Pediatric nephrotic syndrome

　　First, etiology

　　Almost all diseases that can cause glomerular disease can lead to NS, classification:

　　1. Clinical classification is currently the main typing method in China.

　　(1)Simple nephrotic syndrome: Patients with the four clinical characteristics of nephrotic syndrome, with more males than females, and simple nephrotic syndrome is more common in clinical practice.

　　(2)Nephritic nephrotic syndrome: In addition to the typical symptoms, it also has one of the following characteristics, including hypertension [in pre-school children, blood pressure higher than 16/10.7kPa (120/80mmHg), in school-age children higher than 17.3/12kPa (130/90mmHg)]; hematuria (red blood cells higher than 10 per HP under centrifugal urine microscopy); azotemia (BUN>10.7mmol/L, >30mg/dl) and persistent low complementemia.

　　(3)Congenital nephrotic syndrome: Within or shortly after birth (within

　　(4)Refractory nephrotic syndrome: According to the diagnostic criteria proposed by the Chinese Pediatric Nephritis Research Group:

　　①Insufficient response to adequate hormone therapy (such as prednisone 2mg/kg per day) after 8 weeks or partial response.

　　② Frequent recurrence or frequent recurrence (≥2 times in half a year, ≥3 times in a year),

　　③ Hormone dependence.

　　2, Pathological classification

　　(1) Minimal change type (including minimal change type): children are mainly with minimal change.

　　(2) Focal, segmental glomerulosclerosis.

　　(3) Mesangial proliferative nephritis.

　　(4) Membranous lesions.

　　3, Classification by clinical convention

　　(1) Primary or idiopathic: that is, the primary lesion occurs in the glomerulus of the kidney, according to the current clinical classification in China, among primary glomerular diseases, acute glomerulonephritis, rapid progressive glomerulonephritis, chronic glomerulonephritis, and glomerulonephritis can all appear in the course of the disease, in pathology, minimal change, focal segmental glomerulosclerosis, membranous nephropathy, membranoproliferative glomerulonephritis, and the glomerulonephritis with lipoprotein, collagen III glomerulonephritis, fibrous glomerulonephritis, and collapsing glomerulonephritis found in recent years are mainly manifested as NS, and mesangial proliferative glomerulonephritis can also occur NS.

　　(2) Secondary nephrotic syndrome: that is, NS secondary to systemic diseases, the etiology is extensive and complex, and is briefly summarized as follows:

　　① Infectious diseases: many infections can cause NS, which are listed below according to the pathogen:

　　A, Viral infections: infections with hepatitis B and C viruses, cytomegalovirus, Epstein-Barr virus, HIV type 1, herpes zoster virus, coxsackievirus, and adenovirus, etc.

　　B, Bacterial infections: such as Streptococcus, Staphylococcus, pneumococcus, Salmonella, leprosy bacillus, and Treponema pallidum, etc. infections,

　　C, Protozoan infections: such as Plasmodium (with Plasmodium malariae being more common) and toxoplasmosis infections,

　　D, Parasitic infections: various types of schistosomiasis [especially Manson schistosomiasis], trypanosomes, and filariae, etc.

　　② Multi-system and connective tissue diseases: such as systemic lupus erythematosus, systemic small vessel vasculitis, rheumatoid arthritis, Sjögren's syndrome, ulcerative colitis, dermatomyositis, allergic purpura, eczema herpetiformis, sarcoidosis, and psoriasis, etc.

　　③ Allergens: such as snake bite, bee sting, pollen, serum, vaccine, poison oak, ivy, D860, penicillamine, and probenecid, etc.

　　④ Metabolic diseases: such as diabetic nephropathy, amyloidosis, lipoprotein nephropathy, and myxedema, etc.

　　⑤ Nephrotoxic substances: such as mercury, bismuth, gold, and trimethylketone, etc.

　　⑥ Tumors: such as Hodgkin's disease, lymphoma, chronic lymphocytic leukemia, multiple myeloma, colorectal cancer, lung cancer, breast cancer, gastric cancer, and renal cancer, etc.

　　⑦ Other: such as preeclampsia, renal artery stenosis, renal vein thrombosis, reflux nephropathy, chronic rejection of renal transplantation, chronic ileitis, chronic heart failure, and constrictive pericarditis, etc.

　　(3) Congenital and genetic diseases: such as Alport syndrome, Fabry disease, nail-patella syndrome, congenital (Finnish type) nephrotic syndrome, and sickle cell disease, etc.

　　2. Pathogenesis

　　1. Pathogenesis

　　(1) Sialic acid theory: that is, the classic pathogenesis, due to the swelling and fusion of the glomerular epithelial foot processes, which destroys the original sialic acid glycoprotein structure, causing the disappearance of negative charge, allowing negatively charged albumin to pass and form proteinuria.

　　(2) Immunological pathogenesis:

　　① Participation of humoral immunity: includes factors such as immune complexes (IC), abnormal immunoglobulins (low IgG in blood, increased catabolism, decreased synthesis), reduced antibody production, and many other factors.

　　② Abnormal cell-mediated immunity: a series of abnormal changes appear due to reduced numbers and function of T lymphocytes in the circulation.

　　③ Complement system: includes insufficient B factor in the bypass pathway affecting the body's regulatory ability to encapsulated Escherichia coli, pneumococcus, decreased complement activity, and the appearance of C5b-9 (membrane attack complex).

　　(3) Other factors: include direct damage to glomeruli by antibodies, release of proteolytic enzymes by neutrophilic polymorphonuclear leukocytes (PMN), production of reactive oxygen species, release of cationic proteins, aggregation of monocytes to release various proteases, collagenase, oxygen free radicals, cytokines, platelet activating factor, and other factors, all of which participate in the pathogenesis of nephritis.

　　(1) Edema: The mechanism of edema in nephrotic syndrome has seen many advances in recent years. In addition to the low blood volume accounting for only 7% to 38%, which can be explained by traditional views, more studies have shown that many renal factors also play a role.

　　(2) Hyperlipidemia: Refractory nephrotic syndrome resistant to hormones is type IV hyperlipidemia, characterized by elevated very low-density lipoprotein (VLDL) and decreased high-density lipoprotein (HDL), which affects cholesterol clearance. The危害 of hyperlipidemia is not only due to the increased risk of atherosclerosis but also because VLDL has nephrotoxicity, can bind to polyvalent anions of GBM and enter the mesangial area to cause renal damage, reducing negative charge, increasing membrane permeability, causing large molecular weight lipoproteins to deposit in the mesangial area, ultimately leading to glomerulosclerosis. In addition, hyperlipidemia not only increases blood viscosity but also causes cholesterol deposition to roughen the capillary endothelial wall, alter negative charge, causing negatively charged platelets to deposit and form thrombi. At the same time, the fibrinolysis system undergoes a series of changes, including increased plasma fibrinogen, coagulation cofactors (V, VIII), β-thromboglobulin, increased platelet count, enhanced adhesion and aggregation function, decreased activity of plasmin and antithrombin III (ATIII), and decreased enzyme factors (II, X, etc.).

　　1. Infection

　　Infection is a common complication and cause of death in nephrotic syndrome. Common infections include pneumococcal pneumonia, streptococcus, Haemophilus influenzae, Klebsiella pneumoniae, and other bacterial infections; occasionally, Pneumocystis carinii infection may occur, which often affects the peritoneum, lungs, and skin. The reasons for the high incidence of infection in this disease, in addition to fluid, cellular immune deficiency, and complement factors, include the fact that ascites can become a culture medium, and the use of hormones and immunosuppressants can further reduce immune function, making infections more likely.

　　2. Hypovolemic shock and acute renal failure

　　1. Hypovolemic shock:

　　Some children have low blood volume and are in a 'fragile' state, and are prone to hypovolemic shock if they experience triggers such as vomiting, diarrhea, insufficient intake, infection, etc. If a large dose of hormone is taken for a long time and suddenly stops, it may present with 'adrenal crisis'.

　　2. Acute renal failure:

　　Renal pre-renal, renal, and post-renal acute renal failure can be caused by various factors such as hypovolemia, interstitial edema of the kidney, and/or renal tubular obstruction, and acute renal vein thrombosis (RVT).

　　3. Hypercoagulability and thromboembolism:

　　When kidney patients suddenly experience back pain (costovertebral angle tenderness), hematuria, renal function impairment, and hypertension, RVT should be highly suspected. Thromboembolic complications can also occur in the veins or arteries, with an incidence rate of 8.5% to 44%; thrombophlebitis can also be seen in the femoral vein, pulmonary artery, femoral artery, mesenteric artery, cerebral artery, coronary artery, and thrombophlebitis of the lower leg.

　　4. Disturbance of renal tubular function:

　　Multiple substance transport disorders may occur, such as glycosuria, aminoaciduria, increased urine potassium, and decreased urine concentration.

　　5. Protein and calorie intake:

　　Malnutrition is caused by the loss of a large amount of protein in urine over a long period of time.

　　6. Deficiency of other trace elements:

　　Deficiency of zinc, copper, and iron due to the loss of zinc-binding protein, ceruloplasmin, and transferrin in urine; the impairment of 1,25-(OH)2D3 synthesis and long-term hormone use can lead to renal osteopathy and growth retardation.

　　1. Edema

　　The degree of edema in NS varies, with obvious looseness of the tissue and lower body position. Edema moves with the force of gravity, and is most prominent in the eyelids, posterior head, or sacral area in the morning or after a long period of lying down, while after getting up and moving around, edema in the lower limbs becomes more noticeable. In severe cases, there may be generalized edema, scrotal edema, or pleural and peritoneal effusion, even pericardial effusion. In cases of severe edema, the local skin may become shiny, thin, and even show white streaks (commonly seen in the abdomen, buttocks, and thighs). When the skin is damaged, tissue fluid leakage is persistent. Serous cavity effusion often produces compressive symptoms, such as chest tightness, shortness of breath, or difficulty breathing, and chest and abdominal effusions are often milky white, containing emulsified lipids, with a very low protein content (1-4g/L), a specific gravity below 1.016, negative Rivalta test, indicating an exudate. The degree of edema is not related to the severity of the disease or the condition, although it is related to hypoalbuminemia, it is not closely related. Microscopic nephrotic syndrome often presents with severe generalized edema, while membranous nephropathy and membranoproliferative glomerulonephritis often present with moderate lower limb edema when NS occurs. Edema is an outstanding manifestation at a certain stage in the process of glomerular disease, and some patients can regress spontaneously after several months or 1-2 years. The degree of edema is often affected by the intake of sodium and salt, and urine output decreases before and during the onset of edema.

　　Two, Hypertension

　　About 20% to 40% of adult NS patients have hypertension, and about half of those with significant edema have hypertension. Hypertension can be renin-dependent or volume-dependent. Persistent hypertension is mainly related to underlying renal lesions, such as membranous proliferative glomerulonephritis and focal segmental glomerulosclerosis, where about half of the patients have hypertension. Membranous nephropathy has hypertension in only about 1/4 of patients, and minimal change disease even less. Even if hypertension occurs, most cases are transient, and blood pressure returns to normal when edema subsides. It is generally believed that hypertension caused by glomerular diseases, especially in NS, is mainly volume-dependent but closely related to pathological changes. Hypertension in minimal change disease and membranous nephropathy is often volume-dependent; in proliferative and sclerotic glomerulonephritis, the NS has hypertension that is both volume-dependent and renin-dependent, and most cases have both. In recent years, some people believe that plasma renin activity in glomerular diseases may not necessarily increase, and even some patients may have decreased plasma renin. At the same time, many evidence suggests that sodium excretion disorder is a cause of hypertension in glomerular diseases. Hypertension is usually moderate, with blood pressure often between 18.7-22.7/12.7-14.7 kPa (140-170/95-110 mmHg). Therefore, hypertension crisis or hypertensive encephalopathy is rarely seen in NS.

　　Three, Hypoproteinemia and Malnutrition

　　Long-term and persistent proteinuria can lead to malnutrition, which is well known. Patients may exhibit symptoms such as thinning hair, dryness, and yellowish hair, pale skin, emaciated muscles, and white lines across the nails (Muchreke lines) as signs of malnutrition. When hypoproteinemia is obvious, the concentration of other proteins in plasma also changes. Proteins with a smaller molecular weight and similar charge to albumin often decrease, mainly lost through urine, such as thyroid-binding globulin (molecular weight 36,500), vitamin D-binding protein (molecular weight 59,000), antithrombin III (molecular weight 65,000), transferrin (molecular weight 80,000), and the B factor of the complement system (molecular weight 80,000), which are excreted in increased amounts in urine. Clinically, corresponding symptoms may appear.

　　1, Thyroid Function Decreased:

　　NS patients often present with a low metabolic state, with reduced oxygen consumption possibly related to general edema and reduced skin blood flow. Thirty years ago, it was found that the protein-bound iodine in their plasma decreased, and the protein-bound iodine in urine increased. Administering high doses of thyroxine to the patients does not lead to a hypermetabolic state, and the thyroid iodine uptake rate is normal or increased. These data indicate that triiodothyronine (T3) and thyroxine (T4) are excreted more from urine, leading to reduced plasma concentrations, causing the patient to be in a low metabolic state. However, the plasma free T3 and T4 are often normal.

　　2, Hypocalcemia:

　　Due to the loss of vitamin D binding protein from urine, the concentration of plasma 25-OHD3 and 1,25-(OH)2D3 decreases, leading to impaired intestinal calcium absorption and the destruction of bone's response to parathyroid hormone, causing hypocalcemia and secondary hyperparathyroidism in the patient, leading to osteomalacia and cystic fibrosis of bone. The decrease in serum calcium is balanced with the decrease in serum albumin. It is generally believed that a decrease of 10g/L in serum albumin corresponds to a decrease of 0.25mmol/L in serum calcium, and a decrease of 0.05～0.07mmoL/L in serum free calcium, which is due to the reduction of albumin-bound calcium. A decrease of 10g/L in serum albumin leads to an increase of 3.7mmol/L in HCO3-, and a decrease of 3mmoL/L in the anion gap. Therefore, in cases of severe hypoalbuminemia, metabolic alkalosis may occur.

　　3, Iron Deficiency Anemia:

　　Due to the continuous loss of transferrin from urine, the patient may develop iron deficiency anemia, which often fails to respond to iron treatment in this hypochromic microcytic anemia.

　　Four, Secondary Infection

　　Due to immune dysfunction (B factor,调理素and IgG reduction), the loss of a large amount of protein, malnutrition and other factors make the patient prone to secondary infections. Deficiency of complement system B factor, loss of serum调理activity, combined with increased renal immunoglobulin degradation metabolism and loss in urine, lead to reduced body's ability to resist infections, hence the susceptibility to secondary infections. The common infections in NS include respiratory tract infections, urinary tract infections, skin infections, and peritonitis, etc. These infections often worsen NS further. Before the widespread use of antibiotics, infections were the main cause of death in NS. The routine use of corticosteroids and anticytotoxic drugs for NS has not reduced the incidence of secondary infections. The use of antimicrobial drugs to control and prevent bacterial infections has led to an increasing trend in the incidence of viral infections and fungal infections. Therefore, infection is still an important complication of NS.

　　Fifth, hypercoagulable state

　　Most NS patients are in a hypercoagulable state and have a tendency to form thrombi. Addis (1948) first reported the occurrence of leg vein thrombosis in NS patients, followed by reports of thrombosis in pulmonary artery, axillary, subclavian, external jugular, coronary artery, humeral, and mesenteric artery, etc. Renal vein thrombosis was first discovered by Raver (1840). It is more common in patients with lupus nephritis, amyloid nephropathy, membranous nephropathy, and membranoproliferative glomerulonephritis, but it is rare in focal segmental glomerulosclerosis, minimal change disease, and diabetic nephropathy. The reasons for the hypercoagulable state in NS are multifaceted. Many scholars confirm that platelet dysfunction plays an important role in the glomerular damage of chronic immune complex nephritis. Intra-vascular coagulation is a decisive factor leading to irreversible glomerular damage. In 1972, Cochrene et al. pointed out that the induction of platelet aggregation by immune complexes is the first step in the chronic fibrin deposition within glomeruli. It is now known that components C432, C3b, and C6 of the complement, and IgG2 and IgG4 of immune complexes can cause platelet aggregation and release the third factor of platelets. Glomerular capillary endothelial injury, collagen exposure, and platelet aggregation (release ADP) can promote the activation of coagulation factor XII, leading to intravascular coagulation. Hyperlipidemia is one of the factors that cause an increase in plasma viscosity.

　　Other macromolecular proteins, such as alpha2-globulin (molecular weight 8.2×10^5), beta-globulin (molecular weight 3.2×10^5), and beta-prelipoprotein (molecular weight 5×10^6 to 2×10^7) all significantly increase. In coagulation factors, fibrinogen (Ⅰ), labile factor (Ⅴ), stable factor (Ⅶ), antihemophilic globulin (Ⅷ), and Stuart factor (X) all increase, while anticoagulant protein III decreases. These are important signs of increased blood coagulability. Some people believe that a decrease in fibrinolytic activity is also closely related, and it has been proven that antithrombin III inhibitor (alpha2-antiplasmin) increases during NS. Overuse of corticosteroids and diuretics during the course of the disease can make the hypercoagulable state more severe. Hypercoagulable state is prone to promote the formation of thrombi in the blood vessels, extensive fibrin deposition in glomeruli, further deterioration of renal function, and exacerbation of edema and proteinuria. If renal vein thrombosis occurs during the NS process, renal congestion becomes more severe, the kidney volume increases, renal function further deteriorates, and edema and proteinuria worsen.

　　Sixth, renal insufficiency

　　Renal insufficiency can occur in all pathological types of nephrotic syndrome. There are two types of renal insufficiency associated with nephrotic syndrome, namely acute and chronic. Clinically, those with acute onset present with acute glomerulonephritis syndrome and are prone to oliguric acute renal failure. Microscopic polyangiitis and mild renal lesions are more likely to develop acute renal failure. In addition to renal intrinsic lesions, factors such as decreased effective blood volume, reduced cardiac output, and electrolyte imbalance are also triggering factors. The prognosis is closely related to renal intrinsic lesions. During the period of marked edema or active phase of lesions, renal insufficiency often occurs, with increased serum urea nitrogen and creatinine. After the edema subsides, it returns to normal. Even if the edema of nephrotic syndrome due to chronic glomerulonephritis completely subsides, renal function often cannot return to normal. Persistent severe proteinuria patients may be accompanied by renal tubular atrophy and interstitial fibrosis, presenting with Fanconi syndrome, renal tubular toxicity, rickets, or osteomalacia, which symbolize poor prognosis. In terms of pathological type, patients with minimal change nephrotic syndrome who are sensitive to corticosteroids generally have normal renal function and are unlikely to develop chronic renal insufficiency. Focal segmental glomerulosclerosis often has reduced creatinine clearance, about 10% have azotemia, and patients diagnosed early with focal segmental glomerulosclerosis.

　　About 40% of patients progress to renal failure within 10 years. Membranous nephropathy has normal renal function at the initial stage, followed by a slow decline, and develops into chronic renal failure in 15 years, accounting for 50% in adults and 10% to 15% in children. Nephrotic syndrome caused by membranoproliferative glomerulonephritis usually has renal function decline at the onset, about half of which develop into renal failure within 10 to 15 years. The onset can be acute or chronic, with symptoms such as respiratory tract infection or skin infection before onset, or without any precipitating cause. Severe edema is an outstanding symptom of the disease, often accompanied by decreased urine output. Some children have hematuria (gross or microscopic hematuria), some have hypertension, and some severe edema patients with renal disease may have pleural effusion and ascites.

　　Onset of the disease is often associated with various infections and nephrotoxic substances such as mercury, bismuth, gold, and dimethylglyoxime. It is necessary to actively prevent and treat various infections, enhance physical fitness, and prevent contact with various nephrotoxic substances. Keep the living environment fresh, avoid crowded places, maintain skin cleanliness, prevent skin injuries, prevent infections, and treat infections promptly. Consume easily digestible and light diet. Pay attention to the combination of physical and mental work and rest, enhance the body's immunity, and pay attention to physical exercise. Regularly re-examine routine urine tests and renal function.

　　1. Urinalysis

　　Urinary protein is significantly increased, the diagnostic criteria for qualitative urine protein examination are not uniform, the International Society of Pediatric Nephrology (ISKDC) takes >40mg/(h·m2) as the standard, and some advocate taking >50mg/(kg·d) as the range of proteinuria in nephrotic syndrome. Considering the difficulty of collecting 24h urine in children, some advocate measuring the ratio of urinary protein/urinary creatinine in morning urine, when the ratio (in mg/mg) is >3.5, it is considered as nephrotic level proteinuria.

　　2. Plasma protein

　　Total protein in plasma is lower than normal, and the decrease in albumin is more obvious, often

　　3. Serum cholesterol

　　Significantly increased, other lipids such as triglycerides, phospholipids, etc., can also be increased, and due to the increase in lipids, the serum can appear milky white.

　　4. Renal function examination

　　Generally normal, in cases with very little urine volume in simple cases, there may be transient azotemia, a few patients with nephritis may have azotemia and low complement levels, routine ultrasound, X-ray, and electrocardiogram examinations are performed. Generally, renal biopsy is not necessary for initial cases. For cases that are resistant to hormones, frequently recur, or are dependent on hormones, or whose condition changes during the course of the disease and there is a suspicion of interstitial nephritis or crescent formation, or when there is a slow decline in renal function, biopsy should be performed to clarify the pathological type and guide treatment.

　　Nephrotic syndrome is a chronic consumptive disease, and the prominent manifestation seen by parents is generalized edema. The child's urine contains a large amount of protein, leading to hypoalbuminemia (decreased plasma albumin content, normally 6~7 grams per 100 milliliters of blood) and hypercholesterolemia (increased blood lipids, normally 190~200 milligrams per 100 milliliters of blood) due to the long-term excretion of protein in urine. In view of the above conditions, the diet chosen should be high in calories, high in protein, low in fat, low in sodium, high in calcium, and rich in vitamins. However, children often have poor appetite and are unwilling to eat, so it is difficult to supplement high protein and high calories. Therefore, it is necessary to improve cooking techniques as much as possible, pay attention to the color, smell, and taste of food, reduce the amount of food, and improve the quality to meet the requirements of nephrotic nutritional therapy. To maintain sufficient energy for the body to recover, high carbohydrate foods can be provided, in addition to rice and noodles, more candied fruits or glucose can be eaten. To supplement the lost protein and maintain the needs of growth and development, protein should be supplied at a rate of 3~5 grams per kilogram of body weight, with an appropriate ratio of animal protein to plant protein being half and half. Fats should be obtained from plant foods such as vegetable oil and margarine. Foods such as fruits and vegetables contain pectin and fiber, which have a long-term lowering effect on cholesterol.

　　I. Treatment

　　For patients with kidney disease resistant to hormones, renal biopsy should be performed to understand the nature of renal lesions to guide treatment.

　　1. Diet therapy:

　　The principle is to provide a diet rich in calories, low in protein and fat, the rational dietary composition ratio is carbohydrates > 60% (sucrose less than 1/3, high fiber and polysaccharides at least 1/2); protein 8% to 10% (i.e., 1.2 to 1.8g/kg per day, high-quality protein is preferred); fat

　　2. Drug therapy:

　　(1) Glucocorticoid preparations: They are still the first choice for inducing kidney disease remission, generally using medium-effect preparations prednisone (Prednisone) or prednisolone (Prednisolone), the plan is:

　　① Short-term therapy: That is, giving prednisone (2mg/kg per day; maximum dose ≤ 60mg per day), achieving complete remission in 4 weeks can be changed to intermittent therapy (taking the original dose every other morning), gradually reducing to discontinuation, total course 8-12 weeks, suitable for primary cases sensitive to hormones, if treatment fails, it should be changed to medium to long-term therapy,

　　② Medium to long-term therapy: A. Induction therapy: Administering a sufficient dose of prednisone (2mg/kg per day, ≤ 60mg per day) for 4-8 weeks (even if sensitive to prednisone, the minimum course of treatment should be at least 4 weeks); if the urine protein does not turn negative after 8 weeks of sufficient dose, the course can be extended to 10 weeks, but not more than 12 weeks, complete remission can be achieved in some cases (delayed response), B. Intermittent therapy: For patients who have achieved remission with hormone induction therapy, intermittent therapy can be changed, that is, taking the original dose every other morning, and then reducing 2.5-5mg every 2 weeks until discontinuation, total course 6 months (medium course), for cases insensitive to hormones, intermittent therapy with slow reduction of dose every other day can be adopted, total course 1 year or longer (long course),

　　③ Methylprednisolone pulse therapy: Methylprednisolone (Methylprednisone) is a highly effective, short-acting preparation with powerful anti-inflammatory, immunosuppressive, and renal function improvement effects. The treatment plan is to administer 15-30mg/kg dissolved in 10% glucose solution (entering within 1 hour), once a day, for 3 days as a course, with a 1-2 week interval, and the second and third courses can be repeated if necessary. During the pulse therapy, electrocardiogram monitoring is required, and attention should be paid to the other side effects of the drug,

　　④ Tail dragging therapy: In recent years, some people have advocated the use of this therapy for patients with frequent recurrence of nephrotic syndrome, the hormone dose of this therapy is ≤ 0.5mg/kg (e.g., 5-10mg, once every other day), this small dose is greater than the threshold dose for recurrence, long-term maintenance, this therapy has few side effects, not only reducing the frequency of recurrence, but also making it easier to control the condition and achieve remission once recurrence occurs.

　　(2) Immunosuppressive agents: The application of immunosuppressive agents can significantly reduce the recurrence of kidney disease, extend the remission time, but the side effects of immunosuppressive agents cannot be ignored, appropriate dosage and timing should be mastered, and caution should be exercised during the pubertal period,

　　① Cyclophosphamide: It is the first choice of immunosuppressive drugs, and its use can increase the sensitivity of renal patients to hormone therapy, known as the 'softening' effect.

　　A, Oral administration: 2.5mg/kg per day, once a day, in the morning, total dose ≤ 200mg/kg per day (course 2-3 months),

　　B. Intravenous method: 0.5g/m2/time, once a month, the course of treatment is half a year (6 times), suitable for minimal change nephropathy.

　　② Benzyl mustard: 0.1-0.2mg/kg/day, oral administration, total dose

　　③ Azathioprine: 1-3mg/kg/day, the course of treatment is 3 months, or thioguanine (6-TG): 1.5mg/kg/day, the course of treatment is yet to be explored.

　　④ Cyclosporine (cyclosporine, CS): In recent years, there have been reports that this drug is used to treat patients with hormone-dependent nephrotic syndrome. Observations show that CS at low doses not only reduces the recurrence rate but also most patients' growth is not affected, and it also reduces obesity and other hormone side effects. However, the drug is expensive and has side effects such as nephrotoxicity, which limits its application. The treatment plan for CS is to start using CS after the remission of hormone therapy, with a dose of 3-5mg/kg/day, then adjust to 200-400mg/ml blood level to maintain for 6 months (high-dose CS); then reduce CS to 2.5mg/kg/day, use for 12 months (low-dose CS).

　　(3) Other:

　　① Traditional Chinese medicine:

　　A. Tripterygium glycosides tablets: 1mg/kg/day (

　　B. Ferulic acid piperazine (Bao Shen Kang) (50mg/tablet): 10mg/kg/day, the course of treatment is 3 months or longer, it is effective in reducing plasma fibrinogen.

　　C. Chuanxiong lignans (50mg/tablet): 10mg/kg/day, the course of treatment is yet to be explored. There are reports that this drug can reduce the level of interleukin-2 (IL-2) in plasma, which is helpful for the remission of nephropathy.

　　② Immunomodulators: Used for patients with recurrent infections.

　　A. Transfer factor: 1 vial/time, twice a week, intramuscular injection, the course of treatment is 4-8 weeks.

　　B. Thymosin (Thymopeptide): 5mg/time, once a day, intravenous injection, a skin test is required before use, the course of treatment is 2-4 weeks.

　　③ Lipid-lowering drugs: such as inositol nicotinate 0.2/time, 3 times a day.

　　3. Symptomatic supportive therapy:

　　(1) Infusion of plasma, human gamma globulin, etc.: Used for patients with recurrent infections.

　　(2) Low molecular weight dextran: 50-200ml/d, once a day, can reduce blood viscosity and prevent thrombosis.

　　(3) Diuretic therapy: Furosemide (Lasix) can be administered at a dose of 1mg/kg, either by intramuscular injection or after dilution for intravenous injection.

　　(4) Human serum albumin intravenous infusion therapy: There is controversy, it was previously believed that the infusion of human serum albumin could supplement the loss of protein in urine, and the infusion of furosemide (Lasix) can achieve a good diuretic effect. Recent reports suggest that if the infusion of human serum albumin exceeds 20g/d, it can lead to protein overload nephropathy, damage glomerular epithelial cells, and patients with minimal change nephropathy may experience two adverse consequences after the infusion of human serum albumin: one is that the infusion of human serum albumin interferes with the pharmacokinetics of prednisone, thus delaying the response to corticosteroid therapy; the other is that the infusion of human serum albumin may damage glomerular epithelial cells, causing a relatively long-term and persistent pathological change, manifested as frequent recurrence.

　　4. Treatment of complications:

　　(1) Prevention and treatment of infection: It is an important link to reduce mortality. In addition to bacterial infection, we need to increase awareness of opportunistic pathogen infection and make correct diagnosis and treatment in a timely manner.

　　(2) Rational diet: Pay attention to ensure that the patient's diet has sufficient calories and a rationalized structural ratio, and supplement the necessary vitamins and trace elements.

　　(3) Anticoagulation therapy: When patients have severe hypoalbuminemia and severe hypercholesterolemia, they often have high levels of plasma fibrinogen. Pay attention to check the prothrombin time, platelet count, and plasma fibrinogen to guide and monitor the use of the following anticoagulation therapy to avoid bleeding side effects. Anticoagulation therapy includes the following drug composition:

　　① Anticoagulants: Heparin, Warfarin, Coumarin, etc.

　　② Fibrinolytic drugs: Urokinase, snake anticoagulant enzyme, paeoniflorin piperazine (Bao Shen Kang), etc.

　　③ Platelet aggregation inhibitors: Dipyridamole (Persantin), Aspirin, etc.

　　II. Prognosis

　　For half a century, effective antimicrobial drugs, adrenal cortical hormones, and immunosuppressants have been successively introduced, significantly improving the prognosis of pediatric nephrotic syndrome. The 5-year mortality rate has decreased from 60% to 70% in the era without antimicrobial drugs to about 10% in the era of prednisone use; the mortality rate has further decreased after the use of immunosuppressants, especially in the minimal change type. It should be pointed out that the prognosis and outcome of this condition are closely related to the pathological type and resistance to hormones. According to the 1-18 year follow-up observation by Habib et al. (1971), the cases developing into chronic renal failure or death include 7% with minimal change, 38% with focal segmental sclerosis, 80% with membranous nephropathy, and 41.5% with membranoproliferative glomerulonephritis.