Skip to main content

Advertisement

SpringerLink
Log in

The salt paradox and its possible implications in managing hypertensive diabetic patients

  • Published:
Current Hypertension Reports Aims and scope Submit manuscript

Abstract

Diabetes mellitus is one of the leading causes of end-stage renal disease. The pathogenesis of diabetic nephropathy is still poorly understood, but glomerular injury has been ascribed, at least in part, to glomerular hyperfiltration, which occurs early in the course of diabetes mellitus. Therefore, a better understanding of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. In this review, we discuss the pathophysiology for the paradoxical relationship between dietary salt and glomerular filtration rate observed in early diabetes mellitus and possible implications in managing diabetic patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. The Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulindependent diabetes mellitus. N Engl J Med 1993, 329:977–986.

    Article  Google Scholar 

  2. Abbate M, Zoja C, Corna D, et al.: In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation. J Am Soc Nephrol 1998, 9:1213–1224.

    PubMed  CAS  Google Scholar 

  3. Abbate M, Remuzzi G: Proteinuria as a mediator of tubulointerstitial injury. Kidney Blood Press Res 1999, 22:37–46.

    Article  PubMed  CAS  Google Scholar 

  4. Mauer SM, Steffes MW, Ellis EN, et al.: Structural functional relationships in diabetic nephropathy. J Clin Invest 1984, 74:1143–1155.

    PubMed  CAS  Google Scholar 

  5. Bohle A, Mackensen Haen S, von Gise H, et al.: The consequences of tubulointerstitial changes for renal function in glomerulopathies: a morphometric and cytological analysis. Pathol Res Pract 1990, 186:135–144.

    PubMed  CAS  Google Scholar 

  6. D’Amico G, Ferrario F, Rastaldi MP: Tubulointerstitial damage in glomerular diseases: its role in the progression of renal damage. Am J Kidney Dis 1995, 26:124–132.

    PubMed  CAS  Google Scholar 

  7. Eddy AA, Schnaper HW: The nephrotic syndrome: from the simple to the complex. Semin Nephrol 1998, 18:304–316.

    PubMed  CAS  Google Scholar 

  8. Mogensen CE, Christensen CK: Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 1984, 311:89–93.

    Article  PubMed  CAS  Google Scholar 

  9. Mogensen CE: Early glomerular hyperfiltration in insulindependent diabetics and late nephropathy. Scand J Clin Lab Invest 1986, 46:201–206.

    PubMed  CAS  Google Scholar 

  10. Rudberg S, Persson B, Dahlquist G: Increased glomerular filtration rate as a predictor of diabetic nephropathy—an 8-year prospective study. Kidney Int 1992, 41:822–828.

    PubMed  CAS  Google Scholar 

  11. Chiarelli F, Verrotti A, Morgese G: Glomerular hyperfiltration increases the risk of developing microalbuminuria in diabetic children. Pediatr Nephrol 1995, 9:154–158.

    Article  PubMed  CAS  Google Scholar 

  12. Lervang HH, Jensen S, Brochner-Mortensen J, Ditzel J: Does increased glomerular filtration rate or disturbed tubular function early in the course of childhood type 1 diabetes predict the development of nephropathy? Diabet Med 1992, 9:635–640.

    Article  PubMed  CAS  Google Scholar 

  13. Yip JW, Jones SL, Wiseman MJ, et al.: Glomerular hyperfiltration in the prediction of nephropathy in IDDM: a 10-year follow-up study. Diabetes 1996, 45:1729–1733.

    Article  PubMed  CAS  Google Scholar 

  14. Vallon V, Blantz RC, Thomson S: Glomerular hyperfiltration and the salt paradox in early type 1 diabetes mellitus: a tubulo-centric view. J Am Soc Nephrol 2003, 14:530–537.

    Article  PubMed  Google Scholar 

  15. Vallon V: Tubuloglomerular feedback and the control of glomerular filtration rate. News Physiol Sci 2003, 8:169–174.

    Google Scholar 

  16. Thomson SC, Vallon V, Blantz RC: Kidney function in early diabetes: the tubular hypothesis of glomerular filtration. Am J Physiol Renal Physiol 2004, 286:F8-F15.

    Article  PubMed  CAS  Google Scholar 

  17. Hannedouche TP, Delgado AG, Gnoinsahe DA, et al.: Renal hemodynamics and segmental tubular sodium reabsorption in early type 1 diabetes. Kidney Int 1990, 37:1126–1133.

    PubMed  CAS  Google Scholar 

  18. Brochner Mortensen J, Stockel M, Sorensen PJ, et al.: Proximal glomerulotubular balance in patients with type 1 (insulin dependent) diabetes mellitus. Diabetologia 1984, 27:189–192.

    Google Scholar 

  19. Bank N, Aynedjian HS: Progressive increases in luminal glucose stimulate proximal sodium absorption in normal and diabetic rats. J Clin Invest 1990, 86:309–316.

    PubMed  CAS  Google Scholar 

  20. Pollock CA, Lawrence JR, Field MJ: Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus. Am J Physiol 1991, 260:F946-F952.

    PubMed  CAS  Google Scholar 

  21. Vallon V, Blantz RC, Thomson SC: Homeostatic efficiency of tubuloglomerular feedback is reduced in established diabetes mellitus in rats. Am J Physiol 1995, 269:F876-F883.

    PubMed  CAS  Google Scholar 

  22. Vallon V, Richter K, Blantz RC, et al.: Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol 1999, 10:2569–2576. This study provides evidence that in early experimental type 1 diabetes, a primary increase in reabsorption upstream to the macula densa, which is at least, in part, due to increased Na+-glucose cotransport, lowers the Na+, K+, and Cl-concentrations at the macula densa and causes glomerular hyperfiltration via the TGF mechanism.

    PubMed  CAS  Google Scholar 

  23. Thomson SC, Deng A, Bao D, et al.: Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes. J Clin Invest 2001, 107:217–224. This study indicates the role of proximal tubular growth in the primary increase in proximal reabsorption and glomerular hyperfiltration in early experimental type 1 diabetes.

    PubMed  CAS  Google Scholar 

  24. Vestri S, Okamoto MM, de Freitas HS, et al.: Changes in sodium or glucose filtration rate modulate expression of glucose transporters in renal proximal tubular cells of rat. J Membr Biol 2001, 182:105–112.

    Article  PubMed  CAS  Google Scholar 

  25. Schnermann J, Briggs J: Concentration-dependent sodium chloride transport as the signal in feedback control of glomerular filtration rate. Kidney Int 1982, 22(Suppl12):S82-S89.

    Google Scholar 

  26. Vallon V, Osswald H, Blantz RC, et al.: Potential role of luminal potassium in tubuloglomerular feedback. J Am Soc Nephrol 1997, 8:1831–1837.

    PubMed  CAS  Google Scholar 

  27. Thomson S, Bao D, Deng A, et al.: Adenosine formed by 5′-nucleotidase mediates tubuloglomerular feedback. J Clin Invest 2000, 106:289–298.

    Article  PubMed  CAS  Google Scholar 

  28. Vallon V, Osswald H: Dipyridamole prevents diabetesinduced alterations of kidney function in rats. Naunyn Schmiedebergs Arch Pharmacol 1994, 349:217–222.

    Article  PubMed  CAS  Google Scholar 

  29. Vallon V, Wead LM, Blantz RC: Renal hemodynamics and plasma and kidney angiotensin II in established diabetes mellitus in rats: effect of sodium and salt restriction. J Am Soc Nephrol 1995, 5:1761–1767.

    PubMed  CAS  Google Scholar 

  30. Vallon V, Kirschenmann D, Wead LM, et al.: Effect of chronic salt loading on kidney function in early and established diabetes mellitus in rats. J Lab Clin Med 1997, 130:76–82.

    Article  PubMed  CAS  Google Scholar 

  31. Vallon V, Huang DY, Deng A, et al.: Salt-sensitivity of proximal reabsorption alters macula densa salt and explains the paradoxical effect of dietary salt on glomerular filtration rate in diabetes mellitus. J Am Soc Nephrol 2002, 13:1865–1871. This study in experimental type 1 diabetes indicates that an increased salt-sensitivity of proximal tubular reabsorption, which inversely links GFR to salt intake via the TGF mechanism, forms the pathophysiologic basis for the salt paradox in early diabetes.

    Article  PubMed  Google Scholar 

  32. Miller JA: Renal response to sodium restriction in patients with early diabetes mellitus. J Am Soc Nephrol 1997, 8:749–755.

    PubMed  CAS  Google Scholar 

  33. Luik PT, Hoogenberg K, Van Der Kleij FG, et al.: Short-term moderate sodium restriction induces relative hyperfiltration in normotensive normoalbuminuric type I diabetes mellitus. Diabetologia 2002, 45:535–541. Following the earlier study by Miller [32], this is the second study that provides evidence for the salt paradox in type 1 diabetic patients.

    Article  PubMed  CAS  Google Scholar 

  34. De’Oliveira JM, Price DA, Fisher ND, et al.: Autonomy of the renin system in type II diabetes mellitus: dietary sodium and renal hemodynamic responses to ACE inhibition. Kidney Int 1997, 52:771–777.

    Article  PubMed  CAS  Google Scholar 

  35. Campese VM, Wurgaft A, Safa M, et al.: Dietary salt intake, blood pressure and the kidney in hypertensive patients with non-insulin dependent diabetes mellitus. J Nephrol 1998, 11:289–295.

    Article  PubMed  CAS  Google Scholar 

  36. Parmer RJ, Stone RA, Cervenka JH: Renal hemodynamics in essential hypertension: racial differences in response to changes in dietary sodium. Hypertension 1994, 24:752–757.

    PubMed  CAS  Google Scholar 

  37. Bank N, Lahorra MAG, Aynedjian HS, et al.: Sodium restriction corrects hyperfiltration of diabetes. Am J Physiol 1988, 254:F668-F676.

    PubMed  CAS  Google Scholar 

  38. Allen TJ, Waldron MJ, Casley D, et al.: Salt restriction reduces hyperfiltration, renal enlargement, and albuminuria in experimental diabetes. Diabetes 1997, 46:19–24.

    Article  PubMed  CAS  Google Scholar 

  39. Trevisan R, Bruttomesso D, Vedovato M, et al.: Enhanced responsiveness of blood pressure to sodium intake and to angiotensin II is associated with insulin resistance in IDDM patients with microalbuminuria. Diabetes 1998, 47:1347–1353.

    Article  PubMed  CAS  Google Scholar 

  40. Birk C, Richter K, Huang DY, et al.: The salt paradox of the early diabetic kidney is independent of renal innervation. Kidney Blood Press Res 2003, 26:344–350. This study in early experimental type 1 diabetes indicates that the salt paradox is not mediated by the renal nerves.

    Article  PubMed  CAS  Google Scholar 

  41. American Diabetes Association. Position Statement: Nutrition recommendations and principles for people with diabetes mellitus. Diabetes Care 1998, 21:S32-S35.

    Article  Google Scholar 

  42. Johansson BL, Sjoberg S, Wahren J: The influence of human C peptide on renal function and glucose utilization in type 1 (insulin dependent) diabetic patients. Diabetologia 1992, 35:121–128.

    Article  PubMed  CAS  Google Scholar 

  43. Huang DY, Richter K, Breidenbach A, et al.: Human C-peptide acutely lowers glomerular hyperfiltration and proteinuria in diabetic rats: a dose-response study. Naunyn Schmiedebergs Arch Pharmacol 2002, 365:67–73.

    Article  PubMed  CAS  Google Scholar 

  44. Burns KD, Li N: The role of angiotensin II-stimulated renal tubular transport in hypertension. Curr Hypertens Rep 2003, 5:165–171.

    Article  PubMed  Google Scholar 

  45. Heeg JE, de Jong PE, van der Hem GK, et al.: Efficacy and variability of the antiproteinuric effect of ACE inhibition by lisinopril. Kidney Int 1989, 36:272–279.

    PubMed  CAS  Google Scholar 

  46. Ishii H, Jirousek MR, Koya D, et al.: Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996, 3:728–731.

    Article  Google Scholar 

  47. Pfaff IL, Wagner H-J, Vallon V: Immunolocalization of protein kinase C isoenzymes alpha, beta I and beta II in rat kidney. J Am Soc Nephrol 1999, 10:1861–1873.

    PubMed  CAS  Google Scholar 

  48. Efendiev R, Budu CE, Cinelli AR, et al.: Intracellular Na+ regulates dopamine and angiotensin II receptors availability at the plasma membrane and their cellular responses in renal epithelia. J Biol Chem 2003, 278:28719–28726.

    Article  PubMed  CAS  Google Scholar 

  49. Pfaff IL, Vallon V: Protein kinase C beta isoenzymes in experimental diabetes mellitus and their relation to nephroprotective actions of the ACE inhibitor lisinopril. Kidney Blood Press Res 2002, 25:329–340.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Medicine and Pharmacology, University of California San Diego & VASDHS, 3350 La Jolla Village Drive (9151), 92161, San Diego, CA, USA

    Volker Vallon MD, Roland Blantz MD & Scott Thomson MD

Authors
  1. Volker Vallon MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roland Blantz MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott Thomson MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vallon, V., Blantz, R. & Thomson, S. The salt paradox and its possible implications in managing hypertensive diabetic patients. Current Science Inc 7, 141–147 (2005). https://doi.org/10.1007/s11906-005-0089-x

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11906-005-0089-x

Keywords

Search

Navigation