Methods and compositions for diagnosis and prognosis of renal injury and renal failure

Abstract

It is an object of the present invention to provide a combination of a functional assessment of renal function together with biomarker results in order to improve assessment of patient at risk of or having, an acute kidney injury. A loop diuretic such as furosemide inhibits luminal active chloride transport throughout the thick ascending limb of Henle, thereby preventing sodium reabsorption and resulting in natriuresis and increased urine flow. Loop diuretic-induced increases in urine output might be a method to assess the integrity of the renal tubular function in the setting of early AKI, and so a kidney's response, or lack thereof, to a diuretic challenge as a clinical assessment of tubular function can identify patients with severe tubular injury before it is clinically apparent (e.g. a rise in creatinine).

1 . A method of evaluating a patient for acute kidney injury progression, comprising:
 performing a biomarker assay on a body fluid sample obtained from the patient to provide an assay result, wherein the biomarker(s) in the biomarker assay are correlated to a risk of acute kidney injury;   correlating the assay result to the patient's risk of acute kidney injury relative to a risk in a predetermined population of individuals;   classifying the patient's suitability for receiving a diuresis stress evaluation using the patient's risk of acute kidney injury;   if the patient is classified as suitable, performing the diuresis stress evaluation on the patient to provide a diuresis-induced urine output value; and   correlating the diuresis-induced urine output value to a risk of acute kidney injury progression.   
     
     
         2 . The method of  claim 1 , wherein the biomarker assay comprises measuring a concentration of one or more biomarkers selected from the group consisting of Metalloproteinase inhibitor 2, Thrombospondin-1, Antileukoproteinase, Insulin-like growth factor-binding protein 7, Metalloproteinase inhibitor 4, Metalloproteinase inhibitor 1, Hyaluronic acid, Transmembrane glycoprotein NMB, Follistatin, Hepatocyte growth factor, Tumor necrosis factor receptor superfamily member 6, Growth-regulated alpha protein, C—C motif chemokine 24, Metalloproteinase inhibitor 3, C—X—C motif chemokine 6, Tumor necrosis factor receptor superfamily member 11B, Cystatin-C, Beta-2-microglobulin, Serum albumin, Clusterin, Interleukin-8, Neutrophil gelatinase-associated lipocalin, Interleukin-2 receptor alpha chain, Hepatitis A virus cellular receptor 1, Chitinase-3-like protein 1, Serum creatinine, and Hyaluronic acid. 
     
     
         3 . The method of  claim 2 , wherein the biomarker assay comprises measuring a concentration of Metalloproteinase inhibitor 2. 
     
     
         4 . The method of  claim 3 , wherein the biomarker assay comprises measuring a concentration of Insulin-like growth factor-binding protein 7. 
     
     
         5 . The method of  claim 4 , wherein classifying the patient's suitability for receiving a diuresis stress evaluation further comprises using a baseline urine output value for the patient. 
     
     
         6 . The method  claim 4 , wherein the classifying the patient's suitability for receiving a diuresis stress evaluation further comprises using a baseline change in serum creatinine for the patient. 
     
     
         7 . The method of  claim 4 , wherein the classifying the patient's suitability for receiving a diuresis stress evaluation further comprises determining if the patient has experienced 6 hours of oliguria defined as a urine output of <0.5 ml/kg/hour, or a 0.3 mg/dL rise in serum creatinine, or an increase of 150-200% above a baseline serum creatinine concentration. 
     
     
         8 . The method of  claim 4 , wherein the classifying step comprises identifying the patient as suitable to receive a diuresis stress evaluation if the patient's relative risk is greater than 1.0. 
     
     
         9 . The method of  claim 4 , wherein the classifying step comprises identifying the patient as suitable to receive a diuresis stress evaluation if the patient's relative risk is about 1.5 or greater, and identifying the patient as unsuitable to receive a furosemide stress evaluation if the patient's relative risk is less than about 1.5. 
     
     
         10 . The method of  claim 4 , wherein the classifying step comprises identifying the patient as suitable to receive a diuresis stress evaluation if the patient's relative risk is about 2.0 or greater, and identifying the patient as unsuitable to receive a furosemide stress evaluation if the patient's relative risk is less than about 2.0. 
     
     
         11 . The method of  claim 4 , wherein the classifying step further comprises identifying the patient as suitable to receive a diuresis stress evaluation if the patient is not suffering from an acute kidney injury. 
     
     
         12 . The method of  claim 4 , wherein performing the diuresis stress evaluation comprises (ii) determining a baseline urine output value for the patient prior to intravenous administration of a loop diuretic, (ii) administering the loop diuretic intravenously to the patient in an amount effective to cause diuresis, (ii) and determining the loop diuretic-induced urine output value. 
     
     
         13 . The method of  claim 12 , wherein correlating the loop diuretic-induced urine output value to a risk of acute kidney injury progression comprises comparing the loop diuretic-induced urine output value to a cutoff value, wherein the cutoff value identifies patients that will progress to acute kidney failure with a sensitivity of at least 50% and a specificity of at least 50%. 
     
     
         14 . The method of  claim 13 , wherein correlating the loop diuretic-induced urine output value to a risk of acute kidney injury progression comprises comparing the loop diuretic-induced urine output value to a cutoff value, wherein the cutoff value identifies patients that will progress to acute kidney failure with a sensitivity of at least 75% and a specificity of at least 75%. 
     
     
         15 . A method according to  claim 4 , wherein fluid is administered to the patient intravenously to balance the diuresis-induced urine output. 
     
     
         16 . A method according to  claim 15 , wherein the diuresis-induced urine output value is measured continuously. 
     
     
         17 . A method according to  claim 16 , wherein the diuresis-induced urine output value is determined by a sensor operably connected to a controller comprising a microprocessor which receives an electronic signal from the sensor and calculates therefrom the diuresis-induced urine output value. 
     
     
         18 . A method according to  claim 17 , wherein the controller is further operably connected to a fluid infusion system, wherein the diuresis-induced urine output value calculated by the microprocessor is used to control delivery of fluid to the patient by the fluid infusion system to balance the diuresis-induced urine output. 
     
     
         19 . A method according to one of  claims 12 , wherein the loop diuretic is selected from the group consisting of furosemide, bumetanide, ethacrynic acid, and torsemide. 
     
     
         20 . A method according to  claim 19 , wherein the loop diuretic is furosemide. 
     
     
         21 . A method according to  claim 1 , wherein the diuresis stress evaluation comprises administering one or more diuretics selected from the group consisting of mannitol, furosemide, bumetanide, ethacrynic acid, torsemidehydrochlorothiazide, bendroflumethiazide, hydroflumethiazide, chlorothiazide, polythiazide, trichlormethiazide, cyclopenthiazide, methyclothiazide, cyclothiazide, and mebutizide. 
     
     
         22 . A method according to  claim 1 , wherein the diuresis stress evaluation further comprises measuring an amount of the diuretic administered in the diuresis stress evaluation appearing in the urine. 
     
     
         23 . A method according to  claim 22 , wherein the amount of the diuretic appearing in the urine is used to determine of the patient is suffering from a pre-renal kidney injury or an acute tubular kidney injury. 
     
     
         24 . A method according to  claim 1 , wherein the patient is selected on the basis of a diagnosis of heart failure. 
     
     
         25 . A method according to  claim 24 , wherein the patient is selected on the basis of a diagnosis of acute decompensated heart failure. 
     
     
         26 . A method according to  claim 1 , wherein the patient is selected on the basis of a diagnosis of chronic kidney disease. 
     
     
         27 . A method according to  claim 1 , wherein fluid is administered to the patient intravenously during the diuresis stress evaluation comprises albumin. 
     
     
         28 . A method according to  claim 4 , further comprising treating the patient based on a determination that the patient's risk of progression to acute kidney failure is above a predetermined cutoff value, wherein the treatment comprises one or more of initiating renal replacement therapy, withdrawing delivery of compounds that are known to be damaging to the kidney, delaying or avoiding procedures that are known to be damaging to the kidney, and modifying diuretic administration. 
     
     
         29 . A method according to  claim 1 , wherein the biomarker assay comprises introducing the body fluid sample into an assay instrument which (i) contacts all or a portion of the body fluid sample with a specific binding reagent which specifically binds each of the biomarker(s), and (ii) generates an assay result indicative of binding of each of the biomarker(s) to its respective specific binding reagent. 
     
     
         30 . A method for evaluating a kidney injury in a patient, comprising:
 (i) determining a baseline urine output value for the patient;   (ii) administering a diuretic intravenously to the patient in an amount effective to cause diuresis and determining a diuretic-induced urine output value;   (iii) measuring an amount of the diuretic administered appearing in the urine; and   (iv) determining if the patient is suffering from a pre-renal kidney injury or an acute tubular kidney injury from the amount of the diuretic appearing in the urine, the baseline urine output value, and the diuretic-induced urine output value.   
     
     
         31 . A method according to  claim 30 , wherein fluid is administered to the patient intravenously to balance the diuresis-induced urine output. 
     
     
         32 . A method according to  claim 31 , wherein the diuresis-induced urine output value is measured continuously. 
     
     
         33 . A method according to  claim 32 , wherein the diuresis-induced urine output value is determined by a sensor operably connected to a controller comprising a microprocessor which receives an electronic signal from the sensor and calculates therefrom the diuresis-induced urine output value. 
     
     
         34 . A method according to  claim 33 , wherein the controller is further operably connected to a fluid infusion system, wherein the diuresis-induced urine output value calculated by the microprocessor is used to control delivery of fluid to the patient by the fluid infusion system to balance the diuresis-induced urine output. 
     
     
         35 . A method according to  claim 30 , wherein the diuretic is a loop diuretic. 
     
     
         36 . A method according to  claim 35 , wherein the loop diuretic is selected from the group consisting of furosemide, bumetanide, ethacrynic acid, and torsemide. 
     
     
         37 . A method according to  claim 35 , wherein the loop diuretic is furosemide. 
     
     
         38 . A method according to  claim 30 , wherein the diuresis stress evaluation comprises administering one or more diuretics selected from the group consisting of mannitol, furosemide, bumetanide, ethacrynic acid, torsemidehydrochlorothiazide, bendroflumethiazide, hydroflumethiazide, chlorothiazide, polythiazide, trichlormethiazide, cyclopenthiazide, methyclothiazide, cyclothiazide, and mebutizide. 
     
     
         39 . A method according to  claim 30 , further comprising treating the patient based on a determination that the patient's risk of progression to acute kidney failure is above a predetermined cutoff value, wherein the treatment comprises one or more of initiating renal replacement therapy, withdrawing delivery of compounds that are known to be damaging to the kidney, delaying or avoiding procedures that are known to be damaging to the kidney, and modifying diuretic administration.