NGAL time-courses.

<p>Urinary and plasma NGAL concentration time-courses for the scenario of a 50% loss of GFR with no additional loss of nephrons for the Healthy (black lines), Hyperfiltering (blue lines) and CKD kidneys (red lines). Measured plasma and urinary NGAL values following a cardiac arrest in a 90 kg male with a history of hypertrophic obstructive cardiomyopathy and severely impaired left ventricular function who suffered a cardiac arrest in the emergency department and subsequently lost approximately 70% of GFR (Case A in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101288#pone.0101288-Pickering1" target="_blank">[14]</a>).</p

The distribution of single nephron GFRs.

<p>Histograms for the Healthy model (dark gray; ), Hyperfilter model (black; ) and CKD model (light gray; ). The Healthy model had 2,000,000 nephrons and GFR of (), the Hyperfilter model maintained a GFR of with 33.3% fewer nephrons, and the CKD model had a reduced GFR of with 66.7% fewer nephrons.</p

Structural-AKI thresholds for severity stages based on equivalent sensitivity (62%) to Functional-AKI.

<p>Structural-AKI thresholds for severity stages based on equivalent sensitivity (62%) to Functional-AKI.</p

Single Nephron Models.

<p>A: Water reabsorption. B: Preformed biomarkers such as -GST are excreted at a rate (E) dependent on the initial (remaining) mass of biomarker and the production rate (P) of new biomarker. C: Induced biomarkers such as KIM-1 are excreted at a rate approximating a log-normal distribution. D: Filtered biomarkers such as Cystatin C are filtered at a rate (F) dependent on the plasma concentration and single nephron GFR and then reabsorbed at a rate dependent on the number of available transporters (T). Some biomarkers are also secreted (S). The final excretion rate is the sum of the gains minus the losses. The final concentration depends on the excretion rate divided by the urine flow rate. Modified after <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101288#pone.0101288-Endre2" target="_blank">[34]</a>.</p

Filtered multiple-nephron fold concentration increase at 48 hours post-insult.

<p>Filtered biomarker concentration increases in Healthy, Hyperfiltering and CKD kidneys. Each line of iso-intensity represents the fold increase 48-hours following insult of a preformed biomarker relative to the pre-injury concentration in a Healthy Kidney with 2 million nephrons and a GFR of . Four GFR scenarios (no change in GFR [ for Healthy and Hyperfiltering kidneys, and for CKD kidney], one-third, one-half, and two-thirds reduction in GFR) were combined with four nephron number scenarios (no loss [2 M for Healthy, 1.33 M for Hyperfiltering, and 0.67 M for CKD kidneys], one-third, one-half, and two-thirds loss) to produce 16 scenarios. From each of these the fold increase in biomarker concentration at 48-hours following insult was extracted. The iso-intensity lines of fold increase were then interpolated. Each scenario from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101288#pone-0101288-g002" target="_blank">figure 2</a> is represented for no change in GFR, one-third, one-half, and two-thirds reduction. All scenarios are for a receptor production rate constant and loss rate constant .</p

Patients in the Development cohort versus Validation cohort, n (% of total patients in each cohort).

<p>Functional-AKI: Plasma creatinine >26.4 µmol/L (0.3 mg/dl) in 48 hours or 50% in 7 days.</p><p>Structural-AKI: Urinary NGAL >140 ng/ml.</p

Induced Biomarkers: multiple-nephron maximum fold concentration increase.

<p>Induced biomarker concentration increases in Healthy, Hyperfiltering and CKD kidneys. Each line of iso-intensity represents the maximal fold increase of a preformed biomarker relative to the pre-injury concentration in a Healthy Kidney with 2 million nephrons and a GFR of . Four GFR scenarios (no change in GFR [ for Healthy and Hyperfiltering kidneys, and for CKD kidney], one-third, one-half, and two-thirds reduction in GFR) were combined with four nephron number scenarios (no loss [2 M for Healthy, 1.33 M for Hyperfiltering, and 0.67 M for CKD kidneys], one-third, one-half, and two-thirds loss) to produce 16 scenarios. From each of these the maximum fold increase in biomarker concentration was extracted. The iso-intensity lines of fold increase were then interpolated. All scenarios are for a peak at 6 hours (), half the total excretion occurs within 12 hours (), and a scaling factor () of 1000.</p

Illustrative biomarker time course following a cardiac arrest.

<p>Baseline creatinine was 96 µmol/l. Horizontal dotted lines represent the thresholds for Functional-AKI (26.4 µmol/l increase over baseline) and Structural-AKI (140 ng/ml). If the diagnosis of Structural-AKI and Functional-AKI were to be made at only one time point then the patient would be initially negative for both classifications before becoming positive for Structural-AKI for a short period whilst remaining negative for Functional-AKI. From 2 to 16 hours the patients is positive for both Structural and Functional-AKI before becoming negative again for Structural-AKI.</p

Filtered Biomarkers: multiple-nephron maximum fold concentration increase.

<p>Filtered biomarker concentration increases in Healthy, Hyperfiltering and CKD kidneys. Each line of iso-intensity represents the maximal fold increase of a preformed biomarker relative to the pre-injury concentration in a Healthy Kidney with 2 million nephrons and a GFR of . Four GFR scenarios (no change in GFR [ for Healthy and Hyperfiltering kidneys, and for CKD kidney], one-third, one-half, and two-thirds reduction in GFR) were combined with four nephron number scenarios (no loss [2 M for Healthy, 1.33 M for Hyperfiltering, and 0.67 M for CKD kidneys], one-third, one-half, and two-thirds loss) to produce 16 scenarios. From each of these the maximum fold increase in biomarker concentration was extracted. The iso-intensity lines of fold increase were then interpolated. All scenarios are for a receptor production rate constant and loss rate constant .</p

Demographics of the Development and Validation cohorts.

<p>Data presented as n(%), means ± sd, or median (interquartile range). APACHE: Acute Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment; CKD: Chronic Kidney Disease; eGFR: estimated Glomerular Filtration Rate using the Modification of Diet in Renal Disease (MDRD) formula.</p