United States
United States of America
A game by any other name just wouldn't be the same. Apropos for the game of football: simultaneously the most and one of the least popular sports in the nation. This year, the USA enters The Tournament as serious contenders in the FIFA World Cup. After a 4 decade hiatus from the World Cup (1950-1990), the USA is back in the game and is assured of having two consecutive appearances in the big dance (2022 in Qatar and 2026 as co-host nation). While the FIFA World Cup team hopes to achieve its highest ranking since the 1930 Cup (3rd place finish), the NephroWorldCup squad is sure to be an exciting competitor.
Figure 1: The deleterious effects of steroids in children | Presented at the 2018 American Society of Nephrology Kidney Week annual meeting | Courtesy of Dr. Juan Kupferman (zoom in for details)
This year's NephroWorldCup team focuses on the plight of pediatric patients who suffer with nephrotic syndrome. These children are subjected to a mixture of immunosuppressive therapeutic agents whose adverse effects are often difficult for adult nephrotic syndrome patients to bear. For those "lucky" enough to respond to first-line treatment with steroids, the deleterious effects of chronic glucocorticoid exposure are always real and present (Figure 1).
Figure 2: Treatment options for SRNS and FRNS | Presented at the 2018 Apex Board Review Course | Courtesy of Dr. Aakash Shingada (zoom in for details)
What happens to the "unlucky" ones who are either steroid-resistant (steroid-resistant nephrotic syndrome or SRNS) or require constant steroid exposure (frequently relapsing nephrotic syndrome or FRNS)? Currently their fate involves being exposed to additional toxic immunosuppressive agents. It's a cruel necessity in order to mitigate end-stage kidney disease (Figure 2).
Thankfully, this year's USA NephroWorldCup team has something to say about that (Video 1).
The researchers of the USA squad leverage an interesting and not-yet fully explained phenomenon. Stimulation of the vagus nerve (cranial nerve X) can modulate the immune system. Historically, vagal nerve stimulation has been used to treat rheumatoid arthritis, epilepsy, depression, and lupus. In each of these applications, the link between the vagus nerve and the immune system was exploited to provide symptomatic relief.
Figure 3: Auricular branch of the vagus nerve (purple zone)
So how is the vagus nerve stimulated? In previous studies a vagal nerve stimulator was implanted into the patient. Today, the auricular branch of the vagus nerve is stimulated using a transcutaneous electrical nerve stimulator (TENS) (Figure 3).
Consolidating all this information resulted in an ingenious Team USA hypothesis. Vagus nerve stimulation would lower immune system activity (specifically through levels of TNF-alpha and/or B-cell activity) and reduce a) the number of relapses in patients with FRNS and b) reduce proteinuria in patients with SRNS.
Three (3) children with FRNS and four (4) with SRNS participated in this pilot study. While being maintained on stable doses of immunosuppression, the pediatric patients were given daily TENS for a five (5) minute duration over a 26-week period. Prior to the intervention, the FRNS children experienced two (2) relapses in the last six (6) months and up to four (4) relapses in the last twelve (12) months.
FRNS children experienced zero relapses in the 26-week study period, representing the longest stretch of time in which they were relapse-free.
Those suffering with SRNS saw a 25-76% reduction in proteinuria during the study period (Figure 4).
Figure 4: Trend in proteinuria during and after taVNS intervention (dotted red line)
Let's take stock of what has Team USA uncovered with this small study. The team introduced a novel intervention to the field of Nephrology; one that has enough biological plausibility from previous applications to be considered. They applied it to treat individuals in one of the most vulnerable patient populations we have. And thus far, it has worked!
Audio 1: Team USA Goal chant
This may be the year that Team USA finishes as strong (or even better) than it did way back in 1930. Does taVNS give the USA a Tournament-winning strategy? Perhaps now is a good time to chant along (Audio 1) or, even better, hear directly from one of the leaders in taVNS (Video 1).
Video 1: taVNS | Courtesy of Dr. Christine Sethna