Membranous glomerulonephritis

　　One, Etiology

　　This disease is caused by multiple etiologies. Idiopathic membranous nephropathy accounts for about 50% of adult nephrotic syndrome. This section mainly introduces idiopathic membranous nephritis, which needs to be excluded in the diagnosis, associated with membranous nephropathy caused by other various reasons:

　　1, Drugs: penicillamine, gold, thiopropyl aprotinin, etc.

　　2, Connective tissue disease: such as Sjögren's syndrome, systemic lupus erythematosus.

　　3, Mixed connective tissue disease, etc.

　　4, Infection antigens and certain parasites: such as malaria, schistosomiasis, etc.

　　5, Hepatitis virus: Hepatitis B virus-induced hepatitis B-related nephritis (HBV-ASGN) and hepatitis C virus membranous nephropathy.

　　6, Malignant solid tumor: About 22% of patients with membranous nephropathy over 60 years old have malignant tumors, and in cancer-related nephritis, the most common is membranous nephropathy accounting for 60% to 70%. Common tumors include lung, breast, gastrointestinal tract, ovary, renal cell carcinoma, lymphoma, leukemia, and sarcoidosis, etc.

　　7. Other accompanying conditions may include: diabetes, sarcoidosis, thyroiditis, myasthenia gravis, sickle cell anemia, idiopathic thrombocytopenic purpura, polyarteritis nodosa, gangrenous pyoderma, and bullous pemphigoid, etc.

　　2. Pathogenesis

　　1. This disease is characterized by the long-term and slow deposition of immune complexes under the epithelial cells (also known as chronic immune complex deposition disease). Generally, it does not cause an inflammatory cell response, but through the terminal components of complement C3b to C9, which is the complement's membrane attack complex, leading to basement membrane damage. Immunofluorescence shows granular IgG and C3 deposition on the glomerular basement membrane. In animal experiments, Dixon et al. induced chronic serum sickness in rabbits by injecting low-dose heterologous protein daily, leading to membranous nephropathy due to the deposition of circulating immune complexes.

　　2. The immune complexes in the basement membrane epithelial side of this disease are mainly formed in situ. The antigen can be pre-implanted, or it can be glycoproteins on the surface of the visceral epithelial cells that form immune complexes with corresponding antibodies on the surface of the epithelial cells, which then fall off onto the basement membrane.

　　3. Cell-mediated immune dysfunction is also one of the immunological characteristics of this disease. Some data suggest that especially during the exacerbation of nephrotic syndrome, abnormalities in T lymphocyte subsets, such as CD4 and CD8 cell percentages and absolute values, with the former being higher and the latter being lower.

　　4. Primary membranous nephropathy is significantly associated with immunogenetic markers; in Europe, such as in the United Kingdom, Germany, Spain, and Finland, the detection rate of HLA-DR3 in patients with primary membranous nephropathy is significantly increased, and patients with primary membranous nephropathy in the United States show B cell antigen MT2, while patients with primary membranous nephropathy in Japan have a significantly higher detection rate of HLA-DR2. Patients with B18-BfF1-DR3 monotype positivity in the United States and the United Kingdom often have poorer prognosis than other types.

　　1. Etiology

　　The main reason for the decreased resistance to infection in infected nephrotic syndrome patients is:

　　1. Large amounts of IgG are lost in the urine.

　　2. The lack of factor B (component of the alternative complement pathway) leads to a defect in the immune调理ing effect against bacteria.

　　3. During malnutrition, the body's non-specific immune response ability is weakened, causing damage to the body's immune function.

　　4. Large amounts of transferrin and zinc are lost in the urine. Transferrin is essential for maintaining normal lymphocyte function, and the concentration of zinc ions is related to thymulin synthesis.

　　5. Local factors. Skin rupture and severe edema caused by pleural effusion, ascites, and highly edematous skin lead to dilution of local body fluid factors and weakened defense function, all of which are susceptible factors for nephrotic syndrome patients. Before the advent of antibiotics, bacterial infection was one of the main causes of death in nephrotic syndrome patients, with severe infections mainly occurring in children and the elderly, while they are less common in adults. Common clinical infections include: primary peritonitis, cellulitis, respiratory tract infections, and urinary tract infections. Once an infection diagnosis is established, immediate treatment should be provided.

　　Symptoms

　　High coagulability and venous thrombosis exist in nephrotic syndrome due to changes in blood coagulation factors. This includes the decrease of factors IX and XI, the increase of factors V, VIII, X, fibrinogen, β-thromboglobulin, and platelet levels. The adhesion and aggregation of platelets are enhanced. The activity of antithrombin III and antifibrinolytic enzymes is reduced. Therefore, the increase of procoagulant and coagulation factors, the decrease of anticoagulant and anticoagulation factors, and the damage to the fibrinolysis mechanism are the reasons for the high coagulability of nephrotic syndrome. The application of antibiotics, hormones, and diuretics is a contributing factor for the exacerbation of venous thrombosis. Hormones act through coagulation proteins, while diuretics make the blood concentrated and increase blood viscosity.

　　If massive proteinuria is the main manifestation in adults, especially in patients with nephrotic syndrome, the possibility of this disease should be considered, and the diagnosis of this disease mainly relies on renal biopsy pathology. After diagnosis, it should also be distinguished between primary and secondary.

　　1. Early membranous nephropathy should be differentiated from minimal change or focal glomerulosclerosis:Sometimes it is not distinguishable under light microscopy, and it mainly relies on electron microscopy of renal tissue.

　　2. Exclude other secondary causes of membranous nephropathy:Such as autoimmune diseases, systemic lupus erythematosus, etc.; ANA, anti-ds-DNA antibody, Sm antibody, RNP, and serum complement can be tested, combined with clinical manifestations; Membranous nephropathy related to hepatitis B: in addition to the history of hepatitis B and serum immunological markers, it mainly relies on the deposition of HBsAg immune complexes or HBV-DNA in renal tissue for diagnosis; In elderly patients over 60 years old, it manifests as refractory nephrotic syndrome, and various related imaging examinations should be performed to exclude membranous nephropathy related to malignant tumors.

　　3. Whether there are complications:If pulmonary embolism, acute lumbar pain, unexplained hematuria, increased proteinuria, acute renal function damage with unilaterality or bilaterality of renal volume increase, and other clinical symptoms appear, it should be highly suspected that renal vein thrombosis has occurred. Imaging examinations such as computed tomography (CT), ultrasound, Doppler ultrasound blood flow imaging, and renal venography should be performed. Currently, the most widely used clinical method is percutaneous femoral vein puncture selective renal venography. If vascular filling defects or venous branch non-imaging can be found, it can be diagnosed. If only a local delay in the drainage of contrast agent is observed, it should be suspected that there is a small thrombus in that area. The chronic type, especially when it occurs in the left kidney, sometimes can also be seen with collateral circulation.

　　Nephrotic syndrome progresses slowly, even to a standstill, with a natural remission rate of 30% to 50% in children, and about 15% to 20% in adults. However, 15% of patients may develop uremia after 5 to 10 years of onset, and about 50% of patients enter the terminal stage of renal failure within 15 to 20 years. The prognosis is related to various factors:

　　1、年龄：儿童较好。

　　1. Age: Children are better.

　　2. Gender: Women are better than men.

　　3. Clinical manifestations at the time of consultation: large amounts of proteinuria, especially >10g/d, those with early onset of hypertension and renal function damage often have poor prognosis.

　　5. Patients with severe complications are also poor. In renal transplantation, this disease is rarely recurrent.

　　The diagnosis of this disease mainly relies on renal biopsy pathology.

　　1. Microscopic examination

　　Through urine protein qualitative test and urine sediment microscopic examination, it can be preliminarily judged whether there is glomerular lesion.

　　2. Urinalysis

　　The urine color is generally normal, the amount of urine protein is generally not much, and the number of white blood cells in the urine sediment increases (in the acute phase, it is often full of the field of vision, in the chronic phase, 5 per high-power field), and sometimes white blood cell casts may occur.

　　3. Urine bacterial examination

　　When there is a large amount of bacteria in the urine, approximately 90% can be found in the Gram stain of the urine sediment, which is simple and has a high positive rate.

　　4. Urine cell count

　　In recent years, the one-hour counting method has been widely used, which is considered more accurate and convenient than the 12-hour urine sediment counting. The standard is that the white blood cell count greater than 300,000 per hour is positive, less than 200,000 per hour can be considered within the normal range, and between 200,000 and 300,000 per hour should be combined with clinical judgment; the red blood cell count greater than 100,000 per hour is positive.

　　In addition to conventional treatment, attention should also be paid to the following aspects in diet for membranous glomerulonephritis patients: high-nutrition, easily digestible foods. Reasonable dietary搭配 should be made. It should also be avoided to eat spicy and irritating foods.

　　Due to the long course, slow progression, and great differences in clinical course of membranous nephropathy, some cases may have the possibility of spontaneous remission, and the efficacy is difficult to estimate. Treatment includes:

　　1. Symptomatic treatment

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

　　2. Diet management (1) When there is less urine and excessive blood volume, water intake should be restricted. (2) Caloric intake: For patients with nephrotic syndrome and edema, the daily caloric intake should reach 7530-8370 kJ (1800-2000 kcal) to prevent an increase in protein decomposition. (3) Sodium restriction: One of the main reasons for edema is water and sodium retention, so a low-sodium diet is one of the basic measures. Adults should consume 2-3g of sodium per day, and children should consume less. (4) Protein: Due to many reports in recent years confirming that high-protein diet can cause glomerular hyper负荷 and hyperfiltration, leading to damage. We believe that in cases with obvious hypoalbuminemia but no damage to renal function, it is appropriate to supplement protein intake, with 1-1.5g/(kg·d) as appropriate, mainly high-quality protein containing essential amino acids. In necessary cases, appropriate intravenous albumin administration can be used to increase colloid osmotic pressure, increase plasma volume, enhance diuresis, and alleviate symptoms.

　　The application of diuretics is appropriate when there is marked edema and no hypovolemia, with reduced urine output. When sodium restriction is ineffective, diuretics such as furosemide and spironolactone should be appropriately used.

　　Secondly, hormones and other immunosuppressants

　　Due to the slow progression of the disease course, 25% of cases can spontaneously remit, and it is difficult to evaluate the efficacy of hormones and other immunosuppressants, and there is still controversy about their application. Donadio et al. conducted a retrospective analysis of 140 patients with primary membranous nephropathy, of whom 116 had nephrotic syndrome, 51 were treated with prednisone 60mg/D for continuous 2 months, and another group was treated with immunosuppressants in combination. There was no significant difference in the remission rate of urinary protein, renal function, mortality, and the incidence of end-stage renal failure between the two groups. Ponticelli et al. reported that in the treatment of primary membranous nephropathy, the treatment group of 43 patients alternated the use of hormones and busulfan for 6 months, while the control group of 40 patients was followed up for 5 years. There was a significant difference in the remission rate of proteinuria between the treatment group (70%) and the control group (28%). The serum creatinine concentration in the treatment group was also better than that in the control group. Wehrmann et al. also believed that the alternating use of hormones and busulfan in the treatment of primary membranous nephropathy was effective. Cattran et al. reviewed the literature on the use of hormones in the treatment of primary membranous nephropathy over the past 20 years, carefully analyzing the effects of hormone treatment on renal function and proteinuria, and found that the results reported by different authors were quite different. In addition, West et al. treated 20 cases of nephrotic syndrome in primary membranous nephropathy with CTX for 23 months, with a control group of 17 cases. The improvement in renal function and the significant reduction in proteinuria in the treatment group were significantly better than those in the control group. In recent years, there have been reports of the use of cyclosporine A in China and abroad, with recent efficacy, but the recurrence rate after discontinuation can be as high as 80% or more. According to our own experience, for patients with primary membranous nephropathy syndrome, a moderate dose of hormones (0.5-1.0mg/(kg·d)) is used, and the treatment is observed for 6-8 weeks. For those who are ineffective, the medication is reduced quickly to discontinuation. For those who are effective, the dosage is gradually reduced to alternate-day therapy, maintaining it for a long time. For those with renal dysfunction, a more potent regimen, such as the combination of hormones and CTX, is used. In addition, it is best to design a prospective, controlled treatment plan for long-term follow-up observation to obtain reasonable and meaningful data.

　　3. Subcutaneous Injection of Low Molecular Weight Heparin

　　Treatment for hypercoagulable syndrome and renal vein thrombosis in patients with membranous nephropathy, in addition to hypercoagulable syndrome, intrarenal coagulation plays a certain role in the occurrence and development of the disease. Most people advocate routine prophylactic treatment for patients with nephrotic syndrome. In our hospital, heparin 1-2mg/(kg·d) is commonly added to 250-500ml of 5% glucose solution for slow intravenous infusion, and the course of treatment is 2-4 weeks. After the course of treatment is completed, warfarin 2.5mg/d and dipyridamole 25-50mg, three times a day, can be taken for a long time. In recent years, low molecular weight heparin has also been used for subcutaneous injection.

　　In addition to anticoagulation therapy for the above treatments, proteinuria can be reduced and renal function can be improved. Given the potential risk of bleeding associated with anticoagulation therapy, close monitoring should be strengthened. Some people do not advocate anticoagulation therapy for all patients with membranous nephropathy and nephrotic syndrome, and anticoagulation therapy is given only after confirmation of renal vein thrombosis. In patients with renal vein thrombosis, in addition to the above treatments, thrombolytic drugs such as urokinase can be locally administered through renal artery catheterization early (within 3 days after onset). Our hospital has also achieved good results. In cases of acute renal vein thrombosis with conservative treatment failure, especially in cases of bilateral kidneys, solitary kidney, or large thrombosis of the right kidney (the right kidney thrombosis is difficult to establish collateral circulation, and thrombectomy can be considered), anticoagulation therapy should be actively given in conjunction with the treatment of nephrotic syndrome, and factors that increase hypercoagulability should be prevented and controlled, such as rational use of corticosteroids and diuretics, treatment of hyperlipidemia, etc. Pay close attention to the occurrence of embolic complications such as pulmonary embolism.