Hepatitis B virus-associated nephritis in children

　　What causes pediatric HBV-related glomerulonephritis?

　　First, Etiology

　　HBV is a spherical particle with a diameter of 42-45nm (dane particle), a DNA virus composed of a double shell and a core, containing double-stranded DNA and DNA polymerase. One negative strand is a long chain of about 3.2kb, and the other positive strand is a short chain of about 2.8kb. The long chain DNA contains HBsAg, HBcAg, HBeAg, DNA polymerase, and X protein. In HBV-related glomerulonephritis, the main antigens deposited in the glomerular capillary wall are HBsAg and HBeAg. Ozawa and Hattor have respectively eluted and found anti-HBsAg antibody and anti-HBeAg antibody from the renal tissue of HBV-GN patients. Immunoelectron microscopy shows that the above HBV antigens and immunoglobulins are deposited at the same site in the glomerulus. These results all support that HBV-GN is an immune complex glomerulonephritis caused by HBV antigen components.

　　Second, Pathogenesis

　　Nephrotic syndrome is the most common pathological type of HBV-GN in children, and it is currently believed that the immune complexes under the glomerular basement membrane are formed in situ. Animal experiments suggest that antigenic polypeptide molecules that can penetrate the glomerular basement membrane and locate under the epithelium generally have a molecular weight of less than 300-500kd. The molecular weight of HBeAg is small, and even when combined with IgG, it does not exceed 300kd, and it carries a positive charge (PI 4.3-4.8), which meets the conditions for causing nephrotic syndrome. HBsAg is above 3.7Md and PI is about 4.0, HbcAg is above 8Md and PI is 3.7-4.0. Not only is the molecular weight too large, but it also carries a negative charge, so it is unlikely to penetrate the basement membrane and form an in situ complex under the epithelium, but it may deposit in the mesangial area and cause disease. Despite this, most HBV-GN children in clinical practice still have HBsAg deposition under the glomerular epithelium. Therefore, some people believe that the HBsAg deposited under the epithelium at this time is not a complete molecule, but a subunit containing antigenic determinants produced after metabolism. Its molecular weight is small, can penetrate the basement membrane and implant in situ, and ultimately lead to the occurrence of nephrotic syndrome. In addition, some people believe that HBV infection can induce autoantibodies and cause HBV-GN. Since HBV can directly infect the kidney and cause disease, this is also possible. However, both pathogenic mechanisms are still controversial and need further research to be confirmed. Pathological studies, the Asian Pediatric Nephropathy Research Society reported that 66.1% of children with HBV-GN have nephrotic syndrome, 16.1% have minimal change, and 8.1% have membranoproliferative glomerulonephritis. The histological changes are different from typical nephrotic syndrome:

　　1, Mesangial cell proliferation often occurs with mild to moderate mesangial cell proliferation, and the proliferating mesangium has insertion, but it is mostly limited to the parmesangial area and rarely extends to the subendothelial space of the distal capillaries.

　　2, More immunoglobulin deposits in the basement membrane and mesangial area, making the immunofluorescence show coarse granules or even clumps under the immunofluorescence microscope, rather than the fine granular appearance of primary membranous nephropathy. Immunofluorescence or enzyme marker examination with anti-HBsAg and HBeAg antibodies can detect the deposition of HBeAg and/or HBsAg in the glomeruli, which is also a necessary condition for the diagnosis of HBV-GN.

　　Children with hepatitis B virus-related nephritis often have the following diseases: chronic hepatitis, and some may develop hepatic failure, have ascites, renal insufficiency, hypertension, hypoalbuminemia, and so on.

　　One, Chronic Hepatitis

　　Chronic hepatitis usually refers to the condition where acute hepatitis B or acute hepatitis C does not heal after long-term treatment, with the course lasting over half a year, and then turning into chronic hepatitis. There are also many cases of chronic hepatitis where people are infected with hepatitis virus, and the onset is hidden, and it has become chronic hepatitis when found. The main symptoms are as follows:

　　1, Loss of appetite:

　　Loss of appetite, feeling of dullness in the epigastrium after eating, and aversion to greasy food.

　　2, Fatigue:

　　Lack of strength in the limbs, and general fatigue and drowsiness.

　　3, Costal pain:

　　Pain often increases or decreases due to changes in mood.

　　4, Abdominal distension:

　　Feeling stuffy in the epigastrium, and abdominal distension.

　　Two, Hepatic Failure

　　When the liver is damaged by certain pathogenic factors, it can cause the destruction of liver morphology and structure (degeneration, necrosis, liver cirrhosis) and abnormal liver function. However, due to the liver's huge reserve and regeneration capacity, mild damage generally does not cause obvious functional abnormalities through the liver's compensatory function. If the damage is severe and widespread (either once or long-term repeated damage), it can cause obvious changes in liver function, such as significant disorders in material metabolism, reduced detoxification function, obstruction in the formation and excretion of bile, and tendency to hemorrhage, which is called hepatic insufficiency (hepatic insufficiency). Severe liver function damage that cannot eliminate toxic metabolic products in the blood or a disorder in material metabolism balance can cause functional disorders of the central nervous system (hepatic encephalopathy), which is called hepatic failure (hepatic failure).

　　Three, Ascites

　　Under normal conditions, there is a small amount of fluid in the abdominal cavity of the human body (generally less than 200ml), which plays a lubricating role in intestinal peristalsis. Any pathological condition that causes an increase in the amount of fluid in the abdominal cavity, exceeding 200ml, is called ascites (ascites). Physical examination of ascites often has signs of the primary disease in addition to mobile dullness.

　　Four, renal insufficiency

　　In the early stage of renal insufficiency, only the symptoms of the primary disease are present clinically, which can affect various organs and tissues in the body and appear corresponding symptoms.

　　Five, hypertension

　　Without the use of antihypertensive drugs, systolic blood pressure ≥139mmHg and/or diastolic blood pressure ≥89mmHg, hypertension is divided into grades 1, 2, and 3 according to blood pressure levels. Systolic blood pressure ≥140mmHg and diastolic blood pressure

　　Six, hypoproteinemia

　　Refers to the decrease in total plasma proteins, especially plasma albumin.

　　1. Onset

　　Most cases occur in the pre-school and school age periods, with boys significantly more than girls, mostly insidious onset, often found to be abnormal during accidental urinalysis.

　　2. Edema

　　Most symptoms are not prominent, and there is no obvious oliguria, but there are also a few children with obvious caved-in edema and abdominal effusion.

　　3. Hematuria

　　Almost all patients have microscopic hematuria, which persists, often after the proteinuria becomes negative, microscopic hematuria still persists for a period of time, and some patients develop paroxysmal gross hematuria on this basis.

　　4. Proteinuria

　　All patients have varying degrees of proteinuria, which shows a significant fluctuation, sometimes light and sometimes severe. The ASRSC reported that about 61.3%表现为肾病综合征, but generally have no response to adrenal cortical hormone treatment.

　　5. Hypertension

　　Most symptoms are not prominent, and mainly seen in patients with membranous proliferative nephritis.

　　6. Renal insufficiency

　　Rare.

　　7. Liver symptoms

　　Most symptoms are not prominent, about half of the children have liver enlargement or abnormal liver function, manifested as elevated transaminases, but jaundice is rare.

　　How to prevent hepatitis B virus-related nephritis in children?

　　The key to preventing this disease lies in the active prevention and treatment of hepatitis B, especially perinatal vertical infection. In recent years, significant progress has been made in the research of hepatitis B vaccine, which has been listed as a planned immunization program and widely applied, creating good conditions for the prevention and treatment of hepatitis B. The key measures for preventing hepatitis B are:

　　1. Vaccination against hepatitis B.

　　2. Screening blood donors, using disposable syringes.

　　Before contacting a hepatitis B patient, vaccination should be administered, which has a significant effect. Within 7 days after contacting a hepatitis B patient, intramuscular injection of hepatitis B immune globulin is also effective. In a long-term follow-up observation of recipients of hepatitis B vaccination to prevent perinatal vertical infection from HBe antigen-positive pregnant women, 47 of the 53 cases (89%) were positive for HBs antibody after the age of 5, and no HBs antigen-positive cases were found, achieving good results. It is believed that in the near future, with the control of hepatitis B, the incidence of this disease will inevitably decrease.

　　1. Urine

　　Hematuria and proteinuria may occur, as well as tubular urine, with the main urine protein being albumin.

　　2. Blood biochemistry

　　There is often a decrease in albumin, an increase in cholesterol, and the alanine aminotransferase and aspartate aminotransferase may be elevated or normal. The plasma protein electrophoresis α2 and β-globulin are elevated, while γ-globulin is often normal.

　　3. Hepatitis B serological markers and HBV-DNA

　　Most patients are HBV大三阳(HBsAg, HBeAg, and HBcAb positive), a few patients are HBV小三阳(HBsAg, HBeAb, and HBcAb positive), and those with only HBsAg positive are rare. HBV-DNA in blood is generally positive.

　　4. Immunological examination

　　Some people think that blood IgG and IgA levels are elevated, but there are also reports that 50 or more cases of HBV-GN membranous nephropathy children have no increased IgG and IgA, on the contrary, about 1/3 show decreased blood IgG, complement C3 is slightly decreased or at the lower limit of normal, renal biopsy is the final means to determine HBV-GN, and it is a necessary condition for diagnosing HBV-GN. Other routine examinations include ultrasound, electrocardiogram, etc.

　　Avoid spicy foods.

　　Spicy foods are prone to cause dampness and heat in the digestive tract, leading to imbalance of liver and gallbladder Qi, and weakened digestive function. Therefore, it is advisable to avoid eating spicy foods.

　　Avoid smoking.

　　Cigarettes contain various toxic substances that can damage liver function, inhibit the regeneration and repair of liver cells, so liver disease patients must quit smoking.

　　Avoid drinking alcohol.

　　90% of alcohol is metabolized in the liver. Alcohol can interfere with and destroy the normal enzyme system of liver cells, directly damaging liver cells and causing necrosis. Patients with acute or chronic active hepatitis will have their condition relapse or change even if they drink a small amount of alcohol.

　　Avoid processed food.

　　Eat less canned or bottled drinks and food. This is because canned and bottled drinks and food often contain preservatives, which have varying degrees of toxicity to the liver.

　　Avoid滥用 hormones and antibiotics.

　　“Medicine has three parts of toxicity”, any medicine can damage the liver and kidneys, so liver disease patients must take medicine under the correct guidance of a doctor.

　　Avoid taking supplements randomly.

　　Dietary balance is the basic condition for maintaining good health. If not properly nourished, the function of the internal organs will be disrupted, and the balance will be broken, which can affect health.

　　Avoid excessive protein diet.

　　For severe hepatitis patients, due to the edema of the gastric mucosa, the thickening and shortening of the villi in the small intestine, and the imbalance of bile secretion, the function of digestion and absorption is reduced. If too much high-protein food such as eggs, turtle, and lean meat is eaten, it can cause indigestion and bloating and other symptoms.

　　Avoid high copper diet.

　　When the liver function is incomplete, it cannot regulate the balance of copper in the body well, and copper is prone to accumulate in the liver. Studies have shown that the storage of copper in the liver of liver disease patients is 5-10 times that of normal people, and the content of copper in the liver of patients with biliary cirrhosis is 60-80 times higher than that of normal people. Medical experts point out that an excessive amount of copper in the liver can lead to necrosis of liver cells, and at the same time, an excessive amount of copper in the body can cause renal insufficiency. Therefore, liver disease patients should eat less seafood, cuttlefish, shrimp, snails, and other foods rich in copper.

　　Avoid irregular lifestyle.

　　The principle of 'three parts for treatment and seven parts for nourishment' emphasizes the importance of adequate sleep, reasonable nutrition, regular lifestyle, and the daily practice of morning exercises, as well as the combination of work and rest.

　　10. Avoid emotional discomfort

　　Patients with liver disease should avoid anger, pessimism, anxiety, and other emotional disorders, because patients with liver disease often have long-term treatment and are prone to anxiety, overthinking, and easy to get angry, which can damage the liver and lead to liver qi stagnation and accumulation of lumps.

　　How should children with hepatitis B virus-related nephritis be treated?

　　First, treatment

　　1. General treatment

　　This includes a low-salt diet, a moderate amount of high-quality protein diet; diuretics should be administered when edema is significant, with various oral diuretics given, and furosemide (furosemide, Lasix) 1-2mg/(kg·time) may be administered intravenously for severe edema; for hypertension, nifedipine (nifedipine,心痛定) 0.25-0.5mg/(kg·time), 3-4 times a day, or ACEI drugs can be taken orally, such as captopril (captopril, thienameth) 1-2mg/(kg·d), 2-3 times a day.

　　2. Treatment with adrenal cortical hormones and immunosuppression

　　The treatment with adrenal cortical hormones has always been controversial. Adrenal cortical hormones and immunosuppressants should be avoided as much as possible for children with mild to moderate proteinuria to prevent exacerbation of viral replication. For HBV-GN with a large amount of proteinuria, some people have tried short-term prednisone therapy to reduce proteinuria. However, recent studies believe that HBV-GN has little effect on corticosteroids, and long-term clinical observations show that adrenal cortical hormones are harmful without any benefits. Therefore, it should be prohibited to use adrenal cortical hormones alone for treatment, and immunosuppressants are even more unsuitable for use.

　　3. Antiviral treatment

　　There are mainly interferon α (α-interferon), cytosine arabinoside (Ara-A), lamivudine (lamivudine-he), and so on. Currently, interferon α treatment for HBV-GN has achieved significant effects, with excellent long-term effects. The dose is 200,000U/(kg·time) of interferon α, injected intramuscularly or subcutaneously once every other day, and the course of treatment should not be less than half a year. Almost all patients can achieve good efficacy, often promoting the negative conversion of HBeAg around 4 months after medication. A few children may still achieve the negative conversion of HBsAg around 10 months after treatment. Proteinuria can be significantly reduced or significantly improved. Fever and flu-like symptoms may occur in the early stage of injection, which will disappear after a few days. Cytosine arabinoside (Ara-A) is also an antiviral drug, first used by Lin's family in Taiwan for the treatment of HBV-GN, achieving certain efficacy. The dose is 15mg/(kg·d), administered intravenously slowly, with a course of 2 weeks. Thymosin can also be used to enhance efficacy, with a dose of 0.2-0.5mg/(kg·d), once a day, for a course of half a year. The adverse reactions of cytosine arabinoside (Ara-A) are significant, and its efficacy is not as good as interferon α, so it has been replaced by α-INF. Lamivudine is a new nucleic acid antiviral drug, with a daily dose of 100mg orally for older children, for a course of more than half a year. Its efficacy for hepatitis B is close to that of interferon α, and it is used less for the treatment of HBV-GN, with efficacy waiting for more data to be determined.

　　4. Antithrombotic Drugs

　　Dipyridamole (dipyridamole; persantin, persantin) 5 to 8mg/(kg·d), 3 times/d, taken orally.

　　5. Angiotensin Converting Enzyme Inhibitors (ACEI)

　　Captopril (captopril) can be used at 0.5 to 1mg/(kg·time), 2 to 3 times/d; or enalapril 2.5 to 5mg/time, 2 to 3 times/d; cilazapril 5 to 10mg/d, 1 time/d; fosinopril 5 to 10mg/d, 1 time/d; benazepril 5mg/d, 1 time/d, etc., which have certain effects on reducing proteinuria and protecting the kidneys.

　　6. Traditional Chinese Medicine and Herbs

　　Traditional Chinese medicine has certain effects on liver protection and inhibiting HBV proliferation. The author once tried Sanpu hepatitis B healthy, A, B tablets 2 to 3 tablets/time, 3 times/d, treated for 3 to 6 months, with satisfactory results; in addition, it can also be selected to take hepatitis B Ning and hepatitis B detoxification capsules for a long time.

　　II. Prognosis

　　There is no specific treatment for this disease, and symptomatic treatment is the main approach. There is controversy regarding the use of hormones and immunosuppressants. However, for patients with nephrotic syndrome, it may be possible to try adrenal cortical hormones under close medical observation. Shanghai Medical University Hospital treated 10 patients with HBV-related nephritis manifesting as nephrotic syndrome with hormones, 7 cases were membranous nephropathy, among which 5 had partial response and 2 were ineffective. However, after 2 to 9 years of follow-up, all 7 cases were relieved, 3 cases of membranoproliferative nephritis were ineffective, including 2 cases with persistent proteinuria for 4 to 9 years and renal insufficiency, and 1 case died of uremia 7 years later. Peking University First Hospital's Department of Pediatrics treated 11 patients with HBV-related nephritis complicated with nephrotic syndrome with prednisone, all showed no effect at 8 weeks, but half of them were relieved after reducing the dose and continuing treatment. The average follow-up was 46.5 months from 10 months to 9.5 years, with 1 case dying of jaundice due to gastrointestinal infection and 1 case developing renal dysfunction at 5 years of disease course, the remaining 9 cases all achieved clinical remission, among which 3 cases had 1 to 3 recurrences during the disease course and were relieved after re-administration of prednisone. The prednisone treatment plan can be referred to primary nephrotic syndrome, but the use of cytotoxic drugs needs to be cautious, as immunosuppressants can accelerate HBV replication and worsen HBV infection.

　　Therefore, it is best not to use it when there is active hepatitis or HBV replication markers (such as high-titer HBcIgM) or positive HBeAg, for those with abnormal liver function, liver protection therapy can be added, such as glucuronic acid (Gan Tai Le), Yunzhi Gan Tai and various vitamins, etc., the diet should be light, less greasy, pay attention to rest, avoid overwork, regular follow-up, and can also take traditional Chinese medicine treatment. In recent years, interferon therapy can be tried for those with persistent HBsAg positivity, currently the interferon used is mostly genetically engineered interferon, which has antiviral effects, mainly through the binding of interferon to interferon receptors on the cell membrane, inducing a variety of antiviral proteins to hinder the synthesis of viral nucleic acids and proteins, inhibit viral replication, but cannot exclude the virus from the body. In Japan, the interferon administration is 100,000 U/(kg·d) for 28 days continuously or 7 days continuously in the first week, then once every other day, three times a week, for a total of 7 weeks (28 days), the former is more widely used, 11 of 16 cases (62%) became negative within a year after the end of the course, but there was no difference in the conversion rate of serum in adults treated with the same method, China commonly used interferon is 1a, 2b, etc., the dose is 3 million U for adults once, every other day or three times a week; children can use 100U, every other day or three times a week, subcutaneous or intramuscular injection, course of 3 to 6 months, fever may occur at the beginning of treatment, antipyretics can be added if necessary, the recent efficacy (at the end of the course) of HBV-DNA and HBeAg conversion rate is 30% to 50%, and about 25% to 50% of patients relapse within a year after discontinuation of medication, the conversion rate of HBsAg is low.