Use of soluble urokinase plasminogen activator receptor levels in the management of patients with cardiovascular disease

Abstract

The disclosure is directed to methods for preventing or treating cardiovascular disease and kidney dysfunction in certain patient populations which involve determining the level of soluble urokinase plasminogen activator receptor (suPAR) protein in a sample obtained from a subject, and performing various therapeutic interventions based on the suPAR level in the sample.

1 . A method for treating cardiovascular disease in a subject, which method comprises:
 (a) determining the level of soluble urokinase plasminogen activator receptor (suPAR) protein in a sample obtained from a subject suffering from cardiovascular disease;   (b) performing bypass surgery on the subject if the level of suPAR in the sample is greater than a threshold level; or   (c) stenting one or more coronary arteries in the subject if the level of suPAR in the sample is less than the threshold level, whereby the cardiovascular disease in the subject is treated.   
     
     
         2 . The method of  claim 1 , wherein the threshold level is based on an algorithm that incorporates at least the age, renal function, and gender of the subject. 
     
     
         3 . The method of  claim 1 , wherein the threshold level is about 3 ng/mL. 
     
     
         4 . The method of  claim 1 , wherein the cardiovascular disease is coronary artery disease (CAD). 
     
     
         5 . The method of  claim 4 , wherein the coronary artery disease is triple-vessel disease (TVD). 
     
     
         6 . The method of  claim 1 , wherein stenting is performed by percutaneous coronary intervention (PCI). 
     
     
         7 . A method of treating stable cardiovascular disease or preventing cardiovascular disease in a subject, which method comprises:
 (a) measuring the level of soluble urokinase plasminogen activator receptor (suPAR) protein in a sample obtained from a subject suffering from stable cardiovascular disease or a subject at high risk for cardiovascular disease;   (b) determining that the level of suPAR in the sample is greater than a threshold level; and   (c) administering a statin, an immunomodulatory therapy, and/or an anti-suPAR therapy to the subject, whereby the cardiovascular disease in the subject is treated or prevented.   
     
     
         8 . The method of  claim 7 , wherein the threshold level is based on an algorithm that incorporates at least the age, renal function, and gender of the subject. 
     
     
         9 . The method of  claim 7 , wherein the threshold level is about 2.5 ng/mL. 
     
     
         10 . The method of  claim 7 , wherein the subject suffers from stable cardiovascular disease. 
     
     
         11 . The method of  claim 10 , wherein the cardiovascular disease is coronary artery disease. 
     
     
         12 . The method of  claim 7 , wherein the subject is at high risk for cardiovascular disease and the method prevents cardiovascular disease in the subject. 
     
     
         13 . The method of  claim 7 , which comprises administering a statin to the subject. 
     
     
         14 . The method of  claim 7 , which comprises administering an immunomodulatory therapy to the subject. 
     
     
         15 . The method of  claim 14 , wherein the immunomodulatory therapy is methotrexate, metformin, cananikumab, or a mineralocorticoid receptor antagonist. 
     
     
         16 . The method of  claim 7 , wherein the anti-suPAR therapy is a monoclonal antibody which specifically binds to suPAR or plasmapheresis using suPAR-specific cartridges. 
     
     
         17 . A method of treating or preventing cardiovascular disease using chelation therapy, which method comprises:
 (a) measuring the level of soluble urokinase plasminogen activator receptor (suPAR) protein in a sample obtained from a subject at risk of cardiovascular disease;   (b) determining that the level of suPAR in the sample is greater than a threshold level; and   (c) administering a chelation therapy to the subject, thereby treating or preventing cardiovascular disease in the subject.   
     
     
         18 . The method of  claim 17 , wherein the threshold level is based on an algorithm that incorporates at least the age, renal function, and gender of the subject. 
     
     
         19 . The method of  claim 17 , wherein the threshold level is about 3 ng/mL. 
     
     
         20 . The method of  claim 17 , wherein the chelation therapy comprises administering ethylenediaminetetraacetic acid (EDTA), dimercaptosuccinic acid, or dimercaprol to the subject. 
     
     
         21 . A method of treating congestive heart failure in a subject with concomitant kidney, dysfunction, which method comprises:
 (a) determining the level of soluble urokinase plasminogen activator receptor (suPAR) protein in a sample obtained from a subject suffering from congestive heart failure with concomitant kidney dysfunction;   (b) performing dual organ transplantation of the heart and kidney or mechanical circulatory support on the subject if the level of suPAR in the sample is greater than a threshold level; or   (c) performing, single organ heart transplantation if the level of suPAR in the sample is less than the threshold level, whereby the congestive heart failure in the subject is treated.   
     
     
         22 . The method of  claim 21 , wherein the threshold level is based on an algorithm that incorporates at least the age, renal function, and gender of the subject. 
     
     
         23 . The method of  claim 21 , wherein the threshold level is about 5 ng/mL. 
     
     
         24 . The method of  claim 21 , wherein the mechanical circulatory support s a left ventricular assist device, a right ventricular assist device, or a total artificial heart. 
     
     
         25 . The method of  claim 1 , wherein the level of suPAR is determined or measured by immunoassay, immunoprecipitation, Western blot, flow cytometry, or protein microarray. 
     
     
         26 . A method of treating heart failure with preserved ejection fraction (HFpEF) in a subject in need thereof, which method comprises:
 (a) measuring the level of soluble urokinase plasminogen activator receptor (suPAR) protein in a sample obtained from a subject suffering from HFpEF;   (b) determining that the level of suPAR in the sample is greater than a threshold level; and   (c) administering a HFpEF treatment to the subject, whereby HFpEF is treated in the subject.   
     
     
         27 . The method of  claim 26 , wherein the HFpEF treatment is a mineralocorticoid receptor antagonist, a diuretic, spironolactone, an anti-suPAR therapy, or a combination of any of the foregoing. 
     
     
         28 . A method of treating kidney dysfunction in a subject in need thereof, which method comprises:
 (a) measuring the level of soluble urokinase plasminogen activator receptor (suPAR) protein in a sample obtained from a subject suffering from kidney dysfunction;   (b) determining that the level of suPAR in e sample is greater than a threshold level; and   (c) administering a treatment for kidney dysfunction to the subject, whereby the kidney dysfunction is treated in the subject.   
     
     
         29 . The method of  claim 28 , wherein the kidney dysfunction is acute kidney injury. 
     
     
         30 . The method of  claim 28 , wherein the kidney dysfunction is chronic kidney disease (CKD) 
     
     
         31 . The method of  claim 28 , wherein the treatment is a statin, an angiotensin-converting enzyme (ACE) inhibitor, and angiotensin II receptor blocker, an anti-suPAR therapy, a kidney transplant, dialysis, or a combination of any of the foregoing. 
     
     
         32 . The method of  claim 1 , wherein the sample is blood or urine.