Pediatric Medical Genetics - S.I. Smiian 2003

Hereditary nephropathies

Hereditary Nephropathies are Kidney diseases whose development is associated with a mutation in a single Gene (monogenic inheritance) or multiple genes (polygenic inheritance), as well as kidney diseases arising from a hereditary predisposition.

Among children with kidney diseases, Hereditary and Congenital disorders account for 14 to 20%. The cause of developmental anomalies can be attributed to genopathies in 20% of cases, to Chromosomal aberrations in 10%, and to intrauterine infections, predominantly of viral Etiology, in 10%. Combined Malformations of the renal tissue and the Urinary System result in complex uropathies that are difficult to diagnose. These diseases are characterized by an unfavorable course, with The Development of chronic renal failure and high mortality. Chronic renal failure (CRF) is present in 43% of children with hereditary nephropathies, and 9.5% present with an unfavorable Nephrotic Syndrome. Childhood disability becomes not only a medical but also a social problem.

Treatment presents significant challenges. Some hereditary nephropathies require lifelong treatment, while certain developmental defects necessitate complex surgical intervention or sophisticated therapies (artificial kidney, kidney transplantation), with the prognosis worsening significantly in cases of bilateral kidney involvement.

The vast number of these diseases and physicians' lack of awareness regarding all types of congenital and hereditary renal pathologies lead to underdiagnosis or late Diagnosis at the stage of CRF, which worsens the prognosis. This is also exacerbated by the slow or even latent progression of the disease, where clinical symptoms only manifest in the end-stage. Currently, more than 600 such diseases have been described, but this is far from exhaustive.

Etiology. Etiological factors leading to the occurrence of congenital and hereditary nephropathies can be divided into 3 groups:

1. A gene mutation whose manifestation is independent of environmental influences. The environment can only affect the severity of the disease symptoms.

2. A gene mutation whose penetrance requires the presence of adverse environmental factors.

3. External influences: microbes, Viruses, toxins, hypothermia, radiation, poisoning, which manifest in individuals with a genetic predisposition.

Pathological anatomy. Morphological changes occurring in the Kidneys are highly diverse across different forms of hereditary and congenital pathology. Dysplasia with thinning of the cortex is frequently detected in the renal parenchyma (hypoplasia, various malformations of the tubules and the urinary system, sclerosis, cystic transformation of the kidneys). In nephropathies associated with Metabolic Disorders, nephrocalcinosis, proliferative-infiltrative Changes in the interstitium, tubular epithelial dystrophy, fibrosis, and salt crystals in the renal tissue are observed.

Bilateral, functionally silent forms of pathology are initially characterized by mild or focal morphological changes in the renal tissue. As they gradually progress, they become widespread, more diverse, and often lead to the development of CRF. In some diseases, severe bilateral lesions of the renal Structure may be observed, such as Polycystic Kidney Disease, which indicates significant disruption of renal development processes, particularly during the early Cytology/cytology/21.html">Stages of intrauterine development. Both overt and silent changes can be familial, pointing to the hereditary Nature of the pathology. In other cases, isolated foci of embryonic-type structures or immature morphological elements are found in the kidneys, indicating hypoplasia and dysplasia of the renal tissue, which result from embryopathy. These changes may manifest prominently as early as the first year of life.

A third pattern of histological abnormalities is possible, characterized by mild and partially reversible hypoplastic processes in the renal parenchyma, delayed development of nephrons, their glomeruli, and tubular segments, which likely arise As a result of fetopathies—pathological impacts on partially formed renal tissue.

Classification of Congenital and hereditary kidney diseases.

There is no single classification for this pathology. From a genetic standpoint, they can all be divided into 3 groups:

1. Nephropathies in Chromosomal Disorders (Edwards, Down, Patau syndromes, etc.).

2. Nephropathies associated with Gene Mutations (monogenic and polygenic).

3. Multifactorial nephropathies: manifestation of a mutant gene only under certain adverse environmental conditions.

For Monogenic Diseases, classification is based on the mode of inheritance:

1. Autosomal dominant type.

2. Autosomal recessive type.

3. X-linked type.

From the perspective of genetic factors, hereditary kidney diseases can be classified as follows:

1. Chromosomal aberrations:

Trisomy D — Hydronephrosis, polycystic kidney disease.

Trisomy E — duplication, Horseshoe kidney.

Trisomy 21 — Renal Hypoplasia.

4p deletion: horseshoe kidney, duplication.

XO syndrome: ureteral duplication, renal malrotation, urethral stenosis.

2. Gene mutations:

Hereditary nephritis.

Tubulopathies: Primary and secondary.

Hereditary structural Anomalies of the urinary system. Renal dysplasia.

Renal Amyloidosis.

3. Acquired nephropathies with hereditary predisposition.

Autoimmune diseases with nephropathy (systemic lupus erythematosus and others).

Congenital structural anomalies of the urinary system, tubulopathies leading to interstitial nephritis and secondary Pyelonephritis.

Intravascular coagulation disorders (hemorrhagic tubulopathies, hemolytic uremic syndrome).

Recently, views on so-called “purely exogenous” kidney diseases have changed dramatically. When multiple family members are infected with nephritogenic streptococci, the question arises: is it the virulence of the streptococcus or genetic predisposition that led to the development of familial kidney disease? Furthermore, the individualization of the disease in the presence of a genetic defect accounts for the “uniqueness” of the pathology in each patient and within each affected family.

Not all hereditary kidney diseases are congenital, as they manifest at different stages of life. Late onset may be due to the mutant gene being in a recessive state, with the enzyme or structural protein defect manifesting as the child develops.

Nosological classification of congenital and hereditary nephropathies based on clinical manifestations:

I. Associated with anatomical anomalies of the kidneys and Urinary Tract:

1. Renal malformations (agenesis, aplasia, supernumerary kidney, dystopia, Nephroptosis, S-shaped, horseshoe kidneys, etc.).

2. Ureteral malformations (changes in number, caliber, etc.).

3. Anomalies of the Urinary Bladder and Urethra.

4. Renal vascular anomalies.

II. Impaired differentiation of renal tissue (histological anomaly):

1. With cysts (polycystic kidney disease, etc.).

2. Without cysts (segmental or hypoplastic dysplasia, etc.).

III. Hereditary nephritis:

1. Without deafness.

2. With deafness (Alport syndrome).

IV. Tubulopathies:

1. Primary:

a) with polyuria (nephrogenic diabetes insipidus, etc.);

b) with bone deformities (Phosphate Diabetes, De Toni-Debré-Fanconi disease);

c) with renal and bone involvement (Renal Tubular Acidosis);

d) with Nephrolithiasis (cystinuria, oxaluria, etc.).

2. Secondary — associated with hereditary metabolic disorders (galactosemia, cystinosis, etc.).

V. Dysmetabolic nephropathies (calcium oxalate crystalluria).

VI. Renal amyloidosis (hereditary, associated with familial Mediterranean fever).

VII. Embryonal Renal Tumors (Wilms' Tumor).