Fanconi syndrome pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
- Proximal convoluted tubule (PCT) of nephrons is responsible for most of the reabsorption capacity of the kidneys. Filtered Glucose, aminoacides, proteins, albumin, Bicarbonate, sodium, chloride, phosphate, and uric acid are the main ingredients reabsorbed back to the plasma in the PCTs. And importantly PCT is the exclusive site for the absorption of glucose,aminoacides and proteins.
- The absorption process through PCTs mostly involves sodium (Na+) gradient-dependent and megalin-/cubilin-mediated endocytic pathways transport systems. The electrochemical gradient of Na+ required for the transportations is produced by the function of basolateral 3Na+-2K+-ATPase pump. Besides, the pump net function also leads to a negative intracellular potential. This renal sodium regulation is one of the major energy consuming processes in the kidneys and probably accounts for high overall renal energy demand which is more than ~10% of total body expenditure while kidneys consist only about 1% of body weight.
- The powerful electrochemical gradient of Na+ is then utilized for multiple transportation processes as they are synced with the flow of extracellular Na+ to inside the PCT cells.
- Glucose absorption is coupled to Na+ by SGLT1 and SGLT2 proteins.
- Aminoacides absorption is mainly mediated by members of the heterodimeric amino-acid transporters family (HAT), SLC3A1 (rBAT) and SLC7A9 (b0, þ AT).
- Phosphate is similalry absorbed by the NaPi2a, NaPi2c channels.
- Bicarbonate absorption consists a more complicated process; apical Na+-H+ exchanger, drives H+ ions out of the cell in exchange for Na+ enterance. The extracellular hydrogen ions combine with filtered bicarbonate ions to form carbonic acid which is then converted into water and carbon dioxide by carbonic anhydrase IV. Co2 diffuses into the proximal tubular cells via aquaporin 1 , where is hydroxylated to form bicarbonate by the act of intracellular carbonic anhydrase II. Intracellular HCO3 is co-transported with Na+ at the basolateral -membrane via NBCe1 co-transporter.
- Low molecular weight proteins and albumin are essentialy absorbed by the Cubilin-Megalin protein complex function.
- Vitamin D which is mostly attached to a carrier protein in blood is also filtered with its carrier through nephrons and reabsorbed by megalin function in PCT.
Pathophysiology
Pathogenesis
As Fanconi syndrome affects most of the PCT's normal function, the underlying causes mainly deteriorate the Na+ and/or megalin-/cubilin-mediated pathways or interfere with the normal vitality of PCT cells leading to inappropriately high amounts of mentioned electrolytes and metabolites excretions. According to the various mechanisms involved in each of the initial causes, here we categorize the most important causes of the disease and provide a brief review of their effect mechanisms as well.
Genetic
- Cystinosis: A lysosomal storage disease due to lysosomal cystine transporter cystinosin mutation. It functions as a proton/cystine cotransporter and is driven by the high proton content within the lysosomal lumen. It is characterized by the accumulation of cystine in all organs, mainly kidney, bone marrow, cornea, thyroid, liver, lymph nodes and spleen, the undelying mechanism linking cysteine accumulation in the cell and Fanconi syndrome incidence is not fully understood, however, evidence of ATP depletion reduced expression of multi-ligand megalin and cubilin receptor and NaPi2a channel are reported.
- Tyrosinemia: A disease of tyrosine aminoacid metabolism caused by a mutation in the fumarylacetoacetate hydrolase (FAH) gene which codes for the last enzyme in the tyrosine catabolic chain; this enzyme catabolizes the conversion of fumarylacetoacetate (FAA) into fumarate and acetoacetate. FAH is mostly expressed in the liver and kidneys, where during its malfucnction maleylacetoacetate (MAA) and FAA and their derivates succinylacetone accumulate and leads to liver damage and renal Fanconi syndrome.
- Galactosemia: A disease of the galactose metabolism caused by defective galactose-1-phophate uridyltransferase. Patients commonly present with severe symptoms including jaundice, lethargy, liver disease cataract, sepsis, and Fanconi syndrome in their neonatal period after first intake of galactose.
- Wilson: An inborn error of copper (Cu) metabolism, Wilson disease is caused by a mutation in the gene ATP7B that encodes a mitochondrial P-type Cu-transporting ATPase beta polypeptide enzyme (ATP7B) inhibiting the normal excretion of Cu in the biliary system and also presenting defects in the Cu-ceruloplasmin conjugation leading to multi-organ failure. The most highlighted clinical view includes liver failure and neuro-degeneration. Excessive Cu accumulation in the kidneys leads to proximal renal tubular dysfunction and Fanconi syndrome.
- Lowe syndrome: Oculo Cerebro Renal Syndrome of Lowe (OCRL) is an X-linked recessive multisystem disorder resulting from loss-of-function mutations in OCRL which encodes for thephosphatidylinositol 4,5-bisphosphate 5-phosphatase enzyme. The most affected organs are kidneys, brain and eyes. It is suggested that OCRL enzyme plays a role in intracellular trafficking, sorting, and recycling of apical membrane multi-ligand receptors megalin–cubilin.
- Dent disease: A disease caused by inactivating mutations in the CLCN5 gene, which encodes for a kidney exclusive chloride channel, ClC-5 co-expressed with vacuolar H+-ATPase. Abnormal endocytosis secondary to CLCN5 malfunction disturbs normal recycling of megalin and cubilin to the luminal membrane leading to reduced luminal expression of these receptors. Dent 2 disease is renal exclusive phenotype that is believed to be a result of OCRL gene similar to Lowe syndrome and these 2 disease are considered as 2 ends of one phenotypic spectrum.
- Mitochondriopathies: The high energy demand of PCT duties,(moslty to maintain Na+ gradient) signifies mitochondria’s fundamental role in maintaining functional PCT cells. Mitochondriopathies are also multi-systemic diseases which can be the result of various mutation and molecular defects. Fanconi syndrome secondary to mitochondriopathies commonly present with complete dysfunctional PCTs and all of them present in early childhood except the A3243G mutation of the tRNA gene which is the only known mitochondrial mutation that leads to adult onset Faconi syndrome.
Exogenous
- Aminoglycoside antibiotics are Cationic particles that can electrostatically attach to anionic phospholipids membrane and cause swelling with phospholipid material and impair generation of ATP resulting in reduced cell energy formation, destroyed normal cellular trafficking and disrupted apical membrane function.
- Valproic acid therapy has been reported to cause an increase in kidney reactive oxygen species (ROS) concentration and induce lipid peroxidation. This drug leads to depletion of Renal glutathione (GSH) reservoirs and tissue antioxidant capacity reduction in the treated animals.
- Chinese herbs containing aristolochic acids specifically induce proximal tubular renal damage by Tubular proteinuria (mainly β2-microglobulinuria and albumin), endopeptidase enzymuria, and decreased megalin expression.
- Reverse transcriptase inhibitors: Including adefovir, cidofovir, and tenofovir which are used as anti-human immunodeficiency virus (HIV) therapies enter into PCT cells by activated organic anion transporters(OAT) in the basolateral membrane. However, as the multidrug-resistance protein 2 (MRP) is inactivated in the luminal membrane their efflux into the tubular lumen slows down and their gradual accumulation in the proximal tubule cells leads to tubular toxicity and mitochondrial damage.
- Ifosfamide: This chemotherapeutic drug leads to decreased total carnitine, intra-mitochondrial CoA-SH, ATP and ATP/ADP ratio, and most prominently reduced glutathione (GSH) in kidney tissues. It is suggested that preservation of the glutathione synthetase peroxidase or antioxidase system can partially protect against ifosfamide-induced Fanconi syndrome in rats.
- Cisplatin administration, increase renal vascular resistance and induces a decrease in renal blood flow, besides by the generation of (ROS), affects p53 tumor-suppressor protein, induces apoptosis via the tumor necrosis factor(TNF) receptor interaction and activates intrinsic caspases, causes mitochondrial dysfunction and also influences the calcium signaling in the cell via affecting the endoplasmic reticulum (ER)
- Cadmium damages mitochondria metabolism by producing free radicals and inhibition of H+-ATPase pump.
Acquired
- Sjögren syndrome: leads chronic interstitial nephritis, with diffuse or focal plasmacytoid lymphocytic infiltration that damages PCT cells.
- Multiple myeloma Gamaglubolin light chains slowly accumulate in the PCT epithelial cells, forming crystals resistant to proteolysis by several enzymes such as cathepsin, damaging the PCT cells.
- PNH iron and hemosiderin deposits accumulation occur mainly in proximal tubules leading to extensive tubular damage and interstitial nephritis.
Genetics
- [Disease name] is transmitted in [mode of genetic transmission] pattern.
- Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3].
- The development of [disease name] is the result of multiple genetic mutations.
Associated Conditions
Common associated conditions found in all forms of Fanconi syndrome regardless of underlying cause include:
- Bone deformities & Osteomalacia
- Normal preserved GFR(if not compromised by the underlying cause)
- Growth retardation
- Systemic acidosis
- Electrolyte disturbances
Gross Pathology
- On gross pathology, osteomalatic bones, and rickets muscoloscletal features are characteristic findings of Fanconi syndrome.
Microscopic Pathology
- Due to the molecular and cellular nature of the Fanconi syndrome, usually there are no evident common characteristics found in routine microscopic investigations of the patients’ kidneys. And specific characteristics are found (usually via electron microscopy) only based on the underlying cause of the disease (but not Fanconi syndrome itself), for example cysteine, light chain crystals and abnormal mitochondria in PCT cells plasma found in cystinosis, multiple myeloma and mitochondriopathies respectively.