In human IgA nephropathy uteroglobin does not play the role inferred from transgenic mice

Abstract

Background: Uteroglobin (UG)-knockout and UG-antisense transgenic mice develop clinical and pathological features of immunoglobulin A (IgA) nephropathy with heavy proteinuria. These models suggested that UG, an anti-inflammatory protein with high affinity for fibronectin (Fn), prevents the formation of IgA-Fn complexes and mesangial deposits in mice. We aim to elucidate whether similar mechanisms underlie the development and severity of human IgA nephropathy. Methods: Specific enzyme-linked immunosorbent assays were devised to detect serum levels of UG binding to Fn or incorporated into IgA-Fn complexes and IgA binding to Fn or collagen IV. Sera from 75 patients with IgA nephropathy with normal renal function and various degrees of proteinuria (0.2 to 5 g/d of protein) stable over the previous 3 months without therapy were investigated and compared with healthy controls. Results: Levels of UG binding to Fn were similar in patients with IgA nephropathy and healthy controls. UG incorporated into circulating IgA-Fn complexes, as well as levels of IgA-Fn complexes and IgA binding Fn and collagen IV, were significantly greater in patients than healthy controls. Greater amounts of UG incorporated into IgA-Fn complexes reduced the risk for proteinuria with protein greater than 1 g/d (odds ratio = 0.67; P < 0.001). Logistic regression analysis assigned a predictive value for proteinuria persistently greater than 1 g/d of protein to lower amounts of UG incorporated into IgA-Fn complexes (R = −0.267; P = 0.008) and increased binding of IgA to collagen IV (R = 0.214; P = 0.0003). Conclusion: This first report of human IgA nephropathy after the publication of the mouse model shows that UG is not reduced in circulation and is even increased in IgA-Fn complexes. Because aberrant IgA1 glycosylation is the event initiating IgA nephropathy in humans, we speculate that the enhanced incorporation of UG into IgA-Fn complexes might represent feedback to reduce the formation of macromolecular aggregates. © 2002 by the National Kidney Foundation, Inc.