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Lupus glomerulonephritis. summary Etiology and pathogenesis Morphologic classification and clinical relevance Class switching in follow-up biopsies Alternative.

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Presentation on theme: "Lupus glomerulonephritis. summary Etiology and pathogenesis Morphologic classification and clinical relevance Class switching in follow-up biopsies Alternative."— Presentation transcript:

1 lupus glomerulonephritis

2 summary Etiology and pathogenesis Morphologic classification and clinical relevance Class switching in follow-up biopsies Alternative markers for activity

3 Chimerism occurs twice as often in lupus nephritis as in normal kidneys GvH, HvG, repair? Kremer Hovinga I., 2007, 2008

4 Feliers D., KI 2009: decreased renal VEGF predicts loss of renal function in lupus nephritis

5 The binding of anti-double-stranded DNA (anti-dsDNA) autoantibodies to the glomerular basement membrane (GBM) in lupus nephritis can be explained by two mechanisms: (1) direct crossreactive binding to intrinsic glomerular antigens; (2) binding to heparan sulfate in the GBM mediated by nucleosomes derived from apoptotic cells. (van Bavel KI 2007)

6 Potential for glomerular C4d as an indicator of thrombotic microangiopathy in lupus nephritis Activation of the classical pathway of complement plays a pathogenic role in TMA, irrespective of the type of circulating antibody present Cohen D e.a., Arthritis Rheum 2008

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8 Lupus Nephritis ISN/RPS classification Class I: minimal mesangial lupus glomerulonephritis (LGN) Class II: mesangial proliferative LGN Class III: focal LGN (involving less than 50% of the total number of glomeruli) Class IV: diffuse LGN (involving 50% or more of the total number of glomeruli) Class V: membranous LGN Class VI: advanced sclerotic LGN (>90% of glomeruli globally sclerosed without residual activity)

9 Class I: minimal mesangial lupus glomerulonephritis (LGN) normal glomeruli by LM, but mesangial immune deposits by IF and/or EM

10 Class II: mesangial proliferative lupus glomerulonephritis

11 Class III: focal lupus glomerulonephritis (involving less than 50% of the total number of glomeruli) - III (A) active focal proliferative LGN - III (A/C) active and sclerotic focal proliferative LGN -III (C) inactive sclerotic focal LGN

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16 fingerprint-like crystalline pattern of deposits: cryoglobulins?

17 myxovirus-like particles or tubuloreticular inclusions in endothelial cells/lymphocytes, localised in dilated rough and smooth endoplasmic reticulum; dd other viral infections (HIV)

18 Class IV: diffuse segmental (IV-S) or global (IV-G) LGN (involving 50% or more of the total number of glomeruli either segmentally or globally) class IV is further subdivided into diffuse segmental (IV-S) when >50% of the involved glomeruli have segmental lesions, and diffuse global (IV-G) when >50% of the involved glomeruli have global lesions - IV-S(A), IV-G(A): diffuse segmental or global proliferative LGN - IV-S(A/C), IV-G(A/C): diffuse segmental or global proliferative and sclerotic LGN - IV-S(C), IV-G(C): diffuse segmental or global sclerotic LGN

19 Segmental lesions are most often necrotic in nature (more hematuria, ‘vasculitis type’) and have a different pathogenesis and worse prognosis than global proliferative lesions which are most often purely proliferative (Korbet AJKD 2000; Hill KI 2005; Schwartz Sem Nephrol 2007)

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22 chronicity at presentation dictates prognosis, not S-G Hiramatsu, Reumatol 2008 Kaplan-Meier analysis with doubling serum creatinine as the end point

23 No difference in prognosis S-G (7 yr follow-up serum creat) Grootscholten NDT 2008 Class IV-G LN respond more poorly to induction therapy with i.v. Cyclophosphamide pulse than class IV-S LN. Kim Rheumatol. 2008

24 Kojo et al., J Rheumatol 2009 In class IV, the IV-G group tended to exhibit a worse renal outcome compared with the IV-S group, but the difference was not significant (log-rank test, p = 0.4330; retrospective analysis of 99 biopsy-proven subjects with lupus nephritis)

25 Lupus Nephritis WHO/ISN/RPS classification Class I: minimal mesangial lupus glomerulonephritis (LGN) Class II: mesangial proliferative LGN Class III: focal LGN (involving less than 50% of the total number of glomeruli) Class IV: diffuse LGN (involving 50% or more of the total number of glomeruli) Class V: membranous LGN Class VI: advanced sclerotic LGN (>90% of glomeruli globally sclerosed without residual activity)

26 Daleboudt, NDT 2009 Follow-up biopsies: Patients with proliferative lesions in the original biopsy rarely switch to a pure non-proliferative nephritis during a flare. Therefore, a repeat biopsy during a lupus nephritis flare is frequently not necessary if proliferative lesions were found in the reference biopsy. However, in the case of a non-proliferative lesion in the reference biopsy, class switches are frequently found and repeat biopsies are advisable.

27 What about alternative markers for activity of lupus nephritis?

28 Wang, G. et al. Rheumatology 2009 Regulatory T lymphocytes (Tregs) probably play an important role in the pathogenesis of SLE. FOXP3, a critical regulator for the development and function of Tregs

29 Copyright restrictions may apply. Wang, G. et al. Rheumatology 2009 Comparison of mRNA expression of FOXP3 in urinary sediment among patient groups

30 Copyright restrictions may apply. Wang, G. et al. Rheumatology 2009 Relations between mRNA expression of FOXP3 in urinary sediment and (A) histological activity index, (B) histological chronicity index, (C) glomerular scarring and (D) tubulointerstitial scarring

31 Since its publication, the ISN/RPS classification has been used successfully in a number of clinical-pathologic studies. Several studies addressing the relationship between LN IV-S and LN IV-G have failed to identify a significantly worse outcome in IV-S than IV-G, although there were some differences in presenting clinical and pathologic features. Importantly, the ISN/RPS classification has achieved its goal of improved interobserver reproducibility. Its use has increased the percentage of LN biopsies meeting criteria for class IV. As it gains widespread acceptance, the ISN/RPS classification is already providing a standardized approach to renal biopsy interpretation needed to compare outcome data across centers. Markowitz KI 2007

32 summary Etiology and pathogenesis Morphologic classification and clinical relevance Class switching in follow-up biopsies Alternative markers for activity


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