Method for predicting the risk of incidence of chronic kidney disease
Inventors
Bergmann, Andreas • Melander, Olle
Assignees
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Publication Number
US-11598781-B2
Publication Date
2023-03-07
Expiration Date
Abstract
The present invention relates to means and methods suitable for risk prediction of chronic kidney disease (CKD) using Pro-Enkephalin or fragments thereof as biomarker. The risk prediction methods of the invention are intended for healthy subjects and for subjects suffering from diseases such as hypertension, cardiovascular diseases and events, diabetes, metabolic syndrome, obesity, or autoimmune diseases. Subject matter of the invention is also a method of predicting the worsening or improvement of kidney function or dysfunction in healthy and diseased individuals.
Core Innovation
The invention relates to measuring the level of a Pro Enkephalin protein comprising the amino acid sequence of SEQ ID NO:1 or fragments thereof in a sample of bodily fluid obtained from a subject. The method is carried out in a context where, before obtaining the sample, a prior sample of bodily fluid exhibited a level above 30 pmol/L and the subject was subjected to therapeutic measures to prevent development of chronic kidney disease. The prior-sample timing is constrained to subjects that are healthy or diseased subjects that do not have chronic kidney disease and that had an estimated glomerular filtration rate of greater than 60 ml/min/1.73 m2 for greater than three months.
The disclosed approach specifies fragments of Pro Enkephalin comprising SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO:10, and also describes mid-regional Pro-Enkephalin (MR-PENK; SEQ ID NO:6; Pro-Enkephalin 119-159) in bodily fluids. The disclosure correlates PENK/MR-PENK levels to chronic kidney disease risk using an elevated-threshold concept and describes prediction of incidence of chronic kidney disease and worsening or improvement of kidney function in subjects without chronic kidney disease, including healthy and disease-risk populations.
The elevated-threshold concept is described as an inflammation-independent biomarker concept using a threshold for elevated risk for MR-PENK generally in the range of 30-80 pmol/L, with preferred ranges of 35-60 pmol/L and most preferred ranges of 41-49 pmol/L. The disclosure also includes use of immunoassay or mass spectrometry to determine PENK/MR-PENK levels, repeated timepoints for monitoring, and clinical/epidemiology study results showing higher baseline MR-PENK associated with greater decline in eGFR and higher incident chronic kidney disease risk after long follow-up.
Claims Coverage
The provided excerpt includes two independent methods. Across the independent claims, the inventive coverage centers on defined Pro Enkephalin sequence targets, subject condition constraints, and elevated levels above 30 pmol/L in a prior sample or in a prepared sample.
Measuring Pro Enkephalin SEQ ID NO:1 or fragments in bodily fluid with elevated prior level context
A method comprising measuring the level of a Pro Enkephalin protein comprising the amino acid sequence of SEQ ID NO:1 or fragments thereof in a sample of bodily fluid obtained from a subject, wherein before obtaining the sample a prior sample exhibited a level above 30 pmol/L and the subject was subjected to therapeutic measures to prevent development of chronic kidney disease, and wherein the subject at the time of the prior sample was a healthy subject or a diseased subject without chronic kidney disease having estimated glomerular filtration rate greater than 60 ml/min/1.73 m2 for more than 3 months, and wherein the fragments comprise SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, or SEQ ID NO:10.
Preparing a sample with a binder bound to Pro Enkephalin SEQ ID NO:1 or fragments above an elevated level
A method for preparing a sample comprising obtaining a sample of bodily fluid from a subject and adding to the sample a binder that binds to a Pro Enkephalin protein comprising the amino acid sequence of SEQ ID NO:1 or one or more fragments thereof, wherein the fragments comprise SEQ ID NO:2, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10 or SEQ ID NO:11, wherein at the time of obtaining the sample the subject is a healthy subject or a diseased subject that does not have chronic kidney disease and has had estimated glomerular filtration rate greater than 60 ml/min/1.73 m2 for more than 3 months, and wherein in the sample the binder is bound to the Pro Enkephalin or one or more of the fragments at a level above 30 pmol/L.
Across the independent claims, the disclosed invention is grounded in measuring or binder-capturing Pro Enkephalin (SEQ ID NO:1) and specifically enumerated Pro Enkephalin fragments, combined with subject selection of healthy or diseased subjects without chronic kidney disease and use of an elevated threshold context above 30 pmol/L.
Stated Advantages
Improved stratification and monitoring over repeated timepoints.
Higher baseline MR-PENK is associated with greater decline in eGFR and higher incident chronic kidney disease risk after long follow-up.
A single inflammation-independent threshold is emphasized.
Documented Applications
Predicting incidence of chronic kidney disease and worsening or improvement of kidney function in subjects without chronic kidney disease, including healthy and disease-risk populations such as hypertension/CVD/diabetes/metabolic syndrome/autoimmune disease.
Monitoring chronic kidney disease risk using repeated timepoints based on MR-PENK levels.
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