VIDAS NEPHROCHECK
Device Facts
| Record ID | K210793 |
|---|---|
| Device Name | VIDAS NEPHROCHECK |
| Applicant | Biomérieux SA |
| Product Code | PIG · Clinical Chemistry |
| Decision Date | Jul 8, 2022 |
| Decision | SESE |
| Submission Type | Traditional |
| Regulation | 21 CFR 862.1220 |
| Device Class | Class 2 |
Indications for Use
VIDAS® NEPHROCHECK® is an automated test for use on the VIDAS® 3 instrument for the immunoenzymatic quantitative determination of TIMP-2 (Tissue Inhibitor of Metalloproteinase-2) and IGFBP-7 (Insulin-like Growth Factor-Binding Protein 7) proteins in human urine using the ELFA technique (Enzyme Linked Fluorescent Assay) for calculation of the AKIRISK™ Score. The VIDAS® NEPHROCHECK® assay is intended to be used in conjunction with clinical evaluation in patients 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 acute kidney injury (AKI) within 12 hours of patient assessment. The VIDAS® NEPHROCHECK® test is intended to be used in patients 21 years of age or older.
Device Story
VIDAS® NEPHROCHECK® is a quantitative immunoassay for human urine. It measures TIMP-2 and IGFBP-7 proteins using an Enzyme-Linked Fluorescent Assay (ELFA) on the VIDAS® 3 instrument. The device uses a sandwich immunoassay principle where sample proteins bind to monoclonal antibodies fixed to a Solid Phase Receptacle (SPR). Alkaline phosphatase-labeled conjugates catalyze a substrate to produce a fluorescent signal measured at 450 nm. The instrument automatically calculates the AKIRISK™ Score using the formula: (TIMP-2 × IGFBP-7) / 1000. Used in central laboratories by healthcare professionals, the output provides a risk score to aid clinicians in assessing the likelihood of moderate or severe AKI within 12 hours. Results must be interpreted alongside clinical and laboratory data. The test benefits patients by providing early risk stratification for AKI in critically ill populations, potentially facilitating timely clinical intervention.
Clinical Evidence
Retrospective multi-center study using 526 banked urine samples from ICU patients (400 from Topaz cohort, 126 from Opal cohort). Primary endpoints were sensitivity and specificity for AKI risk assessment. In the Topaz subset (n=399), sensitivity was 89.9% (95% CI: 80.5-95.0%) and specificity was 45.2% (95% CI: 39.9-50.5%). In the Opal cohort (n=126), sensitivity was 82.8% (95% CI: 65.5-92.4%) and specificity was 40.2% (95% CI: 31.0-50.2%).
Technological Characteristics
Quantitative ELFA immunoassay. Components: Reagent strips, Solid Phase Receptacles (SPR) coated with mouse monoclonal IgG anti-IGFBP-7 and anti-TIMP-2. Energy source: VIDAS 3 instrument. Detection: Fluorescence at 450 nm. Connectivity: Integrated with VIDAS 3 instrument. Sterilization: Not specified. Software: Automated calculation of AKIRISK Score via instrument firmware.
Indications for Use
Indicated for ICU patients aged 21+ with current or recent (within 24h) acute cardiovascular or respiratory compromise to aid in risk assessment for moderate or severe acute kidney injury (AKI) within 12 hours of assessment.
Regulatory Classification
Identification
An acute kidney injury test system is a device that is intended to measure one or more analytes in human samples as an aid in the assessment of a patient's risk for developing acute kidney injury. Test results are intended to be used in conjunction with other clinical and diagnostic findings, consistent with professional standards of practice, including confirmation by alternative methods.
Special Controls
Acute kidney injury test systems must comply with the following special controls: 1) Premarket notification submissions must detail an appropriate end user device training program that will be offered while marketing the device as part of your efforts to mitigate the risk of failure to correctly interpret test results. 2) As part of the risk management activities performed as part of your 21 CFR 820.30 design controls, you must document the appropriate end user device training program provided in your premarket notification submission to satisfy special control (1) that will be offered while marketing the device as part of your efforts to mitigate the risk of incorrect interpretation of test results. 3) Robust clinical data demonstrating the positive predictive value, negative predictive value, sensitivity and specificity of the test in the intended use population must be submitted as part of the premarket notification submission.
*Classification.* Class II (special controls). The special controls for this device are:(1) Premarket notification submissions must detail an appropriate end user device training program that will be offered while marketing the device as part of your efforts to mitigate the risk of incorrect interpretation of test results. (2) As part of the risk management activities performed as part of your 21 CFR 820.10(c) design and development activities, you must document the appropriate end user device training program provided in your premarket notification submission to satisfy the special control in paragraph (b)(1) of this section that will be offered while marketing the device as part of your efforts to mitigate the risk of incorrect interpretation of test results. (3) Robust clinical data demonstrating the positive predictive value, negative predictive value, sensitivity and specificity of the test in the intended use population must be submitted as part of the premarket notification submission.
Predicate Devices
- NEPHROCHECK Test System (K171482)
Related Devices
- DEN130031 — NEPHROCHECK TEST SYSTEM · Astute Medical, Inc. · Sep 5, 2014
- K171482 — NEPHROCHECK Test System · Astute Medical, Inc. · Nov 16, 2017
- K153165 — NEPHROCHECK Test Kit, ASTUTE140 Meter, NEPHROCHECK Liquid Controls Kit, NEPHROCHECK Calibration Verification (Cal Vers) Kit · Astute Medical, Inc. · Jun 1, 2016
Submission Summary (Full Text)
{0}
FDA U.S. FOOD & DRUG ADMINISTRATION
# 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY
ASSAY ONLY
## I Background Information:
A 510(k) Number
K210793
B Applicant
bioMérieux SA
C Proprietary and Established Names
VIDAS® NEPHROCHECK®
D Regulatory Information
| Product Code(s) | Classification | Regulation Section | Panel |
| --- | --- | --- | --- |
| PIG | Class II | 21 CFR 862.1220 - Acute Kidney Injury Test System | CH - Clinical Chemistry |
## II Submission/Device Overview:
A Purpose for Submission:
New device
B Measurand:
The test reports an AKIRISK score derived from the measurement of insulin-like growth factor-binding protein (IGFBP-7) and tissue-inhibitor of metalloproteinases 2 (TIMP-2).
C Type of Test:
Quantitative Immunoassay
Food and Drug Administration
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
www.fda.gov
{1}
K210793 - Page 2 of 14
# III Intended Use/Indications for Use:
## A Intended Use(s):
See Indications for Use below.
## B Indication(s) for Use:
VIDAS® NEPHROCHECK® is an automated test for use on the VIDAS® 3 instrument for the immunoenzymatic quantitative determination of TIMP-2 (Tissue Inhibitor of Metalloproteinase-2) and IGFBP-7 (Insulin-like Growth Factor-Binding Protein 7) proteins in human urine using the ELFA technique (Enzyme Linked Fluorescent Assay) for calculation of the AKIRISK™ Score.
The VIDAS® NEPHROCHECK® assay is intended to be used in conjunction with clinical evaluation in patients 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 acute kidney injury (AKI) within 12 hours of patient assessment. The VIDAS® NEPHROCHECK® test is intended to be used in patients 21 years of age or older.
## C Special Conditions for Use Statement(s):
Rx - For Prescription Use Only
The test should not be used as a “standalone test”; test results should be evaluated in the context of all clinical and laboratory data available.
Test results should be used in patients 21 years of age and older.
This test system is for central laboratory use only. It is not for point-of-care use.
## D Special Instrument Requirements:
VIDAS 3 Instrument
# IV Device/System Characteristics:
## A Device Description:
Each VIDAS NEPHROCHECK kit contains 60 tests. The kit is comprised of 60 Reagent Strips, 60 Solid Phase Receptacles (SPR), 1 control, and 1 calibrator (Table 1).
Components of the VIDAS NEPHROCHECK
| Kit component | | Description |
| --- | --- | --- |
| 60 Reagent Strips | STR | Ready-to-use. |
| 60 SPR devices
2 X 30 | SPR | Ready-to-use.
Interior of SPR devices coated with mouse monoclonal IgG anti-IGFBP7 and anti-TIMP-2 + stabilizer of animal origin + preservative. |
| S1 Calibrator
1 x 1.6 ml (liquid) | C1 | Ready-to-use.
Buffer containing proteins + stabilizer of animal origin + preservative. |
| C1 Control
1 x 1.2 ml (liquid) | S1 | Ready-to-use.
Buffer containing proteins + stabilizer of animal origin + preservative. |
{2}
The strips consist of 10 wells covered with a labeled foil seal and composed as follows:
Reagent strip components
| Well | Reagents |
| --- | --- |
| 1 | Sample well: dispense 100 μL of calibrator, control, or sample. |
| 2 | Conjugate: buffer containing alkaline phosphatase-labeled anti-IGFBP-7 monoclonal IgG (mouse) + alkaline phosphatase-labeled anti-TIMP-2 monoclonal IgG (rabbit) + stabilizer of animal origin + preservative. |
| 3 | Wash buffer containing preservative |
| 4 | Empty well |
| 5 | Acid wash buffer |
| 6-7-8 | Wash buffer containing preservative. |
| 9 | Substrate: 4-Methyl-umbelliferyl phosphate (0.6 mmol/L) + preservative. |
| 10 | Reading cuvette with substrate: 4-Methyl-umbelliferyl phosphate (0.6 mmol/L) + preservative. |
B Principle of Operation:
The assay principle combines a one-step sandwich enzyme immunoassay method with a final fluorescence detection, also known as enzyme-linked fluorescent assay (ELFA). The sample is transferred into the well containing anti-IGFBP-7 and anti-TIMP-2 antibodies labeled with alkaline phosphatase (conjugate). The sample/conjugate mixture is cycled in and out of the Solid Phase Receptacle (SPR) device several times. This operation enables the two proteins to bind with the immunoglobulins that are fixed to the interior wall of the SPR device and to the conjugate to form a sandwich. Unbound components are eliminated during washing steps. Two detection steps are carried out successively. During each detection step, the substrate (4-Methyl-umbelliferyl phosphate) is cycled in and out of the SPR device. The conjugate enzyme catalyzes the hydrolysis of this substrate into a fluorescent product (4-Methyl-umbelliferone), the fluorescence of which is measured at 450 nm. For each protein, the intensity of the fluorescence is proportional to the concentration in the sample. At the end of the assay, the protein concentrations are calculated by the VIDAS® 3 instrument in relation to the two calibration curves, one corresponding to each protein, and encoded in the MLE (Master Lot Entry) data. The concentration from each protein, TIMP-2 and IGFBP-7, is converted into a single numerical result called the AKIRISK Score. The VIDAS® NEPHROCHECK® Test result, known as the AKIRISK Score, is automatically calculated by the instrument as the product of the concentrations of the two biomarkers, in ng/mL, divided by 1000, according to the following formula:
$$
\mathrm{AKIRISK\ Score} = (\mathrm{TIMP-2} \times \mathrm{IGFBP-7}) / 1000
$$
V Substantial Equivalence Information:
A Predicate Device Name(s):
NEPHROCHECK Test System
K210793 - Page 3 of 14
{3}
B Predicate 510(k) Number(s):
K171482
C Comparison with Predicate(s):
| Device & Predicate Device(s): | K210793 | K171482 |
| --- | --- | --- |
| Device Trade Name | VIDAS® NEPHROCHECK® | NEPHROCHECK Test System |
| General Device Characteristic Similarities | | |
| Intended Use/Indications for Use | For use in conjunction with clinical evaluation in patients 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 acute kidney injury (AKI) within 12 hours of patient assessment. For use in patients 21 years of age or older. | Same |
| Intended users | Laboratory healthcare professionals | Same |
| Specimen | Urine | Same |
| Sample volume | 100 μL | Same |
| Analyte | TIMP-2 and IGFBP-7 | Same |
| Assay principle | Labeled antibody competition method | Same |
| Reportable interval for the AKIRISK Score | 20-400 ng/mL for IGFBP-7
2-25 ng/ml for TIMP-2
0.04-10.00 for AKIRISK Score | Same |
| Cutoff | 0.3 AKIRISK Score | Same |
| General Device Characteristic Differences | | |
| Antibody type | Monoclonal antibodies | Polyclonal and monoclonal antibodies |
| Assay Technique | Enzyme-linked fluorescent assay (ELFA) | Sandwich immunoassay technique. Lateral flow with fluorescent detection. |
| Automated Instrument | VIDAS 3 instrument | ASTUTE140 Meter |
K210793 - Page 4 of 14
{4}
VI Standards/Guidance Documents Referenced:
- CLSI EP05-A3, Evaluation of Precision of Quantitative Measurement Procedures; Approved Guideline - Third Edition
- CLSI EP07-Ed3, Interference Testing in Clinical Chemistry
- CLSI EP09-A3c, Measurement Procedure Comparison and Bias Estimation Using Patient Samples - Third Edition
- CLSI EP12-A2, User Protocol for Evaluation of Qualitative Test Performance; Approved Guideline - Second Edition
- CLSI EP17-A2, Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures; Approved Guideline – Second Edition
- CLSI EP28-A3c, Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline - Third Edition
VII Performance Characteristics (if/when applicable):
A Analytical Performance:
1. Precision/Reproducibility:
The device precision was evaluated using a 20-day precision study conducted at 3 clinical laboratories according to CLSI guideline EP05-A3 using 7 pooled native urine samples that included samples below the AKIRISK Score cutoff (Samples S1, S2, and S3), and samples to span the range of the AKIRISK Score (Samples S4, S5, S6, and S7). All samples were tested in duplicate, 2 times per day, for 20 days with a single reagent lot and a single instrument at each site. Each sample was measured 80 times at each site, for a total of 240 measurements per sample. The sponsor assessed Within-Run, Between-Run, Between-Day, and Total Imprecision (Between Site/Instrument/Lot variation).
The sponsor provided information to support the expected imprecision of the individual analytes used in the calculation of the AKIRISK score.
All Sites/Lots (n=240)
| Test Specimen | Risk Score Mean | Within-Run | | Between Run | | Between Day | | Total Imprecision (Between-Site/Instrument/Lot) | |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
| | | SD | %CV | SD | %CV | SD | %CV | SD | %CV |
| S1 | 0.05 | 0.01 | 18.2 | 0.00 | 0.0 | 0.00 | 0.0 | 0.01 | 22.1 |
| S2 | 0.05 | 0.01 | 10.5 | 0.00 | 0.0 | 0.00 | 6.7 | 0.01 | 16.1 |
| S3 | 0.19 | 0.01 | 5.7 | 0.01 | 3.5 | 0.00 | 0.0 | 0.01 | 7.3 |
| S4 | 0.71 | 0.04 | 5.5 | 0.02 | 2.1 | 0.02 | 3.4 | 0.07 | 10.2 |
| S5 | 1.73 | 0.07 | 3.9 | 0.05 | 2.7 | 0.02 | 1.1 | 0.14 | 7.9 |
| S6 | 4.28 | 0.19 | 4.5 | 0.07 | 1.6 | 0.07 | 1.5 | 0.24 | 5.6 |
| S7 | 7.48 | 0.37 | 4.9 | 0.00 | 0.0 | 0.15 | 2.0 | 0.49 | 6.5 |
A second study was also performed (8 samples, 2 replicates per run, 2 runs per day, 8 days per lot, 3 lots) that demonstrated that lot-to-lot variation was not a significant contributor to assay imprecision.
K210793 - Page 5 of 14
{5}
| Test Specimen | Risk Score Mean | Repeatability (Within-run precision) | | Within-lot Precision | | Within-laboratory precision (between-lot, within-instrument) | |
| --- | --- | --- | --- | --- | --- | --- | --- |
| | | SD | %CV | SD | %CV | SD | %CV |
| S1 | 0.05 | 0.00 | 8.7 | 0.00 | 9.7 | 0.01 | 12.0 |
| S2 | 0.06 | 0.01 | 15.7 | 0.01 | 15.9 | 0.01 | 15.9 |
| S3 | 0.19 | 0.01 | 5.9 | 0.01 | 7.0 | 0.01 | 7.1 |
| S4 | 0.24 | 0.02 | 6.5 | 0.02 | 7.7 | 0.02 | 8.2 |
| S5 | 0.73 | 0.04 | 6.0 | 0.05 | 6.3 | 0.06 | 8.0 |
| S6 | 1.73 | 0.08 | 4.4 | 0.10 | 5.5 | 0.15 | 8.7 |
| S7 | 4.25 | 0.18 | 4.3 | 0.20 | 4.7 | 0.31 | 7.4 |
| S8 | 7.46 | 0.37 | 5.0 | 0.40 | 5.4 | 0.55 | 7.4 |
2. Linearity:
The reportable range of the AKIRISK Score is 0.04 – 10.0. The component measurements of the AKIRISK score (IGFBP-7 and TIMP-2 measurements) were assessed and found to be linear across the reportable range of the AKIRISK Score. However, the AKIRISK Score itself is not expected to be linear.
Low concentration urine was spike with purified recombinant proteins to measure the hook effect at AKIRISK scores approaching 1000. No high dose hook effect was observed for the AKIRISK Score at these values.
3. Analytical Specificity/Interference:
Interference studies were conducted in accordance with CLSI EP07-Ed3 using pooled human urine samples. Interferents were selected from medications, contrast agents, plasma expanders, other urine constituents, isoforms of TIMP and IGFBP, and other biomarkers which have been reported as elevated in the literature in AKI. The sponsor performed testing with substances identified as potentially interfering with IGFBP-7 and TIMP-2.
Concentrations were selected based on guidelines in CLSI EP37, expected values for this patient population identified from literature references or concentrations previously tested for similar devices. Two lots of the VIDAS NEPHROCHECK assay were tested using 8 VIDAS 3 instruments. A sample with a high AKIRISK Score, as well as a sample close to the clinical cutoff were used. Interference was defined as any interferents that exhibited greater than $\pm 10\%$ interference in the AKIRISK Score test result.
$$
\% \text{ observed interference} = \frac{[\text{Mean Assay Result (Test Pool)} - \text{Mean Assay Result (Control Pool)}]}{\text{Mean Assay Result (Control Pool)} \times 100}
$$
If interference was observed at the highest concentration, the effect of the interference was characterized by a dose-response experiment to determine the degree of interference as a function of the interfering substance concentration.
K210793 - Page 6 of 14
{6}
Test substance and highest concentration tested that did not interfere with assay performance
| No. | Test Substance | Highest concentration tested with <10% interference (mg/L) |
| --- | --- | --- |
| Contrast Agents | | |
| 1 | Visipaque (Iodixanol) | 4,941 |
| 2 | Omniscan (Gadodaimide) | 177 |
| 3 | Omnipaque (Iohexol) | 14,085 |
| 4 | Magnevist (Gadopentetate Dimeglumine) | 422 |
| 5 | Optiray (Ioversol) | 4,944 |
| Plasma Expanders | | |
| 6 | Dextran 40 | 22 |
| 7 | Pentastarch | 9 |
| 8 | Hydroxyethyl starch | 6 |
| Drugs and Other Substances | | |
| 9 | Acetaminophen (Paracetamol) | 201 |
| 10 | Acetone | 697 |
| 11 | Acetylcysteine | 1665 |
| 12 | Acetyl salicylic acid (Aspirin) | 652 |
| 13 | Acyclovir | 66 |
| 14 | Albumin | 6,900 |
| 15 | Albuterol | 0.4 |
| 16 | Amiodarone | 42 |
| 17 | Ammonia | 1000 |
| 18 | Amoxicillin | 75 |
| 19 | Amphotericin | 82 |
| 20 | Ascorbic acid | 52.5 |
| 21 | Atorvastatin | 80 |
| 22 | Bicarbonates | 2940 |
| 23 | Bilirubin conjugated | 400 |
| 24 | Bumetanide | 30 |
| 25 | Caffeine | 108 |
| 26 | Caspofungin | 86 |
| 27 | Cefepime | 9 |
| 28 | Ceftriaxone | 840 |
| 29 | Cephalexin | 126 |
| 30 | Ciprofloxacin | 12 |
| 31 | Clopidogrel | 225 |
| 32 | Dexmedetomidine (Precedex) | 0.2 |
| 33 | Diltiazem (Cardizem) | 43 |
| 34 | Dipyrone | 9600 |
| 35 | Dopamine | 1 |
| 36 | Doripenem | 1050 |
| 37 | Epinephrine | 6 |
| 38 | Ethacryinc acid | 19 |
| 39 | Ethanol | 6000 |
| 40 | Fenoldopam | 484 |
K210793 - Page 7 of 14
{7}
K210793 - Page 8 of 14
| No. | Test Substance | Highest concentration tested with <10% interference (mg/L) |
| --- | --- | --- |
| 41 | Fentanyl | 100 |
| 42 | Fluconazole | 75 |
| 43 | Fluvastatin | 80 |
| 44 | Furosemide | 60 |
| 45 | Gentamicin | 30 |
| 46 | Glucose | 9909 |
| 47 | Human Anti-Mouse Antibodies (HAMA) | 2 |
| 48 | Hemoglobin | 60 |
| 49 | Heparin | 21 |
| 50 | Hydralazine | 600 |
| 51 | Hydrochlorothiazide | 6 |
| 52 | Hydrocodone | 0.2 |
| 53 | Hydrocortisone | 720 |
| 54 | Ibuprofen | 500 |
| 55 | Insulin | 0.003 |
| 56 | Ketorolac | 166 |
| 57 | Lansoprazole | 90 |
| 58 | Linezolid | 48 |
| 59 | Lisinopril | 0.3 |
| 60 | Lorazepam | 1 |
| 61 | Low Molecular Weight Heparin | 30 |
| 62 | Mannitol | 18000 |
| 63 | Metformin | 40 |
| 64 | Methylene blue | 3.9 |
| 65 | Metolazone | 60 |
| 66 | Metoprolol | 5 |
| 67 | Metronidazole | 123 |
| 68 | Midazolam | 3.76 |
| 69 | Morphine | 7.8 |
| 70 | Moxifloxacin | 1200 |
| 71 | Myoglobin | 5 |
| 72 | Nitroglycerin | 0.02 |
| 73 | Norepinephrine | 204 |
| 74 | Omeprazole | 8.4 |
| 75 | Ondansetron | 0.342 |
| 76 | Pancuronium | 8 |
| 77 | Pantoprazole (Protonix) | 85 |
| 78 | Phenobarbital | 690 |
| 79 | Phenylephrine | 30 |
| 80 | Pravastatin | 80 |
| 81 | Prednisone | 3 |
| 82 | Propofol | 48 |
| 83 | Ranitidine | 10.5 |
| 84 | Riboflavin | 12 |
| 85 | Rocuronium | 126 |
{8}
K210793 - Page 9 of 14
| No. | Test Substance | Highest concentration tested with <10% interference (mg/L) |
| --- | --- | --- |
| 86 | Salicylic Acid | 599 |
| 87 | Theophylline | 60 |
| 88 | Tobramycin | 33 |
| 89 | Torsemide | 12 |
| 90 | Urobilinogen, synthetic | 12 |
| 91 | Valproic Acid (Valproate) | 499 |
| 92 | Vancomycin | 120 |
| 93 | Vasopressin | 5 |
| 94 | Vecuronium | 21 |
| 95 | Warfarin (Coumadin) | 75 |
| Common Urine Constituents | | |
| 96 | Calcium | 600 |
| 97 | Chloride | 5,600 |
| 98 | Creatinine | 1,800 |
| 99 | Magnesium | 240 |
| 100 | Phosphate | 2,800* |
| 101 | Potassium | 4,000 |
| 102 | Sodium | 3,600 |
| 103 | Sulfate | 4,800 |
| 104 | Urea | 23,000 |
| 105 | Uric Acid | 700 |
| Other Proteins Tested | | |
| 106 | Cystatin C | 3 |
| 107 | Interleukin-18 (IL-18) | 0.001 |
| 108 | Kidney Injury Molecule 1 (KIM 1) | 0.02 |
| 109 | Liver Type Fatty Acid Binding Protein (L-FABP) | 1 |
| 110 | N-acetyl-beta-D glucosaminidase (NAG) | 0.00004 |
| 111 | Neutrophil Gelatinase Associated Lipocalin (NGAL) | 3 |
| 112 | Pi-Glutathione-S-transferase (p-GST) | 0.1 |
| Potential Cross-Reactive Proteins | | |
| 113 | Insulin like growth factor- Binding Protein 1 (IGFBP-1) | 0.1 |
| 114 | Insulin like growth factor- Binding Protein 2 (IGFBP.2) | 0.25 |
| 115 | Insulin like growth factor- Binding Protein 3 (IGFBP-3) | 1.2 |
| 116 | Insulin like growth factor- Binding Protein 4 (IGFBP-4) | 1.2 |
| 117 | Insulin like growth factor- Binding Protein 5 (IGFBP-5) | 1.2 |
| 118 | Insulin like growth factor- Binding Protein 6 (IGFBP-6) | 1.2 |
| 119 | Insulin like growth factor 1 (IGF-1) | 1.5 |
{9}
| No. | Test Substance | Highest concentration tested with <10% interference (mg/L) |
| --- | --- | --- |
| 120 | Insulin like growth factor 2 (IGF-2) | 1.5 |
| 121 | Cysteine-rich motor neuron 1 protein (CRIM1) | 1.2 |
| 122 | Agrin | 1.2 |
| 123 | Serine protease HTRA1 (HTRA1) | 1.2 |
| 124 | Insulin-like growth factor binding protein-like 1 IGFBPL1 | 1.2 |
| 125 | Metalloproteinase inhibitor 1 (TIMP-1) | 3 |
| 126 | Metalloproteinase inhibitor 3 (TIMP-3) | 2.5 |
| 127 | Metalloproteinase Inhibitor 4 (TIMP-4) | 0.6 |
| 128 | Matrix Metalloproteinase-2 (MMP-2) | 0.03 |
| 129 | Matrix Metalloproteinase-9 (MMP-9) | 0.03 |
* The sponsor claims no interference from phosphate up to 1,100 mg/L in their labeling despite testing a higher concentration.
Due to the potential of hemoglobin to interfere with results, urine samples with AKIRISK Scores between 0.30 and 0.46 should also be tested with a urine dipstick test for the presence of hematuria. If the blood result is high positive (3+) or the urine sample has some indications of blood in the urine (e.g., pink/red color), the AKIRISK Score may be falsely elevated, and should not be used. Hemoglobin levels above 60 mg/L can lead to a 20% increase in the AKIRISK™ Score.
The effect of pH on AKIRISK Scores around and above the cutoff using samples with AKIRISK Score of 0.3 and 5.0 were evaluated. Pooled human urine samples targeting these AKIRISK Scores were adjusted to target pH values of approximately 4, 6, 8, and 10. There was no significant interference detected at any tested pH level.
4. Assay Reportable Range:
The analytical measuring interval was determined in the linearity and detection limit studies, which support the analytical measuring interval for AKIRISK Score as 0.04 – 10, corresponding to the AKIRISK Score calculation with the two lower limits and the two upper limits of the protein ranges.
5. Traceability, Stability, Expected Values (Controls, Calibrators, or Methods):
Metrological Traceability:
The IGFBP-7 and TIMP-2 values obtained with the VIDAS NEPHROCHECK assay were assigned to be traceable to the commercially available predicate device.
Sample Stability:
Sample stability studies were reviewed and found acceptable. Urine samples should be centrifuged within 1 hour of collection. The results support the storage of centrifuged samples for up to 5 hours at 18-25°C in plastic tubes with no additives, or in Low Protein
K210793 - Page 10 of 14
{10}
Binding tubes for up to 5 hours at 18-25°C, 24 hours at 2-8°C, and 6 months at ≤ 60°C (with up to two freeze-thaw cycles).
## 6. Detection Limit:
Detection limit studies were conducted in accordance with CLSI EP17-A2. Three lots of the assay and 1 instrument were used in the studies. One calibration was performed for each lot of the assay.
### 1. Limit of blank (LoB):
The LoB of each protein was determined using 4 urine samples, tested in duplicate in a single run per day for 8 days, corresponding to 64 values for each of the blank samples.
### 2. Limit of detection (LoD) and limit of quantitation (LoQ):
The LoD and LoQ of IGFBP-7 were determined using 4 individual urine samples obtained from individual healthy donors. The LoD and LoQ of TIMP-2 were determined using 5 individual urine samples obtained from individual healthy donors. Low-level samples were tested in five replicates in a single run per day for 8 days, corresponding to 40 values per sample. The LoD was determined for each lot and each protein consistent with the classical approach described in CLSI EP17-A2. The final LoD for each protein was defined as the maximum LoD value obtained for any of the lots. The final LoD for the VIDAS NEPHROCHECK assay was defined as the AKIRISK Score calculated with the LoD defined for the two proteins by applying the Score formula.
The classical approach described in the CLSI EP17-A2 was used to determine the LoQ. For each lot and each protein the LoQ was defined as 20% total within-lot precision. The final LoQ for each protein was defined as the maximum LoQ value obtained for any of the lots. The final LoQ for the VIDAS NEPHROCHECK assay was defined as the AKIRISK Score calculated with the LoQ defined for the two proteins by applying the Score formula.
The results are presented below.
| Detection limits | |
| --- | --- |
| | AKIRISK Score |
| LoB | 0.002 |
| LoD | 0.003 |
| LoQ | 0.003 |
## 7. Assay Cut-Off:
The assay cut-off is an AKIRISK score of 0.3. This single cut-off value is based on the package insert of the predicate device, as well as the literature, and was validated in the clinical study.
## B Comparison Studies:
### 1. Method Comparison with Predicate Device:
Not applicable. Please refer to section VII.C below.
K210793 - Page 11 of 14
{11}
2. Matrix Comparison:
Not applicable. The assay is intended for use with urine samples only.
C Clinical Studies:
The sponsor conducted a retrospective, multi-center clinical study. Sample sets previously collected in the US from two distinct cohorts were used: A) a sample subset of 400 banked human urine samples from Study A (called Cohort A, or Topaz cohort), and B) a sample set of 126 banked urine samples from Study B (called Cohort B, or Opal cohort). The complete Cohort A and Cohort B were previously evaluated in the predicate's clinical study DEN130031. The subjects in the study were 21 years or older and were ICU patients with respiratory and/or cardiovascular compromise. AKI status for each subject was determined by clinical diagnosis established through independent central adjudication. The Cohort A subset included 69 AKI-positive and 331 non-AKI patients (one of which was excluded due to sample turbidity, resulting in 330 non-AKI patients). The samples available for evaluation were representative of the overall cohort. Cohort B included 29 AKI-positive patients and 97 non-AKI patients. The banked samples were tested at 4 testing sites.
Four lots of the assay were used at each site and 2 calibration cycles per lot were performed.
Comparison of AKIRISK Score > 0.30 and <0.30 to AKI Status for the subset of Cohort A
| Subset of Cohort A | AKI status | | Total number of VIDAS NEPHROCHECK test results |
| --- | --- | --- | --- |
| | AKI | No AKI | |
| AKIRISK Score > 0.30 | 62 True Positive | 181 False Positive | 243 |
| AKIRISK Score < 0.30 | 7 False Negative | 149 True Negative | 156 |
| Total number of VIDAS NEPHROCHECK test results | 69 | 330 | 399 |
Performance characteristic of the subset of Cohort A
| Performance characteristic | Value | 95% CI |
| --- | --- | --- |
| Sensitivity (TPR) | 89.9% | [80.5 - 95.0]% |
| Specificity (TNR) | 45.2% | [39.9 – 50.5]% |
| NPV | 95.5% | [91.0 – 98.2]% |
| PPV | 25.5% | [20.4 – 31.3]% |
| False Positive Rate (FPR) | 54.8% | [49.5 – 60.1]% |
| False Negative Rate (FNR) | 10.1% | [5.0 – 19.5]% |
K210793 - Page 12 of 14
{12}
Comparison of AKIRISK Score > 0.30 and < 0.30 to AKI Status for Cohort B
| Opal Cohort | AKI status | | Total number of VIDAS NEPHROCHECK test results |
| --- | --- | --- | --- |
| | AKI | No AKI | |
| AKIRISK Score > 0.30 | 24
True Positive | 58
False Positive | 82 |
| AKIRISK Score < 0.30 | 5
False Negative | 39
True Negative | 44 |
| Total number of VIDAS NEPHROCHECK test results | 29 | 97 | 126 |
Performance characteristic of Cohort B
| Performance characteristic | Value | 95%CI |
| --- | --- | --- |
| Sensitivity (TPR) | 82.8% | [65.5 - 92.4]% |
| Specificity (TNR) | 40.2% | [31.0 - 50.2]% |
| NPV | 88.6% | [76.0 - 95.0]% |
| PPV | 29.3% | [20.5 - 39.9]% |
| FPR (1-Specificity) | 59.8% | [49.8 - 69.0]% |
| FNR (1-Sensitivity) | 17.2% | [7.6 - 34.5]% |
1. Clinical Sensitivity:
See above.
2. Clinical Specificity:
See above.
3. Other Clinical Supportive Data (When 1. and 2. Are Not Applicable):
Not applicable.
D Clinical Cut-Off:
The clinical cutoff is an AKIRISK Score > 0.30. Please refer to section VII.C above.
E Expected Values/Reference Range:
A reference range study was conducted in accordance with CLSI EP28-A3. Banked urine samples from apparently healthy US subjects (378) and US subjects with stable chronic morbidities (372), were tested at 3 sites. Three assay lots were used per site and 2 calibration cycles per lot were performed. The overall reference interval for apparently healthy subjects was <0.04 to 2.50 and for subjects with stable chronic morbidities was <0.04 to 2.66. The reference intervals were comparable for apparently healthy subjects and subjects with stable chronic morbidities, and for males and females from the two cohorts. A breakdown by sex is shown below.
K210793 - Page 13 of 14
{13}
K210793 - Page 14 of 14
Reference range across different groups
| Cohort | Gender | Number of subjects | AKIRISK Score Central 95% Interval |
| --- | --- | --- | --- |
| Apparently Healthy Subjects | Female | 191 | [<0.04, 2.81] |
| | Male | 187 | [<0.04, 3.06] |
| | All | 378 | [<0.04, 2.50] |
| Subjects with Stable Chronic Morbidities | Female | 191 | [<0.04, 2.91] |
| | Male | 181 | [<0.04, 2.63] |
| | All | 372 | [<0.04, 2.66] |
VIII Proposed Labeling:
The labeling supports the finding of substantial equivalence for this device.
IX Conclusion:
The submitted information in this premarket notification is complete and supports a substantial equivalence decision.
