Alport syndrome in children clinical guidelines. Alport syndrome treatment. Alport syndrome - diseases of the urinary system in children. Complications and consequences. Clinical manifestations of Alport syndrome

- a hereditary kidney disease caused by a change in the synthesis of type IV collagen, which forms the basement membranes of the renal glomeruli, the structure of the inner ear, and the lens of the eye. Men suffer from an advanced form of the disease with severe symptoms. Women are often carriers of the gene, remaining healthy, or their manifestations of the disease are mild. The main symptoms are microhematuria, proteinuria, renal failure, sensory hearing loss, deformity and dislocation of the lens, cataracts. The diagnosis is established according to clinical and anamnestic data, the results of a general urinalysis, kidney biopsy, audiometry and ophthalmological examination. Treatment is symptomatic, including ACE inhibitors and ARBs.

ICD-10

Q87.8 Other specified congenital anomaly syndromes, not elsewhere classified

General information

Familial cases of hematuric nephropathy first came to the attention of researchers in 1902. Almost 30 years later, in 1927, the American physician A. Alport discovered the frequent association of hematuria with hearing loss and uremia in men, while women had no or mild symptoms. He suggested the hereditary nature of the disease, which was later named Alport's syndrome. Synonyms -, hematuric nephritis, familial glomerulonephritis. The prevalence is low - 1 case per 5 thousand people. Pathology accounts for 1% of patients with renal failure, 2.3% of patients undergoing kidney transplantation. The disease is diagnosed in people of all races, but the ratio of different forms is not the same.

The reasons

By its nature, the syndrome is a heterogeneous hereditary disease - its development is provoked by a defect in the genes that encode the structure of the various chains of type IV collagen. Genetic changes are represented by deletions, splicing, missense and nonsense mutations. Their localization determines the type of inheritance of the disease:

• X-linked dominant. It is associated with a mutation in the COL4A5 locus, which is located on the X sex chromosome. The gene encodes the a5-chain of type 4 collagen. This genetic defect causes 80-85% of cases of hereditary nephritis. The disease is fully manifested in boys and men; in females, the remaining normal gene on the X chromosome compensates for the production of functional collagen.
• Autosomal recessive. It develops on the basis of mutations in the C0L4A3 and COL4A4 genes. They are localized on the second chromosome and are responsible for the structure of the a3 and a4 collagen chains. Patients with this variant of the syndrome make up about 15% of patients. The severity of symptoms does not depend on gender.
• Autosomal dominant. Nephritis results from mutations in the COL4A3-COLA4 genes located on chromosome 2. As in the case of the autosomal recessive form of the disease, the synthesis of a4 and a3 collagen chains of the fourth type is disrupted. The prevalence is 1% of all cases of genetic nephritis.

Pathogenesis

The glomerular basement membrane has a complex structure, it is formed by a strict geometric sequence of type 4 collagen molecules and polysaccharide components. In Alport syndrome, there are mutations that determine the defective structure of the helical collagen molecules. At the first stages of the disease, the basement membrane becomes thinner, begins to split and exfoliate. At the same time, thickened areas with uneven enlightenments appear. A fine-granular substance accumulates inside. The progression of the disease is accompanied by complete destruction of the basal glomerular membrane of the glomerular capillaries, tubules of the kidneys, structures of the inner ear and eyes. Thus, Alport's syndrome is pathogenetically represented by four links: a gene mutation, a defect in the structure of collagen, destruction of basement membranes, and kidney pathology (sometimes hearing and vision impairment).

Symptoms

The most common manifestation of Alport syndrome is hematuria. Microscopically, this symptom is determined in 95% of women and 100% of men. During routine examination of boys, hematuria is detected already in the first years of life. Another common symptom of the disease is proteinuria. The excretion of protein in the urine in male patients with X-linked syndrome begins in early childhood, in the rest - later. In girls and women, the level of protein excretion increases slightly, cases of severe proteinuria are extremely rare. All patients have a steady progression of the symptom.

Often, patients develop sensorineural hearing loss. Hearing impairment makes its debut in childhood but becomes noticeable in adolescence or early adulthood. In children, hearing loss applies only to high-frequency sounds, it is detected in specially created conditions - with audiometry. As the syndrome matures and progresses, the auditory perception of medium and low frequencies, including human speech, is impaired. With X-linked syndrome, hearing loss is present in 50% of male patients by the age of 25, and in 90% by the age of 40. The severity of the hearing loss is variable, from changes in the audiogram results alone to total deafness. There are no pathologies of the vestibular apparatus.

Visual disturbances include anterior lenticonus - protrusion of the center of the lens of the eye forward and retinopathy. Both pathologies are manifested by a progressive deterioration in visual function, redness, and pain in the eyes. Some patients have dysembryogenesis stigmas - anatomical anomalies of the urinary system, eyes, auricles, limbs. There may be a high location of the sky, shortening and curvature of the little fingers, fusion of the toes, widely spaced eyes.

Complications

The lack of treatment of patients with Alport's syndrome leads to the rapid progression of deafness and blindness, the formation of cataracts. Some patients develop polyneuropathy - nerve damage, accompanied by muscle weakness, pain, convulsions, tremors, paresthesias, decreased sensitivity. Another complication is thrombocytopenia with a high risk of bleeding. The most dangerous condition in hereditary nephritis is the end-stage renal failure. Men with the type of inheritance linked to the sex X chromosome are most susceptible to it. By the age of 60, 100% of patients in this group need hemodialysis, peritoneal dialysis, and donor kidney transplantation.

Diagnostics

Nephrologists, urologists, internists and geneticists take part in the diagnostic process. During the survey, the age of onset of symptoms, the presence of hematuria, proteinuria, or deaths due to chronic renal failure in first-line relatives are found out. Alport syndrome is characterized by an early onset and a burdened family history. Differential diagnosis is aimed at excluding the hematuric form of glomerulonephritis, secondary nephropathies. To confirm the diagnosis, the following procedures are carried out:

1. Physical examination. Pallor of the skin and mucous membranes, reduced muscle tone, external and somatic signs of dysembryogenesis - high palate, anomalies in the structure of the limbs, increased distance between the eyes, nipples are determined. In the early stages of the disease, arterial hypotension is diagnosed, in the later stages - arterial hypertension.
2. General urine analysis. Erythrocytes and increased protein content are found - signs of hematuria and proteinuria. The indicator of urine protein directly correlates with the severity of the syndrome; the progression of the pathology, the likelihood of nephrotic syndrome, and chronic renal failure are assessed by its change. There may be signs of leukocyturia of an abacterial nature.
3. Examination of a kidney biopsy. Microscopy visualizes a thinned basement membrane, splitting and separation of its layers. At the late stage, there are thickened dystrophic areas with "honeycombs" of enlightenment, zones of complete destruction of the layer.
4. Molecular genetic study. Genetic diagnostics is not mandatory, but it allows you to make a more accurate prognosis, choose the optimal treatment regimen. The structure of genes, mutations in which cause the development of the syndrome, is being studied. Most patients have mutations in the COL4A5 gene.
5. Audiometry , ophthalmological examination . Additionally, patients can be assigned diagnostic consultations of an audiologist and an ophthalmologist. Audiometry reveals hearing loss: in childhood and adolescence - bilateral high-frequency hearing loss, in adulthood - low-frequency and mid-frequency hearing loss. The ophthalmologist determines the distortion of the lens shape, retinal damage, the presence of cataracts, decreased vision.

Alport Syndrome Treatment

There is no specific therapy. From an early age, active symptomatic treatment is carried out, which reduces proteinuria. It helps prevent damage and atrophy of the renal tubules, the development of interstitial fibrosis. With the help of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, it is possible to stop the progression of the disease, achieve regression of glomerulosclerosis, tubulointerstitial and vascular changes in the kidneys. Patients with end - stage chronic renal failure are prescribed hemodialysis , peritoneal dialysis , and the question of the advisability of kidney transplantation is being decided .

Forecast and prevention

The syndrome is prognostically favorable in cases where hematuria occurs without proteinuria, there are no visual disturbances and hearing loss. In addition, the prognosis is good in most women - even in the presence of hematuria, the disease progresses slowly, does not worsen the general condition. Due to the hereditary nature of the pathology, it is impossible to prevent its development. In families where the presence of the X-linked form of the syndrome has been established, prenatal diagnosis is possible. Genetic screening is especially recommended for women who are carrying boys.

• SENSORY HEARING LOSS
• ALPORT SYNDROME

We observed a familial case of Alport's syndrome in a 15-year-old boy. The disease was hidden. At the age of 8, the child suffers from pyelonephritis. Sensory hearing loss is diagnosed at age 12. At the age of 15, she complained of headache, blurred vision, swelling, pain in the legs and increased blood pressure. After examination and history taking, Alport's syndrome was diagnosed.

• Assessment of neurological manifestations in children with various clinical variants of rheumatoid arthritis
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• Electrocardiographic features in children of the first year of life

Recently, there has been an increase in hereditary pathology, which is associated with a lack of control by the state and the healthcare system as a whole. There is no law prohibiting family marriages, and hence the growth of hereditary pathology.

Alport syndrome (familial glomerulonephritis) is a rare genetic disorder characterized by glomerulonephritis, progressive renal failure, sensorineural hearing loss, and eye involvement. The disease was first described by British physician Arthur Alport in 1927. Alport syndrome is very rare with a frequency of 17 per 100,000 children. The genetic basis of the disease is a mutation in the a-5 gene of the type IV collagen chain. This type is universal for the basement membranes of the kidney, cochlear apparatus, lens capsule, retina and cornea of ​​the eye, which has been proven in studies using monoclonal antibodies against this collagen fraction.

According to the literature data, the disease begins at an early age, less often preschool. We diagnosed a familial case of Alport's syndrome in a 15-year-old adolescent child. The boy was admitted for examination at the Andijan City Medical and Medical Center with complaints of severe weakness, headache, pastosity of the face, severe muscle pain in the legs, and bedwetting.

From the anamnesis: a child from the 1st pregnancy, the 1st birth was born from young parents at the term with a weight of 3700g. The marriage is unrelated. But, in the family on both sides, closely related marriages were observed. The mother's pregnancy proceeded against the background of moderate anemia and toxicosis of the second half of pregnancy in the form of nephropathy. The child was vaccinated according to age. Past illnesses: at the age of 8 he had pyelonephritis. He was not registered, but during preventive examinations in urine tests, protein and erythrocytes were constantly detected. Treatment at the place of residence was not carried out, since nothing bothered the child. Sensory hearing loss was diagnosed at the age of 12. Since December 2015, he noted visual impairment. The boy's mother has chronic renal failure, stage IV. She was in the intensive care unit at the time of the child's hospitalization. A cousin was diagnosed with Alport syndrome at the age of 10, who died of CRF at the age of 13. In the family of the child, Alport's syndrome was subsequently diagnosed in a sibling born in 2004, in whom the disease manifested itself at the age of 11. My sister was born in 2007, the disease manifested itself at the age of 8, and changes were also found in the analysis of urine and pathology of the organs of vision. The mother of this child and her older brother died of chronic renal failure.

On examination: the boy is of satisfactory nutrition. Physical development corresponds to age. Weight 53kg. The child's condition is moderately severe. Consciousness is clear. Answers questions. The position is passive. Pallor of the skin and visible mucous membranes is expressed. The skin is pale, dry. Pastosity of the eyelids is noted. Connective tissue stigmas were revealed: hypertelorism, high palate, malocclusion, abnormal shape of the auricles (ears are small and close to the skull and the complete absence of lobes), "sandal gap" on the feet. Peripheral lymph nodes are not enlarged. Movement in the legs causes muscle pain. Joints are calm. Vesicular breathing in the lungs. Heart sounds are sharply muffled, bradycardia. Pulse - 60 beats per minute, BP 110/70 mm Hg. The tongue is clean, the papillae of the tongue are smoothed. Zev is calm. The abdomen is soft, palpation painless. The liver and spleen are not enlarged. Pasternatsky's symptom is negative on both sides. Urinating little, daily diuresis 600 ml. The chair is designed, 1 time per day.

The following examination was carried out: Complete blood count: Hb-56 g/l, erythrocytes-2.5x10 12 , color index-0.5, leuk.8.7x10 9 , stab-2%, segmented-68%, lymphocytes-28% , monocytes-5%, eosinophils-2%, ESR-30mm/h.

In the analysis of urine: straw-yellow, wt-1015, pH-5.5, protein-0.099g / l, glucose-abs, renal epithelium - units, leukocytes in large numbers, erythrocytes changed - 6-8, erythrocyte cylinders - 2-3, salts of uric acid.

Blood biochemistry: urea - 15.7 mmol / l, residual nitrogen - 58 g / l, total protein - 48 g / l.

Ultrasound of the kidneys: right 71x30, reduced in size, contours are uneven, fuzzy, not differentiated in places, echogenicity is increased; the left kidney is 71x71 cm, the contours are uneven, indistinct, blurred in places, the echogenicity of the cortical layer is sharply increased.

Ophthalmologist's consultation: 2-sided hypermetropia, moderate degree

The conclusion of the ENT doctor according to audiometry: 2-sided hearing loss of mixed type II-III degree. (Fig.1)

Figure 1. Audiometry of a patient with Alport's syndrome.

1. Bed rest followed by exercise restriction
2. Diet, table 7
3. Ceftriaxone 1.0 every 12 hours IM No. 7;
4. Pyridoxine hydrochloride 2 ml 1 time per day intramuscularly No. 10;
5. ATP - 1 ml intramuscularly every other day No. 10;
6. Aevit 1 capsule per day for 2 weeks;
7. Lespenefril 1 tsp. 2 times a day under the control of azotemia
8. Erythropoietin subcutaneously 2000ME 2 times a week - 1 month, then 2000ME 1 time per week - 1 month
9. Albumin 20% 100.0 intravenously drip №3
10. Heparin 1500 IU every 8 hours subcutaneously around the navel under the control of blood clotting
11. Askorutin 1 tab 3 times a day 20 minutes before meals No. 10

In the course of the treatment, the patient's condition in dynamics temporarily improved. Edema subsided, diuresis increased. The headache disappeared, appetite and mood appeared. Blood urea and urinalysis returned to normal.

Discharged under the supervision of a nephrologist at the place of residence and relevant recommendations. The child repeatedly subsequently received inpatient treatment in the nephrology department of the ODMC.

Thus, family doctors, pediatricians should be wary of hereditary diseases. Clinical examination of the child population requires a more thorough examination with a complex of necessary studies not only of a blood test for hemoglobin, but also of a general urine test, and, according to indications, a more detailed examination of children. All young families should be screened for early detection of hereditary pathology.

Bibliography

1. Ignatova M.S. Pediatric Nephrology// Manual for Physicians 3rd edition. 2011 p.200-202
2. Shabalov N.P. Children's diseases // St. Petersburg - 6th edition. 2009 c.251
3. Ignatova M.S. Hereditary kidney diseases occurring with hematuria / S. Ignatova, .V.V. Length//Russian Bulletin of Perinatology and Pediatrics-2014.-vol.59.№3.-p.82-90

Alport Syndrome Karpov Dmitry Olenchuk Vladislav Ogorodnishchuk Maxim Shcherbakova Olga

Alport syndrome Historical background: The first mention of the pathology known as Alport's syndrome belongs to L. Guthrie, who in 1902 described a family with hematuria in several generations. A. Hurst in 1915 observed the development of uremia in the same family. In 1927, A. Alport, describing deafness in several relatives with hematuria, noted that men developed uremia earlier than women. In 1972, uneven expansion and stratification of the dense plate of glomerular basement membranes in Alport syndrome was revealed, the severity of which correlated with age and gender, determining the progression of the disease. In the 70s M.S. Ignatova and V.V. Fokeeva, based on the observation of 200 children, a hypothesis was expressed about the most important role in the development of hereditary nephritis of connective tissue pathology, excretion of hydroxylysing glycosides was studied as a criterion for the state of glomerular basement membranes.

Alport syndrome Genetics: Genes: Col IV AIII Col IV AIV Col IV AV Col IV AVI Chromosome location: Col IV AIII, AIV is localized on the 2nd human chromosome at position q35-37 Col IV AV is localized on the X chromosome at position q22-23 Heredity : Alport syndrome is inherited in X-linked dominant or recessive type - type III, or autosomal dominant or autosomal recessive type - type I and II Cell type, place of expression: Basal glomerular membrane. It is a cell-free matrix with a thickness of nm, which is a structural support for the capillary wall. Its main components are type IV collagen, proteoglycans, laminin and nidogen. Fetal collagen is replaced with adult collagen with age. In cases of mutation, the structure of the basement membrane of the glomeruli is distorted in patients with Alport's syndrome, which leads to the appearance of hematuria as a sign of renal pathology, and hematuria is the cause of mild proteinuria.

Alport syndrome COL4A5 COL4A3-4

Alport Syndrome Genetics: Number and type of mutations: Type IV collagen consists of three domains tightly twisted together in the normal state. When the gene (more often COL4A5) is mutated, anomalies in the twisting of type IV collagen are observed. If there is a deletion of COL4A5, which we noted in the DNA of 5 out of 16 examined families, a large part of the gene exons will fall out. In these cases, the twisting of the domains is broken. The disease has a severe progressive course with the development of extrarenal manifestations and the formation of CRF. There is also a sharp deformation of glomerular BM. Electron microscopy (EM) of the renal biopsy shows pronounced dystrophic changes in BM with areas of clearing and accumulation of fine granular matter. This leads to the appearance of proteinuria with subsequent changes in the angiotensin II and transforming growth factor beta (TGF-β) system. Experimental data confirm the importance of TGF-β in the progression of Alport syndrome]. In cases where only a single nucleotide substitution in the gene is noted, i.e., a point mutation occurs, collagen twisting disorders are detected only in certain areas, the BM remains thin, and clinically the patient has isolated hematuria. It is these cases of SA and TBM that present great difficulties in making a differential diagnosis.

Alport syndrome Formation of basement membrane molecules from collagen IV alpha chains: 1 - normal, 2 - COL4A5 gene divisions, 3 - COL4A5 gene point mutation

Alport Syndrome Protein: Composition: Collagen type 4 Composition Col IV AIII amino acid residues Col IV AIV amino acid residues, including 38 amino acids of a signal peptide cleaved off during maturation Location: Col IV is located in basement membranes. The basement membrane has a thickness of about 1 micron and consists of two plates: light (lamina lucida) and dark (lamina densa). The main components of basement membranes are type IV collagen, laminin, and heparan sulfate-containing proteoglycans (SHPG). At the same time, the insolubility and mechanical stability of the basement membranes is provided by type IV collagen molecules, which are organized into a support network. This elastic three-dimensional network forms the structural framework to which the other basement membrane components attach. In the renal glomeruli, the basement membrane serves as a semi-permeable filter that prevents the passage of macromolecules from the plasma into the primary urine.

Alport syndrome Protein: Structural features: The collagen molecule is a right-handed helix of three α-chains. One turn of the α-chain helix contains three amino acid residues. The molecular weight of collagen is about 300 kDa, length 300 nm, thickness 1.5 nm. The α chain is made up of triads of amino acids. In triads, the third amino acid is always glycine, the second is proline or lysine, the first is any other amino acid, except for the three listed. The primary structure of collagen is characterized by the sequential arrangement of amino acid residues and their number in its polypeptide chains. Amino acids can be referred to as aliphatic, carbocyclic and heterocyclic. Depending on the structure of the side chain, amino acid residues are divided into types, the composition of which, % of the total number of amino acid residues, is given below. Without a side chain (glycocol) 33.34 With a hydrophilic side chain: acidic (aspartic and glutamine amino acids) 12.38 basic (lysine, oxylysine, arginine, histidine) 8.96 Sulfur-containing (methionine) 0.70 Containing hydroxyl, for except for oxylysine (oxyproline, tyrosine, serine, threonine) 13.54 Not containing nitrogen and oxygen in the side chain (alanine, leucine, isoleucine, valine, phenylalanine, proline) 31.48 With an imino group (proline and hydroxyproline) 21.40 Elements of the secondary collagen structures - helical protein polypeptides, the so-called α-chains - are the main unit of the tertiary structure - a tropocollagen particle, consisting of three polypeptide chains with a common axis.

Alport syndrome

Alport Syndrome Protein: Functionality: Protein (collagen type IV molecules) provides insolubility and mechanical stability of the basement membranes, which are organized into a supporting network. This elastic three-dimensional network forms the structural framework to which the other basement membrane components attach. In the renal glomeruli, the basement membrane serves as a semi-permeable filter that prevents the passage of macromolecules from the plasma into the primary urine. In which organisms it is present: Type 4 collagen is found mainly in eukaryotes.

Alport syndrome Signs of the disease in the body: Main symptoms: The clinical picture of Alport syndrome, regularly recurring in the family, usually corresponds to a phenotype, although the severity of symptoms may vary from person to person and depending on age and sex. Most families with this pathology fit well into the following classification: Dominant juvenile nephritis with hearing loss. X-linked juvenile nephritis with hearing loss. X-linked nephritis with hearing loss in adults. X-linked nephritis without extrarenal manifestations. Autosomal dominant nephritis with hearing loss and thrombocytopathy, corresponding to McKusick category N (Epstein's syndrome). Autosomal dominant nephritis of youthful type with hearing loss. The juvenile variant of Alport's syndrome is considered to be those cases when chronic renal failure develops before the age of 31.

Alport Syndrome Signs of the disease in the body: Relationship with genetic diseases: In Charcot-Marie-Tooth disease, the family combination of nephropathy, hearing loss, focal segmental glomerulosclerosis and delamination of the dense plate of glomerular basement membranes is accompanied by muscle atrophy. Nephropathy and hearing loss in Branchio-Oto-Renal syndrome are associated with rudimentary remnants of gill slits. Muckle-Wales syndrome is characterized by autosomal dominant inheritance, increased ESR, frequent development of chronic renal failure, chills and urticarial rash (in the debut), hearing loss, glaucoma and nephrotic syndrome (subsequently). In Alström's syndrome, pigmentary retinal degeneration, sensorineural hearing loss and nephropathy are combined with diabetes mellitus and obesity. Sebastian syndrome is difficult to differentiate from type V Alport syndrome due to the general hematological picture. In combination with hearing loss, autosomal dominant interstitial nephritis with the development of chronic renal failure in adulthood, renal tubular acidosis, and familial cases of IgA nephropathy have been described. Among family cases of glomerulonephritis, observations of autosomal dominant inheritance of this pathology are more common. Hematuria is also accompanied by congenital deficiency of the 3rd complement fraction. X-linked inheritance of progressive hearing loss often mimics Alport syndrome due to the allelicity of their genes

Alport Syndrome Signs of the disease in the body: Types of affected cells: Neurons, hair cells Unusual features of the disease: Nerve damage (polyneuropathy), Myasthenia gravis, Loss of memory and intelligence, Thrombocytopenia. Animal model for the disease: Outbred white rats.

Alport Syndrome Cellular and Molecular Biology: Organelle damage: Basement membranes are affected. The basement membrane is a dense cell-free formation on which epithelial or endothelial cells are located. The basement membrane consists of glycoproteins, glycosaminoglycans and collagen. The basement membrane performs a supporting function, maintaining the shape of organs and blood vessels. The tissue pathology and clinical features in Alport syndrome result from the expression of collagen α3, α4, α5, and possibly α6 (IV) chains in the basement membrane. These circuits are usually absent or underexpressed in the basement membranes of individuals with Alporte syndrome, so that the networks they form are absent or, if present, defective in structure and function.

Alport Syndrome Cellular and Molecular Biology: Normal Functions: In a normally developing kidney, initially collagen α1(IV) and collagen α2(IV) chains predominate in the glomerular basement membrane of immature renal glomeruli. The formation of capillary loops during glomerular maturation is associated with the appearance of collagen α3, α4, and α5(IV) chains in the glomerular basement membrane. As maturation progresses, α3, α4, and α5 (IV) chains become the predominant type of collagen IV in glomerular basement membrane chains. This process has been termed "isotype switching". Proteinuria and renal failure, as well as sensorineural deafness, occurred as a result of processes initiated by the absence of the collagen α3-α4-α5 (IV) chain rather than following directly from the absence of these chains.

Alport Syndrome Cellular and Molecular Biology: How Mutations Change Organelle Function: The Pathology of Allelic Variants The vast majority of COL4A5 mutations are guanine substitutions in the first or second positions of glycine codons. Such mutations are thought to interfere with the normal plexus of mutated α5 collagen (IV) with other types of collagen. The side chain lacks glycine, and the presence of a bulky amino acid at the glycine position presumably creates a kink or triple helix unfolds. The replacement of hycine in the collagen α1 (I) chain causes osteogenesis imperfecta. An improperly folded collagen triple helix has an increased susceptibility to proteolytic degradation. Mutations in the genes Col IV AIII Col IV AIV Col IV AVI have the same variety.

Alport syndrome is a genetically determined inflammatory disease of the kidneys, accompanied by damage to the auditory and visual analyzers. This is a fairly rare hereditary pathology that occurs in 1 out of 10 thousand newborns. According to WHO, persons with Alport syndrome make up 1% of all patients with kidney dysfunction. According to ICD-10, the disease has the code Q87.8.

In Alport's syndrome, the gene encoding the structure of the collagen protein located in the basement membrane of the renal tubules, inner ear and organ of vision is affected. The main function of the basement membrane is to support and separate tissues from each other. Hereditary non-immune glomerulopathy is manifested by hematuria, sensorineural hearing loss, visual impairment. As the syndrome progresses, patients develop renal failure, which is accompanied by diseases of the eyes and ears. The disease is progressive and untreatable.

Hereditary nephritis or familial glomerulonephritis are names for the same pathology. It was first described in 1927 by British scientist Arthur Alport. He followed members of one family who suffered from hearing loss and had red blood cells in urine tests. A few years later, eye lesions were detected in individuals with this disease. And only in 1985, scientists established the cause of such anomalies. It was a mutation of the gene responsible for the synthesis and structure of type IV collagen.

Most often, this ailment causes severe renal dysfunction in males. Women can pass the mutant gene on to their children without any clinical symptoms. The syndrome manifests from the first years of life. But most often found in babies aged 3-8 years. Affected children first show signs of kidney damage. Hearing and vision problems develop somewhat later. In late childhood and adolescence, a severe pathology of the kidneys, loss of vision and hearing is formed.

According to the mode of inheritance of anomalies, 3 forms of pathology are distinguished: X-linked dominant, autosomal recessive, autosomal dominant. Each form corresponds to certain morphological and functional changes in the internal organs. In the first case, the classical form develops, in which inflammation of the kidney tissue is manifested by blood in the urine and is accompanied by a decrease in hearing and vision. In this case, the disease has a progressive course, kidney failure develops rapidly. The histological feature of such processes is the thinning of the basement membrane. In the second case, the congenital ailment is much easier and is characterized by isolated inflammation of the kidneys with hematuria. The autosomal dominant form is also considered benign, has a favorable prognosis, and is manifested only by hematuria or is asymptomatic.

Detect hereditary inflammation of the kidneys by chance, during a physical examination or diagnostic examination of other diseases.

Etiology

The true etiopathogenetic factors of pathology are still not fully understood. It is believed that Alport syndrome is a hereditary disease caused by a mutation of a gene located in the long arm of the X chromosome and encoding type IV collagen protein. The main function of collagen is to ensure the strength and elasticity of connective tissue fibers. With this syndrome, damage to the vascular wall of the kidneys, the organ of Corti, and the lens capsule is noted.

The mutant gene is most often passed from parents to children. There are main forms of inheritance of pathology:

• The dominant X-linked type of inheritance is characterized by the transmission of the affected gene from the mother to the son or daughter, and from the father only to the daughter. The syndrome is more severe in boys. Sick fathers produce healthy sons and sick daughters.
• The autosomal recessive type is characterized by receiving one gene from the father, and the second from the mother. Sick children are born in 25% of cases, and equally often among both girls and boys.

In a family with hereditary diseases of the urinary system, the probability of having sick children increases significantly. If a sick child is born in a family where all members have perfectly healthy kidneys, the cause of the syndrome is a spontaneous genetic mutation.

Factors contributing to the development of the disease:

1. relatives with kidney pathologies;
2. family marriages;
3. shifts in the immune system;
4. hearing loss at a young age;
5. acute infections of bacterial or viral origin;
6. vaccination;
7. physical stress.

Expression of the mutant gene in different individuals varies from mild to severe clinical manifestations of hereditary nephritis. The process of destruction of the basement membrane is directly dependent on the severity of the pathological process.

Pathogenesis

Pathogenetic links of the syndrome:

• violation of collagen biosynthesis or its deficiency,
• destruction of the basement membrane of the kidneys, inner ear and eye apparatus,
• germination of collagen fibers of types V and VI,
• glomerular injury,
• immunonegative glomerulitis,
• glomerular hyalinosis, tubular atrophy and renal stromal fibrosis,
• glomerulosclerosis,
• accumulation of lipids and lipophages in the renal tissue,
• a decrease in the blood level of Ig A, an increase in IgM and G,
• decreased activity of T- and B-lymphocytes,
• violation of the filtration function of the kidneys,
• dysfunction of the organ of vision and hearing,
• accumulation of toxins and metabolic products in the blood,
• proteinuria,
• hematuria,
• development of acute renal failure,
• death.

The disease develops gradually with renal symptoms. In the early stages of the pathology, the kidneys work fully, there are traces of protein, leukocytes and blood in the urine. Pollakiuria and nocturia are accompanied by hypertension and other signs of urinary syndrome. In patients, the calyces and pelvises of the kidneys expand, aminoaciduria occurs. After some time, hearing loss of neurogenic origin joins.

Men are most prone to developing kidney dysfunction. If untreated, death occurs at the age of 15-30 years. Women usually suffer from a latent form of pathology with signs of hematuric syndrome and a slight hearing loss.

Symptoms

Hereditary nephritis in children can proceed according to the glomerulonephrotic or pyelonephrotic type. Clinical signs of Alport's syndrome are conditionally divided into two large groups - renal and extrarenal.

The main manifestations of renal symptoms are: hematuria - blood in the urine and proteinuria - protein in the urine. Erythrocytes in the urine of sick children appear immediately after birth. At first it is asymptomatic microhematuria. Closer to 5-7 years, the blood in the urine becomes clearly visible. This is a pathognomonic sign of Alport's syndrome. The intensity of hematuria increases after acute infectious diseases - SARS, chicken pox, measles. Active physical activity and preventive vaccinations can also provoke a significant increase in red blood cells. Somewhat less often, boys develop proteinuria. In girls, this symptom is usually absent. The loss of protein in the urine is accompanied by edema, increased blood pressure, and general intoxication of the body. Possible leukocyturia without bacteriuria, anemia.

Developing, Alport's disease is complicated by the development of renal failure. Its classic signs are dry, yellowish skin, decreased turgor, dry mouth, oliguria, hand tremors, aching muscles and joints. In the absence of proper treatment, the terminal stage of pathology occurs. In such cases, only hemodialysis will help maintain the vitality of the body. Timely replacement therapy or transplantation of a diseased kidney can prolong the life of patients.

Extrarenal symptoms include:

1. hearing loss caused by neuritis of the auditory nerve;
2. visual impairment associated with cataracts, changes in the shape of the lens, the appearance of white or yellow patches on the retina in the macula region, myopia, keratoconus;
3. delay in psychophysical development;
4. congenital defects - high palate, syndactyly, epicanthus, deformity of the ears, malocclusion;
5. leiomyomatosis of the esophagus, trachea, bronchi.

Nonspecific general intoxication signs of pathology include:

• headache,
• myalgia,
• dizziness,
• sharp fluctuations in blood pressure,
• dyspnea,
• fast, shallow breathing
• noise in ears,
• skin pallor,
• frequent urge to urinate
• dyspepsia,
• loss of appetite
• disruption of sleep and wakefulness,
• itchy skin,
• convulsions,
• chest pain,
• confusion.

Patients develop compensated glomerular and tubular insufficiency, impaired transport of amino acids and electrolytes, the concentration ability of the kidneys, acidogenesis, and the system of nephron tubules is affected. As the pathology progresses, the signs of the urinary syndrome are supplemented by severe intoxication, asthenia and anemia of the body. Similar processes develop in boys with an affected gene. In girls, the disease is much milder, they do not develop persistent kidney dysfunction. Only during pregnancy, girls suffer from symptoms of the disease.

Complications of Alport's syndrome develop in the absence of adequate therapy. Patients develop signs of kidney failure: edema appears on the face and extremities, hypothermia, hoarseness, oliguria or anuria. Often a secondary bacterial infection joins - pyelonephritis or purulent otitis develops. In this case, the prognosis is unfavorable.

Diagnostics

Alport syndrome is diagnosed and treated by pediatricians, nephrologists, geneticists, ENT doctors, and ophthalmologists.

Diagnostic measures begin with the collection of an anamnesis and listening to the patient's complaints. The family history is of particular importance. Specialists find out whether there were cases of hematuria or proteinuria in relatives, as well as deaths from kidney dysfunction. Data from genealogical analysis and obstetric history are important for making a diagnosis.

1. A specific lesion of the basement membrane in patients is detected by the results of a biopsy.
2. In the general analysis of urine - erythrocytes, protein, leukocytes.
3. Genetic research - detection of gene mutations.
4. Audiometry detects hearing loss.
5. Examination by an ophthalmologist reveals a congenital pathology of vision.
6. Ultrasound examination of the kidneys and ureters, magnetic resonance imaging, x-rays and scintigraphy are additional diagnostic techniques.

Treatment

Alport syndrome is an incurable disease. The following recommendations of experts will help slow down the development of kidney failure:

• Rational and vitaminized nutrition,
• Optimal physical activity
• Frequent and long walks in the fresh air,
• Sanitation of foci of chronic infection,
• Prevention of infectious diseases,
• Prohibition of standard vaccinations for sick children,
• Phytocollection of nettle, yarrow and chokeberry is indicated for sick children with hematuria,
• Vitamin therapy and biostimulants to improve metabolism.

Proper nutrition is the use of easily digestible foods with a sufficient content of essential nutrients. Salinity and smoked meats, spicy and spicy dishes, alcohol, products with artificial dyes, stabilizers, flavors should be excluded from the diet of patients. In case of impaired renal function, it is necessary to limit the intake of phosphorus and calcium. Such recommendations should be followed by patients throughout their lives.

Medical symptomatic therapy:

1. To eliminate hypertension, ACE inhibitors are prescribed - Captopril, Lisinopril and angiotensin receptor blockers - Lorista, Vasotens.
2. Pyelonephritis develops as a result of infection. In this case, antibacterial and anti-inflammatory drugs are used.
3. To correct violations of water-electrolyte metabolism, Furosemide, Veroshpiron, intravenous saline, glucose, calcium gluconate are prescribed.
4. Anabolic hormones and iron-containing drugs are indicated for the accelerated formation of red blood cells.
5. Immunomodulatory therapy - Levamisole.
6. Antihistamines - Zirtek, Cetrin, Suprastin.
7. A complex of vitamins and drugs that improve metabolism.

Hyperbaric oxygen therapy has a positive effect on the severity of hematuria and kidney function. With the transition of renal failure to the terminal stage, hemodialysis and kidney transplantation are required. Surgery is performed after the patient reaches the age of fifteen. Recurrence of the disease in the graft is not observed. In some cases, the development of nephritis is possible.

Gene therapy for the syndrome is currently being actively developed. Its main goal is to prevent and slow down the deterioration of kidney function. This promising treatment option is now being introduced into medical practice by Western medical laboratories.

Forecast and prevention

Alport syndrome is a hereditary disease, which is simply impossible to prevent. Compliance with all doctor's prescriptions and maintaining a healthy lifestyle will help improve the general condition of patients.

The prognosis of the syndrome is considered favorable if patients have hematuria without proteinuria and hearing loss. Renal failure also does not develop in women without damage to the auditory analyzer. Even in the presence of persistent microhematuria, their disease practically does not progress and does not worsen the general condition of patients.

Hereditary nephritis, combined with the rapid development of renal failure, has a poor prognosis in boys. They develop early kidney, eye, and ear dysfunctions. In the absence of timely and competent treatment, patients die at the age of 20-30 years.

Alport syndrome is a dangerous disease that, without the provision of qualified medical care, worsens the quality of life of patients and ends in their death. To alleviate the course of hereditary nephritis, it is necessary to strictly follow all medical recommendations.

Video: lecture on Alport syndrome

Alport syndrome is a hereditary disease that is directly characterized by a consistent decrease in kidney function, coupled with pathology of hearing and even vision. At the moment, in our country, this kind of illness among children (mainly) is approximately 17: 100,000.

Main reasons

According to experts, Alport syndrome occurs due to abnormalities in the gene, which is located on the long arm of the X chromosome in the so-called zone 21-22q. In addition, a violation of the integral structure of the so-called type 4 collagen is also the cause of this disease. Collagen is understood in science as such a protein, which is a direct component of the connective tissue, ensuring its elasticity and continuity.

Symptoms

Alport syndrome usually first manifests itself in children between the ages of five and ten and manifests itself in the form of hematuria (blood in the urine). Most often, this diagnosis is detected randomly, that is, during the next examination by a specialist. In addition, Alport's syndrome also manifests itself in the form of the so-called stigmas of dysembryogenesis. These are relatively small deviations that do not play a special role in the functioning of the main body systems. Doctors note epicanthus (a small fold at the inner corner of the eye), a high palate, a slight deformation of both auricles, and other signs. Consistent is also a sure sign of this disease, and hearing loss is much more often diagnosed in boys. All of the above symptoms are most often found in adolescence, while the common chronic one makes itself felt only during adulthood.

Diagnosis

Alport syndrome in children is usually diagnosed based on the presence of this kind of ailment in other family members. For example, to confirm the disease, it is enough to meet three of the five criteria listed below:

• hearing loss;
• cases of death from chronic renal failure of close relatives;
• confirmation of hematuria in family members;
• vision pathology;
• the presence of specific changes during a kidney biopsy.

In the absence of specific therapy, doctors must first slow the development of kidney failure. With such a diagnosis as Alport's disease, physical activity is strictly prohibited for children, they are prescribed. Important attention is paid to the sanitation of the so-called infectious foci. The use of cytostatics and various kinds of hormonal drugs in the treatment improves the condition. However, it is most often prescribed as a primary method of treatment. It should be noted that when hematuria is detected without significant hearing impairment, the overall prognosis for the course of the disease is somewhat more favorable. In a situation of this kind, renal failure is diagnosed extremely rarely.

Alport's syndrome is a hereditary disease characterized by a progressive decline in kidney function in combination with hearing and visual impairment. In Russia, the prevalence of the disease among the child population is 17:100,000.

Causes of Alport Syndrome

It has been established that the gene located in the long arm of the X chromosome in the zone 21-22 q is responsible for the development of the disease. The cause of the disease is a violation of the structure of type IV collagen. Collagen is a protein, the main component of connective tissue, which provides its strength and elasticity. In the kidneys, a defect in the collagen of the vascular wall is detected, in the region of the inner ear - the organ of Corti, in the eye - the lens capsule.

Symptoms of Alport Syndrome

With Alport's syndrome, there is a significant variability in external manifestations. As a rule, the disease manifests itself at the age of 5-10 years with hematuria (the appearance of blood in the urine). Hematuria is usually discovered incidentally during examination of the child. Hematuria can occur with or without proteinuria (the appearance of protein in the urine). With a pronounced loss of protein, nephrotic syndrome may develop, which is characterized by edema, increased blood pressure, symptoms of poisoning the body with harmful products with a decrease in kidney function. It is possible to increase the number of leukocytes in the urine in the absence of bacteria.

In most patients, the stigmas of dysembryogenesis attract attention. Stigmas of dysembryogenesis are small external deviations that do not significantly affect the functioning of the body. These include: epicanthus (fold at the inner corner of the eye), deformation of the auricles, high palate, an increase in the number of fingers or their fusion.

Epicant. Syndactyly.

Very often, the same stigmas of dysembryogenesis are detected in diseased family members.

Hearing loss as a result of acoustic neuritis is also characteristic of Alport's syndrome. Hearing loss often develops in boys and is sometimes detected earlier than kidney damage.

Visual anomalies are manifested in the form of lenticonus (change in the shape of the lens), spherophakia (spherical shape of the lens) and cataracts (clouding of the cornea).

Symptoms of kidney disease usually appear during adolescence. Chronic renal failure is diagnosed in adulthood. Sometimes rapid progression of the disease is possible with the formation of terminal renal failure already in childhood.

Diagnosis of Alport's syndrome

It is possible to assume Alport syndrome on the basis of pedigree data on the presence of the disease in other family members. To diagnose the disease, three of the five criteria must be identified:

The presence of hematuria or mortality from chronic renal failure in the family;
the presence of hematuria and / or proteinuria in family members;
detection of specific changes in kidney biopsy;
hearing loss;
congenital pathology of vision.

Alport Syndrome Treatment

In the absence of specific treatment, the main goal is to slow the development of renal failure. Children are prohibited from physical activity, a full-fledged balanced diet is prescribed. Particular attention is paid to the sanitation of infectious foci. The use of hormonal drugs and cytostatics does not lead to a significant improvement in the condition. Kidney transplantation remains the main method of treatment.

An unfavorable prognosis for the course of the disease, which is characterized by the rapid development of terminal renal failure, is most likely if the following criteria are present:

Male gender;
- high concentration of protein in the urine;
- early development of renal dysfunction in family members;
- deafness.

If isolated hematuria is detected without proteinuria and hearing impairment, the prognosis of the course of the disease is favorable, renal failure is not formed.

Therapist, nephrologist Sirotkina E.V.

Alport syndrome or hereditary nephritis is a kidney disease that is inherited. In other words, the disease affects only those who have a genetic predisposition. Men are most susceptible to the disease, but there is an ailment in women. The first symptoms appear in children from 3 to 8 years. The disease itself may be asymptomatic. Most often, it is diagnosed during a routine examination or during the diagnosis of another, background disease.

Etiology

The etiology of hereditary nephritis is still not fully established. The most likely cause is considered to be a mutation of the gene that is responsible for the synthesis of proteins in the kidney tissue.

The following factors can contribute to the development of the pathological process:

• severe infectious diseases;
• excessive physical activity;
• vaccinations.

In medical practice, there have been cases when the development of hereditary nephritis could provoke even the usual one. Therefore, children who have a genetic predisposition should have a full examination more often.

It is noteworthy that hereditary nephritis has a dominant type of inheritance. This means that if the carrier is a man, then only a healthy son will be born to him. The daughter will not only be the carrier of the gene, but will also pass it on to both sons and daughters.

General symptoms

The clinical picture of Alport's syndrome has well-defined symptoms. At the initial stages of development, the following is observed:

• decreased vision;
• hearing impairment (in some cases up to deafness in one ear);
• blood in the urine.

As hereditary nephritis develops, the signs of the disease become more pronounced. There is a strong intoxication of the body and. The latter is due to a significant and sharp decrease in red cells in the blood. Typical symptoms of Alport syndrome:

• headache and muscle pain;
• fatigue even with minor physical exertion;
• dizziness;
• unstable blood pressure;
• shallow breathing, shortness of breath;
• constant tinnitus;
• violation of the biological rhythm (especially in children).

Insomnia at night and drowsiness during the day most often worries children and the elderly. The severity of symptoms also depends on the general condition of the patient, his age.

In the chronic form of the disease, the following clinical picture is observed:

• general malaise and weakness;
• frequent urination that does not bring relief (possibly with an admixture of blood);
• nausea and vomiting;
• lack of appetite and consequent weight loss;
• bruising;
• itching of the skin;
• pain in the chest area;
• convulsions.

In some cases, in the chronic stage of Alport's syndrome, the patient has confusion and seizures of unconsciousness. In children, such signs are diagnosed very rarely.

Forms of the development of the disease

In official medicine, it is customary to distinguish three forms of the course of the disease:

• the first - rapidly progresses to renal failure, the symptoms are well expressed;
• the second - the course of the disease is progressive, but there is no hearing loss and visual impairment;
• the third is a benign course. There are no symptoms and the progressive nature of the disease.

Diagnostics

First of all, when diagnosing Alport syndrome, a family history is taken into account.

If you suspect hereditary nephritis in children, you should immediately contact your pediatrician. The study uses both laboratory and instrumental analyzes. After a personal examination and clarification of the anamnesis, the doctor may prescribe the following laboratory tests:

The standard program of instrumental research includes the following:

• kidney x-ray;
• kidney biopsy.

In some cases, the doctor may prescribe special genetic studies. Additionally, you may need to consult a medical geneticist and a nephrologist.

Treatment

Drug treatment of Alport syndrome is combined with a diet. It is worth noting that there are no specific drugs aimed specifically at eliminating this genetic disease. All drugs are aimed at normalizing the work of the kidneys.

For children, the diet is prescribed strictly individually. In most cases, the patient needs to adhere to such a diet for life.

In some cases, surgical intervention is necessary. For children, such operations are carried out only when they reach the age of 15-18. Kidney transplantation can completely eliminate the disease.

Diet

The following products should not be present in the patient's diet:

• too salty, fatty, smoked;
• spicy, spicy dishes;
• products with artificial colors.

Alcohol is almost completely excluded. On the recommendation of a doctor, the patient can drink red wine.

The diet should contain the required amount of vitamins and minerals. Food should be high in calories, not high in protein.

Physical activity is excluded. Sports activities should only take place as prescribed by a doctor. Especially, the last circumstance concerns children.

Possible Complications

The most serious complication is As medical practice shows, in most cases, boys from the age group of 16-20 years old suffer from insufficiency. Without treatment and proper lifestyle, death occurs before the age of 30.

Prevention

There is no prevention of hereditary nephritis. This genetic disease cannot be prevented. If a child is diagnosed with an ailment, then one should strictly adhere to all the recommendations of a competent doctor and lead a correct lifestyle. The most effective method of treatment today is organ transplantation.

Alport syndrome (familial glomerulonephritis) is a rare genetic disorder characterized by glomerulonephritis, progressive renal failure, sensorineural hearing loss, and eye involvement.

The disease was first described by British physician Arthur Alport in 1927.

Alport syndrome is very rare, but in the US it is responsible for 3% of ESRD in children and 0.2% in adults, and is also considered the most common type of familial nephritis.

The type of inheritance of Alport syndrome can be different:

X-linked dominant (XLAS): 85%.
Autosomal recessive (ARAS): 15%.
Autosomal dominant (ADAS): 1%.

The most common X-linked form of Alport syndrome results in end-stage renal disease in men. Hematuria usually occurs in boys with Alport syndrome in the first years of life. Proteinuria is usually absent in childhood, but the condition often develops in men with XLAS and in both sexes with ARAS. Hearing loss and eye involvement are never detected at birth but occur in late childhood or adolescence, shortly before kidney failure develops.

Causes and mechanism of development of Alport syndrome

Basement membranes are thin film structures that support tissues and separate them from each other. In violation of the synthesis of type IV collagen, the glomerular basement membranes in the kidneys are not able to normally filter toxic products from the blood, passing proteins (proteinuria) and red blood cells (hematuria) into the urine. Abnormalities in type IV collagen synthesis lead to kidney failure and kidney failure, which is the main cause of death in Alport syndrome.

Clinic

Proteinuria is usually absent in childhood, but sometimes develops in boys with X-linked Alport syndrome. Proteinuria is usually progressive. Significant proteinuria in female patients is rare.

Hypertension is more commonly present in male patients with XLAS and in patients of both sexes with ARAS. The frequency and severity of hypertension increases with age and as renal failure progresses.

Sensorineural hearing loss (hearing impairment) is a characteristic manifestation of Alport syndrome, which is observed quite often, but not always. There are entire families with Alport syndrome who suffer from severe nephropathy but have normal hearing. Hearing impairment is never detected at birth. Bilateral high-frequency sensorineural hearing loss usually presents in the first years of life or early adolescence. At an early stage of the disease, hearing impairment is determined only by audiometry.

As it progresses, the hearing loss extends to low frequencies, including human speech. After the onset of hearing loss, kidney involvement should be expected. American scientists claim that with X-linked Alport syndrome, 50% of men suffer from sensorineural hearing loss by the age of 25, and by the age of 40 - about 90%.

Anterior lenticonus (protrusion of the central part of the lens of the eye forward) occurs in 25% of patients with XLAS. Lenticonus is not present at birth, but over the years it leads to a progressive deterioration of vision, which forces patients to change their glasses frequently. The condition is not accompanied by eye pain, redness, or impaired color vision.

Retinopathy is the most common manifestation of Alport's syndrome on the part of the organ of vision, affecting 85% of men with an X-linked form of the disease. The onset of retinopathy usually precedes kidney failure.

Posterior polymorphic corneal dystrophy is a rare condition in Alport syndrome. Most have no complaints. Mutation L1649R in the collagen gene COL4A5 can also cause retinal thinning, which is associated with X-linked Alport syndrome.

Diffuse leiomyomatosis of the esophagus and bronchial tree is another rare condition seen in some families with Alport syndrome. Symptoms appear in late childhood and include swallowing disorders (dysphagia), vomiting, epigastric and retrosternal pain, frequent bronchitis, shortness of breath, cough. Leiomyomatosis is confirmed by computed tomography or MRI.

Autosomal recessive form of Alport syndrome

Autosomal dominant form of Alport syndrome

Diagnosis of Alport's syndrome

British experts, based on new data (2011) on genetic mutations in patients with X-linked Alport syndrome, recommend testing for COL4A5 gene mutation if the patient meets at least two diagnostic criteria according to Gregory, and analysis of COL4A3 and COL4A4 if the COL4A5 mutation is not autosomal inheritance is found or suspected.

Alport Syndrome Treatment

Some researchers suggest that ciclosporin may reduce proteinuria and stabilize renal function in patients with Alport syndrome (studies have been small). But reports say that patients' response to ciclosporin is highly variable, and sometimes the drug can precipitate interstitial fibrosis.

In renal failure, standard therapy includes erythropoietin to treat chronic anemia, drugs to control osteodystrophy, correction of acidosis, and antihypertensive therapy to control blood pressure. Hemodialysis and peritoneal dialysis are used. Kidney transplantation is not contraindicated for patients with Alport's syndrome: transplantation experience in the USA has shown good results.

Gene therapy for various forms of Alport syndrome is a promising treatment option, which is currently being actively studied by Western medical laboratories.

Konstantin Mokanov

Alport syndrome (SA) is an inherited type IV collagen disorder characterized by a combination of progressive hematuric nephritis with ultrastructural changes and sensorineural hearing loss. Visual disturbances are also common in this syndrome. Microhematuria, detected in the early stages of life, is a constant characteristic sign of the disease.

Recurrent episodes of gross hematuria occur in about 60% of patients under 16 years of age, but are rare in adults. Over time, it joins and the disease progresses with age, depending on the gender of the patient and the type of inheritance of the disease. is a late sign.

Bilateral sensorineural hearing loss, affecting high and medium frequency hearing, is progressive in children, but may come to light later. There are reports of several types of visual disturbances, also progressive with age. Anterior lenticonus is a cone-shaped protrusion of the anterior part of the lens. Yellowish spots appear on the retina of the eye, which are asymptomatic. Both types of lesions are specific and occur in about a third of patients. There are also reports of recurrent corneal erosions in SA patients.

Morphology

Under light microscopy, kidney tissue obtained in the early stages of AS appears normal. Focal and segmental thickening of the capillary walls of the glomeruli, better detected by silver staining, become visible with the progression of the disease. They are associated with nonspecific tubular lesions and interstitial fibrosis. Standard immunofluorescence is usually negative. However, faint and/or focal grade G and M deposits and/or complement fraction C3 may be detected. The main damage is detected by the ultrastructural method. They are characterized by thickening (up to 800-1200 nm) with splitting and fragmentation of the lamina densa into several fibers forming a basket-like network. Changes can be fragmentary (heterogeneous), alternating with areas of normal or reduced thickness. In general, the most prominent feature in children is the uneven alternation of very thick and very thin areas of the GBM. Diffuse thinning of the GBM is found in about 20% of patients with AS.

At the genetic level, AS is a heterogeneous disease: mutations in COL4A5 on the X chromosome are associated with X-linked AS, while mutations in COL4A3 or COL4A4 on chromosome 2 are associated with autosomal forms of the disease.

X-linked Alport syndrome.

clinical symptoms.

The X-linked variant is the most common form of AS, characterized by a more severe course of the disease in male patients than in female patients, and the absence of transmission through the male line. Availability hematuria is a necessary criterion for diagnosis. gradually increases with age and can subsequently lead to the development of nephrotic syndrome. In all male patients, the disease progresses to end-stage kidney disease. There are two types of AS - juvenile, in which ESRD develops around the age of 20 in men with maternal transmission, and adult, characterized by a more variable course and development of ESRD around the age of 40. In heterozygous females, hematuria is found only in adulthood. It is absent in less than 10% of women (carriers). The risk of developing ESRD in women under the age of 40 is about 10-12% (against 90% in men), but increases after age 60. Most heterozygotes never develop ESRD. Bilateral sensorineural hearing loss progresses in most male patients and in some females. Changes in the organ of vision, anterior lenticonus and/or perimacular spots are observed in 1/3 of patients. In families with AS, women may have diffuse esophageal leiomyomatosis, which also includes lesions of the tracheobronchial tree and genital tract of women and sometimes congenital cataracts.

Molecular genetics made it possible to establish the features of mutations in the COL4A5 gene. They cause differences in clinical manifestations, course and prognosis.

Autosomal recessive Alport syndrome

Alport syndrome is inherited in an autosomal recessive manner in about 15% of affected families in Europe. This type of inheritance is more common in countries with higher levels of consanguineous marriages. Clinical symptoms and ultrastructural changes are identical to those observed in X-linked AS. However, some signs clearly indicate recessive inheritance: consanguineous marriages, severe disease in female patients, absence of severe disease in parents, microhematuria in the father. The disease, as a rule, progresses early to ESRD, almost always there are hearing impairments, not always - damage to the organ of vision.

Among heterozygotes, persistent or intermittent microhematuria is noted.

Autosomal dominant Alport syndrome

Autosomal dominant inheritance, characterized by transmission through the male line, is rare. The clinical phenotype is the same for men and women. The course is milder than in the X-linked form, with late and inconsistent progression to the development of ESRD and hearing loss. Heterozygous mutations in the COL4A3 or COL4A4 genes have been identified in some families.

Diagnosis and treatment of Alport's syndrome. Diagnosis of AS and determination of the type of inheritance are important for therapeutic management, prognosis, and genetic counseling of patients and their families. The issue is easily resolved if hematuria is combined with deafness or eye damage and if the hereditary history is sufficiently informative to establish the type of inheritance. Each incidentally discovered hematuria requires examination of other family members. The early onset of hematuria and the identification of sensorineural hearing loss, lenticonus, or maculopathy on careful examination may suggest SA, but the mode of inheritance remains uncertain. Determination of mutations in the COL4A5, COL4A3, or COL4A4 genes is critical for diagnosing the disease, but molecular analysis is a costly and time-consuming procedure due to the large size of the type IV collagen gene and the wide variety of mutations.

It is important to differentiate Alport syndrome from thin basement membrane disease (TBM) early. This is best done on the basis of family history: the presence in the family of adult men over 35 years of age with hematuria and intact renal function with a high probability allows us to make a diagnosis of TBM.

In the absence of hearing loss, diagnosis is quite difficult: if a kidney biopsy is done too early (before 6 years), you can not see the changes characteristic of Alport syndrome that will develop later, and electron microscopy is not available everywhere. In this regard, it is promising to introduce an immunohistochemical method for determining the expression of various type IV collagen chains in the renal tissue or in the skin.

Sporadic hematuria with proteinuria, detected in the absence of extrarenal manifestations, is the reason for a renal biopsy to exclude other hematuric glomerulopathies (IgA nephropathy, etc.). Progression to end-stage kidney disease is inevitable in X-linked SA in men and in all patients with autosomal recessive SA. To date, there is no specific treatment. The main treatment is blockade of the renin-angiotensin system to reduce and possibly slow down the progression. Kidney transplantation leads to satisfactory results, however, about 2.5% of all patients with SA develop anti-GBM due to the formation of a "different" donor GBM, which leads to graft rejection.