Methods and compositions for diagnosis and prognosis of renal injury and renal failure
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 G 0 /G 1 cell cycle arrest, and/or inducing cell cycle progression. As demonstrated below, even a single administration of a compound which induces G 0 /G 1 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.
1. A method of prophylactically treating a subject at risk of an acute kidney injury, comprising:
(i) measuring a Tissue Inhibitor of Metalloproteinases-2 (TIMP-2) level in combination with an Insulin-like Growth Factor Binding Protein-7 (IGFBP7) level in a first body fluid sample obtained from the subject to provide a first TIMP-2 assay result and a first IGFBP7 assay result;
(ii) following obtaining the first body fluid sample, 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 (ARF);
(iii) measuring TIMP-2 and IGFBP7 levels in a second body fluid sample obtained from the subject 24 hours after the administering step to provide a second TIMP-2 assay result and a second IGFBP7 assay result;
comparing the first TIMP-2 assay result to the second TIMP-2 assay result and the first IGFBP7 assay result to the second IGFBP7 assay result, wherein
if the first TIMP-2 assay result is not elevated relative to the second TIMP-2 assay result, and the first IGFBP7 assay result is elevated relative to the second IGFBP7 assay result, identifying the subject as having been successfully treated prophylactically.
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 pathogen-associated molecular pattern (PAMP), and a damage-associated molecular pattern (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 claim 1 , 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 claim 1 , wherein when the subject is not identified as having been successfully treated prophylactically, 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.
7. A method according to claim 1 , wherein when the subject is identified as having been successfully treated prophylactically, 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.
8. A method according to claim 1 , 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.
9. A method according to claim 1 , wherein the subject is in the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) stage 0 or R at the time of the administering step.
10. A method according to claim 1 , wherein the subject has sepsis.