Music City USA is home to The Grand Ole Opry, The Music Hall of Fame and from October 31st to November 2nd, was home to the 2019 North American Cystic Fibrosis Conference (NACFC). More than 5,000 researchers and care providers from around the world gathered for the 33rd annual conference and as a first time attendee, NACFC quickly won my heart.
The timely FDA approval of the newest triple modulator therapy, Trikafta (elexacaftor/ivacaftor/tezacaftor), was a large focus of the conference and rightly so. Cystic Fibrosis (CF) is an autosomal recessive genetic defect caused by a mutation in the cystic fibrosis transmembrane regulator (CFTR) gene. CFTR is primarily responsible for the transport of chloride into the interstitium of sweat duct glands. Patients with CF have absent, faulty, or reduced number of CFTR channels resulting in thick, stickier mucus production. The lungs are the primary organ affected by a buildup of thick mucus due to reduced mucociliary clearance leading to chronic infection, long term use of antibiotics and steady respiratory decline.
The new Trikafta breakthrough therapy for CF has promise to provide treatment for 90% of the population with CF. Of the population with CF, 90% of patients have at least one copy of the Phe508del CFTR mutation (there are over 1700 known mutations) and until Trikafta, the previous modulator regimens were ineffective against this specific mutation. Trikafta is a combination therapy – it combines elexacaftor, ivacaftor, and tezacaftor to effectively increase the CFTR expression. The elexacaftor and tezacaftor in Trikafta work together to bind to the CFTR protein and facilitate the cellular processing of F508del-CFTR. This combination helps increase the amount of CFTR protein being delivered to the cell surface. The ivacaftor portion aids in the gating of the CFTR protein at the cell surface. This is huge news! Tikafta is a potential new therapy that will help a large population of the CF community. The excitement and hope with the discussions of Trikafta illuminated throughout the conference and it was inspiring to say the least.
As I wandered through the rows upon rows of posters, I noticed a growing focus on non-pulmonary related complications in CF. While the respiratory tract, digestive tract, urogenital tract, and sweat glands are the primary source of concern, they aren’t the only affected organs. CFTR is ubiquitously expressed on epithelial cells and has been identified on endothelial cells, pancreas, liver, and kidney. This growing focus on non-pulmonary complications in CF is important as the life expectancy continues to rise in this population and age-related diseases emerge.
One poster across from mine caught my attention in particular, ‘Acute Kidney Injury in Cystic Fibrosis Patients Treated with Intravenous Colistimethate Sodium Versus Tobramycin’. I knew the CFTR channel was expressed in the kidney, but had not thought about how this would impact acute kidney injury (AKI) or reduced kidney function, so this poster was intriguing. People with CF experience frequent pulmonary exacerbations that result in hospitalization and intensive antibiotic therapy to eliminate lung infection. Pseudomonas aeruginosa is a common multidrug resistant bacteria that results in pulmonary exacerbations and the few treatments that are effective against it are associated with high rates of nephrotoxicity. The authors of this poster had a goal to characterize if AKI occurred more frequently in people with CF receiving colistimethate sodium treatment versus tobramycin treatment, two nephrotoxic drugs. The overall hypothesis was that AKI would occur more frequently in patients with CF treated with IV colistimethate sodium compared to those treated with tobramycin. AKI was defined using the RIFLE criteria (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) and patients had to only reach injury and above to be included.
The RIFLE criteria is as follows:
Risk = serum creatinine increase by factor of 1.5
Injury = serum creatinine increase by factor of 2
Failure = serum creatinine increase by factor of 3
Loss = Loss of function x4 weeks
ESKD = for > 3 months
Despite the hypothesis, there was an overall lower than expected frequency of AKI in their population with CF at 9.5% of hospital encounters, regardless of treatment with colistimethate sodium (6.9%) or tobramycin (9.9%). Potential explanations were that the dose of colistimethate sodium was lower compared to other institutions or enhanced kidney clearance of parent drug, leaving less active drug present.
Additionally, I came across articles researching strategies to prevent antibiotic-associated AKI in patients with CF. Chronic use of intensive antibiotics (many of which are directly nephrotoxic) can result in kidney damage. Therefore, it is no surprise kidney disease is a growing concern in a population of patients with life-long antibiotic use. Overall, I’m intrigued by the growing interest in how the kidney may be impacted by CF. At the meeting I viewed and discussed posters on volume repletion protocols for nephrotoxic medications, serum creatinine and lean body mass, and learned about animal models of CF. It was exciting to see that kidney care in patients with CF is a priority and that many labs around the world are working to better understand CFTR function in the kidney.
So what do we know about CFTR in the kidney? The use of real time RT-PCR, immunocytochemistry, and patch-clamp analysis have provided ample evidence of the expression of CFTR in the kidney. It functions in chloride secretion in the distal tubule, and the principal cells of the cortical and medullary collecting ducts resulting in a reduced excretion of NaCl. Several studies have demonstrated that not only does CFTR regulate chloride transport, but it secretes adenosine triphosphate (ATP) and can directly decrease single sodium channel activity by downregulation of Cl-. Perhaps the most surprising finding I came across is that the chloride secretion through CFTR in the polycystic kidney contributes largely to the cyst enlargement.
Zhang and colleagues investigated the potential role of CFTR dysregulation in the development of kidney fibrosis. Utilizing the combination of kidney epithelial cell lines, unilateral ureteral obstruction induced-fibrotic mouse models (CFTR deltaF508 mouse model – generated on the C57BL/6 background), and samples from human fibrotic kidneys (no mention of etiology), the authors demonstrated that CFTR expression is reduced in mouse models of kidney fibrosis and in human kidneys demonstrating fibrosis. This downregulation CFTR in kidney epithelial cells leads to an alteration in numerous downstream genes involved in transport and kidney fibrosis. One pathway, the Wnt/β-catenin, was overactivated in CFTR mutant mice that were injured leading to excessive kidney fibrosis. Thus, ion channels, like CFTR may be involved in many signaling pathways more than their canonical role in ion transport!
As always, I left NACFC mentally and physically exhausted, yet filled with new questions, intriguing ideas, connections, and hope. I have begun tackling some of those new interests, particularly the role of CFTR and kidney dysfunction, and am excited to challenge myself in new fields of CF research. However, hope is the most important one, because as a young researcher in the CF community, I am beyond excited for new modulators to continue to emerge and the hope for a cure to end CF. See you next year North American Cystic Fibrosis Conference (NACFC)!
Casey Derella
@derella_casey
PhD Student at Augusta University
