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Membranous Nephropathy Associated With Fluconazole Treatment
Membranous Nephropathy Associated With Fluconazole Treatment Gyu-Tae Shin, MD, Hyunee Yim, MD, Jieun Park, MD, and Heungsoo Kim, MD About 6% to 9% of cases of membranous nephropathy develop secondary to exposure to drugs. Fluconazole is a widely used antifungal agent that was never implicated in the development of membranous nephropathy. We report the case of a patient found to have membranous nephropathy secondary to fluconazole treatment. This patient had recurrent episodes of nephrotic syndrome caused by readministration of fluconazole. This is the first reported case of membranous nephropathy caused by fluconazole treatment and the first case report of the clinical course of recurrent membranous nephropathy caused by reexposure to this medication. Am J Kidney Dis 49:318-322. © 2007 by the National Kidney Foundation, Inc. INDEX WORDS: Membranous nephropathy; fluconazole; proteinuria.
M
embranous nephropathy is the most common cause of nephrotic syndrome in adults. It usually is idiopathic, and 21% to 25% of cases occur secondary to such identifiable causes as systemic lupus nephritis, malignancies, hepatitis B, and use of drugs.1 Drugs appear to be the cause of membranous nephropathy in 6% to 9% of cases, and a variety of drugs were reported in association with its development.1 Gold and penicillamine used in patients with rheumatoid arthritis are typical examples of causative drugs.2,3 Nonsteroidal anti-inflammatory drugs also were implicated in the development of membranous nephropathy.4,5 Anti–tumor necrosis factor ␣ agents used in patients with rheumatological diseases and 2-mercaptopropionylgycine to treat cystinuria also were associated with membranous nephropathy.6,7 Fluconazole is a widely used synthetic triazole antifungal agent. It generally is well tolerated and never was reported as a cause of nephropathies. We report the case of a patient administered a From the Department of Nephrology, Ajou University School of Medicine, Suwon, Korea. Received September 13, 2006; accepted in revised form November 9, 2006. Originally published online as doi:10.1053/j.ajkd.2006.11.033 on January 3, 2007. Support: None. Potential conflicts of interest: None. Address reprint requests to Gyu-Tae Shin, MD, Ajou University School of Medicine, Department of Nephrology, Youngtong-gu, Wonchon-dong, San 5, Suwon, South Korea 442-749. E-mail: [email protected] © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/4902-0018$32.00/0 doi:10.1053/j.ajkd.2006.11.033 318
once-weekly dose of fluconazole8,9 for resistant tinea pedis who subsequently developed membranous nephropathy. CASE REPORT A 58-year-old woman presented with increasing generalized edema accompanied by nausea and indigestion for 3 weeks in February 2005. The patient had a history of hypertension for 10 years and cervical cancer (carcinoma in situ), for which she underwent total abdominal hysterectomy in 1998, and had been followed up with yearly Papanicolaou smears thereafter. She had been administered amlodipine for hypertension, and recently, hydrochlorothiazide, metoclopramide, and levosulpiride (Levopride; SK Pharmaceuticals, Korea) were prescribed by a primary care physician. No other medication history was obtained at initial presentation. Physical examination showed blood pressure of 146/97 mm Hg, clear breath sounds, and 3⫹ lower-extremity pitting edema. Serum creatinine level was 2.6 mg/dL (230 mol/L). Serum albumin level was 1.7 g/dL (17 g/L). Urinary protein excretion was 21 g/d by means of urinary protein-creatinine ratio. Serological test results for antinuclear antibody, antineutrophil cytoplasmic antibody, hepatitis B surface antigen, and hepatitis C antibody were negative. Immunologic test results for antistreptolysin O titer, C3, C4, and C-reactive protein were within normal range. Urine microscopy showed 8 red blood cells and 10 white blood cells per high-power field. Abdomen and kidney ultrasound study findings were unremarkable. One week after initial presentation, a percutaneous renal biopsy was performed. Light microscopy showed 15 glomeruli, 1 of which was globally sclerotic. Glomerular tufts showed normal cellularity, and the glomerular capillary wall did not seem to be thickened. Immunofluorescence studies showed granular staining mainly for immunoglobulin G and C3 along the glomerular basement membrane (GBM). Electron microscopy showed subepithelial immune deposits along the GBM and epithelial foot-process effacement. Immune deposits were widely dispersed and separated by uninvolved GBM. These findings indicate that the patient had stage I membranous nephropathy (Fig 1).
American Journal of Kidney Diseases, Vol 49, No 2 (February), 2007: pp 318-322
Fluconazole-Induced Nephropathy
319
Figure 1. Renal biopsy findings. Electron microscopy shows subepithelial dense deposits and foot-process effacement. Arrows represent subepithelial immune deposits. Note that immune deposits are widely dispersed and separated by uninvolved GBM.
After the diagnosis, the patient was sent back to the cancer center, where cervical cancer surgery was performed to evaluate for recurrence. There was no evidence of recurrence. Esophagogastroduodenoscopy, colonoscopy, and mammogram were all negative for malignancy. Two months after initial presentation, she returned to our renal clinic and underwent follow-up blood and urine tests. Surprisingly, urine test results were negative for protein, and serum albumin level was 4.0 g/dL (40 g/L). At this clinic visit, amlodipine was changed to valsartan therapy. Follow-up tests in 1 month confirmed recovery from nephrotic syndrome. Approximately 5 months after initial presentation, the patient returned to the clinic with reports of increasing pedal edema. Laboratory tests showed relapse of nephrotic syndrome. Because her clinical course was difficult to understand, she was asked to return to the clinic in 2 weeks for repeated laboratory tests. Surprisingly, repeated tests showed resolution of proteinuria, again with increasing serum albumin levels. The patient was questioned about whether she was using drugs other than those prescribed by our clinic, and she reported that she had been using once-weekly doses of fluconazole for tinea pedis, prescribed by a doctor in her hometown. The drug store in her hometown was contacted, and prescription records were obtained; she had been using fluconazole, 150 mg/wk, continuously for 1 year until 3 weeks before the initial presentation, and then intermittently after that, only when she returned to her hometown. The temporal relationship between nephropathy onset and fluconazole intake seemed apparent; hence, she was instructed not to use the fluconazole. In addition, valsartan therapy was discontinued without prescribing other antihypertensive drugs to remove any confounding factors. Laboratory tests in 3 weeks confirmed recovery from proteinuria. About 6½ months after the initial presentation,
the patient returned to the clinic with relapsing pedal edema, and her laboratory tests showed relapse of nephrotic syndrome. The patient reported that she could not resist resuming fluconazole therapy because of her annoying tinea pedis, and this was confirmed by recontacting the drug store. The instruction was emphasized, and she was sent home with amlodipine and torasemide therapy. Off fluconazole therapy, the patient went into complete remission again in approximately 2 months. Since this episode, she has not resumed fluconazole therapy and has had no relapse observed during the past 10 months. Her clinical course is shown in Fig 2.
DISCUSSION
Fluconazole is a widely used antifungal agent that has never been described as a cause of nephropathies. In this report, for the first time, we describe a case implicating fluconazole in the development of membranous nephropathy. Additionally, this report describes clinical events of membranous nephropathy when the causative drug is readministered after resolution of the disease. When nephrotic syndrome recurred in our patient, she was instructed to stop using fluconazole; however, she resumed fluconazole therapy on returning to her hometown and subsequently developed nephrotic syndrome again. Although unfortunate for the patient, this episode mimicking a prospective rechallenge experiment made the relationship between fluconazole and membranous nephropathy more evident. The observa-
320
Shin et al
Figure 2. The clinical course of the presenting patient with fluconazole-induced membranous nephropathy. Short-term use of medications given on an as-needed basis (eg, torasemide and metoclopramide) is not shown. To convert serum creatinine (Cr) in mg/dL to mol/L, multiply by 88.4; serum albumin in g/dL to g/L, multiply by 10.
tion that she remained disease free during 10 months while off fluconazole therapy further supports the association of this drug and the development of membranous nephropathy. At initial presentation, time to resolution of proteinuria was approximately 3 months after the last dose of fluconazole in January 2005. Previous reports described variable speeds of spontaneous recovery of proteinuria. Proteinuria resolved spontaneously by 6 to 24 months with gold2 and by to 6 to 18 months for penicillamine3 after cessation of therapy. Nonsteroidal antiinflammatory drug–induced membranous nephropathy appears to recover more rapidly. Radford et al5 reported that proteinuria decreased soon after nonsteroidal anti-inflammatory drug therapy cessation, with a decrease to protein of less than 1 g/d by 9 to 64 weeks. Remarkably, proteinuria in captopril-associated membranous nephropathy was reported to disappear within 10 days after withdrawal of the drug.10 It is intriguing that our patient’s membranous nephropathy relapsed with such rapidity after the
restart of fluconazole therapy, as was improvement after its withdrawal. We do not know whether this is a usual feature of membranous nephropathy because we were not able to find other reports describing the clinical course of recurrent membranous nephropathy due to a rechallenge with the drug. Rapid relapse may be explained by the presence of sensitization through previous use of the drug, whereas such rapid resolution may be unpredicted given that removal of subepithelial immune deposits is slow because of their separation from the circulation by the GBM. Our speculation for this question is that the factors prerequisite for proteinuria, other than immune deposits, may disappear faster in the relapsed event than the initial one. Such factors could be complement activation and C5b-9 formation, which are indispensable for the development of proteinuria in patients with membranous nephropathy.11 Hoorntje et al10 found that immune deposits in patients with captopril-associated membranous nephropathy were persistent in the follow-up biopsy tissue, although proteinuria resolved.
Fluconazole-Induced Nephropathy
The pathogenesis of membranous nephropathy remains uncertain. The nephritogenic antigen and its antibody may form an immune complex in the circulation or in situ in the subepithelial area that subsequently forms subepithelial immune deposits. Although the nephritogenic antigen remains unknown, it is certain that the implicated drugs should have a key role in the production of immune complexes in patients with drug-induced membranous nephropathy. In gold-associated membranous nephropathy, it was suggested that antigens released from damaged proximal tubules, which also are constituents of podocytes, provoke autoantibody production, as in Heymann nephritis.11 Other investigators showed that gold triggered T-cell clones leading to polyclonal B-cell proliferation and antibody production.12 Likewise, it can be speculated that fluconazole may damage proximal tubular cells, leading to the release of nephritogenic antigens with subsequent antibody production. Another speculation is that fluconazole may induce antibody production through fluconazole-specific T cells, or it may act as hapten by being bound to blood proteins,13 and induce a secondary antibody response. At present, we do not know whether this patient has a predisposing factor to develop membranous nephropathy when exposed to fluconazole. It was reported that some patients have a genetic predisposition to membranous nephropathy. For example, in patients with primary membranous nephropathy, HLA-DR3 frequency was significantly greater in patients than in a control population.14 Similarly, there was a high frequency of DQB1*0603 in subjects with hepatitis B–associated membranous nephropathy compared with controls.15 We expect more cases to be recognized in the future after fluconazole is on the list of causes; therefore, we will be able to better understand the predisposing mechanisms for this disease. It usually is impossible to differentiate idiopathic from secondary membranous nephropathy on morphological grounds; however, there are some characteristic renal biopsy findings suggestive of secondary membranous nephropathy, such as mesangial and extraglomerular immune deposits and endocapillary proliferation. In addition, Graham and Nagle16 observed the pattern of electron-dense deposit distribution along the
321
GBM and found that deposits were spaced more closely and ordered regularly in patients with primary membranous nephropathy, whereas deposits were dispersed widely and might be separated by long stretches of uninvolved GBM in patients with secondary membranous nephropathy. In our patient, we also were able to observe the same characteristics of electron-dense deposits of secondary membranous nephropathy as described by Graham and Nagle.16 In summary, we present a case of membranous nephropathy associated with fluconazole treatment. Membranous nephropathy secondary to fluconazole should be included in the differential diagnosis when patients develop proteinuria during fluconazole treatment. REFERENCES 1. Cahen R, Francois B, Trolliet P, Gilly J, Parchoux B: Aetiology of membranous glomerulonephritis: A prospective study of 82 adult patients. Nephrol Dial Transplant 4:172-180, 1989 2. Hall CL, Fothergill NJ, Blackwell MM, Harrison PR, MacKenzie JC, MacIver AG: The natural course of gold nephropathy: Long term study of 21 patients. Br Med J 295:745-748, 1987 3. Hall CL, Jawad S, Harrison PR, et al: Natural course of penicillamine nephropathy: A long term study of 33 patients. BMJ 296:1083-1086, 1988 4. Campistol JM, Galofre J, Botey A, Torras A, Revert L: Reversible membranous nephritis associated with diclofenac. Nephrol Dial Transplant 4:393-395, 1989 5. Radford MG, Holley KE, Grande JP, et al: Reversible membranous nephropathy associated with the use of nonsteroidal anti-inflammatory drugs. JAMA 276:466469, 1996 6. Stokes MB, Foster K, Markowitz GS, et al: Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis. Nephrol Dial Transplant 20:14001406, 2005 7. Lindell A, Denneberg T, Enestrom S, Fich C, Skogh T: Membranous glomerulonephritis induced by 2-mercaptopropionylglycine (2-MPG). Clin Nephrol 34:108-115, 1990 8. Lesher JL Jr: Oral therapy of common superficial fungal infections of the skin. J Am Acad Dermatol 40:S31S34, 1999 (suppl 6) 9. Del Aguila R, Gei FM, Robles M, Perera-Ramirez A, Male O: Once-weekly oral doses of fluconazole 150 mg in the treatment of tinea pedis. Clin Exp Dermatol 17:402-406, 1992 10. Hoorntje SJ, Donker AJ, Prins EJ, Weening JJ: Membranous glomerulopathy in a patient on captopril. Acta Med Scand 208:325-329, 1980
322 11. Nangaku M, Shankland SJ, Couser WG: Cellular response to injury in membranous nephropathy. J Am Soc Nephrol 16:1195-1204, 2005 12. Romagnoli P, Spinas GA, Sinigaglia F: Gold-specific T cells in rheumatoid arthritis patients treated with gold. J Clin Invest 89:254-258, 1992 13. Joh K, Shibasaki T, Azuma T, et al: Experimental drug-induced allergic nephritis mediated by antihapten antibody. Int Arch Allergy Appl Immunol 88:337-344, 1989
Shin et al 14. Klouda PT, Manos J, Acheson EJ, et al: Strong association between idiopathic membranous nephropathy and HLA-DRW3. Lancet 2:770-771, 1979 15. Bhimma R, Hammond MG, Coovadia HM, Adhikari M, Connolly CA: HLA class I and II in black children with hepatitis B virus-associated membranous nephropathy. Kidney Int 61:1510-1515, 2002 16. Graham AR, Nagle RB: Quantitative electron microscopic study of membranous glomerulopathy. Am J Clin Pathol 80:816-821, 1983
M
embranous nephropathy is the most common cause of nephrotic syndrome in adults. It usually is idiopathic, and 21% to 25% of cases occur secondary to such identifiable causes as systemic lupus nephritis, malignancies, hepatitis B, and use of drugs.1 Drugs appear to be the cause of membranous nephropathy in 6% to 9% of cases, and a variety of drugs were reported in association with its development.1 Gold and penicillamine used in patients with rheumatoid arthritis are typical examples of causative drugs.2,3 Nonsteroidal anti-inflammatory drugs also were implicated in the development of membranous nephropathy.4,5 Anti–tumor necrosis factor ␣ agents used in patients with rheumatological diseases and 2-mercaptopropionylgycine to treat cystinuria also were associated with membranous nephropathy.6,7 Fluconazole is a widely used synthetic triazole antifungal agent. It generally is well tolerated and never was reported as a cause of nephropathies. We report the case of a patient administered a From the Department of Nephrology, Ajou University School of Medicine, Suwon, Korea. Received September 13, 2006; accepted in revised form November 9, 2006. Originally published online as doi:10.1053/j.ajkd.2006.11.033 on January 3, 2007. Support: None. Potential conflicts of interest: None. Address reprint requests to Gyu-Tae Shin, MD, Ajou University School of Medicine, Department of Nephrology, Youngtong-gu, Wonchon-dong, San 5, Suwon, South Korea 442-749. E-mail: [email protected] © 2007 by the National Kidney Foundation, Inc. 0272-6386/07/4902-0018$32.00/0 doi:10.1053/j.ajkd.2006.11.033 318
once-weekly dose of fluconazole8,9 for resistant tinea pedis who subsequently developed membranous nephropathy. CASE REPORT A 58-year-old woman presented with increasing generalized edema accompanied by nausea and indigestion for 3 weeks in February 2005. The patient had a history of hypertension for 10 years and cervical cancer (carcinoma in situ), for which she underwent total abdominal hysterectomy in 1998, and had been followed up with yearly Papanicolaou smears thereafter. She had been administered amlodipine for hypertension, and recently, hydrochlorothiazide, metoclopramide, and levosulpiride (Levopride; SK Pharmaceuticals, Korea) were prescribed by a primary care physician. No other medication history was obtained at initial presentation. Physical examination showed blood pressure of 146/97 mm Hg, clear breath sounds, and 3⫹ lower-extremity pitting edema. Serum creatinine level was 2.6 mg/dL (230 mol/L). Serum albumin level was 1.7 g/dL (17 g/L). Urinary protein excretion was 21 g/d by means of urinary protein-creatinine ratio. Serological test results for antinuclear antibody, antineutrophil cytoplasmic antibody, hepatitis B surface antigen, and hepatitis C antibody were negative. Immunologic test results for antistreptolysin O titer, C3, C4, and C-reactive protein were within normal range. Urine microscopy showed 8 red blood cells and 10 white blood cells per high-power field. Abdomen and kidney ultrasound study findings were unremarkable. One week after initial presentation, a percutaneous renal biopsy was performed. Light microscopy showed 15 glomeruli, 1 of which was globally sclerotic. Glomerular tufts showed normal cellularity, and the glomerular capillary wall did not seem to be thickened. Immunofluorescence studies showed granular staining mainly for immunoglobulin G and C3 along the glomerular basement membrane (GBM). Electron microscopy showed subepithelial immune deposits along the GBM and epithelial foot-process effacement. Immune deposits were widely dispersed and separated by uninvolved GBM. These findings indicate that the patient had stage I membranous nephropathy (Fig 1).
American Journal of Kidney Diseases, Vol 49, No 2 (February), 2007: pp 318-322
Fluconazole-Induced Nephropathy
319
Figure 1. Renal biopsy findings. Electron microscopy shows subepithelial dense deposits and foot-process effacement. Arrows represent subepithelial immune deposits. Note that immune deposits are widely dispersed and separated by uninvolved GBM.
After the diagnosis, the patient was sent back to the cancer center, where cervical cancer surgery was performed to evaluate for recurrence. There was no evidence of recurrence. Esophagogastroduodenoscopy, colonoscopy, and mammogram were all negative for malignancy. Two months after initial presentation, she returned to our renal clinic and underwent follow-up blood and urine tests. Surprisingly, urine test results were negative for protein, and serum albumin level was 4.0 g/dL (40 g/L). At this clinic visit, amlodipine was changed to valsartan therapy. Follow-up tests in 1 month confirmed recovery from nephrotic syndrome. Approximately 5 months after initial presentation, the patient returned to the clinic with reports of increasing pedal edema. Laboratory tests showed relapse of nephrotic syndrome. Because her clinical course was difficult to understand, she was asked to return to the clinic in 2 weeks for repeated laboratory tests. Surprisingly, repeated tests showed resolution of proteinuria, again with increasing serum albumin levels. The patient was questioned about whether she was using drugs other than those prescribed by our clinic, and she reported that she had been using once-weekly doses of fluconazole for tinea pedis, prescribed by a doctor in her hometown. The drug store in her hometown was contacted, and prescription records were obtained; she had been using fluconazole, 150 mg/wk, continuously for 1 year until 3 weeks before the initial presentation, and then intermittently after that, only when she returned to her hometown. The temporal relationship between nephropathy onset and fluconazole intake seemed apparent; hence, she was instructed not to use the fluconazole. In addition, valsartan therapy was discontinued without prescribing other antihypertensive drugs to remove any confounding factors. Laboratory tests in 3 weeks confirmed recovery from proteinuria. About 6½ months after the initial presentation,
the patient returned to the clinic with relapsing pedal edema, and her laboratory tests showed relapse of nephrotic syndrome. The patient reported that she could not resist resuming fluconazole therapy because of her annoying tinea pedis, and this was confirmed by recontacting the drug store. The instruction was emphasized, and she was sent home with amlodipine and torasemide therapy. Off fluconazole therapy, the patient went into complete remission again in approximately 2 months. Since this episode, she has not resumed fluconazole therapy and has had no relapse observed during the past 10 months. Her clinical course is shown in Fig 2.
DISCUSSION
Fluconazole is a widely used antifungal agent that has never been described as a cause of nephropathies. In this report, for the first time, we describe a case implicating fluconazole in the development of membranous nephropathy. Additionally, this report describes clinical events of membranous nephropathy when the causative drug is readministered after resolution of the disease. When nephrotic syndrome recurred in our patient, she was instructed to stop using fluconazole; however, she resumed fluconazole therapy on returning to her hometown and subsequently developed nephrotic syndrome again. Although unfortunate for the patient, this episode mimicking a prospective rechallenge experiment made the relationship between fluconazole and membranous nephropathy more evident. The observa-
320
Shin et al
Figure 2. The clinical course of the presenting patient with fluconazole-induced membranous nephropathy. Short-term use of medications given on an as-needed basis (eg, torasemide and metoclopramide) is not shown. To convert serum creatinine (Cr) in mg/dL to mol/L, multiply by 88.4; serum albumin in g/dL to g/L, multiply by 10.
tion that she remained disease free during 10 months while off fluconazole therapy further supports the association of this drug and the development of membranous nephropathy. At initial presentation, time to resolution of proteinuria was approximately 3 months after the last dose of fluconazole in January 2005. Previous reports described variable speeds of spontaneous recovery of proteinuria. Proteinuria resolved spontaneously by 6 to 24 months with gold2 and by to 6 to 18 months for penicillamine3 after cessation of therapy. Nonsteroidal antiinflammatory drug–induced membranous nephropathy appears to recover more rapidly. Radford et al5 reported that proteinuria decreased soon after nonsteroidal anti-inflammatory drug therapy cessation, with a decrease to protein of less than 1 g/d by 9 to 64 weeks. Remarkably, proteinuria in captopril-associated membranous nephropathy was reported to disappear within 10 days after withdrawal of the drug.10 It is intriguing that our patient’s membranous nephropathy relapsed with such rapidity after the
restart of fluconazole therapy, as was improvement after its withdrawal. We do not know whether this is a usual feature of membranous nephropathy because we were not able to find other reports describing the clinical course of recurrent membranous nephropathy due to a rechallenge with the drug. Rapid relapse may be explained by the presence of sensitization through previous use of the drug, whereas such rapid resolution may be unpredicted given that removal of subepithelial immune deposits is slow because of their separation from the circulation by the GBM. Our speculation for this question is that the factors prerequisite for proteinuria, other than immune deposits, may disappear faster in the relapsed event than the initial one. Such factors could be complement activation and C5b-9 formation, which are indispensable for the development of proteinuria in patients with membranous nephropathy.11 Hoorntje et al10 found that immune deposits in patients with captopril-associated membranous nephropathy were persistent in the follow-up biopsy tissue, although proteinuria resolved.
Fluconazole-Induced Nephropathy
The pathogenesis of membranous nephropathy remains uncertain. The nephritogenic antigen and its antibody may form an immune complex in the circulation or in situ in the subepithelial area that subsequently forms subepithelial immune deposits. Although the nephritogenic antigen remains unknown, it is certain that the implicated drugs should have a key role in the production of immune complexes in patients with drug-induced membranous nephropathy. In gold-associated membranous nephropathy, it was suggested that antigens released from damaged proximal tubules, which also are constituents of podocytes, provoke autoantibody production, as in Heymann nephritis.11 Other investigators showed that gold triggered T-cell clones leading to polyclonal B-cell proliferation and antibody production.12 Likewise, it can be speculated that fluconazole may damage proximal tubular cells, leading to the release of nephritogenic antigens with subsequent antibody production. Another speculation is that fluconazole may induce antibody production through fluconazole-specific T cells, or it may act as hapten by being bound to blood proteins,13 and induce a secondary antibody response. At present, we do not know whether this patient has a predisposing factor to develop membranous nephropathy when exposed to fluconazole. It was reported that some patients have a genetic predisposition to membranous nephropathy. For example, in patients with primary membranous nephropathy, HLA-DR3 frequency was significantly greater in patients than in a control population.14 Similarly, there was a high frequency of DQB1*0603 in subjects with hepatitis B–associated membranous nephropathy compared with controls.15 We expect more cases to be recognized in the future after fluconazole is on the list of causes; therefore, we will be able to better understand the predisposing mechanisms for this disease. It usually is impossible to differentiate idiopathic from secondary membranous nephropathy on morphological grounds; however, there are some characteristic renal biopsy findings suggestive of secondary membranous nephropathy, such as mesangial and extraglomerular immune deposits and endocapillary proliferation. In addition, Graham and Nagle16 observed the pattern of electron-dense deposit distribution along the
321
GBM and found that deposits were spaced more closely and ordered regularly in patients with primary membranous nephropathy, whereas deposits were dispersed widely and might be separated by long stretches of uninvolved GBM in patients with secondary membranous nephropathy. In our patient, we also were able to observe the same characteristics of electron-dense deposits of secondary membranous nephropathy as described by Graham and Nagle.16 In summary, we present a case of membranous nephropathy associated with fluconazole treatment. Membranous nephropathy secondary to fluconazole should be included in the differential diagnosis when patients develop proteinuria during fluconazole treatment. REFERENCES 1. Cahen R, Francois B, Trolliet P, Gilly J, Parchoux B: Aetiology of membranous glomerulonephritis: A prospective study of 82 adult patients. Nephrol Dial Transplant 4:172-180, 1989 2. Hall CL, Fothergill NJ, Blackwell MM, Harrison PR, MacKenzie JC, MacIver AG: The natural course of gold nephropathy: Long term study of 21 patients. Br Med J 295:745-748, 1987 3. Hall CL, Jawad S, Harrison PR, et al: Natural course of penicillamine nephropathy: A long term study of 33 patients. BMJ 296:1083-1086, 1988 4. Campistol JM, Galofre J, Botey A, Torras A, Revert L: Reversible membranous nephritis associated with diclofenac. Nephrol Dial Transplant 4:393-395, 1989 5. Radford MG, Holley KE, Grande JP, et al: Reversible membranous nephropathy associated with the use of nonsteroidal anti-inflammatory drugs. JAMA 276:466469, 1996 6. Stokes MB, Foster K, Markowitz GS, et al: Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis. Nephrol Dial Transplant 20:14001406, 2005 7. Lindell A, Denneberg T, Enestrom S, Fich C, Skogh T: Membranous glomerulonephritis induced by 2-mercaptopropionylglycine (2-MPG). Clin Nephrol 34:108-115, 1990 8. Lesher JL Jr: Oral therapy of common superficial fungal infections of the skin. J Am Acad Dermatol 40:S31S34, 1999 (suppl 6) 9. Del Aguila R, Gei FM, Robles M, Perera-Ramirez A, Male O: Once-weekly oral doses of fluconazole 150 mg in the treatment of tinea pedis. Clin Exp Dermatol 17:402-406, 1992 10. Hoorntje SJ, Donker AJ, Prins EJ, Weening JJ: Membranous glomerulopathy in a patient on captopril. Acta Med Scand 208:325-329, 1980
322 11. Nangaku M, Shankland SJ, Couser WG: Cellular response to injury in membranous nephropathy. J Am Soc Nephrol 16:1195-1204, 2005 12. Romagnoli P, Spinas GA, Sinigaglia F: Gold-specific T cells in rheumatoid arthritis patients treated with gold. J Clin Invest 89:254-258, 1992 13. Joh K, Shibasaki T, Azuma T, et al: Experimental drug-induced allergic nephritis mediated by antihapten antibody. Int Arch Allergy Appl Immunol 88:337-344, 1989
Shin et al 14. Klouda PT, Manos J, Acheson EJ, et al: Strong association between idiopathic membranous nephropathy and HLA-DRW3. Lancet 2:770-771, 1979 15. Bhimma R, Hammond MG, Coovadia HM, Adhikari M, Connolly CA: HLA class I and II in black children with hepatitis B virus-associated membranous nephropathy. Kidney Int 61:1510-1515, 2002 16. Graham AR, Nagle RB: Quantitative electron microscopic study of membranous glomerulopathy. Am J Clin Pathol 80:816-821, 1983