Inherited chronic progressive nephritis in children

Introduction to pediatric hereditary chronic progressive nephritis Hereditary nephritis, also known as Alportssyndrome (AS), hereditary chronic progressive nephritis, familial nephritis, eye-ear-kidney syndrome and AIPort syndrome, is a familial chronic progressive nephritis with clinical features characterized by hematuria. Some cases may be characterized by 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. basic knowledge The proportion of illness: 0.001% Susceptible people: children Mode of infection: non-infectious Complications: strabismus, renal failure

Pediatric hereditary chronic progressive nephritis

(1) Causes of the disease

The root cause of the lesion is the mutation of different -chain (1-a6) of type IV collagen, which is an important component of the basement membrane. The gene encoding it is called COL4A1-COL4A6, which is located on different chromosomes. About 85% of AS patients are sexually linked. Sexual inheritance (X-Linked AS, XLAS), the disease-causing gene is located in the middle section of the X chromosome, Xq 22, which is caused by a mutation in the type IV collagen 5 chain (COL4A5) gene. The remaining patients were autosomal recessive AS (ARAS) and autosomal dominant AS (ADAS). The former disease-causing gene was COL4A3 or COL4A4 gene, while the latter had genetic multi-source, using immunity. Histochemical techniques to detect the expression of different alpha chains of type IV collagen in kidney tissue and skin tissue can help diagnose the disease clinically and determine the genetic pattern. On the other hand, people not only determine the pathogenic genes of Alport syndrome, but also More than 300 XLAS and several ARAS mutant genes were detected by various methods, and the relationship between patient genotype and phenotype was gradually explored.

(two) pathogenesis

Hereditary chronic progressive nephritis is a glomerular basement membrane (BM) disease characterized by hematuria and progressive renal damage, which may be accompanied by extra-renal manifestations of the eyes, ears, and underlying electron microscope. For diffuse thickness and unevenness, there may be stratification, which is a characteristic pathological change. However, in terms of pathogenesis, single or multiple base mutations from the type IV collagen coding gene, to the corresponding lesions on the BM, due to Lack of dynamic, systematic research, people are still not clear about many of these specific links, the establishment and research of animal models are currently underway, the early kidney volume is normal or increased, the kidney volume gradually shrinks after the disease progresses, in the light microscope Normal or mild epithelial cell hyperplasia and mesangial matrix increase, late mesangial cell hyperplasia, glomerular and tubular basement membrane thickening, stratification, thickening of the cyst wall and progression to glomerular sclerosis, Renal tubular cell atrophy or partial dilatation, there may be focal inflammatory cell infiltration in the protein tubular interstitial, but also in fibrosis, 40% of cases in the interstitial junction of the cortex and medulla Infiltration of foam cells, the cytoplasm of this foam cell contains neutral fat, mucopolysaccharide, cholesterol and phospholipids. Electron microscopy is typical of glomerular and tubular basement membrane thinning and irregular thickening, glomerular thickening The basement membrane is accompanied by dense layer splitting, or overlapping lamellar changes, which contain electron-dense particles. In recent years, the glomerular basement membrane (GBM) has been found to be thinner, thicker and inter-phase lesions, and the thinned GBM can reach The normal thickness is 1/4, and the thickened GBM can reach 2 to 5 times of the normal thickness. It is a segmental thinning and thickening of GBM. The glomerular epithelial part of the foot can be fused or formed with microvilli. Immunofluorescence is usually negative, and occasionally some immunoglobulins such as IgM, complement C3, etc. are slightly deposited in the glomerulus; it is generally considered to have non-specific adhesion to the diseased glomerulus, no pathogenic significance. .

Pediatric hereditary chronic progressive nephritis prevention

The disease belongs to a familial chronic progressive nephritis. About 85% of patients with hereditary chronic progressive nephritis are sexually linked and dominant, which is caused by gene mutation; the rest of the patients are autosomal recessive and autosomal dominant. The former disease-causing gene is COL4A3 or COL4A4 gene, and the latter has genetic multi-source. Therefore, family survey should be carried out in detail, genetic counseling should be carried out, and birth guidance should be carried out. Hereditary diseases are important causes affecting the health of infants and children, affecting birth. The quality of the population, in order to reduce and reverse the incidence of birth defects, prevention should be from pre-pregnancy to prenatal:

1. Premarital medical examination plays an active role in the prevention of hereditary diseases: the size of the effect depends on the examination items and contents, mainly including serological examination (such as hepatitis B virus, treponema pallidum, HIV), reproductive system examination (such as screening the cervix) Inflammation), general physical examination (such as blood pressure, electrocardiogram) and asking about the family history of the disease, personal medical history, etc., do a good job in genetic disease counseling.

2. Pregnant women should avoid harmful factors as far as possible: including away from smoke, alcohol, drugs, radiation, pesticides, noise, volatile harmful gases, toxic and harmful heavy metals, etc., in the process of antenatal care during pregnancy, systematic screening of birth defects is required. Including regular ultrasound examination, serological screening, etc., if necessary, chromosomal examination, if abnormal results occur, it is necessary to determine whether to terminate the pregnancy; the safety of the fetus in the uterus; whether there is sequelae after birth, whether it can be treated, How to prognose, etc., take practical measures for diagnosis and treatment.

Pediatric hereditary chronic progressive nephritis complications Complications, strabismus, renal failure

Complicated with bronchial, esophageal, and genital leiomyoma.

In addition, hypertension occurs in the later stages of the disease, and renal function declines, and it develops into renal failure. At the same time there are strabismus, myopia, vision loss, cataract. Neurological deafness is also progressively worse.

Pediatric hereditary chronic progressive nephritis symptoms common symptoms nephrotic syndrome bleeding tendency intermittent hematuria dysphagia proteinuria lens protrusion dyspnea nystagmus thrombocytopenia

1. Renal manifestations: Most of them are characterized by persistent or intermittent hematuria. Hematuria is glomerular. It can also express proteinuria and nephropathy-like proteinuria of varying degrees. It is often exacerbated by acute infection, and the incidence of affected boys. As early as the first year after birth, the incidence and severity of blood pressure increase with age, and most occur in boys, almost all of the kidneys of affected boys will develop into end-stage renal disease, but the rate of progress is different There are differences, according to the age of end-stage renal failure, can be divided into adolescent (pre-31 years old) and adult (31 years old).

2. Neurological deafness: About 30% to 40% of patients may be accompanied by high frequency area (4000 ~ 8000Hz) neurological deafness. With the increase of age, children gradually appear in the school age, especially in men, both sides The degree of deafness may not be completely symmetrical, but for progressive, deafness will gradually become full-range, and brainstem audiometry will show that hearing impairment occurs in the cochlea.

3. Eye lesions: About 15% of patients 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. It is confirmed that this lesion often needs to be examined by ophthalmic slit lamp. Common eye abnormalities are pigmentation changes around the macula, dense microparticles around the fovea of the macula, congenital cataracts, nystagmus, etc.

4. Abnormal blood system: The giant thrombocytopenia associated with kidney disease has been reported. The blood platelet count of patients with this disease is mostly (30 ~ 70) × 109 / L, the platelets are spherical, clinical manifestations of mild bleeding There is a tendency to cause severe bleeding after surgery, and granulocytes and even inclusion bodies in macrophages can be seen in peripheral blood smears.

5. Diffuse leiomyomas: Some adolescent Alport syndrome families or patients with significant smooth muscle hypertrophy, often affected by the esophagus, trachea and female reproductive tract (such as clitoris, labia majora and uterus), corresponding Symptoms such as difficulty swallowing, difficulty breathing, etc.

Pediatric hereditary chronic progressive nephritis

1. Urine examination: hematuria is continuous microscopic hematuria. After episodes or fatigue, paroxysmal gross hematuria may occur. Heterozygous may be intermittent hematuria. In the early stage, there may be microalbuminuria, which may develop into nephropathy-like proteinuria. Often suggest a poor prognosis.

2. Blood test: The platelets are huge and the number is reduced. It is often in the range of (30-70)×109/L, and has a spherical diameter of about 5-15 m (normal 1-2 m). In addition, blood smears can be seen as white blood cell inclusions, and urea can be present. , creatinine increased.

3. Renal function test: Most of the normal period in young children, after the male patients gradually decline in renal function, most of them appear renal failure in 20 to 30 years old, accounting for 3% of children with renal failure, and occasionally female patients enter the kidney during puberty Incomplete function.

4. Kidney biopsy:

(1) Light microscopy: no pathological changes with special significance, such as tubulointerstitial inflammatory changes, focal capillary wall sclerosis, mild irregularization of mesangial area, focal cyst thickening, focal Sexual endothelium or mesangial cell proliferation, etc., the glomeruli and blood vessels of children before the age of 5 are normal or basically normal. The abnormality that may be found is that the cortical glomeruli are infant-like glomerular changes.

(2) Electron microscopy: Electron microscopy is the only diagnostic method. The typical lesion is diffuse thickening of the glomerular basement membrane (GBM). The dense layer is torn, but the GBM is also thinned. It is not a unique lesion of Alport syndrome. Under electron microscope, all or part of the dense layer of GBM can be thickened up to 1200 nm (normally 100-350 nm), and there are irregular inner and outer contours, which are also visible in the dense layer. Electron dense deposits with a diameter of about 20-90 nm, GBM tear, distortion and density unevenness. In early childhood, women or early disease, GBM diffuse thinning, routine X-ray examination, B-ultrasound, EEG, Electrocardiogram examination, fundus examination, electrical audiometry, etc., electrical audiometry examination can be found, bilateral neurological deafness, slit lamp examination found cataract, corneal pigmentation and other abnormalities, X-ray bone fragments see limb osteolysis Lesions and esophagus, bronchi, genital leiomyoma.

Diagnosis and differential diagnosis of pediatric hereditary chronic progressive nephritis

diagnosis

1. Rely on clinical symptoms, signs, combined with pathological examination to diagnose.

(1) urine test: hematuria, most accompanied by unequal amount of proteinuria, hematuria mainly under the microscope, or accompanied by intermittent episodes of gross hematuria, 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, cleft palate, and coexist with the thinned basement membrane. The interstitial may have more foam cell infiltration. This kind of cells can also be seen in chronic nephritis. Membrane glomerulonephritis of lipid-induced nephropathy, but the characteristics of the number and distribution (more skin and medulla junction) are also helpful for diagnosis. If there are 3 items in the above several conditions, the pathology can be diagnosed. Changes in the glomerular basement membrane are indispensable.

2. Molecular biology techniques: 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), which can be diagnosed at the gene level, in addition to kidney tissue and skin biopsy tissue. Detection of the expression of 5 chain of type IV collagen, such as lack of base film 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 asymptomatic genes in women. Carrier.

Differential diagnosis

1. Benign familial hematuria: The patient may have a positive family history. The main clinical manifestations are asymptomatic simple hematuria. The renal lesions are not progressive, so it is also known as benign hematuria. The pathological changes are normal under light microscope, and the characteristics under the electron microscope are diffuse. The GBM is thinner, which is 1/3 to 2/3 of the thickness of normal people. There is no electron dense deposit in the glomerulus. In recent years, there has been variation in type IV collagen 4 (COL4A4) in familial thin basement membrane disease (TBMD). Some patients with sexually-linked hereditary chronic progressive nephritis can have thin basement membrane lesions at the same time.

2. IgA nephropathy: the clinical manifestations are mainly recurrent hematuria, a few cases are only asymptomatic proteinuria, or hematuria with proteinuria, or even nephritic nephropathy symptoms, may have high blood pressure, edema, massive proteinuria, pathology Mesangial proliferative nephritis was more common, followed by mild lesions and focal proliferative nephritis. In a few cases, diffuse proliferative nephritis and focal crescent formation were formed, and sometimes the glomerular basement membrane became thin. In immunopathology, IgA or IgA-based immunoglobulin is deposited in the glomerular mesangial area, usually in the form of granules or lumps. In some cases, IgA deposition also occurs on the capillary wall, while hereditary nephritis There is no immunoprecipitation, and renal biopsy has no pathological changes of hereditary nephritis under electron microscope.

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