CHAPTER X
Sulfonamides in Relation to "Shock Kidney"
No discussion of renal failure in the wounded of World War II wouldbe complete without consideration of the possible role of sulfonamide injuryof the kidneys. Two forms of this type of injury are generally recognized.One is the purely mechanical process of crystalluria, with precipitationof the crystals in the ureters, renal pelves, and perhaps in some instancesin the collecting tubules. The second is a more complex process involvingtrue parenchymal damage to the kidney; it appears to be relatively independentof dosage and is believed by many to belong in the category of hypersensitivereactions along with other recognized sulfonamide lesions such as dermatitis,myocarditis, and pneumonitis.
The problem is difficult because this renal lesion is a characteristiclower nephron nephrosis, usually although not invariably associated withthe precipitation of hemoglobin-like products in the tubules and henceindistinguishable from transfusion kidney, crush kidney, or shock kidney.With present knowledge, distinction is impossible on the basis of renalmorphology.
Sulfonamide Therapy in Battle Casualties
During the period in which the cases studied by the Board were collected,sulfonamides were still extensively used in forward installations (aidstations, collecting stations, and clearing stations) in the Fifth ArmyArea, although their use in hospitals had greatly diminished with the arrivalof large supplies of penicillin. In the aid stations a sulfonamide dressingalmost universally was applied. This might or might not be supplementedby indeterminate amounts of sulfonamide powder dusted onto or into thewounds, and more of the drug by mouth, the most frequent total oral dosebeing 4 grams. In the field and evacuation hospitals, sulfonamide therapyusually was stopped and penicillin sub-
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stituted. Notable exceptions, however, were in some cases of abdominalwounds with incipient peritonitis. Many surgeons placed from 5 to 10 Gm.of sulfadiazine in the abdominal cavity before closing it, and some continuedsulfonamide treatment by mouth for several days. There was no standardpractice since this was considered a matter for individual surgical judgment.
Blood Sulfonamide Levels
Relationship to Sulfonamide Intake
Blood sulfonamide levels were determined in 50 of our patients. Thetests were made for free sulfonamide only, whereas the total of free andacetylated blood sulfonamide would probably have been a more valuable indexof sulfonamide retention by the kidney. As would be expected, there seemedto be a general relationship between the blood levels of the drug and thequantity administered, as shown in Table 94. However, the fluctuationswithin each group are too great and the number of cases is too small tojustify further analysis. It is noteworthy that no patient tested failedto show at least a trace of sulfonamide in the blood stream, and in twoof six patients with no recorded chemotherapy, levels of 7.0 and 10.6 mg.per 100 cc. were observed. Furthermore, characteristic sulfonamide crystalswere found at necropsy in the renal tubules in several other patients withno history of exposure to sulfonamide
TABLE 94.-BLOOD SULFONAMIDELEVELS IN 50 PATIENTS
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and no records of chemical tests for it. The only possible conclusionsare that the records were grossly unreliable so far as sulfonamide therapywas concerned, and that, regardless of their histories, virtually all ofthese patients must have received some sulfonamide therapy.
Relationship to Renal Insufficiency
The 50 patients on whom blood sulfonamide levels were determined wereclassified on the basis of urinary suppression and nonprotein nitrogenlevel (with or without high azotemia). In the upper two quarters of Chart38 the patients have been divided into those with normal urinary outputand those with oliguria. In the lower two the separation is on the basisof nitrogen retention.
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It is evident that blood sulfonamide levels above 8 mg. per 100 cc.were observed only in patients suffering from oliguria, or high azotemia,or both. Attempts at closer analysis are disappointingly inconclusive.The average blood sulfonamide level in 36 azotemic patients was 5.7 mg.per 100 cc. as compared with 2.3 mg. per 100 cc. in the control group of14, but again the variations are too wide in proportion to the number ofsamples to warrant statistical analysis. The mean blood sulfonamide levelin 38 oliguric patients was 5.4 and in 12 without oliguria, 2.5 milligramsper 100 cubic centimeters.
The results are similar when the cases are divided, in an attempt toexclude the influence of variation in dosage, into two groups as follows:Group A, those patients who had external medication only, and Group B,those who received internal medication (oral, intraperitoneal, or intravenous).Eight patients could not be classified because of inadequate informationregarding therapy. Of the 18 patients in Group A, 12 were azotemic, 6 werenot. The mean blood sulfonamide level in the former was 1.7 mg. per 100cc., with a standard error of ± 1.1; of the latter 1.32 with a standarderror of ± 0.8. Obviously the difference is not significant. InGroup B, 17 azotemic patients showed a mean blood sulfonamide level of7.8 mg. per 100 cc., with a range of 0.4 to 39; and 7 patients with noazotemia, a level of 3.7 mg. per 100 cc., with a range of 0.2 to 7.8. Witha range of this magnitude in such a small number of cases, the calculationof standard errors has little meaning. Similar results followed effortsto establish any correlation of average blood sulfonamide levels with oliguria.
Very high blood sulfonamide levels (10 mg. per 100 cc. or higher) wereseen only in patients with symptoms of renal insufficiency. Nothing inthis relationship serves to distinguish between cause and effect. It isobvious, however, that with continued administration of a drug eliminatedalmost solely by the kidney, its level in the blood must mount with theonset of renal insufficiency. Two cases are worthy of individual attention.
Cases in Point
Case 21.-This patient was not a battle casualty.As treatment for a urethral discharge, the patient medicated himself with12 Gm. of sulfathiazole in 24 hours. The following day ureteral colic developed.Crystalline concretions were observed in both ureteral orifices on cystoscopy.He was treated by pelvic lavage and had no further symptoms. It is evidentthat his trouble was purely mechanical.
Case 90.-This patient was a battle casualty; asevere abdominal wound had resulted in evisceration of several loops ofbowel, perforation of the diaphragm, and lacerations of
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the liver and right kidney. The patient was in moderateshock on entry to the hospital. For the first week postoperatively he voidedadequate quantities of urine and did not show nitrogen retention, but hewas febrile. On the ninth day signs of consolidation developed in the lowerlobe of the left lung. He was given 66 Gm. of sulfadiazine between theseventh and twelfth days. Within 24 hours the plasma nonprotein nitrogenlevel rose to 143 mg. per 100 cc. and later to 166 mg. per 100 cc., andthe blood sulfonamide level to 51.6 mg. per 100 cc. (free sulfonamide 34.4,acetylated 17.2). Following cessation of sulfonamide therapy, the nonproteinnitrogen level fell to 41 mg. per 100 cc. in the course of 17 days. Oliguriadid not develop during the period of nitrogen retention. It is possiblethat this may have been a case of sulfonamide injury of the renal parenchyma,but the relative importance of the simultaneous spreading infection cannotbe assessed.
One other line of argument must be explored before conclusion. As wasstated in the introduction, there are reasons for believing that the sulfonamideform of lower nephron nephrosis is dependent upon hypersensitivity. Onereason for this belief is the frequent association of this lesion withinflammatory lesions of other tissues and organs; for example, dermatitis,myocarditis, interstitial pancreatitis, hepatitis, arteritis, and a formof pneumonitis. In the present series of cases, the only such associatedlesion observed was pneumonitis. It is the personal opinion of the writer(T.B.M.) that pneumonitis can occur in uremia independently of sulfonamidetreatment and that, therefore, its presence cannot be accorded great diagnosticweight.
SUMMARY
Grounds have been found for believing that the records of sulfonamidetherapy in the group of battle casualties upon which this report is basedwere grossly inaccurate, but that it is a reasonable assumption that fewif any patients escaped exposure to the drug. Very high blood sulfonamidelevels were observed only in patients with renal insufficiency. Exceptfor these extreme instances, the variation in the blood sulfonamide levelswas too great in all categories studied to yield reliable correlation betweenblood level and renal insufficiency. In only two cases did clinical evidencepoint toward a sulfonamide etiology. A strong argument against such a causativemechanism was the failure to observe any instance of other forms of sulfonamideinjury such as arteritis, myocarditis, dermatitis, hepatitis, or pancreatitis.
