Nephrotic Syndrome: Symptoms, Types, Causes and Treatment

Nephrotic syndrome is a complex kidney disorder that can affect both children and adults, leading to a range of symptoms and serious health complications. Understanding this condition is essential for patients, families, and healthcare providers alike. In this article, we will walk through the key symptoms to watch for, the main types of nephrotic syndrome, what causes the syndrome, and current treatment strategies — all based on up-to-date scientific research.

Symptoms of Nephrotic Syndrome

Nephrotic syndrome presents with a collection of symptoms that, while common to many affected people, can sometimes be mistaken for other illnesses. Recognizing these signs early can make a significant difference in diagnosis, management, and outcomes.

Symptom	Description	Frequency/Severity	Sources
Edema	Swelling in legs, ankles, face, or abdomen	Often severe, can be sudden	2 3 4 5
Proteinuria	Excess protein in the urine	Hallmark, always present	2 3 4 5
Hypoalbuminemia	Low levels of albumin in blood	Consistent finding	2 3 4 5
Hyperlipidemia	High cholesterol and lipid levels	Common, especially in adults	2 3 4 5 13
Fatigue	Tiredness and low energy	Variable	3 7
Infections	Increased risk due to immune suppression	Especially in children	1 7
Thrombosis	Blood clots (venous, sometimes fatal)	Not rare in severe cases	3 7 13
Hematuria	Blood in urine (less common)	Occasional, especially in congenital forms	1

Table 1: Key Symptoms

Edema and Fluid Accumulation

Edema is the most noticeable and often the earliest symptom. Swelling typically starts in the lower legs and around the eyes but can progress to the abdomen (ascites) or even the whole body in severe cases. This swelling is due to the kidneys losing their ability to retain proteins, leading to fluid leaking into tissues 2 3 4 5.

Proteinuria: The Hallmark

Heavy protein loss in the urine (proteinuria) is the defining feature of nephrotic syndrome. This is often detected as frothy or foamy urine, and lab tests reveal more than 3.5 grams of protein loss per day 4.

Hypoalbuminemia and Hyperlipidemia

Low albumin levels in the blood (hypoalbuminemia) result directly from protein loss and contribute to swelling. The liver tries to compensate by producing more proteins and fats, leading to high cholesterol and triglycerides (hyperlipidemia) 2 3 4 5 13. This increases the risk of cardiovascular issues and further complicates the disease.

Additional Symptoms and Complications

• Fatigue: Often reported, likely due to anemia, fluid overload, or kidney dysfunction 3 7.
• Infections: The loss of proteins important for immune defense makes patients more prone to infections, particularly in children 1 7.
• Thrombosis: There is a substantial risk of blood clots, which can be life-threatening 3 7 13.
• Hematuria: Although not always present, some patients may have blood in their urine, particularly in congenital nephrotic syndrome 1.

Types of Nephrotic Syndrome

Nephrotic syndrome is not a single disease but a group of disorders with similar symptoms. Understanding its types helps tailor treatment and predict outcomes.

Type	Description	Age Group or Key Feature	Sources
Primary (Idiopathic)	No underlying disease; glomerular origin	All ages	3 4 5 8
Secondary	Due to systemic disease or medication	All ages	3 4 5
Congenital	Genetic; manifests in infancy	Infants	1 10 12
Minimal Change Disease (MCD)	Most common in children; responds to steroids	Children, some adults	5 6 7 9
Focal Segmental Glomerulosclerosis (FSGS)	Often steroid-resistant, risk of kidney failure	All ages	3 5 6 7 10
Membranous Nephropathy	Common in adults	Adults	3 11

Table 2: Major Types of Nephrotic Syndrome

Primary (Idiopathic) Nephrotic Syndrome

This type occurs without any underlying systemic disease. The kidney’s filtering units (glomeruli) are directly affected. Subtypes based on kidney biopsy include:

• Minimal Change Disease (MCD): Most common in children; responds well to steroids 5 6 7 9.
• Focal Segmental Glomerulosclerosis (FSGS): Seen in both children and adults; often resistant to steroids, with higher risk of progression to kidney failure 3 5 6 7 10.
• Membranous Nephropathy: Common in adults; may respond to immunosuppressive therapies 3 11.

Secondary Nephrotic Syndrome

Secondary nephrotic syndrome is caused by another underlying condition, such as:

• Diabetes mellitus
• Systemic lupus erythematosus (SLE)
• Certain medications or infections 3 4 5

Congenital Nephrotic Syndrome

This rare form presents in infancy, often within the first three months of life, and is typically due to inherited genetic mutations affecting proteins critical to the kidney’s filtration barrier 1 10 12. Finnish-type nephrotic syndrome (NPHS1 gene mutation) is a classic example.

Molecular and Genetic Stratification

Recent advances have identified subgroups based on genetics and molecular mechanisms:

• Genetic (monogenic) NS: Especially in congenital and steroid-resistant forms; linked to mutations in podocyte and glomerular basement membrane proteins 8 10 14.
• Immune-driven NS: Reflects abnormal immune responses, sometimes overlapping with genetic forms 8 14.

Causes of Nephrotic Syndrome

The underlying causes of nephrotic syndrome vary by age, type, and individual risk factors. Understanding these causes is key to accurate diagnosis and effective treatment.

Cause Type	Examples or Mechanisms	Predominant in	Sources
Genetic	NPHS1, NPHS2, WT1, PLCE1 mutations	Infants, some children	1 10 12
Immune-mediated	Circulating factors, immune dysregulation	Children, adults	6 8 14
Systemic Disease	Diabetes, lupus, infections	Adults, some children	3 4 5
Medications/Toxins	NSAIDs, infections, others	All ages	3 5
Unknown (Idiopathic)	No identifiable cause	Many cases	3 6 8

Table 3: Causes of Nephrotic Syndrome

Genetic Causes

Mutations in genes that encode crucial proteins for the glomerular filtration barrier (such as NPHS1, NPHS2, WT1, and PLCE1) can disrupt kidney function and lead to congenital or early-onset nephrotic syndrome. Genetic forms are especially prominent in infants and in children with steroid-resistant disease 1 10 12.

Immune System Dysregulation

Many cases, especially minimal change disease, are thought to result from immune system abnormalities, leading to the release of circulating factors that damage the podocytes (specialized kidney cells). This is also the case in some steroid-resistant and relapsing forms 6 8 14. Immune triggers may be environmental, infectious, or idiopathic.

Systemic Diseases

Diseases that affect the whole body, such as diabetes and SLE, can damage the kidneys and result in secondary nephrotic syndrome. Chronic infections and some cancers are less common causes 3 4 5.

Medications and Toxins

Certain medications, notably nonsteroidal anti-inflammatory drugs (NSAIDs), and exposure to toxins can precipitate nephrotic syndrome in susceptible individuals 3 5.

Unexplained (Idiopathic) Cases

Despite advances, many cases of nephrotic syndrome remain idiopathic, with no clear underlying cause identified. These cases often fall under the "primary" category and are managed based on clinical presentation and response to therapy 3 6 8.

Treatment of Nephrotic Syndrome

The approach to treating nephrotic syndrome depends on the underlying cause, disease severity, response to therapy, and the presence of complications. The primary goals are to reduce proteinuria, manage symptoms, and prevent complications.

Treatment Type	Purpose/Target	Common Agents or Measures	Sources
Supportive Care	Symptom control, complication prevention	Diuretics, sodium/fluid restriction, statins	3 4 5 13
Immunosuppression	Reduce immune-mediated damage	Corticosteroids, calcineurin inhibitors, ACTH, rituximab	3 5 6 11 14
Genetic/Targeted	Address specific mutations	Supportive; experimental targeted therapies	8 10 12 14
Anticoagulation	Prevent/treat blood clots	Heparin, warfarin (in select cases)	3 7 13
Treatment of Underlying Causes	Address systemic disease	Diabetes/lupus management, infection treatment	3 4 5
Renal Replacement	End-stage kidney disease	Dialysis, transplantation	12 14

Table 4: Treatment Approaches

Supportive Care

Supportive care is fundamental for all patients:

• Edema management: Sodium and fluid restriction, loop diuretics.
• Dyslipidemia: Statins, fibrates, and, in some cases, newer lipid-lowering agents to reduce cardiovascular risk 13.
• Blood pressure control: Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) not only lower blood pressure but also decrease proteinuria 3 4.

Immunosuppressive Therapy

• Corticosteroids: The first-line treatment for most children (especially those with minimal change disease), and often adults. Most children respond within weeks, but some require longer or alternative therapies 5 6 14.
• Calcineurin inhibitors (cyclosporin, tacrolimus): Used in steroid-resistant or frequently relapsing cases, especially in children. These drugs are effective for many, but not all, patients 6 14.
• Other immunosuppressants: Mycophenolate mofetil, rituximab, cyclophosphamide, and adrenocorticotropic hormone (ACTH) gel may be used in resistant cases or when side effects from other drugs are problematic 11 14.
• Immunosuppressive regimens are tailored to disease type, response, and patient age 3 5 6 14.

Genetic and Targeted Therapies

For children with genetic forms of nephrotic syndrome, immunosuppressive therapies are typically less effective. Supportive care, genetic counseling, and, in the future, molecularly targeted treatments may play a growing role 8 10 12 14.

Anticoagulation

Given the increased risk of thrombosis, blood thinners may be prescribed in select high-risk patients, but routine use is not recommended without other risk factors 3 7 13. Careful assessment is needed to balance risks and benefits.

Renal Replacement Therapy

In cases of end-stage kidney disease, dialysis or kidney transplantation may be necessary, particularly in congenital and steroid-resistant forms 12 14. Some genetic types have a risk of disease recurrence after transplantation, requiring special management 10 14.

Management of Complications

• Infection prevention: Prompt recognition and treatment of infections, and in some cases, prophylactic antibiotics or immunizations 7.
• Monitoring for relapse: Frequent relapses may require long-term or rotating immunosuppressive therapy 4 6 14.

Conclusion

Nephrotic syndrome is a multifaceted kidney disorder with a variety of causes, types, and treatments. Early recognition of its symptoms and understanding its underlying mechanisms are essential for effective management. Advances in research, especially in genetics and targeted therapies, are paving the way for more personalized care.

Key Takeaways:

• Nephrotic syndrome is defined by proteinuria, hypoalbuminemia, edema, and often hyperlipidemia 2 3 4 5.
• Types include primary, secondary, congenital, and subtypes like minimal change disease and FSGS 3 4 5 6 7.
• Causes are diverse: genetic mutations, immune dysregulation, systemic diseases, medications, and idiopathic forms 1 3 4 5 6 8 10.
• Treatment is multidisciplinary, involving supportive care, immunosuppression, anticoagulation, and management of underlying or genetic causes 3 4 5 6 10 11 12 13 14.
• Complications such as infections and blood clots require vigilant monitoring and prompt intervention 3 7 13.
• Future therapies aim for more targeted, individualized approaches based on molecular and genetic insights 8 10 14.

With ongoing research and patient-centered care, the outlook for individuals with nephrotic syndrome continues to improve.