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Biomarkers of acute kidney injury
Epidemiology of acute kidney injury in the intensive care unit
Acute kidney injury (AKI) is a significant problem in intensive care unit (ICU) patients and carries a high mortality rate and long-term morbidity. AKI is defined according to the Kidney Diseases Improving Global Outcomes (KDIGO) criteria, including three alternatively applied components: (1) serum creatinine increase (from baseline of >27 micromol/L or >0.3 mg/dL within a maximum of 48 hours or >50% within a maximum of 7 days), (2) reduced urine output (<0.5 mL/kg/hr over 6 hours), or (3) initiation of acute renal replacement therapy. Incidence of AKI in the ICU has been reported to be about 50%, with 32% at stage 1, 16% at stage 2, and 52% at stage 3. In 13.5% of patients treated in the ICU, renal replacement therapy is initiated. AKI requiring renal replacement therapy in the ICU has a high mortality rate, often reaching over 50%. The most common causes of AKI in the ICU include sepsis/septic shock, major surgical procedures, acute cardiac decompensation/cardiac shock, and nephrotoxins. , Approximately 30% of patients have preadmission chronic kidney disease.
A major obstacle to the development of improved treatment strategies for AKI in critically ill patients is the absence of sensitive and specific biomarkers available to the clinician with a short laboratory turn-around time. Therapeutic measures are sometimes started late in the course of AKI. The optimum time to start renal replacement therapy in the ICU is unknown. Therefore there is a need to understand whether and how novel kidney biomarkers with short turn-around time may be able to complement clinical decisions in ICU patients.
This chapter briefly highlights biologic characteristics of current tools in AKI diagnosis and of novel kidney biomarkers with short turn-around times and test results available to the clinician within 2 hours. This is followed by information on clinical characteristics of such biomarkers of AKI. Biologic and clinical characteristics of other published novel kidney biomarkers are summarized at the end of the chapter.
Biologic characteristics of current tools in AKI
Serum creatinine (SCr) and urine output are used to diagnose AKI. Creatinine is generated in muscles from the nonenzymatic conversion of creatine and phosphocreatine. SCr concentrations carry the highest validity under stable physiologic conditions, but SCr is not sensitive or specific in the setting of AKI. SCr may change because of nonrenal factors independent of kidney function (e.g., age, gender, race, muscle mass, nutritional status, total parenteral nutrition, and infection). , Also, inhibition of tubular secretion (e.g., during intake of piperacillin/tazobactam) may increase SCr concentrations. Moderate to severe abnormalities of thyroid or adrenal gland function may affect SCr independent of kidney function, with lower SCr concentrations in the setting of hyperthyroidism or hypercortisolism. SCr is not sensitive to the loss of kidney function reserve, as evidenced by the small change in SCr after the loss or donation of a kidney with one normal remaining kidney. Alterations in SCr may lag several days behind actual changes in glomerular filtration rate (GFR). ,
Both a decrease and lack of decrease of urine output are frequently not helpful in diagnosing or ruling out AKI. Urine output and urine output–modifying circumstances (e.g., hypovolemia) and treatments (fluids, diuretics) carry inherent impediments, limiting their sensitivity and specificity in AKI diagnosis. Specifically, diuretic administration in the setting of hypervolemia management or fluid administration in the setting of hemodynamic instability might limit the use of urine output for diagnosing or ruling out AKI. However, diuretic administration applied in euvolemic patients as a tubular stress test may assess kidney tubular responsiveness.
A biomarker independent of SCr and urine output limitations or a biomarker that is released into the blood or urine by the injured kidney may be a more sensitive and specific marker of AKI. In addition, earlier detection of AKI with a kidney-specific biomarker may result in earlier nephrology consultation, more optimal dosing of antibiotics in ICU patients, avoidance of nephrotoxic agents, and even patient-individualized timing of initiation of renal replacement therapy (RRT).
Biologic characteristics of novel AKI biomarkers with short turn-around times
Recently, clinically available biomarkers of AKI with short laboratory turn-around times to the clinician have been described, including cystatin C, neutrophil gelatinase–associated lipocalin (NGAL), and cell-cycle arrest markers (TIMP-2/IGFBP7). All of those are available on clinical laboratory platforms or point-of-care devices with biomarker measurements of less than 60 minutes. Cystatin C, NGAL, and cycle arrest markers have CE marking, making the tests commercially available in Europe for supporting the clinician estimating AKI risk in critically ill patients. Cystatin C measurements are approved by the Food and Drug Administration (FDA) as an aid in the diagnosis and treatment of renal diseases. Cell-cycle arrest markers (TIMP-2/IGFBP7) have also been approved by the FDA to be used in conjunction with clinical evaluation in patients 21 years of age or older who currently have or have had within the past 24 hours acute cardiovascular and/or respiratory compromise and are ICU patients as an aid in the risk assessment for moderate or severe AKI within 12 hours of patient assessment. Renal handling of these biomarkers is shown in Fig. 96.1 .
Novel biomarkers of AKI that are not clinically available within a short turn-around time are summarized next, including IL-6, IL-18, KIM-1, and L-FABP.
Serum cystatin C
Cystatin C is a 13-kDa protein produced by all nucleated cells at a constant rate. It is freely filtered by the glomerulus, completely reabsorbed by the proximal tubules, and is not secreted by the renal tubules. Thus some of the limitations of SCr—for example, the effect of muscle mass, diet, gender, and tubular secretion—may not be a problem with cystatin C. Cystatin C is a better marker of GFR than SCr. Increases in cystatin C occur sooner after changes in kidney function than change in SCr. , In critically ill patients, serum cystatin C correlated better with GFR than did creatinine and was diagnostically superior to creatinine. Serum cystatin C was found to be better than SCr in the detection of AKI in critically ill children.
There are limitations to the use of cystatin C as a marker of GFR. Abnormalities of thyroid function and glucocorticoid therapy , may affect cystatin C independent of kidney function, with higher serum cystatin C concentrations in the setting of hyperthyroidism or prednisolone intake >10 mg/d. However, in critically ill patients, the effect of thyroid function appears to be nonclinically relevant. The evidence regarding the impact of inflammation is limited; however, in a study with 327 ICU patients, the impact of sepsis on the levels of serum cystatin C in AKI and non-AKI patients was determined. The change in cystatin C or creatinine did not differ significantly between the septic and nonseptic patients with or without AKI. Similarly, in a study with critically ill children, levels of cystatin C were not substantially increased in the setting of sepsis.
Neutrophil gelatinase–associated lipocalin
NGAL was originally isolated from the supernatant of activated neutrophils and identified as a polypeptide covalently bound to gelatinase. It is expressed in a variety of human tissues, including lung, liver, and kidney, in various pathologic states. Human NGAL is a polypeptide with a molecular weight of 25 kDa covalently bound to gelatinase from human neutrophils. Although the majority of NGAL is in a monomeric form, NGAL also occurs as dimers and trimers and in a complex with neutrophil gelatinase. The 25-kDa monomeric NGAL form is secreted by injured kidney tubule epithelial cells, whereas the dimeric form is predominantly secreted by neutrophils. The major ligands for NGAL are siderophores, which are ferric ion-specific chelating compounds. The iron status of NGAL is a critical determinant of biologic activity. Iron-containing NGAL binds to cell surface receptors such as megalin, gets internalized, and releases its bound iron. The increased intracellular iron concentration drives the regulation of iron-dependent genes. NGAL has been implicated in the differentiation of renal tubule epithelial cells and nephrons. Preclinical studies identified NGAL to be one of the most up-regulated genes and proteins in the kidney early after AKI in animal models. NGAL protein expression was detected predominantly in tubule epithelial cells that were undergoing proliferation and regeneration, suggesting a role in the repair process. NGAL protein was also detected in the urine and plasma in animal models of AKI, where it preceded the increase in plasma creatinine concentrations. Urine NGAL is derived predominantly from epithelial cells of the distal nephron, although a fraction may come from the systemic pool escaping reabsorption because of proximal tubular injury. Plasma NGAL originates not only from the damaged kidneys (via tubular backleak) but also from extrarenal organs. Recent evidence has emerged to implicate a potentially important pathophysiologic link between NGAL and cardiorenal syndrome. NGAL induces cardiomyocyte apoptosis by increasing intracellular iron accumulation. Renal NGAL expression rapidly increased after acute inflammation and/or injured renal tubular epithelia, in particular after damage from ischemia-reperfusion injury (IRI) and toxin exposure. A reporter mouse responsive to ischemia/reperfusion or toxic stimuli allowed detection of NGAL expression in “real time” in vivo. Volume depletion did not cause NGAL expression in the kidney or in the urine, thus indicating that NGAL can be an important clinical tool to discriminate patients with “prerenal azotemia” from those with AKI and therefore “true” structural damage. Finally, NGAL levels peak approximately 6 hours after tubular injury and follow a dose-response curve with respect to severity of injury. ,
Cell-cycle arrest markers
Replication is one of the most energy-consuming processes cells undergo. If, during the cell cycle, the cell will have not sufficient energy to replicate, the cell will undergo cell-cycle arrest to avoid cell death as a result of energy failure. Therefore cell-cycle arrest is considered to be a major mechanism of down-regulation of energy expenditure that tubular epithelial cells may use to resist or recover from different insults. Even if insults may not actually destroy cells, tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP7) may signal in autocrine and paracrine fashions. Therefore TIMP-2 and IGFBP7 have been recently described as an “alarm” spreading to adjacent cells, although this has not yet been shown for the kidney. The cellular source and pathophysiologic role of these markers in AKI are unknown’ however, one study showed that nonrenal organ failures in sepsis did not result in increased [TIMP-2]∙[IGFBP7], and other studies showed no increase of [TIMP-2]∙[IGFBP7] in critically ill patients without AKI. TIMP-2 and IGFBP7 have been found to be predictors of the development of human AKI. Both cell-cycle arrest markers are inducers of G1 cell-cycle arrest occurring during the early phases of cellular stress, , a key mechanism implicated in AKI. TIMP-2 and IGFBP7 may increase in response to inflammation, oxidative stress, ultraviolet radiation, drugs, and toxins. , , Sustained cell-cycle arrest will result in a senescent cell phenotype and lead to fibrosis. In turn, urine TIMP-2 and IGFBP7 values were not elevated in patients with stable chronic morbidities who did not have AKI.
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