Story of Discovery: IgA Nephropathy—Shedding Light on a Form of Kidney Disease
Immunoglobulin A nephropathy (IgAN) is a kidney disorder that occurs when a complex of two immune system proteins that helps the body fight infections settles in the kidneys, eventually disrupting kidney function. While the mechanisms underlying this condition have remained mysterious, recent NIDDK-supported discoveries have provided important insights into molecular mechanisms that play an important role in this disease.
What Is IgAN?
IgAN is a caused by the abnormal deposition of immune system proteins in the small blood vessels within the kidneys. These proteins, which are types of antibodies called IgA and IgG, normally help the body fight infections, but when they form abnormal complexes that settle in the kidneys, serious problems can result. As these protein complexes accumulate over many years, they can lead to inflammation and scarring of the kidneys’ filtering units, or glomeruli. This damage, along with the accompanying development of fibrotic scar tissue, can impair the kidneys’ ability to effectively filter waste products and excess fluids and salts from the blood, and result in the leakage of blood and sometimes protein into the urine. Unchecked, this process can lead to a decline in kidney function or to kidney failure.
Because these proteins are part of the patient's own immune system, IgAN is considered to be an “autoimmune” disease. In conditions such as this, the body’s defense mechanism that is designed to protect against outside threats, such as bacteria and viruses, somehow turns inward, attacking the body’s own cells or molecules.
As is the case with many forms of chronic kidney disease, IgAN is often a “silent” condition. Many people with IgAN will not show symptoms for years, or perhaps decades. Unfortunately, about 25 percent of adults with IgAN will develop kidney failure, also called end-stage renal disease, requiring dialysis or a kidney transplant to live.1
IgAN can occur at any age, though it is less common in the very young and the very old. It is more likely to occur in men than in women. It is more common among Caucasians and Asians, and less common among African Americans.
Currently, there is no treatment that specifically addresses the disease mechanism that underlies IgAN. In formulating treatment strategies, physicians aim to ameliorate the consequences of the disease, using approaches that reduce tissue scarring in the kidney and controlling blood pressure (which, when elevated, can also result in kidney damage). However, recent discoveries have opened a window through which researchers are able to glimpse hints of the disease’s underlying cause, providing hope for those seeking new treatments, whether they are patients or investigators.
History and Pathogenesis of IgAN
IgAN was first identified as a distinct clinical diagnosis in 1968, based on the accumulation in the glomeruli of the proteins IgA and IgG. IgAN remains a diagnosis that is characterized by the identification of deposits of these proteins in kidney biopsy tissue.
IgA, IgG, and Immune Complexes Research results published in the early- to mid-1990s suggested that patients with IgAN had IgA antibodies that were deficient in a sugar called galactose. Specifically, researchers showed that IgA from the blood of patients with IgAN is deficient in galactose and that this deficiency occurs in a specific part of the antibody called the hinge region. The deficiency of galactose in the hinge region of IgA unmasks the presence of GalNAc (a sugar derivative of galactose called N-acetylagalctosamine), which is subsequently recognized by naturally occurring IgG and IgA autoantibodies in the circulation. Hence, an autoimmune condition is established when normal IgG and IgA antibodies now recognize the aberrant IgA as foreign and form immune complexes. In a study of European patients with IgAN, researchers found that increased blood levels of both normal IgA and/or IgG autoantibodiesparalleled the severity of disease progression. In addition, patients with the highest levels of IgG autoantibodies against the aberrant IgA antibody at the time of diagnosis had the highest risk of kidney failure. In a similar study conducted in a Chinese population with IgAN, elevated blood levels of aberrant IgA were found to be associated with poor prognosis.
To understand and explore the mechanism(s) that lead to the formation of galactose-deficient IgA associated with IgAN, cell lines from circulating IgA1-producing B lymphocytes derived from patients with IgAN were established in the laboratory. The cell lines were shown to produce galactose-deficient IgA and allowed for the identification of the specific step in the biological pathway responsible for the addition of galactose to the IgA antibody. Thus, these cell lines may be a valuable resource in the development of new therapeutic strategies for IgAN. As IgAN disease onset and progression often coincides with an upper respiratory tract infection, the researchers evaluated immune-system regulatory molecules called cytokines for their ability to add sugar molecules such as galactose to IgA using the above mentioned cell lines. Cytokines are released from immune cells such as monocytes and macrophages. The study findings indicated that the cytokines interleukin-6 and (to a lesser extent) interleukin-4 significantly worsened galactose deficiency of IgA via the coordinated regulation of key enzymes.
Further research investigating the IgG autoantibody from IgAN patients using a cell culture approach revealed a change in the amino acid structure of the antibody; the IgG autoantibody has an “alanine” to “serine” amino acid substitution in the part of the antibody important for binding to its target—the aberrant IgA. In a proof of principle experiment, the investigators genetically engineered the serine-substituted IgG to contain the normal alanine amino acid and assessed its ability to bind aberrant IgA. The alanine-containing IgG was determined to have dramatically less binding capacity for aberrant IgA.
IgA Deposits
Researchers have shown that immune complexes containing aberrant IgA specifically associated with human mesangial cells more efficiently in laboratory experiments than did aberrant IgA alone. Mesangial cells are located within the central portion of the glomerulus and provide structural support. In addition, a greater amount of circulating immune complexes from a patient with IgAN bound to mesangial cells than did immune complexes from a healthy volunteer. Because mesangial cells are critical for kidney glomerular function, investigators systematically evaluated kidney biopsy tissues from patients with IgAN to begin to discover the molecular mechanisms that take place when IgA deposits in the mesangium. Previous research showed that many tissues and cell types use the “MAPK/ERK” signaling pathway in processes such as survival, inflammatory responses, and cell growth control, and investigators sought to determine whether this pathway was involved when IgA deposits in the mesangium. The study showed that the MAPK/ERK signaling pathway was activated in the mesangium of patients with IgAN having significant loss of kidney function. In contrast, kidney biopsy tissues from IgAN patients having better kidney function did not show activation of the MAPK/ERK signaling pathway.
Genetics of Disease
Researchers measured aberrant IgA levels in patients with IgAN, their relatives, and other volunteers without the disease. High levels of aberrant IgA were detected in blood from patients with IgAN compared to controls. Somewhat surprisingly, approximately half of the family members of IgAN patients also had elevated levels of aberrant IgA but did not display disease symptoms. The study results suggest that the defect in sugar addition to IgA antibodies is an inherited trait, but that additional factors—either genetic or environmental—are required for kidney disease to develop. A genome-wide association study of people of Chinese and European ancestry with IgAN has identified several regions of the genome (loci) associated with this disease. Genome-wide association studies involve rapidly scanning markers across the genome to find genetic variations associated with a particular disease. Scientists conducting these types of studies analyze genetic differences between people with a particular disease and healthy people.
Of the five loci contributing to significant risk for IgAN, one localized to the major histocompatibility complex (MHC)—a cluster of genes that play an important role in the immune system. MHC determines compatibility of donors for organ transplant as well as one’s susceptibility to an autoimmune disease via crossreacting immunization.
The other loci contain genes associated with the immune response, leading to models of the disease as a multi-step process. Producing high levels of aberrant IgA can lead to the disease in individuals who are genetically predisposed to develop kidney injury due to an overactive or aberrant immune or inflammatory response.
Looking Forward
Despite recent progress toward discovering the molecular underpinnings of this multifaceted disease, an effective treatment for IgAN remains elusive. The NIDDK continues its robust support of basic research into normal kidney function and clinical research into the diseases that impair normal kidney function at the cellular and molecular levels. For example, the Institute established the “Cure Glomerulopathy Network” (CureGN) consortium in 2013 to support translational and clinical research that promotes therapeutic development for primary glomerular diseases, including IgAN (https://curegn.org). Research studies of families in which IgAN is prevalent continue in order to identify and understand the genes and genetic factors that influence disease onset and progression.
Through multiple avenues of research, the NIDDK aims to advance progress toward the development of new intervention strategies.