Hereditary nephritis

　　1. Etiology

　　The fundamental cause of the disease is the mutation of different alpha chains (α1-α6) of type IV collagen, an important component of the basement membrane, whose encoding genes are called COL4A1-COL4A6, located on different chromosomes. About 85% of AS patients have X-linked dominant inheritance (X-Linked AS, XLAS), with the pathogenic gene located in the middle segment of the long arm of the X chromosome, Xq22, caused by the mutation of the gene encoding the alpha 5 chain of type IV collagen (COL4A5); the remaining patients have autosomal recessive inheritance (autosomal recessive AS, ARAS) and autosomal dominant inheritance AS (autosomal dominant AS, ADAS), the former with COL4A3 or COL4A4 gene as the pathogenic gene, while the latter has genetic polygenicity. The use of immunohistochemical technology to detect the expression of different alpha chains of type IV collagen in renal tissue and skin tissue can help in the clinical diagnosis of the disease and determine the genetic pattern. On the other hand, people have not only identified the pathogenic genes of Alport syndrome but have also detected more than 300 mutations of XLAS and several mutations of ARAS through various methods, and have begun to gradually explore the relationship between the genotype and phenotype of patients.

　　2. Pathogenesis

　　Hereditary chronic progressive nephritis is a glomerular basement membrane (basement membrane, BM) disease characterized by hematuria and progressive renal damage. It may be accompanied by extrarenal manifestations such as eye and ear. Under the electron microscope, the basement membrane shows diffuse thickness and unevenness, and may have stratification phenomena, which is a characteristic pathological change. However, in terms of pathogenesis, from single or multiple base mutations in the IV collagen encoding gene to the corresponding lesions on the BM, due to the lack of dynamic and systematic research, many specific links are still unclear. Currently, the establishment and research of related animal models are underway. In the early stage, the renal volume is normal or increased, and as the disease progresses, the renal volume gradually decreases. Under light microscopy, the glomeruli show normal or mild epithelial cell proliferation and mesangial matrix increase. In the late stage, mesangial cell proliferation, thickening and stratification of glomerular and tubular basement membranes, thickening of the capsule wall, and progression to glomerulosclerosis occur. Renal tubular cells may atrophy or be partially expanded, with protein casts and interstitial infiltration of inflammatory cells. It can also progress to fibrosis. In 40% of cases, foam cells infiltrate the interstitium at the cortex-medulla junction, the cytoplasm of which contains neutral fats, mucopolysaccharides, cholesterol, and phospholipids. The typical electron microscopic finding is the thinning and irregular thickening of the glomerular and tubular basement membranes, with thickened basement membranes associated with dense layer splitting or interlaced lamellar changes, containing electron-dense particles. In recent years, it has been found that the glomerular basement membrane (GBM) can thin, thicken, and have alternating lesions. The thinned GBM can reach 1/4 of the normal thickness, while the thickened GBM can reach 2-5 times the normal thickness. The GBM with segmental thinning and thickening coexists. The foot processes of the renal epithelium may fuse or be accompanied by the formation of microvilli. Immunofluorescence examination is usually negative, and occasionally, some immunoglobulins such as IgM and complement C3 can be seen to be slightly deposited in the glomeruli. It is generally believed that this is non-specific adhesion to the lesion glomeruli and has no pathogenic significance.

　　What diseases can a child with hereditary chronic progressive nephritis be complicated with?

　　In the late stage of the disease, hypertension occurs, renal function deteriorates progressively, leading to renal failure, and sensorineural deafness becomes progressively severe. At the same time, there is a decrease in vision, myopia, strabismus, cataracts, and in addition, esophageal, bronchial, and genitourinary smooth muscle tumors may also occur concurrently.

　　1. Renal manifestations:Mostly manifested as persistent or intermittent hematuria, which is glomerular hematuria. It can also show varying degrees of proteinuria and nephrotic proteinuria. It often worsens during acute infection. The onset of the disease in affected boys can be as early as the first year after birth. The incidence and severity of hypertension increase with age, and it often occurs in boys. The kidneys of affected boys almost all develop into end-stage renal disease, but the progression speed varies among families. According to the age of onset of end-stage renal failure, it can be divided into juvenile type (occurring before 31 years of age) and adult type (occurring after 31 years of age).

　　2. Sensorineural hearing loss:About 30% to 40% of patients may have high-frequency (4000～8000Hz) sensorineural hearing loss. With the increase of age, children gradually appear the above symptoms during the school age, and males are more common. The degree of deafness in both ears may not be completely symmetrical, but it is progressive, and deafness will gradually affect the entire frequency range. Brainstem auditory evoked response shows that hearing impairment occurs at the cochlear level.

　　3. Ocular lesions:About 15% of patients have ocular lesions, the most characteristic of which is the anterior cone-shaped lens, that is, the central part of the lens protrudes forward to the anterior chamber. Confirmation of this lesion often requires slit lamp examination by ophthalmology. Other common ocular abnormalities include changes in pigmentation around the macula, dense particle deposition around the fovea of the macula, congenital cataracts, nystagmus, etc.

　　4. Abnormalities of the blood system:There have been reports of thrombocytopenia associated with kidney disease. The platelet count in the blood smear of these patients is usually between (30～70)×109/L, and the platelets are spherical. Clinically, they may show mild tendency to hemorrhage, but severe postoperative hemorrhage rarely occurs. At the same time, granulocytes and even macrophage inclusions can be seen in peripheral blood smears.

　　5. Diffuse leiomyoma:Certain families or patients with Alport syndrome have significant smooth muscle hypertrophy, which often affects the esophagus, trachea, and female reproductive tract (such as clitoris, labia majora, and uterus, etc.), resulting in corresponding symptoms such as difficulty in swallowing and breathing difficulty.

　　How to prevent hereditary chronic progressive nephritis in children:

　　1. This condition belongs to a familial chronic progressive nephritis, about 85% of patients with hereditary chronic progressive nephritis have X-linked dominant inheritance caused by gene mutation; the rest of the patients have autosomal recessive and autosomal dominant inheritance. The pathogenic gene of the former is COL4A3 or COL4A4 gene, while the latter has genetic polygenic inheritance, so detailed family investigation should be carried out, and genetic counseling and reproductive guidance should be provided. Genetic diseases are an important reason affecting the health of infants and children, affecting the quality of the population born. In order to reduce and reverse the incidence rate of birth defects, prevention should start from pre-pregnancy to prenatal:

　　2. Pre-marital physical examination plays a positive role in the prevention of genetic diseases. The extent of its role depends on the examination items and content, mainly including serological tests (such as hepatitis B virus, syphilis spirochete, HIV), reproductive system examination (such as cervical inflammation screening), general physical examination (such as blood pressure, electrocardiogram), and inquiries about family history of diseases and personal medical history, etc. Good genetic counseling work should be done.

　　3. Pregnant women should try to avoid harmful factors, including staying away from smoke, alcohol, drugs, radiation, pesticides, noise, volatile harmful gases, toxic and harmful heavy metals, etc. During the prenatal care process of pregnancy, systematic screening for birth defects should be carried out, including regular ultrasound examination, serological screening, etc. Chromosome examination may also be necessary if necessary. Once abnormal results are found, it is necessary to determine whether to terminate the pregnancy; the safety of the fetus in the womb; whether there are sequelae after birth, whether they can be treated, and what the prognosis is, etc., and to adopt practical and feasible diagnostic and treatment measures.

　　One, Urine examination

　　Hematuria is persistent microscopic hematuria, which may appear as paroxysmal gross hematuria after upper respiratory tract infection or fatigue. Heterozygotes may have intermittent hematuria. In the early stage, there is微量proteinuria, which may later develop into nephrotic-range proteinuria, often indicating poor prognosis.

　　Two, Blood examination

　　Platelets are large and in reduced number, usually in the range of (30-70)×10^9/L, with spherical diameter, about 5-15μm (normal 1-2μm). In addition, blood smears may show leukocyte inclusions, and there may be elevated levels of urea and creatinine.

　　Three, Renal function examination

　　Mostly normal in childhood, after which the renal function of male patients gradually deteriorates, and most of them develop renal failure between the ages of 20 and 30, accounting for about 3% of pediatric renal failure. Occasionally, female patients may enter renal insufficiency at the age of puberty.

　　Four, Renal biopsy

　　1. Light microscopy: There are no pathologic changes of special significance. Renal tubular interstitial inflammatory changes can be seen, focal capillary wall sclerosis, mild irregular widening of the mesangial area, focal cyst thickening, focal endothelial or mesangial cell proliferation, etc. Generally, the glomeruli and blood vessels in children under 5 years of age are normal or basically normal, and the possible abnormality is the cortical glomeruli showing infantile glomerular changes.

　　2. Electron microscopy: Electron microscopy examination is the only method with diagnostic value. The typical lesion is diffuse thickening of the glomerular basement membrane (GBM), tearing of the dense layer, but also thinning of GBM can be seen. This lesion change is not specific to Alport syndrome. Under electron microscopy, the dense layer of GBM can be seen to be thickened in full or in part, up to 1200nm (normal is 100-350nm), and irregular inner and outer contour lines are present. Inhomogeneous dense layers also show electron-dense deposits of about 20-90nm in diameter. GBM tearing, twisting, and uneven density are observed. In young children, women, or in the early stages of the disease, GBM becomes diffusely thin. Routine X-ray examination, ultrasound, electroencephalogram, electrocardiogram, fundus examination, and audiometric examination are performed. The audiometric examination can detect bilateral sensorineural hearing loss. Slit lamp examination may reveal cataracts, corneal pigmentation, and other abnormalities. X-ray films show bone resorption lesions at the extremities and smooth muscle tumors in the esophagus, bronchi, and reproductive organs.

　　In terms of diet, it should be regular and reasonable, that is, to take high-protein and high-vitamin foods as the mainstay. Choose high-nutritive value plant or animal proteins, such as milk, eggs, fish, lean meat, various bean products, etc.

　　I. Treatment

　　1. General treatment focuses on symptomatic treatment, control of complications, active prevention of secondary urinary tract infection, prevention of overexertion and intense sports, and avoidance of nephrotoxic drugs when infection occurs. Animal experiments show that strict control of protein, fat, calcium, and phosphorus intake can help delay renal function decline and inhibit the progression of glomerular lesions.

　　2. In the terminal stage of renal failure, dialysis therapy is used to maintain life and wait for kidney transplantation. Due to the lack of basement membrane antigen in the body of Alport syndrome patients, anti-GBM antibodies can be produced after kidney transplantation, leading to anti-GBM nephritis (Goodpasture syndrome). Therefore, some authors suggest that these patients should be closely monitored for urine routine, renal function, and serum anti-GBM antibody levels for at least one year after kidney transplantation.

　　3. Part of the Alport gene has been identified, making the next step of gene therapy possible, but the actual implementation of gene therapy is still pending.

　　II. Prognosis

　　The prognosis of hereditary chronic progressive nephritis is related to the characteristics of gene mutation and the mode of inheritance. Recurrent hematuria can last for many years, and its prognosis is closely related to gender. Male patients usually gradually enter chronic renal insufficiency after the age of 20. According to the aforementioned EDTA data, 479 male patients entered chronic renal insufficiency at an average age of 24.3 years, and alternative therapy is needed. Female patients are relatively mild and rarely enter renal failure. According to 77 cases of materials in China, 25 out of 48 male patients (52%) died of renal failure, of whom 91.2% had died before the age of 20, and 6 out of 29 female patients died of the disease.