1. Małgorzata Wągrowska-Danilewicz1, Marian Danilewicz2
Clinicopathological characteristics of segmental (IV-S) and global (IV-G) active subclasses of class IV lupus nephritis
Małgorzata Wągrowska-Danilewicz1, Marian Danilewicz2
1 Department of Nephropathology, Medical University of Łódź, Poland
2 Department of Pathomorphology, Medical University of Łódź, Poland
Disclosure statement: no conflict of interest

2. Lupus nephritis occurs in up to 50%- 80% of SLE patients, usually within the first year of disease onset
The clinical manifestation of SLE-associated renal disease are extremely diverse, ranging from asymptomatic hematuria and proteinuria to full nephrotic syndrome and rapidly progressive renal failure
A kidney biopsy is essential in establishing diagnosis and prognosis, and guiding treatment
The pathologic manifestations of renal disease in SLE patients are heterogeneous, however most patients have immune-mediated glomerular disease, with variable tubulointerstitial and vascular lesions

3. Class IV is the most common form of active lupus nephritis
This class is divided into diffuse segmental (IV-S) lupus nephritis when ≥50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) lupus nephritis when ≥50% of the involved glomeruli have global lesions.
Segmental is defined as a glomerular lesion that involves less than half of the glomerular tuft
This definitions might cause misclassifications of the two subclasses because they are sensitive to sampling error: sample sizes are often small
It is suggested that IV-S/A and IV-G/A lupus nephritis have different pathogenesis
The data concerning outcome in patients with IV-S/A and IV-G/A are controversial, however in the majority of studies no significant differences in outcomes were detected (Mittal et al. Am J Kidney Dis, 2004, Yokoyama et al. Kidney Int 2004, Catharina M et al. J Am Soc Nephrol, 2012, Grootscholten et al., Nephrol Dial Transplant, 2007).

4. Active diffuse proliferative lupus nephritis may demonstrate:
LM:
Wire loops
Hyaline thrombi
Endocapillary hypercellularity
Mesangial hypercellurality
Necrotizing lesions
Cellular crescents
IF : reveals deposition of immunoglobulin and complement components in both mesangium and in the peripheral capillary walls („full-house pattern”- staining of IgG, IgA, IgM and complement components C1q, C3)
EM: reveals the presence of subendothelial depositis in capillary loops, in mesangium, and occasionally accompanied by subepithelial deposits.

5. The purpose of the study was to compare in class IVA/S LN and IVA/G LN
The clinical & laboratory data
Immunofluorescence findings
Morphological glomerular active features

6. IV-S/A (n=9) IV-G/A (n=25)
Material
- consisted of 34 renal biopsies from adult patients with IV Class lupus nephritis who underwent renal biopsy in Department of Nephropathology in Medical University of Lodz. Patients 18 years of age and older who met four American College of Rheumatology criteria for systemic lupus erythematosus (SLE)
Renal biopsy specimens were routinely processed by light microscopy, immunofluorescence, and in some cases by electron microscopy.
Criteria applied to the biopsy specimens: mnimal number of 10 glomeruli for LM analysis, and 5 glomeruli for IF analysis
The diffuse glomerular lesions in IV Class LN were reclassified using classification ISN/RPS system (Weening et al. Kidney Int, 2004).
IV-S/A
(n=9)
IV-G/A
(n=25)
Age (years)
31.2± 9.3
29.5±8.2
Female
8 (89%)
19 (76%)
Male
1 (11%)
6 (24%)

7. The presence of hypertension
Clinical & laboratory data
The presence of hypertension
proteinuria <2g/24h
hematuria
nephrotic syndrome
acute renal failure
chronic renal failure
We compared:

8. Endocapillary hypercellularity
Microscopic glomerular active features
we compared
Endocapillary hypercellularity
Cellular crescents
Wire loops
Hyaline thrombi
Necrosis of capillary loops (karyorrhexsis, fibrinoid necrosis, capillary wall disruption)

9. Segmental endocapillary hypercellularity
Segmental necrosis of glomerular tuft

10. Cellular crescent
Segmental active features

11. Global features: wire loops, hyaline thrombi, hypercellularity
Global active features

12. Immunofluorescence study
The intensity of staining:
0,+1,+2, +3
Immunoglobulin:
(IgG, IgA, IgM)
Complement components:
(C1q, C3)
peripheral capillary wall staining
Mesangial
and
Immunofluorescence study

13. Mesangial and paramesangial deposits

14. Subepithelial deposits

15. Statistical analysis
The differences between groups were assessed using chi² test.
Results were considered statistically significant if P < 0.05.
Laboratory&clinical data:
The presence of hypertension
Nephrotic syndrome
Acute renal failure
Chronic renal failure
Proteinuria <2g/24h
Hematuria
Immunofluorescence findings:
Strong mesangial staining /or strong peripheral wall staining
Immunoglobulin: (IgG, IgA, IgM) and component of complement (C3, C1q)
The intensity of immunoglobulin and complement component staining (0, +1, +2, +3)
Light microscopy:
Endocapillary hypercellularity
Cellular crescents
Necrosis of glomerular tuft (disruption of capillary wall, fibrinoid necrosis, karyorrhexis)
Hyaline thrombi
Wire loops

16. RESULTS: Clinical manifestation of the disease - the percentage of patients presented with chronic renal failure, acute renal failure, nephrotic syndrome, hematuria, proteinuria <0.2g/24h, and hypertension in IV-S/A and IV-G/A group

17. P<0.0001
The percentage of biopsies with the dominance of mesangial or peripheral capillary wall staining in IV-S/A and IV-G/A group

18. The percentage of biopsies with IgG (0), IgG(+1), IgG(+2), and IgG(+3) staining in IV-S/A and IV-G/A group

19. The percentage of biopsies with IgA (0), IgA(+1), IgA(+2), and IgA(+3) staining in IV-S/A and IV-G/A group

20. The percentage of biopsies with IgM (0), IgM(+1), IgM(+2), and IgM(+3) staining in IV-S/A and IV-G/A group

21. The percentage of biopsies with C3 (0), C3(+1), C3(+2), and C3(+3) staining in IV-S/A and IV-G/A group

22. The percentage of biopsies with C1q(0), C1q(+1), C1q(+2), and C1q(+3) staining in IV-S/A and IV-G/A group

23. The percentage of biopsies with fibrinoid necrosis, hyaline thrombi, wire loops, cellular crescents, capillary wall disruption, karyorrhexis and endocapillary hypercellularity in IV-S/A and IV-G/A group

24. Summary: the comparison – subclass IV-S/A LN vs. subclass IV-G/A LN
In IV–S/A LN:
More often hematuria and proteinuria <2g/24h
The dominance of mesangial deposits
The intensity of Immunoglobulin staining was lower in IV-S/A than in IV-G/A group
High rate of fibrinoid necrosis
Endocapillary hypercellularity was less frequently found than in IV-G/A group
In IV-G/A LN:
More often nephrotic syndrome and hypertension
The dominance of peripheral wall staining
The intensity of immunoglobulin staining was stronger inIV-G/A than in IV-S/A group
Hyaline thrombi was detected only in IV-G/A
Wire loops were more often found in IV-G/A than in IV-S/A
Endocapillary hypercellularity was more often found in IV-G/A than in IV-S/A

25. Gao JJ et al. Rheumatol Int 2012
Gao JJ et al. Rheumatol Int Class IV-G had higher score of immunofluorescence index. Class IV-S had a higher percentage of glomerular fibrinoid necrosis
Monova D et al. ISRN Immunology The serum creatine levels, proteinuria. and diastolic blood pressure were significantly greater in the class IV-G. Histologically combined lesions with segmental endocapillary proliferation and fibrinoid necrosis were more frequent in the class IV-S.
Grootscholten C et al. Nephrol Dial Transplant More endocapillary proliferation and higher scores for wire loops were present in the biopsies categorized as class IV-G.
Hill GS et al. Kidney Int, Patients with IV-G lesions had worse proteinuria. Patients with class IV-G lesions had greater overall immune deposits and subendothelial deposits on IF and greater hyaline deposits on LM. By contrast, class IV-S showed predominant mesangial deposits and a much higher rate of glomerular fibrinoid necroses
Jourde-Chiche N et al. Clin Nephrol Class IV-S and Class IV-G display very distinct histologic patterns, and may also have distinct pathogenic mechanisms. Class IV-S is associated with more frequent tuft necrosis, whereas Class IV-G may exhibit larger amounts of IgG deposition in the capillary wall, forming wire loops and hyaline thrombi.
Mittal B et al. Am J Kidney Dis The percentage of glomeruli with cellular crescents also was greater in the IV-S group, but the difference was not significant.

26. Conclusions:
the clinicopathologic differences in IV-S/A and IV-G/A LN, may confirm the suggestion that these lesions have a different pathogenesis,
however our study had several limitation including a small number of patients.
Further studies should be conducted to clarify whether morphological and clinical differences between IV-S/A and IV-G/A lupus nephritis are important for predicting the course of disease and response to therapy

27. Thanks for yours attention