Pediatric Medical Genetics - S.I. Smiyan 2003

Hereditary Nephropathies
Semiotics of congenital and hereditary renal diseases

Clinical Diagnosis of Hereditary Nephropathies is typically highly challenging. The leading syndromes characteristic of Urinary System diseases may be absent during the Initial Stages of the disease. This pathology rarely presents acutely and usually has an indolent course for some time. As the disease progresses gradually, children and adolescents adapt to the slow onset of homeostatic disturbances and do not notice them until decompensation occurs, when symptoms of end-stage renal failure develop.

Urinary syndrome in Hereditary and Congenital nephropathies is often the sole manifestation of the disease. A distinguishing feature from acquired diseases is its resistance to conventional Treatment. Furthermore, there is no clear correlation between the severity of the urinary syndrome and the manifestations of toxicosis.

Abnormalities in urinalysis are usually detected incidentally during routine check-ups, examinations following intercurrent illnesses, or when There is a family history of Kidney disease.

The hematuric variant of urinary syndrome can range from occasional red Blood Cells per high-power field to gross Hematuria and can be caused by various factors. In particular, a glomerular origin of hematuria is characteristic of hereditary nephritis and renal Dysplasia. Hereditary dysmetabolic nephropathies (oxaluria, cystinuria, uraturia) are accompanied by tubular-type hematuria.

The proteinuric variant of urinary syndrome in congenital and hereditary nephropathies is caused by glomerular and tubular mechanisms. Proteinuria is rarely isolated. This syndrome is most pronounced in congenital and familial Nephrotic Syndrome. Moderate proteinuria is observed in renal dysplasia and Nephroptosis.

The pyuric variant of urinary syndrome, characterized by predominant bacteriuria and leukocyturia, occurs mainly when a bacterial infection is superimposed on a congenital disease. However, in cases of pronounced interstitial Changes in the Kidneys, isolated leukocyturia with a predominance of lymphocytes in the urinary sediment can be observed.

A mixed variant of urinary syndrome, where urinalysis reveals mild proteinuria and the sediment contains red blood cells, white blood cells, and sometimes Bacteria and salt crystals, is typically characteristic of the Cytology/cytology/16.html">Early stages of congenital and hereditary nephropathies. However, similar changes can also be observed during The Development of chronic renal failure.

Hypertensive syndrome in pediatrics is in most cases caused by renal factors and manifests as an elevation of both systolic and diastolic blood pressure. However, diastolic pressure is more frequently elevated. Clinically, patients present with Complaints of headache and paleness. In hereditary and congenital nephropathies, this syndrome is characterized by resistance to conventional treatment.

Hypotensive syndrome is characteristic of hereditary renal pathologies such as hereditary nephritis. It is more commonly observed in children without deafness. It has been proven that in this case, the Pathogenesis of hypotension involves functional insufficiency of the adrenal cortex, possibly due to morphological immaturity. However, similar abnormalities are also observed in children with tubulopathies.

Edematous syndrome of renal origin presents in several variants. Widespread peripheral edema progressing to anasarca is possible in cases of massive proteinuria and hypoproteinemia, and is associated with the development of secondary aldosteronism. Another variant of edematous syndrome clinically manifests as puffiness. Even with significant proteinuria, patients do not exhibit hypoproteinemia. This is attributed to impaired vascular permeability, which is frequently observed in renal dysplasia.

Endogenous Intoxication syndrome, presenting as paleness, lethargy, headache, and loss of appetite, occurs in congenital and hereditary nephropathies independently of the urinary syndrome and can be the first sign of the disease. In acquired diseases, the severity of this syndrome is related to The activity of the pathological process and depends on the severity of the urinary syndrome.

Stigmata of dysembryogenesis always accompany clinical manifestations in Chromosomal aberrations. Impaired Connective Tissue formation during Embryogenesis coincides with critical periods in kidney development. Although these signs are not significant in most hereditary and congenital nephropathies, the presence of several stigmata of dysembryogenesis should alert the clinician to a hereditary pathology.

Manifestations of renal failure in genetic, chromosomal, and inherited diseases can be the first sign of the illness. ACUTE RENAL FAILURE syndrome is possible even in the neonatal period in cases of congenital renal agenesis. In other congenital and hereditary pathologies, this syndrome typically does not occur. However, severe hereditary illness often manifests as chronic renal failure. Polyuric syndrome is characteristic of Fanconi nephronophthisis and nephritis-like dysplasia.

Acidosis syndrome is characteristic of Renal Tubular Acidosis, but always in combination with polyuria, hyposthenuria, severe osteopathy, and Nephrolithiasis.

Osteodystrophy is a manifestation of hereditary kidney diseases such as Phosphate Diabetes and De Toni-Debré-Fanconi Syndrome, in which it is the primary systemic manifestation, alongside other multifaceted Features of the disease. Osteodystrophy can also be observed in chronic renal failure.

Potassium deficiency syndrome (hypokalemia) occurs in diseases such as De Toni-Debré-Fanconi syndrome and other hereditary tubulopathies.

Azotemic syndrome, as the first sign of renal function decompensation, is found in Fanconi nephronophthisis and some other cystic renal transformations. However, in many hereditary and congenital diseases, this syndrome begins abruptly, and the degree of homeostatic disturbance may not correlate with the morphological changes observed at autopsy.

Despite nosological polymorphism, hereditary nephropathies are characterized by A number of common Clinical Features:

1. Genetic history: the presence of similar diseases in the family, which are clearly revealed when constructing a pedigree.

2. Long-term latent course with isolated urinary syndrome.

3. Multiple external and somatic stigmata of dysembryogenesis (minor anomalies). The most common include a high arched palate, high nasal bridge, Malformations of the auricles, polydactyly, and varus deviation of digit V.

4. Early decline in renal function, typically of the tubular type.

5. Development of renal failure.

Hereditary nephritis — Nephritis hereditaria — is a genetically determined congenital kidney disease phenotypically manifested by hematuria, microproteinuria, and progressive decline in renal function, often associated with visual and Hearing impairments. It typically features an X-linked dominant inheritance pattern. It is more common than diagnosed, often masquerading as so-called latent hematuric nephritis. Two variants of hereditary nephritis are distinguished:

— HN without deafness;

— HN with deafness (Alport syndrome).

Several terms used for this disease reflect changing views on its nature (hereditary familial congenital hematuric nephritis, hereditary interstitial Pyelonephritis, hereditary nephropathy with deafness, diffuse familial nephropathy). With the accumulation of experience, clear understanding of inheritance patterns, and insights into the pathogenesis of the disease, classifying hereditary nephritis as an independent clinical entity became appropriate.

This disease occurs with approximately equal frequency in Eurasia, North and South America, and Australia.

Pathomorphology reveals signs of renal structural remodeling: splitting of the glomerular basement membranes, dystrophy of nephron elements, and manifestations of sclerosis and fibrosis of renal cells.

Based on the clinical course, hematuric and nephrotic forms of the disease are distinguished.

The hematuric form primarily manifests as urinary syndrome, predominantly in preschool-aged children: macro- or microhematuria, mild proteinuria, and transient moderate leukocyturia, which is typically abacterial. Urinary syndrome is often detected incidentally during routine pediatric check-ups or examinations following intercurrent illnesses.

It has an insidious onset and is characterized by gradual, steady progression against the Background of a fluctuating disease course. Chronic renal failure (CRF) gradually develops. Patients' survival ranges from 6 months to 50 years, averaging 20–40 years.

Extrarenal symptoms are mild at the onset of the disease. Signs of intoxication gradually appear: pale Skin, headache, increased fatigue, and a tendency toward hypotension. With the development of CRF, Hypertension, myasthenia, and neurological disorders emerge. In Alport syndrome, there is a decline in hearing, memory, and intellect. Some patients exhibit ocular lesions, such as spherophakia, lenticonus, cataracts, and myopia.

The nephrotic form manifests in the first days and weeks of a child's life with generalized edema, massive proteinuria, and cylindruria. It follows a malignant course. The familial type of the nephrotic form has a more benign course, characterized by the same symptoms and often arterial hypertension in several family members.

Diagnosis of the classical form of Alport syndrome is straightforward. The diagnostic criteria include a combination of hematuria and deafness. In the presence of persistent hematuria or proteinuria without deafness, the patient's family history must be thoroughly investigated. Sometimes, renal involvement can be traced through 4–5 generations, while some relatives present with deafness alone. HN differs from immune Glomerulonephritis by the absence of edema and hypertension, whereas in the nephrotic form, these symptoms appear very early. Isolated hematuria can be observed in Polycystic Kidney Disease, urolithiasis, toxic irritation, tuberculosis, and other renal lesions, but these conditions are characterized by their own specific symptoms.

The prognosis for males is unfavorable. This is due to them having only a single X chromosome with the mutant Gene. The disease progresses and leads to a fatal outcome at the age of 30–35 years. The nephrotic form causes mortality in the first months of a child's life. In females, who possess a normal X chromosome In addition to the affected one, the disease manifests only as the hematuric form, follows a more benign course, and they live to old age.

Treatment. There are no Methods of Pathogenetic Therapy for HN. However, long-term research and observation of patients have allowed the development of certain recommendations:

Children should receive a complete, balanced diet, taking into account the functional state of their kidneys. Physical activity is somewhat restricted, as physical exertion promotes the occurrence of gross hematuria.

Dietary correction is performed in the event of hypertensive and edematous syndromes. Restriction of physical activity is indicated during the acute phase.

In the subcompensated stage of the process, various hemostatic agents are prescribed: rutin, calcium gluconate, preparations of nettle, chokeberry, and yarrow.

In the decompensated stage of the process, There are two treatment approaches: prednisolone 1.5–2 mg/kg/day for 2–4 weeks, leukeran 0.2 mg/kg/day for 6–8 weeks, or azathioprine 3 mg/kg/day also for 6–8 weeks.

The Use of so-called "metabolic activators": pyridoxine, cocarboxylase, ATP. These agents improve the general condition and renal function, and reduce hematuria. If a

decline in cellular Immunity is identified, the administration of thymalin, thymosin, or levamisole may be beneficial.

Currently, preference is given to the second treatment approach, as in some patients, the use of corticosteroids and cytostatics produces a negative effect. Indomethacin is not used at all in HN.

During the period of remission, eradication of infection foci, restorative therapy, and continuous follow-up monitoring are carried out.

In CRF, hemodialysis and renal transplantation are indicated; however, the child's relatives should not be used as Donors, as the possibility of transplanting a kidney with a latent disease cannot be ruled out.

Prevention of HN consists of Genetic Counseling. The high risk of giving birth to affected children must be taken into account. It is particularly important to inform affected women, whose sons and daughters have an almost 50% chance of being affected or heterozygous.