Pediatric Congenital Nephrotic Syndrome
Introduction
Introduction to congenital nephrotic syndrome in children Congenital nephrotic syndrome in children is a rare disease. The disease is not a single disease, but a group of diseases caused by different causes; its common clinical manifestations are edema, proteinuria, hypoproteinemia and hyperlipidemia at birth or within six months after birth. Congenital nephrotic syndrome (CNS) refers to nephrotic syndrome that develops within 3 months after birth. It has the same clinical manifestations as children with nephrotic syndrome, that is, a large amount of proteinuria, high edema, hyperlipidemia and hypoproteinemia at birth or within 3 months after birth. However, its etiology, pathological changes, and prognosis are different from those of older children or adults. basic knowledge The proportion of the disease: the incidence rate is about 0.001% -0.002% Susceptible people: children Mode of infection: non-infectious Complications: anemia, rickets, chronic renal insufficiency
Cause
The cause of congenital nephrotic syndrome in children
(1) Causes of the disease
According to the cause classification, they are usually divided into two categories:
1. Primary: including Finnish congenital nephrotic syndrome, diffuse mesangial sclerosis, minimal lesions, focal segmental sclerosis.
2. Secondary: can be secondary to infection (congenital syphilis, congenital venomous protozoa, congenital giant cell inclusion disease, rubella, hepatitis, malaria, AIDS, etc.), mercury poisoning, infant systemic lupus erythematosus, Hemolytic uremic syndrome, hyperthyroidism syndrome, Drash syndrome, renal vein thrombosis, etc.
(two) pathogenesis
1. Pathogenesis: It is clear that the Finnish congenital nephrotic syndrome is an autosomal recessive hereditary disease. Its gene is located on the long arm of chromosome 19, and the pathogenesis is gradually elucidated. In 1966, Norio performed on 57 Finnish families. Genetic investigation, clear this sign is an autosomal recessive hereditary disease, it is known that its defective gene is located in the long arm of chromosome 19 13.1, in 1983 Vernier et al detected 5 cases of congenital nephrotic syndrome with cationic probe PEI, found GBM The number of anion sites is reduced. The authors believe that the reduction of heparan sulfate is responsible for the increase in protein permeability in the intrinsic glomerular filtration membrane. In 1998, Karl Tryggrason et al reported that the disease has glomerular foot processes. The abnormality of nephrin on the septal septum is caused by the mutation of the NpHSI gene encoding nephrin.
2. Pathological changes: Pathological findings may vary from disease to disease. In the early stage of the disease, the glomeruli may be normal, and focal segmental sclerosis, mesangial cells and mesangial matrix hyperplasia may occur. Diffuse kidneys are present. The cystic dilatation of the tubules, in the advanced stage of the disease, the glomerular capillaries collapse and present a diffuse sclerosis. The renal tubules expand extensively and shrink. Interstitial inflammatory cell infiltration and fibrosis, some people have said that the most characteristic change in the intrinsic is the cystic dilatation of the proximal convoluted tubule, known as "microcystic disease", but the lesion of the renal tubule may be found Acquired is due to persistent large amount of proteinuria and/or obstruction of urinary flow in the tubule, resulting in cystic changes in the tubules of the incompletely mature nephrons. Immunofluorescence does not have Ig and complement deposition in the early stage of the disease. Immunoelectron microscopy shows Nephrin abnormalities on the interprosthetic septal septum, electron microscopy showed endothelial cell swelling, epithelial cell foot process fusion, basement membrane shrinkage and so on.
Prevention
Prevention of congenital nephrotic syndrome in children
It has been clarified that this sign is an autosomal recessive hereditary disease, and attention should be paid to genetic disease counseling and prenatal diagnosis. At 13 weeks of gestation, the fetal alpha-fetoprotein concentration peaks. When the fetus develops proteinuria, AFP enters with urine protein. In amniotic fluid, prenatal diagnosis is often based on the detection of alpha-fetoprotein concentration in amniotic fluid. AFP for detecting amniotic fluid can help prenatal diagnosis in pregnant women who have given birth to this disease at 11 to 18 weeks of re-pregnancy. Due to the study of the NpHSI gene sequence, it is expected to make a prenatal diagnosis, secondary to various infections, should actively prevent, strengthen prevention and treatment of health, strengthen pregnancy care and prenatal examination.
Complication
Pediatric congenital nephrotic syndrome complications Complications, anemia, chronic renal insufficiency
Concurrent with various infections, embolism, hypothyroidism, anemia, rickets, chronic renal insufficiency, etc.
Symptom
Symptoms of Congenital Nephrotic Syndrome in Children Common Symptoms Hypothyroidism Edema of the nose, low abdominal distension, secondary infection, urinary protein, diffuse mesangial sclerosing, ascites, proteinuria, hypercoagulable state
1. Family history and production history A large proportion of children with CNS have a positive family history. Most of the children have a premature birth of 35 to 38 weeks. The body weight is low, often breech. There is often a history of intrauterine asphyxia, and the Apgar score is low. Meconium in amniotic fluid, the intrinsic feature is the large placenta, the normal placenta does not exceed 25% of the fetal weight, while Huttenen reported that the placenta accounted for 0.42, while the normal control was 0.18. The mother was often accompanied by pregnancy poisoning, amniotic fluid. Increased AFP levels are characteristic changes in children, due to intrauterine proteinuria, AFP levels in amniotic fluid increased during the 16 to 22 weeks of gestation.
2. Clinical features
(1) Special appearance: common special appearance after birth, such as low nose bridge, wide eye distance, low ear, wide cranial suture, wide anterior and posterior malleolus, common hip, knee and elbow flexion deformity, followed by common Bloating, ascites, umbilical hernia.
(2) Edema: Half of the edema is seen within 1 to 2 weeks after birth, or it can be found for parents after a few months.
(3) Proteinuria: The proteinuria of the child is obvious and persistent. It is initially highly selective proteinuria, and the selectivity is decreased in the later stage of the disease. The child has obvious hypoalbuminemia and hyperlipidemia.
(4) Growth and development backwardness: Due to protein malnutrition, children often have growth and development, and there are reports of gastroesophageal reflux and pyloric stenosis.
3. Secondary changes often lead to other pathophysiological changes due to persistent kidney disease status, such as:
(1) Low immunity: due to the loss of Ig in the urine and the B factor of the complement system, the D factor causes low immunity, and multiple secondary infections (such as pneumonia, sepsis, peritonitis, meningitis, urinary tract infection, etc.) occur; It is the main cause of intrinsic death.
(2) thrombosis, embolism: children often hypercoagulable state, and even thrombosis, embolism, 10% of Mahan et al. have such complications, can be seen in multiple blood vessels such as peripheral arteries, sagittal sinus, Kidney, lungs and other veins.
(3) Others: hypothyroidism due to loss of T4 and thyroid binding protein in the urine; iron deficiency anemia caused by loss of transferrin; loss of vitamin D binding protein and insufficient vitamin D.
(4) renal dysfunction: with the increase of age, renal function gradually decreases slowly, GFR is often <50ml/(min·1.73m2) in the second year after birth, and there is corresponding blood biochemical change of chronic renal dysfunction, most of the sick children At the age of 3, dialysis or transplantation has been required. The nephrotic syndrome that occurs within 3 months of birth is congenital nephrotic syndrome.
Examine
Examination of congenital nephrotic syndrome in children
1. Increased amniotic fluid AFP levels: It is a characteristic change in children with CNS. Due to intrauterine proteinuria, AFP levels in amniotic fluid increase during the 16th to 22nd week of pregnancy; congenital neural tube hypoplasia can also occur in amniotic fluid AFP The level is increased, but the level of cholinesterase is often increased at the same time.
2. Changes in urine: often manifested as massive proteinuria and microscopic hematuria.
3. Hypoproteinemia: The level of serum albumin in children with CNS is very low, usually less than 10g/L.
4. Renal insufficiency: Renal function is often in the normal range.
5. Secondary CNS has laboratory characteristics of primary disease, such as congenital syphilis, positive VDRL test, Toxoplasma gondii, rubella, giant cell, hepatitis virus infection, elevated antibody titer, mercury poisoning, Toxoplasma gondii , rubella, giant cells, hepatitis virus infection, etc., often present the pathological changes of immune complex nephritis. In addition, in patients infected with giant cells, giant cell inclusion bodies are present in endothelial cells.
6. Light microscopy: In the early stage of the disease, the glomeruli may be normal, and may also present focal segmental sclerosis, mesangial cells and mesangial matrix hyperplasia; renal tubules exhibit cystic dilatation, in the advanced stage of the disease, kidney The capillaries of the small ball collapse and present a diffuse sclerosis; the renal tubules expand extensively and shrink. Interstitial inflammatory cell infiltration and fibrosis, in the early stage of DMS only the enlargement of the podocyte, the fusion of the foot process, the proliferation of mesangial matrix; in the advanced stage, most of the glomeruli are shrunken and hardened capillary ridge The vacuolar degeneration of epithelial cells, tubule atrophy, inflammatory cell infiltration, interstitial fibrosis, congenital syphilis infection often shows membranous or proliferative glomerulonephritis, occasionally accompanied by the formation of crescent. Invasive inflammatory cells with extensive interstitial.
7. Immunofluorescence: early normal; late in the mesangial area may have a small amount of IgM and C3 deposition, congenital syphilis infection immunofluorescence can be found in the mesangial deposition area of the presence of Treponema pallidum antigen.
8. Others: Imaging examinations should be routinely performed, such as B-ultrasound examinations and X-ray examinations.
Diagnosis
Diagnosis and diagnosis of congenital nephrotic syndrome in children
diagnosis
Finnish type
(1) Clinical diagnosis depends on
1 family history.
There are proteinuria in the 2 uterus. When the symptoms appear in the clinic, the albumin in the blood has been <10g/L. When the albumin in the blood is corrected to 15g/L, the protein in the urine can be >20g/L.
3 placenta is large (> 25% of birth weight).
4 clinical manifestations and GFR is still normal within 6 months.
5 Except for other known causes.
6 kidney biopsy.
(2) Prenatal diagnosis: Prenatal diagnosis often relies on alpha-fetoprotein in amniotic fluid. AFP is a normal fetal protein synthesized from fetal liver, yolk sac and digestive tract. Its molecular size and electrochemical properties are related to The blood albumin is similar. The fetal blood concentration peaks at 13 weeks of gestation. When the fetal proteinuria occurs, AFP enters the amniotic fluid with the urine protein. Therefore, the pregnant woman who has given birth to the disease is re-pregnancy 11-18. Weekly detection of amniotic fluid AFP can contribute to prenatal diagnosis, but it should be noted that this protein increase can also be seen in children with neural tube defects, but in addition to increased AFP in amniotic fluid, cholinesterase is also increased in neural tube defects. It can be identified, in addition, AFP can also be seen in twins, Turner syndrome, etc. In recent years, due to the study of the NpH-SI gene sequence, it is expected to make a prenatal diagnosis.
2. Non-Finnish type: This disease is also an autosomal recessive disease, which occurs mostly in children between 3 months and 3 years old, and occasionally at birth or within 3 months after birth. The pathological feature is glomerular diffuseness. Mesangial sclerosis or proliferative sclerosis, focal segmental sclerosis, cystic dilatation of the renal tubules, most prominent in the deep cortex, clinically most of these children present with nephrotic syndrome, and more rapidly progress to the end stage Kidney disease.
3. Drash syndrome: Drash syndrome manifests as congenital nephrotic syndrome, complicated by Wilms tumor and/or male pseudohermaphroditism, other related lesions such as cataract, corneal opacity, small head, strabismus, nystagmus and eye distance Too wide, etc., the syndrome appears in siblings, does not respond to treatment, and can recur after renal allografts. These patients have re-transplantation of nephrotic syndrome after transplantation due to cytomegalovirus infection or transplant rejection, although Male pseudohermaphroditism 46XY and ocular abnormalities are common concomitant symptoms of Drash syndrome, but it has been reported in a 46XY female patient. The renal pathology is diffuse mesangial sclerosis, due to the high incidence of bilateral Wilms tumors. Some people recommend a preventive nephrectomy.
4. Galloway-Mowat syndrome and Roos syndrome: Galloway-Mowat syndrome also manifests as congenital nephrotic syndrome. The typical renal pathology is that there are flocs and fines on the structurally distorted glomerular basement membrane. Filament (6-8nm) deposition, expressed as small head, infantile spasm, psychomotor block Roos syndrome, is also a familial disease, it is often accompanied by nephrotic syndrome in infants, Roos syndrome kidney Pathological manifestations of focal segmental glomerular sclerosis with extensive mesangial disintegration, spinal epithelial dysplasia, mental retardation, conductive hearing loss and retinitis pigmentosa, also with focal segmental kidney in infancy Spherical sclerosis and syndrome associated with nephrotic syndrome.
5. Secondary congenital nephropathy
(1) Clinical manifestations: In addition to the clinical manifestations of nephropathy, secondary CNS is often accompanied by clinical symptoms of some unique primary diseases, which can be differentiated from primary CNS.
(2) Laboratory examination: In addition to the similar laboratory test results of the primary CNS, the secondary CNS also has some laboratory examination features of the primary disease, such as congenital syphilis patients, the VDRL test is positive; Such as Toxoplasma gondii, rubella, giant cells, hepatitis virus infection, and its antibody titer is elevated.
(3) Pathology: With the different causes, secondary CNS often have their own characteristics in pathological changes.
1 congenital syphilis infection: light microscopy often manifests as membranous or proliferative glomerulonephritis, occasionally accompanied by the formation of crescentic, extensive interstitial inflammatory cell infiltration; immunofluorescence can be found in the mesangial deposition area with syphilis The presence of spirochete antigens, under electron microscopy, can be found along the basement membrane with small nodule compacts deposited under the endothelium.
2 Mercury poisoning, Toxoplasma gondii, rubella, giant cells, hepatitis virus infection: often presents the pathological changes of immune complex nephritis; in addition, in patients with giant cell infection, the presence of giant cell inclusions can be seen in endothelial cells.
Differential diagnosis
Should be the first to exclude the secondary cause of the known cause, because the treatment of primary disease (such as secondary to syphilis treatment of anti-mei) can be expected to relieve kidney disease, combined with other clinical and laboratory performance of the primary disease itself caused by secondary More clearly diagnosed, small infants have unexplained nephrotic syndrome with external genital abnormalities, should consider Drash syndrome, this Drash reported in 1970, manifested as renal embryonal tumor (Wilm tumor), male pseudohermaphroditism and Kidney involvement (can be expressed as nephrotic syndrome). Some cases have only two manifestations. The renal pathology is diffuse mesangial sclerosis and tubular atrophy. The lesions in the renal cortical surface are more important than the near medulla. Primary congenital nephrotic syndrome, in addition to Finnish congenital nephrotic syndrome can be caused by diffuse mesangial sclerosis, the disease is not abnormal during the perinatal period, the placental size is normal, although the onset can also be early in the neonatal period But more than 3 months after birth.
The disease entered renal dysfunction earlier, died of uremia, pathologically early mesangial sclerosis, glomerular capillary collapse, no cell proliferation; later glomerular sclerosis and renal tubules, interstitial fibrosis In addition, occasionally caused by microscopic lesions, pathological changes of focal segmental sclerosis, the effect of treatment on adrenal cortex hormones is the same as that of older children, infantile nephrotic syndrome (INS) and CNS. In the first year after birth, but the onset of INS is later than the CNS, often starting in the second half of the first year, especially in the first 3 months after birth, it is currently believed to be mainly due to the glomerular basement membrane. The integrity is compromised and its increased permeability results in a large amount of proteinuria being filtered out.
