‘A golden age’: Long neglected in medicine, rare kidney diseases see a surge in research

As much as she tried, Judy Akin couldn’t shed the baby weight. So she’d spend hours hiking the breathtaking coast of Oahu almost every day, planning her treks around shifts as a catering manager at a local hotel. There’s a picture of her in her early forties, smiling into a camera, wearing an electric blue tank top that’s still not as blue as the water behind her. Her young, shaggy-haired son, Alexander, is strapped to her back.

After having her son, Akin got sick much more often than before, and her blood pressure was on the rise, but she led a busy, active life. The ailments were a consequence of stress, she imagined. Doctors told her she just had to shed some pounds to feel better.

It took years, and a dramatic turn of events, for her to find out that she actually had a very rare form of a very common kidney disease. In less than six months in 2019, she went from 170 pounds to 140, despite eating the same amount as before. Soon thereafter, she had a “mini stroke” from her out-of-control blood pressure.

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A check-up with her worried primary care doctor in Kailua led to an answer: she had stage 3 chronic kidney disease. Then came what felt like a million rounds of lab work over the course of a few weeks: sit down, arm out, tourniquet on, blood flow. The series of blood and urine tests showed Akin’s kidney function was rapidly plummeting, worse each time on the crucial measure of glomerular filtration rate (GFR).

By the time she was admitted to the hospital in August of that year, Akin’s GFR was 22 — a level seen in patients with stage 4 chronic kidney disease. Doctors immediately put her on immune system-dampening steroids so they could extract a tiny piece of her kidney, which they studied for a cause. (Biopsy is the gold standard for kidney disease diagnosis). Within a few days, she learned she had a little-known condition, IgA nephropathy.

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IgA nephropathy has no cure; not even transplants are a lasting fix for patients, who are often diagnosed in their 20s and 30s. And for a long time, as nephrology research in general languished, there was only a single FDA-approved treatment. But in the last decade, a simpler, faster regulatory path has opened the door for dozens of other possible IgAN treatments, ushering in a new era of innovation in rare kidney diseases, researchers, pharma executives and advocates told STAT. “It’s a golden age of IgA nephropathy,” said Jonathan Barratt, an IgAN researcher who has been a consultant and scientific adviser to numerous pharmaceutical companies interested in developing therapies for the disease.

The surge in research on rare conditions can also elucidate a lot about normal kidney function and the ways it can go haywire. “That really gives us hope for targeting some of these interesting pathways, not just for the rare conditions, but also perhaps for the more common ones by extension,” said Kirk Campbell, a physician-researcher, and director of the Nephrology Fellowship Program at the Icahn School of Medicine at Mount Sinai in New York.

Chronic kidney disease is common — about 37 million people in the United States have it, according to the Centers for Disease Control and Prevention — and experts think up to nine in 10 people who have CKD just don’t know it. But there are only an estimated 150,000 to 200,000 people in the United States with IgAN.

IgAN is the most common in a class of uncommon illnesses, called glomerular diseases. Unlike other forms of kidney disease, it is caused by an autoimmune dysfunction and a cascade of harm that’s not fully understood.

This class of kidney diseases damages the glomeruli — tiny, tangled nests of blood vessels and special kidney cells that sieve waste, protein and other components out of the blood (there are about a million glomeruli in each kidney). Bits of trash go out with the urine. But diseases like IgAN break the filter, letting protein and blood cells slip through the cracks, out into the toilet bowl.

IgAN patients have a harmful version of a normal antibody, Immunoglobulin A. IgA, in its helpful form, is in the slick linings of the body — in the spit, tears, gastrointestinal fluids, and more — and prevents harmful bacteria and other bad actors from proliferating. But people with IgA nephropathy have a sticky, mutant version of the antibody that clings to other proteins. Those protein tumbleweeds get lodged in the delicate glomeruli and destroy their ability to filter by causing inflammation and scarring.

Proteins, chemicals and blood cells that should be picked out by glomeruli start slipping through, into the tubules (pipes that turn waste to urine), potentially damaging another part of the filter mechanism. With two vital components broken, overall kidney function staggers.

This is what was happening in Akin’s body. She stared down a bleak path: researchers estimate around 40% of IgAN patients go on dialysis within 20 years of a diagnosis.

What Akin didn’t know when she went to the hospital on that evening in August 2019 was that her diagnosis was fairly new to medicine. It was not until the late 1960s, after a reagent had become available that could stain Immunoglobulin A, that a French pathologist named Jean Berger used the reagent on some kidney samples under a microscope. The kidney filters lit up. They were full of IgA.

Nephrology in general poked along, underfunded, as other research fields boomed. A full 50 years after Berger described the unusual condition, IgAN remained relatively unknown and incurable. Most people with the illness have been diagnosed by chance, upon seeing a doctor about an upper respiratory tract infection or finding blood in their urine; sometimes the regular urine tests given to pregnant people are the first sign there might be a kidney problem. When Akin was diagnosed, her specialist wasn’t well-versed in IgAN, and pretty much all clinicians had to work with were blood pressure-lowering medications and a slate of steroids that sledgehammered the immune system, heavily taxing patients’ quality of life.

“We are lagging decades behind the cancer doctors, in terms of the number of therapies they have available, how they put them together, how they target treatment to specific types of cancers and specific types of types of cancers,” Barratt said.

Judy Akin and her son, Alexander (Courtesy) Courtesy Judy Akin

Akin was put on a high dose of prednisone, an intense corticosteroid meant to reduce her kidney inflammation by muffling her malfunctioning immune response. The drug helped boost her kidney function, but the side effects — the terrible insomnia, exhaustion, fits of anger, and constant tremors, on top of an already-destabilizing diagnosis — were unbearable. She became so irritable that she barely recognized herself, and felt tremendous guilt for subjecting her child to her mood swings. And that was just at home.

At work, she’d “shake so bad that I couldn’t even hold a pen in my hand,” she told STAT. Her nephrologist tapered down the dose until eventually, Akin could stop taking prednisone altogether. It was during those early months that she also started an educational course, “Aloha Kidney,” that doctors on the island sent patients to when they were approaching end-stage renal disease, or kidney failure.

“I realized I was being prepped for dialysis. It was scary.”

“It was in that class that I realized I was being prepped for dialysis,” Akin said. “It was scary.”

Dialysis is often the fate of people with severe chronic kidney disease. Once kidneys fail, the body needs another way to filter the blood or a person will die from the toxic buildup, so in steps the hemodialysis machine. Patients often must travel to dialysis clinics three times per week, spending three to five hours at a time having their blood sucked out, filtered, and pumped back into their system. It’s a burdensome non-solution; average life expectancy on dialysis is five to 10 years.

The only other option, and what’s considered by many to be the best option for kidney failure, is an organ transplant. It’s a laborious, expensive and long process, but a kidney transplant can extend a person’s life significantly. But since IgAN is an immune system-related illness, even a healthy kidney transplant isn’t a cure. The body would once again clog up the glomeruli with protein clumps. Akin tries to explain this to her best friend each time she offers up her kidney. “I’m going to take a healthy kidney from somebody, and put it in my body and damage it,” Akin said. “So do I ask someone to give me a kidney?”

The “Aloha Kidney” class made Akin realize she had to do whatever it took to avoid dialysis. She learned that some studies suggested plant proteins were softer on the kidneys than animal proteins. She cut out all animal products and started finding ways to cut salt from her diet, making her own sauces and breads and broths. (In July, Akin was hired as a paid patient advocate for Calliditas Therapeutics, a Swedish pharmaceutical company that is developing IgAN drugs and a disease education program, IgAN Connect.)

By the start of 2020, her GFR — that marker of how well kidneys are filtering blood – had gone up by around 10 points, pointing to an improvement in her condition. Then the Covid pandemic hit, and Akin was laid off from her catering job. She decided to stay home, given her immunocompromised status, and her GFR went up again — from the upper 30s to 54. “And to date, that’s the highest my GFR has gotten,” she said. “My stress level was so low, because I was sitting at home every day doing nothing. That was another huge eye-opener.”

Akin has been able to manage her IgAN to the point where she only takes fish oil, vitamin D3 and 25 milligrams of losartan, a blood pressure-lowering drug. She keeps a close eye on her diet and maintains her GFR around 40 to 45 (stage 3 kidney disease levels). But she knows IgAN isn’t behind her. If her disease accelerates, she might need to turn to other drugs.

That’s where advocates like Bonnie Schneider come in. Schneider never foresaw leaving her comfortable marketing job in Manhattan to start the IgA Nephropathy Foundation on a volunteer basis. But when her son, Eddie, was diagnosed with the disease in 2004, she couldn’t find any resources for families and patients. At age 13, just as he hit puberty, Eddie was put on aggressive steroids that, for a year and a half, left him moody, unable to sleep and swollen-faced. He missed 40 days of school that year. There had to be a better way, Schneider thought.

“When we started the foundation, our mission, my husband and I, was to make sure that we get better treatments on the market and an ultimate cure. And to visually see it happening before us…it’s a very exciting time to be in the IgA nephropathy space,” she said.

The foundation has given “well over $1 million” to fund work at the University of Alabama at Birmingham, where researchers are finding biological markers that drug companies can use to develop potential therapies, Schneider said. “That little bit of funding gets the wheels turning.”

IgAN Foundation also gathered a group of patients to tell leaders at the Food and Drug Administration and the National Kidney Foundation about their disease, how it’s affected their life, and how only having steroid drugs has been damaging to them.

In September 2012, the American Society of Nephrology and the FDA formed a public-private partnership, the Kidney Health Initiative. The KHI project identified “surrogate endpoints” for IgAN and other glomerular diseases — early signs that suggest a drug is working, evidence which the FDA can use to grant accelerated approval, shorter by months or years.

In just a few years, from 2016 to 2019, there was a surge of activity that has only picked up since. In December, a milestone: the FDA granted accelerated approval to Tarpeyo, a formulation of the corticosteroid budesonide, as the first approved therapy for IgAN. The budesonide tablets, sold by Calliditas, hit the market earlier this year.

In November, the FDA will decide the fate of another drug, sparsentan, which is made by Travere Therapeutics. There are dozens more clinical trials in the works, and even more IgAN drugs in early stages of the pipeline.

Akin doesn’t need these drugs yet. But she’s reassured that if her kidney function declines again, she’ll have options.

“My whole goal when I got diagnosed was no matter what, I have to make it to 18, I have to see my son graduate. And then once we get to 18, we’ll take it from there,” she said. “I should’ve started with, ‘I want to see my son get out of elementary school,’ but I went big.”

Akin’s son, Alexander, is 9. She’s almost at that first goal post.

This article was supported by a grant from Bloomberg Philanthropies.