Diabetic nephropathy pathophysiology: Difference between revisions

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{{Diabetic nephropathy}}
{{Diabetic nephropathy}}
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==Overview==
==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 arteries. 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. A 2010 classification has been proposed that correlated the histopathological findings with the severity of disease. 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.  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 arteries. 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. A 2010 classification has been proposed that correlated the histopathological findings with the severity of disease.
The hallmark of diabetic nephropathy is [[Mesangial cell|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==
==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:<ref name="pmid25342915">{{cite journal |vauthors=Lim AKh |title=Diabetic nephropathy - complications and treatment |journal=Int J Nephrol Renovasc Dis |volume=7 |issue= |pages=361–81 |year=2014 |pmid=25342915 |pmc=4206379 |doi=10.2147/IJNRD.S40172 |url=}}</ref><ref name="book">{{cite book |last= Kasper |first=Dennis |date=2015 |title=Harrison's Principles of Internal Medicine |url= |location= New York, New York |publisher= McGraw-Hill |page= |isbn=0071802150}}</ref>
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]] results in increased glomerular hydrostatic pressure and hyperfiltration. These effects are mediated by:
*[[Hemodynamic]] factors: the imbalance between the arteriolar resistance of the [[afferent]] and [[efferent]] arterioles results in increased [[Hydrostatic pressure|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]] is associated with greater [[albuminuria]] and [[nephropathy]].
**Activation of the [[RAS|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|endothelin I]] and urotensin II contribute to [[vasoconstriction]].
**Increased levels of [[endothelin|endothelin I]] and urotensin II contribute to [[vasoconstriction]].
**Dysregulation of the amounts of [[nitric oxide]] ([[NO]]) and [[nitric oxide synthase]] ([[NOS]]).
**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.  
*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.  
*[[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]].
*[[Inflammation]]: much of the pathogenesis of diabetic nephropathy is related to the production of proinflammatory [[cytokines]] and the recruitment of [[macrophages]] and [[T-lymphocytes]].
The onset of diabetic nephropathy generally takes place 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.<ref name="pmid11978659">{{cite journal| author=Drummond K, Mauer M, International Diabetic Nephropathy Study Group| title=The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. | journal=Diabetes | year= 2002 | volume= 51 | issue= 5 |pages= 1580-7 | pmid=11978659 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11978659  }} </ref> This process is called "GBM thickening", a linear process that is caused by the accumulation of extracellular matrix.<ref name="pmid11978659">{{cite journal| author=Drummond K, Mauer M, International Diabetic Nephropathy Study Group| title=The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. | journal=Diabetes | year= 2002 | volume= 51 |issue= 5 | pages= 1580-7 | pmid=11978659 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11978659  }} </ref><ref name="pmid3699305">{{cite journal| author=Hørlyck A, Gundersen HJ, Osterby R| title=The cortical distribution pattern of diabetic glomerulopathy. | journal=Diabetologia | year= 1986 | volume= 29| issue= 3 | pages= 146-50 | pmid=3699305 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3699305  }} </ref> 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.<ref name="pmid4533587">{{cite journal| author=østerby R| title=Early phases in the development of diabetic glomerulopathy. |journal=Acta Med Scand Suppl | year= 1974 | volume= 574 | issue=  | pages= 3-82 | pmid=4533587 |doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4533587  }} </ref><ref name="pmid1513095">{{cite journal| author=Mauer SM, Sutherland DE, Steffes MW| title=Relationship of systemic blood pressure to nephropathology in insulin-dependent diabetes mellitus. |journal=Kidney Int | year= 1992 | volume= 41 | issue= 4 | pages= 736-40 | pmid=1513095 | doi= |pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1513095  }} </ref><ref name="pmid12829652">{{cite journal| author=Drummond KN, Kramer MS, Suissa S, Lévy-Marchal C, Dell'Aniello S, Sinaiko A et al.| title=Effects of duration and age at onset of type 1 diabetes on preclinical manifestations of nephropathy. | journal=Diabetes | year= 2003 | volume= 52 | issue= 7| pages= 1818-24 | pmid=12829652 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12829652  }} </ref> While an increase in cellularity is often observed early in the disease, mesangial expansion without hypercellularity is common as the disease further progresses.<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy. |journal=Contrib Nephrol | year= 2011 | volume= 170 | issue=  | pages= 36-47 | pmid=21659756 |doi=10.1159/000324942 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref> 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.<ref name="pmid21422926">{{cite journal| author=Alpers CE, Hudkins KL| title=Mouse models of diabetic nephropathy. | journal=Curr Opin Nephrol Hypertens | year= 2011 | volume= 20 | issue= 3 |pages= 278-84 | pmid=21422926 | doi=10.1097/MNH.0b013e3283451901 | pmc=PMC3658822 |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21422926  }} </ref>


Advanced diabetic nephropathy is typically seen approximately 15 years after the onset of diabetes type I.<ref name="pmid20167701">{{cite journal| author=Tervaert TW, Mooyaart AL, Amann K, Cohen AH, Cook HT, Drachenberg CB et al.| title=Pathologic classification of diabetic nephropathy. |journal=J Am Soc Nephrol | year= 2010 | volume= 21 | issue= 4 | pages= 556-63 | pmid=20167701 |doi=10.1681/ASN.2010010010 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20167701  }} </ref> It is characterized by the abundant sclerosis of the mesangium and mesangial expansion in an irregular nodular (round/oval) pattern, called Kimmelstiel-Wilson nodules.<ref name="pmid21659756">{{cite journal|author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy.|journal=Contrib Nephrol | year= 2011 | volume= 170 | issue= | pages= 36-47 |pmid=21659756 |doi=10.1159/000324942 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756 }} </ref> These nodules are acellular or pauci-cellular nodules with a lamellated appearance that stain positively by silver methenamine stain.<ref name="pmid21659756">{{cite journal|author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy.| journal=Contrib Nephrol | year= 2011 |volume= 170 | issue=  | pages= 36-47 |pmid=21659756 | doi=10.1159/000324942 | pmc=|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref> 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.<ref name="pmid21659756">{{cite journal|author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy.|journal=Contrib Nephrol | year= 2011 | volume= 170 | issue=  | pages= 36-47 |pmid=21659756 |doi=10.1159/000324942 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref>
=== 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 "[[Glomerular basement membrane|GBM]] thickening", a linear process that is caused by the accumulation of [[extracellular matrix]].<ref name="pmid11978659">{{cite journal| author=Drummond K, Mauer M, International Diabetic Nephropathy Study Group| title=The early natural history of nephropathy in type 1 diabetes: II. Early renal structural changes in type 1 diabetes. | journal=Diabetes | year= 2002 | volume= 51 |issue= 5 | pages= 1580-7 | pmid=11978659 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11978659 }} </ref> 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 mellitus|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 [[Glomerular basement membrane|GBM]] lamina densa.


Of note, Kimmelsteil-Wilson nodules may be found in several disease entities, as listed below<ref name="pmid19970254">{{cite journal| author=Kimmelstiel P, Wilson C| title=Intercapillary Lesions in the Glomeruli of the Kidney. | journal=Am J Pathol | year= 1936 | volume= 12 | issue= 1 |pages= 83-98.7 | pmid=19970254 | doi= | pmc=PMC1911022 |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19970254 }} </ref><ref name="pmid2766585">{{cite journal| author=Alpers CE, Biava CG| title=Idiopathic lobular glomerulonephritis (nodular mesangial sclerosis): a distinct diagnostic entity. | journal=Clin Nephrol | year= 1989 | volume= 32 | issue= 2 | pages= 68-74 | pmid=2766585 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2766585 }} </ref>:
=== Advanced disease ===
*Diabetic nephropathy
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.<ref name="pmid21659756">{{cite journal|author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy.|journal=Contrib Nephrol | year= 2011 | volume= 170 | issue= | pages= 36-47 |pmid=21659756 |doi=10.1159/000324942 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756 }} </ref> These nodules are acellular or pauci-cellular nodules with a lamellated appearance that stain positively by silver methenamine stain.<ref name="pmid21659756">{{cite journal|author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy.| journal=Contrib Nephrol | year= 2011 |volume= 170 | issue=  | pages= 36-47 |pmid=21659756 | doi=10.1159/000324942 | pmc=|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref> 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.<ref name="pmid21659756">{{cite journal|author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy.|journal=Contrib Nephrol | year= 2011 | volume= 170 | issue= | pages= 36-47 |pmid=21659756 |doi=10.1159/000324942 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756 }} </ref> Kimmelsteil-Wilson nodules may also be found in other disease entities, such as [[multiple myeloma]] and other gammopathies, [[Membranoproliferative glomerulonephritis|membranoproliferative glomerulopathies]], [[post-infectious glomerulonephritis]], [[amyloidosis]], as well as [[Nodular glomerulosclerosis|idiopathic nodular glomerulosclerosis]] in patients with no renal disease.


*Multiple myeloma and other gammopathies
Hyalinosis, defined as the exudation of hyaline material (usually lipid particles) between the [[basement membrane]] of [[Bowman's capsule]] and the parietal epithelium.<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy. |journal=Contrib Nephrol | year= 2011 | volume= 170 | issue=  | pages= 36-47 | pmid=21659756 |doi=10.1159/000324942 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref> 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 [[Glomerular basement membrane|GBM]].<ref name="pmid17536064">{{cite journal| author=Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M| title=Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. | journal=Diabetes | year= 2007 | volume= 56 | issue= 8 |pages= 2155-60 | pmid=17536064 | doi=10.2337/db07-0019 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17536064  }} </ref> 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'' [[Glomerular basement membrane|GBM]].<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy. | journal=Contrib Nephrol | year= 2011 | volume= 170 | issue=  |pages= 36-47 | pmid=21659756 | doi=10.1159/000324942 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref>


*Membranoproliferative glomerulopathies
==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 [[atrophy|atrophic]], with diffuse [[glomerulosclerosis]].


*Post-infectious glomerulonephritis
==Microscopic Pathology==
 
{| style="float: right; width: 350px;"
*Amyloidosis
| [[Image:Nodular glomerulosclerosis.jpeg|right|400px|thumb|Nodular glomerulosclerosis in two kidney glomeruli - Public Domain, https://commons.wikimedia.org/w/index.php?curid=2740312]]
 
|}
*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.<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy. |journal=Contrib Nephrol | year= 2011 | volume= 170 | issue=  | pages= 36-47 | pmid=21659756 |doi=10.1159/000324942 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref> 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.<ref name="pmid17536064">{{cite journal| author=Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M| title=Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. | journal=Diabetes | year= 2007 | volume= 56 | issue= 8 | pages= 2155-60 |pmid=17536064 | doi=10.2337/db07-0019 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17536064  }} </ref> Podocyte injury first starts with widening of the podocyte foot processes with consequent detachment from the GBM.<ref name="pmid17536064">{{cite journal| author=Toyoda M, Najafian B, Kim Y, Caramori ML, Mauer M| title=Podocyte detachment and reduced glomerular capillary endothelial fenestration in human type 1 diabetic nephropathy. | journal=Diabetes | year= 2007 | volume= 56 | issue= 8 |pages= 2155-60 | pmid=17536064 | doi=10.2337/db07-0019 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17536064  }} </ref>24) As podocytes are lost, glomerulotubular junctions are exposed to further injury and formation of atubular glomeruli.<ref name="pmid16565248">{{cite journal| author=Najafian B, Crosson JT, Kim Y, Mauer M| title=Glomerulotubular junction abnormalities are associated with proteinuria in type 1 diabetes. | journal=J Am Soc Nephrol | year= 2006 | volume= 17 | issue= 4 Suppl 2 | pages= S53-60| pmid=16565248 | doi=10.1681/ASN.2005121342 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16565248  }} </ref><ref name="pmid12660325">{{cite journal| author=Najafian B, Kim Y, Crosson JT, Mauer M| title=Atubular glomeruli and glomerulotubular junction abnormalities in diabetic nephropathy. | journal=J Am Soc Nephrol | year= 2003 | volume= 14 | issue= 4 | pages= 908-17 | pmid=12660325 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12660325  }} </ref> 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.<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy. | journal=Contrib Nephrol | year= 2011 | volume= 170 | issue=  |pages= 36-47 | pmid=21659756 | doi=10.1159/000324942 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref>
 
 
In summary, a list of renal abnormalities may ensue following the metabolic abnormalities in diabetes<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB|title=Pathology of human diabetic nephropathy. | journal=Contrib Nephrol | year= 2011 | volume= 170 | issue=  | pages= 36-47 | pmid=21659756 | doi=10.1159/000324942 | pmc=|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref>:
===Glomerular Lesions<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy. | journal=Contrib Nephrol | year= 2011 |volume= 170 | issue=  | pages= 36-47 | pmid=21659756 | doi=10.1159/000324942 | pmc=|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref>===
===Glomerular Lesions<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy. | journal=Contrib Nephrol | year= 2011 |volume= 170 | issue=  | pages= 36-47 | pmid=21659756 | doi=10.1159/000324942 | pmc=|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref>===
====''Light Microscopy''====
====''Light Microscopy''====
*Glomerular hypertrophy and possible hypercellularity
*[[Glomerular]] [[hypertrophy]] and possible hypercellularity
*Thickened capillary basement membranes
*Thickened capillary [[Basement membrane|basement membranes]]
*Diffuse irregular mesangial expansion and sclerosis
*Diffuse irregular [[Mesangial cell|mesangial]] expansion and [[sclerosis]]
*Nodular mesangial sclerosis
*Nodular mesangial [[sclerosis]]
*Mesangiolysis
*Mesangiolysis
*Capillary micro-aneurysms
*Capillary micro-aneurysms
*Hyaline deposition
*Hyaline deposition
====''Immunofluorescence''====
====''Immunofluorescence''====
*Linear staining of capillary basement membrane for IgG  
*Linear staining of capillary [[basement membrane]] for [[IgG]]
*Linear staining of capillary basement membrane for albumin
*Linear staining of capillary [[basement membrane]] for [[albumin]]
====''Electron Microscopy''====
====''Electron Microscopy''====
*Thickened basement membranes
*Thickened [[basement membranes]]
*Increased mesangial extracellular matrix and possible hypercellularity
*Increased mesangial [[extracellular matrix]] and possible hypercellularity
*Non-amyloidotic extracellular matrix
*Non-amyloidotic [[extracellular matrix]]
*Podocyte loss
*[[Podocyte]] loss
 
===Lesions of Tubules & Interstitium<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy. | journal=Contrib Nephrol|year= 2011 | volume= 170 | issue=  | pages= 36-47 | pmid=21659756 | doi=10.1159/000324942 | pmc=|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref>===
===Lesions of Tubules & Interstitium<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB| title=Pathology of human diabetic nephropathy. | journal=Contrib Nephrol|year= 2011 | volume= 170 | issue=  | pages= 36-47 | pmid=21659756 | doi=10.1159/000324942 | pmc=|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref>===
====''Light Microscopy''====
====''Light Microscopy''====
*Atrophy
*[[Atrophy]]
*Thickened tubular basement membrane
*Thickened tubular [[basement membrane]]
*Interstitial fibrosis
*Interstitial [[fibrosis]]
====''Immunofluorescence''====
====''Immunofluorescence''====
*Linear staining of tubular basement membrane for IgG
*Linear staining of tubular [[basement membrane]] for [[IgG]]
*Linear staining of tubular basement membrane for albumin
*Linear staining of tubular [[basement membrane]] for [[albumin]]
====''Electron Microscopy''====
====''Electron Microscopy''====
*Thickened tubular basement membranes
*Thickened tubular [[Basement membrane|basement membranes]]
*Increased presence of interstitial collagen
*Increased presence of interstitial [[collagen]]
*Tubular atrophy
*Tubular [[atrophy]]
===Blood Vessels<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB|title=Pathology of human diabetic nephropathy. | journal=Contrib Nephrol | year= 2011 | volume= 170 | issue=  | pages= 36-47 | pmid=21659756 | doi=10.1159/000324942 | pmc=|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref>===
===Blood Vessels<ref name="pmid21659756">{{cite journal| author=Najafian B, Alpers CE, Fogo AB|title=Pathology of human diabetic nephropathy. | journal=Contrib Nephrol | year= 2011 | volume= 170 | issue=  | pages= 36-47 | pmid=21659756 | doi=10.1159/000324942 | pmc=|url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21659756  }} </ref>===
====''Light Microscopy''====
====''Light Microscopy''====
*Hyalinosis of afferent and efferent arterioles
*Hyalinosis of [[Afferent arterioles|afferent]] and [[efferent arterioles]]
*Intimal sclerosis
*Intimal [[sclerosis]]
====''Immunofluorescence''====
====''Immunofluorescence''====
*No specific changes
*No specific changes
====''Electron Microscopy''====
====''Electron Microscopy''====
*Subendothelial and transmural hyaline arterial deposition in small arteries and arterioles
*Subendothelial and transmural hyaline arterial deposition in small [[arteries]] and [[arterioles]]


==References==
==References==


{{Reflist|2}}
{{Reflist|2}}
<references />

Latest revision as of 13:47, 26 July 2018

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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:

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

Nodular glomerulosclerosis in two kidney glomeruli - Public Domain, https://commons.wikimedia.org/w/index.php?curid=2740312

Glomerular Lesions[2]

Light Microscopy

Immunofluorescence

Electron Microscopy

Lesions of Tubules & Interstitium[2]

Light Microscopy

Immunofluorescence

Electron Microscopy

Blood Vessels[2]

Light Microscopy

Immunofluorescence

  • No specific changes

Electron Microscopy

  • Subendothelial and transmural hyaline arterial deposition in small arteries and arterioles

References

  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.
  2. ↑ 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.
  3. ↑ 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.
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