Lupus Nephritis
Background and Demographics
ystemic lupus erythematosus (SLE) is a systemic autoimmune and chronic disease
It is more prevalent in woman than man across all age groups and populations; women to men ratio is highest at productive age, ranging between 8:1 and 15:1 and lower in prepubertal children at about 4:3
The prevalence of SLE and the chances of developing lupus nephritis (LN) vary significantly between different areas of the globe and different races and ethnicities
In the United States, the higher frequency of LN in African-American populations persists after adjustment for socioeconomic factors. The prevalence in U.S. is ranging widely between 4.8 to 87.5 per 100,000. This difference in prevalence of the disease can be explained perhaps by genetic predisposition as some “high-risk” genotypes and autoantibodies are more frequent in black patients
African Americans and Hispanic SLE patients develop LN earlier, and have worse outcomes than white patients with SLE, including death and end-stage kidney disease.
Patients with LN have a higher standardized mortality ratio (6–6.8 versus 2.4) and die earlier than SLE patients without LN.
10-year survival improves from 46% to 95% if disease remission can be achieved.
Pathogenesis
Multiple pathologic triggers and mechanisms are able of causing glomerular injury in SLE, and this triggers heterogeneity is reflected in the variable patterns of injury seen on renal biopsy and the different clinical presentations with lupus nephritis. There are at least two accepted hypothesis regarding the pathogenesis of LN:
Circulating immune-complex disease: it is supported by serologic studies that showing high levels of circulating immune complexes, double-stranded DNA, other nuclear antigens and consumption of classic complement components (C1, C4, and C3). Serologic findings associated with circulating immune complexes and activation of complement correlate best with large subendothelial deposits seen by pathologic microscopy examination in class III/IV LN.
In situ immune-complex disease: This theory implies specifically to membranous lupus nephritis as the result of the in situ reaction of unbound antibody with antigen.
Clinical presentation and laboratory testing
The clinical manifestations of LN are often subtle and most commonly will be discovered by examination of the urine as opposed to physical examination.
SLE patient should be evaluated at initial diagnosis and annually for renal involvement, even if they don’t have any signs and symptoms of renal disease. The evaluation is basically lab tests included renal function and urine analysis
If there is a clinical suspicion of renal involvement, a renal biopsy is highly recommend step because early diagnosis and treatment of LN have a good prognosis
However; there is no standardized guideline or indications when to do renal biopsy in SLE. In general, proteinuria more than 500 mg/ day or any level of proteinuria or hematuria with impaired kidney function that cannot be attributed to another cause, these findings might prompt the clinician to perform renal biopsy
The disease could have subclinical course “Silent lupus”, even with class III/IV.
There are other mechanisms that result in renal injury rather than immune-complex mechanism which can only be diagnosed with a biopsy, and require a different management like, thrombotic microangiopathy and lupus podocytopathy
Other laboratory tests that should be considered that might correlate with disease activity: Anti-nuclear antibody (ANA), anti-double stands DNA antibody (anti-dsDNA), anti-cardiolipin antibody, anti-phosphlipid antibody, and serum complements level.
Grading of Lupus Nephritis
The most recent acceptable classification of lupus nephritis, published simultaneously in 2004 and modified in 2018 in kidney international and the journal of American Society of nephrology and it is called the “Modified International Society of Nephrology/Renal Pathology Society ISN/RPS Classification of Lupus Glomerulonephritis (2004,2018) (Table 1). The classification provides a standardized definition of each class, eliminating ambiguous findings and improving interobser agreement among renal pathologists. Of note, the classification is based on light microscopy and immunofluorescence findings because most of centers outside the United States might have no electron microscopy. Also it is recommended to provide the severity and the activity of the disease to provide prognostic information, and to guide the clinicians to better approach for treatment (Table-2).
Table 1 . Modified ISN/RPS Classification of Lupus Glomerulonephritis
Table 2. Modified NIH Lupus Nephritis Activity and Chronicity Scoring System
Figure.1. Lupus nephritis class II. The glomerulus demonstrating mild-moderate mesangial hypercellularity (Silver stain, X200)
Figure.2. Lupus nephritis class II. Immunofluorescence studies show small granular immune deposits predominately in mesangium (Immunofluorescence, X100)
Figure.3. Lupus nephritis class II. Electron microscopy examination demonstrating electron-dense deposits present in mesangium (yellow arrow). No deposits involving the peripheral capillary loops. Inset picture shows tubuloreticular inclusions (red arrow) in the cytoplasm of endothelium (electron micrograph, X12000, inset, X40000
Figure 4. 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)
Figure 5. 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 6. Lupus nephritis class IV with large subendothelial electron-dense deposits ( yellow arrows) with numerous tubuloreticular inclusions ( red arrows) ( electron micrograph, X40000)
Figure 7. 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 8. 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)
Pathology of Lupus Nephritis
A wide range of pathologic changes might be observed in LN. These changes involve all compartments of renal parenchyma including glomeruli, tubules, interstation and vessels. The pathologic changes are characterized by non-prolferative, proliferative, inflammatory, and sclerotic lesions of different severities and extents. Although light microscopy examination (LM) and immunofluorescence studies (IF) provide reliable information with reasonable certainty regarding the class of LN. The EM information might provide crucial information and confirm the classification of the disease.
Class I: Minimal mesangial lupus nephritis
Mildest form of LN with minimal clinical manifestations
On light microscopy examination: Normal glomeruli with minimal tubulointerstitial changes
On immunofluorescence studies: Detection of IgG deposits in the mesangial areas is essential for diagnosis. It is usually accompanied by IgA, IgM, C3, and C1q (full house). Kappa and lambda are staining equal, and IgG subclass reveals IgG1 and IgG3 predominate
Electron microscopy helps to confirm LM and IF pictures and identify subtle findings especially in clinically “silent” SLE patients. The electron dense deposits are noted chiefly in mesangium. Tubuloreticular inclusion bodies are seen in the cytoplasm of endothelial cells
Class II: Mesangial proliferative lupus nephritis
It accounts about 8-17% of biopsies
Approximately 60% of the patients present with asymptotic proteinuria, or hematuria or both with preservation of renal function.
On by light microscopy examination:
Mesangial hypercellularity with 4 or more nuclei surrounded by matrix in mesangial area (excluding hilar area) (Figure 1)
No endocapillary proliferation, necrosis, or crescents should present.
On immunofluorescence studies: Full house deposits chiefly in the mesangial areas are noted ( Figure 2)
On electron microscopy: Dense electron deposits are present predominately in the mesangium with occasional, scattered, and small subepitheial or subenotheial deposits. Tubuloreticular inclusions might be seen in the cytoplasm of endothelium (Figure 3)
Of note: The presence of confluent small endothelial deposits might increase the likelihood for transformation to higher class (like III/IV), and thus requires close clinical follow-up.
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 4)
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.
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 5 and 6)
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
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 7)
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 8)
Sparse small subendothelial and paramessangial immune deposits may present.
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
