Membranous nephropathy

Introduction to membranous nephropathy Membranous nephropathy (MN), also known as membranous glomerulonephritis (membranous glomerulonephritis), pathological features of glomerular basement membrane epithelial cells diffuse immune complex deposition with diffuse thickening of the basement membrane, clinical nephrotic syndrome ( NS) or asymptomatic proteinuria is the main manifestation. basic knowledge The proportion of patients: more common in people over 40 years old, the incidence rate is about 0.004% - 0.009% Susceptible population: peaks are 30 to 40 years old and 50 to 60 years old Mode of infection: non-infectious Complications: renal vein thrombosis, interstitial nephritis, renal failure

Cause of membranous nephropathy

Primary and secondary factors (30%):

1. Immune disease systemic lupus erythematosus, rheumatoid arthritis, diabetes, Hashimoto's thyroiditis, Graves' disease, mixed connective tissue disease, Sjogren's syndrome, primary biliary cirrhosis, ankylosing spondylitis And acute infectious polyneuritis.

2. Infection: Hepatitis B, hepatitis C, syphilis, leprosy, filariasis, schistosomiasis and malaria.

3. Drugs and poisons organic gold, mercury, D-penicillamine, captopril and probenecid.

4. Tumor lung cancer, colon cancer, breast cancer and lymphoma.

5. Other sarcoidosis, transplanted kidney recurrence, sickle cell disease and vascular lymphoid hyperplasia (Kimura disease), but 75% of membranous nephropathy can not find the above reasons, that is, primary membranous nephropathy.

Potential pathogenic antigen (25%):

Although some scholars have reported a series of antigens including DNA, thyroglobulin, tumor-associated antigen, renal tubular epithelial antigen, hepatitis B virus, etc. in the glomerular subepithelial deposition complex of patients with membranous nephropathy, only the above proteins The sediment does not necessarily cause disease, and the antibody to the pathogenic antigen that causes the deposition of the subcutaneous immune complex of the glomerular basement membrane of the disease is not yet clear.

Subepithelial immune complex (25%):

(1) Circulating immune complex deposition: Dioxon and Germuth use small doses of heterologous protein (2.5mg/d) daily injection to cause chronic serum disease in rabbits. The renal lesions are similar to membranous nephropathy, and the immune complex is deposited under the epithelium. In the circulation, only small immune complexes are found. On the contrary, if rabbits receive different doses and methods of heterologous proteins, larger immune complexes will appear, and the deposition site is mesangial rather than subcutaneous, Germuth. It is emphasized that the immune complex in the membranous nephropathy cycle should have the characteristics of small molecular weight and a large amount of negative charge. However, these two points are not easily available in the body at the same time, and there is still doubt about the reliability of the circulating immune complex theory.

(2) In situ formation of immune complexes caused by non-renal antigens: This theory indicates that lesions can be caused by the reaction of circulating antibodies with a glomerular innate antigen, which is due to certain basement membranes. Biochemical properties and electrostatic affinity are previously "implanted" into the glomerulus to form an in situ immune complex, thereby damaging the glomerulus.

(3) In situ formation of immune complexes caused by renal antigen: This is an in situ immune complex formed by the local intrinsic antigen component of the glomerulus and circulating antibodies, which is a well-recognized doctrine since the 1980s. .

Complement mediated (5%):

In 1980, Salant and Couser proposed for the first time in the passive Heymann nephritis model that complement activation is a necessary condition for pathogenesis. Studies have confirmed that inflammatory cell infiltration is not found in the glomeruli of membranous nephropathy, and there is no classical complement activation pathway. A cleavage product such as C5a was produced, but a membrane attack complex (C5b-9 mem-brane attack complex, MAC) containing the complement component Csb-9 was found.

This membrane attack complex (MAC) can be inserted into the phospholipid bilayer structure of the glomerular epithelial cell membrane, causing damage to the cell membrane structure, affecting the synthesis of the glomerular basement membrane, repairing, changing capillary permeability, and confirming membrane attack by immunoelectron microscopy. The complex can be transferred from the basement membrane side to the renal capsule side by the epithelial cells, and discharged to the urine by exocytosis, so that the excretion of the urine membrane attack complex increases in the early stage of the membranous nephropathy or during the immune activity. MAC can also activate glomerular epithelial cells to release local inflammatory mediators and oxygen free radicals directly acting on the basement membrane. A large number of oxygen free radicals release lipids, causing glomerular epithelial cells and basement membrane IV collagen. It degrades and increases the permeability of the low-protein membrane to cause proteinuria. After adding probucol, the proteinuria is reduced by 85%.

The study found that glomerular epithelial cells are versatile, such as glomerular epithelial cell membrane contraction, can resist 4.76kPa (35mmHg) transmembrane hydrostatic pressure, epithelial cells are an important part of the glomerular filtration barrier; epithelial cells Reacts with the cell adhesion molecule integrin 31; releases a variety of cytokines and inflammatory mediators, including: 1 bioactive esters: such as arachidonic acid epoxidase product PGE2, TXA2, etc. and lipoxygenase product 12-hydroxy Decaenoic acid (12-HETE), 2 matrix metalloproteinase (MMP)-9 and a matrix metalloproteinase tissue inhibitor (TIMP), 3 fibrinolysis factor: tissue and urokinase-type plasminogen activator Agents and inhibitors, 4 growth factors and differentiation factors: transforming growth factor (TGF), platelet growth factor (PDGF), epidermal growth factor (EGF), 5 cytokines related to inflammation, immune recognition, chemotaxis: such as interleukins class.

In addition, there are receptors for complement and various growth factors on the surface of epithelial cells. There are antigens related to membrane nephropathy on the surface of SD rats in experimental animals; glomerular epithelial cells play an important role in the synthesis and repair of basement membrane; The podocyte cells can synthesize matrix components such as IV collagen and fibronectin. Animal models and clinical studies suggest that matrix synthesis of laminin, heparin sulfate proteoglycan, and IV collagen is increased in membranous nephropathy. These are mediated by TGF-2. Changes in the composition of the extracellular matrix are one of the causes of thickening of the basement membrane.

Membranous nephropathy prevention

1. Pay attention to rest, avoid fatigue, prevent infection, diet with low protein, pay attention to vitamin supplements, and avoid using drugs that damage the kidneys.

2. During the drug treatment, every 1 to 2 weeks outpatient visit, observe urine routine, liver and kidney function, children should pay attention to growth and development to guide the completion of the treatment.

3. After the control of active lesions and after the completion of the course of treatment, renal biopsy should be repeated to observe the pathological changes of renal tissue to determine whether there is a chronic tendency, so as to take timely measures.

4. Pay attention to the protection of residual renal function, correct various factors that reduce renal blood flow (such as hypoproteinemia, dehydration, hypotension, etc.) and prevent infection, which are important links in prevention, affecting the efficacy of patients and Complications of long-term prognosis should be actively treated:

(1) Infection: Hormone therapy is prone to infection. Once it is found, it should be promptly treated with antibiotics that are sensitive to pathogenic bacteria, strong and non-neotoxic, and those with clear infection should be removed as soon as possible.

(2) thrombosis and embolism complications: It is generally believed that when the plasma albumin concentration is lower than 20g/L, it indicates that there is a hypercoagulable state, that is, preventive anticoagulant therapy should be started. Anticoagulants should generally be used for more than half a year. Both coagulation and thrombolytic therapy should avoid excessive bleeding leading to bleeding.

(3) Acute renal failure: nephrotic syndrome complicated with acute renal failure can be life-threatening if not treated properly. Most patients are expected to recover if given timely treatment.

Membranous nephropathy Complications renal vein thrombosis interstitial nephritis renal failure

1. Renal venous thrombosis: Clinical observation and continuous renal biopsy data prove that the disease is a chronic progressive disease, such as a sudden increase in urinary protein during the course of the disease, or a sudden deterioration of renal function, suggesting that renal vein thrombosis may be combined Formation, concurrency rate of up to 50%, predisposing factors include serum albumin too low (<2.0 ~ 2.5g / dl), strong excessive diuretic, long-term bed rest.

2. Acute interstitial nephritis: renal tubular necrosis or crescentic nephritis is a common complication of MN.

3. Renal failure: advanced renal function deterioration, decreased urine output, elevated urine creatinine, elevated urea nitrogen, prone to renal failure.

4. Infection: Due to the large loss of immunoglobulin from the urine, the body's resistance is reduced, and various infections are often combined in the course of the disease.

Membranous nephropathy symptoms common symptoms edema lower extremity edema nephrotic syndrome hematuria proteinuria protein diuretic rheumatoid arthritis

The disease can be seen at any age, but most patients are over 30 years old at the time of diagnosis. The average age of onset is 40 years old. The peak age of onset is 30-40 years old and 50-60 years old. Most membranous nephropathy is slowly onset. There is no history of pre-existing upper respiratory tract infection. A small number of patients have asymptomatic proteinuria. Most patients (70%-80%) have a large amount of proteinuria, which is characterized by nephrotic syndrome. The MN incubation period is usually several weeks to several months. The glomerular subepithelial sediment gradually formed, but the increase of urinary protein excretion has not reached enough to form clinical symptoms, causing the patient's attention. 80% of patients with edema as the first symptom, 20% due to proteinuria, idiopathic membrane Urinary protein excretion of nephropathy is usually 5-10g per day, or up to 20g/d, mostly non-selective proteinuria. The amount of urine protein is different due to daily protein intake, body position, activity, and renal hemodynamics. The fluctuation is very large, generally no gross hematuria, 50% of adults and most children have microscopic hematuria. Unlike many acute post-infectious nephritis, there is no hypertension in the early stage of the disease, but 30% to 50% of patients develop with the disease. Increased blood pressure, early renal function is more normal, from weeks to months due to glomerular filtration decline, interstitial lesions and other factors can gradually appear renal insufficiency and uremia, the disease is easy to be associated with renal vein thrombosis, China The incidence rate can reach 40%, and the predisposing factors include too low serum albumin (<2.0-2.5g/dl), strong excessive diuresis, and prolonged bed rest.

Laboratory tests for primary membranous nephropathy include proteinuria, hypoalbuminemia, hyperlipidemia, and lipourea, usually with normal levels of serum C3, C4, and other complement components and no circulating immune complexes. In the period, the C5b-9 in the urine is obviously elevated. To exclude the secondary cause, it is necessary to carry out immunological tests such as hepatitis B virus, hepatitis C virus, syphilis, lupus nephritis and other connective tissue diseases and tumor indicators.

MN patients with insidious onset, often manifested as a typical nephrotic syndrome, may be associated with hypertension or microscopic hematuria, gross hematuria is rare; low proteinuria selectivity, increased urine C3, C5b-9, blood C3 is generally normal; It remains unchanged for many years, and some of it can be naturally relieved. According to the above clinical features, MN can be diagnosed, but the final diagnosis still requires renal biopsy.

The disease needs to be differentiated from other pathological types of nephrotic syndrome and secondary MN such as SLE. In MN, nearly 2/3 is primary, and the remaining 1/3 are secondary, and many antigens can cause MN to occur. In lupus nephritis, membrane proliferative nephritis and IgA nephropathy, in addition to the deposition of immune complexes, there is a large amount of cell proliferation; while primary MN can hardly see cell proliferation, and it is not easy to relapse after kidney transplantation. Children MN should be highly suspicious of and exclude secondary glomerular diseases, especially hepatitis B-associated nephritis and lupus nephritis. Older MN should be alert to the presence of tumors; it is reported that 40% of elderly MN patients are caused by malignant tumors, but in malignant About 10% of adult tumor patients have primary nephrotic syndrome; 15% of solid tumors are associated with MN, and 1.5% of MN patients have malignant tumors.

Examination of membranous nephropathy

Almost all cases have proteinuria, more than 80% of cases urinary protein 3.5g / 24h, severe 20g / 24h, usually non-selective proteinuria, but 20% of cases can be selective proteinuria, urine Increased C5b-9, C3, suggesting that MN is in active phase. In severe proteinuria, C5b-9 in urine can also increase. Usually there is microscopic hematuria, but gross hematuria is rare. Patients with severe renal disease can see markedly low protein. Blood, other such as IgG can also be reduced; elevated blood lipids, showing low density and very low density lipoprotein increased, but with the reduction of urine protein, hyperlipidemia can return to normal.

Primary MN, regardless of whether or not complement is found in glomerular immune deposits, serum complement levels are normal. If MN patients are found to have low serum complement levels, the primary disease may be a systemic disease (such as SLE).

Cold blood globulinemia can occur in MN caused by SLE, B, hepatitis C, etc. In patients with MN activity, C5b-9 can be elevated in patients' urine; patients with deep vein thrombosis can develop high cellulose protein blood. Symptoms, blood anticoagulant factors decline, some patients may have red blood cells.

For example, elderly patients with intestinal abnormalities, weight loss, and hemoptysis should be checked for potential tumors.

Pathological anatomy

From a general anatomy, the kidneys are yellow and the volume is enlarged. Because all glomerular lesions in MN are almost uniform, the characteristics of kidney hypertrophy in other chronic kidney diseases are not seen in MN, which seems to explain the kidneys. The reason why the cortical surface is relatively smooth is even in cases where the disease progresses. In patients with renal failure, there may be scar formation under the capsule.

2. Light microscopy

Light microscopy showed thickening of the diffuse glomerular capillary wall caused by immunoprecipitation. Because the basement membrane protrusions were surrounded by stained immunostains, silver staining was spiked, and early glomerular lesions were diffusely visible, glomeruli. Capillary spasm stiffness, capillary wall thickening, no obvious cell proliferation, PAM staining, typical cases can be seen on the capillary vasospasm and epithelial deposition of immune complexes, advanced lesions aggravated, capillary wall thickening, The lumen is narrowed, occluded, the mesangial matrix is broadened, and further development may result in glomerular sclerosis and hyaline degeneration, foamy changes in the proximal convoluted tubule epithelial cells (characteristic changes in nephrotic syndrome); arteries with hypertension Small arteriosclerosis is obvious, and infiltration of inflammatory cells can be seen in the interstitial. Mononuclear macrophages and lymphocytes are the main cell types in the interstitium, and the auxiliary/inducing T lymphocytes predominate.

3. Electron microscopy

The entire glomerular capillary sputum shows characteristic epithelial electron dense deposits, which may be the only change in early lesions. It can also be found that large immune complexes are deposited on epithelial cells with electron dense deposits and are nailed. Separated by the protrusions, the foot processes of the foot processes are normalized, and the GBM is normal at the beginning, and then the depression is formed due to the deposition of the dense matter. Finally, the GBM completely encapsulates the dense substance, and the other feature is that the electron dense substance disappears, and the translucent area appears in the corresponding area. According to electron microscopy, some residual basement membrane areas appear to be repaired on the outer side. Primary MN often has interstitial fibrosis and tubule atrophy.

4. Immunofluorescence

It can be seen that the subepithelial immunoglobulin and complement components are characterized by uniform fine fine particles deposited on the capillary wall, and the appearance of capillary vasospasm is revealed. Among them, IgG is the most common, and more than 95% of cases have C3 deposition, and there may be IgA, IgM or even IgE deposition, the amount of deposition varies with the course of the disease; initially less, then gradually increase, and finally reduced, HBsAg and CEA can be found in some cases, MN kidney disease can be divided into 4 according to pathology:

Stage I: also known as early epithelial cell deposition, no obvious pathological changes under light microscope. In some cases, the basement membrane can be slightly thickened. Under electron microscope, a small amount of immune complex deposition can be seen under the epithelium. In the deposition area, the foot process can be seen. Fusion, it is worth mentioning that in the early stage I, the electron microscopy is normal, and the immunofluorescence is positive, suggesting that immunofluorescence is more sensitive for early diagnosis.

Stage II: Also known as the period of nail formation, capillary microscopic thickening can be seen under light microscopy, GBM reactive hyperplasia, comb-like changes - nail formation, immunofluorescence examination showed a large number of immune complex deposition under the epithelium.

Stage III: Also known as the basement membrane deposition stage, the glomerulus begins to harden under light microscopy, the capillary lumen is blocked, and the nail process gradually joins into a piece, enveloping the sediment, forming a double track, and the sediment boundary is unclear under electron microscope.

Stage IV: Also known as the hardening period, GBM is severely irregularly thickened, capillaries are twisted, glomeruli are collapsed and fibrosis occurs, and nails disappear; renal interstitial cells are infiltrated and fibrotic with tubular atrophy, electron microscopy The lower sediment is difficult to identify in the basement membrane, and immunofluorescence is often negative at this time.

Diagnosis and differentiation of membranous nephropathy

diagnosis

According to statistics, in addition to the primary MN, 10% to 20% of MN is lupus kidney, 1% to 3% is caused by gold preparation, 7% is rheumatoid arthritis patients using penicillamine, and there is close to hepatitis B. Related MN, secondary MN generally has the clinical features of its primary disease, in addition to clinical features, primary and secondary MN is difficult to distinguish only by renal biopsy, it should be combined with clinical features, experimental examination, pathological examination and test Sexual treatment and other assistance to diagnose.

The diagnosis of primary membranous nephropathy is based on the exclusion of secondary factors, followed by several common secondary membranous nephropathy:

Differential diagnosis

1. Membrane-type lupus nephritis: its pathological changes and idiopathic membranous nephropathy are very similar; histological changes have implications for lupus nephritis: electron dense deposits on the basement membrane of the tubule (100%) , deposition of subendothelial electron dense matter (77%), deposition of electron dense substance in mesangial area (63%) and tubular corpuscular inclusion body (61%), type IV lupus nephritis, diffuse proliferative nephritis, after intensive treatment It is mainly changed to membrane damage, but this type of anti-DNA, anti-nuclear antibody titer is higher than the membrane type lupus nephritis, unless the blood creatinine is elevated at the time of onset, pathological tissue has inflammatory cell infiltration, membrane type lupus nephritis and special The same prognosis is good for membranous nephropathy, the 10-year survival rate is above 85%, and the incidence of renal vein thrombosis is also high. It differs from idiopathic membranous nephropathy in addition to routine serological examination. Pathologically, mesangial cells and endothelial cells proliferated, and there were also immune complex deposition under the renal endothelium in the mesangial area. IgG, IgM, IgA, and C3 were all positive, which was helpful for identification.

2. Membrane nephropathy caused by tumor: a variety of tumors, especially lung cancer, gastrointestinal and breast malignant lesions can cause membranous nephropathy, evidence of renal immunological damage caused by tumor: 1 tumor-specific antigen in glomerular immune complex ; 2 soluble immune complexes were detected in the serum of patients with tumor associated with membranous nephropathy, containing tumor-specific antibodies.

The immune pathogenesis may be: the tumor-associated antigen stimulates the host to produce anti-tumor antibodies, and the antigen and the antibody form a soluble immune complex deposited on the glomerulus; the tumor patient has a defect in immune surveillance function, and stimulates the body to produce an immune complex when exposed to an antigen. This causes kidney damage.

It has been reported that nephrotic syndrome often occurs 12 to 18 months before the diagnosis of the tumor, and it is particularly necessary to be alert to the tumor in the elderly with nephrotic syndrome.

3. Hepatitis virus infection and glomerulonephritis: The most common pathological type of hepatitis B virus-associated nephritis is membranous nephropathy, which is more common in male children. In the population of hepatitis B virus carrying rate of 0.1% to 1.0% in European and American countries, membranous nephropathy The detection rate of HBsAg in the serum of children is 20% to 64%, and in the population of hepatitis B virus in the population of 2% to 20% in Asia can be as high as 80% to 100%.

Hepatitis C virus infection is complicated by mesangial capillary glomerulonephritis (MCGN), but in recent years, membranous nephropathy has also been reported. Hepatitis C virus complicated with membranous nephropathy has no cryoglobulinemia, normal complement level, rheumatoid Factor negative, these indicators are different from hepatitis C with mesangial capillary nephritis.

4. Renal transplant recurrence after renal transplantation: The recurrence rate of the disease after renal transplantation is about 10%, usually proteinuria occurs from 1 week to 25 months after surgery, and the recipient often has severe nephrotic syndrome, and in 6 months. Loss of kidney transplant in ~10 years, increased dose of steroids is ineffective.

5. Drug-induced membranous nephropathy: organic gold, mercury, D-penicillamine, captopril (captopril), non-steroidal anti-inflammatory drugs have reported membranous nephropathy, should pay attention to medication history Timely withdrawal may ease the condition.

Early membranous nephropathy is often missed and misdiagnosed, so conventional electron microscopy and immunofluorescence can help diagnose.

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