Diabetic nephropathy pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]
Overview
Thickening of glomerular basement membrane, accumulation of eosinophilic material in the mesangium and intraglomerular hypertension are the major pathophysiologic changes taking place in the nephrons in long standing diabetes mellitus. Uncontrolled systemic hypertension, high serum blood glucose and cholesterol levels, cytokines and insulin-like growth hormone increase the rate of progression of diabetic nephropathy.
Pathophysiology
The onset of diabetic nephropathy generally takes place at least 15 years after the onset of diabetes mellitus. A list of renal abnormalities may ensue following the metabolic abnormalities in diabetes[1]:
- Podocytopathy and loss of podocytes
- Thickened glomerular basement membrane (GBM)
- Nodular diffuse mesangial expansion (intercapillary sclerosis) called Kimmelstiel-Wilson nodules[2]
- Arteriolar hyaline accumulation in afferent and efferent arterioles
- Segmental sclerosis causing atubular glomeruli
- Interstitial inflammation and interstitial fibrosis
- Tubular thickening with or without atrophy
In fact, 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.[3] This process is called "GBM thickening", a linear process that is caused by the accumulation of extracellular matrix.[3][4] 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.[5][6][7] While an increase in cellularity is often observed early in the disease, mesangial expansion without hypercellularity is common as the disease further progresses.[1] 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.[8]
Advanced diabetic nephropathy is typically seen approximately 15 years after the onset of diabetes type I.[9] It is characterized by the abundant sclerosis of the mesangium and mesangial expansion in an irregular nodular (round/oval) pattern, called Kimmelstiel-Wilson nodules.[1] These nodules are acellular or pauci-cellular nodules with a lamellated appearance that stain positively by silver methenamine stain.[1] 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.[1]
Of note, Kimmelsteil-Wilson nodules may be found in several disease entities, as listed below[2][10]:
- Diabetic nephropathy
- Multiple myeloma and other gammopathies
- Membranoproliferative glomerulopathies
- Post-infectious glomerulonephritis
- Amyloidosis
- 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.[1] 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.[11] Podocyte injury first starts with widening of the podocyte foot processes with consequent detachment from the GBM.[11]24) As podocytes are lost, glomerulotubular junctions are exposed to further injury and formation of atubular glomeruli.[12][13] 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.[1]
Histopathological findings directly correlate with clinical signs and symptoms. The extent of mesangial expansion is inversely associated with the estiamted glomerular filtration rate (GFR) and albumin excretion rate (AER).[14][15][16] Podocyte injury is also correlated with the degree of proteinuria in diabetic patients; proteinuria is frequently seen when more than 20% of podocytes are denuded from the GBM.[11]
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Najafian B, Alpers CE, Fogo AB (2011). "Pathology of human diabetic nephropathy". Contrib Nephrol. 170: 36–47. doi:10.1159/000324942. PMID 21659756.
- ↑ 2.0 2.1 Kimmelstiel P, Wilson C (1936). "Intercapillary Lesions in the Glomeruli of the Kidney". Am J Pathol. 12 (1): 83–98.7. PMC 1911022. PMID 19970254.
- ↑ 3.0 3.1 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.
- ↑ Hørlyck A, Gundersen HJ, Osterby R (1986). "The cortical distribution pattern of diabetic glomerulopathy". Diabetologia. 29 (3): 146–50. PMID 3699305.
- ↑ østerby R (1974). "Early phases in the development of diabetic glomerulopathy". Acta Med Scand Suppl. 574: 3–82. PMID 4533587.
- ↑ Mauer SM, Sutherland DE, Steffes MW (1992). "Relationship of systemic blood pressure to nephropathology in insulin-dependent diabetes mellitus". Kidney Int. 41 (4): 736–40. PMID 1513095.
- ↑ Drummond KN, Kramer MS, Suissa S, Lévy-Marchal C, Dell'Aniello S, Sinaiko A; et al. (2003). "Effects of duration and age at onset of type 1 diabetes on preclinical manifestations of nephropathy". Diabetes. 52 (7): 1818–24. PMID 12829652.
- ↑ Alpers CE, Hudkins KL (2011). "Mouse models of diabetic nephropathy". Curr Opin Nephrol Hypertens. 20 (3): 278–84. doi:10.1097/MNH.0b013e3283451901. PMC 3658822. PMID 21422926.
- ↑ Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB; et al. (2010). "Pathologic classification of diabetic nephropathy". J Am Soc Nephrol. 21 (4): 556–63. doi:10.1681/ASN.2010010010. PMID 20167701.
- ↑ Alpers CE, Biava CG (1989). "Idiopathic lobular glomerulonephritis (nodular mesangial sclerosis): a distinct diagnostic entity". Clin Nephrol. 32 (2): 68–74. PMID 2766585.
- ↑ 11.0 11.1 11.2 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.
- ↑ Najafian B, Crosson JT, Kim Y, Mauer M (2006). "Glomerulotubular junction abnormalities are associated with proteinuria in type 1 diabetes". J Am Soc Nephrol. 17 (4 Suppl 2): S53–60. doi:10.1681/ASN.2005121342. PMID 16565248.
- ↑ Najafian B, Kim Y, Crosson JT, Mauer M (2003). "Atubular glomeruli and glomerulotubular junction abnormalities in diabetic nephropathy". J Am Soc Nephrol. 14 (4): 908–17. PMID 12660325.
- ↑ Mauer SM, Steffes MW, Ellis EN, Sutherland DE, Brown DM, Goetz FC (1984). "Structural-functional relationships in diabetic nephropathy". J Clin Invest. 74 (4): 1143–55. doi:10.1172/JCI111523. PMC 425280. PMID 6480821.
- ↑ Ellis EN, Steffes MW, Goetz FC, Sutherland DE, Mauer SM (1986). "Glomerular filtration surface in type I diabetes mellitus". Kidney Int. 29 (4): 889–94. PMID 3712971.
- ↑ Caramori ML, Kim Y, Huang C, Fish AJ, Rich SS, Miller ME; et al. (2002). "Cellular basis of diabetic nephropathy: 1. Study design and renal structural-functional relationships in patients with long-standing type 1 diabetes". Diabetes. 51 (2): 506–13. PMID 11812762.