Hepatitis C virus infection and glomerulonephritis

　　The correlation between HCV and cryoglobulinemia was first reported in 1990. Recent studies have found that 95% of patients with type II cryoglobulinemia and 50% of patients with type III cryoglobulinemia have evidence of HCV infection, including: the presence of circulating anti-HCV antibodies in serum, polyclonal IgG anti-HCV antibodies in cryoprecipitates, and the presence of HCV-RNA in plasma and cryoprecipitates. Cryoglobulinemic MPGN associated with HCV was first reported in 1994. Later, HCV-related proteins were detected in renal tissue sections of patients with cryoglobulinemic MPGN using monoclonal antibodies specific for HCV antigens. In 8 of the 12 HCV-positive patients with cryoglobulinemic MPGN, HCV antigens were detected in the glomerular capillary wall and mesangial area, while in 8 HCV-negative patients with cryoglobulinemic MPGN, HCV antigens were not detected. It is now believed that HCV cryoglobulinemic MPGN is mediated by HCV immune complexes, with HCV antigen-antibody immune complexes deposited beneath the endothelium and in the mesangium, activating complement and leading to secondary cell proliferation and inflammatory cell infiltration. However, it is not yet clear whether HCV antigens independently mediate glomerular damage independent of cryoglobulin. The classification of HCV infectious glomerulonephritis is as follows:

　　1. Cryoglobulinemic membranous proliferative glomerulonephritis Cryoglobulinemia refers to the presence of gamma-globulins that are reversibly precipitated at 4°C in serum, which are divided into 3 types due to different compositions: Type I cryoglobulin is a monoclonal immunoglobulin secondary to monoclonal gamma-globulin lesions such as multiple myeloma; Type II cryoglobulin is a mixed cryoglobulin, composed of polyclonal IgG and monoclonal IgM targeting the IgGFc segment, among which IgM has rheumatoid factor activity; Type III cryoglobulin is a mixed polyclonal immunoglobulin, which is more common in inflammatory and autoimmune diseases such as systemic lupus erythematosus. About 50% of patients with Type II cryoglobulinemia develop nephritis, while it is rare in patients with Type III cryoglobulinemia.

　　2. Non-cryoglobulinemic membranous proliferative glomerulonephritis The pathological and clinical course of non-cryoglobulinemic MPGN is similar to that of cryoglobulinemic MPGN. The role of HCV in the pathogenesis of non-cryoglobulinemic MPGN is still controversial.

　　3. Membranous nephropathy: A few HCV patients have renal damage as MN, and the clinical manifestations are nephrotic syndrome, with normal complement levels in serum, negative cryoglobulins and rheumatoid factors. HCV-related proteins are also detected in the renal tissue sections of patients.

　　Complications of hepatitis C virus infection and glomerulonephritis include renal insufficiency, chronic hepatitis, liver failure, and others.

　　1. Renal insufficiency:Caused by various reasons, severe damage to the glomeruli, causing the body to appear clinical syndromes in the excretion of metabolic waste and the regulation of water and electrolyte balance, acid-base balance, and other aspects. It is divided into acute renal insufficiency and chronic renal insufficiency. The prognosis is serious, and it is one of the main diseases threatening life. Renal insufficiency can be divided into four stages: renal reserve compensation period, renal insufficiency period, renal failure period, and uremia period.

　　2. Chronic hepatitis:Due to the long-term treatment of acute hepatitis B and acute hepatitis C without remission.

　　1. Clinical manifestations of hepatitis C: The incubation period of this disease is 2-26 weeks, with an average of 7.4 weeks. The incubation period of hepatitis C caused by blood products is short, usually 7-33 days, with an average of 19 days. The clinical manifestations are generally milder than those of hepatitis B, mostly subclinical without jaundice, with common single ALT elevation, long-term persistent or recurrent fluctuations. The average ALT and serum bilirubin levels of patients are low, and the duration of jaundice is short, but there are also severe cases that are difficult to distinguish from hepatitis B clinically.

　　Hepatitis C virus infection is more likely to become chronic than hepatitis B virus infection. Observations show that 40% to 50% develop chronic hepatitis, 25% develop liver cirrhosis, and the rest have self-limiting courses. Acute hepatitis C often develops into chronic without jaundice, with long-term fluctuating ALT levels that do not decrease, and persistent high-titer positive serum anti-HCV. Therefore, clinical attention should be paid to the changes in ALT and anti-HCV, although the clinical manifestations of hepatitis C are generally mild, severe hepatitis can also occur, and chronic hepatitis B complicated with HCV infection is the most common cause of severe hepatitis C.

　　2. The manifestations of HCV cold agglutinin glomerulonephritis: Cold agglutininemia is a systemic vasculitis lesion, and HCV cold agglutinin glomerulonephritis patients can have various non-specific clinical manifestations, such as purpura, joint pain, peripheral neuropathy, low complement levels, etc. Renal manifestations include hematuria, proteinuria (usually within the scope of nephrotic syndrome), significant hypertension, and varying degrees of renal insufficiency. About 25% of patients present with nephrotic syndrome as the initial manifestation, often with mild elevation of transaminases. Some patients have normal transaminases, and some may not have a history of acute hepatitis.

　　The serological examination for hepatitis C has only recently been gradually improved, but hepatitis C is associated with cold agglutinin glomerulonephritis, and in addition to autoimmune active hepatitis, cold agglutinins and circulating immune complexes can appear in various acute and chronic liver diseases. In addition to common purpura, weakness, joint pain, hepatitis, nephritis, and vasculitis, which can appear in mixed cold agglutininemia, hepatitis C antigenemia is also common. In mixed cold agglutininemia, serum HCV-RNA (hepatitis C virus RNA) is positive in patients with renal damage, anti-HCVAg is positive, and the cold precipitate is positive. The cold precipitate includes HCV-RNA viral core antigen and IgG anti-HCV antibody. However, HCV-RNA has not been localized in the immune deposits in the glomerulus. A 39-year-old woman with hepatitis C antibody positivity and a history of drug abuse presented with weakness, purpura, joint pain, facial and bilateral lower limb edema. This patient had renal proteinuria, renal function impairment, and mixed cold agglutininemia. Therefore, the clinical manifestations of this disease are not specific.

　　HCV is unevenly distributed worldwide, with a higher prevalence of anti-HCV positivity in populations from Southern Europe, the Middle East, South America, and some Asian countries, while in Western Europe, North America, and Australia, the positivity rate of anti-HCV is lower. It is estimated that there are at least 100 million HCV carriers worldwide, with 170,000 new cases annually in the United States and Western Europe, 350,000 in Japan, and an increasing trend. The survey results from 30 provinces, municipalities, and autonomous regions in China from 1992 to 1995 showed a prevalence of hepatitis C of 3.2%, with Liaoning Province having the highest rate (5.1%) and Shanghai the lowest (0.9%). The peak areas are concentrated in the age group of 15 and above. The occurrence of nephritis related to hepatitis C virus should be consistent with HCV. The source of infection for hepatitis C virus is patients and asymptomatic viral carriers, and the role of blood and plasma donors carrying HCV is particularly important. The main transmission routes of HCV include the following aspects:

　　1. Blood transmission of HCV HCV is mainly transmitted through blood or blood products. The infection rate of HCV after blood transfusion varies greatly in reports from abroad, which may be related to blood source, blood transfusion volume, and the HCV carriage rate of the population. The transmission of HCV through blood products also occurs frequently. China once had an outbreak of hepatitis C caused by blood cross-contamination during the process of plasma collection and red blood cell retransfusion, and an outbreak of hepatitis C caused by factor VIII imported from the United States.

　　People frequently exposed to blood, such as hemophiliacs, obstetricians and gynecologists, surgeons, anesthetists, extracorporeal circulation patients during thoracic surgery, renal transplant hemodialysis patients, and cancer patients, are highly susceptible to hepatitis C infection when receiving a large amount of blood or multiple blood transfusions. Intravenous drug abusers are also at high risk of HCV infection. According to an analysis of 441 drug addicts in Kunming, Yunnan, the positive rate of anti-HCV was 60.54%.

　　2. Sexual contact transmission Regarding the sexual contact transmission of hepatitis C, there are different opinions, but the more倾向于的意见 still believes that the sexual contact transmission of HCV should not be ignored.

　　3. Mother-to-child transmission of HCV The mother-to-child transmission of HCV and its transmission rate have always been controversial, with great differences in various reports. Due to the high mutation rate of HCV, analyzing the homology of HCV sequences between mothers and infants is helpful to determine the mother-to-child transmission of HCV. Honda et al. found that the homology of the cDNA sequences of HCV in 3 pairs of HCVRNA-positive mother-child HCV was 95.8%, 97.7%, and 94.0%, respectively, significantly higher than that of the same gene fragment sequence in 23 controls (non-family members). It is generally believed that the mother-to-child transmission rate of HCV is relatively low.

　　4. Household contact transmission Although blood transmission is the most effective transmission method for hepatitis C, at least 15% to 30% of散发型 hepatitis C patients have no history of blood or extraintestinal exposure. HCVRNA positivity has been found in seminal fluid, saliva, and vaginal secretions of hepatitis C patients, suggesting that sexual contact and daily life contact may transmit HCV, but the probability is relatively low.

　　1. Urinalysis may show hematuria and proteinuria, tubular urine, with urinary protein mainly being albumin, and mostly within the range of nephrotic syndrome proteinuria. Acute jaundice-type hepatitis patients may have positive bilirubin and urobilinogen in urine before the onset of jaundice.

　　2. Blood tests show that the total white blood cell count is normal or slightly low, the count of neutrophils may decrease, and the relative count of lymphocytes may increase. When accompanied by renal insufficiency, increased blood urea nitrogen, creatinine, and hypoalbuminemia may be observed.

　　3. Liver function tests can be performed on patients with acute hepatitis symptoms as follows:

　　(1) Serum bilirubin: During the jaundice period, the serum bilirubin level increases day by day, and usually reaches its peak within 1 to 2 weeks.

　　(2) Serum enzyme determination: Alanine aminotransferase (ALT) begins to rise before the appearance of jaundice, reaches its peak during the extreme stage of the disease. Acute hepatitis can have extremely high enzyme activity. During the recovery period, the enzyme activity decreases slowly with the decrease of serum bilirubin. In chronic hepatitis, ALT can fluctuate repeatedly. In severe hepatitis, when the bilirubin level rises sharply, ALT may反而 decrease, which is called 'enzyme-jaundice dissociation', indicating a serious condition.

　　Aspartate aminotransferase (AST) is approximately 4/5 located in the cell mitochondria (ASTm) and 1/5 in the cell fluid (ASTs). When the mitochondria are damaged, the serum AST significantly increases, reflecting the severity of liver cell lesions.

　　In cases of acute viral hepatitis, the ALT value is higher than the AST value. When the lesions of chronic viral hepatitis are continuously active, the ratio of ALT/AST is close to 1. In liver cirrhosis, the increase of AST is often more significant than that of ALT.

　　ALT and AST can increase not only during the active phase of viral hepatitis but also in other liver diseases (such as liver cancer, toxins, drug-induced or alcoholic liver damage, etc.), biliary tract diseases, pancreatitis, myocardial lesions, heart failure, and a variety of other diseases. It is necessary to be identified.

　　Serum lactate dehydrogenase (LDH), cholinesterase (ChE), and r-glutamyl transferase (rGT) can all be altered during acute and chronic liver damage, but their sensitivity and degree of change are far less than that of transaminases. Serum alkaline phosphatase (ALP) can significantly increase in cases of biliary obstruction, liver mass lesions, and can increase in cases of cholestasis and liver cell damage, which can be used to differentiate whether the increase of ALP is related to liver and biliary diseases. Excessive alcohol consumption can also cause an increase in rGT. In chronic hepatitis, after excluding biliary diseases, an increase in rGT indicates that the lesion is still active. In liver failure, the liver cell mitochondria are severely damaged, the synthesis of rGT decreases, and the blood rGT also decreases.

　　(3) Protein metabolism function test: Hypoproteinemia (A1b) is an important indicator of liver disease. Hypoalbuminemia and hyperglobulinemia are characteristic serological indicators for the diagnosis of liver cirrhosis. Serum pre-A1b, due to its half-life of only 1.9 days, is more sensitive to changes in liver parenchymal damage, and its decrease is consistent with the degree of liver cell damage, and its mechanism of change is similar to that of Alb.

　　① Alpha-fetoprotein (AFP): During acute viral hepatitis, chronic hepatitis, and active liver cirrhosis, there may be a short-term low to moderate increase. The increase of AFP indicates the active regeneration of liver cells. In patients with extensive liver cell necrosis, the increase of AFP may indicate a better prognosis. When patients have extremely high serum AFP levels, the possibility of hepatocellular carcinoma is the highest.

　　② Blood ammonia measurement: In severe hepatitis liver failure, ammonia cannot be synthesized into urea for excretion. In patients with well-functioning portosystemic collateral circulation in liver cirrhosis, blood ammonia levels can increase. Ammonia intoxication is one of the main causes of hepatic coma. However, the level of blood ammonia may not be consistent with the occurrence and severity of encephalopathy.

　　(4) Prothrombin time (PT) and activity (PTA): The synthesis of related coagulation factors is reduced in liver disease, which can cause PT prolongation. The degree of PT prolongation indicates the degree of liver cell necrosis and liver function failure, and the half-life of related coagulation factors is very short, such as factor VII (4-6h), factor X (48-60h), factor II (72-96h), so it can quickly reflect the condition of liver failure. The PTA in severe hepatitis is usually below 40%, and when the PTA falls below 20%, it often indicates a poor prognosis. PT prolongation can also be seen in patients with congenital coagulation factor deficiency, disseminated intravascular coagulation, and vitamin K deficiency, etc.

　　(5) Tests related to lipid metabolism: The total cholesterol (TC) level is significantly reduced in severe hepatitis. Some people believe that TC

　　4, The serological diagnosis of liver fibrosis in chronic liver disease is the imbalance of extracellular matrix (ECM) formation and degradation, leading to excessive ECM deposition and fibrosis. The detection of matrix components, their degradation products, and enzymes involved in metabolism can be used as serological markers for the diagnosis of liver fibrosis.

　　For patients with cryoglobulinemic MPGN, the pathology is similar to primary type I MPGN, but there is a more dense infiltration of macrophages, and transparent thrombi can be seen in the glomerular capillary lumen. Under the electron microscope, dense deposits are fingerprint-like in structure. A few patients may have pathological changes similar to primary type III MPGN, with mononuclear cell infiltration and a large number of immune complexes deposited in the renal biopsy.

　　First, dietary principles

　　The intake of protein should be determined according to the condition. If the patient has renal insufficiency or azotemia, protein intake should be restricted. When the blood urea nitrogen exceeds 60mg%, the daily protein supply should be 0.5 grams per kilogram of body weight, and high biological value proteins such as milk and eggs should be used to reduce the burden on the kidney excretion of nitrogenous substances. If there is severe renal insufficiency or azotemia, protein intake should be further reduced. To reduce the intake of non-essential amino acids in staple foods, corn starch, lotus root starch, wheat starch, and other substitutes for staple foods can be used. If there is no such condition or the condition improves, protein intake can be gradually increased, and 1 gram of protein per kilogram of body weight can be supplied daily.

　　The intake of carbohydrates and fats generally does not need to be restricted. It is necessary to ensure an adequate supply of calories.

　　For patients with edema and hypertension symptoms, food with low salt, no salt, or low sodium should be adopted according to the condition. Low salt refers to a daily salt intake of less than 3 grams; no salt means that no salt is added to the diet, and no salt-containing foods are consumed; low sodium food refers to a daily dietary sodium content not exceeding 1000 milligrams, in addition to salt, foods with high sodium content (such as alkali) should also be controlled.

　　4. Patients with persistent oliguria and hyperkalemia should avoid foods high in potassium content, such as fruits and various fruit juices.

　　5. Ensure the supply of foods rich in vitamin A, B-group vitamins, and vitamin C, especially fresh vegetables and fruits should be eaten as much as possible.

　　In addition, attention should also be paid to related dietary taboos for the primary disease hepatitis.

　　Secondly, dietary taboos for hepatitis patients

　　1. Avoid spicy food. Spicy food is easy to cause dampness and heat in the digestive tract, which leads to imbalance of liver and gallbladder Qi and weakened digestive function. Therefore, spicy food should be avoided.

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

　　3. Avoid drinking alcohol. 90% of alcohol is metabolized in the liver. Alcohol can interfere with and destroy the normal enzyme system of liver cells, so it directly damages liver cells and causes necrosis. Patients with acute or chronic active hepatitis will experience recurrence or changes in their condition even if they drink a small amount of alcohol.

　　4. Avoid processed foods. 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.

　　5. Avoid滥用hormones and antibiotics "Three parts of the drug are toxic", any medicine can damage the liver and kidney, so hepatitis patients must take medicine under the correct guidance of a doctor.

　　6. Avoid taking supplements. Dietary balance is the basic condition for maintaining good health. If not properly nourished, the function of the internal organs will be out of balance, the balance will be broken, and it will affect health.

　　7. Avoid high copper diet. Poor liver function 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 food containing a lot of copper, such as jellyfish, cuttlefish, shrimp, snails, etc.

　　1. The treatment of HCV renal damage is similar to the treatment of proteinuric glomerulonephritis, including low-salt diet, moderate-quality protein diet; when hypertension is present, active control of hypertension and hypercholesterolemia is required, nifedipine (nifedipine,心痛定) 0.25-0.5mg/(kg?time), 3-4 times/d; if necessary, angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists may be used to reduce proteinuria, and ACEI drugs may be taken orally, such as captopril (captopril,巯甲丙脯酸) 1-2mg/(kg?d), 2-3 times/d.

　　2. Specific treatment for HCV renal damage includes antiviral treatment with interferon alpha and ribavirin.

　　(1) Numerous reports have confirmed the efficacy of interferon alpha (IFN-α) in treating HCV renal damage. In 14 patients with HCV MPGN with or without cryoglobulinemia, interferon alpha (IFN-α) 3 million units was administered subcutaneously three times a week, and after 6 to 12 months of treatment, approximately 50% of patients had negative serum HCV RNA and a 60% decrease in urinary protein. In another prospective study, 60% of HCV cryoglobulinemic MPGN patients had negative HCV RNA, decreased cryoglobulin titers, and improved renal function after receiving interferon alpha (IFN-α) 3 million units subcutaneously three times a week for 6 months. However, it was found that most patients would have recurrence of viremia, cryoglobulinemia, and renal disease after stopping interferon alpha (IFN-α) treatment. For patients who fail to respond to conventional dose interferon alpha (IFN-α) treatment, higher doses of interferon alpha (IFN-α) may be effective. There is a report of a patient with HCV MPGN who was given interferon alpha (IFN-α) 3 million units subcutaneously three times a week for 6 months without response. The dose of interferon alpha (IFN-α) was then increased to 10 million units subcutaneously twice a week, followed by 10 million units subcutaneously three times a week for 6 weeks, resulting in negative HCV RNA and cryoglobulin, and the renal lesions were alleviated. Extending the interferon alpha (IFN-α) treatment duration to 18 months has been confirmed to be beneficial for HCV liver lesions, reducing the activity of liver histology, maintaining normal transaminases, but it has not yet been evaluated in HCV renal damage. The main side effects of interferon alpha (IFN-α) are influenza-like symptoms, insomnia, and discomfort. In some patients with HCV infection, interferon alpha (IFN-α) may induce or worsen renal lesions, and attention should be paid to renal damage in some patients when using interferon alpha (IFN-α). Currently, for patients with HCV renal damage, a standard treatment regimen is considered to be the subcutaneous injection of interferon alpha (IFN-α) 3 million units three times a week for at least 12 months. The treatment regimen extended to 18 months has also been tried. For the treatment of acute severe HCV renal damage patients (such as those with acute renal failure or neuropathy), plasma exchange combined with immunosuppressive therapy should be used first to remove circulating cryoglobulins and prevent the formation of new antibodies. The treatment method is plasma exchange with a volume of 3L per time, 3 times a week for 2 to 3 weeks; intravenous infusion of methylprednisolone 0.5 to 1g/d for 3 consecutive days followed by routine oral prednisone; cyclophosphamide 2mg/kg for 2 to 4 months. Interferon alpha (IFN-α) antiviral treatment can be initiated when the prednisone dose is reduced to 20mg/d.

　　(2) Ribavirin (triazine nucleoside, ribavirin, ribavirin) is a nucleoside analog of antiviral drugs, and when combined with interferon alpha (IFN-α) to treat HCV infection, it can achieve a better sustained remission of viremia than interferon alpha (IFN-α) alone. The recommended regimen is oral ribavirin 1-1.2g/d and subcutaneous injection of interferon alpha (IFN-α) 3 million U, three times a week, for 6 months. However, there is no research on the combined use of ribavirin and interferon alpha (IFN-α) in the treatment of HCV renal damage, and there is a case report that the combined use of drugs is effective in treating HCV cryoglobulinemic MPGN. Considering the effective clearance of HCV virus in patients with combined treatment, as many HCV MPGN patients have high levels of HCVRNA, it can be predicted that the combined treatment of ribavirin and interferon alpha (IFN-α) is more effective than interferon alpha (IFN-α) alone. However, ribavirin is mainly excreted by the kidneys, in Ccr

　　Prognosis

　　The clinical course of patients with HCV renal damage is variable, but the general prognosis is still good. If patients have severe proteinuria, renal insufficiency, high viral load, and renal biopsy shows severe mononuclear cell infiltration and a large amount of glomerular immune complexes, it indicates an increased risk of kidney disease progression.