Ramy Hanna, MD

As the treatment landscape for IgAN continues to expand, clinicians are increasingly focused on identifying patients earlier, accurately assessing progression risk, and intervening before irreversible kidney damage develops.

In this Q&A, Ramy Hanna, MD, associate professor, disease expert, and clinical trial principal investigator in nephrology, discusses the challenges of early recognition in glomerular disease, evolving approaches to IgA nephropathy (IgAN) management, and the importance of timely evaluation to preserve kidney function.

Q&A: Early Detection and Treatment Advances in IgA Nephropathy, With Ramy Hanna, MD

HCPLive: What are some of the biggest challenges with recognizing glomerular diseases early, including IgAN?

 The problem with most glomerular diseases is that the only signs that you're going to have initially, and even into the medium term, are laboratory signs. You're going to have hematuria and proteinuria as the 2 cardinal signs, and that's early on.

Then, if you wait a little bit longer, you start to see a decline of kidney function. We call that GFR. We usually measure that through one of several measures, whether it be creatinine or cystatin C.

The problem is by the time that you actually have the decline in kidney function, it has been a long time — decades often — and when you look at biopsies, you see irreversible tissue death and fibrosis. So you're dealing with tissue that is no longer viable.

There are people walking around with 1000 mg of protein, 500 mg of protein. Those are significant biopsy thresholds. If they're not going to see a doctor, their doctor is not well informed, or they are not willing to undergo an invasive procedure for diagnosis, those patients are going to be missed.

The gold standard for glomerular diseases, most of them — not all of them at this point; there are a couple exceptions — would be kidney biopsy. It is an invasive procedure that does come with some risks. However, it is the only way to actually detect the immune involvement, and then in doing so, triage it, stage it, and plan treatment.

That's the problem. You have to catch people early. Patients have to go to the doctor. Their doctor has to be well informed. After that, they have to get a proper biopsy, and that's a lot of ducks to line up in a row. Sometimes those ducks don't line up perfectly.

HCPLive: What early warning signs should clinicians and patients be watching for, and when should a patient be referred to a nephrologist?

 There are 2 different sets of things you have to worry about as a patient.

I think patients need to look out for blood in the urine. That could actually be tiny little drops that we catch on a laboratory test. We catch 2 to 3 RBCs, or 4 RBCs, in a urinalysis, and that needs to be looked into.

In many cases, though, the urine will just turn bright red, and that obviously brings people in quickly. I imagine especially as a man, you see that and think, "Whoa, okay."

The other thing you look for is foam or protein in the urine. Now, I have to be careful because I have a couple cases in my mind of people who had organic acids, who were producing what looked like foam, or where the actual stream of urine was disrupting the water and CO₂ was mixing in and creating a panic.

I don't want to create a mass panic for everybody who generates foam in the toilet bowl. But if you are urinating into a steady collecting surface, like a cup when you provide a sample, or you're pretty sure you are not agitating the water as much and you are seeing lots of foam — almost like the head on a beer — realize that is what happens to protein when this process occurs.

It precipitates, and when it precipitates, it creates that head. That is when you think, "Okay, this is actually protein coming out of solution."

When you get that foam, or when you get blood in the urine, those are immediate warning signs.

Also, if you have chronic kidney disease and nobody knows why, that should prompt curiosity. I have a very high bar for physicians personally. We should be able to diagnose almost everything at this point. Not everything — there are always things beyond our ability to figure out — but we should make an effort to diagnose everything.

We can't cure everything. We should certainly try. And as physicians, we need to have the mindset of kidney success rather than kidney failure.

Editor’s Note: Hanna reports relevant disclosures with Alexion Pharmaceuticals, Novartis, AstraZeneca, and others.

Stamellou E, Seikrit C, Tang SCW, et al. IgA nephropathy. 

 2023;9(1):67. doi:10.1038/s41572-023-00476-9.

Lee M, Suzuki H, Nihei Y, Matsuzaki K, Suzuki Y. Ethnicity and IgA nephropathy: worldwide differences in epidemiology, timing of diagnosis, clinical manifestations, management and prognosis. 

 2023;16(suppl 2):ii1-ii8. doi:10.1093/ckj/sfad199.

Articles

Early recognition of IgA nephropathy is impeded by a long asymptomatic phase in which abnormalities are primarily laboratory-based, notably hematuria and proteinuria. Declines in GFR often reflect decades of injury and may coincide with irreversible fibrosis on biopsy. Meaningful proteinuria can go uninvestigated due to limited access, variable clinician awareness, and reluctance to undergo invasive diagnostic procedures. Kidney biopsy remains central for confirming immune-mediated pathology, staging disease, and guiding therapy. Gross hematuria and persistent foamy urine warrant prompt evaluation.

Ramy Hanna, MD, discusses early IgAN recognition, biopsy decisions, and how emerging therapies are reshaping disease management.


Early Detection and Treatment Advances in IgA Nephropathy, With Ramy Hanna, MD

, 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.

Why Does IgA Nephropathy Affect More Men? With Ramy Hanna, MD

For Ramy Hanna, MD, an Associate Professor, Disease Expert, and Clinical Trial Principal Investigator in Nephrology, 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 

IgAN shows a consistent male predominance in many populations, although rates vary by geography.

Researchers have not identified the mechanism responsible for this sex disparity.

Potential explanations include genetic differences, hormonal signaling, epigenetic regulation, and immune responses.

The IgA-producing mucosal immune system may be an important area for future research.

Genetic testing may be appropriate for selected patients with suspected inherited kidney disease.

Why Is IgA Nephropathy More Common in Men?

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.

How Could Sex Differences Influence IgA Nephropathy Biology?

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.

What Research Is Needed to Understand 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.

Should Patients With IgA Nephropathy Consider Genetic Testing?

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. 

Videos

IgA nephropathy shows a male predominance, but researchers have not identified why. Ramy Hanna, MD explores possible biological explanations.
