Diagnostic and prognostic stratification in the emergency department using urinary biomarkers of nephron damage

Akutes Nierenversagen (AKI) ist nach wie vor ein häufiger und ernst zu nehmender klinischer Befund. Besonders oft führt eine Form des Nierenversagens, das Intrinsische Nierenversagen (iAKI) zu ungünstigen klinischen Verläufen. Diese Form des Nierenversagens ist mit strukturellen Nierenschädigungen assoziiert, was im Unterschied zu anderen Formen des Nierenversagens andere therapeutische Konsequenzen hat. Deshalb ist eine möglichst frühe Unterscheidung der einzelnen Formen des Nierenversagens notwendig. Die herkömmliche Diagnostik beruht größtenteils auf Messungen von Kreatininwerten, wobei eine Unterscheidung der verschiedenen Formen des Nierenversagens kaum möglich ist. In den letzten Jahren wurden deshalb verschiedene Urin-Biomarker auf die Detektion von Intrinsischem Nierenversagen hin untersucht. In der vorliegenden Arbeit wird der diagnostische und prognostische Wert von fünf verschiedenen Urin-Biomarker untersucht und mit der konservativen Diagnostik mit Serum-Kreatinin verglichen. Die in der vorliegenden Arbeit untersuchten Urin-Biomarker sind: Urin-Neutrophilen- Gelatinase- assoziiertes Lipocalin [uNGAL], Urin-Kidney Injury Molecule 1 [uKIM-1], Urin-Leber-Typ- Fettsäure-bindendes Protein [uLFABP], Urin- Interleukin 18 [uIL 18] und Urin-Cystatin C [uCysC]. Es wurde eine prospektiven Kohortenstudie mit 543 unselektierten Notaufnahmepatienten durchgeführt. Diese Kohorte war Teilkohorte einer multizentrischen Studie [1] von 1635 Notaufnahmepatienten. Ziel war es, Angaben über den Wert jedes einzelnen Biomarkers im Vergleich zum Serum- Kreatinin bei der Diagnosestellung von Intrinsischem Nierenversagen, bei der Vorhersage von Schwere und Dauer von iAKI und bei der Vorhersage klinischer Ergebnisse wie Tod oder Dialysebeginn zu erhalten. Es wurde im Ergebnis deutlich, dass jeder der fünf Biomarker mit unterschiedlicher Signifikanz bei iAKI erhöht war. Der beste Marker war uNGAL (WB) mit einer Spezifität von 83% und Sensitivität von 68% bei einem Cutoff von 90 µg/ml. Auch für die Schwere und die Dauer von iAKI erwies sich uNGAL als der beste Prädiktor. Bekanntlich ist iAKI sehr häufig mit ungünstigen klinischen Endpunkten assoziert. Auch in der vorliegenden Studie wurde das belegt. Die häufigsten Fälle von Tod oder Dialysebeginn wurden bei Patienten mit iAKI im Vergleich zu Patienten mit anderen Formen des Nierenversagens verzeichnet. Die Urin-Biomarker uNGAL in Kombination mit uLFABP waren dabei die besten Prädiktoren für ein negatives klinisches Ergebnis. Jeweils in Kombination mit sCr-Werten konnte sowohl uNGAL als auch uLFABP die Risikoeinschätzung verbessern. Eine Gruppe in der Kohorte wurde gefunden, die zwar niedrige sCr-Werte, aber hohe Biomarkerwerte von uNGAL und uLFABP zeigten. Diese Patienten wären bei der alleinigen Messung von Serum- Kreatinin mit der konventionellen Diagnostik nicht der richtigen Risikoklasse zugeordnet und als Risikopatienten übersehen worden. Im Ergebnis kann gesagt werden, dass die Biomarker die diagnostische und auch prognostische Einteilung der Patienten in der Notaufnahme verbessern können.Acute kidney injury (AKI) is a ubiquitous event in clinical practice, frequently with severe consequences. Intrinsic acute kidney injury (IAKI) is a variant of it. It is associated with structural kidney damage (nephron injury) and leads frequently to an unfavorable clinical outcome.The usual diagnostics with creatinine exhibits deficits in the ability to distinguish different forms of kidney injury. That motivated studies with a variety of urine biomarkers with respect to detection of iAKI. In this prospective cohort study, we determine the diagnostic and prognostic value of several urinary biomarkers for iAKI in the emergency department and compare it with currently used diagnostics. Five biomarkers (urinary neutrophil gelatinase–associated lipocalin [uNGAL],kidney injury molecule-1 [uKim-1], urinary liver-type fatty acid binding protein[LFABP], urinary interleukin-18 [u-IL-18], and cystatin C [u-cysC])were measured in 543 unselected emergency department patients at the time of hospital admission. We assesed the performance of the biomarkers for detection of severity and duration of iAKI and the predictive power for poor clinical outcome. UNGAL performed best in diagnosing iAKI out of the 5 (specifity 83%, sensitivity 68% withacutoff at 90 µg/l).It also proved to be the best predictor of the severity and duration of iAKI. iAKI was more frequently associated with the negative combined clinical outcome death or in- hospital dialysis compared to other clinical diagnoses.The best predictive value for negative clinical outcome had uNGAL combined with uLFABP.Risk assessment of both uNGAL and uLFABP individually was imporved if each was combined with sCr-values. We also identified a subgroup in the cohort with low creatinine values but elevated uNGAL and uLFABP. The biomarker values allowed for correct patient classification. This group would have gone unnoticed as patients at risk with currently used diagnostics. In summary, prognostic and diagnostic stratification in the emergency department is possible by the use of biomarkers

Urinary NGAL-Positive Acute Kidney Injury and Poor Long-term Outcomes in Hospitalized Patients

Neutrophil gelatinase−associated lipocalin (NGAL) is a widely studied biomarker of renal tubular injury. Urinary NGAL (uNGAL) during acute kidney injury (AKI) predicts short-term adverse outcomes. However, the long-term predictive value is unknown. Methods: We performed a prospective observational study of 145 patients with hospital-acquired AKI according to Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) criteria and analyzed the long-term predictive value of uNGAL at the time of AKI. We defined a composite outcome of all-cause mortality and the development of end-stage renal disease (ESRD). Results: In all, 61 AKI patients died and 22 developed ESRD within 6 months. The uNGAL levels were significantly higher in patients with poor long-term outcomes. uNGAL levels ≥362 μg/l (highest quartile) and uNGAL levels between 95 and 362 μg/l (third quartile) were associated with hazard ratios of 3.7 (95% confidence interval, 2.1–6.5) and 1.9 (1.1–3.5), respectively, compared with uNGAL levels <95 μg/l (lower quartiles). After 6 months, 67% and 43% of patients within the highest and third uNGAL quartile, respectively, had either progressed to ESRD or died, compared to only 21% of patients with uNGAL in the lower 2 quartiles (P < 0.001). In multivariable Cox regression analyses accounting for conventional predictors, uNGAL was the strongest independent predictor of adverse long-term outcomes. The association of uNGAL levels and poor long-term outcomes remained significant in the subgroup of 107 AKI survivors discharged without requiring dialysis (P = 0.002). Discussion: These data indicate that elevated uNGAL levels at AKI diagnosis predict poor long-term outcomes

Does NGAL reduce costs? A cost analysis of urine NGAL (uNGAL) & serum creatinine (sCr) for acute kidney injury (AKI) diagnosis.

Urine neutrophil gelatinase-associated lipocalin (uNGAL) is a sensitive and specific diagnostic test for acute kidney injury (AKI) in the Emergency Department (ED), but its economic impact has not been investigated. We hypothesized that uNGAL used in combination with serum creatinine (sCr) would reduce costs in the management of AKI in patients presenting to the ED in comparison to using sCr alone.A cost simulation model was developed for clinical algorithms to diagnose AKI based on sCr alone vs. uNGAL plus sCr (uNGAL+sCr). A cost minimization analysis was performed to determine total expected costs for patients with AKI. uNGAL test characteristics were validated with eight-hundred forty-nine patients with sCr ≥1.5 from a completed study of 1635 patients recruited from EDs at two U.S. hospitals from 2007-8. Biomarker test, AKI work-up, and diagnostic imaging costs were incorporated.For a hypothetical cohort of 10,000 patients, the model predicted that the expected costs were $900 per patient (pp) in the sCr arm and$950 in the uNGAL+sCr arm. uNGAL+sCr resulted in 1,578 fewer patients with delayed diagnosis and treatment than sCr alone (2,013 vs. 436 pts) at center 1 and 1,973 fewer patients with delayed diagnosis and treatment than sCr alone at center 2 (2,227 vs. 254 patients). Although initial evaluation costs at each center were $50 pp higher in with uNGAL+sCr, total costs declined by$408 pp at Center 1 and by $522 pp at Center 2 due to expected reduced delays in diagnosis and treatment. Sensitivity analyses confirmed savings with uNGAL + sCr for a range of cost inputs.Using uNGAL with sCr as a clinical diagnostic test for AKI may improve patient management and reduce expected costs. Any cost savings would likely result from avoiding delays in diagnosis and treatment and from avoidance of unnecessary testing in patients given a false positive AKI diagnosis by use of sCr alone

Correction: Does NGAL reduce costs? A cost analysis of urine NGAL (uNGAL) & serum creatinine (sCr) for acute kidney injury (AKI) diagnosis.

[This corrects the article DOI: 10.1371/journal.pone.0178091.]

Simulation model.

<p>A cost simulation model was developed for competing testing strategies to evaluate for AKI; 1) Scr alone, vs. 2) uNGAL plus Scr (uNGAL+Scr). Since the uNGAL+Scr treatment arm provided more diagnostic information, it was regarded as the “gold standard” relative to Scr alone in terms of whether patients should be treated or whether treatment should be delayed.</p

Sensitivity analysis.

<p>The sensitivity analysis recalculates the net expected cost of each strategy (Scr vs. uNGAL+Scr), varying one model input at a time to its high and low values relative to its baseline value. At both sites, costs of uNGAL+Scr remain lower for each scenario examined in the sensitivity analysis. At NYP-Allen and SIUH, the results are most sensitive to hospital costs and length of stay, costs of additional testing, and the percent of patients with CKD.</p

Effects on cost per patient.

<p>Effects on Cost Per Patient at NYP-Allen and SIUH. At NYP-Allen, the use of uNGAL+Scr would lead to an expected cost savings of $408 per patient on average, and to similar cost savings of$522 per patient at SIUH. These savings were reflected in lower per patient hospitalization costs and lower additional testing costs.</p

Model input values for each site.

<p>Model input values for each site.</p