Diabetic nephropathy is a clinical syndrome characterized by the following:
Persistent albuminuria (>300 mg/d or >200 μg/min) that is confirmed on at least 2 occasions 3-6 months apart
Progressive decline in the glomerular filtration rate (GFR)
Elevated arterial blood pressure
Proteinuria was first recognized in diabetes mellitus in the late 18th century. In the 1930s, Kimmelstiel and Wilson described the classic lesions of nodular glomerulosclerosis in diabetes associated with proteinuria and hypertension.
By the 1950s, kidney disease was clearly recognized as a common complication of diabetes, with as many as 50% of patients with diabetes of more than 20 years having this complication.
Currently, diabetic nephropathy is the leading cause of chronic kidney disease in the United States and other Western societies. It is also one of the most significant long-term complications in terms of morbidity and mortality for individual patients with diabetes. Diabetes is responsible for 30-40% of all end-stage renal disease (ESRD) cases in the United States.
Generally, diabetic nephropathy is considered after a routine urinalysis and screening for microalbuminuria in the setting of diabetes. Patients may have physical findings associated with long-standing diabetes mellitus
Good evidence suggests that early treatment delays or prevents the onset of diabetic nephropathy or diabetic kidney disease. This has consistently been shown in both type 1 and type 2 diabetes mellitus.
Regular outpatient follow-up is key in managing diabetic nephropathy successfully
Recently, attention has been called to atypical presentations of diabetic nephropathy with dissociation of proteinuria from reduced kidney function. Also noted is that microalbuminuria is not always predictive of diabetic nephropathy.Nevertheless, a majority of the cases of diabetic nephropathy present with proteinuria, which progressively gets worse as the disease progresses, and is almost uniformly associated with hypertension.
Signs and symptoms of diabetic nephropathy:
Management of diabetic nephropathy:
Several issues are key in the medical care of patients with diabetic nephropathy.[4, 5]These include glycemic control, management of hypertension, and reducing dietary salt intake and phosphorus and potassium restriction in advanced cases.
Agents for glycemic control in patients with diabetes who have kidney disease include the following:
Dipeptidyl peptidase inhibitors
Alpha-glucosidase inhibitors
Sodium-glucose cotransporter 2 (SGLT2) inhibitors
Glucagonlike peptide-1 (GLP-1) receptor agonists or incretin mimetics
Amylin analogs
Nonsteroidal, selective mineralocorticoid receptor (MR) antagonists
Pathophysiology
Three major histologic changes occur in the glomeruli of persons with diabetic nephropathy. First, mesangial expansion is directly induced by hyperglycemia, perhaps via increased matrix production or glycation of matrix proteins. Second, thickening of the glomerular basement membrane (GBM) occurs. Third, glomerular sclerosis is caused by intraglomerular hypertension (induced by dilatation of the afferent renal artery or from ischemic injury induced by hyaline narrowing of the vessels supplying the glomeruli). These different histologic patterns appear to have similar prognostic significance.
The key change in diabetic glomerulopathy is augmentation of extracellular matrix. The earliest morphologic abnormality in diabetic nephropathy is the thickening of the GBM and expansion of the mesangium due to accumulation of extracellular matrix. The image below is a simple schema for the pathogenesis of diabetic nephropathy.
Light microscopy findings show an increase in the solid spaces of the tuft, most frequently observed as coarse branching of solid (positive periodic-acid Schiff reaction) material (diffuse diabetic glomerulopathy). Large acellular accumulations also may be observed within these areas. These are circular on section and are known as the Kimmelstiel-Wilson lesions/nodules.
Immunofluorescence microscopy may reveal deposition of albumin, immunoglobulins, fibrin, and other plasma proteins along the GBM in a linear pattern, most likely as a result of exudation from the blood vessels, but this is not immunopathogenetic or diagnostic and does not imply an immunologic pathophysiology. The renal vasculature typically displays evidence of atherosclerosis, usually due to concomitant hyperlipidemia and hypertensive arteriosclerosis.
Electron microscopy provides a more detailed definition of the structures involved. In advanced disease, the mesangial regions occupy a large proportion of the tuft, with prominent matrix content. Further, the basement membrane in the capillary walls (ie, the peripheral basement membrane) is thicker than normal.
The severity of diabetic glomerulopathy is estimated by the thickness of the peripheral basement membrane and mesangium and matrix expressed as a fraction of appropriate spaces (eg, volume fraction of mesangium/glomerulus, matrix/mesangium, or matrix/glomerulus).
The glomeruli and kidneys are typically normal or increased in size initially, thus distinguishing diabetic nephropathy from most other forms of chronic renal insufficiency, wherein renal size is reduced (except renal amyloidosis and polycystic kidney disease).
In addition to the renal hemodynamic alterations, patients with overt diabetic nephropathy (dipstick-positive proteinuria and decreasing glomerular filtration rate [GFR]) generally develop systemic hypertension. Hypertension is an adverse factor in all progressive renal diseases and seems especially so in diabetic nephropathy. The deleterious effects of hypertension are likely directed at the vasculature and microvasculature.
Etiology
The exact cause of diabetic nephropathy is unknown, but various postulated mechanisms are hyperglycemia (causing hyperfiltration and renal injury), advanced glycation products, and activation of cytokines. Many investigators now agree that diabetes is an autoimmune disorder, with overlapping pathophysiologies contributing to both type 1 and type 2 diabetes; and recent research highlights the pivotal role of innate immunity (toll-like receptors) and regulatory T-cells (Treg). [9]
Glycemic control reflects the balance between dietary intake and gluconeogenesis and tissue uptake or utilization through storage as glycogen or fat and oxidation. This balance is regulated by insulin production from the β cells in the pancreas. Insulin regulates serum glucose through its actions on liver, skeletal muscle, and fat tissue. When there is insulin resistance, insulin cannot suppress hepatic gluconeogenesis, which leads to hyperglycemia. Simultaneously, insulin resistance in the adipose tissue and skeletal muscle leads to increased lipolysis and reduction in disposal of glucose causing hyperlipidemia in addition to hyperglycemia.
Evidence suggests that when there is insulin resistance, the pancreas is forced to increase its insulin output, which stresses the β cells, eventually resulting in β-cell exhaustion. The high blood glucose levels and high levels of saturated fatty acids create an inflammatory medium, resulting in activation of the innate immune system, which results in activation of the nuclear transcription factors-kappa B (NF-κB), and release of inflammatory mediators, including, interleukin (IL)–1β and tumor necrosis factor (TNF)–α, promoting systemic insulin resistance and β-cell damage as a result of autoimmune insulitis. Hyperglycemia and high serum levels of free fatty acids and IL-1 lead to glucotoxicity, lipotoxicity, and IL-1 toxicity, resulting in apoptotic β-cell death.
Hyperglycemia also increases the expression of transforming growth factor-β (TGF-β) in the glomeruli and of matrix proteins, specifically stimulated by this cytokine. TGF-β and vascular endothelial growth factor (VEGF) may contribute to the cellular hypertrophy and enhanced collagen synthesis and may induce the vascular changes observed in persons with diabetic nephropathy. [10, 11] Hyperglycemia also may activate protein kinase C, which may contribute to renal disease and other vascular complications of diabetes. [12]
Familial or perhaps even genetic factors also play a role. Certain ethnic groups, particularly African Americans, persons of Hispanic origin, and American Indians, may be particularly disposed to renal disease as a complication of diabetes.
It has been argued that the genetic predisposition to diabetes that is so frequent in Western societies, and even more so in minorities, reflects the fact that in the past, insulin resistance conferred a survival advantage (the so-called thrifty genotype hypothesis).
Some evidence has accrued for a polymorphism in the gene for angiotensin-converting enzyme (ACE) in either predisposing to nephropathy or accelerating its course. However, definitive genetic markers have yet to be identified. More recently, the role of epigenetic modification in the pathogenesis of diabetic nephropathy has been highlighted. [13]
A study by Bherwani et al suggested that an association exists between decreased serum folic acid levels and diabetic nephropathy. In the study, which involved 100 patients with diabetes mellitus, including 50 with diabetic nephropathy and 50 without it, multivariate logistic regression analysis indicated that reduced folic acid levels increased the risk of diabetic nephropathy by 19.9%.
Evidence suggests that hypertension associated with obesity, metabolic syndrome, and diabetes may play an important role in the pathogenesis of diabetic nephropathy. Central obesity, metabolic syndrome, and diabetes lead to increased blood pressure.
A prospective 5-year cohort study by Kitagawa et al indicated that in patients with type 2 diabetes, an association exists between isolated high home systolic blood pressure (IH-HSBP) and the development of diabetic nephropathy. The adjusted odds ratio for diabetic nephropathy arising in individuals with IH-HSBP was found to be 2.39, with the investigators also reporting that the association was more pronounced in younger study patients; the adjusted odds ratio for diabetic nephropathy development was 3.06 in persons under age 65 years and 1.68 in individuals aged 65 years or older. [6]
Central obesity induces hypertension initially by increasing renal tubular reabsorption of sodium and causing a hypertensive shift of renal-pressure natriuresis through multiple mechanisms, including activation of the sympathetic nervous system and renin-angiotensin-aldosterone system, as well as physical compression of the kidneys. [7] Hypertension, along with increases in intraglomerular capillary pressure and the metabolic abnormalities (eg, dyslipidemia, hyperglycemia) likely interact to accelerate renal injury.
Similar to obesity-associated glomerular hyperfiltration, renal vasodilation, increases in the glomerular filtration rate and intraglomerular capillary pressure, and increased blood pressure also are characteristics of diabetic nephropathy. [8] Increased systolic blood pressure further exacerbates the disease progression to proteinuria and a decline in the glomerular filtration rate, leading to end-stage kidney disease.
Etiology
The exact cause of diabetic nephropathy is unknown, but various postulated mechanisms are hyperglycemia (causing hyperfiltration and renal injury), advanced glycation products, and activation of cytokines. Many investigators now agree that diabetes is an autoimmune disorder, with overlapping pathophysiologies contributing to both type 1 and type 2 diabetes; and recent research highlights the pivotal role of innate immunity (toll-like receptors) and regulatory T-cells (Treg). [9]
Glycemic control reflects the balance between dietary intake and gluconeogenesis and tissue uptake or utilization through storage as glycogen or fat and oxidation. This balance is regulated by insulin production from the β cells in the pancreas. Insulin regulates serum glucose through its actions on liver, skeletal muscle, and fat tissue. When there is insulin resistance, insulin cannot suppress hepatic gluconeogenesis, which leads to hyperglycemia. Simultaneously, insulin resistance in the adipose tissue and skeletal muscle leads to increased lipolysis and reduction in disposal of glucose causing hyperlipidemia in addition to hyperglycemia.
Evidence suggests that when there is insulin resistance, the pancreas is forced to increase its insulin output, which stresses the β cells, eventually resulting in β-cell exhaustion. The high blood glucose levels and high levels of saturated fatty acids create an inflammatory medium, resulting in activation of the innate immune system, which results in activation of the nuclear transcription factors-kappa B (NF-κB), and release of inflammatory mediators, including, interleukin (IL)–1β and tumor necrosis factor (TNF)–α, promoting systemic insulin resistance and β-cell damage as a result of autoimmune insulitis. Hyperglycemia and high serum levels of free fatty acids and IL-1 lead to glucotoxicity, lipotoxicity, and IL-1 toxicity, resulting in apoptotic β-cell death.
Hyperglycemia also increases the expression of transforming growth factor-β (TGF-β) in the glomeruli and of matrix proteins, specifically stimulated by this cytokine. TGF-β and vascular endothelial growth factor (VEGF) may contribute to the cellular hypertrophy and enhanced collagen synthesis and may induce the vascular changes observed in persons with diabetic nephropathy. [10, 11] Hyperglycemia also may activate protein kinase C, which may contribute to renal disease and other vascular complications of diabetes. [12]
Familial or perhaps even genetic factors also play a role. Certain ethnic groups, particularly African Americans, persons of Hispanic origin, and American Indians, may be particularly disposed to renal disease as a complication of diabetes.
It has been argued that the genetic predisposition to diabetes that is so frequent in Western societies, and even more so in minorities, reflects the fact that in the past, insulin resistance conferred a survival advantage (the so-called thrifty genotype hypothesis).
Some evidence has accrued for a polymorphism in the gene for angiotensin-converting enzyme (ACE) in either predisposing to nephropathy or accelerating its course. However, definitive genetic markers have yet to be identified. More recently, the role of epigenetic modification in the pathogenesis of diabetic nephropathy has been highlighted.
A study by Bherwani et al suggested that an association exists between decreased serum folic acid levels and diabetic nephropathy. In the study, which involved 100 patients with diabetes mellitus, including 50 with diabetic nephropathy and 50 without it, multivariate logistic regression analysis indicated that reduced folic acid levels increased the risk of diabetic nephropathy by 19.9%.
Prognosis
Diabetic nephropathy accounts for significant morbidity and mortality.
Proteinuria is a predictor of morbidity and mortality. (See Workup.) The overall prevalence of microalbuminuria and macroalbuminuria in both types of diabetes is approximately 30-35%. Microalbuminuria independently predicts cardiovascular morbidity, and microalbuminuria and macroalbuminuria increase mortality from any cause in diabetes mellitus. Microalbuminuria is also associated with increased risk of coronary and peripheral vascular disease and death from cardiovascular disease in the general nondiabetic population.
Patients in whom proteinuria has not developed have a low and stable relative mortality rate, whereas patients with proteinuria have a 40-fold higher relative mortality rate. Patients with type 1 DM and proteinuria have the characteristic bell-shaped relationship between diabetes duration/age and relative mortality, with maximal relative mortality in the age interval of 34-38 years (as reported in 110 females and 80 males).
ESRD is the major cause of death, accounting for 59-66% of deaths in patients with type 1 DM and nephropathy. In a prospective study in Germany, the 5-year survival rate was less than 10% in the elderly population with type 2 DM and no more than 40% in the younger population with type 1 DM.
The cumulative incidence of ESRD in patients with proteinuria and type 1 DM is 50% 10 years after the onset of proteinuria, compared with 3-11% 10 years after the onset of proteinuria in European patients with type 2 DM.
A study by Zhang et al suggested that the presence of diabetic retinopathy is an independent risk factor for the advancement of diabetic nephropathy to ESRD in patients with type 2 DM. [19]
A study by Jiang et al indicated that a higher number of comorbidities in patients with type 2 DM increases the likelihood that diabetic nephropathy will progress. Dividing the study’s patients into four groups—low comorbidity/low treatment, low comorbidity/high treatment, moderate comorbidity/high insulin use, and high comorbidity/moderate treatment—the investigators found the subjects’ 5-year diabetic nephropathy progression rates to be 11.8%, 18%, 16.5%, and 27.7%, respectively. [20]
A study by Rosolowsky et al reported that despite renoprotective treatment, including transplantation and dialysis, patients with type 1 diabetes and macroalbuminuria remain at high risk for ESRD. [21]
Although both type 1 and type 2 DM lead to ESRD, the great majority of patients are those with type 2 diabetes. The fraction of patients with type 1 DM who develop renal failure seems to have declined over the past several decades. However, 20-40% still have this complication. On the other hand, only 10-20% of patients with type 2 DM develop uremia due to diabetes. Their nearly equal contribution to the total number of patients with diabetes who develop kidney failure results from the higher prevalence of type 2 DM (5- to 10-fold).
Cardiovascular disease is also a major cause of death (15-25%) in persons with nephropathy and type 1 DM, despite their relatively young age at death.
Patient Education
Patient education is key in trying to prevent diabetic nephropathy. Appropriate education, follow-up, and regular doctor visits are important in prevention and early recognition and management of diabetic nephropathy.
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