|Year : 2008 | Volume
| Issue : 4 | Page : 537-544
|Improvements in the Diagnosis of Acute Kidney Injury
Vyacheslav Y Melnikov, Bruce A Molitoris
Division of Nephrology, Department of Medicine, Indiana University School of Medicine, and the Roudebush V.A. Medical Center, Indianapolis, Indiana, USA
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| Abstract|| |
Acute kidney injury (AKI) represents a wide range of heterogeneous clinical conditions with a high mortality rate. Despite improvements in our understanding of the disease processes, mortality has only marginally improved and remains unacceptably high. An additional consequence of AKI is the marked acceleration of pre-existing chronic kidney disease to endstage renal disease. A major limitation in improving outcomes of AKI has been the lack of common standards for diagnosis and severity stratification. Serum creatinine is a late marker of kidney dysfunction and injury. Presently, no available commercial test offers diagnosis, nor the ability to stratify patients by severity of injury, early in the course of disease when therapy may be beneficial. The Acute Dialysis Quality Initiative (ADQI) group proposed a standard definition and classification system for the syndrome of acute renal failure. Based on data that even small changes of serum creatinine result in increased mortality, the Acute Kidney Injury Network (AKIN) has recently proposed modified criteria. Both staging systems emphasize changes in serum creatinine and urine output. There is also potential that a number of serum and urine bio-markers developed in preclinical studies and currently being investigated and validated, will enable the early diagnosis of AKI.
Keywords: Acute, Kidney, Injury, Diagnosis, Biomarkers
|How to cite this article:|
Melnikov VY, Molitoris BA. Improvements in the Diagnosis of Acute Kidney Injury. Saudi J Kidney Dis Transpl 2008;19:537-44
| Clinical Challenges in Diagnosing AKI|| |
Despite improvements in therapeutics, the morbidity and mortality associated with acute kidney injury (AKI) remain high. Acute kidney injury occurs in anywhere from 1 to 25% of critically ill patients  depending on the population being studied and the criteria used to define its presence. Epidemiologic studies have demonstrated that the incidence of AKI is increasing, and mortality has only marginally improved.  There is emerging recognition of the fact that even minor, short-term changes in serum creatinine are associated with increased mortality. , Other important consequences of AKI include hastening progression of pre-existing chronic kidney disease to end-stage renal disease. , Thus, poor outcomes still occur despite significant advances in our understanding of the pathophysiology of AKI and in overall supportive care for critically ill patients.
A major limitation in improving outcomes of AKI has been the lack of common standards for diagnosis and classification. Previous studies have used an assortment of definitions for AKI, including those based on changes in serum creatinine, absolute levels of serum creatinine, changes in urine output or blood urea nitrogen concentrations. Sometimes ARF is used in reference to the patients with an acute need for dialysis support. The lack of a universal definition has resulted in substantial differences in reported incidence, and outcomes of this clinical condition. Because the best way to improve outcomes of AKI is prevention, the definition should have a high diagnostic accuracy and allow early detection of acute kidney injury. Quantifying the extent of injury will also prove valuable to guide therapeutic recommendations and allow reasonable comparisons of outcomes between various treatment strategies.
| RIFLE and AKIN criteria|| |
In 2002, the Acute Dialysis Quality Initiative (ADQI) group proposed a standard definition and classification system for the syndrome of acute renal failure through a broad consensus of experts across disciplines and international boundaries. The classification system coins the acronym RIFLE and has three levels: Risk, Injury, and Failure; and two outcomes: persistent acute renal failure (termed Loss) and End-stage kidney disease.
A unique feature of the RIFLE classification is that it provides retrospectively for three grades of severity of renal dysfunction on the basis of a maximum change in serum creatinine, reflecting changes in GFR or duration and severity of decline in urine output from the baseline. The RIFLE criteria have the potential advantage of providing definitions for the stage at which kidney injury still can be prevented (risk), when the kidney has already been damaged (injury), and when renal failure is established (failure). The RIFLE criteria have been evaluated in clinical practice and seem to be at least coherent with regard to outcomes in patients with AKI. ,,,, How-ever, the RIFLE classification is not a diagnostic one, but a staging system based, retrospectively, upon the maximum serum creatinine. This has created confusion as the stage (risk, injury or failure) can and does evolve in the same patient from risk to failure depending upon when the diagnosis is completed. For instance, a patient with severe AKI will satisfy the criteria for risk, then injury and finally failure as the serum creatinine rises daily. In epidemiologic studies, this patient would be counted as failure. Therefore, RIFLE does not offer real time quantitative diagnosis regarding severity of injury that can be used to stratify patients for clinical therapeutic studies.
| At Risk|| |
According to RIFLE classification, Risk (R) is defined as an increase of baseline serum creatinine 1.5-2.0 folds or decrease of urine output 0.5 ml/kg per h for 6 h. Urine output was included as a diagnostic criterion because in intensive care unit patients it often portends renal dysfunction before the onset of changes in serum creatinine. Recent studies showed that even small changes in serum creatinine were associated with increased morbidity and mortality. Lassnigg et al  demonstrated a two-fold increase in the risk for death for patients who experienced no change or a small increase (0.5 mg/dl) in SCr 48 h after cardiothoracic surgery compared with patients who experienced a small decline in serum creatinine (SCr). Loef et al found an association between a 25% increase in SCr during the first postoperative week and short- and long-term mortality.  Based on the findings that small alterations of serum creatinine result in adverse outcomes, the Acute Kidney Injury International collaborative Network (AKIN) recently changed the definition of Risk group to include patients with an increase in serum creatinine of 0.3 mg/dl [Table 1]. The proposed diagnostic and staging criteria for AKI are designed to facilitate acquisition of knowledge and to validate the emerging concepts. Serum creatinine is the most widely used parameter for everyday assessment of glomerular filtration rate (GFR), but it has poor sensitivity and specificity in AKI because serum creatinine lags behind both renal injury and renal recovery. Furthermore, creatinine is produced nonenzymatically in skeletal muscle, and the amount of creatinine is directly related to muscle mass. A number of GFR estimating equations have been developed to overcome some of the limitations of estimating GFR from serum creatinine. The Cockroft-Gault equation was developed in 1973 and is used widely. A newer equation, the MDRD Study equation, was developed in 1999 and since then has been validated in a number of populations and is now recommended by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Kidney Foundation (NKF), and American Society of Nephrology for use in clinical practice. These equations assume stable serum creatinine and cannot be used to estimate GRF in patients with AKI and rapidly changing serum creatinine.
Decreased urine output is another important criterion of AKI staging. AKIN proposed documented oliguria of less than 0.5 ml/kg/ hour for more than six hours to define stage 1 if AKI (Risk stage by RIFLE classification). The urine output criterion was included based on the predictive importance of this measure but with the awareness that urine output may not be measured routinely in non-intensive care unit settings.
The differential diagnosis between prerenal AKI and acute tubular necrosis (ATN) is particularly important because restoration of circulating volume may improve renal function and/or prevent further progression of AKI. The differential diagnosis should be based on history of illness, physical findings, and lab results. Urine microscopy should be performed on every patient with AKI. Evaluation of urine sediment and urine chemistries helps to differentiate between renal vasoconstriction with intact tubular function and established ARF.  The fraction of filtered sodium that is reabsorbed by intact tubules of the vasoconstricted kidney is greater than 99% resulting in low fractional excretion of sodium (< 1%). FeNa may not be diagnostic in patients with preexisting chronic kidney disease (CKD) or patients taking diuretics because both conditions result in FeNa > 1% even in patients with pre-renal azotemia. On the other hand, contrast induced nephropathy and some cases of myoglobinuria may actually be associated with FeNa less than 1% during the early period post injury. 
| Renal Injury|| |
Injury stage is defined as a doubling of serum creatinine or urine output below 0.5 ml/kg/h during 12 hours of longer by RIFLE classification. AKIN proposed no changes of this stage of AKI. In one retrospective cohort study 5,383 ICU patients were evaluated. Patients with Injury stage of AKI (26.7% of total) had in-hospital mortality rate 11.4% compared with 5.5% for patients without acute kidney injury. More than 50% of the patients with RIFLE class R progressed to RIFLE class I within the next day. 
As the severity of AKI progresses, the urine-concentrating capacity is abolished. At this stage of AKI, kidney concentrating capacity, assessed by urinary osmolality may complement the use of fractional excretion of sodium in the differential diagnosis of renal vasoconstriction from established ATN. Urine osmolality is usually higher in patients with pre-renal azotemia (> 500 mOsm/kg) and lower in those with ATN (<400 mOsm/ kg) This diagnostic parameter may be less sensitive than fractional excretion of sodium in patients with advanced age or with low protein intake.
| Failure|| |
Failure stage of AKI in RIFLE classification is defined as a 3- of higher fold increased serum creatinine or higher than 4 mg/dl.Failure stage also is confirmed by urine output criteria: urine output below 0.3 mg/kg/h for 24 hours or anuria for 12 hours.
AKIN proposed to use the same criteria for defining stage 3 of AKI. Additionally, the AKIN classification considers patients receiving renal replacement therapy to have met criteria for stage 3.
The role and time of initiation of RRT in AKI is not well defined nor supported by evidence-based studies. Hyperkalemia, severe metabolic acidosis, diuretic unresponsive pulmonary edema, and uremic symptoms are universally accepted indications for RRT in patients with AKI. Since the consequences of these complications are likely to be more severe for critically ill patients with ARF, ADQI recommends initiation of renal replacement therapy prior to their development.
| The potential role of new biomarkers|| |
As noted in the previous section, small increases in serum creatinine may reflect significant renal insult and be associated with significant morbidity in patients with AKI. Extensive preclinical investigation has led to the identification of several potential biomarkers that may herald AKI prior to a rise in serum creatinine. This may be important because early intervention in the course of ARF may lower the extent of injury, the need for renal replacement therapy and may possibly decrease morbidity and mortality.
Numerous potential biomarkers have been identified in pre-clinical AKI studies and are now beginning to be tested in clinical validation studies. However, very few prospective studies have validated initial findings in diverse patients in multiple institutions, or done so using well-established standardization of all steps in the biomarker development process. The extreme nature of human biologic heterogeneity, coupled with the uncertainties in many disease processes, contributes to the variability in clinical outcomes. To be clinically useful, a biomarker must be relevant to the individual patient, not just to a population of patients.  While a rapid and convenient method to determine the patients' actual GFR would be preferable; no such diagnostic tool exists.
We will focus on a few of the most developed and promising emerging biomarkers of AKI for use in clinical practice, specifically interleukin-18 (IL-18), cystatin C, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM1). These biomarkers are heterogeneous in their expression (i.e. severity of insult, timing of detection, duration of detection, various etiologies). As a consequence, there has been a suggestion that these biomarkers should be incorporated into an "AKI panel" of biomarkers that will hopefully yield reliable methods for detecting, distinguishing, classifying and predicting the clinical course of AKI across a range of clinical presentations.
| Urinary interleukin-18|| |
Inflammation is known to play an important role in ischemic ARF. Preclinical experimental studies have found that IL-18, a pro-inflammatory cytokine and likely mediator of tubular injury, can be detected in the urine in ischemic AKI.  IL-18 was found significantly increased in the urine of patients with established AKI when compared with urine from those with prerenal azotemia, urinary tract infection, CKD or healthy controls.  In a study of patients receiving cardiac surgery with cardiopulmonary bypass, IL-18 was detected within 4-6 h after surgery and peaked at12 h for those subsequently developing AKI. Moreover, when AKI was defined conventionally as an increase of at least 50% in SCr, AKI was not detected until approximately 48-72 h after bypass.  In addition, the early postoperative increases in IL-18 were found to have predictive ability for the future development of AKI at 24 h (area under the receiver operating characteristics curve 73%). Similarly, elevated urinary IL18 at 4 h after surgery was correlated with the duration of AKI and renal recovery, defined by the number of days required for SCr to fall to below the 50% increase in baseline.
| Serum cystatin C|| |
Cystatin C is an endogenous cysteine proteinase inhibitor of low molecular weight. It is synthesized at a relatively constant rate and released into plasma by all nucleated cells in the body.  It holds many ideal features for use as a surrogate marker of kidney function and estimate of GFR and has been shown superior to serum creatinine. , The production of cystatin C has been extensively reported to be independent of and unaffected by sex, age, height, weight, and muscle mass.  Cystatin C levels have been found to be influenced by abnormal thyroid function, use of immunosuppressive therapy and the presence of systemic inflammation. ,,, Cystatin C is not secreted or reabsorbed; however, it is nearly completely metabolized by proximal renal tubular cells. Serum cystatin C concentrations have demonstrated good inverse correlations with radionuclide derived measurements of GFR. The diagnostic value of cystatin C as an estimate of GFR has now been investigated in multiple clinical studies. , There is a suggestion that cystatin Cbased estimates of GFR may perform better in selected patient populations, in particular those with lower SCr concentrations such as elderly patients, children, renal transplant recipients, cirrhotics and those that are malnourished. , Cystatin C was more sensitive to early and mild changes of kidney function compared with creatinine.  Herget-Rosenthal et al  prospectively evaluated 85 patients at high risk to develop ARF and demonstrated that cystatin C may allow detection of AKI one to two days earlier than serum creatinine.
| Kidney injury molecule-1|| |
KIM-1 is a type 1 transmembrane glycoprotein that is normally minimally expressed in kidney tissue. It shows, however, marked upregulation in proximal renal tubular cells in response to ischemic or nephrotoxic AKI. ,,, The ectodomain segment of KIM-1 is shed from proximal cells and detected in the urine by immunoassay. Kidney biopsies from patients with AKI show increased and significantly greater KIM-1 tissue expression compared with other acute and chronic kidney diseases (i.e. urinary tract infection, contrast nephropathy, post renal disease).  In a large study of patients with established ARF, KIM-1 levels served as useful surrogates for the severity of ARF and may have a prognostic utility that is similar to or better than conventionally used severity markers, such as the urine output and serum creatinine level. This study supports the hypothesis that urinary markers can be used to predict adverse outcomes in hospitalized patients with ARF of mixed severity and cause. 
| Neutrophil gelatinase-associated lipocalin|| |
Human neutrophil gelatinase-associated lipocalin (NGAL) was originally identified as a 25 kDa protein covalently bound to gela tinase from neutrophils. NGAL is normally expressed at very low levels in several human tissues, including kidney, lungs, stomach, and colon. NGAL expression is markedly induced in injured epithelial cells. Early results suggested NGAL may be an early and sensitive urinary biomarker of ischemic and nephrotoxic AKI. In a crosssectional study, human adults in the intensive care unit with established ARF (defined as a doubling of the serum creatinine in less than 5 days) secondary to sepsis, ischemia, or nephrotoxins displayed a greater than ten-fold increase in plasma NGAL and a greater than 100-fold increase in urine NGAL compared with normal controls.  A small prospective study examined NGAL in patients undergoing coronary angiography, as well as correlations between NGAL and other markers of kidney function: cystatin C, eGFR and serum creatinine. It showed that NGAL correlated with cystatin C, serum creatinine and eGFR in patients with normal serum creatinine undergoing coronary angiography. 
Another study tested the hypothesis whether NGAL could represent an early biomarker of contrast-induced nephropathy in 100 patients with normal serum createnine undergoing percutaneous coronary interventions. The incidence of contrast induced nephropathy in this study defined as an increase in serum creatinine > 25% of the baseline was 11%. Serum NGAL levels were elevated in 2 hours, and urine NGAL levels were elevated in 4 hours after percutaneous coronary intervention in patients who developed contrast induced nephropathy compared with those who did not. 
In summary, AKI remains an increasingly important clinical condition with a poor outcome. Rapid and significant clinical advances will be possible when diagnostic criteria and "biomarkers" allowing for rapid diagnosis and quantitative staging of the extent of injury are developed, validated and proven useful in the individual patient.
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Bruce A Molitoris
Division of Nephrology, 950 West Walnut Street, R2-202, Indianapolis IN 46202
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