IgA nephropathy shows a male predominance, but researchers have not identified why. Ramy Hanna, MD explores possible biological explanations.
IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, affects patients of all sexes, but men account for a disproportionate share of diagnosed cases in many populations. Despite decades of observation, researchers have not identified why IgAN demonstrates this consistent male predominance.
Studies have reported higher rates of IgAN among men, particularly in Western cohorts, although the magnitude of this difference varies across geographic regions. Differences in screening practices, kidney biopsy patterns, and genetic background may contribute to these variations.1,2
For Ramy Hanna, MD, associate professor in the Division of Nephrology, Hypertension and Kidney Transplantation at UC Irvine School of Medicine and director of the Center for Rare Kidney Diseases and Glomerulonephritis at UC Irvine Health, the question represents one of the many remaining opportunities to better understand IgAN biology.
“Whenever there’s a disparity by gender, you have to think of two things: genetics and environment,” Hanna said in an interview with HCPLive.
The reason for IgAN’s male predominance remains unknown, but Hanna said potential explanations may involve differences in genetics, hormonal signaling, and environmental influences.
One possibility involves differences in sex chromosome biology. Hanna noted that women have 2 X chromosomes, whereas men have 1 X chromosome and 1 Y chromosome, creating fundamental biological differences between sexes.
However, he emphasized that this concept has not been established as a specific explanation for IgAN. Instead, it represents one possible framework for understanding how genetic differences may influence disease susceptibility.
Beyond chromosomes, Hanna pointed to the potential role of hormones and epigenetic changes, biological processes that influence whether genes are turned on or off, as additional factors that may contribute to differences between men and women.
Hanna said the immune system may be central to understanding why IgAN affects men more frequently.
IgAN is driven by abnormal immune activity involving IgA production and immune responses at mucosal surfaces, including tissues such as the tonsils and Peyer patches. Because immune pathways can respond differently to hormonal signals, Hanna suggested that sex-based differences in immune regulation could influence disease development.
“Something about genetics, epigenetics, or hormonal androgen levels may affect the IgA-producing Peyer patches and mucosal surfaces differently,” Hanna said.
Still, he cautioned that these mechanisms remain hypotheses and have not been proven to explain the observed sex disparity.
“I could be wrong, but this would be a great NIH question,” Hanna said, emphasizing the need for additional research into the molecular basis of sex differences in IgAN.
According to Hanna, answering why men are more likely to develop IgAN will require translational research that combines genetics, immunology, and experimental models.
He said the question will likely require collaboration among investigators across the United States, Europe, and Asia, where IgAN represents a significant clinical burden.
As new therapies continue to expand treatment options for IgAN, understanding why certain patients develop disease may become increasingly important for identifying risk factors and improving individualized care.
Although the reason behind IgAN’s male predominance remains unresolved, Hanna emphasized the broader role of genetics in kidney disease.
“Keep in mind that approximately 20% of kidney disease has a genetic basis,” Hanna said. “We have genetic testing available, and IgAN is no exception.”
Familial forms of IgAN have been described, although they represent a small proportion of cases. Hanna said clinicians should consider genetic evaluation in selected patients, particularly those with a strong family history of kidney disease or features suggesting an inherited condition.
Editor’s Note: Hanna reports relevant disclosures with Alexion Pharmaceuticals, Novartis, AstraZeneca, and others.
