Lipoprotein glomerulopathy

Introduction to lipoprotein glomerulopathy Lipoprotein glomerulopathy (lipoprotein glomerulopathy) is a new kidney disease recognized in recent years. Its pathological features are the presence of lipoprotein emboli in the glomerular capillaries and extrarenal lipoprotein embolism. The clinical manifestations were similar to type III hyperlipidemia with elevated plasma apolipoprotein E (apoE). basic knowledge The proportion of illness: 0.001% Susceptible people: no specific population Mode of infection: non-infectious Complications: hyperlipidemia, renal failure

The cause of lipoprotein glomerulopathy

(1) Causes of the disease

Genetic studies have shown that the disease is autosomal recessive.

(two) pathogenesis

The pathogenesis of lipoprotein glomerulopathy has not been fully elucidated. Most of them are thought to be associated with abnormal lipid metabolism. It is known that abnormal lipid metabolism can cause glomerular injury; glomerular lesions also affect lipid metabolism. Many systemic diseases (including rare Fabry disease, Nieman Pick, and Gaucher disease) increase intrarenal lipid deposition. It is quite common that intrarenal lipid deposition is secondary to nephrotic syndrome, and hyperlipidemia is characteristic. Sexual performance, because nephrotic syndrome is effectively treated to normalize plasma lipids, in which case hyperlipidemia is a consequence of kidney disease.

The main pathway of lipoprotein metabolism is the metabolic pathway of its receptor. Apolipoprotein is the signal and marker of receptor recognition lipoprotein. Apo E is one of the most important components of apolipoprotein. Apo E can bind to chyle. Microparticle residue receptors can also bind to low-density lipoprotein receptors, so apo E is an important factor affecting blood lipid levels. Current studies have found that different gene phenotypes of apoE have different receptor binding activities, so these have different The active apo E isomer may affect the metabolism of blood lipids. For example, the E4/4 gene phenotype body, the apo E receptor binding activity is significantly enhanced, the clearance rate of chylomicron residues is accelerated, and the blood lipid level is decreased; The apo E gene phenotype of familial type III hyperlipoproteinemia is homozygous apoE2/2, a defect in the ability of this apo E isoform to bind to lipoprotein receptors.

Therefore, lipoprotein metabolism disorder, plasma lipid levels are elevated, and the apo E gene phenotype heterozygote apoE2/2 is dominant in this disease. Therefore, it is believed that this isoform also has defects in binding ability to lipoprotein receptors and causes plasma. Increased lipoprotein levels, this disease and familial type III hyperlipidemia have many similarities: plasma total cholesterol, triglyceride and apo E water increased, electrophoresis showed that the pre-beta lipoprotein band broadened, with kidney disease The performance of the syndrome, etc., but the latter has a tendency to develop early atherosclerosis, often with yellow tumors, prone to intermittent claudication, hyperuricemia, etc. These clinical manifestations do not appear in lipoprotein glomerulopathy , indicating that there are differences, by speculating on the apo E gene phenotype, it is speculated that heterozygous E2 may have a tendency to produce lipoprotein glomerulopathy.

Other scholars have found that the primary structure of these isomers is different from the amino acid analysis of apo E isomers, and it is speculated whether it is easy to be in the glomerulus due to the amino acid substitution, affecting the structure of apolipoproteins and affecting the structure of lipoproteins. Internal deposition directly causes damage to the glomerulus. For example, it has been found that apo E3 contains one cysteine, apo E4 does not contain cysteine, and apo E2 contains two cysteines but one less than apo E3. Arginine, precisely because of the exchange of cysteine/arginine, reflects the difference in charge between them, and the glomerular basement membrane always has a positive charge, presumably apo E2 and basement membrane The combination is not easy to remove from the capillaries and the disease occurs.

Oikawa et al also found that the apo E isoforms of three patients with lipoprotein glomerulopathy were special. The 145 arginine was replaced by valine. The foreign name was named after the place name (Sendai), called apo E. Sendai is apo E Sendai. Because the nitrogen atom in the proline structure is in a rigid five-membered ring, it forms a peptide bond with no hydrogen on the nitrogen atom, so it is impossible to form a hydrogen bond. It is generally believed that any ammonia is present in the peptide chain. At the site of the acid residue, the peptide chain turns to be unable to form an -helix, so proline is the "killer" of the -helix. In apo E Sendai, the proline destroys the helical structure of the apo E protein, resulting in the entire Or local distortion, further deposition in the glomerulus, causing glomerular lesions.

It can be seen from the above that the research focus of the pathogenesis of lipoprotein glomeruli is mainly focused on the relationship between the gene phenotype of apo E and lipoprotein metabolism and the change of the primary structure of the amino acid of apo E isoform. The problem of pathogenicity, while Watanabe et al. proposed the in situ pathogenesis of lipoprotein nephropathy. Saito et al. also observed by electron microscopy that lipoprotein deposition initially occurs in the mesangial membrane, and excess lipoprotein can protrude into the glomerular capillaries. The vascular lumen forms a lipoprotein thrombus. The components in the lipoprotein thrombus depend on the composition and content of various lipids in patients. An Hang Yang et al. believe that the gene phenotype is not very much in the pathogenesis of lipoprotein glomerulopathy. Important, changes in the local environment of the capillaries may be more important in the occurrence of this disease, they use the antioxidant Probucol (Probucol, probucol) to treat the disease is effective, it is speculated that lipoprotein deposition may be associated with glomerular capillary local Environmental abnormalities and pre-oxidation status are related to the exact pathogenesis of lipoprotein glomerulopathy.

Lipoprotein glomerulopathy prevention

The disease is a hereditary disease. At present, there is no effective preventive measures to prevent it from happening. For patients with definite diagnosis, it is necessary to actively reduce blood fat and symptomatic treatment to control the development of the disease and prevent the occurrence of renal failure.

Lipoprotein glomerulus complications Complications, hyperlipidemia, renal failure

Complicated with varying degrees of hyperlipidemia and slowly progressing renal failure, this disease may also be associated with IgA nephropathy, lupus nephritis, and membranous nephropathy.

Lipoprotein glomerular disease symptoms Common symptoms Highly expanded capillary vasospasm glomerular volume increased proteinuria Renal failure Hematuria glomeruli pathological changes Renal glomerular hyperplasia

Lipoprotein glomerulopathy mainly affects the kidney, and is mainly caused by glomerular damage. All patients have proteinuria, and some gradually progress to proteinuria in the range of nephropathy. A few cases are accompanied by microscopic hematuria, despite the disease. Patients with plasma cholesterol, triglyceride and VLDL increased, but often no extrarenal manifestations, lipoproteins do not form embolism outside the kidney, most patients showed resistance to hormone therapy, slowly progressing to renal failure.

Examination of lipoprotein glomerulopathy

Urine check

All patients had different degrees of proteinuria, 1g ~ 3g / 24h, with microscopic hematuria.

2. Blood test

Patients have varying degrees of hyperlipidemia. Saito et al. compared hyperlipidemia in patients with lipoprotein glomerulopathy and primary nephrotic syndrome and found plasma triacylemia in patients with lipoprotein glomerulopathy. Glycerol levels appear to be significantly higher than their total cholesterol levels; they further analyzed that their cholesterol is mainly characterized by very low-density lipoprotein and medium-density lipoprotein, a feature of familial type III hyperlipoproteinemia. Very similar, the most characteristic of the laboratory examination is that all cases showed a significant increase in plasma apolipoprotein E levels (103 ~ 388mg / L), apo E gene phenotype detection found that E2 containing gene performance Type dominates.

3. Light mirror

The characteristic lesion under light microscope is the high expansion of the glomerular capillary lumen. The cavity is filled with a lot of light stains, filled with reticular materials, and the capillaries are balloon-like changes. Some people call it capillary angiogenesis-like expansion. Special staining, including PAS, PASM, MASSON staining, negative Sudan 3 and oil red 0 staining showed that there were a lot of positive lipid droplets in the dilated capillary lumen, and scattered small lipid droplets and glomeruli were also seen in the surrounding renal tubular cells. Mesangial cells and matrix often show mild hyperplasia, and may also present mesangial lysis, mesangial and basement membrane separation, and mesangial insertion in a double-orbital manner. The glomerular basement membrane is generally free of thickening and spike formation. There were no significant changes in tubulointerstitial, no signs of abnormal lipid deposition such as foam cells, no abnormalities in renal blood vessels, and repeated renal biopsy. As the disease progressed, capillary lipoprotein embolization occurred. The sample material gradually decreased, the mesangial cells and the matrix showed obvious hyperplasia, with segmental mesangial insertion and sclerosis, and the lipoprotein thrombus-like substance gradually replaced the hyperplastic mesangial membrane. Now the respective tubular atrophy, interstitial lymphocytic and mononuclear cell infiltration and fibrosis and other diseases.

4. Electron microscopy

It is characterized by the obvious expansion of capillaries. The cavity is filled with a large number of particles of different sizes and electron densities. These particles can be arranged in stripes, similar to the fingerprint structure, and there are also cavities in the cavity filled with different sizes. Clustered or layered, the red blood cells and endothelial cells in the lumen are squeezed between the lipoprotein thrombus-like material and the capillary wall.

The early mesangial area only showed mild hyperplasia. When the lesion progressed, the mesangial area was significantly widened. Mesangial cells and mesangial matrix proliferated. Sometimes mesenteric insertion, mesangial lysis, etc., glomerular basement membrane See thickening, dense deposits.

5. Immunofluorescence

Conventional immunofluorescence staining such as IgG, IgA, IgM, C1q, Fg staining showed no characteristic changes. The staining of -lipoprotein and apo E in the glomerular capillary lumen was observed by monoclonal antibody against lipoprotein and apolipoprotein. In addition, a small amount of fine-grained apolipoprotein deposits were observed in the mesangial area, and -lipoprotein staining was negative.

The disease can also be combined with IgA nephropathy, lupus nephritis, membranous nephropathy, etc. At this time, immunofluorescence, light microscopy and electron microscopy each show its characteristic changes, which is of great value in diagnosis.

Diagnosis and identification of lipoprotein glomerulopathy

Diagnostic criteria

Under normal circumstances, the kidneys may contain a small amount of lipids. When the kidneys have a large amount of unusual lipid deposits or involve specific structures, they can be considered as renal lipidosis, which can be clinically classified into primary. And secondary two major categories should be identified with lipoprotein glomerulopathy.

In summary, for pathologically characteristic morphological changes - increased glomerular volume, highly swelled capillary sputum, kidney disease patients with layered changes in the "embolic", should pay attention to the existence of Lipoprotein glomerulopathy, if histochemical staining for lipoprotein is negative, evidence of lipoprotein embolization and extrarenal lipoprotein embolism confirmed by electron microscopy, combined with experimental evidence of abnormal lipid metabolism, the diagnosis of lipoprotein glomerulopathy can be established .

Differential diagnosis

Primary lipid deposition disease

(1) Fabry disease: a congenital lysosomal storage disease caused by a deficiency of the innate lysosomal enzyme -galactosidase A, which occurs in men, and the disease can affect almost all tissues of the body. Clinically, Mainly manifested as paresthesia, pain in the extremities, skin vascular keratomatosis, more common in the middle of the trunk, often involving the scrotum, buttocks, thigh roots, umbilical and oral mucosa, rash red with purple, pressure does not fade, puberty lesions especially Obviously, cardiovascular and cerebrovascular diseases can be manifested as angina pectoris, myocardial infarction, ischemic stroke, other diseases include corneal opacity or atrophy, retinal or membrane distortion, cataract, etc., renal changes manifest as mild proteinuria, occasionally complicated by hematuria , rare nephrotic syndrome, mild hypertension, a small number of patients with more severe renal tubular dysfunction, such as renal diabetes insipidus or distal renal tubular acidosis, pathological examination showed glomerular visceral epithelial cells are highly swollen And vacuolization is a typical change of the disease, sometimes lesions can affect the parietal epithelial cells, a few cases in glomerular endothelial cells, mesangial cells can also Similar to vacuoles, ultrastructural observation of electron microscopy refers to the vacuolated cells seen under light microscopy as "inclusion bodies". This special structure is mostly in the lysosome, with a membrane structure surrounding, also known as Zebra body, myelin-like changes, etc., can also be seen in the process of foot process fusion, endothelial cells and mesangial cells in the "inclusion body" is smaller and less, if the "inclusion body" amount can occupy the entire cavity.

(2) Niemann-Pick disease: due to the lack of sphingosine phosphatase in the body, the sphingomyelin can not be hydrolyzed and deposited in the reticuloendothelial system, hepatocytes, renal tubular epithelial cells, nerve cells and some other cells. Causes cell dysfunction. Since a large number of foam cells accumulate in the reticuloendothelial system including the bone marrow, liver, spleen and superficial lymph nodes can be enlarged. This disease is a rare autosomal dominant hereditary disease with kidney involvement. The main feature is a large number of foam cells in the epithelial cells of the renal tubules (especially the distal tubules and the medullary tendon). Sometimes the whole small tube is foam-denatured. Under the electron microscope, the distal renal tubules and the medullary epithelial cells are covered with a large amount of lipids. Body occupancy, inconsistent size and shape, can be zebra-like or concentrically arranged, clinically, superficial lymphadenopathy with renal insufficiency and / or proteinuria should be considered to rule out the disease.

(3) Metachromatic white matter atrophy: the brain is the main affected organ of the disease, and the renal lipid deposition occurs in the distal tubules, the collecting duct, the cells of the medullary sac, and occasionally in the lumen, the kidney Small balls and proximal convoluted tubules are rarely involved, and renal function is often unaffected.

(4) Mucosal lipid disease: It is a congenital abnormal substance storage disease. This substance contains the comprehensive characteristics of mucopolysaccharide and lipid. The disease mainly involves fibroblasts. The kidney is mainly affected by renal fibroblasts and kidney. The glomerular epithelial cells are balloon-like, containing a large number of clear vacuoles, and the proximal tubules are rarely affected.

(5) Wolman's disease: abnormal lipid deposition disease caused by congenital lysosomal acid esterase deficiency. This disease mainly affects neonates and children. It is characterized by vomiting, diarrhea and abdominal distension. A large amount of esterified cholesterol and triacylglycerol accumulate in the liver, spleen and adrenal gland. The kidney is not the main affected organ. When the kidney is involved, vacuolar cells are formed in the mesangial area and pericardium, and the renal tubules are basically normal.

(6) Batten's disease: a group of congenital diseases, the classification of each lesion is blurred, their common manifestations are mental disorders, various neurological symptoms, neuronal and glial cells with unknown components of complex lipid storage In the kidney, lipid storage occurs in glomerular endothelial cells and distal convoluted tubule epithelial cells.

(7) familial lecithin cholesterol acyltransferase (LCAT) deficiency: the disease is mainly characterized by corneal opacity, anemia, arteriosclerosis, etc., kidney damage is also one of its main manifestations, patients may appear proteinuria, under the microscope Hematuria, end-stage renal failure can sometimes occur in the late stage. The pathological manifestation is the accumulation of foam cells (significantly altered endothelial cells) in the glomerulus and the mesangial area. A large number of dense irregular particles appear under the endothelium. Abnormal lipids), the above seven hereditary lipid metabolic diseases are not filled with glomerular capillary lipoprotein thrombus-like substance, which is different from lipoprotein glomerulopathy.

(8) Familial hyperlipoproteinemia: This disease is the most common type of lipid metabolism abnormality. According to the characteristics of lipoprotein electrophoresis, it can be divided into I, IIa, IIb, III, IV, V six, this Occasionally, the symptoms of kidney involvement and the formation of lipid-like thrombosteroids in the glomerular capillaries may be present. Patients may present with nephrotic syndrome, progressive proteinuria, and renal insufficiency in the advanced stage. Plasma total cholesterol, triglyceride and pre--lipoprotein increased significantly, immunofluorescence examination of thrombus-like substances is or pre--lipoprotein, lipoprotein glomerulopathy and the disease have many similarities, However, lipoprotein glomerulopathy lacks corneal arch, xanthomas, is prone to atherosclerosis and intermittent claudication and other typical clinical manifestations and signs of familial hyperlipoproteinemia, laboratory examination of lipoprotein glomerulopathy with plasma Apo E levels were characterized by immunofluorescence, which indicated that apolipoprotein thrombus contained apo E component. In addition, the detection of apo E gene phenotype was found to be significantly different from familial hyperlipoproteinemia.

2. Secondary lipid deposition disease

(1) Nephrotic syndrome: nephrotic syndrome caused by any cause, a large number of lipid substances are filtered, and after reabsorption, it will cause renal deposition, which mainly involves the proximal tubules, showing a vacuolization change. In addition, it can also affect the basement membrane of the renal tubule, causing thickening, tearing and vacuolar deformation of the basement membrane, involving the interstitial cells to become foam cells, occasionally glomerular podocytes, mesangial cells and endothelial cells. It can also be affected, even forming cholesterol granuloma in the stroma.

(2) Alport syndrome: There is no abnormal plasma lipid level in this disease, often accompanied by hearing loss and eye diseases. Kidney lesions mainly manifest as thickening of basement membrane, tearing and thinning, etc. Microscopically, a large number of foam cells were found in the renal interstitium, and obvious lipid droplets appeared in the renal tubules.

(3) Liver cirrhosis: The main manifestations of liver disease involving the kidney are the widening of the mesangial area, the proliferation of mesangial matrix, and the formation of dense irregular lipid particles in the mesangial area and under the endothelium.

(4) fatty liver in idiopathic pregnancy: the disease is relatively rare, the main lesions in the liver are characterized by a large amount of lipid accumulation, renal tubular cells can also appear lipid droplets.

(5) Other lipid deposition diseases: some poisons or drugs, ischemic injury and other causes can cause lipid accumulation in the kidney. In addition, some chronic infectious diseases such as yellow granulomatous pyelonephritis may also have foam cells. The accumulation of all these diseases, glomerular lesions and laboratory tests are different from lipoprotein glomerulopathy.

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