bubble_chart Overview

Membranous glomerulonephritis is clinically characterized by massive proteinuria or nephrotic syndrome. Pathologically, it is an independent disease featuring uniform thickening of the glomerular capillary basement membrane, diffuse subepithelial immune complex deposits, and absence of significant cellular proliferation.

bubble_chart Etiology

This disease is caused by multiple etiological factors. Idiopathic membranous nephropathy accounts for approximately 50% of adult nephrotic syndrome cases. This section primarily focuses on idiopathic membranous nephritis, which requires exclusion of membranous nephropathy associated with various other causes during diagnosis: ① Drugs: such as penicillamine, gold, captopril, etc. ② Connective tissue diseases: like Sjögren's syndrome and systemic lupus erythematosus. ③ Mixed connective tissue diseases, etc. ④ Infectious antigens and certain Chinese Taxillus herbs or parasites: such as malaria and schistosomiasis. ⑤ Hepatitis viruses: HBV-associated glomerulonephritis (HBV-ASGN) caused by hepatitis B virus and hepatitis C virus-related membranous nephropathy. ⑥ Malignant solid tumors: Among membranous nephropathy patients over 60 years old, about 22% have malignancies, with cancer-associated nephritis most commonly presenting as membranous nephropathy (60-70%). Common tumors include lung, breast, gastrointestinal, ovarian, renal cell carcinoma, lymphoma, leukemia, and sarcoma-like tumors. ⑦ Other associated conditions may include diabetes, sarcoidosis, thyroiditis, myasthenia gravis, sickle cell anemia, idiopathic thrombocytopenic purpura, polyarteritis nodosa, pyoderma gangrenosum, and bullous pemphigoid.

bubble_chart Pathogenesis

This disease involves the long-term, slow deposition of immune complexes beneath epithelial cells (also known as chronic immune complex deposition abdominal mass disease). It generally does not provoke an inflammatory cell response but instead causes basement membrane injury through the terminal components of complement, C_3b～C₉, which constitute the membrane attack system of complement. Immunofluorescence reveals granular deposits of IgG and C₃ along the glomerular basement membrane. In animal experiments, Dixon et al. induced chronic serum sickness in rabbits by daily injections of 2 mg of heterologous protein, leading to circulating immune complex deposition and resulting in membranous nephropathy.

In this disease, the immune complexes on the epithelial side of the basement membrane primarily form in situ. The antigens may be "planted" beforehand or may arise from the interaction between glycoproteins on the surface of visceral epithelial cells and corresponding antibodies, forming immune complexes on the epithelial cell surface that subsequently detach and deposit on the basement membrane.

Cell-mediated immune dysfunction is also one of the immunological features of this disease. Data suggest that, particularly during the attack stage of nephrotic syndrome, abnormalities in T-lymphocyte subsets occur, such as altered percentages and absolute values of CD4 and CD8 cells, with the former being elevated and the latter reduced.

Primary membranous nephropathy is strongly associated with immunogenetic markers. In European countries such as the UK, Germany, Spain, and Finland, the detection rate of HLA-DR3 is significantly higher in patients with primary membranous nephropathy. In the US, these patients exhibit B-cell antigen MT₂

, while in Japan, the detection rate of HLA-DR₂ is notably elevated. In the US and UK, patients with the haplotype B₁₈-BfF₁-DR₃ often have a poorer prognosis compared to other types.

bubble_chart Pathological Changes

This disease is characterized by the long-term, slow deposition of immune complexes beneath the epithelial cells (also known as chronic immune complex deposition abdominal mass disease). It generally does not incite an inflammatory cell response but instead causes basement membrane injury through the terminal components of complement, C_3b～C₉, which constitute the membrane attack system of complement. Immunofluorescence reveals granular deposits of IgG and C₃ along the glomerular basement membrane. In animal experiments conducted by Dixon et al., chronic serum sickness was induced in rabbits by daily injections of 2 mg of heterologous protein, leading to circulating immune complex deposition and resulting in membranous nephropathy.

In this disease, the immune complexes on the epithelial side of the basement membrane are primarily formed in situ. The antigens may be pre-"planted" or may arise from the formation of immune complexes between glycoproteins on the surface of visceral epithelial cells and corresponding antibodies, which then detach and deposit on the basement membrane.

Cell-mediated immune dysfunction is also one of the immunological features of this disease. Data suggest that, particularly during the stage of attack in nephrotic syndrome, abnormalities in T lymphocyte subsets occur, such as deviations in the percentages and absolute counts of CD4 and CD8 cells, with the former being elevated and the latter reduced.

Primary membranous nephropathy shows a significant correlation with immunogenetic markers. In Europe—including countries such as the UK, Germany, Spain, and Finland—the detection rate of HLA-DR3 is significantly higher in patients with primary membranous nephropathy. In the US, primary membranous nephropathy patients exhibit B-cell antigen MT₂

, while in Japan, the detection rate of HLA-DR₂ is notably elevated. In the US and UK, patients with this disease who carry the haplotype B₁₈-BfF₁-DR₃ often have a poorer prognosis compared to other types.

bubble_chart Clinical Manifestations

Primary membranous nephropathy can occur at any age but is more common in adults, with an average age of around 35 and a male-to-female ratio of approximately 1.5–2:1. The onset is insidious, with a few cases triggered by preceding infections. About 15–20% of patients present with asymptomatic proteinuria as the initial symptom, while 80% manifest as nephrotic syndrome with non-selective proteinuria. Microscopic hematuria is observed in about 60% of adults, while gross hematuria may occur in children, though red blood cell casts are rare. Blood pressure is usually normal in the early stages, but hypertension develops in about 50% of patients as the disease progresses, often resolving with remission of the nephropathy. Renal function is typically normal in the early stages. Edema of varying degrees is present in 80% of cases, with severe cases potentially developing pleural effusion, ascites, or other body cavity effusions due to multifactorial mechanisms. Primary membranous nephropathy has two serious complications: 1. **Hypercoagulability and renal vein thrombosis**: Due to increased levels of clotting factors, enhanced platelet adhesion and aggregation, and elevated antithrombin III and antifibrinolytic activity in nephrotic syndrome, hypercoagulability occurs. Steroid use may exacerbate this condition. The incidence of renal vein thrombosis is about 50%, with the chronic type being more common, often asymptomatic but worsening nephrotic syndrome. The acute type may present with sudden, severe lumbago, accompanied by flank tenderness, hematuria (often gross hematuria), leukocyturia, a sudden increase in proteinuria, hypertension, and acute kidney injury. Bilateral renal vein thrombosis may lead to oliguria or acute kidney failure, with possible enlargement of the affected kidney. Chronic cases may exhibit tubular dysfunction, such as renal glycosuria, aminoaciduria, or renal tubular acidosis. Additionally, pulmonary embolism or extrarenal thrombosis (e.g., in the brain, heart, or lower limbs) may occur. Definitive diagnosis requires renal vein or renal arteriography, while renal scintigraphy and CT are also helpful. 2. **Anti-glomerular basement membrane (anti-GBM) crescentic glomerulonephritis**: Damage to the basement membrane may expose or release membrane antigens, leading to anti-GBM antibody formation. Anti-GBM antibodies or antineutrophil cytoplasmic antibodies (ANCA) may be detected in the serum. Therefore, if a previously stable patient experiences rapid renal function decline and rapidly progressive glomerulonephritis-like symptoms, this complication should be highly suspected.

bubble_chart Diagnosis

In adults presenting with significant proteinuria, especially nephrotic syndrome, the possibility of this disease should be considered, and its definitive diagnosis relies mainly on renal biopsy pathology. After diagnosis, it is essential to distinguish between primary and secondary causes. 1. Early membranous nephropathy should be differentiated from minimal change disease or focal segmental glomerulosclerosis: Sometimes, they cannot be distinguished under light microscopy and require electron microscopic examination of renal tissue. 2. Exclude other secondary causes of membranous nephropathy: - Autoimmune diseases such as systemic lupus erythematosus: Tests may include ANA, anti-dsDNA antibodies, Sm antibodies, RNP, and blood complement levels, combined with clinical manifestations. - Hepatitis B-associated membranous nephropathy: In addition to a history of hepatitis B and serum immunological markers, diagnosis relies on the detection of HBsAg immune complex deposits or HBV-DNA in renal tissue. - In elderly patients over 60 years old presenting with refractory nephrotic syndrome, relevant imaging studies should be performed to exclude malignancy-associated membranous nephropathy. 3. Assess for complications: - Clinical manifestations such as pulmonary embolism, acute abdominal pain, unexplained hematuria, increased proteinuria, or acute renal impairment with unilateral or bilateral kidney enlargement should raise suspicion of renal vein thrombosis. - Imaging studies, including computed tomography (CT), B-ultrasound, Doppler ultrasound flow imaging, or renal venography, should be performed. Currently, percutaneous femoral vein puncture selective renal venography is the most widely used clinical method. The presence of filling defects or non-visualization of venous branches confirms the diagnosis. Even localized delayed contrast drainage suggests small thrombus formation. - In chronic cases, particularly involving the left kidney, collateral circulation may sometimes be observed.

bubble_chart Treatment Measures

Due to the prolonged and slow progression of membranous nephropathy, with significant variability in clinical course and the possibility of spontaneous remission in some cases, treatment efficacy is difficult to estimate. Treatment includes:

(1) Symptomatic Treatment

1. Rest: During nephrotic syndrome with edema, rest is recommended to improve renal blood flow.

2. Dietary Management: ① For oliguria with excessive blood volume, water intake should be restricted. ② Caloric intake: For nephrotic syndrome with edema, daily caloric intake should reach 7530–8370 kJ (1800–2000 kcal) to prevent increased protein catabolism. ③ Sodium restriction: Since one of the main causes of edema is water and sodium retention, a low-salt diet is essential. Adults should limit sodium intake to 2–3 g/day, with children consuming proportionally less. ④ Protein: Recent studies have confirmed that high-protein diets can lead to glomerular hyperfiltration and damage. For patients with significant hypoalbuminemia but preserved renal function, protein intake should be moderately supplemented at 1–1.5 g/(kg·d), focusing on high-quality proteins containing essential amino acids. Intravenous albumin may be administered if necessary to increase colloid osmotic pressure, enhance circulating plasma volume, and promote diuresis to alleviate symptoms.

3. Use of Diuretics: In cases of significant edema without hypovolemia and reduced urine output, diuretics such as furosemide or spironolactone may be used if sodium restriction is ineffective.

(2) Hormones and Other Immunosuppressants Due to the slow progression of the disease and spontaneous remission in 25% of cases, the efficacy of corticosteroids and other immunosuppressants is difficult to evaluate, and their use remains controversial. Donadio et al. retrospectively analyzed 140 patients with primary membranous nephropathy, including 116 with nephrotic syndrome. Among them, 51 received prednisone 60 mg/day for 2 months, while another group received combined immunosuppressant therapy. No significant differences were observed between the two groups in terms of proteinuria remission rate, renal function, mortality, or progression to end-stage renal failure. Ponticelli et al. reported on 43 patients with primary membranous nephropathy treated with alternating corticosteroids and chlorambucil for 6 months, compared to 40 controls. After 5 years of follow-up, the proteinuria remission rate was 70% in the treatment group versus 28% in the control group, with significantly better serum creatinine levels in the treatment group. Wehrmann et al. also found alternating corticosteroid and chlorambucil therapy effective for primary membranous nephropathy. Cattran et al. reviewed literature spanning over 20 years on corticosteroid treatment for primary membranous nephropathy, analyzing its effects on renal function and proteinuria. They noted significant variability in reported outcomes. Additionally, West et al. treated 20 patients with primary membranous nephropathy and nephrotic syndrome with cyclophosphamide (CTX) for 23 months, compared to 17 controls. The treatment group showed significantly better renal function improvement and proteinuria reduction. In recent years, cyclosporine A has been reported to have short-term efficacy, but relapse rates exceed 80% after discontinuation. Based on our hospital’s experience, for primary membranous nephropathy with nephrotic syndrome, moderate-dose corticosteroids (0.5–1.0 mg/(kg·d)) are administered for 6–8 weeks. If ineffective, the dose is tapered and discontinued quickly. For responders, gradual tapering to alternate-day therapy with long-term maintenance is recommended. For patients with renal impairment, more aggressive regimens, such as corticosteroids combined with CTX, are used. Furthermore, prospective, controlled treatment protocols with long-term follow-up are preferable to obtain meaningful and rational data.

(3) Treatment of Hypercoagulability and Renal Vein Thrombosis In patients with membranous nephropathy, in addition to hypercoagulability, intrarenal coagulation plays a role in the onset and progression of the disease. Most experts advocate routine prophylactic treatment for nephrotic syndrome in such cases. In our hospital, for these patients, heparin 1–2 mg/(kg·d) is typically administered by slow intravenous drip in 250–500 ml of 5% glucose solution, with a treatment course lasting 2–4 weeks. After the course, oral warfarin 2.5 mg/d and dipyridamole 25–50 mg three times daily may be taken for an extended period. Recently, low-molecular-weight heparin has also been used for subcutaneous injection.

In addition to anticoagulation, the aforementioned treatments can also reduce proteinuria and improve renal function. Given the potential risk of bleeding associated with anticoagulation therapy, close monitoring is essential. Some experts do not advocate anticoagulation for all patients with membranous nephropathy and nephrotic syndrome, reserving it only for those with confirmed renal vein thrombosis. For patients with renal vein thrombosis, in addition to the treatments mentioned above, local administration of fibrinolytic agents such as urokinase via renal stirred pulse catheterization can be performed early (within 3 days of onset). Our hospital has achieved favorable results with this approach. In cases of acute massive renal vein thrombosis where conservative treatment fails, especially in bilateral kidneys, solitary kidneys, or large right renal thrombi (where collateral circulation is less likely to develop), surgical thrombectomy may be considered. Following renal vein thrombosis, while continuing anticoagulation therapy, active treatment of nephrotic syndrome is crucial to address factors exacerbating hypercoagulability, such as judicious use of hormones and diuretics, and management of hyperlipidemia. Close attention should be paid to potential embolic complications, such as pulmonary embolism.

bubble_chart Prognosis

Membranous nephropathy progresses slowly and may even remain static. The natural remission rate is 30–50% in children and about 15–20% in adults. However, 15% of patients develop uremia within 5–10 years after onset, and approximately 50% progress to end-stage renal failure within 15–20 years. The prognosis is associated with several factors: ① Age: Children have a better prognosis. ② Gender: Females fare better than males. ③ Clinical manifestations at the time of diagnosis: Massive proteinuria, especially >10g/d, early-onset hypertension, and renal impairment often indicate a poor prognosis. ④ Pathological staging on renal biopsy: Stage I often shows remission or even recovery, Stage II is also relatively favorable, while Stages III–IV and/or significant tubulointerstitial or vascular lesions indicate a poor prognosis. ⑤ Severe complications also worsen the prognosis. In renal transplantation, recurrence of this disease is rare.