**4. International Society of Nephrology and Renal Pathology Society Classification (2003)**

The classifications of LN are based on glomerular morphologic lesions in different classes of LN and aim to identify patients at risk of progressing to chronic renal failure.

The morphological changes are based mainly under LM, although the combined analysis of IF and EM provide more effective study. The original World Health Organization (WHO) classification, formulated in 1974, defined 5 classes: Classes I-Normal glomeruli, II-Pure Mesangial Proliferation, III-Focal and segmental proliferative GN (<50% of glomeruli), IV-Diffuse Proliferative GN (≥50% of glomeruli) and V-Membranous GN. In 1995, the WHO classification was modified by the inclusion of subclasses enphasizing active and chronic lesions. However, the introduction of many subclasses has made it difficult to apply in practice. The subclasses of the membranous form of LN (class V) with proliferative lesions of class III (Vc) and class IV (Vd) were very controversial. The class V with additional proliferative features (Vc and Vd) showed a worse prognosis than pure class V, demonstrating that the prognosis was related to proliferative lesions and not to class V. These subcategories were eliminated, and instead, such complex lesions should be diagnosed as association of class V with classes III or IV [11]. The WHO classification has more recently evolved into the 2003 International Society of Nephrology and Renal Pathology Society classification (ISN/RPS) [22] (**Table 1**). The ISN/RPS nomenclature described only the immune-complex LN, not addressing other lesions such as thrombotic microangiopathy and podocytopathies. The ISN/RPS system classifies LN on the basis of where immune complexes accumulate in glomeruli, the presence or absence of mesangial or endocapillary proliferation, the overall extent of glomerular involvement (focal or diffuse; global or segmental) and whether glomerular injury is active (inflammatory) or chronic (sclerotic).

The schema ISN/RPS retains the major criteria of WHO classification with a revision and/or inclusion of pathologic details for each class. The "normal"category of the class I of WHO was eliminated, being replaced by the presence of mesangial deposits by IF and/or EM with normal LM. Class II besides deposits by IF or EM presents mesangial proliferation by LM. Classes III and IV present both mesangial and capillary deposits with endocapillary proliferation, and are separated based on the percentage of glomeruli affected by active and chronic lesions. The most


#### **Table 1.**

*International Society of Nephrology and Renal Pathology Society Classification of lupus Nephritis-2003 (ISN/RPS).*

**27**

occur in class V lesions.

**5. Activity and chronicity indices**

*Lupus Nephritis: Renal Biopsy Guiding the Clinician DOI: http://dx.doi.org/10.5772/intechopen.97169*

controversial aspect was the introduction of a subdivision of class IV based on whether the lesions are predominantly segmental or global [23]. Previous studies have suggested that a subgroup of LN with severe segmental lesions involving most of the glomeruli, may have a different pathogenesis than the global proliferative lesions of class III or IV. These severe segmental lesions often had necrosis and crescents, similar to pauci-immune necrotizing and crescentic GN. About 20% of patients with apparent necrotizing and crescentic LN, with rare or absent subendothelial deposits and without significant endocapillary proliferation, have positive ANCA suggesting a coexistence of LN and ANCA-associated necrotizing and crescentic GN [24]. Features of activity and chronicity was clearly delineated in the subcategories of class III and IV. Class IV has a higher risk of progression to chronic renal failure and large subendothelial deposits, necrosis and crescents have a worse prognosis. Due to the higher frequency of biopsied patients with more aggressive kidney injury, most series show a higher percentage of class IV [11]. The class VI was defined with glomerular sclerosis ≥90% of glomeruli without residual activity. Severe tubular atrophy, interstitial fibrosis, inflammation, and arteriosclerosis usually accompany the glomerular sclerosis. Chronic lesions, such as segmental or global sclerosis, are interpreted as sequelae of previous more aggressive lesions in the current classification. Thus, a segmentally sclerosing lesion producing an adhesion to Bowman's capsule, most likely represents an organization of a lesion with endothelial proliferation and/or necrosis and crescents, and should be interpreted as a chronic lesion of class III or IV. Globally sclerosed glomeruli can be particularly challenging, because ischemic collapse of the glomerular tuft with collagenous material in Bowman's space occur with aging and benign nephrosclerosis. This kind of lesion overlaps with sclerosed glomerulus with a fibrous crescent after an inflammatory process. Excess cells in the collagenous area, evidence of proliferative injury in the glomerular tuft with adhesion to the retracted and lamellate Bowman's capsule can help distinguish sclerosis due to LN from other causes of sclerosis [8]. Therefore, immune complex formation in the mesangium causes class I and II lesions, subendothelial deposits causes classes III and IV and subepithelial deposits

It has been known that immunosuppressive therapy is capable of reducing the amount of immune deposits and the degree of inflammatory process in the kidney. However, reduction of histological activity was not always accompanied by clinical improvement and, on the other hand, active lesions on the biopsy may be associated with a silent clinical presentation. These findings demonstrate the importance of renal biopsy in monitoring patients. Investigators have attempted to analyze renal biopsy specimens of LN with respect to active and chronic features as predictors of outcome and guides to therapy. Active lesions are potentially treatable and only the most severe ones become chronic, whereas chronic lesions represent irreversible damage with great impact in the outcome [25]. The concept of activity and chronicity indices was adopted in the studies of National Institutes of Health (NIH) (**Table 2**). According to this system, the activity (AI) and chronicity indices (CI) are graded on a scale of 0 to 24 and 0 to 12, respectively, by calculating the sum of individual scores (0 to 3+). In a group of patients with diffuse proliferative disease (Class IV), Austin *et al* [25] found that AI is moderately predictive of outcome, with 60% 10-year survival with AI greater than 12. Another study [26] showed 40% of impairment of renal function in 4 years with AI > 12 compared to 7% in the group with AI < 12. The CI was more predictive of renal outcome than

#### *Lupus Nephritis: Renal Biopsy Guiding the Clinician DOI: http://dx.doi.org/10.5772/intechopen.97169*

*Lupus - Need to Know*

**Classes Type of Lesion**

Class II-Mesangial Proliferative LN

Class III-Focal LN III (A)-active lesions III (A/C)-active and chronic

III (C)-chronic lesions

IV-S (A/C) or IV-G (A/C) active and chronic lesions IV-S (C) or IV-G (C)-glomerular scars

Class VI-Advanced sclerosing

Class IV-Diffuse LN IV-S (A) or IV-G (A)-active

lesions

lesions

LN

*(ISN/RPS).*

**Table 1.**

Class I-Mesangial LN Normal LM, deposits IF or EM

Mesangial hipercellularity and immune deposits by IF or EM

< 50% glomeruli affected by segmental or global endo and/or extracapillary proliferation, subendothelial deposits, necrosis and

≥50% glomeruli affected by segmental or global endo and/or extracapillary proliferation, subendothelial deposits, necrosis and

90% sclerosed glomeruli. Absence of residual activity.

crescents. Active and chronic lesions.

crescents. Active and chronic lesions.

Class V-Membranous LN Subepithelial deposits with thickening of GBM

*International Society of Nephrology and Renal Pathology Society Classification of lupus Nephritis-2003* 

The morphological changes are based mainly under LM, although the combined

analysis of IF and EM provide more effective study. The original World Health Organization (WHO) classification, formulated in 1974, defined 5 classes: Classes I-Normal glomeruli, II-Pure Mesangial Proliferation, III-Focal and segmental proliferative GN (<50% of glomeruli), IV-Diffuse Proliferative GN (≥50% of glomeruli) and V-Membranous GN. In 1995, the WHO classification was modified by the inclusion of subclasses enphasizing active and chronic lesions. However, the introduction of many subclasses has made it difficult to apply in practice. The subclasses of the membranous form of LN (class V) with proliferative lesions of class III (Vc) and class IV (Vd) were very controversial. The class V with additional proliferative features (Vc and Vd) showed a worse prognosis than pure class V, demonstrating that the prognosis was related to proliferative lesions and not to class V. These subcategories were eliminated, and instead, such complex lesions should be diagnosed as association of class V with classes III or IV [11]. The WHO classification has more recently evolved into the 2003 International Society of Nephrology and Renal Pathology Society classification (ISN/RPS) [22] (**Table 1**). The ISN/RPS nomenclature described only the immune-complex LN, not addressing other lesions such as thrombotic microangiopathy and podocytopathies. The ISN/RPS system classifies LN on the basis of where immune complexes accumulate in glomeruli, the presence or absence of mesangial or endocapillary proliferation, the overall extent of glomerular involvement (focal or diffuse; global or segmental) and whether glomerular injury is active (inflammatory) or chronic (sclerotic). The schema ISN/RPS retains the major criteria of WHO classification with a revision and/or inclusion of pathologic details for each class. The "normal"category of the class I of WHO was eliminated, being replaced by the presence of mesangial deposits by IF and/or EM with normal LM. Class II besides deposits by IF or EM presents mesangial proliferation by LM. Classes III and IV present both mesangial and capillary deposits with endocapillary proliferation, and are separated based on the percentage of glomeruli affected by active and chronic lesions. The most

**26**

controversial aspect was the introduction of a subdivision of class IV based on whether the lesions are predominantly segmental or global [23]. Previous studies have suggested that a subgroup of LN with severe segmental lesions involving most of the glomeruli, may have a different pathogenesis than the global proliferative lesions of class III or IV. These severe segmental lesions often had necrosis and crescents, similar to pauci-immune necrotizing and crescentic GN. About 20% of patients with apparent necrotizing and crescentic LN, with rare or absent subendothelial deposits and without significant endocapillary proliferation, have positive ANCA suggesting a coexistence of LN and ANCA-associated necrotizing and crescentic GN [24]. Features of activity and chronicity was clearly delineated in the subcategories of class III and IV. Class IV has a higher risk of progression to chronic renal failure and large subendothelial deposits, necrosis and crescents have a worse prognosis. Due to the higher frequency of biopsied patients with more aggressive kidney injury, most series show a higher percentage of class IV [11]. The class VI was defined with glomerular sclerosis ≥90% of glomeruli without residual activity. Severe tubular atrophy, interstitial fibrosis, inflammation, and arteriosclerosis usually accompany the glomerular sclerosis. Chronic lesions, such as segmental or global sclerosis, are interpreted as sequelae of previous more aggressive lesions in the current classification. Thus, a segmentally sclerosing lesion producing an adhesion to Bowman's capsule, most likely represents an organization of a lesion with endothelial proliferation and/or necrosis and crescents, and should be interpreted as a chronic lesion of class III or IV. Globally sclerosed glomeruli can be particularly challenging, because ischemic collapse of the glomerular tuft with collagenous material in Bowman's space occur with aging and benign nephrosclerosis. This kind of lesion overlaps with sclerosed glomerulus with a fibrous crescent after an inflammatory process. Excess cells in the collagenous area, evidence of proliferative injury in the glomerular tuft with adhesion to the retracted and lamellate Bowman's capsule can help distinguish sclerosis due to LN from other causes of sclerosis [8].

Therefore, immune complex formation in the mesangium causes class I and II lesions, subendothelial deposits causes classes III and IV and subepithelial deposits occur in class V lesions.
