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.
ICD 10
Q87.8 N07
Meaning
The prevalence of hereditary nephritis, according to American specialists in the field of nephrology, is 0.01-0.02%. 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 X-linked inheritance.
Causes
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 improper 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
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 headache, 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 long 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, resulting in urolithiasis. With an increase in the functional load on the kidneys, it is possible to develop OPN 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:
- 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 evidenced 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, renal 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.
Treatment
Effective etiopathogenetic therapy of the disease has not been proposed. The administration of hormones and immunosuppressants is usually ineffective. Renoprotection is recommended for patients with a hereditary form of nephritis: a low-protein diet, restriction of physical activity, rehabilitation of foci of chronic infection, caution when carrying out routine vaccination and prescribing drugs with nephrotoxic effect. To prevent the early development of interstitial fibrosis, active antiproteinuric therapy is prescribed to prevent damage and atrophy of the epithelial cells of the renal tubules:
- Angiotensin converting enzyme (ACE) inhibitors. They are first-line drugs; cause dilation of blood vessels, improve renal blood flow, reduce increased intraclubular pressure, reduce sodium and water reabsorption. Due to the inhibition of angiotensin II, they have an antifibrogenic effect and inhibit the development of tubulointerstitial fibrosis.
- Angiotensin receptor blockers (ARBs). They are used as a means of the second line. They bind AT-1 receptors of angiotensin II, blocking its action. Although the renal effects of ARBs are generally similar to ACE inhibitors, drugs of this group affect more gently and pointwise, do not affect the angiotensin-converting enzyme system, ion channels, and other receptors.
Antiproteinuric treatment is supplemented with vitamin complexes, vitamin-like preparations, drugs with immunomodulatory and anabolic effects, calcineurin inhibitors, hyperbaric oxygenation. The appearance of signs of terminal renal insufficiency serves as an indication for renal replacement therapy — hemodialysis, peritoneal dialysis, hemofiltration.
The only way to radically improve the patient’s condition is kidney transplantation, although such an operation has specific indications and contraindications compared to other types of nephrological pathology. When choosing a relative donor, it should be taken into account that he may also have an asymptomatic hereditary predisposition to nephritis, which decompresses after removal of one of the kidneys. In addition, the presence of a normal alpha chain of collagen present in the basement membranes of the transplanted organ can provoke an immune response and rejection of the kidney.
Prognosis and prevention
The disease is characterized by a progressive course, an early violation of the kidneys. The prognosis of hereditary nephritis is unfavorable: CRF can form even in children, causing early disability of the patient. However, adequate symptomatic or substitution therapy can slow down the progression of the pathological process. An important link in prevention is early diagnosis of the disease in medical and genetic laboratories. If the hereditary nature of glomerulopathy is suspected, all family members are screened, especially those with a history of hypertension, diseases of the organs of vision and hearing, multiple small developmental anomalies.