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Małgorzata Wągrowska-Danilewicz1, Marian

Danilewicz2

1 Department of Nephropathology, Medical University of Łódź, Poland2 Department of Pathomorphology, Medical University of Łódź, Poland

Disclosure statement: no conflict of interest

Clinicopathological characteristics of segmental (IV-S) and global (IV-G) active subclasses of class IV lupus

nephritis

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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

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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).

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Active diffuse proliferative lupus nephritis may demonstrate:

LM: Wire loopsHyaline thrombiEndocapillary hypercellularityMesangial hypercelluralityNecrotizing lesionsCellular 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.

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

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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%)

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).

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The presence of

hypertension

proteinuria <2g/24h hematuria

nephrotic syndrome

acute renal failure

chronic renal failure

Clinical & laboratory data

We compared:

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Endocapillary hypercellularity Cellular crescents

Wire loops Hyaline thrombi

Necrosis of capillary loops (karyorrhexsis, fibrinoid necrosis, capillary wall disruption)

Microscopic glomerular active featureswe compared

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Segmental endocapillary hypercellularity

Segmental necrosis of glomerular tuft

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Cellular crescent

Segmental active features

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Global features: wire loops, hyaline thrombi, hypercellularity

Global active features

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The intensity of staining: 0,+1,+2, +3

Immunoglobulin:

(IgG, IgA, IgM)

Complement components:

(C1q, C3)

Mesangial and

peripheral capillary wall

staining

Immunofluorescence study

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Mesangial and paramesangial deposits

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Subepithelial deposits

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Statistical analysisThe differences between groups were assessed using chi² test. Results were considered statistically significant if P < 0.05.

Laboratory&clinical data:The presence of hypertensionNephrotic syndromeAcute renal failureChronic renal failureProteinuria <2g/24hHematuriaImmunofluorescence findings:Strong mesangial staining /or strong peripheral wall stainingImmunoglobulin: (IgG, IgA, IgM) and component of complement (C3, C1q) The intensity of immunoglobulin and complement component staining (0, +1, +2, +3)Light microscopy: Endocapillary hypercellularityCellular crescentsNecrosis of glomerular tuft (disruption of capillary wall, fibrinoid necrosis, karyorrhexis)Hyaline thrombiWire loops

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hypertension

proteinuria <2g/24h

hematuria

nephrotic syndrome

acute renal failure

chronic renal failure

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

33%

67%

100%

11%

33%

22%

72%

20%

64%

52%

20%

48%

IV-G/A Kolumna1

P<0.05

P<0.02

P<0.04

P<0.04

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

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the dominance of peripheral capillary wall staining

the dominance of mesangial staining

0% 20% 40% 60% 80% 100%

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89

84

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RESULTS: Immunofluorescence : mesangial vs. peripheral capillary wall staining

IV-G/AKolumna1

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

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IgG-0

IgG (+1)

IgG (+2)

IgG (+3)

11%78%

11%

0%

0%

12%

52%

36%

RESULTS: Immunofluorescence – the intensity of glomerular IgG staining

IV-G/A IV-S/A

P<0.04

P<0.04

P<0.0002

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

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IgA-0

IgA (+1)

IgA (+2)

IgA (+3)

89%

11%

0%

0%

16%

52%

28%

4%

P<0.0001

P<0.04

NS

NS

RESULTS: Immunofluorescence - the intensity of glomerular IgA staining

IV-G/A IV-S/A

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

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IgM 0

IgM (+1)

IgM (+2)

IgM (+3)

78%

22%

0%

0%

16%

36%

40%

8%

P<0.0008

P<0.03

RESULTS: Immunofluorescence- the intensity of glomerular IgM staining IV-G/A IV-S/A

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

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C3 - 0

C3 (+1)

C3 (+2)

C3 (+3)

33%

33%

22%

11%

8%

24%

40%

28%

RESULTS: Immunofluorescence – the intensity of glomerular C3 staining (P>0.05 NS)

IV-G/A IV-S/A

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

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C1q - 0

C1q (+1)

C1q (+2)

C1q (+3)

11%

44%

33%

11%

12%

52%

28%

8%

RESULTS: Immunofluorescence – the intensity of glomerular C1q staining (P>0.05, NS)

IV - G/A IV- S/A

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

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endocapillary proliferation

Karyorrhexis

capillary wall disruption

cellular crescents

wire loops

hyaline thrombi

fibrinoid necrosis

33%

33%

22% 89%

11%

0%55%

88%

52%

12%56%

60%

36%

20%

RESULTS: Light microscopy: Percentage of biopsies with the glomerular histologic active features

IV G/A IV S/AP<0.05

P<0.04

P<0.02

P<0.002

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

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In IV–S/A LN: More often hematuria and proteinuria <2g/24hThe dominance of mesangial depositsThe intensity of Immunoglobulin staining was lower in IV-S/A than in IV-G/A group High rate of fibrinoid necrosisEndocapillary hypercellularity was less frequently found than in IV-G/A group

In IV-G/A LN: More often nephrotic syndrome and hypertensionThe dominance of peripheral wall stainingThe intensity of immunoglobulin staining was stronger inIV-G/A than in IV-S/A groupHyaline thrombi was detected only in IV-G/AWire loops were more often found in IV-G/A than in IV-S/AEndocapillary hypercellularity was more often found in IV-G/A than in IV-S/A

Summary: the comparison – subclass IV-S/A LN vs. subclass IV-G/A LN

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Gao JJ et al. Rheumatol Int 2012. 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 2011. 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 2008. 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, 2005. 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 2011. 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 2004. The percentage of glomeruli with cellular crescents also was greater in the IV-S group, but the difference was not significant.

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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

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Thanks for yours attention