Based on several years of research work, we showed that IgA nephropathy is an autoimmune disease, in which the kidneys are damaged as innocent bystanders. These findings led us to propose a multi-hit mechanism for the development of the disease. IgA1 is a protein in the blood and has a unique region with attached side chains, also called sugars or glycans. These side chains in healthy individuals have the normal content of a special type of sugar, galactose. Patients with IgA nephropathy have elevated serum levels of IgA1 with some glycans that are deficient in galactose (Hit #1). This galactose-deficient IgA1 is recognized by autoantibodies (Hit #2) to form circulating immune complexes (Hit #3). Some complexes deposit on support cells (mesangial cells) in the glomerular structures in the kidney to cause damage (Hit #4), manifested as blood and protein in the urine, and often chronic kidney disease.
Our research has focused on discovery of the precise mechanisms of disease to provide laboratory tests to diagnose and monitor the course of IgA nephropathy and, later, to develop disease-specific treatment. Specifically, our research seeks to:
- Define the precise structural characteristics of the galactose deficiency of the IgA1 protein.
- Identify pathways leading to aberrant glycosylation (the galactose deficiency) of IgA1.
- Define the specific properties of the circulating antibodies that recognize galactose-deficient IgA1 to form immune complexes.
- Clarify features of IgA1 immune complexes in the blood of patients that induce kidney injury.
- Develop laboratory models and a small-animal model to evaluate potential approaches to disease-specific treatment.
- Evaluate compounds that may lead to disease-specific treatment.
Our proposed multi-hit hypothesis is now widely accepted in the scientific community and is being used as a “blueprint” for planning research studies. We want to develop, test, and validate noninvasive or minimally invasive tests for IgA nephropathy that could then be used for the diagnosis, prognosis, and assessment of treatment response of patients. In our research, we have developed tests to measure blood levels of galactose-deficient IgA1 (Hit #1) and antibodies directed against galactose-deficient IgA1 (Hit #2). Furthermore, we have shown that both measurements, determined at the time of kidney biopsy, were associated with long-term clinical outcomes.
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See further discussion on Dr. Renfrow's page