Acute kidney injury (AKI) is a syndrome that is frequently and commonly observed among hospitalized and especially critically ill patients. The incidence of AKI varies based on the criteria used to diagnose the disorder, but it ranges from 4% to 20% and reaches 60% among patients in the intensive care unit (ICU). Patients affected by AKI usually require admission to the ICU and are often burdened by long ICU and in-hospital lengths of stay as well as poor short- and long-term outcomes. Although many advances have been made in understanding the pathophysiology of AKI and in the development of renal replacement therapy (RRT), significant morbidity and mortality rates (up to 80%) have been reported.
Diagnosis of AKI is often complicated by the heterogeneity of etiology and onset and by the heterogeneity of disease severity and comorbidities. Moreover, for some time, the absence of a consensus definition of AKI further complicated the diagnosis and staging of this syndrome.
Avoiding AKI is probably the best way to improve outcomes of critically ill patients with renal dysfunction. However, if AKI occurs, improved renal support (pharmacologic and nonpharmacologic) and the avoidance of further nephron insults (e.g., the use of nephrotoxic drugs) may reduce the progression of AKI and the development of complications, and it may also improve outcome. An early identification of AKI is essential to define prognosis and to guide clinical decision-making in these patients.
Clinical Acute Kidney Injury
The definition, diagnosis, and staging of AKI are currently based on indices that estimate the glomerular filtration rate (GFR). The GFR is widely accepted as the best overall index of renal function in health and disease. However, it is difficult to measure; thus it is usually estimated from the serum level of endogenous filtration markers, such as creatinine.
Risk, Injury, Failure, Loss, and End-Stage Renal Disease Classification
The first widely accepted AKI definition, validated in more than half a million patients worldwide, was proposed in 2004. The Acute Dialysis Quality Initiative (ADQI) first suggested the use of serum creatinine (SCr) and urinary output (UOP) to univocally define AKI and summarize different stages of severity and outcome into the RIFLE classification (see Table 55-1 ). The RIFLE classification had the unquestioned advantage of providing a uniform and broadly accepted definition of AKI. The acronym RIFLE delineates classes of increasing severity (Risk, Injury, and Failure) and outcome (Loss and End-Stage Renal Disease [ESRD]). The three severity grades are defined on the basis of the changes in SCr or UOP, in which the worst measurement is used. The two outcome criteria, Loss and ESRD, are defined by the duration of loss of kidney function (see Table 55-1 ).
| SCr Criteria | UOP Criteria | ||
|---|---|---|---|
| RIFLE | AKIN | KDIGO | |
| Risk Increase in SCr 1.5-fold from baseline or GFR decrease >25% | Stage 1 Increase of ≥0.3 mg/dL (≥26.5 μmol/L) or increase to ≥150%-200% (1.5- to 2-fold) from baseline | Stage 1 Increase in SCr 1.5- to 1.9-fold from baseline or ≥0.3 mg/dL (≥26.5 μmol/L) | <0.5 mL/kg/hr for >6 hr |
| Injury Increase in SCr 2-fold from baseline or GFR decrease >50% | Stage 2 Increase to >200-300% (>2- to 3-fold) from baseline | Stage 2 Increase in SCr 2- to 2.9-fold from baseline | <0.5 mL/kg/hr for >12 hr |
| Failure Increase in SCr 3-fold from baseline, or SCr >4 mg/dL (>354 μmol/L) with an acute increase >0.5 mg/dL (>44 μmol/L) or GFR decrease >75% | Stage 3 Increase to >300% (>3-fold) from baseline, or ≥4.0 mg/dL (≥354 μmol/L) with an acute increase of at least 0.5 mg/dL (44 μmol/L), or on RRT | Stage 3 Increase in SCr 3- fold from baseline or increase in SCr to ≥4.0 mg/dL (≥353.6 μmol/L) or initiation of RRT In patients <18 yr, decrease in estimated GFR to <35 mL/min/1.73 m 2 | <0.3 mL/kg/hr for 24 hr or anuria for 12 hr |
| Loss Complete loss of kidney function >4 weeks | |||
| ESRD ESRD >3 months | |||
This classification system primarily considers the change in some measure of renal function from baseline. In a patient without known chronic kidney disease and in whom the baseline value of SCr is unknown, the Modification of Diet in Renal Disease formula with a creatinine clearance of 75 mL/min per 1.73 m 2 provides an estimated baseline. The UOP, often unreliably measured outside of the ICU, has been discarded in several studies. However, comparing the results obtained with RIFLE classification with and without UOP data indicates that elimination of UOP delays or completely misses the diagnosis of AKI and is associated with a higher rate of AKI-associated mortality.
Acute Kidney Injury Network Classification
In 2007, the Acute Kidney Injury Network (AKIN) introduced small but important modifications to the RIFLE classification, suggesting that use of less profound changes in SCr would make the RIFLE criteria more sensitive and reliable (see Table 55-1 ). Increasing evidence from different settings has suggested that even modest changes in SCr levels can be associated with increased mortality. In particular, a creatinine increase of 0.3 mg/dL (26.4 μmol/L) constitutes an independent risk factor for death in several different studies. Moreover, the AKIN classification introduced a temporal dimension into the definition of AKI. Thus progressive and modest changes in SCr were not considered for AKI definition. In particular, an acute increase of SCr over a threshold value within a 48-hour period could be used to define AKI.
In contrast to RIFLE, in AKIN an individual’s baseline SCr is not estimated. Indeed, the AKIN classification requires two SCr measurements: one initial (corresponding to the baseline in RIFLE) and a second obtained after 48 hours. Finally, patients who received RRT were included in the highest level of the staging system, regardless of their SCr or UOP at the time that RRT was started.
Kidney Disease: Improving Global Outcomes Classification
More recently, the Kidney Disease: Improving Global Outcomes (KDIGO) AKIN group proposed additional changes in AKI staging (see Table 55-1 ). This classification covers the AKIN and RIFLE criteria, incorporating changes in SCr within 48 hours or a decline in the GFR over 7 days. Moreover, to simplify the staging of AKI for patients reaching Stage 3 with SCr criteria (SCr > 4.0 mg/dL [>354 μmol/L]), KDIGO requires that the patient first achieve the change in SCr specified in the AKI definition (either >0.3 mg/dL [>26.5 μmol/L] within a 48-hour time window or an increase of >1.5 times baseline). For pediatric patients, including infants and children with low muscle mass who may not reach an SCr of 4.0 mg/dL (354 μmol/L), the criteria used a change in estimated creatinine clearance (eCrCl) based on the Schwartz formula. These patients automatically reach Stage 3 if they have an eCrCl < 35 mL/min per 1.73 m 2 .
Limitations of Clinical Classifications
Although the definition, diagnosis, and staging of AKI is currently as detailed as previously mentioned, several confounding factors may affect the clinical reliability of these markers. In particular, drugs such as diuretics and the concomitant presence of tubular damage may reduce the sensitivity and specificity of UOP. Hydration status may highly affect UOP and SCr in critical care patients. Indeed, fluid loading may dilute SCr, delaying diagnosis or producing an “atypical AKI.” Moreover, SCr mainly depends on nonrenal factors such as age, gender, and muscle mass. Creatinine metabolism varies widely during AKI, and clearance is altered by treatment with several drugs (e.g., cimetidine). Creatinine is freely filtered through the glomerulus and partially secreted in the proximal tubules (10% to 20% of the urinary excreted load). Thus use of creatinine clearance will overestimate GFR. The contribution of tubular creatinine secretion to clearance may reach 50% when GFR is reduced, and this process is highly variable among individuals. In contrast, the tubules increase reabsorption of creatinine in clinical settings, such as decompensated heart failure and uncontrolled diabetes.
In addition, the renal functional reserve maintains SCr within the normal range until at least 50% of nephrons have been lost, mainly through recruitment and hyperfiltration of undamaged nephrons. Finally, in the RIFLE, AKIN, and KDIGO classifications, the SCr and UOP criteria require specific changes over a specific period of time. Major clinical repercussions may lead to deviations that hamper these specific characteristics, making the diagnosis and staging of AKI through these clinical classifications retrospective (see Fig. 55-1 ).
Subclinical Acute Kidney Injury
Only recently has kidney damage without glomerular function loss been identified and its presence associated with worse renal and overall outcomes. This condition has been termed subclinical AKI, and it has challenged the traditional view that kidney dysfunction is clinically relevant only when there is loss of filtration (i.e., kidney dysfunction), making diagnosis with the RIFLE, AKIN, or KDIGO classifications possible. Conversely, if a metabolic stressor (e.g., iodinated contrast media, nephrotoxic drugs, mediators of systemic inflammation during sepsis, etc.) is applied, kidney damage that is not reflected in SCr or UOP may occur, especially in the early phase. Damage that does not alter SCr or UOP has been termed “subclinical AKI.” Prolonged stress may increase kidney damage until the condition reduces GFR and thus becomes clinically manifest as kidney dysfunction.
Subclinical AKI may also lead to the development of complications and worse outcome. If subclinical AKI cannot be prevented, then it should be identified and treated as early as possible. This process requires the measurement of specific biomarkers of kidney damage. The use of biomarkers could more fully delineate an acute kidney syndrome, the entire spectrum of which would encompass subclinical kidney damage and clinical kidney dysfunction. A recently proposed, more generic term, kidney attack, highlights the importance of all clinical and subclinical presentations of AKI, including loss of nephrons and functional reserve and their relation to the patient outcome.
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