© 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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