Renal aminoaciduria

　　First, Etiology

　　This disease is caused by hereditary membrane transport defects, leading to an increased excretion of amino acids in urine, and the occurrence of this disease is the consequence of changes in membrane carriers caused by autosomal recessive hereditary diseases. Normally, amino acids filtered by the glomerulus are almost completely reabsorbed in the proximal renal tubules through specific energy transport processes. In congenital amino acid metabolism disorders, amino acids that are not well metabolized increase in concentration in the plasma and appear in urine, which is due to increased ultrafiltration load, not tubular transport defects. When there is a defect in amino acid transport in the proximal renal tubules, it can lead to reabsorption impairment and amino aciduria, as well as a decrease in amino acid levels in the blood. When the reabsorption of a certain amino acid is impaired, the reabsorption of other amino acids through the same transport system can also be reduced, leading to more widespread amino aciduria, such as cystinuria. When there is an abnormal metabolism of a certain amino acid, it can accumulate in the body, leading to excessive ultrafiltration, which can inhibit the reabsorption of other amino acids in the same transport system, such as in the case of β-alanine aminotransferase abnormality, which can lead to hyperalaninemia, and a large amount of taurine, isobutyric acid, and β-alanine can appear in the urine. When the brush border or basal membrane of the renal tubular epithelial cells leaks, the reabsorbed amino acids can reflux into the lumen of the tubules, causing widespread amino aciduria, such as Fanconi syndrome and lysinuria. When a certain metabolic product accumulates in the tubular epithelial cells, it can inhibit the reabsorption rate, causing amino aciduria, such as galactosemia and congenital fructose intolerance, where phosphogalactose or phosphofructose can accumulate in renal tubule cells.

　　Second, Pathogenesis

　　The content of amino acids in the glomerular filtrate of normal people is approximately equal to that in plasma, with the vast majority being reabsorbed by the proximal tubules. The main amino acids excreted in urine include glycine (70-200mg/d), histidine (10-300mg/d), bile acid (85-320mg/d), and methylhistidine (50-210mg/d). When the renal tubules have a transport obstacle for a certain amino acid, that amino aciduria appears.

　　In various amino acid transport defects, such as cystinuria, dibasic amino aciduria, Hartnup disease, iminoglycinuria, and dicarboxylic amino aciduria, the symptoms are abnormal transport of structurally similar amino acids, indicating the presence of gene-specific membrane receptors or transporters on the membrane. The fact that these transport defects only affect the transport of one amino acid suggests the existence of a substrate-specific transport system. All these defects involve the transport system in the kidney and/or intestine, without affecting other tissues. In type I pure cases of this disease, there is a lack of intestinal transport mediated by cysteine, lysine, arginine, and ornithine, while the heterozygous form has a normal amino acid urine excretion type. In type II pure cases, there is a lack of transport mediated by intestinal lysine, but the ability to transport cysteine is preserved, and the heterozygous form shows a moderate increase in urine excretion of four amino acids. In type III pure cases, the ability to transport these four amino acids within the small intestine is preserved, and the heterozygous form only shows a slight increase in the excretion of lysine and cysteine in urine.

　　1, Cystinuria:It is an autosomal recessive genetic disease. The pathogenesis is the loss of sites for the transport of cysteine and lysine, arginine, and ornithine in the proximal renal tubular brush border membrane and the gastrointestinal tract, which causes the massive loss of this group of histidineuria. Later, it was found that the renal tubules also have reabsorption disorders for the mixed disulfide formed by cysteine-homocysteine. In the blood of cystinuria patients, the concentration of cysteine and other three amino acids is not increased, while the clearance rate of these amino acids in the kidney is significantly increased, with the cysteine clearance rate being more than 30 times higher than that of normal. After cystinuria patients consume lysine and ornithine, the blood concentration does not increase, but a large amount of these amino acids appear in the feces. The study of active transport with jejunal mucosal tissue specimens also confirms the transport defect. The average monthly urine excretion of cysteine in cystinuria patients is 3036.8 mmol (the normal maximum value is about 74.88 mmol/g creatinine), which is obviously supersaturated and has a low solubility, which can only dissolve 1248-1664 mmol/L in urine with pH 5-7. Therefore, it is prone to crystallization, and when the urine is concentrated, the crystallization increases easily, forming stones, causing symptoms such as renal colic, urinary tract obstruction, or infection.

　　2, Hartnup disease:It is caused by the transport disorders of neutral amino acids and monocarboxyl amino acids in the proximal renal tubular epithelial cells and the mucosa of the jejunum. The amino acids with transport disorders include alanine, serine, threonine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, histidine, glutamic acid, and aspartic acid. Among them, the most important is the transport defect of tryptophan. Tryptophan is lost in large quantities in urine and feces, leading to insufficient formation of niacin, resulting in psoriasis-like skin damage and neurological symptoms. In addition, indole and serotonin produced by the intestinal degradation of tryptophan-like substances, phenylethylamine produced by phenylalanine, tyramine produced by tyrosine, and other amines are all significantly higher than the detoxification capacity of the liver, entering the blood circulation to cause central nervous system symptoms, manifested as episodic cerebellar ataxia and psychiatric symptoms. The disease has two types: type I with intestinal dysfunction; type II without dysfunction.

　　It can be complicated with urinary stones, growth and development disorders, intellectual disabilities, hypocalcemia, hyperuricemia, muscle atrophy, cerebellar ataxia, pancreatitis, pigmentary retinopathy, and others.

　　The clinical manifestations of various aminoaciduria have both commonalities and individual characteristics. The common point of the clinical manifestations of various aminoaciduria is growth and development disorders, short stature, and varying degrees of intellectual development delay. The characteristic manifestations are often different due to the different types of aminoaciduria.

　　1, Cystinuria:This disease usually manifests and is diagnosed soon after birth, but it is often not明显 until the age of 20 to 30. The main clinical manifestations are:

　　1, Specific renal aminoaciduria:Urine contains a large amount of cysteine and three types of dibasic amino acids (lysine, arginine, and ornithine). In cases with a large amount of cysteine excretion (average daily excretion can reach 730mg), cysteine crystals can be seen in the concentrated urine sediment. Cysteine, lysine, arginine, and ornithine are all positive in the urine of homozygotes of the three subtypes. In the urine of heterozygotes of Type II and III patients, cysteine and lysine are also positive.

　　2, Urinary tract cystine stones:Due to a large amount of cysteine exceeding the saturation in urine, its solubility in hard urine decreases, forming stones. Cystine stones account for 1% to 2% of kidney stones, are yellow-brown, hard, of varying sizes, with the larger ones sometimes presenting in the form of a deer's antler. They are often multiple, not completely radiopaque, with faint shadows. Due to the presence of disulfides, they are less dense than calcium stones. The stones react positively with sodium nitroprusside, which can be used as a screening diagnostic test. Urinary tract stones are often an important clue for diagnosis in patients, and commonly cause symptoms such as renal colic, hematuria, urinary tract obstruction, and secondary urinary tract infection. In the late stage, they can lead to renal insufficiency.

　　If the excretion of cysteine in urine is less and the concentration remains below saturation, it is called non-stone cystinuria. Research suggests that in the pedigrees of cystinuria patients, there may also be several mild cystinuria patients without stones.

　　3, Short stature and delayed intellectual development:It may be related to the loss of a large amount of amino acids (especially lysine).

　　4, Pyrrolidine and pyridineuria:Due to the poor absorption of these amino acids by the jejunum, a large amount of lysine and ornithine are degraded in the intestines to produce cadaverine and putrescine, which are reduced to pyrrolidine and pyridine and excreted in urine after absorption.

　　5, Others:A few patients may have complications such as hyperuricemia, hypocalcemia, hemophilia, muscular atrophy, pancreatitis, pigmentary retinopathy, and others.

　　Dibasic amino aciduria:This disease is an autosomal recessive genetic disorder, the result of a gene mutation encoding the transport protein. Since this protein is only used for the transport of lysine, arginine, and ornithine, while cysteine reabsorption is normal.

　　Clinical manifestations:Type I usually has no symptoms, while a few homozygotes may have intellectual decline. Type II has more severe dibasic amino aciduria than Type I, with decreased plasma dibasic amino acid concentration. In recent years, it has been found that liver cells in patients with this type may have transport disorders, due to the lack of substrate lysine and arginine, leading to ornithine cycle disorders, inability to detoxify completely, and hence, the patient appears with protein intolerance, manifested as hyperammonemia, vomiting, diarrhea, growth and intellectual development disorders, splenomegaly, and even hepatic encephalopathy. Diagnosis relies on family history and amino acid analysis in urine.

　　Three, Hypercystinuria:This disease is a rare autosomal recessive genetic disorder, with only the renal tubules having a transport disorder for cysteine, while the jejunum does not have a corresponding transport disorder. The patient's urine only shows a slight increase in cysteine excretion, with normal excretion of dibasic amino acids, and generally no urinary tract stones.

　　Four, Hartnup disease:Clinical manifestations are episodic, and symptoms often appear during childhood and adolescence, and then resolve spontaneously. The main manifestations of the disease are systemic:

　　1, Pellagra-like rash:The skin exposed areas are red, dry with scales, or cracked, blistered, and exuding. There is photosensitivity, and the symptoms worsen after sun exposure. The response to niacin treatment is good.

　　2, Episodic cerebellar ataxia:It often occurs in the severe stage of the disease, manifested as unsteady gait, tremors of the limbs, involuntary dancing movements, poor ocular convergence, nystagmus, frequent diplopia, and in severe cases, episodes of fainting or syncope. Occasionally, there may be psychiatric symptoms and emotional instability, hallucinations, delirium, or dementia, etc. The attacks usually do not last more than one week, resolve spontaneously, and leave no sequelae. Intelligence is generally normal or slightly impaired, and the stature is relatively short.

　　3, Specific amino aciduria:The normal excretion of threonine, serine, histidine, alanine, and hydroxyproline can be distinguished from total amino aciduria. The normal excretion of glycine, proline, and hydroxyproline can be distinguished from iminoglycineuria. The normal excretion of dibasic amino acids in urine can be distinguished from cystinuria.

　　4, Intestinal transport disorder:Due to the decomposition of amino acids in the intestine, especially tryptophan, by bacteria, a large number of indole metabolic products are produced, including indole-3-acetic acid and indole-3-sulfonic acid (urobilinogen), which can appear in urine.

　　5, Stool examination:In addition to tryptophan in the feces, there are a large number of branched-chain amino acids, phenylalanine, and other amino acids. The disease has a small impact on the growth and development of children, and the height is only slightly affected, while the intellectual development is basically normal.

　　Five, amino-glycine urine syndrome:This disease is an autosomal recessive genetic disorder, including proline, hydroxyproline, and glycine, caused by the transport disorder of the common transport system of the above three amino acids in the renal tubular epithelial cells or the selective transport system of glycine or hypoglycine. Patients are generally asymptomatic, occasionally with delayed intellectual development, convulsions, and increased protein in cerebrospinal fluid. The disease can be divided into 4 types: Type I has jejunal transport disorder, while Types II, III, and IV do not have jejunal transport disorder. The prognosis of the disease is good, neonatal glycineuria often reflects the total amino aciduria during the first 6 months of normal development after birth, persistent glycineuria appears in infants with Fanconi syndrome, and pure glycineuria is usually benign and asymptomatic.

　　Six, di-carboxyl amino aciduria:This disease is an autosomal recessive genetic disorder caused by the transport disorder of glutamic acid and aspartic acid in the renal tubules and small intestine. Clinically, it is divided into two types: Type I has malabsorption of the jejunum, manifested as hypoglycemia and ketoacidosis in fasting (which may be related to the deficiency of amino acids related to glycogenolysis), developmental and intellectual developmental disorders in children, congenital hypothyroidism, intermittent hypoglycemia, reduced CO2 binding capacity, increased blood proline, and large amounts of glutamic acid and aspartic acid in urine. Type II shows malabsorption of the jejunum, which is very rare in clinical practice, usually asymptomatic, and only with increased excretion of urinary carboxyl amino acids.

　　Seven, Methionine malabsorption syndrome:This disease is rare and is caused by transport disorders of sulfur-containing amino acids in renal and intestinal epithelial cells. The main clinical manifestations are premature graying, edema, intellectual decline, paroxysmal hyperpnea, intermittent convulsions, a special smell of celery in the urine (due to methionineuria and its degradation product α-hydroxybutyrate), and a large amount of phenylalanine and tyrosine in the urine.

　　Eight, β-amino aciduria:There is a large amount of β-amino aciduria, taurine, β-alanine, and β-isobutyric acid in total amino aciduria. Normally, too much meat and seafood can also appear in the urine of people. The clinical manifestations of the disease are epilepsy-like seizures and coma, and the activity of β-alanine-α-ketoglutarate transaminase is reduced.

　　The etiology of this disease is unclear and may be related to autosomal recessive inheritance, usually associated with consanguineous marriage. The disease cannot be prevented directly. Genetic screening should be performed for patients with a suspected family history of chromosomal abnormalities to avoid the disease in offspring due to chromosomal inheritance after marriage. At the same time, attention should be paid to strengthening pregnancy nutrition, reasonable diet, and avoiding adverse stimuli that affect embryo development, such as emotional excitement.

　　Renal amino aciduria is a group of diseases with different amino acids in a urine sample, so the laboratory examination is also different.

　　One, Cystinuria

　　1, Hexagonal flat crystals can be seen in the urine sediment under microscopic examination or after acidification, concentration, and freezing of the urine sediment.

　　2, The nitroprusside test of urine is positive.

　　3, Urinary chromatography determines that the excretion of cystine in the urine is greater than 300mg/L per day, in addition, pyrrolidine and pyrimidine can also be detected in the urine.

　　4, The urine contains a large amount of cystine, lysine, and ornithine

　　Two, Dibasic amino aciduria:A large amount of dibasic amino acids is detected in the urine, while the excretion of cystine is normal, and the corresponding amino acids in the blood are reduced.

　　Three, Hypercystinuria:This disease only has a transport disorder of cystine in the renal tubules, and there is no corresponding transport disorder in the jejunum. The excretion of cystine in the urine of patients is only slightly increased, and the excretion of dibasic amino acids is normal.

　　Four, Hartnup disease:Laboratory examination found mainly specific amino aciduria, with threonine, serine, histidine, alanine, and hydroxyproline in the urine, while the excretion of hydroxyproline is normal, which can distinguish it from total amino aciduria. Glycine, proline, and hydroxyproline are excreted normally, which can distinguish it from iminoglycinuria. The excretion of dibasic amino acids in the urine is also normal, which can distinguish it from cystinuria. Due to intestinal transport disorders, amino acids in the intestines, especially tryptophan, are decomposed by bacteria to produce a large amount of indole metabolites, such as indole-3-acetic acid, which can be detected in the urine. Stool examination found tryptophan, large amounts of branched-chain amino acids, phenylalanine, and other amino acids.

　　Five, Imidazoleglycineuria:The urine of this disease includes proline, hydroxyproline, and glycine.

　　Six, Dihydroxy amino aciduria:This disease is manifested by hypoglycemia and ketosis acidosis during fasting due to the transport disorder of glutamic acid and aspartic acid in the small intestine (which may be related to amino acid deficiency related to glycogenolysis), and there is specific amino aciduria, and urine examination shows an increase in glutamic acid and aspartic acid.

　　Seven, Methionine malabsorption syndrome:There is a large amount of phenylalanine and tyrosine in urine, and there is also a special smell of celery (caused by methionineuria and its degradation product α-hydroxybutyric acid).

　　Eight, β-amino aciduria:β-amino aciduria in urine, taurine, β-alanine, and β-isobutyric acid appear in total amino aciduria, and taurine can also appear in urine when normal people consume too much meat and seafood.

　　Routine X-ray abdominal flat film, contrast, and B-ultrasound examination can often find bilateral urinary tract multiple stones, with faint shadows and varying sizes.

　　1. Protein:The metabolic products in the human body mainly come from the protein components in food, especially animal and plant proteins, such as meat, rice, noodles, and soy products. Therefore, in order to reduce the workload of the remaining healthy renal units, the amount of protein intake for patients must be adapted to the excretion capacity of the kidneys. That is to say, the protein intake of kidney failure patients should be reduced accordingly based on the degree of renal function decline. For example: when the blood creatinine level is between 170～440umol/L, the protein intake should be 0.6g per kilogram of body weight per day, and for those with a large amount of proteinuria, an additional 1.5g of protein can be supplemented for every 1g of urinary protein lost. When the blood creatinine level exceeds 440umol/L, the protein intake should be further reduced, and it is better not to exceed 30g (0.4g/kg). However, it must be emphasized that if protein intake is excessively restricted, it will lead to malnutrition, decreased physical fitness, and poor results. Therefore, under the premise of reducing the total amount of protein intake, it is necessary to selectively supplement high-nutrient protein to meet the body's essential nutritional needs, which is to increase the intake of certain animal proteins (such as milk, eggs, fish, lean meat, etc.), and reduce the amount of plant proteins. The former contains more varieties and quantities of essential amino acids than the latter. Since grains contain a lot of plant proteins, it is recommended to eat starch foods such as wheat starch, corn starch, lotus root starch, potatoes, sweet potatoes, etc. (protein content is only 0.4%), instead of ordinary staple foods such as rice and noodles (protein content is 7-10%).

　　2. Caloric intake:To maximize the utilization of ingested protein and prevent its conversion into energy that is consumed, while adopting a low-protein diet, it is also necessary to supplement energy. At least 35 calories per kilogram of body weight per day are required. These calories are mainly provided by sugar, which can include fruits, sugar products, chocolate, jam, honey, etc., and fat can also provide some calories, with no restriction on vegetable oil.

　　First, treatment

　　Since this disease is a genetic disease, there is currently no curative method. The main treatment principle is early detection, and different dietary control and symptomatic treatment are carried out according to the type of amino aciduria to reduce complications. For patients with cystinuria, a low methionine diet should be provided. For patients with tryptophan, phenylalanine, and tyrosine aminoaciduria, a high-protein diet should be provided, and niacin should be supplemented; however, protein should be avoided if ataxia and psychiatric symptoms occur.

　　1. Treatment of cystinuria

　　(1) Water therapy: Drink plenty of water, especially ensure a certain amount of water intake at night to prevent the precipitation of cystine crystals when urine becomes concentrated; the water intake should be at least 4L in 24 hours to dilute the concentration of urinary cystine and keep it below 250mg/L.

　　(2) Diet control: A diet low in methionine (the most important precursor of cysteine) can sometimes moderately reduce cystineuria.

　　(3) Alkalization of urine: Oral sodium bicarbonate or sodium citrate (10-38g/d) can be taken to increase urine pH to >7.5, thereby increasing the solubility of cysteine and preventing stone formation. When the urine pH is 7.5, the solubility of cysteine is the highest (about 280mg/L), but it may promote the deposition of calcium phosphate, so 250-500mg of acetazolamide (acetazolamide) can also be taken before bedtime.

　　(4) Oral penicillamine: Penicillamine (dimethylcysteine) can react with cysteine to form a water-soluble cysteine-penicillamine disulfide excreted from the urine, and can also reduce about 50% of free cysteine in the urine, thus having the effect of preventing stone formation. This drug not only has a preventive effect, but can also dissolve stones that are already forming. Specific usage: 1-2g/d, taken orally in 3-4 divided doses. Due to its adverse effects such as serum sickness-like reactions (such as rash, fever, joint pain, and bone marrow suppression), renal damage (nephrotic syndrome), etc., it is not suitable as a routine application drug and is only used for patients with cystine stones that cannot be controlled or are severe. Currently, newer drugs include N-acetyl-D-penicillamine and thiopurine (methylglycine), which have the same effect and lower toxicity.

　　(5) Treatment: For patients with kidney stones, extracorporeal shock wave lithotripsy or surgical stone removal can be considered, and Chinese herbal medicine for stone expulsion can also be taken. Control secondary infection, relieve urinary tract obstruction, and for those with uremia, dialysis or kidney transplantation can be provided.

　　2. Treatment of Dibasic Aciduria

　　(1) Limit protein intake: due to hyperammonemia and protein intolerance in patients, daily protein intake should be limited, especially in type II patients. Adult daily protein intake

　　(2) Supplement the corresponding amino acids: mainly intravenous administration of arginine, ornithine, or citrulline. Due to malabsorption in the small intestine, oral arginine and ornithine are often ineffective. Citrulline is a neutral amino acid, with a different transport site, and it can be metabolized into arginine and ornithine after absorption, so oral citrulline and lysine are effective, which can prevent hyperammonemia and correct plasma amino acid concentration.

　　3. Treatment of Hartnup's Disease:There is no根治method for this disease, but patients can relieve it spontaneously with age, especially after puberty.

　　(1) High-protein diet: generally give a high-protein diet, supplement 50-100mg of niacinamide per day, and 50-250mg of niacinamide (nicotinamide) per day, taken orally in divided doses, which can alleviate the symptoms of pellagra and maintain the health of patients. If there are symptoms of cerebellar ataxia and psychiatric symptoms, high-protein intake should be prohibited, and intravenous glucose can be administered to provide sufficient energy.

　　(2) Oral sodium bicarbonate: to increase the excretion of urinary indole metabolites, reduce the decarboxylation of branched-chain amino acids in the colon.

　　(3) Oral neomycin: kill intestinal bacteria and prevent intestinal infection in time, as it can induce severe symptom attacks, it should also be lavaged or cleaned enema.

　　4. Treatment of Iminoglycinuria:This disease does not require treatment, and the prognosis is good.

　　5. Treatment of Dicarboxylic Aciduria:Type I patients can try glutamic acid, take it continuously day and night, which can prevent the occurrence of hypoglycemia. Type II does not require treatment.

　　6. Methionine Malabsorption Syndrome:A low methionine diet can improve symptoms and intelligence.

　　II. Prognosis

　　The disease is a recessive genetic disease, and the clinical characteristics of different types are not the same, and the prognosis is also inconsistent. Most patients can reduce complications and have a good prognosis after diagnosis and symptomatic treatment. Some patients may develop renal insufficiency due to complications if not treated for a long time.