Journal of Inherited Metabolic Disease

, Volume 41, Issue 6, pp 955–963 | Cite as

Polycystic kidney features of the renal pathology in glycogen storage disease type I: possible evolution to renal neoplasia

  • Monika Gjorgjieva
  • Laure Monteillet
  • Julien Calderaro
  • Gilles Mithieux
  • Fabienne Rajas
Glycogen Storage Disease


Glycogen storage disease type I (GSDI) is a rare genetic pathology characterized by glucose-6 phosphatase (G6Pase) deficiency, translating in hypoglycemia during short fasts. Besides metabolic perturbations, GSDI patients develop long-term complications, especially chronic kidney disease (CKD). In GSDI patients, CKD is characterized by an accumulation of glycogen and lipids in kidneys, leading to a gradual decline in renal function. At a molecular level, the activation of the renin-angiotensin system is responsible for the development of renal fibrosis, eventually leading to renal failure. The same CKD phenotype was observed in a mouse model with a kidney-specific G6Pase deficiency (K.G6pc−/− mice). Furthermore, GSDI patients and mice develop frequently renal cysts at late stages of the nephropathy, classifying GSDI as a potential polycystic kidney disease (PKD). PKDs are genetic disorders characterized by multiple renal cyst formation, frequently caused by the loss of expression of polycystic kidney genes, such as PKD1/2 and PKHD1. Interestingly, these genes are deregulated in K.G6pc−/− kidneys, suggesting their possible role in GSDI cystogenesis. Finally, renal cysts are known to predispose to renal malignancy development. In addition, HNF1B loss is a malignancy prediction factor. Interestingly, Hnf1b expression was decreased in K.G6pc−/− kidneys. While a single case of renal cancer has been reported in a GSDI patient, a clear cell renal carcinoma was recently observed in one K.G6pc−/− mouse (out of 36 studied mice) at a later stage of the disease. This finding highlights the need to further analyze renal cyst development in GSDI patients in order to evaluate the possible associated risk of carcinogenesis, even if the risk might be limited.



We would like to thank the members of Animaleries Lyon Est Conventionnelle et SPF (ALECS, Université Lyon 1, SFR Santé Lyon Est) for the animal care and the members of the Plateforme de Recherche Anatomopathologique– Centre Leon Bérard, Lyon.” We also thank Fabiola Terzi for reading of and editing the article.

Funding information

This work was supported by research grants from the Agence Nationale de la Recherche (ANR16-CE14-0022-02) and the Association Francophone des Glycogénoses. LM and MG are recipients of funding of the Fondation pour la Recherche Médicale (FRM grant number ECO20160736048) and the Ligue nationale contre le cancer, respectively.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10545_2018_207_MOESM1_ESM.docx (73 kb)
ESM 1 Material and Methods (DOCX 73 kb)


  1. Baker L, Dahlem S, Goldfarb S, Kern EFO, Stanley CA, Egler J, Olshan JS, Heyman S (1989) Hyperfiltration and renal disease in glycogen storage disease, type I. Kidney Int 35:1345–1350CrossRefGoogle Scholar
  2. Bienaimé F, Canaud G, El Karoui K, Gallazzini M, Terzi F (2016) Molecular pathways of chronic kidney disease progression. Nephrol Ther 12(Suppl 1):S35–S38CrossRefGoogle Scholar
  3. Bingham C, Bulman MP, Ellard S, Allen LI, Lipkin GW, Hoff WG, Woolf AS, Rizzoni G, Novelli G, Nicholls AJ et al (2001) Mutations in the hepatocyte nuclear factor-1beta gene are associated with familial hypoplastic glomerulocystic kidney disease. Am J Hum Genet 68:219–224CrossRefGoogle Scholar
  4. Bonsib SM (2009) Renal cystic diseases and renal neoplasms: a mini-review. Clin J Am Soc Nephrol 4:1998–2007CrossRefGoogle Scholar
  5. Bosniak MA (1986) The current radiological approach to renal cysts. Radiology 158:1–10CrossRefGoogle Scholar
  6. Bruni N, Rajas F, Montano S, Chevalier-Porst F, Maire I, Mithieux G (1999) Enzymatic characterization of four new mutations in the glucose-6 phosphatase (G6PC) gene which cause glycogen storage disease type 1a. Ann Hum Genet 63:141–146CrossRefGoogle Scholar
  7. Buchner A, Castro M, Hennig A, Popp T, Assmann G, Stief CG, Zimmermann W (2010) Downregulation of HNF-1B in renal cell carcinoma is associated with tumor progression and poor prognosis. Urology 76:507CrossRefGoogle Scholar
  8. Calderaro J, Labrune P, Morcrette G, Rebouissou S, Franco D, Prévot S, Quaglia A, Bedossa P, Libbrecht L, Terracciano L et al (2013) Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I. J Hepatol 58:350–357CrossRefGoogle Scholar
  9. Chen YT (1991) Type I glycogen storage disease: kidney involvement, pathogenesis and its treatment. Pediatr Nephrol 5:71–76CrossRefGoogle Scholar
  10. Chevalier-Porst F, Bozon D, Bonardot AM, Bruni N, Mithieux G, Mathieu M, Maire I (1996) Mutation analysis in 24 French patients with glycogen storage disease type 1a. J Med Genet 33:358–360CrossRefGoogle Scholar
  11. Clar J, Gri B, Calderaro J, Birling M-C, Hérault Y, Smit GPA, Mithieux G, Rajas F (2014) Targeted deletion of kidney glucose-6 phosphatase leads to nephropathy. Kidney Int 86:747–756CrossRefGoogle Scholar
  12. Clissold RL, Hamilton AJ, Hattersley AT, Ellard S, Bingham C (2015) HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum. Nat Rev Nephrol 11:102CrossRefGoogle Scholar
  13. Dambska M, Labrador EB, Kuo CL, Weinstein DA (2017) Prevention of complications in glycogen storage disease type Ia with optimization of metabolic control. Pediatr Diabetes 18:327–331CrossRefGoogle Scholar
  14. Devarajan P (2010) Review: neutrophil gelatinase-associated lipocalin: a troponin-like biomarker for human acute kidney injury. Nephrology 15:419–428CrossRefGoogle Scholar
  15. Donadieu J, Barkaoui M, Bézard F, Bertrand Y, Pondarré C, Guibaud P (2000) Renal carcinoma in a patient with glycogen storage disease Ib receiving long-term granulocyte colony-stimulating factor therapy. J Pediatr Hematol Oncol 22:188–189CrossRefGoogle Scholar
  16. Eccles MR, Stayner CA (2014) Polycystic kidney disease—where gene dosage counts. F1000Prime Rep 6:24CrossRefGoogle Scholar
  17. Edghill EL, Bingham C, Ellard S, Hattersley AT (2006) Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. J Med Genet 43:84–90CrossRefGoogle Scholar
  18. Eknoyan G (2009) A clinical view of simple and complex renal cysts. J Am Soc Nephrol 20:1874–1876CrossRefGoogle Scholar
  19. Faguer S, Decramer S, Chassaing N, Bellanné-Chantelot C, Calvas P, Beaufils S, Bessenay L, Lengelé J-P, Dahan K, Ronco P et al (2011) Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood. Kidney Int 80:768–776CrossRefGoogle Scholar
  20. Fedeles SV, Gallagher A-R, Somlo S (2014) Polycystin-1: a master regulator of intersecting cystic pathways. Trends Mol Med 20:251–260CrossRefGoogle Scholar
  21. Fischer E, Legue E, Doyen A, Nato F, Nicolas J-F, Torres V, Yaniv M, Pontoglio M (2006) Defective planar cell polarity in polycystic kidney disease. Nat Genet 38:21CrossRefGoogle Scholar
  22. Follit JA, Li L, Vucica Y, Pazour GJ (2010) The cytoplasmic tail of fibrocystin contains a ciliary targeting sequence. J Cell Biol 188:21–28CrossRefGoogle Scholar
  23. Franco LM, Krishnamurthy V, Bali D, Weinstein DA, Arn P, Clary B, Boney A, Sullivan J, Frush DP, Chen Y-T et al (2005) Hepatocellular carcinoma in glycogen storage disease type Ia: a case series. J Inherit Metab Dis 28:153–162CrossRefGoogle Scholar
  24. Froissart R, Piraud M, Boudjemline AM, Vianey-Saban C, Petit F, Hubert-Buron A, Eberschweiler PT, Gajdos V, Labrune P (2011) Glucose-6-phosphatase deficiency. Orphanet J Rare Dis 6:27CrossRefGoogle Scholar
  25. Garcia-Gonzalez MA, Menezes LF, Piontek KB, Kaimori J, Huso DL, Watnick T, Onuchic LF, Guay-Woodford LM, Germino GG (2007) Genetic interaction studies link autosomal dominant and recessive polycystic kidney disease in a common pathway. Hum Mol Genet 16:1940–1950CrossRefGoogle Scholar
  26. Gjorgjieva M, Raffin M, Duchampt A, Perry A, Stefanutti A, Brevet M, Tortereau A, Dubourg L, Hubert-Buron A, Mabille M et al (2016) Progressive development of renal cysts in glycogen storage disease type I. Hum Mol Genet 25:3784–3797CrossRefGoogle Scholar
  27. Graumann O, Osther SS, Osther PJS (2011) Characterization of complex renal cysts: a critical evaluation of the Bosniak classification. Scand J Urol Nephrol 45:84–90CrossRefGoogle Scholar
  28. Gresh L, Fischer E, Reimann A, Tanguy M, Garbay S, Shao X, Hiesberger T, Fiette L, Igarashi P, Yaniv M et al (2004) A transcriptional network in polycystic kidney disease. EMBO J 23:1657–1668CrossRefGoogle Scholar
  29. Harris PC (2002) Molecular basis of polycystic kidney disease: PKD1, PKD2 and PKHD1. Curr Opin Nephrol Hypertens 11:309–314CrossRefGoogle Scholar
  30. Harris PC, Torres VE (2009) Polycystic kidney disease. Annu Rev Med 60:321–337CrossRefGoogle Scholar
  31. Hiesberger T, Shao X, Gourley E, Reimann A, Pontoglio M, Igarashi P (2005) Role of the hepatocyte nuclear factor-1beta (HNF-1beta) C-terminal domain in Pkhd1 (ARPKD) gene transcription and renal cystogenesis. J Biol Chem 280:10578–10586CrossRefGoogle Scholar
  32. Horikawa Y, Iwasaki N, Hara M, Furuta H, Hinokio Y, Cockburn BN, Lindner T, Yamagata K, Ogata M, Tomonaga O et al (1997) Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat Genet 17:384–385CrossRefGoogle Scholar
  33. Hosseini M, Antic T, Paner GP, Chang A (2014) Pathologic spectrum of cysts in end-stage kidneys: possible precursors to renal neoplasia. Hum Pathol 45:1406–1413CrossRefGoogle Scholar
  34. Igarashi P, Shao X, McNally BT, Hiesberger T (2005) Roles of HNF-1beta in kidney development and congenital cystic diseases. Kidney Int 68:1944–1947CrossRefGoogle Scholar
  35. Iwasaki N, Ogata M, Tomonaga O, Kuroki H, Kasahara T, Yano N, Iwamoto Y (1998) Liver and kidney function in Japanese patients with maturity-onset diabetes of the young. Diabetes Care 21:2144–2148CrossRefGoogle Scholar
  36. Jiang S-T, Chiou Y-Y, Wang E, Lin H-K, Lin Y-T, Chi Y-C, Wang C-KL, Tang M-J, Li H (2006) Defining a link with autosomal-dominant polycystic kidney disease in mice with congenitally low expression of Pkd1. Am J Pathol 168:205–220CrossRefGoogle Scholar
  37. Jilg CA, Drendel V, Bacher J, Pisarski P, Neeff H, Drognitz O, Schwardt M, Gläsker S, Malinoc A, Erlic Z et al (2013) Autosomal dominant polycystic kidney disease: prevalence of renal neoplasias in surgical kidney specimens. Nephron Clin Pract 123:13–21CrossRefGoogle Scholar
  38. Karoui KE, Viau A, Dellis O, Bagattin A, Nguyen C, Baron W, Burtin M, Broueilh M, Heidet L, Mollet G et al (2016) Endoplasmic reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2. Nat Commun 7:10330CrossRefGoogle Scholar
  39. Kim S, Nie H, Nesin V, Tran U, Outeda P, Bai C-X, Keeling J, Maskey D, Watnick T, Wessely O et al (2016) The polycystin complex mediates WNT/Ca2+ signaling. Nat Cell Biol 18:752–764CrossRefGoogle Scholar
  40. Kishnani PS, Austin SL, Abdenur JE, Arn P, Bali DS, Boney A, Chung WK, Dagli AI, Dale D, Koeberl D et al (2014) Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics. Genet Med e1:16Google Scholar
  41. Kornfeld J-W, Baitzel C, Könner AC, Nicholls HT, Vogt MC, Herrmanns K, Scheja L, Haumaitre C, Wolf AM, Knippschild U et al (2013) Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature 494:111–115CrossRefGoogle Scholar
  42. Labrune P (2002) Glycogen storage disease type I: indications for liver and/or kidney transplantation. Eur J Pediatr 161:S53–S55CrossRefGoogle Scholar
  43. Lan HY (2011) Diverse roles of TGF-β/Smads in renal fibrosis and inflammation. Int J Biol Sci 7:1056–1067CrossRefGoogle Scholar
  44. Lantinga-van Leeuwen IS, Dauwerse JG, Baelde HJ, Leonhard WN, van de Wal A, Ward CJ, Verbeek S, Deruiter MC, Breuning MH, de Heer E et al (2004) Lowering of Pkd1 expression is sufficient to cause polycystic kidney disease. Hum Mol Genet 13:3069–3077CrossRefGoogle Scholar
  45. Le Corre S, Viau A, Burtin M, El-Karoui K, Cnops Y, Terryn S, Debaix H, Bérissi S, Gubler M-C, Devuyst O et al (2015) Cystic gene dosage influences kidney lesions after nephron reduction. Nephron 129:42–51CrossRefGoogle Scholar
  46. Lee SH, Somlo S (2014) Cyst growth, polycystins, and primary cilia in autosomal dominant polycystic kidney disease. Kidney Res Clin Pract 33:73–78CrossRefGoogle Scholar
  47. Leonhard WN, Happe H, Peters DJM (2016) Variable cyst development in autosomal dominant polycystic kidney disease: the biologic context. J Am Soc Nephrol 27:3530–3538CrossRefGoogle Scholar
  48. Liu Z, Zhu Y, Wang Y, Fu Q, Fu H, Wang Z, Zhang J, Li G, Xu J, Dai B (2017) Prognostic value of granulocyte colony-stimulating factor in patients with non-metastatic clear cell renal cell carcinoma. Oncotarget 8:69961Google Scholar
  49. Loftus H, Ong ACM (2013) Cystic kidney diseases: many ways to form a cyst. Pediatr Nephrol 28:33–49CrossRefGoogle Scholar
  50. Lu W, Shen X, Pavlova A, Lakkis M, Ward CJ, Pritchard L, Harris PC, Genest DR, Perez-Atayde AR, Zhou J (2001) Comparison of Pkd1-targeted mutants reveals that loss of polycystin-1 causes cystogenesis and bone defects. Hum Mol Genet 10:2385–2396CrossRefGoogle Scholar
  51. Madariaga L, Morinière V, Jeanpierre C, Bouvier R, Loget P, Martinovic J, Dechelotte P, Leporrier N, Thauvin-Robinet C, Jensen UB et al (2013) Severe prenatal renal anomalies associated with mutations in HNF1B or PAX2 genes. Clin J Am Soc Nephrol 8:1179–1187CrossRefGoogle Scholar
  52. Martens DHJ, Rake JP, Navis G, Fidler V, van Dael CML, Smit GPA (2009) Renal function in glycogen storage disease type I, natural course, and renopreservative effects of ACE inhibition. Clin J Am Soc Nephrol 4:1741–1746CrossRefGoogle Scholar
  53. Massa F, Garbay S, Bouvier R, Sugitani Y, Noda T, Gubler M-C, Heidet L, Pontoglio M, Fischer E (2013) Hepatocyte nuclear factor 1β controls nephron tubular development. Development 140:886–896CrossRefGoogle Scholar
  54. Meng X-M, Tang PM-K, Li J, Lan HY (2015) TGF-β/Smad signaling in renal fibrosis. Front Physiol 6:82CrossRefGoogle Scholar
  55. Muglia VF, Prando A (2015) Renal cell carcinoma: histological classification and correlation with imaging findings. Radiol Bras 48:166–174CrossRefGoogle Scholar
  56. Mundy HR, Lee PJ (2002) Glycogenosis type I and diabetes mellitus: a common mechanism for renal dysfunction? Med Hypotheses 59:110–114CrossRefGoogle Scholar
  57. Okechuku GO, Shoemaker LR, Dambska M, Brown LM, Mathew J, Weinstein DA (2017) Tight metabolic control plus ACE inhibitor therapy improves GSD I nephropathy. J Inherit Metab Dis 40:703–708CrossRefGoogle Scholar
  58. Ong ACM, Harris PC (2005) Molecular pathogenesis of ADPKD: the polycystin complex gets complex. Kidney Int 67:1234–1247CrossRefGoogle Scholar
  59. Pei Y (2001) A “two-hit” model of cystogenesis in autosomal dominant polycystic kidney disease? Trends Mol Med 7:151–156CrossRefGoogle Scholar
  60. Pritchard L, Sloane-Stanley JA, Sharpe JA, Aspinwall R, Lu W, Buckle V, Strmecki L, Walker D, Ward CJ, Alpers CE et al (2000) A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Hum Mol Genet 9:2617–2627CrossRefGoogle Scholar
  61. Rajas F, Labrune P, Mithieux G (2013) Glycogen storage disease type 1 and diabetes: learning by comparing and contrasting the two disorders. Diabetes Metab 39:377–387CrossRefGoogle Scholar
  62. Rake JP, Visser G, Labrune P, Leonard JV, Ullrich K, Smit GPA (2002) Glycogen storage disease type I: diagnosis, management, clinical course and outcome. Results of the European Study on Glycogen Storage Disease Type I (ESGSD I). Eur J Pediatr 161(Suppl 1):S20–S34CrossRefGoogle Scholar
  63. Rebouissou S, Vasiliu V, Thomas C, Bellanné-Chantelot C, Bui H, Chrétien Y, Timsit J, Rosty C, Laurent-Puig P, Chauveau D et al (2005) Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas. Hum Mol Genet 14:603–614CrossRefGoogle Scholar
  64. Reitsma-Bierens WCC, Smit GPA, Troelstra JA (1992) Renal function and kidney size in glycogen storage disease type I. Pediatr Nephrol 6:236–238CrossRefGoogle Scholar
  65. Rogers KA, Moreno SE, Smith LA, Husson H, Bukanov NO, Ledbetter SR, Budman Y, Lu Y, Wang B, Ibraghimov-Beskrovnaya O et al (2016) Differences in the timing and magnitude of Pkd1 gene deletion determine the severity of polycystic kidney disease in an orthologous mouse model of ADPKD. Physiol Rep 4Google Scholar
  66. Seeger-Nukpezah T, Geynisman DM, Nikonova AS, Benzing T, Golemis EA (2015) The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease. Nat Rev Nephrol 11:515–534CrossRefGoogle Scholar
  67. Soty M, Gautier-Stein A, Rajas F, Mithieux G (2017) Gut-brain glucose signaling in energy homeostasis. Cell Metab 25:1231–1242CrossRefGoogle Scholar
  68. Thivierge C, Kurbegovic A, Couillard M, Guillaume R, Coté O, Trudel M (2006) Overexpression of PKD1 causes polycystic kidney disease. Mol Cell Biol 26:1538–1548CrossRefGoogle Scholar
  69. Thomas R, Sanna-Cherchi S, Warady BA, Furth SL, Kaskel FJ, Gharavi AG (2011) HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort. Pediatr Nephrol 26:897–903CrossRefGoogle Scholar
  70. Verhave JC, Bech AP, Wetzels JFM, Nijenhuis T (2016) Hepatocyte nuclear factor 1β–associated kidney disease: more than renal cysts and diabetes. J Am Soc Nephrol 27:345–353CrossRefGoogle Scholar
  71. Viau A, Karoui KE, Laouari D, Burtin M, Nguyen C, Mori K, Pillebout E, Berger T, Mak TW, Knebelmann B et al (2010) Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J Clin Invest 120:4065–4076CrossRefGoogle Scholar
  72. Walters W, Braasch WF (1934) Surgical aspect of polycystic kidney. Surg Gynec Obstet 58:647–650Google Scholar
  73. Warren KS, McFarlane J (2005) The Bosniak classification of renal cystic masses. BJU Int 95:939–942CrossRefGoogle Scholar
  74. Wu G, D’Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, Maeda Y, Le TC, Hou H, Kucherlapati R et al (1998) Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93:177–188CrossRefGoogle Scholar
  75. Wu Y, Dai X-Q, Li Q, Chen CX, Mai W, Hussain Z, Long W, Montalbetti N, Li G, Glynne R et al (2006) Kinesin-2 mediates physical and functional interactions between polycystin-2 and fibrocystin. Hum Mol Genet 15:3280–3292CrossRefGoogle Scholar
  76. Wu X, He Y, Jing Y, Li K, Zhang J (2010) Albumin overload induces apoptosis in renal tubular epithelial cells through a CHOP-dependent pathway. OMICS 14:61–73CrossRefGoogle Scholar
  77. Yiu WH, Pan C-J, Ruef RA, Peng W-T, Starost MF, Mansfield BC, Chou JY (2008a) The angiotensin system mediates renal fibrosis in glycogen storage disease type Ia nephropathy. Kidney Int 73:716–723CrossRefGoogle Scholar
  78. Yiu WH, Pan C-J, Ruef RA, Peng W-T, Starost MF, Mansfield BC, Chou JY (2008b) Angiotensin mediates renal fibrosis in the nephropathy of glycogen storage disease type Ia. Kidney Int 73:716–723CrossRefGoogle Scholar
  79. Yu T-M, Chuang Y-W, Yu M-C, Chen C-H, Yang C-K, Huang S-T, Lin C-L, Shu K-H, Kao C-H (2016) Risk of cancer in patients with polycystic kidney disease: a propensity-score matched analysis of a nationwide, population-based cohort study. Lancet Oncol 17:1419–1425CrossRefGoogle Scholar

Copyright information

© SSIEM 2018

Authors and Affiliations

  • Monika Gjorgjieva
    • 1
    • 2
    • 3
  • Laure Monteillet
    • 1
    • 2
    • 3
  • Julien Calderaro
    • 4
    • 5
  • Gilles Mithieux
    • 1
    • 2
    • 3
  • Fabienne Rajas
    • 1
    • 2
    • 3
    • 6
  1. 1.Institut National de la Santé et de la Recherche by InsermLyonFrance
  2. 2.Université de LyonLyonFrance
  3. 3.Université Lyon1VilleurbanneFrance
  4. 4.Inserm UMR-1162, Université Paris Descartes, Labex Immuno-OncologyUniversité Paris Diderot, Université Paris 13ParisFrance
  5. 5.APHP, Assistance-Publique Hôpitaux-de-Paris, Département de PathologieHôpital Henri MondorCréteilFrance
  6. 6.Inserm U1213Université Lyon 1 LaennecLyon Cedex 08France

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