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Vancomycin-induced interstitial nephritis
LETTERS
VANCOMYCIN-INDUCED
INTERSTITIAL
TO THE EDITOR
NEPHRlllS
To the Editor: Acute interstitial nephritis (AIN) has long been recognized as a form of drug-induced renal disease, and antibiotics, particularly beta-lactams, have long been incriminated as causative agents [l]. I wish to report a case of renal insufficiency with features strongly suggestive of AIN associated with vancomycin use. A 32-year-old black female former intravenous drug user was admitted to St. Luke’s Hospital Center complaining of a painful, edematous right arm. She knew of no allergies. Examination was notable for a temperature of 38.8OC, blood pressure 140184 mm Hg, heart rate 92 beats/minute, and respirations 18/minute. There was shotty cervical lymphadenopathy, a diffusely edematous right arm, and a tender axillary cord. Results of the remainder of the examination were unremarkable. The white blood cell count was 12,400/mm3 without eosinophilia, the hemoglobin level was 9.4 g/dl, and the hematocrit was 27.7 percent. Chemistry values were notable for a urea nitrogen of 17 mg/dl and creatinine of 1.5 mg/dl. A diagnosis of septic thrombophlebitis was made and therapy was instituted with vancomycin and gentamicin. Methadone, alpha-methyldopa (taken by the patient intermittently for 10 years), heparin, and acetaminophen with codeine were administered. Blood cultures grew Staphylococcus aureus resistant to nafcillin. Reduced fever and improvement in the arm over the first four days led to the discontinuation of gentamicin. On Hospital Day 7, she was afebrile and the arm much improved. The white blood cell count was 6,500/mm3, urea nitrogen level 34 mg/dl, and the creatinine level 3.0 mg/dl. Urinalysis revealed a specific gravity of 1.025 and pH 5.5. Protein, glucose, bilirubin, ketones, and blood were absent by dipstick. Microscopic examination showed zero to two red and white blood cells, a few epithelial cells, and otherwise normal findings. An abdominal sonogram revealed normal kidneys and was otherwise unremarkable. Over the next several days, oliguria developed, the serum creatinine level continued to rise, and she was treated with reduced doses of vancomycin (maintaining peak levels of 20 to 29 pg/ml). Fever recurred, reaching 40.6’C; heparin, alpha-methyldopa, and vancomycin were discontinued as shown in Figure 1. On Hospital Day 16, an erythematous, maculopapular rash typical of a drug eruption appeared over the extremities. The white blood cell count was 5,700/mm3 with 18 percent eosinophils. Urinalysis showed specific gravity 1.015, pH 6.5, five to 10 white blood cells (predominantly eosinophils) per high-power field, and five to 10 red blood cells per high-power field. No casts were seen. The urea nitrogen level rose to 47 mg/dl and the creatinine level to 6.0 mg/dl. Over the ensuing 10 days, the arm continued to improve, fever abated, the rash disappeared, eosinophilia and eosinophiluria declined, and the serum creatinine level fell to 3.8 mg/dl. Results of serologic work-up were negative for hepatitis B surface antigen, complement component abnormalities, antinuclear antibodies, Venereal Disease Research Laboratory (VDRL) testing, and rheumatoid factor. Findings on blood and urine cultures remained negative throughout the illness. A 24-hour collection of urine
Gentamycin Voncomycin Heporin Alpha-methyldopa Erythromycin Clindamycin Rifompin Methadone Rash
I
’
L
7-l
Creotinine l;ll
4 41
4
8
12
I6
20
24
28
32
36
Days
Figure 1. Time course of fever, medication usage, rash, and measurement of serum creatinine and serum glutamic oxaloacetic transaminase (aspartate aminotransferase) (SGOT) in the patient. See text for details. T = temperature in degrees centigrade.
contained 620 mg of protein. She remained afebrile and the arm continued to improve with alternative antibiotics, but she signed out of the hospital against medical advice on the 38th hospital day and has been lost to follow-up. There is, to the best of my knowledge, only one case in which vancomycin was described as the causative agent of AIN [2]. The clinical picture of AIN usually suggests a hypersensitivity reaction; fever, skin rash, and the acute onset of renal insufficiency are typical, occurring in most patients [3]. Definitive diagnosis is possible by examination of renal biopsy material showing focal or diffuse interstitial infiltrates composed of lymphocytes, plasma cells, and eosinophils. In the absence of such material, a presumptive diagnosis must be made based on a high index of suspicion and typical clinical features [4]. I believe my patient had AIN on the basis of a recrudescence of fever after an initial defervescence, a maculopapular rash most consistent with a drug eruption, acute onset of renal insufficiency with oliguria, eosinophiluria, peripheral eosinophilia, and a prompt response to withdrawal of vancomycin. Since the patient I have described was receiving multiple medications when renal insufficiency developed, another drug could be incriminated, as could immune complex gloMarch
1988
The American
Journal
of Medicine
Volume
84
581
LETTERS TO THE EDITOR
merulopathy or acute tubular necrosis. Vancomycin was reported to cause AIN in a patient with quite a similar illness, and I concur with the conclusion of Eisenberg et al [2] that vancomycin should be included in the list of medications that may cause AIN. Given the increasing utilization of the drug in areas with emerging resistance of Staphylococci to beta-lactam agents, clinicians should be aware of this association.
AARON
University
Submitted
SCOTT J. RATNER, M.D. St. Luke’s/Roosevelt Hospital Center Amsterdam Avenue at 114th Street New York, New York 10025 1.
2. 3.
4.
DIABETES
April
24,
1987,
and
accepted
in revised form December 28, 1987
CLINICAL ASSESSMENT OF EXTRACELLULAR FLUID VOLUME IN HYPONATREMIA To the Editor: In their recent valuable article, Chung et al (Am J Med 1987; 83: 905-908) point out that the history and physical examination are frequently unreliable in predicting the volume status and response of non-edematous hyponatremic patients to normal saline. On the other hand, the concentration of sodium in a spot urine sample was found to be very useful in making this determination-a low urinary sodium concentration suggested a saline-responsive patient. Although I doubt the authors intended to imply that the history and physical examination are of little use in the assessment of hyponatremic patients, I am concerned that casual readers may infer precisely this. It needs to be emphasized that the urinary sodium level alone can never be relied upon to provide an accurate measure of volume status. For example, as the authors note, occasional salineresponsive patients will have high urinary sodium concentrations (e.g., with diuretic use or mineralocorticoid deficiency), whereas some saline-unresponsive patients have low urinary sodium levels (e.g., in heart failure) (Sherman RA, Eisinger RP: The use (and misuse) of urinary sodium and chloride measurements. JAMA 1982; 247: 3 12 I-31 24). There is little doubt that the determination of volume status can at times be quite difficult, even for seasoned physicians. In such circumstances, the urinary sodium concentration is indeed very helpful, but should always be viewed in the context of a clinical assessment. By remembering this principle, physicians will avoid the error of giving saline to a patient in heart failure whose urinary sodium level is low, before having performed a thorough bedside examination.
562
March
1968
The American
Journal
of Medicine
Volume
MELLITUS
M.D.
7, 1987, and accepted
IN ELDERLY
December
16, 1987
PATlENTS
To the Editor: The article on diabetes mellitus in elderly patients by Morley et al (Am J Med 1987; 83: 533-544) described the many complications that occur in type II diabetes. In the summary, there are two conclusions. (1) “Older diabetic patients appear to have just as much, if not more, risk of micro- and macrovascular complications.” (2) “Good control of the diabetes appears to be as important for retarding the development of these complications and improving the quality of life.” There is not one reference in 136 cited to justify these conclusions nor were these questions addressed in any part of the article. Whether tight control will prevent complications is still unanswered in type I diabetes and surely not in type II. The authors state that “most elderly diabetic patients are not overweight and the introduction of a weight-reducing diabetic diet in those over the age of 70 can have disastrous consequences.” At least one study found that 70 to 80 percent of type II diabetic patients “are either obese when they present or have been so in the past (Genuth S: Med Clin North Am 1982; 66: 1193). The references concerning the disastrous consequences of weight loss do not apply to diabetic patients who are obese, most of whom are.
Kleinknecht D, Vanhille PI, MoreCMaroger L, et al: Acute interstitial nephritis due to drug hypersensitivity. An up-to-date review with a report of 19 cases. Adv Nephrol 1983; 12: 277-308. Eisenberg ES, Robbins N, Lenci M: Vancomycin and interstitial nephritis (letter). Ann Intern Med 1981; 95: 658. Linton AL, Clark WF, Driedger AA, Turnbull Dl, Lindsay RM: Acute interstitial nephritis due to drugs; review of the literature with a report of nine cases. Ann Intern Med 1980; 93: 735-741. Appel GB, Kunis CL: Acute tubulo-interstitial nephritis. In: Cotran RS, ed. Contemporary issues in nephrology, vol X. New York: Churchill-Livingstone, 1983; 151-157. Submitted
December
SPITAL,
of Rochester School of Medicine Rochester General Hospital Rochester, New York 14621
DAVID
MORRIS,
M.D.
Greenwich Hospital Association Greenwich, Connecticut 06830 Submitted
October
15,1987,
and accepted
December
3.1987
The Reply: Although agreeing that no prospective study has shown the need for good control in diabetes in the elderly, we based our conclusion that good control (not “tight” control) is important in older diabetic patients on the following findings, all cited in the original article: 1. The correlation between retinopathy and diabetic control in patients between 55 and 75 [ 11. 2. The deleterious effect of elevated glucose levels on pain perception-an important quality-of-life issue [2]. 3. The effect of elevated glucose levels on cognitive impairment and the finding that older diabetic patients have cognitive impairment [3]. 4. The hyperzincuria occurring in diabetic patients that appears to be related to hyperglycemia [4]. 5. The increase in mortality seen in older diabetic patients compared with the older population in general [5]. 6. The poor prognosis following cerebrovascular accidents in patients with elevated glucose levels [6].
64
VANCOMYCIN-INDUCED
INTERSTITIAL
TO THE EDITOR
NEPHRlllS
To the Editor: Acute interstitial nephritis (AIN) has long been recognized as a form of drug-induced renal disease, and antibiotics, particularly beta-lactams, have long been incriminated as causative agents [l]. I wish to report a case of renal insufficiency with features strongly suggestive of AIN associated with vancomycin use. A 32-year-old black female former intravenous drug user was admitted to St. Luke’s Hospital Center complaining of a painful, edematous right arm. She knew of no allergies. Examination was notable for a temperature of 38.8OC, blood pressure 140184 mm Hg, heart rate 92 beats/minute, and respirations 18/minute. There was shotty cervical lymphadenopathy, a diffusely edematous right arm, and a tender axillary cord. Results of the remainder of the examination were unremarkable. The white blood cell count was 12,400/mm3 without eosinophilia, the hemoglobin level was 9.4 g/dl, and the hematocrit was 27.7 percent. Chemistry values were notable for a urea nitrogen of 17 mg/dl and creatinine of 1.5 mg/dl. A diagnosis of septic thrombophlebitis was made and therapy was instituted with vancomycin and gentamicin. Methadone, alpha-methyldopa (taken by the patient intermittently for 10 years), heparin, and acetaminophen with codeine were administered. Blood cultures grew Staphylococcus aureus resistant to nafcillin. Reduced fever and improvement in the arm over the first four days led to the discontinuation of gentamicin. On Hospital Day 7, she was afebrile and the arm much improved. The white blood cell count was 6,500/mm3, urea nitrogen level 34 mg/dl, and the creatinine level 3.0 mg/dl. Urinalysis revealed a specific gravity of 1.025 and pH 5.5. Protein, glucose, bilirubin, ketones, and blood were absent by dipstick. Microscopic examination showed zero to two red and white blood cells, a few epithelial cells, and otherwise normal findings. An abdominal sonogram revealed normal kidneys and was otherwise unremarkable. Over the next several days, oliguria developed, the serum creatinine level continued to rise, and she was treated with reduced doses of vancomycin (maintaining peak levels of 20 to 29 pg/ml). Fever recurred, reaching 40.6’C; heparin, alpha-methyldopa, and vancomycin were discontinued as shown in Figure 1. On Hospital Day 16, an erythematous, maculopapular rash typical of a drug eruption appeared over the extremities. The white blood cell count was 5,700/mm3 with 18 percent eosinophils. Urinalysis showed specific gravity 1.015, pH 6.5, five to 10 white blood cells (predominantly eosinophils) per high-power field, and five to 10 red blood cells per high-power field. No casts were seen. The urea nitrogen level rose to 47 mg/dl and the creatinine level to 6.0 mg/dl. Over the ensuing 10 days, the arm continued to improve, fever abated, the rash disappeared, eosinophilia and eosinophiluria declined, and the serum creatinine level fell to 3.8 mg/dl. Results of serologic work-up were negative for hepatitis B surface antigen, complement component abnormalities, antinuclear antibodies, Venereal Disease Research Laboratory (VDRL) testing, and rheumatoid factor. Findings on blood and urine cultures remained negative throughout the illness. A 24-hour collection of urine
Gentamycin Voncomycin Heporin Alpha-methyldopa Erythromycin Clindamycin Rifompin Methadone Rash
I
’
L
7-l
Creotinine l;ll
4 41
4
8
12
I6
20
24
28
32
36
Days
Figure 1. Time course of fever, medication usage, rash, and measurement of serum creatinine and serum glutamic oxaloacetic transaminase (aspartate aminotransferase) (SGOT) in the patient. See text for details. T = temperature in degrees centigrade.
contained 620 mg of protein. She remained afebrile and the arm continued to improve with alternative antibiotics, but she signed out of the hospital against medical advice on the 38th hospital day and has been lost to follow-up. There is, to the best of my knowledge, only one case in which vancomycin was described as the causative agent of AIN [2]. The clinical picture of AIN usually suggests a hypersensitivity reaction; fever, skin rash, and the acute onset of renal insufficiency are typical, occurring in most patients [3]. Definitive diagnosis is possible by examination of renal biopsy material showing focal or diffuse interstitial infiltrates composed of lymphocytes, plasma cells, and eosinophils. In the absence of such material, a presumptive diagnosis must be made based on a high index of suspicion and typical clinical features [4]. I believe my patient had AIN on the basis of a recrudescence of fever after an initial defervescence, a maculopapular rash most consistent with a drug eruption, acute onset of renal insufficiency with oliguria, eosinophiluria, peripheral eosinophilia, and a prompt response to withdrawal of vancomycin. Since the patient I have described was receiving multiple medications when renal insufficiency developed, another drug could be incriminated, as could immune complex gloMarch
1988
The American
Journal
of Medicine
Volume
84
581
LETTERS TO THE EDITOR
merulopathy or acute tubular necrosis. Vancomycin was reported to cause AIN in a patient with quite a similar illness, and I concur with the conclusion of Eisenberg et al [2] that vancomycin should be included in the list of medications that may cause AIN. Given the increasing utilization of the drug in areas with emerging resistance of Staphylococci to beta-lactam agents, clinicians should be aware of this association.
AARON
University
Submitted
SCOTT J. RATNER, M.D. St. Luke’s/Roosevelt Hospital Center Amsterdam Avenue at 114th Street New York, New York 10025 1.
2. 3.
4.
DIABETES
April
24,
1987,
and
accepted
in revised form December 28, 1987
CLINICAL ASSESSMENT OF EXTRACELLULAR FLUID VOLUME IN HYPONATREMIA To the Editor: In their recent valuable article, Chung et al (Am J Med 1987; 83: 905-908) point out that the history and physical examination are frequently unreliable in predicting the volume status and response of non-edematous hyponatremic patients to normal saline. On the other hand, the concentration of sodium in a spot urine sample was found to be very useful in making this determination-a low urinary sodium concentration suggested a saline-responsive patient. Although I doubt the authors intended to imply that the history and physical examination are of little use in the assessment of hyponatremic patients, I am concerned that casual readers may infer precisely this. It needs to be emphasized that the urinary sodium level alone can never be relied upon to provide an accurate measure of volume status. For example, as the authors note, occasional salineresponsive patients will have high urinary sodium concentrations (e.g., with diuretic use or mineralocorticoid deficiency), whereas some saline-unresponsive patients have low urinary sodium levels (e.g., in heart failure) (Sherman RA, Eisinger RP: The use (and misuse) of urinary sodium and chloride measurements. JAMA 1982; 247: 3 12 I-31 24). There is little doubt that the determination of volume status can at times be quite difficult, even for seasoned physicians. In such circumstances, the urinary sodium concentration is indeed very helpful, but should always be viewed in the context of a clinical assessment. By remembering this principle, physicians will avoid the error of giving saline to a patient in heart failure whose urinary sodium level is low, before having performed a thorough bedside examination.
562
March
1968
The American
Journal
of Medicine
Volume
MELLITUS
M.D.
7, 1987, and accepted
IN ELDERLY
December
16, 1987
PATlENTS
To the Editor: The article on diabetes mellitus in elderly patients by Morley et al (Am J Med 1987; 83: 533-544) described the many complications that occur in type II diabetes. In the summary, there are two conclusions. (1) “Older diabetic patients appear to have just as much, if not more, risk of micro- and macrovascular complications.” (2) “Good control of the diabetes appears to be as important for retarding the development of these complications and improving the quality of life.” There is not one reference in 136 cited to justify these conclusions nor were these questions addressed in any part of the article. Whether tight control will prevent complications is still unanswered in type I diabetes and surely not in type II. The authors state that “most elderly diabetic patients are not overweight and the introduction of a weight-reducing diabetic diet in those over the age of 70 can have disastrous consequences.” At least one study found that 70 to 80 percent of type II diabetic patients “are either obese when they present or have been so in the past (Genuth S: Med Clin North Am 1982; 66: 1193). The references concerning the disastrous consequences of weight loss do not apply to diabetic patients who are obese, most of whom are.
Kleinknecht D, Vanhille PI, MoreCMaroger L, et al: Acute interstitial nephritis due to drug hypersensitivity. An up-to-date review with a report of 19 cases. Adv Nephrol 1983; 12: 277-308. Eisenberg ES, Robbins N, Lenci M: Vancomycin and interstitial nephritis (letter). Ann Intern Med 1981; 95: 658. Linton AL, Clark WF, Driedger AA, Turnbull Dl, Lindsay RM: Acute interstitial nephritis due to drugs; review of the literature with a report of nine cases. Ann Intern Med 1980; 93: 735-741. Appel GB, Kunis CL: Acute tubulo-interstitial nephritis. In: Cotran RS, ed. Contemporary issues in nephrology, vol X. New York: Churchill-Livingstone, 1983; 151-157. Submitted
December
SPITAL,
of Rochester School of Medicine Rochester General Hospital Rochester, New York 14621
DAVID
MORRIS,
M.D.
Greenwich Hospital Association Greenwich, Connecticut 06830 Submitted
October
15,1987,
and accepted
December
3.1987
The Reply: Although agreeing that no prospective study has shown the need for good control in diabetes in the elderly, we based our conclusion that good control (not “tight” control) is important in older diabetic patients on the following findings, all cited in the original article: 1. The correlation between retinopathy and diabetic control in patients between 55 and 75 [ 11. 2. The deleterious effect of elevated glucose levels on pain perception-an important quality-of-life issue [2]. 3. The effect of elevated glucose levels on cognitive impairment and the finding that older diabetic patients have cognitive impairment [3]. 4. The hyperzincuria occurring in diabetic patients that appears to be related to hyperglycemia [4]. 5. The increase in mortality seen in older diabetic patients compared with the older population in general [5]. 6. The poor prognosis following cerebrovascular accidents in patients with elevated glucose levels [6].
64