Nodular GN

• Nodular glomerulosclerosis has classically been described in patients with long-standing diabetes mellitus. The remaining causes of a nodular glomerulosclerosis are much less frequent and include monoclonal immunoglobulin deposition disease (MIDD), other conditions with paraprotein deposition in the glomeruli (e.g., amyloidosis), and healed or chronic ('burnt-out') immune complex-mediated glomerulonephritides, which result in a membranoproliferative pattern of injury, such as MPGN. Thrombotic angiopathies with significant mesangiolysis during an active episode can also present with a nodular type of glomerulosclerosis in the healed (chronic) stage. Idiopathic nodular glomerulosclerosis is a diagnosis of exclusion.

Diffuse and nodular diabetic glomerulosclerosis

• Histopathology: • In advanced disease, marked mesangial expansion, with formation of pauci-

cellular Kimmelstiel-Wilson nodules in many segments; the nodules are sometimes rather cellular (suggestive of superimposed renal disease of other etiology)

• Peripheral capillary loops are diffusely thickened and microaneurysms are frequently seen

• Insudation of plasma proteins into the capillary wall (fibrin cap), Bowman's capsule (capsular drop), or vessel wall (hyaline arteriolosclerosis)

• Advanced tubular atrophy with thickening of tubular basement membranes, associated with dense interstitial fibrosis and non-specific, predominantly mononuclear cell inflammatory infiltrate

• Advanced diabetic renal disease is usually associated with severe vascular sclerosis

• Congo red stain is negative

• Immunofluorescence: • Mild linear reactivity for albumin and IgG along the capillary loops; no immune

deposits

• Electron microscopy: • Visceral epithelial cells: Focal but sometimes

extensive effacement of visceral epithelial cell foot processes, in the absence of electron-dense deposits

• Glomerular basement membranes: Irregularly thickened

• Glomerular endothelial cells: Various non-specific changes; do not contain tubuloreticular structures

• Mesangium: Normal cell elements and nodular expansion of extracellular matrix in the absence of electron-dense deposits

Monoclonal immunoglobulin deposition disease (MIDD)

• Definition: • Monoclonal immunoglobulin deposition

disease (MIDD) includes a group of diseases (LCDD, HCDD, LHCDD) with deposition of abnormal immunoglobulin components in all compartments of renal parenchyma, without substructural organization of the deposits.

• Etiology: • The disease is caused by deposition of abnormally truncated

monoclonal immunoglobulin in all compartments of renal parenchyma. This deposition elicits increased production of mesangial matrix, resulting in nodular glomerulosclerosis

• Clinical: • Proteinuria, commonly nephrotic-range, with or without

nephrotic syndrome• Microhematuria• Hypertension• Monoclonal gammopathy• Half of patients have overt multiple myeloma or B-cell

lymphoma

• Histopathology: • Marked mesangial expansion, with formation of distinct nodules

(nodular glomerulosclerosis)• Nodules may show hypercellularity, some may be hypocellular and

laminated• No fibrin caps, capsular drops, or prominent hyalinosis• The tubular basement membranes show marked thickening, with

refractile appearance• The vessel walls may be thickened• Congo red stain is negative

• Immunofluorescence: • There is immunofluorescence reactivity restricted to abnormal

truncated protein (one of the light chains - kappa or lambda, or a single heavy chain - gamma, mu, alpha)

• Electron microscopy: • Visceral epithelial cells: Focal, sometimes marked effacement of

visceral epithelial cell foot processes• Glomerular basement membranes: Markedly thickened, with

band-like, sometimes laminated deposition of powdery, very dense fine granular material. The deposits show no substructural organization. Usual place of deposition is within lamina rara interna and inner portion of lamina densa; similarly, in tubular basement membranes, the deposits are found on the interstitial side of the membrane

• Glomerular endothelial cells: Loss of fenestrations and other non-specific changes

• Mesangium: Deposition of powdery, very dense fine granular material; the deposits show no substructural organization

Thrombotic microangiopathy, chronic (CTMA)

• Thrombotic microangiopathies are a diverse group of disorders that affect small vasculature and/or glomerular capillary walls. In chronic TMAs, there are no active thrombotic lesions, but there is a membranoproliferative type of glomerular injury, with widespread glomerular capillary loop double contour formations, in the absence of immune complex or paraprotein deposition. Chronic TMAs present with chronic renal insufficiency.

• Etiology: • Etiology varies between different entities in this group of

disorders (see classification). Common pathogenic denominators are endothelial cell injury and platelet activation and consumption in acute TMAs; alternating injury and repair lead to complex remodeling of vascular and glomerular capillary wall elements, as seen in chronic TMAs

• Clinical: • Progressive chronic renal failure• Clinical history reveals thrombophilia (acquired or inherited),

autoimmune disease, previous episode of HUS/TTP, chemotherapy/ immunosuppressive regimens, malignancy, or other factors that may have resulted in vascular injury

• Histopathology: • Lobular appearance of glomeruli on low-power

magnification• Mesangial expansion by matrix and increase in cell

elements• Peripheral capillary loops are markedly thickened; on

PAS and silver stains, there are prominent double contour formations (“tram tracking”)

• Immunofluorescence: • Reactivity for fibrin can be demonstrated in thrombi

within glomeruli and small vessels

• Electron microscopy: • Visceral epithelial cells: Usually focal, sometimes marked

effacement of visceral epithelial cell foot processes• Glomerular basement membranes: Prominent subendothelial

widening by basement membrane material and interposed cellular elements, in the absence of electron-dense or organized deposits. A new, usually irregular and thin layer of basement membrane is seen under the regenerated endothelium (double contours); cellular interposition between the two layers of basement membrane is common

• Glomerular endothelial cells: Loss of fenestrations, detachment from the original basement membranes, and focal swelling; they do not contain tubuloreticular structures

• Mesangium: Cellular debris may be deposited, but electron-dense deposits are not seen

Idiopathic nodular glomerulosclerosis

• Definition: • Idiopathic nodular glomerulosclerosis (ING)

is characterized by diffuse and nodular glomerulosclerosis in the absence of electron-dense or organized deposits, in patients without clinical evidence of metabolic or inflammatory disease. ING is the diagnosis of exclusion

• Histopathology: • Glomerular hypertrophy, with diffuse and nodular

glomerulosclerosis due to increased amount of mesangial matrix, with or without increase in mesangial cellularity

• The mesangial nodules are argyrophilic (stain black with silver stains) and Congo red-negative

• The peripheral capillary loops are usually thickened• Different degrees of tubulointerstitial scarring• Different degrees of arterial and arteriolar sclerosis and

hyalinosis

• Immunofluorescence: • Negative or non-specific

• Electron microscopy: • Visceral epithelial cells: Focal but sometimes

extensive effacement of visceral epithelial cell foot processes, in the absence of electron-dense deposits

• Glomerular basement membranes: Irregularly thickened

• Glomerular endothelial cells: Various non-specific changes; do not contain tubuloreticular structures

• Mesangium: Normal cell elements and nodular expansion of extracellular matrix in the absence of electron-dense deposits

Amyloidosis

• Definition: • Amyloidosis is a disorder marked by

extracellular deposition of different proteins that have in common Congo red positive reaction by light microscopy, with an apple green birefringence under polarized light, and non-branching, randomly arranged, 8-12 nm in diameter fibrils by electron microscopic studies.

• Etiology: • Caused by accumulation of abnormal proteins with certain common

characteristics (Congo red positive, fibrillary ultrastructure)• AL amyloid is the most common form seen in the kidney, composed

of a light chain molecule (most commonly of lambda light chain specificity)

• AA amyloid is associated with chronic inflammatory processes (e.g., rheumatoid arthritis {1}, tuberculosis {2}, ulcerative colitis {3}, Crohn disease {4}), familial Mediterranean fever {5}, etc.

• Clinical: • Proteinuria, frequently nephrotic-range (sometimes heavy), with or

without nephrotic syndrome• Renal insufficiency is common• AA amyloid: chronic inflammatory processes• AL amyloid: B-cell dyscrasia

• Histopathology: • Marked mesangial expansion, with accumulation of acellular, amorphous,

usually pale, and in places nodular material, with extension into the capillary loops• In some cases, long 'spikes' extending from the capillary walls may be seen

particularly well on PAS- and silver-stained sections• The proteins are congophilic, with apple-green birefringence by polarized

light microscopy of Congo red-stained thick sections• Accumulated material appears pale on PAS-stained sections and can be seen

in glomeruli, blood vessels, and tubulointerstitium; the material is also non-argyrophilic (negative on silver-stained sections)

• Immunofluorescence: • In AL amyloid, there is immunofluorescence reactivity restricted to one of the

light chains, most commonly lambda. AA amyloid may be confirmed using antiserum specific for amyloid A protein, by immunofluorescence or immunoperoxidase