Membranous Nephropathy: Symptoms, Types, Causes and Treatment

Membranous nephropathy (MN) is a complex kidney disorder that remains a leading cause of nephrotic syndrome, particularly in adults. This article provides a comprehensive overview of its symptoms, emerging types, underlying causes, and current treatment strategies, synthesizing the latest scientific advances and clinical guidelines. Whether you are a patient, caregiver, or healthcare professional, understanding the evolving science of MN can empower better care and informed decision-making.

Symptoms of Membranous Nephropathy

Membranous nephropathy often presents subtly, but recognizing its hallmark symptoms is crucial for early diagnosis and management. The most frequent clinical presentation is nephrotic syndrome—a collection of signs reflecting severe protein loss in the urine—which can lead to a cascade of other health issues. However, not all patients have the full-blown syndrome, and symptoms can vary in severity and progression.

Main Symptom	Description	Frequency/Severity	Source(s)
Proteinuria	High levels of protein in urine	80% nephrotic, 20% non-nephrotic	1 4 8
Edema	Swelling (especially in legs, ankles, eyes)	Common in nephrotic syndrome	1 4 8
Hypoalbuminemia	Low blood albumin due to protein loss	Accompanies nephrotic syndrome	1 4 8
Hyperlipidemia	High blood cholesterol/triglycerides	Often present	1 4 8
Hypertension	High blood pressure	Variable (not always present)	1 4 8
Renal Impairment	Reduced kidney function	Progressive or stable in some	1 4 8
Thrombotic Events	Blood clots (e.g., DVT, pulmonary embolism)	Increased risk in nephrotic state	5

Table 1: Key Symptoms

Understanding the Symptoms

Proteinuria and Nephrotic Syndrome

• Proteinuria (excess protein in urine) is the defining feature of MN. In about 80% of cases, this reaches nephrotic levels (>3.5g/day), causing nephrotic syndrome 1 4 8.
• Nephrotic syndrome manifests as a combination of proteinuria, low blood albumin (hypoalbuminemia), swelling (edema), and high cholesterol (hyperlipidemia) 1 4 8.

Edema and Additional Manifestations

• Edema arises as fluid leaks into tissues due to low oncotic pressure from lost albumin. It typically affects legs, ankles, and sometimes the face and abdomen.
• Hyperlipidemia is a compensatory response to protein loss but increases cardiovascular risk.
• Hypertension may occur, but is not universal.
• Renal impairment can develop over time, but some patients maintain stable kidney function for years 1 4.
• Thrombotic risk is elevated in nephrotic syndrome due to changes in blood clotting factors, so complications like deep vein thrombosis can occur 5.

Course and Prognosis

• Some patients experience spontaneous remission (up to one-third), especially with low or absent disease-specific antibodies 1 4.
• Others may progress to chronic kidney disease or end-stage renal disease (ESRD) without treatment 1 4.

Types of Membranous Nephropathy

The landscape of membranous nephropathy has evolved significantly with the discovery of new disease subtypes. MN is now classified based on underlying causes and target antigens, which has major implications for diagnosis and therapy.

Type	Key Features	Typical Population	Source(s)
Primary (Idiopathic)	Autoimmune; PLA2R, THSD7A, NELL-1, Sema3B antigens	Adults, some children	1 2 3 4 6 8
Secondary	Associated with systemic diseases, drugs, infection, malignancy	Variable	5 8
PLA2R-associated	Most common antigen; autoantibodies	Adults	1 4 6 8 9 12
THSD7A-associated	Rare antigen target	Adults	1 9 12
NELL-1-associated	Subset of primary and malignancy-linked cases	Older adults, cancer patients	2 5
Sema3B-associated	Distinct type mainly in children	Pediatrics	3
NEP-associated	Alloimmune, neonatal cases	Neonates	7

Table 2: Types of Membranous Nephropathy

Classification Explained

Primary (Idiopathic) MN

• Primary MN is an autoimmune disease where antibodies target podocyte antigens in the kidney 1 4 8.
• PLA2R (Phospholipase A2 Receptor): Most common antigen (~70–80% of primary cases). Presence of anti-PLA2R antibodies is diagnostic and correlates with disease activity 1 4 6 8 9 12.
• THSD7A (Thrombospondin Type-1 Domain-Containing 7A): Present in a minority (1–5%) 1 9 12.
• NELL-1 (Neural Epidermal Growth Factor-Like 1): Recently identified antigen, found in some primary and many malignancy-associated cases 2 5.
• Semaphorin 3B: A rare antigen especially associated with pediatric presentations, sometimes in infants 3.

Secondary MN

• Secondary MN is caused by systemic diseases (e.g., lupus), infections (hepatitis B/C), medications, or cancer 5 8.
• Malignancy-associated MN: NELL-1 antigen is more frequently found in these cases, particularly in older adults with cancer 5.

Special Cases

• NEP-associated MN: Occurs in neonates due to maternal alloimmunization against neutral endopeptidase, a rare scenario 7.
• Other rare or unidentified subtypes may exist, as new antigens continue to be discovered 1 2 3.

Clinical Relevance

Identifying the MN type guides workup, prognosis, and treatment choices. For instance, anti-PLA2R positivity suggests primary MN, while negative PLA2R/THSD7A but positive NELL-1 in an older adult with cancer points to a paraneoplastic process 5 12.

Causes of Membranous Nephropathy

The causes of membranous nephropathy are diverse, ranging from idiopathic autoimmunity to secondary triggers such as infections, drugs, and cancer. Understanding the pathogenesis is vital for targeted intervention and risk stratification.

Main Cause	Mechanism/Trigger	Typical Context	Source(s)
Autoimmunity	Antibodies against podocyte antigens (PLA2R, THSD7A, NELL-1, Sema3B)	Primary MN	1 2 3 4 6 8 9 12
Malignancy	Paraneoplastic autoimmunity, NELL-1 antigen	Secondary MN (older adults)	5
Infection	Hepatitis B/C, HIV, etc.	Secondary MN	5 8
Drugs/Toxins	Gold, penicillamine, NSAIDs, etc.	Secondary MN	5 8
Autoimmune Disease	SLE (lupus nephritis)	Secondary MN	5 8
Alloimmunization	Maternal anti-NEP antibodies	Neonatal MN	7
Unknown	Undiscovered antigens/triggers	Some cases	1 2 3

Table 3: Causes of Membranous Nephropathy

Pathogenesis in Depth

Autoimmune Mechanisms

• The vast majority of primary MN cases result from autoantibodies targeting specific antigens on podocytes, specialized cells in the kidney’s filtering units 1 4 8 9.
  • PLA2R is the main autoantigen; anti-PLA2R antibodies can be measured in blood and correlate with disease activity 1 4 6 8 9 12.
  • THSD7A, NELL-1, and Semaphorin 3B represent additional, less common antigenic targets, with NELL-1 having a special association with malignancy 2 3 5.
• These immune complexes deposit along the glomerular basement membrane, activating complement and causing damage 1 8 9.

Secondary Causes

• Cancer: Paraneoplastic processes, especially in older adults, can trigger MN via tumor-related antigens (notably NELL-1) 5.
• Infections: Chronic viral infections (hepatitis B, C; HIV) can incite immune complex deposition 5 8.
• Medications: Certain drugs (e.g., gold, penicillamine, NSAIDs) are classical triggers 5 8.
• Autoimmune diseases: Systemic lupus erythematosus (SLE) is a common secondary cause (lupus nephritis) 5 8.

Alloimmunization and Neonatal Disease

• NEP-associated MN: In rare neonatal cases, maternal antibodies attack fetal kidney antigens due to genetic absence of NEP in the mother, leading to severe but uncommon disease 7.

Genetic and Environmental Factors

• Genetic susceptibility plays a role, especially in PLA2R-associated MN, with certain HLA types increasing risk 8 9.
• Environmental exposures (e.g., pollution, chronic inflammation) may influence antigen exposure and autoimmune activation, though more research is needed 9.

Treatment of Membranous Nephropathy

Treating membranous nephropathy requires a personalized approach, balancing the natural course of the disease with the risks and benefits of immunosuppressive therapies. Advances in serology and understanding of disease mechanisms have revolutionized risk stratification and management.

Approach	Purpose/Indication	Key Points	Source(s)
Supportive Care	All patients	BP/proteinuria control, edema management	1 4 14
Observation	Mild/asymptomatic cases	Spontaneous remission possible	1 4 14
Steroids + Cyclophosphamide	Nephrotic/progressive MN	First-line for high-risk	1 4 13 14
Calcineurin Inhibitors	Alternative to cyclophosphamide	Risk of relapse after withdrawal	1 4 10 14
Rituximab (B-cell depletion)	Alternative/adjunctive therapy	Effective, good safety profile	1 10 13 14
Mycophenolate + Steroids	Second-line/adjunctive in some cases	Less effective as monotherapy	4
ACTH (adrenocorticotropic hormone)	For selected refractory cases	Promising, but limited evidence	4
Treat Underlying Disease	Secondary MN (cancer, infection, etc.)	Can induce remission	5 14

Table 4: Treatment Approaches

Modern Management Strategies

Supportive Care

• Universal for all patients from diagnosis onward:
  • Blood pressure control (ACE inhibitors/ARBs)
  • Reduction of proteinuria
  • Cholesterol-lowering agents
  • Diuretics for edema
  • Anticoagulation in high-risk thrombosis cases 1 4 14

Risk Stratification

• Observation is appropriate for those with mild proteinuria or high likelihood of spontaneous remission (especially with low anti-PLA2R levels) 1 4 14.
• Active immunosuppression is reserved for:
  • Nephrotic syndrome with persistent proteinuria (>3.5 g/day)
  • Declining kidney function
  • Severe symptoms or complications 1 4 14

Immunosuppressive Therapies

• Steroids + Cyclophosphamide: Cyclical regimens are first-line for high-risk cases, with proven efficacy in inducing remission and preserving kidney function 1 4 13 14.
• Calcineurin Inhibitors (cyclosporine/tacrolimus): Effective but higher relapse rates after discontinuation. Useful as alternatives or in specific scenarios 1 4 10 14.
• Rituximab: B-cell–depleting antibody increasingly used as first-line or adjunctive therapy. Comparable or superior efficacy to calcineurin inhibitors, often with fewer side effects 10 13 14.
• Mycophenolate mofetil: Not effective as monotherapy but may be used with steroids in some cases 4.
• ACTH: Limited data, but prolonged treatment may induce remission in refractory disease 4.

Treating Secondary Causes

• Cancer-associated MN: Management of the underlying malignancy can lead to MN remission. Immunosuppression may be avoided or used cautiously 5.
• Infection- or drug-induced MN: Treat infection or remove the offending drug as the primary intervention 5.

Monitoring and Individualized Care

• Serology-based monitoring (especially anti-PLA2R antibody levels) guides treatment timing and predicts response or relapse 12.
• Long-term follow-up is essential due to risk of relapse or progression to chronic kidney disease 1 4.

Conclusion

Membranous nephropathy is a multifaceted kidney disease, with advances in immunopathology and serology transforming its diagnosis and management. An individualized approach—based on disease type, risk profile, and emerging biomarkers—offers the best outcomes for patients.

Key Takeaways:

• Symptoms: Proteinuria and edema are the most common, often heralding nephrotic syndrome.
• Types: MN is classified by antigenic target (PLA2R, THSD7A, NELL-1, Sema3B) and by primary vs. secondary causes.
• Causes: Autoimmunity dominates, but infections, drugs, cancer, and rare neonatal cases are important secondary triggers.
• Treatment: Supportive care for all; immunosuppression for high-risk or progressive disease, with rituximab, steroids, and cyclophosphamide as mainstays; treating underlying causes is crucial in secondary MN.

Ongoing research continues to uncover new disease mechanisms and therapeutic options, offering hope for even more personalized and effective care in membranous nephropathy.