Renal amyloidosis

Introduction to renal amyloidosis Amyloidosis is a systemic disease in which amyloid fibers are deposited extracellularly in an insoluble form due to different causes, resulting in structural and functional damage to multiple organs. Kidney lesions caused by deposition of amyloid in the kidney are called renal amyloidosis. Nephrotic syndrome is its main clinical manifestation, which can lead to kidney failure and death. basic knowledge The proportion of sickness: 0.007% Susceptible people: no special people Mode of infection: non-infectious Complications: nephrotic syndrome uremia renal vein thrombosis

Cause of renal amyloidosis

(1) Causes of the disease

In recent years, scholars have carried out detailed chemical analysis and research on sediments in diseased tissues, and found that 85% to 95% of all amyloid deposits are fiber components, which are precursor proteins of amyloid substances. Water soluble and low ionic strength buffer with molecular weight between 4000 and 25000 Da. So far, more than 20 amyloid precursor proteins have been identified. These proteins have different primary structures and can be dissolved. It can also exist in the form of fibers. When present in the form of fibers, X-ray diffraction can see that these amyloid fibers have a common core structure, that is, an anti-parallel -sheet-like structure perpendicular to the long axis of the amyloid fiber, and therefore Some scholars believe that amyloidosis is a secondary disease of protein. Studies have also found that these proteins are not only of etiological significance, but also directly related to clinical manifestations, related diseases, treatment and prognosis. Therefore, it is recommended that clinicians establish starch. After the diagnosis of degeneration, further analysis of the chemical composition of amyloid deposits, the following briefly introduces several major starches Derived precursor protein.

The amyloid-protein light chain derived (AL) is an abnormal structural protein derived from the monoclonal immunoglobulin light chain or a partial fragment thereof. The molecular weight is 5,000 to 16000 Da, which can be excreted with urine. The most common light chain component is light. The Lamada () type of the chain, a few of which are Kappa () type, the former is about twice as large as the latter. It is found that not all fragments of the light chain have the same characteristics of starch-forming fibers, and the variable thereof The region V is most closely related to amyloidosis, and patients with V monoclonal immunoglobulin are more likely to have renal involvement and less associated with myeloma, and 90% of patients have a constant-chain sequence in the light chain component. Anti-light chain serum that specifically binds to the constant region can be used clinically to detect the disease. For patients with another 10% of the sediment without constant region, anti-lambage chain or anti-kappa chain antiserum can be used for detection. Protein-induced amyloidosis is the most common systemic amyloidosis. This disease can be complicated by plasma cell disease of B cell clones, such as multiple myeloma, lymphoma, macroglobulinemia, AL-type amyloidosis. Nearly 15% of patients with myeloma, most patients with AL amyloidosis have a very low degree of malignant immunoglobulin disease, using sensitive methods such as concentrated urine immunofixation, can be used in 86% of patients with urine A monoclonal component was found.

The AA protein (amyloid-protein A, AA) is derived from the serum acute phase reaction protein serum amyloid protein A (SAA), with a molecular weight of 4500 to 9200 Da and a fiber peptide subunit of 76. The amino acid N-terminal splitting fragment, SAA is a high-density lipoprotein, which is synthesized in the liver. At the onset of inflammation, the blood concentration of SAA protein and C-reactive protein produced by the liver increases simultaneously, and the production of SAA protein is affected by interleukin- 1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF) and other cytokine regulation, Benditt et al reported that the amino acid composition of the AA protein and the amino acid amino acid residue arrangement order is different from the AL protein. Arranged in the order of arginine-serine-phenylalanine-phenylalanine-serine-, or serine-phenylalanine-phenylalanine-serine-, this AA protein lacks cysteine and threonine The acid component, while the content of proline and proline is also very small, thus determining that the AA protein is not related to immunoglobulin, and the amyloidosis induced by the AA protein can be seen in any patient with persistent serum acute phase reaction, such as Secondary amyloid in chronic inflammation Sexually transmitted diseases, familial Mediterranean fever, Muckle-Well syndrome.

Amyloid-transthyretin (A-TTR) is a familial amyloidotic polyneuropathy (FAP), familial amyloidotic cardiomyopathy (FAC), and vitreous amyloidosis. Of amyloid fibrils, at least 70 mutants are currently known to be involved in amyloidosis in 127 sites of TTR, and the most common mutations associated with FAP are the proline at position 30 by methionine. Substituted, and related to FAC is that 122 proline is replaced by isoleucine. It should be noted that in some elderly people, systemic amyloidosis involving the heart is due to the normal intrinsic thyroid transporter in the blood. For a prolonged period of time, the wild-type thyroid transporter is deposited as an amyloid protein in the myocardium and other tissues, called senile systemic amyloidosis (SSA).

Amyloid-apolipoprotein AI (AApoAI) is a major component of high-density lipoprotein. Ten kinds of precursor proteins of amyloidosis of this protein are known, 7 of which are single base substitutions, and other mutations. There are insertions or deletions in the way, the disease is an autosomal dominant genetic disease, and the clinical manifestations of visceral amyloidosis, mainly myocardial lesions and polyneuropathy, liver lesions are also extensive but liver function is good, kidney damage is obvious Most of them eventually develop into kidney failure.

The amyloid-fibrinogen chain (AFib) mutant encodes amyloid fibrils, and four mutants are known to be associated with disease, two of which are frameshift mutations, including the codon 524 3 base deletions and 522 codon deletions, resulting in 554 arginine substitution by leucine, other mutations 526 glutamate replaced by proline, clinical manifestations of hereditary renal amyloidosis, but family The history is not obvious. Most patients have proteinuria or hypertension in middle age, and progress to chronic renal failure in 4 to 10 years.

Amyloid-2 microglobilin (A-2M) is a 2-microglobulin with a molecular weight of about 12,000 Da. It is an invariant chain of MHC class I molecules and is expressed in all nucleated cells. It is free in the circulation and can be filtered by glomerulus and reabsorbed and decomposed by the proximal convoluted tubule. In 1980, 2 microglobulin amyloidosis was first reported, which occurred in long-term hemodialysis patients, long-term dialysis, especially hemodialysis, resulting in blood. In the accumulation of 2 microglobulin, the dialyzer removes less 2 microglobulin, and the accumulated 2-M is deposited on the tendon near the ulnar nerve and wrist joint. The affected bone has cystic changes, and the clinical manifestations are mainly dyskinesia of the wrist joint. , gradually involving other joints.

In addition to the above protein fibril components, the tissue starch deposits contain some non-fibrous components, mainly including serum amyloid P-component (SAP), apolipoprotein E, heparin sulfate proteoglycan and the like.

SAP protein is a cytoplasmic glycoprotein, a non-fibrous amyloid with a molecular weight of 23,500 Da. It is produced by hepatocytes and is only decomposed in hepatocytes. The circulating half-life is 24 h. SAP has homology with C-reactive protein. Structure, but SAP does not increase in blood concentration during inflammation. This is different from SAA protein. SAP has a specific pentameric structure, a cationic ligand binding site, and a monomer-dependent calcium-dependent manner. In combination with ligands, in the amyloidosis, the serum SAP remained at a high concentration, suggesting that it may be involved in the pathogenic process of amyloidosis. The structure of the SAP pentamer can bind to amyloid and inhibit its degradation, using the SAP gene. Knock-out mice confirmed the promotion of SAP to amyloidosis, the deposition rate of amyloid was significantly reduced in the absence of SAP, and the intravenously purified SAP was selectively bound to amyloid deposits. It is used clinically to locate and quantify amyloid deposits in amyloidosis patients using radiolabeled SAP.

Apolipoprotein E is found in starch deposits of all amyloidosis patients. Apolipoprotein E4 is closely related to Alzheimer's disease and is also a high-risk genetic factor for other forms of amyloidosis, but its pathogenesis remains unclear. Heparin sulfate proteoglycan It is a basement membrane component, also found in all amyloid deposits. Its pathological effect is still unclear. An anionic sulfate that can bind to it can reduce the starchy fiber deposition of guinea pig acquired amyloidosis. Come as an effective treatment.

(two) pathogenesis

1. Amyloidosis may be related to abnormal immune function, abnormal protein metabolism and degeneration of connective tissue, but it is thought to be due to a family of protein deposition. This group of proteins has common characteristics. Helps its deposition, especially in patients with multiple myeloma associated with AL amyloidosis.

2. In the secondary amyloidosis and familial Mediterranean fever, serum AA apolipoprotein, which is partially synthesized in the acute phase, can be deposited as AA amyloid; amyloidosis caused by 2-M, 2- Increased serum levels of M are due to excessive production or decreased secretion or degradation, but deposition is not related to serum levels, while some believe that serum levels of 2-M increase enough to cause amyloidosis in tissues, long-term hemodialysis The possible pathogenesis of A2-M deposition in patients is as follows:

(1) Loss of renal function in patients with uremic hemodialysis, decreased 2-M in glomerular filtration, increased accumulation of 2-M in blood, long-term use of general dialyzer for hemodialysis, due to copper imitation membrane and cellulose membrane There is very little removal of 2-M. For example, switching to PAN membrane, polysulfone membrane or methyl carbonate membrane dialyzer, A2-M is increased due to convective removal of A2-M, and adsorption of 2-M on the membrane surface is increased. The increase in M clearance increases the level of 2-M in the blood.

(2) Endotoxin contamination and dialysis membrane function in dialysate can activate mononuclear macrophages and lymphocytes, resulting in the production of cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF) and transforming growth factor (TGF). It is increased and released into the bone matrix and cartilage, causing A2-M to cause disease in bone deposition, which promotes bone resorption more than parathyroid hormone.

3. In some amyloid proteins, especially ASC proteins or AE proteins, due to the substitution of a single amino acid, the deposited protein is different from the normal analog, so it is considered that the deposition may directly change with the changes in molecular biochemical characteristics caused by the change of the peptide sequence. Related to, in the AL-type amyloidosis, the deposited light chain is often a hydrolyzed fragment of the original light chain, occasionally the original light chain.

4. Due to partial mutation and decomposition of the possible mediators of amyloid deposition, in the 2-M deposition, the proteins involved are more acidic and higher glycosylated than normal 2-M, and glycosylated 2-M can be It causes a transient increase in chemokines in TNF-, IL-1 and monocytes.

5. It is true that all amyloid proteins are often deposited with aminopolysaccharides and amyloid P substances (ie, SAP proteins), and the molecular mechanism of amyloid deposition is still under investigation.

Kidney amyloidosis prevention

The prevention of this disease should be based on active treatment of the primary disease that can induce the disease. In recent years, tuberculosis and empyema have been rare, indicating that prevention is an effective measure, and limited type can sometimes be surgically removed; AL with myeloma 50% to 60% of alkylating agents and prednisone can be relieved. Primary AL can also be treated with the above treatment or with dimethyl sulfoxide and alkylating agent, colchicine for familial Mediterranean fever. The induced AA amyloidosis has a positive preventive effect, but the effect of other AL, AA treatment is inconsistent, supportive therapy helps to prolong survival, including the rational use of diuretics can improve heart and kidney function, antibiotic use can improve the infection The consequences and so on.

Renal amyloidosis complications Complications nephrotic syndrome uremia renal vein thrombosis

Amyloidosis is a systemic disease. In addition to kidney involvement, there are other organs involved. It takes 1 to 3 years for kidney involvement to develop from nephrotic syndrome to uremia. The common complication is renal vein thrombosis. The degree of amyloid deposition of glomeruli is poorly correlated with renal function.

Symptoms of renal amyloidosis Common symptoms with hypertension, sudden death, heart expansion, hematuria, joint swelling, polyuria, renal concentrating dysfunction, hepatosplenomegaly, conduction block, nodules

Amyloidosis is a systemic disease. In addition to kidney involvement, there are other organs involved. Because of the different organs, the severity of the disease and the location of the lesion, the clinical manifestations are different. Secondary is due to the foundation. Different diseases have different clinical manifestations, and there is also no obvious systemic involvement, and kidney involvement is the first manifestation.

1. Classification: There are several types of amyloidosis, each of which can be distinguished by the immunochemical properties of amyloid fibrils. These basic features are: beta sheet structure examined by X-ray diffraction; electron microscopy Fine fiber non-branched performance; after Congo red staining, apple green birefringence under polarized light microscope, according to these biochemical characteristics, combined with pathological features and clinical manifestations are divided into 6 types.

(1) AL type (ie, primary amyloidosis): Primary amyloidosis refers to an amyloidosis that occurs when the cause is unknown and there are no other diseases, mainly affecting the heart, digestive tract, tongue, and skin. And the nervous system, kidney involvement accounted for 40%.

(2) AA type (ie secondary amyloidosis): Secondary amyloidosis refers to the occurrence of other diseases, the common causes are:

1 chronic infection accounted for 50%, mostly recurrent chronic suppurative infections, such as lung abscess, empyema, bronchiectasis, osteomyelitis, etc.; in addition, it can also be seen in tuberculosis, syphilis, leprosy and other infectious diseases.

2 malignant tumors, such as medullary thyroid carcinoma, islet cell tumors, etc.

3 kinds of rheumatoid arthritis with amyloidosis accounted for 20% to 60%.

4 diabetes.

5 pemphigus.

6 ulcerative colitis.

The main affected organ of secondary amyloidosis is the kidney, accounting for 25%. In addition, the liver, spleen and adrenal gland are also common organs.

(3) plasma cell disease with amyloidosis: multiple myeloma and other plasma cell disease associated with amyloidosis accounted for 6% to 15%.

(4) hereditary familial amyloidosis: hereditary familial amyloidosis syndrome is rare, including a variety of diseases, usually Familial Mediterranean Fever FMF, is an autosomal recessive genetic disease, Renal amyloidosis is common with proteinuria (usually nephrotic syndrome) and progressive renal insufficiency, often with recurrent urticaria and deafness symptoms, and other Finnish Amyloidosis, hereditary familial amyloidosis Can be divided into nephropathy type, neuropathic type and mixed type.

(5) Localized amyloidosis: Localized amyloidosis refers to amyloid lesions found only in individual organs or tissues, such as the brain, cardiovascular, skin and urethra. The former two are more common in elderly patients.

(6) dialysis associated amyloidosis (or 2-microglobulin amyloidosis): long-term hemodialysis patients due to 2-M accumulation, often deposited in the synovial membrane and long bone, causing cystic bone disease, injury Arthropathy and carpal tunnel syndrome, but rarely deposited in the internal organs.

2. Renal performance: More than 3/4 of patients with amyloidosis have kidney disease, and the clinical manifestations of kidney involvement are divided into 4 stages.

(1) Preclinical stage (Phase I): There are no symptoms and signs of any symptoms, and there is no abnormality in the test. Only a kidney biopsy can make a diagnosis. This period can last for 5 to 6 years.

(2) proteinuria (stage II): found in 76% of patients, proteinuria is the earliest manifestation, more than half of the patients are mainly large molecular weight, low selective proteinuria, varying degrees, the degree of proteinuria and amyloid in the kidney The deposition site and extent of the small ball can be expressed as asymptomatic proteinuria, which lasts for several years. The microscopic hematuria and cell cast are rare, and those with hypertension account for 20% to 50%. The orthostatic hypotension is independent. Characteristic manifestations of neuropathy.

(3) stage of nephrotic syndrome (stage III): a large number of proteinuria, hypoalbuminemia and edema, hyperlipidemia is rare, a small number of only a small amount of proteinuria, renal vein thrombosis is the most common concomitant nephrotic syndrome Symptoms, mostly insidious onset, manifested as refractory nephrotic syndrome, a small number of cases of acute onset, abdominal pain, hematuria, increased proteinuria and deterioration of renal function, abdominal plain film or B-ultrasound found that the kidney is significantly larger than before The nephrotic syndrome is caused by AA protein, accounting for 30% to 40%, and AL protein is 35%. Once nephrotic syndrome occurs, the disease progresses rapidly and the prognosis is poor. The survival rate is less than 10% in 3 years.

(4) uremia period (stage IV): following nephrotic syndrome, progressive renal dysfunction occurs, as many as half of them have azotemia, severe dying from uremia, renal tubules and renal interstitial couples may be affected. The latter manifested as polyuria and even showed diabetes insipidus. In a few cases, there were electrolyte disorders such as renal glucosuria, renal tubular acidosis and hypokalemia. It took 1 to 3 years for nephrotic syndrome to develop uremia. The degree of amyloid deposition of glomeruli is poorly correlated with renal function.

3. Performance of extrarenal organs:

(1) Primary amyloidosis: common weight loss, weakness and fatigue, common multiple organ involvement.

1 The kidney is the most common, accounting for 50%.

2 heart (40%) is violated, causing myocardial lesions, heart enlargement, arrhythmia and conduction block, severe cases can be sudden death, 50% died of congestive heart failure and arrhythmia, the most common for the primary AL protein type Common causes of death.

3 gastrointestinal mucosal involvement can cause constipation, diarrhea, malabsorption and intestinal obstruction and other symptoms, submucosal vascular involvement may be associated with gastrointestinal bleeding, or even massive bleeding, tongue involvement, giant tongue, patient speech, difficulty swallowing, supine The giant tongue hangs down and makes a loud snoring. When the stomach is affected, symptoms such as stomach cancer, repeated vomiting are difficult to eat.

4 autonomic or peripheral nerve involvement (19%) manifested as multiple peripheral neuritis, abnormal acral sensation (feeling numbness in gloves or socks-like distribution) and hypotonia and hypotonic reflexes; ulnar nerve damage and peripheral tendon due to starch The deposition of the sample is manifested as carpal tunnel syndrome; it can lead to autonomic dysfunction, manifested as orthostatic hypotension, gastrointestinal dysfunction, bladder dysfunction or impotence, and dementia in elderly patients with central nervous system involvement.

5 bone marrow involvement can cause compensatory polycythemia, smooth muscle and skeletal muscle involvement manifested as muscle weakness.

6 joint involvement manifested as multiple joint swelling, pain, or bone cystic changes due to bone involvement.

7 liver damage is 16%, skin purpura is 5% to 15%.

(2) secondary renal amyloidosis: the symptoms of kidney disease are often concealed by the symptoms of primary disease, liver and spleen are also the main affected organs, liver, splenomegaly, liver pain, severe liver function decline Portal pressure is increased, ascites may occur, jaundice is rare, and it is more common in the late stage of the disease. In addition, the adrenal gland is often involved. The lesion is most severe in the cortex near the medulla. The adrenal cortex is enlarged, often due to adrenal venous thrombosis. Causes tissue necrosis, dysfunction, manifested as Edison's disease.

(3) Renal amyloidosis associated with multiple myeloma: the main symptoms are unbearable bone pain, X-ray film sees bone destruction or fracture phenomenon, bone destruction often causes elevated blood calcium, secondary high Uric acidemia, abnormal increase in serum globulin, and clotting protein in the urine.

(4) senile amyloidosis: occurs in the brain, heart, pancreas, aorta, seminal vesicles and bone and joint tissues. Due to amyloid deposition, the cell dysfunction and death of the depositional organs are caused, and the blood vessel wall of the lesion is visible. Congo red stained amyloid fibrin deposition caused by vasculitis, vascular wall involvement is characteristic of amyloidosis in the elderly, so it is believed that this amyloid protein is derived from the circulatory system, and the chemical structure of amyloid is different due to different underlying diseases. .

(5) Hemodialysis-related amyloidosis: The amyloid protein (A2-M) in the blood 2 microglobulin multimer in patients with long-term hemodialysis is abnormally increased, which is closely related to the bone and joint complications of patients. The performance is as follows:

1 carpal tunnel syndrome (CTS): 1 patient or both hands with pain, numbness and dyskinesia, the incidence of dialysis less than 5 years is low, the incidence of dialysis for 9 years is 13 times that of 5 years, dialysis exceeds The incidence rate was 100% in 17 years, and A2-M deposition was found in carpal tunnel tissue, ulnar nerve and peripheral tendon sheath.

2 amyloid arthritis: shoulder, hip, knee, wrist, chest lock, interphalangeal, sacral, elbow, cervical and lumbar joints can be affected in long-term dialysis patients, the former four most affected, joint swelling and pain, limited function, Tonic, X-ray film shows that the joint cavity is narrow, bone destruction, bone damage in the cystic light-transmitting area can be seen near the joint. When the finger joint is involved, the trigger can be caused by tendon sheath inflammation, and the tendon is broken.

3 pathological fractures: cystic bone damage occurs in the femoral head, pathological fractures can occur in the femoral neck or acetabulum.

4A2-M extra-bone deposition: rare, A2-M can be deposited in the gastrointestinal tract, heart, liver, spleen, lung, adrenal gland, prostate, testicular and other extra-bone tissues, A2-M amyloid deposits can be seen in the vessel wall of the affected site. The conditions caused by different deposition sites are also different.

Examination of renal amyloidosis

1. Urine examination: urine protein can be seen. Patients with M protein in the urine also have a large amount of proteinuria. The urine test results in a positive rate of 86% of monoclonal abnormal proteins. Occasionally, microscopic hematuria, urinary sediment has particles or Fat tube type.

2. Blood biochemical examination: visible fibrinogen reduction, fibrinolysis and lack of coagulation factors, Howell-Jolly body was found in peripheral blood, suggesting that the spleen was involved, and severe liver function abnormalities were observed, and jaundice was rare.

3. About 2/3 of the patients' serum electrophoresis or immunoelectrophoresis can detect monoclonal abnormal proteins. Immunoelectrophoresis and immunofixation are sometimes used to determine trace proteins in blood or urine. Immunoglobulin concentration determination is helpful for multiple myeloma. In the classification diagnosis, the patient has a peri-bank protein in the urine, which can react with the anti-serum of the kappa chain and the lambda chain, but cannot react with the heavy chain of any one immunoglobulin.

4. Determination of blood SAA protein level, AA protein evolved from its predecessor SAA protein, elevated blood SAA concentration suggests secondary amyloidosis caused by AA protein, in rheumatoid arthritis, ulcerative colitis, In the acute phase of tuberculosis, tumor, and chronic infection, SAA is elevated and accompanied by elevated C-reactive protein, so SAA can be used to distinguish whether the infection is active, SAA>0.2g/ml is seen in active inflammation, SAA after infection control The level is reduced. When the long-term dialysis patients have bone disease manifestations, the abnormal increase of 2-M in the blood can help diagnose the osteomyelitis.

5. Pathological examination: pathological examination is the most reliable method for diagnosis. The visceral biopsy makes the prenatal diagnosis rate greatly improved, and the proteinuria is obvious. The positive rate of renal biopsy is close to 100%. It is easy to bleed after renal biopsy, but not as good as liver. Liver biopsy is considered to be more serious than liver biopsy. It has become the main method for the diagnosis of renal amyloidosis. The positive rate of liver biopsy is low, only 50%, which may cause serious bleeding. It should be cautious and bone marrow biopsy. The positive rate is about 50%. The rectal mucosa biopsy should be deep. It should include the lamina propria of the mucosa. The positive rate is 73%. In AL, or AA amyloidosis, the amyloid deposit can also be seen in the ascites. The positive rate of diagnosis is 70%-80%. Other possible tissue examination sites include gums, skin (low sensitivity), gastric mucosa and small intestine. By endoscopic brushing cytology and biopsy, the positive rate of gastric examination can be improved. The synovial tissue removed after the carpal tunnel is relaxed is definitely positive, but usually these tissues are not diagnosed.

The biopsy specimens were treated with 5% potassium permanganate and then stained with Congo red. The AA protein was sensitive to potassium permanganate, and had a low affinity with Congo red. The coloring test was negative, while the affinity between AL protein and Congo red was large. It is positive, so this method can be used to identify the lesions caused by AA protein or AL protein, so it is helpful to distinguish between primary and secondary amyloidosis.

Bone biopsy is the best method for early diagnosis of A2-M deposition in bone. Potassium permanganate-Congo red staining is positive, while staining negative in AA or AF amyloid protein is helpful for differential diagnosis. Irregularly curved, amyloid fibers with a diameter of 8 to 10 nm can be diagnosed.

(1) Light microscopy: The histological manifestations of primary and secondary amyloidosis are similar. The changes of early glomeruli are not obvious. Only the special staining is used to make a correct diagnosis in the glomerular membrane. Peripheral capillary wall and blood vessel deposits were stained with Congo red as brick red. Under the polarizing microscope, apple green double-emitted phenomenon, hematoxylin-violet staining showed discoloration, and thioflavin-T staining was visible under ultraviolet light. Fluorescence, in the rectum, interlobular vessels, small arteries, collecting ducts and intercellular substance, similar amyloid deposits can be observed with thick slices, and interstitial deposits may be associated with tubule dysfunction, such as renal diabetes or Damage to the tubules reabsorbs HCO3-.

On the HE-stained sheet, the mesangial membrane appears as a solidified eosin-like substance. As the condition worsens, the glomerulus becomes less cells and is replaced by amyloid deposits. At this stage, standard optical microscopy Under the condition, it is difficult to distinguish between diabetic glomerulosclerosis, light chain deposition disease and non-specific chronic glomerulonephritis. In some patients, the capillary wall is obviously thickened, and the silver staining is positive and nail-like, which is pseudo-eibulous membranous nephropathy. In familial Ostertaag variants, there are giant cells around the amyloid deposits and amyloid casts in the renal tubules.

(2) Fluorescent immunoassay: its performance varies, but the most common is the amorphous mass of Ig, light chain and C3 weakly stained in capillaries and mesangial membrane. Gallo et al applied fluorescence immunoassay and anti- Ig serum, anti-light chain protein serum and anti-AA protein serum were used to identify AA and AL types. Other proteins, including albumin and fibrinogen, were also found in sediments. The performance of fluorescent immunoassays was not sufficiently specific for diagnosis. In the sediments of primary amyloidosis, the corresponding light chain can be found.

(3) Electron microscopy: The performance of ultrastructure is of great value in the diagnosis of amyloidosis. The characteristic lesion is that the fine fibers with a diameter of 8-10 nm are disordered or bundled. Due to its lack of periodicity, it is very Easy to distinguish from collagen fibers, which can occur in the basement membrane of the mesangial, subepithelial or subendothelial. In mild lesions, only the mesangial membrane is involved. As the condition worsens, the capillary of the amyloid fibrils deposits. The vessel wall is also involved, with occasional needle-like deposits under the endothelium. A group of studies suggest that fibrous amyloid deposits are likely to be composed of AA-type amyloidosis, and granular amyloid deposits are likely AL type composition.

6. Congo red test: This method can be used to indirectly distinguish between amyloid AA protein and AL protein. It is a simple and convenient auxiliary diagnostic test. Amyloid protein is oxidized with 5% potassium permanganate and then Congo red stained. The protein has a strong affinity with Congo red, so Congo red is colored and not easy to fade, but the AA protein has poor affinity with Congo red, so it is not easy to color with Congo red. After injecting a certain amount of Congo red, the normal human absorption rate is 10%. Glomerulonephritis 1h absorption rate is 20%, 40% in nephropathy, and renal amyloidosis, 20min absorption rate is 30%, such as 1h absorption rate is greater than 60% positive, for early primary amyloidosis The diagnosis is of little significance. Because the amyloid deposits in the early affected organs are less, the absorption of Congo red is less, so it is often a negative result. In addition, when the serum albumin is low, the absorption rate is affected. When the amount of proteinuria is calculated, the absorption rate is calculated. The amount of Congo red absorbed in the urine should be excluded. This method is less reliable and is rarely used.

7. Amino acid sequence analysis of amyloid: The amino acid composition of amyloid and the order of the residues help to identify the AL protein and the AA protein.

8. Other inspections:

(1) X-ray abdominal plain film, ultrasound examination or intravenous pyelography: If you see an enlarged kidney shadow (especially with renal vein thrombosis), it can help diagnosis, but the size of the kidney shadow is normal or the late renal shadow is reduced, and the diagnosis cannot be ruled out. .

(2) Renal venography is helpful in diagnosing renal vein thrombosis.

(3) Radionuclide scanning: It has been applied to determine amyloidosis. 99mTc-dimercaptosuccinate (9mTc-DMSA) can be reabsorbed by proximal tubules. When renal tubules and renal interstitial are involved, proximal tubule reabsorption declines. The intake of 99mTc-DMSA is reduced, but the sensitivity of the analysis is not used. The use of 123I-labeled serum amyloid P substance to diagnose AA and AL amyloidosis has a good prospect. It has been reported that intravenous 2 is injected intravenously. -M to detect amyloidosis containing 2-M.

(4) Two-dimensional echocardiography has a high sensitivity in determining amyloidosis in the heart.

Diagnosis and differentiation of renal amyloidosis

diagnosis

Because of the lack of understanding of the diversity of the symptoms of this disease, clinicians must always pay attention to the possibility of the disease, especially for myeloma or other plasma cell diseases and inflammation that cannot be cured after long-term treatment. A biopsy should be performed in time to suspect the diagnosis to confirm the diagnosis.

The kidney is the most common and early-affected organ of amyloidosis, and should be further examined to determine if there is any renal amyloidosis:

1. Patients with multiple myeloma or patients with M protein in serum or urine for unknown reasons, accompanied by massive proteinuria, renal insufficiency, congestive heart failure, peripheral nerve sensation or movement disorder, carpal tunnel syndrome or liver spleen Swollen.

2. Middle-aged and elderly patients have unexplained proteinuria, nephrotic syndrome, chronic renal failure and the kidney volume is not reduced.

3. There are clear rheumatoid arthritis, seronegative spondyloarthropathy or chronic infectious diseases or inflammation (such as tuberculosis, bronchiectasis, osteomyelitis, chronic pyelonephritis, nodular polyarteritis, etc.), proteinuria or nephropathy Signs and other clinical manifestations related to amyloidosis.

4. Patients with long-term dialysis have carpal tunnel syndrome, arthropathy or osteolytic injury.

Pathological examination is the most reliable method for diagnosis. 85%95% is positive for renal biopsy, the positive rate of liver biopsy is low, and there is danger of major bleeding. Therefore, it should be cautious, rectal mucosa, gums, tongue, oral mucosa, skin and tendon. Specimens such as abdominal wall fat are easily obtained, and the positive rate can reach 90%. It can also be prioritized. The biopsy tissue is positive for Congo red staining, and it has characteristic red-green birefringence under polarized light microscope. This is the key to diagnose this disease. Index, tissue electron microscopy showed that the unbranched fine fiber filament-like structure has certain characteristics, and should be examined at the same time. Due to the different extent and extent of tissue lesions, negative biopsy can not rule out the disease.

SAP radiographic imaging began in 1988 to detect the presence, sensitivity, specificity, comprehensiveness, non-invasiveness and quantitation of systemic amyloid deposits. The 123I-labeled highly purified SAP was injected intravenously to specifically display amyloid. The deposition site has a sensitivity rate of 100% for AA protein and 90% for AL protein. It does not show adverse reactions within the allowable range of radiation dose, and is an ideal screening test for amyloidosis.

Further clarifying the chemical composition and properties of tissue sediments is an important part of the diagnosis, which helps to determine the relevant treatment options and the judgment of the prognosis. If the tissue specimens are treated with 5% potassium permanganate and then Congo red staining, this method It can be used to indirectly distinguish between amyloid AA protein and AL protein, which is simple and easy to perform. AL protein Congo red is not easy to fade, while AA protein has poor affinity with Congo red, so it is not easy to color. The more accurate method is immunohistochemistry and reliable. , specifically showing various amyloid precursor proteins, most of the monoclonal antibodies of the aforementioned amyloid proteins (such as AL, AA, TTR, 2-M, kappa light chain, lambda light chain, Alys, Afib, etc.) have been commercialized. Chemical.

Differential diagnosis

1. AL-type amyloidosis and multiple myeloma: Bone marrow examination of AL-type amyloidosis often shows an increase in plasma cell count, and both amyloid proteins are AL-type, making it difficult for multiple occasions. Myeloma identification, if the number of bone marrow plasma cells is less than 25%, there is a small amount of monoclonal protein in blood or urine, no associated anemia, hypercalcemia and osteolytic damage, the possibility of AL amyloidosis is greater .

2. AA-type amyloidosis and its various causes should be noted.

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