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A Fatal Human Case of Urolithiasis Medicamentosa Caused by Sulfadiazine
A FATAL HUMAN CASE OF UROLITHIASIS MEDICAMENTOSA CAUSED BY SULFADIAZINE ANTONIO ROTTINO
AND
OSWALD LA ROTONDA
From the Departments of Medicine and Pathology, St. Vincent's Hospital, New York, N. Y.
In 1941 Gross, Cooper and Hagan reported the occurrence of uroliths in mice fed sulfadiazine by mouth and suggested the possibility of the same occurring in man. It is our purpose to report what we believe is the first fatality of this complication in the human. CASE REPORT
A. M., an Italian male aged 53 years, was admitted to St. Vincent's Hospital January 15, 1942 acutely ill. In his past history it was revealed that he had had type 22 pneumonia 3 years before from which he recovered in 6 weeks. His present illness began on January 1 with a heavy cold, chills, fever, cough and pain in the right chest. On January 13, he felt particularly bad, coughing up bloody sputum, having 2 chills followed by high fever and marked weakness. The patient appeared very sick. He had dyspnea and cyanosis. Frank signs of consolidation were elicited in the right upper lobe. There were no other pertinent findings. A blood count done immediately revealed 17,000 white blood cells of which 80 per cent were polymorphonuclear leucocytes, 18 per cent lymphocytes and monocytes 2 per cent. A type 3 pneumococcus was demonstrated in the sputum. Believing the patient was suffering from pneumonia, immediately sulfadiazine therapy was instituted. An initial dose of 5 gm. was given, after which it was followed in amounts of 1 gm. every 4 hours. While there appeared to be some improvement in the condition of the patient it was not spectacular. During the first week the temperature fluctuated between 102° and 100°, the sputum was copious and bloody. For the next 7 days the temperature had dropped from 101 ° to 100°. Sulfadiazine was continued for 11 days, at the end of which a total of 61 gm. had been administered. A blood level of 20.7 and 23 mg. per cent of the drug was maintained. On the eighth hospital day he complained of dysuria. Urinalysis disclosed, microscopically, red blood cells, white blood cells and sulfadiazine crystals. On admission urine examination had been entirely negative. The same abnormal findings were present on the tenth and twelfth days. On the thirteenth day the blood urea determination revealed a total of 107 mg. per cent, blood creatinine 12 mg. per cent. Throughout, the patient maintained a urinary output between 700 and 800 cc, while the fluid intake was between 1500 and 2200 cc. On January 27 his abdomen became distended. The following day dyspnea and cyanosis developed. He lapsed into coma and died. Necropsy findings. Both kidneys were large, smooth, pale, weighing together 325 grams. On section, the cortex of each exhibited swelling, pallor and obscured markings. In sharp contrast, the pyramids stood out dark red with 310
FATAL HUMAN CASE OF L,ROLITHIASIS MEDICAMENTOSA
311
prorninent markings, converging towards the papillae. Many of the latter appeared flattened and covered with small, sharp, gritty brown-colored gravel-like material (fig. 1). The same depm,it was observed both in the pelvis and calyces and in the substance of the pyramids. Neither of the former 2 was dilated. Their mucosa, however, presented an intensely red appearance and contained small hemorrhages. The lumen of the right ureter close to its junction ,Yith the pelvis \YaB plugged for a distance of l cm. ,vith tightly packed gravel similar to that in the kidney. The same was seen in the terminal -! cm. of the left ureter (fig. 2). The ureteral mucosa throughout was intensely congested. There was no dilatation of the bladder. Except for edema and deep congestion uhout the left ureteral orifice the bladder mucosa ,ms pale.
Fm. 1. Close-up view of a pyramid with its papilla projecting into a non-dilated calyx filled "·ith crystalline matter. The same can be seen in tho substance of tlw pyramid.
The left lung vrns edematous and congested. In the right lung, upper lobe, were found extensive bronchiectasis and bronchiectatic abscesses measuring up to 2~3 cm. in diameter. Between them the lung parenchyma was stony hard, grey and fibrotic. There ,vas congestion and edema of the other lobes. The heart was generally hypertrophied, weighing 525 gm. There was no vakular disease. Except for moderate enlargement of the spleen, which weighed 325 gm., other organs were normal. ilficroscopic examination. Study of the kidney disclosed pronouncecl changc:cs in excretory and minor alterations in secretory tubules and glomeruli. l\Im,t excretory tubules ,vere dilated, some to such an extent that they herniated and ruptured through the perircnal capsule coycring the hilar surface of the kidney (fig. 3). "\Vithin their lumen one found a variety of substances; polymorphonuclear leucocytes, coagula and crystals. Polymorphonuclear leucocytes ,vcrc found in large numbers in some tuhule:-i. Crystals were best demonstrated in
312
ANTONIO ROTTINO AND OS\VALD LA ROTONDA
sections prepared by frozen section. They appeared large and fan-shaped (fig. 4). The solutions used in preparing tissue for paraffin sections caused the crystals to dissolve. In these sections, therefore, instead of crystals one found spaces surrounded by the following, alone or combined, lymphocytes, polymorphonu-
Frn. 2. Terminal portion of the left ureter and the bladder. the lumen.
K ote concretions filling
Frn. 3. Hematoxylin and Eosin stain showing a dilated excretory tubule, c, herniated into pcrircnal capsule, b. Note flattening of the tubular epithelium, ulceration at the point of herniation covered by coagulum, d. Adjacent tubules ate contain polymorphonuclear leucocytes.
clear leucocytes and a coagulum, homogeneous or fibrillated (fig. 5). Tubular epithelium varied in appearance, being uniformly swollen and darkly staining in some, flat in others and in still others swollen at one pole and flat at the other. The surfacr:s of some tubules were ulcerated and covered with an eosinophilic
FATAJ, Hl:MAN CASE OF UROLITHIASIS :VIEDICAMENTOSA
staining coagulum in which were variable numbers of lymphocytes, mononuclear cells and polymorphonuclear leucocytes (fig. 6). In many instances the ('Xudatc extended through and beyond tubules into adjoining interstitial tiRsue. At the hilar surface the same infiltration was observed proceeding from tubules into the perirenal capsule and neighboring peripelvic fat.
Fm. 4. High power frozen section showing a dilated excretory tubule containing a large: fan-shaped crystal having a scalloped surface.
Fm. 5. Dilated tubule containing in its center an oval, clear mass traversed by thin strands of an eosinophilic hemogeneous substance. The same was observed at its periphery. Such masses were interpreted as dissolved crystals. Surrounding it one finds a thick collar of lymphocytes and polymorphonuclcar leucocytes.
In convoluted ascending and descending tubules a few red and white cells were seen. An occasional Henle's loop contained large numbers of polymorphonuclear leucocytes. From some of these the cells infiltrated be?ond the confines of the epithelium into the interstitial tissue. Glomeruli were numerous and large. Many were ischaemic though their capillaries appeared widely dilated. Epithelial and endothelial cells :seemed well
314
ANTONIO ROTTINO AND OSWALD LA ROTONDA
preserved, Rwollen but not hyperplastic. An occaRional glomerular capillary ,vas adherent to Bowman's capsule. One glomerulus was found in which all cellR of Reveral capillaries appeared necrotic (fig. 7).
,A
FIG. 6. Showing a dilated tubule, one pole of which is ulcerated and covered with coagulum
FIG. 7. A localized interstitial lesion found in the cortex composed of lymphocytes and pale reticular cells. In the center is a peculiar giant cell.
Cellular infiltrations were observed both in the cortex and medulla. In the former region they were seen chiefly at the surface where they appeared as circumRcribed areas composed of lymphocytes bathed in edema fluid. Deeper in
FATAL HUMAN CASE OF 1:ROLITHIASIS MEDICAMEXTOSA
315
the cortex these cellular aggregations ,vere fewer in number and smaller in size. Some, in addition to lymphocyte,;, contained large, pale cells arranged in reticulum fashion. In one of these a giant cell was found (fig. 8). In none were there cry,;talR or spaces resembling crystals. Interstitial cellular infiltration was al,;o observed in the medulla. Here it waR not only circumscribed but also diffuse, spreading from ·within tubules into the surrounding tissue (fig. 3). In the diffusely spreading lesions, one found in addition to lymphocytes man:v polymorphonuclear leucocytes. Small fresh hemorrhages were seen scattered through the medulla. Ko bacteria ·were demonstrable with Gram and Gimsa stains. Sections from the peripelvic fat, calyces, pelvis and ureters revealed more or less the :canw picture. In the peripelvic fat there was lymphocytic and large round cell infiltration, most intense close to surfaces it covered. The walls of the calyces were swollen and much of the lining epithelium had desquamated. The remainder of the walls was edematom,, congested, hemorrhagic and infiltrated with numerous lymphocytes and some polymorphonuclear leucoc.vtes.
FIG. 8. Glomerulus, the central portion of which is necrotic
A similar picture was seen in the pelvis and ureters. The bladder wall and prostate were normal. l\1icroscopic findings in other organs ·were not particularly pertinent. The changeR seen in the lung confirmed the gross diagnosis. 2\/Iyofibrils were fragmented and hypertrophied. In the liver one saw mild fatty change and some periportal round cell infiltration. Sections of spleen, pancreas and esophagus ,vere normal. There waR some fibrosis of the testis. One kidney was studied chemically by Herman D. Ratisch. 1 The following is the report he wm-; kind enough to submit to us. "Considerable precipitate wa,.: found in the calyces, pale red in color, gritty in consistency. The color washed off in ,vater but the particles did not dissolve. The substance was negative for free sulfonamide with the Bratton-Marshall test but became strongly positive after hydrolyRis with 4 K HCl. A sample of the concretions was cleaned, dissolved in hot alcohol and recrystallized. The melting point of these proved to be 250.5-2,52°C. When mixed with sulfadiazine crystals the melting point fell to 1
Littauer Pneumonia Research Fund, New York l~niversity :\Iedical College.
316
AKTONIO RO'l"l'INO AND OSWALD LA RO'l'OKDA
220°C. The recrystallized particles were also tested for sulfonamide and were only positive after hydrolysis. A portion of the kidney was macerated and treated with trichloracetic acid. Qualitative test of this product revealed both free and conjugated sulfadiazine. The quantitative estimate was 27 mg. per cent free form, 123 mg. per cent acetyl sulfadiazine." Final diagnosis: Acetyl sulfadiazine urolithiasis and pyelonephritis of both kidneys, obstruction of both ureters, chronic bronchiectasis, multiple abscesses and fibrosis of the upper lobe of the right lung. COMMENT
The case is of intereRt Rince it illustrates a rare but fatal complication following the use of sulfadiazine. To our knowledge it is the first reported human case in which this complication has taken place. Death was due to uremia caused by intrarenal disease as well as bilateral blockage of the ureters by crystals. ]\,fore of the same were found deposited in the pelvis and calyces of each kidney. Significant was the observation of crystalline matter distending tubule8 and cauRing injury to their lining epithelium. Chemical analysis revealed that practically all the deposit was acetyl sulfadiazine. Unlike the soft, innocuous qualities of the free form of the drug, the acetylated crystals were firm, gritty, sharp and irritating. In addition to the physical presence of precipitated matter, there was present in each kidney a pyelonephritis. This raised the question of its etiology. Was it chemical, physical or of bacteriological causation? Sections stained for bacteria failed to show organisms. 2 Though it is not our primary intention to a8cribe the pyelonephritis to the drug, it is certainly more than probable that it caused injury to tubular epithelium and was then followed by the reactive phenomenon described. That a relationship exists between the tubular damage and some of the inflammatory reaction is supported by the finding of a unique histological picture. This consisted in swelling of some tubular epithelial cells, flattening of others, loss of cells with resulting ulceration, adhesion over such areas of a coagulum, infiltration, of the latter with cellular exudate and extension of this exudate through the tubule into the surrounding interstitium. Whether the entire reaction is due to the drug, in part to stagnant urinary products, undisclosed bacteria or their products are questions we can not answer. The same pertains to the more circumscribed granulomatous lesions in the cortex. The finding of a giant cell is interesting but its significance obscure. Injury to tubules and reactive phenomenon were noted by Gross, Cooper and Hagan in one-quarter of their mice fed sulfadiazine. Careful examination by them of areas adjacent to the crystalline masses failed to reveal evidence of inflammation. Their conclusion seems to be that the cellular infiltration denotes secondary infection. No bacteriological study is described to substantiate this. Climenko and Wright using monkeys and feeding them sulfapyridine and sulfathiazol noted that crystalline matter precipitated in excretory tubules when excessive amounts of drug were administered. Most interesting since it is re' Sections positive for bacteria were stained simultaneously for control.
FATAL HUCV!AN CASE OF l:ROLITHL\SIS i\IEDIC,UU<;NTOSA_
317
lated to the finding in our case was the observation of injury to tubular epithelium, ulceration and reaction by polymorphonuclear leucocytes. SUMMARY AND CONCLUSIONS
A report of a patient is presented -who died in memia during treatment for pneumonia with sulfadiazine. Crystalline matter was found in the calyces, pelvis and ureters, all of which were plugged by the drug. Crystals were likewiRc found in the renal parenchyma. Chemical analysis revealed that the crystalline matter was acetyl sulfadiazine. The damage to the renal parenchyma and the reaction thereto is described. It is believed that this injury is due to the crystals. REFERENCES CLIMN,;Ko, D.R., AND WRIGHT, A. W.: Effect of continued administration of sulfathiazole and sulfapyridinc in monkeys. Arch. Path., 32: 794, 1941. Gnoss, P., CooP1m, B. F., AND HAGAN, L. M.: l:"rolithiasis rneclicarnentosa caused by sulfacliazine. Arn . .J . Clin. Path., 11: 882, 1941.
AND
OSWALD LA ROTONDA
From the Departments of Medicine and Pathology, St. Vincent's Hospital, New York, N. Y.
In 1941 Gross, Cooper and Hagan reported the occurrence of uroliths in mice fed sulfadiazine by mouth and suggested the possibility of the same occurring in man. It is our purpose to report what we believe is the first fatality of this complication in the human. CASE REPORT
A. M., an Italian male aged 53 years, was admitted to St. Vincent's Hospital January 15, 1942 acutely ill. In his past history it was revealed that he had had type 22 pneumonia 3 years before from which he recovered in 6 weeks. His present illness began on January 1 with a heavy cold, chills, fever, cough and pain in the right chest. On January 13, he felt particularly bad, coughing up bloody sputum, having 2 chills followed by high fever and marked weakness. The patient appeared very sick. He had dyspnea and cyanosis. Frank signs of consolidation were elicited in the right upper lobe. There were no other pertinent findings. A blood count done immediately revealed 17,000 white blood cells of which 80 per cent were polymorphonuclear leucocytes, 18 per cent lymphocytes and monocytes 2 per cent. A type 3 pneumococcus was demonstrated in the sputum. Believing the patient was suffering from pneumonia, immediately sulfadiazine therapy was instituted. An initial dose of 5 gm. was given, after which it was followed in amounts of 1 gm. every 4 hours. While there appeared to be some improvement in the condition of the patient it was not spectacular. During the first week the temperature fluctuated between 102° and 100°, the sputum was copious and bloody. For the next 7 days the temperature had dropped from 101 ° to 100°. Sulfadiazine was continued for 11 days, at the end of which a total of 61 gm. had been administered. A blood level of 20.7 and 23 mg. per cent of the drug was maintained. On the eighth hospital day he complained of dysuria. Urinalysis disclosed, microscopically, red blood cells, white blood cells and sulfadiazine crystals. On admission urine examination had been entirely negative. The same abnormal findings were present on the tenth and twelfth days. On the thirteenth day the blood urea determination revealed a total of 107 mg. per cent, blood creatinine 12 mg. per cent. Throughout, the patient maintained a urinary output between 700 and 800 cc, while the fluid intake was between 1500 and 2200 cc. On January 27 his abdomen became distended. The following day dyspnea and cyanosis developed. He lapsed into coma and died. Necropsy findings. Both kidneys were large, smooth, pale, weighing together 325 grams. On section, the cortex of each exhibited swelling, pallor and obscured markings. In sharp contrast, the pyramids stood out dark red with 310
FATAL HUMAN CASE OF L,ROLITHIASIS MEDICAMENTOSA
311
prorninent markings, converging towards the papillae. Many of the latter appeared flattened and covered with small, sharp, gritty brown-colored gravel-like material (fig. 1). The same depm,it was observed both in the pelvis and calyces and in the substance of the pyramids. Neither of the former 2 was dilated. Their mucosa, however, presented an intensely red appearance and contained small hemorrhages. The lumen of the right ureter close to its junction ,Yith the pelvis \YaB plugged for a distance of l cm. ,vith tightly packed gravel similar to that in the kidney. The same was seen in the terminal -! cm. of the left ureter (fig. 2). The ureteral mucosa throughout was intensely congested. There was no dilatation of the bladder. Except for edema and deep congestion uhout the left ureteral orifice the bladder mucosa ,ms pale.
Fm. 1. Close-up view of a pyramid with its papilla projecting into a non-dilated calyx filled "·ith crystalline matter. The same can be seen in tho substance of tlw pyramid.
The left lung vrns edematous and congested. In the right lung, upper lobe, were found extensive bronchiectasis and bronchiectatic abscesses measuring up to 2~3 cm. in diameter. Between them the lung parenchyma was stony hard, grey and fibrotic. There ,vas congestion and edema of the other lobes. The heart was generally hypertrophied, weighing 525 gm. There was no vakular disease. Except for moderate enlargement of the spleen, which weighed 325 gm., other organs were normal. ilficroscopic examination. Study of the kidney disclosed pronouncecl changc:cs in excretory and minor alterations in secretory tubules and glomeruli. l\Im,t excretory tubules ,vere dilated, some to such an extent that they herniated and ruptured through the perircnal capsule coycring the hilar surface of the kidney (fig. 3). "\Vithin their lumen one found a variety of substances; polymorphonuclear leucocytes, coagula and crystals. Polymorphonuclear leucocytes ,vcrc found in large numbers in some tuhule:-i. Crystals were best demonstrated in
312
ANTONIO ROTTINO AND OS\VALD LA ROTONDA
sections prepared by frozen section. They appeared large and fan-shaped (fig. 4). The solutions used in preparing tissue for paraffin sections caused the crystals to dissolve. In these sections, therefore, instead of crystals one found spaces surrounded by the following, alone or combined, lymphocytes, polymorphonu-
Frn. 2. Terminal portion of the left ureter and the bladder. the lumen.
K ote concretions filling
Frn. 3. Hematoxylin and Eosin stain showing a dilated excretory tubule, c, herniated into pcrircnal capsule, b. Note flattening of the tubular epithelium, ulceration at the point of herniation covered by coagulum, d. Adjacent tubules ate contain polymorphonuclear leucocytes.
clear leucocytes and a coagulum, homogeneous or fibrillated (fig. 5). Tubular epithelium varied in appearance, being uniformly swollen and darkly staining in some, flat in others and in still others swollen at one pole and flat at the other. The surfacr:s of some tubules were ulcerated and covered with an eosinophilic
FATAJ, Hl:MAN CASE OF UROLITHIASIS :VIEDICAMENTOSA
staining coagulum in which were variable numbers of lymphocytes, mononuclear cells and polymorphonuclear leucocytes (fig. 6). In many instances the ('Xudatc extended through and beyond tubules into adjoining interstitial tiRsue. At the hilar surface the same infiltration was observed proceeding from tubules into the perirenal capsule and neighboring peripelvic fat.
Fm. 4. High power frozen section showing a dilated excretory tubule containing a large: fan-shaped crystal having a scalloped surface.
Fm. 5. Dilated tubule containing in its center an oval, clear mass traversed by thin strands of an eosinophilic hemogeneous substance. The same was observed at its periphery. Such masses were interpreted as dissolved crystals. Surrounding it one finds a thick collar of lymphocytes and polymorphonuclcar leucocytes.
In convoluted ascending and descending tubules a few red and white cells were seen. An occasional Henle's loop contained large numbers of polymorphonuclear leucocytes. From some of these the cells infiltrated be?ond the confines of the epithelium into the interstitial tissue. Glomeruli were numerous and large. Many were ischaemic though their capillaries appeared widely dilated. Epithelial and endothelial cells :seemed well
314
ANTONIO ROTTINO AND OSWALD LA ROTONDA
preserved, Rwollen but not hyperplastic. An occaRional glomerular capillary ,vas adherent to Bowman's capsule. One glomerulus was found in which all cellR of Reveral capillaries appeared necrotic (fig. 7).
,A
FIG. 6. Showing a dilated tubule, one pole of which is ulcerated and covered with coagulum
FIG. 7. A localized interstitial lesion found in the cortex composed of lymphocytes and pale reticular cells. In the center is a peculiar giant cell.
Cellular infiltrations were observed both in the cortex and medulla. In the former region they were seen chiefly at the surface where they appeared as circumRcribed areas composed of lymphocytes bathed in edema fluid. Deeper in
FATAL HUMAN CASE OF 1:ROLITHIASIS MEDICAMEXTOSA
315
the cortex these cellular aggregations ,vere fewer in number and smaller in size. Some, in addition to lymphocyte,;, contained large, pale cells arranged in reticulum fashion. In one of these a giant cell was found (fig. 8). In none were there cry,;talR or spaces resembling crystals. Interstitial cellular infiltration was al,;o observed in the medulla. Here it waR not only circumscribed but also diffuse, spreading from ·within tubules into the surrounding tissue (fig. 3). In the diffusely spreading lesions, one found in addition to lymphocytes man:v polymorphonuclear leucocytes. Small fresh hemorrhages were seen scattered through the medulla. Ko bacteria ·were demonstrable with Gram and Gimsa stains. Sections from the peripelvic fat, calyces, pelvis and ureters revealed more or less the :canw picture. In the peripelvic fat there was lymphocytic and large round cell infiltration, most intense close to surfaces it covered. The walls of the calyces were swollen and much of the lining epithelium had desquamated. The remainder of the walls was edematom,, congested, hemorrhagic and infiltrated with numerous lymphocytes and some polymorphonuclear leucoc.vtes.
FIG. 8. Glomerulus, the central portion of which is necrotic
A similar picture was seen in the pelvis and ureters. The bladder wall and prostate were normal. l\1icroscopic findings in other organs ·were not particularly pertinent. The changeR seen in the lung confirmed the gross diagnosis. 2\/Iyofibrils were fragmented and hypertrophied. In the liver one saw mild fatty change and some periportal round cell infiltration. Sections of spleen, pancreas and esophagus ,vere normal. There waR some fibrosis of the testis. One kidney was studied chemically by Herman D. Ratisch. 1 The following is the report he wm-; kind enough to submit to us. "Considerable precipitate wa,.: found in the calyces, pale red in color, gritty in consistency. The color washed off in ,vater but the particles did not dissolve. The substance was negative for free sulfonamide with the Bratton-Marshall test but became strongly positive after hydrolyRis with 4 K HCl. A sample of the concretions was cleaned, dissolved in hot alcohol and recrystallized. The melting point of these proved to be 250.5-2,52°C. When mixed with sulfadiazine crystals the melting point fell to 1
Littauer Pneumonia Research Fund, New York l~niversity :\Iedical College.
316
AKTONIO RO'l"l'INO AND OSWALD LA RO'l'OKDA
220°C. The recrystallized particles were also tested for sulfonamide and were only positive after hydrolysis. A portion of the kidney was macerated and treated with trichloracetic acid. Qualitative test of this product revealed both free and conjugated sulfadiazine. The quantitative estimate was 27 mg. per cent free form, 123 mg. per cent acetyl sulfadiazine." Final diagnosis: Acetyl sulfadiazine urolithiasis and pyelonephritis of both kidneys, obstruction of both ureters, chronic bronchiectasis, multiple abscesses and fibrosis of the upper lobe of the right lung. COMMENT
The case is of intereRt Rince it illustrates a rare but fatal complication following the use of sulfadiazine. To our knowledge it is the first reported human case in which this complication has taken place. Death was due to uremia caused by intrarenal disease as well as bilateral blockage of the ureters by crystals. ]\,fore of the same were found deposited in the pelvis and calyces of each kidney. Significant was the observation of crystalline matter distending tubule8 and cauRing injury to their lining epithelium. Chemical analysis revealed that practically all the deposit was acetyl sulfadiazine. Unlike the soft, innocuous qualities of the free form of the drug, the acetylated crystals were firm, gritty, sharp and irritating. In addition to the physical presence of precipitated matter, there was present in each kidney a pyelonephritis. This raised the question of its etiology. Was it chemical, physical or of bacteriological causation? Sections stained for bacteria failed to show organisms. 2 Though it is not our primary intention to a8cribe the pyelonephritis to the drug, it is certainly more than probable that it caused injury to tubular epithelium and was then followed by the reactive phenomenon described. That a relationship exists between the tubular damage and some of the inflammatory reaction is supported by the finding of a unique histological picture. This consisted in swelling of some tubular epithelial cells, flattening of others, loss of cells with resulting ulceration, adhesion over such areas of a coagulum, infiltration, of the latter with cellular exudate and extension of this exudate through the tubule into the surrounding interstitium. Whether the entire reaction is due to the drug, in part to stagnant urinary products, undisclosed bacteria or their products are questions we can not answer. The same pertains to the more circumscribed granulomatous lesions in the cortex. The finding of a giant cell is interesting but its significance obscure. Injury to tubules and reactive phenomenon were noted by Gross, Cooper and Hagan in one-quarter of their mice fed sulfadiazine. Careful examination by them of areas adjacent to the crystalline masses failed to reveal evidence of inflammation. Their conclusion seems to be that the cellular infiltration denotes secondary infection. No bacteriological study is described to substantiate this. Climenko and Wright using monkeys and feeding them sulfapyridine and sulfathiazol noted that crystalline matter precipitated in excretory tubules when excessive amounts of drug were administered. Most interesting since it is re' Sections positive for bacteria were stained simultaneously for control.
FATAL HUCV!AN CASE OF l:ROLITHL\SIS i\IEDIC,UU<;NTOSA_
317
lated to the finding in our case was the observation of injury to tubular epithelium, ulceration and reaction by polymorphonuclear leucocytes. SUMMARY AND CONCLUSIONS
A report of a patient is presented -who died in memia during treatment for pneumonia with sulfadiazine. Crystalline matter was found in the calyces, pelvis and ureters, all of which were plugged by the drug. Crystals were likewiRc found in the renal parenchyma. Chemical analysis revealed that the crystalline matter was acetyl sulfadiazine. The damage to the renal parenchyma and the reaction thereto is described. It is believed that this injury is due to the crystals. REFERENCES CLIMN,;Ko, D.R., AND WRIGHT, A. W.: Effect of continued administration of sulfathiazole and sulfapyridinc in monkeys. Arch. Path., 32: 794, 1941. Gnoss, P., CooP1m, B. F., AND HAGAN, L. M.: l:"rolithiasis rneclicarnentosa caused by sulfacliazine. Arn . .J . Clin. Path., 11: 882, 1941.