Type: Exploratory
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Progression of diabetic nephropathy is poorly treated today, and its management outcomes are less than satisfactory. However, today the pathogenesis of kidney damage in diabetes type II is better understood than a decade ago.

Diabetes mellitus is a growing public concern. Primarily, this is a disorder of insulin activity and related glucose metabolism. Should absolute or relative insulin deficiency develop numerous negative consequences occur. In type I diabetes, the pancreas fails to produce insulin. Thus, the patient needs to inject the hormone regularly to overcome its deficiency. In type II diabetes, the amounts of insulin may be sufficient, but these are the tissues that become resistant to its action. Sometimes, however, absolute insulin deficiency takes place. This type of diabetes, at least at the early stages, can be treated with oral remedies that enhance tissues’ sensitivity to insulin. Type II diabetes, formerly known as adult type, or non-insulin dependent, is due to genetic factors, as well as life style. However not all genes responsible for insulin resistance have been identified. It must be noted that genetic factors determine the risk of diabetic nephropathy as well. Most people of type II diabetes are obese, predominantly in the abdominal region.

Carbohydrates that the human digests are converted to simple molecules. Glucose is a monosaccharide that serves as the main source of energy. Glucose is the key molecule for both aerobic and anaerobic respiration. Through the process of its breakdown, chemical bounds in glucose oxidizes to CO2 and H20 to yield energy. Thus, glucose plays a major role in human metabolism. Insulin is the principal hormone to regulate blood glucose level. Its molecules provide intake of glucose into the cells within the tissues of the body. The most dependent of insulin are muscle cells and fat cells. Neurons do not depend on insulin and are capable to uptake glucose on without assistance.

Insulin is a peptide hormone produced by the beta-cells of the pancreas. Insulin causes cells of the muscles, the liver and the fat to take up glucose from the blood. Insulin synthesis depends on the stimuli, the most important to consider is the glucose itself. When glucose or carbohydrates containing glucose are digested, the level of glucose in the blood elevates. This stimulates the previously stored insulin release from the beta-cells. With time, synthesis of insulin is activated, and the second phase of response starts – the long acting insulin release in answer to the glucose stimulus. Finally, insulin degrades on promoting glucose intake by peripheral tissues.

The Physiological Effects of Insulin

The physiological effects of insulin are numerous, extending far from glucose level regulation:

–   glucose uptake

–   amino acids uptake regulation

–    modification of activity of enzymes

–   anabolic: enhancing glycogen and lipid synthesis, protein synthesis

–  decreasing lipolysis and gluconeogenesis

–   potassium uptake (in concordance with glucose)

–  regulation of muscle tone.

In the light of numerous effects of insulin, it is transparently evident why the World Health Organization. would define diabetes as ‘a metabolic disorder of multiple etiology characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from insulin secretion, insulin action, or both’. As for type II diabetes, the report explains:

‘Whereas patients with this form of diabetes may have insulin levels that appear normal or elevated, the high blood glucose, the high blood glucose levels in these diabetic patients would be expected to result in even higher insulin values had their beta-cell function been normal. Thus, insulin secretion is defective and insufficient to compensate for the insulin resistance’

Chronic elevations of glucose in diabetes result in vascular complications. In spite of the fact that in type II diabetes hyperglycemia is often not severe enough to provoke noticeable elevations of glucose for many years, these patients are at increased risk of developing micro- and macro- vascular complications. In type II diabetes hyperglycemia starts after the forties, when the kidneys have already suffered from history of elevated blood pressure, smoking, obesity of aging.

Diabetic Nephropathy

Diabetic nephropathy is a grave microvascular complication of diabetes. This is the leading cause of end-stage kidney disease, but current therapies remain unsatisfactory. Type II diabetes accounts for 44 percent of all new cases of renal failure. According to the National Diabetes Statistics, type II diabetes is the leading contributor to end-stage renal disease in the US, living on chronic dialysis or waiting for organ transplantation. In the United States, diabetes affects 8.3% of the population, and type II found in 90–95% of all diagnosed cases of adult diabetes. Diabetes increases the risk of end-stage kidney disease 12-fold. In the United States, diabetic nephropathy has increased 150 percent in the past decade. In addition, diabetic patients require more financial resources than non-diabetics on dialysis. In 1996, 4.6 billion USD in the US had been spent to manage the disorder. Between 20 to 40 percent of diabetic patients develop nephropathy, although the exact reason why others do not is still unknown.

The natural history of renal disorders in diabetes type II has been described in detail by Adler et al (2003) on a cohort of more than 5,000 patients. One quarter of diabetic patients by ten years develop microalbuminuria or worsen nephropathy. Half of patients develop microalbuminuria through the period of 19 years. From any stage of nephropathy, the risk to deteriorate is 2 to 3 percent annually. However, macroalbuminuria and elevated creatinine levels place the patient at evidently higher risks as compared to those with microalbuminuria.

The kidneys are affected in diabetes through numerous interactions:

–  the kidneys are in charge for nearly a half of insulin clearance

– should glucose blood level elevate, glycosuria takes place. Thus, glycation of renal tissues starts. Non-enzymatic glycolation of tissue proteins and amino acids affect the glomerular basal membrane contributing to diabetic nephropathy

–   the kidneys are capable of gluconeogenesis and may contribute to body glucose release

–   the kidneys are affected by insulin resistance.

The Pathogenesis of Nephropathy in Diabetes Type II

Diabetic nephropathy is a progressive kidney abnormality in patients with diabetes caused by microvascular abnormalities. Hyperglycemia is the leading pathophysiological factor for the development of nephropathy in diabetes type II. Hyperglycemia causes mesangial cell proliferation and hypertrophy and podocyte disarrangements, however it does not account fully for the development of nephropathy (Dronavalli et al, 2008). Overall, diabetic nephropathy lies in morphological disorders that coexist with functional violations. In diabetes, elevated levels of cytokines provoke accumulation of extracellular matrix, leading to hypertrophy. Thus, the structural abnormalities in diabetic nephropathy include hypertrophy of the kidney, increase in glomerular basement membrane thickness. On the later stages, nodular and diffuse glomerulosclerosis, tubular atrophy, and interstitial fibrosis develop.

Aging per se is an important contributing factor in type II diabetic nephropathy. For example, nonspecific age-related changes and atherosclerotic type disorders may coexist. Thus, in type II diabetes, nephropathy may be a heterogeneous mixture of different diseases and pure diabetic nephropathy is expected with early onset of diabetes evaluated at the stage of microalbuminuria. In diabetes, toxic oxygen radicals are produced in excess, promoting protein damage. Hyperglycemia is capable to induce oxidative stress even before diabetes is clinically evident, causing damage to proteins, DNA and other cell structures within the mesangial matrix and the glomeruli. Glucose derived products, such as Amadori products (methylglyoxal) are also a concern, as far as glycation products are capable to deposit within the cells.

Podocytes seem to play a key role in renal function impairment, for podocyte loss correlate well with nephropathy progress according to biopsy data. Wolf and Rotz (2003) suggest some lesions in diabetes type II nephropathy are actually missed, because light microscopy might fail to detect many changes in podocytes.

Lim and Tesch (2012) suggest inflammation might play an essential role in the pathogenesis of nephropathy in diabetes type II. The authors claim, innate immunity, rather than adaptive immunity is the major force to induce the inflammatory response in diabetic kidneys. Most probably, diabetic factors (hyperglycemia, immune complexes) activate numerous immune response chain links (chemokines, cell adhesion molecules), which in turn provoke infiltration of the kidneys by monocytes and lymphocytes. These further release proinflammatory cytokines reactive oxygen species. Thus, the lymphocyte activity is amplified, cell injury develops, and renal fibrosis activates. The contributors emphasize renal biopsies in diabetic patients indicate inflammatory infiltrates. Dronavalli et al (2008) agree hyperglycemia per se stimulates cytokine activation, that in turn mediate fibrosis and increase the permeability of the glomerular filtration barrier to proteins.

According to Remuzzi et al (2002), urinary albumin is appropriate to quantify stages of nephropathy in diabetes type II. Most patients with proteinuria will reach end-stage renal disease within the nearest 10 years. Albeit, the extent to which protein is excreted by the kidneys correlates poorly to actual creatinine clearance.

Should a parent suffer from proteinuria, the offspring chance to develop proteinuria rises from 14 percent to 23 percent. When both parents have proteinuria, the probability is almost 50 percent.

As Remuzzi et al (2002) emphasize, the first clinical sign of diabetic nephropathy in type II diabetes is albuminuria. Progression from microalbuminuria to macroalbuminuria should be a concern since creatinine clearance declines, thus leading to end-stage renal disease. Usually, but not uniformly, structural defects in the kidneys are reflected by microalbuminuria:

‘Thickening of the glomerular basement membrane causing textural abnormalities and abnormal chemical composition as well as loss of negative electric charges had in the past been thought to be the major cause of microalbuminuria. More recently, disturbances of the number and function of podocytes and specifically the function of the slit membrane are thought to be at least equally important’

Microalbuminuria as a Factor of Nephropathy

Microalbuminuria is not a predictive factor of nephropathy in the future per se, this is more an indicator of existing nephropathy. Patients without microalbuminuria remain free from nephropathy for a period of 19 years. Progression from microalbuminuria to profound stage of nephropathy develops in 20-40% of Caucasians within 10 years, and approximately 20% of those with overt nephropathy progress to end stage renal disease over a period of 20 years.

From the study of Fioretto et al (1996) it became evident that as many as 30 percent of diabetic type II with microalbuminuria have structurally normal glomeruli. Accordingly, it may be assumed that microalbuminuria is a marker of overall vascular pathology in diabetes, making it a mirror of systemic vascular involvement in diabetes:  ‘The dogma of microalbuminuria as a specific reflection of disturbed glomerular permselectivity has recently come under critique, however, because disturbances of proximal tubular reabsorption of albumin have been shown to be a major component of albuminuria in experimental models and in diabetic patients’.

Different authors agree that should microalbuminuria be present, morphological findings vary. However, as soon as macroalbuminuria develops, with clinically evident impaired renal function, glomerulosclerosis is uniformly detected. On the other hand, these features cannot predict the disease progression.

The Stages and the Risk Factors of Diabetic Nephropathy

The functional deteriorations in diabetic nephropathy evolve from elevation in glomerular filtration rate to glomerular hypertension, proteinuria, arterial hypertension and lead to loss of excretory function. To classify these changes into stages is a difficult clinical task, because of numerous confounding factors. However, Mongessen (1976) recognized five stages of diabetic nephropathy :

1) early nephropathy, when glomerular filtration rate increases. This is the stage of functional changes, which occur in the nephron before any measurable clinical manifestations. The pathophysiological reason for elevated glomerular filtration rate lies in decreased resistance of efferent and afferent arteries of the glomeruli due to autoregulation and renin-angiotensin-aldosterone system disorders.

2) silent period, when morphological changes begin (glomerular hypertrophy, thickening of the basal membrane, mesangial expansion etc)

3) microalbuminuria, the earliest clinically significant stage when arterial hypertension starts. Most patients with diabetes type II have this stage shortly after diabetes diagnosed. This is so because the disease has been present for years before diagnosis of diabetes evaluated. However, its progression to macroalbuminuria is often unpredictable. Moreover, some suggest microalbuminuria reflects more of a cardiovascular, not the renal risk

4) overt nephropathy with gross proteinuria

5) end stage kidney disease.

The risk factors of diabetic nephropathy are the following:

1) race: the incidence and severity of diabetic nephropathy is greater in African Americans, Mexican Americans, Indians and Hispanics

2) genetics: in patients with diabetes type II, the polymorphism in angiotensin converting enzyme has been linked to increased risk to develop diabetic nephropathy, more severe proteinuria, or end stage kidney disease. In those patients with a relative suffering from nephropathy the probability to develop diabetic nephropathy is markedly increased.

3) arterial hypertension: blood pressure profile has strong correlations with renal events in diabetes type II

4) blood glucose: unreliable sugar control is linked to proteinuria

5) smoking: vascular lesions are enhanced by smoking

6) gender: in type II diabetes, male gender is associated with 2.6-fold increase in developing nephropathy

7) dyslipidemia: the level of cholesterol is positively related with urinary albumin in diabetes type II. Small lipids, derived from arachidonic acid, contribute to mesangial cell proliferation and extracellular matrix accumulation.

8) age: increasing age is significantly associated with urinary albumin excretion.

In conclusion, the profound understanding of pathophysiology of nephropathy in diabetes type II may give clinicians as well as their patients the ability to prevent or to treat this devastating disorder.

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