AJKDAtlas of Renal Pathology: Diabetic Nephropathy
Behzad Najafian, MD,1 Agnes B. Fogo, MD,2Mark A. Lusco, MD,2 and Charles E. Alpers, MD1
Clinical and Pathologic Features
Diabetic nephropathy is the most commoncause of ESRD and develops in 20% to 30% of patients with diabetes. Time todevelop overt diabetic nephropathy is typically 15 years in type 1 diabetes,with a less clear time course in type 2 diabetes (because its onset may not beknown precisely). While patients typically develop albuminuria followed byovert proteinuria and glomerular filtration rate (GFR) loss, the degree ofalbuminuria is not necessarily linked to disease progression. Patientsinitially have hyperfiltration and increased GFRs, with progressive decline.
Light microscopy: Classic findings includemesangial expansion mainly due to increased mesangial matrix, which can bediffuse and, as kidney disease progresses, more typically nodular(Kimmelstiel-Wilson nodules). The nodules are round with a hypocellular matrixcore surrounded by patent capillary loops, resembling a sunflower.Microaneurysms of glomerular capillaries are often seen along withmesangiolysis or nodules. Segmental glomerulosclerosis, especially at thetubular outlet (ie, tip lesion), is common in later stages of diabeticnephropathy. Hyalinosis may be present within the glomerular tuft under theendothelial cells or under the parietal epithelial cells (capsular drop).Hyalinosis of afferent and efferent arterioles is common and although notpathognomonic, is rare in other conditions. In type 1 diabetes, interstitialfibrosis and tubular atrophy follow glomerular lesions and may be less severeor proportional to diabetic glomerulopathy. In type 2 diabetes, in whicharteriosclerosis is commonly present, the lesions are more heterogeneous, andchronic tubulointerstitial injury may be more severe than the diabeticglomerulopathy.
Immunofluorescence microscopy: Diffuselinear accentuation of glomerular and tubular basement membranes with IgG (andk and l light chains) and albumin is typical. Nonspecific segmental staining ofhyaline deposits or glomerular sclerotic regions for IgM, C3, and C1q is commonin advanced disease.
Electron microscopy: Diffuse thickening ofGBMs is usually the earliest structural change. Tubular basement membranes ofnonatrophic tubules are also thickened. Mesangial regions are expanded,predominantly due to accumulation of mesangial matrix. There are no immunecomplexes. Podocytes show variable foot process effacement, especially inadvanced stages.
Etiology/Pathogenesis
Hyperglycemia is the main initiator ofdiabetic kidney disease. Hyperlipidemia and insulin resistance are additionalcontributors in type 2 diabetes. Increased oxidative stress, inflammation, andaberrant growth factors are all implicated as mechanisms of injury.Accumulation of extracellular matrix in the mesangium is the key morphologicfinding. The classic KimmelstielWilson nodules are postulated to be theconsequence of repeated mesangiolysis, with an exuberant repair response.Podocyte and endothelial cell injuries also play important roles in theprogression of the disease.
DifferentialDiagnosis
Nodular glomerulosclerosis can also be seenin monoclonal immunoglobulin deposition disease (MIDD), amyloidosis, idiopathicnodular glomerulosclerosis, membranoproliferative glomerulonephritides, andmore rarely in fibrillary and immunotactoid glomerulopathy, fibronectinglomerulopathy, collagen type III glomerulopathy, congenital cyanotic heartdisease, and cystic fibrosis. Immune complex membranoproliferativeglomerulonephritis is typically associated with prominent mesangialhypercellularity. Immunofluorescence and electron microscopy studies can ruleout most of these conditions. Congo Red staining should be performed whenamyloidosis is suspected. Idiopathic nodular glomerulosclerosis may closelymimic diabetic nephropathy and is a diagnosis of clinical exclusion. The linearGBM staining in anti-GBM glomerulonephritis istypically much stronger than the dulland modest linear staining in diabetic nephropathy. Moreover, albumin stainingis absent in anti-GBM glomerulonephritis, while diffuse in diabeticnephropathy.
KeyDiagnostic Features
Increasedmesangialmatrix, nodularglomerulosclerosis
Diffuse GBM thickening by electronmicroscopy
Concomitant hyalinosis of afferent andefferent arterioles
Figure1. (A) Diabetic nephropathy with diffuse mesangialexpansion and arteriolar hyalinosis (red arrow). (B) Diabetic nephropathy withnodular mesangial expansion (Kimmelstiel-Wilson nodules) and concomitanthyalinosis of afferent and efferent arterioles (red arrows; Jones silverstain).
Figure2. Advanced diabetic nephropathy withKimmelstielWilson nodule (upper asterisk) with adjacent mesangiolysis (yellowarrow) and a microaneurysm (white arrow) with prominent arteriolar hyalinosis(red arrow). There is a capsular drop (lower asterisk) on Bowman capsule (Jonessilver stain).
Figure3. Advanced diabetic nephropathy with prominentthickening of glomerular basement membranes with expanded mesangium,predominantly due to increased mesangial matrix. There is segmental footprocess effacement, indicative of podocyte injury (electron microscopy).
Figure4. Diabetic nephropathy with tubular basementmembrane thickening in nonatrophic tubules (electron microscopy).
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