Fanconi syndrome (Fanconi syndrome) is a variety of proximal renal tubular reabsorption dysfunction due to various causes, the clinical highlights of which are amino aciduria, nephrogenic glycosuria, and phosphaturia, all three of which are present in complete Fanconi syndrome, and incomplete Fanconi syndrome when two manifestations are present. It is often combined with excessive loss of low molecular protein, bicarbonate and uric acid, resulting in hypophosphatemia, low molecular proteinuria, hyperchloremic metabolic acidosis (proximal renal tubular acidosis), hypouricemia, and long-term disorders of calcium and phosphorus metabolism that can lead to vitamin D-resistant metabolic bone disease, including rickets in children and osteochondrosis in adults. Patients with Fanconi syndrome in children are mostly genetic in origin, while adult patients are mostly acquired diseases, the latter often secondary to drug allergy (penicillin, etc.) or toxicity (aminoglycoside antibiotics, guanfacine, cisplatin, etc.), hematological diseases (myeloma, amyloidosis plasma cell disease), desiccation syndrome, heavy metal (mercury, lead, cadmium, etc.) kidney damage.
Western medical name: Fanconi syndrome
English name: Fanconi Syndrome other names: Fanconi’s syndrome, Fanconi’s syndrome
Affiliation：Nephrology, Pediatrics
Site of disease: kidney
Main symptoms: renal glucosuria, amino acid urine, phosphatiduria
Main causes: drugs or toxins, genetic disorders
Disease classification.
1) Idiopathic: the cause is unknown and relatively rare;
2) Hereditary: due to genetic defects, rare;
3) Secondary: due to toxins, drugs, immune factors, etc., most common.
Causes of pathogenesis
Hereditary.
Cystinosis, tyrosinemia. mitochondrial disease, Lowe syndrome, galactosemia, hereditary fructose intolerance, ARC (joint curvature, tubular abnormalities, cholestasis), Wilson’s disease
Secondary.
Heavy metal poisoning: chromium, lead
Drug toxicity: cisplatin, aminoglycoside antibiotics, isophosphamide, sodium valproate, adefovir, cidofovir, tenofovir, ranitidine, aristolochic acid (guanfacine, guanfacine, cyanogenic, etc.), sodium sulforaphane, lysine, yohimbe acid
Abnormal proteinemia: multiple myeloma, light chain protein, amyloidosis
Autoimmune disease: dry syndrome, focal segmental glomerulosclerosis, membranous nephropathy, interstitial nephritis
Pathophysiology
The pathogenesis has not been fully elucidated. It is currently thought to be different from a single substance transport abnormality, i.e., not due to a specific carrier or receptor defect. There are currently four main hypotheses: 1) defective cell membrane hypothesis: defective renal tubular cell membranes that do not allow adequate solute reabsorption, and 2) abnormal energy metabolism hypothesis: insufficient energy metabolism in proximal tubular epithelial cells to support normal transport. Some toxicants or drug intoxication and genetic metabolic diseases make certain metabolites accumulate too much in the renal tubules affecting the intracellular oxidative phosphorylation process, insufficient ATP production, and insufficient energy to support tubular transport of substances. 3) paracellular reflux hypothesis, which refers to the reflux of substances reabsorbed by the renal tubules from the tubular epithelium paracellular or peritubular capillaries, resulting in the inability to reabsorb effectively. 4) specific sub organelle abnormality hypothesis. Whatever the mechanism can ultimately lead to abnormal transport of multiple substances in the proximal tubule, including amino acids, glucose, sodium, potassium, calcium, phosphorus, bicarbonate, uric acid, and protein.
Clinical manifestations
1. Renal glycosuria: In the presence of normal blood glucose, positive urine glucose and +-4+ in routine urine tests for GLU (glucose: glucose). However, abnormalities may not be detected by routine urine method in mild patients, and more sensitive 24-hour urine glucose determination is needed, such as urine glucose > 500mg/24 hours as positive.
2. Renal amino acid urine: quantitative urine amino acid measurement is greater than normal, but rarely leads to amino acid deficiency and usually does not cause corresponding symptoms.
3. Phosphaturia: It can lead to hypophosphatemia, and vitamin D can be reduced in some patients, which can lead to rickets and adult osteochondrosis in those with longer disease duration.
Low molecular proteinuria: Low molecular protein (molecular weight less than 70,000 daltons) can be freely filtered from the glomerulus and reabsorbed by the proximal tubules. in Fanconi syndrome, low molecular protein cannot be effectively reabsorbed, resulting in low molecular proteinuria. Usually urine protein is less than 2g/d and urine protein electrophoresis suggests predominantly low molecular protein. Renal tubular function tests reveal elevated RB protein, lysozyme and beta2 microglobulin. Because of normal glomerular function, albumin is not lost and therefore does not usually cause a decrease in blood albumin.
5. Hyperchloremic metabolic acidosis: Impaired base (HCO3-) reabsorption by the proximal tubule leads to metabolic acidosis, with blood biochemistry suggesting reduced carbon dioxide binding (T-CO2), often combined with hypokalemia and hyperchloremia. Unlike distal tubular acidosis, renal calculi rarely occur in these patients.
6. Hypouricemia; impaired uric acid reabsorption in the proximal tubule, resulting in lower than normal blood uric acid; or no significant increase in blood uric acid in the presence of elevated creatinine.
7. renal failure; in Fanconi syndrome caused by drugs or heavy metal poisoning, some patients may be combined with acute or chronic renal failure. Patients with other types of Fanconi syndrome may also suffer from renal failure if the disease continues to progress.
8. Other: hypokalemia, hyponatremia, hypovolemia, metabolic bone disease due to disorders of calcium and phosphorus metabolism, secondary hyperparathyroidism, developmental delay in children, etc.
Acquired Fanconi syndrome
Acquired Fanconi syndrome is not rare, in fact, it is much more common than hereditary Fanconi syndrome. Zheng Farai et al. at Peking Union Medical College Hospital observed 42 patients with Fanconi syndrome, 21 with idiopathic or unknown etiology, 8 with chronic interstitial nephritis (drug-related), and 5 with desiccation syndrome. The more important etiologies were 1) drug intoxication: aristolochic acid (guanxi, guanxi, cyanogen, etc.), aminoglycoside antibiotics, cisplatin, isophosphamide, sodium valproate, adefovir, cidofovir, ranitidine, sodium sulforaphane, lysine, yohimbe acid; 2) abnormal proteinemia due to neoplastic diseases: multiple myeloma, light chain protein, amyloidosis; 3) heavy metal toxicity: chromium, lead poisoning; 4) immune factors: dry syndrome or drug allergy, etc.
Aristolochic acid nephropathy is one of the important causes of Fanconi syndrome in China. Hu Weixin of Nanjing General Hospital of Nanjing Military Region observed 20 cases of aristolochic acid nephropathy due to the use of guanmutong, and nearly half of the patients had different degrees of Fanconi syndrome, mainly manifested as renal diabetes, amino acid urine and renal failure, and the incidence was higher in those who took large doses of the drug. In addition to Guanmutong, other Chinese herbs such as Qingmu Xiang and Guang Fangji also contain aristolochic acid, and some proprietary Chinese medicines contain the above herbs (e.g. Fenqing Wulian Wan, Guanxin Suhe Wan, Stone Drainage Punch, Gentian Diarrhea Liver Pill, etc.), which can also lead to Fanconi syndrome. Under the appeal of the majority of nephrologists, domestic pharmaceutical manufacturers have stopped using nephrotoxic herbs such as Guanmutong to make ready-made drugs in recent years, but there are still people who are sick due to the previous use of drugs.
Hereditary Fanconi syndrome
Cystine accumulation disorder: an autosomal recessive genetic disorder in which the causative gene is located on the short arm of chromosome 17, causing the disease due to deposition of cystine in the lysosomes of cells. In normal humans, intracellular proteins are degraded within the lysosomes to produce amino acids that are reused by importing them into the cytoplasm through the lysosomal membrane transport system. The disease is caused by defective intra-lysosomal cystine transporters that allow cystine to accumulate in the lysosome, thereby disrupting the integrity of the lysosome and allowing lysosomal enzymes to leak into the cytosol, resulting in impaired function. Depending on the course of the disease and the level of intracellular cystine, cystinosis can be divided into 3 types: 1) benign or adult cystinosis, in which cystine crystals are present only in the cornea and bone marrow, with mildly elevated intracellular cystine and no renal involvement; 2) infantile or nephrotic cystinosis, the most common type, with markedly elevated intracellular cystine levels and renal involvement in infancy (usually at 7-12 months of age). It manifests as Fanconi syndrome, rickets, and growth retardation. Renal calcium deposits are common, but renal calculi rarely occur. It usually progresses to uremia before puberty. Photophobia is a common symptom in children, often progressively worsening, and visual impairment and blindness may occur. The presence of crystals within the cornea seen on slit lamp strongly supports this diagnosis. Biopsy pathology reveals intracellular cystine crystals in the renal tubules and intestinal epithelium, and polarized light microscopy reveals refractive crystals. Intracellular cystine crystals can be seen on electron microscopy, resulting in the “dark cells” unique to this disease.
Lowe syndrome: Also known as oculo-cerebral-renal syndrome, this is an X-linked recessive disorder. It is characterized by congenital cataracts (bilateral) with congenital glaucoma, severe visual impairment, nystagmus and photophobia; mental retardation, low muscle tone, reduced or absent tendon reflexes; renal tubular dysfunction: amino acid urine, phosphate urine, bicarbonate urine, renal tubular acidosis, and more lysine and tyrosine excretion in the urine. Late stage may lead to renal failure.
Hepatomegaly (Wilson’s disease): a rare autosomal recessive metabolic disorder with the causative gene located at 13q14-21, characterized by a defect in plasma copper cyanine (ceruloplasmin). Copper cyanobactin has ferrous oxidase activity and plays an important role in copper detoxification and storage as well as iron metabolism. Defects in this protein lead to large copper deposits in the liver, brain, cornea, and renal tubules causing the corresponding symptoms: copper deposits in the brain and liver cause extrapyramidal neurological symptoms and cirrhosis, and copper deposits in the cornea cause Kayser-Fleischer rings. Copper deposition in the proximal and distal renal tubules may be associated with bicarbonate loss and renal calcium deposition with hypercalciuria, tubular acidosis, renal calcification, and renal calculi.
④Hereditary fructose intolerance: an autosomal recessive disorder. It is caused by the lack of fructose 1-phosphate aldolase or decreased activity of fructose 1,6-diphosphate aldolase in liver and kidney tissues, which prevents fructose 1-phosphate from being cleaved and accumulates in the cells to produce lesions. Continuous low doses of fructose can lead to abnormal development, hepatomegaly, jaundice, cirrhosis, and renal calcification. Large intakes of fructose can produce Fanconi syndrome, which may resolve completely after a few days or weeks of fructose withdrawal.
⑤ Tyrosinemia (tyrosinemia): is due to the patient’s lack of p-hydroxyphenylpyruvic acid oxidase (hydroxyphenyl puruvic acid
(hydroxyphenyl puruvic acid oxidase) and causes abnormal tyrosine metabolism. It is characterized by a significant increase in blood tyrosine, phenylalanine, methionine, and alanine, with little increase in other amino acids. Tyrosine, phenylalanine, methionine and p-hydroxyphenyl pyruvate are excreted in the urine, and the phenolic acid metabolites of p-hydroxyphenylacetic acid are increased. There are two clinical types: Type I tyrosinemia, which is transient hypertyrosinemia. Type II is characterized by persistent hypertyrosinemia with persistent progression, severe mental retardation, skin abnormalities, cataracts, and slow growth without significant hepatic or renal damage, and its p-hydroxyphenylpyruvate oxidase activity is normal.
(6) Cytochrome C oxidase deficiency: This can cause Fanconi syndrome, which is due to the lack of the enzyme in the mitochondria of renal tubular epithelial cells, resulting in impaired ATP synthesis and oxidative phosphorylation processes in the electron transport chain. Patients mostly develop 11-13 weeks after birth, mainly manifesting as mitochondrial myopathy, lactic acidosis and renal tubular dysfunction such as renal glycosuria, amino aciduria and phosphaturia.
(7) Plasmacytosis (multiple myeloma, amyloidosis, etc.): In plasmacytosis, abnormally increased light chain proteins (κ or λ chain proteins) cause damage to renal tubular epithelial cells and lead to Fanconi syndrome. There may be renal tubular insufficiency manifested by renal glycosuria, amino aciduria, phosphatiduria, nephrogenic uremia, and tubular acidosis. Characterized by the presence of monoclonal proteins in blood and urine, among which multiple myeloma may manifest with bone pain, fatigue, anemia, pathological fracture, etc.
(8) Fanconi syndrome caused by drugs or other toxic substances: aminoglycoside antibiotics can damage the renal tubules leading to this disease, which can cause acute renal failure in severe cases. Expired tetracycline can lead to Fanconi syndrome due to its degradation products being nephrotoxic. It is characterized by myopathy, vertigo, acidosis, polyuria, and hypokalemia. Although recovery may occur after discontinuation of the drug, the course of the disease can last for more than 2 years in some cases.
9 Other: dry syndrome, focal segmental glomerulosclerosis, membranous nephropathy, interstitial nephritis, etc.
Idiopathic Fanconi syndrome
Some patients do not have a clear etiology and are called idiopathic (i.e., unknown etiology). It is mostly disseminated and may run in families, but is not a specific disease as described above.
Diagnosis
The diagnosis is made by the presence of the following typical manifestations: nephrogenic glycosuria, amino aciduria, phosphatiduria, all three of which are considered to be complete Fanconi syndrome, while the presence of only two is called incomplete Fanconi syndrome. Further attention must be paid to finding secondary causes and the presence of a family history of the disease.
Differential diagnosis
1. Infantile Fanconi syndrome: It should be distinguished from other causes of proximal tubular acidosis, rickets or congenital metabolic disease;
2. In adult Fanconi syndrome, attention should be paid to the presence of drugs, heavy metal poisoning, tumors, immunity and other specific etiologies.
Treatment principles
1. Etiological treatment: secondary Fanconi syndrome should be treated for the underlying disease. Stop the use of toxic and harmful substances or drugs, Wilson’s disease or heavy metal poisoning can be given symptomatic treatment. Genetic metabolic diseases reduce metabolic toxin deposition and mitigate damage to renal tubules by controlling diet. For cystine storage disease, a low cystine diet and symptomatic treatment should be given. Bone disease can be treated with vitamin D
250,000 to 500,000 U or vitamin D3 2000 to 1000 U.
2. Symptomatic treatment
(1) Correction of acidosis: supplementation with alkali according to the loss of bicarbonate, 2-10 mmol/(kg-d), bicarbonate, citrate, lactate, etc. can be used, given 4-5 times a day in divided doses, with the return of normal bicarbonate levels in the blood as the standard. Sodium supplementation can aggravate hypokalemia and should be detected with care; for those with existing hypokalemia, it is appropriate to supplement potassium with 2-4 mmol/(kg-d) at the same time. If the amount of alkali is too large for the patient to tolerate, hydrochlorothiazide (dihydrocortisone) 2~3mg/(kg-d) can be added, which can shrink the extracellular fluid and promote the reabsorption of bicarbonate, but care should be taken to prevent the decrease of glomerular filtration rate.
(2) Correction of hypovolemia: Fanconi syndrome often results in dehydration due to polyuria. In addition to treatment for the cause, salt-containing fluids (including sodium, potassium, calcium, etc.) should be replenished, which can be given orally at regular intervals and temporarily added when necessary.
(3) Correction of hypophosphatemia: apply neutral phosphate 1 to 3 g daily, divided into 5 doses. The dosage can be reduced if there is diarrhea or abdominal discomfort. Note that phosphorus supplementation can aggravate hypocalcemia and bone disease, so it should be combined with vitamin D 5000 U daily or 1,25(OH)2D3 0.25-0.5 μg daily
The dosage should be increased gradually from a small amount to the full amount. To prevent renal calcification, the urinary calcium excretion should be monitored and should not exceed 0.6g per day.
(4) Hypouricemia, amino aciduria and proteinuria generally do not require treatment.
(5) Dialysis or renal transplantation is appropriate for renal failure.
Prognosis
In cases secondary to drugs, poisoning and other factors, the condition may improve to varying degrees after early removal of the cause. However, in cases of congenital disease, the disease often continues to progress and some patients enter uremia.
Prevention
Avoid drug abuse and exposure to toxins, and for hereditary Fanconi syndrome, prenatal diagnosis and eugenics should be performed whenever possible.
Reference.
Zheng F. L., Zhao S. M., Li X. M. et al. Clinical features and biochemical abnormalities of Fanconi syndrome. Chinese Journal of Internal Medicine, 2000,39:735-738
Hu W X, Liu Z H, Cheng Z Z et al. Clinical and pathological characteristics of renal damage in the Chinese medicine Mouton, Journal of Nephrology and Dialysis Renal Transplantation 2003,6,504-511
Chinese nephrology / edited by Lai Laishi, Liu Zhihong – Beijing; People’s Military Medical Press, 2008.8.
Izzedine H, Launay-Vacher V, Isnard-Bagnis C, et al. Drug-induced Fanconi’s
syndrome.Am J Kidney Dis. 2003,41:292-309.