, Volume 37, Issue 2, pp 195–201 | Cite as

Glomerular size-and charge selectivity in Type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy

  • M. -A. Gall
  • P. Rossing
  • A. Kofoed-Enevoldsen
  • F. S. Nielsen
  • H. -H. Parving


In an attempt to evaluate the mechanisms of proteinuria in diabetic kidney disease, we measured the renal clearances of albumin, total IgG, and IgG4 in 20 male Type 2 (non-insulin-dependent) diabetic patients with diabetic glomerulosclerosis (biopsy proven), in 10 male Type 2 diabetic patients without nephropathy (urinary albumin excretion rate < 30 mg/24 h), and in 10 healthy male subjects. The fractional clearance of albumin was increased in patients with nephropathy: 659 (42–4355) · 10−6 (median (range)), compared to 2.6 (0.2–14.2) · 10−6 in patients without nephropathy, and 2.3 (0.4–4.2) · 10−6 in healthy subjects. The fractional clearance of total IgG (neutral) and of IgG4 (anionic) was 40–50 times higher in patients with nephropathy compared to the two other groups. The IgG/IgG4 selectivity index was not significantly different in the three groups, being: 1.12 (0.06–5.65), 1.16 (0.45–3.72) and 1.35 (0.65–3.34) in patients with nephropathy, patients without nephropathy, and healthy subjects, respectively. The IgG/albumin selectivity index was decreased in patients with nephropathy: 0.27 (0.01–1.26) compared to 1.29 (0.07–2.67) (p < 0.05) and 1.23 (0.76–7.84) (p < 0.001) in patients without nephropathy and healthy subjects, respectively. No significant change in IgG/albumin selectivity index was observed between patients without nephropathy and healthy subjects. The systolic blood pressure was elevated in the patients with nephropathy: 164 ± 21 mm Hg (mean ± SD) compared to patients without nephropathy: 145 ± 20 mm Hg (p < 0.05) and to healthy subjects: 133 ± 19 mm Hg (p < 0.005). The diastolic blood pressure was higher in patients with and without nephropathy: 92 ± 7 vs 90 ± 10 mm Hg compared to 79 ± 8 mm Hg (p < 0.005) in healthy subjects. Our cross-sectional study suggests that impaired barrier size selectivity, probably due to an increase in large pore area (“shunt pathway”) in the glomerular capillary wall and systemic hypertension are the major pathogenic mechanisms of proteinuria in Type 2 diabetic patients with diabetic nephropathy.

Key words

Type 2 (non-insulin-dependent) diabetes mellitus diabetic nephropathy IgG IgG4 IgG/albumin selectivity index IgG/IgG4 selectivity index 


  1. 1.
    Hostetter TH (1991) Diabetic nephropathy. In: Brenner BM, Rector FC Jr (eds) The kidney. 4 th edn. Saunders, Philadelphia, pp 1695–1727Google Scholar
  2. 2.
    Hostetter TH, Rennke HG, Brenner B (1982) The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am J Med 72: 375–380PubMedCrossRefGoogle Scholar
  3. 3.
    Anderson S, Brenner B (1988) Pathogenesis of diabetic glomerulopathy: hemodynamic considerations. Diabetes Metab Rev 4: 163–177PubMedGoogle Scholar
  4. 4.
    Tomlanovich S, Deen WM, Jones HW III, Schwartz HC, Myers B (1987) Functional nature of the glomerular injury in progressive diabetic glomerulopathy. Diabetes 36: 556–565PubMedCrossRefGoogle Scholar
  5. 5.
    Nakamura Y, Myers BD (1988) Charge selectivity of proteinuria in diabetic glomerulopathy. Diabetes 37: 1202–1211PubMedCrossRefGoogle Scholar
  6. 6.
    Deckert T, Feldt-Rasmussen B, Djurup R, Deckert M (1988) Glomerular size and charge selectivity in insulin-dependent diabetes mellitus. Kidney Int 33: 100–106PubMedCrossRefGoogle Scholar
  7. 7.
    Deckert T, Kofoed-Enevoldsen A, Vidal P, Nørgaard K, Andreasen HB, Feldt-Rasmussen B (1993) Size-and charge selectivity of glomerular filtration in type 1 (insulin-dependent) diabetic patients with and without albuminuria. Diabetologia 36: 244–251PubMedCrossRefGoogle Scholar
  8. 8.
    Viberti GC, Mackintosh D, Keen H (1983) Determinants of the penetration of proteins through the glomerular barrier in insulin-dependent diabetes mellitus. Diabetes 32 [Suppl 2]: 92–95PubMedGoogle Scholar
  9. 9.
    Gall M-A, Rossing P, Skøtt P et al. (1991) The prevalence of micro-and macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in european type 2 (non-in-sulin-dependent) diabetic patients. Diabetologia 34: 655–661PubMedCrossRefGoogle Scholar
  10. 10.
    Parving H-H, Gall M-A, Skøtt P et al. (1992) Prevalence and causes of albuminuria in non-insulin-dependent diabetic patients. Kidney Int 41: 758–762PubMedCrossRefGoogle Scholar
  11. 11.
    Hother-Nielsen O, Faber O, Sørensen NS, Beck-Nielsen H (1988) Classification of newly diagnosed diabetic patients as insulin-requiring or non-insulin-requiring based on clinical and biochemical variables. Diabetes Care 11: 531–537PubMedCrossRefGoogle Scholar
  12. 12.
    Faber OK, Binder C (1977) C-peptide response to glucagon: a test for the residual β-cell function in diabetes mellitus. Diabetes 26: 605–610PubMedCrossRefGoogle Scholar
  13. 13.
    Mortensen HB (1980) Quantitative determination of hemoglobin A1c by thinlayer isoelectric focusing. J Chromatogr 182: 325–333PubMedCrossRefGoogle Scholar
  14. 14.
    Ullmann R, Bonitz K (1976) Vollmechanisierte kinetische Messung von Kreatinin. Medizinische Laboratorium 29: 137–145PubMedGoogle Scholar
  15. 15.
    Brøchner-Mortensen J, Giese J, Rossing N (1969) Renal inulin clearance versus total plasma clearance of 51 Cr-EDTA. Scand J Clin Invest 26: 5–11Google Scholar
  16. 16.
    Christensen C, Ørskov C (1984) Rapid screening PEG radioimmunoassay for quantitation of pathological micro-albuminuria. Diabetic Nephropathy 3: 92–94Google Scholar
  17. 17.
    Fomsgaard A, Feldt-Rasmussen B, Deckert M, Dinesen B (1987) Micro-ELISA for the quantitation of human urinary IgG. Scand J Clin Lab Invest 47: 195–198PubMedCrossRefGoogle Scholar
  18. 18.
    Scandling JD, Myers B (1992) Glomerular size-selectivity and microalbuminuria in early diabetic glomerular disease. Kidney Int 41: 840–846PubMedCrossRefGoogle Scholar
  19. 19.
    Pietravalle P, Morano S, Christina G et al. (1991) Charge selectivity of proteinuria in type 1 diabetes explored by Ig sub-class clearance. Diabetes 40: 1685–1690PubMedCrossRefGoogle Scholar
  20. 20.
    Bangstad HJ, Kofoed-Enevoldsen A, Dahl-Jørgensen K, Hansen KF (1992) Glomerular charge selectivity and the influence of improved blood glucose control in type 1 (insulin-dependent) diabetic patients with microalbuminuria. Dia-betologia 35: 1165–1169Google Scholar
  21. 21.
    Vernier RL, Steffes MW, Sisson-Ross S, Mauer SM (1992) Heparan sulfate proteoglycan in the glomerular basement membrane in type 1 diabetes mellitus. Kidney Int 41: 1070–1080PubMedCrossRefGoogle Scholar
  22. 22.
    Mogensen CE, Sølling K (1977) Studies on renal tubular protein reabsorption: partial and near complete inhibition by certain amino acids. Scand J Clin Lab Invest 37: 477–486PubMedCrossRefGoogle Scholar
  23. 23.
    Friedman S, Jones HW III, Golbetz HV, Lee JA, Little HL, Myers BD (1983) Mechanisms of proteinuria in diabetic nephropathy II. A study of the size-selective glomerular filtration barrier. Diabetes 32 [Suppl 2]: 40–46PubMedGoogle Scholar
  24. 24.
    Myers BD, Nelson RG, Williams GW et al. (1991) Glomerular function in Pima Indians with noninsulin-dependent diabetes mellitus of recent onset. J Clin Invest 88: 524–530PubMedCrossRefGoogle Scholar
  25. 25.
    Deen WM, Bridges CR, Brenner BM, Myers BD (1985) Heteroporous model of size-selectivity: application to normal and nephrotic humans. Am J Physiol 249: F374-F389PubMedGoogle Scholar
  26. 26.
    Christensen EI, Carone FA, Rennke HG (1981) Effect of molecular charge on endocytic uptake of ferritin in renal proximal tubule cells. Lab Invest 44: 351–358PubMedGoogle Scholar
  27. 27.
    Christensen EI, Rennke HG, Carone FA (1983) Renal tubular uptake of protein: effect of molecular charge. Am J Physiol 244: F436-F441PubMedGoogle Scholar
  28. 28.
    Deen WM, Satvat B (1981) Determinants of the glomerular filtration of proteins. Am J Physiol 214: F162-F170Google Scholar
  29. 29.
    Parving H-H, Smidt UM, Friisberg B, Bonnevie-Nielsen V, Andersen AR (1981) A prospective study of glomerular filtration rate and arterial blood pressure in insulin-dependent diabetics with diabetic nephropathy. Diabetologia 20: 457–461PubMedCrossRefGoogle Scholar
  30. 30.
    Mogensen CE (1982) Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy. BMJ 285: 685–688PubMedCrossRefGoogle Scholar
  31. 31.
    Gall M-A, Nielsen FS, Smidt UM, Parving H-H (1993) The course of kidney function in type 2 (non-insulin-dependent) diabetic patients with nephropathy. Diabetologia 36: 1071–1078PubMedCrossRefGoogle Scholar
  32. 32.
    Parving H-H, Kastrup J, Smidt UM, Andersen AR, Feldt-Rasmussen B, Christiansen JS (1984) Impaired autoregulation of glomerular filtration rate in type 1 (insulin-dependent) diabetic patients with nephropathy. Diabetologia 27: 547–552PubMedCrossRefGoogle Scholar
  33. 33.
    Oliver JD, Anderson S, Troy JL, Brenner B, Deen WM (1991) Normal glomerular filtration barrier is more size-restrictive than previously determined. J Amer Soc Nephrol 2: 525 (Abstract)Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • M. -A. Gall
    • 1
  • P. Rossing
    • 1
  • A. Kofoed-Enevoldsen
    • 1
  • F. S. Nielsen
    • 1
  • H. -H. Parving
    • 1
  1. 1.Steno Diabetes CenterGentofteDenmark

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