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).
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.
Patients with nephrotic syndrome are at risk of chronic kidney disease and end-stage renal disease. Nephrotic syndrome is associated with significant morbidity and mortality, therefore these patients require specialized input and assessment.
This topic 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, ethnicity, and the presence of specific comorbidities (e.g., diabetes, amyloidosis, or systemic lupus erythematosus).
The most common cause of nephrotic syndrome in young children is minimal change disease (MCD). Renal biopsy is not performed if children with MCD are steroid sensitive (steroid sensitive nephrotic syndrome). Children with steroid resistant nephrotic syndrome (SRNS) undergo renal biopsy, with the pathology most likely to be focal segmental glomerulosclerosis (FSGS). In older children/adolescents, the incidence of MCD starts to decrease, and other causes of nephrotic syndrome increase in incidence.
In adults, FSGS is an increasingly common cause of nephrotic syndrome. FSGS incidence is similar to, or exceeds that of, the most common historical cause of unexplained nephrotic syndrome in adults, membranous nephropathy. Membranous nephropathy remains the most common cause of nephrotic syndrome in older people.
Diabetic nephropathy is the most common cause of nephrotic syndrome in adults with a history of long-standing diabetes.
Patients with IgA nephropathy, membranoproliferative glomerulonephritis, and postinfectious glomerulonephritis may demonstrate some features of nephrotic syndrome (nephrotic range proteinuria with a low serum albumin). However, these causes of renal disease are predominantly nephritic and investigations will reveal hematuria, red cell casts, and possibly renal dysfunction.
Minimal change disease (MCD)
MCD accounts for approximately 95% of cases of nephrotic syndrome in children before adolescence. In children younger than 10 years, MCD accounts for 70% to 90% of cases of nephrotic syndrome. This figure decreases to 50% in older children, and to between 10% and 20% in adults.
MCD is a major cause of idiopathic nephrotic syndrome. In a minority of cases, it may be associated with an underlying secondary cause, such as nonsteroidal anti-inflammatory drug (NSAID) use or Hodgkin lymphoma. In 20% to 30% of patients with MCD, there may be an associated acute kidney injury. Risk factors for the development of acute kidney injury include male sex, age >50 years, severe nephrotic syndrome, known hypertension, and arteriosclerosis.
"Minimal change" refers to light microscopic findings that often reveal normal glomeruli or mild mesangial proliferation with negative immunofluorescence and no immune complex deposition. Electron microscopy, however, classically demonstrates diffuse effacement of the epithelial cell foot processes. MCD is typically responsive to steroids. If resistance is noted, alternative etiologies should be considered, in particular FSGS.
Focal segmental glomerulosclerosis (FSGS)
FSGS can be either primary (idiopathic), secondary, or genetic. 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).
Secondary causes of FSGS can be divided into those caused by conditions such as HIV infection, reflux nephropathy, class III obesity (BMI 40 or above), chronic glomerular hyperfiltration from a solitary kidney, or any other cause of extensive nephron loss (e.g., renal obstruction, prior glomerulonephritis), or to certain drugs (such as pamidronate or heroin). HIV is associated with collapsing FSGS, characterized by collapse and sclerosis of the entire glomerular tuft (nonsegmental).
Genetic forms of FSGS usually present in childhood. A recessive mutation in one of four genes (NPHS1, NPHS2, LAMB2, WT1) accounts for 85% of cases of SRNS presenting by 3 months, and 66% presenting in the first year of life.
When FSGS cannot be classified by clinicopathologic assessment, genetic analysis may be offered. This is particularly relevant in young adult patients. A cohort study demonstrated that a single-gene cause of SRNS was found in 29.5% of patients presenting before the age of 25.
FSGS commonly presents with hematuria, hypertension, and reduced renal function. Edema may be present. Light microscopy shows segmental areas of mesangial collapse and sclerosis affecting some but not all glomeruli (focal disease). 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 older adults but is rare in children. 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.
The majority of cases of membranous nephropathy are primary (70%), with the remaining 30% associated with malignancy, infections (e.g., hepatitis B, hepatitis C, syphilis, malaria, or tuberculosis), autoimmune disease (e.g., lupus membranous nephropathy), or drugs (e.g., gold, penicillamine, and NSAIDs).
In primary membranous nephropathy, antibodies to M-type phospholipase A2 receptor (PLA2R) have been identified in 70% to 80% of patients. Measurement of anti-PLA2R antibody titer is now a routine part of clinical care, contributing to the diagnosis and prognosis, as well as helping to guide treatment decisions.
About 20% to 30% of patients with type 1 or type 2 diabetes develop evidence of diabetic nephropathy. This is usually heralded by microalbuminuria (≥30 mg/day). Left untreated, persistent microalbuminuria will progress to frank proteinuria in a proportion of patients over the subsequent 10 to 15 years. These patients are at risk of progressing to end-stage renal disease.
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.
AL primary amyloid, a light-chain dyscrasia where monoclonal light chains form amyloid fibrils; can affect several organs and have differing presentations
AA amyloid, which is associated with chronic inflammation (e.g., rheumatoid arthrtis, inflammatory bowel disease) and chronic infections; usually affects the kidneys
Hereditary amyloidosis, usually caused by transthyretin (TTR) amyloidosis; a multisymptom disease that most commonly presents with a neuropathy, but can cause nephropathy, gastrointestinal impairment, cardiomyopathy, or ocular deposition.
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. Together these crucial structures are known as the glomerular filtration barrier, with the connection between adjacent podocyte foot processes called slit diaphragms.
Glomerular proteinuria develops when the components of the filtration barrier are disrupted by disease. The podocyte is the major target of pathologic processes resulting in the development of high-grade glomerular proteinuria.
In FSGS, the podocyte is the target of an unknown circulating factor. In membranous nephropathy, the podocyte is the target of an antibody response, and in genetic causes of SRNS, the genetic mutation affects the podocyte or the filtration barrier.
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. The lipid abnormalities correlate with the extent of proteinuria. These lipid abnormalities increase the patient’s risk of cardiovascular disease.
Hypercoagulability and thrombosis
Hypercoagulability and thrombosis (deep vein thrombosis, pulmonary emboli, renal vein thrombosis) is a recognized life-threatening complication of nephrotic syndrome. It occurs as a result of loss of anti-thrombin III, protein C, and protein S in the urine; increased hepatic synthesis of pro-coagulant factors; and increased platelet activation.
Edema is due to a combination of a decrease in oncotic pressure from hypoalbuminemia, as well as a primary renal sodium retention in the collecting tubules. Patients with nephrotic syndrome are at increased risk of infection due to loss of immunoglobulins, complement, and other compounds in the urine. Immunotherapy may exacerbate the infection risk.
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. In adults, nephrotic syndrome has an incidence of around 3 new cases per 100,000 each year. Incidence varies among adults depending on the incidence of underlying causes for the condition, particularly diabetes mellitus.
In most cases, family history, drug history, symptom history, examination, and investigations (of which a renal biopsy is key) lead to the diagnosis of an underlying cause for nephrotic syndrome.
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.
Nephrotic syndrome is an uncommon presentation of rare renal diseases such as Fabry disease, Alport syndrome, and nail-patella syndrome. Rarely accelerated phase hypertension can present this way.
Nephrotic syndrome may cause of severe edema (or anasarca). It can be differentiated from edema caused by congestive heart failure (CHF) or hepatic disease by the presence of severe proteinuria, which makes examination of the urine mandatory. Patients with edema from nephrotic syndrome can often 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.
- Minimal change disease
- Focal segmental glomerulosclerosis (FSGS)
- Membranous nephropathy
- Diabetic nephropathy
- Multiple myeloma-associated AL amyloidosis
- IgA nephropathy
- Membranoproliferative (mesangiocapillary) glomerulonephritis
- Lupus nephritis
- Fabry disease
- Alport syndrome
- Nail-patella syndrome
- Malignant hypertension
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