Posted by Carla Rothaus
What are some of the manifestations of IgG4-related disease and how is it treated?
Membranous nephropathy is caused by the gradual accumulation of immune deposits in the subepithelial aspect of the glomerular basement membrane, which leads to podocyte damage and proteinuria. Read the NEJM Case Records of the Massachusetts General Hospital here.
Q: What is the target antigen in most cases of primary membranous nephropathy?
A: Primary membranous nephropathy — an isolated kidney disease that results from autoantibodies directed against endogenous podocyte-specific antigens in the absence of an identifiable cause — accounts for most cases. Alternatively, membranous nephropathy can be secondary to a predisposing condition, such as autoimmune disease (e.g., systemic lupus erythematosus), infection (e.g., hepatitis B or syphilis), medication use (e.g., use of nonsteroidal antiinflammatory drugs), cancer, or allogeneic stem-cell transplantation. The M-type phospholipase A2 receptor is the target antigen in approximately 70% of patients with primary membranous nephropathy.
Q: Describe ways in which primary and secondary membranous nephropathy differ.
A: In secondary membranous nephropathy, the target antigen is extrinsic to the podocyte and reaches the glomerular basement membrane through the circulation. This often results in the generation of subendothelial and mesangial deposits in addition to the subepithelial deposits that are characteristic of membranous nephropathy. Furthermore, the dominant immunoglobulin in primary membranous nephropathy is of the IgG4 subclass, whereas the other IgG subclasses predominate in most causes of secondary membranous nephropathy. The presence of concomitant tubulointerstitial nephritis is strongly suggestive of a disease process other than primary membranous nephropathy.
Morning Report Questions
Q: What are some of the manifestations of IgG4-related disease and how is it treated?
A: IgG4-related disease is a systemic fibroinflammatory condition that was first recognized as a unifying disease process in the early 2000s. Many conditions that were previously thought to be isolated entities — including type 1 autoimmune pancreatitis, Mikulicz’s disease, chronic sclerosing sialadenitis (called Küttner’s tumor when submandibular glands are involved), fibrous thyroiditis (Riedel’s thyroiditis), and many cases of idiopathic retroperitoneal fibrosis (Ormond’s disease) — are now known to be manifestations of IgG4-related disease. The most common renal manifestations are tubulointerstitial nephritis and membranous nephropathy. Regardless of the involved organ, the disease is characterized by two dominant histopathological features: a lymphoplasmacytic infiltrate with IgG4+ plasma cells and storiform fibrosis. Tissue eosinophilia and obliterative phlebitis are also common findings in some organs. Glucocorticoids are the cornerstone of treatment for IgG4-related disease. Although glucocorticoids are initially effective in most patients, the rate of relapse after the course is tapered or discontinued is high. A growing body of evidence suggests that B-cell depletion is effective in IgG4-related disease because of its direct effect on cells of the B-lymphocyte lineage and its indirect effect on CD4+ cytotoxic T lymphocytes, which are thought to be crucial to disease pathophysiology.
Q: Can marked weight loss be a feature of IgG4-related disease?
A: Exocrine pancreatic failure, which is often underappreciated as an important form of damage in IgG4-related disease, is the most common explanation for the dramatic weight loss that can be seen in patients with IgG4-related disease; the patients cannot absorb sufficient calories and nutrients because of the absence of pancreatic enzymes. Patients frequently report weight loss of 18 kg (40 lb) or more.
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