Background/Purpose:

Lupus nephritis (LN) is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE) with proteinuria being the predominant common manifestation and may therefore reflect podocyte injury. Podocytes are highly specialized cells that have a relevant role in the glomerular filtration barrier and alteration in the expression of their biomarkers has been shown to be associated with podocyte dysfunction in some glomerulopathies.

A systematic analysis of podocyte-associated molecules encompassing different subcellular compartments was performed in a large series of LN biopsies. Expression of Wilms´ tumor protein (WT1), Synaptopodin (Synpo) and glomerular epithelial protein 1 (GLEPP1) with nuclear, cytoplasmic and membrane distribution respectively, were evaluated attempting to identify if podocyte phenotype is distinct in proliferative and membranous nephritis. Possible association of molecular expression alterations with long term proteinuria severity and outcome in lupus was also investigated.

Methods:

Immunohistochemistry analysis was performed using monoclonal antibodies to WT1, Synpo  and GLEPP1 proteins in 52 biopsies from patients with lupus nephritis fulfilling the revised ACR criteria for SLE. Demographic, clinical and laboratorial data at the time of biopsy were analyzed.  

Results:

Thirty-nine (75%) biopsies were classified as proliferative LN and thirteen (25%) as pure membranous class V. Immunohistochemistry analysis in normal kidney revealed preserved staining of WT1, Synpo and GLEPP1 podocyte biomarkers along the capillary walls. Preserved and concomitant WT1 and Synpo staining was observed in a significant higher frequency in pure class V biopsies than in proliferative LN (69.23 vs. 2.56%, p<0.0001). Likewise, preserved GLEPP1 expression was also more frequent in pure class V LN (53.85 vs. 2.86%, p=0.0002). Proteinuria and serum albumin levels at the time of biopsy did not statistically differ in the two groups (p=0.87 and p=0.41) whereas in the mean long-term follow-up of four years a tendency of lower proteinuria (p=0.050) was observed in those patients with biopsies expressing preserved WT1/Synpo staining.

Conclusion:

This is the first study comparing proliferative and membranous lupus nephritis which evaluated simultaneously the expression of proteins in different subcellular podocyte compartments and provided novel evidence of preserved podocyte structural architecture predominantly in membranous lesions which may account for a better long term outcome of patients with this LN histological class. These findings suggest possible different underlying mechanisms for proteinuria in both conditions.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/podocyte-injury-in-membranous-and-proliferative-lupus-nephritis-distinct-underlying-mechanisms/