Nephrotic syndrome is defined as the presence of proteinuria (>3.5 g/24 hours), hypoalbuminaemia (<30 g/L), oedema, and hyperlipidaemia. This is in contrast to nephritic syndrome, which is typically defined as the presence of acute kidney injury (renal dysfunction), hypertension, and an active urinary sediment (red cells and red cell casts). Patients presenting with proteinuria without the other components of nephrotic syndrome are described as having nephrotic-range proteinuria. Nephrotic syndrome is not a disease; it is a constellation of several symptoms that can be caused by several renal diseases. The challenge is to determine any underlying disease causing the nephrotic syndrome in any given patient. Generally, patients with either nephrotic or nephritic syndrome require sub-specialty treatment, and prompt consultation with a nephrologist is advised.
Probable aetiology differs depending on the patient's age and the presence of specific comorbidities (e.g., diabetes). The most common cause in children is minimal change disease.  The most common cause in younger adults is focal segmental glomerulosclerosis (FSGS), followed by minimal-change nephropathy. Membranous nephropathy is the most common cause in older people,   and diabetic nephropathy in adults with a history of long-standing diabetes.
Each kidney has approximately 1 million glomeruli, which are the sites of blood filtration. The layers of the glomeruli include the fenestrated endothelium of the capillary, the glomerular basement membrane, and the foot processes of the podocytes. The main barrier to filtration is the connection between adjacent podocyte foot processes called slit diaphragms. Glomerular proteinuria develops when the components of this filtration barrier are disrupted by disease. The primary insult leading to the development of nephrotic syndrome is the development of high-grade glomerular proteinuria, and the heavier the protein loss the more likely the development of the full-blown syndrome and worsening of renal function. Patients become hypoalbuminaemic due to the urinary loss of albumin. The liver tries to compensate for this protein loss by increasing the synthesis of albumin, as well as other molecules including LDL and VLDL and lipoprotein(a), contributing to the development of lipid abnormalities.  Hypercoagulability results from the loss of inhibitors of coagulation in the urine and increased synthesis of procoagulatory factors by the liver.  The oedema is due to a decrease in oncotic pressure from the hypoalbuminaemia, as well as a primary defect in sodium excretion.   Patients with nephrotic syndrome are also at increased risk of infection due to loss of immunoglobulins and complement and other compounds being lost in the urine.
Nephrotic syndrome is a relatively rare but important manifestation of kidney disease. In the US, its annual incidence among children is reported to be 2 to 7 cases per 100,000.      Incidence varies among adults depending on the incidence of underlying causes for the condition, particularly diabetes mellitus. Nephrotic syndrome has an incidence of around 3 new cases per 100,000 each year in adults. 
Clinically, categorising glomerular renal disease into syndromes, such as nephrotic syndrome and nephritic syndrome, helps to narrow the differential diagnosis. The differential diagnosis is generally the same for patients with nephrotic syndrome and for nephrotic-range proteinuria.
Common differential diagnoses of nephrotic syndrome include minimal change nephropathy, FSGS, membranous nephropathy, diabetic nephropathy, membranous nephropathy, primary glomerular diseases (e.g., IgA nephropathy), fibrillary glomerulopathies (the most common being amyloidosis), lupus nephritis, and multiple myeloma (e.g., light-chain deposition diseases).  Membranoproliferative glomerulonephritis is a relatively rare cause of nephrotic syndrome, though more common as a cause of isolated non-visible hematuria and proteinuria.
An uncommon presentation of rare renal diseases such as Fabry's disease, Alport's syndrome, and nail-patella syndrome would be nephrotic syndrome. Rarely also accelerated phase hypertension can present this way. In most cases, family history, drug history, symptom history, examination, and investigations lead to the diagnosis of an underlying cause for nephrotic syndrome.
Nephrotic syndrome is one cause of severe oedema (or anasarca). The other 2 common causes of severe oedema are severe hepatic disease and CHF. In contrast to these other 2 disorders, patients with oedema from nephrotic syndrome often can comfortably lie flat, allowing them to develop facial oedema. Generally, patients with CHF or severe liver disease cannot comfortably lie flat and tend not to develop facial oedema. The key feature differentiating renal disease from the other 2 diseases is the presence of severe proteinuria, which makes examination of the urine mandatory.