Diabetic nephropathy pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]
Overview
The hallmark of diabetic nephropathy is mesangial expansion. Nonetheless, diabetic nephropathy is characterized by the presence of abnormalities in the glomeruli, such as glomerular hypertrophy, in the tubules and interstitium, such as tubular atrophy and interstitial fibrosis, and in the blood vessels, such as arteriosclerosis in both the afferent and the efferent renal arterioles. Findings on histopathological analysis may be evident very early in diabetes, but are often clinically present approximately 15 years after the onset of metabolic abnormalities. Diabetic nephropathy (DN) is characterized by the presence of proteinuria or decreased renal function in patients with diabetes mellitus. Diabetic nephropathy may be early or overt.
Pathophysiology
The pathophysiology of diabetic nephropathy is related to chronic hyperglycemia. However, it is not completely understood. It is thought to be related to the effects of the following:
- Hemodynamic factors: the imbalance between the arteriolar resistance of the afferent and efferent arterioles results in increased glomerular hydrostatic pressure and hyperfiltration. These effects are mediated by:
- Activation of the renin-angiotensin-aldosterone (RAS) system: results in efferent vasoconstriction. In addition, the high levels of ACE are associated with greater albuminuria and nephropathy.
- Increased levels of endothelin I and urotensin II contribute to vasoconstriction.
- Dysregulation of the amounts of nitric oxide (NO) and nitric oxide synthase (NOS).
- Metabolic factors: oxidative stress and the production of reactive oxygen species (ROS) contribute to the damage seen in diabetic nephropathy.
- Growth factors: TGF-ß and its downstream product, CTGF, induce extracellular matrix (ECM) formation. In addition, they mediate the fibrosis seen in the later stages of diabetic nephropathy.
- Inflammation: much of the pathogenesis of diabetic nephropathy is related to the production of proinflammatory cytokines and the recruitment of macrophages and T-lymphocytes.
Early disease
The onset of diabetic nephropathy generally occurs at least 15 years after the onset of diabetes mellitus. The pathogenesis of diabetic nephropathy occurs in distinct stages. Early pathogenesis - which may start as early as 2 years after the onset of diabetes - may include no visible lesions with mild global and diffuse hypertrophy of the renal glomeruli only. This process is called "GBM thickening", a linear process that is caused by the accumulation of extracellular matrix.[1] These changes may not be detectable by light microscopy and require electron microscopy to identify. When the accumulation of the extracellular matrix becomes significant, pathological changes on light microscopy will be evident, typically first seen 5 years after onset of type 1 diabetes and usually occurs at a faster frequency after 15 years of onset. While an increase in cellularity is often observed early in the disease, mesangial expansion without hypercellularity is common as the disease further progresses. Disorganized mesangial expansion - the hallmark of diabetic nephropathy - is not a linear process and is in fact the result of a vicious circle that is characterized by the presence of frequently mesangiolysis followed by the formation of micro-aneurysms and balloon formation of glomeruli, hyaline accumulation, and mesangial repair with concomitant thickening of the GBM lamina densa.
Advanced disease
Advanced diabetic nephropathy is typically seen approximately 15 years after the onset of diabetes type I. It is characterized by the abundant sclerosis of the mesangium and mesangial expansion in an irregular nodular (round/oval) pattern, called Kimmelstiel-Wilson nodules.[2] These nodules are acellular or pauci-cellular nodules with a lamellated appearance that stain positively by silver methenamine stain.[2] They are a non-specific finding in diabetic nephropathy but are frequently found in glomerular tufts in up to 25% of patients with advanced diabetic nephropathy.[2] Kimmelsteil-Wilson nodules may also be found in other disease entities, such as multiple myeloma and other gammopathies, membranoproliferative glomerulopathies, post-infectious glomerulonephritis, amyloidosis, as well as idiopathic nodular glomerulosclerosis in patients with no renal disease.
Hyalinosis, defined as the exudation of hyaline material (usually lipid particles) between the basement membrane of Bowman's capsule and the parietal epithelium.[2] Meanwhile, the irreversible loss of podocytes plays a crucial role in the disease pathogenesis and the clinical finding of proteinuria in patients with diabetic nephropathy. Podocyte injury first starts with widening of the podocyte foot processes with consequent detachment from the GBM.[3] As podocytes are lost, glomerulotubular junctions are exposed to further injury and formation of atubular glomeruli. Typically, patients with diabetic nephropathy do not demonstrate any specific findings on immunofluorescence, but IgG deposition is common in these patients. The presence of IgG is not believed to be a cause of the disease, but rather as a by-product due to the presence of an abnormal sticky GBM.[2]
Gross Pathology
In the early stages of diabetic nephropathy, there is renal hypertrophy, due to expansion of the glomeruli. The resultant increase in kidney size is due to enlargement of the mesangium, the glomerular basement membrane, as well as the afferent and efferent renal arterioles. However, in the later stages of diabetic nephropathy and ESRD, the kidneys become small and atrophic, with diffuse glomerulosclerosis.
Microscopic Pathology
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Glomerular Lesions[2]
Light Microscopy
- Glomerular hypertrophy and possible hypercellularity
- Thickened capillary basement membranes
- Diffuse irregular mesangial expansion and sclerosis
- Nodular mesangial sclerosis
- Mesangiolysis
- Capillary micro-aneurysms
- Hyaline deposition
Immunofluorescence
- Linear staining of capillary basement membrane for IgG
- Linear staining of capillary basement membrane for albumin
Electron Microscopy
- Thickened basement membranes
- Increased mesangial extracellular matrix and possible hypercellularity
- Non-amyloidotic extracellular matrix
- Podocyte loss
Lesions of Tubules & Interstitium[2]
Light Microscopy
- Atrophy
- Thickened tubular basement membrane
- Interstitial fibrosis
Immunofluorescence
- Linear staining of tubular basement membrane for IgG
- Linear staining of tubular basement membrane for albumin
Electron Microscopy
- Thickened tubular basement membranes
- Increased presence of interstitial collagen
- Tubular atrophy
Blood Vessels[2]
Light Microscopy
- Hyalinosis of afferent and efferent arterioles
- Intimal sclerosis
Immunofluorescence
- No specific changes
Electron Microscopy
- Subendothelial and transmural hyaline arterial deposition in small arteries and arterioles
References
- ↑ Drummond K, Mauer M, International Diabetic Nephropathy Study Group (2002). "The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes". Diabetes. 51 (5): 1580–7. PMID 11978659.
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Najafian B, Alpers CE, Fogo AB (2011). "Pathology of human diabetic nephropathy". Contrib Nephrol. 170: 36–47. doi:10.1159/000324942. PMID 21659756.
- ↑ Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M (2007). "Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy". Diabetes. 56 (8): 2155–60. doi:10.2337/db07-0019. PMID 17536064.