How to Treat Kidney Disease

Abstract

The present disclosure provides compositions and methods for treating kidney disease with the chemokine protein stromal cell-derived factor 1 (SDF-1), e.g., a method for treating a subject suffering from or at risk of developing kidney disease, comprising administering a therapeutically effective amount of SDF-1 to the kidney of the subject.

Description

[Background technology]

[0001] Chronic kidney disease (CKD), also known as chronic kidney disease or chronic renal failure, is the progressive loss of kidney function over months or years.CKD can be caused by a variety of conditions and mechanisms and affects humans as well as other animals, such as companion animals.For example, CKD is one of the most common causes of illness and death in aging cats.

[0002] New therapeutic options are needed for the treatment of kidney disease. Summary of the Invention

[0003] Provided herein is a method for treating a subject suffering from or at risk of developing kidney disease, comprising administering to the subject (e.g., to the kidney of the subject) a therapeutically effective amount of stromal cell-derived factor 1 (SDF-1).In some embodiments, the kidney disease is acute renal failure, chronic kidney disease, end-stage renal disease or anemia.In some embodiments, the kidney disease is chronic interstitial nephritis.

[0004] In some embodiments, the method further comprises administering to the subject an angiogenic growth factor (eg, vascular endothelial growth factor (VEGF)) in combination with said SDF-1.

[0005] Further provided is a sterile injectable composition for treating kidney disease, comprising SDF-1 and an aqueous carrier.In some embodiments, the composition comprises collagen or gelatin.In some embodiments, the composition further comprises angiogenic growth factor (e.g., vascular endothelial growth factor (VEGF)).

[0006] Also provided is SDF-1 or a vector encoding SDF-1 as described herein for use in practicing a method of treating a subject suffering from or at risk of developing kidney disease, or for use in preparing a medicament for practicing a method of treating a subject suffering from or at risk of developing kidney disease.

[0007] 1A-1D show histology (Masson's Trichrome staining) of kidney tissues from different control and treatment groups. [Brief description of the drawings]

[0008] [Figure 1A] FIG. 1 shows histology of kidney tissue from a control subject. [Figure 1B] FIG. 1 shows histology of kidney tissue from an injured subject without treatment. [Figure 1C] FIG. 1 shows histology of kidney tissue from an injured subject receiving carrier injection. [Figure 1D] Figure 1 shows histology of kidney tissue from an injured subject receiving an injection of SDF-1 in a carrier.Administration of SDF-1 restores a more normal cortex-medullary structure to the tissue. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The present disclosure provides compositions and methods for the treatment of kidney disease with the chemokine protein, stromal cell-derived factor 1 (SDF-1).

[0010] The disclosures of all patent documents cited herein are hereby incorporated by reference to the extent that they are consistent with the disclosures described herein. In the present specification and the appended claims, the singular forms "a", "an" and "the" as used herein are intended to include the plural forms as well, unless the context clearly dictates otherwise. As used herein, "and / or" and " / " refer to and include any and all possible combinations of one or more of the associated listed items, as well as the lack of combination when interpreted in the alternative ("or").

[0011] As used herein, "treating" refers to any type of treatment that provides a benefit to a subject or patient, particularly improving renal function, delaying or slowing the onset or progression or worsening of renal insufficiency or signs or symptoms thereof, and the like.

[0012] As used herein, "pharmacologically acceptable" means that the compound or composition is suitable for administration to a subject without undue adverse side effects having regard to the severity of the disease and the need for treatment.

[0013] "Kidney disease" refers to any type of disease or disorder that can impair one or more kidney functions, including, but not limited to, acute kidney failure (e.g., caused by poison, trauma, shock, infection, obstruction such as kidney stones, heart failure, etc.), chronic kidney disease (CKD) (e.g., gradual loss of kidney function due to aging, genetics, obstruction such as kidney stones, diabetes, infection, dental disease, immune disease, hypertension, thyroid disorder, cancer, congenital kidney anomalies, congenital polycystic kidney disease, etc.), end-stage renal disease, anemia, etc. By way of example, interstitial nephritis (inflammation of the kidney's interstitium surrounding the renal tubules) may be acute interstitial nephritis or chronic interstitial nephritis, which can ultimately lead to kidney failure.

[0014] As used herein, generally, "subject" or "patient" refers to an animal subject susceptible to kidney disease, including both human and non-human animal subjects (e.g., dogs, cats, horses, birds, etc.) for research or veterinary purposes. The subject may be male or female and may be of any appropriate age, including neonatal, infant, child, adolescent, adult, and geriatric subjects.

[0015] 1. Active compounds The active compound used herein is the chemokine protein stromal cell-derived factor 1 (SDF-1). This compound is also known as CXC motif chemokine 12 (CXCL12), and in humans, it is encoded by the CXCL12 gene. SDF-1 is known and described, for example, in M. D'Apuzzo et al., The chemokine SDF-1, stromal cell-derived factor 1, attracts early stage B cell precursors via the chemokine receptor CXCR4, Eur. J. Immunol., vol. 27, pp. 1788-1793 (1997); Y. Tabata, U.S. Pat. No. 8,435,953, and Penn et al., U.S. Pat. Nos. 8,513,213 and 8,513,007; and S. Itescu, U.S. Pat. No. 7,662,392, the disclosures of which are incorporated herein by reference in their entireties. See also JK Williams, WO 2015 / 171417.

[0016] As used herein, SDF-1 may include, in addition to SDF-1α or its mature form, isoforms such as SDF-1β, SDF-1γ, SDF-1δ, SDF-1ε and SDF-1φ and their mature forms, or mixtures of these in any ratio. SDF-1 in the present invention includes SDF-1α, SDF-1β, or mixtures of these in any ratio. See U.S. Patent No. 8,435,953.

[0017] In the present invention, as long as SDF-1 has activity as a chemokine, SDF-1 may be substituted, deleted and / or added by one or more amino acids in the amino acid sequence. Similarly, SDF-1 may be substituted, deleted and / or added by a sugar chain. SDF-1 may form a salt (preferably an acid addition salt) with a physiologically acceptable acid (e.g., inorganic acid or organic acid) or base (e.g., alkali metal salt). Examples of salts include salts with inorganic acids (e.g., hydrochloric acid, phosphoric acid, hydrobromic acid or sulfuric acid) and salts with organic acids (e.g., acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid or benzenesulfonic acid).

[0018] The SDF-1 used in the present invention may be derived from a mammal, such as a human, or a non-human animal, such as a monkey, sheep, cow, horse, pig, dog, cat, rabbit, rat or mouse. For example, in some embodiments, when the composition of the present invention is for use in humans, the composition of the present invention may be produced using human SDF-1 (e.g., SDF-1α (GeneBank Accession No. NP_954637) or SDF-1β (GeneBank Accession No. NP_000600)). As another example, in some embodiments, when the composition of the present invention is for use in domestic cats, the composition of the present invention may be produced using feline SDF-1 (e.g., GeneBank Accession No. NP_001009847 (Felis catus)). As a further example, in some embodiments, where the composition is for use in domestic dogs, the compositions of the invention may be produced using canine SDF-1 (e.g., GeneBank Accession No. AAU89475 (Canis lupus familiaris) or GeneBank Accession No. NP_001121569 (Canis lupus familiaris)).

[0019] In some embodiments, SDF-1 may be purified to a level where the action of SDF-1 is not inhibited by other contaminants. Preferably, SDF-1 may be purified so as to be usable as a pharmaceutical preparation.

[0020] In the present invention, SDF-1 may be obtained from natural sources or produced by genetic engineering technology. When obtained from natural sources, SDF-1 can be extracted from various organs, such as the spleen, of mammals, such as humans or non-human animals (e.g., monkeys, sheep, cows, horses, dogs, cats, rabbits, rats, or mice), in which SDF-1 is known to exist. Specific examples of organs in which SDF-1 is known to exist include, for example, SDF-1 is known to exist in large amounts in organs to which tumor cells expressing CXCR4, an SDF-1 receptor, frequently metastasize. On the other hand, when produced by genetic engineering technology, a gene encoding SDF-1 from a mammal, such as humans or non-human animals (e.g., monkeys, sheep, cows, horses, pigs, dogs, cats, rabbits, rats, or mice), is inserted into a suitable vector, which is then introduced into a suitable host cell for transformation, thereby making it possible to obtain the target recombinant SDF-1 from the culture supernatant of the transformant. The host cells herein are not limited, and various host cells, such as Escherichia coli (E. coli), various insect cells, such as yeast cells, silkworm cells, and various animal cells, commonly used in genetic engineering technology, may be used.

[0021] The active compounds disclosed herein, as described above, can be prepared in the form of their pharma- ceutically acceptable salts. Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts are (a) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like, and organic acids, such as acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; (b) salts formed from elemental anions such as chlorine, bromine, and iodine; and (c) salts derived from bases such as ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.

[0022] In some embodiments, SDF-1 may be administered directly onto and / or into renal tissue, e.g., by injection, or by administering a nucleic acid vector (e.g., integrating and non-integrating viral vectors, retroviral vectors, plasmid vectors, linear DNA vectors, etc.) that encodes SDF-1 and expresses (e.g., transiently or constitutively expresses) SDF-1 in renal tissue (e.g., by injection). Generally, such vectors include a nucleic acid segment encoding SDF-1 as described above that is operably associated with a promoter (e.g., a CMV promoter) that is operable in the tissue. Suitable vectors, including plasmid vectors, are known or will be apparent to those of skill in the art based on this disclosure, and include, but are not limited to, the plasmids deposited at the American Type Culture Collection under accession number PTA-13320, as described in U.S. Patent Nos. 8,513,213 and 8,513,007 to Penn et al., the disclosures of which are incorporated herein by reference.

[0023] 2. Pharmaceutical preparations The above-mentioned active compounds may be formulated in pharmaceutical carriers for administration according to known techniques. For example, see Remington, The Science And Practice of Pharmacy (9th Edition, 1995). In the manufacture of pharmaceutical preparations according to the present invention, the active compounds (including their physiologically acceptable salts) are typically mixed with, inter alia, acceptable carriers. Of course, the carrier must be acceptable in the sense of being compatible with any other ingredients in the preparation and not harmful to the patient. The carrier may be solid or liquid, or both, and is preferably formulated with the compound as a unit dose preparation, for example, a tablet, which may contain 0.01% or 0.5% to 95% or 99% by weight of the active compound. One or more active compounds may be incorporated into the preparation of the present invention, which may be prepared by any of the well-known techniques of pharmacy, including mixing with the components, which may include one or more auxiliary ingredients.

[0024] The formulations of the present invention suitable for parenteral administration include sterile aqueous and non-aqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient. Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, saline or water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0025] For example, in one embodiment of the present invention, a stable injectable sterile composition is provided, which comprises active compound or its salt in a sealed container in a unit dosage form.The compound or salt is provided in a lyophilized form, which can be reconstituted with a suitable pharma-ceutically acceptable carrier to form a liquid composition suitable for injection into a subject.The unit dosage form typically contains about 10 mg to about 10 grams of the compound or salt.When the compound or salt is substantially water-insoluble, a sufficient amount of a physiologically acceptable emulsifier can be used in an amount sufficient to emulsify the compound or salt in an aqueous carrier.One of such useful emulsifiers is phosphatidylcholine.

[0026] Non-limiting examples of sterile carriers include endotoxin-free or pyrogen-free water or saline.

[0027] In addition to the active compound, the pharmaceutical composition may contain other additives, such as pH adjusting additives. Particularly useful pH adjusting additives include acids such as hydrochloric acid, bases such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate or sodium gluconate, or buffers. In addition, the composition may contain microbial preservatives. Useful microbial preservatives include methylparaben, propylparaben and benzyl alcohol. Microbial preservatives are typically used when the formulation is placed in a vial designed for multi-dose use. Of course, as indicated, the pharmaceutical composition of the present invention may be lyophilized using techniques well known in the art.

[0028] The pharmaceutical composition may be formulated for immediate and / or sustained release of SDF-1, for example, in a sustained release composition containing a hydrogel using modified gelatin having carboxyl and / or sulfo groups. See, for example, U.S. Patent No. 8,435,953 to Tabata. In some embodiments, the composition may include collagen and / or gelatin.

[0029] 3. Dosage and route of administration As noted above, the present invention provides pharmaceutical formulations comprising an active compound (including pharma- ceutically acceptable salts thereof) in a pharma- ceutically acceptable carrier for parenteral administration.

[0030] Direct administration to an organ (e.g., direct injection onto and / or into a portion or portions of the kidney) can be performed by any suitable technique. Administration by injection can be performed by continuous infusion or by single or multiple boluses. See, for example, U.S. Patent Application Publication No. 2009 / 0306625 to Pereira-Kamath et al.

[0031] In some embodiments, direct administration to an organ may be guided by imaging techniques, e.g., by ultrasound guidance. In some embodiments, administration is by direct administration (e.g., direct injection or infusion) to one or more sites (e.g., 1, 2, or 3 to 7, 8, 9, or 10 sites) in the mesonephric cortex. In some embodiments, administration is by intra-arterial infusion into the kidney.

[0032] The therapeutically effective dosage of any particular compound, the use of which is within the scope of the present invention, may vary somewhat between compounds and between patients, and depends on the condition of the patient and the route of delivery.Generally, for direct injection of SDF-1 into organ, depending on the subject (e.g., human subject or companion animal subject), an amount of about 10 or 50 nanograms to 400, 800 or 1000 nanograms per administration, or an amount of about 10 or 50 micrograms to 400, 800 or 1000 micrograms per administration may be suitable, and each subject may receive one injection into organ tissue per treatment session, or multiple injections (e.g., 2, 3, 4, 5, 6 injections) into different sites of organ tissue in each treatment session (e.g., sites distributed around the periphery of organ or its part (e.g., around the dorsal pole of kidney)).

[0033] Treatment sessions may be repeated periodically (e.g., once every two or four months) as deemed appropriate. When a nucleic acid vector is administered, the vector can be administered in an amount effective to achieve a corresponding level of expression of SDF-1 at or near the injection site.

[0034] 4. Combination Therapy In some embodiments, SDF-1 is administered in combination with an angiogenic growth factor, such as vascular endothelial growth factor (VEGF). See, e.g., U.S. Pat. No. 6,352,975 to Schreiner et al.; Chade et al., Reversal of renal dysfunction by targeted administration of VEGF into the stenotic kidney: a novel potential therapeutic approach, Am J Physiol Renal Physiol, May 15, 2012, Vol. 302(10): F1342-50; U.S. Patent Application Publication No. 2016 / 077618 to Chade et al.

[0035] Administration of two or more agents, such as SDF-1 and VEGF, "in combination" means that the two agents are administered close enough in time that the presence of one alters the biological effect of the other. The two agents can be applied simultaneously (concomitantly or contemporaneously) or sequentially. Administration according to some embodiments can be within a period ranging from a few minutes (e.g., 1, 5, 10, 30, 60 or 90 minutes or more) to several days (e.g., 1, 2, 5, 8 or 10 days or more), as needed for effective treatment.

[0036] Simultaneous, concomitant, or contemporaneous administration may be accomplished by mixing the agents in the same composition prior to administration, or by administering the agents at the same time but at different sites on the body or organ, or using different types of administration, or may apply sufficiently close in time that the results observed are substantially the same as the results that would be achieved if the agents were administered at the same time.

[0037] Sequential application of agents may be accomplished by administering one agent at the same time before another agent is administered, such that the previous administration potentiates the effect of the subsequent administration.

[0038] SDF-1, which may be combined with VEGF, may also be administered in combination with one or more treatments, such as fluid therapy to address dehydration, surgery to remove blockages, antibiotics to treat infections, angiotensin-converting enzyme (ACE) inhibitors to control high blood pressure, dietary restrictions (e.g., diets low in protein, phosphorus, calcium and / or sodium) and / or supplements (e.g., phosphorus binders, vitamin D supplements), etc. For example, supplements such as antioxidants, mitochondrial cofactors, etc. may be provided in the food composition. See, for example, U.S. Patent No. 8,859,613 to Zicker et al. EXAMPLES

[0039] The invention is described in further detail in the following non-limiting examples.

[0040] [Example 1] Chronic kidney disease (CKD) affects an estimated 1% to 3% of all cats. The prevalence of CKD in felines increases with age, with approximately 30% to 50% of cats over the age of 15 having CKD, and the prevalence of CKD appears to be increasing.

[0041] Treatment for CKD in cats is largely symptomatic. In the early stages of CKD, dietary changes that reduce serum phosphorus concentrations are effective in reversing serum markers of CKD (Polzin et al., Dietary management of feline chronic renal failure. Where are we now? In what direction are we headed?, J Feline Med Surg, 2000, vol. 2, pp. 75-82). As the disease progresses, angiotensin-converting enzyme inhibitors and calcium channel blockers are used to reduce proteinuria and normalize systemic and intraglomerular blood pressure (Chakrabarti et al., Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease, J Vet Intern Med, 2012, 26, 275-281; ​​King et al., Tolerability and efficacy of benazepril in cats with chronic kidney disease, J Vet Intern Med, 2006, 20, 1054-1064; Mizutani et al., Evaluation of the clinical efficacy of benazepril in the treatment of chronic renal insufficiency in cats, J Vet Intern Med, 2006, 20, 1074-1079; Jepson et al., Effect of control of systolic blood pressure on survival in cats with systemic hypertension, J Vet Intern Med, 2006, 20, 1074-1079). Intern Med, 2007, vol. 21, pp. 402-409). In the later stages of CKD, treatments tend to focus on limiting the clinical signs associated with declining kidney function. Although these treatments can prolong life and provide a higher quality of life, they do not provide a cure.

[0042] The chemokine CXCL12 (often called stromal-derived factor-1 or SDF-1) mediates cell trafficking and homing of progenitor cells to sites of injury through a receptor (CXCR4 / CXCR7) mechanism and enhances cell survival when at the site of injury (Nagasawa, CXC chemokine ligand 12 (CXCL12) and its receptor CXCR4, J Mol Med (Berl), (2014) 92(5), 433-9; Lau et al., Stromal cell-derived factor-1 (SDF-1): homing factor for engineered regenerative medicine, Expert Opin Biol Ther., (2011) 11(2), 189-97; Herberg et al., Stromal cell-derived factor-1β mediates cell survival through enhancing autophagy in bone marrow-derived mesenchymal stem cells, PLoS One, (2013) 8(3), e58207; Ara et al., Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny, Immunity, (2003) 19(2), 257-67; Zisa et al., Intramuscular VEGF activates an SDF1-dependent progenitor cell cascade and an SDF1-independent muscle paracrine cascade for cardiac repair, Am J Physiol Heart Circ Physiol, (2011) 6, 2422-243). One group reported that CXCL12 is involved in the recruitment of bone marrow cells to the kidney in a mouse model of acute kidney injury.

[0043] [method] CXCL12 is administered directly into the kidneys of cats with experimentally induced chronic kidney disease.

[0044] Safety and Feasibility Study. This study will use six adult female cats. Three cats will receive carrier injections only (no CXCL12) injected into five sites (0.25 ml each) equidistant from each other (probably about 1 cm apart) along the dorsal pole of the left kidney. These injections will be made at the level of the mesonephric cortex. The other three cats will receive the same injections except with 40 ng / mL human recombinant CXCL12 (added to the carrier solution saline) injected into the same sites for a total of 200 ng CXCL12. The injections will be ultrasound guided and injected into the mesonephric cortex.

[0045] CBC, BUN, creatinine, urinalysis, SDMA test kit from IDEXX (to test glomerular filtration function and kidney function) are evaluated prior to injection. This is used as a surrogate for and is highly correlated with standard GFR (filtration fraction). These measurements are repeated 4 weeks after injection and then again 4 weeks later.

[0046] Efficacy study. This study included 14 adult female cats; two were control cats. There were three treatment arms: 1) unilateral CKD induction / no treatment (n=4); 2) CKD induction / vehicle injection (n=4); and 3) CKD induction / vehicle and CXCL12 injection (n=4).

[0047] Induction of ischemia / reperfusion injury to the left kidney. When the kidney is injected as described above for the safety study, blood and urine evaluations are repeated 4 and 8 weeks after injury. Blood and urine analysis are repeated 4 and 8 weeks after injection. CBC, BUN, creatinine, urinalysis, SDMA (to test glomerular filtration function and kidney function) are evaluated.

[0048] Creation of CKD in cats. Using the procedure published by Schmiedt et al. (Unilateral Renal Ischemia as a Model of Acute Kidney Injury and Renal Fibrosis in Cats, Vet Pathol., January 2016, Vol. 53(1), pp. 87-101). Injections are performed at the level of the mesonephric cortex as described above.

[0049] [Example 2] Four groups were tested: SDF-1 (4), vehicle (4), no Tx (4), and control (1). CKD models were surgically created in cats (n=12) as described above. Retroperitoneal injections of a total dose of 200 ng were performed in the left kidney (n=6) with three injections of 66.7 ng each into the left renal cortex under ultrasound guidance.

[0050] [result]

[0051] [Table 1]

[0052] [Table 2]

[0053] [Table 3]

[0054] [Conclusion] There was a beneficial effect of CXCL12 on kidney volume, and blood and urine measures. However, injection of collagen-containing carrier (see WO 2015 / 171417) may cause some renal pathology and / or some adverse changes in these measures. Histological analysis shown in Figure 1A to Figure 1D demonstrates that injury leads to renal cortex-medulla, fibrosis and cell damage, and SDF-1 (CXCL12) restores a more normal cortex-medulla structure. The results are promising, but due to the small number of animals tested, there is no statistical significance at present.

[0055] The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. The present invention is defined by the following claims, with equivalents of the claims to be included therein.

Claims

1. A medicament for treating a subject suffering from or at risk of developing kidney disease by causing a reduction in renal cell destruction and / or fibrosis, said medicament being administered directly to the kidney of said subject by injection directly onto and / or into the kidney tissue, said medicament comprising a therapeutically effective amount of stromal cell-derived factor 1 alpha (SDF-1α); The medicine, wherein the kidney disease is acute renal failure, chronic kidney disease, end-stage renal disease or anemia.

2. The pharmaceutical composition of claim 1 , wherein the subject is a human subject.

3. The pharmaceutical according to claim 1 , wherein the subject is a non-human mammalian subject.

4. The method of claim 1 , wherein the subject is a cat, dog or horse.

5. The method of claim 1 , wherein the subject is a domestic cat.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the kidney disease is chronic interstitial nephritis.

7. The pharmaceutical composition according to any one of claims 1 to 6, further comprising a pharma- ceutically acceptable carrier, wherein the SDF-1 is provided in the pharma- ceutically acceptable carrier.

8. The pharmaceutical of claim 7, wherein the pharma- ceutically acceptable carrier is sterile (e.g., endotoxin-free or pyrogen-free water, or a saline solution of endotoxin-free or pyrogen-free water).

9. The pharmaceutical composition of claim 1 , wherein the direct administration is performed at multiple sites on and / or in the renal tissue.

10. The pharmaceutical agent of claim 1 or claim 9, wherein the direct administration is into the mesonephric cortex.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the SDF-1α is human SDF-1α.

12. The pharmaceutical composition according to any one of claims 1 to 10, wherein the SDF-1α is feline SDF-1α or canine SDF-1α.

13. 13. The medicament of any one of claims 1 to 12, wherein the SDF-1α is contained as a nucleic acid vector encoding the SDF-1α, and the administration is by injecting the nucleic acid vector into the kidney, whereby the acetate vector expresses the encoded SDF-1α.

14. The pharmaceutical according to claim 13 , wherein the vector is a plasmid vector or a viral vector.

15. The pharmaceutical agent according to any one of claims 1 to 14, wherein the administration comprises administering to the subject an angiogenic growth factor (e.g., vascular endothelial growth factor (VEGF)) in combination with the SDF-1α.

16. 1. A sterile injectable composition for the treatment of kidney disease by direct injection onto and / or into kidney tissue comprising SDF-1α and an aqueous carrier, wherein the SDF-1α is present in an amount effective to result in reduced cell destruction and / or reduced fibrosis in the kidney when administered directly to the kidney of a subject by direct injection onto and / or into the kidney tissue, and wherein the kidney disease is acute renal failure, chronic kidney disease, end stage renal disease or anemia.

17. The sterile injectable composition of claim 16, comprising gelatin.

18. 17. The sterile injectable composition of claim 16, further comprising VEGF.

19. Use of SDF-1α or a vector encoding SDF-1α in the preparation of a medicament for the practice of a method of treating a subject suffering from or at risk of developing kidney disease by direct injection onto and / or into kidney tissue, wherein said SDF-1α or a vector encoding SDF-1α is present in an amount effective to result in reduced cell destruction and / or reduced fibrosis in the kidney of said subject, and said kidney disease is acute renal failure, chronic kidney disease, end stage renal disease or anemia.

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