Renal Glucosuria 

  • Author: Rajendra Bhimma, MB, ChB, MD, DCH (SA), FCP (Paeds)(SA), MMed (Natal); Chief Editor: Craig B Langman, MD   more...
 
Updated: Aug 19, 2011
 

Background

Renal glucosuria is the excretion of glucose in the urine in detectable amounts at normal blood glucose concentrations in the absence of any signs of generalized proximal renal tubular dysfunction. The inherited from of this disorder is called familial renal glucosuria (FRG). In general, renal glucosuria is a benign condition and does not require any specific therapy. Glucosuria may be associated with tubular disorders such as Fanconi-de Toni-Debre syndrome, cystinosis, Wilson disease, hereditary tyrosinemia, or oculocerebrorenal osteodystrophy (Lowe syndrome). Renal glucosuria has also been reported in patients with acute pyelonephritis in the presence of a normal blood glucose level. Glucose loss in the urine may vary from a few grams to more than 100g (556 mmol) per day. Whereasmild renal glucosuria is relatively frequent, "heavy glucosuria" is extremely rare.

Next

Pathophysiology

Glucose is freely filtered by the glomerulus with a fractional excretion of less than 0.1%. In normal adults the kidney reabsorbs approximately 180 g of glucose from the glomerular filtrate each day.[1, 2] Glucose transporters are predominately found in the proximal tubule that result in less than 0.5 g/d (range, 0.03-0.3 g/d) of glucose excreted in the urine.[3]

Two means of glucose transport are noted: facilitative and secondary active transport. Facilitative transport occurs in essentially all cell types and is driven by the concentration gradient across cellular membranes. This form of glucose transport is predominantly mediated by members of the GLUT transporter family. Secondary active transport occurs in the intestine and the kidney tubules (predominantly proximal tubule) and is mediated by members of the SGLT transporter family. GLUTs are encoded by the SLC2 genes, and the SGLTs are encoded by the SLC5 genes.[4]

Reabsorption of glucose predominantly occurs on the brush border membrane of the convoluted segment of the proximal tubule. Glucose enters the tubular cells by an active carrier-mediated transport process, which is sodium-dependent, and exits via the basolateral membrane by facilitated diffusion by a glucose transporter, which is sodium-independent. The sodium-dependent glucose cotransporters are a family of glucose transporters found in the intestinal mucosa of the small intestine (SGLT1) and the proximal tubule of the nephron (SGLT2, predominantly, and SGLT1). These transporters initially bind sodium, before binding glucose, and the electrochemical sodium gradient generated by the Na+/K+-ATPase is the driving force for the symporter activity.

SGLT2 is the major contributor to renal glucose reabsorption. SGLT1 and SGLT2 are members of the SLC5A gene family (also known as the sodium substrate symporter gene family [SSSF]). Twelve of these have been identified in the human genome, which has over 230 members; several of these (including SGLT1 and SGLT2) are associated with sodium glucose transport.[5, 6] SGLT2 is a low-affinity sodium/glucose cotransporter responsible for the bulk of tubular reabsorption of filtered glucose. The SGLT2 sodium/glucose cotransporter contains 672 amino acid residues and is almost exclusively expressed in the luminal brush border of the proximal tubule of the renal cortex.[7] It is the principal transporter that mediates glucose resorption in the kidneys. SGLT2 is expressed in the S1 segment of the proximal tubule and is localized to chromosome 6.

SGLT1 contains 664 amino acid residues and is a high amino acid cotransporter protein that is strongly expressed in the small intestine and, to some extent, in the kidney. It is responsible for reabsorption for the bulk of the remaining glucose. These 2 cotransporters have significant homology; 59% of the amino acids are identical after alignment. Despite the homology between the two, only one mutation is common: Arg137His. The human intestinal SGLT1 has been localized to chromosome 22.

Several other cotransporters in this family include SGLT4, SGLT5, SGLT6, and SMIT1 that are expressed in several tissues, including the kidneys. SGLT3 is a glucose-gated ion channel expressed in cholinergic neurons and the neuromuscular junction and may play a role in diet-trigged intestinal motility.[8]

The facilitative glucose transporters have isoforms GLUT 1-5. GLUT2 is mainly associated with glucose transport in the convoluted portion of the proximal tubule. In segments with high reabsorptive rates (S1 and S2 segments), the carrier is high capacity, low affinity. At birth, a high-affinity, low-capacity pathway is also present to compensate for the reduced activity of the high-capacity, low-affinity pathway.

Familial renal glycosuria (FRG) is a rare renal tubular disorder caused by mutations with the SLCA2 gene (FRG, McKusick 233100).[9] This gene is mapped to chromosome 16p11.2. The first report of such a gene mutation was in 2000.[10] The mode of inheritance that best fits FRG has been suggested to be codominance with incomplete penetrance. Many heterozygous individuals display mild glucosuria (< 10 g/1.73 m2/24 h), whereas homozygous or compound heterozygous individuals usually have severe renal glycosuria in excess of 10 g/1.73 m2/24 h.[11]

However, not all individuals with similar or identical mutations have the same degree of increased glucose excretion, suggesting a role of nongenetic factors or other genes that may play a role in glucose transport.[12] Also other SGLTs that are known to be expressed in the kidney and whose functions have not yet been clarified are candidates for modified genes in FRG. The role of other candidate genes is also supported by the finding of at least 3 patients in whom sequencing of the entire coding region of SLC5A2 showed no mutations.[13, 14]

Glucose reabsorption is age dependent. In premature infants born at less than 30 weeks' gestation, glucosuria is quite common because the filtered load of glucose delivered to the kidney is often too high for the immature nephron to handle. Glucosuria normally occurs when the plasma glucose content is above 300 mg/dL, but some glucose may be seen in the urine at plasma glucose levels as low as 150 mg/dL because the glucose-handling capacity of individual nephrons widely varies. This variability arises from variation in the length of the proximal tubule and differences in glomerular size and location.

Tubular maximum for glucose (Tm glucose, mg/min/1.73 m2) corrected for the glomerular filtration rate (GFR) varies as a function of age. Tm glucose/GFR (mg/mL) presents as follows:

  • Infants - 0.9-2.94 mg/mL
  • Children - 1.82-2.94 mg/mL
  • Adults - 2.31-2.70 mg/mL

The Tm glucose for children expressed in mg/min/1.73 m2 is as follows:

  • Premature infants - 25-190 mg/min/1.73 m2
  • Term infants - 36-288 mg/min/1.73 m2
  • Children - 254-401 mg/min/1.73 m2
Previous
Next

Epidemiology

Frequency

United States

Incidence is estimated at 0.16-6.3%. Prevalence rates vary depending on the diagnostic criteria used for reporting FRG.

Mortality/Morbidity

Renal glucosuria is a benign condition, affected individuals do not have any complaints, and only very rarely a propensity to hypovolemia and hypoglycemia has been described. However, morbidity is significant in Fanconi syndrome, Lowe syndrome, and cystinosis (see Differentials).

Race

To date, no predilection in any particular racial or ethnic group has been reported.

Sex

The disease has not been reported to occur in any increased frequency in either males or females.

Age

Although several reports describe younger patients, the condition can occur in all age groups.

Previous
Proceed to Clinical Presentation
 
 
Contributor Information and Disclosures
Author

Rajendra Bhimma, MB, ChB, MD, DCH (SA), FCP (Paeds)(SA), MMed (Natal)  Associate Professor of Pediatrics, Principal Specialist, Department of Pediatrics and Child Health, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, South Africa

Rajendra Bhimma, MB, ChB, MD, DCH (SA), FCP (Paeds)(SA), MMed (Natal) is a member of the following medical societies: American Association for the Advancement of Science, International Pediatric Transplant Association, International Society of Nephrology, South African Medical Association, South African Paediatric Association, and South African Transplant Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Laurence Finberg, MD  Clinical Professor, Department of Pediatrics, University of California, San Francisco, School of Medicine and Stanford University School of Medicine

Laurence Finberg, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Luther Travis, MD  Professor Emeritus, Departments of Pediatrics, Nephrology and Diabetes, University of Texas Medical Branch School of Medicine

Luther Travis, MD is a member of the following medical societies: Alpha Omega Alpha, American Federation for Medical Research, International Society of Nephrology, and Texas Pediatric Society

Disclosure: Nothing to disclose.

Howard Trachtman, MD  Program Director, Pediatrics Research, Schneider Children's Hospital, Department of Pediatrics, Division of Nephrology, Professor, Albert Einstein College of Medicine

Howard Trachtman, MD is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, American Society of Pediatric Nephrology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD  The Isaac A Abt, MD, Professor of Kidney Diseases, Northwestern University, The Feinberg School of Medicine; Division Head of Kidney Diseases, Children's Memorial Hospital

Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and International Society of Nephrology

Disclosure: Merck Grant/research funds None; NIH Grant/research funds None; Raptor Pharmaceuticals, Inc Grant/research funds None; Alexion Pharmaceuticals, Inc. Grant/research funds None

Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Leonard G Feld, MD, PhD, to the development and writing of this article.

References

  1. Brown GK. Glucose transporters: structure, function and consequences of deficiency. J Inherit Metab Dis. May 2000;23(3):237-46. [Medline].

  2. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. Jan 2007;261(1):32-43. [Medline].

  3. Kloeckener-Gruissem B, Vandekerckhove K, Nürnberg G, Neidhardt J, Zeitz C, Nürnberg P. Mutation of solute carrier SLC16A12 associates with a syndrome combining juvenile cataract with microcornea and renal glucosuria. Am J Hum Genet. Mar 2008;82(3):772-9. [Medline].

  4. Wright EM, Turk E. The sodium/glucose cotransport family SLC5. Pflugers Arch. Feb 2004;447(5):510-8. [Medline].

  5. Ganapathy V, Thangaraju M, Gopal E, Martin PM, Itagaki S, Miyauchi S, et al. Sodium-coupled monocarboxylate transporters in normal tissue and in cancer. AAPS J. 2008;10:193-199.

  6. Hediger MA, Coady MJ, Ikeda TS, Wright EM. Expression cloning and cDNA sequencing of the Na+/glucose co-transporter. Nature. Nov 26-Dec 2 1987;330(6146):379-81. [Medline].

  7. Kanai Y, Lee WS, You G, Brown D, Hediger MA. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest. Jan 1994;93(1):397-404. [Medline].

  8. Diez-Sampedro A, Hirayama BA, Osswald C, Gorboulev V, Baumgarten K, Volk C. A glucose sensor hiding in a family of transporters. Proc Natl Acad Sci U S A. Sep 30 2003;100(20):11753-8. [Medline].

  9. Calado J, Soto K, Clemente C, Correia P, Rueff J. Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria. Hum Genet. Feb 2004;114(3):314-6. [Medline].

  10. Calado J, Loeffler J, Sakallioglu O, Gok F, Lhotta K, Barata J. Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting. Kidney Int. Mar 2006;69(5):852-5. [Medline].

  11. Calado J, Sznajer Y, Metzger D, Rita A, Hogan MC, Kattamis A. Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion. Nephrol Dial Transplant. Dec 2008;23(12):3874-9. [Medline].

  12. Quamme GA, Freeman HJ. Evidence for a high-affinity sodium-dependent D-glucose transport system in the kidney. Am J Physiol. Jul 1987;253(1 Pt 2):F151-7. [Medline].

  13. Santer R, Kinner M, Lassen CL, et al. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. Nov 2003;14(11):2873-82. [Medline]. [Full Text].

  14. Freitas HS, D'Agord Schaan B, da Silva RS, Okamoto MM, Oliveira-Souza M, Machado UF. Insulin but not phlorizin treatment induces a transient increase in GLUT2 gene expression in the kidney of diabetic rats. Nephron Physiol. 2007;105(3):p42-51. [Medline].

  15. Oemar BS, Byrd DJ, Brodehl J. Complete absence of tubular glucose reabsorption: a new type of renal glucosuria (type 0). Clin Nephrol. Mar 1987;27(3):156-60. [Medline].

  16. De Paoli P, Battistin S, Jus A, Reitano M, Villalta D, De Marchi S. Immunological characterization of renal glycosuria patients. Clin Exp Immunol. May 1984;56(2):289-94. [Medline].

  17. Gotzsche O. Renal glucosuria and aminoaciduria. Acta Med Scand. 1977;202(1-2):65-7. [Medline].

  18. Sankarasubbaiyan S, Cooper C, Heilig CW. Identification of a novel form of renal glucosuria with overexcretion of arginine, carnosine, and taurine. Am J Kidney Dis. May 2001;37(5):1039-43. [Medline].

  19. Bingham C, Ellard S, Nicholls AJ, Pennock CA, Allen J, James AJ. The generalized aminoaciduria seen in patients with hepatocyte nuclear factor-1alpha mutations is a feature of all patients with diabetes and is associated with glucosuria. Diabetes. Sep 2001;50(9):2047-52. [Medline].

  20. Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol. Jan 2010;5(1):133-41. [Medline].

  21. Brodehl J, Franken A, Gellissen K. Maximal tubular reabsorption of glucose in infants and children. Acta Paediatr Scand. Jul 1972;61(4):413-20. [Medline].

  22. Calado J, Loeffler J, Sakallioglu O, Gok F, Lhotta K, Barata J. Familial renal glucosuria: SLC5A2 mutation analysis and evidence of salt-wasting. Kidney Int. Mar 2006;69(5):852-5. [Medline].

  23. Crombie DL. Incidence of glycosuria and diabetes. Proc R Soc Med. 1961;55:205.

  24. De Marchi S, Cecchin E, Basile A, Proto G, Donadon W, Schinella D. Is renal glycosuria a benign condition?. Proc Eur Dial Transplant Assoc. 1983;20:681-5. [Medline].

  25. Desjeuz JF, Turk E, Wright E. Congenital selective Na+ D-glucose co-transport defects leading to renal glycosuria and congenital selective intestinal malabsorption of glucose and galactose. In: The Metabolic and Molecular Basis of Inherited Diseases. 1995:3563-80.

  26. Elias LJ, Longo N. Glucose transporters. Ann Rev Med. 1992;43:377-393. [Medline].

  27. Elsas LJ, Rosenberg LE. Familial renal glycosuria: a genetic reappraisal of hexose transport by kidney and intestine. J Clin Invest. Oct 1969;48(10):1845-54. [Medline]. [Full Text].

  28. Francis J, Zhang J, Farhi A, Carey H, Geller DS. A novel SGLT2 mutation in a patient with autosomal recessive renal glucosuria. Nephrol Dial Transplant. Nov 2004;19(11):2893-5. [Medline].

  29. Francis J, Zhang J, Farhi A, et al. A novel SGLT2 mutation in a patient with autosomal recessive renal glucosuria. Nephrol Dial Transplant. Nov 2004;19(11):2893-5. [Medline].

  30. Freitas HS, Anhê GF, Melo KF, Okamoto MM, Oliveira-Souza M, Bordin S. Na(+) -glucose transporter-2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor-1alpha expression and activity. Endocrinology. Feb 2008;149(2):717-24. [Medline].

  31. Harkness J. Prevalence of glycosuria and diabetes mellitus. A comprehensive survey in an urban community. Br Med J. Jun 2 1962;5291:1503-7. [Medline].

  32. Jackson WP, Marine N, Vinik AI. The significance of glycosuria. Lancet. May 4 1968;1(7549):933-6. [Medline].

  33. Jones DP, Chesney RW. Development of tubular function. Clin Perinatol. Mar 1992;19(1):33-57. [Medline].

  34. Kamran M, Peterson RG, Dominguez JH. Overexpression of GLUT2 gene in renal proximal tubules of diabetic Zucker rats. J Am Soc Nephrol. Jun 1997;8(6):943-8. [Medline].

  35. Keller DM. Glucose excretion in man and dog. Nephron. 1968;5(1):43-66. [Medline].

  36. Kleta R, Stuart C, Gill FA, Gahl WA. Renal glucosuria due to SGLT2 mutations. Mol Genet Metab. May 2004;82(1):56-8. [Medline].

  37. Loo DD, Wright EM, Zeuthen T. Water pumps. J Physiol. Jul 1 2002;542(Pt 1):53-60. [Medline].

  38. Magen D, Sprecher E, Zelikovic I, Skorecki K. A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessiverenal glucosuria and aminoaciduria. Kidney Int. Jan 2005;67(1):34-41. [Medline].

  39. Marble A. Nondiabetic melituria. In: Marble A, White P, Bradley RF, et al eds. Joslin's Diabetes Mellitus. 11th ed. Philadelphia, Pa: BC Decker Inc; 1971.

  40. Oemar BS, Byrd DJ, Brodehl J. Complete absence of tubular glucose reabsorption: a new type of renal glucosuria (type 0). Clin Nephrol. Mar 1987;27(3):156-60. [Medline].

  41. Oemar BS, Byrd DJ, Brodehl J. Complete absence of tubular glucose reabsorption: a new type of renal glucosuria (type 0). Clin Nephrol. Mar 1987;27(3):156-60. [Medline].

  42. Pajor AM, Wright EM. Cloning and functional expression of a mammalian Na+/nucleoside cotransporter. A member of the SGLT family. J Biol Chem. Feb 25 1992;267(6):3557-60. [Medline].

  43. Renal glycosuria. In: Brodehl J, Edelmann CM Jr, eds. Pediatric Kidney Disease. 2nd ed. Little Brown & Co; 1992:1801-10.

  44. Pontoglio M, Prié D, Cheret C, Doyen A, Leroy C, Froguel P. HNF1alpha controls renal glucose reabsorption in mouse and man. EMBO Rep. Oct 2000;1(4):359-65. [Medline].

  45. Santer R, Kinner M, Lassen CL, Schneppenheim R, Eggert P, Bald M. Molecular analysis of the SGLT2 gene in patients with renal glucosuria. J Am Soc Nephrol. Nov 2003;14(11):2873-82. [Medline].

  46. Simmons RA. Cell glucose transport and glucose handling during fetal and neonatal development. In: Rolin RA, Fox WW, eds. Fetal and Neonatal Physiology. 2nd ed. Philadelphia, PA: WB Saunders Co; 1998:585-90.

  47. Spitzer A. The developing kidney and the process of growth. In: The Seldin DW, Giebisch G, eds. Kidney: Physiology and Pathophysiology. 1985.

  48. Wells RG, Pajor AM, Kanai Y, Turk E, Wright EM, Hediger MA. Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter. Am J Physiol. Sep 1992;263(3 Pt 2):F459-65. [Medline].

  49. Woolf LI, Goodwin BL, Phelps CE. T-m-limited renal tubular reabsorption and the genetics of renal glucosuria. J Theor Biol. May 1966;11(1):10-21. [Medline].

  50. Wright EM, Hirayama BA, Loo DF. Active sugar transport in health and disease. J Intern Med. Jan 2007;261(1):32-43. [Medline].

  51. Wu CJ. Transient renal glycosuria in a patient with acute pyelonephritis. Intern Med. Jun 2001;40(6):519-21. [Medline].

  52. Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature. Dec 5 1996;384(6608):455-8. [Medline].

  53. Zelikovic I. Aminoaciduria and glycosuria. In: Barratt TM, Avner ED, Harmon WE, eds. Pediatric Nephrology. 4th ed. Lippincott Williams & Wilkins; 1999:507-27.

 
Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.