Introduction to hereditary progressive nephritis (Alport syndrome)

Introduction Hereditary nephritis, also known as Alports syndrome (AS), is a familial chronic progressive nephritis with clinical features characterized by hematuria and some cases of proteinuria or nephrotic syndrome. Often accompanied by neurological hearing impairment and progressive renal dysfunction. Nowadays, the understanding of hereditary methods, clinical manifestations and pathological features has been relatively clear, and with the rapid development of molecular biology in the past 10 years, the research on AS has entered the molecular level and the genetic level. Etiology (1) Pathogenesis The underlying cause of the disease is the mutation of different α-chain (α1-αa6) of type IV collagen, an important component of the basement membrane, and its coding gene is called COL4A1-COL4A6, which are located on different chromosomes. About 85% of patients with AS are X-Linked AS (XLAS), and the disease-causing gene is located in the middle of the long X segment of X chromosome, which is caused by mutation of the type IV collagen α5 chain (COL4A5) gene; the remaining patients It is autosomal recessive AS (ARAS) and autosomal dominant AS (ADAS), the former causative gene is COL4A3 or COL4A4 gene, and the latter has genetic multi-source. The use of immunohistochemical techniques to detect the expression of different α-chains of type IV collagen in kidney tissue and skin tissue can help to diagnose the disease clinically and determine the genetic pattern. On the other hand, people not only identified the pathogenic genes of Alport syndrome, but also detected more than 300 XLAS and several ARAS mutant genes by various methods, and began to gradually explore the relationship between patient genotype and phenotype. relationship. (B) the pathogenesis of hereditary chronic progressive nephritis is a glomerular basement membrane (BM) disease with hematuria, progressive renal damage, may be associated with extraocular manifestations such as eyes, ears. Under electron microscopy, the basement membrane is characterized by diffuse thickness and unevenness, which may have stratification, which is a characteristic pathological change. However, in terms of pathogenesis, from the single or multiple base mutations in the type IV collagen-encoding gene to the corresponding lesions on the BM, many specific links are not known due to the lack of dynamic and systematic studies. The establishment and research of relevant animal models are currently underway. Early kidney volume was normal or increased, and the kidney volume gradually decreased after the disease progressed. Normal or mild epithelial cell proliferation and mesangial matrix increase under light microscopy. Late mesangial cell hyperplasia, glomerular and tubular basement membrane thickening, stratification, thickening of the cyst wall and progression to glomerular sclerosis. Renal tubular cells are atrophied or partially dilated, and there may be focal inflammatory cell infiltration in the protein tubular stroma, or fibrosis. In 40% of cases, there was foam cell infiltration in the stroma of the cortex and medulla. The cytoplasm of such foam cells contains neutral fat, mucopolysaccharide, cholesterol and phospholipids. Electron microscopy is typically characterized by thinning and irregular thickening of the glomerular and tubular basement membrane. The glomerular thickened basement membrane is accompanied by dense layer splitting, or overlapping lamellar changes, containing electron dense particles. In recent years, it has been found that the glomerular basement membrane (GBM) has thinning, thickening and interphase lesions. The thinned GBM can reach 1/4 of the normal thickness, and the thickened GBM can reach 2 to 5 times of the normal thickness, which is a coexistence of the segmental thinning and thickening GBM. Some of the glomerular epithelial foot processes can be fused or formed with microvilli. Immunofluorescence is usually negative. Occasionally, some immunoglobulins such as IgM and complement C3 are slightly deposited in the glomerulus; it is generally considered to have non-specific adhesion to the diseased glomerulus and has no pathogenic significance. Symptoms 1. Most of the renal manifestations are persistent or intermittent hematuria, and hematuria is glomerular. It can also express proteinuria of varying degrees and nephropathy-like proteinuria, often exacerbated by acute infections. The incidence of affected boys can be as early as the first year after birth. The incidence and severity of elevated blood pressure increase with age and occur mostly in boys. Almost all of the kidneys of the affected boy will progress to end-stage renal disease, but the rate of progression varies from family to family. According to the age of end-stage renal failure, it can be divided into adolescent type (pre-31 years old) and adult type (31). After the age). 2. About 30% to 40% of patients with neurological deafness may be accompanied by high frequency area (4000 ~ 8000 Hz) neurological deafness. With the increase of age, children gradually appear in the school age, especially in men. The degree of deafness on both sides may not be completely symmetrical, but for progressive, deafness will gradually become full range. Brainstem audiometry shows that hearing impairment occurs in the cochlea. 3. About 15% of patients with ocular lesions have ocular lesions. The most characteristic ocular abnormality is the anterior conical lens, that is, the central part of the lens protrudes into the anterior chamber. Confirmation of this lesion often requires an ophthalmic slit lamp examination. Other common eye abnormalities are pigmentation changes around the macula, dense microparticles around the fovea of the macula, congenital cataracts, nystagmus, and the like. 4. The abnormal blood platelet syndrome associated with kidney disease has been reported. The blood plate smear count of this patient is mostly (30 ~ 70) × 109 / L, platelets are spherical, clinical manifestations of mild bleeding tendency However, there is very little postoperative severe bleeding. At the same time, peripheral blood smears can also be seen in granulocytes, even macrophage inclusion bodies. 5. Diffuse leiomyoma Some adolescent Alport syndrome families or patients with significant smooth muscle hypertrophy, often affected by esophagus, trachea and female reproductive tract (such as clitoris, labia majora and uterus), corresponding Symptoms such as difficulty swallowing, difficulty breathing, etc. Diagnosis 1. Dependence on clinical symptoms, signs, combined with pathological examination to diagnose (1) urine test: hematuria, most with varying amounts of proteinuria. Hematuria is mainly microscopic, or accompanied by intermittent episodes of gross hematuria. Those who appear in the form of nephrotic syndrome also need to be vigilant. (2) Positive family history: has important reference value. (3) Accompanying symptoms: such as high-frequency neurological deafness, and/or ocular cataract, conical lens, etc. have diagnostic value. (4) Renal pathology: It shows that the glomerular basement membrane is extensively irregularly thickened and cleaved, and coexists with the thinned basement membrane. The interstitial may have more foam cell infiltration. This kind of cells can also be seen in chronic glomerulonephritis, membranous glomerulonephritis of fatty kidney disease, but the characteristics of the number and distribution (more skin and medulla junction) are also helpful for diagnosis. If there are 3 of the above conditions, it can be diagnosed, but the pathological changes in the glomerular basement membrane are indispensable. 2. Molecular Biology Technology In recent years, molecular biology techniques have been used to study the Alport gene, especially the COL4A5 gene (about 240 bases in length, 51 exons), and the diagnosis reaches the gene level. In addition, the expression of α5 chain of type IV collagen in kidney tissue and skin biopsy tissue, such as lack of basement membrane on the epithelium, can also be highly regarded as X-linked dominant hereditary nephritis with a sensitivity rate of about 75%. In addition, it can detect female asymptomatic carriers of disease-causing genes. Identification 1. Benign familial hematuria patients may have a positive family history. The main clinical manifestations are asymptomatic simple hematuria, and the renal lesions are not progressive, so it is also known as benign hematuria. Pathological changes were normal under light microscopy. Electron microscopy is characterized by diffuse GBM thinning, which is 1/3 to 2/3 of the thickness of normal people, and no electron dense deposits in the glomeruli. In recent years, it has been found that familial thin basement membrane disease (TBMD) has a variant of type IV collagen α4 (COL4A4), and some patients with sexually-linked hereditary chronic progressive nephritis can have a thin basement membrane lesion at the same time. 2. The clinical manifestations of IgA nephropathy are mainly recurrent hematuria. In a few cases, only asymptomatic proteinuria, or hematuria with proteinuria or even nephritic nephropathy. Can have high blood pressure, edema, and a lot of proteinuria. Pathological changes were more common with mesangial proliferative nephritis, followed by mild lesions and focal proliferative nephritis. A small number of cases are diffuse proliferative nephritis and focal crescent formation, sometimes the glomerular basement membrane is thin. The disease is defined as immunoglobulin showing IgA or IgA-based immunoglobulin deposition in the glomerular system. Membrane area. Generally distributed in granular or block form, some cases also have IgA deposition on the capillary wall, while hereditary nephritis has no immune deposition. Renal biopsy has no pathological changes in hereditary nephritis under electron microscope. Complications occur in the later stages of the disease, hypertension, progressive decline in renal function, and development of renal failure. Neurological deafness is also progressively worse. At the same time, there are vision loss, myopia, strabismus, and cataract. In addition, esophagus, bronchus, genital leiomyoma. Treatment of Western medicine for hereditary chronic progressive nephritis is a congenital hereditary disease, and there is no specific treatment. 1. General treatment is based on symptomatic and controlled complications, actively preventing secondary urinary tract infections, preventing excessive fatigue and strenuous physical exercise. Avoid the use of nephrotoxic drugs in the event of an infection. Animal experiments have shown that strict control of protein, fat, calcium, and phosphorus intake may be helpful in delaying renal dysfunction and inhibiting the progression of glomerular lesions. 2. The end stage renal failure stage relies on dialysis therapy to maintain life and wait for kidney transplantation. Due to the lack of basement membrane antigen in patients with Alport syndrome, antibodies against GBM can be produced after kidney transplantation, so that the transplanted kidney develops anti-GBM nephritis (Goodpasture syndrome). Therefore, some authors advocate that after renal transplantation in these patients, urine routine, renal function and serum anti-GBM antibodies should be closely followed for at least 1 year. 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