Neurological manifestations of Fanconi disease in children. Fanconi syndrome: symptoms, diagnosis and treatment. Symptoms and signs

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Description and reasons

De Toni-Debreu-Fanconi disease is manifested by severe tubular dysfunction, as a result of which the process of reabsorption of substances and ions beneficial to the body is disrupted. At the same time, the release of bicarbonates increases, and general metabolic failures are detected. Peculiarities:

a drop in the content of calcium and phosphorus in the blood plasma;
failure in the acid-base balance, which is manifested by low acidity and bicarbonates in the blood;
normal excretion of calcium in the form of a final metabolite in the urine with increased rates of natural cleansing of the body from phosphates;
pathologically high alkaline phosphatase activity;
the appearance of sugar in the urine;
general disruption of the production and excretion of amino acid synthesis products;
increased volumes of urine excreted with reduced density.

Fanconi syndrome develops in both children and adults. There are congenital and acquired types of pathology. Based on the severity of symptoms, as well as the type and severity of metabolic disorders, 2 forms of the disease are distinguished:

The first type manifests itself in the form of a pronounced lag in physical development with obvious deformation of the skeletal bones, a severe clinical picture, frequent fractures against the background of a sharp lack of calcium due to poor absorption of the substance in the intestine.
The second option manifests itself in the form of a moderate degree of delayed physical development, mild symptoms with mild bone destruction, and sufficient calcium levels.

Causes of the disease

Provoking factors are divided into those that cause the acquired form of de Toni-Debreu-Fanconi syndrome, and those that are responsible for the appearance of congenital pathology. The following conditions are recognized as provocateurs of a secondary disorder:

fructose intolerance;
lack of cellular enzymes;
chronic poisoning by toxins;
acute vitamin D deficiency.

The syndrome itself is caused by one bad heredity or a fresh mutation of the gene responsible for metabolic processes. De Toni-Debreu-Fanconi syndrome often develops not alone, but together with cystinosis, galactosemia, Wilson's syndrome, primary tyrosinemia, and fructose intolerance. This form is more often recorded in children than in adults.

Provoking factors

Fanconi syndrome is more likely to occur in people with the following inherited disorders:

failure in the metabolic processes of cystine (amino acids in proteins);
intolerance to dairy products (even breast milk);
defects in various enzymes responsible for the synthesis and breakdown of glycogen;
failure in the metabolism of aromatic amino acids;
fructose intolerance;
problems with copper metabolism (Konovalov-Wilson disease);
disruption of myelin metabolism and dysfunction of the enzyme sulfatase;
constant exposure to toxins on the body (medicines, poisons, heavy metals);
failure in metabolic processes involving protein, which leads to the deposition of a specific complex - amyloid;
acute vitamin D deficiency.

Congenital and acquired

Fanconi syndrome is a severe rickets-like disease that can be primary (congenital) or secondary (acquired).

Congenital pathology de Toni-Debra-Fanconi is hereditary, that is, transmitted from parents to offspring. Often develops together with others genetic disorders. The condition is characterized by an acute disturbance of metabolic processes, as a result of which, along with dysfunction of the renal tubules, blindness, enlarged liver syndrome, and a syndrome with a persistent decrease in the concentration and tissue activity of thyroid hormones develop. The mechanism of inheritance of the syndrome is determined by the type of pathology with which it develops.

Acquired de Toni-Debreu-Fanconi syndrome is often provoked by various medications:

chemotherapy drugs used in the treatment of cancer;
antiretroviral medications;
obsolete tetracycline.

Provocateurs for the development of secondary forms of pathology are complicated kidney transplantation, oncological diseases blood, severe deficiency conditions (mainly with a lack of vitamin D). If a congenital disease develops in utero and is recorded mainly in children, then a secondary form can also develop in adults.

Mechanism of development and flow

De Toni-Debreu-Fanconi syndrome is caused by a congenital mutation of the gene responsible for metabolic processes, but there have been cases of recent transformation caused by other pathologies. Due to impaired absorption of many useful substances and ions, severe deficiency conditions develop:

with a lack of amino acids, severe dystrophy appears, growth and physical development slow down;
when removing phosphorus and bicarbonates - failure of the mineralization process with the beginning of destruction bone tissue;
with the accumulation of sugar in the urine - a violation of the regulation of carbohydrate metabolism;
when excreting potassium in urine - muscle atrophy, blood pressure drops to 80 mm RT. Art. and below;
in case of large-scale metabolic disorders - destruction of renal tissue (narrowing of the lumen with flattening of the epithelium and shortening of the tubules in which reabsorption occurs).

Symptoms in children and adults

The first manifestations of congenital de Toni-Debreu-Fanconi syndrome appear in the first year of life, less often - from 1.5 years. The baby urinates frequently, low-grade fever (up to 37-38°C), constipation, and vomiting are observed. By the age of 6, if left untreated, children cannot walk, and by the age of 12, their kidneys fail, which can lead to death. Patients are uncommunicative, complex, and fearful. Mental and thinking function is normal. Consequences of the syndrome - problems with the nervous system and vision, development of chronic immunodeficiency, dysfunction genitourinary organs and gastrointestinal tract.

Symptoms in children develop mostly due to phosphate deficiency (type phosphate diabetes) and manifest themselves:

unsteadiness of gait;
short stature;
low mobility;
roundness of the legs;
curvature of the skeletal bones (in particular the spine);
bone pain, which is why the baby does not want to walk;

a sharp increase in the volume of urine excreted;
a drop in specific gravity against the background of a qualitative change in the composition of urine;
muscle atony;
bone pain;
hypertonic disease;
chronic renal failure(in the absence of treatment);
osteoporosis, osteopenia due to a decrease in bone density.

Fanconi syndrome is a congenital metabolic pathology that involves the cessation of absorption (reabsorption) of glucose, phosphoric and carbonic acid salts, and amino acids by the renal tubules. As a result, a pathology is formed that can be classified as a special type of diabetes or rickets.

Another more detailed name for the disease - de Toni-Debreu-Fanconi syndrome or glucose-phosphate-amine diabetes - is associated with a clarification of the description of the disease by three authors. Since the first was the Swiss pediatrician Fanconi, who discovered characteristic features protein and glucose in the urine of a child with dwarfism and rickets, it is more popular in medicine to mention one name.

The disease often accompanies other hereditary metabolic pathologies (fructose intolerance, galactosemia, tyrosinemia). The prevalence is 1 case per 350 thousand live births.

Causes

Modern genetic studies have established the role of changes in chromosome 15 (encoded as 15q15.3). Inheritance of a mutant gene can occur in three types:

autosomal recessive (optional);
autosomal dominant (obligatory);
linked to the X chromosome.

Mutations that occur for the first time are also found in children who do not have similar changes in their relatives.

Clinicians distinguish depending on the cause:

primary Fanconi syndrome is an X-linked disease that is difficult to predict due to both recessive and dominant modes of inheritance;
secondary – often accompanies other metabolic disorders.

Secondary disease occurs:

with hereditary changes in the kidneys;
possible development as a result of transplantation with insufficient tissue compatibility of the kidney of the donor and the patient;
poisoning with mercury, lead salts, cadmium, uranium compounds;
the influence of toluene, lysol and maleic acid in chemical production;
therapy with platinum-based drugs, antibiotics Gentamicin and Tetracyclines ( special meaning uses expired medications).

How the disease develops

The main pathology develops in the mitochondria of cells. These intracellular structures are the “energy production factory” for all activities. To obtain the necessary kilocalories, a phosphorylation process involving oxygen occurs in the mitochondria.

A biochemical reaction requires a set of enzymes for step-by-step transformations. But in Fanconi syndrome they are absent in the cells of the renal tubular epithelium. Consequently, mitochondria cannot supply the required amount of energy. Reabsorption of necessary substances into the blood suffers.

Electron microscopy view of mitochondria, insufficient energy production deprives the organ and tissue of the ability to function

Excreted in urine:

glucose;
albumins;
phosphates;
amino acids;
bicarbonates.

A deficiency of these substances is registered in the blood and the overall metabolism changes:

a lack of amino acids and bicarbonates leads to a shift in the acid-base balance towards acidification (acidosis), while the breakdown of bone tissue increases;
The absorption of potassium and calcium in the renal tubules is further reduced, and the elements are removed in the urine.

The child's skeleton shows signs of rickets. Closer to adulthood, a process of softening of bone tissue occurs - osteomalacia.

Symptoms in children

Symptoms of the disease are noticed in a child after 6 months of age:

children move little;
appetite is significantly reduced;
muscles develop poorly;
constantly asked to drink;
vomiting often occurs;
temperature rises without connection with signs of infection;
are lagging behind in weight gain and physical development;
excrete a lot of urine (polyuria);
dry, dehydrated skin.

A clearer picture is formed in the second year of life, and sometimes at 5-6 years. Here the first place is taken by:

manifestations of deformation of bone tissue and skeleton;
paralysis caused by hypokalemia.

The lag in physical and mental development is beyond doubt. The child grows up fearful and unsociable.

Up to a year, the child should be examined monthly by a pediatrician

Bone changes appear:

in leg deformities;
"duck" gait;
violation of form chest and spine;
changed structure humerus and forearms;
significantly reduced muscle tone.

Bones become brittle. For this reason, the child often experiences fractures. The patient's height is shorter than his peers.

Based on the degree of metabolic disturbance and the severity of the patient’s condition, there are 2 clinical variants of Fanconi syndrome:

The first is that the delay in physical and intellectual development is significant, the course of the disease is dominated by severe disorders with severe hypocalcemia (up to 1.6-1.8 mmol/l), bone fractures and deformities, calcium absorption decreases not only in the renal tubules, but also in the intestine .
The second is that the delay in physical development is less pronounced, the child is mentally almost normal, bone deformations are minor, the course is assessed as mild, there is a sufficient concentration of calcium in the blood, and the intestines absorb calcium well.

The result of the disease is:

pathological changes in the nervous system;
blurred vision;
defects in the development of the genitourinary organs;
chronic intestinal diseases;
state of immunodeficiency;
renal failure.

Manifestation of the syndrome in adults

In adulthood, a person develops secondary Fanconi syndrome. It manifests itself:

frequent excessive urination (polyuria);
complaints of weakness;
bone pain;
decreased muscle tone;
tendency to recurrent fractures;
changes in the kidneys lead to persistent hypertension.

The disease is most severe in postmenopausal women, when hormonal influences on the electrolyte balance are added. Brittle bones lead to severe fractures:

spine;
head of the femur.

This means complete disability, the impossibility of fusion of bone tissue. Kidney failure develops gradually. The glomerular epithelium atrophies and is replaced by scar tissue.

Compression fracture of the vertebrae is dangerous due to compression of the spinal cord

Diagnostics

Detection of the disease is based on radiological and biochemical laboratory methods. X-rays reveal:

various deformations of the bones of the limbs;
thinning and atrophy of the cortical layer in the tubular bones;
looseness in growth zones;
violation of the structure and shape of the spine;
poorly healing fractures;
osteoporosis of all bone tissue of varying severity;
lag in growth rate according to the child’s age.

Among the biochemical disorders detected in the blood:

decrease in calcium and phosphorus concentrations;
growth of the enzyme alkaline phosphatase;
hypokalemia;
excess parathyroid hormone;
disturbance of the acid-base balance towards acidosis.

Urine contains:

normal or increased calcium secretion;
increased content of phosphate salts;
glucose content far exceeds the renal threshold (20–30 g/l and above);
natriuria;
significant levels of amino acids.

Differential diagnosis

For an accurate diagnosis, it is necessary to distinguish the identified signs from rickets-like diseases and complications of hereditary and other diseases. They are distinguished by an additional more complete examination of blood, urine, kidney function, and bone marrow.

Such conditions include:

juvenile nephronophthisis;
galactosemia;
cystinosis;
tyrosinemia;
glycogenosis;
fructose intolerance;
multiple myeloma;
hepatobiliary dystrophy;
amyloidosis;
hyperfunction of the parathyroid glands;
consequences of kidney transplantation;
Sjögren's syndrome;
nephrotic syndrome,
toxic kidney damage due to poisoning with heavy metal salts;
overdose medicinal substances, including vitamin D.

Differential diagnosis is carried out by a qualified specialist

How is the treatment carried out?

Treatment consists of:

in compensation for losses of electrolytes (potassium, phosphates, calcium);
adding alkali to maintain acid-base balance (in the form of sodium bicarbonate solution, citrate mixtures).

Doctors use:

Asparkam or Panangin eliminate the loss of potassium.
Calcium supplements are prescribed in courses.
A restorative massage is indicated.
Prescribed drugs to stimulate the immune system.
Courses of balneological therapy with baths from natural sources help strengthen bone tissue and muscles.
In the presence of renal failure, hemodialysis with selection of dialysate composition is indicated.

To prevent irreversible pathology, the disease must be treated at the first manifestations. Therefore, you should carefully monitor the child’s development and unusual symptoms in an adult.

Fanconi syndrome (or Toni-Debreu-Fanconi, glucose-phosphatamine diabetes) is congenital pathology metabolism, inherited predominantly in an autosomal recessive manner and manifested by impaired absorption of amino acids, phosphate, bicarbonate and glucose. Such changes are provoked by a complex of clinical and biochemical lesions of the renal tubules. As a result, the child develops a pathology similar to a special type of rickets or. In some cases, such metabolic disorders are also observed in adults - they are provoked by various acquired diseases.

In this article we will introduce you to the causes, manifestations, methods of identifying and treating Fanconi syndrome. This information will help you get an idea of this pathology, and you will be able to suspect the onset of its development in time and seek medical help.

This syndrome was first described by pediatrician Fanconi in 1931. He covered the clinical case of one child with signs of rickets, dwarfism, albuminuria and glycosuria. After 2 years, Dr. de Toni added hypophosphatemia to the description of the pathology, and a little later, Dr. Debre included in clinical picture disease aminoaciduria.

Fanconi syndrome often occurs against the background of other hereditary pathologies metabolism:

fructose intolerance;
cystinosis;
galactosemia.

According to statistics, this disease is observed in 1 newborn out of 350 thousand births. In children, this syndrome causes development, weakening of muscle tissue and developmental delays.

Causes

medicines

Depending on the causes of development, Fanconi syndrome may be:

congenital (or familial) – develops as a result of a genetic mutation;
acquired (or secondary) - provoked by other diseases leading to the same metabolic disorders.

Familial variants of Fanconi syndrome are caused by a mutation on chromosome 15 – 15q15.3. Such genes are inherited in the following types:

autosomal recessive;
autosomal dominant;
linked to the X chromosome.

According to the observations of specialists, sometimes there are cases of Fanconi syndrome when the gene mutation was not inherited from the parents (that is, it occurred for the first time and is “fresh”).

Fanconi syndrome most often appears with the following hereditary disorders:

cysteine metabolism disorder;
intolerance to dairy products;
disturbance of aromatic amino acid metabolism;
defects in the enzymes responsible for the breakdown of glycogen;
fructose intolerance;
Wilson's disease (copper metabolism disorders);
dysfunction of the enzyme sulfatase and impaired myelin metabolism;
acute vitamin D deficiency;
constant toxic effects of drugs, heavy metals and poisons.

Acquired Fanconi syndrome develops mainly in adults against the background of the following pathologies:

congenital kidney anomalies;
poisoning with cadmium salts, lead, mercury and uranium compounds;
oncological diseases of the blood;
toxic effects of platinum-based drugs, chemotherapy drugs, antiretrovirals (cidofovir, didanosine) or antibiotics (especially expired tetracyclines or gentamicin);
work at chemical plants with fumes of maleic acid, lysol and toluene;
insufficient tissue compatibility of the donor organ and the patient’s tissues after kidney transplantation;
amyloidosis;
severe hypovitaminosis D;
heavy.

According to experts, Fanconi syndrome is more often a congenital pathology and is usually detected in children rather than adults.

How the disease develops

Due to impaired absorption of various ions and substances in Fanconi syndrome, the following changes occur:

due to a lack of amino acids, physical development slows down and dystrophy develops;
due to excessive excretion of phosphorus and bicarbonates, the process of mineralization of bone tissue is disrupted and bone destruction occurs;
due to excretion of potassium in the urine (up to 80 and below mmHg);
Due to glucosuria, carbohydrate metabolism is disrupted.

In patients with Fanconi syndrome, constant progression of metabolic disorders and large-scale changes in metabolism lead to the destruction of kidney tissue. Excreted in urine:

glucose;
phosphates;
amino acids and proteins;
bicarbonates.

As a result, a deficiency of these substances is detected in the blood. The child develops signs of rickets and acidosis, and in adulthood, the breakdown of bone tissue intensifies to osteomalacia (softening of the bones).

Symptoms

In children

The severity of symptoms in the hereditary form of the disease depends on the severity of metabolic disorders.

With congenital Fanconi syndrome, the disease first manifests itself in the first year of a child’s life (usually after the first 6 months). Parents may notice the following symptoms:

adynamic;
loss of appetite;
frequent vomiting;
thirst;
muscle wasting;
bone pain (the child does not want to stand or walk);
polyuria (excretion of urine in large quantities);
causeless increase in temperature;
dry and dehydrated skin;
chronic;
poor weight gain and retarded physical development.

In the absence of treatment, by the age of 2 years (sometimes by 5-6 years of age), the child’s bone tissue begins to deform and signs of potassium deficiency appear in the form of hypokalemic paralysis. He is lagging behind in both physical and mental development. Those around him may note his unsociability and timidity.

When examining the musculoskeletal system, the following abnormalities are revealed:

leg deformities (varus or valgus);
and chest deformation;
changes in the structure of the forearms and humerus;
significant decrease in skeletal muscle tone;
"duck" gait.

Due to insufficient absorption of calcium and impaired bone mineralization, children with Fanconi syndrome often occur. The height of such a child is significantly lower than that of his peers.

As a result, by the age of 10-12 years, the consequences of the syndrome, expressed to one degree or another, are revealed:

deviations in the functioning of the nervous system;
blurred vision;
abnormalities in the functioning of the cardiovascular system;
chronic intestinal diseases;
defects in the development of the urinary system;
pathologies of ENT organs;
endocrine disorders and immunodeficiencies.

Depending on the severity of metabolic changes and symptoms, experts distinguish two variants of the course of congenital Fanconi syndrome:

I – delay in both physical and mental development, bone deformations and frequent fractures – severe symptoms, calcium is poorly absorbed not only in the kidneys, but also in the intestines, hypocalcemia up to 1.6-1.8 mmol/l;
II – delay in physical development is less pronounced, mental development the child is practically not affected, the bone deformations are minor, the symptoms are assessed as mild, the intestines absorb calcium well, the level of calcium in the blood remains normal.

In adults

The development of secondary Fanconi syndrome usually occurs in adulthood and leads to the following symptoms:

frequent and copious urination;
severe weakness;
weakening of skeletal muscle tone;
bone pain.

Metabolic disorders lead to a tendency to fractures. Over time, persistent hypertension and renal failure develop.

The symptoms of secondary Fanconi syndrome are most severe in women who have survived the period. Accompanying this natural condition, changes in hormone and electrolyte levels that cause osteoporosis lead to even more fragile bones. Patients may experience severe fractures of the femoral head and spine, and healing of bone tissue damage takes a very long time.

Diagnostics

A doctor may suspect the development of Fanconi syndrome based on a set of characteristic complaints from the patient or abnormalities identified during the assessment of the results of X-rays or urine tests. To make an accurate diagnosis, the patient is prescribed the following studies:

and and ;
urine analysis for glucose, amino acids and phosphates;
x-ray of bones;

To assess the degree of violations, the examination is supplemented with the following methods:

radioisotope research;
bone biopsy;

When studying x-rays in patients with Fanconi syndrome, the following abnormalities are revealed:

deformations of the chest, limb bones and spinal column;
thinning or atrophy of the cortical layer on the tubular bones;
looseness in the growth zone;
slow bone growth.

Blood tests reveal the following abnormalities:

hypocalcemia;
decreased levels of phosphorus and sodium in the blood;
hypokalemia;
increased levels of the enzyme alkaline phosphatase;
excess parathyroid hormone;
metabolic acidosis.

Urine tests reveal the following abnormalities:

increased phosphate content;
normal or increased calcium secretion;
natriuria;
glucosuria (20-30 g/l and above);
increase in urine pH more than 6.0;
tubular proteinuria.

Differential diagnosis for Fanconi syndrome is carried out with rickets-like pathologies, hereditary and acquired diseases:

juvenile nephronophthisis;
tyrosinemia;
Lowe's syndrome;
cystinosis;
glycogenosis;
congenital fructose intolerance;
Rod-cone dystrophy;
hepatobiliary dystrophy;
nephrotic syndrome;
diabetes;
amyloidosis;
poisoning with drugs and toxic substances;
poisoning with salts of heavy metals;
condition after renal transplantation.

Treatment

Treatment for secondary Fanconi syndrome is aimed at treating the disease that caused its development - its symptoms significantly decrease or disappear completely with successful treatment of the underlying disease. For congenital syndrome, therapy should begin as early as possible and be comprehensive. Its main goals are aimed at replenishing the deficiency of electrolytes (calcium, potassium bicarbonates and phosphorus) and eliminating acidosis. In addition, it is assigned symptomatic therapy. In case of severe consequences of Fanconi syndrome, surgical treatment is also performed.

Diet

To eliminate the deficiency of calcium, potassium bicarbonates and phosphorus and prevent the excretion of amino acids, patients with Fanconi syndrome are recommended to follow a special diet:

introducing into the diet dishes from potatoes and cabbage, milk, dried fruits (raisins, dried apricots, prunes), fruit juices;
limiting the consumption of table salt;
drinking plenty of water.

In case of severe potassium deficiency, in addition to following a diet, it is necessary to take potassium-containing products (Asparkam, Panangin).

Drug therapy

To eliminate disturbances in phosphorus-calcium metabolism, medications with vitamin D are prescribed. Initially, the drugs are administered at a dose of 10-15 thousand IU per day, and then the dosage is gradually increased to the permissible maximum - 100 thousand IU. While taking these medications, control blood tests are performed to determine calcium and phosphorus levels. When these indicators stabilize, vitamin D intake is stopped.

In addition, patients with congenital Fanconi syndrome are prescribed a course of calcium and phytin supplements. If signs of renal failure and other consequences of the disease appear, symptomatic treatment is carried out.

For secondary Fanconi syndrome, an appointment is prescribed medicines for the treatment of the underlying disease.

Vet clinic

Fanconi syndrome is an inherited kidney pathology in Basenji dogs; it is in these patients that the majority veterinarians carry out diagnostics of this disease. Nevertheless, many cases of the occurrence of the syndrome in dogs of other breeds have been described, both as a primary pathology and as a result of various diseases or while taking certain medications. Fanconi syndrome has also been described in cats.

Anatomy and physiology of the kidneys

As is known, structural and functional unit the kidney is a nephron. It begins with a spherical structure - Bowman's capsule, consisting of outer and inner leaves. The outer layer is a continuation of the epithelium of the renal tubule. The inner layer is formed by highly specialized cells - podocytes. Podocytes have multiple stalked processes that come into contact with the stalks of neighboring cells and thus cover the capillaries of the glomerulus. Blood enters the capillaries through the afferent arteriole, which divides into many thin loops, which then combine to form the efferent arteriole. Between the capillary endothelium and podocytes there is a basement membrane, which is an important part of the filtration barrier.

The formation of urine begins with the process of ultrafiltration. The entire volume of plasma is filtered approximately 100 times per day. The main components of the renal filter are the endothelium of the glomerular capillaries, the basement membrane and podocytes of the inner layer of Bowman's capsule. Most of the glomerular filtrate is formed due to the high hydrostatic pressure of the arterial blood and selective permeability of the renal barrier. Water and substances dissolved in it pass through the filter, and large protein molecules are retained in the bloodstream. This results in a very large volume of renal filtrate. Next, the reabsorption of the necessary components occurs in the renal tubules. About 99% of sodium chloride and water are adsorbed. The structure of the renal tubules correlates with their function. For example, the epithelium of the proximal renal tubules has a well-developed brush border (to increase surface area) and a large number of mitochondria (energy reserve of cells). The main part of the transport functions occurring in these cells is energy-dependent, so they are very sensitive to ischemic effects. In addition, the renal tubular epithelium may be exposed to the toxic effects of excreted substances. Large amounts of sodium and chloride are actively reabsorbed in the proximal tubule, while water is absorbed passively, thereby absorbing 60–80% of the renal filtrate entering the proximal renal tubule. The tubules and peritubular capillaries are in close proximity for the most rapid removal of absorbed sodium and water. In addition to sodium and water, glucose, amino acids, calcium phosphates, uric acid, proteins and potassium are absorbed in the proximal tubule.

Next is the loop of Henle, which descends from the cortex into the medulla and then returns back. The thick descending part of the loop of Henle is lined with simple cuboidal epithelium, the thin descending and ascending parts are lined with simple squamous epithelium, the microvilli of these cells are less pronounced or not expressed at all, they contain fewer mitochondria. The thin part of the loop of Henle, closely intertwined with capillaries (vasa recta), plays a major role in the concentration of urine. This is followed by the thick part of the ascending loop of Henle, lined by simple cuboidal epithelium, reminiscent of the epithelium of the proximal tubules, but with less pronounced villi, which are located in the cortical region. The cells adjacent to the afferent arteriole are an integral part of the juxtaglomerular apparatus. After the loop of Henle, the distal convoluted tubule is located; it is quite short and structurally resembles the epithelium of the proximal convoluted tubule, but with less pronounced villi, but with a significant number of mitochondria (sometimes exceeding the number of mitochondria in the epithelium of the proximal tubule). Following the distal tubule is the connecting tubule, followed by the collecting duct. The collecting ducts are a continuation of the nephron, but have a different origin. The main function of this part of the urinary system is to concentrate urine due to the absorption of water under the influence of antidiuretic hormone.

Pathophysiology

Fanconi syndrome is a condition in which there is a decrease in reabsorption in the proximal convoluted tubules of the kidneys. As a result, most of the products that should be returned to the bloodstream after the filtration of primary urine are eliminated from the body. There is a loss of glucose, phosphates, amino acids, bicarbonate, calcium, potassium and other ions in the urine. Impaired absorption of bicarbonate results in a condition called renal tubular acidosis. There are two types of renal tubular acidosis: proximal and distal.

In distal tubular acidosis (type 1), urine acidification is impaired. In such patients, nephroliths often develop, bone demineralization occurs, and hypokalemia develops. A defect in the proximal renal tubule results in impaired bicarbonate reabsorption, a condition called proximal tubular acidosis (type 2).

Patients with Fanconi syndrome also suffer from loss of bicarbonates, but in addition, loss of glucose, phosphates, uric acid, and amino acids develops. Fanconi syndrome is often called loss syndrome. At the same time, an increased content of substances such as glucose, sodium, potassium, phosphorus, bicarbonate and amino acids is noted in the urine, while a decrease in these indicators may be observed in the blood.

In an animal with Fanconi syndrome, glycosuria is often detected with normoglycemia (if possible causes such as leptospirosis and pyelonephritis are excluded), which is an indication for further diagnosis.

There are two different types of Fanconi syndrome: congenital and idiopathic. Congenital Fanconi syndrome occurs in Basenji dogs.

Idiopathic Fanconi syndrome has been described in dogs of many breeds: Border Terriers, Norwegian Elkhounds, Whippets, Yorkshire Terriers, Labradors, greyhounds, cocker spaniels of some colors, mixed breeds (usually there is data on isolated cases).

There is also acquired Fanconi syndrome. It develops in dogs due to the toxic effects of drugs and various substances, eating “Chinese delicacies”, hypoparathyroidism, and liver diseases accompanied by the accumulation of copper.

Cases of acquired Fanconi syndrome have been described in cats during chemotherapy with chlorambucil.

Congenital Fanconi syndrome

Fanconi syndrome in the Basenji is a hereditary disease characterized by the development of proximal tubular failure of the kidneys. Fanconi syndrome was first described in 1936 by Swiss physician Guido Fanconi. In dogs, the first description of Fanconi syndrome in Basenjis dates back to 1976.

Basenji Fanconi syndrome is caused by a mutation in the FAN1 (Fanconi anemia-associated nuclease 1) gene, which is part of the myotubularin tyrosine phosphatase gene family. Fanconi anemia and Fanconi syndrome are caused by a mutation in the same gene, but the diseases are different. In Fanconi syndrome, a mutation in the FAN1 gene leads to hypersensitivity of the cells of the proximal tubules of the kidneys to a minimal amount of damaging substances. Since each individual dog may be exposed to a different number of different damaging factors, the onset of development clinical symptoms may occur in animals different ages. Typically, the first symptoms of the disease appear in animals aged 4–7 years. The pathology of sodium and phosphate absorption in the Basenji develops in a little more early age(3 years), absorption of glucose and amino acids decreases by 4 years. Glomerular filtration rate may also be impaired.

Basenji Fanconi syndrome is inherited in an autosomal recessive manner. From two clinically healthy parents an affected dog may be produced and both parents are heterozygous. In this case, 25% of the offspring are affected, 50% are asymptomatic carriers and 25% are healthy dogs without carrying a mutant gene. A test has now been developed to determine the presence of a mutation in the FAN1 gene. According to various sources, the incidence ranges from 10 to 30% among Basenji dogs.

Development of Fanconi syndrome in dogs with hepatopathy accompanied by copper accumulation

Copper accumulation can occur as a result of both a primary metabolic disorder and impaired copper excretion due to diseases associated with cholestasis. Identifying the exact etiology can be challenging as histopathological examination will show signs of fibrosis, inflammation and cirrhosis regardless of the underlying cause.

Copper storage disease (similar to Wilson's disease in humans) has been described in many dog breeds: West Highland White Terrier, Doberman Pinscher, Bedlington Terrier, Skye Terrier, Labrador Retriever, Dalmatian. However, the genetic basis has only been found in Bedlington Terriers, in which copper accumulation is associated with a defect in the MURR-1 gene.

Copper accumulates in the liver, contributing to the development of hepatitis and later cirrhosis of the liver, which further aggravates copper excretion. During the development of the disease, copper accumulations are observed not only in the liver parenchyma, but also in the kidney tissue and brain. When the epithelium of the proximal renal tubules is damaged, signs of Fanconi syndrome may occur. This condition is quite often described in people with the development of Wilson's disease.

To detect copper in organs and tissues, special staining of histological sections is used. Therefore, to identify this condition, histopathological examination of liver tissue and renal cortex is necessary. It is worth noting that in people with Wilson's disease it is not always possible to detect accumulation of copper in the epithelium of the liver and kidneys. This may be due to the uneven distribution of copper in the parenchyma or the diffuse presence of copper in the cytoplasm, which does not allow it to be visualized by staining. There are also methods quantification copper in tissues.

Hypoparathyroidism

A case of the development of Fanconi syndrome in a dog secondary to hypoparathyroidism is described. The exact mechanism of development of lesions of the proximal renal tubules is unclear, but there is an assumption that it is associated with a decrease in the concentration of 1,25-dihydroxycholecalciferol in the blood. In humans and rats, the development of Fanconi syndrome with vitamin D deficiency, regardless of the level of parathyroid hormone, has been described. In this animal, the decrease in the level of 1,25-dihydroxycholecalciferol was caused by hypofunction of the parathyroid gland. Symptoms of proximal tubular failure disappeared after replacement therapy underlying disease.

"Chinese delicacies"

IN last years A large number of cases of acquired Fanconi syndrome have been described after feeding dogs treats produced in China. Most often these are small breed dogs, weighing no more than 10 kg. Cases were recorded in different countries and on different continents: in Australia, North America, Japan, Europe. The time from the start of feeding these products to the development of clinical symptoms varies from 0.3 to 78 weeks. This is believed to be related to the amount of treats consumed, individual tolerance, batch differences, and the owner's onset of clinical symptoms. Accurate etiological factor has not yet been determined. It is assumed that they may be salmonella, heavy metals, pesticides, antibiotics, antiviral drugs, mycotoxins, rodenticides, previously known nephrotoxins or endotoxins.

The development of classic symptoms of Fanconi syndrome, which disappear after the abolition of “Chinese delicacies,” was noted. As a rule, after symptomatic treatment and normalization of feeding, animals are completely cured, although there have been cases of the development of chronic liver disease.

Cats

Fanconi syndrome is extremely rarely described in cats. Development of proximal tubular failure was noted in four cats treated with chlorambucil. Chlorambucil has been prescribed as chemotherapy in the treatment of alimentary lymphoma or inflammatory disease intestines. Symptoms of Fanconi syndrome in these patients developed 2–26 weeks after the start of chemotherapy. It is important that not a single cat had symptoms of polydipsia and polyuria, which are common manifestations of Fanconi syndrome in dogs. Partial or complete resolution of nephropathy was noted within three months in 3 out of 4 cats.

Symptoms of Fanconi syndrome

Clinical manifestations of Fanconi syndrome can vary greatly in severity and typically include depression, vomiting, anorexia, dehydration, diarrhea, polydipsia, polyuria, weight loss, and poor coat quality. The most common symptom reported by owners is polydipsia and polyuria (not described in cats).

To confirm the diagnosis, a biochemical analysis of blood and urine is necessary. When conducting laboratory research the most common finding is glycosuria in normoglycemia, which requires further evaluation. The next step to make a diagnosis is to detect aminoaciduria. Proteinuria is usually moderate. Decreased bicarbonate reabsorption leads to the development metabolic acidosis. With prolonged course of the disease, hypokalemia and muscle weakness may occur.

Treatment and prognosis

An important aspect of the treatment of Fanconi syndrome is the exclusion of any possible reasons. In patients with leptospirosis and pyelonephritis, signs of proximal renal tubular failure may disappear within 2–3 months after the start of specific therapy. Treatment of Fanconi syndrome is limited to controlling metabolic acidosis and replacing electrolytes lost in the urine.

If severe changes develop, hospitalization and aggressive infusion therapy are carried out in order to normalize the patient's condition.

In stable patients, treatment can be carried out on an outpatient basis. Since polydipsia and polyuria are common symptoms, it is worth paying attention Special attention normal hydration of the patient. Animals should always have access to fresh water. If necessary, subcutaneous fluid administration is possible in stable patients; the duration of therapy can range from several weeks to months. The choice of solution depends on the severity of electrolyte disturbances; as a rule, alkalizing solutions are required, such as lactated Ringer's solution, Normosol-R, Plasmalit 156. If it is necessary to compensate for potassium losses, appropriate infusion therapy is carried out in an intensive care unit with constant monitoring electrolytes.

In case of development of nausea and vomiting, refusal to eat, it is necessary to use antiemetics and antacids. Patients with uremia or ketonuria often develop nausea and refusal to feed. It is also necessary to pay attention to nutrition. There is no need to reduce the amount of protein consumed in stable, non-uremic animals. Some authors recommend additional nutritional supplements, containing vitamins and minerals for long-term nutritional support.

The development of the disease in Basenjis may vary; according to some data, Fanconi syndrome may not affect the life expectancy of affected dogs. The progression of pathology in dogs of other breeds, as a rule, proceeds quite quickly, but cases of spontaneous recovery have also been described. Some dogs may develop chronic renal failure within a few months, while others remain clinically stable for several years. However, most often the prognosis for animals with acquired Fanconi syndrome remains good with appropriate therapy.

Bibliography:

Masaya Igase, Kenji Baba, Takako Shimokawa Miyama, Shunsuke Noguchi, Takuya Mizuno and Masaru Okuda. Acquired Fanconi syndrome in a dog exposed to jerky treats in Japan. J. Vet. Med. Sci. 77 (11): 1507–1510, 2015.

Natalie C Reinert and David G Feldman. Acquired Fanconi syndrome in four cats treated with chlorambucil. Journal of Feline Medicine and Surgery. 2016, Vol. 18(12) 1034–1040

Hill T. L., Breitschwerdt E. B., Cecere T. and Vaden S. Concurrent Hepatic Copper Toxicosis and Fanconi’s Syndrome in a Dog. J Vet Intern Med. 2008; 22: 219–222.

Ruth A. Darrigrand-Haag, Sharon A. Center, John F. Randolph, Robert M. Lewis and Philip A. Wood. Congenital Fanconi Syndrome Associated With Renal Dysplasia in 2 Border Terriers. Journal of Veterinary Infernal Medicine, Vol 70, No 6 (November-December), 1996: pp 412–419.

DiBartola S. Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice, 4th ed. St. Louis, MI: Saunders Elsevier, 2013.

Fanconi Renal Disease Management Protocol for Veterinarians By Steve Gonto, M. M. Sc., Ph. D. Revised February 29, 2016.

Ashley N. Hooper, DVM, Brian K. Roberts, DVM, DACVECC. Fanconi Syndrome in Four Non-Basenji Dogs Exposed to Chicken Jerky Treats. JAAHA | 47:6 Nov/Dec 2011.

Lisa M. Freeman, Edward B. Breitschwerdt, Bruce W. Keene, Bernie Hansen. Fanconi's Syndrome in a Dog With Primary Hypoparathyroidism. Journal of Veterinary Internal Medicine, Vol8, No 5 (September-October), 1994: pp 349–354.

James C. M. Chan, Jon I. Scheinman, Karl S. Roth. Renal Tubular Acidosis. Pediatrics in Review Vol. 22 No. 8 August 2001, 277–287.

Appleman E. H., Cianciolo R., Mosenco A. S., Bounds M. E. and S. Al-Ghazlat. Transient Acquired Fanconi Syndrome Associated with Copper Storage Hepatopathy in 3 Dogs. J Vet Intern Med. 22: 1038–1042, 2008.

Roger A. Hostutler, DVM; Stephen P. DiBartola, DVM, DACVIM; Kathryn A. Eaton, DVM, PhD, DACVP. Transient proximal renal tubular acidosis and Fanconi syndrome in a dog. JAVMA, Vol 224, No. 10, May 15, 2004.

Hooijberg E. H., Furman E., Leidinger J., Brandstetter D., Hochleitner C., Sewell A. C., Leidinger E. and Giger U. Transient renal Fanconi syndrome in a Chihuahua exposed to Chinese chicken jerky treats. Tierarztl Prax Ausg K Kleintiere Heimtiere. 43(3): 188–192, 2015.

La Abraham, D Tyrrell Ja Charles. Transient renal tubulopathy in a racing Greyhound. Australian Veterinary Journal. Volume 84, No. 11, November 2006.

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Neurological manifestations of Fanconi disease in children. Fanconi syndrome: symptoms, diagnosis and treatment. Symptoms and signs

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