They focus on dose, not exposure, overlooking physiologic barriers making it difficult to raise serum 25D to targeted levels, such as adipose related increases in volume of distribution, impaired hepatic activation in CKD and obesity, and increased catabolism due to upregulation of CYP24A1 (cytochrome P450 24-hydroxylase), the vitamin D catabolic enzyme.2 This evidence concerns the gene CYP24A1 and chronic kidney disease.