The morphological and clinical value of repeat biopsy in lupus nephritis: a retrospective multicenter international study

Franco Ferrario – Renal Immunopathology Center
San Carlo Borromeo Hospital – Milan - Italy

Introduction:
The morphologic changes in the renal biopsy from a patient with Systemic Lupus Erithematosus comprise a spectrum of glomerular, tubulointerstitial and vascular lesions.
A new classification of glomerulonephritis has recently been put forth by the ISN/RPS consensus conference held at Columbia University (NY) in May 2002 and published by JASN and Kidney International in 2004.
This classification seeks to rectify some of the problems that have arisen over the years with the WHO classification, dating from 1982, revised in 1995 and introduces several important modifications concerning “quantitative” and “QUALITATIVE” differences between class III and in particular IV lesions.
One of the main advantages of the current revised classification (ISN/RPS) is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies.
A brief summary of the ISN/RPS classification is as follows:
Class I: Minimal mesangial lupus glomerulonephritis (LGN). Normal glomeruli by LM, but mesangial immune deposits by IF and/or EM.
Class II: Mesangial proliferative LGN. Purely mesangial hypercellularity of any degree and/or mesangial matrix expansion by LM with immune deposits, predominantly mesangial with none or few, isolated subepithelial and/or subendothelial deposits by IF and/or EM not visible by LM.
Class III: Focal LGN (involving less than 50% of the total number of glomeruli). Active or inactive focal, segmental and/or global endo- and/or extracapillary GN, typically with focal, subendothelial immune deposits, with or without focal or diffuse mesangial alterations.
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). Active or inactive diffuse, segmental or global endo and/or extracapillary GN with diffuse subendothelial immune deposits, with or without mesangial alterations.
This class is divided into: diffuse segmental (IV-S), when >50% of the glomeruli have segmental lesions, and diffuse global (IV-G), when >50% of the involved glomeruli have global lesions.
Class V: Membranous Lupus Nephritis. Class V may occur in combination with class III and IV in which case both will be diagnosed.
Class VI: Advanced sclerosing Lupus Nephritis. >90% of glomeruli globally sclerosed without residual activity.

The most important changes have come in Class IV lupus glomerulonephritis, formerly called diffuse proliferative lupus nephritis involving, by definition more than 50% of glomeruli.
Class IV is now subdivided into 2 subclasses according to whether the majority of lesions involve the glomeruli in segmental fashion or in global fashion showing diffuse proliferative lesions and deposits.
The crucial problem is to better understand if these morphological differences are an expression of different pathogenetic mechanisms and provide beneficial information relevant to long term renal outcome and optimal therapy preventing ESRF in patients with Lupus Nephritis.
In recent years some studies investigated the morphological and clinical usefulness of the new ISN/RPS SLE classification.
Their conclusions are here reported:
C. Najafi: On the basis of our observations, the recommendation that category III > 50%(now IV-S) and category IV biopsies represent a continuum that ultimately results in the global inflammation of diffuse glomerulonephritis appears to be an oversimplifaction that ignores both the characteristic morphologic features of each lesion and the clinical course and response to therapy. Patients with severe segmental glomerulonephritis (>50% glomerular involvement) have a poorer prognosis than patients with diffuse global proliferative glomerulonephritis and warrant being separated if only to acknowledge this difference.
G. Hill: There are definite clinical and morphologic differences between class IV-S and IV-G lesions. Data suggest that class IV-G lesions behave as an immune complex disease, having positive correlations with extent of immune deposits and negative correlations with serum complement levels, the model traditionally assumed for lupus nephritis as a whole. However, in class IV-S lesions, the presence of proportionally greater glomerular fibrinoid necrosis and lack of correlation with extent of immune deposits suggest that these lesions may have a different pathogenesis. It is to be hoped that a more specific therapy may ultimately be developed for these lesions.
H. Yokoyama: Our data show that the focal and segmental glomerular lesions of LGN were characterized by segmental endocapillary proliferation, fibrin deposition, and an intense inflammatory lesion with karyorrhexis, cell wall destruction, and crescents. Moreover, such segmental lesions showing necrosis were similar to the lesions of systemic vasculitis, suggesting a role of cellular immunity  in the pathologic process. In addition to quantitative (<50% or more than 50%) factor, qualitative changes may also be an important factor for the renal outcome of human LGN as well as developing new therapeutic strategies.
B. Mittal: Our data do not support the creation of a distinct categorization of class IV into IV-S and IV-G. Conversely, IV-S could represent an earlier stage of IV-G. No significant difference in outcomes of the IV-S and IV-G groups of class IV lupus nephritis was observed.  However, the follow-up period may be shorter in this study.
There still remain some differences of opinion and conflicting results regarding prognostic data among the Authors and further studies are needed to better clarify the validity of the new classification.

Taking into account all these assumptions a prospective and/or retrospective study on repeat biopsies in SLE nephritis can prove valuable in understanding the possible different pathogenetic mechanisms in the different classes (in particular Class IV-S and IV-G), the possible transformation from one to another class, providing an opportunity to evaluate the morphological and  pathogenetic equivalent of changes in renal function and assess which of the varied changes in initial biopsies predict the subsequent course of the disease.
The histological transformation among different classes of SLE nephritis has been reported in some previous studies: all of them are retrospective with usually few patients and based on previous WHO classification (so are not comparable with new concept of ISN/RPS classification). The conclusions of these works are similar: a single biopsy may not be sufficient to manage lupus nephritis throughout the course of  disease. Repeat biopsy appears to have clinical utility, as the majority of patients had a change in their management based on the histological findings noted in their second biopsy.
Moreover in a prospective study of repeat biopsies in 75 diffuse SLE nephritis (according to the new classification) G. Hill concluded: there was no significant difference in response to therapy and recovery or progression of renal disease between patients with class IV-S and IV-G lesion at the first biopsy. However, in the biopsy after treatment at 6 months, persistence of pathologic features of class IV-G lesions appeared to be associated with a much worse survival than those patients who manifested class IV-S lesions at the second biopsy.
Although protocol biopsies at a regular interval in the 1st year of diagnosis of lupus nephritis (particularly Classes III, IV and V) are not routinely performed, a significant number of cases require a second biopsy. The common reasons for a repeat biopsy can be divided into 3  different categories:
-New clinical renal findings with or without a systemic lupus flare
-To make therapeutic decisions such as efficacy of therapy, to institute a change  in therapy or discontinue treament, based on existing disease activity or chronicity
-To assess prognostic significance.

“One renal biopsy is a picture, the second biopsy is more a movie”.

Study Protocol – Proposal
Multicenter International retrospective study on repeat biopsy in Lupus Nephritis.
RPS can take a leadership role to devise such a study of a large number of cases, particularly with participation of an International network of Renal Pathologists.  Most of those pathologists who are directly involved in the consensus conference of new SLE nephritis classification (giving the study a standardized/uniform assessment opinion to score biopsies).

Inclusion criteria
All patients with Lupus Nephritis that performed 2 or more renal biopsies (with approximate interval no more than 5 years from I and II RB)
Objectives

Methods
The Board of Directors and the memberships(business meeting) of Renal Pathology Society approved to nominate two main coordinators of the study with the responsibility of renal biopsy collection (and scoring) in their Continent and other Countries connected with the coordinator’s Centers.
Coordinators and referral Countries:
-FRANCO FERRARIO (Renal Immunopathology Center-San Carlo Borromeo Hospital-Via Pio II 3-  20153  -Milan-Italy)
   WEST-EAST EUROPE ; JAPAN ; CHINA ; BRASIL (possibly other South American Countries).

-SURYA SESHAN (Department of Pathology-The New York Hospital-Cornell Medical Center-525 East 68th St.,Starr 1028- New York,NY 10021-USA). Email: svs2002@med.cornell.edu
   USA ; CANADA ; INDIA ; AUSTRALIA

All interested Centers have to provide glass slides of renal biopsies I and II(and from additional biopsies?) renal biopsies to the coordinator center with the following stains:
-H and E
-PAS
-Trichrome-
-Silver
-If possible 5-6 unstained fixed formalin sections for the study of leukocyte population with monoclonal antibodies.

Additionally, all centers have to send corresponding data for better biopsies (if available):
- Immunofluorescence data :  scored by local Center.
- Electron Microscopy data: if performed report of local center.
- Clinical datasets with the essential information for clinico-pathological correlations.

All these data forms will be provided by the Coordinators.

The coordinators will try to find funding for scientific meetings(discussion of histopathological forms, establish criteria for inclusion, exchange of information and data ,better standardise the results of scored biopsies) and organization and administrative assistance(circulation of slides, data manager, statistic evaluation etc).

All pathological and clinical data will be sent to the central coordinating center of the study(Franco Ferrario, Chair, Research Committee, RPS) for final evaluation of data.
The study duration could span (about) 3 years starting from Spring 2008.

Franco Ferrario
Renal Immunopathology Center
San Carlo Borromeo Hospital
Via Pio II, 3
20153 Milan – Italy
Tel. +39-2-4022.2343
Fax +39-2-4022.2222  or  39-2-40090019
e-mail: franco.ferrario@oscb.sined.net

Research Committee
Chair: Franco Ferrario
Members: Randolf Hennigar, Gilbert Moeckel, Ian Roberts
BIBLIOGRAFIA