© Borgis - Postępy Nauk Medycznych 3/2013, s. 216-219
Władysław Grzeszczak1, Grzegorz Wystrychowski1, *Edward Franek2, 3
Rola czynników hemodynamicznych i metabolicznych w powstawaniu nefropatii cukrzycowej
The role of haemodynamic and metabolic factors in the development of diabetic nephropathy
1Department of Internal Medicine, Diabetology and Nephrology, Medical University of Silesia, Katowice
Head of Department: prof. Władysław Grzeszczak, MD, PhD
2Department of Internal Medicine, Endocrinology and Diabetology, Central Clinical Hospital of the Ministry of Interior, Warszawa
Head of Department: prof. Edward Franek, MD, PhD
3Department of Human Epigenetics, Mossakowski Medical Research Centre Polish Academy of Sciences, Warszawa
Head of Department: prof. Monika Puzianowska-Kuźnicka, MD, PhD
Nefropatia cukrzycowa jest wynikiem interakcji wielu różnych czynników patofizjologicznych (metabolicznych, hemodynamicznych, neurogennych i toksycznych) u chorego predysponowanego genetycznie. Występuje ona nawet u 50% chorych. Praca niniejsza opisuje rolę czynników hemodynamicznych i metabolicznych w powstawaniu nefropatii cukrzycowej. Najpierw omówiono rolę zmian ciśnienia tętniczego wewnątrz kłębuszka nerkowego i czynniki mogące je w wielu mechanizmach patogenetycznych modyfikować. Następnie opisano czynniki metaboliczne, takie jak hiperglikemia, dyslipidemia i nadmiar białka w diecie. Szczególną uwagę poświęcono hiperglikemii. Opisano cztery mechanizmy, w których może ona przyczyniać się do rozwoju nefropatii u chorych na cukrzycę: glukotoksyczność, nieenzymatyczną glikację, aktywację szlaku poliolowego oraz stres oksydacyjny. Wydaje się zatem, że leczenie nefropatii cukrzycowej powinno być także wieloczynnikowe.
Diabetic nephropathy results from the interaction of various factors (metabolic, hemodynamic, neurogenic, and toxic ones) in a genetically predisposed diabetic patient. Up to 50% of diabetics are affected. This manuscript reviews the role of hemodynamic and metabolic factors in the development of diabetic nephropathy. First, the role of glomerular blood pressure changes is described, together with different factors that may influence it in different mechanisms. Then, metabolic factors like hyperglycemia, dyslipidaemia and excess dietary protein intake are addressed. Special attention was paid to hyperglycemia. Four mechanisms associated with it are described, Glucotoxicity, non-enzymatic glycosylation, polyol pathway activation and oxidative stress, all may contribute to development of nephropathy in patients with diabetes. Therefore it seems that also treatment of this complication should be multifactorial.
Overt diabetic nephropathy develops in 20-40% of diabetic patients (1-4). Although pathogenesis of diabetic nephropathy is not entirely elucidated, it is evident from numerous studies that hemodynamic as well as metabolic factors play an important role in its development. Diabetic nephropathy is thus a result of an interplay between those patophysiologic factors, although the basal pathogenetic factor is of course hyperglycemia.
Glomerular hyperfiltration is an independent risk factor of diabetic nephropathy both in type 1 and type 2 diabetes (5, 6). It seems that it depends directly upon haemodynamic factors active in the kidneys. Blood pressure and haemodynamics in the glomeruli are under control of and results from an interplay of contracting or dilating afferent and efferent arterioles. Changes in that interplay can be evoked by various factors. In patients with diabetes, all these factors (tab. 1), as well as variation in systemic blood pressure, result in high blood pressure in glomerular capillaries. This may lead, especially in genetically predisposed patients, to stiffening of glomerular vessels (in a process similar to that that occurs in diabetic retinopathy) and results in transmission of blood pressure onto mesangium with later damage of the latter structure, and in glomerular hyperfiltration. Glomerular hypertension contributes also to damage, apoptosis and separation of podocytes, resulting in proteinuria (7).
Table 1. Chosen factors influencing intracapillary blood pressure (according to 13).
|Atherosclerosis and atherothrombosis|
Insulin-like growth factor-1
Intracellular sorbitol abundance and myo-inositol deficiency
Prostaglandins and bradykinin
In many studies it was shown that glomerular filtration may be affected by following factors: renal blood flow, transcapillary hydrostatic pressure, oncotic pressure and ultrafiltration coefficient (8). These factors are also responsible for hyperfiltration developing in diabetic kidney, in which decrease in the tonus of afferent glomerular arterioles and increase (even if only relative) of it in the efferent arterioles results in increase of intracapillary pressure (9). As angiotensin receptor blockers and angiotensin converting enzyme inhibitors exert a beneficial effect in diabetic nephropathy, and it is known that in diabetic animals and patients the systemic activity of renin-angiotensin-aldosterone system (RAAS) is rather decreased (10), it is believed that it is overactivity of the local renin-angiotensin system that is responsible for these abnormalities.
Similarly, as RAAS inhibiting agents seem to be effective in decreasing of proteinuria also in doses not lowering systemic blood pressure (11), their effectiveness must be dependent upon improvement of local hemodynamic, but also improvement of neural (decrease of adrenergic system activation) and other local factors (decrease of oxidative stress and of local proinflammatory and profibrotic factors) (12).
Hyperglycemia leads to structural and functional disturbances in all diabetic patients (14, 15). In 20-30% of patients who are genetically predisposed renal injury happens faster and is more abundant. Numerous studies revealed an increased risk of glomerular filtration (GFR) decline and albuminuria with elevated HbA1c levels (16-19). Improved glycemic control reduces the risk of micro- or macroalbuminuria, although does not eliminate it. For example, in the Diabetes Control and Complications Trial (DCCT) it has been shown that in type 1 diabetes a more intensive hypoglycemic treatment diminishes the risk of nephropathy by 34-56%, depending on the stage of the disease at baseline (20). In type 2 diabetes intensive glucose-lowering therapy decreases the risk of nephropathy by 33-72% (17, 21). Among newer studies, the ADVANCE trial has shown that an improved glycemic control with the use of gliclazide (as well as a better blood pressure control with perindopril and indapamide) was associated with a 33% reduction of the risk of a new-onset or progression of a previously present nephropathy (22). It is not clear whether a threshold level of HbA1c exists, below which advance of nephropathy is significantly slower. Some studies suggested that this level is at ~8% (21, 23).
It should be added that hyperglycemia is also a risk factor of chronic kidney disease, and a good glycemic control can delay end-stage renal disease (24-26).
Among metabolic mediators of kidney injury due to hyperglycemia, glucotoxicity, non-enzymatic glycosylation, activation of polyol pathway of glucose metabolism, and oxidative stress can be named.
This term describes a direct toxic effect of high glucose concentrations on cells and organs. In kidneys high glucose levels increase extracellular matrix production, number of mesangial cells, and influences expression of different proteins, and cytokines and enzymes. Among them collagen, laminin and fibronectin (27), transforming growth factor β (TGF-β) (28) and matrix metaloproteinases (29) seem to be most important.
Non-enzymatic glycosylation of proteins
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1. Krolewski AS, Warram JH, Christlieb AL et al.: The changing natural history of nephropathy in type 1 diabetes. A J Med 1985; 78: 785-794.
2. Hasslacher C, Ritz E, Wahl P, Michael C: Similar risk of nephropathy in patients with type I or type II diabetes mellitus. Nephrol Dialysis Transplant 1989; 4: 859-863.
3. Ravid M, Savin H, Jutrin I et al.: Long-term stabilizing effect of angiotensin converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993; 118: 577-581.
4. Adler A, Stevens RJ, Manley SE et al.: UKPDS Group Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int 2003; 63: 225-232.
5. 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.
6. Nelson DG, Benett PH, Beck GJ: Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. N Engl J Med 1991; 335: 1636-1642.
7. Stieger N, Worthmann K, Schiffer M: The role of metabolic and hemodynamic factors in podocyte injury in diabetes. Diabetes Metab Res 2011; 27: 207-215.
9. Bosh JP, Lew S, Glabman S, Lauer A: Renal hemodynamic changes in humans. Response to protein loading in normal and diseased kidneys. Am J Med 1986; 81: 809-815.
10. Hajashi K, Epstein M, Lountzelhiser R, Forster H: Impaired myogenic responsiveness of the afferent arteriole in streptozotocin-induced diabetic rats: role of eicosanoid derangements. J Am Soc Nephrol 1992; 2: 1578-1586.
11. Ruggenenti P, Cravedi P, Remuzzi G: The RAAS in the pathogenesis and treatment of diabetic nephropathy. Nat Rev Nephrol 2010; 6(6): 319-330.
12. Siragy HM, Carey RM: Role of intrarenal renin-angiotensin – aldosterone system in chronić kidney disease. Am J Nephrol 2010; 31: 541-550.
13. Grzeszczak W: Nefropatia cukrzycowa. [W:] Sieradzki J (red.): Cukrzyca. ViaMedica, Gdańsk 2006.
14. Alaveras A: Promotors of progression of diabetic nephropathy the relatives roles of blood glucose and blood pressure control. Nephrol Dial Transplant 1997; 12: 71-74.
15. Wolf G, Thaiss F: Hyperglyceamia – pathophysiological aspects of the cellular level. Nephrol Dial Transplant 1995; 10: 1109-1112.
16. The Diabetes Control and Complications Trial (DCCT) Research group Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complication. Trial Kidney Int 1995; 47: 1703-1720.
17. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-853.
18. UK Prospective Diabetes Study (UKPDS) Group: Effect of intensive blood – glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) (published erratum appears in Lancet). Lancet 1998; 352: 854-865.
19. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin – dependent diabetes mellitus. N Engl J Med 1993; 329: 977-986.
20. Jackle-Meyer I, Szukics B, Neubauer K: Extracellural matrix proteins as early marker in diabetic nephropathy. Eur J Clin Chem Biochem 1995; 33: 211-219.
21. Shichiri M, Kishikawa H, OhkuboY, Wake N: Long-term results of the Kumamoto study on optimal diabetes control in type 2 diabetic patients. Diabetes Care 2000; 23: B21-B29.
22. Zoungas S, deGalan BE, Ninomiya T et al.: Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with diabetes: New results from the ADVANCE trial. Diabetes Care 2009; 32: 2068-2074.
23. The absence of glycemic treshold for the development of long – term complications: the perspective of Diabetes Control and Complications Trial. Diabetes 1996; 45: 1289-1298.
24. Eastman RC, Javitt JC, Herman WH: Model of complications of NIDDM. II. Analysis of the health benefits and cost – effectiveness of treating NIDDM with the goal of normoglycemia. Diabetes Care 1997; 20: 735-744.
25. Diabetes Control and Complications Trial Research Group. Lifetime benefits and costs of intensive therapy as practiced in the diabetes control and complications trial. JAMA 1996; 276: 1409-1415.
26. Eastman RC, Ritz E: Effect of control of diabetes mellitus on progression of renal failure. Kidney Int 1987; Suppl. 22: S53-S56.
27. Suzuki D, Miyazaki M, Jinde K: In situ hybridization studies of matrix metalloproteinase-3, tissue inhibitor of metalloproteinase-1 and type IV collagen in diabetic nephropathy. Kidney Int 1997; 52: 11-119.
28. Reeves WB, Anohedi TE: Transforming growth factor beta contributes to progressive diabetic nephropathy. Proc Neth Acod Sci USA 2000; 97: 7667-7669.
29. McLennan SV, Mortell SKY, Ycle DK: Effect of mesangium glycation on matrix metaloproteinase activities: possible role in diabetic nephropathy. Diabetes 2002; 51: 2612-2618.
30. Czekalski S: Nefropatia cukrzycowa. [In:] Książek A, Rutkowski B: Nefrologia. Czelej, Lublin 2004: 346-371.
31. Viberti G: Diabetic nephropathy. [In:] Kahn CR, Weir GC (ed.): Joslins diabetes mellitus. Lea and Febiger 1994: 191-196.
32. Polizzi FC, Andican G, Cetin E et al.: Increased DNA glycation in type 2 diabetes mellitus: The effect of thiamine and pyridoxine therapy. Exp Clin Endocrinol Diabetol 2012 (epub ahead of print).
33. Lewis EJ, Greene T, Spitalewitz S et al.: Pyridorin in type 2 diabetic nephropathy. J Am Soc Nephr 2012; 23: 131-136.
34. Ishibashi Y, Matsui T, Takeuchi M, Yamagishi SI: Beneficial effect of metformin and irbesartan on advanced glycation end products (AGEs) – RAGE-induced proximal tubular cel injury. Pharmacol Res 2011 (epub ahead of print).
35. Alaveras A: Promotors of progression of diabetic nephropathy the relatives roles of blood glucose and blood pressure control. Nephrol Dial Transplant 1997; 12: 71-74.
36. Reeves WB, Rawal BB, Abdel-Rahman EM, Awad AS: Therapeutic Modalities in Diabetic Nephropathy: Future Approaches. Open J Nephrol 2012; 2(2): 5-18.
37. Chang SY, Chen YW, Chenier I et al.: Angiotensin II type II receptor deficiency accelerates the development of nephropathy in type 1 diabetes via oxidative stress and ACE2. Exp Diabetes Res 2011; 2011: 521076.
38. Kashihara N, Haruna Y, Kondeti VK, Kanwar YS: Oxidative stress in diabetic nephropathy. Curr Med Chem 2010; 17: 4256-4269.
39. Orchard TJ, Chang YF, Ferrell RE et al.: Nephropathy in type 1 diabetes: a manifestation of insulin resistance and multiple genetic susceptibilities? Further evidence from the Pittsburg Epidemiology of Diabetes Complication Study. Kidney Int 2002; 62: 963-970.
40. Wanner Ch, Zimmermann J, Quaschning T: Lipid disorders in diabetic nephropathy. [In:] Hasslacher Ch (ed.): Diabetic nephropathy, John Wileu & Sons 2001: 175-202.
41. Moorhead JF, El-Nahas M, Chan MK, Vorghese Z: Lipid nephrotoxicity in chronic progressive glomerular and tubulo-interstitial disease. Lancet 1982; 2: 1309-1311.
42. Schlöndorff D: Cellular mechanisms of lipid injury in the glomerulus. Am J Kidney Dis 1993; 22: 279-285.
43. Zoja C, Corna D, Gagliardini E et al.: Adding a statin to a combination of ACE inhibitor and ARB normalizes proteinuria in experimental diabetes, which translates into full renoprotection. Am J Physiol Renal Physiol 2010; 299: F1203-1211.
44. Mason JC: The statins – therapeutic diversity in renal disease? Curr Opin Nephrol Hypertens 2005; 14: 17-24.
45. Koya D, Haneda M, Inomata S et al.: Long-term effect of modification of dietary protein intake on the progression of diabetic nephropathy: a randomised controlled trial. Diabetologia 2009; 52: 2037-2045.