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Chapter IX



Pathology of the Kidney in Traumatic Shock

The kidney lesion associated with the clinical syndrome of renal insufficiency following resuscitation from shock is constant but not pathognomonic. Lucké,1 in a study of material from the Army Institute of Pathology, has shown that a similar lesion, which he has called "lower nephron nephrosis," develops in a variety of conditions such as mismatched blood transfusion, infusion of human hemoglobin, the crush syndrome, heat stroke, blackwater fever, thermal burns, carbon tetrachloride poisoning, mushroom poisoning (Amanita phalloides) and sulfonamide sensitivity. The author, from his own experience, can add to the list of etiologic agents chemical burns, anaphylactic shock following therapeutic use of antipneumococcus rabbit serum, and hemolytic reactions following transurethral resections in which the operative field is irrigated with tap water. Many years ago F. B. Mallory2 noted the lesion in an occasional patient with hemolytic streptococcus infection. There can be little doubt that with increasing breadth of experience many other causal agents will be brought to light.

Descriptions of the lesion in various stages may be found in innumerable case reports under such titles as transfusion kidney,3 hemoglobinuric nephrosis,4 interstitial nephritis,5 hepatorenal syndrome,6 and other terms, but surveys of

    1LUCKÉ, B.: Lower nephron nephrosis (renal lesions of crush syndrome, of burns, transfusions, and other conditions affecting lower segments of nephrons). Mil. Surgeon 99: 371-396, November 1946.
    2MALLORY, F. B.: Personal communication.
    3DENAVASQUEZ, S.: Excretion of haemoglobin, with special reference to "transfusion" kidney. J. Path. & Bact. 51: 413-425, November 1940.
    4MALLORY, T. B.: Hemoglobinuric nephrosis in traumatic shock. Am. J. Clin. Path. 17: 427-443, June 1947.
    5KIMMELSTIEL, P.: Acute hematogenous interstitial nephritis. Am. J. Path. 14: 737-761, November 1938.
    6HELWIG, F. C., and ORR, T. G.: Traumatic necrosis of liver with extensive retention of creatinine and high grade nephrosis. Arch. Surg. 24: 136-144, January 1932.


any considerable mass of material are few. The most notable contributions are those of Lucké7 and of Bywaters and Dible8 in their studies of the crush syndrome. The present study is based primarily on a review of material from 60 out of 63 necropsies on patients studied by the Board, but is fortified by experience gained from review of more than 150 similar nephropathies at the 15th Medical General Laboratory. The records and material from the 60 cases, correlated with the clinical and biochemic data, provided the means for surveying the lesion in all stages of development as manifested in wounded soldiers resuscitated from shock by human plasma or whole blood transfusions.

Microscopic Pathology

The characteristic features of the lesion emphasized to a greater or lesser degree by different authors are seven: pigment casts; internal hydronephrosis; degeneration of epithelial elements, particularly in the lower segments of the nephrons; rupture of tubules with extrusion of their content into the stroma; interstitial inflammation; granulomatous inflammation, and thrombophlebitis of small intrarenal veins. Let us examine them successively.

Pigment Casts

Pigment casts, as in other forms of lower nephron nephrosis, are the most conspicuous feature of the "shock kidney." They were present in all cases of proved renal insufficiency in the present series in which the survival period was 3 days or longer. Their absence in many of the more acute cases is an interesting feature which will be considered later.

The pigment casts were found in the distal convoluted and collecting tubules and in the ducts of Bellini, their relative frequency in these respective locations varying considerably from case to case. The number of nephrons involved was difficult to estimate in routine sections, since only portions of each nephron were visualized. In most cases with clinically demonstrated renal insufficiency, the proportion was obviously high but the range was wide, probably from 20 to 80 percent.

    7See footnote 1.
    8BYWATERS, E. G. L., and DIBLE, J. H.: Renal lesion in traumatic anuria. J. Path. & Bact. 54: 111-120, January 1942.


The pigment, when viewed in unstained sections or sections only lightly stained with hematoxylin, shaded from orange through orange-green to a muddy greenish-brown. It might precipitate as separate coarse globules 4 to 8 microns in diameter (which are frequently mistaken on casual examination for red blood cells); as ropes of globules, rather like strings of sausages; or as granular debris usually embedded in a cast-like matrix. The staining reactions of the pigment were not consistent. A portion of it almost always showed the usual staining reactions of hemoglobin; namely, an affinity for eosin and for the fuchsin in the Masson trichrome, a dense blue color with phosphotungstic acid hematoxylin, and a positive benzidine reaction. Another portion of the pigment, indistinguishable in the unstained or eosin-stained preparations, failed to accept the fuchsin in the Masson or the hematoxylin in the phosphotungstic stain, and was benzidine-negative. Characteristic staining reactions with hematoxylin and eosin, phosphotungstic acid hematoxylin, and Masson trichrome are illustrated in Figures 1, 2, and 3.

Although there were some exceptions, two generalizations could be made regarding the staining reactions of the pigment: First, the shorter the time interval between injury and death, the greater was the proportion of pigment which gave the staining reactions of hemoglobin. Second, the farther down the nephron the pigment was located, the less was this tendency. Figures 4 and 5 illustrate this difference in the pigment casts of the cortex and medulla. The obvious conclusion is that with the passage of time and with the chemical changes in the glomerular filtrate as it passed along the tubule, the original hemoglobin-like material was altered, presumably by a process of degradation in the direction of acid hematin. This degradation never reached the point where iron could be demonstrated with the ferrocyanide reaction. One other differential point has been noted: The hemoglobin-like pigment rarely excited a significant inflammatory reaction, whereas the altered pigment sometimes attracted leukocytes in considerable number (Fig. 6).

Internal Hydronephrosis

Many authors have described marked dilatation of portions of the nephron above the obstructing pigment casts. Their illustrations often show great dilatation of proximal tubules and of Bowman's capsule. Our experience suggests that this apparent dilatation is largely a shrinkage artefact. If formalin-fixed kidney tissue is rapidly dehydrated and embedded in paraffin, shrinkage is


difficult to avoid. The glomeruli appear as tiny spheres occupying less than half of the capsular space, and the diameter of the lumen of the proximal tubules is from 50 to 70 percent of the external diameter of the tubule. If the tissue is Zenkerized before embedding, the shrinkage is reduced and primary embedding in Zenker-formol or in Zenker with acetic acid lessens it still further. In such sections Bowman's capsule is rarely dilated, although some dilatation of tubules may be apparent. A still better check upon this debatable issue is provided by the examination of frozen sections in which the factor of dehydration is excluded.

The following statements are based primarily upon the examination of frozen sections which were prepared from almost every case in this series. No dilatation of Bowman's capsule was observed, but tubular dilatation of moderate but unmistakable degree was usual, with the proximal convoluted tubule the segment most commonly involved. Dilatation was not observed before the third day after injury, was almost constant between the third and fifth days, and became less frequent in the cases with longer periods of survival. Dilatation of distal convoluted tubules and upper collecting tubules, usually those situated in the cortical rays, was less common and was ordinarily seen in the more chronic stages from the sixth day onward. In some cases, however, dilatation was marked in these segments and minimal or absent in the proximal tubules (Figs. 7 and 8).

Dilatation of proximal tubules, to judge from frozen sections, correlated well with two characteristic phenomena noted on gross examination: enlargement of the kidney, particularly widening of the cortex, and a wet surface wherever freshly cut.

Degeneration and Regeneration of Tubular Epithelium

Degenerative changes in the epithelial cells were rare in the proximal tubules, absent in the descending limb of Henle's loop, usual in the ascending limb and the distal convoluted tubule, and inconstant in the collecting tubules. The proximal tubule was usually normal except for slight to moderate dilatation. The brush border was well maintained, the cells were not swollen, and the cytoplasmic granules were normal in size and distribution. The tubular lumens frequently contained granular nonpigmented precipitate, but this is not surprising in view of the constant albuminuria demonstrable in patients with severe trauma and constitutes no proof of tubular injury.

In only five cases were the proximal tubules clearly abnormal. In two there



FIGURE 1. Stain: Hematoxylin and eosin. The glomerulus is normal. The distal convoluted tubules contain orange
colored casts of precipitated hemoglobin. X 200

FIGURE 2. Stain: Masson trichrome. The casts stain deep red as do red cells with this stain.

FIGURE 3. Stain: Phosphotungstic acid hematoxylin. The deep blue staining of the pigment casts is characteristic of the
reactions of hemoglobin with this stain. The proximal convoluted tubules are dilated and contain precipitated albumin,
but the epithelial cells show no degenerative changes.



FIGURE 4. Stain: Phosphotungstic acid hematoxylin. Renal cortex, low magnification, showing blue-staining casts in the distal convoluted tubules. The proximal tubules are uniformly slightly dilated and contain precipitated albumin but they are otherwise normal. X 80

FIGURE 5. Stain: Phosphotungstic acid hematoxylin. Section from the kidney pyramid of the case shown in Figure 4. This patient died 3 days after injury. A considerable proportion of the pigment casts have lost their ability to stain blue with the phosphotungstic acid stain. X 80

FIGURE 6. Stain: Masson trichrome. Note the acute exudation into the distal tubules about the masses of pigment which have begun to lose their hemoglobin-like staining reactions.


was extensive fat vacuolation; in the two others the cells were swollen, the brush border was obscured, and the cytoplasm filled with hyaline, presumably albuminous droplets. Nothing in the clinical picture served to distinguish these cases from others of the series. The infrequency of albuminous droplets in the cells of the proximal tubules under conditions of marked albuminuria might be interpreted as evidence of failure of resorptive function in this segment of the nephron. Such functional paralysis would also explain the surprising fact that only once in 200 hemoglobinuric cases was absorption of hemoglobin by the proximal tubules observed. In one instance (Case 86) there were numerous foci of complete coagulative necrosis of proximal tubular epithelium. The possibility of direct traumatic injury of the kidneys could not be excluded here.

The descending limbs of Henle's loops frequently contained considerable amounts of orange pigment, which was not iron-positive with ferrocyanide but accepted the fuchsin counterstain as does so-called hemofuchsin. It was sometimes weakly sudanophilic, and because of its orange-yellow color was difficult to distinguish from fat in Sudan preparations. Since this pigment was also frequently found in cases of sudden death used as controls, we believe it to be a normal phenomenon.

The earliest and most frequent evidence of tubular degeneration appeared in the form of fat vacuolation in the ascending limbs of Henle's loops. The vacuoles were extremely small, mostly from 1 to 2 microns; were hard to identify in paraffin sections; were intensely red in frozen sections stained with Sudan IV; and were not doubly refractile under polarized light. In some cases they were found only in a limited segment of the ascending limb, always the portion closest to the corticomedullary junction; in others the process extended almost to the apex of the pyramid, involving the entire ascending limb (Figs. 9 and 10). A rough quantitation of the severity of this change was attempted by visual estimation, using a 1- to 4-plus scale.

Well-marked (2- to 4-plus) fat vacuolation was present in 6 of 8 cases in this study in which death followed injury by less than 48 hours, including Case 77 with a survival period of only 20 hours. It was present, usually in 3- or 4-plus grade, in 14 of the 15 cases in which death occurred between the second and fourth days. From the fifth day onward it decreased in frequency and intensity; it was found in only 14 of the 27 cases and in only 1 was it above 2-plus grade. A more extensive discussion of this process will be found in Chapter XII in connection with similar observations on other organs.



FIGURE 7. (Left) Moderate dilatation of both proximal and distal convoluted tubules is shown in a case of 6 days' duration.
A rare sulfonamide crystal is present. Stain: Hematoxylin and eosin.

FIGURE 8. (Right) Marked dilatation of the distal convoluted tubules with comparatively slight widening of the proximal
ones is apparent. Stain: Hematoxylin and eosin.


FIGURE 9. (Left) Stain: Sudan IV. Fat vacuolation limited to a segment of the ascending limb adjacent to the corticomedullary junction.

FIGURE 10. (Right) Stain: Sudan IV. Diffuse fat vacuolation of entire ascending limb of Henle's loop.


Occasionally on the third or fourth day, but always by the fifth, other forms of epithelial reaction were obvious. The cells became shrunken, their nuclei pyknotic, and they frequently lost their attachment to the basement membrane and desquamated. At almost the same period, mitoses became apparent and sometimes so numerous that two or three were seen in a single cross-section of a tubule. These degenerative and regenerative changes were frequently limited to, and always most severe in a comparatively limited zone close to the corticomedullary junction.

Distal Convoluted Tubules.-The distal convoluted tubules in apparently normal individuals frequently contain small granules of lipid. In some cases of shock it was evident that the sudanophilic material was increased in amount, but variation in the normal range makes the significance of this observation very difficult to assess. By the fourth or fifth day after injury, degenerative and regenerative changes sometimes became apparent in the distal tubule. They were never as marked or as widespread as in the ascending limbs, but the difference was quantitative, not qualitative.

Collecting Tubules.-Alterations in the character of the epithelium of the collecting tubules are difficult to recognize with certainty, since these tubules are particularly susceptible to postmortem degeneration, including desquamation. Fat stains do not help, since lipoid degeneration rarely occurs. In well-fixed material, however, it was often evident that the cells were hyperchromatic. Frank necrosis was rarely seen, yet mitoses were not infrequent. In other cases reduplication of the epithelial layer was evident and sometimes, where no desquamation was apparent, sheets of epithelial cells filled the lumina of the tubules and encircled or even invaded the pigment casts. Sometimes mitoses were numerous in these detached or semidetached cells. In the collecting tubules, in contrast to other segments of the nephron, the epithelial changes closely paralelled the presence of pigment casts in the affected segments.

Interstitial Inflammation

Interstitial inflammation was not noted before the third day; from the third to the fourth day it was found in half the cases, and from the fifth day onward it was a constant phenomenon. It was first manifested as focal infiltration limited to a fairly narrow zone at the corticomedullary junction. The component cells were predominantly lymphocytes and plasma cells, but variable proportions of neutrophils and eosinophils were usually mingled with them (Fig. 11). The



FIGURE 11. Interstitial inflammatory infiltrate between tubules near the corticomedullary junction in case of 8 days' duration. Lymphocytes and plasma cells predominate. Stain: Hematoxylin and eosin.

FIGURE 12. Stain: Masson trichrome. Low-power view of corticomedullary junction, showing interstitial edema of moderate grade and both diffuse and granulomatous inflammatory reaction. Some extruded casts are visible. Case of 8 days' duration.

FIGURE 13. Case of 12 days' duration. The formation of a second zone of interstitial inflammatory reaction beneath the capsule is shown. Stain: Masson trichrome.



FIGURE 14. Stain: Hematoxylin and eosin. A nonpigmented cast found in the process of extrusion from a ruptured tubule. The cells of the tubule show pyknosis and reduplication of nuclei.

infiltrate tended to be most marked in the neighborhood of the blood vessels and also to run in strands between the straight tubules. Edema, though usually present, was rarely a conspicuous feature (Fig. 12). As days passed, the zone of inflammatory infiltration widened and new foci appeared both in the cortex and the medulla. In the former, they tended to be concentrated about the distal convoluted tubules. In a few of the most severe lesions, a clearly-defined second zone of inflammatory infiltration was noted in the outer millimeter of the cortex beneath the capsule (Fig. 13).

Tubular Rupture

The distinctive phenomenon of tubular rupture was generally apparent in any well-developed lesion from the fifth day onward. It was usually associated with the presence of hyaline, non-pigmented casts in the affected segment, which was most commonly the ascending limb but sometimes the distal convoluted tubule. These casts were chromophobic with hematoxylin and eosin or phosphotungstic acid hematoxylin, but stained a fairly bright green in the Masson trichrome. In the affected segments containing the casts, portions of the epithelial lining and of the underlying basement membrane disappeared


without trace as if by solution. The casts at this point were frequently seen half within the tubular remnant and half extruded into the stroma (Fig. 14).

Interstitial Granulomas

In the process of tubular rupture and cast extrusion, the advancing margin of the cast abutting on the stromal cells was quickly surrounded by histiocytes. With further extrusion or with complete destruction of the tubular segment, the cast became completely surrounded by histiocytes which occasionally but rarely fused to form giant cells (Figs. 15 and 16). The histiocytes soon invaded the cast and appeared to break it up into comparatively small fragments. It was possible to observe all stages from the original encapsulation to complete disintegration, leaving a focal aggregate of histiocytes with no trace of the original cast material (Fig. 17).

Although this process unquestionably accounts for many, perhaps for most, of the granulomatous lesions found in these kidneys, the evidence is inadequate to prove that it was the only mechanism for their formation. Granulomas were frequently found in the walls of veins and occasionally in the capsule of the kidney, separated from the nearest tubule by apparently intact fibrous tissue of considerable density. Some of these lesions were quite similar in appearance to the Aschoff bodies of rheumatic fever.

Hyaline masses, indistinguishable from the intratubular casts by any staining method tried, were also occasionally found in the walls of veins, even jutting into the lumen to become the basis for thrombus formation (Fig. 18). The question whether these represent extruded casts which have wandered surprisingly from their original location or which have developed in situ in some entirely different manner cannot be answered at present. It is of interest that on only one occasion in over 200 cases studied did the author note extrusion of a pigment cast and consequent granuloma formation.


In a considerable proportion of cases of 5 or more days' duration, thrombi were readily found in the large but thin-walled veins of the corticomedullary junction. These thrombi were attached to a portion of the vein wall and they jutted into and narrowed but almost never occluded the lumen. Beneath some points of attachment a mass of hyaline material as described in the preceding



FIGURE 15. (Left) A granulomatous reaction is developing around several extruded casts. Stain: Masson trichrome.

FIGURE 16. (Right) Beginning collection of histiocytes about an extruded hyaline cast and invasion of the cast by the same cells. The adjacent tubule shows a mitotic figure. Stain: Phosphotungstic acid hematoxylin.

FIGURE 17. (Left) Severe granulomatous inflammatory reaction between the straight tubules. No trace of an extruded cast persists. Stain: Masson trichrome.

FIGURE 18. (Right) Stain: Masson trichrome. Wall of a vein showing a hyaline mass resembling an extruded cast projecting into the lumen with a surrounding granulomatous reaction.


paragraph was found; beneath others were well-developed granulomas with or without traces of hyaline material. The vein walls were frequently invaded by lymphocytes, polymorphonuclear leukocytes, or eosinophils, apparently extending from focal concentrations of the interstitial infiltrate, such concentrations being characteristically clustered about these veins.

Summary of Histologic Findings in Chronologic Sequence

The earliest change noted in the "shock kidney" was lipoid degeneration of the ascending limbs of the loops of Henle, which usually made its appearance about 18 hours after injury, progressed in severity until the third day, then tended to wane. Precipitation of the hemoglobin-like pigment in the distal convoluted and collecting tubules was infrequently observed short of 24 hours and was inconstant before 48 hours. The pigment at first stained like hemoglobin but later lost this characteristic. Moderate dilatation of the proximal convoluted tubules was evident following the development of pigment casts.

By the third and fourth days, an interstitial inflammatory infiltrate and frank necrobiotic changes in the cells of the ascending limbs were occasionally seen, and from the fifth day onward both of these findings were constant. Rarely on the third or fourth day, but usually by the fifth, tubular rupture with extrusion of nonpigmented casts was apparent, and coincidentally stromal granulomas were found in moderate numbers. From the fifth day onward, thrombophlebitis of the small veins was found in an increasing proportion of the cases.

Gross Pathology

The kidney might or might not show gross abnormalities (Figs. 19, 20, 21, and 22). Enlargement was noted as early as the second day but was not usual before the fourth. It tended to become more frequent and more extensive with duration of the lesion; the largest pair of kidneys observed, 625 grams, was found in Case 93 with the unusual survival period of 13 days. In patients with from 7- to 10-day survival periods, kidneys weighing up to 500 grams were usual (Figs. 20 and 21).

Enlarged kidneys were almost without exception pale, whereas kidneys of normal size, regardless of duration of the lesion, were usually congested. On section it became apparent that the enlargement was chiefly due to swelling



FIGURE 19. Kidney from Case 70. Death from crush syndrome 4 days after injury. The pyramids are dark in color, resembling mahogany. The kidney is normal in size and not swollen.

FIGURE 20. Kidney from Case 69. Death from crush syndrome 10 days after injury. The organ is markedly swollen. The pallor of the cortex is in striking contrast to the still dark pyramids. Fine hemorrhages are apparent beneath the mucosa of the renal pelvis.


FIGURE 21. (Left) Kidney from Case 47. The patient died of pigment nephropathy 8 days after wounding. The pallor of the organ is slightly exaggerated by the fixation. The cortex is swollen and the pyramids are almost chocolate in shade.

FIGURE 22. (Right) Left kidney from case of mismatched transfusion (Case 9). Gross appearance is identical with that of Case 47 except for size. The enlargement of this left kidney was partly due to a congenital hypoplasia of its mate.

of the cortex, which would measure from 9 to 12 microns in thickness. The corticomedullary junction was unusually sharp, since the cortex was pale and the pyramids either unchanged or darker than normal. A zone of intense congestion sometimes further intensified the distinction. A constant finding was the unusual wetness of the freshly cut cortical surface.

Petechial hemorrhages beneath the pelvic mucosa were the only other gross manifestation which was at all frequent (Fig. 20). They were commonest in cases of long duration with high grades of azotemia and are reminiscent of similar hemorrhagic changes in advanced "decompensated" nephrosclerosis with renal insufficiency. They may be merely a phenomenon of the uremic state.




Two factors which are evidently of outstanding importance in the development of the renal lesion may appear in severely traumatized persons. One is pigment excretion in the urine and the other is the physiologic state known as shock. A survey of the first hundred cases of pigment nephropathy studied at the 15th Medical General Laboratory provided interesting figures regarding the relative frequency of the lesion in different types of Army hospitals. In base hospitals (station and general hospitals), nephropathy was found in only 6 percent of the necropsies, in evacuation hospitals the percentage rose to 18, and in the field hospitals (to which only the most severely wounded, nontransportable cases were admitted) to 30 percent. Clearly pigment nephropathy occurred in direct relation to severity of injury and, by implication, to the profundity of shock.

The cases studied by the Board offer more direct evidence. Whenever possible, a clinician who was a member of the Board made the examination and recorded his impression regarding the presence and severity of shock. When shock was recognized, it was classified as slight, moderate, or severe. In 183 cases so classified pigment nephrosis was proved at necropsy in thirty-seven. (There were actually 38 proved cases in the Board's entire series, but 1 had not been classified as to degree of shock.) Their distribution in the various shock categories is shown in Table 92.

The decreasing frequency of renal involvement from those with marked shock to those with lesser degrees of shock is apparent, but the six patients



who were not considered to be in shock confuse the picture. This group, which consists of Cases 9, 22, 69, 70, 120, and 132, is therefore considered in detail.

"No Shock" Group.-Case 9 is an example of a frank transfusion accident. Between 100 and 125 cc. of group A blood had been given in error to a group O recipient before a characteristic reaction developed and the transfusion was interrupted. Hemoglobinemia and hemoglobinuria were demonstrated. This case belongs in a different category and requires no further consideration.

The patient in Case 22 did not present evidence of shock at the time of entry to the hospital 3 hours after wounding, or at any subsequent period of observation. He belonged to blood group A and received 2 units of blood, presumably group A, not from the theater blood bank and not checked by any member of the Board. There was no clinical evidence of reaction to these transfusions which were given on the fourth day of disease, only 2 days before his death. On the following day the nonprotein nitrogen level in the plasma was 294 mg. per 100 cc., so the renal lesion must have antedated these transfusions. The three early transfusions on the day of wounding were of the usual theater bank blood and were given without incident. The Rh reaction of the patient was not determined. No etiology for a hemolytic reaction was discovered, yet large amounts of free hemoglobin, 193 mg. per 100 cc., were found in the bladder urine at the time of necropsy.

Cases 69, 70, and 132 are examples of the crush syndrome with severe grades of myoglobinuria. Judged by the usual clinical criteria--blood pressure, pulse, pallor, coldness of extremities, anxiety--these patients did not impress the examiner as being in shock. Each of them, however, clearly exhibited one phenomenon which is emphasized by many students of shock: hemoconcentration, as shown by hematocrit values of 71, 80, and 57, respectively. If shock itself was not present, there is no doubt that a closely allied physiologic abnormality was.

In Case 120 the patient was wounded in the right thigh by a shell fragment which completely transected the femoral artery, vein, and nerve. Hemorrhage was severe and he was given 1,000 cc. of plasma en route to the hospital. On arrival he seemed in good condition and was operated upon without further preparation, but 1,500 cc. of whole blood were given during the operation. Immediately after operation the blood pressure was 110 mm. Hg systolic and 62 diastolic, but 7 hours later it dropped to 70/40 and throughout the day the systolic level ranged between 60 and 70 millimeters of mercury. Nevertheless the patient's color was good and his skin remained warm. The pathologist has


the temerity to suggest that in consideration of this case also shock can scarcely be excluded.

Pigment Excretion

In Chapter IV it was shown that all patients with clinical evidence of renal involvement following traumatic injury excreted benzidine-positive pigment in the urine, although the amounts varied widely. In excellent correlation with this observation is the histologic evidence of pigment precipitation in the lower nephron segments of all patients with fatal nephropathy. These related phenomena deserve further consideration.

The Nature of the Pigment

Numerous clinical studies9 10 11 have established the two pigments found in the urine as hemoglobin and the closely related myoglobin. In histologic sections they react identically with all methods employed (the benzidine reaction, hematoxylin and eosin, Masson's trichrome and Mallory's phosphotungstic acid hematoxylin stains). It has generally been considered a safe inference that the pigment casts found in the tubules were precipitates of the same material spectroscopically identified in its soluble form in the urine, though the possibility that they might be oxidized or otherwise chemically altered forms could not be excluded. Harrison et al.12 provided spectroscopic proof that in the lesions produced in dogs by arsine hemolysis the casts consisted predominantly of methemoglobin. No pigments such as hemochromagen or hematin which would be insoluble at the pH of urine were formed.

Efforts to identify myoglobin by chemical means in the kidneys of patients who died of the crush syndrome were disappointingly unsuccessful. (See Ap-

    9BYWATERS, E. G. L.; DELORY, G. E.; RIMINGTON, C., and SMILES, J.: Myohaemoglobin in urine of air raid casualties with crushing injury. Biochem. J. 35: 1164-1168, November 1941.
    10MAEGRAITH, B. G.; HAVARD, R. E., and PARSONS, D. S.: Renal syndrome of wide distribution induced possibly by renal anoxia. Lancet 2: 293-296, September 8, 1945.
    11MINAMI, S.: Über Nierenveränderungen nach Verschüttung. Virchow's Arch. f. path. Anat. 245: 246-267, 1923.
    12HARRISON, H. E.; BUNTING, H.; ORDWAY, N. K., and ALBRINK, W. S.: The pathogenesis of renal injury produced in the dog by hemoglobin or methemoglobin. J. Exp. Med. 86: 339-356, October 1947.


pendix C for the method used.) The data are presented in the following tabulation.

Extraction of Myoglobin from Kidneys 

Type of case

Case No.

Gm. of myoglobin per Kg. of tissue

Control (sudden death)



Shock, no pigment casts



Shock, pigment nephropathy



Crush syndrome



It is obvious that the kidneys in the crush cases, which one might reasonably expect to be loaded with myoglobin, did not show significantly more than those in cases of sudden death selected as controls; actually they contained considerably less myoglobin than did the kidneys in shock cases with or without nephropathy in which the urine never contained myoglobin. It seems probable that this failure to recover myoglobin correlates with the fairly rapid alteration in the staining reactions of the pigment in the lower nephron segments already described and may be attributed to a chemical degradation. Under field conditions it was impractical to attempt further identification of these products.

Acidity of the Urine and Precipitation of Pigment in the Tubules

One widely accepted explanation of the development of a pigment nephropathy is that the pigment is precipitated from solution when the glomerular filtrate becomes acid in reaction upon reaching the distal convoluted tubule. It is of interest to compare the acidity of the initial pigment-containing urines from patients in whom nephropathy was proved with those from patients with no evidence of a renal lesion other than pigment excretion. A control group in which the urine was consistently free from benzidine-positive material is also compared in Table 93 with the two pigment-containing groups.


The ranges overlap widely, and the differences in the means are slight and not significant. Acidity of the urine can be eliminated as the determining factor in precipitation of pigment in the lower nephron. With acidity eliminated, we are left without explanation for the phenomenon of pigment precipitation. Presumably it is due to some change in renal physiology, particularly prone to occur in, but not limited to shock. Possibly it is nothing more remarkable than stagnation of the glomerular filtrate secondary to the renal ischemia which is known to be present. Possibly it is due to increased concentration of some unknown, perhaps abnormal, metabolic product as suggested by Oliver.13

One is tempted to speculate upon the possibility of a reciprocal relationship between the degree of shock and pigment concentration in relation to nephropathy: When pigment excretion is great, as in the crush syndrome, some burns, and transfusion accidents, little or no shock is necessary; when shock is severe and prolonged, minimal pigment excretion may be required. Many of our data would appear to support this concept, but the exceptions are too numerous and striking to permit such a conclusion.

Clinicopathologic Correlation

Any attempt to correlate form and function in the kidney is hazardous in the extreme, but its fascination is irresistible. The first effect of shock upon the function of the kidney is oliguria, followed quickly by retention of metabolic products which are both nitrogenous, such as urea and creatinine, and inor-

    13OLIVER, J.: New directions in renal morphology; method, its results and its future. Harvey Lect. (1944-1945) 40: 102-155, 1945.


ganic, such as phosphates. Both of these effects were manifested within a few hours of the onset of shock, whereas the first recognizable morphologic change, the appearance of lipoid vacuoles in the ascending loops, developed about 18 hours after onset, and pigment casts appeared still later. The initial renal insufficiency is, therefore, functional rather than structural in basis. The studies of Cournand and his associates14 have established the early onset of renal ischemia in shock and adequately explain the initial functional changes.

Ischemia with consequent anoxemia also serves as a logical explanation of the appearance of demonstrable lipid in the parenchymal cells. As will be shown in Chapter XII, a similar phenomenon in shock was found in the liver, the heart, and other organs in which the relationship of fatty degeneration to anoxemia has received more attention. Further knowledge of renal circulation and of the relative susceptibility of various portions of the nephron to anoxemia is necessary to an understanding of the localization of the changes. The hypothesis of Trueta et al.15 that blood is shunted from the cortex into the vasa recta of the pyramids is not a satisfactory explanation, since the degenerative changes were maximal in the very areas which, according to his theory, receive the largest quantities of blood.

The lipoid vacuolation became more intense on the second and third days after the onset of shock. This, however, cannot be interpreted as evidence that the initial causative factor necessarily persisted. A form of "chain reaction" which required time for its complete development may have been inaugurated by the initial insult.

An interesting feature of the development of the "shock kidney" is the apparent delay in the appearance of the pigmented casts. Pigment casts were present in significant numbers in only two of the nine Board cases in which death occurred within 48 hours of injury. Even in Cases 32 and 34, in which death occurred between the second and third days, only traces of pigment could be found. It is obvious from examination of the histories of this group that none of them, with the possible exception of one (Case 34), was ever adequately resuscitated from shock. In the case records of scores of other fatal shock cases

    14COURNAND, A.; RILEY, R. L.; BRADLEY, S. E.; BREED, E. S.; NOBLE, R. P.; LAUSON, H. D.; GREGERSEN, M. I., and RICHARDS, D. W.: Studies of the circulation in clinical shock. Surgery 13: 964-995, June 1943.
    15TRUETA, J.; BARCLAY, A. E.; DANIEL, P.; FRANKLIN, K. J., and PRICHARD, M. M. L.: Renal pathology in the light of recent neurovascular studies. [Preliminary communication.] Lancet 2: 237-238, August 17, 1946.


reviewed in the Pathology Section of the 15th Medical Laboratory as controls, unless there had been a transfusion accident, pigment casts were seldom recorded when death had occurred short of 24 hours, although in one burn case they were numerous at 14 hours. They were not seen with any regularity until from 36 to 48 hours had elapsed since injury.

A simple explanation for this phenomenon which invokes no new mechanism would be the suppression of glomerular filtration during shock, either because of the depressed systemic blood pressure or because of specific renal ischemia. The presence of pigment casts, therefore, may logically be considered histologic evidence of glomerular function, either continued or at least temporarily resumed.

Functional Significance of the Pigment Casts

Although it is certain that the pigment casts play no role in the initiation of renal insufficiency following shock, no such dogmatism is possible in defining their possible effect in the later stages of the lesion. Controversy has hinged on the thesis that the casts cause suppression of urine primarily by mechanical blockage of the tubules. The morphologic evidence for this is inconclusive. It is suggested by the high proportion of apparently blocked tubules in many cases and by the dilatation of portions of the nephron proximal to the cast. In our cases dilatation of moderate degree was a fairly constant phenomenon from the third day onward. It was not seen in the absence of casts, and the possibility of a mechanical block cannot be denied. The number of pigmented casts varied widely from case to case, but their number was difficult to estimate in routine sections and we did not use serial sections or microdissection to confirm our impressions of the proportion of occluded nephrons. It is doubtful that they were numerous enough to explain the almost complete urinary suppression in certain cases. Experimental evidence that the glomeruli of nephrons whose tubules are plugged with pigmented casts are nonfunctional was provided by Harrison et al.16 in the study on dogs previously cited.

It is interesting that in other forms of renal disease, chronic glomerular nephritis and lipoid nephrosis for instance, casts form in the nephrons but are readily swept in great numbers into the urine. In pigment nephropathy, al-

    16See footnote 12.


though casts may regularly be found in the sediment, it is rare that large numbers of them are passed.

Tubular Degeneration

The initial evidence of tubular degeneration has invariably been fat vacuoles in the ascending limbs of Henle's loops and less regularly in the distal convoluted tubules. This change evidently antedated and was independent of pigment precipitation, since it was frequently seen in the absence of the latter. By the fourth and fifth days lipid tended to disappear from the tubules, but frank necrosis and regeneration of the epithelium became evident and affected the same segment of the nephron. These phenomena were never observed in the shock cases in the absence of pigment precipitation, although in sulfonamide injury to the kidney they were occasionally seen without pigment. Although the pigment deposit appears to be a sine qua non, the mechanism of its effect is obviously indirect, since the maximal degenerative change occurred at a higher level in the nephron than did the first pigment deposits. Degeneration was most pronounced in the ascending limbs, whereas pigment deposits began in the distal convoluted tubules.

The functional significance of this tubular degeneration is of interest. In lipoid nephrosis extensive tubular degeneration is associated with oliguria. It has been suggested that the injured tubular cells permit rediffusion of the glomerular filtrate back into the vascular system. In pigment nephropathy tubular degeneration was constant, and such a mechanism may be involved in this syndrome as well. One point of difference between the two syndromes should be noted, however, before accepting the hypothesis. In lipoid nephrosis the gravity of the urine is well maintained or even concentrated above usual limits. In pigment nephropathy fixation at a low level is almost constant. This could be readily explained by the theory of mechanical blockage, since only a few unobstructed nephrons can still function.

The focal rupture of tubules, so frequently noted from the fifth day onward, has, in the author's opinion, little functional significance. It is a late phenomenon, whereas the entire syndrome--oliguria, azotemia, pigment excretion, and hypertension, together with fixation of gravity--is established before it appears. Furthermore, if actual extravasation of glomerular filtrate occurred through these ruptures, it seems inevitable that interstitial edema would be a more conspicuous feature of the histologic process.



A clinicopathologic survey of necropsy findings in 60 severely wounded casualties provided 38 examples of lower nephron nephrosis in all stages of development. The initial change, appearing from 18 to 24 hours after injury, was found to be lipoid degeneration of a segment of the nephron, particularly the ascending limb of Henle's loop, less markedly the distal convoluted tubule. The second stage was the precipitation of pigment, either hemoglobin or myoglobin, in the distal convoluted and collecting tubules, seldom occurring short of 24 hours after injury, more commonly between 32 and 72 hours. Moderate dilatation of proximal and sometimes distal convoluted tubules followed pigment precipitation. Sometimes on the third, regularly on the fourth and fifth days, necrosis and regeneration of epithelium in the ascending limbs and distal tubules became evident, and simultaneously lymphocytes appeared between the tubules and about the vessels. From five days onward, rupture of tubules with herniation of their contents into the stroma and consequent granuloma formation became frequent. The last development in many cases was the formation of nonocclusive mural thrombi in many of the small, thin-walled veins.

In clinicopathologic correlation it was shown that two factors were constant in the nephropathy cases, inconstant in the remainder. These are (1) the excretion of benzidine-positive pigment in the urine, and (2) (with one apparent exception) a state of shock or, at least, a related physiologic abnormality.

Renal insufficiency was found to antedate all structural change, but was never progressive in the absence of a demonstrable pigment nephropathy. The effects of myoglobin and of hemoglobin precipitation upon the kidney were indistinguishable. Our evidence does not support the hypothesis that acidity of the urine is the factor responsible for pigment precipitation in the nephrons.

Although pigment precipitation is an essential factor in the development of the "shock kidney," the mechanism of its effect upon the kidney remains unexplained. The possibility that it is in part mechanical cannot be disregarded, but the complex chain of degenerative and inflammatory phenomena demands another explanation. Controlled experimentation will be necessary before many of these uncertainties can be resolved.

For Cases of Special Interest in this chapter, see page 282.