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Microvascular Damage and Hemodynamic Alterations in Diabetic Nephropathy

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Diabetic Nephropathy

Abstract

Microvascular damage has a central role in the origination and progression of diabetic nephropathy. Manifestations of microvascular damage include rarefaction (reduced capillary density) and endothelial dysfunction. These alterations lead to hemodynamic abnormalities, contributing to the progression of diabetic nephropathy. Furthermore, besides microvascular damage in the kidney itself, diabetic nephropathy is also associated with microvascular changes in several other tissues. This suggests a common systemic microvascular damaging mechanism, which may include a variety of hypertension- and hyperglycemia-associated molecular pathways. The nature and extent of these pathways have yet to be fully uncovered and are subject to changing views. This also touches upon finding the optimal treatment to halt or reverse microvascular damage in diabetic nephropathy. New classes of antidiabetic drugs like SGLT2-inhibitors, DDP-4 inhibitors, and GLP-1 receptor agonist have shown promising results with regard to clinical outcomes but need to be further studied with regard to their effects on the renal microcirculation. Also, due to the involvement of a wide variability of mechanisms, finding one therapeutic agent optimally targeting the microcirculation will probably remain complicated.

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References

  1. Levy BI, Ambrosio G, Pries AR, Struijker-Boudier HA. Microcirculation in hypertension: a new target for treatment? Circulation. 2001;104(6):735–40.

    Article  CAS  PubMed  Google Scholar 

  2. Ince C. The microcirculation is the motor of sepsis. Crit Care. 2005;9(Suppl 4):S13–9.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Struijker Boudier HA, le Noble JL, Messing MW, Huijberts MS, le Noble FA, van Essen H. The microcirculation and hypertension. J Hypertens Suppl. 1992;10(7):S147–56.

    CAS  PubMed  Google Scholar 

  4. Meinders AJ, Nieuwenhuis L, Ince C, Bos WJ, Elbers PW. Haemodialysis impairs the human microcirculation independent from macrohemodynamic parameters. Blood Purif. 2015;40(1):38–44.

    Article  CAS  PubMed  Google Scholar 

  5. Ocak I, Kara A, Ince C. Monitoring microcirculation. Best Pract Res Clin Anaesthesiol. 2016;30(4):407–18.

    Article  PubMed  Google Scholar 

  6. Zafrani L, Ince C. Microcirculation in acute and chronic kidney diseases. Am J Kidney Dis. 2015;66(6):1083–94.

    Article  PubMed  Google Scholar 

  7. Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia. 1989;32(4):219–26.

    Article  CAS  PubMed  Google Scholar 

  8. Berhane AM, Weil EJ, Knowler WC, Nelson RG, Hanson RL. Albuminuria and estimated glomerular filtration rate as predictors of diabetic end-stage renal disease and death. Clin J Am Soc Nephrol. 2011;6(10):2444–51.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hallan SI, Matsushita K, Sang Y, Mahmoodi BK, Black C, Ishani A, et al. Age and association of kidney measures with mortality and end-stage renal disease. JAMA. 2012;308(22):2349–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Astor BC, Matsushita K, Gansevoort RT, van der Velde M, Woodward M, Levey AS, et al. Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. Kidney Int. 2011;79(12):1331–40.

    Article  CAS  PubMed  Google Scholar 

  11. Fox CS, Matsushita K, Woodward M, Bilo HJ, Chalmers J, Heerspink HJ, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet. 2012;380(9854):1662–73.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Gaspari F, Ruggenenti P, Porrini E, Motterlini N, Cannata A, Carrara F, et al. The GFR and GFR decline cannot be accurately estimated in type 2 diabetics. Kidney Int. 2013;84(1):164–73.

    Article  CAS  PubMed  Google Scholar 

  13. Chade AR. Small vessels, big role: renal microcirculation and progression of renal injury. Hypertension. 2017;69(4):551–63.

    Article  CAS  PubMed  Google Scholar 

  14. Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol. 2001;281(5):F887–99.

    Article  CAS  PubMed  Google Scholar 

  15. Maric-Bilkan C, Flynn ER, Chade AR. Microvascular disease precedes the decline in renal function in the streptozotocin-induced diabetic rat. Am J Physiol Renal Physiol. 2012;302(3):F308–15.

    Article  CAS  PubMed  Google Scholar 

  16. Bohle A, Mackensen-Haen S, Wehrmann M. Significance of postglomerular capillaries in the pathogenesis of chronic renal failure. Kidney Blood Press Res. 1996;19(3–4):191–5.

    Article  CAS  PubMed  Google Scholar 

  17. Futrakul N, Vongthavarawat V, Sirisalipotch S, Chairatanarat T, Futrakul P, Suwanwalaikorn S. Tubular dysfunction and hemodynamic alteration in normoalbuminuric type 2 diabetes. Clin Hemorheol Microcirc. 2005;32(1):59–65.

    CAS  PubMed  Google Scholar 

  18. Futrakul N, Futrakul P. Renal microvascular disease predicts renal function in diabetes. Ren Fail. 2012;34(1):126–9.

    Article  CAS  PubMed  Google Scholar 

  19. Futrakul N, Kulaputana O, Futrakul P, Chavanakul A, Deekajorndech T. Enhanced peritubular capillary flow and renal function can be accomplished in normoalbuminuric type 2 diabetic nephropathy. Ren Fail. 2011;33(3):312–5.

    Article  CAS  PubMed  Google Scholar 

  20. Matsumoto M, Tanaka T, Yamamoto T, Noiri E, Miyata T, Inagi R, et al. Hypoperfusion of peritubular capillaries induces chronic hypoxia before progression of tubulointerstitial injury in a progressive model of rat glomerulonephritis. J Am Soc Nephrol. 2004;15(6):1574–81.

    Article  PubMed  Google Scholar 

  21. Helal I, Fick-Brosnahan GM, Reed-Gitomer B, Schrier RW. Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol. 2012;8(5):293–300.

    Article  CAS  PubMed  Google Scholar 

  22. Magee GM, Bilous RW, Cardwell CR, Hunter SJ, Kee F, Fogarty DG. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia. 2009;52(4):691–7.

    Article  CAS  PubMed  Google Scholar 

  23. Amin R, Turner C, van Aken S, Bahu TK, Watts A, Lindsell DR, et al. The relationship between microalbuminuria and glomerular filtration rate in young type 1 diabetic subjects: the Oxford Regional Prospective Study. Kidney Int. 2005;68(4):1740–9.

    Article  PubMed  Google Scholar 

  24. Dahlquist G, Stattin EL, Rudberg S. Urinary albumin excretion rate and glomerular filtration rate in the prediction of diabetic nephropathy; a long-term follow-up study of childhood onset type-1 diabetic patients. Nephrol Dial Transplant. 2001;16(7):1382–6.

    Article  CAS  PubMed  Google Scholar 

  25. Yip JW, Jones SL, Wiseman MJ, Hill C, Viberti G. Glomerular hyperfiltration in the prediction of nephropathy in IDDM: a 10-year follow-up study. Diabetes. 1996;45(12):1729–33.

    Article  CAS  PubMed  Google Scholar 

  26. Ficociello LH, Perkins BA, Roshan B, Weinberg JM, Aschengrau A, Warram JH, et al. Renal hyperfiltration and the development of microalbuminuria in type 1 diabetes. Diabetes Care. 2009;32(5):889–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cotroneo P, Manto A, Todaro L, Manto A Jr, Pitocco D, Saponara C, et al. Hyperfiltration in patients with type I diabetes mellitus: a prevalence study. Clin Nephrol. 1998;50(4):214–7.

    CAS  PubMed  Google Scholar 

  28. Bulum T, Kolaric B, Prkacin I, Duvnjak L. Hyperfiltration in normoalbuminuric type 1 diabetic patients: relationship with urinary albumin excretion rate. Coll Antropol. 2013;37(2):471–6.

    CAS  PubMed  Google Scholar 

  29. van Brussel PM, van de Hoef TP, de Winter RJ, Vogt L, van den Born BJ. Hemodynamic measurements for the selection of patients with renal artery stenosis: a systematic review. JACC Cardiovasc Interv. 2017;10(10):973–85.

    Article  PubMed  Google Scholar 

  30. Ritz E, Keller C, Bergis K, Strojek K. Pathogenesis and course of renal disease in IDDM/NIDDM: differences and similarities. Am J Hypertens. 1997;10(9 Pt 2):202S–7S.

    Article  CAS  PubMed  Google Scholar 

  31. Hollenberg NK, Stevanovic R, Agarwal A, Lansang MC, Price DA, Laffel LM, et al. Plasma aldosterone concentration in the patient with diabetes mellitus. Kidney Int. 2004;65(4):1435–9.

    Article  CAS  PubMed  Google Scholar 

  32. Bojestig M, Nystrom FH, Arnqvist HJ, Ludvigsson J, Karlberg BE. The renin-angiotensin-aldosterone system is suppressed in adults with type 1 diabetes. J Renin-Angiotensin-Aldosterone Syst. 2000;1(4):353–6.

    Article  CAS  PubMed  Google Scholar 

  33. Cronin CC, Barry D, Crowley B, Ferriss JB. Reduced plasma aldosterone concentrations in randomly selected patients with insulin-dependent diabetes mellitus. Diabet Med. 1995;12(9):809–15.

    Article  CAS  PubMed  Google Scholar 

  34. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet. 2000;355(9200):253–9.

    Google Scholar 

  35. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861–9.

    Article  CAS  PubMed  Google Scholar 

  36. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345(12):851–60.

    Article  CAS  PubMed  Google Scholar 

  37. Price DA, Porter LE, Gordon M, Fisher ND, De’Oliveira JM, Laffel LM, et al. The paradox of the low-renin state in diabetic nephropathy. J Am Soc Nephrol. 1999;10(11):2382–91.

    CAS  PubMed  Google Scholar 

  38. Graciano ML, Cavaglieri Rde C, Delle H, Dominguez WV, Casarini DE, Malheiros DM, et al. Intrarenal Renin-Angiotensin system is upregulated in experimental model of progressive renal disease induced by chronic inhibition of nitric oxide synthesis. J Am Soc Nephrol. 2004;15(7):1805–15.

    Article  CAS  PubMed  Google Scholar 

  39. Yang T, Xu C. Physiology and pathophysiology of the Intrarenal Renin-Angiotensin system: an update. J Am Soc Nephrol. 2017;28(4):1040–9.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Anderson S, Jung FF, Ingelfinger JR. Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations. Am J Phys. 1993;265(4 Pt 2):F477–86.

    CAS  Google Scholar 

  41. Zimpelmann J, Kumar D, Levine DZ, Wehbi G, Imig JD, Navar LG, et al. Early diabetes mellitus stimulates proximal tubule renin mRNA expression in the rat. Kidney Int. 2000;58(6):2320–30.

    Article  CAS  PubMed  Google Scholar 

  42. Choi KC, Kim NH, An MR, Kang DG, Kim SW, Lee J. Alterations of intrarenal renin-angiotensin and nitric oxide systems in streptozotocin-induced diabetic rats. Kidney Int Suppl. 1997;60:S23–7.

    CAS  PubMed  Google Scholar 

  43. Carey RM, Siragy HM. The intrarenal renin-angiotensin system and diabetic nephropathy. Trends Endocrinol Metab. 2003;14(6):274–81.

    Article  CAS  PubMed  Google Scholar 

  44. Park JH, Jang HR, Lee JH, Lee JE, Huh W, Lee KB, et al. Comparison of intrarenal renin-angiotensin system activity in diabetic versus non-diabetic patients with overt proteinuria. Nephrology (Carlton). 2015;20(4):279–85.

    Article  CAS  Google Scholar 

  45. Lorenz JN. Chymase: the other ACE? Am J Physiol Renal Physiol. 2010;298(1):F35–6.

    Article  CAS  PubMed  Google Scholar 

  46. Park S, Bivona BJ, Kobori H, Seth DM, Chappell MC, Lazartigues E, et al. Major role for ACE-independent intrarenal ANG II formation in type II diabetes. Am J Physiol Renal Physiol. 2010;298(1):F37–48.

    Article  CAS  PubMed  Google Scholar 

  47. Park S, Bivona BJ, Ford SM Jr, Xu S, Kobori H, de Garavilla L, et al. Direct evidence for intrarenal chymase-dependent angiotensin II formation on the diabetic renal microvasculature. Hypertension. 2013;61(2):465–71.

    Article  CAS  PubMed  Google Scholar 

  48. Wysocki J, Ye M, Soler MJ, Gurley SB, Xiao HD, Bernstein KE, et al. ACE and ACE2 activity in diabetic mice. Diabetes. 2006;55(7):2132–9.

    Article  CAS  PubMed  Google Scholar 

  49. Ye M, Wysocki J, Naaz P, Salabat MR, LaPointe MS, Batlle D. Increased ACE 2 and decreased ACE protein in renal tubules from diabetic mice: a renoprotective combination? Hypertension. 2004;43(5):1120–5.

    Article  CAS  PubMed  Google Scholar 

  50. Tikellis C, Brown R, Head GA, Cooper ME, Thomas MC. Angiotensin-converting enzyme 2 mediates hyperfiltration associated with diabetes. Am J Physiol Renal Physiol. 2014;306(7):F773–80.

    Article  CAS  PubMed  Google Scholar 

  51. Soler MJ, Wysocki J, Ye M, Lloveras J, Kanwar Y, Batlle D. ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice. Kidney Int. 2007;72(5):614–23.

    Article  CAS  PubMed  Google Scholar 

  52. Kobori H, Nangaku M, Navar LG, Nishiyama A. The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease. Pharmacol Rev. 2007;59(3):251–87.

    Article  CAS  PubMed  Google Scholar 

  53. Ichihara A, Inscho EW, Imig JD, Michel RE, Navar LG. Role of renal nerves in afferent arteriolar reactivity in angiotensin-induced hypertension. Hypertension. 1997;29(1 Pt 2):442–9.

    Article  CAS  PubMed  Google Scholar 

  54. Inscho EW, Imig JD, Deichmann PC, Cook AK. Candesartan cilexetil protects against loss of autoregulatory efficiency in angiotensin II-infused rats. J Am Soc Nephrol. 1999;10(Suppl 11):S178–83.

    CAS  PubMed  Google Scholar 

  55. Bell TD, DiBona GF, Wang Y, Brands MW. Mechanisms for renal blood flow control early in diabetes as revealed by chronic flow measurement and transfer function analysis. J Am Soc Nephrol. 2006;17(8):2184–92.

    Article  PubMed  Google Scholar 

  56. Pugliese G, Pricci F, Barsotti P, Iacobini C, Ricci C, Oddi G, et al. Development of diabetic nephropathy in the Milan normotensive strain, but not in the Milan hypertensive strain: possible permissive role of hemodynamics. Kidney Int. 2005;67(4):1440–52.

    Article  CAS  PubMed  Google Scholar 

  57. Ge Y, Fan F, Didion SP, Roman RJ. Impaired myogenic response of the afferent arteriole contributes to the increased susceptibility to renal disease in Milan normotensive rats. Physiol Rep. 2017;5(3):e13089.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Parving HH, Kastrup H, Smidt UM, Andersen AR, Feldt-Rasmussen B, Christiansen JS. Impaired autoregulation of glomerular filtration rate in type 1 (insulin-dependent) diabetic patients with nephropathy. Diabetologia. 1984;27(6):547–52.

    Article  CAS  PubMed  Google Scholar 

  59. Schjoedt KJ, Christensen PK, Jorsal A, Boomsma F, Rossing P, Parving HH. Autoregulation of glomerular filtration rate during spironolactone treatment in hypertensive patients with type 1 diabetes: a randomized crossover trial. Nephrol Dial Transplant. 2009;24(11):3343–9.

    Article  CAS  PubMed  Google Scholar 

  60. Christensen PK, Akram K, Konig KB, Parving HH. Autoregulation of glomerular filtration rate in patients with type 2 diabetes during isradipine therapy. Diabetes Care. 2003;26(1):156–62.

    Article  CAS  PubMed  Google Scholar 

  61. Burke TJ, Duchin KL. Glomerular filtration during furosemide diuresis in the dog. Kidney Int. 1979;16(6):672–80.

    Article  CAS  PubMed  Google Scholar 

  62. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4,400 patients observed between 1947 and 1973 (3rd and last part) (author’s transl). Diabete Metab. 1977;3(4):245–56.

    CAS  PubMed  Google Scholar 

  63. Parving HH, Hommel E, Mathiesen E, Skott P, Edsberg B, Bahnsen M, et al. Prevalence of microalbuminuria, arterial hypertension, retinopathy and neuropathy in patients with insulin dependent diabetes. Br Med J (Clin Res Ed). 1988;296(6616):156–60.

    Article  CAS  Google Scholar 

  64. Baumann M, Burkhardt K, Heemann U. Microcirculatory marker for the prediction of renal end points: a prospective cohort study in patients with chronic kidney disease stage 2 to 4. Hypertension. 2014;64(2):338–46.

    Article  CAS  PubMed  Google Scholar 

  65. Lee MK, Han KD, Lee JH, Sohn SY, Hong OK, Jeong JS, et al. Normal-to-mildly increased albuminuria predicts the risk for diabetic retinopathy in patients with type 2 diabetes. Sci Rep. 2017;7(1):11757.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Wheelock KM, Jaiswal M, Martin CL, Fufaa GD, Weil EJ, Lemley KV, et al. Cardiovascular autonomic neuropathy associates with nephropathy lesions in American Indians with type 2 diabetes. J Diabetes Complicat. 2016;30(5):873–9.

    Article  Google Scholar 

  67. Brownrigg JRW, Hughes CO, Burleigh D, Karthikesalingam A, Patterson BO, Holt PJ, et al. Microvascular disease and risk of cardiovascular events among individuals with type 2 diabetes: a population-level cohort study. Lancet Diabetes Endocrinol. 2016;4(7):588–97.

    Article  PubMed  Google Scholar 

  68. Freedman BI, Sink KM, Hugenschmidt CE, Hughes TM, Williamson JD, Whitlow CT, et al. Associations of early kidney disease with brain magnetic resonance imaging and cognitive function in African Americans with type 2 diabetes mellitus. Am J Kidney Dis. 2017;70:627.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Sink KM, Divers J, Whitlow CT, Palmer ND, Smith SC, Xu J, et al. Cerebral structural changes in diabetic kidney disease: African American-Diabetes Heart Study MIND. Diabetes Care. 2015;38(2):206–12.

    Article  CAS  PubMed  Google Scholar 

  70. Uzu T, Kida Y, Shirahashi N, Harada T, Yamauchi A, Nomura M, et al. Cerebral microvascular disease predicts renal failure in type 2 diabetes. J Am Soc Nephrol. 2010;21(3):520–6.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Fuchs D, Dupon PP, Schaap LA, Draijer R. The association between diabetes and dermal microvascular dysfunction non-invasively assessed by laser Doppler with local thermal hyperemia: a systematic review with meta-analysis. Cardiovasc Diabetol. 2017;16(1):11.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Martens RJ, Henry RM, Houben AJ, van der Kallen CJ, Kroon AA, Schalkwijk CG, et al. Capillary rarefaction associates with albuminuria: the Maastricht Study. J Am Soc Nephrol. 2016;27(12):3748–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. von Scholten BJ, Hansen CS, Hasbak P, Kjaer A, Rossing P, Hansen TW. Cardiac autonomic function is associated with the coronary microcirculatory function in patients with type 2 diabetes. Diabetes. 2016;65(10):3129–38.

    Article  CAS  Google Scholar 

  74. Imamura S, Hirata K, Orii M, Shimamura K, Shiono Y, Ishibashi K, et al. Relation of albuminuria to coronary microvascular function in patients with chronic kidney disease. Am J Cardiol. 2014;113(5):779–85.

    Article  CAS  PubMed  Google Scholar 

  75. Miao J, Brismar K, Nyren O, Ugarph-Morawski A, Ye W. Elevated hip fracture risk in type 1 diabetic patients: a population-based cohort study in Sweden. Diabetes Care. 2005;28(12):2850–5.

    Article  PubMed  Google Scholar 

  76. Napoli N, Chandran M, Pierroz DD, Abrahamsen B, Schwartz AV, Ferrari SL, et al. Mechanisms of diabetes mellitus-induced bone fragility. Nat Rev Endocrinol. 2017;13(4):208–19.

    Article  CAS  PubMed  Google Scholar 

  77. Shanbhogue VV, Hansen S, Frost M, Brixen K, Hermann AP. Bone disease in diabetes: another manifestation of microvascular disease? Lancet Diabetes Endocrinol. 2017;5(10):827–38.

    Article  PubMed  Google Scholar 

  78. Stehouwer CD. Endothelial dysfunction in diabetic nephropathy: state of the art and potential significance for non-diabetic renal disease. Nephrol Dial Transplant. 2004;19(4):778–81.

    Article  PubMed  Google Scholar 

  79. Goligorsky MS, Chen J, Brodsky S. Workshop: endothelial cell dysfunction leading to diabetic nephropathy : focus on nitric oxide. Hypertension. 2001;37(2 Pt 2):744–8.

    Article  CAS  PubMed  Google Scholar 

  80. Nakagawa T, Sato W, Glushakova O, Heinig M, Clarke T, Campbell-Thompson M, et al. Diabetic endothelial nitric oxide synthase knockout mice develop advanced diabetic nephropathy. J Am Soc Nephrol. 2007;18(2):539–50.

    Article  CAS  PubMed  Google Scholar 

  81. De Vriese AS, Stoenoiu MS, Elger M, Devuyst O, Vanholder R, Kriz W, et al. Diabetes-induced microvascular dysfunction in the hydronephrotic kidney: role of nitric oxide. Kidney Int. 2001;60(1):202–10.

    Article  PubMed  Google Scholar 

  82. Stehouwer CD, Nauta JJ, Zeldenrust GC, Hackeng WH, Donker AJ, den Ottolander GJ. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet. 1992;340(8815):319–23.

    Article  CAS  PubMed  Google Scholar 

  83. Stehouwer CD, Fischer HR, van Kuijk AW, Polak BC, Donker AJ. Endothelial dysfunction precedes development of microalbuminuria in IDDM. Diabetes. 1995;44(5):561–4.

    Article  CAS  PubMed  Google Scholar 

  84. Clausen P, Jensen JS, Jensen G, Borch-Johnsen K, Feldt-Rasmussen B. Elevated urinary albumin excretion is associated with impaired arterial dilatory capacity in clinically healthy subjects. Circulation. 2001;103(14):1869–74.

    Article  CAS  PubMed  Google Scholar 

  85. Salmon AH, Ferguson JK, Burford JL, Gevorgyan H, Nakano D, Harper SJ, et al. Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction. J Am Soc Nephrol. 2012;23(8):1339–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Reitsma S, Slaaf DW, Vink H, van Zandvoort MA, oude Egbrink MG. The endothelial glycocalyx: composition, functions, and visualization. Pflugers Arch. 2007;454(3):345–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Nieuwdorp M, Mooij HL, Kroon J, Atasever B, Spaan JA, Ince C, et al. Endothelial glycocalyx damage coincides with microalbuminuria in type 1 diabetes. Diabetes. 2006;55(4):1127–32.

    Article  CAS  PubMed  Google Scholar 

  88. Broekhuizen LN, Lemkes BA, Mooij HL, Meuwese MC, Verberne H, Holleman F, et al. Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus. Diabetologia. 2010;53(12):2646–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. van den Hoven MJ, Rops AL, Bakker MA, Aten J, Rutjes N, Roestenberg P, et al. Increased expression of heparanase in overt diabetic nephropathy. Kidney Int. 2006;70(12):2100–8.

    Article  PubMed  CAS  Google Scholar 

  90. Garsen M, Lenoir O, Rops AL, Dijkman HB, Willemsen B, van Kuppevelt TH, et al. Endothelin-1 induces proteinuria by Heparanase-mediated disruption of the glomerular glycocalyx. J Am Soc Nephrol. 2016;27(12):3545–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rosenzweig LJ, Kanwar YS. Removal of sulfated (heparan sulfate) or nonsulfated (hyaluronic acid) glycosaminoglycans results in increased permeability of the glomerular basement membrane to 125I-bovine serum albumin. Lab Investig. 1982;47(2):177–84.

    CAS  PubMed  Google Scholar 

  92. van den Born J, van den Heuvel LP, Bakker MA, Veerkamp JH, Assmann KJ, Berden JH. A monoclonal antibody against GBM heparan sulfate induces an acute selective proteinuria in rats. Kidney Int. 1992;41(1):115–23.

    Article  PubMed  Google Scholar 

  93. Boels MGS, Koudijs A, Avramut MC, Sol W, Wang G, van Oeveren-Rietdijk AM, et al. Systemic monocyte chemotactic protein-1 inhibition modifies renal macrophages and restores glomerular endothelial glycocalyx and barrier function in diabetic nephropathy. Am J Pathol. 2017;187:2430.

    Article  CAS  PubMed  Google Scholar 

  94. Trevisan R, Bruttomesso D, Vedovato M, Brocco S, Pianta A, Mazzon C, 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(8):1347–53.

    CAS  PubMed  Google Scholar 

  95. Strojek K, Grzeszczak W, Lacka B, Gorska J, Keller CK, Ritz E. Increased prevalence of salt sensitivity of blood pressure in IDDM with and without microalbuminuria. Diabetologia. 1995;38(12):1443–8.

    Article  CAS  PubMed  Google Scholar 

  96. He FJ, Marciniak M, Markandu ND, Antonios TF, MacGregor GA. Effect of modest salt reduction on skin capillary rarefaction in white, black, and Asian individuals with mild hypertension. Hypertension. 2010;56(2):253–9.

    Article  CAS  PubMed  Google Scholar 

  97. Greene AS, Lombard JH, Cowley AW Jr, Hansen-Smith FM. Microvessel changes in hypertension measured by Griffonia simplicifolia I lectin. Hypertension. 1990;15(6 Pt 2):779–83.

    Article  CAS  PubMed  Google Scholar 

  98. Hansen-Smith FM, Morris LW, Greene AS, Lombard JH. Rapid microvessel rarefaction with elevated salt intake and reduced renal mass hypertension in rats. Circ Res. 1996;79(2):324–30.

    Article  CAS  PubMed  Google Scholar 

  99. Hernandez I, Cowley AW Jr, Lombard JH, Greene AS. Salt intake and angiotensin II alter microvessel density in the cremaster muscle of normal rats. Am J Phys. 1992;263(3 Pt 2):H664–7.

    CAS  Google Scholar 

  100. Houben AJ, Willemsen RT, van de Ven H, de Leeuw PW. Microvascular adaptation to changes in dietary sodium is disturbed in patients with essential hypertension. J Hypertens. 2005;23(1):127–32.

    Article  CAS  PubMed  Google Scholar 

  101. Morris RC Jr, Schmidlin O, Sebastian A, Tanaka M, Kurtz TW. Vasodysfunction that involves renal vasodysfunction, not abnormally increased renal retention of sodium, accounts for the initiation of salt-induced hypertension. Circulation. 2016;133(9):881–93.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Oberleithner H, Peters W, Kusche-Vihrog K, Korte S, Schillers H, Kliche K, et al. Salt overload damages the glycocalyx sodium barrier of vascular endothelium. Pflugers Arch. 2011;462(4):519–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Oberleithner H, Riethmuller C, Schillers H, MacGregor GA, de Wardener HE, Hausberg M. Plasma sodium stiffens vascular endothelium and reduces nitric oxide release. Proc Natl Acad Sci U S A. 2007;104(41):16281–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Nakagawa T, Tanabe K, Croker BP, Johnson RJ, Grant MB, Kosugi T, et al. Endothelial dysfunction as a potential contributor in diabetic nephropathy. Nat Rev Nephrol. 2011;7(1):36–44.

    Article  PubMed  Google Scholar 

  105. Triggle CR, Ding H. A review of endothelial dysfunction in diabetes: a focus on the contribution of a dysfunctional eNOS. J Am Soc Hypertens. 2010;4(3):102–15.

    Article  CAS  PubMed  Google Scholar 

  106. Sakata F, Ito Y, Mizuno M, Sawai A, Suzuki Y, Tomita T, et al. Sodium chloride promotes tissue inflammation via osmotic stimuli in subtotal-nephrectomized mice. Lab Investig. 2017;97(4):432–46.

    Article  CAS  PubMed  Google Scholar 

  107. Menne J, Eulberg D, Beyer D, Baumann M, Saudek F, Valkusz Z, et al. C-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria. Nephrol Dial Transplant. 2017;32(2):307–15.

    PubMed  Google Scholar 

  108. Norgaard K, Feldt-Rasmussen B, Borch-Johnsen K, Saelan H, Deckert T. Prevalence of hypertension in type 1 (insulin-dependent) diabetes mellitus. Diabetologia. 1990;33(7):407–10.

    Article  CAS  PubMed  Google Scholar 

  109. Ali A, Taj A, Amin MJ, Iqbal F, Iqbal Z. Correlation between microalbuminuria and hypertension in type 2 diabetic patients. Pak J Med Sci. 2014;30(3):511–4.

    PubMed  PubMed Central  Google Scholar 

  110. Hansen-Smith F, Greene AS, Cowley AW Jr, Lombard JH. Structural changes during microvascular rarefaction in chronic hypertension. Hypertension. 1990;15(6 Pt 2):922–8.

    Article  CAS  PubMed  Google Scholar 

  111. Hashimoto H, Prewitt RL, Efaw CW. Alterations in the microvasculature of one-kidney, one-clip hypertensive rats. Am J Phys. 1987;253(4 Pt 2):H933–40.

    CAS  Google Scholar 

  112. Prewitt RL, Chen II, Dowell R. Development of microvascular rarefaction in the spontaneously hypertensive rat. Am J Phys. 1982;243(2):H243–51.

    CAS  Google Scholar 

  113. Prewitt RL, Chen II, Dowell RF. Microvascular alterations in the one-kidney, one-clip renal hypertensive rat. Am J Phys. 1984;246(5 Pt 2):H728–32.

    CAS  Google Scholar 

  114. Serne EH, Gans RO, ter Maaten JC, Tangelder GJ, Donker AJ, Stehouwer CD. Impaired skin capillary recruitment in essential hypertension is caused by both functional and structural capillary rarefaction. Hypertension (Dallas, Tex: 1979). 2001;38(2):238–42.

    Article  CAS  Google Scholar 

  115. Antonios TF, Singer DR, Markandu ND, Mortimer PS, MacGregor GA. Structural skin capillary rarefaction in essential hypertension. Hypertension (Dallas, Tex: 1979). 1999;33(4):998–1001.

    Article  CAS  Google Scholar 

  116. Prasad A, Dunnill GS, Mortimer PS, MacGregor GA. Capillary rarefaction in the forearm skin in essential hypertension. J Hypertens. 1995;13(2):265–8.

    Article  CAS  PubMed  Google Scholar 

  117. Kanoore Edul VS, Ince C, Estenssoro E, Ferrara G, Arzani Y, Salvatori C, et al. The effects of arterial hypertension and age on the sublingual microcirculation of healthy volunteers and outpatients with cardiovascular risk factors. Microcirculation. 2015;22(6):485–92.

    Article  PubMed  Google Scholar 

  118. Cheng C, Diamond JJ, Falkner B. Functional capillary rarefaction in mild blood pressure elevation. Clin Transl Sci. 2008;1(1):75–9.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Park JB, Schiffrin EL. Small artery remodeling is the most prevalent (earliest?) form of target organ damage in mild essential hypertension. J Hypertens. 2001;19(5):921–30.

    Article  CAS  PubMed  Google Scholar 

  120. Schiffrin EL. Vascular remodeling in hypertension: mechanisms and treatment. Hypertension. 2012;59(2):367–74.

    Article  CAS  PubMed  Google Scholar 

  121. Boari GE, Rizzoni D, De Ciuceis C, Porteri E, Avanzi D, Platto C, et al. Structural alterations in subcutaneous small resistance arteries predict changes in the renal function of hypertensive patients. J Hypertens. 2010;28(9):1951–8.

    Article  CAS  PubMed  Google Scholar 

  122. Rizzoni D, Porteri E, Guelfi D, Muiesan ML, Valentini U, Cimino A, et al. Structural alterations in subcutaneous small arteries of normotensive and hypertensive patients with non-insulin-dependent diabetes mellitus. Circulation. 2001;103(9):1238–44.

    Article  CAS  PubMed  Google Scholar 

  123. Endemann DH, Pu Q, De Ciuceis C, Savoia C, Virdis A, Neves MF, et al. Persistent remodeling of resistance arteries in type 2 diabetic patients on antihypertensive treatment. Hypertension. 2004;43(2):399–404.

    Article  CAS  PubMed  Google Scholar 

  124. Vallon V, Richter K, Blantz RC, Thomson S, Osswald H. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol. 1999;10(12):2569–76.

    CAS  PubMed  Google Scholar 

  125. Trevisan R, Dodesini AR. The Hyperfiltering kidney in diabetes. Nephron. 2017;136(4):277–80.

    Article  CAS  PubMed  Google Scholar 

  126. Singh A, Ramnath RD, Foster RR, Wylie EC, Friden V, Dasgupta I, et al. Reactive oxygen species modulate the barrier function of the human glomerular endothelial glycocalyx. PLoS One. 2013;8(2):e55852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Singh A, Friden V, Dasgupta I, Foster RR, Welsh GI, Tooke JE, et al. High glucose causes dysfunction of the human glomerular endothelial glycocalyx. Am J Physiol Renal Physiol. 2011;300(1):F40–8.

    Article  CAS  PubMed  Google Scholar 

  128. Giugliano D, Marfella R, Coppola L, Verrazzo G, Acampora R, Giunta R, et al. Vascular effects of acute hyperglycemia in humans are reversed by L-arginine. Evidence for reduced availability of nitric oxide during hyperglycemia. Circulation. 1997;95(7):1783–90.

    Article  CAS  PubMed  Google Scholar 

  129. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414(6865):813–20.

    Article  CAS  PubMed  Google Scholar 

  130. Jha JC, Banal C, Chow BS, Cooper ME, Jandeleit-Dahm K. Diabetes and kidney disease: role of oxidative stress. Antioxid Redox Signal. 2016;25(12):657–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Bhattacharjee N, Barma S, Konwar N, Dewanjee S, Manna P. Mechanistic insight of diabetic nephropathy and its pharmacotherapeutic targets: an update. Eur J Pharmacol. 2016;791:8–24.

    Article  CAS  PubMed  Google Scholar 

  132. Forbes JM, Coughlan MT, Cooper ME. Oxidative stress as a major culprit in kidney disease in diabetes. Diabetes. 2008;57(6):1446–54.

    Article  CAS  PubMed  Google Scholar 

  133. Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):23–33.

    Article  Google Scholar 

  134. Gnudi L, Coward RJM, Long DA. Diabetic nephropathy: perspective on novel molecular mechanisms. Trends Endocrinol Metab. 2016;27(11):820–30.

    Article  CAS  PubMed  Google Scholar 

  135. Orchard TJ, Chang YF, Ferrell RE, Petro N, Ellis DE. Nephropathy in type 1 diabetes: a manifestation of insulin resistance and multiple genetic susceptibilities? Further evidence from the Pittsburgh Epidemiology of Diabetes Complication Study. Kidney Int. 2002;62(3):963–70.

    Article  CAS  PubMed  Google Scholar 

  136. Yip J, Mattock MB, Morocutti A, Sethi M, Trevisan R, Viberti G. Insulin resistance in insulin-dependent diabetic patients with microalbuminuria. Lancet. 1993;342(8876):883–7.

    Article  CAS  PubMed  Google Scholar 

  137. Goligorsky MS. Vascular endothelium in diabetes. Am J Physiol Renal Physiol. 2017;312(2):F266–F75.

    Article  CAS  PubMed  Google Scholar 

  138. Sung SH, Ziyadeh FN, Wang A, Pyagay PE, Kanwar YS, Chen S. Blockade of vascular endothelial growth factor signaling ameliorates diabetic albuminuria in mice. J Am Soc Nephrol. 2006;17(11):3093–104.

    Article  CAS  PubMed  Google Scholar 

  139. Lindenmeyer MT, Kretzler M, Boucherot A, Berra S, Yasuda Y, Henger A, et al. Interstitial vascular rarefaction and reduced VEGF-A expression in human diabetic nephropathy. J Am Soc Nephrol. 2007;18(6):1765–76.

    Article  CAS  PubMed  Google Scholar 

  140. Kim BS, Chen J, Weinstein T, Noiri E, Goligorsky MS. VEGF expression in hypoxia and hyperglycemia: reciprocal effect on branching angiogenesis in epithelial-endothelial co-cultures. J Am Soc Nephrol. 2002;13(8):2027–36.

    Article  CAS  PubMed  Google Scholar 

  141. Ismail-Beigi F, Craven TE, O'Connor PJ, Karl D, Calles-Escandon J, Hramiak I, et al. Combined intensive blood pressure and glycemic control does not produce an additive benefit on microvascular outcomes in type 2 diabetic patients. Kidney Int. 2012;81(6):586–94.

    Article  CAS  PubMed  Google Scholar 

  142. Ruospo M, Saglimbene VM, Palmer SC, De Cosmo S, Pacilli A, Lamacchia O, et al. Glucose targets for preventing diabetic kidney disease and its progression. Cochrane Database Syst Rev. 2017;6:CD010137.

    PubMed  Google Scholar 

  143. Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes. Arch Intern Med. 2012;172(10):761–9.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Zoungas S, Arima H, Gerstein HC, Holman RR, Woodward M, Reaven P, et al. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes Endocrinol. 2017;5(6):431–7.

    Article  PubMed  Google Scholar 

  145. Group SR, Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103–16.

    Article  CAS  Google Scholar 

  146. Group AS, Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575–85.

    Article  CAS  Google Scholar 

  147. Sabino B, Lessa MA, Nascimento AR, Rodrigues CA, Henriques M, Garzoni LR, et al. Effects of antihypertensive drugs on capillary rarefaction in spontaneously hypertensive rats: intravital microscopy and histologic analysis. J Cardiovasc Pharmacol. 2008;51(4):402–9.

    Article  CAS  PubMed  Google Scholar 

  148. Hamar P, Kerjaschki D. Blood capillary rarefaction and lymphatic capillary neoangiogenesis are key contributors to renal allograft fibrosis in an ACE inhibition rat model. Am J Physiol Heart Circ Physiol. 2016;311(4):H981–H90.

    Article  PubMed  Google Scholar 

  149. Gohlke P, Kuwer I, Schnell A, Amann K, Mall G, Unger T. Blockade of bradykinin B2 receptors prevents the increase in capillary density induced by chronic angiotensin-converting enzyme inhibitor treatment in stroke-prone spontaneously hypertensive rats. Hypertension. 1997;29(1 Pt 2):478–82.

    Article  CAS  PubMed  Google Scholar 

  150. Staessen J, Lijnen P, Fagard R, Verschueren LJ, Amery A. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol. 1981;91(3):457–65.

    Article  CAS  PubMed  Google Scholar 

  151. Sowers JR, Whaley-Connell A, Epstein M. Narrative review: the emerging clinical implications of the role of aldosterone in the metabolic syndrome and resistant hypertension. Ann Intern Med. 2009;150(11):776–83.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Bolignano D, Palmer SC, Navaneethan SD, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease. Cochrane Database Syst Rev. 2014;4:CD007004.

    Google Scholar 

  153. Rabelink TJ, de Zeeuw D. The glycocalyx--linking albuminuria with renal and cardiovascular disease. Nat Rev Nephrol. 2015;11(11):667–76.

    Article  CAS  PubMed  Google Scholar 

  154. Buelli S, Perico L, Benigni A. Untangling the knot in diabetic nephropathy: the unanticipated role of glycocalyx in the antiproteinuric effect of endothelin receptor antagonists. Diabetes. 2016;65(8):2115–7.

    Article  CAS  PubMed  Google Scholar 

  155. Lewis EJ, Lewis JB, Greene T, Hunsicker LG, Berl T, Pohl MA, et al. Sulodexide for kidney protection in type 2 diabetes patients with microalbuminuria: a randomized controlled trial. Am J Kidney Dis. 2011;58(5):729–36.

    Article  CAS  PubMed  Google Scholar 

  156. Gambaro G, Kinalska I, Oksa A, Pont'uch P, Hertlova M, Olsovsky J, et al. Oral sulodexide reduces albuminuria in microalbuminuric and macroalbuminuric type 1 and type 2 diabetic patients: the Di.N.A.S. Randomized trial. J Am Soc Nephrol. 2002;13(6):1615–25.

    Article  CAS  PubMed  Google Scholar 

  157. Olde Engberink RH, Rorije NM, Lambers Heerspink HJ, De Zeeuw D, van den Born BJ, Vogt L. The blood pressure lowering potential of sulodexide–a systematic review and meta-analysis. Br J Clin Pharmacol. 2015;80(6):1245–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Olde Engberink RH, Heerspink HJ, de Zeeuw D, Vogt L. Blood pressure-lowering effects of sulodexide depend on albuminuria severity: post hoc analysis of the sulodexide microalbuminuria and macroalbuminuria studies. Br J Clin Pharmacol. 2016;82(5):1351–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Badal SS, Danesh FR. Strategies to reverse endothelial dysfunction in diabetic nephropathy. Kidney Int. 2012;82(11):1151–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zhang Y, Sun X, Icli B, Feinberg MW. Emerging roles for MicroRNAs in diabetic microvascular disease: novel targets for therapy. Endocr Rev. 2017;38(2):145–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Wenstedt, E.F.E., Vogt, L. (2019). Microvascular Damage and Hemodynamic Alterations in Diabetic Nephropathy. In: Roelofs, J., Vogt, L. (eds) Diabetic Nephropathy. Springer, Cham. https://doi.org/10.1007/978-3-319-93521-8_16

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