Treating kidney disease

Abstract

Disclosed herein are thiazolidinediones for the treatment of kidney disease, glomerular disease, and nephrotic syndrome.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 169,678, filed April 1, 2021. The disclosure of that priority application is incorporated by reference in its entirety into this application.

[0002] The present disclosure relates to therapeutic agents and methods for treating glomerular diseases and nephrotic syndrome. [Background technology]

[0003] Many diseases adversely affect kidney function by attacking the glomeruli, the small blood-cleaning units found within the kidney. Glomerular diseases include conditions with a variety of genetic and environmental causes, but they fall into two major categories: (1) glomerulonephritis, which involves inflammation of the membrane tissue in the kidney that acts as a filter to separate waste products and excess fluid from the blood; and (2) glomerulosclerosis, which involves scarring or hardening of the small blood vessels within the kidney. Although glomerulonephritis and glomerulosclerosis have different causes, they can both lead to kidney failure.

[0004] Patients with glomerular disease have significant amounts of protein in their urine, which at very high levels can be called the "nephrotic range." Red blood cells in the urine are also frequently found, especially in some forms of glomerular disease.

[0005] Glomerular disease can result from a variety of factors. It can be a direct result of infection or toxic drugs to the kidney; or it can result from diseases that affect the entire body, such as diabetes or lupus erythematosus. Many different types of diseases can cause swelling or scarring of the nephrons or glomeruli. Glomerular disease can also be idiopathic. Glomerular disease can be the result of: Autoimmune diseases (such as systemic lupus erythematosus (SLE), anti-GBM (Goodpasture's syndrome), or immunoglobulin A (IgA) nephropathy); hereditary nephritis or Alport syndrome; infection-associated glomerular diseases (such as poststreptococcal acute glomerulonephritis (PSGN), bacterial endocarditis, and human immunodeficiency syndrome (HIV)); sclerosing diseases (such as diabetic nephropathy and focal segmental glomerulosclerosis (FSGS)); other glomerular diseases (such as membranous nephropathy and minimal change disease (MCD)); and chronic kidney disease.

[0006] Renal failure is the acute or chronic loss of 85% or more of kidney function. End-stage renal disease (ESRD) is kidney failure that is treated with dialysis or kidney transplantation. Depending on the form of glomerular disease, kidney function may be lost within days or weeks, or it may deteriorate slowly over decades.

[0007] Acute renal failure includes several forms of glomerular disease that cause a very rapid deterioration of renal function. For example, PSGN can cause severe symptoms (hematuria, proteinuria, edema) within 2-3 weeks of the onset of a sore throat or skin infection. Such patients may temporarily require dialysis to replace renal function. This rapid loss of renal function is called acute renal failure (ARF). ARF can be life threatening if it continues, but renal function usually returns after the cause of renal failure is treated. In many patients, ARF is not associated with any permanent damage. However, some patients may recover from ARF and subsequently develop chronic kidney disease.

[0008] Nephrotic syndrome is one of the most common kidney diseases seen in children and adults. It is a relapsing and remitting disease characterized by massive loss of serum proteins into the urine through a damaged glomerular filtration barrier, resulting in hypoalbuminemia and generalized body swelling (edema). Podocytes are the main component of the kidney's filtration barrier, and during nephrotic syndrome, they undergo dramatic structural changes in the foot processes that attach these cells to the glomerular basement membrane.

[0009] For the past 50 years, the first-line therapy for nephrotic syndrome has been oral glucocorticoids. Unfortunately, glucocorticoids have serious side effects, and in approximately 20% of patients, they are ineffective in inducing clinical remission of the disease (i.e., steroid-resistant nephrotic syndrome). Thus, there is a great need for alternative therapies with higher efficacy and / or fewer side effects. Thiazolidinediones are a novel therapeutic strategy that can slow, stop, or reverse causative disease processes in diseases including glomerular disease, renal failure, and end-stage renal disease (such as acute renal failure, renal failure, and nephrotic syndrome). Summary of the Invention

[0010] Disclosed herein is a method of protecting renal cells from damage and improving cell viability, comprising contacting the cells with an effective amount of a thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the thiazolidinedione is not rosiglitazone.

[0011] In some embodiments, the renal cells are derived from a renal tissue selected from renal cortex, renal medulla, renal papilla, renal pyramid, renal trabecula, fibrous capsule, renal hilus, renal artery, renal vein, renal pelvis, ureter, major calyx, and minor calyx. In some embodiments, the renal cells are renal glomerular wall cells, renal glomerular podocytes, renal proximal tubule brush border cells, cells of the thin limb of Henle's loop, cells of the thick ascending limb of Henle's loop, renal distal tubule cells, collecting duct principal cells, collecting duct interstitial cells, and renal interstitial cells. In some embodiments, the cells are animal cells. In some embodiments, the cells are human cells. In some embodiments, the cells are treated in vitro. In some embodiments, the cells are treated ex vivo. In some embodiments, the cells are treated in vivo.

[0012] In some embodiments, the cells are in a subject having or at risk for a disease or disorder. In some embodiments, the cells are derived from an animal having or at risk for a disease or disorder selected from any one or more of the following: Age-related glomerular nephropathy, AL amyloidosis, Alport syndrome, amyloidosis, ANCA vasculitis, anti-glomerular basement membrane disease (Goodpasture syndrome), C1q nephropathy, C3 glomerulopathy, collapsing glomerulopathy, collapsing glomerulonephropathy, congenital nephrotic syndrome of the Finnish type (CNSF), cryoglobulinemia, diabetes, Denys-Drash syndrome, diabetic glomerulonephropathy, diabetic nephropathy, diffuse mesangial sclerosis (DMS), Fabry disease, fibrillary glomerulonephritis (GN), focal segmental glomerulosclerosis (FSGS), heavy chain deposition disease, hypertensive nephropathy, IgA vasculitis, Ig A nephropathy, IgM nephropathy, immune and inflammatory glomerular nephropathy, immunotactoid glomerulopathy, light chain deposition disease, lupus erythematosus, lupus nephritis, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), mesangial proliferation, mesangial sclerosis, myeloma nephropathy, minimal change disease, nephrotic syndrome, post-infectious glomerulonephritis (GN), thin basement membrane disease (TBM), thrombotic microangiopathy (TMA), or conditions related thereto. In some embodiments, the nephrotic syndrome is frequently relapsing nephrotic syndrome, steroid-dependent nephrotic syndrome, or steroid-resistant nephrotic syndrome.

[0013] Also disclosed herein are methods of treating a disease or disorder in a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the thiazolidinedione is not rosiglitazone.

[0014] In some embodiments, the disease or disorder is age-related glomerular nephropathy, AL amyloidosis, Alport syndrome, amyloidosis (amyloid nephropathy), ANCA vasculitis, anti-glomerular basement membrane disease, C1q nephropathy, C3 glomerulopathy, collapsing glomerulopathy, collapsing glomerulopathy, glomerulonephropathy, CNSF, cryoglobulinemia, diabetes, Denys-Drash syndrome, diabetic glomerular nephropathy, diabetic nephropathy, DMS, Fabry disease, fibrillary GN, FSGS, heavy chain deposition disease, hypertensive nephropathy, IgA vasculitis, IgA nephropathy, IgM nephropathy, immune and inflammatory glomerular nephropathy, immunotactoid glomerulopathy, light chain deposition disease, lupus erythematosus, lupus nephritis, membranous nephropathy, MPGN, mesangial proliferation, mesangial sclerosis, myeloma nephropathy, minimal change disease, nephrotic syndrome, post-infectious GN, TBM, TMA, or any of the conditions related thereto. In some embodiments, the nephrotic syndrome is frequently relapsing nephrotic syndrome, steroid-dependent nephrotic syndrome, or steroid-resistant nephrotic syndrome. In some embodiments, the disease or disorder is selected from any one or more of chronic kidney disease, nephrotic syndrome, glomerular disease, focal segmental glomerulosclerosis (FSGS), and mesangial sclerosis. In some embodiments, the subject is a mammal. In some embodiments, the mammal is a non-human animal. In some embodiments, the mammal is a human. In some embodiments, the thiazolidinedione is administered at a dose of 0.01 mg or more. In some embodiments, the thiazolidinedione is administered at a dose of 0.01-5000 mg / day.

[0015] Also disclosed herein is the use of a thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to reduce the level of protein excreted in urine. In some embodiments, the level of protein excreted in urine is measured as the frequency at which protein excretion occurs. In some embodiments, the level of protein excreted in urine is measured as the rate at which protein excretion occurs.

[0016] Also disclosed herein is the use of a thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to reduce the use of glucocorticoids in the treatment of kidney disease, such as nephrotic syndrome or glomerular disease. In some embodiments, the nephrotic syndrome is FRNS or SDNS.

[0017] Also disclosed herein is the use of a thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone to reduce the risk of glucocorticoid-induced toxicity in a subject with renal disease.

[0018] Also disclosed herein is the use of a thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone, to slow, stop, or reverse the progression of kidney disease.

[0019] In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the thiazolidinedione is not rosiglitazone.

[0020] Also disclosed herein is a method of treating nephrotic syndrome in a mammal comprising administering to the mammal an effective amount of a thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone, hi some embodiments, the nephrotic syndrome is FRNS or SDNS.

[0021] Also disclosed herein is a method of treating a glomerular disease in a mammal comprising administering to the mammal an effective amount of a thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone, In some embodiments, the glomerular disease is focal segmental glomerulosclerosis (FSGS), minimal change disease, or membranous nephropathy.

[0022] In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the thiazolidinedione is not rosiglitazone. [Brief description of the drawings]

[0023] [Figure 1] 1 shows the effect of disclosed compounds on the proliferation of renal cells (CIHP-1) pretreated with puromycin aminonucleoside (PAN) for 3 days. [Diagram 2] 1 shows the effect of disclosed compounds on the proliferation of CIHP-1 cells pretreated with PAN for 5 days. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Disclosed herein is a method of treating a disease or disorder disclosed herein with a thiazolidinedione, where the disease or disorder is related to the kidney as disclosed herein.

[0025] The term "thiazolidinedione" refers to a class of heterocyclic glitazone compounds containing a five-membered C3NS ring, including prodrugs, salts, solvates, hydrates, cocrystals, optical isomers, and deuterated forms thereof. As used herein, thiazolidinediones include, but are not limited to, one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, balaglitazone, and other thiazolidinedione molecules. In some embodiments disclosed herein, the method includes using any thiazolidinedione. In some embodiments, the thiazolidinedione is lobeglitazone. In some embodiments, the method specifically excludes the use of one or more thiazolidinediones disclosed herein. In some embodiments, the thiazolidinedione is not pioglitazone. In some embodiments, the thiazolidinedione is not rosiglitazone.

[0026] Lobeglitazone (Duvie®, Chong Kun Dang) is a thiazolidinedione with the chemical name 5-(4-(2-((6-(4-methoxyphenoxy)pyrimidin-4-yl)(methyl)amino)ethoxy)benzyl)thiazolidine-2,4-dione. As an agonist for both PPARα and PPARγ, lobeglitazone acts as an insulin sensitizer by binding to the PPAR receptors in fat cells, making them more responsive to insulin.

[0027] As used herein, the terms "treat," "treating," or "treatment" refer to alleviating, reducing, or eliminating one or more symptoms or characteristics of a disease, and may be curative, palliative, preventative, or slow the progression of a disease.

[0028] The term "effective amount" refers to an amount that results in a reduction in damage to the kidney as can be detected or identified, and that provides the desired effect or outcome. The term "therapeutically effective amount" refers to an amount of thiazolidinedione, including but not limited to one or more of pioglitazone, rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, balaglitazone, and other thiazolidinedione molecules, alone or in combination with other active ingredients, that produces a desired biological or pharmacological response, for example, effective to prevent, alleviate, or ameliorate the symptoms of a disease or disorder; effective to slow, stop, or reverse the process or progression of an underlying disease; effective to partially or completely restore cellular function; or effective to prolong the survival of a treated subject. In some embodiments, the thiazolidinedione is not pioglitazone. In some embodiments, the thiazolidinedione is not rosiglitazone.

[0029] The term "patient" or "subject" includes mammals and non-human animals, particularly including humans. In one embodiment, the patient or subject is a human. In another embodiment, the patient or subject is a male. In another embodiment, the patient or subject is a female. In another embodiment, the patient or subject is of any age.

[0030] The terms "significant" or "significantly" are determined by a t-test at the 0.05 level of significance.

[0031] The method is based on the surprising finding that thiazolidinediones can significantly protect podocytes against puromycin aminonucleoside (PAN)-induced injury (designed to mimic nephrotic syndrome-associated injury) as determined by both cell survival and actin cytoskeleton integrity. Thus, disclosed herein is the use of one or more thiazolidinediones for the treatment of kidney disease, glomerular disease, and nephrotic syndrome, including frequently relapsing nephrotic syndrome [FRNS], steroid-dependent nephrotic syndrome [SDNS], or steroid-resistant nephrotic syndrome.

[0032] Kidney diseases caused by damage that reduces kidney function and that may be treated by the thiazolidinediones disclosed herein include chronic kidney disease, kidney stones, glomerular disease or glomerulonephritis, polycystic kidney disease, urinary tract infections, or conditions related thereto.

[0033] Glomerular diseases caused by injury to the glomerulus include, but are not limited to: Age-related glomerulopathy, AL amyloidosis, Alport syndrome, amyloidosis (amyloid nephropathy), ANCA (antineutrophil cytoplasmic antibody) vasculitis, anti-glomerular basement membrane disease (Goodpasture syndrome), C1q nephropathy, C3 glomerulopathy, collapsing glomerulopathy, collapsing glomerulopathy glomerulonephropathy, Congenital Nephrotic Syndrome, Finnish Type (CNSF), Cryoglobulinemia, Diabetes Mellitus, Dennis-Drash Syndrome, Diabetic Glomerulonephropathy, Diabetic Nephropathy, Diffuse Mesangial Sclerosis (DMS), Anderson-Fabry Disease, Fibrillary Glomerulonephritis (GN), Focal Segmental Glomerulosclerosis (FSGS), Heavy Chain Deposition Disease, Hypertensive Nephropathy, IgA Vasculitis (formerly Henoch-Schönlein Purpura or HSP), IgA Nephropathy, IgM Nephropathy, Immune and Inflammatory Glomeruli Nephropathy, immunotactoid glomerulopathy, light chain deposition disease, lupus erythematosus, lupus nephritis, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), mesangial proliferation, mesangial sclerosis, myeloma nephropathy, minimal change disease, nephrotic syndrome (including, but not limited to, frequently relapsing nephrotic syndrome [FRNS], steroid-dependent nephrotic syndrome [SDNS], and steroid-resistant nephrotic syndrome), post-infectious glomerulonephritis (GN), thin basement membrane disease (TBM), thrombotic microangiopathy (TMA), or a condition related thereto.

[0034] In some aspects, the disclosure provides a method of exerting a protective effect in a cell comprising contacting the cell with an effective amount of a thiazolidinedione. As used herein, the term "effective amount" refers to an amount of a thiazolidinedione that produces a desired effect or result, e.g., an amount that produces a protective effect.

[0035] In some aspects, the disclosure provides a method of increasing cell viability comprising contacting a cell with an effective amount of a thiazolidinedione.

[0036] In some embodiments, the cells referred to herein are renal cells derived from renal tissue selected from renal cortex, renal medulla, renal papilla, renal pyramid, renal trabecula, fibrous capsule, renal hilus, renal artery, renal vein, renal pelvis, ureter, major calyx, and minor calyx. In some embodiments, the renal cells are selected from renal glomerular wall cells, renal glomerular podocytes, renal proximal tubule brush border cells, cells of the thin limb of Henle's loop, cells of the thick ascending limb of Henle's loop, renal distal tubule cells, collecting duct principal cells, collecting duct interstitial cells, and renal interstitial cells.

[0037] In some embodiments, the cell is an animal cell, e.g., a mammalian cell. In some embodiments, the cell is a human cell or a non-human cell. In some embodiments, the cell is treated in vitro, in vivo, or ex vivo. In some embodiments, the cell is a diseased cell. In some embodiments, the cell is a diseased cell from a patient suffering from a disease or disorder disclosed herein.

[0038] Also disclosed herein is a method of treating an animal having a disease or disorder, to benefit from a protective effect on cells, or to prevent the onset of the disease or disorder in the animal, or to reduce the risk of developing the disease or disorder, comprising administering to the animal a therapeutically effective amount of a pharmaceutical composition comprising a thiazolidinedione. In some embodiments, the animal is a mammal. In some embodiments, the mammal is a human or non-human mammal. In some embodiments, the mammal is a human. In some embodiments, the disease or disorder is caused by an injury that reduces kidney function. In some embodiments, the disease is selected from one or more of chronic kidney disease, kidney stones, glomerular disease or glomerulonephritis, polycystic kidney disease, urinary tract infection, or conditions related thereto. In some embodiments, the disease is a glomerular disease caused by injury to the glomerulus.

[0039] Also disclosed herein is a method for treating a disease or disorder that results in accelerated damage to the kidney in an animal or for extending cell survival in a patient with a disease or disorder that results in damage to the kidney. In some embodiments, the method comprises administering to the animal a therapeutically effective amount of a pharmaceutical composition comprising a thiazolidinedione. In some embodiments, the animal is a mammal. In some embodiments, the mammal is a human or non-human mammal. In one embodiment, the disease or disorder is selected from, but not limited to, the following: Chronic kidney disease, kidney stones, glomerular disease or glomerulonephritis, polycystic kidney disease, urinary tract infection, age-related glomerulonephropathy, AL amyloidosis, Alport syndrome, amyloidosis, ANCA vasculitis, anti-glomerular basement membrane disease (Goodpasture syndrome), C1q nephropathy, C3 glomerulopathy, collapsing glomerulopathy, collapsing glomerulopathy glomerulonephropathy, Congenital Nephrotic Syndrome, Finnish Type (CNSF), Cryoglobulinemia, Diabetes Mellitus, Denys-Drash Syndrome, Diabetic Glomerulonephropathy, Diabetic Nephropathy, Diffuse Mesangial Sclerosis (DMS), Anderson-Fabry Disease, Fibrillary Glomerulonephritis (GN), Focal Segmental Glomerulosclerosis (FSGS), Heavy Chain Deposition Disease, Hypertensive Nephropathy, IgA Vasculitis (formerly Henoch-Schönlein Purpura or HSP), IgA Nephropathy, IgM Nephropathy, Immune and Inflammatory Threads Glomerular nephropathy, immunotactoid glomerulopathy, light chain deposition disease, lupus erythematosus, lupus nephritis, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), mesangial proliferation, mesangial sclerosis, myeloma nephropathy, minimal change disease, nephrotic syndrome (including, but not limited to, frequently relapsing nephrotic syndrome [FRNS], steroid-dependent nephrotic syndrome [SDNS], and steroid-resistant nephrotic syndrome), post-infectious glomerulonephritis (GN), thin basement membrane disease (TBM), thrombotic microangiopathy (TMA), or related conditions.

[0040] Also disclosed herein are methods of treating nephrotic syndrome. In some embodiments, nephrotic syndrome includes primary nephrotic syndrome and secondary nephrotic syndrome. In some embodiments, primary nephrotic syndrome is idiopathic. In some embodiments, secondary nephrotic syndrome is due to a disease such as diabetes, cancer, or infection, or a side effect of a drug. In some embodiments, nephrotic syndrome includes frequently relapsing nephrotic syndrome (FRNS), steroid-dependent nephrotic syndrome (SDNS), or steroid-resistant nephrotic syndrome.

[0041] In another aspect, the disclosure provides a method of lowering protein excreted in urine, in terms of the frequency or rate at which protein excretion occurs; reducing the use of glucocorticoids for the treatment of kidney disease, such as nephrotic syndrome and glomerular disease; reducing the risk of glucocorticoid-induced toxicity in the treatment of kidney disease; or slowing, halting, or reversing the progression to chronic kidney disease.

[0042] In another aspect, disclosed herein are methods of treating an animal having a disease or disorder with symptoms that are prevented, alleviated, or ameliorated by cytoprotection; or an animal with a disease process or progression that is slowed, halted, or reversed by cytoprotection, the methods comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a thiazolidinedione. In some embodiments, the thiazolidinedione is lobeglitazone.

[0043] In a related aspect, disclosed herein is a method of treating nephrotic syndrome, in one embodiment, nephrotic syndrome includes primary nephrotic syndrome and secondary nephrotic syndrome.

[0044] The present disclosure further provides the use of a thiazolidinedione for the preparation of a therapeutic medicament for treating a human having any one of the diseases or disorders disclosed herein, or for use in any of the methods of the present disclosure, comprising administration of the thiazolidinedione to the human.

[0045] In another aspect, the present disclosure provides an in vitro method for screening a candidate therapeutic agent for its cytoprotective ability, the method comprising: (a) exposing PAN-treated podocytes to the candidate therapeutic agent; and (b) comparing the number of viable cells between the podocytes exposed to the candidate therapeutic agent and control cells, e.g., PAN-treated podocytes not exposed to the candidate therapeutic agent (i.e., non-exposed PAN-treated podocytes).

[0046] The pharmaceutical composition of the present disclosure comprises a therapeutically effective amount of a thiazolidinedione and at least one pharma- ceutically acceptable excipient. The term "excipient" refers to a pharma- ceutically acceptable inactive substance used as a carrier for the pharma- ceutically active ingredient, the thiazolidinedione, and includes anti-adherents, binders, coatings, disintegrants, fillers, diluents, solvents, flavorings, bulking agents, coloring agents, glidants, dispersants, wetting agents, lubricants, preservatives, adsorbents, and sweeteners. The choice of excipient depends on factors such as the specific mode of administration and the nature of the dosage form. Solutions or suspensions used for injection or infusion may include the following components: Sterile diluents (such as water for injection, saline, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents); antibacterial agents (such as benzyl alcohol or methyl parabens); antioxidants (such as ascorbic acid or sodium bisulfite); chelating agents (such as ethylenediaminetetraacetic acid); buffers (such as acetate, citrate or phosphate), and agents to adjust isotonicity (such as sodium chloride or dextrose). pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. Parenteral preparations may be enclosed in ampoules, disposable syringes, including autoinjectors, or multiple dose vials made of glass or plastic.

[0047] The pharmaceutical formulation of the present disclosure may be in any pharmaceutical dosage form. The pharmaceutical formulation may be, for example, a tablet, a capsule, a nanoparticle material, such as a granular particulate material or powder, a lyophilized material for reconstitution, a solution, a suspension, an emulsion or other liquid form, an injectable suspension, a solution, an emulsion, etc., a suppository, or a topical or transdermal formulation or patch. The pharmaceutical formulation generally comprises about 1% to about 99% by weight of the thiazolidinedione and 99% to 1% by weight of a suitable pharmaceutical excipient. In one embodiment, the dosage form is an oral dosage form. In another embodiment, the dosage form is a parenteral dosage form. In another embodiment, the dosage form is an enteral dosage form. In another embodiment, the dosage form is a topical application dosage form. In one embodiment, the pharmaceutical dosage form is a unit dose. The term "unit dose" refers to the amount of thiazolidinedione administered to a patient in a single dose.

[0048] In some embodiments, the pharmaceutical compositions disclosed herein are delivered to a subject via a parenteral route, an enteral route, or a topical route.

[0049] Examples of suitable parenteral routes of administration for use with the disclosed pharmaceutical compositions include, but are not limited to, any one or more of the following: Intraperitoneal, intra-amniotic, intra-arterial, intra-articular, intra-bile duct, intra-bronchial, intra-synovial, intra-cardiac, intra-cartilage, intra-sacral, intracavernous, intra-cavity, intra-brain, intra-sac, intra-cornea, intra-tooth crown, intra-coronary artery, intra-cavernous, intra-cranial, intradermal, intra-discal, intra-duct, intra-duodenal, intra-dural, intra-epidermal, intra-esophageal, intra-gastric, intra-gingival, intra-ileal, intralesional, intra-luminal, intra-lymphatic, intramedullary, intra-meningeal, intra-muscular, intraocular, intra-ovarian, intra-pericardial, intra-peritoneal, intra-pleural, intra-prostatic, intrapulmonary, intraocular, intra-sinus, intrathecal, intra-synovial, intra-tendon, intra-testicular, intra-arachnoid, intra-thoracic, intra-renal tubule, intra-tumor, intra-tympanic, intra-uterine, intravascular, intravenous (bolus or infusion), intraventricular, intra-bladder, and / or subcutaneous. In some embodiments, the route of administration is not oral buccal or sublingual, hi some embodiments, the route of administration is not nasal.

[0050] Enteral routes of administration include administration to the digestive tract via the mouth (oral), stomach (intragastric), and rectum (intragastric). Intragastric administration typically involves the use of a tube through the nose (NG tube) or a tube in the esophagus that leads directly to the stomach (PEG tube). Rectal administration typically involves a rectal suppository.

[0051] Topical administration includes administration to a body surface such as the skin or mucous membranes, including pulmonary administration. Transdermal dosage forms include creams, foams, gels, lotions or ointments. Pulmonary dosage forms include liquids and powders, such as liquid sprays.

[0052] Dosage may vary depending on the dosage form used, the sensitivity of the patient, and the route of administration. Dosage and administration are adjusted to provide sufficient levels of active substances or to maintain desired effects. Factors that may be considered include the severity of the condition, the subject's general health, age, weight, and sex, diet, timing and frequency of administration, drug combinations, reaction sensitivity, and tolerance / response to therapy.

[0053] In one embodiment, the daily dose of the thiazolidinedione administered to the patient is selected from up to 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 30 mg, 25 mg, 20 mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg, 5 mg, 4 mg, 3 mg, 2 mg, 1 mg, 0.9 mg, 0.8 mg, 0.7 mg, 0.6 mg, 0.5 mg, 0.45 mg, 0.4 mg, 0.3 mg, 0.2 mg, 0.1 mg, 0.08 mg, 0.05 mg, 0.03 mg, 0.02 mg, or up to 0.01 mg. In another embodiment, the daily dose is at least 0.01 mg, 0.02 mg, 0.05 mg, 0.08 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.45 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 21 mg, 22 mg, 23 mg, 24 mg, 25 mg, 26 mg, 27 mg, 28 mg, 29 mg, 30 mg, 31 mg, 32 mg, 33 mg, 34 mg, 35 mg, 36 mg, 37 mg, 38 mg, 39 mg, 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 63 mg, 64 mg, 65 mg, 66 mg, 67 mg, 68 mg, 69 mg, 70 mg, 71 mg, 72 mg, 73 mg, 74 mg, 75 mg, 76 mg, 77 mg, 78 mg, 79 mg, 80 mg, 81 mg, 82 mg, 83 mg, 84 mg, 85 mg, mg, 20mg, 25mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 125mg, 150mg, 175mg, 200mg, 300mg, 400mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1,000mg, 2,000mg, 3,000mg, 4,000mg, or at least 5,000mg.In another embodiment, the daily dose is 0.01-0.0.2 mg, 0.02-0.05 mg, 0.05-0.08 mg, 0.08-0.1 mg, 0.1-0.2 mg, 0.2-0.4 mg, 0.4-0.6 mg, 0.6-0.8 mg, 0.8-1 mg, 1-2 mg, 2-4 mg, 1-5 mg, 5-7.5 mg, 7.5-10 mg, 10-15 mg, 10-12.5 mg, 12.5-15 mg, 15-17.7 mg, 17.5-20 mg, 20-25 mg, 20-22.5 mg, 22.5-25 mg, 25-30 mg, 25-27.5 mg, 26-30 mg, 27-30 mg, 28-30 mg, 29-40 mg, 30-31 mg, 31-32 mg, 32-33 mg, 33-34 mg, 34-35 mg, 35-36 mg, 36-37 mg, 37-38 mg, 38-39 mg, 39-40 mg, 40-41 mg, 41-42 mg, 42-43 mg, 43-44 mg, 44-45 mg, 45-46 mg, 47-48 mg, 48-49 mg, 49-50 mg, 50-51 mg, 51-52 mg, 52-53 mg, 53-54 mg, 54-55 mg, 55-56 mg, 56-57 mg, 57-58 mg, 58-59 mg, 59-60 mg, 60-61 mg, 61-62 mg, 27.5-30 mg, 30-35 mg, 35-40 mg, 40-45 mg, or 45-50 mg, 50-75 mg, 75-100 mg, 100-125 mg, 125-150 mg, 150-175 mg, 175-200 mg, 5-200 mg, 5-300 mg, 5-400 mg, 5-500 mg, 5-600 mg, 5-700 mg, 5-800 mg, 5-900 mg, 5-1,000 mg, 5-2,000 mg, 5-5,000 mg, or greater than 5,000 mg, or any range defined by a pair of these values.

[0054] In another embodiment, the single dose of thiazolidinedione administered to the patient is selected from: 0.01mg, 0.02mg, 0.05mg, 0.08mg, 0.1mg, 0.2mg, 0.3mg, 0.4mg, 0.45mg, 0.5mg, 0.6mg, 0. 7mg, 0.8mg, 0.9mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 12mg, 13mg, 14mg, 1 5mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg , 30mg, 35mg, 40mg, 45mg, 50mg, 100mg, 110mg, 120mg, 130mg, 140mg,150mg, 160mg, 170mg , 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, 300mg, 310mg, 320mg, 330mg, 340mg, 350mg, 360mg, 370mg, 380mg, 390mg, 400mg, 410mg, 420mg, 430mg, 440mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 600mg, 700mg, 800mg, 900mg, 1,000mg, 2,000mg, 3,000mg, 4,000mg, or 5,000mg, or any range defined by a pair of these values. In one embodiment, the single dose is administered orally. In another embodiment, the single dose is administered by injection, e.g., subcutaneously, intramuscularly, or intravenously. In another embodiment, the single dose is administered by inhalation. In some embodiments, the thiazolidinedione is lobeglitazone.

[0055] As a non-limiting example, the dose of a thiazolidinedione such as lobeglitazone administered by oral administration may be about 0.01-50 mg / day administered in divided doses. A single dose of a thiazolidinedione such as lobeglitazone administered by subcutaneous injection may be about 0.01-50 mg, preferably about 0.1-10 mg, 0.2-1 mg, 0.3-0.6 mg or 0.5 mg, or any range defined by these value pairs. Other embodiments include the range of about 0.05-5,000 mg, preferably about 0.1-10 mg, 0.2-5 mg, 0.3-1 mg, or 0.5 mg, or any range defined by these value pairs. Subcutaneous infusion may be preferred in patients requiring division of the injection into more than 10 doses per day.

[0056] A fine particle dose of a thiazolidinedione, such as lobeglitazone, administered by pulmonary administration, e.g., by inhalation using a pressurized metered dose inhaler (pMDI), dry powder inhaler (DPI), soft mist metered dose inhaler, nebulizer, or other device, can be in the range of about 0.1 to 50 mg, preferably about 0.2 to 10 mg, 0.3 to 1 mg, or 0.5 mg, or any range defined by these value pairs. Other embodiments include in the range of about 0.05 to 5,000 mg, preferably about 0.1 to 1,000 mg, 0.2 to 100 mg, 0.3 to 1 mg, 0.4 to 0.5 mg, or 0.5 mg, or any range defined by these value pairs. The nominal dose (ND), i.e., the amount of drug metered into a container (also known as a metered dose), of a thiazolidinedione such as lobeglitazone administered by pulmonary administration may be, for example, in the range of 0.1 to 15 mg, 0.1 to 10 mg, 0.1 to 1 mg, 0.2 to 0.3 mg, 0.3 to 0.4 mg, 0.4 to 0.5 mg, 0.5 to 0.6 mg, 0.6 to 0.7 mg, 0.7 to 0.8 mg, 0.8 to 0.9 mg, or 0.9 to 1 mg, or any range defined by these value pairs. Other embodiments include the range of about 0.05 to 5,000 mg, preferably about 0.1 to 1,000 mg, 0.2 to 10 mg, 0.3 to 1 mg, 0.4 to 0.5 mg, or 0.5 mg, or any range defined by these value pairs.

[0057] Long-acting pharmaceutical compositions may be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more times per day (preferably 10 or fewer times per day), every two days, every 3-4 days, every week, or once every two weeks depending on the half-life and clearance rate of the particular formulation.

[0058] In one embodiment of any of the above methods and compositions, the thiazolidinedione, or salts, solvates, hydrates, and co-crystals thereof, is a racemic mixture of the R and S enantiomers, or is enriched in the R enantiomer (i.e., the ratio of R to S enantiomer administered is between 1.1:1 and 1,000:1, between 10:1 and 10,000:1, or between 100:1 and 100,000:1, or the total thiazolidinedione enantiomers in the composition are at least 98% R enantiomer, 99% R enantiomer, 99.5% R enantiomer, or 99.5% S enantiomer). the total thiazolidinedione enantiomers in the composition are at least 98% S enantiomer, 99% S enantiomer, 99.5% S enantiomer, 99.9% S enantiomer, or have no observable amounts of the R enantiomer), or enriched in the S enantiomer (i.e., the ratio of S enantiomer to R enantiomer administered is between 1.1:1 and 1,000:1, 10:1 and 10,000:1, or 100:1 and 100,000:1, or the total thiazolidinedione enantiomers in the composition are at least 98% S enantiomer, 99% S enantiomer, 99.5% S enantiomer, 99.9% S enantiomer, or have no observable amounts of the R enantiomer).

[0059] The present disclosure further provides an in vitro or ex vivo method of reducing cell damage, the method comprising contacting a cell with an effective amount of a thiazolidinedione.

[0061] Suitably, the cell has, or is at risk of, or is at risk of suffering from a disease or disorder selected from any one or more of the following: Chronic kidney disease, kidney stones, glomerular disease or glomerulonephritis, polycystic kidney disease, urinary tract infection, age-related glomerulonephropathy, AL amyloidosis, Alport syndrome, amyloidosis, ANCA vasculitis, anti-glomerular basement membrane disease, C1q nephropathy, C3 glomerulopathy, collapsing glomerulopathy, collapsing glomerulopathy glomerulonephropathy, Congenital Nephrotic Syndrome, Finnish Type (CNSF), Cryoglobulinemia, Diabetes Mellitus, Denys-Drash Syndrome, Diabetic Glomerulonephropathy, Diabetic Nephropathy, Diffuse Mesangial Sclerosis (DMS), Fabry Disease (Anderson-Fabry Disease), Fibrillary Glomerulonephritis (GN), Focal Segmental Glomerulosclerosis (FSGS), Heavy Chain Deposition Disease, Hypertensive Nephropathy, IgA Vasculitis (formerly Henoch-Schönlein Purpura or HSP), IgA Nephropathy, IgM Nephropathy, Immune and Inflammatory Glomerulonephropathy disease, immunotactoid glomerulopathy, light chain deposition disease, lupus erythematosus, lupus nephritis, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), mesangial proliferation, mesangial sclerosis, myeloma nephropathy, minimal change disease, nephrotic syndrome (including, but not limited to, frequently relapsing nephrotic syndrome or FRNS, steroid-dependent nephrotic syndrome or SDNS, and steroid-resistant nephrotic syndrome), post-infectious glomerulonephritis (GN), thin basement membrane disease (TBM), and thrombotic microangiopathy (TMA), or a condition related thereto.

[0060] Suitably, in the methods, compositions and / or second medical uses of the compositions of the present disclosure, the thiazolidinedione may be administered or formulated for administration in a dose of 0.01 mg or more. Suitably, the thiazolidinedione is administered in a dose of 0.1-5000 mg / day.

[0061] Suitably, in the methods, compositions and / or second medical uses of the compositions of the present disclosure, the thiazolidinedione may be administered or formulated for administration in any suitable manner, for example parenterally, enterally or topically.

[0062] Suitably, in the methods, compositions and / or second medical uses of the compositions of the present disclosure, the thiazolidinedione may be administered or formulated for oral, pulmonary, intravenous, intramuscular or subcutaneous administration.

[0063] Another embodiment of the present disclosure involves the use of thiazolidinediones to reduce cell damage or improve cell viability.

[0064] Another embodiment of the present disclosure involves the use of thiazolidinediones to reduce urinary protein excretion.

[0065] One embodiment involves the use of thiazolidinediones to reduce the use of glucocorticoids for the treatment of nephrotic syndrome and other kidney diseases.

[0066] Another embodiment involves the use of thiazolidinediones to reduce refractory nephrotic syndrome.

[0067] Working Example The present invention is not limited in scope by the specific embodiments described herein. Indeed, various modifications of the present invention in addition to those described herein will be apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to be within the scope of the appended claims.

[0068] Further, it should be understood that all numerical values ​​are approximate and are provided for illustrative purposes. All references cited and discussed herein are incorporated by reference in their entirety as if each reference was individually incorporated by reference.

[0069] Example 1: Thiazolidinediones improve cell viability methodology cell culture The human podocyte cell line (CIHP-1) is a primary cell line isolated from human kidney. Podocytes are highly specialized and terminally differentiated cells with complex cellular architecture. They are the main component of glomerular filtration. Cell cycle control, growth arrest and differentiation are important for the in vivo biology of podocytes. The conditionally immortalized podocyte line allows an in vitro process of maturation similar to podocyte development and maturation in vivo. The result is a homogeneous and stable source of cells that show expression of key antigen markers of differentiated in vivo podocytes. They include the novel podocyte proteins nephrin, podocin, CD2AP and synaptopodin. This stable cell line has been extensively characterized and validated.

[0070] The growth medium for CIHP-1 cells (Ximbio) was RPMI1640 with 10% fetal bovine serum (FBS), 1x ITS (insulin / transferrin / selenium), and 1x Pen / Strep. Culture conditions were 5% CO2 at 33°C. Cell detachment solution was Accutase® for 5 min at 33°C. Cell line passage ratio was 1:3 every 3 or 4 days.

[0071] PAN injury podocyte viability assay Differentiated podocytes were pretreated with either dimethyl sulfoxide (DMSO), lobeglitazone, pioglitazone, rosiglitazone, or dexamethasone as vehicle, followed by puromycin aminonucleoside (PAN) treatment (5 μg / ml). Viability assays were performed 3 or 5 days after treatment. Positive control cells (100% viable) did not receive PAN treatment. For compound treatment, compounds were diluted to 20, 2, 0.2, 0.02, and 0.002 mM in DMSO. A volume of 1.8 μL of compound was taken and mixed with 358.2 μL of medium. Medium was aspirated from the plates. A volume of 100 μL of compound-supplemented medium was added to each plate. The plates were placed in an incubator for 4 hours.

[0072] On day 0, CIHP-1 cells were seeded into two 96-well white plates using 5000 cells / well (plate 1) for 3 days or 2500 cells / well (plate 2) for 5 days treatment.

[0073] For compound treatment on the first day, the medium was aspirated. Fresh medium containing compound was added for 4 hours at 100 μl / well for each cell plate. DMSO was used as a control. After compound treatment for 4 hours, PAN was added to a final concentration of 5 μg / ml. No PAN treatment was used for negative control. No medium change was performed throughout the entire process.

[0074] On day 4, for the first plate, the Cell Titer-Glo (CTG) assay was used by adding 60 μl of CTG reagent to each well of the first plate, incubating at room temperature with shaking for 20 minutes, then reading on an EnVision plate reader.

[0075] On day 6, for the second plate, the CTG assay was used by adding 60 μl of CTG reagent to each well of the second plate, incubating at room temperature with shaking for 20 minutes, then reading on an EnVision plate reader.

[0076] result Lobeglitazone and pioglitazone prevent PAN-induced podocyte injury

[0077] To test the direct protective effects of lobeglitazone, pioglitazone, rosiglitazone, and dexamethasone on cultured podocytes, cells were injured with 5 μg / ml PAN for 3 or 5 days, which resulted in reduced viability of 70-80% and 30-40%, respectively, compared to untreated cells (Figures 1 and 2).

[0078] Pretreatment of cells with lobeglitazone or pioglitazone for 4 h significantly increased podocyte viability in a concentration- and time-dependent manner (Figure 1). Specifically, pretreatment with 10 μM lobeglitazone increased viability to 105% after 3 days of PAN exposure; on the other hand, simultaneous treatment with 0.01, 0.1, or 1 μM lobeglitazone increased viability to 103% of that of untreated control cells. Similarly, pioglitazone increased viability to 91–94% with 10 μM pretreatment. Similar viability results were observed after treatment with 0.01, 0.1, and 1 μM pioglitazone after 3 days of PAN exposure. The relatively low viability in pioglitazone-treated cells may be due to drug toxicity to podocytes, although lobeglitazone toxicity was only observed at 100 μM. Lobeglitazone and pioglitazone showed significant protection against PAN-injured podocytes, whereas rosiglitazone as well as the glucocorticoid dexamethasone did not show any protection against PAN-injured podocytes at the concentrations used (0.01-100 μM; Table 1).

[0079] [Table 1]

[0080] Less clear changes in viability were observed after 5 days of PAN injury (Figure 2). None of the drugs showed significant improvement in podocyte viability after treatment with lobeglitazone, pioglitazone, rosiglitazone, or dexamethasone at concentrations between 0.01 and 100 μM. More frequent or more sustained compound administration would improve podocyte viability (Table 2).

[0081] [Table 2]

[0082] Unless otherwise specifically indicated, all numerical values ​​expressing the amounts of ingredients and properties such as molecular weights, reaction conditions, etc. used in the specification and claims are to be understood in all cases as modified by the term "about". The terms "about" and "approximately" herein mean within 10-15%, preferably within 5-10%. Thus, unless otherwise specifically indicated, the numerical parameters in the specification and the appended claims are approximations that may vary depending on the desired properties sought to be obtained by the present invention. At the very least, and without intending to limit the application of the principles consistent with the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values ​​set forth in the specific examples are reported as precisely as possible. However, any numerical value inherently contains certain errors necessarily resulting from the standard deviation of their respective testing measurements.

[0083] The terms "a", "an", "the" and similar referents used in the context of describing the present invention (especially in the context of the appended "claims") should be considered to include both the singular and the plural, unless otherwise expressly stated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended as a shorthand method of referring to each different value within the range individually. Unless otherwise expressly stated herein, each individual value is incorporated herein as if it were individually recited herein. Any of the methods described herein can be performed in any suitable order, unless otherwise expressly stated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended merely to facilitate a better understanding of the present invention and does not limit the scope of the invention or the claims of the "claims". No language in this specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0084] Grouping of alternative elements or embodiments of the invention disclosed herein should not be considered limiting. Each member of a group may be referred to or claimed individually or in any combination with other members of the group or other elements described herein. It is understood that one or more elements of a group may be included or deleted for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to include the group as modified to satisfy all Markush group descriptions used in the appended "claims."

[0085] Certain embodiments of the present invention are described herein, including the best mode of carrying out the invention known to the inventors. Of course, variations on these described embodiments will be apparent to those of skill in the art upon reading the above description. The inventors believe that such variations will be employed by those of skill in the art as appropriate, and the inventors intend that the invention be practiced otherwise than as specifically described herein. Accordingly, the present invention includes all modifications and equivalents of the subject matter recited in the "claims" appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is included in the present invention unless otherwise expressly indicated herein or otherwise clearly contradicted by context.

[0086] Specific embodiments disclosed herein may be further limited in the Claims using the phrases "consisting of" or "consisting essentially of." When used in a Claim, whether added at the time of filing or an amendment, the transitional phrase "consisting of" excludes any element, step, or ingredient not expressly specified in the Claim. The transitional phrase "consisting essentially of" limits the Claim to particular materials or steps, and to materials or steps that do not materially affect the essential and novel characteristics. Embodiments of the invention so claimed are essentially or explicitly described and embodied herein.

[0087] Additionally, numerous patents and printed publications are referenced throughout this application. Each reference and each printed publication cited above is herein individually incorporated by reference in its entirety.

[0088] Finally, it is to be understood that the embodiments of the invention disclosed herein are illustrative of the principles of the invention. Other variations that may be employed are also within the scope of the invention. Thus, by way of example, but not of limitation, alternative configurations of the invention may be utilized in accordance with the teachings of this specification. Thus, the invention is not limited to that precisely as described and illustrated.

Claims

1. A thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone for use in reducing the level of protein excreted in the urine.

2. A thiazolidinedione for use according to claim 1, wherein the level of protein excreted in the urine is measured as the frequency of occurrence of protein excretion.

3. A thiazolidinedione for use according to claim 1, wherein the level of excreted protein in the urine is measured as the rate at which protein excretion occurs.

4. A thiazolidinedione for use according to claim 1, wherein the azolidinedione is lobeglitazone.

5. A thiazolidinedione for use according to claim 1, wherein the thiazolidinedione is not rosiglitazone.

6. The urine is selected from the group consisting of age-related glomerular nephropathy, AL amyloidosis, Alport syndrome, amyloidosis (amyloid nephropathy), ANCA vasculitis, anti-GBM disease (Goodpasture's syndrome), C1q nephropathy, C3 glomerulopathy, collapsing glomerulopathy, collapsing glomerulonephropathy, Finnish congenital nephrotic syndrome (CNSF), cryoglobulinemia, diabetes, Dennis-Drash syndrome, diabetic glomerular nephropathy, diabetic nephropathy, diffuse mesangial sclerosis (DMS), Fabry's disease, fibrillary glomerulonephritis (GN), focal segmental glomerulosclerosis (FSGS), heavy chain deposition disease, 2. The thiazolidinedione for use according to claim 1, derived from a mammal having a disease or disorder selected from one or more of the following: hypertensive nephropathy, IgA vasculitis, IgA nephropathy, IgM nephropathy, immune and inflammatory glomerular nephropathy, immunotactoid glomerulopathy, light chain deposition disease, lupus, lupus nephritis, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), mesangial proliferation, mesangial sclerosis, myeloma nephropathy, minimal change disease, nephrotic syndrome, post-infectious glomerulonephritis (GN), thin basement membrane disease (TBM), thrombotic microangiopathy (TMA), and conditions related thereto.

7. Age-related glomerular nephropathy, AL amyloidosis, Alport syndrome, amyloidosis (amyloid nephropathy), ANCA vasculitis, anti-GBM disease (Goodpasture syndrome), C1q nephropathy, C3 glomerulopathy, collapsing glomerulopathy, collapsing glomerulonephropathy, Finnish congenital nephrotic syndrome (CNSF), cryoglobulinemia, diabetes, Dennis-Drash syndrome, diabetic glomerulonephropathy, diabetic nephropathy, diffuse mesangial sclerosis (DMS), Fabry disease, fibrillary glomerulonephritis (GN), focal segmental glomerulosclerosis (FSGS), heavy chain deposition disease, hypertensive nephropathy, IgA vasculitis, IgA nephropathy, IgM nephropathy, immune and inflammatory glomerular nephropathy, immunotact 2. A thiazolidinedione selected from one or more of rosiglitazone, lobeglitazone, ciglitazone, darglitazone, englitazone, netoglitazone, rivoglitazone, troglitazone, and balaglitazone for use in slowing, halting, or reversing the progression of a disease or disorder selected from one or more of the following: id glomerulopathy, light chain deposition disease, lupus, lupus nephritis, membranous nephropathy, membranoproliferative glomerulonephritis (MPGN), mesangial proliferation, mesangial sclerosis, myeloma nephritis, minimal change disease, nephrotic syndrome, post-infectious glomerulonephritis (GN), thin basement membrane disease (TBM), thrombotic microangiopathy (TMA), and conditions related thereto.

8. A thiazolidinedione for use according to claim 7, wherein the thiazolidinedione is lobeglitazone.

9. A thiazolidinedione for use according to claim 7, wherein the thiazolidinedione is not rosiglitazone.

10. A thiazolidinedione for use as described in claim 7, wherein the disease or disorder includes nephrotic syndrome.

11. The thiazolidinedione for use according to claim 7, wherein the disease or disorder comprises a glomerular disease.

12. A thiazolidinedione for use as described in claim 7, wherein the disease or disorder includes nephrotic syndrome.

13. The thiazolidinedione for use according to claim 12, wherein the nephrotic syndrome is frequently relapsing nephrotic syndrome, steroid-dependent nephrotic syndrome, or steroid-resistant nephrotic syndrome.

14. The thiazolidinedione for use according to claim 7, wherein the disease or disorder comprises a glomerular disease.

15. The thiazolidinedione for use according to claim 14, wherein the glomerular disease is focal segmental glomerulosclerosis (FSGS), minimal change disease, or membranous nephropathy.

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