Nodular glomerulosclerosis (GN) can be caused by long-standing diabetes mellitus, monoclonal immunoglobulin deposition disease, amyloidosis, or healed immune complex glomerulonephritides. Histologically, it is characterized by nodular mesangial expansion and thickening of peripheral capillary loops. Idiopathic nodular GN is a diagnosis of exclusion when no underlying cause is identified.

1. Nodular GN

2. • 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.

3. 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

4. • 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

8. 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.

9. • 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

10. • 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)

11. • 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

14. 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.

15. • 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

16. • 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

18. • 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

22. 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

23. • 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

24. • 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

26. 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.

27. • 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

28. • 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