Kidney Biopsy of the Month: Lupus Nephritis

Our last post on lupus nephritis focused on pathogenesis ,clinical presentation, grading and class I/II disease. The next segment this month will cover class III-VI disease.

Class III: Focal lupus nephritis

It accounts for about 9-24% of lupus nephritis biopsies.
On light microscopy:
- Focal (less than 50% of total glomeruli) endocapillary hypercellularity characterized by increase of inflammatory cells within capillary loops associated with reactive changes of endothelial cells
- Focal crescentic lesions (defined as 2 or more cells thick associated with involvement of 10% or more of the capsule). Crescentic lesion can be classified into cellular/ fibrocellular crescents and fibrous crescents to evaluate the activity and chronicity of the disease.
- Karyorrhexis, fibrinoid necrosis and associated with disruption of capillary tufts are also noted. (Figure 1)
- Segmental or global glomerulosclerosis may occur in chronic status.
On immunofluorescence studies:
- Full house staining patterns with coarse granular deposits in segmental distribution along capillary walls chiefly in subendothelial location accompanied by mesangial deposits.
- Scattered subepitheial deposits might be seen.
- Tubulointerstitial and vascular immune deposits might be seen.
On electron microscopy:
- Segmental electron dense deposits in subendothelial and mesangial areas
- Scattered (less than 50% of glomerular surface area) subepitheial deposits may present
- Deposit in tubular basement membranes can be identified
- Numerous tubuloreticular inclusion bodies can be identified

Note: If the subepithelial deposits are seen in more than 50% of glomerular surface area in at least 50% of the glomeruli, additional diagnosis of membranous lupus nephritis (class V) should be warranted.

**Figure 1. Lupus nephritis class III with focal crescentic (while arrow) and necrotizing lesions (red arrow). A background of mild segmental mesangial hypercellularity is noted (Silver stain, X400)**

Class IV: Diffuse lupus nephritis

Patients usually have active serologic markers with about 70% have active urinary sediments.
On light microscopy:
- Active and /or chronic endocapillary and / or extracapillary glomerulonephritis involving more than 50% of the glomeruli
- May show diffuse endocapillary hypercellularity, extensive subendothelial deposits forming a wire-loops lesions, hyaline thrombi, necrotizing lesions and crescents in different combinations
- Mesangial proliferative features are also present.
- Progress to segmental or global glomerulosclerosis might be seen in chronic condition.
- Various degree of acute and chronic tubulointerstitial injury is present and correlated with the severity of acute and chronic glomerular lesion.
On immunofluorescence studies: Same staining pattern of class III in diffuse fashion.
On electron microscopy: Same findings as class III lupus nephritis in diffuse fashion (Figure 2 and 3)

Note: If the subepithelial deposits are seen in more than 50% of glomerular surface areas in at least 50% of the glomeruli, additional diagnosis of membranous lupus nephritis (class V) should be warranted

Figure 2. Lupus nephritis class IV. Electron micrograph shows confluent and circumferential subendothelial electron -dense deposits ( red arrow) with numerous mesangial deposits ( yellow-circle) (electron micrograph, 4000)

**Figure 3. Lupus nephritis class IV with large subendothelial electron-dense deposits ( yellow arrows) with numerous tubuloreticular inclusions ( red arrows) ( electron micrograph, X40000).**

Class V: Membranous lupus nephritis

Patients usually present with heavy proteinuria and nephrotic syndrome
Hematuria can be seen in half of the patients
Membranous lupus nephritis could represent an initial clinical presentation without systemic manifestations of lupus
Patients are at risk for renal vein thrombosis
On light microscopy:
- In early stages, light microscopic findings may be subtle with slight thickening of glomerular basement membranes
- Later, a full picture of membranous nephropathy is obvious with thickening of capillary wall with spikes and pinholes noted (figure 4)
- Mesangial proliferative features are also present
- In chronic cases, segmental or global glomerulosclerosis might develop
On immunofluorescence:
- Full house staining patterns with coarse granular deposits in the subepitheial sites with mesangial deposits.
- Occasional small sized subendothelial deposits can been seen
- Extraglomerular deposits can be also seen in the tubular basement membranes and vessels
On electron microscopy:
- Sizable subepitheial electron-dense deposits along the glomerular basement membranes (figure 5)
- Sparse small subendothelial and paramessangial immune deposits may present.

Figure 4. Lupus nephritis class V. There is marked thickening of peripheral capillary loops with pinholes along the glomerular basement membranes (red circle) accompanied with mild segmental mesangial hypercellularity (silver stain, X400)

Figure 5. Lupus nephritis class V. Electron micrograph shows diffuse sizable subepithelial electron-dense deposits along the capillary loops (red arrows) with extension to expanded mesangium (yellow circle). Inset picture demonstrates tubuloreticular inclusions in the cytoplasm of endothelium (electron microscopy X 4000, inset, x 40000).

Class VI: Advanced sclerosing lupus nephritis

Extensive glomerular scarring with more than 90% global glomerulosclerosis without evidence of residual activity
This class was introduced to identify cases of aggressive and inactive disease in which aggressive therapy is no long indicated.

Differential diagnosis:

Type II mixed cryoglobulinemia
- Usually with microtubular substructure type of immune deposits by electron microscopy
- Often associated with hepatitis C virus
Membranoproliferative glomerulonephritis with immune deposits
Primary membranous glomerulonephritis
- Absent of extraglomerular deposits
- Absence of subendothelial and mesangial immune-deposits
- Often positive (70%) to phospholipase A2 receptors antibodies
Lupus-like glomerulonephritis in HIV patients
- Can be found in about 20% of renal biopsies in HIV-infected patients
- Negative to low titer of ANA and DsDNA serologies
Drug-induced lupus nephritis
- Culprits include hydralazine, isoniazid and procainamide
- Improvement in renal function after drug withdrawal
Sjogren syndrome
- Often tubulointerstitial nephritis present before the glomerular manifestations
- Positive serologies for Sjogren antibodies