Pulmonary hemorrhage-nephritic syndrome
Introduction
Introduction to pulmonary hemorrhage-nephritis syndrome Pulmonary hemorrhagic-nephritis syndrome, also known as anti-base glomerulonephritis, Goodpasture syndrome or Goodpasture disease, may be caused by viral infection and/or inhalation of certain chemical substances. It is a serious damage of the glomerular and alveolar wall basement membrane caused by anti-base membrane antibody, clinical manifestations of pulmonary hemorrhage, rapid glomerulonephritis and serum anti-glomerular basement membrane (GBM) antibody-positive triad. Most patients progress rapidly and the prognosis is dangerous. basic knowledge Sickness ratio: 0.0001% Susceptible people: no special people Mode of infection: non-infectious Complications: high blood pressure, blood in the stool
Cause
Pulmonary hemorrhage - the cause of nephritis syndrome
Infection (30%):
Respiratory tract infections and influenza virus infection are the most common causes of this disease. Recent studies have found that patients with acquired immunodeficiency disease are infected with Pneumocystis Carinii Pneumonia, and the body is prone to produce anti-GBM antibodies. Calderon et al reported 4 cases. Three of the HIV-infected patients were positive for anti-type IV collagen 3 chain antibody (anti-GBM antibody), suggesting that alveolar damage can induce pulmonary hemorrhagic-nephritis syndrome in Pneumocystis carinii pneumonia.
Scleroderma (5%):
Scleroderma is a connective tissue disease characterized by localized or diffuse skin and connective tissue fibrosis, sclerosis and atrophy. Its main features are fibrosis or hardening of the skin, synovium, skeletal muscle, blood vessels and esophagus. Scleroderma is a connective tissue disease characterized by localized or diffuse skin and connective tissue fibrosis, sclerosis and atrophy. Its main features are fibrosis of the skin, synovium, skeletal muscle, blood vessels and esophagus. Or harden.
Smoking (3%):
Inhaled cocaine Perez et al reported that a patient with long-term smoking developed pulmonary hemorrhagic-nephritis syndrome after 3 weeks of cocaine use. Contact with gasoline vapor hydroxylates, turpentine and inhalation of various hydrocarbons.
Pathogenesis
Because some causes cause the body to produce anti-alveolar, glomerular basement membrane antibodies, and thus attack the glomerulus and lung, type II allergic reaction, as well as the deposition of immune complexes to the alveoli and glomeruli There is no definitive explanation for the pathogenesis of activation of complement (type III allergy).
In 1962, Steblay et al. confirmed that glomerular basement membrane (GBM) damage in pulmonary hemorrhagic-nephritis syndrome was mediated by anti-GBM antibodies, and a large amount of research work focused on the isolation and study of GBM components in search of antibodies. The corresponding antigen and the molecular structure and characteristics of the antigen. In recent years, with the rapid development of molecular biology and biochemistry, the NC1 domain of the 3(IV) chain was confirmed in the newly discovered 3(IV) chain of collagen IV. It is Goodpasture's own antigen, also known as Goodpasture antigen, and then cloned the antigen gene Co14A3, which is located in the q35-37 region of the second chromosome.
Indirect immunofluorescence and immunoelectron microscopy confirmed that Goodpasture antigen is not only found in GBM, but also in renal tubular basement membrane (TBM), alveolar capillary basement membrane (ABM) and other tissue basement membranes (such as choroid, cornea, crystal, retinal blood vessels). The basement membrane and so on, but the pathogenic Goodpasture antigen is mainly distributed in GBM, TBM and ABM. The occultity of the antigen causes the reversibility of the exposure process. The 3NC1 structure can be exposed in vitro by 6 mol of guanidine hydrochloride or a strong acid condition of pH 3. Domain, but how the body antigen is exposed and produces an immune response damage GBM is not fully understood, it is speculated that under physiological conditions Goodpasture antigen is concealed in the collagen IV3NC1 domain, various predisposing factors (toxins, viral infections, bacterial infections, tumors, Immune genetic factors and endotoxin can activate epithelial, endothelial and mesangial cell proliferation, and release inflammatory mediators (IL-1, RDS, prostaglandins, neutral proteases, etc.), GBM, etc. under the action of cellular enzymes, collagen IV high-level structure dissociation, exposure of Goodpasture antigenic determinants, stimulation of the body to produce antibodies, resulting in immune damage, due to the whole body hair In the vascular endothelium, only the endothelial layer of the glomerular capillaries has a window, so that the antibody can be directly contacted with the GBM antigen and cause disease, while the ABM is only subject to certain external factors (such as infection, smoking, inhalation of gasoline or organic solvents). After the effect, the integrity of the basement membrane antigen is exposed to the lungs after exposure, which is why the kidney is most susceptible and the degree of involvement is consistent with the antibody titer, and the degree of involvement of the lung is inconsistent with the antibody titer.
The frequency of HLA-DR2 and other antigens in patients with this disease was significantly increased (up to 89%, normal control was only 32%), and the use of gene DNA restriction fragment length polymorphism analysis also showed that the disease and HLA-DR4, HLA-DQ chain gene DQWLb and DQW3 related, indicating that HLA class II antigen-associated lymphocytes play a role in this disease. Some experiments have found that if only anti-GBM antibodies are given to the test animals, GBM can form a line-like deposition, but it does not occur, only the diseased animals are simultaneously input. After T cells, the test animals only developed disease, which confirmed that T cells play an important role in the pathogenesis of this disease. Recent studies have also found that certain cytokines such as tumor necrosis factor and IL-1 can aggravate the development of this disease.
Pulmonary lesions showed pulmonary fullness and swelling, and there were many bleeding spots on the surface. Under the light microscope, there were a lot of red blood cells in the alveolar cavity and many macrophages containing hemosiderin. The alveolar wall was focally thickened and fibrosis. The alveolar cells are hypertrophied. Under the electron microscope, the alveolar basement membrane is thickened and broken. The electron dense substance under the endothelium is spotted, while the endothelial cells are normal. Immunofluorescence shows that there are IgG in the capillary wall, and C3 is continuous or discontinuous. Deposition.
Renal lesions can be seen in soft kidneys with grayish white color, with many small bleeding spots on the surface. Most of the light microscopic lesions are characterized by crescentic nephritis, but the proliferation of endothelial and mesangial cells is generally not heavy, and capillary fibrinoid necrosis is seen. Late glomerular fibrosis, renal interstitial inflammatory cell infiltration and interstitial arteritis, tubular degeneration, atrophy and necrosis, electron microscopically visible balloon epithelial cell hyperplasia, formation of crescentic, mesangial matrix hyperplasia, basal Membrane rupture, glomerular capillary wall is generally no dense deposit, occasionally there is a dense deposit of electron dense substance under the endothelium, immunofluorescence examination shows IgG (100%), C3 (60% ~ 70%) along the glomerulus The capillary wall is linearly deposited, and some patients are positive for antibody IgG on the basement membrane of the distal convoluted tubule.
Previously, this symptom was mainly caused by the desorption of the basement membrane (GBM) antibody. Immunofluorescence showed that IgG was deposited along the glomerular basement membrane. Only a part of this disease can be diagnosed as pulmonary hemorrhagic-nephritis syndrome, and another part of the patient. The clinical resembles pulmonary hemorrhagic-nephritis syndrome, but its immunofluorescence shows that IgG is deposited along the GMB in granular form, and the anti-GBM antibody is negative in the blood. Actually, this part of the case is immune complex nephritis (ICGN), and the autoimmune mechanism starts from this disease. The important role, manifested as ICGN, is caused by the deposition of immune complexes in the corresponding parts of the glomerulus and alveoli. Clinically, the lung lesions appear before the renal lesions, and the renal function is rapidly deteriorated, which can be several weeks to several months. death.
Prevention
Pulmonary hemorrhage - nephritis syndrome prevention
Pulmonary hemorrhage - nephritis syndrome can quickly kill. The cause of death is often pulmonary hemorrhage and respiratory failure. In the acute phase, tracheal intubation is often required, assisted ventilation and hemodialysis. Subsequent treatment relies on the use of high-dose corticosteroids (methylprednisolone daily 7-15 mg/kg, divided intravenously), immunosuppressive cyclophosphamide and repeated hemodialysis to exclude anti-glomerular base Membrane antibody. The course of immunosuppressive therapy has changed a lot.
Complication
Pulmonary hemorrhage - complications of nephritis syndrome Complications, high blood pressure, blood in the stool
The vast majority of patients have anemia, a large number of or even fatal pulmonary hemorrhage can occur, respiratory failure can occur; in the presence of nephrotic syndrome, renal dysfunction develops rapidly, about 81% of cases develop renal failure; hypertension can occur Liver splenomegaly, enlarged heart, abnormal fundus changes, purpura, blood in the stool, etc.
Symptom
Pulmonary hemorrhage - nephritis syndrome symptoms common symptoms dyspnea fever with cough, slightly... pulmonary hemorrhage protein urinary short hemoptysis
The disease can occur at any age, but most of the young men between the ages of 20 and 30, the general performance of the patient unless there is a cold, more fever, often fatigue, weakness, weight loss, etc., its clinical characteristics are triad: lung Bleeding, rapid glomerulonephritis and serum anti-GBM antibody positive.
1, pulmonary hemorrhage
Typical patients do not have fever unless they are infected. The most important manifestation of the lungs is hemoptysis. About 49% of patients have hemoptysis as the first symptom, ranging from hemoptysis to massive hemoptysis. Severe stagnation (especially smokers) is more than hemoptysis and even suffocation. Patients with multiple shortness of breath, cough and asthma, difficulty breathing, sometimes chest pain symptoms, lung percussion are voiced, auscultation can smell wet voice, lung CO uptake rate (Kco) is an early and sensitive indication of lung function changes, in the kidney This value decreases in patients with aging and pulmonary edema, and increases in pulmonary hemorrhage.
General lung symptoms can occur several days, weeks, or years before the kidneys. Pulmonary hemorrhage can be light or severe, or severely life-threatening. Iron deficiency anemia can occur in large or persistent bleeding. Once chest pain occurs, Should pay attention to the exclusion of systemic lupus erythematosus, vasculitis or pulmonary embolism and other lesions, lung X-ray shows diffuse point-like infiltration shadow, scattering from the hilar to the periphery, the lung tip is often clear, hemoptysis and lung infiltration is a lung lesion feature.
2, kidney disease
The clinical manifestations of renal lesions are diverse. Patients with mild glomerular damage, urine analysis and renal function can be normal. The main clinical manifestations are repeated hemoptysis. The renal biopsy can still show the typical immunological characteristics of linear anti-basement membrane antibody deposition. Typical patients with renal dysfunction develop faster, with oliguria or no urine, serum creatinine concentration increased day by day, reaching uremia level within 3 to 4 days; no oliguria, kidney damage is often rapid development, serum creatinine concentration It rises every week and develops into uremia within a few months. Most patients are characterized by progressive renal impairment. According to statistics, 81% of patients develop renal failure within 1 year, and blood pressure is normal or slightly elevated. Urine analysis showed hematuria and proteinuria, often with red blood cell casts, and a small number of patients had a large number of proteinuria and nephrotic syndrome.
3, special performance
(1) Pulmonary hemorrhage-nephritis syndrome is transformed into glomerular diseases of other pathological types: Elder et al reported that one patient had typical lung-kidney pathological manifestations and clinical manifestations, renal function remained good, and serum and tissue anti-GBM antibodies were present. Positive, significant iron deficiency anemia, anemia improved after immunosuppressive therapy, serum anti-GBM antibody disappeared, nephrotic syndrome occurred 9 months later, renal biopsy showed membranous nephropathy without anti-GBM antibody intrarenal deposition.
(2) Other pathological types of glomerular disease to pulmonary hemorrhagic-nephritis syndrome: Thitiarchakul reported a case of idiopathic membranous nephropathy, acute deterioration of renal function during the course of the disease, accompanied by hemoptysis, severe hypertension and serum anti-GBM The antibody was positive, and the renal tissue examination showed typical anti-GBM immunopathological manifestations. The use of large doses of hormones, CTX and plasma exchange were ineffective.
(3) Pulmonary hemorrhage - nephritis syndrome is limited to one lung or kidney: Patron et al reported 1 case of simple pulmonary hemorrhagic-nephritis syndrome, Perez et al reported 1 case of cocaine-induced pulmonary hemorrhagic-nephritis syndrome, only typical kidney Change, alveolar basement membrane without IgG and C3 line-like deposition, other anti-basement membrane antibody binding to the choroid, eyes, ears, even can cause corresponding performance, such as fundus hemorrhage and exudation, the incidence can be as high as 11%, It may be due to the rapid development of high blood pressure.
Examine
Pulmonary hemorrhage-nephritis syndrome
1, urine examination: microscopic hematuria, red blood cell cast, granule cast, leukocytosis, mostly moderate urine protein, a small number of proteinuria can be seen.
2, sputum examination: sputum microscopy can be seen with hemosiderin-containing macrophages and bloody sputum.
3, blood test: If the intrapulmonary hemorrhage is severe or long-lasting, there may be more serious small cells, hypochromic anemia, Comb test is negative, half of patients with white blood cells more than 10 × 109 / L.
4, blood biochemistry : early BUN, Scr, Ccr normal, but with the progress of the disease and BUN and Scr progressive increase, Ccr progressive reduction, severe renal function decline GFR <5ml / min.
5. Specificity examination : In the early stage of the disease, the indirect immunofluorescence method and radioimmunoassay were used to measure the circulating anti-base membrane antibody in the blood. The serum anti-GBM antibody was mostly positive, and the sensitivity of the indirect immunofluorescence method was 80%. Radioimmunoassay The sensitivity of the assay is greater than 95%, and the specificity of both is up to 99%. It is possible to measure anti-NC1 antibody by immunoblotting and ELISA, and specifically diagnose pulmonary hemorrhagic-nephritis syndrome.
6, imaging examination: lung X-ray shows diffuse point-like infiltration shadow, scattering from the hilum to the periphery, the lung tip is often clear, lung infiltration is a feature of lung lesions, lung X-ray changes early and similar to pulmonary edema The hemoptysis can be absorbed in the short term after stopping.
7, electron microscopy:
(1) typical lung lesions are alveolar hemorrhage, hemosiderin deposition and fibrosis, electron microscopy showed alveolar wall capillary basement membrane degeneration, fracture and focal hyperplasia, visible electron dense deposits, immunofluorescence showed IgG and C showed Linear deposition.
(2) typical renal lesions, first, diffuse glomerular damage, kidney often increased and a large number of crescent formation, crescentic body is a peripheral type (extravascular proliferative nephritis), may be associated with capillary necrosis, GBM has IgG deposition, and the second is severe glomerular atrophy with diffuse glomerular fibrosis and interstitial fibrosis. Electron microscopy shows glomerular basement membrane degeneration, shrinkage or diffuse thickening.
8. Light microscopy : visible focal or diffuse necrosis, glomerular anti-glomerular basement membrane antibody deposition, epithelial cell proliferation formed crescent moon accounted for more than 50%.
9. Immunofluorescence : visible along the glomerular basement membrane endothelial deposits (mainly IgG, IgA, IgM, C3 and fibrinogen), if the sediment is rugged particles, it is the lung caused by other diseases , renal syndrome.
Diagnosis
Diagnosis and diagnosis of pulmonary hemorrhagic-nephritis syndrome
diagnosis
1. The key to the diagnosis of pulmonary hemorrhagic-nephritis syndrome is to determine whether the body has anti-GBM-alveolar basement membrane autologous immunity process, and the characteristic performance of this process exists.
(1) Serum anti-GBM antibody is positive.
(2) IgG was deposited in the alveolar and renal basement membranes.
2, the diagnosis of a typical patient fully meets the following triads
(1) Pulmonary hemorrhage, alveolar basement membrane IgG is linearly deposited.
(2) Rapid progressive nephritic syndrome, a large number of crescentic formation of the kidney (extravascular proliferative nephritis), may be associated with capillary necrosis, and GBM has IgG deposition.
(3) Serum anti-GBM antibody is positive.
3, pulmonary hemorrhage - nephritis syndrome diagnosis
(1) Some patients have mild manifestations of lungs and/or kidneys, or two organs are not synchronized, and sometimes the anti-basement autoimmune process occurs only in any organ in the lungs or kidneys.
(2) Anti-GBM nephritis sometimes changes with other types of glomerular diseases (mainly membranous nephropathy) (see clinical manifestations).
(3) Occasionally, autoimmune dysfunction produces non-specific basement membrane antibodies and can cause organ damage other than lung and kidney.
(4) In some cases, if the autoimmune is highly active, a large amount of anti-GBM antibody deposition may occur, and a transient serum anti-GBM antibody may be negative. One patient with typical pulmonary hemorrhagic-nephritis syndrome clinical and pathological findings has been reported. At the same time, with lung damage, serum anti-GBM antibody is negative, he believes that this may be due to a large amount of antibody deposition in the target organs during high activity.
(5) pulmonary hemorrhage-nephritis syndrome and vasculitis coexist, Rydel et al reported a case of 18-year-old male pulmonary hemorrhagic-nephritis syndrome, refractory epilepsy occurred during plasma exchange and cytotoxic drugs, MRI showed Multiple Lacunar Infarcts, cerebrospinal biopsy showed vasculitis, but serum ANCA continued to be negative, after administration of high-dose corticosteroids and cytotoxic drugs, anti-epileptic drugs can be used for symptomatic control, Kalluri et al. 1 patient with nodular pulmonary infiltration and acute renal failure, c-ANCA positive, renal tissue examination showed crescentic and necrotizing nephritis, IgG and C3 in the glomerular line-like deposition, serum with high titer anti-GBM - IgG.
Differential diagnosis
1. Pulmonary and renal syndrome: diseases that can cause pulmonary and renal syndrome besides pulmonary hemorrhagic-nephritis syndrome, such as ANCA-related systemic vasculitis, SLE and nephritis caused by infection, in addition, renal vein thrombosis Caused by pulmonary embolism, congestive heart failure caused by end-stage renal failure can also occur hemoptysis, Ent et al reported 2 cases of children, immune complex deposition also caused pulmonary hemorrhage and glomerulonephritis, Hernandez reported a case of special hair Acute glomerulonephritis occurs in patients with Idiopathic Bronchiolitis Obliterans, and histological examination of large amounts of IgA deposits occurs in both the lung and kidney.
In immune complex nephritis, glomerular capillaries have granular deposits. Electron microscopy shows electron dense substances, serum anti-GBM antibodies are negative, and circulating immune complexes can be positive, which is not difficult to distinguish from pulmonary hemorrhagic-nephritis syndrome.
2, lupus nephritis: this patient with acute nephritis, acute renal failure with pulmonary hemorrhage symptoms, easy to be confused with pulmonary hemorrhagic-nephritis syndrome, but the disease is more common in young women, generally have skin, joints, etc. Systemic multi-system damage, serum immunological examination can help diagnose.
3, small vasculitis nephritis: such diseases may have pulmonary hemorrhage performance and approximate pulmonary hemorrhage - nephritis syndrome, but the disease is more common in the elderly aged 50 to 70 years old, with fatigue, low fever, weight loss and other systemic symptoms, blood Anti-neutrophil ytoplasmic antigens (ANCA) are positive, and Wegener's granulomatosis may be interstitial inflammation, and both may exist at the same time.
In many vasculitis, there are two types of small vasculitis, Wegener granulomatosis and microscopic vasculitis. The target antigens of these two small vasculitis are Proteinase 3 and Myeloperoxidase, respectively. Antibodies (c-ANCA and p-ANCA) are the original sin antigens that cause small vessel damage and have important diagnostic value for small vasculitis. In Wegener granulomatosis and microscopic vasculitis, the upper and lower respiratory tract and kidney are most often affected, Wegener granulation. The morphological changes of the swelling are various, and the ulceration changes mainly in the oropharynx, paranasal sinus, trachea, etc., and the granulomatous changes are optional, so histological examination, especially small biopsy When we can not easily rule out the diagnosis of Wegener granulomatosis, Wegener granulomatosis and microscopic vasculitis can be characterized as focal segmental necrotic glomerulonephritis in the kidney, often accompanied by crescent formation, glomerular Immunoprecipitation is rare.
4, acute nephritis with left heart failure: this disease may have blood stasis and dyspnea performance, similar to pulmonary hemorrhagic-nephritis syndrome, but the disease is more common in adolescent patients, more history of streptococcal infection, often due to severe hypertension, water Sodium edema and edema, congestive heart failure, renal biopsy can be identified.
5, rapid progressive nephritis: rapid onset nephritis (crescent nephritis) immune pathogenesis in addition to anti-GBM nephritis, immune complex nephritis and cellular immune vasculitis can also cause typical crescentic nephritis and acute renal failure .
6. Idiopathic pulmonary hemosiderosis: the hemoptysis of this disease, the hemosiderin cells in the sputum and the X-ray findings of the lungs are very similar to pulmonary hemorrhagic-nephritis syndrome, but the disease mostly occurs at the age of 16 The following adolescents, the disease progresses slowly, the prognosis is good, and lung and kidney biopsy can help identify.
