Hereditary jade
Hereditary nephritis is a genetically determined nonimmune glomerulopathy that often leads to kidney failure. It is manifested by asthenic, intoxication syndromes, delayed physical development in children, macrohematuria, polyuria, nocturia, edema, arterial hypertension. It is diagnosed using a general urinalysis, puncture biopsy, electron microscopy. Symptomatic therapy with ACE inhibitors, angiotensin receptor blockers, immunomodulators, anabolics, calcineurin inhibitors is recommended. With terminal CRF, replacement therapy and kidney transplantation are indicated.
The prevalence of hereditary nephritis, according to foreign experts in the field of nephrology, is 0.01-0.02%. In Russia, the disease is detected in 0.017% of children. The first observations of patients with familial forms of glomerulopathy leading to uremia were carried out in 1902-1923.
In 1927, British scientist Arthur Alport identified a variant of the hereditary combination of uremia and hearing loss, which was later named after him – Alport syndrome. The genetic basis of inherited variants of jade was established in 1985. In more than 80% of cases, the disease debuts at the age of 3-10 years and proceeds more severely in male patients, which is associated with the predominance of the X-linked type of inheritance.
Reasons
The disease is inherited and is associated with a genetic defect in which the biosynthesis of type IV collagen fibers, which are part of the basement membranes of nephrons and a number of other organs, is disrupted. Several genes (C0L4A5, C0L4A3, C0L4A4) located on different chromosomes are responsible for encoding the collagen chains that form glomerular membranes.
Hereditary forms of nephritis are genetically heterogeneous, which affects the severity of clinical symptoms, the rate of development of the disease, the time of onset of decompensation. Most often, the COL4A5 gene encoding the α-5 chain of collagen fibers undergoes deletions, point mutations, and splicing disorders. In 80% of patients, the disease is inherited by the X-linked type, in 15% — by autosomal recessive, in 5% – by autosomal dominant.
Pathogenesis
The mechanism of development of pathological changes in hereditary nephritis is based on a violation of the normal structure of the basement membranes in the tissues of the kidneys and some other organs. Mutation of the C0L4A5 gene, which is located at the Xq21.3 locus on the long arm of the X chromosome, changes the structure of the α-5 chain of type 4 collagen. Damage to the C0L4A3, C0L4A4 genes localized in the 2nd chromosome is accompanied by a violation of the synthesis of α-3 and α-4 chains of collagen fibers.
Anomalies of any of these chains affect the formation of the basement membranes of glomeruli, distal tubules, and collecting tubules. Due to the denser multilayer interlacing or incorrect spatial distribution of fibers, the basement membranes thicken, delaminate, and thin. Mesangiocytes proliferate in the renal corpuscles, the mesangial matrix accumulates, the glomeruli are sclerosed, while local glomerulosclerosis is replaced by segmental, global and aggravated by hyalinosis.
At the same time, tubules atrophy, interstitial fibrosis develops, in addition to normal interstitial cells, foamy cellular elements appear. Pathomorphological changes are clinically manifested by impaired filtration and reabsorption functions. Since similar collagen fibers are part of the specific membranes of the lens and the cortical organ, patients, in addition to urological pathology, have hereditary forms of visual and hearing impairment.
Classification
When systematizing the forms of hereditary nephritis, the nature and severity of clinical manifestations of nephrological pathology, the dynamics of the development of the disease, the time of occurrence of renal failure, the presence of signs of damage to other organs are taken into account. The existence of various variants of pathology is due to the type and degree of expression of mutated genes. Specialists in the field of clinical urology and medical genetics distinguish the following forms of hereditary nephropathy:
Type I: juvenile nephritis with kidney damage, hearing loss and visual impairment (Alport syndrome). It manifests itself when the C0L4A5 gene is damaged (X-linked dominant inheritance). Manifests early, differs in a progressive course with the development of CPN. In 50% of patients, end—stage renal failure occurs before the age of 25, in 90% – before the age of 40.
Type II: hereditary form of nephritis without hearing loss. It is transmitted by an autosomal recessive mechanism. Mutations are detected in both alleles of the COL4A3 or COL4A4 genes. The clinical picture shows renal symptoms. The disease has a progressive course, terminal renal failure is formed by the age of 30.
Type III: benign familial hematuria. It is inherited by an autosomal dominant type and is associated with a mutation of one of the genes of the 2nd chromosome (COL4A3 or COL4A4). It manifests itself later, sometimes in adulthood. It is characterized by a low-grade course with moderately pronounced nephrological symptoms and a low probability of developing CRF.
Symptoms of hereditary nephritis
At an early stage of the disease, the clinical picture is characterized by general disorders: a slowdown in growth and physical development, intoxication syndrome, manifested by weakness, fatigue, dizziness, pallor and dryness of the skin, decreased appetite, decreased muscle tone, frequent headaches, tinnitus, insomnia.
With the progression of nephritis, symptoms such as frequent urination, an increase in the volume of urine released at night, pain in the abdomen or pelvis, the appearance of morning edema, visible blood in the urine (macrohematuria), a persistent increase in blood pressure. In addition, a patient with hereditary glomerulopathies may have stigmas (small anomalies of embryogenesis) – deformation of the auricles, epicanthus, high palate, asymmetry of the chest, syndactyly (fusion of two or more fingers).
In 30-50% of patients, signs of hearing impairment are detected — from minor changes detected on an audiogram to complete sensorineural deafness. In 15-30% of cases, anomalies of the lens structure and visual disturbances are diagnosed in the form of anterior lenticonus, myopia, hypermetropia, astigmatism, cataracts, keratoconus, spherophakia, retinitis pigmentosa, amaurosis, nystagmus, etc.
Complications
With a prolonged course of hereditary nephritis, a gradual death of nephrons occurs, as a result of which the disease is usually complicated by increasing renal insufficiency. In juvenile forms of nephropathy, CRF occurs by the age of 16-20 and, in the absence of adequate treatment, leads to the death of the patient before the age of 30. Genetically determined nephritis, accompanied by a violation of metabolic processes, can lead to excessive formation and deposition of salts, as a result of which urolithiasis develops. With an increase in the functional load on the kidneys, it is possible to develop acute renal failure with the need for emergency therapy.
Diagnostics
Careful genealogical research plays an important role in the diagnosis of hereditary nephritis. In 80% of patients, it is possible to identify family forms of urological pathology in the genus, inherited hearing loss, vision with more pronounced symptoms in men. When the disease is suspected to be associated with genetic abnormalities, research methods are recommended that reveal signs of damage to the basement membranes, functional kidney failure, morphological changes in the parenchyma characteristic of hereditary forms of nephritis:
General urinalysis. At least two urine samples collected at different times show altered red blood cells in the amount of 3 units in the field of vision or more. Proteinuria (more than 0.35 g/ l), leukocyturia, and cylindruria are characteristic, increasing with the development of the disease.
Puncture biopsy of the kidneys. Histological examination of the kidney biopsy reveals clusters of erythrocytes in the tubules, interstitial tissue is infiltrated, glomeruli are compacted. Immunofluorescence analysis reveals atypical type 4 collagen.
Electron microscopy. At the initial stages of nephritis, the glomerular basement membranes are thinned, at later stages they thin or thicken, become layered, split. The proliferation of mesangiocytes, the expansion of the mesangium is characteristic.
Methods aimed at identifying a mutated gene are currently rarely used due to the technical complexity and high cost of research. The development of renal insufficiency, complicating the course of hereditary nephritis, is indicated by changes in blood biochemistry (an increase in creatinine, uric acid, urea nitrogen, a decrease in total protein levels) and corresponding changes in urine analysis (positive renal tests).
The disease is differentiated with paraneoplastic nephropathy, kidney tuberculosis, acute and chronic glomerulonephritis, pyelonephritis, urolithiasis, gouty interstitial nephritis, glomerular lesions in systemic connective tissue diseases. In addition to the examination of a nephrologist or urologist, the patient is recommended to consult a medical geneticist, according to indications — an otorhinolaryngologist, ophthalmologist, therapist, endocrinologist, rheumatologist, immunologist, oncologist, oncohematologist.
