Disturbance of podocyte function as well as podocyte loss or injury are a hallmark of a variety of primary or secondary proteinuric glomerular diseases such as minimal change disease (such as e.g. minimal change nephropathy, or steroid hormone refractory minimal change nephropathy), focal segmental glomerulosclerosis (FSGS) and membraneous nephropathy (such as e.g. membranous glomerulonephritis). These diseases may present as a nephrotic syndrome, which is characterized by proteinuria (typically >3 g/day, or >3.5 g per 1.73 m2 per 24 hours), edema (which may be associated with weight gain), hypoalbuminemia (typically albumin level ≦2.5 g/dL), hyperlipidemia (e.g. hypercholesterolemia, hypertriglyceridemia, or both in combined hyperlipidemia, particularly hypercholesterolemia, mainly elevated LDL, usually with concomitantly elevated VLDL) and optionally (sometimes) hypertension. Lipiduria may also occur, but is not essential for the diagnosis of nephrotic syndrome. Hyponatremia may also occur with a low fractional sodium excretion.
Injury to the podocyte results in proteinuria and often leads to progressive kidney disease. As podocytes have limited ability to repair and/or regenerate, the extent of podocyte injury is a major prognostic determinant in diabetic nephropathy and other common causes of end-stage renal disease. Therapies aimed at preventing or limiting podocyte injury and/or at promoting podocyte repair or regeneration therefore have major potential clinical and economic benefits. Many current therapies—including glucocorticosteroids (e.g. prednisone, prednisolone), cyclophosphamide, cyclosporine, rituximab and calcineurin antagonists—have some effects on podocytes. However there are conditions of nephrotic syndrome which are or become resistant or refractory (relapsing) to conventional therapy, e.g. to steroid treatment. Further, the nonspecific natures of these conventional agents can lead to undesirable systemic adverse effects.
If protein excretion can not be controlled by adequate therapy, these diseases often progress to end-stage renal disease. This is particularly true for steroid hormone refractory minimal change nephropathy and focal segmental glomerulosclerosis (FSGS). The “normal” (steroid sensitive) minimal change nephropathy usually responds well to treatment with steroids. With steroid hormone refractory minimal change nephropathy and focal segmental glomerulosclerosis (FSGS), however, there remain clinical circumstances where no effective treatment is available today.
Nephrotic syndrome has many causes and may either be the result of a disease limited to the kidney, called primary nephrotic syndrome, or a condition that affects the kidney and other parts of the body, called secondary nephrotic syndrome.
Primary nephrotic syndrome:
Primary causes of nephrotic syndrome are usually described by the histology, i.e. minimal change disease (MCD) such as minimal change nephropathy which is the most common cause of nephrotic syndrome in children, focal segmental glomerulosclerosis (FSGS) and membraneous nephropathy (MN) such as membraneous glomerulonephritis which is the most common cause of nephrotic syndrome in adults.
They are considered to be “diagnoses of exclusion”, i.e. they are diagnosed only after secondary causes have been excluded.
Secondary nephrotic syndrome:
Secondary causes of nephrotic syndrome have the same histologic patterns as the primary causes, though may exhibit some differences suggesting a secondary cause, such as inclusion bodies. They are usually described by the underlying cause.
Secondary causes by histologic pattern:
Membranous nephropathy (MN):                Hepatitis B & Hepatitis C        Sjögren's syndrome        Systemic lupus erythematosus (SLE)        Diabetes mellitus        Sarcoidosis        Drugs (such as corticosteroids, gold, intravenous heroin)        Malignancy (cancer)        Bacterial infections, e.g. leprosy & syphilis        Protozoal infections, e.g. malaria        
Focal segmental glomerulosclerosis (FSGS):                Hypertensive nephrosclerosis        HIV        Obesity        Kidney loss        
Minimal change disease (MCD):                Drugs, especially NSAIDs in the elderly        Malignancy, especially Hodgkin's lymphoma        Leukemia        
Accordingly, nephrotic syndrome within the meaning of this invention includes, is caused by or is associated with minimal change disease (MCD, e.g. minimal change nephropathy, such as steroid hormone refractory minimal change nephropathy), membranous nephropathy (MN, e.g. membranous glomerulonephritis) and/or focal segmental glomerulosclerosis (FSGS).
USPTO Backgrounds
USPTO Backgrounds