Invited commentary by Dr. Jean Francis
Over the past few years, great advances have improved our understanding of and approach to some of the most common glomerulonephritides (GNs). New diagnostic tests are on the horizon to accurately diagnose some of them in a non-invasive manner. Our understanding of the disease has paved the path for new agents that block or modulate specific immunologic and pathogenic processes. The present review by Hogan et al in AJKD delineates the major advances in the field of glomerular diseases and focuses on four important causes of GN: IgA nephropathy (IgAN), focal and segmental glomerulosclerosis (FSGS), C3 glomerulopathy (C3GN), and membranous nephropathy (MN).
IgAN is the most common GN worldwide, and frequently progresses to ESRD. As described in the review, it is now evident that patients with IgAN have high circulating levels of IgA1 that are hypo-galactosylated in the hinge region of the antibody. The formation of this galactose deficient IgA1 is thought to be the first hit required for the preferential deposition in the mesangial area of the glomerular tuft. The second hit usually involves the development of auto-antibodies against this abnormal galactose deficient IgA1, forming immune complexes that could lead to clinical disease. The detection of these galactose deficient IgA1 and their auto-antibodies are promising for the diagnosis of IgAN and for monitoring response to therapy. Corticosteroids remain the most effective therapy for IgAN in patients failing a conservative approach with angiotensin converting enzyme inhibitors or angiotensin type 1 receptor blockers. The results from trials using other agents that may expand the list of effective treatments, including cyclophosphamide, mycophenolate mofetil (MMF), tacrolimus, and rituximab, are pending.
FSGS is characterized by diffuse effacement of podocyte foot processes. A permeability factor inducing this phenotype has remained elusive. Recent investigation implicates a possible role of Soluble Urokinase Receptor (suPAR) in causing FSGS. suPAR binds and activates Beta3 integrin on the podocyte, which subsequently leads to foot process effacement. suPAR levels are elevated in patients with primary FSGS and in patients with recurrent FSGS after kidney transplantation, and correlate with the clinical activity of the disease. It is noteworthy that the levels of suPAR are also elevated in patients with secondary FSGS, chronic kidney disease not caused by FSGS, and septic shock with AKI. Despite its potential, it remains to be determined how to utilize this test for the diagnosis of primary FSGS.
Newer understanding of the pathophysiology of membranoproliferative GN (MPGN) resulted in the reclassification of this disease. The classical MPGN is usually characterized by glomerular deposits of both complement component C3 and immunoglobulin, and is often secondary to infection, autoimmune disorders, and monoclonal gammopathy. C3GN is usually characterized by dominant C3 deposits with minimal or no immunoglobulin deposits. Dysregulation of the alternative complement pathway due to loss of activity of inhibitors (Factor H or Factor I deficiencies secondary to mutations or autoantibodies) resulting in relentless complement activation and C3 deposition in glomeruli have been implicated in C3GN, a new class of MPGN. The treatment of C3GN is challenging and non-specific. Targeted therapy is possible now with better understanding of the pathophysiology of many of these C3GNs. Eculizumab, a humanized antibody directed against complement component C5, inhibits the formation of MAC and C5a (chemotaxin), and may prevent cellular damage induced by the alternative pathway of complement activation. However, randomized trials are required to further define the role of this costly drug in the management of C3GN.
Hogan et al review membranous nephropathy (MN), the most common cause of primary nephrotic syndrome in Caucasians. The discovery of the M-type phospholipase A2 receptor (PLA2R) as a target antigen in primary MN represents the major advance in this field. PLA2R is expressed on the podocyte, and 70 to 80% of the patients with primary MN have a detectable circulating anti-PLA2R antibody in their serum. These patients also stain positive for PLA2R in the deposits on their kidney biopsies. Anti-PLA2R appears to be highly specific for primary MN, and it is rapidly becoming a diagnostic biomarker to differentiate primary MN from secondary MN or other glomerular diseases. Testing for anti-PLA2R is already available in Europe and will soon be available in the USA. Anti-PLA2R serum levels can serve as a marker of disease activity, recurrence of MN after kidney transplant, and therapeutic response.
Overall, the review by Hogan et al provides an excellent summary of the recent advances in the diagnostic and therapeutic management of the most common GNs. However, more exciting development is in progress with ongoing clinical trials to translate these discoveries into evidence based management of GN.
Jean Francis, MD
Assistant Professor of Medicine
Boston University, Boston Medical Center