Nephrotic syndrome

Introduction to nephrotic syndrome Nephrotic syndrome (NS) is not an independent disease but a group of clinical syndromes in glomerular diseases. Typical performance is a large amount of proteinuria (>3.5g/1.73m2 body surface area per day), hypoalbuminemia (plasma albumin <30g/L), edema with or without hyperlipidemia, diagnostic criteria should be a large number of proteins Urine and hypoproteinemia. A large amount of proteinuria is a feature of glomerular disease, and it is rare to have such a large amount of proteinuria in renal vascular disease or tubulointerstitial disease. Because hypoproteinemia, hyperlipidemia, and edema are the consequences of large amounts of proteinuria, it is believed that the criteria for diagnosis should be based on large amounts of proteinuria. basic knowledge The proportion of illness: 0.006% Susceptible people: no specific population Mode of infection: non-infectious Complications: rapid glomerulonephritis interstitial nephritis uremia

Causes of nephrotic syndrome

Causes

In general, any factor that can cause glomerular filtration membrane damage can lead to nephrotic syndrome. According to the cause, it can be divided into primary and secondary. The former diagnosis mainly relies on the exclusion of secondary nephrotic syndrome. The cause of primary nephrotic syndrome is unknown. The results suggest that the immune mechanism, especially the cellular immune changes, may be related to the pathogenesis. In addition, lipid metabolism disorders, changes in coagulation factors and large amounts of proteinuria are also involved in the disease, secondary nephropathy. The common causes of syndromes are as follows.

Infection (25%):

Bacterial infection, found in streptococcal infection after nephritis, bacterial endocarditis, shunt nephritis, leprosy, syphilis, tuberculosis, chronic pyelonephritis with reflux nephropathy, etc., viral infections found in hepatitis B, cytomegalovirus, infectious single Pneumocytosis, human immunodeficiency virus, parasitic infections are found in malaria parasites, toxoplasmosis, helminths, schistosomiasis, and filariasis.

Drugs (22%):

Poisoning, allergies, organic or inorganic mercury, organic gold and silver, penicillamine, diacetin, probenecid, non-steroidal anti-inflammatory drugs, trimethesic and other drugs, bee sting, snake venom, pollen, vaccine, anti-toxin, etc. allergy.

Tumor (15%):

Lung, stomach, colon, breast, ovary, thyroid and other tumors, leukemia and lymphoma, Willm tumors, etc.

Systemic disease (10%):

Systemic lupus erythematosus, mixed connective tissue disease, dermatomyositis, Sjogren's syndrome, allergic purpura, amyloidosis, etc.

Metabolic disease (5%):

Diabetes, thyroid disease.

Hereditary diseases congenital nephrotic syndrome, Alport syndrome, Fabry disease, sickle cell anemia, nail-sacral syndrome, fat malnutrition, familial renal syndrome.

Others: eclampsia, chronic rejection of transplanted kidney, malignant renal sclerosis, renal artery stenosis, etc.

In China's secondary nephrotic syndrome, systemic lupus erythematosus, diabetic nephropathy, and allergic purpura are the most common, and the primary nephrotic syndrome is highlighted here. The common histopathological changes in primary nephrotic syndrome in children are mainly small lesions, while adults are mainly focal segmental nephritis, membranous nephropathy and minimal lesions.

In recent years, the etiology of adult nephrotic syndrome has changed significantly. Membrane nephropathy was the most common cause from 1970 to 1980, followed by minimal lesion nephropathy and focal segmental glomerulosclerosis. Some people think that focal segmental glomeruli Hardening should not occur nephrotic syndrome, but clinical renal biopsy confirmed that focal segmental glomerulosclerosis surpassed membranous nephropathy, Mark et al reported that membranous nephropathy accounted for 36% from 1976 to 1979, and microscopic lesions were 23%. Focal segmental sclerosis (FSGS) accounted for 15%, and FSGS was the main cause of nephrotic syndrome from 1995 to 1997, accounting for 35%. They also found that in the 1995-1997 group, FSGS accounted for 50% of black nephrotic syndrome. And 67% of the age is less than 45 years old, the small lesion nephrotic syndrome shows a decreasing trend, and the membrane proliferative nephritis also shows a decreasing trend, while the mesangial IgA nephropathy increases year by year. The data show that 10% of the cases are over 44 years old. AL amyloidosis, but failed to confirm multiple myeloma and paraglobulinemia.

Pathogenesis

Primary nephrotic syndrome has different pathogenesis due to its different pathological types.

1. Several pathological types common to nephrotic syndrome

(1) Minimal lesions (MCNS): The glomeruli are basically normal under light microscopy, occasionally epithelial cells are swollen, slight mesangial cell proliferation, no positive fluorescence immunofluorescence, even micro-immunoglobulin and complement C3 deposition, electron microscopy The broad fusion of the lower foot is disappeared, accompanied by vacuolar degeneration of epithelial cells, microvilli formation, and no electron dense deposits. It is the most common pathological type of pediatric nephrotic syndrome.

(2) Mesangial proliferative nephritis (MSPGN): diffuse glomerular mesangial cell proliferation with increased matrix is a characteristic change of the disease, glomerular mesangial cell proliferation under light microscopy, each mesangial cell In more than 3, mesangial matrix increased, severe lesions of mesangial matrix expansion oppressed local capillary vasospasm, leading to stenosis of the lumen, small arteriolar hyaline degeneration, and some can develop focal segmental glomerular sclerosis, interstitial Inflammatory cell infiltration and fibrosis, tubular atrophy, renal blood vessels are generally normal, under the electron microscope, mesangial cell proliferation and matrix increase, severe segmental mesenteric insertion, electron dense deposit under the mesangial area, severe protein The urinary visible visceral epithelial cells swell and the light and medium unequal foot process fusion, and the mesangial area may have IgG, IgM and/or complement C3 deposition.

(3) focal segmental glomerulosclerosis (FSGS): characterized by focal lesions, affecting a small number of glomeruli (focal) and glomerular local (segment), starting from the proximal medullary kidney The ball is involved, the light involves only a few capillary sacral areas, and the majority affects most of the glomeruli. The lesions are uniform and have no cell- or cell-free hyaline degeneration. Severely see balloon adhesion, the other is Focal glomerular sclerosis, renal tubular epithelial cells of the affected nephron often atrophy, peripheral cells see cell infiltration, fibrosis, electron microscopically showing most glomeruli or all glomerular foot processes, epithelial cells and The foot process and the basement membrane are detached from the early pathological changes of the disease, and electron dense deposits are deposited at the endothelial cells and mesangial cells. IgM and C3 are irregular, lumps, nodular deposits, and no diseased kidneys in the hardened area. The ball is negative or diffuse IgM, C3 deposits, IgA, IgG is rare.

(4) Membrane proliferative nephritis (MPGN): also known as mesangial capillary nephritis, pathological changes with mesangial cell proliferation, capillary vasospasm and double-track of the basement membrane as the main features, diffuse mesangial cell proliferation, proliferation The mesangial matrix is inserted between the endothelium and the basement membrane, and the basement membrane undergoes a double-track change. MPGN is classified into type III according to the deposition site of the electron dense substance. The type I subendothelial and mesangial areas have electron dense substances, and immunofluorescence shows IgG. , IgM, C3, C4 deposited along the basement membrane, strip-shaped electron dense substance in type II basement membrane, immunofluorescence is mainly C3 deposition, immunoglobulin is rare, type III subendothelial, subepithelial and mesangial area There are electron dense substances, immunofluorescence is mainly C3 deposition, with or without IgG, IgM deposition, often accompanied by interstitial mononuclear cell infiltration, fibrosis and tubular atrophy.

(5) Membranous nephropathy (MN): capillary wall thickening can be seen under light microscopy, immune complex deposition under glomerular basement epithelial cells, multiple fine spikes on the basement membrane, and proliferation of glomerular cells It is not obvious that the advanced lesions may be aggravated, and it may develop into a sclerotherapy and hyaline-like change. The vacuolar degeneration of the proximal convoluted tubule epithelial cells may be observed by electron microscopy, and there may be deposition of electron dense deposits under the epithelial cells, which are separated by the nail processes and the podocytes are fused. Immunofluorescence showed that the subepithelial immunoglobulin was characterized by fine granular deposition, with IgG being the most common, and 1/3 of cases had C3 deposition. The stage was stage I for early epithelial cell deposition and stage II for nail formation. Stage III is the deposition period in the basement membrane and stage IV is the hardening period.

(6) IgA nephropathy: significant IgA deposition in the mesangial area, WHO classified the histological manifestations of IgA nephropathy into 5 grades: grade I mild lesions, grade II minimal lesions with small segmental proliferation, grade III focal segmental glomeruli Ball nephritis, grade IV diffuse mesangial lesion with proliferation and sclerosis, grade V diffuse sclerosing glomerulonephritis involving more than 80% of glomeruli, tubulointerstitial lesions are important markers of progressive glomerular damage, renal tubules Patients with severe interstitial lesions suggest poor prognosis.

Pathological studies have found that immunoglobulins, complement proteins, lymphoid hematopoietic cells and electron denses corresponding to immune deposition exist in human kidney biopsy specimens. The rigorous analysis of experimental animal model results is an immunological pathogenesis of glomerular lesions. The understanding of the mechanism provides the basis for various types of human glomerulonephritis mediated by the activated immune system. The immunological pathogenesis of glomerular lesions can be divided into primary and secondary mechanisms, and the primary mechanism focuses on causing kidneys. Primary factors of glomerular lesions (although the primary factors rarely cause significant lesions alone), the humoral immune system relies on activated antibodies produced by lymphocytes, and the humoral immune system causes glomerular lesions through two basic mechanisms: 1 antibody and Glomerular in situ antigen response (which may or may not lead to the formation of immune complexes), 2 antibody binding to circulating soluble antigens leads to deposition of immune complexes in the glomerulus, secondary mechanism refers to the primary mechanism Pathways mediated by inflammatory mediators, including polymorphonuclear leukocytes, monocytes, platelets, and activated supplements Body composition, activated glomerular endothelial cells, mesangial cells and epithelial cells are involved in the inflammatory response, and mediators involved in secondary mechanisms include: cytokines, growth factors, reactive oxygen species, bioactive lipids, proteases, vasoactive substances ( Endothelin and endothelium-derived relaxing factor).

2. Humoral immune mechanism inducing glomerular lesions

Antibody-mediated glomerular lesions are mainly caused by the immune response involved in B cells. There are a large number of immunoglobulin molecules on the surface of B cell membrane, which can be combined with antigens presented by macrophages and dendritic cells. T helper cells By direct contact or release of soluble B cell growth factor involved in the above process, activated B cells further proliferate and differentiate, and form antibody-secreting plasma cells and memory cells, T helper cells can be inhibited by T suppressor cells, antibody production and The activity can be blocked by anti-idiotypic antibodies (binding to the hypervariable region of the primary antibody), which recognizes antigens that bind to MHC class II molecules, so it is inferred that certain MHC class II genes are immune-mediated glomerulonephritis Related, the natural components of the glomerular basement membrane, such as collagen IV, laminin, fibronectin, heparin glycoprotein, etc., can become targets of autoantibody attack, leading to the occurrence of anti-glomerular basement membrane nephritis The pathogenesis of anti-glomerular basement membrane nephritis may be: 1 cross-reactivity (molecular simulation) of foreign antigen with glomerular basement membrane antigen, The original concealed antigenic determinant is exposed, 3 glomerular basement membrane produces new antigen or glomerular basement membrane physiological component changes stimulate the production of circulating antibodies and glomerular basement membrane binding, the antibody and glomerular basement membrane directly lead to kidney Changes in the structure and function of the globules, experiments have shown that in the absence of inflammatory mediators (such as complement proteins, lymphoid hematopoietic cells), infusion of isolated kidneys with anti-glomerular basement membrane antibodies can lead to glomerular capillary wall charges Destruction of the barrier, resulting in proteinuria, and decreased glomerular filtration rate, ultrastructural changes to glomerular basement laminin rearrangement, foot process fusion, loss of anion binding site in the glomerular basement membrane and Cell damage, although the mesangial matrix and the glomerular basement membrane have some common components, there may be some antigens specific to the mesangial matrix as the target of immune attack. The monoclonal antibody against the mesangial matrix component can be injected into the mouse. Lead to the deposition of electron denses, but no histological changes and proteinuria were found. The literature reported that anti-mesis was found in the serum and kidney eluate of an IgA nephropathy patient. Matrix antibodies, there are three experimental animal models associated with glomerular intrinsic cell surface antigen-binding antibodies, antibodies against epithelial cells can lead to active or passive Heymann nephritis, and antibodies against mesangial cells can cause anti- Thy-1 antibody nephritis, antibodies against endothelial cells can cause angiotensin I-converting nephritis. These glomerular lesions are related to the formation of glomerular in situ immune complexes, some with normal cells. It is related to dysfunction and has nothing to do with the formation of immune complexes.

The implantation of exogenous macromolecules in the glomerulus can also be the target of antibody attack, leading to the formation of in situ immune complexes, which can explain human exposure to certain drugs, toxins, microorganisms or tumors. Many types of immune complex nephritis, endogenous antigens far from the kidney can cause kidney disease through a similar mechanism.

Circulating immune complexes can also cause human glomerulonephritis. The putative antigens are: exogenous serum proteins, drugs, food antigens, infectious microorganisms (bacteria, parasites, viruses, fungi, mycoplasmas) and some endogenous sources. Sexual antigens such as nucleic acids, thyroid antigens, tumor antigens, nuclear non-DNA materials, erythrocyte antigens, and renal tubular antigens. In the 1950s, the role of soluble circulating immune complexes in causing glomerular lesions was recognized. The combination of factors determines the deposition of circulating immune complexes in the glomerulus and causes glomerular lesions. The antigen must be immunogenic, which is often determined by the dose and route of the antigen used. The antigen must remain in the circulation for a sufficient period of time. In order to bind to the antibody, the size of the immune complex depends on the antigen-antibody ratio. The number of antibody binding sites determines the size of the immune complex and the manner in which it is deposited in the glomerulus. Immune complexes containing multivalent antigens are often deposited. Mesangial cells, and immune complexes containing low-cost antigens are deposited along the glomerular capillary wall, antigen Chargeability affects the binding of antigen to glomeruli and the formation of in situ immune complexes. The nephrotoxicity of cationic antigens is stronger than that of neutral or negative antigens. If glomerular lesions persist, high levels of circulating antigen persist. To alleviate glomerular lesions, it may be that the antigen changes the lattice structure of the immune complex that binds to the glomerulus and converts it into a small soluble immune complex. It is also possible that excess antigen can promote the clearance of the subepithelial immune complex, antibody The amount and affinity also affect the physiological properties of the immune complex. The immune complex of the antigenic antibody close to the equivalent large lattice structure can be effectively eliminated by the mononuclear phagocytic system, and the small immune complex can pass freely through the glomerulus. Only moderately large immune complexes are retained in the glomerulus, and the affinity of the antibody (binding to the antigen) affects the stability of the immune complex and ultimately affects the size of the immune complex, with low affinity antibodies. The prepared immune complexes are easily dissociated and recombine on the glomerular capillary wall, and high affinity antibodies form stable immune complexes that often occur in mesangial cells.

The mononuclear phagocytic system plays an important role in the clearance of circulating immune complexes. The occurrence of glomerulonephritis is related to the saturation of the mononuclear phagocytic system. The primate soluble antigen-antibody complex binds to the erythrocyte CR1 receptor, and the red blood cells can immunize. The complex is carried to the liver for clearance, a process that relies on the activation of complement.

3. Cellular immune mechanism that induces glomerular lesions

Unlike B cells, T lymphocytes cannot directly bind antigens, antigen-presenting cells process and present antigens to T helper cells. T cell receptors recognize complexes on the surface of antigen-presenting cells and antigen molecules, and T helper cells differentiate and proliferate. Secretion of a variety of soluble cytokines, help T, B cells and macrophage immune responses, can make direct effects of activated T cells, such as T cell killing and delayed type allergic reaction (DTH), aggregated monocytes are The main effector cells of tissue damage, sensitized T lymphocytes are involved in most humoral immune responses, and many observations suggest that human renal micropathy is a lymphocyte-mediated disease, and microscopic disease proteinuria may be Mediated by lymphokines, these lymphokines are produced locally in the kidney and cannot be measured at the overall level.

4. Secondary mediators of glomerular lesions

After initiation of the primary immune pathogenesis of glomerular lesions, a series of secondary mediators are activated and aggregate, resulting in an inflammatory response. Polymorphonuclear leukocytes appear in a variety of glomerulonephritis, activated complement proteins C3a, C5a It has chemotactic characteristics and attracts polymorphonuclear leukocytes to accumulate in the inflammation site. Polymorphonuclear leukocytes can also directly bind to antibodies implanted in the glomerular basement membrane through Fc receptors. There are a considerable number of receptors on the surface of polymorphonuclear leukocyte membranes. It can bind to endothelial cells and matrix molecules (which may be exposed during inflammation), and polymorphonuclear leukocytes synthesize and store multiple toxic substances in the azurophilic particles and other special particles, which are released when polymorphonuclear leukocytes are activated. Extracellular, in which proteolytic enzymes are involved in the development of glomerular lesions, serine proteases (elastase, cathepsin) and two metalloproteinases (polymorphonuclear leukocyte collagenase, gelatinase) can degrade matrix proteins, while the kidneys are small Degradation of the basement membrane of the ball leads to proteinuria, many polymorphonuclear leukocyte-derived substances can cause glomerular lesions, and proteolytic enzymes can activate other A plasma protein cascade reaction, such as a coagulation cascade, a cationic protein released by polymorphonuclear leukocytes can bind to and neutralize the anion site of the glomerular basement membrane, and polymorphonuclear leukocytes can synthesize phospholipid metabolites (prostaglandins, thromboxane) , leukotrienes and platelet activating factor) and vasoactive substances (histamine) and active oxygen metabolites.

Monoclonal antibody binding to human kidney biopsy specimens has been found to be involved in a variety of glomerular diseases with mononuclear macrophages, especially crescentic and post-infectious glomerulonephritis, although most mononuclear macrophages are infiltrated from circulation. The glomerulus, but it can also be propagated in situ. In theory, the mechanism of aggregation of mononuclear macrophages and polymorphonuclear leukocytes is largely the same, but experiments have also been shown to be through non-complement-dependent mechanisms. Infiltration of monocytes in the allergic reaction is mediated by soluble lymphokines released by activated T lymphocytes, which appear to have the characteristics of mononuclear macrophage chemokines, especially for mononuclear cells in the crescent. The adhesion of cells to glomerular endothelial cells is a basic step in the migration of mononuclear macrophages to glomerular lesions. Mononuclear macrophages have similar membrane adhesion molecules to polymorphonuclear leukocytes, and thus can interact with endothelial cells and The corresponding receptor binding on the extracellular matrix component, 1 integrin, VLA-4 (expressed in mononuclear macrophages, but not in polymorphonuclear leukocytes) can bind to fibronectin and VCAM-1. The possible role of nuclear macrophages in glomerular lesions is: 1 phagocytosis: can assist in the removal of immune reactants, but also activate other biosynthesis reactions, 2 antigen presentation: infiltrating mononuclear macrophages mostly express MHC class II antigens And trigger glomerular in situ cellular immune response, 3 produce cytokines, mediate glomerular inflammatory response, 4 procoagulant and fibrinolytic activity, 5 platelet activating factor, 6 matrix degrading enzyme: matrix degrading enzyme degradable kidney Small ball basement membrane, 7 other: protease, assists in the dissolution of immune complexes bound to glomeruli, 8 reactive oxygen metabolites, 9 vasoactive substances, 10 cationic proteins.

The mechanism of platelet aggregation in glomerular lesions is still unclear. Some substances released by platelets may damage glomeruli. Bioactive lipids include platelet activating factor and thromboxane A2, a vasoconstrictor that reduces kidney. Small ball filtration rate, platelet-derived growth factor can promote mesangial proliferation and contraction, and can promote the chemical attraction of mesangial leukocytes, amplify the inflammatory response, platelet factor IV is not only a leukocyte chemotactic factor, but also a cation Protein, in lupus nephritis, membranous glomerulonephritis, membranous proliferative glomerulonephritis and segmental glomerulosclerosis, platelet factor IV can be found in combination with glomerular capillary wall anion sites, platelets Source heparanase can also disrupt the anion barrier of the glomerular basement membrane. Other platelet activities and products that may cause glomerular lesions include: C3 and C5, which activate the complement cascade, and vasoactive amines such as histamine and serotonin. The latter has direct nephrotoxicity, platelet activating factor has inflammation, smooth muscle contraction, activity of raising blood pressure, platelet activating factor from blood Small plate, polymorphonuclear leukocytes, monocytes, endothelial cells, renal medullary stromal cells and mesangial cells release, endotoxin, C3, C5, immunoglobulin Fc segment, leukotrienes, platelet-derived Growth factors, calcium ions, and vasoactive peptides are involved in the process of phagocytosis. Platelet activating factor can cause platelet aggregation, activation and degranulation, chemotaxis and activation of leukocytes, activation and contraction of mesangial cells to produce arachidonic acid metabolites and activities. Oxygen metabolites, which alter the permeability and tone of the microcirculation, activate complement and have immunosuppressive effects. Growth factors and cytokines are polypeptide molecules that bind to specific receptors on the surface of target cells and initiate a series of cellular responses. Some of these factors are produced by the cells and/or inflammatory cells of the kidney itself, acting in a paracrine manner on adjacent cells or acting in an autocrine manner. Recently, efforts have been made to identify various factors for glomerular cells. The biological effects can be predicted in the 21st century. This area of research will provide new insights into the pathogenesis of immune-mediated glomerular lesions.

Some glomerular diseases have fibrin deposition in the glomerulus, suggesting that the coagulation system plays a role in crescent formation. Some believe that sustained fibrin deposition leads to hardening of the kidney, and morphological studies suggest that when the initial lesion When the glomerular basement membrane fragment and Hageman factor are released into the Bauman capsule, activation of the endogenous coagulation pathway produces fibrin, a leukocyte chemotactic agent, which leads to monocyte aggregation and crescent formation, fibrin degradation products. It has toxic effects on endothelial cells and mesangial cells. In addition to its procoagulant and fibrinolytic activities, Hageman factor also has many biological effects such as chemotaxis and activation of leukocytes, activation of complement, production of kallikrein and bradykinin, and small renal growth. Related to ball lesions, it has been proven that fibrin, which is involved in immune glomerular disease, is mostly produced by exogenous coagulation pathways. Monocytes that invade the glomeruli are a key source of tissue factor procoagulant activity, and mononuclear cells cooperate with T. The cell produces at least 3 different procoagulant factors, immune complexes, cell-binding antibodies, endotoxin and phytohemagglutinin that trigger mononuclear fines The procoagulant activity of the cells, monocytes also release mononuclear factors (such as TNF or IL-1) to stimulate the tissue factor activity of endothelial cells, and the decrease in fibrin degradation rate also promotes fibrin-related glomerular lesions.

The complement system has a dual role in preventing the deposition of immune complexes in tissues and also promoting immune responses. Complements cause glomerular lesions through two different mechanisms: 1C5a triggers leukocyte response, 2MAC (membrane attack complex) direct damage Capability, C4a, C3a, C5a have chemotactic activity after complement activation, which can lead to aggregation and activation of polymorphonuclear leukocytes. Polymorphonuclear leukocytes can also immunoadhere with activated complement components via CR1 and CR3. MAC can directly lead to kidney. Small-ball lesions without the need for cell-mediated renal biopsy specimens in patients with human immune complex-mediated glomerulonephritis (lupus nephritis, membranous glomerulonephritis, IgA nephropathy, streptococcal infectious glomerulonephritis) MAC can be found on the MAC, MAC can destroy the integrity of the cell membrane, leading to the influx of calcium ions, disrupting the intracellular metabolic function, the formation of MAC eventually leads to glomerular lesions and proteinuria. In vitro experiments show that the complement component involved in the classical pathway can be Maintaining the solubility of circulating immune complexes by interfering with the aggregation of immune complexes by phagocytosis by the mononuclear phagocytic system, complement can be conditioned The role of promoting hepatocyte clearance immune complex, in vitro complement replacement activation pathway can dissolve the precipitated immune complex, the incidence of glomerulonephritis is increased in patients with hereditary complement deficiency.

Active metabolites include superoxide anion, hydrogen peroxide, hydroxyl radicals and hypochlorous acid, active oxygen metabolites, interactions with cell membrane unsaturated fatty acids, nucleotides of DNA and thiol groups of proteins. Active oxygen metabolites can be directly or Indirectly inhibits the glomerular basement membrane by activating proteases (collagenase, gelatinase) to facilitate the degradation of the glomerular basement membrane, and the glomerular structure is halogenated by interaction with hypochlorous acid derivatives to mediate cytotoxicity and cytotoxicity. Membrane cell lysis, expansion of microcirculation leads to changes in glomerular intrinsic cellular metabolic activity (cAMP increase, arachidonic acid metabolism, RAF and TNF synthesis), indirect effects of reactive oxygen metabolites include: leukocyte chemotaxis and adhesion, immune complexation Cross-linking, changing cellular immunity.

Eicostable unsaturated fatty acids are autologous effective substances derived from arachidonic acid and other polyunsaturated fatty acids. Prostaglandins and thromboxane are derived from the cyclooxygenase pathway, leukotrienes are derived from the lipoxygenase pathway, prostaglandins E2 can reduce the deposition of immune complexes, inhibit collagen synthesis, reduce glomerular sclerosis, inhibit the function of T and B lymphocytes, inhibit macrophage aggregation and express Ia antigen, and inhibit cytokines (tumor necrosis factor and interleukin). -1), release of lysosomal enzymes and active oxygen metabolites, can maintain renal blood flow to maintain glomerular filtration rate, mesangial cells are the main source of prostaglandin E2, thromboxane A2 can reduce glomerulus Filtration rate, leukotriene B4 has a chemotactic effect on leukocytes, which can promote the expression of complement receptor 1 and release lysosomal enzymes and reactive oxygen species metabolites, and also increase their adhesion to endothelial cells.

Endothelin includes a group of peptide substances whose effects on renal function include: increased renal vascular resistance, decreased glomerular filtration rate, renal blood flow and ultrafiltration coefficient, altered sodium transport, and glomerular endothelin from the endothelium. Cells and mesangial cells are produced, mesangial cells express endothelin receptor, transforming growth factor beta, thrombin and thromboxane can stimulate cultured mesangial cells to produce endothelin, which can contract and proliferate mesangial cells. And synthetic 20-carbon unsaturated fatty acids, platelet-derived growth factor and platelet activating factor, several endothelial-derived factors can cause vasodilation, endothelium-derived relaxing factor is synonymous with nitrogen-containing oxide, and endothelium-derived relaxing factor can be increased The cyclic guanosine monophosphate level of mesangial cells inhibits mitosis, inhibits angiotensin II-induced mesangial contraction, and inhibits platelet adhesion and aggregation.

Nephrotic syndrome prevention

The onset and prognosis of this disease are related to many factors. Prevention should start from its own health, pay attention to reasonable diet, enhance physical fitness, improve immunity, avoid contact with toxic substances, harmful drugs and chemicals to reduce its damage to the body. Active prevention of infection and various diseases, an important factor affecting the efficacy and long-term prognosis of renal syndrome patients is the complications of nephrotic syndrome, and should be actively prevented and treated.

Nephrotic syndrome complications Complications, progressive glomerulonephritis, interstitial nephritis, uremia

(a) infection

The main reason for the decline in resistance to infection in patients with nephrotic syndrome is due to: 1 a large amount of IgG is lost in the urine. The lack of factor 2B (an alternative pathway component of complement) leads to defects in the immunomodulatory effects of bacteria. 3 malnutrition, the body's non-specific immune response is weakened, resulting in impaired immune function. 4 Transferrin and zinc are largely lost from the urine. Transferrin is necessary for maintaining normal lymphocyte function, and zinc ion concentration is related to thymosin synthesis. 5 local factors, pleural effusion, ascites, skin edema caused by skin rupture and severe edema caused local humoral factors to dilute, weakened defense function, are all susceptible factors for patients with nephrotic syndrome, before the advent of antibiotics, bacterial infection was One of the main causes of death in patients with nephrotic syndrome, severe infections mainly occur in children and the elderly, and adults are less common. Clinically common infections include: primary peritonitis, cellulitis, respiratory infections and urinary tract infections. The diagnosis of infection is established and should be treated immediately.

(B) hypercoagulable state and venous thrombosis

There is hypercoagulability in nephrotic syndrome, mainly due to changes in blood coagulation factors, including IX, XI factor decline, V, VIII, factor X, fibrinogen, -thromboglobulin and platelet levels, platelet adhesion Increased cohesion, decreased antithrombin III and anti-plasmin activity, therefore, increased agglutination and procoagulant factors, decreased anticoagulation and anticoagulant factors, and damage to fibrinolytic mechanism, is a comprehensive disease of nephropathy The cause of hypercoagulable state, the application of antibiotics, hormones and diuretics is an aggravating factor for venous thrombosis, hormones play a role in coagulation proteins, while diuretics concentrate blood and increase blood viscosity.

In nephrotic syndrome, when plasma albumin is less than 2.0g/d1, the risk of renal vein thrombosis increases. Most people think that thrombus first forms in the small vein, then extends, eventually involving the renal vein, renal vein thrombosis, in the membrane. Up to 50% of patients with renal disease, in other pathological types, the incidence rate is 5% to 16%, acute type of renal vein thrombosis can be characterized by sudden onset of low back pain, hematuria, leukocyteuria, increased urine protein and Renal dysfunction, chronic patients without any symptoms, but the renal pelvis blood after thrombosis often makes proteinuria worse, or poor response to treatment, due to thrombus shedding, extra-thrombotic embolism is common, pulmonary embolism can occur, but also There are renal tubular dysfunction, such as diabetes, amino acid urinary and renal tubular acidosis, clear diagnosis requires renal venography, Doppler ultrasound, CT, IMR and other non-invasive examinations are also helpful for diagnosis, plasma beta thromboprotein increased potential Thrombosis, increased 2-anti-plasmin in blood is also considered to be a marker of renal vein thrombosis, and the rate of peripheral deep vein thrombosis is about 6%, which is common in small Deep veins, only 12% have clinical symptoms, 25% can be found by Doppler ultrasound, the incidence of pulmonary embolism is 7%, 12% still have no clinical symptoms, other veins are rare, arterial thrombosis is rare, but in children Although the incidence of thrombosis is quite low, arteries are as common as venous involvement.

(three) acute renal failure

Acute renal failure is the most serious complication of nephrotic syndrome, often requiring dialysis treatment. Common causes are: 1 hemodynamic changes: nephrotic syndrome often has hypoproteinemia and vascular disease, especially in elderly patients with renal small Arteriosclerosis, very sensitive to blood volume and blood pressure drop, so when acute blood loss, vomiting, fluid loss caused by diarrhea, surgical injury, ascites, massive diuresis and the use of antihypertensive drugs, can further reduce blood pressure, leading to renal perfusion A sudden decrease, which in turn reduces glomerular filtration rate, and due to swelling, degeneration and necrosis of tubular epithelial cells after acute ischemia, leading to acute renal failure. 2 renal interstitial edema: hypoproteinemia can cause peripheral tissue edema, also lead to renal interstitial edema, renal interstitial edema compression of the renal tubules, so that the proximal tubules of the capsule hydrostatic pressure increased, GFR decreased. 3 acute interstitial nephritis caused by drugs. 4 bilateral renal vein thrombosis. 5 vasoconstriction: patients with partial nephrotic syndrome see increased renin concentration in hypoproteinemia, renin shrinks renal arteries, and GFR decreases. This condition is more common in elderly patients with vascular lesions. 6 Concentrated protein casts block distal tubules: may be involved in one of the mechanisms of acute renal failure in nephrotic syndrome. 7 nephrotic syndrome is often accompanied by extensive fusion of glomerular epithelial foot processes, and the fracture holes disappear, which effectively reduces the effective filtration area. 8 rapid glomerulonephritis. 9 urinary tract obstruction.

(four) renal tubular dysfunction

Renal tubular dysfunction in nephrotic syndrome, more common in children, the mechanism is believed to be a large amount of reabsorption of the filter protein by the renal tubule, which causes damage to the tubular epithelial cells, often manifested as diabetes, amino aciduria, high phosphate urine, kidney Small tube loss of potassium and high chloride acidosis, where a variety of renal tubular dysfunction often lead to poor prognosis.

(5) Abnormal bone and calcium metabolism

In the nephrotic syndrome, the VitD-binding protein (Mw65000) and the VitD complex in the blood circulation are lost from the urine, causing the blood level of 1,25(OH)2VitD3 to decrease, resulting in intestinal calcium malabsorption and bone tolerance to PTH. Nephrotic syndrome often presents with hypocalcemia, sometimes with fibrous softening and fibrocystic osteitis caused by hyperparathyroidism, and bone malnutrition associated with renal failure in nephrotic syndrome, generally less than non-renal disease Uremia is more serious.

(6) Endocrine and metabolic abnormalities

Renal disease syndrome urinary loss of thyroid-binding protein (TBG) and corticosteroid-binding protein (CBG), clinical thyroid function can be normal, but serum TBG and T3 often decline, free T3 and T4, TSH levels are normal, due to blood CBG and 17-hydroxycortisol is reduced, free and bound cortisol ratio can be changed, tissue cortisol response to pharmacological dose is also different from normal, due to ceruloplasmin (Mw151000), transferrin (Mw80000) and albumin lost from urine Nephrotic syndrome often has serum copper, iron and zinc concentrations decreased, zinc deficiency can cause impotence, taste disturbance, wound refractory and cell-mediated immune damage, etc. Continuous transferrin reduction can cause clinical treatment of iron Resistant small cell hypochromic anemia, in addition, severe hypoproteinemia can lead to persistent metabolic alkalosis, plasma protein bicarbonate will be reduced by 3mmol / L due to a 10g / L reduction in plasma protein.

Symptoms of nephrotic syndrome common symptoms proteinuria hypoproteinemia post-renal renal failure edema urine oil systemic persistent edema extrarenal obstruction nails semi-circular glomerular "three high" glomerular basement membrane moth

There are four main features of nephrotic syndrome, namely massive proteinuria, hypoproteinemia, hypercholesterolemia, and systemic significant edema.

1, a large amount of proteinuria

A large amount of proteinuria is a marker of nephrotic syndrome. The main component is albumin, which also contains other plasma protein components. The permeability of glomerular basement membrane is the basic cause of proteinuria, charge barrier and mechanical barrier (glomerulus capillary). Changes in vascular pore barrier), renal tubular epithelial cell reabsorption and catabolic capacity also have an effect on the formation of proteinuria, glomerular filtration rate, plasma protein concentration and protein intake directly affect the degree of proteinuria, kidney When the filtration rate of the ball is lowered, the proteinuria is reduced. In severe hypoproteinemia, urinary protein excretion can be increased, and a high protein diet can increase urinary protein excretion. Therefore, only the daily protein quantification method can not accurately determine the degree of urinary protein, can further make albumin clearance rate, urine protein / creatinine (> 3.5 often nephropathy range proteinuria), urine protein electrophoresis detection of urinary IgG components Increased suggestion that the selectivity of urinary protein is low, and the clinical value of urinary protein selectivity is not positive, and it has been used sparingly.

2, hypoproteinemia

It is the second characteristic of nephrotic syndrome. Serum albumin is less than 30g/L. The synthesis of albumin is increased in the liver during nephrotic syndrome. When enough protein and calories are given in the diet, the liver of the patient synthesizes albumin every day. About 22.6g, which is significantly higher than the normal person's daily 15.6g. When the compensatory effect of liver synthetic albumin is not enough to make up for the loss of urine protein, hypoproteinemia, hypoproteinemia and urine protein excretion will occur. The difference is not the same.

Patients with nephrotic syndrome usually have a negative nitrogen balance. At high protein load, they can be converted to a positive nitrogen balance. High protein load may increase urinary protein excretion due to increased glomerular filtration protein, so plasma protein elevation is not obvious. However, taking an angiotensin-converting enzyme inhibitor at the same time can inhibit the excretion of urine protein, and the albumin concentration can be significantly increased.

It is worth noting that in the case of hypoproteinemia, the binding of the drug to albumin is reduced, and the concentration of free drug in the blood is increased, which may increase the toxicity of the drug.

In the nephrotic syndrome, a variety of plasma protein components can be changed, 2 and globulin increase, 1 globulin is normal, IgG level is significantly decreased, and IgA, IgM, IgE levels are normal or elevated, fibrinogen, coagulation factor V, VII, VIII, X may increase, may be related to increased liver synthesis, with an increase in platelet count, decreased antithrombin III (heparin-related factor), normal or increased C protein and S protein concentrations, but decreased activity This will contribute to the hypercoagulable state, the increase of urinary fibrin degradation products (FDP), reflecting the changes of glomerular permeability, in short, the various pro-factors of blood coagulation and agglutination are increased, The mechanism of anti-agglomeration and fibrinolysis is impaired. Due to the combined effects of hypercholesterolemia and hyperfibrinogenemia, plasma viscosity increases, and when the vascular endothelium is damaged, spontaneous thrombosis is likely to occur.

In addition, transporters are also reduced, such as protein with important metal ions (copper, iron, zinc), proteins that bind to important hormones (thyroxine, cortisol, prostaglandin) and active 25-(OH)D3. Decreased, the latter can lead to secondary hyperparathyroidism, calcium and phosphorus metabolism disorders, causing renal bone disease, sustained transferrin reduction, changes in the ratio of hormones that glucocorticoids are free and bound in the treated patients , leading to changes in the metabolism and efficacy of the drug.

3, hyperlipidemia

The disease has a significant increase in total cholesterol, triglyceride, low-density lipoprotein (LDH), very low-density lipoprotein (VLDH) levels, hyperlipidemia associated with hypoalbuminemia, and LDL/HLDL only in serum white. When the protein is lower than 10-20g/L, the high-density lipoprotein (HDL) is normal or decreased, and the LDL/HDL ratio is increased, which increases the risk of atherosclerotic complication, hyperlipidemia and thrombosis. And progressive glomerular sclerosis.

The patient may present with lipid urine, a birefringent fat body in the urine, possibly a cholesterol-containing epithelial cell or a fat body cast.

4, edema

The most noticeable symptom of the patient is a progressive increase in systemic edema, initial eyelids, edema on the face and ankle.() (ANP)

Laboratory inspection

124h0.1g/kg

2(<30g/L<25g/L)(>5.7mmol/L>5.1mmol/L)

3

4C3

5IgG0.1()0.5()

6DNASmRNP

7(FDP)

8N---(NAG)-

Other inspection

1B

2

diagnosis

3.5g/d30g/L

Differential diagnosis

1IgAIgAC3

22040ds-DNASMC3

310Kimmelstiel-Wilson

4

5WegnerIgGIgA

635

7

810%125610

9D-()()

10(HIV-AN)AIDSHIVHIV(HIV)HIVHIVHIV()HIV-ANHIV-AN20%HIV-AN(80%90%HIV-AN)

11RNPSM5%

122050

131/3

141%20%3050

15406060%70%50%T

16

1714593050%(PAS)PAS

18

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