Medical Staff Conference
Refer to: Methicillin induced interstitial nephritis-Medical Staff Conference, University of California, San Francisco. West J Med 123:380-385, Nov 1975
Methicillin Induced Interstitial Nephritis These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr., Assistant Professor of Medicine, and H. David Watts, Assistant Professor of Medicine, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, CA 94143.
DR. SMITH: * This morning the topic for Medical Grand Rounds is methicillin induced interstitial nephritis. Dr. Barry Zacherle from the Division of Nephrology will discuss the topic and a patient recently seen on the Medical Service will be presented by Dr. McCurley. DR. MCCURLEY: t A 73-year-old white woman was admitted to the University of California Medical Center with exfoliative erythroderma. Twelve days before admission an erythematous papular rash developed on her chest. During the week before admission the rash became generalized, her skin became edematous and fever, chills and malaise were present. There had been similar episodes of generalized erythroderma at 3 to 4 year intervals since age 16. On physical examination, the patient appeared to be acutely ill. The pulse was 90 beats per minute, temperature 36.9°C (98.4°F) and blood pressure 150/72 mm of mercury. The skin was diffusely erythematous and scaly on face, trunk and extremities, and there was generalized edema which was nonpitting. A *Lloyd H. Smith, Jr., MD, Professor and Chairman, Department of Medicine. tThomas McCurley, MD, Intem in Medicine.
380
NOVEMBER 1975 *
123 * 5
grade II/VI systolic murmur at the left lower sternal border was noted. The admission laboratory data were pertinent as follows: hematocrit was 39.1 percent, leukocyte count was 16,500 per cu mm; the differential was 51 polymorphonuclear cells, 6 banded cells, 6 eosinophils and 37 percent lymphocytes. The peripheral smear had toxic granulation and vacuolation of the polymorphonuclear leukocytes. The serum creatinine was 1.1 mg per dl with blood urea nitrogen of 18 mg per dl. Findings on urinalysis showed no protein, 4 to 5 leukocytes and no red cells per high-power field. The exfoliative erythoderma resolved after a seven-day course of high dose parenteral and topical steroids. Five of nine blood cultures drawn after admission grew Staphylococcus aureus and on December 26, 1974, the patient was started on 8 grams per day of methicillin. Fourteen days later the patient had a hard-shaking chill associated with a temperature of 390C (102.20F). Findings on urinalysis showed no protein, 4 to 5 leukocytes per high-power field and no red cells. Serum creatinine was 1 mg per dl. Fever continued, and three days later serum creatinine was 6.9 mg per dl with 8 percent eosinophils on dif-
INTERSTITIAL NEPHRITIS Af,
~
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7
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o-
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Figure I.-Section of kidney.
a normal
Figure 2.-Section of a kidney biopsy specimen from patient with methicillin interstitial nephritis.
ferential leukocyte cell count. On testing, urine had 3 + proteinuria, 1 to 3 tubular epithelial cells per high-power field and 4 to 5 red blood cells per high-power field. Findings on intravenous pyelogram and renal scan showed bilaterally poorly functioning kidneys without obstruction. Serum complement levels were normal. A renal biopsy specimen was taken, the histology of which showed an interstitial nephritis. Treatment with parenteral steroids was begun and after one week the creatinine level had fallen to 2.1 mg per dl. Steroids were discontinued and creatinine rose to 4.6 mg per dl. At that time there were 16 percent eosinophils on differential count and results of urinalysis showed 1 + proteinuria with 3 to 5 tubular epithelial cells and 1 to 2 red cells per high-power field. Administration of prednisone (40 mg per day) was begun again and four days later the serum creatinine level was 2.6 mg per dl. DR. ZACHERLE: * In the patient presented this morning, acute renal failure was present due to an interstitial nephritis which appeared to be secondary to methicillin. Today I would like to discuss interstitial nephritis in general with the emphasis on drug-induced acute interstitial nephritides, particularly methicillin nephritis. The latter is the interstitial nephritis with which we are most apt to be confronted clinically today. Interstitial nephritis is primarily a histologic diagnosis. Figure 1 shows a section of a normal kidney biopsy specimen. The glomeruli are normal with open capillary loops, thin lacey capillary basement membranes and a normal amount
of mesangial substance and cellularity. The tubules are plentiful, filling up most of the remaining space, and appear normal. Those vessels present are also normal. The interstitial substance located between the glomeruli, tubules and vessels is essentially inapparent; this is the normal histology. Interstitial nephritis is, as the name implies, an inflammation of the interstitium without much change in the other structures (glomeruli, tubules or vessels). The interstitium becomes prominent; in the acute situation this is due to edema, but if the process becomes more chronic, fibrosis occurs. There is also a cellular inflammatory response which usually consists of polymorphonuclear leukocytes acutely and round cell infiltration later. Figure 2 is a section from the kidney biopsy specimen in the case under discussion today. The interstitial material is very apparent and there is an active cellular inflammatory response which is particularly prominent around the tubules. Although not apparent in this picture, many of the inflammatory cells are eosinophils. Clinically, as well as histologically, interstitial nephritis may be categorized as acute or chronic. Table 1 lists several of the systemic illnesses associated with both types. Although chronic disease is usually indolent and slowly progressive in its course, acute nephritis is more apt to be associated with an acute illness and a rapid deterioration of renal function. Before the introduction of antibiotics this was most -commonly seen in children with acute febrile illnesses, particularly scarlet fever and diphtheria. Currently it is occasionally seen associated with leptospirosis and brucellosis, but that which we are most likely to see as
a
biopsy specimen of
*Barry Zacherle, MD, Assistant Clinical Professor of Medicine and of Ambulatory and Community Medicine.
THE WESTERN JOURNAL OF MEDICINE
381
INTERSTITIAL NEPHRITIS
practicing physicians in 1975 is acute interstitial nephritis associated with a drug reaction. The first descriptions of such drug reactions involved the sulfonamides. In the early 1940's drug reactions to the sulfonamide antibiotics were described and included glomerulonephritis, vasculitis and interstitial nephritis. The same changes have been reported as reactions to other drugs such as the anticoagulant phenindione, diphenylhydantoin and more recently, methicillin, penicillin and ampicillin. In 1973, Lyons and coworkers' suggested that the same clinical features might occur also with thiazide diuretics. The latter is not surprising because the thiazides are chemically related to the sulfonamide drugs. The first reports of methicillin associated renal disease appeared in the early 1960's. Sporadic case reports then appeared throughout the mid 1960's, and in 1968 Baldwin and his associates2 compiled the cases of seven patients who had been receiving either methicillin or penicillin G, or both, and who had fairly distinct clinical features associated with acute interstitial nephritis noted on kidney biopsy. In the typical clinical presentation, fever is usually the first sign noted and then eosinophilia with or without rash appears. Subsequently the renal manifestations appear, although this sequence somewhat is variable. In fact, Baldwin had one patient in his group of seven in whom fever did not develop until after renal insufficiency was already present. In most of the cases reported in the literature the systemic manifestations are followed variably by hematuria, pyuria proteinuria and renal insufficiency, TABLE 1.-Interstitial Nephritides ACUTE
Infections Scarlet fever Diphtheria Leptospirosis Brucellosis Drugs Sulfonamides Phenindione Diphenylhydantoin Methicillin-penicillin-ampicillin-thiazides-furosemide CHRONIC
Pyelonephritis Analgesic abuse Ischemia Radiation Balkan nephritis Sarcoid Lead
Sjogren's syndrome
382
NOVEMBER 1975 * 123 * 5
and on kidney biopsy an acute interstitial nephritis is seen. This renal insufficiency is usually of a moderate degree, and recovery usually follows cessation of the administration of the antibiotic. Figure 3 shows the pertinent features of the case presented today. The patient was admitted with erythroderma, and because there was exfoliation, administration of prednisone was begun promptly. Eosinophilia was present when the patient came into the hospital, and there was no fever. The erythroderma cleared rapidly when the patient was taking prednisone and the dosage of prednisone was tapered shortly after admission. Results of three separate sets of blood cultures were positive for penicillin-resistant Staphylococcus aureus and she was begun on intravenous methicillin, 8 gm per day. The blood cultures were subsequently negative for S. aureus. The patient remained afebrile, serum creatinine ranged between 0.9 and 1 mg per dl and urine output was appropriate for fluid intake. Body weight did not change appreciably during the entire course of the time spent in hospital. After two weeks of methicillin therapy it was discontinued and oral administration of dicloxacillin was begun as indicated in Figure 3. During that period, the erythroderma flared slightly and fever developed. On the third day of that febrile episode, administration of methicillin was again begun and there were two days of both methicillin and dicloxacillin therapy. On the third day of that febrile episode it was noted that the serum creatinine level had risen to 6.9 and the patient was anuric. At this juncture, the usual features of methicillin nephritis appear to have been present-except for the anuria, which is unusual. With the possibility of vasculitis in mind, administration of prednisone was begun again and a renal biopsy specimen was obtained. When the renal biopsy specimen was examined and showed a typical interstitial nephritis, the prednisone was discontinued. During that period, urine output increased, renal function improved and serum creatinine fell to a level of 2.1 mg per dl. The patient became afebrile very quickly. A week after the prednisone was discontinued, there was a spiking temperature and the serum creatinine level rose again to almost 5 mg per dl. The patient was extensively evaluated at this point for any other cause of renal insufficiency and none was found. Administration of prednisone
INTERSTITIAL NEPHRITIS
PREDNISONE
Ou
(mg/day)
40200 CLOXACILLIN METHICILLIN
I
CLINDAMYCIN
I
PERIPHERAL 6%
EOSINOPHYLLIA
(PERCENT)
%F IV
9%
- F.
2%
46 ru
3%
%P tu
3% 8X 26% &Ulu %P Iru
W lu
1iIL 10
41.
TEMPERATURE 4039 (OC)
SERUM
%P-%f 09
CREATININE
1. kf 1i0
0.9 19 69 V.S. 92 71744 3321 1. %# W.%# 1.1 ---v %0.4 &..I
W. V
(mg%)
46 47 39
Ir.%P -7.1 %F.U
21 - &..I
3
URINE VOLUME
21
iml/day)
0-
I
I
28 DAYS O 14 7 21 35 59 42 Figure 3.-Clinical course of patient with methicillin interstitial nephritis. ED is an abbreviation used for erythroderma.
was started again and serum creatinine, which may have begun to decrease before the prednisone therapy was begun, fell to 2.1 mg per dl. Most of the features of typical methicillin interstitial nephritis were present in this patient. There are several peculiarities, however, that merit special attention. One is the extreme degree
of renal insufficiency. The second is that although the methicillin was discontinued and the renal function did improve initially, it deteriorated again later. The third is the question of what role prednisone may have had in the waxing and waning course of renal function in the patient. There are 24 cases of methicillin-associated interstitial nephritis in the literature. In four of the patients there was severe renal insufficiency; in the rest the usual features of only moderate renal insufficienty were seen. One case has been reported3 in which the patient was anuric. Therefore, although the usual feature is mild or moderate renal insufficiency, in approximately 15 percent of the cases very severe renal insufficiency and even anuria may develop. Second, what about the cessation of methicillin? It is very clear in the literature that, in most of the cases,
the patients do get better. However, there is one well-documented case in which the patient's renal function continued to deteriorate for several weeks following the cessation of penicillin and methicillin; this is also the only recorded case in the literature in which there was a clear response in the patient to steroid administration. The degree of ultimate recovery of function has not been carefully evaluated. In at least three patients, there was significant, persistent renal insufficiency. So, although recovery is usual, it may not always follow cessation of the antibiotic administration and may be significantly incomplete. Finally, among 24 of the previously reported patients, only three have been treated with steroids. In one5 there was an immediate improvement in the eosinophilia and fever and no change in renal function. In another3 there was an immediate improvement in renal function; however, administration of prednisone was begun at the same time that methicillin was discontinued. In the third case,4 clear-cut response to steroid therapy occurred on two occasions during the patient's course.
Steroid therapy also appears to have been helpTHE WESTERN JOURNAL OF MEDICINE
383
INTERSTITIAL NEPHRITIS
ful in the treatment of acute interstitial nephritis associated with thiazide administration. Lyons and co-workers' described a group of four patients who had nephrotic syndrome. Findings from renal biopsies done during the course of evaluation of nephrotic syndrome showed glomerular disease with very little interstitial involvement. These patients were all treated with a number of medications including thiazide diuretics and furosemide, and over a course of several months there was pronounced deterioration of renal function in all of them. Of these four patients, two had peripheral eosinophilia, and two did not. Biopsy studies were done again and at that point pronounced acute interstitial nephritis was noted. Those four patents were treated with steroids and in all a significant clinical response was obtained over a short length of time. If drug-induced interstitial nephritis is a distinct entity, why does it occur and what is the pathophysiology? The pathogenesis is not understood, but it is probably an immunologic disease. This was first suggested by the clinical features which include rash, eosinophilia and fever. There are two patients in the literature who have been carefully evaluated from an immunological standpoint, one patient in Baldwin's study2 and another patient described by Border and his associates5 in 1974. Both of these investigators made antibody to a dimethoxyphenyl penicilloyl moeity which is the haptenic or antigenic portion of methicillin. With that antibody to methicillin they were able to show staining of kidney basement membranes of their patients. In one case staining was found only on tubular basement membrane, and in the other case it was found on both tubular and glomerular basement membrane. This staining was shown to be very specific for the methicillin antigen; the authors were unable to obtain similar staining in tissue from normal persons, or from patients with other renal diseases. Antiserum against the benzylpenicilloyl moeity, the antigen of penicillin G, did not cause staining. Furthermore, both authors were able to block staining by absorption with methicillin, methicillin coated red cells or the univalent dimethoxyphenyl penicilloyl moeity. So it appears that in both, an antigenic portion of the methicillin molecule could be detected on at least the tubular basement membrane. Border5 was also able to find a circulating factor in the serum of his patient which indirectly stained normal human or monkey basement membrane. This 384
NOVEMBER 1975 * 123 * 5
staining could be blocked by absorption against human tubular basement membrane, but not against methicillin or methicillin coated red cells. Thus, it appeared that this factor in the serum was directed at the tubular basement membrane and not the methicillin. Steblay and Rudofsky6 produced in rabbits an antiserum against renal tubular basement membrane which they were able to inject into guinea pigs and produce not only staining of the tubular basement membrane but also an active interstitial nephritis. This animal model may or may not be analogous to the human disease. Border and coworkers5 were unable to produce interstitial nephritis in monkeys by injecting them with the antibasement membrane factor from their patient, in spite of their ability to detect by fluorescent staining the presence of basement membrane factor in the tubules. They postulate that this may have been due to the lower antibody titer in their own preparation. Although the experimental, immunologic data are not entirely clear, they do offer suggestions as do the clinical data, and a hypothesis regarding pathogenesis can be formulated with which most of our information fits. In some patients who for unknown reasons are susceptible, a portion of the methicillin molecule is bound to tubular basement membrane protein. Penicillin, methicillin and ampicillin are all organic acids and are secreted by the proximal tubular epithelial cells. It is of interest that the thiazides are also organic acids and are secreted in the same location by the same mechanism. The tubular basement membranemethicillin complex thus formed may then act as an immunogen which stimulates the production of an immunoglobulin G (IgG) antibody directed against the tubular basement membrane. The resulting tissue response to the subsequent antigenantibody reaction is an interstitial nephritis. In conclusion, interstitial nephritis may occur as an acute illness, and in most of our clinical practices it will appear as a reaction to a drug. This reaction is probably mediated by a series of immunologic events. The usual clinical presentation of this entity is well described, and most cases fit into the pattern described. However, it is now apparent that there are clinically important variations from this usual course. In approximately 15 percent of cases, patients may experience profound renal insufficiency, even anuria. It is also clear that although interstitial nephritis usually improves when the offending drug or
INTERSTITIAL NEPHRITIS
agent is discontinued, rarely it may continue to progress. Furthermore, although renal function usually returns, in a small fraction of instances there may be significant residual renal damage. The role of corticosteroid therapy in this disease has not been clarified. However, in view of the data available and the occasional poor prognosis of the underlying illness, there may be at least some cases of acute interstitial nephritis in which glucocorticosteroid therapy will be beneficial and necessary for optimal recovery.
REFERENMES 1. Lyons H, Pinn VW, Cortell S, et al: Allergic interstitial nephritis causing reversible renal failure in four patients with idiopathic nephrotic syndrome. N Engl J Med 288:124-128, Jan 18, 1973 2. Baldwin DS, Levine BB, McCluskey RT, et al: Renal failure and interstitial nephritis due to penicillin and methicillin. N Engl 3 Med 279:1245-1252, Dec 5, 1968 3. Simenhoff ML, Guild WR, Dammin GJ: Acute diffuse interstitial nephritis. Am J Med 44:618-625, Apr 1968 4. Gilbert DN, Gourley R, d'Agostino A, et al: Interstitial nephritis due to methicillin, penicillin and ampicillin. Ann Allergy 28:378-385, 1970 5. Border WA, Lehman DH, Egan JD, et al: Antitubular basement-membrane antibodies in methicillin associated interstitial nephritis. N Engl J Med 291:381-384, Aug 22, 1974 6. Steblay RW, Rudofsky V: Transfer of experimental autoimmune renal cortical tubular and interstitial disease in guinea pigs by serum. Science 180:966-968, 1973
Clomiphene (Clomid®): Is it Teratogenic? The advantages of using clomiphene citrate far outweigh the possible disadvantages of using the drug . . . It is much safer to treat patients who have problems with anovulation as the cause of their infertility with clomiphene than to use the other agent that is available-human menopausal gonadotropin. Clomiphene citrate is a safe drug. Those ten percent of patients who have anovulation or oligo-ovulation as the cause of their infertility have a high chance of conceiving with treatment with clomiphene citrate. And if it is used correctly, with the pelvic examination done before each treatment, of course, there is no increased incidence of congenital abnormalities of the babies. Of course, a physician should take special precautions by doing a pelvic examination insuring the patient is not pregnant before each treatment course. And legally, the patient should be informed as to the possibility of multiple births. Other than these, physicians should continue to use clomiphene for the treatment of those infertility patients who do not ovulate or ovulate infrequently. They should not use the drug in the treatment of infertility patients in whom there are other causes for infertility. In our clinic, we have been using clomiphene citrate at higher than the recommended dosage-higher than 100 mg per day for five days. We have treated patients with as much as 250 mg per day for five days. At the higher dosages, some of the patients have conceived where they have not ovulated or conceived at the lower dosages. In our series of 24 babies born with treatment with this graduated sequential increasing medication regime of clomiphene citrate, we have had only one of the babies born with congenital abnormalities-a congenital heart defectand in this case the recommended dosage of 50 mg per day for five days was given. Therefore, it is my opinion that clomiphene continues to be a safe drug and is extremely useful for a patient with infertility who does not ovulate. Physicians do not have to be concerned about teratogenic effects of this agent. -DANIEL R. MISHELL, JR., MD, Los Angeles Extracted from Audio-Digest Obstetrics and Gynecology, Vol. 21, No. 11, in the Audio-Digest Foundation's subscription series of tape-recorded programs. For subscription information: 1930 Wilshire Blvd., Suite 700, Los Angees, CA 90057.
THE WESTERN JOURNAL OF MEDICINE
385
Refer to: Methicillin induced interstitial nephritis-Medical Staff Conference, University of California, San Francisco. West J Med 123:380-385, Nov 1975
Methicillin Induced Interstitial Nephritis These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr., Assistant Professor of Medicine, and H. David Watts, Assistant Professor of Medicine, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, CA 94143.
DR. SMITH: * This morning the topic for Medical Grand Rounds is methicillin induced interstitial nephritis. Dr. Barry Zacherle from the Division of Nephrology will discuss the topic and a patient recently seen on the Medical Service will be presented by Dr. McCurley. DR. MCCURLEY: t A 73-year-old white woman was admitted to the University of California Medical Center with exfoliative erythroderma. Twelve days before admission an erythematous papular rash developed on her chest. During the week before admission the rash became generalized, her skin became edematous and fever, chills and malaise were present. There had been similar episodes of generalized erythroderma at 3 to 4 year intervals since age 16. On physical examination, the patient appeared to be acutely ill. The pulse was 90 beats per minute, temperature 36.9°C (98.4°F) and blood pressure 150/72 mm of mercury. The skin was diffusely erythematous and scaly on face, trunk and extremities, and there was generalized edema which was nonpitting. A *Lloyd H. Smith, Jr., MD, Professor and Chairman, Department of Medicine. tThomas McCurley, MD, Intem in Medicine.
380
NOVEMBER 1975 *
123 * 5
grade II/VI systolic murmur at the left lower sternal border was noted. The admission laboratory data were pertinent as follows: hematocrit was 39.1 percent, leukocyte count was 16,500 per cu mm; the differential was 51 polymorphonuclear cells, 6 banded cells, 6 eosinophils and 37 percent lymphocytes. The peripheral smear had toxic granulation and vacuolation of the polymorphonuclear leukocytes. The serum creatinine was 1.1 mg per dl with blood urea nitrogen of 18 mg per dl. Findings on urinalysis showed no protein, 4 to 5 leukocytes and no red cells per high-power field. The exfoliative erythoderma resolved after a seven-day course of high dose parenteral and topical steroids. Five of nine blood cultures drawn after admission grew Staphylococcus aureus and on December 26, 1974, the patient was started on 8 grams per day of methicillin. Fourteen days later the patient had a hard-shaking chill associated with a temperature of 390C (102.20F). Findings on urinalysis showed no protein, 4 to 5 leukocytes per high-power field and no red cells. Serum creatinine was 1 mg per dl. Fever continued, and three days later serum creatinine was 6.9 mg per dl with 8 percent eosinophils on dif-
INTERSTITIAL NEPHRITIS Af,
~
'i
ob
~
7
.e
At
10e'
.f..-.94 ON ~~.
o-
J.a.'
~~ j;~~~V V J
1. 4 ..
Figure I.-Section of kidney.
a normal
Figure 2.-Section of a kidney biopsy specimen from patient with methicillin interstitial nephritis.
ferential leukocyte cell count. On testing, urine had 3 + proteinuria, 1 to 3 tubular epithelial cells per high-power field and 4 to 5 red blood cells per high-power field. Findings on intravenous pyelogram and renal scan showed bilaterally poorly functioning kidneys without obstruction. Serum complement levels were normal. A renal biopsy specimen was taken, the histology of which showed an interstitial nephritis. Treatment with parenteral steroids was begun and after one week the creatinine level had fallen to 2.1 mg per dl. Steroids were discontinued and creatinine rose to 4.6 mg per dl. At that time there were 16 percent eosinophils on differential count and results of urinalysis showed 1 + proteinuria with 3 to 5 tubular epithelial cells and 1 to 2 red cells per high-power field. Administration of prednisone (40 mg per day) was begun again and four days later the serum creatinine level was 2.6 mg per dl. DR. ZACHERLE: * In the patient presented this morning, acute renal failure was present due to an interstitial nephritis which appeared to be secondary to methicillin. Today I would like to discuss interstitial nephritis in general with the emphasis on drug-induced acute interstitial nephritides, particularly methicillin nephritis. The latter is the interstitial nephritis with which we are most apt to be confronted clinically today. Interstitial nephritis is primarily a histologic diagnosis. Figure 1 shows a section of a normal kidney biopsy specimen. The glomeruli are normal with open capillary loops, thin lacey capillary basement membranes and a normal amount
of mesangial substance and cellularity. The tubules are plentiful, filling up most of the remaining space, and appear normal. Those vessels present are also normal. The interstitial substance located between the glomeruli, tubules and vessels is essentially inapparent; this is the normal histology. Interstitial nephritis is, as the name implies, an inflammation of the interstitium without much change in the other structures (glomeruli, tubules or vessels). The interstitium becomes prominent; in the acute situation this is due to edema, but if the process becomes more chronic, fibrosis occurs. There is also a cellular inflammatory response which usually consists of polymorphonuclear leukocytes acutely and round cell infiltration later. Figure 2 is a section from the kidney biopsy specimen in the case under discussion today. The interstitial material is very apparent and there is an active cellular inflammatory response which is particularly prominent around the tubules. Although not apparent in this picture, many of the inflammatory cells are eosinophils. Clinically, as well as histologically, interstitial nephritis may be categorized as acute or chronic. Table 1 lists several of the systemic illnesses associated with both types. Although chronic disease is usually indolent and slowly progressive in its course, acute nephritis is more apt to be associated with an acute illness and a rapid deterioration of renal function. Before the introduction of antibiotics this was most -commonly seen in children with acute febrile illnesses, particularly scarlet fever and diphtheria. Currently it is occasionally seen associated with leptospirosis and brucellosis, but that which we are most likely to see as
a
biopsy specimen of
*Barry Zacherle, MD, Assistant Clinical Professor of Medicine and of Ambulatory and Community Medicine.
THE WESTERN JOURNAL OF MEDICINE
381
INTERSTITIAL NEPHRITIS
practicing physicians in 1975 is acute interstitial nephritis associated with a drug reaction. The first descriptions of such drug reactions involved the sulfonamides. In the early 1940's drug reactions to the sulfonamide antibiotics were described and included glomerulonephritis, vasculitis and interstitial nephritis. The same changes have been reported as reactions to other drugs such as the anticoagulant phenindione, diphenylhydantoin and more recently, methicillin, penicillin and ampicillin. In 1973, Lyons and coworkers' suggested that the same clinical features might occur also with thiazide diuretics. The latter is not surprising because the thiazides are chemically related to the sulfonamide drugs. The first reports of methicillin associated renal disease appeared in the early 1960's. Sporadic case reports then appeared throughout the mid 1960's, and in 1968 Baldwin and his associates2 compiled the cases of seven patients who had been receiving either methicillin or penicillin G, or both, and who had fairly distinct clinical features associated with acute interstitial nephritis noted on kidney biopsy. In the typical clinical presentation, fever is usually the first sign noted and then eosinophilia with or without rash appears. Subsequently the renal manifestations appear, although this sequence somewhat is variable. In fact, Baldwin had one patient in his group of seven in whom fever did not develop until after renal insufficiency was already present. In most of the cases reported in the literature the systemic manifestations are followed variably by hematuria, pyuria proteinuria and renal insufficiency, TABLE 1.-Interstitial Nephritides ACUTE
Infections Scarlet fever Diphtheria Leptospirosis Brucellosis Drugs Sulfonamides Phenindione Diphenylhydantoin Methicillin-penicillin-ampicillin-thiazides-furosemide CHRONIC
Pyelonephritis Analgesic abuse Ischemia Radiation Balkan nephritis Sarcoid Lead
Sjogren's syndrome
382
NOVEMBER 1975 * 123 * 5
and on kidney biopsy an acute interstitial nephritis is seen. This renal insufficiency is usually of a moderate degree, and recovery usually follows cessation of the administration of the antibiotic. Figure 3 shows the pertinent features of the case presented today. The patient was admitted with erythroderma, and because there was exfoliation, administration of prednisone was begun promptly. Eosinophilia was present when the patient came into the hospital, and there was no fever. The erythroderma cleared rapidly when the patient was taking prednisone and the dosage of prednisone was tapered shortly after admission. Results of three separate sets of blood cultures were positive for penicillin-resistant Staphylococcus aureus and she was begun on intravenous methicillin, 8 gm per day. The blood cultures were subsequently negative for S. aureus. The patient remained afebrile, serum creatinine ranged between 0.9 and 1 mg per dl and urine output was appropriate for fluid intake. Body weight did not change appreciably during the entire course of the time spent in hospital. After two weeks of methicillin therapy it was discontinued and oral administration of dicloxacillin was begun as indicated in Figure 3. During that period, the erythroderma flared slightly and fever developed. On the third day of that febrile episode, administration of methicillin was again begun and there were two days of both methicillin and dicloxacillin therapy. On the third day of that febrile episode it was noted that the serum creatinine level had risen to 6.9 and the patient was anuric. At this juncture, the usual features of methicillin nephritis appear to have been present-except for the anuria, which is unusual. With the possibility of vasculitis in mind, administration of prednisone was begun again and a renal biopsy specimen was obtained. When the renal biopsy specimen was examined and showed a typical interstitial nephritis, the prednisone was discontinued. During that period, urine output increased, renal function improved and serum creatinine fell to a level of 2.1 mg per dl. The patient became afebrile very quickly. A week after the prednisone was discontinued, there was a spiking temperature and the serum creatinine level rose again to almost 5 mg per dl. The patient was extensively evaluated at this point for any other cause of renal insufficiency and none was found. Administration of prednisone
INTERSTITIAL NEPHRITIS
PREDNISONE
Ou
(mg/day)
40200 CLOXACILLIN METHICILLIN
I
CLINDAMYCIN
I
PERIPHERAL 6%
EOSINOPHYLLIA
(PERCENT)
%F IV
9%
- F.
2%
46 ru
3%
%P tu
3% 8X 26% &Ulu %P Iru
W lu
1iIL 10
41.
TEMPERATURE 4039 (OC)
SERUM
%P-%f 09
CREATININE
1. kf 1i0
0.9 19 69 V.S. 92 71744 3321 1. %# W.%# 1.1 ---v %0.4 &..I
W. V
(mg%)
46 47 39
Ir.%P -7.1 %F.U
21 - &..I
3
URINE VOLUME
21
iml/day)
0-
I
I
28 DAYS O 14 7 21 35 59 42 Figure 3.-Clinical course of patient with methicillin interstitial nephritis. ED is an abbreviation used for erythroderma.
was started again and serum creatinine, which may have begun to decrease before the prednisone therapy was begun, fell to 2.1 mg per dl. Most of the features of typical methicillin interstitial nephritis were present in this patient. There are several peculiarities, however, that merit special attention. One is the extreme degree
of renal insufficiency. The second is that although the methicillin was discontinued and the renal function did improve initially, it deteriorated again later. The third is the question of what role prednisone may have had in the waxing and waning course of renal function in the patient. There are 24 cases of methicillin-associated interstitial nephritis in the literature. In four of the patients there was severe renal insufficiency; in the rest the usual features of only moderate renal insufficienty were seen. One case has been reported3 in which the patient was anuric. Therefore, although the usual feature is mild or moderate renal insufficiency, in approximately 15 percent of the cases very severe renal insufficiency and even anuria may develop. Second, what about the cessation of methicillin? It is very clear in the literature that, in most of the cases,
the patients do get better. However, there is one well-documented case in which the patient's renal function continued to deteriorate for several weeks following the cessation of penicillin and methicillin; this is also the only recorded case in the literature in which there was a clear response in the patient to steroid administration. The degree of ultimate recovery of function has not been carefully evaluated. In at least three patients, there was significant, persistent renal insufficiency. So, although recovery is usual, it may not always follow cessation of the antibiotic administration and may be significantly incomplete. Finally, among 24 of the previously reported patients, only three have been treated with steroids. In one5 there was an immediate improvement in the eosinophilia and fever and no change in renal function. In another3 there was an immediate improvement in renal function; however, administration of prednisone was begun at the same time that methicillin was discontinued. In the third case,4 clear-cut response to steroid therapy occurred on two occasions during the patient's course.
Steroid therapy also appears to have been helpTHE WESTERN JOURNAL OF MEDICINE
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ful in the treatment of acute interstitial nephritis associated with thiazide administration. Lyons and co-workers' described a group of four patients who had nephrotic syndrome. Findings from renal biopsies done during the course of evaluation of nephrotic syndrome showed glomerular disease with very little interstitial involvement. These patients were all treated with a number of medications including thiazide diuretics and furosemide, and over a course of several months there was pronounced deterioration of renal function in all of them. Of these four patients, two had peripheral eosinophilia, and two did not. Biopsy studies were done again and at that point pronounced acute interstitial nephritis was noted. Those four patents were treated with steroids and in all a significant clinical response was obtained over a short length of time. If drug-induced interstitial nephritis is a distinct entity, why does it occur and what is the pathophysiology? The pathogenesis is not understood, but it is probably an immunologic disease. This was first suggested by the clinical features which include rash, eosinophilia and fever. There are two patients in the literature who have been carefully evaluated from an immunological standpoint, one patient in Baldwin's study2 and another patient described by Border and his associates5 in 1974. Both of these investigators made antibody to a dimethoxyphenyl penicilloyl moeity which is the haptenic or antigenic portion of methicillin. With that antibody to methicillin they were able to show staining of kidney basement membranes of their patients. In one case staining was found only on tubular basement membrane, and in the other case it was found on both tubular and glomerular basement membrane. This staining was shown to be very specific for the methicillin antigen; the authors were unable to obtain similar staining in tissue from normal persons, or from patients with other renal diseases. Antiserum against the benzylpenicilloyl moeity, the antigen of penicillin G, did not cause staining. Furthermore, both authors were able to block staining by absorption with methicillin, methicillin coated red cells or the univalent dimethoxyphenyl penicilloyl moeity. So it appears that in both, an antigenic portion of the methicillin molecule could be detected on at least the tubular basement membrane. Border5 was also able to find a circulating factor in the serum of his patient which indirectly stained normal human or monkey basement membrane. This 384
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staining could be blocked by absorption against human tubular basement membrane, but not against methicillin or methicillin coated red cells. Thus, it appeared that this factor in the serum was directed at the tubular basement membrane and not the methicillin. Steblay and Rudofsky6 produced in rabbits an antiserum against renal tubular basement membrane which they were able to inject into guinea pigs and produce not only staining of the tubular basement membrane but also an active interstitial nephritis. This animal model may or may not be analogous to the human disease. Border and coworkers5 were unable to produce interstitial nephritis in monkeys by injecting them with the antibasement membrane factor from their patient, in spite of their ability to detect by fluorescent staining the presence of basement membrane factor in the tubules. They postulate that this may have been due to the lower antibody titer in their own preparation. Although the experimental, immunologic data are not entirely clear, they do offer suggestions as do the clinical data, and a hypothesis regarding pathogenesis can be formulated with which most of our information fits. In some patients who for unknown reasons are susceptible, a portion of the methicillin molecule is bound to tubular basement membrane protein. Penicillin, methicillin and ampicillin are all organic acids and are secreted by the proximal tubular epithelial cells. It is of interest that the thiazides are also organic acids and are secreted in the same location by the same mechanism. The tubular basement membranemethicillin complex thus formed may then act as an immunogen which stimulates the production of an immunoglobulin G (IgG) antibody directed against the tubular basement membrane. The resulting tissue response to the subsequent antigenantibody reaction is an interstitial nephritis. In conclusion, interstitial nephritis may occur as an acute illness, and in most of our clinical practices it will appear as a reaction to a drug. This reaction is probably mediated by a series of immunologic events. The usual clinical presentation of this entity is well described, and most cases fit into the pattern described. However, it is now apparent that there are clinically important variations from this usual course. In approximately 15 percent of cases, patients may experience profound renal insufficiency, even anuria. It is also clear that although interstitial nephritis usually improves when the offending drug or
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agent is discontinued, rarely it may continue to progress. Furthermore, although renal function usually returns, in a small fraction of instances there may be significant residual renal damage. The role of corticosteroid therapy in this disease has not been clarified. However, in view of the data available and the occasional poor prognosis of the underlying illness, there may be at least some cases of acute interstitial nephritis in which glucocorticosteroid therapy will be beneficial and necessary for optimal recovery.
REFERENMES 1. Lyons H, Pinn VW, Cortell S, et al: Allergic interstitial nephritis causing reversible renal failure in four patients with idiopathic nephrotic syndrome. N Engl J Med 288:124-128, Jan 18, 1973 2. Baldwin DS, Levine BB, McCluskey RT, et al: Renal failure and interstitial nephritis due to penicillin and methicillin. N Engl 3 Med 279:1245-1252, Dec 5, 1968 3. Simenhoff ML, Guild WR, Dammin GJ: Acute diffuse interstitial nephritis. Am J Med 44:618-625, Apr 1968 4. Gilbert DN, Gourley R, d'Agostino A, et al: Interstitial nephritis due to methicillin, penicillin and ampicillin. Ann Allergy 28:378-385, 1970 5. Border WA, Lehman DH, Egan JD, et al: Antitubular basement-membrane antibodies in methicillin associated interstitial nephritis. N Engl J Med 291:381-384, Aug 22, 1974 6. Steblay RW, Rudofsky V: Transfer of experimental autoimmune renal cortical tubular and interstitial disease in guinea pigs by serum. Science 180:966-968, 1973
Clomiphene (Clomid®): Is it Teratogenic? The advantages of using clomiphene citrate far outweigh the possible disadvantages of using the drug . . . It is much safer to treat patients who have problems with anovulation as the cause of their infertility with clomiphene than to use the other agent that is available-human menopausal gonadotropin. Clomiphene citrate is a safe drug. Those ten percent of patients who have anovulation or oligo-ovulation as the cause of their infertility have a high chance of conceiving with treatment with clomiphene citrate. And if it is used correctly, with the pelvic examination done before each treatment, of course, there is no increased incidence of congenital abnormalities of the babies. Of course, a physician should take special precautions by doing a pelvic examination insuring the patient is not pregnant before each treatment course. And legally, the patient should be informed as to the possibility of multiple births. Other than these, physicians should continue to use clomiphene for the treatment of those infertility patients who do not ovulate or ovulate infrequently. They should not use the drug in the treatment of infertility patients in whom there are other causes for infertility. In our clinic, we have been using clomiphene citrate at higher than the recommended dosage-higher than 100 mg per day for five days. We have treated patients with as much as 250 mg per day for five days. At the higher dosages, some of the patients have conceived where they have not ovulated or conceived at the lower dosages. In our series of 24 babies born with treatment with this graduated sequential increasing medication regime of clomiphene citrate, we have had only one of the babies born with congenital abnormalities-a congenital heart defectand in this case the recommended dosage of 50 mg per day for five days was given. Therefore, it is my opinion that clomiphene continues to be a safe drug and is extremely useful for a patient with infertility who does not ovulate. Physicians do not have to be concerned about teratogenic effects of this agent. -DANIEL R. MISHELL, JR., MD, Los Angeles Extracted from Audio-Digest Obstetrics and Gynecology, Vol. 21, No. 11, in the Audio-Digest Foundation's subscription series of tape-recorded programs. For subscription information: 1930 Wilshire Blvd., Suite 700, Los Angees, CA 90057.
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