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Science, Technology and Medicine open access publisher.Publish, read and share novel research. Diabetic NephropathyBozidar Vujicic1, Sanjin Racki1, Tamara Turk2, Zeljka Crncevic-Orlic2 and Gordana Dordevic3[1] Department of Nephrology and Dialysis, Clinical Hospital Centre Rijeka, Rijeka,, Croatia[2] Department of Endocrinology, Diabetes and Metabolic Diseases, Clinical Hospital Centre Rijeka, Rijeka,, Croatia[3] Department of Pathology and Pathologic Anatomy, Faculty of Medicine, University of Rijeka, Rijeka,, Croatia1. Part of the excess glucose in chronic hyperglycemia binds to free amino acids of circulating or tissue proteins. The activation of protein kinase C (PKC) is one of the main mediators of hyperglycemia-induced tissue injury.
Diabetes can severely affect a person’s eyes and vision if the damage goes undetected and untreated.
We’ve provided comprehensive eye exams, contact lenses, eyeglasses, sunglasses and medical treatment of eye disease such as cataract treatment in Columbus, Ohio, for over 35 years. Photography shows delicate structure of normal glomerulus with thin glomerular basement membrane and unrecognizable mesangium. Mesangial regions are also expanded by excess mesangial matrix-like material (electron microscopy, arrow, 7.1 k)Table 2. IntroductionDiabetes mellitus (DM) is the most frequent cause of chronic kidney failure in both developed and developing countries [1]. This non-enzymatic process produces reversible early glycation products, and later, irreversible advanced glycation end products (AGEs), which accumulate in the tissues and contribute to the development of microvascular complications of DM [35].AGEs modulate the cell activation, signal transduction, and cytokine and growth factor expression through the activation of R-dependent and R-independent signal pathways.
PCK activation leads to increased vascular permeability, increased synthesis of extracellular matrix components, and increased production of reactive oxygen species (ROS), which are important mediators of kidney injury [40].Heparanase ExpressionThe regulation of heparanase expression plays an important role in the pathogenesis of diabetic nephropathy. Come see an optometrist at one of our Columbus locations – Downtown, West Columbus, Dublin, Westerville and Reynoldsburg.
Diffuse expansion of mesangium (star) and diffuse thickening of the glomerular basement membrane (arrow).
It is caused by insudation and accumulation of glycosilated plasma proteins between the glomerular endothelium and the glomerular basement membrane. Bonding to their podocyte receptors, AGEs may induce expression of some factors considered to play the key role in the pathogenesis of diabetic nephropathy, such as transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) [36].
The reduction in heparin sulfate on the surface of endothelial cell changes the negative charge of glycocalyx and consequently increases albumin permeability of the glomerular filtration membrane [41].Reactive Oxygen SpeciesIncreasing evidence shows the importance of reactive oxygen species (ROS) in the pathogenesis of diabetic nephropathy.
Diabetes decreases the blood flow to the retinal tissue, which results in an insufficient amount of oxygen to the retinal cells.
Afferent and efferent arteriolar hyalinosis is characteristic for diabetic nephropathy (star). Although the ROS production may be influenced by numerous mechanisms, the most important role in their production is played by superoxide produced by glycolysis and oxidative phosphorylation in the mitochondria. ROS activate all important pathogenetic mechanisms, such as increased production of AGEs, increased glucose entry into the polyol pathway, and PKC activation [42]. All of these are much easier to treat and have a better prognosis when found and treated early.
GBM, glomerular basement membrane.a On the basis of direct measurement of GBM width by EM, these individual cutoff levels may be considered indicative when other GBM measurements are used.
In addition, ROS directly damage endothelial glycocalyx, which leads to albuminuria without the concurrent damage to the GBM itself.ProreninIncreased serum prorenin plays a role in the development of diabetic nephropathy in children and adolescents [43].
People with no history of diabetic retinopathy are recommended to have yearly dilated exams, and those with mild retinopathy may be required to have more frequent exams. Prorenin binds to a specific tissue receptor, leading to the activation of the signal pathway of mitogen-activating protein kinases (MAPK), which potentiate the development of kidney damage [44]. The size of the kidneys is increased by approximately 20% and renal plasma flow is increased by 10%-15%, while albuminuria and blood pressure remain within the normal range. This stage starts approximately two years after the onset of the disease and is characterized by kidney damage with basement membrane thickening and mesangial proliferation.
Furthermore, the expression of bone morphogenic protein 7 (BMP-7) in DM is decreased, and the expression of profibrinogenic TGF-beta is increased [50,51].Nephrine ExpressionNephrine is a transmembrane protein, the main structural element in slit diaphragm and as such, it is important for the maintenance of filtration membrane integrity.
More recent studies have shown the association between the decreased expression of nephrine and albuminuria progression in the model of human diabetic nephropathy [52,53].5.
They can be divided into those that cannot be altered (genetic factors, age, and race) and those that can and must be changed (hyperglycemia, hypertension, dyslipidemia, and GFR) [53].Genetic Predisposition Genetic predisposition substantially determines the occurrence and severity of diabetic nephropathy [18,40].
The likeliness of diabetic nephropathy is higher in siblings and children of parents with diabetic nephropathy, independently of the type of DM [54].
There is a 14% probability for a child of the parents without proteinuria to develop clinical proteinuria, 23% probabilities in cases where one of the parents has proteinuria, and 46% probability in case that both parents have proteinuria.
This increased risk cannot be explained by the duration of DM, increased blood pressure or gycemic regulation. However, genetic predisposition for excessive salt intake and arterial hypertension could play a role. Although likeliness of chromosomes 3, 7, 18, and 20 to be associated with diabetic nephropathy is relatively high, we still cannot confirm the role of particular predisposing genetic determinants due to inconsistent results of the studies of genetic factors important in the development of this disease.Race The incidence of diabetic nephropathy is increased in African American, Mexican American, and Asian Indian ethnic groups. Occurrence and severity of the disease are higher in Blacks (3- to 6-fold in comparison with Caucasians), American Mexicans, and especially in Pima Indians in the North West part of the United States [55]. This observation in genetically incongruent populations suggests that socioeconomic factors, such as nutrition and poor control of glycemia, blood pressure, and body weight, play the key role.AgeIn patients with type 2 DM, age and duration of DM increase the risk for albuminuria [53].
EpidemiologyThe prognostic value of a small amount of albumin in urine for the development of kidney damage in patients with type 1 or 2 DM was confirmed in the early 1980’s. In the population study of 1586 Pima Indians with type 2 DM, subjects diagnosed with DM before age 20 had a higher risk of developing terminal kidney failure (25 vs. This stage of kidney damage was called the microalbuminuria stage or initial nephropathy [7]. Approximately 20-30% of the patients develop microalbuminuria after 15 years of disease duration and less than half develop real nephropathy [8]. According to the United Kingdom Prospective Diabetes Study (UKPDS), the annual incidence of microalbuminuria in patients with type 2 DM in Great Britain is 2% and the prevalence is 25% ten years after the diagnosis [2]. Moreover, at least three factors have been shown to contribute to the development of increased arterial pressure in this metabolic disorder including hyperinsulinemia, excessive extracellular fluid volume, and increased arterial rigidity. Proteinuria develops in approximately 15-40% patients with type 1 DM, usually after 15-20 years of DM duration [11].
Hyperinsulinemia contributes to the development of increased arterial pressure via insulin resistance in type 2 DM or via administration of insulin per se. Diabetic nephropathy is more frequent in African Americans, Asian Americans, and Native Americans [12]. In Caucasians, the progressive kidney disease is more frequent in patients with type 1 than type 2 DM, although its overall prevalence in the diabetic population is higher in patients with type 2 DM because this type of DM is more prevalent [13].


This hypertensive response, although not reported in all clinical studies, is most likely mediated by weight gain combined with pro-hypertensive effect of insulin. Hyperinsulinemia could be the link between overweight and increased blood pressure in patients with or without DM, since it increases sympathetic activity and retention of sodium in the kidneys.Sodium and water retention are induced by insulin itself, while the increased filtration of glucose is induced by hyperglycemia. According to a study published in 1990, around 50% of Pima Indians with type 2 DM developed nephropathy after 20 years of the disease, and 15% of them were already in the terminal stage of kidney failure [14].In the United States, the occurrence of diabetic nephropathy in patients beginning kidney replacement therapy doubled in the 1991-2001 period [12].
The excess filtered glucose is reabsorbed (as long as there is a moderate hyperglycemia) in the proximal tubule via sodium-glucose co-transport, which concurrently leads to the increase in sodium reabsorption [59].
Fortunately, the trend has been decreasing, most likely due to the better prevention and earlier diagnosis and treatment of DM [15].3. Sodium reabsorption increases blood pressure, which may be prevented and regulated by salt-free diet.Patients with DM have increased arterial stiffness, which develops due to the increased glycation of proteins and consequent development of arteriosclerosis. Decreased arterial elasticity in patients with glucose intolerance or DM contributes to the increased systolic pressure as an independent mortality risk factor [60].Glomerular Filtration RateIncreased GFR at diagnosis is a risk factor for the development of diabetic nephropathy.
As opposed to other capillaries in the body, glomerular capillaries are highly permeable to water (hydraulic conductivity) and relatively impermeable to large molecules. In approximately half of the patients with type 1 DM lasting up to five years, GFR value is approximately 25-50% above normal range.
Such permeability is possible because of the unique three-layer structure of glomerular filtration membrane consisting of endothelial glycocalyx, glomerular basement membrane, and podocytes (glomerular visceral epithelial cells). These patients have a higher risk of developing diabetic nephropathy [61].Dynamics of structural and hemodynamic changes is influenced by increased intraglomerular pressure, with the resulting glomerular hyperfiltration and hypertrophy and damage to the endothelial wall. Pathological changes develop in the glomeruli of patients with long-duration DM before the appearance of microalbuminuria.The severity of glomerular damage is proportional to GFR value, DM duration, and blood glucose regulation [16,17].
Strict glycemic control, limited protein intake, and blood pressure control may slow down the progress of renal disease in type 1 DM [62]. The main pathohystological changes in diabetic nephropathy include the thickening of the glomerular basement membrane (GBM), mesangial expansion, nodular sclerosis – Kimmelstiel-Wilson change, diffuse glomerular sclerosis, tubular interstitial fibrosis, and arteriosclerosis and hyalinosis of kidney blood vessels (Figures 1-3). Figure 1.Photography shows delicate structure of normal glomerulus with thin glomerular basement membrane and unrecognizable mesangium. More than 45% of patients with type 2 DM at diagnosis have GFR that is two standard deviations higher than that in their age-matched no-DM or overweight controls [63].
Patients with type 2 DM are older and, therefore, have greater likelihood of developing atherosclerotic vascular changes that influence GFR and glomerular size [64]. The role of intraglomerular hypertension in the pathogenesis of diabetic nephropathy explains why systemic hypertension is such an important risk factor for the development of this kidney disease [65].
As a result, increased blood pressure does not induce the expected vasoconstriction in the afferent arteriole, which would reduce the influence of systemic hypertension on intraglomerular pressure [66].Glycemic Regulation Diabetic nephropathy often develops in patients with poor glycemic control. Mallory stain, X 100.Among other pathological lesions, we should mention hyalinosis, the so-called fibrin cap, which consists of accumulated hyaline material between endothelial cells and glomerular basement membrane (Figure 4) [18]. Fibrin cap is present in approximately 60% of the cases and is believed to be associated with chronic ischemia [19].
Furthermore, adequate diet and reduction in body weight decrease proteinuria and improve kidney function in these patients [69]. The role of overweight as a risk factor for diabetic nephropathy (independent of DM and glycemic control) has not been clearly confirmed. SmokingAlthough recent studies have shown the association between smoking and progression of diabetic nephropathy, a large prospective study by Hovind et al.
PAS stain, X 200.There is a significant overlap between the described changes in patients in different stages of albuminuria, independent of their type of DM [16]. However, the fact that the expansion of mesangium and glomerular sclerosis do not occur simultaneously indicates their different pathogenesis within diabetic nephropathy [20]. Each of the above-described factors increases the risk of diabetic nephropathy, but none is predictive enough for the development of diabetic nephropathy in an individual patient.6. Under light microscopy, the reduction in the podocyte number is easily noticed in patients with type 1 DM and 2 [21].Since histological changes in both types of DM overlap to a great extent, the Scientific Committee of the Society for Pathological Anatomy established the Pathologic Classification of Diabetic Nephropathy, where diabetic nephropathy is histologically divided into four stages of glomerular damage (Table 2).
Association between diabetic nephropathy and retinopathyPatients with type 1 DM and nephropathy almost always have other complications related to the underlying disease, such as retinopathy and neuropathy [9].
Retinopathy has easily recognizable clinical manifestations and always precedes the clinically manifest signs of nephropathy in the same patient. A small number of patients with advanced retinopathy have glomerular histological changes and microalbuminuria, but most have no biopsy evidence of kidney disease [72]. The association between diabetic nephropathy and retinopathy is weaker in patients with type 2 DM.
Diabetic retinopathy was present in 15 of these 27 patients and in none of the eight patients without diabetic nephropathy. Further analysis showed that approximately one-third of patients without retinopathy had no biopsy evidence of diabetic nephropathy [74].Thus, patients with type 2 DM and significant proteinuria and retinopathy were most likely to develop diabetic nephropathy, whereas those with proteinuria but without retinopathy had a greater likelihood of having an underlying non-diabetic kidney disease [75].
Kidney biopsy with a complete analysis of the sample (light, immunofluorescent, and electron microscopies) represents the gold standard in the diagnostic workup of patients with non-diabetic renal disease.
In the study by Schwartz et al, biopsy was performed in 36 patients with type 2 DM and nephropathy.
In 17 of them, biopsy showed visible glomerulosclerosis with Kimmelstiel-Wilson nodules, whereas in the remaining 15 patients, biopsy showed changes characteristic of diabetic nephropathy (mesangial sclerosis), but with no classical nodules present. There was no difference in the duration of disease and glycemic regulation between patients with and those without nodules.
PathogenesisPathogenesis of diabetic nephropathy is very complicated and results from the interaction of hemodynamic and metabolic factors.Glomerular hyper filtrationIncreased intraglomerular pressure and hyper filtration as early changes in the development of diabetic nephropathy were described by Stadler and Schmidt in 1959 [26]. A strong association was found between severe retinopathy and presence of Kimmelstiel-Wilson nodules. In the 1970's, Mogensen emphasized that as many as 40% newly found DM cases had increased glomerular filtration [27].Although the mechanism of development of hyper filtration is not completely understood, several factors have been found to play a role in its development. HormonesThe role of hormones was experimentally demonstrated in the study by Serri et al, who showed that the infusion of somatostatin analogues (octreotide) partly led to the decrease in hyperfiltration and kidney size. In case that no retinopathy is present, non-diabetic causes of kidney disease should be investigated. In their study, glycemic regulation, plasma glucagon, and growth hormone levels remained unchanged, but the concentration of insulin-like growth factor-1 (IGF-1) decreased [28]. Pathogenetic role of IGF-1 has not been completely elucidated, but it is known that exogenous administration of his hormone in non-DM patients leads to afferent arteriolar dilation and GFR increase, which are the changes also observed in initial diabetic nephropathy [29]. Biomarkers of diabetic nephropatyAlbuminuria remains the only biomarker acceptable for diagnostic purposes, although some growth factors are expected to replace albuminuria in future. The identical hemodynamic changes, along with the increase in kidney size, occur in experimental animal models after the infusion of IGF-1 [30].
It is known that values of TGF beta, vascular endothelial growth factor (VEGF), and CTGF are increased in the plasma and urine of patients with diabetic nephropathy [78-80].8. Non-diabetic kidney disease Proteinuria is sometimes present in DM because of the primary glomerular disease rather than diabetic nephropathy.


In that case, possible caused of kidney damage may include membrane nephropathy, minimal change disease, IgA nephropathy, focal glomerulosclerosis, Henoch-Schonlein purpura, proliferative glomerulonephritis, and so on. The main clinical signs of primary glomerular disease are as follows:Proteinuria, which started in the first five years after the diagnosis of type 1 DM. The same study showed that the addition of angiotensin-converting enzyme inhibitor (ACEI) resulted in a decrease in blood pressure in both men and women, but GFR decreased only in women [31].Sorbitol The enzyme aldose reductase converts intracellular glucose to sorbitol, which remains in the cell.
Although research in patients with type 1 DM and known hyperfiltration has shown that the infusion of aldose reductase inhibitor (tolrestat) decreases GFR to normal values, a possible therapeutic use of this agent should be confirmed in more studies [32].Increased sodium reabsorption and tubuloglomerular feedbackIncreased renal tubular sodium reabsorption due to increased sodium-glucose co-transport leads to the increase in extracellular fluid volume, which then increases GFR [33]. This period is probably the same in type 2 DM, but the exact time of the onset of the disease is difficult to determine.Acute onset of kidney disease.
In an experimental DM model, it was shown that hyperinsulinemia and mild hyperglycemia stimulate reabsorption of sodium in the proximal tubules, resulting in the decreased fluid flow to distal tubules, which then activates the so-called tubuloglomerular feedback mechanism in the macula densa [34]. The presence of erythrocytes (mostly acanthocytes) and rouleaux formations in urine sediment. In this case, the renal hyper filtration response to the imbalance caused by increased sodium reabsorption in the proximal tubules consequently increases fluid retention.
Patients with microscopic hematuria may have a benign familial hematuria, which is present in approximately 9% of population with or without diabetic nephropathy [81]The absence of diabetic retinopathy or neuropathy in patients with type 1 DM. Although the role of glomerular hyperfiltration in the pathogenesis of diabetic nephropathy is unquestionable, it itself is not sufficient to cause kidney damage. Nephrosclerosis Proteinuria and kidney failure in patients with DM may also be caused by other diseases apart from primary glomerular diseases. The most frequent cause is atherosclerotic vascular disease (nephrosclerosis) in older patients with type 2 DM [82]. This disease cannot be clinically discerned from diabetic nephropathy without kidney biopsy.
However, kidney biopsy is not necessary in most cases, because the correct diagnosis in this patient group is not clinically important. What speaks in favor of nephrosclerosis is the significant increase in serum creatinine after the introduction of ACEI or ARB for the treatment of hypertension or slowing down the progress of chronic kidney disease.
TreatmentStrict Glycemic ControlThe effect of strict glycemic control depends on the DM stage in which it was started and consequent normalization of glucose metabolism.
Intensified insulin therapy that keeps glucose values within normal ranges decreases the development or progress of diabetic nephropathy. It stabilizes or decreases the elimination of proteins in patients with pronounced proteinuria. This effect is not apparent in patients who are not relatively normogycemic during two years. Strict Blood Pressure ControlStrict blood pressure control is important in the prevention of progress of diabetic nephropathy and other complications in patients with type 2 DM.
According to the UKPDS study, a reduction in systolic blood pressure by 10 mm Hg decreases the risk of development of diabetic complications by 12%; the risk is the lowest where systolic blood pressure values are below 120 mm Hg [85]. Antihypertensive therapy may be started even when blood pressure values are in the upper normal range.Inhibition of Renin-Angiotensin-Aldosterone SystemAngiotensin II is the most effective factor of renin-angiotensin-aldosterone system (RAAS), resulting from a range of proteolytic reactions that begin with the conversion of angiotensinogen to angiotensin I through the catalytic action of renin (Figure 7). RAAS is directly associated with blood pressure regulation, body fluid volume, and vascular response to injury and inflammation.
Inappropriate activation of this system increases the blood pressure and has anti-inflammatory, prothrombotic, and proatherogenic effects, which in the long run lead to irreversible damage of target organs. Although aldosterone, renin, and end-products of angiotensin degradation are also involved in this process, majority of the RAAS effects on target organs are mediated by angiotensin II, which is present in the bloodstream and tissues. Angiotensin II, which is produced in the heart, brain, and kidneys through alternative pathways by kinase and endopeptidase activity, is more effective than angiotensin II produced in the bloodstream [88]. AT1 receptor activation is responsible for vasoconstriction, release of aldosterone, vascular remodeling, oxidative stress, and has anti-inflammatory, proatherogenic, and prothrombotic effects [89]. The activation of AT2 receptors leads not only to vasodilatation, growth inhibition, and antiatherogenic effects, but also to heart hypertrophy and poorer revascularization after the obstruction of coronary or peripheral artery [90]. Later studies have confirmed that angiotensin II plays the key role in the functional and structural changes linking proteinuria with the development of diabetic nephropathy. Along with pleiotropic effects, angiotensin II has effects on the structure of glomerular filtration membrane, inducing the remodeling of the podocytic cytoskeleton and causing their apoptosis, which contributes to easier ultrafiltration of plasma proteins [93]. Renoprotective effect of ACEI and ARB has been confirmed in a meta-analysis showing that ACEI and ARB decrease albuminuria in patients with DM more effectively than antihypertensive medications whose mechanism of action excludes RAAS [94]. Early treatment with ACEI may prevent microalbuminuria, which is the early sign of glomerular damage and marker of cardiovascular risk in patients with DM. Delayed treatment with ACEI or ARB in patients with type 2 DM, diabetic nephropathy, and proteinuria is not effective enough. Increasing ACEI and ARB dosages above the recommended values for the treatment of hypertension or their combination is very effective in reducing albuminuria [95]. Aggressive plasma lipid reduction is an important therapeutic intervention, because patients with DM have an increased risk of coronary disease.
Treating dyslipidemia with statins slows down the progression of diabetic nephropathy [97]. In addition to statins, fenofibrate also decreases the progression of albuminuria in patients with DM [98].
In addition to anti-inflammatory effect, it decreases the production of collagen type 1 in mesangial cells via nuclear peroxisome proliferator-activated receptors (PPAR) alpha [99]. Intensive glycemic control, blood pressure control by RAAS inhibitors, and decreasing serum lipid concentration is an optimal therapeutic approach in patients with DM and diabetic nephropathy (including the microalbuminuria stage).
The Role of Other FactorsTransforming growth factor beta (TGF-beta) has effects on cell hypertrophy and increased collagen synthesis. Inhibition of TGF-beta in experimental DM model prevented the development and progression of diabetic nephropathy [100]. Experimental studies have shown that non-dihydropyridine calcium channel blocker (diltiazem) slows down the progression of most morphological changes in diabetic nephropathy [101]. On the other hand, diltiazem monotherapy leads to the increased tubulointerstitial fibrosis and global, but not segmental, glomerulosclerosis.
Peroxisome proliferator-activated receptors (PPAR) play a significant role in the regulation of adipogenesis, lipid metabolism, insulin sensitivity, inflammation, and blood pressure control; however, they also seem to play a significant role in the development of diabetic nephropathy in type 2 DM patients [102]. In an experimental animal model of diabetic nephropathy, PPAR gamma agonists, such as tiazolidinedones (oral hypoglicemic agents), were shown to reduce fibrosis, mesangial proliferation, and inflammation [103].




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