Nephrotic syndrome is defined as the presence of proteinuria (>3.5 g/24 hours), hypoalbuminemia (<3.0 g/dL), and peripheral edema. Hyperlipidemia and thrombotic disease are also frequently seen. Despite heavy proteinuria and lipiduria, the urine contains few cells or casts. 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 isolated heavy proteinuria without the other components of nephrotic syndrome are described as having nephrotic-range proteinuria and is usually indicative of an underlying glomerulopathy. In this case, the underlying etiology is more likely due to focal segmental glomerulosclerosis (FSGS).
Nephrotic syndrome is not a single disease; it is a constellation of several symptoms that can be caused by several renal diseases. The challenge is to determine the underlying etiology causing the nephrotic syndrome in any given patient. Generally, patients with any type of nephrotic syndrome require subspecialty treatment, and prompt consultation with a nephrologist is advised.
This monograph provides an overview of the evaluation of nephrotic syndrome and the individual diseases that cause heavy proteinuria.
Nephrotic syndrome may occur in connection with a large assortment of primary and secondary diseases. The probable etiology differs depending on the patient's age and the presence of specific comorbidities (e.g., diabetes, amyloidosis, or systemic lupus erythematosus). The most common cause in children is minimal change disease.  In adults, primary glomerular diseases are more frequent in males (55%), whereas secondary glomerular disease is more frequent in females (72%).
The most common cause in younger adults is 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.
Nephrotic syndrome can also develop in patients with IgA nephropathy, membranoproliferative glomerulonephritis, and postinfectious glomerulonephritis. However, these patients usually have a nephritic pattern with hematuria and red cell casts as the predominant feature.
Minimal change disease accounts for 90% of nephrotic syndrome cases in children <10 years.  In adults, it may occur without an identified cause (idiopathic), in relation to NSAIDs, or due to Hodgkin lymphoma. "Minimal change" refers to light microscopic findings that often reveal normal glomeruli or mild mesangial proliferation. Immunofluorescence typically shows no immune complex deposition. Electron microscopy, however, classically demonstrates diffuse effacement of the epithelial cell foot processes. Minimal change disease is typically responsive to steroids; however, if resistance is noted then alternative etiologies should be considered.
FSGS accounts for between 35% and 50% of idiopathic nephrotic syndrome cases in adults.  Light microscopy shows segmental areas of mesangial collapse and sclerosis affecting some but not all glomeruli (focal disease). FSGS can be either primary (idiopathic) or secondary to HIV, obesity, and reflux nephropathy. 
Differentiating between primary and secondary FSGS is key in determining management as the former responds to immunosuppression, while secondary causes are treated with reducing intraglomerular pressure (renin-angiotensin blockade). HIV is associated with collapsing FSGS, where histology demonstrated collapse and sclerosis of the entire glomerular tuft (nonsegmental).
FSGS commonly presents with hematuria, hypertension, and reduced renal function. Patients are often resistant to steroids and renal biopsy is required to confirm diagnosis.
Membranous nephropathy is the most common cause of nephrotic syndrome in adults. Microscopy demonstrates basement membrane thickening without associated cellular proliferation or infiltration. Immunofluorescence reveals diffuse, granular IgG deposition throughout the capillary walls and electron microscopy shows electron dense deposits in the subepithelial space. New basement membrane growth between subepithelial immune deposits leads to the classic "spike and dome" appearance.
Although membranous nephropathy is usually idiopathic (and associated with autoantibodies, especially to phospholipase A2 receptor present on podocytes), many cases are secondary to hepatitis B, autoimmune disease, malignancy, and adverse drug reactions (including gold, penicillamine, and NSAIDs). 
Both type 1 and type 2 diabetes mellitus can cause diabetic nephropathy in around one third of people with diabetes. This is usually heralded by microalbuminuria, then a progressive fall in GFR. A combination of pathogenic processes occurs including glomerular hyperfiltration, hyperglycemia, and glycation of matrix proteins. Rarely, the heaviness of proteinuria caused by diabetic nephropathy can lead to nephrotic syndrome. Diabetic nephropathy is defined by characteristic mesangial expansion, glomerular basement membrane thickening, and glomerular sclerosis leading to the development of Kimmelstiel-Wilson nodules.
Amyloidosis is responsible for around 10% of nephrotic syndrome cases. There are two major subtypes:
AL primary amyloid, which is a light-chain dyscrasia where monoclonal light chains form amyloid fibrils;
AA amyloid, which is associated with chronic inflammatory disease.
Investigations should search for the presence of a monoclonal paraprotein in the urine or plasma.
Each kidney has approximately one 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.
There are 3 categories of proteinuria: glomerular, tubular, and overflow.
Glomerular proteinuria develops when the components of the 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 hypoalbuminemic 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 including hypercholesterolemia and hypertriglyceridemia.  Lipiduria occurs in the form of: lipid sediment, fatty casts, oval fat bodies, or free fat droplets in the urine (which appear as Maltese crosses under polarized light).
Hypercoagulability results from the loss of inhibitors of coagulation in the urine and increased synthesis of procoagulatory factors by the liver.  The edema is due to a combination of a decrease in oncotic pressure from the hypoalbuminemia, as well as a primary renal sodium retention in the collecting tubules.   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, categorizing 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, 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 disease, Alport 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 edema (or anasarca). The other 2 common causes of severe edema are severe hepatic disease and CHF. In contrast to these other 2 disorders, patients with edema from nephrotic syndrome often can comfortably lie flat, allowing them to develop facial edema. Generally, patients with CHF or severe liver disease cannot comfortably lie flat and tend not to develop facial edema. The key feature differentiating renal disease from the other 2 diseases is the presence of severe proteinuria, which makes examination of the urine mandatory.
Professor of Cardio-Renal Medicine
Member of the Faculty of Translational Medicine
King's Health Partners AHSC
DJAG has done consultancy work for Sanofi, Otsuka, Relypsa, and Astra-Zeneca.
NIHR Academic Clinical Fellow in Neurology
University College London
OJZ declares that he has no competing interests.
Dr David J.A. Goldsmith and Dr Oliver J. Ziff would like to gratefully acknowledge Dr Michael S. Gersch, a previous contributor to this monograph. MSG declares that he has no competing interests.
Professor of Renal Medicine
The John Walls Renal Unit
Leicester General Hospital
JF declares that he has no competing interests.
Washington Hospital Center
JHV declares that she has no competing interests.
Department of Medicine
CC declares that she has no competing interests.
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