IgA nephropathy (IgAN) is a rare kidney disease that disproportionately affects men at twice the rate of women in North America, a striking reversal of the typical pattern seen in autoimmune disorders. This unusual sex difference has puzzled nephrologists for years, and new insights from kidney disease specialists are shedding light on why men face elevated risk for this condition and why it often goes undetected until significant kidney damage has already occurred.

Why Does IgA Nephropathy Affect Men More Than Women?

The reasons for this male predominance remain largely a mystery, but emerging research points to a complex interplay between sex hormones, immune function, and genetics. Unlike most autoimmune diseases, which are more common in women due to their naturally stronger immune response, IgAN appears to follow a different biological pattern. Women's immune systems are evolutionarily adapted to protect developing pregnancies, making them more prone to autoimmune conditions overall. Men, by contrast, seem to have a vulnerability specific to IgAN.

"The reasons for sex discrepancies in IgAN incidence and progression have yet to be elucidated. I believe the culprit may lie in the interplay between the reproductive endocrine system and the immune system," explained Ramy Hanna, MD, director of the Center for Rare Kidney Diseases and Glomerulonephritis at the University of California, Irvine, School of Medicine.

Ramy Hanna, MD, Director of the Center for Rare Kidney Diseases and Glomerulonephritis, University of California, Irvine

Several biological mechanisms may explain this disparity. Estrogen and other female hormones may protect against the production of galactose-deficient IgA, a malformed antibody that triggers the disease, while testosterone may increase vulnerability. Additionally, sex hormones could influence immune function in the gut lining, where IgAN originates with the production of aberrant mucosal antibodies that leak into the bloodstream. Differences between men and women in diet, stress, environmental exposures, and other immune system factors may also play a role.

The epidemiological evidence is compelling: men in Western countries are twice as likely to develop IgAN compared with women, and even in Asia, where the disease is more common overall, men still face 1.4 times higher risk. Men also progress more rapidly toward kidney function decline, with studies showing they are at significantly increased risk for a 30% decline in estimated glomerular filtration rate (eGFR), a key measure of kidney function, compared with women.

Why Is IgA Nephropathy Often Missed Until It's Advanced?

One of the most troubling aspects of IgAN is that many patients remain undiagnosed until their kidneys have already sustained substantial damage. Early warning signs like protein in the urine (proteinuria) and blood in the urine (hematuria) are frequently overlooked, particularly in younger male patients who might not expect kidney problems. Doctors must take these symptoms seriously and pursue aggressive diagnostic workup.

Currently, the only way to definitively diagnose IgAN is through a kidney biopsy, a procedure in which a small sample of kidney tissue is removed and examined under a microscope. While a biopsy provides crucial diagnostic and prognostic information, it carries real risks. Although most bleeding complications after biopsy are minor, the potential for significant bleeding, the need for coil embolization (a procedure to stop bleeding), or even kidney removal are not negligible concerns.

This diagnostic challenge has led to a gap in early detection. Many nephrologists have traditionally waited until patients show proteinuria levels of 1,000 milligrams per day before recommending a biopsy, but increasingly, professional guidelines such as KDIGO (Kidney Disease: Improving Global Outcomes) recommend considering biopsy at lower thresholds of 500 milligrams per day. A "liquid biopsy," which would allow diagnosis through a simple blood test rather than an invasive tissue biopsy, is not yet available for IgAN because the markers for galactose-deficient IgA must first be standardized for widespread clinical use.

Steps to Improve Early Detection and Diagnosis of IgAN

• Heightened Clinical Awareness: Nephrologists and primary care physicians must take proteinuria and hematuria in young patients, especially males, extremely seriously and pursue diagnostic workup with urgency rather than waiting for symptoms to worsen.
• Comprehensive Screening Protocol: When hematuria is detected, doctors should perform genetic testing to rule out collagen defects like Alport thin basement membrane disease, review medications for potential kidney toxicity, and conduct urological evaluation before considering other diagnoses.
• Lower Biopsy Thresholds: Following updated KDIGO guidelines, nephrologists should consider kidney biopsy at proteinuria levels of 500 milligrams per day rather than waiting for levels to reach 1,000 milligrams per day, enabling earlier diagnosis and treatment initiation.
• Community Education Outreach: Expanding educational programs for community nephrologists and primary care providers is essential to increase awareness of IgAN presentation and screening, helping identify cases that might otherwise be missed.

What's Blocking Patients From Accessing Newer IgAN Treatments?

Even when IgAN is diagnosed, many patients are not receiving the newest and most effective treatments available. Four recently approved medications for IgAN, sparsentan, targeted-release budesonide, iptacopan, and atrasentan, were prescribed to less than 5% of patients in a 2024-2025 U.S. database analysis. This low uptake is puzzling given that these drugs have demonstrated efficacy in clinical trials, but several systemic barriers are preventing wider adoption.

The primary obstacle is cost and insurance coverage. The U.S. healthcare system faces significant financial hurdles in providing affordable medications, and health insurance companies are reluctant to cover new, expensive brand-name drugs without clear evidence of cost-effectiveness. Beyond economics, there is also a phenomenon called "therapeutic inertia," in which clinicians and patients have become comfortable with older treatments despite evidence of their limitations. For decades, high-dose steroids have been the standard treatment for IgAN, even though major clinical trials like STOPIgAN and TESTING demonstrated that steroids lack efficacy and carry risks of serious infections.

"Therapeutic inertia can be overcome by overhauling nephrology fellowship training programs, CME programs from symposia, and educational activities to create comfort in the nephrology community with using these immune-modulating and immune-suppressing agents," noted Dr. Hanna.

Ramy Hanna, MD, Director of the Center for Rare Kidney Diseases and Glomerulonephritis, University of California, Irvine

To accelerate adoption of newer therapies, the nephrology field must pursue multiple strategies simultaneously. Health-economics analyses need to demonstrate that newer drugs provide better long-term value despite higher upfront costs. Nephrology fellowship training programs and continuing medical education must be redesigned to build clinician confidence in prescribing immune-modulating medications. Academic centers of excellence in IgAN, such as those designated by GlomCon and the International Society of Glomerulonephritis (ISGD), are leading the way in establishing best practices and demonstrating the benefits of newer treatments.

For patients with IgAN, understanding these barriers is important. If you have been diagnosed with IgAN or have risk factors such as proteinuria or hematuria, discussing the full range of treatment options with a nephrologist, particularly one at an academic center specializing in glomerular diseases, may help ensure you receive the most current and effective care available.