Nephrology for Family Physicians - O.I. Bakaliuk 2003

Congenital Nephropathies and Tubulopathies

The Clinical significance of these pathological forms in adults is minor, as most of these conditions result in mortality during childhood. Nevertheless, A brief Overview is provided here to ensure timely detection and appropriate management of this pathology in adults. Part of this topic has been previously covered by us in the section "Pediatric Nephrology."

Alport syndrome serves as a classic example of congenital nephropathies.

The first reports of Hereditary Nephropathies date back to 1881, when W. Dickinson described familial nephritis, followed in 1902 by L. Guthrie's description of so-called "idiopathic familial hereditary Hematuria." In 1927, E. Alport reported the association between hereditary nephritis and deafness. Subsequent observations revealed that Hearing impairments, and occasionally visual defects, may either present in isolation or precede the initial symptoms of renal involvement.

It has been established that Alport syndrome is inherited predominantly in a dominant manner. The mutant Gene is linked to the X chromosome, which accounts for the more severe clinical course observed in males. This dominant trait arises from a deletion or point mutation of the COL4A5 gene located in the Xq22 region of the long arm of the chromosome (F.D. Barker et al., 1990).

According to current understanding, in Gene Mutations, the dominant inheritance pattern is characteristic of conditions caused by structural protein anomalies. This results in alterations within the Collagen protein molecules of the glomerular and tubular basement membranes (specifically the alpha-5 chain of type IV collagen in Alport syndrome), as well as in the structures of the Inner ear and the lens. More detailed information regarding the inheritance pattern of Alport syndrome is presented below.

Morphological Changes in the Kidneys are non-specific and include proliferative or focal segmental glomerulitis, interstitial fibrosis, and variable thickening or thinning of the basement membrane. Immunofluorescence Cell/15.html">Microscopy reveals non-specific deposits of IgM Class IMMUNOGLOBULINS and Complement components within the mesangium and arteriolar walls, whereas electron-dense deposits are typically absent. A more characteristic diagnostic feature is the presence of Cells with foamy inclusions in the interstitium. Inner ear abnormalities manifest as hyperostosis of the cochlear apex.

The Clinical presentation of Alport syndrome in adults is diverse. Early criteria include a decline in the renal concentrating capacity and urinary abnormalities (macro- and microhematuria combined with transient yet significant proteinuria). Occasionally, isolated proteinuria occurs without hematuria. In some cases, leukocyturia is detected in the urinary sediment, which—particularly when combined with positive urine cultures—creates additional diagnostic challenges. As the condition progresses, proteinuria becomes persistent, edema develops, and the nitrogen-excreting function of the kidneys becomes impaired; Hypertension is generally absent. As a rule, patients succumb to progressive renal failure between the ages of 15 and 30. Hearing may remain unaffected for quite some time, with significant deterioration typically appearing alongside the onset of end-stage renal failure. Some patients also develop ocular abnormalities (such as cataracts or spherophakia).

The Diagnosis of Alport syndrome is established based on a genetic history analysis (renal and auditory symptoms spanning three generations) and Clinical Features (patient age, spontaneous onset and disappearance of hematuria, diminished renal concentrating function, impaired hydrogen ion excretion, hyperaminoaciduria, unidirectional Amino acid METABOLISM abnormalities in multiple family members—such as elevated Blood amino acid levels or restricted amino acid profiles—along with audiological evaluation results. In doubtful cases, a needle biopsy of the kidneys is recommended. Renal transplantation remains the sole effective Treatment. The disease does not recur in the graft, as it is a genetically determined basement membrane anomaly.

Death from renal failure at a young age can also occur in Fabry disease (J. Fabry's disease, or angiokeratoma corporis diffusum, a lipid storage disorder)—a hereditary nephropathy caused by deficient activity of the enzyme alpha-galactosidase A. This enzymatic defect leads to elevated blood levels and increased urinary excretion of the glycosphingolipid globotriaosylceramide (ceramide trihexoside). The latter accumulates within vascular walls, impairing endothelial and podocyte function. Simultaneously, Lipid Metabolism is altered, leading to lipid deposition in the vasculature of various Organs and systems (Skin, Heart, Lungs, kidneys, and Central Nervous system). As the disease progresses, segmental and subsequently diffuse glomerulosclerosis develops within the kidneys.

Patients may exhibit keratinized vascular papules of varying sizes, dark blue or black in color, primarily localized on the Lips, Cheeks, distal Phalanges, inguinal skin, and Scrotum, accompanied by hypohidrosis. Manifestations can rapidly include cognitive decline, upper limb paresthesias accompanied by rheumatoid-like pain, irritability, headaches, and visual acuity changes due to corneal opacification. In some instances, cardiorenal syndrome is observed, characterized by lower extremity edema, arterial hypertension, and a systolic murmur over the cardiac apex. Laboratory findings include hypercreatininemia, while functional renal tests reveal isosthenuria and a decreased filtration rate. The earliest sign of renal involvement is progressive proteinuria. The inheritance pattern is X-linked recessive; the defective gene is mapped to the long arm of the X chromosome at Xq22 > q24 (A.H. Cohen et al., 1994).

Diagnosis is primarily based on the evaluation of clinical symptoms (combined involvement of the kidneys, skin, and other organs). Specific targeted therapy does not exist, though Kidney transplantation is effective.

Congenital tubulopathies are characterized by partial or complete blocks in the transport systems of the renal tubules resulting from a mutant gene and the associated impaired synthesis of enzymatic Proteins. These conditions present as isolated lesions affecting the proximal segment (proximal tubular acidosis, type II Renal Tubular Acidosis, indolylacetyluria, Hartnup disease), the distal segment (distal tubular acidosis, type I renal tubular acidosis, Butler-Albright syndrome), or both segments simultaneously (juvenile nephronophthisis, Fanconi Syndrome).

Proximal tubular acidosis, which is driven by impaired bicarbonate reabsorption in the proximal tubules, is frequently associated with hypokalemia, glucosuria, Aminoaciduria, phosphaturia, and hypochloremic acidosis. The diagnosis is based on the combination of these findings with growth retardation and urolithiasis. Proximal tubular acidosis (type II) may manifest as an isolated primary condition or accompany other systemic disorders.

Hartnup disease serves as an example of an isolated primary disorder.

Hartnup disease (A. Baron et al., 1952) is inherited in an autosomal recessive manner. It is underpinned by an enzymatic defect that disrupts the metabolism and transport of Tryptophan within the epithelial Cells of the renal tubules and the colon.

Tryptophan Metabolism can be disrupted across various pathways—the kynurenine pathway, which causes pellagra-like dermatosis and facial pigmentation; and the indolic and serotonin pathways, which lead to neurological disorders (nystagmus, cerebellar ataxia, hyperkinesia, and psychiatric disturbances). Blood amino acid concentrations remain normal, with the exception of a significant reduction in tryptophan levels, serving as an important diagnostic test alongside marked aminoaciduria and indolyuria. Changes in the urinary sediment are non-specific.

Diagnosis relies on the analysis of clinical manifestations and laboratory investigation data (skin lesions, neurological disorders, hypothryptophanemia, aminoaciduria). The prognosis is unfavorable.

Distal tubular acidosis (type I renal tubular acidosis) arises from impaired urine acidification within the distal nephron. This manifests as reduced hydrogen ion excretion, causing a sharp shift in the blood acid-base balance toward acidosis, along with hypokalemia and hypocalcemia resulting from increased potassium and calcium excretion. Systemic acidosis develops, accompanied by corresponding metabolic shifts, urolithiasis, anorexia, Muscle weakness, and Osteoporosis.

Type I distal tubular acidosis may also present either as a syndrome or as an independent pathological entity (Butler-Albright syndrome).

Butler-Albright syndrome is more commonly diagnosed in children (Autosomal Recessive Inheritance) and less frequently in adults (dominant inheritance). The condition was first described in the 1940s (R. Lightwood, 1935; A.M. Butler, F. Albright, 1940).

Diagnosis is based on clinical data (polydipsia, polyuria, adynamia, vomiting, constipation, myopathy, osteopathy, osteoporosis) and laboratory findings (hypochloremic acidosis, hyposthenuria, transient proteinuria, hyperphosphatemia, elevated serum alkaline phosphatase levels, hypercalciuria, hyperkaliuria, and altered urinary pH). Plain radiography and renal ultrasound reveal widespread calcinosis of the renal medulla and pyramids.

An ammonium chloride loading test (administered at 0.1 g/kg of body weight) is employed to diagnose the condition (I.M. Gandzha, 1983). Normally, urinary pH drops to 5.4 or lower within 2–8 hours following ammonium chloride ingestion; if this drop fails to occur and urinary pH remains persistently above 6.0, type II renal tubular acidosis should be suspected (whereas in type I renal tubular acidosis, urinary pH falls below 6.0 following ammonium chloride administration). Without renal transplantation, the prognosis is unfavorable.

Alongside the classic variant of type I tubular acidosis, There is a so-called "atypical" type IV tubular acidosis, characterized by hypokalemia combined with low serum renin and aldosterone levels and/or tubular resistance to aldosterone.

The Cytology/practical/136.html">Differential diagnosis OF various types of tubular acidosis is outlined below.

Fanconi syndrome was described by D. Fanconi in 1951. This pathological condition occurs predominantly in children (juvenile nephronophthisis with an autosomal recessive inheritance pattern) and less frequently in adults (medullary cystic kidney disease with an Autosomal dominant inheritance pattern). In adults, it is characterized by a latent course with clinical manifestations emerging between the ages of 20 and 30. The genes responsible for this condition have not yet been identified. Sporadic cases are rare.

The core of the pathology is a progressively worsening dysfunction across all segments of the tubules, eventually reaching the stage of renal failure. The kidneys appear grossly shrunken and small, with cysts located predominantly in the corticomedullary junction. It is hypothesized that the primary defect may involve impaired Formation of the tubular basement membrane along with the associated weakness of the tubular walls. This leads to The formation of wall outpouchings, their rupture, and the leakage of tubular contents into the interstitium. The clinical presentation is characterized by polyuria and polydipsia, followed later by anemia, seizures, growth retardation, bone pain (osalgia), paresthesias, and muscle weakness. Edema is absent, and blood pressure is not elevated; findings include hyposthenuria, transient glucosuria, phosphaturia, uraturia, aminoaciduria, and proteinuria (up to 1 g/day). Blood tests reveal hypocalcemia and hyperphosphatemia. The diagnosis is based primarily on the aforementioned laboratory findings. The prognosis is unfavorable, with end-stage renal failure developing approximately 5 years after the onset of the initial symptoms (L.W. Welling et al., 1994).