Hereditary and metabolic nephropathy in children: causes, symptoms, diagnosis, treatment

Congenital malformations of the kidneys and urinary tract account for up to 30% of the total number of congenital anomalies in the population. Hereditary nephropathies and renal dysplasia are complicated by chronic renal failure already in childhood and constitute approximately 10% of all cases of terminal chronic insufficiency in children and young adults. It is practically important to identify the "congenital component" in each specific case. To the treatment of congenital and acquired nephropathy in children there are fundamentally different approaches; the acquired kidney diseases that have developed against the background of congenital ones have special features in the flow, in the approach to treatment, in the prognosis; prevention issues for congenital nephropathy often require genetic counseling.

From the standpoint of clinical manifestations, all hereditary and congenital nephropathies can be divided into 7 groups:

1. Anatomical abnormalities in the structure of the urogenital system: anomalies in the number, position, shape of the kidneys, abnormalities in the structure of the bowl-and-pelvis system; anomalies in the development of the ureters, bladder and urethra. This group includes anomalies of the blood and lymphatic kidney vessels.
2. Anomalies in the formation of renal tissue with a deficiency of the parenchyma, or kidney hypoplasia - normonephronic and oligonephronic.
3. Anomalies of renal differentiation, or dysplasia:
   • non-cystic forms - simple total dysplasia, simple focal dysplasia, segmental renal dysplasia;
   • cystic dysplasia - focal cystic, or multilacuncular cyst, total cystic dysplasia, multicystic kidney, medullary cystic disease, or Fanconi nephronophthisis, cortical dysplasia of the kidneys;
   • total polycystic kidney disease of two types - autosomal dominant polycystosis, or adult type, and autosomal recessive polycystosis, or polycystosis of the infantile type;
   • cortical polycystic kidney, or glomerulokistozna kidney;
   • microcystosis of the cortex, including congenital familial nephrosis and nephrosis of the Finnish type.
4. Tubulopathy is primary and secondary.

Primary tubulopathies, manifested by a primary lesion of the proximal tubules, are renal tubular acidosis of the second type, glycinuria, renal melitturia, De Toni-Debreu-Fanconi syndrome, phosphate-diabetes, cystinuria. Primary tubulopathies with predominant involvement of distal tubules and collecting ducts are renal tubular acidosis of the 1st type, nephrogenic diabetes insipidus, pseudohydaldosteronism (Lidl's syndrome), and pseudohyperdodosteronism. Nephronophthisis Fanconi is a variant of tubulopathy, which proceeds with damage to the entire tubular apparatus.

Secondary tubulopathies develop with hereditary pathology of metabolism. This large group includes galactosemia, hepatocerebral dystrophy (Wilson-Konovalov's disease), familial hypercalciuria, purine metabolism disorders, primary hyperparathyroidism, hypophosphaturia, glycogeneses, diabetes mellitus, xanthinuria, Low syndrome, oxaluria, tyrosinosis, Fabry disease, fructoseemia, celiac disease, cystinosis .

5. Hereditary nephritis: Alport syndrome, family chronic nephritis without deafness, nephritis with polyneuropathy, family benign hematuria.
6. Nephro- and uropathy in the structure of chromosomal and monogenic syndromes.
7. Embryonic kidney tumor (Wilms tumor).

Common features of congenital nephropathies:

1. Pathological obstetrical anamnesis and pathological pregnancy by the child-proband. The fact is that the phenotypic manifestations of the pathological gene (or genes) are manifested under the influence of external factors; The penetrance of pathological genes increases with adverse external influences.
2. It is characteristic to identify at an early age (up to 6-7 years).
3. For most types of congenital pathology, there is a long compensated stage, so typical "random" detection.
4. With an in-depth examination in the compensated stage, an early decrease in the partial tubular functions of the nephron is often found.
5. Typical signs of instability of cell membranes: increased concentrations of ethanolamine, phosphatidylethanolamine and 2-aminoethylphosphonate in the blood, increased phospholipases in urine, crystalluria. A significant frequency of these disorders can obviously be seen as a manifestation of the dysembryogenesis at the subcellular level.

Indications for examining children for hereditary and metabolic nephropathies are as follows.

1. Revealing of renal pathology in children of early age (up to 3-4 years).
2. "Accidental" revealing pathology in the urine with routine examinations.
3. Revealing renal pathology in the family, where there are patients with kidney pathology, with early forms of hypertension, with chronic diseases of the digestive system, obesity, hearing and visual impairment.
4. Presence of congenital anomalies of other organs and systems (skeleton, heart, vessels). The most significant signs for diagnosing the congenital nature of nephropathies are the presence of more than 5 so-called "small" stigmas of disembriogenesis, a tendency to arterial hypotension, and oxalate-calcium crystalluria. In the presence of two of the three listed above, the probability that nephropathy is congenital or acquired disease of the organs of the urinary system develops against a background of a congenital or hereditary defect is 75%.

The vast majority of these variants of congenital nephropathies are rare, there are single or dozens of descriptions of reliably documented cases. A detailed description of individual types of hereditary nephropathies can be found in the specialized literature.

One of the clinically important types of tubulopathy is a group of transport defects in the reabsorption of bicarbonate, the excretion of hydrogen ions or both of these factors, defined as renal tubular acidosis (PTA). The prevalence of such defects is not known, but, obviously, much higher than their detection. Clinical variants of disturbance of acid-regulating function of kidneys in children - in most cases congenital defect (hereditary or sporadic cases). Renal tubular acidosis in children of the first months of life can be a manifestation of the functional immaturity of the kidneys. Bony deformations resulting from the compensatory leaching of calcium from bone tissue in response to chronic metabolic acidosis are usually regarded as manifestations of vitamin D deficiency rickets and are not recognized. Usually at the age of 12-14 months the maturation of enzyme systems responsible for acid-regulating function of the kidneys occurs and the infant form of renal tubular acidosis is spontaneously cured. With a number of diseases and poisonings, the development of secondary forms of renal tubular acidosis is possible. Renal tubular acidosis is a hyperchloremic metabolic acidosis with normal renal tubular acidosis (plasma anion deficiency). The formula of renal tubular acidosis is based on the concept of electroneutrality of plasma. It is derived from a simplified Gamble diagram and gives an idea of the concentration of residual, that is, undetectable, anions in the plasma. They include sulfates, phosphates, lactate, anions of organic acids. The normal values of renal tubular acidosis range from 12.0 ± 4.0 mmol / l. Renal tubular acidosis in children is suggested when metabolic acidosis is accompanied by hyperchloremia and normal values of renal tubular acidosis. Metabolic acidosis with elevated levels Renal tubular acidosis is associated with excessive formation or inadequate excretion of anions, rather than with a tubular acidification defect. This variant occurs with ketoacidosis against diabetes mellitus, with fasting, with uremia, with intoxication with methanol, toluene, ethylene glycol, in the development of lactic acidosis due to hypoxia and shock.

According to clinical and pathophysiological features, there are 3 types of renal tubular acidosis:

• I type - distal;
• Type II - proximal;
• III type is a combination of type I and II or variant I of type and is not currently allocated in a separate form;
• IV type - hyperkalemic - is rare and almost exclusively in adults.

The simplest orienting division of renal tubular acidosis into proximal and distal variants can be performed when estimating the excretion of ammonium ions. The proximal variant is accompanied by a normal or increased level of daily excretion of NH ₄, distal - by its decrease. Proximal renal tubular acidosis (type II) is a violation of the reabsorption of bicarbonate in the proximal tubules and a decrease in the renal threshold for the excretion of bicarbonates. Isolated forms of primary proximal renal tubular acidosis are rare. Clinical descriptions of proximal renal tubular acidosis in the literature are very diverse. Obviously, renal tubular acidosis of type II is overwhelmingly combined with other proximal tubular defects. The most noticeable symptom is the lag in growth. Patients do not have nephrocalcosis and uro-tyaza; Rickhitiform deformations are rarely noted. Muscular weakness and pathology of the eyes and oculomotor muscles are possible.

Distal renal tubular acidosis (type I) is the most common form of renal tubular acidosis. The defect is the disturbance of distal acidification, the inability of the kidney to lower the pH of the urine below 5.5 when loaded with ammonium chloride. Cytochemical distinguish 4 variants of violations.

1. Classical, or secretory, absence of the enzyme H-ATPase in the intercalation cells A of the collecting tubes. The enzyme is responsible for the secretion of the proton.
2. Gradient-deficient is manifested by the inability to create a concentration gradient H between the luminal membrane and the intracellular medium due to the increased countercurrent of the already secreted proton. The kidney retains the ability to increase the partial pressure of CO ₂ urine at its maximum alkalization and to normally acidify urine in response to the load with furasemide. This variant is sometimes considered as a secondary defect due to intracellular acidosis of the epithelium of the proximal tubules, which causes initially enhanced ammonium excretion, which leads to damage to the distal structures and the development of a gradient-deficient variant of renal tubular acidosis. Thus, proximal and distal renal tubular acidosis can be considered as an early and late stage of a single process.
3. Proportion-dependent variant is manifested in the inability to maintain the transepithelial potential difference. This variant is manifested by a constant but insignificant metabolic acidosis; after loading with bicarbonate, the partial pressure gradient _of blood-urine CO _{2 is} very small.
4. Voltage-dependent variant, in which there is hyperkalemia due to a violation of potassium secretion. To diagnose this variant, adults are loaded with amiloride for inhibition and bumetamil - to stimulate the voltage-dependent secretion of potassium and hydrogen ions.

The most typical clinical signs of renal tubular acidosis I typa: significant lag in growth; deformation of the skeleton dramatically progresses in the pre-pubertal period; typical of polyuria; hypokalemia with periodically increasing muscle weakness; the constant hypercalciuria, nephrocalcinosis and nephrolithiasis lead to the development of chronic renal failure. Morphologically, young adults are diagnosed with chronic tubulo-interstitial nephritis with an outcome in sclerosis. Possible sensorineural hearing loss. In all cases of renal tubular acidosis, the examination program necessarily includes an audiogram. It is believed that in children with renal tubular acidosis of the distal type - almost always a primary defect, genetically conditioned. There are both family and sporadic cases. It is assumed that the transmission of the defect occurs in an autosomal dominant type, but an extended clinic takes place only in homozygotes. Treatment of renal tubular acidosis is limited to the arrest of chronic acidosis by the appointment of citrate mixtures and alkaline drink and the careful administration of vitamin D in an individual dosage to suppress secondary hyperparathyroidism.

[1], [2], [3]