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Immunoassay for the in vitro quantitative determination of neutrophil gelatinase-associated lipocalin (NGAL) in human urine.

Determination of NGAL is intended to be used in conjunction with clinical evaluation in pediatric patients (≥ 3 months to

The ProNephro AKI™ (NGAL) Reagent Kit contains Reaction Buffer Reagent (R1) and Immunoparticle Suspension Reagent (R2). The R1 reagent is a ready-to-use tris-buffer solution containing murine protein and preservative. The R2 reagent is a ready-to-use suspension of polystyrene microparticles coated with mouse monoclonal antibodies to NGAL that also contains preservative. The ProNephro AKI Reagent Kit provides enough reagents for 100 tests on the Roche cobas c 501 clinical chemistry analyzer. The finished kit will also include a labeled Roche cassette and two funnels for transferring the reagent into the Roche cassette.

The reagents must be transferred to a Roche cassette prior to the cobas c 501. This is done by pouring the R1 reagent into Position B of the cassette and R2 reagent into Position C. The operator will load the cassette onto the instrument and run the ProNephro AKI™ (NGAL) test per the instructions for use.

The ProNephro AKI® (NGAL) Calibrator Kit consists of five (5) individual ready-to-use calibrator solutions (1 mL each) comprised of different concentrations (50-3000 ng/mL) of recombinant human NGAL in a HEPES buffer and a preservative.

The ProNephro AKI™ (NGAL) Control Kit contains ready-to-use High (500 ng/mL target concentration) and Low (200 ng/mL target concentration) Controls comprised of recombinant human NGAL in HEPES buffer and a preservative. There are three (3) 1 mL bottles of each level included with the kit.

Here's a breakdown of the acceptance criteria and study information for the ProNephro AKI™ (NGAL) device, based on the provided text:

Acceptance Criteria and Device Performance

The direct acceptance criteria for the clinical performance are not explicitly stated in a quantifiable manner (e.g., "Sensitivity must be >= X%"). Instead, the document presents the device's performance metrics from the validation study, implying these met the internal criteria for acceptance. The table below summarizes the reported clinical performance.

Table 1: Acceptance Criteria (Implied) and Reported Device Performance

Note: The "Implied Acceptance Criterion" is derived from the performance ranges of the predicate device (NEPHROCHECK® Test System) presented in Table 2 of the document. The device performance for ProNephro AKI™ (NGAL) is directly reported.

Study Information

Here's a breakdown of the requested study information:

1. Sample size used for the test set and the data provenance:

   • Test Set Sample Size: 514 evaluable subjects for the overall clinical performance validation, comprising 422 subjects in Group 1 and 92 subjects in Group 2.
   • Data Provenance: Multi-center prospective clinical study ("GUIDANCE") conducted at 15 sites across the US.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

   • Number of Experts: At least two independent clinical experts.
   • Qualifications of Experts: Not explicitly stated in the document. They are referred to as "independent clinical experts."

3. Adjudication method (e.g., 2+1, 3+1, none) for the test set:

   • Adjudication Method: "The clinical data for each subject were captured and provided to at least two independent clinical experts for adjudication." This implies a consensus-based adjudication, but the exact method (e.g., needing agreement from both, or a tie-breaker if they disagree) is not detailed.

4. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

   • No, a multi-reader multi-case (MRMC) comparative effectiveness study was not done. This device is a quantitative immunoassay for a biomarker (NGAL), not an imaging AI diagnostic that assists human readers.

5. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:

   • Yes, the clinical performance results presented (Sensitivity, Specificity, PPV, NPV) represent the standalone performance of the ProNephro AKI™ (NGAL) test. It is intended to be used "in conjunction with clinical evaluation," meaning the result from the test (NGAL concentration) is an input for the clinician's overall assessment, rather than the device itself being a "human-in-the-loop" AI system.

6. The type of ground truth used (expert consensus, pathology, outcomes data, etc.):

   • Ground Truth Type: Expert consensus for "moderate to severe acute kidney injury (Stage 2 to 3 AKI) 48 to 72 hours after the time of assessment," based on clinical data. The text states: "The clinical data for each subject were captured and provided to at least two independent clinical experts for adjudication."

7. The sample size for the training set:

   • Training Set Sample Size: The clinical cutoff of 125 ng/mL was established using a multi-center prospective clinical study called EARNEST with 257 pediatric patients (203 evaluable subjects). This study served as the "training" or "cutoff establishment" cohort before validation.

8. How the ground truth for the training set was established:

   • The ground truth for the EARNEST study (which established the cutoff) was defined as "moderate to severe acute kidney injury (Stage 2 to 3 AKI) 48 to 72 hours after the time of assessment." The specific method for establishing this ground truth (e.g., based on KDIGO criteria, expert adjudication) is not explicitly detailed for the EARNEST study in the same way it is for the GUIDANCE validation study, but it is implied to be clinical assessment.

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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 AKIRISKTM 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.

Each VIDAS® NEPHROCHECK® kit contains: x60 NEPH Reagent Strips, x60 NEPH Solid Phase Receptacles (SPR), 1 NEPH control and 1 NEPH calibrator. The VIDAS® NEPHROCHECK® principle combines an enzyme immunoassay competition method with a final fluorescent detection (ELFA).

The Solid Phase Receptacle (SPR®) serves as the solid phase as well as the pipetting device for the assay. The interior of the NEPH SPR is coated with mouse monoclonal lgG anti-IGFBP-7 andanti-TIMP-2.

The Reagent Strips consist of 10 wells covered with a labeled foil seal. Well 1 is designated for the sample. Six of the wells contain conjugate, wash buffers and substrate. Last well contains the fluorescence substrate.

All of the assay steps are performed automatically by the instrument.

Two detection steps, one for each protein, are performed successively in Well 10.

· The first step is a classical detection step with measurement of the substrate background and incubation of the substrate in the bottom of the SPR®, to generate the first fluorescent signal, which is specific for the IGFBP-7 protein.

· Before the second detection step, the antibodies and proteins in the bottom of the SPR® are removed using the cleaning solution contained in Well 5. The previously used substrate in Well 10 is removed and replaced by fresh substrate contained in Well 9. A new substrate background is then measured, and the substrate is incubated in the top of the SPR® to generate the second fluorescent signal, which is specific for the TIMP-2 protein.

For each protein, the intensity of the fluorescence is proportional to its concentration in the sample. At the end of the test, the protein concentrations are calculated by the instrument in relation to the two calibration curves, one corresponding to each protein, and encoded in the MLE data.

The instrument calculates the AKIRISK™ Score, which is defined as the product of the concentrations of the two proteins, expressed in ng/mL, divided by 1000:

AKIRISK™ Score = ([TIMP-2] x [IGFBP-7]) / 1000

The result of the VIDAS® NEPHROCHECK® assay is reported as the AKIRISK™ Score.

Here's a breakdown of the acceptance criteria and study information for the VIDAS® NEPHROCHECK® device, based on the provided text:

1. Table of Acceptance Criteria and Reported Device Performance:

The document doesn't explicitly state "acceptance criteria" in a separate section with pass/fail thresholds for a primary clinical endpoint. Instead, it presents various analytical and clinical performance characteristics. The clinical performance is compared implicitly to the predicate device to establish substantial equivalence.

Here's an interpretation of relevant performance characteristics reported:

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The Astute Medical NEPHROCHECK® Test System 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 NEPHROCHECK® Test System is intended to be used in patients 21 years of age or older.

The Astute NEPHROCHECK® Test System is comprised of the NEPHROCHECK® Test Kit, the ASTUTE140® Meter Kit, NEPHROCHECK® Liquid Controls Kit and the NEPHROCHECK® Calibration Verification (Cal Vers) Kit. The system is designed to be used by trained medical professionals in the central laboratory.

The NEPHROCHECK® Test Kit, includes the NEPHROCHECK® Test which is a single-use cartridge comprised of two immunoassays for the protein biomarkers, insulin-like growth factor-binding protein (IGFBP7) and tissue-inhibitor of metalloproteinases 2 (TIMP-2) on a membrane test strip enclosed in a plastic housing. The concentrations of the TIMP-2 and IGFBP-7 proteins are used to derive an AKIRISK® Score. The test procedure involves the operator applying a clinical urine sample mixed with labeled fluorescent conjugate to the NEPHROCHECK® Test cartridge, and then inserting the Test cartridge into the ASTUTE140® Meter for incubation, result calculation and result display. Internal positive and negative procedural controls in each NEPHROCHECK® Test cartridge monitor the function of each test cartridge. If the automatic check of these procedural controls shows that the control value results are not within pre-defined limits, the ASTUTE140® Meter will display an error message and the Test result will not be reported.

Included in the NEPHROCHECK® Test is test buffer and the NEPHROCHECK® Test Conjugate Vial which contains murine monoclonal and goat polyclonal antibodies against TIMP-2 and IGFBP-7, fluorescent dye, stabilizers and excipients. Each Kit has the materials necessary to perform 25 tests. Each NEPHROCHECK® Test Kit also contains a lot-specific radio-frequency identification (RFID) card containing lot and calibration information. The RFID card information must be loaded prior to using a new Test kit lot.

The AsTUTE140® Meter is a bench-top analyzer that converts the fluorescent signal from each of the two immunoassays (TIMP-2 and IGFBP7) contained within the NEPHROCHECK® Test cartridge into the AKIRISK® Score. The NEPHROCHECK® Test result is displayed on the Meter LCD screen in approximately 20 minutes from the addition of the specimen. Only the AKIRISK® Score appears on the Meter display. The ASTUTE140® Meter contains an internal printer that can print the AKIRISK® Score.

The NEPHROCHECK® Low Liquid Control and NEPHROCHECK® High Liquid Control are bi-level, lyophilized control materials prepared from human urine containing human TIMP-2 and human IGFBP7 proteins with protein stabilizers. TIMP-2 and IGFBP-7 proteins have been added to the urine to achieve specified target concentration levels. Each NEPHROCHECK® Liquid Controls Kit also contains a high and low RFID encoded with the Liquid Control Kit lot number, expiration date, and the expected range of concentration values based on + two standard deviations in the measurement of each protein biomarker (TIMP-2 and IGFBP-7) in each Liquid Control level. Each NEPHROCHECK® Liquid Control Kit Vial is intended for single use only.

The NEPHROCHECK® Calibration Verification Kit includes five levels of Iyophilized material prepared from human urine, containing TIMP-2 and human IGFBP-7 to achieve specified target concentration levels that evenly span the reportable range of the AKIRISK® Score. The expected concentrations and standard deviations of the individual biomarkers are printed on an enclosed Values Card.

This document describes a 510(k) premarket notification for a modified NEPHROCHECK® Test System. The submission claims substantial equivalence to a previously cleared device (K153165). Therefore, the "study that proves the device meets the acceptance criteria" in this context is primarily focused on demonstrating that the modifications do not negatively impact the device's performance characteristics or its intended use, rather than a de novo clinical trial establishing efficacy or accuracy.

Based on the provided text, here's a breakdown of the requested information:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly present a table of acceptance criteria with corresponding performance data in a detailed quantitative manner for the modified device's clinical performance. Instead, it states that the modified components "met its specifications in this testing." The acceptance criteria for this 510(k) are implicitly focused on ensuring the new modifications do not degrade the performance previously established for the predicate device.

Implicit Acceptance Criteria (for modifications) and Reported Performance:

Note: The detailed acceptance criteria (e.g., specific ranges for shelf-life, noise levels, etc.) are not provided in this summary document. The document primarily focuses on demonstrating that modifications did not negatively affect performance, relying on previously established performance for the predicate device.

2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)

The document primarily describes engineering and stability testing for the modified components, as opposed to a clinical test set for diagnostic performance.

• Sample Size for Test Set: Not explicitly stated in numerical terms for each tested parameter (e.g., how many cartridges were tested for shelf-life, how many meters for climate testing etc.). The context suggests sufficient samples were used for engineering verification and validation testing, but specific numbers are not disclosed.
• Data Provenance: The nature of the studies (shelf-life, climate testing, electrical/optical performance, etc.) implies laboratory or manufacturing test data. No information on country of origin or whether it was retrospective/prospective is provided, as these are typically not human clinical studies.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)

This section is not applicable to the type of studies described. The document does not describe a clinical study where human experts establish ground truth for diagnostic performance. The tests are engineering and stability evaluations.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

This is not applicable. Adjudication methods are typically used in clinical studies where multiple human readers' interpretations need to be reconciled to establish a "ground truth" for a diagnosis. The studies described are hardware/software verification and shelf-life testing.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

This is not applicable. The NEPHROCHECK® Test System measures biomarkers directly; it is not an AI-assisted diagnostic imaging device that human readers interpret. Therefore, an MRMC study is not relevant to this device.

6. If a standalone (i.e., algorithm only without human-in-the-loop performance) was done

The NEPHROCHECK® Test System is an in vitro diagnostic device that produces a quantitative result (AKIRISK® Score) from a biological sample (urine) using immunoassays. The "algorithm" for this device is the formula used to derive the AKIRISK® Score from the concentrations of TIMP-2 and IGFBP-7.

The device itself, the ASTUTE140® Meter, performs the measurement, calculation, and display of the AKIRISK® Score. Therefore, its performance in generating the AKIRISK® Score from a sample is its "standalone" performance. The document states: "The NEPHROCHECK® Test result is displayed on the Meter LCD screen in approximately 20 minutes from the addition of the specimen. Only the AKIRISK® Score appears on the Meter display."

The initial 510(k) for the predicate device (K153165) would have established the clinical and analytical performance of this standalone functionality. This current submission verifies that the modifications to the device components (e.g., optics board, LCD screen) do not negatively impact this standalone performance.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

For the modifications described in this 510(k) summary, the "ground truth" refers to engineering specifications and established analytical performance. For example:

• Shelf-life: Stability over time, confirming the device components maintain their specified performance characteristics (e.g., calibration, reagent integrity, mechanical function).
• Climate Testing: Performance within specified temperature and humidity ranges.
• Electrical/Optical Performance: Conformance to design specifications for signal detection, noise, and measurement accuracy.
• Cleaning Compatibility: Verification that the device withstands specified cleaning agents without degradation.

For the original clearance of the predicate device (K153165), the ground truth for establishing the clinical aid in risk assessment for AKI would have involved patient outcomes data (e.g., acute kidney injury diagnosis within a certain timeframe based on clinical criteria and/or biomarker levels) correlated with the AKIRISK® Score. However, this 510(k) for a modified device does not present such clinical ground truth data anew.

8. The sample size for the training set

This information is not provided and is likely not relevant to this specific 510(k) submission, as it focuses on modifications to an already cleared device. The original development of the NEPHROCHECK® Test System (predicate device K153165) would have involved extensive data for biomarker correlation and algorithm development, which would conceptually be its "training set," but those details are not in this document.

9. How the ground truth for the training set was established

As with point 8, this information pertains to the original development and clearance of the predicate device (K153165) and is not detailed in this document. For a diagnostic test like NEPHROCHECK®, the "ground truth" for its development would typically involve:

• Clinical Diagnosis of AKI: Based on standard clinical criteria (e.g., KDIGO guidelines, serum creatinine changes, urine output) established by clinicians.
• Correlation with Outcomes: Investigating the relationship between the biomarker levels/AKIRISK® Score and the subsequent development or severity of AKI in patient cohorts.

These studies would have been part of the clinical evidence submitted for the original 510(k) (K153165).

Ask a specific question about this device

The Astute Medical NEPHROCHECK® Test System 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 NEPHROCHECK® Test System is intended to be used in patients 21 years of age or older.

The Astute NEPHROCHECK® Test System is comprised of the NEPHROCHECK® Test Kit, the ASTUTE140® Meter Kit, NEPHROCHECK® Liquid Controls Kit and the NEPHROCHECK® Calibration Verification (Cal Vers) Kit. The system is designed to be used by trained medical professionals in the central laboratory. The NEPHROCHECK® Test Kit, includes the NEPHROCHECK® Test which is a single-use cartridge comprised of two immunoassays for the protein biomarkers, insulin-like growth factor-binding protein (IGFBP7) and tissue-inhibitor of metalloproteinases 2 (TIMP-2) on a membrane test strip enclosed in a plastic housing. The concentrations of the TIMP-2 and IGFBP-7 proteins are used to derive an AKIRISK™ Score. The test procedure involves the operator applying a clinical urine sample mixed with labeled fluorescent conjugate to the NEPHROCHECK® Test cartridge, and then inserting the Test cartridge into the ASTUTE140® Meter for incubation, reading, result calculation and result display. Internal positive and negative procedural controls in each NEPHROCHECK® Test cartridge monitor the function of each test cartridge. If the automatic check of these procedural controls shows that the control value results are not within pre-defined limits, the ASTUTE140® Meter will display an error message and the Test result will not be reported. Included in the NEPHROCHECK® Test is test buffer and the NEPHROCHECK® Test Conjugate Vial which contains murine monoclonal and goat polyclonal antibodies against TIMP-2 and IGFBP-7, fluorescent dye, stabilizers and excipients. Each Kit has the materials necessary to perform 25 tests. Each NEPHROCHECK® Test Kit also contains a lot-specific radio-frequency identification (RFID) card containing lot and calibration information. The RFID card information must be loaded prior to using a new Test kit lot. The AsTUTE140® Meter is a bench-top analyzer that converts the fluorescent signal from each of the two immunoassays (TIMP-2 and IGFBP7) contained within the NEPHROCHECK® Test cartridge into the AKIRISK™ Score. The NEPHROCHECK® Test result is displayed on the Meter LCD screen in approximately 20 minutes from the addition of the specimen. Only the AKIRISK™ Score appears on the Meter display. The AsTUTE140® Meter contains an internal printer that can print the AKIRisk score. The NEPHROCHECK® Low Liquid Control and NEPHROCHECK® High Liquid Control are bi-level, lyophilized control materials prepared from human urine containing human TIMP-2 and human IGFBP7 proteins with protein stabilizers. TIMP-2 and IGFBP-7 proteins have been added to the urine to achieve specified target concentration levels. Each NEPHROCHECK® Liquid Controls Kit also contains a high and low RFID encoded with the Liquid Control Kit lot number, expiration date, and the expected range of concentration values based on + two standard deviations in the measurement of each protein biomarker (TIMP-2 and IGFBP-7) in each Liquid Control level. Each NEPHROCHECK® Liquid Control Kit Vial is intended for single use only. The NEPHROCHECK® Calibration Verification Kit includes five levels of lyophilized material prepared from human urine, containing TIMP-2 and human IGFBP-7 to achieve specified target concentration levels that evenly span the reportable range of the AKIRISK™ Score. The expected concentrations and standard deviations of the individual biomarkers are printed on an enclosed Expected Values Card.

The provided text describes a Special 510(k) submission for modifications to the NEPHROCHECK® Test System. The document focuses on proving that these modifications do not raise new questions of safety or effectiveness and that the modified device remains substantially equivalent to the previously cleared predicate device.

Here's an analysis of the requested information based on the provided text:

1. A table of acceptance criteria and the reported device performance

The document does not explicitly present acceptance criteria in a table format alongside specific quantitative performance (e.g., sensitivity, specificity, accuracy) for the modified device in relation to diagnostic performance for AKI itself. Instead, it refers to various validation studies conducted to ensure the modifications do not negatively impact the device's original specifications. The overall acceptance criterion for this submission is that "The NEPHROCHECK® Test Kit met its specifications" and "No new risks were introduced by the minor modifications."

The studies performed and the implied performance criteria relate to maintaining the original device's integrity after the changes:

2. Sample size used for the test set and the data provenance (e.g., country of origin of the data, retrospective or prospective)

The document lists various performance studies, but it does not specify the sample sizes used for these specific tests (e.g., number of samples for interference, shelf-life, or the second supplier validation).

The data provenance is not explicitly stated beyond referring to general industry standards (CLSI, ASTM, ISTA, BS EN ISO). Given that it's a modification to an existing device, these tests would likely involve laboratory-controlled experiments rather than patient data in the context of this specific submission. The original device's clearance (DEN130031/K131650) would have involved clinical studies, but this document pertains only to changes.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g., radiologist with 10 years of experience)

This section is not applicable to the information provided in this document. The listed studies are technical performance tests (e.g., interference testing, stability testing, detection capability) conducted in a laboratory setting, not clinical studies requiring expert ground truth for patient diagnosis.

4. Adjudication method (e.g., 2+1, 3+1, none) for the test set

This section is not applicable as the document does not describe a clinical study involving human assessment or a ground truth process that would require adjudication.

5. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

This section is not applicable. The NEPHROCHECK® Test System is a diagnostic in-vitro device (an immunoassay system for biomarkers), not an AI-assisted imaging or diagnostic tool that involves human readers.

6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done

The NEPHROCHECK® Test System, as described, is a standalone diagnostic device in the sense that the ASTUTE140® Meter autonomously calculates and displays the AKIRISK™ Score based on the immunoassay results. While it's used "in conjunction with clinical evaluation" by medical professionals, the device itself performs the measurement and calculation without direct human input into the result generation process once the sample is applied and the test cartridge is inserted. The performance data presented here focuses on the stability and accuracy of this automated measurement system.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

For the specific performance studies described in this Special 510(k):

• Interference Testing: Ground truth is established by known concentrations of the interfering substance (myoglobin) and the expected stable measurement of the biomarkers (TIMP-2 and IGFBP-7) in its presence.
• Stability Studies: Ground truth is the initial performance specifications of the device when manufactured and tested under ideal conditions, against which performance after storage, handling, and cycling is compared.
• Second Supplier Validation: Ground truth involves comparing the detection capability of the antibody from the new supplier against the established performance of the original antibody or validated reference standards for TIMP-2 and IGFBP-7.

These are analytical performance ground truths, not clinical ground truths (like pathology or patient outcomes) related to the diagnosis of AKI, as this submission is for modifications, not original market clearance.

8. The sample size for the training set

The document does not mention a training set in the context of machine learning or AI. The NEPHROCHECK® Test System is an immunoassay system, not an AI or machine learning algorithm that requires a training set in that sense. The "AKIRISK™ Score" derivation would have been established and validated during the original device development (DEN130031/K131650), which might have involved statistical modeling but not a "training set" in the common AI context.

9. How the ground truth for the training set was established

As there is no mention of a "training set" in the context of an AI/ML algorithm in this document, this information is not provided. The "ground truth" for the original device's AKIRISK™ Score would have been established through extensive clinical studies comparing the biomarker levels and calculated scores to the actual development of AKI in patients, likely utilizing clinical diagnoses and outcomes as the reference. However, these details are not part of this specific Special 510(k) submission.

Ask a specific question about this device

The Astute Medical NEPHROCHECK® Test System 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 NEPHROCHECK® Test System is intended to be used in patients 21 years of age or older.

The NEPHROCHECK® Test System is comprised of the NEPHROCHECK® Test Kit, the ASTUTE140 Meter, the NEPHROCHECK® Liquid Controls Kit, and the NEPHROCHECK® Calibration Verification (Cal Vers) Materials Kit.

The NEPHROCHECK® Test Kit includes the NEPHROCHECK® Test which is a single-use cartridge comprised of two immunoassays for the protein biomarkers insulinlike growth factor-binding protein (IGFBP7) and tissue-inhibitor of metalloproteinases 2 (TIMP2), on a membrane test strip enclosed in a plastic housing. Internal positive and negative procedural controls in each NEPHROCHECK® Test cartridge monitor the function of each test cartridge. If the automatic check of these procedural controls shows that the control value results are not within pre-defined limits, the Meter will display an error message and the Test result will not be reported. The concentrations of the TIMP-2 and IGFBP-7 proteins are used to derive the AKIRisk Score and these concentrations are not reported.

Also included in the kit is test buffer and the NEPHROCHECK® Test Conjugate Vial which contains murine monoclonal and goat polyclonal antibodies against TIMP-2 and IGFBP-7, fluorescent dye, stabilizers and excipients. A RFID Card that contains lot and calibration information is included with each kit. The RFID card must be loaded prior to using a new kit. Each kit can perform 25 tests.

The ASTUTE140® Meter is a bench-top analyzer that converts the fluorescent signal from each of the two immunoassays contained within the NEPHROCHECK® Test cartridge into the AKIRisk score. Only the AKIRisk score appears on the meter display. The ASTUTE140® Meter contains an internal printer that can print the AKIRisk score

The NEPHROCHECK® Low Liquid Control and NEPHROCHECK® High Liquid Control are bi-level, lyophilized control materials prepared from human urine containing human TIMP-2 and human IGFBP-7 proteins with protein stabilizers. TIMP-2 and IGFBP-7 proteins have been added to the urine to achieve specified target concentration levels. The expected concentrations and standard deviations are printed on the enclosed RFID cards. Each NEPHROCHECK® Liquid Control Kit Vial is intended for single use only.

The NEPHROCHECK® Calibration Verification Kit includes five levels of lyophilized material prepared from human urine, containing TIMP-2 and human IGFBP-7 to achieve specified target concentration levels that evenly span the reportable ranges of the AKIRisk Score. The expected concentrations and standard deviations of the individual biomarkers are embedded on a RFID card enclosed with the NEPHROCHECK® Calibration Verification Kit.

All human source material used to manufacture NEPHROCHECK® Liquid Controls and the NEPHROCHECK® Calibration Verification Kit was non-reactive for antigens to Hepatitis B (HBsAg), negative by tests for antibodies to HIV (HIV-1/HIV-s) and Hepatitis C (HCV), non-reactive for HIV-1 RNA and HCV RNA by licensed NAT, and non-reactive to Serological Test for Syphilis (STS) using testing methods approved by the FDA.

The NEPHROCHECK® Test System is intended to be used in conjunction with clinical evaluation as an aid in risk assessment for moderate or severe acute kidney injury (AKI) within 12 hours.

Here's an analysis of the acceptance criteria and the studies conducted:

1. Table of Acceptance Criteria and Reported Device Performance:

2. Sample Sizes and Data Provenance for the Test Set:

• Study A (Main Clinical Study):
  • Enrollment: 519 patients.
  • Evaluable Cohort (Test Set): 408 patients.
  • Data Provenance: Multicenter, prospective study conducted at 23 geographically diverse sites in the US.
• Study B (Confirmatory Clinical Study):
  • Enrollment: 153 patients.
  • Evaluable Cohort (Test Set): 126 patients.
  • Data Provenance: Multicenter, prospective study conducted at 6 sites in the US.

The patients were ICU patients who currently have or had within the past 24 hours acute cardiovascular and/or respiratory compromise. Patients with known moderate or severe AKI (e.g., RIFLE I, F, or KDIGO stage 2 or 3) were excluded from enrollment.

3. Number of Experts and Qualifications for Ground Truth of the Test Set:

• Number of Experts: An independent panel of expert nephrologists. The exact number is not explicitly stated, but "a panel" suggests more than one.
• Qualifications: "Expert nephrologists." Specific experience years are not provided, but the term "expert" implies significant qualifications in the field of nephrology and AKI diagnosis.

4. Adjudication Method for the Test Set:

• Method: Final diagnoses were adjudicated by an independent panel of expert nephrologists using practice standards to classify patients as "AKI" (moderate or severe AKI present) or "No AKI" within 12 hours of enrollment.
• Blinding: Adjudicators were blinded to the site diagnoses and AKIRisk Score results.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study:

• No MRMC comparative effectiveness study was done as described in the provided text for human readers improving with or without AI assistance. This device is an in-vitro diagnostic test generating a numerical score, not an AI image analysis tool that assists human readers directly in interpreting complex data like medical images. The information provided focuses on the standalone performance of the test.

6. Standalone (Algorithm Only) Performance:

• Yes, a standalone performance study was done. The entire clinical study (Study A and Study B) evaluated the performance of the NEPHROCHECK® Test System (an algorithm-derived score from biomarker measurements) in risk assessment for AKI. The reported sensitivity, specificity, PPV, and NPV are measures of this standalone algorithm's diagnostic performance against the adjudicated clinical outcome. The intended use explicitly states it is used "in conjunction with clinical evaluation," but the performance characteristics (sensitivity, specificity, etc.) are for the test result itself.

7. Type of Ground Truth Used:

• The ground truth for the test set was established through expert consensus based on practice standards. The independent panel of expert nephrologists adjudicated patient outcomes as "AKI" (moderate or severe AKI present) or "No AKI" within 12 hours of enrollment based on accepted clinical practice standards. This is essentially a form of "clinical diagnosis" by experts.

8. Sample Size for the Training Set:

• The document does not explicitly state a separate training set size for the AKIRisk Score algorithm development. It describes the analytical and clinical validation studies. The AKIRisk Score is derived from the measurement of IGFBP7 and TIMP2, and its algorithm would have been developed prior to these validation studies, likely using internal data or other published research. The document focuses on the validation of the device's performance, not its initial development.

9. How Ground Truth for the Training Set Was Established:

• Since a separate training set and its ground truth establishment are not explicitly detailed in the provided document, specific information on this is unavailable. However, for a device like this, the algorithm for combining TIMP-2 and IGFBP-7 into an AKIRisk score would typically be developed (trained) using a cohort of patients with known AKI outcomes, where AKI status is determined by clinical criteria (similar to the adjudication for the test set, or based on established diagnostic criteria like RIFLE/KDIGO). This development process usually precedes the formal clinical validation studies described.

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