Fanconi syndrome pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vahid Eidkhani, M.D.

Overview

  • Proximal convoluted tubule (PCT) of nephrons is responsible for most of the reabsorption capacity of the kidneys. Filtered Glucose, amino acids, 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,amino acids, and proteins[1].
  • The absorption process through PCTs mostly involves sodium (Na+) gradient-dependent and megalin-/cubilin-mediated endocytic pathways transport systems[2]. The electrochemical gradient of Na+ required for the transportations is produced by the function of the 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.
  • amino acids absorption is mainly mediated by members of the solute carrier families(SLC)[3].
  • Phosphate is absorbed by the NaPi2a, NaPi2c channels[4].
  • Bicarbonate absorption consists of a more complicated process; apical Na+-H+ exchanger drives H+ ions out of the cell in exchange for Na+ entrance. 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[5]. 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[6].
  • Low molecular weight proteins and albumin are essentially absorbed by the Cubilin-Megalin protein complex function[7].
  • 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[8]. 

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[9], the underlying mechanism linking cysteine accumulation in the cells and Fanconi syndrome incidence is not fully understood, however, evidence of ATP depletion, cell atrophy and reduced expression of multi-ligand megalin and cubilin receptor and NaPi2a channel are reported[10].
  • 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 malfunction, maleylacetoacetate (MAA) and FAA and their derivative succinylacetone accumulate and lead to liver damage and renal Fanconi syndrome[11].
  • Galactosemia: A disease of the galactose metabolism caused by defective galactose-1-phosphate uridyltransferase. Patients commonly present with severe symptoms including jaundice, lethargy, liver disease cataracts, sepsis, and Fanconi syndrome in their neonatal period after the first intake of galactose[12].
  • 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[13]. Failure the normal excretion of Cu in the biliary system and also presenting defects in the Cu-ceruloplasmin conjugation leads 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[14].
  • 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 the phosphatidylinositol 4,5-bisphosphate 5-phosphatase enzyme[15]. The most affected organs are kidneys, brain, and eyes[16]. It is suggested that OCRL enzyme plays a role in intracellular trafficking, sorting, and recycling of apical membrane multi-ligand receptors megalin–cubilin[17].
  • Dent disease: A disease caused by inactivating mutations in the CLCN5 gene, which encodes for a kidney exclusive chloride channel co-expressed with vacuolar H+-ATPase[18]. Abnormal cellular endocytosis secondary to CLCN5 malfunction disturbs normal recycling of megalin and cubilin to the luminal membrane leading to reduced luminal expression of these receptors[19]. Dent 2 disease is renal exclusive phenotype that is believed to be a result of OCRL gene similar to Lowe syndrome and these 2 diseases are considered as 2 ends of one phenotypic spectrum[20].
  • Mitochondriopathies: The high energy demand for PCT duties,(mostly 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 Fanconi syndrome[21][22].

Exogenous

  • Aminoglycoside[23] antibiotics are Cationic particles that can electrostatically attach to anionic phospholipids membrane and cause swelling with phospholipid material and impair generation of ATP which results in reduced cell energy formation, destroyed normal cellular trafficking and disrupted apical membrane function[24].
  • Valproic acid[25] 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[26]; Besides, it is suggested that valproic acid might directly harm the mitochondria function in PCTs[27].
  • Chinese herbs[28] containing aristolochic acids specifically induce proximal tubular renal damage with Tubular proteinuria and decreased megalin expression.Na-K-ATPase activity is probably affected[29].
  •  Reverse transcriptase inhibitors[30] Including adefovir and cidofovir which are used as anti-human immunodeficiency virus (HIV) therapies enter into PCT cells by activated organic anion transporters(OAT) in the basolateral membrane and notably their efflux to the tubular lumen continues in a slower pace, hence their gradual accumulation in the proximal tubule cells leads to tubular toxicity and mitochondrial damage[31].
  • Ifosfamide[32] 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[33].
  • Cisplatin[34] inhibits peroxisome proliferator-activated receptor-alpha (PPAR-α) in PCT cells which leads to impaired fatty acid oxidation and also down-regulates the gene transcription of glucose and amino acids transporters[35].

Acquired

  • Sjögren syndrome leads to chronic interstitial nephritis, with diffuse or focal plasmacytoid lymphocytic infiltration that damages PCT cells[36].
  • Multiple myeloma causes gammaglobulin light chains slowly accumulate in the PCT epithelial cells, forming crystals resistant to proteolysis by several enzymes such as cathepsin, damaging the PCT cells[37].
  • Paroxysmal nocturnal hemoglobinuria (PNH) results in iron and hemosiderin deposits accumulation occur mainly in proximal tubules leading to extensive tubular damage and interstitial nephritis[38].  

Genetics

  • The following table depicts different underlying genetic disorders which can lead to Fanconi syndrome during their course. Corresponding genes and proteins are also showed.
Overview of genetic causes of Fanconi syndrome
Disease name Inheritance Gene Protein
Cystinosis AR CTNS Cystinosin
Fanconi–Bickel syndrome AR GLUT2 (SLC2A2) Facilitative glucose transporter 2 (GLUT2)
Tyrosinemia type 1 AR FAH Fumaryl-acetoacetate

hydrolase

Galactosemia AR GALT Galactose-1-phosphateuridyl- transferase
Hereditary Fructose Intolerance AR ALDOB Aldose B
Wilson disease AR ATP7B Copper-transporting ATPase (β subunit)
Lowe syndrome XLR OCRL1 Phosphatidyl-inositol 4,5-biphosphate-5-phosphatase
Dent I XLR CLCN5 Chloride channel 5
Dent II XLR OCRL1 Phosphatidyl-inositol 4,5-biphosphate-5-phosphatase
ARC syndrome AR VPS33B Vps33
I-cell disease (mucolipidosis II) AR GNPTAB N-acetylglucosamine-1-phosphotransferase
Mitochondrial diseases Diverse Diverse Diverse
Idiopathic Fanconi syndrome AR,AD Unknown Unknown
FRTS1 AD Unknown Unknown
FRTS2 AR SLC34A1 phosphate transporter NaPi-IIa
FRTS3 AD EHHADH enoyl-coenzyme A hydratase/L-3-hydroxyacyl-coenzyme A dehydrogenase
FRTS4 AD HNF4A hepatocyte nuclear factor 4 alpha

AR: Autosomal recessive/AD: Autosomal dominant /Sources: Wilmer MJ, Schoeber JP, van den Heuvel LP, Levtchenko EN (2011). "Cystinosis: practical tools for diagnosis and treatment.". Pediatr Nephrol. 26 (2): 205–15. PMC 3016220 Freely accessible. PMID 20734088. doi:10.1007/s00467-010-1627-6./ Enriko Klootwijk, Stephanie Dufek, Naomi Issler, Detlef Bockenhauer & Robert Kleta (2016)Pathophysiology, current treatments and future targets in hereditary forms of renal Fanconi syndrome,Expert Opinion on Orphan Drugs, 5:1, 45-54, DOI: 10.1080/21678707.2017.1259560

Associated Conditions

Commonly associated conditions found in almost all Fanconi syndrome patients regardless of the underlying cause include[39][40]:

Gross Pathology

  • On gross pathology, osteomalacic bones, and musculoskeletal  features of rickets are characteristic findings of Fanconi syndrome[39][40].

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[10][37].  

References

  1. ↑ Morris RC (1969). "Renal tubular acidosis. Mechanisms, classification and implications". N Engl J Med. 281 (25): 1405–13. doi:10.1056/NEJM196912182812508. PMID 4901460.
  2. ↑ Bergeron M, Dubord L, Hausser C, Schwab C (1976). "Membrane permeability as a cause of transport defects in experimental Fanconi syndrome. A new hypothesis". J Clin Invest. 57 (5): 1181–9. doi:10.1172/JCI108386. PMC 436771. PMID 1262464.
  3. ↑ Camargo SM, Bockenhauer D, Kleta R (2008). "Aminoacidurias: Clinical and molecular aspects". Kidney Int. 73 (8): 918–25. doi:10.1038/sj.ki.5002790. PMID 18200002.
  4. ↑ Biber J, Hernando N, Forster I, Murer H (2009). "Regulation of phosphate transport in proximal tubules". Pflugers Arch. 458 (1): 39–52. doi:10.1007/s00424-008-0580-8. PMID 18758808.
  5. ↑ Igarashi T, Sekine T, Inatomi J, Seki G (2002). "Unraveling the molecular pathogenesis of isolated proximal renal tubular acidosis". J Am Soc Nephrol. 13 (8): 2171–7. PMID 12138151.
  6. ↑ Boron WF (2006). "Acid-base transport by the renal proximal tubule". J Am Soc Nephrol. 17 (9): 2368–82. doi:10.1681/ASN.2006060620. PMID 16914536.
  7. ↑ Christensen EI, Birn H (2002). "Megalin and cubilin: multifunctional endocytic receptors". Nat Rev Mol Cell Biol. 3 (4): 256–66. doi:10.1038/nrm778. PMID 11994745.
  8. ↑ Chesney RW (2016). "Interactions of vitamin D and the proximal tubule". Pediatr Nephrol. 31 (1): 7–14. doi:10.1007/s00467-015-3050-5. PMID 25618772.
  9. ↑ O'Brien K, Hussain N, Warady BA, Kleiner DE, Kleta R, Bernardini I; et al. (2006). "Nodular regenerative hyperplasia and severe portal hypertension in cystinosis". Clin Gastroenterol Hepatol. 4 (3): 387–94. doi:10.1016/j.cgh.2005.12.013. PMID 16527704.
  10. ↑ 10.0 10.1 Gaide Chevronnay HP, Janssens V, Van Der Smissen P, N'Kuli F, Nevo N, Guiot Y; et al. (2014). "Time course of pathogenic and adaptation mechanisms in cystinotic mouse kidneys". J Am Soc Nephrol. 25 (6): 1256–69. doi:10.1681/ASN.2013060598. PMC 4033369. PMID 24525030.
  11. ↑ Maiorana A, Malamisura M, Emma F, Boenzi S, Di Ciommo VM, Dionisi-Vici C (2014). "Early effect of NTBC on renal tubular dysfunction in hereditary tyrosinemia type 1". Mol Genet Metab. 113 (3): 188–93. doi:10.1016/j.ymgme.2014.07.021. PMID 25172236.
  12. ↑ Bosch AM (2006). "Classical galactosaemia revisited". J Inherit Metab Dis. 29 (4): 516–25. doi:10.1007/s10545-006-0382-0. PMID 16838075.
  13. ↑ Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW (1993). "The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene". Nat Genet. 5 (4): 327–37. doi:10.1038/ng1293-327. PMID 8298639.
  14. ↑ Das SK, Ray K (2006). "Wilson's disease: an update". Nat Clin Pract Neurol. 2 (9): 482–93. doi:10.1038/ncpneuro0291. PMID 16932613.
  15. ↑ Zhang X, Jefferson AB, Auethavekiat V, Majerus PW (1995). "The protein deficient in Lowe syndrome is a phosphatidylinositol-4,5-bisphosphate 5-phosphatase". Proc Natl Acad Sci U S A. 92 (11): 4853–6. PMC 41805. PMID 7761412.
  16. ↑ LOWE CU, TERREY M, MacLACHLAN EA (1952). "Organic-aciduria, decreased renal ammonia production, hydrophthalmos, and mental retardation; a clinical entity". AMA Am J Dis Child. 83 (2): 164–84. PMID 14884753.
  17. ↑ Choudhury R, Diao A, Zhang F, Eisenberg E, Saint-Pol A, Williams C; et al. (2005). "Lowe syndrome protein OCRL1 interacts with clathrin and regulates protein trafficking between endosomes and the trans-Golgi network". Mol Biol Cell. 16 (8): 3467–79. doi:10.1091/mbc.E05-02-0120. PMC 1182289. PMID 15917292.
  18. ↑ Grand T, L'Hoste S, Mordasini D, Defontaine N, Keck M, Pennaforte T; et al. (2011). "Heterogeneity in the processing of CLCN5 mutants related to Dent disease". Hum Mutat. 32 (4): 476–83. doi:10.1002/humu.21467. PMID 21305656.
  19. ↑ Norden AG, Lapsley M, Igarashi T, Kelleher CL, Lee PJ, Matsuyama T; et al. (2002). "Urinary megalin deficiency implicates abnormal tubular endocytic function in Fanconi syndrome". J Am Soc Nephrol. 13 (1): 125–33. PMID 11752029.
  20. ↑ Recker F, Zaniew M, Böckenhauer D, Miglietti N, Bökenkamp A, Moczulska A; et al. (2015). "Characterization of 28 novel patients expands the mutational and phenotypic spectrum of Lowe syndrome". Pediatr Nephrol. 30 (6): 931–43. doi:10.1007/s00467-014-3013-2. PMID 25480730.
  21. ↑ Niaudet P, Rotig A (1997). "The kidney in mitochondrial cytopathies". Kidney Int. 51 (4): 1000–7. PMID 9083263.
  22. ↑ Enriko Klootwijk, Stephanie Dufek, Naomi Issler, Detlef Bockenhauer & Robert Kleta (2016)Pathophysiology, current treatments and future targets in hereditary forms of renal Fanconi syndrome,Expert Opinion on Orphan Drugs, 5:1, 45-54, DOI: 10.1080/21678707.2017.1259560
  23. ↑ Ghiculescu RA, Kubler PA (2006). "Aminoglycoside-associated Fanconi syndrome". Am J Kidney Dis. 48 (6): e89–93. doi:10.1053/j.ajkd.2006.08.009. PMID 17162140.
  24. ↑ Simmons CF, Bogusky RT, Humes HD (1980). "Inhibitory effects of gentamicin on renal mitochondrial oxidative phosphorylation". J Pharmacol Exp Ther. 214 (3): 709–15. PMID 7400973.
  25. ↑ Knorr M, Schaper J, Harjes M, Mayatepek E, Rosenbaum T (2004). "Fanconi syndrome caused by antiepileptic therapy with valproic Acid". Epilepsia. 45 (7): 868–71. doi:10.1111/j.0013-9580.2004.05504.x. PMID 15230715.
  26. ↑ Kürekçi AE, Alpay F, Tanindi S, Gökçay E, Ozcan O, Akin R; et al. (1995). "Plasma trace element, plasma glutathione peroxidase, and superoxide dismutase levels in epileptic children receiving antiepileptic drug therapy". Epilepsia. 36 (6): 600–4. PMID 7555974.
  27. ↑ Lenoir GR, Perignon JL, Gubler MC, Broyer M (1981). "Valproic acid: a possible cause of proximal tubular renal syndrome". J Pediatr. 98 (3): 503–4. PMID 6782217.
  28. ↑ Hong YT, Fu LS, Chung LH, Hung SC, Huang YT, Chi CS (2006). "Fanconi's syndrome, interstitial fibrosis and renal failure by aristolochic acid in Chinese herbs". Pediatr Nephrol. 21 (4): 577–9. doi:10.1007/s00467-006-0017-6. PMID 16520953.
  29. ↑ Krumme B, Endmeir R, Vanhaelen M, Walb D (2001). "Reversible Fanconi syndrome after ingestion of a Chinese herbal 'remedy' containing aristolochic acid". Nephrol Dial Transplant. 16 (2): 400–2. PMID 11158421.
  30. ↑ Earle KE, Seneviratne T, Shaker J, Shoback D (2004). "Fanconi's syndrome in HIV+ adults: report of three cases and literature review". J Bone Miner Res. 19 (5): 714–21. doi:10.1359/jbmr.2004.19.5.714. PMID 15068493.
  31. ↑ Ho ES, Lin DC, Mendel DB, Cihlar T (2000). "Cytotoxicity of antiviral nucleotides adefovir and cidofovir is induced by the expression of human renal organic anion transporter 1". J Am Soc Nephrol. 11 (3): 383–93. PMID 10703662.
  32. ↑ Buttemer S, Pai M, Lau KK (2011). "Ifosfamide induced Fanconi syndrome". BMJ Case Rep. 2011. doi:10.1136/bcr.10.2011.4950. PMC 3246161. PMID 22669992.
  33. ↑ Sayed-Ahmed MM, Hafez MM, Aldelemy ML, Aleisa AM, Al-Rejaie SS, Al-Hosaini KA; et al. (2012). "Downregulation of oxidative and nitrosative apoptotic signaling by L-carnitine in Ifosfamide-induced Fanconi syndrome rat model". Oxid Med Cell Longev. 2012: 696704. doi:10.1155/2012/696704. PMC 3504455. PMID 23213347.
  34. ↑ Cachat F, Nenadov-Beck M, Guignard JP (1998). "Occurrence of an acute Fanconi syndrome following cisplatin chemotherapy". Med Pediatr Oncol. 31 (1): 40–1. PMID 9607432.
  35. ↑ Portilla D, Li S, Nagothu KK, Megyesi J, Kaissling B, Schnackenberg L; et al. (2006). "Metabolomic study of cisplatin-induced nephrotoxicity". Kidney Int. 69 (12): 2194–204. doi:10.1038/sj.ki.5000433. PMID 16672910.
  36. ↑ Kidder D, Rutherford E, Kipgen D, Fleming S, Geddes C, Stewart GA (2015). "Kidney biopsy findings in primary Sjögren syndrome". Nephrol Dial Transplant. 30 (8): 1363–9. doi:10.1093/ndt/gfv042. PMID 25817222.
  37. ↑ 37.0 37.1 Batuman V (2007). "Proximal tubular injury in myeloma". Contrib Nephrol. 153: 87–104. doi:10.1159/000096762. PMID 17075225.
  38. ↑ Hsiao PJ, Wang SC, Wen MC, Diang LK, Lin SH (2010). "Fanconi syndrome and CKD in a patient with paroxysmal nocturnal hemoglobinuria and hemosiderosis". Am J Kidney Dis. 55 (1): e1–5. doi:10.1053/j.ajkd.2009.07.022. PMID 19833423.
  39. ↑ 39.0 39.1 DRABLOS A (1951). "The de Toni-Fanconi syndrome with cystinosis". Acta Paediatr. 40 (5): 438–49. PMID 14885008.
  40. ↑ 40.0 40.1 ENGLE RL, WALLIS LA (1957). "The adult Fanconi syndrome. II. Review of eighteen cases". Am J Med. 22 (1): 13–23. PMID 13381735.

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