Rare transformation in repeat renal biopsies suggests a different pathogenesis of segmental and global lesions in proliferative lupus nephritis.

Heterogeneous histological findings in the renal biopsies of patients with systemic lupus erythematosus were distinguished early into different types of lupus nephritis with different outcomes. The effort to unify the terminology resulted in six classes of the World Health Organization (WHO) classification published in 1982 [1]. Having apart biopsies with normal histology (Class I) and advanced sclerotic lesions (Class VI), it became apparent that there are two main types of lupus nephritis: membranous (Class V) and proliferative (Classes III and IV), although there were also patients with a combination of both membranous and proliferative lesions. Membranous lupus nephritis was shown early to have better outcome than proliferative lupus nephritis, but the relation between focal (Class III) and diffuse (Class IV) lesions remained uncertain. Segmental lesions typical for Class III lupus nephritis resemble the lesions present in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and are very different from global lesions typical for Class IV which, on the other hand, may resemble the immune complex-mediated lesions present, e.g. in idiopathic membranoproliferative glomerulonephritis. According to the new International Society of Nephrology/Renal Pathology Society (ISN/RPS) histological classification [1] segmental lesions may be present both in Class III (focal lupus nephritis) if affecting <50% of glomeruli and in a special subclass of Class IV (diffuse lupus nephritis) called IV-S if affecting >50% of glomeruli. The ISN/RPS Class IV category thus mixes together segmental lesions in >50% of glomeruli (Class IV-S) and diffuse proliferative lesions (Class IV-G) affecting >50% of glomeruli [2]. Although some authors argued that focal segmental lesions may evolve into diffuse global lesions and both of them may regress (after treatment) into mesangial (Class II) lupus nephritis, other authors referred that there are significant differences between WHO Classes III and IV (and ISN/RPS Class IV-S and IV-G) lupus nephritis both concerning the histological characteristics, clinical presentation and outcome, and that the pathogenesis of segmental and global proliferative lesions may be different [3]. In this issue of NDT Pagni et al. evaluated 142 patients with lupus nephritis and repeat biopsies. Although their original main aim was to look at the role of repeat renal biopsies in routine clinical practice, their paper also adds an important contribution to our understanding of the putatively different pathogenesis of different histological classes of (proliferative) lupus nephritis. Patients with IV-G class of lupus nephritis had, at presentation compared with segmental forms of lupus nephritis (Classes III and IV-S), higher proteinuria, serum creatinine and blood pressure and more mesangial proliferation, wire loops and tuft necrosis in the biopsy. The disease was more severe in both first and repeat biopsy in Class IV-G compared with Class III and IV-S patients and repeat renal biopsy predicted better trend of serum creatinine and proteinuria than the first biopsy. Most importantly, although the transitions between different histological classes were quite frequent (40.8%), the transition between segmental (III/IV-S) and mesangial (II/IV-G) forms was extremely rare, strongly suggesting that really both forms may have not only different clinical and histological features, but also different pathogenesis. Important differences in the histology between IV-G and IV-S patients were repeatedly (and relatively consistently) described. Patients with IV-S class had, compared with IV-G class, e.g. fewer glomeruli with wire loops [3, 4] and hyalin thrombi [3], more frequent fibrinoid necrosis [4–7], lower endocapillary proliferation [6], significant trend to the higher proportion of crescents [4], less frequent infiltration of glomeruli with monocyte/macrophages, lower interstitial inflammation [6] and less IgG (or even complete absence of IgG) on immunofluorescence [3]. Histologic differences may be translated into some differences in the clinical presentation. Class IV-G lupus nephritis was shown to present, compared with Class IV-S, with higher serum creatinine, worse proteinuria [4–6] and higher diastolic blood pressure [4, 7] and also lower C3 [5, 6] and lower proportion of patients with the positivity of anticardiolipin antibodies [6]. Patients with Class III were also shown to have a lower prevalence of the positivity of anti-C1q compared with Class IV patients [8] and patients with segmental lesions (Classes III and IV-S) have the lowest levels of complement factor H in SLE and lupus nephritis patients [9]. IN F O C U S