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close up of an IV bag

Carnitine may improve heart function in children receiving CRRT

close up of an IV bag

A first-of-its-kind study demonstrated that IV carnitine supplementation is associated with improvement in myocardial strain and repletion of plasma total and free carnitine in children with AKI receiving CRRT.

Supplementation of a special nutrient could help improve heart function in children receiving continuous dialysis in critical care units. The nutrient carnitine plays an essential role in producing energy for use by heart and skeletal muscles. Critically ill children with acute kidney dysfunction often need a continuous dialysis therapy (also known as CRRT, continuous renal replacement therapy) to help remove toxins while kidneys are not working. An unintended consequence of this CRRT is removal of carnitine. Often these critically ill children are unable to eat by mouth and therefore can’t receive carnitine unless it is supplemented. Children’s National Hospital researchers have proven that intravenous carnitine supplementation is associated with repletion of the body’s carnitine supply and may cause improvement in heart function as shown by heart strain analysis (which detects subclinical cardiac dysfunction that may not be apparent by traditional echocardiography).

In a first-of-its-kind study, the Children’s National researchers, Asha Moudgil, M.D., Kristen Sgambat, M.D., and Sarah Clauss, M.D., investigated carnitine deficiency in children receiving CRRT. They demonstrated for the first time that these children become severely deficient in carnitine after being on CRRT for >1 week, and that carnitine supplementation is associated with carnitine repletion and improved heart function. This knowledge can help to guide clinical care, as carnitine can be easily added to the IV nutritional formulations that are typically given to these patients.

Although little was previously known about carnitine status in patients with acute kidney injury (AKI) receiving CRRT, iatrogenic carnitine deficiency related to chronic hemodialysis (HD) in patients with end stage renal disease is a well-known phenomenon. It was theorized that given the continuous removal of solutes by CRRT in combination with lack of dietary intake and impaired production of endogenous carnitine by the kidney in critically ill children with AKI, carnitine would be rapidly depleted.

The latest controlled pilot study (NCT01941823) of 48 children hypothesized that carnitine supplementation would improve left ventricular function in children receiving CRRT. Children ages 1-21 years with AKI requiring CRRT, who were admitted to the pediatric intensive care unit at Children’s National Hospital from 2015 to 2018 were eligible to prospectively enroll in the “CRRT Intervention group,” if they were total parenteral nutrition (TPN)-dependent and not receiving any enteral or IV carnitine prior to enrollment.

The researchers say that “An exciting collaborative effort between nephrology and cardiology made it possible to use a sophisticated technology known as speckle tracking imaging to study the effects of carnitine on heart in this population.” This technology can identify early changes in heart motion, also known as cardiac strain that may not be detected using standard heart imaging techniques.

This is the first study to demonstrate that IV carnitine supplementation is associated with improvement in myocardial strain and repletion of plasma total and free carnitine in children with AKI receiving CRRT. A cohort of pediatric chronic HD patients demonstrated similar benefits in a prior study conducted by Drs. Moudgil and Sgambat. Compared with chronic HD, carnitine is even more rapidly depleted by CRRT, with losses approximating 80% of intake. The effect of carnitine deficiency and supplementation on cardiovascular function in patients receiving CRRT had not been previously investigated.

The pilot study by Drs. Moudgil, Sgambat, and Clauss was single center and limited by small sample size. The small sample size may have limited the ability to detect significant differences in demographics and clinical characteristics and multivariable analyses could not be performed. However, given that it is a pilot study, the findings provide a solid launching point for future investigations to show how supplementation can be best utilized to optimize cardiac outcomes in children receiving CRRT.

Nichole Jefferson and Patrick Gee

African American stakeholders help to perfect the APOLLO study

Nichole Jefferson and Patrick Gee

Nichole Jefferson and Patrick O. Gee

African Americans who either donated a kidney, received a kidney donation, are on dialysis awaiting a kidney transplant or have a close relative in one of those categories are helping to perfect a new study that aims to improve outcomes after kidney transplantation.

The study is called APOLLO, short for APOL1 Long-Term Kidney Transplantation Outcomes Network. Soon, the observational study will begin to enroll people who access transplant centers around the nation to genotype deceased and living African American kidney donors and transplant recipients to assess whether they carry a high-risk APOL1 gene variant.

The study’s Community Advisory Council – African American stakeholders who know the ins and outs of kidney donation, transplantation and dialysis because they’ve either given or  received an organ or are awaiting transplant – are opening the eyes of researchers about the unique views of patients and families.

Already, they’ve sensitized researchers that patients may not be at the same academic level as their clinicians, underscoring the importance of informed consent language that is understandable, approachable and respectful so people aren’t overwhelmed. They have encouraged the use of images and color to explain the apolipoprotein L1 (APOL1) gene. The APOL1 gene is found almost exclusively in people of recent African descent, however only 13 percent of these people carry the high-risk APOL1 variant that might cause kidney problems.

One issue arose early, during one of the group’s first monthly meetings, as they discussed when to tell patients and living donors about the APOLLO study. Someone suggested the day of the transplant.

“The Community Advisory Council told them that would not be appropriate. These conversations should occur well before the day of the transplant,” recalls Nichole Jefferson.

“The person is all ready to give a kidney. If you’re told the day of transplant ‘we’re going to include you in this study,’ that could possibly stop them from giving the organ,” Jefferson says. “We still remember the Tuskegee experiments. We still remember Henrietta Lacks. That is what we are trying to avoid.”

Patrick O. Gee, Ph.D., JLC, another Community Advisory Council member, adds that it’s important to consider “the mental state of the patient and the donor. As a patient, you know you are able to endure a five- to eight-hour surgery. The donor is the recipient’s hero. As the donor, you want to do what is right. But if you get this information; it’s going to cause doubt.”

Gee received his kidney transplant on April 21, 2017, and spent 33 days in the hospital undergoing four surgeries. His new kidney took 47 days to wake up, which he describes as a “very interesting journey.” Jefferson received her first transplant on June 12, 2008. Because that kidney is in failure, she is on the wait list for a new kidney.

“All I’ve ever known before APOLLO was diabetes and cardiovascular issues. Nobody had ever talked about genetics,” Gee adds. “When I tell people, I tread very light. I try to stay in my lane and not to come off as a researcher or a scientist. I just find out information and just share it with them.”

As he spoke during a church function, people began to search for information on their smart phones. He jotted down questions “above his pay grade” to refer to the study’s principal investigator. “When you start talking about genetics and a mutated gene, people really want to find out. That was probably one of the best things I liked about this committee: It allows you to learn, so you can pass it on.”

Jefferson’s encounters are more unstructured, informing people who she meets about her situation and kidney disease. When she traveled from her Des Moines, Iowa, home to Nebraska for a transplant evaluation, the nephrologist there was not aware of the APOL1 gene.

And during a meeting at the Mayo Clinic with a possible living donor, she asked if they would test for the APOL1 gene. “They stopped, looked at me and asked: ‘How do you know about that gene?’ Well, I’m a black woman with kidney failure.”

Patrick O. Gee received his kidney transplant on April 21, 2017, and spent 33 days in the hospital undergoing four surgeries. His new kidney took 47 days to wake up, which he describes as a “very interesting journey.”

About 100,000 U.S. children and adults await a kidney transplant. APOLLO study researchers believe that clarifying the role that the APOL1 gene plays in kidney-transplant failure could lead to fewer discarded kidneys, which could boost the number of available kidneys for patients awaiting transplant.

Gee advocates for other patients and families to volunteer to join the APOLLO Community Advisory Council. He’s still impressed that during the very first in-person gathering, all researchers were asked to leave the table. Only patients and families remained.

“They wanted to hear our voices. You rarely find that level of patient engagement. Normally, you sit there and listen to conversations that are over your head. They have definitely kept us engaged,” he says. “We have spoken the truth, and Dr. Kimmel is forever saying ‘who would want to listen to me about a genotype that doesn’t affect me? We want to hear your voice.’ ”

(Paul L. Kimmel, M.D., MACP, a program director at the National Institute of Diabetes and Digestive and Kidney Diseases, is one of the people overseeing the APOLLO study.)

Jefferson encourages other people personally impacted by kidney disease to participate in the APOLLO study.

“Something Dr. Kimmel always says is ‘You’re in the room.’ We’re in the room while it’s happening. It’s a line from Hamilton. That’s a good feeling,” she says. “I knew right off, these are not necessarily improvements I will see in my lifetime. I am OK with that. With kidney disease, we have not had advances in a long time. As long as my descendants don’t have to go through the same things I have gone through, I figure I have done my part. I have done my job.”