ORIGINAL ARTICLE
SIGNIFICANCE OF ACTIVITY AND CHRONICITY INDICES OF LUPUS
NEPHRITIS ON RENAL OUTCOME WITH EMPHASIS ON REPEATABILITY EXPERIENCE FROM SOUTHINDIA
Seema H.S1, Isha Garg2, Priya Alexander3
HOW TO CITE THIS ARTICLE:
Seema H.S, Isha Garg, Priya Alexander. “Significance of Activity And Chronicity Indices of Lupus nephritis on
Renal Outcome with Emphasis on Repeatability - Experience From South India”. Journal of Evolution of
Medical And Dental Sciences 2013; Vol2, Issue 51, December 23; Page: 9952-9962.
ABSTRACT: Background:Lupus Nephritis is said to occur in 40 to 60% of people suffering from
Systemic lupus erythematosus and is said to be a harbinger of poor prognosis with involvement of
glomeruli, tubules, interstitium, and blood vessels. The NIH/WHO activity (AI) and chronicity indices
(CI) are known to predict progression to end stage renal failure.
OBJECTIVES:
1. To study significance of AI and CI.
2. To study interobserver variation for AI and CI.
Statistical tools used: Statistical tools used were Kappa coefficient, fisher test and odds ratio.
RESULTS:Of the 118 cases studied, AI and CI index was calculated for 103 cases with more than 5
glomeruli. In this series 43% of cases of class IV had AI≥12. Cellular crescent and interstitial fibrosis
were the only 2 variables associated with poor renal outcome.
Interpretation and conclusion:Average AI and CI indices were highest (13 and 3 respectively) in
class IV lupus nephritis. Histological criteria that were scored based on objectively assessing the
percentage of glomeruli affected (like endocapillaryhypercellularity, hyaline deposits had a stronger
strength of agreement (moderate to very good). We found cellular crescent and interstitial fibrosis
as the only 2 variables associated with poor renal outcome (doubling of serum creatinine).
INTRODUCTION: Systemic lupus erythematosus (SLE) is a multi-system disease of autoimmune
origin. Nephritis is the most serious complication of SLE and the strongest predictor of poor
outcome1. Poor prognosis factors in SLE include WHO classification of diffuse proliferative nephritis,
high activity index and delay in treatment.
Many methods have been described for assessing changes in renal biopsy specimens in lupus
nephritis. Grading of acute and chronic changes to give activity and chronicity indices was developed
at the National institute of health and incorporated in the WHO scheme2. The chronicity index
signifies renal change and nephron loss, whereas the AI describes potentially reversible pathology3.
The NIH/WHO activity and chronicity indices were found by some workers to predict progression to
end stage renal failure. Though activity index at initial biopsy may have little predictive power,
chronicity index was moderately predictive of renal survival 4. High activity indices are associated
with poor outcomes, but may be reversible, especially with aggressive treatment. High chronicity
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ORIGINAL ARTICLE
scores are said to be associated with poor outcome and a lack of response to immunosuppressants.
Some studies indicate that CI in repeat biopsies may be of prognostic significance5.
Alterations in serological parameters have been correlated with histological activity in
patients with lupus nephritis. The presence of cellular crescents and moderate to severe interstitial
fibrosis has been identified as high-risk for doubling serum creatinine6. Dissatisfaction by some
workers with these indices that they are no better predictors of outcome than the ISKDC/WHO
classification of glomerular pathology, is a matter of concern2.
Technical issues regarding accurate quantization and reproducibility of a histologic index
needs to be taken into consideration to evaluate the potential benefit of this parameter.
Histopathologic grading systems, such as the activity and chronicity indices, have been considered
by many workers to be based upon a series of subjective interpretations. Differences among
pathologists or between temporally separate observations by a single pathologist are frequently a
function of observer variation rather than real differences in pathology. Even assuming that the
histological indices are reproducible, a minor amount of chronic disease is said to significantly
elevate the CI7
With this in the background, in our study we have emphasized on the significance of these
indices with respect to doubling of serum creatinine and other clinical parameters like renal failure,
high urine protein excretion and low complement levels and association of high AI and CI with WHO
classification. We have also studied statistical significance of inter-observer variation between 3
consultants of varying experiences.
MATERIALS AND METHODS:The study included renal biopsies from patients diagnosed to have
SLE by ARA criteria, received by the department of pathology, St. John’s Medical College, Bangalore
for six years. The study was both retrospective (January 1999 to January 2003) and prospective
(February 2003 to December 2004). The clinical data and laboratory findings parameters urine
analysis, serum creatinine, and serum complement were retrieved from medical records department
of St. John’s Medical College Hospital in all cases. For this study, all the slides for light microscopy
were examined. Laboratory received renal biopsy specimens with a clinical diagnosis of discoid
lupus, neonatal lupus and drug-induced lupus nephritis were excluded from the study.
Statistical tools used: We used the following statistical tools to analyze our data, they are Kappa
coefficient, fisher test and odds ratio.
Microscopic examination:
1. The types of samples that were obtained were
i. Formalin fixed renal core biopsies which were stained with
1. Haematoxylin and Eosin (H&E)
2. Periodic acid-Schiff (PAS)
3. Periodic acid methenamine silver stain (PAS-M)
ii. Data collected was analyzed based on following observations
 After classifying the renal biopsies according to the 1982 WHOclassification,
activity and chronicity indices were calculated.
 We compared the scores of AI and CI with certain clinical parameters like high
urinary protein excretion, doubling of serum creatinine and low serum
complement
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ORIGINAL ARTICLE

We also studied inter-observer variation between 3 observers with varying
degree of experience, blindly and calculated the AI and CI for 103 cases.
COMPONENTS OF ACTIVITY (AI) AND CHRONICITY (CI) INDICES:THE PUBLISHED CRITERIA FOR
SCORING THE AI AND CI WERE FOLLOWED8.
Activity Index (0 – 24)
Endocapillary hypercellularity
(0- 3+)
Leukocyte infiltration
(0- 3+)
Sub endothelial hyaline deposits
(0- 3+)
Interstitial inflammation
(0 – 3+)
Fibrinoid necrosis / Karyorrhexis 0 – 3+) x 2
Cellular crescents
(0 – 3+) x 2
Maximum total score
24
Components of Activity index
Chronicity Index (0 – 12)
Glomerular sclerosis
(0- 3+)
Fibrous crescents
(0- 3+)
Tubular atrophy
(0- 3+)
Interstitial fibrosis
Maximum total score
(0- 3+)
12
Components of Chronicity index
Glomerular features (including endocapillary proliferation, wire-loop deposits, necrosis,
cellular crescents, sclerosis and fibrous crescents) are scored as follows:
0+- Absent
1+ - < 25% of Glomeruli involved
2+ - 25 to 50% of Glomeruli involved
3+ - > 50% of Glomeruli involved.
Neutrophil exudation is defined as more than 2 neutrophils per glomerulus and scored as
mild (1+), moderate (2+), and severe (3+). Interstitial inflammation, fibrosis and tubular atrophy are
graded as mild (1+), moderate (2+), and severe (3+).
RESULTS:In our study out of 118 cases with lupus nephritis we took 103 renal biopsies with
glomeruli equal to or greater than 5 as adequate for calculating activity and chronicity indices.
Division of cases with AI and CI indices with AI>12 and chronicity index>4 is given in the Table 1.
We then took cases with high activity and chronicity indices and looked for any significant
association with clinical symptoms and details of the parameters are as follows.In our study we
found that 45% of cases with activity index ≥ 12 developed renal failure, whereas only 20% of cases
with activity index < 12 showed renal failure. In our study we also found that 33% of the cases
developed renal failure for both chronicity index less than 4 and greater than or equal to 4. Out of
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ORIGINAL ARTICLE
the 73 cases with activity index >12 only 16 cases had low complement levels. For this we applied
odds ratio (Table 2) and found no significant association. Out of 73 cases with activity index >12
only 17 cases had high urine protein excretion (>3). For this we applied odds ratio and found no
significant association between the two (Table 3).
In this series we also looked for any association between increase in AI and CI and WHO
classification, 43% of the cases of class IV had AI≥12 and 16% of class IV and both the cases of class
VI had CI≥4. (Figure 1 and 2)
We also correlated between individual variable of Activity and chronicity indices and
doubling serum creatinineby applying fisher exact test (Table 4). We found cellular crescent and
interstitial fibrosis as the only 2 variables associated with poor renal outcome (doubling of serum
creatinine).
We also studied inter-observer variation between 3 observers with varying degree of
experience, blindly and calculated the AI and CI for 103 cases by applying Kappa coefficient (Table
5). The strength of agreement varied from moderate to very good. Histological criteria, which
generated moderate strength of agreement (0.41 - 0.60), were interstitial fibrosis, interstitial
inflammation and tubular atrophy (Table 6).
DISCUSSION:The importance of calculating activity and chronicity index in lupus nephritis is always
questioned. Another drawback is the reliability and reproducibility of these indices. Does it have any
significance with clinical outcome like doubling of serum creatinine, renal failure is also to be
evaluated.
In our study out of total cases 103, we found that 45% of cases with activity index ≥ 12
developed renal failure whereas only 20% of cases with activity index < 12 showed renal failure.
33% of the cases developed renal failure for both chronicity index less than 4 and greater
than or equal to 4. A study done by Schwartz et al[7] stated that patients with elevated CI (≥4) may be
at a greater risk of developing renal failure, but in our study, in contrast to it patients with both CI<4
and CI≥4 developed renal failure in 20% of cases. Chronicity index of >4 is said to be associated with
poor renal outcome and patients with CI of >4 is said have only 32% 10-year survival rates.9
The average activity index was highest in class IV that is 13 and average chronicity index was
highest in class IV that is 3 though the average AI was lesser (7.5) in the study done by Nossentet al10
the average chronicity index was same.In concordance with Abraham et al, 11 in our study also 44%
of cases(Class IV) with AI≥12 developed renal failure and only 25% of cases(Class IV)with AI<12
developed renal failure11. In our study 16% of class IV and both the cases of class VI had CI≥4 refer
(Figure 3and 4).
In our study we found no significant association with low complement levels and AI>12 and
also no significant association between high urine protein and AI>12. 29% cases had AI≥12, out of
which 17% showed doubling of serum creatinine. 20% of cases had CI≥4 and out of which
19%showed doubling of serum creatinine. Austin12 et al in his study statistically proved AI≥12 or
CI≥4 had increased probability of doubling serum creatinine. In our study only 7% of cases showed
doubling of serum creatinine, which is too small number to prove or disprove any finding. This is
probably attributed to poor follow up of the cases.
Positive cases of each variable of AI and CI were taken. In that group, the number of cases
showing doubling of serum creatinine was selected and Fisher Exact test was applied. We found
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ORIGINAL ARTICLE
cellular crescents and interstitial fibrosis as the only two parameters, which were significantly
associated with poor outcome (Table 4). Austin et al made a similar comment and said that the
highest-risk group for doubling creatinine consists of patients whose renal biopsy showed extensive
or a modest amount of cellular crescents and moderate to severe interstitial fibrosis12.
In our study we had 3 observers who blindly categorized the activity and chronicity indices
for 103 biopsies. One of the largest opposition factors towards incorporation of the AI and CI as a
prognostic parameter for lupus nephritis was the reliability and reproducibility of the score. Giants
in the field of lupus nephritis have presented conflicting reports on its reproducibility [13].In our
study we applied the Kappa coefficient between observer1&2(Senior and junior consultant),
observer2&3 (junior consultant and trainee), observer1&3 (senior consultant and trainee), and
highlighted strengths of agreement ranging from moderate to very good (table 6).
 Histological criteria that generated moderate strength of agreement (0.41-0.60) were
interstitial fibrosis, interstitial inflammation and tubular atrophy. This could be accounted
for by the subjectivity in assessing degree of cortical involvement.
 A salient point to be stressed in this regard is that the assessors for this were the junior
consultant and trainee.
 Histological criteria that were scored based on objectively assessing the percentage of
glomeruli affected (like endocapillary hypercellularity, hyaline deposits and others, refer
table 6) had a stronger strength of agreement (moderate to very good).
CONCLUSION:Average activity and chronicity indices were highest in class IV lupus nephritis,
reconfirming it to have an adverse outcome. We found cellular crescents and interstitial fibrosis as
the only 2 statistically significant parameters associated with poor renal outcome (doubling serum
creatinine) indicating that they had graded impact on prognosis. Inter-observer agreement for
activity and chronicity indices highlighted strengths of agreement ranging from moderate to very
good for parameters that had objective assessment, indicating the need of simpler objective and
reproducible indices for interpretation.
1.
2.
3.
4.
5.
6.
REFERENCE:
Wernick RM, Smith DL, and Houghton DC, Phillips DS, Booth JL, Runckel DN, et al. Reliability of
histologic scoring for lupus nephritis: A community-based evaluation. Ann Intern Med. 1993; 119:
805-11.
Howie AJ, Turhan N, Adu D. Powerful morphometric indicator of prognosis in lupus nephritis. Q J
Med;96:411-20.
Schwartz MM, Shu-ping Lan, Jay Bernstein, et al. Role of pathology indices in the management of
severe lupus glomerulonephritis. Kidney International1992;42:743-48.
Hill GS, Delahousse M, Nochy D et al. A new morphologic index for the evaluation of renal biopsy in
lupus nephritis. Kidney international 2000;58:1160-73.
Magil AB, Puterman ML, Baloon HS, et al. Prognostic factors in diffuse proliferative lupus
Glomerulonephritis. Kidney International 1988; 34:511-17.
Austin HA, Boumpas DT, Vaughan EM and Balow JE. Predicting renal outcomes in severe lupus
nephritis: Contributions of clinical and histologic data. Kidney International 1994; 45:544-50.
Journal of Evolution of Medical and Dental Sciences/Volume 2/Issue 51/ December 23, 2013
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7. Schwartz MM, Jay Bernstein, Hill GS, et al. Predictive value of renal pathology in diffuse proliferative
lupus glomerulonephritis. Kidney International 1989; 36: 891-96.
8. Austin HA III, Muenz LR, Joyce KM, Antonovych T, Balow JE: Diffuse proliferative lupus nephritis:
Identification of specific pathologic features affecting renal outcome. Kidney international 1984; 25:
689-95.
9. Agati VDD. Connective tissue disease. In: Jennette JC, Olson JL, and Schwartz MM, et al. Heptinstall’s
pathology of kidney. Philadelphia: Lipincott-Raven publishers, 1998; 1:541-62.
10. Nossent HC, Logmans H, Vroom TM, Berden JHM and Swaak TJG. Contribution of renal biopsy data in
predicting outcome in lupus nephritis. Arthritis and rheumatism 1990 July; 33(7): 970-77.
11. Abraham MA, Korula A, Jayakrishnan K, John GT, Thomas PP and Jacob CK. Prognostic factors in
diffuse proliferative lupus nephritis. JAPI 1999; 47(9): 862-65.
12. Austin HA, Boumpas DT, Vaughan EM and Balow JE. High-risk features of lupus nephritis:
importance of race and clinical and histological factors in 166 patients. Nephrol Dial Transplantation
1995; 10: 1620-28.
13. Schwartz MM, Lan SP, Bernstein J, Hill GS, Holley K and Lweis EJ. Irreproducibility of the Activity and
Chronicity indices limits their utility in the management of lupus nephritis. American journal of
kidney disease 1993 April; 21(4): 374-77.
AI and CI indices for 103 adequate cases:
Indices
Total number of cases
Activity Index
> 12
73
Activity Index
< 12
30
Chronicity Index > 4
21
Chronicity Index < 4
82
Table 1. Division of cases-AI and CI indices
AI/complement
Lowc3
Normal
Data not available
Odds ratio
P value
Chi-square Yates corrected
≥12
16
6
8
1.22
0.942
0.01
<12
35
16
22
Table 2. Comparison with AI and Complement levels
AI/Protein
≥12
<12
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ORIGINAL ARTICLE
≥3
<3
17
10
35
26
Data not available
3
12
Odds ratio
1.26
P value
0.7976
Chi-square Yates corrected
0.07
Table 3. High urine protein and activity index
Serum
Serum
No follow
creatinine creatinine
up
doubled not doubled
Activity & chronicity indices
Total
Fisher
test
0.3327
Endocapillaryhypercellularity Positive
7
53
24
84
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
Positive
Negative
0
6
20
7
0
7
0
5
2
5
2
4
3
1
6
6
1
7
0
15
48
1
52
16
47
21
28
40
13
55
18
50
3
65
36
32
36
32
4
24
4
21
7
24
4
14
14
15
13
9
19
3
25
18
10
18
10
19
78
25
80
23
78
25
47
56
33
70
31
72
7
95
60
43
61
42
Leucocyte infiltration
Subendothelial
Interstitial inflammation
Fibrinoid necrosis
Cellular crescent
Glomerular sclerosis
Fibrous crescent
Tubular atrophy
Interstitial fibrosis
0.6653
0.3341
0.1802
0.2293
0.0743
0.1843
0.3299
0.1263
0.0179
Table4. Variables of AI and CI-Doubling serum creatinine
We found cellular crescent and interstitial fibrosis as the only 2 variables associated with
poor renal outcome (doubling of serum creatinine).
INTER OBSERVER VARIATION OF ACTIVITY AND CHRONICITY INDICES:
In our study 3 observers with varying degree of experience blindly calculated the AI and CI for 103
cases. The observers are as follows: Observer 1 –Senior Consultant, Observer 2 – Junior Consultant,
Observer 3 –Trainee.
We measured the degree of agreement between the 3 observers (The test was applied
separately for observer 1&2, observer2&3 and observer1&3) by applying Kappa coefficient.
Value of Kappa
Strength of agreement
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ORIGINAL ARTICLE
<0.20
Poor
0.21-0.40
Fair
0.41-0.60
Moderate
0.61-0.80
Good
0.81-1.00
Very good
Table 5. Value of Kappa and strength of agreement
Activity and
chronicity
indices
Endocapillary
hyercellularity
Observer 1
and 2
( p = 0.0000)
Observer 2
Observer 3
and 3
and 1
(p = 0.0000) (p = 0.0000)
Kappa coefficient
0.6972
0.6004
0.7741
Observed agreement
0.7864
0.7184
0.8447
Kappa coefficient
0.6989
0.6191
0.7618
Observed agreement
0.7766
0.7184
Subendothelial
hyaline
Kappa coefficient
0.6503
0.5488
deposition
Observed agreement
0.7475
0.6699
Interstitial
Kappa coefficient
0.6439
0.4933
inflammation
Observed agreement
0.7572
0.6601
Fibrinoid
Kappa coefficient
0.6375
0.5060
necrosis
Observed agreement
0.7864
0.7184
Cellular
Kappa coefficient
0.7338
0.6370
crescent
Observed agreement
0.8737
0.8349
Glomerular
Kappa coefficient
0.8034
0.6581
sclerosis
Observed agreement
0.9126
0.8543
Fibrous
Kappa coefficient
1.0000
0.6510
crescent
Observed agreement
1.0000
0.9615
Tubular
Kappa coefficient
0.6741
0.5092
atrophy
Observed agreement
0.7961
0.7087
Interstitial
Kappa coefficient
0.6602
0.4986
fibrosis
Observed agreement
0.7864
0.6990
Table 6. Inter observer variation-AI & CI
0.8252
Leucocyte
infiltration
0.7472
0.8155
0.7512
0.8349
0.7810
0.87
0.8538
0.93
0.8032
0.9126
0.7141
0.9708
0.77
0.8543
0.7684
0.8543
WHO class and Activity index ≥ 12:
In this series 43% of the cases of class IV had AI≥12.
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ORIGINAL ARTICLE
Fig. 1: AI distribution for WHO class
WHO class and chronicity index ≥ 4:
In our study 16% of class IV and both the cases of class VI had CI≥4.
Fig .2: CI > 4 in WHO class
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ORIGINAL ARTICLE
Fig. 5: Glomerulus showing endocapillary hypercellularity
with extensive neutrophilic infiltration.
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ORIGINAL ARTICLE
Fig. 6: Glomerulus showing
fibrinoid necrosis
Fig. 7:Two glomeruli one of
which is showing a crescent
Fig.8:Slide showing focal tubular atrophy
AUTHORS:
1. Seema H.S.
2. IshaGarg
3. Priya Alexander
PARTICULARS OF CONTRIBUTORS:
1. Post Graduate Resident, Department of
Pathology, St. John’s Medical College,
Bangalore.
2. Professor, Department of Pathology, St. John’s
Medical College, Bangalore.
3. Assistant Professor, Department of Pathology,
St. John’s Medical College, Bangalore.
NAME ADRRESS EMAIL ID OF THE
CORRESPONDING AUTHOR:
Dr. Seema H.S.,
H.No. 1, Venkateshwara Layout,
Kudlu, Hosur Road,
Bangalore.
Email –drseemapath28@gmail.com
Date of Submission: 26/11/2013.
Date of Peer Review: 28/11/2013.
Date of Acceptance: 05/12/2013.
Date of Publishing: 18/12/2013
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Page 9962