IgA Nephropathy: Uncovering the Secrets of a Mysterious Autoimmune Kidney Disease
Immunoglobulin A nephropathy (IgAN) is an autoimmune glomerular disease with varied clinical manifestations. This blog will provide a perspective on the unique aspects of IgAN and my interests and passion regarding the racial disparities that exist within this fascinating disease.
My fascination with nephrology predates my medical career. Being part of a household that included a physician and a mathematician, I was enthralled by a discussion that began at the dinner table one night during my senior year in high school. The conversation was regarding a woman with preeclampsia and significant proteinuria. What ensued was a prolific discourse that involved the pathophysiology of protein spillage in the urine and the mathematical models on the structure, charge and folding of proteins. This was the first time a glomerulus and a mathematical formula blended into a solidified concept in my inquisitive mind, which had sparked my passion towards becoming a nephrologist. I have always been fascinated with glomerular diseases and aspire to pursue an academic career in nephrology. I am currently a second year nephrology fellow at the University of Alabama at Birmingham and chose to do my fellowship here so that I could work with Dr. Bruce Julian (an expert in IgAN) and Dr. Dana Rizk (a clinical investigator in IgAN) to study and better understand IgAN. I am interested in studying the racial disparities that exist in IgAN, particularly IgAN in Blacks.
IgAN is the most common primary glomerular disease in the world and is a leading cause of chronic kidney disease (CKD) and leads to end-stage kidney disease (ESKD) in over 40% cases in 10-20 years Predicting progression in IgA nephropathy. IgAN was initially described in 1968 by a French pathologist, Dr. Jean Berger and his colleague Dr. Nicole Hinglais as a kidney with “intercapillary deposits of IgA-IgG”. The entity was initially coined Berger’s disease in the 1970s-1980s.
IgAN is considered an autoimmune disease resulting from the formation of circulating immune complexes comprised of galactose-deficient IgA1 bound to an anti-glycan antibody, mainly of the IgG subclass. The multi-hit hypothesis is currently the accepted model for the pathogenesis of IgAN.
Novak et al Kidney Diseases 2015 Multi-Hit Hypothesis for development of IgAN
The incidence of IgAN is estimated at 2-10 per 100,000 person-years. The diagnosis of IgAN currently necessitates a kidney biopsy as there is no other available biomarker that is sufficiently specific and sensitive to supplant the procedure. Serum biomarkers including galactose-deficient IgA1, IgA/IgG autoantibodies against galactose-deficient IgA1, and soluble CD 89-IgA complexes; and urine biomarkers including soluble transferrin receptor, interleukin-6/epidermal growth factor ratio, fractalkine, laminin G-like 3 peptide, and mannan-binding lectin have been identified but are not currently recommended for the diagnosis of IgAN. Markers for the progression of IgA nephropathy Dominant IgA glomerular mesangial deposits are accompanied by mesangial cellular proliferation and matrix expansion on renal biopsy. Recurrent gross hematuria concurrent with a febrile illness is characteristic of IgAN in children and young adults, whereas microscopic hematuria with or without varying degrees of proteinuria is frequently noted among adults. Multiple studies indicate that IgAN belongs to a spectrum of a systemic disease process that includes IgA vasculitis (IgAV), formerly known as Henoch-Schönlein purpura. The mesangial IgA of IgAN has unique features: it is exclusively of the IgA1 subclass and contains more galactose-deficient O-glycans than does the IgA1 in the circulation. To date, there is no disease-specific treatment, but with the elucidation of disease pathogenesis, new therapeutic approaches are currently being tested in clinical trials.
Prevalence of IgAN varies widely among racial groups being
highest in East Asians
moderate in Caucasians
rare in individuals with a sub-Saharan African ancestry.
IgAN accounts for almost 40% of all native-kidney biopsies in Japan, 25% in Europe, 12% in the United States, but less than 5% in central Africa. Some of this variability can be attributed to differences in health screening policies and biopsy practices between various regions, but genetics likely contribute as well. There remains significant heterogeneity in the epidemiology, clinical manifestations, kidney progression and long-term outcomes of IgAN across diverse racial and ethnic populations.
What are the reasons for these differences in prevalence?
Genome-wide association studies (GWAS) have to date identified 18 susceptibility segments (loci) that modulate the risk for IgAN. Genome-wide association study identifies susceptibility loci for IgA nephropathy Variants of 2 genes that encode enzymes important for the O-glycosylation of IgA1 were associated with higher serum levels of galactose-deficient IgA1. The C1GALT1 gene encodes the human core 1 β1-3-galactosyltransferase (C1GALT1) enzyme which is required for the addition of galactose to N-acetylgalactosamine in the IgA1 hinge-region glycans. The C1GALT1C1 gene encodes a molecular chaperone COSMC that stabilizes the activity of the C1GALT1 enzyme. The variants of both genes decrease the activity of their encoded enzymes. Thus, a lesser amount of galactose would be attached to N-acetylgalactosamine in the synthesis of the galactose-deficient IgA1. The genetic variants of these 2 genes account for about 7% of the variability in serum levels of galactose-deficient IgA1 in Europeans, but only about 2% of the variability in East Asians. These findings indicate a genetic influence in the regulation of the synthesis of galactose-deficient IgA1, the autoantigen in IgAN. GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway GWAS have also found variants of several genes that influence the immune response or antigen presentation associated with IgAN. Among them are 3 loci in the major histocompatibility complex (plays an important role in pathogenesis of IgAN in those of white European ancestry) and the genes that encode complement factor H (CFH) and CFH-related (CFHR), components of the alternative complement pathway, with patients with the variant in both genes having a 30% lower risk of IgAN. The frequency distribution of the 18 IgAN-associated risk variants correlated with the ethnic differences in the prevalence of the disease, highest in Chinese, mid-range in Caucasians, and lowest in Blacks.Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.Thus, genetically determined factors may account for some of the geographic and ethnic variance in the prevalence of IgAN.
The reason for a lower prevalence of IgAN in Blacks relative to other kidney diseases remains unclear. IgA consists of two subclasses - IgA1 and IgA2, with IgA1 being the predominant isotype observed in immunofluorescence studies of mesangial deposits of patients with IgAN. However, some Black patients with IgAN have IgA2 deposits in the glomerular mesangium. IgA2 is genetically polymorphic and exists as two allotypes - A2m(1) and A2m(2). A2m(2) has interchain disulfide linkages and is more resistant to proteolytic cleavage. The IgA2 allotypes exhibit racial differences in their frequencies – 98% in Whites, 36% in American Blacks, and 32% in African Blacks. A multicenter study involving 27 Black IgAN patients revealed that the frequencies of the IgA2 allotypes in Black patients with IgAN were similar to those of Black controls thereby refuting the hypothesis that IgA2 allotypes influence the development of IgAN in Black patients. IgA nephropathy in Blacks: Studies of IgA2 allotypes and clinical course Also, serum galactose-deficient IgA1 levels are often elevated in Black patients with IgAN and their first-degree relatives, and aberrant IgA1 glycosylation also appears to be a heritable trait in these patients. Thus, findings related to serum galactose-deficient IgA1 levels are similar in all ethnic groups studied to date. Galactose-Deficient IgA1 in African Americans with IgA Nephropathy: Serum Levels and Heritability. As of now, racial differences in IgAN have not been explained by differences of the IgA immune system in different races and it is quite possible that racial admixture of alleles of a yet unknown gene may be responsible for the increased prevalence of IgAN in Blacks especially in the southeastern United States compared with Blacks in west Africa. Racial admixture accounting for the increased prevalence of insulin-dependent diabetes in American Blacks compared with African Blacks has been clearly documented. My clinical research focuses on the specific characteristics, presentation, progression and outcomes of IgAN in African Americans when compared to other races in the southeastern United States.Hopefully my research can contribute to understanding racial disparities IgAN better.
Arun Rajasekaran, MD
University of Alabama at Birmingham
@Nephronpower