Kidney disease can sneak up on a kid. In the case of Lexi Hatfield, born in 2008, it disguised itself as stomach trouble at first, when she was about 1 year old. Then, when her cheeks and face got puffy and swollen at 18 months, along with a distended belly, it looked like an allergy.
Parents Jake and Erika Hatfield, living in rural southwestern Pennsylvania, were frustrated. “We’d gone to many doctors, urgent care, the pediatrician …” says Ms. Hatfield. “They just kept saying it was allergies. We had her tested. We were avoiding the stuff they said she was allergic to, and nothing was working. It was frustrating.”
Then one night, when she was nearly 4 years old, Lexi’s stomach pain got so severe that the Emergency Room team at her community hospital diagnosed appendicitis, and referred Lexi to UPMC Children’s Hospital of Pittsburgh. After a week of tests at Children’s, massive protein in the urine and a low albumen level in the blood indicated nephrotic syndrome.
FSGS and nephrotic syndrome
A biopsy confirmed a diagnosis of focal segmental glomerulosclerosis (FSGS), a relatively rare kidney disease that accounts for about one sixth of the cases of nephrotic syndrome. FSGS is usually diagnosed by the appearance of the kidney tissue on biopsy: focal (only some of the glomeruli are involved), segmental (only part of each glomerulus is involved), glomerulosclerosis (scarring of the glomerulus, part of the nephron). FSGS has a variety of origins, usually related to a primary disease or other condition that leads to nephropathy. Nephrotic syndrome associated with FSGS can progress to endstage renal disease (ESRD) requiring dialysis and kidney transplantation. In children who present at younger than 2 years of age, FSGS is often genetic and does not respond to therapy.
Lexi was treated aggressively with immunosuppressive therapy, but had no response, and her renal function steadily declined. Although genetic testing was inconclusive, “given her young age, lack of response to therapy, and rapid progression to ESRD, we suspected that Lexi had the genetic form of FSGS,” says Michael Moritz, MD, clinical director, Division of Pediatric Nephrology at Children’s. Her best hope for a normal life, based on this assessment, was a pre-emptive kidney transplant.
Pre-emptive kidney transplant
Timing for the transplant was critical: By late 2014, 6-year-old Lexi was facing renal failure. The Hatfield family and their community responded. More than 30 volunteers stepped forward. A donor was found and qualified, and Lexi was able to receive a pre-emptive kidney transplant in time to avoid the stress of dialysis.
The transplant went well with excellent function and no protein in the urine. After two weeks, however, Lexi’s symptoms returned in the form of proteinuria. Lexi’s FSGS was recurring. “This can happen in 50 percent of cases,” says Dr. Moritz. “But we can’t predict who will have a recurrence and who won’t. The fact that it recurred was a definite sign that we weren’t dealing with genetic FSGS.”
Dr. Moritz and his team treated Lexi with plasmapheresis, a therapy where the plasma is removed from the body and replaced with unaffected protein. The regimen began with four treatments a week, accompanied by blood transfusion because of Lexi’s small size, and gradually decreased to once a week. She responded to this therapy, going into remission after two and a half months.
“It helped that Lexi is an incredibly strong kid,” says Dr. Moritz. “This was almost daily treatment at first, with a lot of needle sticks and a lot of discomfort.”
“Strong” may be an understatement. The way Lexi’s mom tells it, life didn’t slow down at all. “She’d go right from treatment to cheerleading and dance competitions. She didn’t miss a beat.”
But then the therapy hit a wall: When plasmapheresis was tapered to every two weeks, proteinuria recurred. Biopsies showed that FSGS was recurring, and without the weekly plasmapheresis, scarring and ultimately kidney failure would occur. For Lexi, remission from FSGS depended on weekly plasmapheresis, potentially for the rest of her life.
Experimental in the United States
Faced with limited options, Dr. Moritz recommended LDL-apheresis, a therapy used in Japan to treat extremely high cholesterol as well as nephrotic syndrome, most commonly in adults. The therapy is recognized to control hyperlipidemia and promote remission in patients with refractory nephrotic syndrome associated with FSGS.
How this therapy works, whether it works long term, and the extent of its effectiveness, are all still under investigation. Although it is approved and covered by health insurance in Japan, LDL-apheresis is considered experimental by the U.S. Food and Drug Administration. Children’s is one of only eight centers in the United States that offers this therapy to children with FSGS. “Results for this therapy are good in Japan,” says Dr. Moritz. “But there is no comparable data in the U.S. It’s not widely available to treat kidney disease.”
In LDL-apheresis, plasma is passed through a dextran sulfate column and LDL-cholesterol is adsorbed due to an electrostatic interaction between negatively charged dextran sulfate and positively charged apoprotein B on the surface of the lipoprotein. VLDL and LDL are adsorbed, but HDL-cholesterol (with ApoA or other plasma components including albumen) is not. This process can purify 3,000 to 4,000 ml of plasma in two to three hours.
One theory on treating refractory FSGS with LDL-apheresis is that the high levels of LDL-cholesterol produced in patients with FSGS work to defeat medications, and that rapid removal of these high levels of LDL eliminates this resistance. When this treatment was first used for FSGS in 1988 in Japan, researchers observed both the correction of hyperlipidemia and rapid resolution of nephrotic syndrome in response to immunosuppressive therapy.
Stable kidney function
“We turned to LDL-apheresis as a strategy to get Lexi off of weekly plasmapheresis,” says Dr. Moritz. And that’s exactly what happened. Following a nine-week course of LDL-apheresis that was completed in December 2016, Lexi is now in remission without any therapy aside from normal transplant medication. “She has good, stable kidney function without high blood pressure, and the protein in her urine is actually going down further,” says Dr. Moritz. “It’s an outcome like no one has seen before, especially in such a small child. Many similar cases are on lifelong plasmapheresis.”
Dr. Moritz estimates that Lexi is one of probably less than 10 patients in the United States who has benefited from LDL-apheresis. As more becomes known about this novel therapy for a debilitating, life-shortening disease, more good outcomes could potentially follow.
From Jake and Erika Hatfield’s point of view, it’s more than an outcome. It’s a journey that has brought Lexi to a place every parent wants their child to reach: a normal life. The best part? “I can eat hot dogs now!” Lexi says, without hesitation.
It doesn’t get much better than that.