focal segmental glomerulosclerosis
Introduction
Introduction to focal segmental glomerulosclerosis Focal segmental glomerulosclerosis (FSGS) is a common primary glomerular disease in children and adults with nephrotic syndrome (NS). Histopathological features are glomerular segmental scars, with or without With the formation and adhesion of foam cells in the glomerular capillaries. Focality means that only part of the glomerulus is involved (affected glomerulus <50%); segmental means that part of the glomerulus is involved; spherical sclerosis refers to the entire glomerular phase of the glass Change or scar formation. basic knowledge The proportion of illness: the incidence rate is about 0.004% - 0.005% Susceptible people: mostly in children and adolescents Mode of infection: non-infectious Complications: malnutrition nephrotic syndrome nephrotic syndrome hyperlipidemia edema
Cause
The cause of focal segmental glomerulosclerosis
(1) Causes of the disease
FSGS has a variety of pathogenic factors, such as poisoning damage, humoral immunity and hemodynamic changes, which can cause capillary wall damage, macromolecular protein production and retention, and immunoglobulin deposition combined with C1q and C3. It causes the degeneration of podocytes and detachment from the basement membrane. It is found that the phenotype of podocytes changes in primary FSGS, but it is unclear how these lesions of epithelial cells cause capillary collapse and sclerosis. FSGS may be a manifestation of tissue repair after exacerbation of epithelial cell lesions. The rapid recurrence of focal sclerosing lesions after renal transplantation indicates the presence of systemic factors in the pathogenesis of FSGS.
Changes in hemodynamics of residual nephron, causing glomerular capillary-compensated hypertension, hyperperfusion and hyperfiltration, resulting in damage to epithelial cells and endothelial cells, abnormal function of mesangial cells, leading to progressive focal Segmental sclerosis, this pathological process can be aggravated by the intake of a large number of proteins, limiting protein intake and blood pressure lowering treatment, endothelial cell damage causes platelet aggregation and microthrombus formation, and aggravates the development of lesions; many FSGS occur Related to this pathogenesis, such as "chronic" streptococcal infection after nephritis, chronic transplanted kidney rejection, reflux nephropathy and analgesic nephropathy, in addition, glomerular filtration of myelin glomeruli was also observed The rate is higher than that of the glomerulus in the cortical area, and the hemodynamic changes are also the pathogenesis of FSGS.
Both drug use and AIDS can cause typical FSGS nephrotic syndrome and progressive renal failure, which can be the end result of most proliferative glomerulonephritis. However, most cases are special, for the first time. At the time of renal biopsy, histopathological type was found to be FSGS.
In addition to FSGS, segmental sclerosis can also be the end result of proliferative glomerulonephritis (eg, glomerulonephritis after infection) or associated with hyperfiltration nephrotic syndrome, and some patients undergo a focal section. After segmental hyperplasia, segmental necrosis and scarring are formed, which is common in secondary glomerulonephritis.
(two) pathogenesis
The pathogenesis of this disease is still inconclusive, with only a series of observations and inferences:
1. Membrane over-absorption of macromolecules
The study found that intravenous injection of exogenous protein into the test animal can cause changes similar to this disease, suggesting that long-term large amount of proteinuria can cause damage to epithelial cells, and excessive growth of mesangial cells can develop into glomerular foci. , segment hardening.
2. Hemodynamic changes in the glomerulus
In the occurrence of this disease, the role of glomerular capillary vasospasm is very important. The research proves that some or most nephrectomy is performed in the animal model, and the remaining renal tissue is focally and hardened for about half a year, suggesting that the disease may occur. Associated with hemodynamic changes, the mechanism may be compensatory capillary hypertension in the remaining renal tissue, as well as into the ball, dilation of the small arterioles, glomerular capillary vasospasm completely open to the systemic circulation, leading to glomerular hyperperfusion High transmembrane pressure, increased filtration of proteins and other soluble molecules, causing capillary sputum epithelium, endothelial cell damage and mesangial cell dysfunction, such as administration of diet control or angiotensin-converting enzyme inhibitors, making glomeruli Capillary internal hypertension is relieved, and the development of focal and segmental sclerosis is slowed down, which is more indicative of the role of glomerular capillary vasospasm.
3. Hyperlipidemia
The occurrence and development of this disease is positively correlated with hyperlipidemia. The study found that:
1 Adding fat to food can cause glomerular sclerosis in the test animals, and the degree of glomerular lesions is consistent with the degree of increase in blood lipids.
2 Congenital obese rats can naturally occur in the process of growth, segmental glomerular sclerosis.
3 After treatment with lipid-lowering drugs, glomerular damage is also reduced with the decrease of blood lipids.
4 human obesity with blood cholesterol, triglyceride increased and cardiac hypertrophy, the kidney may appear similar to primary focal segmental glomerulosclerosis lesions, such conditions by controlling diet, weight loss to lose weight, followed by urine The protein is reduced and the nephrotic syndrome is relieved.
Hyperlipidemia causes glomerular focal, the mechanism of segmental sclerosis may be that mesangial cells have the ability to take low-density lipoprotein (LDL), oxidized LDL receptors on mesangial cells, so glomeruli It can take up oxidized LDL, which is the most potent lipoprotein that causes atherosclerosis. LDL stimulates mesangial cell proliferation and cell death, leading to glomerular sclerosis, such as the aforementioned glomerular blood flow. Changes in learning and high filtration can lead to glomerular focal, segmental sclerosis and proteinuria. In addition, lipid deposition in the glomerulus is also a focal, segmental sclerosis, mononuclear giant in the glomerulus. The phagocytes or mesangial cells devour the deposited LDL to form foam cells, which play an important role in the development of arteriosclerosis, so they support glomerular focal, segmental sclerosis and arteriosclerosis. There is a common pathogenesis, although blood lipids are higher than this disease in small lesions or membranous nephropathy, but glomerular foam cell infiltration is not as serious as this disease, glomerular fat deposition can also cause glomerular capillaries Endothelium Cellular damage, as well as platelet, macrophage, monocyte aggregation, stimulation of cytokines such as IL-1, TGF, etc., can cause mesangial cells to proliferate, increase extracellular matrix components and glomerular capillaries Coagulation in the lumen.
4. Infiltration of mononuclear macrophages in the glomerulus
Mononuclear macrophages produce a variety of cytokines that stimulate mesangial cell proliferation leading to glomerular sclerosis, and the number of mononuclear macrophages and histocompatibility antigen (MHC)-positive 1a cells increases in this disease. The number of cells is consistent with the degree of focal and segmental sclerosis. This cell and cell adhesion factor (ICAM) activates macrophages, which activates glomerular macrophages and, at the same time, the renal interstitial Nuclear macrophages also infiltrated significantly, and the degree of infiltration was consistent with the degree of proteinuria and renal dysfunction. In addition, the above lesions in the glomerulus were also related to the cholesterol content and the development of obesity. The interstitial list was treated with prednisone. Nuclear macrophage infiltration is alleviated, and renal function is improved, but glomerular cell infiltration and hardening are difficult to alleviate, and proteinuria will not improve.
5. Glomerular capillary vasospasm
Activated platelets can release platelet-activating factor (PAF), platelet-derived growth factor (PDGF), etc. These factors act on mesangial lesions, and experiments have demonstrated the use of anticoagulant drugs such as heparin, warfarin, or thromboxane inhibitors. Can alleviate glomerular focal, segmental sclerosis and reduce proteinuria without affecting renal blood flow and glomerular filtration rate.
6. Plasma factor effects
The disease can be recurred rapidly after renal transplantation, and the recurrence rate can reach 35% to 50%. Therefore, it may be considered that some plasma factor may cause disease. In recent years, some patients have been treated with immunosorbent therapy for this disease, which can reduce the urine protein and stop. After adsorption, the urine protein rises again, and the adsorption again can reduce the urine protein, suggesting that the patient has a substance in the blood that increases the permeability of the glomerular capillary.
7. Visceral epithelial cell lesions
In the occurrence and development of this disease, not only the mesangial matrix proliferation plays an important role, but also the lesion of epithelial cells may be the starting point of the disease. The pathological observation notes that the disease has both visceral epithelial cell hypertrophy at the onset of the disease. (non-proliferation), cytoplasmic dilution, with capillary sputum hypertrophy, so that the filtration area increases and the filtrate leaks poorly, forming pseudo-cells, hypertrophied and dilated capillary vasospasm adheres to the glomerular capsule together with the pseudo-cell Forming a segmental hardening starting spot on which to develop to harden.
8. Genetic factors
Although there are not many reports of this disease in the relatives of the siblings, it is reported that the recurrence rate of the patients with all the same MHC antigens after transplantation is 82%, and the recurrence rate of the incomplete relatives is 53%, while other allogeneic supplies The renal recurrence rate was 35%, which was highly suggestive of hereditary factors, and there was also a significant pedigree tendency in experimental animals.
Prevention
Focal segmental glomerulosclerosis prevention
The clinical course of the disease varies greatly, and the course of the disease varies. Therefore, prevention should start from its own health, usually avoid fatigue, reasonable diet, scientific exercise, enhance physical fitness, improve the body immunity, prevent disease from happening, Patients with complications should actively and effectively prevent and treat the primary disease and complications. For example, if an infection is found, antibiotics that are sensitive to pathogenic bacteria, potent and have no nephrotoxicity should be selected in time, and those with clear infections should be identified. Should be removed as soon as possible, when the plasma albumin concentration is less than 20g / L, suggesting that hypercoagulable state already exists, that is, preventive anticoagulant therapy should be started. For thrombosis, embolism should be as early as possible (within 6h, the best effect, but It is still expected to be effective within 3 days. Systemic or local thrombolysis with urokinase or streptokinase, combined with anticoagulant therapy, and acute renal failure, such as improper treatment can be life-threatening, timely treatment, most patients are expected to recover.
Complication
Focal segmental glomerulosclerosis complications Complications, malnutrition, nephrotic syndrome, nephrotic syndrome, hyperlipidemia, edema
Infection
In association with protein loss, malnutrition, immune dysfunction and the use of glucocorticoid therapy, infection is a common complication of nephrotic syndrome. Due to the application of glucocorticoids, the clinical signs of infection are often not obvious, although there are many antibiotics available. It can be chosen, but if the treatment is not timely or incomplete, the infection is still the main cause of relapse and poor efficacy, and even leads to death of the patient, which should be highly valued.
2. Thrombosis, embolization complications
Increased blood viscosity due to blood concentration and hyperlipidemia; in addition, due to loss of certain proteins and increased compensatory synthetic protein, causing imbalance of blood clotting, anticoagulant and fibrinolysis system, thrombus and embolism are prone to occur complication.
3. Acute renal failure
Patients with nephrotic syndrome may have decreased renal blood flow due to insufficient blood volume, induce pre-renal azotemia, and compress renal tubules due to high renal interstitial edema and massive renal tubular obstruction of renal tubules and renal tubules. High pressure, indirectly causing a sudden decrease in glomerular filtration rate, leading to acute renal failure.
4. Protein and fat metabolism disorders
Long-term hypoproteinemia can lead to malnutrition, pediatric growth and development retardation; immunoglobulin reduction causes low immunity and infection; metal-binding protein loss can make trace elements (iron, copper, zinc, etc.) lack; endocrine combination Insufficient protein can induce endocrine disorders; drug-binding protein reduction may affect the pharmacokinetics of certain drugs (increased plasma free drug concentration, accelerate excretion), affect drug efficacy, increase blood viscosity in hyperlipidemia, promote thrombosis, embolism Complications will also increase cardiovascular complications, promote glomerular sclerosis and tubular-interstitial lesions, and promote chronic progression of renal disease.
Symptom
Focal segmental glomerulosclerosis Symptoms Common symptoms Proteinuria HIV infection Hematuria edema Glomerular sclerosis Renal failure Nephrotic syndrome Urine protein nodules Hypertension
The disease occurs mostly in children and adolescents. Males are slightly more than females. A few patients have upper respiratory tract infections or allergic reactions before onset. The most common clinical symptoms are nephrotic syndrome. About 2/3 of patients have a large amount of proteinuria and severe Edema, urine protein can be 1 ~ 30g / d, about 50% of patients have hematuria, microscopic hematuria is common, occasionally gross hematuria, 30% to 50% of adults with mild persistent hypertension or performance For chronic nephritic syndrome, the patient's 24h urine protein <3.5g / d, edema is not obvious, often hematuria, hypertension and renal insufficiency, and more than 50% can be a manifestation of renal syndrome, there are obvious "three high and one low" The clinical manifestations, a small number of patients with no obvious symptoms, occasionally found in the routine urine test proteinuria, this type of asymptomatic proteinuria can last for a long time, the prognosis is good, a small number of patients can also gradually develop into end-stage renal failure, Most of the proteinuria is non-selective, but it can be highly or moderately selective in the early stage, the serum C3 concentration is normal, the IgG level is decreased, and the proximal renal tubular function is often impaired. The upper respiratory tract infection or allergy can make the above symptoms. plus .
The clinical manifestations of different pathological types of this disease are slightly different. Typical FSGS with glomerular hypertrophy, less urine protein; cell type FSGS often has a large amount of proteinuria (>10g/d), and is prone to renal insufficiency. It has been reported that 60% of patients with cell type FSGS have serum creatinine >2mg/dl, while only 10% of patients with typical FSGS have elevated serum creatinine. Collapsed FSGS also has significant proteinuria, often >10g/d, and renal insufficiency is better than others. The type is more serious, and the hypertension is relatively less. The type is acutely ill and progresses rapidly. It usually enters end-stage renal failure (ESRF) 1 to 2 years after onset.
The clinical manifestations of children are similar to those of adults, mostly nephrotic syndrome, and the incidence of hypertension and renal insufficiency is lower than that of adults. Most (40%-60%) FSGS develops chronically and eventually leads to renal failure. A small number of patients (10% to 15%) progressed faster and had renal failure earlier.
Examine
Examination of focal segmental glomerulosclerosis
Urine routine examination
Microscopic hematuria, proteinuria, often aseptic leukocyte urine, glucoseuria, and renal tubular dysfunction have amino acid urine and phosphate urine, the incidence rate is higher than other types of NS.
2. Blood test
There is significant hypoalbuminemia, plasma albumin is usually less than 25g / L, a few can be less than 10g / L, glomerular filtration rate (GFR) decreased, blood urea nitrogen, creatinine increased, most patients have high fat Blood, serum C3 is normal, IgG level is lowered, C1q is mostly normal, 10% to 30% of patients have positive circulating immune complexes, blood volume is reduced, hematocrit can be increased, white blood cells and classification are normal, and platelets are slightly increased Water retention can cause a decrease in blood sodium concentration, long-term sodium or acquired adrenal insufficiency, which can also lead to a decrease in blood sodium concentration. Hyperlipidemia can cause pseudohyponatemia, which can release potassium ions in vitro. Therefore, spondylosis can also cause pseudohyperkalemia.
3. Kidney biopsy light microscopy
Typical FSGS lesions are characterized by focal segmental lesions of the glomerulus. The lesions involve a small number of glomerular and glomerular segments of the glass-like sclerosis. The lesions often begin with the glomeruli in the deep or near-medullary cortex. Expanded to the renal cortex, the diseased glomerulus is segmental sclerosis, the unaffected glomerulus is normal or the mesangial matrix is increased, the transparent substance is deposited under the endothelial cells of the damaged capillary vasospasm, and foam cells are formed in the hardened area. Common localized epithelial cell hyperplasia, early lesions may only have local epithelial cells detached from the basement membrane, epithelial cells are swollen, vacuolar degeneration, cytoplasm is basophilic, and hardened capillary vasospasm can adhere to the capsule wall, each The extent of glomerular segmental damage is different. When the disease progresses, it can cause global hardening. Cases with fully developed lesions can be mistaken for "non-specific" chronic sclerosing glomerulonephritis, which can be differentially diagnosed by immunofluorescence. Lesions often manifest as focal thickening and atrophy of the basement membrane. For example, focal tubular damage and mild glomerular changes coexist. Highly suspected FSGS, focal in renal tissue, The appearance of glomerular sclerosis is often the manifestation of advanced FSGS, accompanied by severe tubulointerstitial lesions, up to 30% in children, typical hormone-sensitive small lesions in adults, a small number of sclerotic kidneys Small balls should be distinguished from FSGS. In addition to primary FSGS, changes in FSGS can be seen in renal tissues of many diseases, and FSGS can also overlap with primary glomerular diseases.
4. Electron microscopy
In cases with large amounts of proteinuria, most or all of the glomeruli showed diffuse or segmental foot processes, and early appearance of foam cells in the capillary wall and/or mesangial area increased mesangial matrix and partial capillary collapse. There are electron dense deposits in the subendothelial and mesangial areas, mesangial cell proliferation, large electron denses corresponding to glass-like changes under light microscopy and immunofluorescence IgM and C3 deposition, paracellular mesangial area and endothelial cells Fine particulate electron dense deposits are also seen below.
5. Immunofluorescence
In the hardened or necrotic area, C3 or IgM and C1q can be found to be irregular, granular or nodular, and the glomerulus of the lesion is negative. Occasionally, the mesangial area has IgM and C3 distribution, and IgG and IgA are rare.
Diagnosis
Diagnosis and diagnosis of focal segmental glomerulosclerosis
Diagnostic criteria
There is no reliable indicator for the diagnosis of this disease. In the diagnosis of FSGS, renal biopsy should be relied on and all possible secondary factors should be excluded, such as HIV infection, drug abuse, etc., and the medical history and physical examination are carefully asked. Help with differential diagnosis.
For example, patients with nephrotic syndrome or simple proteinuria are associated with proximal tubular dysfunction; persistent nephrotic syndrome with hypertension, microscopic hematuria, non-selective proteinuria; patients who are not sensitive to hormones should Suspected FSGS, a kidney biopsy is helpful for diagnosis.
Typical focal segmental glomerulosclerosis (FSGS) is characterized by focal lesions that affect a small number of glomeruli (focal) and localized glomeruli (segments), starting with a proximal medulla The ball is involved, the light only affects several capillary sacral areas, and the severe ones affect most glomeruli. The lesions are uniform and clear cells without cells or cells (thick foam cells, transparent drops), severe cases See balloon adhesion, visceral epithelial cell proliferation to form a "hat-like" structure, and even "umbilical" lesions, the other is focal glomerular sclerosis, renal tubular epithelial cells often atrophy, surrounding The matrix showed cell infiltration and fibrosis. Electron microscopy showed that most of the glomeruli or all glomerular foot processes were fused, epithelial cells and their foot processes were separated from the basement membrane, and electron dense deposits were deposited at the endothelial cells and mesangial cells. Immunofluorescence In the hardened area, IgM and C3 were found to be irregular, lumpy, nodular deposits, glomeruli with no lesions were negative or diffuse IgM, C3 deposition, IgA, IgG were rare.
The disease is easily misdiagnosed as minimally pathological nephropathy, so it is necessary to combine clinical manifestations, renal histology, response to hormone therapy, and whether there is spontaneous remission or drug-induced remission, which is helpful for the differential diagnosis of FSGS and MCD. In addition to FSGS, focal segmental sclerosis can also be seen in the chronic development of various kidney diseases, such as obstructive nephropathy, reflux nephropathy, AIDS patients and diacetyl morphine addicts; Obese people, therefore, to make a comprehensive diagnosis to make a correct diagnosis.
Differential diagnosis
Non-collapsed focal segmental glomerulosclerosis
At present, the relationship between CG and FSGS is still controversial. Some scholars believe that CG is an independent disease. Most scholars believe that CG is a serious type of non-collapsed focal segmental glomerulosclerosis (NC-FSGS). The difference is that the number of people with urinary protein greater than 10g/d in clinical CG patients is significantly higher than that of NC-FSGS; the proportion of renal insufficiency is high and the renal function deteriorates rapidly. The pathological difference is:
1CG is the collapse of glomerular capillaries, the matrix is obviously dilated, and the lesion segment rarely adheres to the glomerular capsule, whereas NC-FSGS is the opposite.
2CG epithelial cells are hypertrophied and have intracellular granules.
The lesion segment of 3CG is rarely located in the vascular pole of the small ball, and this change is common in NC-FSGS.
4CG tubulointerstitial inflammation, atrophy and fibrosis were more obvious than NC-FSGS. Immunology confirmed that CG glomerular tubules proliferated more than NC-FSGS. However, because CG lesions were mostly segmental focal lesions Distribution, which is still classified as idiopathic focal segmental glomerulosclerosis, but as a special subtype, its clinical manifestations and morphological changes are different from idiopathic FSGS.
2. Human immunodeficiency virus-associated nephropathy (AIDS)
Human immunodeficiency virus-associated nephropathy (HIV-AN) is a kidney complication of AIDS patients. It is more common in the early stage of HIV infection. Before other serious infections, its clinical manifestations, light microscopy, immunofluorescence and pathological features and idiopathic collapse The performance of glomerulopathy is similar, it is difficult to distinguish. The difference between ICG and HIV-AN pathology lies in the electron microscopic appearance. Under the electron microscope, the glomerular endothelial cells of HIV-AN and the interstitial leukocytes have a large number of tube network inclusions (TRI). ), TRI mainly in the endoplasmic reticulum expansion pool, the nucleus pool and the Golgi pool, 80% to 90% of HIV-AN patients have TRI in glomerular endothelial cells, while only 10% of CG patients found TRI, so Patients with HIV susceptibility factors (such as intravenous drug abuse, homosexuality, HIV-prone areas and high-risk populations), early HIV testing and detection of anti-HIV antibodies, combined with other clinical manifestations of HIV (eg, asymptomatic infections, persistent lymph nodes) Swollen, secondary tumors can identify CG and HIV-AN.
3. Focal and segmental proliferative glomerulonephritis
The late lesions can also be similar to the pathological changes of the disease. This lesion is also more common in IgA nephropathy, focal proliferative lupus nephritis and purpuric nephritis, small vasculitis, etc., and its pathological changes are focal segmental endothelial cells and Mesangial cell hyperplasia, with focal and segmental distribution of crescent formation, can be identified according to its corresponding clinical manifestations and characteristic immunofluorescence.
4. Focal glomerular fibrosis
It is a different concept from the pathology of this disease. It is less common. The glomerular contraction of the lesion is stained with collagen fibers, and the staining of silver and PAS is negative.
5. Minimal lesion nephropathy
At present, most scholars believe that MCD and FSGS are two different types of kidney lesions. In the early stage of FSGS, the lesions are mostly confined to the junction of the skin and the marrow. Therefore, renal biopsy is often confused with MCD because it cannot be worn. Therefore, attention should be paid to both. Identification, such as glucocorticoid-insensitive and older, may be early FSGS, repeated renal biopsy if necessary, serial section can improve the diagnosis rate, MCD light microscopy rarely morphological changes, renal tubules Double-folded fat droplets were observed in epithelial cells, vacuolar-like changes were observed in epithelial cells of proximal convoluted tubules, epithelial cells were swollen under electron microscope, lobes were formed into lamellae, clotting of filter pores, vacuolar degeneration of epithelial cells, microvilli morphology, Protein absorption drops and lysosomes increased, immunofluorescence was mostly negative, occasionally IgG and / or IgM, IgA, C3 deposition.
In addition, in the normal population over 40 years old, the subcapsular cortex may have cirrhotic glomeruli, which should be distinguished from this disease.
