title: Treatment of focal segmental glomerulosclerosis with immunophilin modulation: when did we stop thinking about pathogenesis?
abstract: Nephrotic focal segmental glomerulosclerosis (FSGS) represents a difficult therapeutic challenge. FSGS has long been considered a subset of idiopathic nephrotic syndrome, lumping together FSGS and minimal change disease (MCD). The time-honored 'Shalhoub hypothesis' has led to treating FSGS as a T-cell-driven condition in which a lymphokine, considered without proof as being the 'glomerular permeability factor,' induces proteinuria and podocyte functional and structural derangement. This has led to trying, in addition to steroids, every new drug marketed in the field of organ transplantation, first cyclosporine (CsA) and then other immunophilin modulators. The fact that alkylating agents and mycophenolate mofetil have obtained a poor and inconstant favorable effect, and that rituximab may obtain remissions, although inconstantly, has not led to reconsidering the T-cell hypothesis. This wrong thinking has fostered innumerable, mostly uncontrolled, treatment trials with various immunosuppressive agents. In fact, clinicians have not considered the fact that some but not all immunophilin modulators may be effective as nonspecific antiproteinuric agents, rather than as immunosuppressive drugs, and that treatment success does not exclude a non-immunologic pathophysiology. Recent findings on the mode of action of CsA and FK-506 have lent support to this concept. This review should be considered as a plea to reconsider the pathogenesis of nephrotic FSGS, applying all efforts to the identification of the factor, or factors, responsible for nephrotic FSGS, and to fund treatment to counteract the 'factor,' rather than pursuing costly and non-evidence-based immunosuppressive therapeutic trials.
authors.affiliation: Department of Nephrology, University Paris-Descartes, Hôpital Georges Pompidou and Broussais, 20 rue Leblanc, Paris F-75015, France. alain.meyrier@gmail.com
authors.forename: Alain Y
authors.initials: AY
authors.lastname: Meyrier
mesh_terms: D001327:Autoimmune Diseases / Q000209:etiology; D065095:Calcineurin Inhibitors; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D020104:Immunophilins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D009402:Nephrosis, Lipoid / Q000209:etiology; D011507:Proteinuria / Q000188:drug therapy
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D020104:Immunophilins