Pediatric renal amyloidosis

Introduction to renal amyloidosis in children Renal amyloidosis, also known as Muckle-Wells syndrome, is a rare disease in which amyloid deposits cause various organ dysfunction in various tissues and organs. Amyloidosis is caused by kidney-induced lesions called amyloidosis, nephrotic syndrome is its main clinical manifestation, and advanced stage can lead to renal failure. This amyloid reacts brown when it comes into contact with iodine, like starch, hence the name. Children also have this condition, but it is less common than adults. basic knowledge Sickness ratio: 0.0012% Susceptible people: children Mode of infection: non-infectious Complications: hypertension, renal glucosuria, metabolic acidosis, hypokalemia, uremia

Causes of renal amyloidosis in children

Causes:

The etiology of this disease is still unknown. It is reported that it is related to the immune mechanism, that is, the secondary may be related to allergic reaction. The primary disease has a family history of the disease, which is a dominant or recessive genetic disease. The disease is based on the presence or absence of a primary disease. Or the location of amyloid deposition, divided into the following categories:

1. Primary amyloidosis: The main order of invasion of organs is heart, digestive tract, tongue, spleen, liver, kidney and lung.

2. Secondary amyloidosis: often secondary to various chronic infectious diseases and connective tissue diseases and metabolic diseases (diabetes), etc. The main order of invasion of organs is: kidney, spleen, adrenal gland, liver, lymph nodes, Pancreas and so on.

3. Hereditary familial amyloidosis: amyloidosis occurs due to hereditary familial causes, the most common of which is familial Mediterranean fever.

4. Localized amyloidosis: The amyloid is localized in the nasopharynx, lower respiratory tract, skin and other parts. This section mainly deals with renal amyloidosis.

Pathogenesis:

1. amyloid fibrin: amyloid is an amorphous glass-like transparent substance, hematoxylin staining is light pink, Congo red staining is brick red, under the polarizing microscope is apple green birefringence phenomenon, under electron microscope It can be seen that the non-branched small fibers are arranged. The most common feature of these fibers is the -pleated-sheet formation by X-ray diffraction. The amyloid fibrin includes the following eight components, among which AL Protein and AA protein are the main components.

(1) amyloid protein (light chain derived): derived from immunoglobulin light chain fragments, found in more than 50% of patients with primary amyloidosis and 75% of multiple myeloma, serum protein electrophoresis can be seen The peak globulin is mainly type, a few is type, and the molecular weight of AL protein is 500023000D, which can be excreted with urine, and this-week protein belongs to this category.

(2) Amy protein (amyloid protein A): independent of immunoglobulin, its precursor is serum amyloid protein A (SAA), found in secondary amyloidosis and familial Mediterranean fever, AA The protein has the same N-terminal amino acid residue as the SAA protein, but the molecular weight is different. The former component is 4500 to 9200D, and the latter molecular weight is 12500D. The SAA protein is synthesized in the liver and the blood content is very low. In the onset of inflammation, the SAA protein and The concentration of C-reactive protein produced by the liver is simultaneously increased, and the production of SAA protein may be related to the interleukin-1 produced by activated mononuclear macrophages.

(3) amyloid familial protein: hereditary familial neuropathy in patients with amyloidosis, amyloid containing prealbumin, this prealbumin has a high affinity with peripheral nerves.

(4) AMC protein (amyloid senile cardiac protein): contains pre-albumin component, found in familial senile patients with amyloidosis.

(5) AE protein (endocrine-related amyloid protein): This protein component is found in endocrine disorders, such as medullary thyroid carcinoma.

(6) A2-microglobulin (A2-M): more common in long-term hemodialysis patients, easy to deposit in the tendon near the ulnar nerve and wrist joint, causing carpal tunnel syndrome, this amyloid The protein has a molecular weight of about 12,000 D, which is similar in structure to 2-microglobulin, which is rarely deposited in the liver, heart or spleen.

(7) serum amyloid pcomponent: The order of amino acid residues of SAP protein is similar to that of C-reactive protein. SAP does not increase in blood concentration during inflammation, which is different from SAA protein.

(8) Mixed amyloid: Several different types of amyloids are present in the blood of some patients with amyloidosis.

2. Pathogenesis

(1) Excessive production of protein: amyloidosis may be related to abnormal immune function, abnormal protein metabolism and degeneration of connective tissue, but it is believed that this group of proteins has common characteristics due to a family of protein deposition. Excessive production of these proteins contributes to their deposition, especially in patients with multiple myeloma associated with AL amyloidosis.

(2) Secondary amyloidosis: 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; in 2-M In the caused amyloidosis, the increase in serum levels of 2-M is due to excessive production or decreased secretion or degradation, but deposition is not related to serum levels, and there is a report that serum levels of 2-M increase enough to organize The accumulation of amyloidosis caused by accumulation, the possible pathogenesis of A2-M deposition in patients with long-term hemodialysis is as follows:

1 uremia patients with hemodialysis: uremia patients with hemodialysis, loss of renal function, glomerular filtration of 2-M decreased, blood 2-M accumulation increased, long-term application of general dialyzer for hemodialysis, due to copper imitation And the cellulose membrane has very little clearance for 2-M. For example, switching to PAN membrane, polysulfone membrane or methyl carbonate membrane dialyzer, the accumulation of A2-M is increased by convection, and the adsorption of 2-M on the membrane surface is increased. A2-M clearance can be increased, resulting in a decrease in blood 2-M levels.

2 dialysate endotoxin contamination and dialysis membrane function: can activate mononuclear macrophages and lymphocytes, resulting in increased production of cytokines such as interleukin-1 (IL-1), tumor necrosis factor (TNF) and transforming growth factor (TGF) 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) Changes in molecular biochemical properties: 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 be directly due to the change of the peptide sequence. Related to changes in molecular biochemical properties, 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) Mutation and decomposition of amyloid deposition medium: Due to partial mutation and decomposition of possible mediators of amyloid deposition, the proteins involved are more acidic and advanced glycosylation than normal 2-M due to 2-M deposition. The characteristic, glycosylated 2-M can cause a transient increase in TNF-, IL-1 and monocyte chemotaxis.

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

Pediatric amyloidosis prevention

At present, there are no effective preventive measures. Because secondary infections are common in chronic infectious diseases and rheumatism, effective prevention of these diseases will undoubtedly reduce the incidence of this disease. Unger and other studies suggest that when performing androgen antagonism treatment for prostate cancer patients Androgen antagonists may become stimulators of spermatic epithelial cells, induce localized amyloidosis, and deserve clinical attention.

Pediatric amyloidosis complications Complications hypertensive renal glucosuria metabolic acidosis hypokalemia uremia

Can be complicated by hypertension, orthostatic hypotension, hypoproteinemia, polyuria, renal diabetes, metabolic acidosis, hypokalemia, infection, etc., late uremia, damage to various systems, and heart function Failure, secondary vascular embolization complications, and blood and thrombosis.

Pediatric amyloidosis symptoms Common symptoms Kidney involvement Nephrotic syndrome Renal diabetes edema Hypotension Hematuria Renal urinary disintegration Abdominal pain Polyuria hypokalemia

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. 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: 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: found in 76% of patients, proteinuria is the earliest manifestation, before the appearance of proteinuria, amyloids can be detected from the tissue, more than half of them are mainly large molecular weight, low selective proteinuria, degree Inequality, urinary protein is almost all albumin, serum globulin increased, urinary globulin increased, and often this week-week protein, 24h urine protein can reach 20 ~ 30g, and the degree of damage to the small ball and urine protein There is no relationship between the amount, even if a small amount of amyloid deposits in the glomerulus, on the contrary, proteinuria can be seen when the renal function is highly disordered, so the incidence of nephrotic syndrome is also high, which can be expressed as asymptomatic protein. Urine, which lasts for several years, is rare in microscopic hematuria and cell tube type. Recently, statistics with hypertension accounted for 20% to 50%. Postural hypotension is a characteristic manifestation of autonomic neuropathy.

(3) nephrotic syndrome: 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 complication of nephrotic syndrome, mostly The disease is concealed and manifested as refractory nephrotic syndrome. A few cases are acute onset, abdominal pain, hematuria, proteinuria and renal function deterioration. Abdominal plain film or B-ultrasound showed a significant increase in kidney, nephrotic syndrome. 30% to 40% of AA protein, 35% of AL protein, once nephrotic syndrome occurs, the disease progresses rapidly, the prognosis is poor, and the survival rate is less than 10% in 3 years. Patients are often weak and chronic. Infection and early death.

(4) uremia period: 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 can be affected, the latter Polyuria, even in the presence of diabetes insipidus, a few cases have renal disorders such as renal diabetes, renal tubular acidosis and hypokalemia, from the development of nephrotic syndrome to uremia requires 1 to 3 years, glomerular amyloid The degree of deposition is poorly correlated with renal function.

2. The performance of each type is as follows

(1) Primary amyloidosis: the male to female ratio is 5:2, the median age of male onset is 63 years, and the female is 59 years old. Very few before 40 years old, common weight loss, weakness and fatigue , multiple organs are common.

1 Kidney infringement: the most common, 50%.

2 heart invasion: often invade the heart (40%), causing myocardial lesions, heart enlargement, arrhythmia and conduction block, can be sudden death, 50% died of congestive heart failure and arrhythmia, the primary AL protein type The most common cause of death.

3 gastrointestinal involvement: common, 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 is not Clear, swallowing difficulties, when lying on the back, the giant tongue hangs and makes a loud snoring. When the stomach is affected, symptoms such as stomach cancer, repeated vomiting is difficult to eat.

4 autonomic or peripheral nerve involvement (19%): manifested as multiple peripheral neuritis, abnormal acral and low muscle tone and low sacral reflex; ulnar nerve damage and peripheral tendon due to amyloid deposition showed carpal tunnel syndrome. Can lead to autonomic dysfunction, manifested as orthostatic hypotension, gastrointestinal dysfunction, bladder dysfunction or impotence, elderly patients with central nervous system involvement manifested as dementia.

5 bone marrow involvement: can cause compensatory polycythemia.

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

7 other: liver damage is 16%, skin purpura is 5% to 15%, smooth muscle and skeletal muscle involvement is muscle weakness.

(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) 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 , glomerular amyloidosis is common in proteinuria (usually nephrotic syndrome) and progressive renal insufficiency, often with recurrent urticaria and deafness symptoms, and other Finnish Amyloidosis, hereditary familial amyloidosis Sexually transmitted diseases can be divided into nephropathy type, neuropathy type and mixed type.

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

3. Amyloid deposition amyloid deposition in the sympathetic ganglia and adrenal gland can cause orthostatic hypotension, calming in the proximal tubule caused by Fanconi syndrome, sinking in the distal renal tubule caused by high potassium renal tubular acidosis, sinking in The medulla can cause renal diabetes insipidus. The complete diagnosis includes: qualitative diagnosis of amyloidosis, primary disease, type of amyloid, degree of involvement of important organs, and complications.

Examination of renal amyloidosis in children

1. Blood test: Blood biochemical examination of fibrinogen increases plasma fibrinogen causes renal vein thrombosis, increased urine protein, and also leads to renal insufficiency, about 30% of renal vein thrombosis caused by this symptom, peripheral blood found Howell-Jolly Small body, suggesting that the spleen is involved.

2. Protein electrophoresis examination: 2/3 patients with serum electrophoresis or immunoelectrophoresis can find monoclonal abnormal proteins, and the positive rate of urine test can be increased to 86%. Immunoelectrophoresis and immunofixation are sometimes used to determine blood or urine. Microprotein, serum protein electrophoresis, r globulin normal, primary amyloidosis M protein (monoclonal immunoglobulin) high, immunoglobulin concentration determination is helpful for the diagnosis of multiple myeloma, patients in the urine It has a per-week protein that reacts with the anti-serum of the -chain and the -chain, but does not react with the heavy chain of any one of the immunoglobulins.

3. Increase of blood SAA protein: 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 joint Inflammation, ulcerative colitis, tuberculosis, tumor, and acute phase of 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 activity. Inflammation, SAA levels are reduced after infection control, and long-term dialysis patients have bone disease manifestations, abnormal increase in blood 2M can help diagnose amyloidosis.

4. Congo red test: In order to assist the diagnostic test, amyloid has affinity for Congo red. After injecting a certain amount of Congo red, the normal person's 1h absorption rate is 10%, glomerulonephritis 1h absorption rate is 20%, and kidney disease is 40%, and renal amyloidosis, 20min absorption rate is 30%, such as 1h absorption rate is more than 60% positive, the diagnosis of early primary amyloidosis is of little significance, due to early involvement of organ starch The deposition of sample material is less, and the absorption of Congo red is less, so it is often a negative result. In addition, the low serum albumin affects the absorption rate when liver disease is low; the amount of Congo red absorbed in urine should be excluded when calculating the absorption rate of a large number of proteinuria. It is less reliable and is rarely used.

5. 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.

6. 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 are treated with 5% potassium permanganate and then Congo red staining. The AA protein is high manganese. Potassium sensitive, with a small affinity with Congo red, coloring test is negative, and AL protein and Congo red have a strong affinity, coloring test is positive, so this method can be used to identify the lesions caused by AA protein or AL protein, so it helps 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 AA or AF amyloid staining is negative. It is helpful for differential diagnosis. If the alignment is irregular under the electron microscope, amyloid fibers with a diameter of 8-10 nm can be diagnosed.

1. X-ray abdominal plain film, if the ultrasound examination, such as the increase of renal shadow (especially with renal vein thrombosis) can help diagnosis, but the normal size of the kidney shadow or the late renal shadow reduction, can not rule out the diagnosis.

2. Renal venography: Helps diagnose renal vein thrombosis.

3. Radionuclide scanning: It has been applied to determine amyloidosis. 99mTc-dimercaptosuccinate (DMSA) can be reabsorbed by proximal tubules. When renal tubules and renal interstitial are involved, proximal tubule reabsorption is reduced to 99mTc. - The intake of 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 injection of radioactive 2M to detect inclusion. Amyloidosis of 2M.

4. Two-dimensional echocardiography: High sensitivity in determining amyloidosis of the heart.

Diagnosis and differential diagnosis of renal amyloidosis in children

diagnosis

1. Clinical features

(1) Features: In patients with secondary renal amyloidosis, proteinuria, unexplained renal insufficiency, cardiac insufficiency, peripheral neurological disorders, and low incidence of renal tubular acidosis, renal urine Injury, hepatosplenomegaly, malabsorption of the small intestine, macroscopic tongue and visual impairment caused by abnormal corneal crystals should be suspected and the disease.

(2) increase in gamma globulin: manifested by nephrotic syndrome, and the gamma globulin in plasma protein electrophoresis >20%, it is also suspected of this symptom.

(3) Ask about family history: Familial factors and geographical factors must also be considered, and family history should be asked when necessary.

2. Renal biopsy is performed according to renal biopsy. The specimen is stained with Congo red. The general optical microscope is sufficient to confirm the diagnosis.

Differential diagnosis

1. Identification of 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 times. Identification of myeloma, 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 more likely. Big.

2. AA type should pay attention to the identification of each cause.

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