How the sweat gland reveals levels of CFTR activity.

ABSTRACT

CFTR is an anion channel that causes cystic fibrosis (CF) when its activity, equal to channel number x open probability x conductance (n·PO·Î³) is absent or nearly so. CFTR modulators increase CFTR activity, but estimates of in vivo efficacy vary. This review shows how values from the simple and widely used sweat chloride test can be calibrated to provide more accurate estimates of CFTR activity as a percent of the average for healthy control (HC) subjects (hereafter 'CFTR activity'). Sweating stimulated by ß-adrenergic agonists (ß-sweat) is rate-limited by CFTR, producing a near linear, ratio scale of CFTR activity with carriers = 50% and CF = 0% of HC values set = 100%, but the ß-sweat assay is difficult to use. Here, sweat chloride is calibrated to CFTR activity by plotting mean sweat chloride values, taken from numerous studies and the CFTR2 database against mean ß-sweat rates for CF, carriers and HC. The resulting inverse logarithmic relations indicate that sweat chloride values ≥60 mmol/L occur when CFTR activity is below 1.2% -10% of HC. These are lower than most previous estimates, which resulted from setting nasal potential difference (NPD) as linear rather than logarithmic measures of CFTR activity. Features of the sweat gland coil and duct are used to explain why readouts of CFTR activity are linear for ß-sweat and logarithmic for sweat chloride. Sweat chloride values fall steeply for small increments of CFTR activity above zero-the most clinically relevant region. Thus, large health benefits can be achieved by restoring low levels of CFTR activity, especially if this is done before irreversible lung damage. Truncated Abstract CFTR is an anion channel that causes cystic fibrosis (CF) when its activity, equal to channel number x open probability x conductance (n·PO·Î³) is absent or nearly so. CFTR modulators increase CFTR activity, but estimates of in vivo efficacy vary. This review shows how values from the sweat chloride test can be calibrated to provide accurate estimates of CFTR activity as a percent of the average for healthy control (HC) subjects. Sweating stimulated by ß-adrenergic agonists is rate-limited by CFTR, producing a near linear, ratio scale of CFTR activity, but the assay is difficult to use. Here, sweat chloride is calibrated to CFTR activity by plotting it against mean ß-sweat rates for different groups. The resulting logarithmic relations indicate that CF sweat chloride values occur when CFTR activity is below 1.2% -10% of HC, and that large health benefits can be achieved by restoring low levels of CFTR activity if this is done early.