Treatment of glomerulonephritis: Will we ever have options other than steroids and cytotoxics?

Abstract

Glomerulonephritis refers to a collection of primary renal disorders and those secondary to a systemic disease, all characterized by inflammation within the glomerulus. Given the underlying immunologic nature of these disorders, they are routinely treated with corticosteriods and various cytotoxic agents. Although in many instances such therapies are successful, they are associated with significant morbidity; as such, alternatives are clearly necessary. Our understanding of the pathogenesis of immunologic glomerular diseases has grown remarkably, in large part from the study of rodent disease models. Fundamental to each disorder is the development of an antigen-specific immune response followed by the effector stage of inflammation. To block the immune response, antigen-specific therapy can be used to induce tolerance, such as through the use of double-stranded DNA molecules in lupus nephritis. Since other antigen systems are less well characterized, inducing a more generalized impairment in the immune response by blocking costimulatory molecules CD40-CD154 and CD28-CD80/86 is a growing approach to treat various immunologic disorders and transplantation. To reduce glomerular inflammation, a variety of effector systems have been targeted, including complement, cytokines/chemokines, adhesion molecules, and mediators of cellular proliferation. Of these, antibodies targeting C5 in the complement system, and antibody and receptor antagonists of tumor necrosis factor-alpha (TNF-alpha) have already been used in glomerular disorders with some promise. Less specific blockade of receptor-mediated events stimulated by platelet-derived growth factors and cell cycle proteins may soon be applied to glomerulonephritis. Finally, interruption of fibrosing pathways, which lead to glomerulosclerosis and interstitial fibrosis common to the end-stage of all glomerulonephritis, is the subject of intense effort which may yield effective biologic therapies. In spite of all these advances, we still are dependent on steroids and cytotoxics to treat glomerulonephritis. To get past this, we must devote significant resources to take observations made in basic research laboratories to develop therapeutics and prove their utility in human disease.

Lupus Nephritis Susceptibility Loci in Women with Systemic Lupus Erythematosus

“…25 Mesangial cell proliferation is effectively inhibited by anti-PDGF antibodies in animal models of GN with resultant reductions in mesangial matrix deposition and glomerulosclerosis. 26,27 The expression data presented in this report provide evidence that increased PDGFRA mRNA is found in both the renal glomeruli and the tubulointerstitium of patients with LN, suggesting that this gene may mediate the pathogenesis of LN. Integrative analysis of gene expression data, pathway mapping, and coregulation transcriptional networks provided multiple lines of evidence for a key role of PDGFRA in LN.…”

Site-Specific Inhibition of Glomerulonephritis Progression by Targeted Delivery of Dexamethasone to Glomerular Endothelium

“…Based on the underlying immunologic nature of glomerulonephritides, these disorders are frequently treated with glucocorticosteroids in combination with cytotoxic agents (Javaid and Quigg, 2005). Glucocorticosteroids and cytotoxic agents, such as cyclophosphamide, are potent anti-inflammatory and immunosuppressive agents but have their limitations with regard to toxicity and side effects (Chadban and Atkins, 2005;Tam, 2006).…”

Adenosine A2Areceptor activation and macrophage‐mediated experimental glomerulonephritis

“…We still treat immunologically induced inflammatory diseases with nonspecific immunosuppressive drugs that can cause significant morbidity (1). For this reason defining the pathways of organ damage could lead to design of more specific therapies.…”