_Creatinine_ occurs in the urine of adults, and is practically independent of the protein intake. The amount excreted varies with the size, and not with the weight of the body. In other words, it varies with the _volume_ or _mass_ of the _voluntary muscles_, which structures have the highest content of creatinine and creatine. MacLeod, discussing this relationship, tells us that, “in the muscular atrophies creatine excretion is distinctly below normal.” It must, he adds, be the “mass of the muscles rather than their activities that is the determining factor, for the creatine excretion does not become increased by muscular exercises.” Otto Folin, discussing the clinical application of pathological chemistry, observes, “Nothing definite is as yet known concerning the creatinine output in abnormal metabolism, except that in fevers and other diseases there is an increase, sometimes a very large increase.” But this much we do know that creatine, after ingestion, is almost quantitatively excreted in the urine. _Creatine_, in considerable amount, is a normal constituent of children’s urine, but in normal adults hardly a trace occurs, though in some diseases it is met with even in their case. In boys it gradually dwindles and disappears at about seven years of age. On the contrary, in girls creatine is excreted until puberty. Subsequently, its presence in the urine is intermittent, its incidence confined to the menstrual cycles, the period of pregnancy, and for some days after parturition. From our point of view, the most interesting of the above revelations is the fact that the largest percentage amount of creatine and creatinine is located in the _muscular tissues_. On this point we cannot do better than quote the following words of Otto Folin:— “It is to be noted that we are as yet entirely ignorant of the origin and significance of the creatine which is so abundant in muscles, and it is scarcely to be doubted that fundamentally important metabolism problems somehow are connected with the muscle creatine and urinary creatinine, but these are as yet problems of normal metabolism, and it is too early to say whether, or in what way, light may be thrown on clinical problems by studies of these products. The fact that the muscles of mammals, including man, contain 0·3-0·4 per cent. of creatine, and only traces of the chief nitrogenous waste product urea, constitutes to my mind strong presumptive evidence that creatine serves some important function, and it is quite conceivable that metabolism diseases of one kind or another may be associated with this curious substance, but investigations rather than hypotheses are needed in the study of such obscure problems.” INBORN ERRORS OF METABOLISM