**5. Activity and chronicity indices**

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


#### **Table 2.**

*Activity and chronicity indices of lupus nephritis according to National Institutes of Health (NIH).*

AI, demonstrating a 100% 10-year survival with CI ≤ 1, 68% with CI of 2 or 3 and 32% with CI ≥ 4. Although individual activity scores do not show predictive value for disease progression, all the scores of CI were individually predictive of renal failure, particularly tubular atrophy [25]. A combination of different scores also shows impact on the prognosis. There are a high risk of doubled creatinine with a combination of two scores, such as more than 50% of cellular crescents and moderate to severe interstitial fibrosis. Patients with severe disease treated with aggressive immunossuppression showed that AI > 7 and CI > 3 have a high risk of progression [27]. More than 5o% of crescents are a very ominous morpological finding, but even with <50% of crescents but combined with moderate or severe fibrosis the risk of doubled creatinine is high specially in black patients [28].

Renal biopsy does not adequately predict the progression of long-term lesions due to disagreement between signs of clinical and histological activity of the disease. Patients in clinical remission show in repeated biopsies evidence of active inflammatory process. On the other hand, in the absence of histological activity, cases of patients with persistent clinical signs are described. Thus, studies have suggested that serial biopsies during maintenance therapy may help in patient monitoring [7]. Alsuwaida *et al* [29] when analyzing a second renal biopsy at the end of the maintenance therapy, demonstrated that persistence of glomerular hypercellularity and interstitial inflammation presented a higher risk of doubling serum creatinine. Patients with an activity index greater than 2 in the second biopsy showed worse renal survival at 10 years and regarding the chronicity index there was a trend for better renal survival with a CI lower than 3.

## **6. Clinical findings and management**

In order to prevent CKD, all patients with SLE should be evaluated for kidney involvement at initial diagnosis and at follow-up. Assessment of patients with suspected LN are greatly facilitated through information obtained by renal biopsy,

**29**

**chronicity indices**

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

and early diagnosis with response to therapy is correlated with better outcome [7, 9]. The heterogeneous morphological aspects of the disease is accompanied by a variable clinical findings. The different classes of LN guide clinicians in making the most appropriate therapeutic decision. A purely mesangial disease sparing the peripheral glomerular capillaries (classes I and II) usually have a mild disease with low levels of proteinuria and normal renal function. The prognosis is excellent and the patients require only conservative treatment. In many patients it is a stable lesion that may persist for years. However, it can undergo transformation to a more severe injury with increased levels of proteinuria and reduced kidney function [7]. LN with capillary loops injuries (classes III and IV) that shows more endocapillar proliferation, necrosis and crescents, with a coexistence of active and chronic lesions, have more aggressive disease. Tubular and interstitial lesions are nearly universal in diffuse proliferative LN and parallel the distribution of the glomerular lesions. Vascular lesions also occur most frequently in the diffuse proliferative group. The clinical manifestations are represented by high levels of proteinuria with or without nephrotic syndrome and active urinary sediment. In class III renal insufficiency is uncommon and the prognosis is variable. In a small percentage of patients there is poor outcome which results from progression of class III to class IV. The diffuse proliferative LN (class IV) have the most severe and active clinical renal presentation, with nephrotic syndrome in up 50% of the patients and various degrees of renal insufficiency in greater than 50% of the patients [30, 31]. It is a consensus that class IV has a worse prognosis. The proliferative classes with more severe active lesions (III and IV) are treated with potent immunosuppression [1, 8]. Some investigators proposed that class IV-S is pathogenetically distinct and has worse long-term outcome than class IV-G, suggesting important prognostic differences [23]. LN class IV-G has predominantly subendothelial deposits and endocapillary proliferation and patients with class IV-S much higher rate of segmental fibrinoid necrosis [32]. Segmental and global glomerulosclerosis are the consequence of active necrotizing lesions with crescent formation. The prognostic significance of class IV-S versus IV-G has been analyzed in other studies and no

significant differences in outcome were demonstrated [32–34].

portive treatment and/or kidney replacement therapy [7].

reproducibility of both active and chronic lesions [12, 13, 32–35].

All patients with class V LN have proteinuria and 59–70% have the nephrotic syndrome. Renal insufficiency is uncommon. Patients with class V are more likely to present with renal disease before other systemic features of lupus are apparent. When a membranous lesion is associated with the active or chronic lesions of class III or IV, both diagnoses are to be reported. Patients with membranous LN (class V) may be managed conservatively with antiproteinuric therapy when proteinuria is subnephrotic or with immunosuppression with nephrotic proteinuria [7]. Patients with class VI lupus nephritis have severe renal insufficiency and require only sup-

**7. Controversial aspects of ISN/RPS classification and NIH activity and** 

The classification of INS/RPS was proposed to standardize and emphasize the most relevant lesions to guide the treatment of LN. Recently, several retrospective validation studies concerning the utility of the classification were performed. These studies have highlighted the limitations of the classification and of the activity and chronicity indices. In these reports, the main weaknesses of the classification include: 1. Tubulointerstitial and vascular lesions not included in the system; 2. No correlation between the lesions with long-term outcome; 3. Poor interobserver

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

*Lupus - Need to Know*

**Activity Index (0–24)** Endocapillary hypercellularity Subendothelial deposits

Leukocyte infiltration Interstitial inflammation

**Chronicity Index (0–12)** Glomerular sclerosis Fibrous crescents

Tubular atrophy Interstitial fibrosis

**Table 2.**

Necrosis Cellular crescents

**Indices Grades**

AI, demonstrating a 100% 10-year survival with CI ≤ 1, 68% with CI of 2 or 3 and 32% with CI ≥ 4. Although individual activity scores do not show predictive value for disease progression, all the scores of CI were individually predictive of renal failure, particularly tubular atrophy [25]. A combination of different scores also shows impact on the prognosis. There are a high risk of doubled creatinine with a combination of two scores, such as more than 50% of cellular crescents and moderate to severe interstitial fibrosis. Patients with severe disease treated with aggressive immunossuppression showed that AI > 7 and CI > 3 have a high risk of progression [27]. More than 5o% of crescents are a very ominous morpological finding, but even with <50% of crescents but combined with moderate or severe fibrosis the risk of

*Activity and chronicity indices of lupus nephritis according to National Institutes of Health (NIH).*

0 absent

0 absent 1+ mild 2+ moderate 3+ severe

0 absent

0 absent 1+ mild 2+ moderate 3+ severe

1+ <25% of glomeruli 2+ 25–50% of glomeruli (x2) 3+ >50% of glomeruli (x2)

1+ <25% of glomeruli 2+ 25–50% of glomeruli 3+ >50% of glomeruli

Renal biopsy does not adequately predict the progression of long-term lesions

In order to prevent CKD, all patients with SLE should be evaluated for kidney involvement at initial diagnosis and at follow-up. Assessment of patients with suspected LN are greatly facilitated through information obtained by renal biopsy,

due to disagreement between signs of clinical and histological activity of the disease. Patients in clinical remission show in repeated biopsies evidence of active inflammatory process. On the other hand, in the absence of histological activity, cases of patients with persistent clinical signs are described. Thus, studies have suggested that serial biopsies during maintenance therapy may help in patient monitoring [7]. Alsuwaida *et al* [29] when analyzing a second renal biopsy at the end of the maintenance therapy, demonstrated that persistence of glomerular hypercellularity and interstitial inflammation presented a higher risk of doubling serum creatinine. Patients with an activity index greater than 2 in the second biopsy showed worse renal survival at 10 years and regarding the chronicity index there was a trend for

doubled creatinine is high specially in black patients [28].

better renal survival with a CI lower than 3.

**6. Clinical findings and management**

**28**

and early diagnosis with response to therapy is correlated with better outcome [7, 9]. The heterogeneous morphological aspects of the disease is accompanied by a variable clinical findings. The different classes of LN guide clinicians in making the most appropriate therapeutic decision. A purely mesangial disease sparing the peripheral glomerular capillaries (classes I and II) usually have a mild disease with low levels of proteinuria and normal renal function. The prognosis is excellent and the patients require only conservative treatment. In many patients it is a stable lesion that may persist for years. However, it can undergo transformation to a more severe injury with increased levels of proteinuria and reduced kidney function [7]. LN with capillary loops injuries (classes III and IV) that shows more endocapillar proliferation, necrosis and crescents, with a coexistence of active and chronic lesions, have more aggressive disease. Tubular and interstitial lesions are nearly universal in diffuse proliferative LN and parallel the distribution of the glomerular lesions. Vascular lesions also occur most frequently in the diffuse proliferative group. The clinical manifestations are represented by high levels of proteinuria with or without nephrotic syndrome and active urinary sediment. In class III renal insufficiency is uncommon and the prognosis is variable. In a small percentage of patients there is poor outcome which results from progression of class III to class IV. The diffuse proliferative LN (class IV) have the most severe and active clinical renal presentation, with nephrotic syndrome in up 50% of the patients and various degrees of renal insufficiency in greater than 50% of the patients [30, 31]. It is a consensus that class IV has a worse prognosis. The proliferative classes with more severe active lesions (III and IV) are treated with potent immunosuppression [1, 8]. Some investigators proposed that class IV-S is pathogenetically distinct and has worse long-term outcome than class IV-G, suggesting important prognostic differences [23]. LN class IV-G has predominantly subendothelial deposits and endocapillary proliferation and patients with class IV-S much higher rate of segmental fibrinoid necrosis [32]. Segmental and global glomerulosclerosis are the consequence of active necrotizing lesions with crescent formation. The prognostic significance of class IV-S versus IV-G has been analyzed in other studies and no significant differences in outcome were demonstrated [32–34].

All patients with class V LN have proteinuria and 59–70% have the nephrotic syndrome. Renal insufficiency is uncommon. Patients with class V are more likely to present with renal disease before other systemic features of lupus are apparent. When a membranous lesion is associated with the active or chronic lesions of class III or IV, both diagnoses are to be reported. Patients with membranous LN (class V) may be managed conservatively with antiproteinuric therapy when proteinuria is subnephrotic or with immunosuppression with nephrotic proteinuria [7]. Patients with class VI lupus nephritis have severe renal insufficiency and require only supportive treatment and/or kidney replacement therapy [7].
