Therapies for acute renal failure

Abstract

The present invention provides methods for the treatment, and pharmaceuticals for use in the treatment, of mammalian subjects in, or at risk of, acute renal failure, or subject to, or at risk of, inflammation, neutrophil-mediated cell damage, and apoptosis resulting from tissue damage or injury. The methods involve the administration of certain proteins of the osteogenic protein/bone morphogenetic protein (OP/BMP) family within the TGF-β superfamily of proteins.

1 . A method for treating a mammal in, or at risk of, acute renal failure comprising the steps of:
 (a) administering to said mammal a therapeutically effective amount of an OP/BMP renal therapeutic agent, and   (b) monitoring for an improvement in a marker of renal function in said mammal,   wherein said renal therapeutic agent comprises a polypeptide consisting of at least a C-terminal cysteine domain of a protein selected from the group consisting of a pro form, a mature form, and a soluble form of a polypeptide selected from the group consisting of OP-1, OP-2, OP-3, BMP2, BMP3, BMP4, BMP5, BMP6, BMP8, BMP9, BMP10, BMP11, BMP13, BMP15, GDF-1, GDF-3, GDF-5, GDF-6, GDF-7, DPP, Vgl, Vgr-1, 60A, UNIVIN, NODAL, SCREW, ADMP and NEURAL.   
   
   
       2 . A method of for treating a mammal to delay the need for, or reduce the frequency of, dialysis treatments of said mammal, the method comprising the steps of:
 (a) administering to said mammal a therapeutically effective amount of an OP/BMP renal therapeutic agent, and   (b) monitoring for an improvement in a marker of renal function in said mammal,   wherein said renal therapeutic agent comprises a polypeptide consisting of at least a C-terminal cysteine domain of a protein selected from the group consisting of a pro form, a mature form, and a soluble form of a polypeptide selected from the group consisting of OP-1, OP-2, OP-3, BMP2, BMP3, BMP4, BMP5, BMP6, BMP8, BMP9, BMP10, BMP11, BMP13, BMP15, GDF-1, GDF-3, GDF-5, GDF-6, GDF-7, DPP, Vgl, Vgr-1, 60A, UNIVIN, NODAL, SCREW, ADMP and NEURAL.   
   
   
       3 - 5 . (canceled) 
   
   
       6 . The method of  claim 1  wherein said renal therapeutic agent comprises a polypeptide consisting of at least a C-terminal cysteine domain of a protein selected from the group consisting of a pro form, a mature form, and a soluble form of human OP-1. 
   
   
       7 - 12 . (canceled) 
   
   
       13 . The method of  claim 1  wherein said renal therapeutic agent
 (a) induces chondrogenesis in an ectopic bone assay;   (b) prevents, inhibits, delays or alleviates loss of renal function resulting from acute renal failure in an animal model of acute renal failure; or   (c) causes a clinically significant improvement in a standard marker of renal function when administered to a mammal in, or at risk of, acute renal failure.   
   
   
       14 . The method of  claim 1  wherein said renal therapeutic agent is selected from the group consisting of human osteogenic proteins and human bone morphogenic proteins. 
   
   
       15 - 18 . (canceled) 
   
   
       19 . The method of  claim 1  wherein said mammal is afflicted with a condition selected from the group consisting of pre-renal causes of acute renal failure, post-renal causes of acute renal failure, and intrinsic renal causes of acute renal failure. 
   
   
       20 . The method of  claim 19  wherein said mammal is afflicted with a pre-renal cause of acute renal failure selected from the group consisting of decreased cardiac output, hypovolemia, volume redistribution, and altered vascular resistance. 
   
   
       21 . The method of  claim 19  wherein said mammal is afflicted with a post-renal cause of acute renal failure selected from the group consisting of ureteral, pelvic and bladder obstructions. 
   
   
       22 . The method of  claim 19  wherein said mammal is afflicted with an intrinsic renal cause of acute renal failure selected from the group consisting of abnormalities of the vasculature, abnormalities of the glomeruli, acute interstitial nephritis, intratubular obstruction, and acute tubular necrosis. 
   
   
       23 . The method of  claim 1  wherein said mammal is a kidney transplant recipient. 
   
   
       24 . The method of  claim 1  wherein said mammal possesses only one kidney. 
   
   
       25 . The method of  claim 1  wherein said administration is selected from oral, parenteral, intravenous, intraperitoneal, or into the renal capsule. 
   
   
       26 - 29 . (canceled) 
   
   
       30 . The method of  claim 25  wherein a stent has been implanted into said mammal for said administration. 
   
   
       31 . The method of  claim 30  wherein said stent is selected from an intravenous stent, an intraperitoneal stent, or a renal intracapsular stent. 
   
   
       32 - 33 . (canceled) 
   
   
       34 . The method of  claim 25  wherein said administration is by an implanted device. 
   
   
       35 . The method of  claim 1  wherein said administration is daily for a period of at least about one week or a period of at least about one month. 
   
   
       36 . (canceled) 
   
   
       37 . The method of  claim 1  wherein said renal therapeutic agent is administered at a dosage of about 0.01-1000 μg/kg body weight of said mammal or 0.1-100 μg/kg body weight of said mammal. 
   
   
       38 - 52 . (canceled) 
   
   
       53 . The method of  claim 1  wherein monitoring for an improvement in renal function is selected from the group consisting of: monitoring for an improvement in electrolyte imbalance in said mammal, monitoring for an improvement in glomerular filtration rate (GFR) in said mammal, monitoring for an improvement in BUN and monitoring for an improvement in serum creatine. 
   
   
       54 . The method of  claim 53  wherein pre-treatment BUN in said mammal shows a rate of increase in BUN of at least 2 to 4 mmol/L/day (5 to 10 mg/dL/day) or at least 4 to 8 mmol/L/day (10 to 20 mg/dL/day). 
   
   
       55 . The method of  claim 53  wherein pre-treatment serum creatinine in said mammal shows a rate of increase in serum creatinine of at least 20 to 40 μmol/L/day (0.25 to 0.5 mg/dL/day) or at least 40 to 80 μmol/L/day (0.5 to 1.0 mg/dL/day).