Methods and compositions for diagnosis and prognosis of renal injury and renal failure
Inventors
Anderberg, Joseph • McPherson, Paul • Kampf, James Patrick • Nakamura, Kevin • Gray, Jeff • Kwan, Thomas
Assignees
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Publication Number
US-11346846-B2
Publication Date
2022-05-31
Expiration Date
Abstract
The present invention relates to methods and compositions for monitoring, diagnosis, prognosis, and determination of treatment regimens in subjects suffering from or suspected of having a renal injury. In particular, the invention relates to using assays that detect one or more of Metalloproteinase inhibitor 1, Metalloproteinase inhibitor 2, Metalloproteinase inhibitor 4, C—C motif chemokine 15, C—C motif chemokine 18, C—C motif chemokine 23, and/or, C—C motif chemokine 24 as diagnostic and prognostic biomarker assays in renal injuries.
Core Innovation
The invention relates to a method of treating a subject having acute kidney injury by detecting a level of Metalloproteinase inhibitor 2 in a body fluid sample obtained from the subject. The method uses the detected level to identify an increased risk of persistent acute kidney injury when the detected level is above a predetermined threshold level of Metalloproteinase inhibitor 2. Persistent acute kidney injury is defined by a RIFLE-stage criterion using a minimum RIFLE stage during a period no less than 24 hours.
The period used for persistence begins within 7 days after sample collection, linking the detected Metalloproteinase inhibitor 2 level to a time-bounded RIFLE-based persistence assessment. The treated subject is selected based on the increased risk of persistent acute kidney injury, and the treatment comprises renal replacement therapy, withdrawing delivery of compounds that are known to be damaging to the kidney, delaying procedures that are known to be damaging to the kidney, or modifying diuretic administration.
The document also describes ICU biomarker performance and discrimination statistics for acute kidney injury using metalloproteinase inhibitor measurements in EDTA blood and urine. Patients are stratified into persistent versus non-persistent acute kidney injury using RIFLE-based definitions, including serum creatinine-only, urine output-only, or combined criteria, and performance is evaluated across multiple persistence windows.
Claims Coverage
The independent claim coverage centers on detecting Metalloproteinase inhibitor 2 in a body fluid sample, determining increased risk of persistent acute kidney injury using a predetermined threshold, defining persistence by a minimum RIFLE stage over a period beginning after sample collection, and selecting treatment based on that risk. Dependent claims further narrow the RIFLE stage threshold, add quantitative timing constraints, and specify urine as the sample type.
Detecting Metalloproteinase inhibitor 2 and threshold-based risk determination
Detecting a level of Metalloproteinase inhibitor 2 in a body fluid sample obtained from the subject and determining the subject is at an increased risk of persistent acute kidney injury when the detected level is above a predetermined threshold level of Metalloproteinase inhibitor 2.
RIFLE-stage persistence criterion
Persistent acute kidney injury is a minimum RIFLE stage of RIFLE stage R during a period no less than 24 hours, the period beginning within 7 days after sample collection.
Treatment based on increased risk of persistent acute kidney injury
Treating the subject based on the subject's increased risk of persistent acute kidney injury for persistent acute kidney injury, wherein the treatment comprises renal replacement therapy, withdrawing delivery of compounds that are known to be damaging to the kidney, delaying procedures that are known to be damaging to the kidney, or modifying diuretic administration.
Alternative RIFLE persistence criteria
Persistent acute kidney injury is a minimum RIFLE stage of RIFLE stage F during the period, or persistent acute kidney injury corresponds to at least RIFLE stage I during the specified period.
Quantitative persistence period constraints
The period has a minimum duration such as no less than 48 hours, and the period begins within 48 hours after sample collection.
Urine sample
The body fluid sample is a urine sample.
Overall, the claim coverage centers on biomarker detection with a predetermined threshold to identify increased risk of persistent acute kidney injury, where persistence is defined by a minimum RIFLE stage over a post-collection time period. Treatment is then selected from renal replacement therapy and kidney-damaging intervention modifications, while dependent refinements specify alternative RIFLE thresholds, timing constraints, and urine sample use.
Stated Advantages
Provides statistically significant separation between recovery vs non-recovery cohorts and persistent vs non-persistent RIFLE-defined renal outcomes, supported by ROC/AUC performance and discrimination statistics.
Enables persistent acute kidney injury risk stratification using Metalloproteinase inhibitor measurements in EDTA urine/blood samples across multiple recovery/persistence windows and renal-status assessment modes.
Allows distinguishing subjects at increased risk of persistent acute kidney injury based on detected Metalloproteinase inhibitor 2 above a predetermined threshold and RIFLE-based persistence criteria.
Supports treatment selection based on the subject's increased risk of persistent acute kidney injury, including renal replacement therapy or other kidney-damaging-procedure/compound and diuretic modifications.
Documented Applications
Assessing biomarkers in urine to distinguish ICU patients with persistent versus non-persistent acute kidney injury using RIFLE I/F definitions [procedural detail omitted for safety].
Evaluating ROC performance, including AUC, sensitivity/specificity, and odds ratios, when renal status is assessed using serum creatinine only, urine output only, or combined RIFLE criteria [procedural detail omitted for safety].
Evaluating recovery cohorts with ROC metrics for the assessed urine-related measurements [procedural detail omitted for safety].
Assessing effects of EDTA versus non-EDTA sample matrices on the reported urine-related ROC metrics [procedural detail omitted for safety].
Risk-based treatment of ICU patients with acute kidney injury by detecting Metalloproteinase inhibitor measurements in EDTA urine/blood samples and determining increased risk of persistent acute kidney injury according to RIFLE-defined persistence criteria.
Risk assessment of persistent versus non-persistent acute kidney injury using ROC/AUC comparisons of Metalloproteinase inhibitor 2 in urine samples and EDTA blood/urine analyses, with persistence defined by RIFLE criteria over multiple time windows.
Classification of recovered versus non-recovered states using RIFLE criteria based on serum creatinine and urine output, supported by ROC/AUC and statistical comparisons using Metalloproteinase inhibitor 2 measurements.
Extending the concept to other metalloproteinase inhibitors, including Metalloproteinase inhibitor 4, using persistence thresholds based on RIFLE stage criteria such as persistence at RIFLE F and persistence at RIFLE I/F.
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