFR is 75 ml/min/1.73 m2 (see Table III).
|Age (yrs)||Black males||Other males||Black females||Other females|
*Creatine values are all expressed in mg/dl. Adapted from Bellomo et al. Crit Care. 2004 PMID:15312219
This approach has been used in many but not all studies of AKI epidemiology using RIFLE and has recently been validated. Hence, most current data concerning AKI defined by RIFLE criteria are based on estimated baseline creatinines for a large proportion of patients.
Table III shows the range of estimated creatinine obtained by MDRD back calculation for various age, sex, and race categories. When the baseline creatinine is unknown an estimated creatinine can be used, provided there is no evidence of CKD. Fortunately, when there is a history of CKD a baseline creatinine is usually available. Unfortunately, many cases of CKD are not identified, and thus estimating the baseline serum creatinine may risk labeling a patient with AKI when in reality the diagnosis was unidentified CKD.
Importantly, CKD and AKI may coexist. By using all available clinical data (laboratory, imaging, history and physical exam), it should be possible to arrive at both an accurate diagnosis as well as an accurate estimate of baseline creatinine. Importantly, excluding some cases of hemodilution secondary to massive fluid resuscitation (discussed above), the lowest creatinine obtained during a hospitalization is usually equal to or greater than the baseline. This creatinine can be used to diagnose (and stage) AKI.
For example, if no baseline creatinine was available, the diagnosis of AKI can be made using the MDRD estimated creatinine (Table III). If a patient presenting with a creatinine of 1.3 mg/dl were a 70-year-old white female with no evidence or history of CKD, the baseline creatinine would be 0.8 mg/dl and a diagnosis of AKI would be possible even on the day of presentation (1.5x baseline).
However, if the patient were a 20-year-old black male, his baseline creatinine would be estimated at 1.5 mg/dl. However, since his admission serum creatinine is lower, this is assumed to be the baseline creatinine. If later on his creatinine returns to a lower level (say 1.0), we can infer that his actual baseline is this value. These dynamic changes in interpretation are not seen in epidemiologic studies, which are conducted when all the data are present, but are common in clinical medicine.
A number of urinary (and a few plasma) biomarkers have been developed to aid in the early detection of AKI. One of the first such markers was neutrophil gelatinase-associated lipocalin (NGAL) which is available in many countries outside the US. Both urinary and plasma NGAL increase with AKI and this increase precedes changes in serum creatinine by several hours. However, NGAL has been shown to increase with various conditions even without AKI (e.g., sepsis) and also appears to be increased in patients with CKD. Liver fatty acid-binding protein (L-FABP) is available in some countries and may also be helpful in detecting AKI early. The only test approved in the US however, is the NephrocheckTM test which measures urinary [TIMP-2] x [IGFBP7].
In a validation study of 728 adults with critical illness and without evidence of AKI at enrolment the primary endpoint was moderate-severe AKI (stage 2-3) within 12 hours of sample collection, which occurred in 14% of patients. The area under the receiver operating characteristic curve (AUC) was 0.80 for [TIMP-2] x [IGFBP7] and was significantly superior to all previously described markers of AKI (p<0.002) including NGAL, L-FABP, and kidney injury molecule (KIM)-1, none of which achieved an AUC > 0.72.
Diagnostic work-up for AKI: determine the cause
Diagnostic work-up. The following tests may be useful in determining the cause of AKI. It should be recognized that many if not most cases of AKI in the ICU are multifactorial.
a. Physical examination. Particular attention should be given to assessing volume status; looking for rashes or evidence of allergic reactions; assessing for sites of infection; abdomen and pelvis to rule out obstruction and abdominal hypertension.
b. Review medication list. Intravenous radiocontrast and especially intra-arterial contrast given within the prior 2-4 days; antimicrobials, especially aminoglycosides and amphotericin; sulfa-containing drugs (including most diuretics) in anyone with a history of sulfa allergy; drugs that reduce renal plasma flow: calcineurin inhibitors, ACE inhibitors, and nonsteroidals (especially when used in combination).
c. Urine analysis. Blood may indicate trauma to the urinary tract. Heme-positive RBC negative is suggestive of myoglobin. WBCs can indicate infection or allergic interstitial nephritis (eosinophils may also be present). Active urine sediment (very rare) with RBC casts is diagnostic of vasculitis or glomerulonephritis. Muddy brown casts suggest renal tubular cell sloughing and may be due to a variety of injuries.
d. Urine electrolytes (see the section on Pre-renal azotemia).
e. Renal ultrasound. The primary purpose of the renal ultrasound is to look for hydronephrosis. When present, it is diagnostic of obstruction. Unfortunately, the absence of hydronephrosis, especially early on, does not exclude obstruction. The other purpose for renal ultrasound is to evaluate kidney structure (a CT scan is superior for this purpose). Kidney size is important in evaluating a patient who presents with an elevated serum creatinine. Small kidneys are indicative of chronic kidney disease.
f. Hemodynamic assessment. Low urine output is an early sign of hypovolemia but it is also indicative of AKI due to any cause as well as intra-abdominal hypertension and urinary tract obstruction. Thus, the common “knee-jerk” reaction to oliguria of giving fluids should be viewed critically. Nevertheless, oliguria is never normal and should prompt an evaluation. One component of this evaluation is to assess fluid status. Static pressure measurements such as central venous pressure and pulmonary capillary pressure are not reliable estimates of preload responsiveness, whereas dynamic measures such as stroke volume variation and pulse pressure variation (PPV) are.
A PPV greater than 13% in a patient on positive pressure ventilation and NOT spontaneously breathing is highly predictive of response to a fluid challenge (meaning that cardiac output will increase with fluid). It is reasonable to treat such patients with fluid if they have oliguria or other evidence of inadequate tissue perfusion.
g. Sepsis work-up. Given that sepsis is the most common cause of AKI, its presence in any critically ill patient should prompt a work-up for sepsis.
4. Specific Treatment
Treatment for AKI can be divided into three components: emergency management (discussed in Section 2 above), specific therapy tailored to the cause of AKI and supportive care.
Once AKI has been established, the treatment priorities shift toward management of the complications of AKI and facilitating recovery. The general management principles outlined in Section 2 above are still germane, and every effort should be made to avoid further injury to the kidney. In addition, however, established AKI should prompt the clinician to take the following steps:
a. Avoid/reverse volume overload. Patients with AKI frequently have oliguria that is not fluid responsive. The practice of continuing fluid loading in a patient in positive fluid balance will lead to complications (delayed wound healing, pulmonary edema, atrial distention and arrhythmias, impaired gut function) and will not benefit the kidney.
Each liter of “normal” saline has 9 g of sodium. Fluid and sodium overload are common in critically ill patients, and those with AKI have the greatest difficulty handling the load. Diuretics can be useful in managing volume overload but they come at a price. Loop diuretics injure the kidneys, and many are ototoxic as well. Diuretics should not be viewed as the solution to imprudent use of fluids.
b. Consider renal support (see AKI–Renal Replacement Therapy). Timing of renal support (e.g., dialysis, hemofiltration) is controversial. Many authors believe that renal support is initiated too late in many patients, and national trends favor earlier initiation of therapy. In general, patients should be started on renal support (assuming they are candidates for organ support) prior to the development of complications (severe volume overload, life-threatening hyperkalemia, uremic symptoms).
Most patients will be in RIFLE-Failure (stage 3), and this is usually a good time to consider initiation if it has not been started already. The subclavian veins should be avoided (if possible) in this group of patients to reduce the risk of stenosis, which will preclude permanent dialysis access.
c. Adjust drugs. Many drugs are eliminated by the kidneys, and drug selection and dosing should be adjusted to the patient’s renal function.
d. Monitor functional recover and plan for follow-up. Renal function should be monitored in patients with AKI and a plan for long-term follow-up should be put in place. Patients who do not recover renal function will have chronic kidney disease by definition and require management by a qualified practitioner.
Traditionally, mechanisms of azotemia are divided into pre-, intra- and post-renal. While this categorization has utility when it comes to determining cause, it should not be seen as a taxonomy for AKI. Both pre- and post-renal insults will result in parenchymal (intrarenal) injury if not treated promptly, and most forms of AKI in the ICU have an element of more than one mechanism.
The driving force for glomerular filtration is the pressure gradient from the glomerulus to Bowman’s space. Glomerular pressure is primarily dependent on renal blood flow (RBF) and is controlled by combined resistances of renal afferent and efferent arterioles.
a. Pre-renal: Pre-renal mechanisms of AKI result in hypoperfusion of the kidney and may be from a number of different causes. Decreased GFR in the face of reduced RBF is an adaptive response. Severe volume depletion or hypotension in the face of a structurally intact nephron will result in decreased GFR and may fulfil the diagnostic criteria for AKI. For trauma patients, volume loss from internal or external hemorrhage or gastrointestinal (GI) and cutaneous sources (e.g., burns) may result in hypovolemia.
Hypotension appears to be an important risk factor for AKI, and many trauma patients with AKI have sustained at least one episode of hypotension. During this initial phase, renal autoregulatory mechanisms attempt to maintain GFR and RBF by altering the vascular tone of the afferent and efferent arterioles of the glomerulus. Treatment with fluid resuscitation is clearly an important step, but many patients will also require vasoactive therapy (e.g., norepinephrine) to maintain arterial blood pressure.
Despite a common belief among many practitioners, norepinephrine does not increase the risk of AKI compared to dopamine, and in animals with sepsis renal blood flow actually increases with norepinephrine. However, without early medical corrective intervention, the worsening ischemia results in tubular cell injury, and the further tubular cell injury induces intrinsic AKI.
For some patients with abdominal injury, the consequences of elevated intra-abdominal pressure may also manifest as AKI. Abdominal compartment syndrome is a clinical diagnosis in the setting of increased intra-abdominal pressure—pressures less than10 mmHg generally rule it out, while pressures greater than 25 mmHg make it likely.
Baseline blood pressure and abdominal wall compliance influence the amount of intra-abdominal pressure that can be tolerated. As intra-abdominal pressures rise, RBF will become compromised Surgical decompression is the only definitive therapy and should be undertaken before irreversible end-organ damage occurs.
b. Intrinsic AKI: For trauma patients, AKI may result from direct trauma to the kidney or from a number of processes that can damage renal parenchyma. For many years it was assumed that AKI was primarily due to ischemia reperfusion injury because AKI occurs most frequently in patients undergoing major hemodynamic alterations.
Indeed, the duration and magnitude of shock appears to correlate with the risk of AKI. Patients undergoing complex cardiovascular surgery or suffering severe trauma, hemorrhage, sepsis, and/or volume depletion are therefore at high risk for AKI. However, while ischemic AKI does occur, injury to the kidney can arise in response to damage to cells quite distant from the kidney.
For example, myonecrosis is a common cause of AKI in which remote tissue damage causes inflammation and cell damage in the kidney. A variety of so-called damage-associated molecular patterns (DAMPs) will induce activation of dendritic cells within the renal parenchyma (for a review see Murugan et al.). Part of the reason that the kidney is so sensitive to these insults is that the kidney filters the blood and many small molecules are concentrated in the tubular fluid, where they may induce inflammation.
In patients with rhabdomyolysis, additional injury results from ischemia reperfusion and inflammation by neutrophils that infiltrate damage muscle, as well as excess myoglobin from skeletal muscle injury that may obstruct the renal tubules. The other mechanisms involved in the pathogenesis of rhabdomyolysis are direct sarcolemmic injury (e.g., trauma) or depletion of ATP within the myocyte, leading to an unregulated increase in intracellular calcium.
c. Post-renal: Post-renal injury results from obstruction of the outflow tracts of the kidneys. The obstruction can occur at any point in urine flow between the proximal tubules and the external urethral meatus. Distal obstruction at the bladder neck, bilateral ureteric obstruction or unilateral ureteric obstruction may occur from multiple causes.
For trauma patients, post-renal injury may be commonly caused by a mechanical obstruction, such as clots, benign strictures, edema, inadvertent surgical ligature or external compression. During the early stages of obstruction (hours to days), continued glomerular filtration leads to increased intraluminal pressure upstream to the site of obstruction.
As a result, there is gradual distention of the proximal ureters, renal pelvis, and calyces and a fall in GFR. Urinary output may vary in post-renal failure from anuria and oliguria to polyuria. Anuric patients commonly have an obstruction at the bladder level or below. Because post-renal causes are usually reversible if diagnosed promptly, it is imperative to exclude them.
Recovery of renal function is inversely proportional to the duration of the obstruction. Specific gravity and urine sodium are variable. Serum BUN and creatinine levels will be elevated and the BUN/creatinine ratio will be normal (1:20) or elevated. Renal ultrasonography can be used to assess patients for hydronephrosis, as the contrast dye used for CT may further compromise renal function. Importantly, the negative predictive value of ultrasound may be low, particularly early on. A high index of suspicion is important.
Although lacking the ability to directly investigate pathogenesis, human studies of sepsis-induced AKI suggest that AKI is strongly correlated with other organ failures, and both sepsis and AKI are correlated with cytokine activation. Although abnormalities in coagulation are also associated with AKI, the link between inflammation and AKI severity is strongest.
Sustained systemic inflammation seems to be associated with development of AKI as well as other organ failures. Studies are now being conducted using RIFLE criteria to define AKI in animal models, and these animal models are also being designed to better reflect the clinical conditions in which AKI occurs in humans.
Emerging evidence from laboratory and clinical studies suggests that inflammation and its associated molecules could be a key factor in AKI and cause dysfunction of renal cells. Cells in injured tissues release damage-associated molecular pattern molecules that can perpetuate the inflammatory response by acting as a signal to remote organs (including the kidney), leading to the activation of immune cells (such as dendritic cells and T cells) and thus the initiation of inflammation in these remote organs.
After the initial insult has passed, the surviving tubular epithelial cells are able to regenerate and ultimately redifferentiate into mature intrinsic cells. Persistent injury and de novo CKD can occur with continued dysfunction of cell responses in the kidney, and a number of soluble mediators (for example, transforming growth factor beta) initiate a variety of pathophysiological processes that occur when kidney injury is initiated and have a fundamental role in cell proliferation and interstitial fibrosis.
Still, many of the mechanisms that occur during AKI are unknown, and a better understanding of the pathogenesis is important for early diagnosis and to enable the design of improved interventions.
Numerous studies have indicated that AKI is common, is increasing in incidence and is associated with considerable morbidity and mortality. Rates of AKI in hospitalized patients have been reported to be between 3% and 20%, and in the ICU the rate has been reported to be from 22% to as high as 67%. Traditional measures of organ failure, however, likely underestimate the incidence of AKI, as does incomplete application of the available diagnostic criteria.
Although the lack of standard definitions for AKI precludes accurate measures of incidence before 2005, longitudinal studies that applied consistent criteria in the diagnosis of AKI seem to show a dramatic increase in incidence. Using ICD-9 codes to identify patients with AKI from their hospital discharge datasets, the U.S. Centers for Disease Control and Prevention published data on trends in 1980-2005 hospitalizations for kidney disease.
Although the sensitivity and positive predictive value for ICD-9 codes to detect AKI is low, during this 25-year period, a greater than 20-fold increase in the incidence of AKI was observed. Although it is unclear whether AKI was the primary reason for hospitalization or AKI occurred during the hospitalization, the age-adjusted rate of AKI increased from 18 cases per 100,000 population in 1980 to 365 cases per 100,000 population in 2005.
While it is unclear whether this profound increase in AKI is due to increased disease or increased awareness, these data suggest that AKI is emerging as a major public health problem. As the patient population ages in developed countries, the incidence of AKI is projected to increase congruently.
In 2009, the U.S. Renal Data System, a nationally representative monitoring system for end-stage renal disease (ESRD), reported incidence rates of AKI in the U.S. using three different datasets from 1995 to 2007. The largest increase in AKI was seen among older individuals older than 85 years of age. Male sex and black race were also associated with an increased risk of AKI.
The most common cause of hospitalization was AKI itself – accounting for 20-23% of all hospitalizations. Patients with CKD had nearly a seven-fold higher risk of developing AKI than those without, and patients with AKI had post-discharge mortality twice as great as those hospitalized without AKI. In Northern Scotland the attack rate of AKI was 2,147 cases per million population.
Special considerations for nursing and allied health professionals.
What's the evidence?
“A recent clinical practice guideline for AKI has been completed by KDIGO”.
The reader is also directed to:
Kianoush, K. “Discovery and Validation of Cell Cycle Arrest Biomarkers in Human Acute Kidney Injury”. Crit Care. vol. 17. 2013. pp. R25
Kellum, JA, Unruh, ML, Murugan, R. “Acute kidney injury”. Clin Evid (Online). 2011 Mar 28;2011.
For recent reviews on epidemiology and pathophysiology:
Bellomo, R, Kellum, JA, Ronco, C. “Acute kidney injury”. Lancet. 2011.
Murugan, R, Kellum, JA. “Acute kidney injury: what's the prognosis”. Nat Rev Nephrol. vol. 7. 2011 Apr. pp. 209-17.
Singbart, K, Kellum, JA. “AKI in the ICU: Definition, epidemiology, risk stratification and outcomes”. Kidney Int. 2011.
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- 1. Description of the problem
- 2. Emergency Management
- 3. Diagnosis
- 4. Specific Treatment
- Special considerations for nursing and allied health professionals.