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

Abstract

It is an object of the present invention to provide methods and compositions for protection of subjects from acute kidney injury by treating the subject with compounds that modulate the cell cycle. Modulating the cell cycle can comprise inducing G0/G1 cell cycle arrest, and/or inducing cell cycle progression. As demonstrated below, even a single administration of a compound which induces G0/G1 cell cycle arrest can protect subjects from AKI, and may be used prophylactically in advance of, or as a treatment following, various treatments or conditions that are known to be injurious to the kidney, followed optionally by release of the arrest. Once AKI is established, cell cycle progression can be induced to increase replacement of lost and damaged cells.

We claim: 
     
         1 . A method of prophylactically treating a subject at risk of an acute kidney injury, comprising:
 administering an effective amount of one or more agents that modulate G 0 /G 1  cell cycle arrest of renal epithelial cells to the patient for a time sufficient to induce cell cycle arrest in a population of the renal epithelial cells but insufficient to induce nephrotoxicity as measured by progression of the patient to acute renal failure.   
     
     
         2 . A method according to  claim 1 , wherein the one or more agents that modulate G 0 /G 1  cell cycle arrest are selected from the group consisting of cyclosporine A, artesunate, Simvastatin, Bufalin, NC381, Flavopiridol, Everolimus, Lycorine, TIMP-2 IGFBP7, a PAMP, and a DAMP. 
     
     
         3 . A method according to  claim 2 , wherein the agent that modulates G 0 /G 1  cell cycle arrest is cyclosporine A. 
     
     
         4 . A method according to one of  claims 1 - 3 , wherein the subject is further administered one or more agents which inhibit apoptosis in combination with the one or more agents that modulate G 0 /G 1  cell cycle arrest. 
     
     
         5 . A method according to  claim 4 , wherein the one or more agents which inhibit apoptosis comprise one or more glucocorticoids. 
     
     
         6 . A method according to one of  claims 1 - 5 , wherein the method further comprises:
 performing a first biomarker assay on a first body fluid sample obtained from the subject which measures IGFBP7 and/or TIMP-2 to provide a first assay result, wherein the first body fluid sample is obtained from the patient prior to the administering step;   performing a second biomarker assay on a body fluid sample obtained from the subject which measures IGFBP7 and/or TIMP-2 to provide a second assay result, wherein the first body fluid sample is obtained from the patient 48 hours following the administering step; and   comparing the first and second assay result, wherein a subject exhibiting a decrease in the second assay result relative to the first assay result is at a reduced risk of acute kidney injury relative to a patient exhibiting an increase in the second assay result relative to the first assay result.   
     
     
         7 . A method according to  claim 6 , wherein the administering step is terminated when the subject exhibits a decrease in the second assay result relative to the first assay result. 
     
     
         8 . A method according to  claim 6 , wherein when the subject exhibits an increase in the second assay result relative to the first assay result, the subject is further treated by one or more of initiating renal replacement therapy, withdrawing delivery of compounds that are known to be damaging to the kidney, kidney transplantation, delaying or avoiding procedures that are known to be damaging to the kidney, or modifying diuretic administration. 
     
     
         9 . A method according to one of  claims 1 - 8 , wherein the subject undergoes major vascular surgery, coronary artery bypass, other cardiac surgery, or administration of one or more radiopaque contrast agents within 48 hours of the administering step. 
     
     
         10 . A method according to one of  claims 1 - 9 , wherein the subject is selected based on the pre-existence in the subject of one or more known risk factors for prerenal, intrinsic renal, or postrenal ARF. 
     
     
         11 . A method according to one of  claims 1 - 10 , wherein the subject is in RIFLE stage 0 or R at the time of the administering step. 
     
     
         12 . A method according to one of  claims 1 - 11 , wherein the subject has sepsis. 
     
     
         13 . A method of treating a subject having an acute kidney injury, comprising:
 administering an effective amount of one or more agents that modulate cell cycle progression of renal epithelial cells to the patient for a time sufficient to induce cell cycle progression in a population of the renal epithelial cells.   
     
     
         14 . A method according to  claim 13 , wherein the one or more agents that modulate cell cycle progression are selected from the group consisting of Trametinib, Palifermin, antibodies which bind to and inhibit TIMP-2 and antibodies which bind to and inhibit IGFBP7. 
     
     
         15 . A method of assessing and treating a patient, comprising:
 performing a biomarker assay on a body fluid sample obtained from the patient which measures IGFBP7 to provide an IGFBP7 assay result, and assay result;   performing a biomarker assay on a body fluid sample obtained from the patient which measures TIMP-2 to provide an TIMP-2 assay result; and   performing one or both of the following treatment steps:
 when the IGFBP7 assay result is elevated but the TIMP-2 assay result is not, administering an inducer of G 0 /G 1  cell cycle; and/or 
 when the TIMP-2 assay result is elevated but the IGFBP7 assay result is not, administering an inducer of cell cycle progression.