**4.3 Diagnosis of lupus nephritis**

The clinical presentations of LN may differ ranging from asymptomatic haematuria to rapidly progressive GN. All patients with SLE should have urinalysis checked on regular basis to detect renal involvement. Presence of significant proteinuria would trigger the need for a renal biopsy, although many would perform biopsies for reasons such as persistent haematuria and elevated serum creatinine [54]. Biopsy is critical to distinguish between active nephritis, non-glomerular pathology of SLE (such as tubulointerstitial nephritis or thrombotic microangiopathy) and disease chronicity (such as interstitial fibrosis, tubular atrophy and


#### **Table 2.**

*Criteria for SLE diagnosis based on different criteria.*

glomerulosclerosis). Importantly, biopsy findings should be interpreted and correlated carefully with patients' clinical features and serology.

In an analysis by *Ishizaki et al.* of 48 SLE patients who had renal biopsies but no urine abnormality, 36 patients were identified to have some morphologic changes. Although majority had class I/II (72%), six (17%) patients were found to have class III/IV LN [60]. LN has characteristic histological features that differ from other glomerular pathology and may involve lesions in the glomerular, vascular or tubulointerstitial structures. Analysis of 860 renal biopsies by *Kudose S et al.* confirmed 5 histopathological features of LN; 1) "full-house" staining by immunofluorescence (IF) 2) intense C1q staining 3) extraglomerular deposits 4) combined subendothelial and subepithelial deposits and 5) endothelial tubuloreticular inclusion [61].

**41**

**Table 3.**

*Class I*

*Class II*

*Class III* Focal proliferative glomerulonephritis

*Class IV*

*Class V*

Normal glomeruli

Pure mesangial alteration

Diffuse proliferative glomerulonephritis

*Lupus nephritis classification.*

Membranous glomerulonephritis

*indices (total scores of 24 for activity, 12 for chronicity).*

*Lupus Nephritis: Current Updates*

*DOI: http://dx.doi.org/10.5772/intechopen.96891*

The first published classification of glomerular changes in LN was formulated in 1974 under the auspices of the World Health Organisation (WHO; **Table 3**). It divides glomerular changes into five classes, which became the basis of today's classification. Class I applies to biopsies with no detectable changes in glomeruli; class II for pure mesangial disease, class III and IV were defined as proliferative disease, with the former affecting <50% of glomeruli and latter >50%. Class V was for membranous changes. This was modified in 1982, which include replacement of "focal proliferative" term to "focal segmental" GN and addition of a new category,

Due to inconsistencies and ambiguities of the available classification criteria,

The ISN/RPS classification for LN was revised in 2018; among the changes include elimination of the subdivisions of class IV into segmental (IV-S) or global (IV-G), replacement of previous denomination of active (A) and chronic (C) to the actual activity indices (maximum score for activity index is 24 and chronicity index is 12; **Table 4**), and preference for the term "hypercellularity" rather than "proliferation" [64]. The lack of classification for tubulointerstitial and vascular involvement in LN will be addressed and revised after the next (phase 2) international nephropathology working group evaluation and recommendations [64].

**WHO 1974 ISN/RPS 2003 ISN/RPS 2018**

Minimal mesangial lupus nephritis

Diffuse segmental (IV-S) or global (IV-G) lupus nephritis a, b

Advanced sclerosing lupus nephritis

Membranous lupus nephritis c

*\****WHO***: World Health Organisation;* **ISN/RPS***: International Society of Nephrology/Renal Pathology Society;* **a***: indicate the proportion of glomeruli with active and sclerotic lesions;* **b***: indicate the proportion of glomeruli with fibrinoid necrosis and cellular crescents;* **c***: may occur in combination with class III or IV;* **d***: activity and chronicity* 

Mesangial proliferative lupus

Focal lupus nephritis a, b

*Class I*

*Class II*

*Class III*

*Class IV*

*Class V*

*Class VI*

nephritis d

nephritis d

Minimal mesangial lupus

Mesangial proliferative lupus nephritis d

Focal lupus nephritis d

Diffuse lupus nephritis d

Membranous lupus nephritis c, d

Advanced sclerosing lupus

*Class I*

*Class II*

nephritis

*Class III*

*Class IV*

*Class V*

*Class VI*

under the auspices of International Society of Nephrology/Renal Pathology Society (ISN/RPS), a new classification of LN was proposed in 2003 [63]. While keeping the overall architecture of the 6 classes in LN, several significant changes were made and emphasis was given to standardisation of biopsy reports. Definition of class I was changed to normal glomeruli under light microscopy but with mesangial deposits under IF. There was also subdivision of class IV into diffuse segmental (IV-S) or diffuse global (IV-G), while terms active (A), chronic

class VI, which denoted advanced sclerosing GN (**Table 3**) [62].

(C) or acute-on-chronic (A/C) lesions were also introduced.

#### *Lupus Nephritis: Current Updates DOI: http://dx.doi.org/10.5772/intechopen.96891*

*Lupus - Need to Know*

Malar rash Discoid rash Photosensitivity Oral ulcer Arthritis Serositis Renal disease Neurologic disorder Haematologic disorder Immunologic disorder ANA positive

**40**

**Table 2.**

lial tubuloreticular inclusion [61].

*Criteria for SLE diagnosis based on different criteria.*

glomerulosclerosis). Importantly, biopsy findings should be interpreted and

In an analysis by *Ishizaki et al.* of 48 SLE patients who had renal biopsies but no urine abnormality, 36 patients were identified to have some morphologic changes. Although majority had class I/II (72%), six (17%) patients were found to have class III/IV LN [60]. LN has characteristic histological features that differ from other glomerular pathology and may involve lesions in the glomerular, vascular or tubulointerstitial structures. Analysis of 860 renal biopsies by *Kudose S et al.* confirmed 5 histopathological features of LN; 1) "full-house" staining by immunofluorescence (IF) 2) intense C1q staining 3) extraglomerular deposits 4) combined subendothelial and subepithelial deposits and 5) endothe-

correlated carefully with patients' clinical features and serology.

**ACR 1997 SLICC 2012 ACR 2019**

**Clinical Domain** Acute cutaneous lupus Chronic cutaneous lupus

Oral ulcer Synovitis

Serositis Renal Neurologic Haemolytic anaemia Leukopenia or lymphopenia Thrombocytopenia **Immunologic Domain**

ANA Anti dsDNA Anti-Sm

least 1 from each domain

Non-scarring alopecia

Antiphospholipid antibody Low complement Direct Coomb's test

Fulfil the entry criterion, followed by 10

points in additive criteria

*Subcutanoues OR discoid lupus* (4) *Acute cutaneous lupus* (6)

*Pleural/Pericardial effusion* (5) *Acute pericarditis* (6) Musculoskeletal *Joint involvement* (6)

*Proteinuria > 0.5 g/24 h* (4) *Renal biopsy class II or V* (8) *Renal biopsy class III or IV* (10) **Immunology domain** Antiphospholipid antibodies *Anti-cardiolipin OR anti-B2GP1 antibodies OR lupus anticoagulant* (2) Complement proteins *Low C3 OR low C4* (3) *Low C3 AND low C4* (4) SLE-specific antibodies *Anti-dsDNA antibody OR anti-Smith antibody* (6)

Serosal

Renal

**Entry criterion** ANA positive **Additive criteria Clinical domain** Constitutional *Fever* (2) Haematologic *Leukopenia* (3) *Thrombocytopenia* (4) *Autoimmune haemolysis* (4) Neuropsychiatric *Delirium* (2) *Psychosis* (3) *Seizure* (5) Mucocutaneous *Non-scarring alopecia* (2) *Oral ulcers* (2)

4 out of 11 criteria 4 out of 17 criteria, with at

The first published classification of glomerular changes in LN was formulated in 1974 under the auspices of the World Health Organisation (WHO; **Table 3**). It divides glomerular changes into five classes, which became the basis of today's classification. Class I applies to biopsies with no detectable changes in glomeruli; class II for pure mesangial disease, class III and IV were defined as proliferative disease, with the former affecting <50% of glomeruli and latter >50%. Class V was for membranous changes. This was modified in 1982, which include replacement of "focal proliferative" term to "focal segmental" GN and addition of a new category, class VI, which denoted advanced sclerosing GN (**Table 3**) [62].

Due to inconsistencies and ambiguities of the available classification criteria, under the auspices of International Society of Nephrology/Renal Pathology Society (ISN/RPS), a new classification of LN was proposed in 2003 [63]. While keeping the overall architecture of the 6 classes in LN, several significant changes were made and emphasis was given to standardisation of biopsy reports. Definition of class I was changed to normal glomeruli under light microscopy but with mesangial deposits under IF. There was also subdivision of class IV into diffuse segmental (IV-S) or diffuse global (IV-G), while terms active (A), chronic (C) or acute-on-chronic (A/C) lesions were also introduced.

The ISN/RPS classification for LN was revised in 2018; among the changes include elimination of the subdivisions of class IV into segmental (IV-S) or global (IV-G), replacement of previous denomination of active (A) and chronic (C) to the actual activity indices (maximum score for activity index is 24 and chronicity index is 12; **Table 4**), and preference for the term "hypercellularity" rather than "proliferation" [64]. The lack of classification for tubulointerstitial and vascular involvement in LN will be addressed and revised after the next (phase 2) international nephropathology working group evaluation and recommendations [64].


*\****WHO***: World Health Organisation;* **ISN/RPS***: International Society of Nephrology/Renal Pathology Society;* **a***: indicate the proportion of glomeruli with active and sclerotic lesions;* **b***: indicate the proportion of glomeruli with fibrinoid necrosis and cellular crescents;* **c***: may occur in combination with class III or IV;* **d***: activity and chronicity indices (total scores of 24 for activity, 12 for chronicity).*

#### **Table 3.**

*Lupus nephritis classification.*


#### **Table 4.**

*Modified NIH activity and chronicity scoring system (ISN/RPS 2018).*
