Lupus nephritis

　　How is lupus nephritis caused? A brief description is as follows:

　　The etiology of systemic lupus erythematosus (SLE) and lupus nephritis (LN) has not been fully elucidated. It is mainly believed to be caused by multiple factors, such as genetics, viral infection, immune abnormalities, exposure to sunlight or ultraviolet radiation, certain drugs, and estrogen, leading to autoimmune inflammatory diseases, and the induced renal lesions (i.e., LN) are typical autoimmune complex nephritis.

　　1. Immunogenetic defect.The occurrence of SLE is related to genetic factors, with a family incidence rate of up to 3% to 12%, showing a clear tendency of familial aggregation. After extensive research on the HLA system of SLE patients, it has been found that the genes closely related to SLE are mainly located on certain gene loci of HLA, especially in the HLA-DR region, with HLA phenotypes showing polymorphism. Studies have shown that individuals with the haplotype HLAB8/DR2 are more prone to produce cellular and humoral hypersensitive immune reactions; this may be due to the polymorphism of HLA-encoded genes on T and B lymphocytes and antigen-presenting cells, resulting in decreased function of T suppressor cells and increased levels of autoantibodies and globulins. Some people now believe that the susceptibility genes for SLE are genes with different structures of T cell antigen receptors. Recent research has found that some polypeptide structures of the B chain of T cells appear simultaneously with HLA-DR in the same individual, increasing the possibility of SLE onset. In addition, SLE also exists with various complement deficiencies, such as the lack of C2, C1q, C1r, C1s, C4, C5, C8, Bf, TNF, and C1 esterase inhibitor. These complement components or genetic gene defects can affect the classical complement activation pathway, increase the body's sensitivity to infectious and other stimulating factors, and are related to the susceptibility to SLE.

　　2. External environmental factors.There are many external factors that can induce or exacerbate SLE, among which chronic infection, drugs, physical factors, emotional stimulation, and living environment are relatively important.

　　3. Endocrine factors.SLE mainly affects females, with the prevalence of the disease in women of childbearing age being 9 to 13 times higher than that in males of the same age. However, the prevalence of the disease in females before puberty and after menopause is only slightly higher than that in males. Therefore, it is believed that estrogen is related to the occurrence of SLE. Both male and female patients with SLE have significantly increased levels of 16α-hydroxyestrone and estrone. Oral contraceptives for women can sometimes induce a lupus-like syndrome. Studies in humans and animals have shown that estrogen can increase the production of antibodies against DNA by B cells, while androgens can inhibit this reaction. Recently, it has been found that prolactin levels in the serum of SLE patients are elevated, leading to secondary changes in sex hormones, which needs further research to be confirmed.

　　Lupus nephritis may complicate with acute and chronic nephritis syndrome, nephrotic syndrome, and renal tubular syndrome, and may also be associated with larger renal vascular thromboembolism and renal capillary thrombotic microangiopathy, leading to renal function damage, especially renal failure. Renal function remains stable for a long time, and the pathology is often membranous lupus nephritis. The other type, in addition to the symptoms of nephrotic syndrome, is accompanied by hematuria, hypertension, and renal function damage. If not treated in time, most patients may develop uremia within 2 to 3 years, with the pathology often being diffuse proliferative lupus nephritis.

　　What are the symptoms of lupus nephritis? A brief description is as follows:

　　SLE is more common in women, with a male-to-female ratio of 1:13, but both male and female patients have the same high rate of renal involvement. The average age of onset is 27 to 29 years, and 85% of patients are under the age of 55. SLE is a systemic disease that can affect multiple systems and organs, with diverse clinical manifestations. About 70% of patients have clinical manifestations of renal involvement. Combined with renal biopsy tissue immunofluorescence and electron microscopy examination, SLE is 100% associated with renal involvement, often exacerbated by factors such as infection, cold, sunlight exposure, alcoholism, stress, overexertion, or mental tension. It can also be caused by improper use of hormones, rapid reduction in dose, or sudden discontinuation of medication, which may lead to recurrence. Each recurrence may further worsen the damage to the involved organs, even leading to organ failure.

　　1. General symptoms.Most patients may exhibit symptoms such as general fatigue, weight loss, and emaciation. 90% of patients have fever, of which 65% are the initial symptoms, with an indeterminate fever pattern, which may be intermittent fever, remittent fever, continuous fever, or chronic low fever. 40% may exceed 39 degrees Celsius. It should be noted whether the fever is caused by infection, especially in patients receiving high-dose hormone therapy.

　　2. Skin and mucous membrane lesions.SLE's skin and mucous membrane lesions are diverse, with an incidence rate of over 80%, and 50% of patients may present with butterfly-shaped erythema, which is a bullous erythema distributed in a butterfly shape on the bridge of the nose and the cheeks (without skin lesions at the nasolabial grooves), which may have dilated capillaries and scales. In severe cases of exudation, there may be blisters and crusts. After the erythema subsides, scars are generally not left behind. 20% to 30% of patients may develop discoid erythema, which is usually located on the skin of exposed areas and presents as red elevated plaques that are annular, circular, or elliptical. The surface may be covered with scales and keratinous plugs. Scars often remain after the skin lesions subside. Butterfly-shaped erythema and discoid erythema are characteristic skin lesions of SLE, and they may worsen with sunlight or ultraviolet radiation. 35% to 58% of SLE patients may have photosensitivity, and 50% to 71% of patients may experience alopecia, which is one of the sensitive indicators of SLE activity. About 50% of patients may present with vascular skin lesions, which are caused by inflammation or spasm of small vessels and capillaries, including reticular cyanosis, vascular inflammatory skin lesions, Raynaud's phenomenon, periungual erythema, urticarial skin lesions, lupus pernio-like skin lesions, and dilated capillaries, etc. 7% to 14% of patients may present with mucosal erosion or painless ulcers.

　　3. Lesions of joints and muscles.About 95% of patients may experience joint pain and arthritis, commonly in the small joints of the limbs, 5% to 10% of patients may have aseptic femoral head necrosis, often due to long-term, large-scale, and irregular use of corticosteroids, half of the patients have myalgia and myopathy, and even obvious symptoms of muscle weakness or muscle atrophy. Joint and muscle lesions are often related to the activity of the disease.

　　4. Lesions of the lung and pleura.28% to 50% of patients may present with pleurisy and pleural effusion, the effusion is mostly yellow exudative fluid, dominated by monocytes, and needs to be differentiated from tuberculous pleurisy. It is believed that if the ANA titer in pleural effusion is ≥1:160, or the pleural effusion/serum titer is ≥1, or SM antibody is positive, it may help in the diagnosis of SLE pleural effusion. 2.7% to 10.1% have acute lupus pneumonia, with a high mortality rate, mainly due to respiratory failure and pulmonary embolism. Acute lupus pneumonia has severe hypoxia symptoms, and X-ray shows diffuse punctate shadows in both lungs, more in the lower lung fields, with large changes in shadows, and significant response to high-dose corticosteroid therapy.

　　5. Manifestations of the cardiovascular system.50% to 55% of SLE patients may have concomitant cardiac lesions, including pericarditis, myocarditis, valvular lesions, arrhythmias, and hypertension.

　　6. Lesions in the blood system.50% to 75% of patients may present with normochromic normocytic anemia, which may be autoimmune hemolytic anemia, and some may be related to the inflammation, renal insufficiency, hemorrhage, dietary disorders, and drug effects of SLE. 50% to 60% of patients may have leukopenia, usually below 4.0×10^9/L, with lymphopenia (

　　7. Gastrointestinal symptoms.25% to 50% of patients may experience loss of appetite, nausea, vomiting, abdominal pain, and diarrhea, 30% of patients may have liver enlargement and abnormal liver function, and a few may have splenomegaly.

　　8. Manifestations of the central and peripheral nervous system.50% to 60% of patients may experience neurological and psychiatric disorders, with complex and diverse clinical manifestations, including psychiatric abnormalities (such as depression, mania, intellectual defects, mental confusion, etc.), epilepsy, hemiplegia, migraine, chorea, peripheral neuritis, and retinopathy, most of which are related to the activity of lupus, with poor prognosis and being an important cause of death in SLE.

　　9. Other.Irregular menstruation, dysmenorrhea, excessive or insufficient menstrual flow, some patients may have painless lymphadenopathy, parotid swelling, conjunctivitis, and other symptoms.

　　The prevention of renal damage in lupus nephritis mainly depends on the prevention of lupus, early diagnosis and reasonable effective treatment of the primary disease. The prevention of lupus can reduce the occurrence of complications such as renal damage, and reasonable effective treatment can extend the survival time of patients. The main causes of death are infection, renal failure, and central nervous system lesions. In recent years, the 5-year and 10-year survival rates of lupus nephritis SLE are above 95% and 85% respectively, which is closely related to the early diagnosis and reasonable effective treatment of the primary disease.

　　What examinations should be done for lupus nephritis? Briefly as follows.

　　1. Urinalysis:Changes in urine composition are of great significance for the diagnosis and efficacy observation of lupus nephritis, LN patients may have hematuria, proteinuria, leukocyte urine, and cast urine. When renal insufficiency occurs, there may be a decrease in urine specific gravity and symptoms of uremia, with a significant increase in blood urea nitrogen and creatinine.

　　2. Blood routine examination:Patients with lupus nephritis with involvement of the blood system may have:

　　(1) Anemia, with a decrease in hemoglobin, accompanied by an increase in reticulocytes and a positive Coombs test.

　　(2) Leukopenia can be below 4.0×10^9/L. Patients treated with high doses of corticosteroids may have an increase in white blood cells and neutrophils.

　　(3) Thrombocytopenia is often below 100×10^9/L.

　　3. Blood chemistry examination:Patients with active SLE almost all have an increased erythrocyte sedimentation rate, and some patients even have a high sedimentation rate during the remission period. The majority of lupus active patients have hypergammaglobulinemia, mainly increased gamma globulin, and a few patients have cryoglobulinemia and decreased complement levels (C3, C4, CH50, especially C3). There may be an increase in circulating immune complexes (CIC), and an increase in various cytokines in the blood such as IL-1, IL-2, IL-6, IL-2 receptor, and tumor necrosis factor, unless complicated with infection, the C-reactive protein is generally not high.

　　4. Autoantibody examination:During SLE, various autoantibodies can appear in the blood, which are of great significance for diagnosis.

　　5. Renal biopsy and skin examination:Lupus band test (LBT), combined with renal biopsy, immunofluorescence, and electron microscopy, has an almost 100% diagnostic rate for SLE and can determine the pathological type of lupus nephritis and judge the activity and chronicity of the disease.

　　Patients with lupus nephritis should drink more warm water and eat less or no scallion, ginger, garlic, chili, lamb, Sichuan pepper, fennel, cherry, longan, pineapple, and other hot foods and dishes. They can eat bananas, pears, kiwis, star fruits, cucumbers, spinach, eggplants, amaranth, duck eggs, duck meat, rabbit meat, sweet potatoes, mung bean soup, bitter melon, and other bitter things, because according to traditional Chinese medicine, they are cool in nature and good for extinguishing internal heat. However, they should not eat too much at one time, as it may cause diarrhea.

　　The western medical treatment methods for lupus nephritis are briefly described as follows:

　　The treatment plan for lupus nephritis should be determined based on clinical manifestations, laboratory tests, and pathological changes. It is generally believed that for patients with mild clinical symptoms, normal or slight glomerular structure, and mild mesangial proliferation, antimalarial drugs, aspirin (acetylsalicylic acid), and other treatments can be used, and small-dose hormone oral therapy can be added at the same time. For membranous lupus nephritis, hormone therapy combined with cytotoxic drug therapy is often used, but attention should be paid to the fact that proteinuria is difficult to completely resolve after treatment, and the disease course is usually benign. Therefore, during the treatment process, it is necessary to prevent the risk of over-treatment and drug side effects. WHO type III and IV (especially WHO type IV) are often manifested as nephrotic syndrome or rapidly progressive nephritis, and even progressive renal failure. It is often recommended to use combined therapy with hormones and cytotoxic drugs. The following treatment methods are mainly for LN with nephrotic syndrome.

　　1. Glucocorticoids.Since adrenal cortical hormones were first used to treat SLE in 1948, glucocorticoids (commonly referred to as hormones) are still the traditional drugs for the treatment of LN. The general choice is to treat with prednisone at the standard course, i.e., 1-1.5mg/(kg·d) at the beginning of treatment, taken in the morning, and after 8 weeks, the dose is reduced weekly by 10% of the original dose, until the low dose [0.5mg/(kg·d)] is reached. The dose is then maintained for a period of time according to the situation, and further reduced to the maintenance dose (0.4mg/kg every other day). It is now believed that lifelong medication can reduce the risk of recurrence. Some scholars believe that for LN with nephrotic syndrome, if the dose of hormones in the initial treatment stage is insufficient, it is often ineffective, and renal glomerular damage may continue to develop leading to uremia. For patients with severe nephrotic syndrome or accompanied by acute renal failure, prednisolone 0.5-1.0g can be infused intravenously in physiological saline for 3 days of shock therapy, followed by standard prednisone oral treatment. In the initial stage of hormone therapy, it is recommended to use traditional Chinese medicine for nourishing Yin and reducing fire to reduce the side effects of exogenous high-dose hormones. After the dose of hormones is reduced to a low dose, it is advisable to add Chinese medicine for warming the body and tonifying the kidneys to prevent a relapse of the disease and the syndrome of hormone withdrawal.

　　2. Cytotoxic drugs.Clinical practice shows that the efficacy of combination therapy with cytotoxic drugs and hormones is much better than that of hormone therapy alone.

　　3. Cyclosporine.Cyclosporine A (CsA) is increasingly used in the treatment of systemic lupus erythematosus (SLE), especially for lupus nephritis (LN). In 1989, Favre and colleagues reported that 26 patients with LN treated with cyclosporine (CsA) at a dose of 5mg/kg per day for 2 years showed a significant decrease in disease activity index and lymphocyte activation index. Histological examination showed that the lupus activity index and chronic index also decreased significantly, urinary protein was significantly reduced, renal function improved slightly, and the dosage of hormones was reduced.

　　4. Mycophenolate mofetil.Mycophenolate mofetil (MMF) is a new generation of immunosuppressive drug, whose mechanism of action is: selectively inhibiting the classical synthesis pathway of guanine in lymphocyte, inhibiting the proliferation of T and B cells, inhibiting antibody production; it can also block the synthesis of cell surface adhesion molecules, inhibiting the proliferation of vascular smooth muscle cells.

　　5. High-dose immunoglobulin.Since the first successful application of intravenous injection of high-dose immunoglobulin (IVIG) by Imbach et al. in 1981 to treat idiopathic thrombocytopenic purpura, it has been successively applied to the treatment of SLE. Currently, the dose has not been unified, and it is mostly 0.4g/(kg·d), administered intravenously daily for 3 to 5 days as a course, and can be repeated after a month.

　　6. Plasma exchange and immunosorption.For SLE that endangers life, fulminant lupus, rapidly progressive LN, rapidly developing nephritis, highly immunologically active individuals, those who are ineffective to conventional treatment, or those who are ineffective or have contraindications to hormone immunosuppressive drug treatment, it can be considered to apply. Immunosorption is better for clearing pathogenic immunological substances, and currently, protein A is mostly used as an adsorbent. Generally, 40ml of plasma is removed per kilogram of body weight each time, three times a week, for a total of 2 to 6 weeks. This therapy requires the simultaneous use of immunosuppressants, which can prevent or improve the rebound of antibodies produced in the body after plasma exchange. However, a multi-center study on 86 patients with severe active lupus nephritis did not show any superiority of this therapy in renal survival rate and patient survival rate, so further observation is needed.

　　7. Hematopoietic stem cell transplantation.For severe refractory SLE, pre-treatment dose cyclophosphamide (CTX) is used to deeply clear the hematopoietic cells and immune system of patients, followed by autologous or allogeneic hematopoietic stem cell transplantation, so that the immune system of patients can be reconstructed, which may become a method for curing SLE.

　　8. Immunosuppressive therapy.Although immunosuppressive therapy is the main treatment for lupus nephritis, it is not suitable for every patient, and not all patients with lupus nephritis require the aforementioned intensified immunosuppressive drug treatment when renal function damage occurs. The treatment of LN should be individualized and graded, and renal biopsy pathological examination plays an important guiding role in the treatment of LN.