Cation Transport, Hypertension and Diabetic Nephropathy

  • Ruggero Mangili


The hypothesis that diabetic nephropathy may not simply be a result of the metabolic abnormalities of diabetes, but may require the concomitance of a permissive genetic background, was initially suggested by the incidence pattern of proteinuria in insulin-dependent diabetes [1,2], and was later supported by the observation that renal destiny is often concordant among Type 1 diabetic siblings [3,4]. Family clustering of diabetic nephropathy may occur also in Type 2 diabetes, and closer evidence that this complication may reflect inheritance, independent of that of Type 2 diabetes, is restricted to Pima Indians [5]. Exploring parental history of diabetic nephropathy per se may not be feasible in Type 1 diabetes [6], but addressing the relevance of known genetic factors to renal prognosis is otherwise possible, in the hope to identify suitable markers of predisposition, and to provide clues to the molecular and cellular pathophysiology of diabetic kidney disease. Among the candidate issues, the genetic background predisposing to essential hypertension was more extensively explored and discussed in the past few years. As essential hypertension is known to cluster in families and to be characterised by abnormalities in erythrocyte sodium transport with established genetic components, the hypothesis was probed by examining these variables in diabetic nephropathy, in addition to revisiting the chicken-and-egg relationship of blood pressure with urinary albumin excretion.


Diabetic Nephropathy Essential Hypertension Urinary Albumin Excretion Cation Transport Diabetic Kidney Disease 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Krolewski AS, Warram JH, Christlieb AR, Busick EJ, Kahn CR. The changing natural history of nephropathy in Type I diabetes. Am J Med 1985; 78: 785–794.PubMedCrossRefGoogle Scholar
  2. 2.
    Andersen AR, Christiansen JS, Andersen JK, Kreiner S, Deckert T. Diabetic nephropathy in type I (insulin-dependent) diabetes: an epidemiological study. Diabeto-logia 1983; 25: 496–501.CrossRefGoogle Scholar
  3. 3.
    Seaqvist ER, Goetz FC, Rich S, Barbosa J. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989; 320: 1161–1165.CrossRefGoogle Scholar
  4. 4.
    Borch-Johnsen K, Nørgaard K, Hommel E, Mathiesen ER, Jensen JS, Deckert T, Parving H-H. Is diabetic nephropathy an inherited complication? Kidney Int 1992; 41: 719–722.PubMedCrossRefGoogle Scholar
  5. 5.
    Pettitt DJ, Saad MF, Bennett PH, Nelson RG, Knowler WC. Family predisposition to renal disease in two generations of Pima Indians with Type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1990; 33: 438–443.PubMedCrossRefGoogle Scholar
  6. 6.
    Pociot F, Nørgaard K, Hobolth N, Andersen O, Nerup J, and Danish Study Group of Diabetes in Childhood. A nationwide population-based study of the familial aggregation of Type 1 (insulin-dependent) diabetes mellitus in Denmark. Diabetologia 1993; 36: 870–875.PubMedCrossRefGoogle Scholar
  7. 7.
    Borch-Johnsen K, Andersen PK, Deckert T. The effect of proteinuria on relative mortality in type I (insulin-dependent) diabetes mellitus. Diabetologia 1985; 28: 290–596.CrossRefGoogle Scholar
  8. 8.
    Christlieb AR, Warram JH, Ganda OP, Asmal AC, Soeldner JS, Bradley RF. Hypertension: the major risk factor in juvenile-onset insulin-dependent diabetics. Diabetes 1981; 30: suppl. 2: 90–96.PubMedGoogle Scholar
  9. 9.
    Viberti GC, Bilous RW, Mackintosh D, Keen H. Monitoring glomerular function in diabetic nephropathy. A prospective study. Am J Med 1983; 74: 256–264.PubMedCrossRefGoogle Scholar
  10. 10.
    Parving H-H, Andersen AR, Smidt UM, Hommel E, Mathiesen ER, Svendsen PA. Effect of antihypertensive treatment on kidney function in diabetic nephropathy. BMJ 1987; 294: 1443–1447.PubMedCrossRefGoogle Scholar
  11. 11.
    Wiseman MJ, Viberti GC, Mackintosh D, Jarrett RJ, Keen H. Glycaemia, arterial pressure and micro-albuminuria in type I (insulin-dependent) diabetes mellitus. Diabetologia 1984; 26: 401–405.PubMedCrossRefGoogle Scholar
  12. 12.
    Derby L, Warram JH, Laffel LMB, Krolewski AS. Elevated blood pressure predicts the development of persistent proteinuria in the presence of poor glycemic control, in patients with type I diabetes. Diabete Metab 1989; 15: 320–326.PubMedGoogle Scholar
  13. 13.
    Christensen CK, Krusell LR, Mogensen CE. Increased blood pressure in diabetes: essential hypertension or diabetic nephropathy? Scand J Clin Lab Invest 1987; 47: 363–370.PubMedCrossRefGoogle Scholar
  14. 14.
    Microalbuminuria Collaborative Study Group, United Kingdom. Risk factors for development of microalbuminuria in insulin-dependent diabetic patients: a cohort study. BMJ 1993; 306: 1235–1239.CrossRefGoogle Scholar
  15. 15.
    Mathiesen ER, Rønn B, Jensen T, Storm B, Deckert T. Relationship between blood pressure and urinary albumin excretion in the development of microalbuminuria. Diabetes 1990; 39: 245–250.PubMedCrossRefGoogle Scholar
  16. 16.
    Viberti GC, Keen H, Wiseman MJ. Raised arterial pressure in parents of proteinuric insulin dependent diabetics. BMJ 1987; 295: 515–517.PubMedCrossRefGoogle Scholar
  17. 17.
    Krolewski AS, Canessa M, Warram JH, Laffel LMB, Christlieb AR, Knowler WC, Rand LI. Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N Engl J Med 1988; 318: 140–145.PubMedCrossRefGoogle Scholar
  18. 18.
    Jensen JS, Mathiesen ER, Nørgaard K, Hommel E, Borch-Johnsen K, Funder J, Brahm J, Parving H-H, Deckert T. Increased blood pressure and erythrocyte sodium-lithium countertransport activity are not inherited in diabetic nephropathy. Diabetologia 1990; 33: 619–624.PubMedCrossRefGoogle Scholar
  19. 19.
    Nørgaard K, Mathiesen ER, Hommel E, Jensen JS, Parving H-H. Lack of familial predisposition to cardiovascular disease in Type 1 (insulin-dependent) diabetic patients with nephropathy. Diabetologia 1991; 34: 370–372.PubMedCrossRefGoogle Scholar
  20. 20.
    Earle K, Walker J, Hill C, Viberti GC. Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy. N Engl J Med 1992; 326: 673–677.PubMedCrossRefGoogle Scholar
  21. 21.
    Bianchi G, Cusi D, Gatti M, Lupi GP, Ferrari P, Barlassina C, Picotti GB, Bracchi G, Colombo G, Gori D, Velis O, Mazzei D. A renal abnormality as a possible cause of ‘essential’ hypertension. Lancet 1979; i: 173–177.CrossRefGoogle Scholar
  22. 22.
    Tarn AC, Thomas JM, Drury PL. Correlates of blood pressure in young insulin-dependent diabetics and their families. J Hypertens 1990; 8: 795–803.PubMedCrossRefGoogle Scholar
  23. 23.
    Hasstedt SJ, Wu LL, Kuida H, Williams RR. Recessive inheritance of a high number of sodium pump sites. Am J Med Genet 1989; 34: 332–337.PubMedCrossRefGoogle Scholar
  24. 24.
    Cusi D, Fossali E, Piazza A, Tripodi G, Barlassina C, Pozzoli E, Vezzoli G, Stella P, Soldati L, Bianchi G. Heritability estimate of erythrocyte Na-K-Cl cotransport in normotensive and hypertensive families. Am J Hypertens 1991; 4: 725–734.PubMedGoogle Scholar
  25. 25.
    Canessa M, Adragna N, Solomon HS, Connolly TM, Tosteson DC. Increased sodium-lithium countertransport in red cells of patients with essential hypertension. N Engl J Med 1980; 302: 772–776.PubMedCrossRefGoogle Scholar
  26. 26.
    Hasstedt SJ, Wu LL, Ash KO, Kuida H, Williams RR. Hypertension and sodium-lithium countertransport in Utah pedigrees: evidence for major locus inheritance. Am J Hum Genet 1988; 43: 14–22.PubMedGoogle Scholar
  27. 27.
    Boerwinkle E, Turner ST, Weishilboum R, Johnson M, Richelson E, Sing CF. Analysis of the distribution of erythrocyte sodium lithium countertransport in a sample representative of the general population. Genet Epidemiol 1986; 3: 365–378.PubMedCrossRefGoogle Scholar
  28. 28.
    Williams RR, Hasstedt SJ, Hunt SC, Wu LL, Ash KO. Genetic studies of cation tests and hypertension. Hypertension 1987; 10: suppl. I: I-37-I-41.Google Scholar
  29. 29.
    Turner ST, Weidman WH, Michels VV, Reed TJ, Ormson CL, Fuller T, Sing CF. Distribution of sodium-lithium countertransport and blood pressure in Caucasians five to eighty-nine years of age. Hypertension 1989; 13: 378–391.PubMedCrossRefGoogle Scholar
  30. 30.
    Turner ST, Rebbeck TR, Sing CF. Sodium-lithium countertransport and probability of hypertension in Caucasians 47 to 89 years old. Hypertension 1992; 20: 841–850.PubMedCrossRefGoogle Scholar
  31. 31.
    Hunt SC, Stephenson SH, Hopkins PN, Hasstedt SJ, Williams RR. A prospective study of sodium-lithium countertransport and hypertension in Utah. Hypertension 1991; 17: 1–7.PubMedCrossRefGoogle Scholar
  32. 32.
    Mangili R, Bending JJ, Scott G, Li LK, Gupta A, Viberti GC. Increased sodium-lithium countertransport activity in red cells of patients with insulin-dependent diabetes and nephropathy. N Engl J Med 1988; 318: 146–150.PubMedCrossRefGoogle Scholar
  33. 33.
    Woods JW, Falk RJ, Pittman AW, Klemmer PJ, Watson BS, Namboodiri K. Increased red-cell sodium-lithium countertransport in normotensive sons of hypertensive parents. N Engl J Med 1982; 306: 593–595.PubMedCrossRefGoogle Scholar
  34. 34.
    Rota R, Timsit J, Hannedouche T, Ikeni A, Boitard C, Guicheney P. Erythrocyte Na+/Li+ countertransport and glomerular hyperfiltration in insulin-dependent diabetics. Am J Hypertens 1993; 6: 534–537.PubMedGoogle Scholar
  35. 35.
    Jones SL, Trevisan R, Tariq T, Semplicini A, Mattock M, Walker JD, Nosadini R, Viberti GC. Sodium-lithium countertransport in microalbuminuric insulin-dependent diabetic patients. Hypertension 1990; 15: 570–575.PubMedCrossRefGoogle Scholar
  36. 36.
    Elving LD, Wetzels JFM, de Nobel E, Berden JHM. Erythrocyte sodium-lithium countertransport is not different in Type 1 (insulin-dependent) diabetic patients with and without diabetic nephropathy. Diabetologia 1991; 34: 126–128.PubMedCrossRefGoogle Scholar
  37. 37.
    Rutherford PA, Thomas TH, Carr SJ, Taylor R, Wilkinson R. Changes in erythrocyte sodium-lithium countertransport kinetics in diabetic nephropathy. Clin Sci 1992; 82: 301–307.PubMedGoogle Scholar
  38. 38.
    Barzilay J, Warram JH, Bak M, Laffel LMB, Canessa M, Krolewski AS. Predisposition to hypertension: risk factor for nephropathy and hypertension in IDDM. Kidney Int 1992; 41: 723–730.PubMedCrossRefGoogle Scholar
  39. 39.
    Lopes de Faria JB, Friedman R, Tariq T, Viberti GC. Prevalence of raised sodium-lithium countertransport activity in Type 1 diabetic patients. Kidney Int 1992; 41: 877–882.CrossRefGoogle Scholar
  40. 40.
    Elving LD, Wetzels JFM, De Pont JJHHM, Berden JHM. Is increased erythrocyte sodium-lithium countertransport a useful marker for diabetic nephropathy? Kidney Int 1992; 41: 862–871.PubMedCrossRefGoogle Scholar
  41. 41.
    Mangili R, Zerbini G, Barlassina C, Cusi D, Pozza G. Sodium-lithium countertransport and triglycerides in diabetic nephropathy. Kidney Int 1993; 44: 127–133.PubMedCrossRefGoogle Scholar
  42. 42.
    Mangili R, Gabellini D, Pozza G. The concomitants of erythrocyte sodium-lithium countertransport activity in diabetic nephropathy: a critical assessment. Acta Diabetol 1992; 29: 221–226.CrossRefGoogle Scholar
  43. 43.
    Adebayo GI, Hemeryck L, Hall M, Feely J. Sodium-lithium countertransport: does it matter how it is calculated? Eur J Clin Invest 1993; 23: 418–422.PubMedCrossRefGoogle Scholar
  44. 44.
    Canessa M, Zerbini G, Laffel LMB. Sodium activation kinetics of red blood cell Na/Li countertransport in diabetes: methodology and controversy. J Am Soc Nephrol 1992; 3: S41–S49.Google Scholar
  45. 45.
    Rutherford PA, Thomas TH, Wilkinson R. Erythrocyte sodium-lithium countertransport: clinically useful, pathophysiologically instructive or just phenomenology? Clin Sci 1992; 82: 341–352.PubMedGoogle Scholar
  46. 46.
    Brent GA, Canessa M, Dluhy RG. Reversible alteration of red cell lithium-sodium countertransport in patients with thyroid disease. J Clin Endocrinol Metab 1989; 68: 322–328.PubMedCrossRefGoogle Scholar
  47. 47.
    Seely EW, Canessa LM, Graves SW. Impact of diabetes on sodium-lithium countertransport in pregnancy-induced hypertension. Am J Hypertens 1993; 6: 422–426.PubMedGoogle Scholar
  48. 48.
    Hunt SC, Williams RR, Smith JB, Ash KO. Association of three erythrocyte cation transport systems with plasma lipids in Utah subjects. Hypertension 1986; 8: 30–36.PubMedCrossRefGoogle Scholar
  49. 49.
    Hunt SC, Williams RR, Ash KO. Changes in sodium-lithium countertransport correlate with changes in triglyceride levels and body mass index over 2 1/2 years of follow-up in Utah. Cardiovasc Drugs Ther 1990; 4: suppl. 2: 357–362.PubMedCrossRefGoogle Scholar
  50. 50.
    Semplicini A, Mozzato MG, Samà B, Nosadini R, Fioretto P, Trevisan R, Pessina AC, Crepaldi G, Dal Palù C. Na/H and Li/Na exchange in red blood cells of normotensive and hypertensive patients with insulin dependent diabetes mellitus (IDDM). Am J Hypertens 1989; 2: 174–177.PubMedGoogle Scholar
  51. 51.
    Walker JD, Tariq T, Viberti GC. Sodium-lithium countertransport activity in red cells of patients with insulin dependent diabetes and nephropathy and their parents. BMJ 1990; 301: 635–638.PubMedCrossRefGoogle Scholar
  52. 52.
    Cusi D, Barlassina C, Ferrandi M, Lupi P, Ferrari P, Bianchi G. Familial aggregation of cation transport abnormalities and essential hypertension. Clin Exp Hypertens 1981; 3: 871–874.PubMedCrossRefGoogle Scholar
  53. 53.
    Doria A, Fioretto P, Avogaro A, Carraro A, Morocutti A, Trevisan R, Frigato F, Crepaldi G, Viberti GC, Nosadini R. Insulin-resistance is associated with high sodium-lithium countertransport in essential hypertension. Am J Physiol 1991; 261: E684–E691.Google Scholar
  54. 54.
    Nosadini R, Semplicini A, Fioretto P, Lusiani L, Trevisan R, Donadon V, Zanette G, Nicolosi GL, Dall’Aglio V, Zanuttini D, Viberti GC. Sodium-lithium countertransport and cardiorenal abnormalities in essential hypertension. Hypertension 1991; 18: 191–198.PubMedCrossRefGoogle Scholar
  55. 55.
    Lopes de Faria JB, Jones SL, MacDonald F, Chambers J, Mattock MB, Viberti GC. Sodium-lithium countertransport activity and insulin resistance in normotensive IDDM patients. Diabetes 1992; 41: 610–615.CrossRefGoogle Scholar
  56. 56.
    Trevisan R, Nosadini R, Fioretto P, Semplicini A, Donadon V, Doria A, Nicolosi G, Zanuttini D, Cipollina MR, Luisiani L, Avogaro A, Crepaldi G, Viberti GC. Clustering of risk factors in hypertensive insulin-dependent diabetics with high sodium-lithium countertransport. Kidney Int 1992; 41: 855–861.PubMedCrossRefGoogle Scholar
  57. 57.
    Catalano C, Winocour PH, Thomas TH, Walker M, Sum CF, Wilkinson R, Alberti KGMM. Erythrocyte sodium-lithium countertransport activity and total body insulin-mediated glucose disposal in normoalbuminuric normotensive Type 1 (insulin-dependent) diabetic patients. Diabetologia 1993; 36: 52–56.PubMedCrossRefGoogle Scholar
  58. 58.
    Carr S, Mbanya J-C, Thomas T, Keavey P, Taylor R, Alberti KGMM. Increase in glomerular filtration rate in patients with insulin-dependent diabetes and elevated erythrocyte sodium-lithium countertransport. N Engl J Med 1990; 322: 500–504.PubMedCrossRefGoogle Scholar
  59. 59.
    Weder AB. Red-cell lithium-sodium countertransport and renal lithium clearance in hypertension. N Engl J Med 1986; 314: 198–201.PubMedCrossRefGoogle Scholar
  60. 60.
    Weinberger MH, Smith JB, Fineberg NS, Luft FC. Red-cell sodium-lithium counter-transport and fractional excretion of lithium in normal and hypertensive humans. Hypertension 1989; 13: 206–212.PubMedCrossRefGoogle Scholar
  61. 61.
    Hilton PJ. Na+ transport in hypertension. Diabetes Care 1991; 14: 233–239.PubMedCrossRefGoogle Scholar
  62. 62.
    Huot SJ, Aronson PS. Na+-H+ exchanger and its role in essential hypertension and diabetes mellitus. Diabetes Care 1991; 14: 521–535.PubMedCrossRefGoogle Scholar
  63. 63.
    Kinsella JL, Aronson PA. Interactions of NH4 and Li with the renal microvillus membrane Na-H exchanger. Am J Physiol 1981; 241: C220–C226.Google Scholar
  64. 64.
    Ives HE, Yee VJ, Warnock DG. Mixed type inhibition of the renal Na/H antiporter by Li and amiloride. J Biol Chem 1983; 258: 9710–9716.PubMedGoogle Scholar
  65. 65.
    Kahn AM, Allen JC, Cragoe EG Jr., Zimmer R, Shelat H. Sodium-lithium exchange in sarcolemmal vesicles from canine superior mesenteric artery. Circ Res 1988; 62: 478–485.PubMedCrossRefGoogle Scholar
  66. 66.
    Kahn AM, Allen JC, Cragoe EG, Jr., Shelat H. Sodium-lithium exchange and sodium-proton exchange are mediated by the same transport system in sarcolemmal vesicles from bovine superior mesenteric artery. Circ Res 1989; 65: 818–828.PubMedCrossRefGoogle Scholar
  67. 67.
    Jennings ML, Adams-Lackey M, Cook KW. Absence of significant sodium-hydrogen exchange by rabbit erythrocyte sodium-lithium countertransporter. Am J Physiol 1985; 249: C63–C68.Google Scholar
  68. 68.
    Pandey GN, Sarkadi B, Haas M, Gunn RB, Davis JM, Tosteson DC. Lithium transport pathways in human red blood cells. J Gen Physiol 1978; 72: 233–247.PubMedCrossRefGoogle Scholar
  69. 69.
    Kahn AM. Difference between human red blood cell Na-Li countertransport and renal Na-H exchange. Hypertension 1987; 9: 7–12.PubMedCrossRefGoogle Scholar
  70. 70.
    Canessa M, Morgan K, Semplicini A. Genetic differences in lithium-sodium exchange and regulation of the sodium-hydrogen exchanger in essential hypertension. J Cardiovasc Pharmacol 1988; 12: suppl. 3: 92–98.CrossRefGoogle Scholar
  71. 71.
    Semplicini A, Spalvins A, Canessa M. Kinetics and stoichiometry of the human red cell Na/H exchanger. J Membr Biol 1989; 107: 219–228.PubMedCrossRefGoogle Scholar
  72. 72.
    Morgan K, Canessa M. Interactions of external and internal H+ and Na+ with Na+/Na+ and Na+/H+ exchange of rabbit red cells: evidence of a common pathway. J Membr Biol 1990; 118: 193–214.PubMedCrossRefGoogle Scholar
  73. 73.
    Lifton RP, Hunt SC, Williams RR, Pouysségur J, Lalouel J-M. Exclusion of the Na-H antiporter as a candidate gene in human essential hypertension. Hypertension 1991; 17: 8–14.PubMedCrossRefGoogle Scholar
  74. 74.
    Mangili R, Zerbini G, Garbetta F, Cusi D, Pastore MR, Bognetti E, Pozza G. Erythrocyte sodium-lithium countertransport and risk of nephropathy in Type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1990; 33: A12 (Abstract).Google Scholar
  75. 75.
    Haas M, Schooler J, Tosteson DC. Coupling of lithium to sodium transport in human red cells. Nature 1975; 258: 425–427.PubMedCrossRefGoogle Scholar
  76. 76.
    Duhm J, Becker BF. Studies on lithium transport across the red cell membrane. V On the nature of the Na-dependent Li countertransport system of mammalian erythrocytes. J Membr Biol 1979; 51: 263–286.PubMedCrossRefGoogle Scholar
  77. 77.
    Parker JC. Interactions of lithium and protons with the sodium-proton exchanger of dog red blood cells. J Gen Physiol 1986; 87: 189–200.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Ruggero Mangili

There are no affiliations available

Personalised recommendations