Hereditary and metabolic nephropathies 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 nephropathy and renal dysplasia are complicated by chronic renal failure already in childhood and account for approximately 10% of all cases of terminal chronic failure in children and young adults. It is practically important to identify the "congenital component" in each specific case. There are fundamentally different approaches to the treatment of congenital and acquired nephropathy in children; acquired kidney diseases that developed against the background of congenital ones have special features in the course, in the approach to treatment, in the prognosis; issues of prevention 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 anomalies of the structure of the genitourinary system: anomalies of the number, position, shape of the kidneys, anomalies of the structure of the renal pelvis and calyces; anomalies of the development of the ureters, bladder and urethra. This group includes anomalies of the blood and lymphatic renal vessels.
2. Anomalies in the formation of renal tissue with parenchyma deficiency, or renal hypoplasia - normonephronic and oligonephronic.
3. Anomalies of renal differentiation, or dysplasia:
   • acystic forms - simple total dysplasia, simple focal dysplasia, segmental renal dysplasia;
   • cystic dysplasia - focal cystic or multilacunar cyst, total cystic dysplasia, multicystic kidney, medullary cystic disease, or Fanconi nephronophthisis, cortical renal dysplasia;
   • total polycystic kidney disease of two types - autosomal dominant polycystic disease, or adult type, and autosomal recessive polycystic disease, or infantile type polycystic disease;
   • cortical polycystic kidney disease, or glomerulocystic kidney;
   • microcystic cortex, including congenital familial nephrosis and Finnish-type nephrosis.
4. Primary and secondary tubulopathies.

Primary tubulopathies manifested by predominant damage to the proximal tubules are renal tubular acidosis type 2, glycinuria, renal melituria, De Toni-Debre-Fanconi syndrome, phosphate diabetes, cystinuria. Primary tubulopathies with predominant damage to the distal tubules and collecting ducts are renal tubular acidosis type 1, nephrogenic diabetes insipidus, pseudohyperaldosteronism (Lidl's syndrome) and pseudohypoaldosteronism. Fanconi nephronophthisis is a variant of tubulopathy that occurs with damage to the entire tubular apparatus.

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

5. Hereditary nephritis: Alport syndrome, familial chronic nephritis without deafness, nephritis with polyneuropathy, familial benign hematuria.
6. Nephro- and uropathies in the structure of chromosomal and monogenic syndromes.
7. Embryonal renal tumor (Wilms' tumor).

Common features of congenital nephropathies:

1. Pathological obstetric history and pathological pregnancy with a proband child. The fact is that the phenotypic manifestations of a pathological gene (or genes) are manifested under the influence of external factors; the penetrance of pathological genes increases under unfavorable external influences.
2. Typically detected at an early age (up to 6-7 years).
3. For most types of congenital pathology, there is a long compensated stage, so “accidental” detections are typical.
4. During a more detailed examination in the compensated stage, an early decrease in partial tubular functions of the nephron is often detected.
5. Typical signs of instability of cell membranes: increased concentrations of ethanolamine, phosphatidylethanolamine and 2-aminoethylphosphonate in the blood, increased phospholipases in the urine, crystalluria. The significant frequency of these disorders can obviously be considered as a manifestation of dysembryogenesis at the subcellular level.

Indications for examination of children for hereditary and metabolic nephropathies are as follows.

1. Detection of renal pathology in young children (up to 3-4 years old).
2. “Random” detection of pathology in urine during routine examinations.
3. Detection of renal pathology in a family where there are patients with renal pathology, with early forms of hypertension, with chronic diseases of the digestive organs, with obesity, with hearing and vision defects.
4. The presence of congenital anomalies of other organs and systems (skeleton, heart, blood vessels). The most significant signs for diagnosing the congenital nature of nephropathy are the presence of more than 5 so-called "minor" stigmas of dysembryogenesis, a tendency to arterial hypotension and oxalate-calcium crystalluria. In the presence of two of the three listed, the probability that the nephropathy is congenital or the acquired disease of the urinary system develops against the background of a congenital or hereditary defect is 75%.

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

One of the clinically significant types of tubulopathies is a group of transport defects in bicarbonate reabsorption, hydrogen ion excretion, or both, defined as renal tubular acidosis (RTA).The prevalence of such defects is unknown, but is obviously much higher than their detection. Clinical variants of acid-regulating renal function disorders in children are, in most cases, a congenital defect (hereditary or sporadic cases). Renal tubular acidosis in children in the first months of life may be a manifestation of functional immaturity of the kidneys. Bone deformities that occur due to 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 the acid-regulating function of the kidneys occurs and the infantile form of renal tubular acidosis spontaneously heals. With a number of diseases and poisonings, secondary forms of renal tubular acidosis may develop. Renal tubular acidosis is a hyperchloremic metabolic acidosis with normal values of renal tubular acidosis (plasma anion deficit). The formula for renal tubular acidosis is based on the idea of plasma electroneutrality. It is derived from a simplified Gamble diagram and gives an idea of the concentration of residual, i.e. undetectable anions in plasma. They include sulfates, phosphates, lactate, and anions of organic acids. Normal values of renal tubular acidosis fluctuate within 12.0±4.0 mmol/l. Renal tubular acidosis in children is assumed 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 insufficient excretion of anions, and not with a tubular defect of acidification. This variant occurs in ketoacidosis against the background of diabetes mellitus, during starvation, in uremia, intoxication with methanol, toluene, ethylene glycol, in the development of a lactic acidotic state due to hypoxia and shock.

Based on clinical and pathophysiological signs, there are 3 types of renal tubular acidosis:

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

The simplest approximate division of renal tubular acidosis into proximal and distal variants can be performed by assessing the excretion of ammonium ions. The proximal variant is accompanied by a normal or increased level of daily excretion of NH ₄, the distal variant - by its decrease. Proximal renal tubular acidosis(Type II) - impaired bicarbonate reabsorption in the proximal tubules and decreased renal threshold for bicarbonate excretion. Isolated forms of primary proximal renal tubular acidosis are quite rare. Clinical descriptions of proximal renal tubular acidosis type in the literature are very diverse. Apparently, renal tubular acidosis type II in the overwhelming majority is combined with other proximal tubular defects. The most noticeable symptom is growth retardation. Patients do not have nephrocalciosis and urolithiasis; rickets-like deformities are rarely observed. Muscle weakness and pathology of the eyes and extraocular muscles are possible.

Distal renal tubular acidosis(Type I) is the most common form of renal tubular acidosis. The defect consists of a violation of distal acidification, in the inability of the kidney to lower the pH of urine below 5.5 under ammonium chloride load. Cytochemically, 4 variants of disorders are distinguished.

1. Classical, or secretory, absence of the enzyme H-ATPase in the intercalated cells of the A collecting ducts. The enzyme is responsible for proton secretion.
2. Gradient-deficient is manifested by the inability to create a gradient of H concentration between the luminal membrane and the intracellular environment due to the increased countercurrent of already secreted proton. The kidney retains the ability to increase the partial pressure of CO2 _in urine at its maximum alkalization and to normally acidify urine in response to a furasemide load. This variant is sometimes considered as a secondary defect due to intracellular acidosis of the epithelium of the proximal tubules, causing initially increased excretion of ammonium, which leads to damage to the distal structurates and the development of the gradient-deficient variant of renal tubular acidosis. Thus, proximal and distal renal tubular acidosis can be considered as early and late stages of one process.
3. The proportion-dependent variant is manifested by the inability to maintain the transepithelial potential difference. This variant is manifested by a persistent but slight metabolic acidosis; after bicarbonate loading, the blood-urine CO2 partial pressure gradient _is very small.
4. Voltage-dependent variant, in which hyperkalemia occurs due to impaired potassium secretion. To diagnose this variant in adults, amiloride loading is used to inhibit and bumetamyl to stimulate voltage-dependent secretion of potassium and hydrogen ions.

The most typical clinical signs of renal tubular acidosis type I are:significant growth retardation; skeletal deformation progresses sharply in the prepubertal period; polyuria is characteristic; hypokalemia with periodically increasing muscle weakness; constant hypercalciuria, nephrocalcinosis and nephrolithiasis lead to the development of chronic renal failure. Morphologically, chronic tubulointerstitial nephritis with an outcome in sclerosis is determined in young adults. Sensorineural hearing loss is possible. 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 determined. Both familial and sporadic cases are possible. It is assumed that the transmission of the defect occurs according to the autosomal dominant type, but the developed clinical picture occurs only in homozygotes. Treatment of renal tubular acidosis is limited to the relief of chronic acidosis by prescribing citrate mixtures and alkaline drinks and cautiously prescribing vitamin D in an individual dosage to suppress secondary hyperparathyroidism.

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