Diabetic nephropathy is a chronic kidney disease caused by damage to the capillaries in the glomeruli of the kidneys, which are the tiny blood vessels that filter waste products from the blood. It is one of the most common causes of kidney failure and is most frequently seen in people with type 2 diabetes.
It is also known as diabetic kidney disease or diabetic renal disease. The damage to the glomeruli caused by diabetes can lead to chronic inflammation and scarring, reducing the kidneys’ ability to filter waste products from the blood. This can eventually lead to end-stage renal disease (ESRD) and the need for dialysis or a kidney transplant.
Epidemiology
Diabetic nephropathy is a serious complication of type 1 diabetes, though it typically takes 15 to 20 years after the diabetes is detected for the disease to manifest. Structural and functional changes in the kidney lead to proteinuria, hypertension, and progressive reduction of kidney function, hallmarks of diabetic nephropathy. Research indicates that certain racial groups are at higher risk of developing this condition, such as African Americans, Native Americans, and Mexican Americans, and familial clustering suggests a genetic component in the risk of developing diabetic nephropathy.
Additionally, it is difficult to determine the precise onset of type 2 diabetes, which may contribute to why patients with this form of diabetes can present with albuminuria when their diabetes is detected. . Men are more likely to develop diabetic nephropathy than women. Therefore, it is important to monitor the kidney health of people with type 1 and type 2 diabetes, as early detection and treatment of diabetic nephropathy can save lives. The number of people worldwide living with diabetes-related end-stage renal disease (ESRD) has sharply risen over the past two decades.
In the United States alone, the number of diabetic patients starting treatment for ESRD has more than doubled since 2000, increasing from 40,000 to over 50,000 in 2014. Similarly, in China, the incidence and prevalence of diabetic nephropathy (DN) have increased drastically in the past decade, with an estimated 24.3 million patients suffering from chronic kidney disease (CKD). This rising prevalence of diabetes is a global issue, particularly in developing countries. It is likely to lead to an increased prevalence of DN in the near future if preventative strategies are not implemented.
Anatomy
Pathophysiology
In the early stages, high levels of glucose in the blood cause damage to the delicate glomerular capillary walls of the kidneys. This leads to increased levels of albumin in the urine (albuminuria). As the disease progresses, the damaged capillaries become less able to filter waste from the blood, leading to increased levels of waste products in the bloodstream. In addition to the damage to the capillaries, diabetes also causes an increase in the size of the glomeruli, further reducing the kidney’s ability to filter waste. Over time, the kidneys become scarred and unable to perform their normal functions, leading to the development of end-stage renal disease.
The role of the renin-angiotensin-aldosterone system (RAAS) in the progression of diabetic nephropathy (DN) is well-established. RAAS is involved in the regulation of intraglomerular hemodynamics, as well as structural changes in both the glomerulus and tubulointerstitium. Podocytes are known to produce components of RAAS and express RAAS receptors, including Ang-II receptors (AIIR), mineralocorticoids, and prorenin. The regulation of podocytes by Ang-II type 1 receptor (AT1R) is an important function of podocytes, and this regulation has been shown to be essential for the progression of DN.
The inhibition of RAAS has been shown to decrease proteinuria and preserve renal function in CKD, suggesting that it is a crucial pathway in the development of DN. Additionally, RAAS is also important for the regulation of oxidative stress, TGF-β, and connective tissue growth factor (CTGF), all of which have been implicated in DN. Therefore, the inhibition of RAAS is an important target for pharmacological intervention in the prevention and treatment of DN.
Oxidative stress is a condition of oxidative damage to tissues due to an imbalance between oxidants and antioxidants. In diabetes, hyperglycemia is known to be a significant source of oxidative stress, leading to deoxyribonucleic acid (DNA), lipid, and protein damage. Hyperglycemic-induced ROS production stimulates the release of proinflammatory proteins, which can cause local and systemic inflammation. Oxidative stress has also been linked to metabolic and hemodynamic changes in the kidney, including increased Ang-II levels, protein kinase C (PKC) activation, and transforming growth factor-beta (TGF-β) expression.
These pathways can cause direct damage to podocytes, mesangial cells, and endothelial cells, resulting in proteinuria and tubulointerstitial fibrosis. In addition, TGF-β is involved in the production of ROS mediated by NADPH oxidase in mesangial cells exposed to high glucose levels, which causes excessive remodeling of the extracellular matrix in the mesangium and promotes fibrotic processes in the tubular interstitium. Inhibition of oxidative stress has been found to improve a feature associated with streptozotocin-induced diabetic nephropathy, suggesting the importance of oxidative stress in the pathogenesis of DN.
The accumulation of inflammatory cells in the kidney is a key factor contributing to the development and progression of diabetic nephropathy. The infiltration of these cells leads to the production of proinflammatory and fibrogenic cytokines, which can damage the renal architecture and trigger the epithelial-to-mesenchymal transition (EMT) process. This process can cause an increase in the extracellular matrix (ECM) accumulation, leading to kidney injury progression.
In addition to the synthesis of proinflammatory cytokines, the expression of chemoattractant cytokines and adhesion molecules is also upregulated in diabetic animals and kidney cells of diabetic patients. These molecules are important mediators of kidney injury, as they facilitate the entry of circulating leukocytes into kidney tissue. Consequently, the infiltrated cells release cytokines and other inflammatory mediators, which can further contribute to the development and progression of kidney injury and perpetuate inflammatory reactions.
Etiology
Diabetic nephropathy is caused by damage to the kidney’s small blood vessels from long-term, uncontrolled diabetes. This damage can cause the glomerulus to block, which reduces its ability to filter waste from the blood. High blood sugar levels can also damage the kidney tubules, making it harder for the kidneys to function properly. A combination of risk factors, such as hyperglycemia, hypertension, obesity, smoking, race, gender, dyslipidemia, age, and genetic predisposition strongly influences the progression of diabetic nephropathy.
African Americans, Asians, and Native Americans have a higher incidence of DN than Caucasians. In addition, siblings of diabetic patients with nephropathy have a three-fold greater risk of suffering from the same condition than those with no nephropathy. DN is usually divided into 5 stages, with microalbuminuria (albumin excretion rate of 30-300mg/day) preceding overt nephropathy (albumin excretion rate above 300mg/day). The presence of albuminuria is linked to an increased risk of cardiovascular disease and progressive kidney disease.
In patients with Type 1 and 2 diabetes, the rate of decline in glomerular filtration rate (GFR) and the adverse effects of hypertension becomes apparent once DN has occurred. The decline in GFR ranges from 2-20mL/min/year with the progression of DN. Without aggressive intervention, it can lead to end-stage renal disease (ESRD) in an average of 6-7 years. The rate of decline in renal function after DN is variable. It is affected by several additional factors, such as blood pressure, glycemic control and retinopathy, with more severe albuminuria and hypertension resulting in faster progression.
Genetics
Prognostic Factors
Diabetic nephropathy results in high rates of illness and death. It is characterized by the presence of microalbuminuria, which has been shown to increase a patient’s risk of death from cardiovascular disease.
Unfortunately, most individuals suffering from diabetic nephropathy eventually die from end-stage renal disease, which occurs when the kidneys can no longer function properly. It is also worth noting that diabetic nephropathy often coexists with diabetic retinopathy, further contributing to this disease’s complex and debilitating nature.
Clinical History
Clinical History
Diabetic nephropathy is a serious complication of diabetes mellitus that can lead to end-stage renal disease and other serious health problems. It is characterized by excessive urinary protein excretion and is a major cause of morbidity and mortality in people with diabetes. People with DM and poor glycemic control are at higher risk of developing diabetic nephropathy.
Additionally, smoking, uncontrolled hypertension, obesity, hyperlipidemia, and a family history of hypertension or cardiovascular events in first-degree relatives can increase one’s risk. There is likely a genetic component with evidence of family clustering and the discovery of several relevant polymorphisms in the angiotensin-converting enzyme (ACE) and angiotensin receptor genes.
Men are more likely to develop diabetic nephropathy than women. Early in the disease, patients often do not have any symptoms and are diagnosed through screening with creatinine levels between 30 to 300 mg/g. Proteinuria is the most common sign of DN. Individuals with type 1 DM are less likely to have retinopathy, making diabetic nephropathy less likely.
Physical Examination
Physical Examination
Diabetic nephropathy is diagnosed by persistently elevated levels of albumin in the urine, a protein normally filtered by the kidneys. The diagnosis is made when albumin levels are greater than 300 mg over 24 hours or 200 micrograms per minute in two or more separate urine samples taken at least three months apart.
In the early stages of the disease, patients may not have any noticeable symptoms and are typically diagnosed through routine screening for diabetes complications. They may have moderately increased albuminuria levels between 30 to 300 mg over 24 hours, a marker of early diabetic nephropathy. Before making a diagnosis, it is essential to rule out any other causes of albuminuria, such as a urinary tract infection.
This can be done through a urinalysis test. As the disease progresses, patients may experience symptoms such as fatigue, foamy urine, and pedal edema caused by hypoalbuminemia and nephrotic syndrome. These symptoms may also be accompanied by other conditions related to diabetes, such as peripheral vascular disease, hypertension, coronary artery disease, and diabetic retinopathy.
In classic diabetic nephropathy patients, standard therapy focuses on glucose and blood pressure control, intending to halt DN progression and induce albuminuria regression. This albuminuria target is based on the idea that decreased albuminuria in diabetic individuals results in improved renal and cardiovascular outcomes. However, this approach has only been able to slow down the rate of development and does not stop or reverse the disease.
In fact, the prevalence of DN has been increasing; a series of cross-sectional studies conducted in a Japanese diabetic population showed that the prevalence of DN increased from 18.5% in 1996 to 25.6% in 2014. In addition to these approaches, other non-specific measures must be implemented to reduce the risk of developing kidney disease. This includes weight loss, protein restriction, lipid-lowering and smoking cessation. Excess weight and obesity are associated with hyperfiltration, and hormonal dysregulation caused by adipokines, which play a role in DN.
Weight loss in obese diabetic patients has been shown to reduce albuminuria. Protein restriction can reduce the glomerular hyperfiltration caused by high dietary protein intake. Statin therapy effectively reduces lipid levels, while smoking cessation can reduce the risk of DN progression. Aldosterone has a wide range of effects on the body, and its role in regulating sodium balance through mineralocorticoid receptor activation is well-documented.
However, aldosterone has also been linked to increased inflammation and fibrosis, making it a possible target for therapeutic intervention. The use of mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone has been explored to reduce inflammation and fibrosis and offer a slight renoprotective advantage over ACE-inhibitor or ARB therapy. While these medications show promise, they should be used cautiously, as they can increase the risk of hyperkalemia, especially in patients with diabetes and chronic kidney disease (CKD). Patients taking MRAs should be closely monitored for signs of hyperkalemia.
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Diabetic nephropathy is a chronic kidney disease caused by damage to the capillaries in the glomeruli of the kidneys, which are the tiny blood vessels that filter waste products from the blood. It is one of the most common causes of kidney failure and is most frequently seen in people with type 2 diabetes.
It is also known as diabetic kidney disease or diabetic renal disease. The damage to the glomeruli caused by diabetes can lead to chronic inflammation and scarring, reducing the kidneys’ ability to filter waste products from the blood. This can eventually lead to end-stage renal disease (ESRD) and the need for dialysis or a kidney transplant.
Diabetic nephropathy is a serious complication of type 1 diabetes, though it typically takes 15 to 20 years after the diabetes is detected for the disease to manifest. Structural and functional changes in the kidney lead to proteinuria, hypertension, and progressive reduction of kidney function, hallmarks of diabetic nephropathy. Research indicates that certain racial groups are at higher risk of developing this condition, such as African Americans, Native Americans, and Mexican Americans, and familial clustering suggests a genetic component in the risk of developing diabetic nephropathy.
Additionally, it is difficult to determine the precise onset of type 2 diabetes, which may contribute to why patients with this form of diabetes can present with albuminuria when their diabetes is detected. . Men are more likely to develop diabetic nephropathy than women. Therefore, it is important to monitor the kidney health of people with type 1 and type 2 diabetes, as early detection and treatment of diabetic nephropathy can save lives. The number of people worldwide living with diabetes-related end-stage renal disease (ESRD) has sharply risen over the past two decades.
In the United States alone, the number of diabetic patients starting treatment for ESRD has more than doubled since 2000, increasing from 40,000 to over 50,000 in 2014. Similarly, in China, the incidence and prevalence of diabetic nephropathy (DN) have increased drastically in the past decade, with an estimated 24.3 million patients suffering from chronic kidney disease (CKD). This rising prevalence of diabetes is a global issue, particularly in developing countries. It is likely to lead to an increased prevalence of DN in the near future if preventative strategies are not implemented.
In the early stages, high levels of glucose in the blood cause damage to the delicate glomerular capillary walls of the kidneys. This leads to increased levels of albumin in the urine (albuminuria). As the disease progresses, the damaged capillaries become less able to filter waste from the blood, leading to increased levels of waste products in the bloodstream. In addition to the damage to the capillaries, diabetes also causes an increase in the size of the glomeruli, further reducing the kidney’s ability to filter waste. Over time, the kidneys become scarred and unable to perform their normal functions, leading to the development of end-stage renal disease.
The role of the renin-angiotensin-aldosterone system (RAAS) in the progression of diabetic nephropathy (DN) is well-established. RAAS is involved in the regulation of intraglomerular hemodynamics, as well as structural changes in both the glomerulus and tubulointerstitium. Podocytes are known to produce components of RAAS and express RAAS receptors, including Ang-II receptors (AIIR), mineralocorticoids, and prorenin. The regulation of podocytes by Ang-II type 1 receptor (AT1R) is an important function of podocytes, and this regulation has been shown to be essential for the progression of DN.
The inhibition of RAAS has been shown to decrease proteinuria and preserve renal function in CKD, suggesting that it is a crucial pathway in the development of DN. Additionally, RAAS is also important for the regulation of oxidative stress, TGF-β, and connective tissue growth factor (CTGF), all of which have been implicated in DN. Therefore, the inhibition of RAAS is an important target for pharmacological intervention in the prevention and treatment of DN.
Oxidative stress is a condition of oxidative damage to tissues due to an imbalance between oxidants and antioxidants. In diabetes, hyperglycemia is known to be a significant source of oxidative stress, leading to deoxyribonucleic acid (DNA), lipid, and protein damage. Hyperglycemic-induced ROS production stimulates the release of proinflammatory proteins, which can cause local and systemic inflammation. Oxidative stress has also been linked to metabolic and hemodynamic changes in the kidney, including increased Ang-II levels, protein kinase C (PKC) activation, and transforming growth factor-beta (TGF-β) expression.
These pathways can cause direct damage to podocytes, mesangial cells, and endothelial cells, resulting in proteinuria and tubulointerstitial fibrosis. In addition, TGF-β is involved in the production of ROS mediated by NADPH oxidase in mesangial cells exposed to high glucose levels, which causes excessive remodeling of the extracellular matrix in the mesangium and promotes fibrotic processes in the tubular interstitium. Inhibition of oxidative stress has been found to improve a feature associated with streptozotocin-induced diabetic nephropathy, suggesting the importance of oxidative stress in the pathogenesis of DN.
The accumulation of inflammatory cells in the kidney is a key factor contributing to the development and progression of diabetic nephropathy. The infiltration of these cells leads to the production of proinflammatory and fibrogenic cytokines, which can damage the renal architecture and trigger the epithelial-to-mesenchymal transition (EMT) process. This process can cause an increase in the extracellular matrix (ECM) accumulation, leading to kidney injury progression.
In addition to the synthesis of proinflammatory cytokines, the expression of chemoattractant cytokines and adhesion molecules is also upregulated in diabetic animals and kidney cells of diabetic patients. These molecules are important mediators of kidney injury, as they facilitate the entry of circulating leukocytes into kidney tissue. Consequently, the infiltrated cells release cytokines and other inflammatory mediators, which can further contribute to the development and progression of kidney injury and perpetuate inflammatory reactions.
Diabetic nephropathy is caused by damage to the kidney’s small blood vessels from long-term, uncontrolled diabetes. This damage can cause the glomerulus to block, which reduces its ability to filter waste from the blood. High blood sugar levels can also damage the kidney tubules, making it harder for the kidneys to function properly. A combination of risk factors, such as hyperglycemia, hypertension, obesity, smoking, race, gender, dyslipidemia, age, and genetic predisposition strongly influences the progression of diabetic nephropathy.
African Americans, Asians, and Native Americans have a higher incidence of DN than Caucasians. In addition, siblings of diabetic patients with nephropathy have a three-fold greater risk of suffering from the same condition than those with no nephropathy. DN is usually divided into 5 stages, with microalbuminuria (albumin excretion rate of 30-300mg/day) preceding overt nephropathy (albumin excretion rate above 300mg/day). The presence of albuminuria is linked to an increased risk of cardiovascular disease and progressive kidney disease.
In patients with Type 1 and 2 diabetes, the rate of decline in glomerular filtration rate (GFR) and the adverse effects of hypertension becomes apparent once DN has occurred. The decline in GFR ranges from 2-20mL/min/year with the progression of DN. Without aggressive intervention, it can lead to end-stage renal disease (ESRD) in an average of 6-7 years. The rate of decline in renal function after DN is variable. It is affected by several additional factors, such as blood pressure, glycemic control and retinopathy, with more severe albuminuria and hypertension resulting in faster progression.
Diabetic nephropathy results in high rates of illness and death. It is characterized by the presence of microalbuminuria, which has been shown to increase a patient’s risk of death from cardiovascular disease.
Unfortunately, most individuals suffering from diabetic nephropathy eventually die from end-stage renal disease, which occurs when the kidneys can no longer function properly. It is also worth noting that diabetic nephropathy often coexists with diabetic retinopathy, further contributing to this disease’s complex and debilitating nature.
Clinical History
Diabetic nephropathy is a serious complication of diabetes mellitus that can lead to end-stage renal disease and other serious health problems. It is characterized by excessive urinary protein excretion and is a major cause of morbidity and mortality in people with diabetes. People with DM and poor glycemic control are at higher risk of developing diabetic nephropathy.
Additionally, smoking, uncontrolled hypertension, obesity, hyperlipidemia, and a family history of hypertension or cardiovascular events in first-degree relatives can increase one’s risk. There is likely a genetic component with evidence of family clustering and the discovery of several relevant polymorphisms in the angiotensin-converting enzyme (ACE) and angiotensin receptor genes.
Men are more likely to develop diabetic nephropathy than women. Early in the disease, patients often do not have any symptoms and are diagnosed through screening with creatinine levels between 30 to 300 mg/g. Proteinuria is the most common sign of DN. Individuals with type 1 DM are less likely to have retinopathy, making diabetic nephropathy less likely.
Physical Examination
Diabetic nephropathy is diagnosed by persistently elevated levels of albumin in the urine, a protein normally filtered by the kidneys. The diagnosis is made when albumin levels are greater than 300 mg over 24 hours or 200 micrograms per minute in two or more separate urine samples taken at least three months apart.
In the early stages of the disease, patients may not have any noticeable symptoms and are typically diagnosed through routine screening for diabetes complications. They may have moderately increased albuminuria levels between 30 to 300 mg over 24 hours, a marker of early diabetic nephropathy. Before making a diagnosis, it is essential to rule out any other causes of albuminuria, such as a urinary tract infection.
This can be done through a urinalysis test. As the disease progresses, patients may experience symptoms such as fatigue, foamy urine, and pedal edema caused by hypoalbuminemia and nephrotic syndrome. These symptoms may also be accompanied by other conditions related to diabetes, such as peripheral vascular disease, hypertension, coronary artery disease, and diabetic retinopathy.
In classic diabetic nephropathy patients, standard therapy focuses on glucose and blood pressure control, intending to halt DN progression and induce albuminuria regression. This albuminuria target is based on the idea that decreased albuminuria in diabetic individuals results in improved renal and cardiovascular outcomes. However, this approach has only been able to slow down the rate of development and does not stop or reverse the disease.
In fact, the prevalence of DN has been increasing; a series of cross-sectional studies conducted in a Japanese diabetic population showed that the prevalence of DN increased from 18.5% in 1996 to 25.6% in 2014. In addition to these approaches, other non-specific measures must be implemented to reduce the risk of developing kidney disease. This includes weight loss, protein restriction, lipid-lowering and smoking cessation. Excess weight and obesity are associated with hyperfiltration, and hormonal dysregulation caused by adipokines, which play a role in DN.
Weight loss in obese diabetic patients has been shown to reduce albuminuria. Protein restriction can reduce the glomerular hyperfiltration caused by high dietary protein intake. Statin therapy effectively reduces lipid levels, while smoking cessation can reduce the risk of DN progression. Aldosterone has a wide range of effects on the body, and its role in regulating sodium balance through mineralocorticoid receptor activation is well-documented.
However, aldosterone has also been linked to increased inflammation and fibrosis, making it a possible target for therapeutic intervention. The use of mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone has been explored to reduce inflammation and fibrosis and offer a slight renoprotective advantage over ACE-inhibitor or ARB therapy. While these medications show promise, they should be used cautiously, as they can increase the risk of hyperkalemia, especially in patients with diabetes and chronic kidney disease (CKD). Patients taking MRAs should be closely monitored for signs of hyperkalemia.
(Off-Label)
Apply on the affected site 3-4 times daily for 3-4 weeks
After evaluation, if the efficacy is found to decrease, do not increase more than 4 applications each day
medtigo
Diabetic Nephropathy
Updated :
August 24, 2023
Diabetic nephropathy is a chronic kidney disease caused by damage to the capillaries in the glomeruli of the kidneys, which are the tiny blood vessels that filter waste products from the blood. It is one of the most common causes of kidney failure and is most frequently seen in people with type 2 diabetes.
It is also known as diabetic kidney disease or diabetic renal disease. The damage to the glomeruli caused by diabetes can lead to chronic inflammation and scarring, reducing the kidneys’ ability to filter waste products from the blood. This can eventually lead to end-stage renal disease (ESRD) and the need for dialysis or a kidney transplant.
Diabetic nephropathy is a serious complication of type 1 diabetes, though it typically takes 15 to 20 years after the diabetes is detected for the disease to manifest. Structural and functional changes in the kidney lead to proteinuria, hypertension, and progressive reduction of kidney function, hallmarks of diabetic nephropathy. Research indicates that certain racial groups are at higher risk of developing this condition, such as African Americans, Native Americans, and Mexican Americans, and familial clustering suggests a genetic component in the risk of developing diabetic nephropathy.
Additionally, it is difficult to determine the precise onset of type 2 diabetes, which may contribute to why patients with this form of diabetes can present with albuminuria when their diabetes is detected. . Men are more likely to develop diabetic nephropathy than women. Therefore, it is important to monitor the kidney health of people with type 1 and type 2 diabetes, as early detection and treatment of diabetic nephropathy can save lives. The number of people worldwide living with diabetes-related end-stage renal disease (ESRD) has sharply risen over the past two decades.
In the United States alone, the number of diabetic patients starting treatment for ESRD has more than doubled since 2000, increasing from 40,000 to over 50,000 in 2014. Similarly, in China, the incidence and prevalence of diabetic nephropathy (DN) have increased drastically in the past decade, with an estimated 24.3 million patients suffering from chronic kidney disease (CKD). This rising prevalence of diabetes is a global issue, particularly in developing countries. It is likely to lead to an increased prevalence of DN in the near future if preventative strategies are not implemented.
In the early stages, high levels of glucose in the blood cause damage to the delicate glomerular capillary walls of the kidneys. This leads to increased levels of albumin in the urine (albuminuria). As the disease progresses, the damaged capillaries become less able to filter waste from the blood, leading to increased levels of waste products in the bloodstream. In addition to the damage to the capillaries, diabetes also causes an increase in the size of the glomeruli, further reducing the kidney’s ability to filter waste. Over time, the kidneys become scarred and unable to perform their normal functions, leading to the development of end-stage renal disease.
The role of the renin-angiotensin-aldosterone system (RAAS) in the progression of diabetic nephropathy (DN) is well-established. RAAS is involved in the regulation of intraglomerular hemodynamics, as well as structural changes in both the glomerulus and tubulointerstitium. Podocytes are known to produce components of RAAS and express RAAS receptors, including Ang-II receptors (AIIR), mineralocorticoids, and prorenin. The regulation of podocytes by Ang-II type 1 receptor (AT1R) is an important function of podocytes, and this regulation has been shown to be essential for the progression of DN.
The inhibition of RAAS has been shown to decrease proteinuria and preserve renal function in CKD, suggesting that it is a crucial pathway in the development of DN. Additionally, RAAS is also important for the regulation of oxidative stress, TGF-β, and connective tissue growth factor (CTGF), all of which have been implicated in DN. Therefore, the inhibition of RAAS is an important target for pharmacological intervention in the prevention and treatment of DN.
Oxidative stress is a condition of oxidative damage to tissues due to an imbalance between oxidants and antioxidants. In diabetes, hyperglycemia is known to be a significant source of oxidative stress, leading to deoxyribonucleic acid (DNA), lipid, and protein damage. Hyperglycemic-induced ROS production stimulates the release of proinflammatory proteins, which can cause local and systemic inflammation. Oxidative stress has also been linked to metabolic and hemodynamic changes in the kidney, including increased Ang-II levels, protein kinase C (PKC) activation, and transforming growth factor-beta (TGF-β) expression.
These pathways can cause direct damage to podocytes, mesangial cells, and endothelial cells, resulting in proteinuria and tubulointerstitial fibrosis. In addition, TGF-β is involved in the production of ROS mediated by NADPH oxidase in mesangial cells exposed to high glucose levels, which causes excessive remodeling of the extracellular matrix in the mesangium and promotes fibrotic processes in the tubular interstitium. Inhibition of oxidative stress has been found to improve a feature associated with streptozotocin-induced diabetic nephropathy, suggesting the importance of oxidative stress in the pathogenesis of DN.
The accumulation of inflammatory cells in the kidney is a key factor contributing to the development and progression of diabetic nephropathy. The infiltration of these cells leads to the production of proinflammatory and fibrogenic cytokines, which can damage the renal architecture and trigger the epithelial-to-mesenchymal transition (EMT) process. This process can cause an increase in the extracellular matrix (ECM) accumulation, leading to kidney injury progression.
In addition to the synthesis of proinflammatory cytokines, the expression of chemoattractant cytokines and adhesion molecules is also upregulated in diabetic animals and kidney cells of diabetic patients. These molecules are important mediators of kidney injury, as they facilitate the entry of circulating leukocytes into kidney tissue. Consequently, the infiltrated cells release cytokines and other inflammatory mediators, which can further contribute to the development and progression of kidney injury and perpetuate inflammatory reactions.
Diabetic nephropathy is caused by damage to the kidney’s small blood vessels from long-term, uncontrolled diabetes. This damage can cause the glomerulus to block, which reduces its ability to filter waste from the blood. High blood sugar levels can also damage the kidney tubules, making it harder for the kidneys to function properly. A combination of risk factors, such as hyperglycemia, hypertension, obesity, smoking, race, gender, dyslipidemia, age, and genetic predisposition strongly influences the progression of diabetic nephropathy.
African Americans, Asians, and Native Americans have a higher incidence of DN than Caucasians. In addition, siblings of diabetic patients with nephropathy have a three-fold greater risk of suffering from the same condition than those with no nephropathy. DN is usually divided into 5 stages, with microalbuminuria (albumin excretion rate of 30-300mg/day) preceding overt nephropathy (albumin excretion rate above 300mg/day). The presence of albuminuria is linked to an increased risk of cardiovascular disease and progressive kidney disease.
In patients with Type 1 and 2 diabetes, the rate of decline in glomerular filtration rate (GFR) and the adverse effects of hypertension becomes apparent once DN has occurred. The decline in GFR ranges from 2-20mL/min/year with the progression of DN. Without aggressive intervention, it can lead to end-stage renal disease (ESRD) in an average of 6-7 years. The rate of decline in renal function after DN is variable. It is affected by several additional factors, such as blood pressure, glycemic control and retinopathy, with more severe albuminuria and hypertension resulting in faster progression.
Diabetic nephropathy results in high rates of illness and death. It is characterized by the presence of microalbuminuria, which has been shown to increase a patient’s risk of death from cardiovascular disease.
Unfortunately, most individuals suffering from diabetic nephropathy eventually die from end-stage renal disease, which occurs when the kidneys can no longer function properly. It is also worth noting that diabetic nephropathy often coexists with diabetic retinopathy, further contributing to this disease’s complex and debilitating nature.
Clinical History
Diabetic nephropathy is a serious complication of diabetes mellitus that can lead to end-stage renal disease and other serious health problems. It is characterized by excessive urinary protein excretion and is a major cause of morbidity and mortality in people with diabetes. People with DM and poor glycemic control are at higher risk of developing diabetic nephropathy.
Additionally, smoking, uncontrolled hypertension, obesity, hyperlipidemia, and a family history of hypertension or cardiovascular events in first-degree relatives can increase one’s risk. There is likely a genetic component with evidence of family clustering and the discovery of several relevant polymorphisms in the angiotensin-converting enzyme (ACE) and angiotensin receptor genes.
Men are more likely to develop diabetic nephropathy than women. Early in the disease, patients often do not have any symptoms and are diagnosed through screening with creatinine levels between 30 to 300 mg/g. Proteinuria is the most common sign of DN. Individuals with type 1 DM are less likely to have retinopathy, making diabetic nephropathy less likely.
Physical Examination
Diabetic nephropathy is diagnosed by persistently elevated levels of albumin in the urine, a protein normally filtered by the kidneys. The diagnosis is made when albumin levels are greater than 300 mg over 24 hours or 200 micrograms per minute in two or more separate urine samples taken at least three months apart.
In the early stages of the disease, patients may not have any noticeable symptoms and are typically diagnosed through routine screening for diabetes complications. They may have moderately increased albuminuria levels between 30 to 300 mg over 24 hours, a marker of early diabetic nephropathy. Before making a diagnosis, it is essential to rule out any other causes of albuminuria, such as a urinary tract infection.
This can be done through a urinalysis test. As the disease progresses, patients may experience symptoms such as fatigue, foamy urine, and pedal edema caused by hypoalbuminemia and nephrotic syndrome. These symptoms may also be accompanied by other conditions related to diabetes, such as peripheral vascular disease, hypertension, coronary artery disease, and diabetic retinopathy.
In classic diabetic nephropathy patients, standard therapy focuses on glucose and blood pressure control, intending to halt DN progression and induce albuminuria regression. This albuminuria target is based on the idea that decreased albuminuria in diabetic individuals results in improved renal and cardiovascular outcomes. However, this approach has only been able to slow down the rate of development and does not stop or reverse the disease.
In fact, the prevalence of DN has been increasing; a series of cross-sectional studies conducted in a Japanese diabetic population showed that the prevalence of DN increased from 18.5% in 1996 to 25.6% in 2014. In addition to these approaches, other non-specific measures must be implemented to reduce the risk of developing kidney disease. This includes weight loss, protein restriction, lipid-lowering and smoking cessation. Excess weight and obesity are associated with hyperfiltration, and hormonal dysregulation caused by adipokines, which play a role in DN.
Weight loss in obese diabetic patients has been shown to reduce albuminuria. Protein restriction can reduce the glomerular hyperfiltration caused by high dietary protein intake. Statin therapy effectively reduces lipid levels, while smoking cessation can reduce the risk of DN progression. Aldosterone has a wide range of effects on the body, and its role in regulating sodium balance through mineralocorticoid receptor activation is well-documented.
However, aldosterone has also been linked to increased inflammation and fibrosis, making it a possible target for therapeutic intervention. The use of mineralocorticoid receptor antagonists (MRAs) such as spironolactone and eplerenone has been explored to reduce inflammation and fibrosis and offer a slight renoprotective advantage over ACE-inhibitor or ARB therapy. While these medications show promise, they should be used cautiously, as they can increase the risk of hyperkalemia, especially in patients with diabetes and chronic kidney disease (CKD). Patients taking MRAs should be closely monitored for signs of hyperkalemia.
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