THE PERPETUATION OF CLINICAL ERROR CONCERNING AMYLOID REACTIONS

IN RENAL CASTS

HE view that casts showing the reactions of amyloid are found in the urine of patients showing amyloid disease is apparently still held by many clinicians. In fact, some of them teach that amyloid kidney may be diagnosed by the presence of such amyloid casts in the urine. Yet, when asked if they have ever seen a diagnosis of amyloid kidney so made and confirmed, they are obliged to disclaim any personal knowledge of such cases, and throw the responsibility of their statements back upon the text-books of internal medicine and

clinical diagnosis. Consulting the latter we find some statements to support their belief. The adult medical generation of today was brought up chiefly on two great text-books of internal medicine, the Strümpell and the Osler. In the 1891 American edition of the Strümpell we find the statement that "amyloid reaction occurs in the casts, but it is very rare, and, therefore, of no value in diagnosis." In the 1892 Osler, we find, "Occasionally the amyloid reaction can be detected in the hyaline casts.

By the condition of the urine alone it is not possible to recognize amyloid changes in the kidney." In Herrick's article on "Amyloid Disease of the Kidney" in Osler's Modern Medicine (1909) he says, "Mild cases

cannot be recognized by any symptom or sign unless one by good luck finds a cast or mass of debris in the urine that gives the characteristic staining reaction of amyloid, a finding the occurrence of which is disputed by many." In the Osler-McCrae edition (1914) even this statement is omitted, and there is no reference to the occurrence of casts showing an amyloid reaction, although Herrick still retains the statement that "at times the epithelial cells [renal] themselves may show the change." If the latter is true, then casts showing the reaction could be produced by the desquamation of such cells. Text-books on internal medicine published within the last year (Greene, etc.) make no mention of amyloid casts. Turning to the great pathologists of this period we find that Ziegler in his "Specielle pathologische Anatomie” (1902) states that in amyloid kidney "the casts are at times delicate, translucent, and other times firmer, more waxy, and like amyloid may stain browner with iodine than the normal tissues, yet they give no characteristic amyloid reaction." The last edition of the Kaufmann says that in amyloid kidney "hyaline and especially waxy casts occur in the tubules, often in great numbers, staining bright yellow with iodine (rarely brown as amyloid)." The last edition. of Aschoff makes the statement that in amyloid kidney "casts are abundant in the renal tubules, they do not give an amyloid staining, and differ from

ordinary casts only in their thickness and shining appearance (waxy casts)." Consulting American text-books on pathology, Mallory (1914) describes the formation of hyaline casts in the tubules of amyloid kidney, but mentions no amyloid reaction in these. His conception of amyloid is that it is wholly a fibroblastic formation. Such a view of the nature of amyloid is, of course, incompatible with an occurrence of amyloid casts. Adami and McCrae (1912) say that the deposit of amyloid in the glomeruli, basement membranes and vessel walls of the kidney "has nothing to do with the appearance of the waxy, so-called amyloid cast, which is probably a modification of the more frequently seen hyaline cast." MacCallum (1924) describes the urinary changes in amyloid kidney, as follows: "The urine is abundant, with low specific gravity, and pale, but rich in albumin; hyaline casts and epithelial and other cells appear there. It has never been shown, though, that the specifically staining amyloid plays any part in forming these casts." On the other hand, Delafield and Prudden (1922) say that "Homogeneous casts giving the microchemical characters of amyloid are of occasional occurrence in the tubules." Stengel and Fox (1915) make the statement that the urine in amyloid disease "not rarely contains hyaline casts which respond more or less distinctly to the color-tests for amyloid substance, but these are not diagnostic, and it is doubtful whether they are, in reality, composed of amyloid material." McFarland says that in amyloid disease of the kidneys "The tubules may contain casts of waxy, sometimes true, amyloid substance."

We

Likewise, Coplin makes the statement that the urine in amyloid kidney contains "occasionally-not constantly, as commonly believed-waxy casts which may give the amyloid reaction." Warthin (Reference Handbook of the Medical Sciences, Vol. 1, 1900, 1913) says that the hyaline casts in the urine of amyloid disease "never give the amyloid reaction, in spite of the repeated statements that they do." With the conservative and negative statements in the literature against the occurrence of amyloid reactions in urinary casts, one may wonder at the persistence of the positive clinical statements concerning it, and at the source of such an error. need only to turn to the textbooks on Clinical Diagnosis and Clinical Pathology to understand the perpetuation of this error. Almost without exception during the last twenty-five years the text-books of this class published in English have passed along the statements of the occurrence of amyloid casts. We need give but one example here: Simon (1922), "Waxy casts may be divided into two groups-true waxy casts and amyloid casts, but as the latter are not necessarily indicative of the existence of amyloid degeneration of the kidneys such a classification is of only theoretical interest. As has been stated some waxy casts give the amyloid reaction-i.e., they assume a mahogany color when treated with a dilute solution of iodopotassic iodide, which changes to a dirty violet upon the addition of dilute sulphuric acid. It should be remembered, however, that this reaction in casts does not necessarily indicate the existence of amyloid disease of the kidneys, as the

reaction may be absent in this condition, and present where amyloid degeneration does not exist." The essential error in the statements just quoted, and which lies also at the bottom of practically all of the positive statements as to the occurrence of amyloid casts, is the assumption that iodine is a specific test for amyloid. This error goes back to the earliest conceptions of the nature of amyloid by Virchow, about the middle of the last century. He noted that amyloid, the corpora amylacea of the central nervous system and of the prostate and lungs, and other forms of epithelial hyalin might all stain brown with iodine in the fresh state, and he, therefore, conceived of them as genetically related to starch and cellulose. In spite of a common staining reaction he did not regard all of these substances as chemically identical. Nevertheless, his conception of animal starch, as shown in the word amyloid, and the iodine reaction so emphasized by him as characteristic of this substance laid the foundation for the perpetuation of the error that the brown-staining of any homogeneous substance meant an amyloid reaction. The work of later investigators showed that the specific stains of amyloid were the metachromatic reactions with methyl violet, gentian violet, Kresyl violet, methyl green, iodine green, etc. When these specific staining reactions are applied to corpora amylacea and hyaline or waxy casts, no characteristic metachromatic reactions of amyloid are ever seen in them. Saleeby (Jour. Amer. Med. Assoc., January 31, 1925) has recently reported a study on the methyl violet reaction in 50 cases of amyloid kidney occurring in

3047 autopsies performed at the Philadelphia General Hospital during the last three and a half years. In 45 of these cases casts of various kinds were shown in the kidney sections; only one of these, though doubtful whether it was a cast, gave a definite microchemical reaction for amyloid. This cast consisted of pinkish homogeneous material and was not definitely outlined like the other casts, though very suggestive. The accompanying highpower photomicrograph of this supposed cast offers another explanation; the supposed cast is but a portion of the amyloid intertubular capillary wall and basement membrane of the tubule cut on a curve in the tubule wall in the same plane with the oblique sections of the tubule shown. The two tubules at the sides of the one containing the supposed cast also show the shadings off of the amyloid reaction into the lumen of the tubules due to the oblique sectioning. The appearances are purely those of an artefact due to cutting, and the supposed cast cannot be accepted in evidence of amyloid reaction in casts. Saleeby, himself in doubt as to the true nature of the cast concludes that his findings "would throw doubt on the occurrence of amyloid casts in the urine of patients suffering with amyloid kidney and may show that the specifically staining amyloid plays no part in forming any of the casts." The writer has for thirty years been interested in this question of amyloid reaction in renal casts; he has collected during this time specimens of amyloid kidneys from many sources, over 150 cases in all. In his teaching work thousands of sections stained with a specific metachromatic dye,

Kresyl violet, as well as methyl violet, gentian violet and iodine green have been used. In class demonstrations the students have been asked especially to look for casts in the kidney tubules showing a reddish color. Such casts showing the metachromatic reaction have never been observed in this investigation extending over 30 years. The hyaline and waxy casts present in the tubules of all cases of amyloid kidney examined have stained uniformly blue or greenish-blue with

out a suspicion of red in any instance. The writer, therefore, is convinced that no specific metachromatic reaction for amyloid ever occurs in renal casts. This view is wholly in harmony with our present day knowledge of the chemical nature of amyloid-better expressed, as Wells has suggested, by the term chondroitin-it is never an epithelial-cell derivative or product, and, therefore, cannot appear in the renal tubules.

The Skin Manifestations Associated with Leukaemia and Allied Conditions. SIR HUMPHRY ROLLESTON. The British Journal of Dermatology and Syphilis, October, 1924.

An increasing amount of interest is being shown by clinical writers on the subject of the leukaemic and aleukaemic conditions of the skin, and during the last year a number of important articles upon this subject have appeared. Among these articles the monograph by Rolleston is of especial interest because of its comprehensive knowledge of the older literature bearing upon different phases of this subject; and it offers a very good foundation upon which to base some of the newer conceptions of the relationships existing between these conditions that have arisen in recent years. The skin manifestations associated with leukaemia and allied conditions fall into obviously different groups: (1) infiltrations or tumors of the skin histologically identical with the disease, (2) various non-specific disorders and changes in the skin (dermatoses) such as perspiration, pruritus, pigmentation, prurigo, and erythematous, desquamative, vesicular, and bullous eruptions, due to toxins, possibly derived from cell destruction in the haemopoietic system. To such eruptions the term leucimides has been applied by Audry, but the exfoliative erythrodermias are generally not included among the leucimides, although Bordet groups all the cutaneous manifestations of acute leukaemia, with the exception of haemorrhages and growths, under that heading. Rolleston takes up in order acute and chronic leukaemia, chloroma, multiple myeloma, lymphadenoma and mycosis fungoides, and considers each one separately from three standpoints (a) structural invasion of the skin by the disease, (b) manifestations due to poisons manufactured by, or in association with, the morbid process, and conveyed

ANNALS OF CLINICAL MEDICINE, VOL. III, NO. 11

to the skin, such as pruritus and rashes, and (c) the changes in the skin secondary to pruritus.

Acute leukaemia: The cutaneous lesions in acute leukaemia fall into the two distinct groups of definite leukaemic tumors and the dermatoses. The tumors are formed of leukaemic cells resembling those of the blood-stream; they form plum-colored, nodular, discoid, or flattened tumors, usually quite small but they may be very numerous; they are only rarely confluent. On the whole they resemble very much those of chronic leukaemia. They may be associated with either the aleukaemic or leukaemic phase. Cutaneous rashes are commoner in acute than in chronic leukaemia, and are polymorphic, suggesting that their exciting cause is not always the same. Acute leukaemia often presents features suggesting an acute infection, but it differs from any one of the acute exanthems in the various forms of skin eruptions that may occur. The most characteristic and frequent is purpura; it is probably due to thrombosis or leukocytic blocking of the small vessels, but is sometimes the result of secondary infection and due to bacterial emboli. The haemorrhages may be minute or large; haematomas are easily produced by slight trauma. Herpes labialis is not uncommon at the onset; acute and subacute exfoliative erythrodermias may appear, and other forms of rashes, papules, vesicles, haemorrhagic bullae, or morbilliform exudative erythema. Pruritus is rare.

Chronic myeloid leukaemia: Leukaemic tumors or infiltrations are rare, only eight cases having been reported. In one case the lower part of the trunk was thickly covered with nodules resembling half a damson. Haemorrhages are rare, and are found especially in the terminal stages.

Chronic lymphoid leukaemia: The great majority of the examples of true leukaemic tumors of the skin are provided by chronic