538 ABNORMALITIES IN METABOLISM 



(3) None of the known nitrogenous constituents of the urine can be held re- 

 sponsible for all the manifestations of typical uremic poisoning. The highest 

 purine, uric acid and creatinine concentration in a given case may occur entirely 

 independent of uremic conditions/^ the amino-nitrogen is not increased in uremia, 

 urea is not supposed to be toxic in this degree arid uremia may occur without high 

 urea concentration or be absent when there is much urea in the blood. To be sure, 

 an unknown toxic substance may be responsible, but in some cases of uremia the 

 total non-protein nitrogen can be accounted for b}^ the known nitrogenous com- 

 ponents found in the blood (Foster). 



We may consider one of the following alternatives: 



(1) The nerve cells may be made hypersensitive to some one of the 

 known constituents by the excessive amounts of the other metabolites. 

 This is a purely speculative hypothesis, without anj'- actual evidence 

 in its support. 



(2) The portion of unidentified nitrogen usually present in the 

 blood may contain a specific, highly efficient poison. 



In support of this hypothesis is the finding in a series of cases that the pro- 

 portion of noncoagulable blood nitrogen that could not be accounted for by the 

 known nitrogenous metabolites seemed to vary directly with the severity of the 

 symptoms (Woods). ^^ 



Hartman*' has suggested that the substance which causes the characteristic 

 odor of the urine may be responsible for at least some of the intoxication of uremia. 

 This substance, which he has isolated and described under the name "urinod," 

 he believes to be a cyclic ketone with the empirical formula CeHsO; it is highly 

 toxic, and causes mental symptoms. This important observation awaits confirma- 

 tion. 



Foster^* has described the finding of a toxic base in the blood of uremics, 

 absent from the blood in other conditions, which causes death of guinea pigs with 

 symptoms suggestive of the eclamptic type of uremia. Further development of 

 this work is also awaited. 



(3) Uremia may not depend on intoxication of the nerve cells, but 

 upon the mechanical effects of edema involving these cells. 



One of the striking features of autopsies of uremics is often the "wet brain" 

 and the excessive amount of cerebrospinal fluid which, during life, may lie found 

 to be under a heightened pressure. We know that not only general but localized 

 edemas occur in nephritis, and that localized edema in the brain may be associ- 

 ated with and apparently responsible for paralyses, convulsions, hyperirritability 

 and mania. The wet brain of nephritis is similar to the wet brain of acute alco- 

 holism and delirium tremens. Oftentimes the nervous symptoms of uremia are 

 distinctly focal, and a complete hemiplegia from hemorrhage may be exactly 

 simulated; convulsive seizures identical with those of brain tumor may be seen. 

 It is extremely difficult to explain these localizations by the action of a soluble 

 poison, and simple if we assume a local edema. It is, of course, as difficult to 

 explain the localization of the edema, but we know that in nephritis localized 

 edemas do occur, so we have a basis for the assumption of localized cerebral 

 edemas. A general acidosis (q. v.) is usual in nephritis and marked in uremia''^ 

 but we have no means of knowing whether local acidosis occurs in the nervous 

 system that may be responsible for local edemas according to Fischer's hypothe- 

 sis. Or, osmotic effects may be responsible, in view of the demonstrated high 



*i Myers and Fine, Jour. Biol. Chem., 1915 (20), 391. 

 " Arch. Int. Med., 1915 (16), 577. 

 "Ibid., 1915 (16), 98. 



** Trans. Assoc. Amer. Phys., 1915 (30), 305. 



« Henderson, Bull. Johns Hopkins Hosp., 1914 (25), 141; Peabody. Arch. Int. 

 Med., 1915 (16), 955; Sellards, "Principles of Acidosis," Harvard Press, 1917. 



