Congenital nephrotic syndrome

　　1. Etiology

　　According to the etiology classification, it is usually divided into two major categories:

　　1. Primary

　　Including Finnish-type congenital nephrotic syndrome, diffuse mesangial sclerosis, minimal change, focal segmental sclerosis.

　　2. Secondary

　　It can be secondary to infection (congenital syphilis, congenital plasmodium disease, congenital giant cell inclusion disease, rubella, hepatitis, malaria, AIDS, etc.), mercury poisoning, infantile systemic lupus erythematosus, hemolytic uremic syndrome, patellar syndrome, Drash syndrome, renal vein thrombosis, etc.

　　2. Pathogenesis

　　1. Pathogenesis

　　It has been clearly established that Finnish-type congenital nephrotic syndrome is an autosomal recessive genetic disease, with the gene located on the long arm of chromosome 19, and the pathogenesis is gradually being elucidated. In 1966, Norio conducted a genetic survey of 57 Finnish families and clearly identified this sign as an autosomal recessive genetic disease, and it is now known that the defective gene is located on the long arm 13.1 of chromosome 19. In 1983, Vernier et al. detected 5 cases of congenital nephrotic syndrome with cationic probe PEI and found that the number of anionic sites on GBM decreased, and the author believed that the decrease in heparin sulfate was the cause of increased protein permeability of the glomerular filtration membrane in this syndrome. In 1998, Karl Tryggrason et al. reported that there was an abnormality in nephrin on the slit diaphragm between glomerular podocytes in this disease, caused by a mutation in the gene NpHSI encoding nephrin.

　　2. Pathological changes

　　Pathological findings vary with the stage of the disease. In the early stage of the disease, glomeruli may be normal or present focal segmental sclerosis, with mesangial cell and mesangial matrix proliferation; diffuse renal tubular cystic dilation is present. In the late stage of the disease, glomerular capillary loops collapse, presenting with diffuse sclerosis; renal tubules are widely dilated and atrophic; interstitial inflammatory cell infiltration and fibrosis. Some have called the most characteristic change in this syndrome the cystic dilation of the proximal tubules, known as 'microcystic disease', but it has been found that this lesion in the renal tubules may be acquired, due to persistent large amounts of proteinuria and/or obstruction of urinary flow in the tubules, leading to tubular cystic changes in immature renal units. Immunofluorescence examination shows no Ig and complement deposition in the early stage of the disease. Electron microscopy shows podocyte slit diaphragm abnormality. Electron microscopy shows swelling of endothelial cells, fusion of epithelial cell foot processes, and contraction of the basement membrane, etc.

　　1. Infection

　　It is the most common complication of NS and also the main cause of death. Common sites of infection include the respiratory tract, skin, urinary tract, and abdomen. The reasons for easy infection include:

　　1. Low humoral immunity;}

　　2. Abnormal cell-mediated immunity;

　　3. The decrease in complement components, especially B factor and D factor affecting the alternative complement activation pathway, affects opsonization function;

　　4. The loss of transferrin and zinc binding protein from urine affects immune regulation and lymphocyte function;

　　5. Protein malnutrition;

　　6. Edema causes local circulatory disorders;

　　7. Use of corticosteroids and immunosuppressive drugs.

　　II. Hypercoagulability and thrombotic and embolic complications

　　There is a hypercoagulable state in NS, and the reasons include:

　　1. The increase in the substances synthesized by the liver related to coagulation;

　　2. Antithrombin III is lost from the urine;

　　3. The activity of plasminogen in plasma decreases;

　　4. Hyperlipidemia increases blood viscosity and strengthens platelet aggregation;

　　5. Infection or vascular wall damage can activate the endogenous coagulation system;

　　6. Long-term and large amounts of corticosteroids aggravate hypercoagulability;

　　7. Overuse of diuretics aggravates blood concentration.

　　The main thrombotic complications of NS are renal vein thrombosis, manifested as sudden flank pain, the appearance or exacerbation of hematuria, oliguria, and even renal failure. In addition, if there is asymmetric swelling of both lower limbs, consider deep vein thrombosis of the lower extremities; be alert to pulmonary embolism when there are no positive pulmonary signs such as cough, hemoptysis, or dyspnea of unknown cause; consider cerebral embolism when there are sudden symptoms such as hemiplegia, facial palsy, and other neurological symptoms. The clinical symptoms of thrombosis forming slowly are often not obvious.

　　III. Malnutrition

　　In addition to protein malnutrition and growth and development disorders, there are also low levels of thyroid hormone, vitamin D deficiency, and disorders of calcium and phosphorus metabolism.

　　IV. Renal injury

　　1. Acute renal failure

　　Possible causes include: nephrotic necrosis or acute interstitial nephritis caused by antibiotics, diuretics, etc.; severe interstitial edema or tubular obstruction by proteinuria casts; the formation of a large number of crescents on the original pathological basis; decreased blood volume leading to prerenal azotemia or complicated with renal vein thrombosis.

　　2. Tubular function damage

　　NS has an original underlying disease (such as focal segmental glomerulosclerosis) and a large amount of reabsorption and decomposition of urinary protein can cause tubular damage. Clinically, renal glycosuria, aminoaciduria can be seen, and severe cases present with Fanconi syndrome. These children have a poor response to corticosteroid therapy and a poor long-term prognosis.

　　I. Family history and birth history

　　A significant proportion of CNS patients have a positive family history, most of whom are premature at 35-38 weeks, with low birth weight, often in breech position, with a history of intrauterine asphyxia, low Apgar score, meconium in amniotic fluid, and the characteristic is a large placenta. The normal placenta does not exceed 25% of the fetal weight, while in Huttenen's report, the placenta accounts for 0.42 of the weight, and the normal control is 0.18. Maternal pregnancy often complicates preeclampsia, and the level of AFP in amniotic fluid increases as a characteristic change in the fetus. Due to proteinuria in utero, the level of AFP in amniotic fluid increases from 16 to 22 weeks of gestation.

　　2. Clinical characteristics:

　　1. Special appearance:

　　After birth, special appearances are common, such as a low nasal bridge, wide interpalpebral distance, low-positioned ears, wide sutures, large anterior and posterior fontanels, and common curvature deformities of the hip, knee, and elbow joints. Later, abdominal distension, ascites, and umbilical hernia are often seen.

　　2. Edema:

　　Half of the children show edema within 1-2 weeks after birth, and it can also be delayed until several months later when discovered by the parents.

　　3. Proteinuria:

　　Children have significant and persistent proteinuria, initially presenting as highly selective proteinuria, and the selectivity decreases in the later stage of the disease. Children also have obvious hypoalbuminemia and hyperlipidemia.

　　4. Growth and development retardation:

　　Due to protein malnutrition, children often have growth and development retardation, and there are also reports of associated gastroesophageal reflux and pyloric stenosis.

　　3. Secondary changes:

　　Due to the persistent nephrotic state, it often leads to other pathophysiological changes, such as:

　　1. Immune deficiency:

　　Due to the loss of Ig and B factor, D factor of the complement system in urine, leading to decreased immunity and the occurrence of various secondary infections (such as pneumonia, sepsis, peritonitis, meningitis, urinary tract infection, etc.); infection is the main cause of death in this condition.

　　2. Thrombosis and embolism:

　　Children often present with hypercoagulability, even thrombosis, and embolic complications. In the cases of Mahan et al., 10% have such complications, which can occur in multiple blood vessels such as peripheral arteries, sagittal sinus, kidney, lung, and other veins.

　　3. Others:

　　Due to the loss of T4 and thyroid-binding protein, hypothyroidism occurs; iron deficiency anemia due to the loss of transferrin; vitamin D deficiency due to the loss of vitamin D-binding protein.

　　4. Renal function decline:

　　With the increase of age, renal function gradually decreases slowly, the GFR at the second year of life is often

　　It has been confirmed that this condition is an autosomal recessive genetic disease, and attention should be paid to genetic counseling and prenatal diagnosis. The concentration of alpha-fetoprotein in the fetal blood reaches its peak at 13 weeks of gestation. When the fetus develops proteinuria, AFP enters the amniotic fluid along with urinary protein, so prenatal diagnosis is often based on the detection of AFP concentration in amniotic fluid. For pregnant women who have given birth to children with this disease, detecting AFP in amniotic fluid at 11-18 weeks of gestation can help with prenatal diagnosis. In recent years, with the research on the NpHSI gene sequence, it is now possible to make an accurate prenatal diagnosis. Secondary infections should be actively prevented, and health education, strengthening prenatal care and prenatal examination should be strengthened, etc.

　　1. Increased AFP level in amniotic fluid:It is a characteristic change in CNS children, due to proteinuria excreted in utero, the AFP level in amniotic fluid increases during pregnancy 16-22 weeks; congenital malformation of the neural tube can also lead to an increase in AFP level in amniotic fluid, but its cholinesterase level is often increased simultaneously, which can be used to distinguish it.

　　2. Changes in urine:It often manifests as large amounts of proteinuria and microscopic hematuria.

　　3. Hypoproteinemia:CNS children have very low blood albumin levels, usually less than 10g/L.

　　4. Renal insufficiency:Renal function is usually within the normal range.

　　5. Secondary CNS has the characteristics of laboratory examination of the primary disease:For congenital syphilis, VDRL test is positive, toxoplasmosis, rubella, cytomegalovirus infection, and the antibody titer increases, mercury poisoning, toxoplasmosis, rubella, cytomegalovirus infection, etc., often present pathological changes characteristic of immune complex nephritis. In addition, in patients with cytomegalovirus infection, giant cell inclusions can be seen in the endothelial cells.

　　6. Light microscopy:In the early stage of the disease, glomeruli may be normal or present focal segmental sclerosis, with mesangial cell and mesangial matrix proliferation; tubules show cystic dilatation. In the late stage of the disease, glomerular capillary loops collapse and present diffuse sclerosis; tubules widely dilate and atrophy. Interstitial inflammatory cell infiltration and fibrosis, in the early stage of DMS, only podocytes become hypertrophied, podocytes fuse, and mesangial matrix proliferates; in the late stage, most glomeruli present contracted and sclerotic capillary loops along with vacuolar degenerative epithelial cells, tubular atrophy, inflammatory cell infiltration, interstitial fibrosis. Congenital syphilis infection is often manifested as membranous or proliferative glomerulonephritis under light microscopy, occasionally with crescent formation, and widespread inflammatory cell infiltration in the interstitium.

　　7. Immunofluorescence:Early stage is normal; in the late stage, there may be a small amount of IgM and C3 deposition in the mesangial area, and treponemal antigen can be found in the mesangial deposition area in congenital syphilis infection by immunofluorescence.

　　8. Other:Routine imaging examinations should be performed, such as ultrasound examination, X-ray examination, etc.

　　1. Pay attention to dietary salt intake of 1 to 3 grams per day; completely avoid salt during severe edema, and slightly limit water intake. After treatment and increased urine output, increase salt in the diet and provide oral potassium chloride, calcium tablets, and other supplements. Long-term low-salt or salt-free diets can cause hyponatremia, symptoms such as lack of energy, vomiting, irritability, hematuria, and decreased blood pressure.

　　2. Do not reduce or discontinue medication arbitrarily. Treatment of nephritis often requires the use of hormone drugs. Children taking hormones must be under the guidance of a doctor, and the dosage should be gradually reduced until stopped as the condition improves. Parents should督促 their children to take medication on time and in the correct dosage, and should not reduce or discontinue medication arbitrarily to avoid recurrence of the condition.

　　3. Children should not overexert themselves: children have poor self-discipline and are prone to overexertion and insufficient sleep when they find something new and exciting. Parents should pay special attention to arranging their children's rest and activity schedules to ensure they get enough rest.

　　4. Avoid spicy foods and snacks; eat appropriate amounts of vegetables, celery, and apples.

　　First, treatment

　　FNS has a poor response to adrenocortical hormone therapy, often manifesting as resistance to adrenocortical hormones. Most children die within one year of onset, not due to renal failure, but more often from severe infections, malnutrition, diarrhea, electrolyte imbalances, and other conditions. Treatment mainly involves symptomatic and supportive care.

　　1. Reduce Edema

　　Limit salt intake and use diuretics. For those with severe hypoalbuminemia or signs of low blood volume, albumin without salt can be infused. In Finland, it is advocated to intravenously infuse human serum albumin 4 weeks after birth to maintain plasma protein levels above 15g/L, so at this time, general edema can be avoided and growth and development can be close to normal.

　　2. Maintain Nutrition

　　Provide a diet with high calories and sufficient protein.

　　3. Prevention and Treatment of Infection

　　Infection is the main cause of death, and attention should be paid to protection. Once infection occurs, it should be treated actively and promptly, and antibiotics are usually not used prophylactically. Human serum gamma globulin preparations can be used intermittently if necessary.

　　4. Prevention and Treatment of Complications

　　For the treatment of secondary hypothyroidism, those with hypercoagulability are given dipyridamole (Persantin) and low-dose aspirin. Holmberg et al. reported that from 1985 to 1989, 5 of the 17 cases developed embolic complications, and after 1989, 29 cases started to take warfarin for 4 weeks, with no cases developing embolic complications. Generally, the blood pressure of children is normal, and antihypertensive drugs are given to those with increased blood pressure in the later stage.

　　5. Others

　　In recent years, there have been reports of the use of angiotensin-converting enzyme inhibitors (ACEI) and indomethacin (NSAID) for those with proteinuria, which can alleviate their condition.

　　6. Kidney Transplantation

　　The only radical treatment is kidney transplantation, usually performed after 2 years of age or when the weight reaches 7kg. For those with severe proteinuria, a nephrectomy can be performed first (to stop proteinuria) and rely on dialysis to maintain life while waiting for transplantation. In 1992, Mattoo et al. reported that a unilateral nephrectomy can reduce urine protein excretion, while maintaining renal function in the other kidney, and believe that this method can reduce the monthly infusion of human serum albumin.

　　II. Prognosis

　　The prognosis of this condition has greatly improved. Some authors report that 34 cases of kidney transplantation followed up for 3.7 years after 1987, with the survival rate of the transplanted kidneys at 94%, 81%, and 81% at 1, 2, and 3 years respectively; GFR was 73.7% and 75.3% at 1 and 3 years respectively. The children are in good condition, with only 1 case developing chronic rejection and hypertension. The prognosis of secondary CNS varies with the cause, such as those caused by infection, which often improve significantly with strong anti-infection treatment.