Volume 55, Issue 2 , Pages 386-390, February 2010
An Uncommon Cause of Membranous Glomerulonephritis
Article Outline
Index Words: Membranous glomerulonephritis, lupus nephritis, syphilis
Membranous glomerulonephritis (MGN) is one of the most common causes of nephrotic syndrome in the adult population, characterized by the formation of subepithelial immune complexes in the glomerular capillary wall and associated with heavy proteinuria. MGN is not a single disease entity, but a pattern of injury in the kidney with diverse causes. MGN can be primary/idiopathic (cause unknown) or secondary. Known causes of secondary MGN are described under 4 broad categories: (1) drugs/medications, (2) infections, (3) autoimmune disorders, and (4) malignancy.
Unfortunately, based on histological features alone, it often is impossible to delineate primary versus secondary MGN and accurately determine the underlying cause. Histological features that may help include: (1) the distribution pattern of subepithelial immune complex deposits along the glomerular capillary walls (numerous regularly arranged deposits suggest primary idiopathic MGN and fewer irregularly distributed deposits are suggestive of secondary MGN); (2) deposits mainly in the subepithelial (epimembranous) location favor primary MGN, whereas large deposits traversing the entire thickness of the glomerular basement membrane characteristically are seen in systemic lupus erythematosus (SLE)-associated MGN; and (3) the presence of associated mesangial and extraglomerular immune complex deposits also suggests an autoimmune cause, such as SLE. However, in routine practice of kidney pathology, the majority of biopsy specimens with MGN may not show these characteristic distinguishing features, thus precluding definitive conclusions regarding possible cause.
In recent practice, immunofluorescence (IF) staining with antibodies to immunoglobulin G (IgG) subtypes has been used. According to a few recent reports,1, 2 predominant IgG4 staining in the glomerular capillary loops favors idiopathic MGN. Strong IgG1 and IgG3 with or without IgG2 is suggestive of lupus MGN. Predominant IgG2 staining raises the possibility of underlying malignancy. However, IF for IgG subtypes may not be routinely available.
Obtaining such pertinent clinical information as patient age, drug/medication history, history of infection, serological test results or clinical history of autoimmune disease, and possibility of malignancy are important to pathologists and nephrologists for determining the possible cause of MGN to direct appropriate therapy.
We present a case of secondary MGN, the cause of which is very uncommon in the United States and therefore easy to miss.
Case Report
Clinical History and Initial Laboratory Studies
A previously healthy 18-year-old African American woman presented with nausea and vomiting to Mount Carmel East Hospital, Columbus, OH, in May 2008. She had been evaluated 2 weeks before her admission for fatigue and shortness of breath, at which time she was found to be profoundly anemic, with a hemoglobin level of 4.7 g/dL (47 g/L; presumably because of heavy gynecological bleeding, for which she had been prescribed intramuscular progesterone). Two units of packed red blood cells were transfused, and she was discharged from the emergency department. During the ensuing 2 weeks, she was seen several times in the emergency department for nausea and vomiting, eventually requiring admission for further evaluation. During one of these visits, oral fluoroquinolone treatment was started empirically for a presumed urinary tract infection based on the finding of pyuria on urine microscopy.
At the time of the patient's admission, she was noted to have facial (3+) and symmetrical lower-extremity (1+) edema, which according to her report had been noted only in the days immediately before admission. She denied a history of upper respiratory symptoms and noted suprapubic pain and dysuria. Her medical history was significant for excision of a thoracic neuroblastoma as an infant. She had no history of alcohol or illicit drug use or family history of kidney disease.
On physical examination, the patient was noted to be afebrile and normotensive. Faint crackles were present at the bases on pulmonary auscultation, she had multiple tattoos on the skin, and no rash was noted. Admission laboratory study results were remarkable for leukocytosis, severe albuminuria by means of urine dipstick, serum creatinine level of 0.9 mg/dL (68.6 μmol/L), estimated glomerular filtration rate greater than 60 mL/min/1.73 m2 (>1 mL/s/1.73 m2, based on the 4-variable Modification of Diet in Renal Disease [MDRD] Study equation), and profound hypoalbuminemia, with a serum albumin level of 1 g/dL (10 g/L). Urine sediment showed isomorphic red blood cells and occasional oval fat bodies. Spot urine protein-creatinine ratio was markedly increased at 19 mg/mg. A kidney biopsy was arranged before obtaining results of broad serological testing.
Kidney Biopsy
Biopsy tissue contained renal cortex and medulla, with a total of 29 well-perfused glomeruli. Glomeruli were unremarkable by means of hematoxylin and eosin (Fig 1), periodic acid–Schiff, Jones methenamine silver, and trichrome stains. There was no interstitial inflammation, interstitial fibrosis, or tubular atrophy, but mild acute tubular injury was seen. Direct immunofluorescence (DIF) with our routine panel of antibodies (albumin, IgG, IgA, IgM, C1q, C3, fibrinogen, and κ and λ light chains) showed bright diffuse granular glomerular capillary wall staining for IgG and C3, moderate intensity staining for κ and λ light chains, and mild granular glomerular capillary staining for IgM. DIF staining with antibodies to IgG subtypes showed moderate (2+) IgG1 and mild (1+) IgG3. Staining for IgG2 and IgG4 was trace to negative (Fig 2). Ultrastructural examination showed small subepithelial electron-dense immune-type deposits (Ehrenreich and Churg glomerular stage I) with variable distribution in glomerular capillary loops (Fig 3). A few small mesangial immune-type deposits were identified. Endothelial tubuloreticular inclusions also were present (Fig 4). Podocyte foot-process effacement was diffuse.
Figure 1.
Hematoxylin and eosin–stained paraffin-embedded section. The glomerulus looks unremarkable (original magnification ×400).
Figure 2.
Staining pattern for immunoglobulin G (IgG) subtypes. (A) Direct immunofluorescence shows moderate granular staining for IgG1 along the glomerular capillary wall, (B) absent staining for IgG2, (C) mild granular staining for IgG3 along the glomerular capillary wall, and (D) absent staining for IgG4 (frozen section; original magnification ×400).
Figure 3.
Electron micrograph shows scattered subepithelial electron-dense immune-type deposits, irregularly distributed (arrows) (uranyl acetate lead citrate staining; original magnification ×12,000).
Figure 4.
Electron micrograph shows endothelial tubuloreticular inclusion (arrow) (uranyl acetate lead citrate staining; original magnification ×30,000).
Diagnosis
A diagnosis of MGN was made, noting that in the appropriate clinical setting, the findings could be consistent with early lupus membranous nephritis (International Society of Nephrology/ Renal Pathology Society [ISN/RPS] class V).
Clinical Follow-up
Considering the clinical presentation of fulminant nephrotic syndrome, the decision was made to initiate corticosteroid treatment before the biopsy result was available. Unfortunately, shortly after the patient's admission, she developed a severe headache. She was evaluated further by means of magnetic resonance imaging and magnetic resonance venography, which showed superior sagittal sinus thrombosis. She was treated with intravenous heparin and warfarin. Later in her stay, she additionally was found to have pulmonary embolism on computed tomography and pulmonary arteriography. Although the severe hypoalbuminemia was believed to be the most likely risk factor for the hypercoagulable state, she was evaluated for alternative explanations for thrombophilia.
Given the initial kidney pathological results and in the absence of serological evidence to the contrary, it was believed that the patient's clinical course was most consistent with ISN/RPS class V lupus nephritis, and immunosuppression therapy was initiated, initially with corticosteroids and eventually with mycophenolate mofetil. However, as more laboratory data became available (Table 1), an alternate explanation became apparent. She showed a positive rapid plasma reagin test result, as well as a positive fluorescent treponemal antigen result. It was believed that the MGN was caused by underlying syphilis. Therefore, high-dose intramuscular penicillin was administered. Interestingly, even before this, a spot urine protein test (unfortunately performed without concomitant urine creatinine measurement) showed less than 6 mg/dL (<60 mg/L) of protein. Only 48 hours after the initiation of penicillin therapy, she was noted to have near-complete resolution of edema, and 24-hour urine protein level had decreased to only 150 mg/d. Immunosuppression therapy was discontinued, and a series of 3 weekly injections of intramuscular penicillin was planned.
Table 1. Laboratory Test Results
| Test | Result | Normal Range |
|---|---|---|
| Antinuclear antibody (enzyme immunoassay) | Negative | |
| C3 (mg/mL) | 126 | 90-180 |
| C4 (mg/mL) | 26 | 10-40 |
| Cryoglobulins | Negative | |
| Human immunodeficiency virus | Negative | |
| Hepatitis B surface antigen | Negative | |
| Hepatitis B surface antibody | Borderline | |
| Hepatitis C antibody | Negative | |
| Rapid plasma reagin titer | 1:64 | |
| Fluorescent treponemal antibody | Reactive | |
| Immunoglobulin M anticardiolipin antibody (GPL) | 10.8 | <15 |
| Immunoglobulin G anticardiolipin antibody (MPL) | 40.1 | <12 |
| Anti–β2 glycoprotein I antibody | Negative |
Discussion
Syphilis is a well-known cause of secondary MGN,3, 4, 5, 6 but is not commonly diagnosed in the United States. According to data from the 2001 to 2004 National Health and Nutrition Examination Surveys, US population-based estimates of syphilis seroprevalence show overall seroreactivity of 0.71% in the general population (aged 18 to 49 years), with substantial disparity by race/ethnicity.7, 8, 9
In a patient with a known history of syphilis (even latent syphilis) who develops MGN,6 the possibility of syphilis as the underlying cause is not very difficult to diagnose. However, in a young patient with undiagnosed/subclinical syphilis and findings of MGN on kidney biopsy, both the nephropathologist and nephrologist may not consider syphilis as the underlying cause of MGN because of the rarity of this infection in the United States. Of the infection-related causes of secondary MGN, hepatitis B is much more common.11, 12 There is only 1 case report describing subclinical acquired syphilis presenting as MGN in a patient from Malaysia.10 However, it is important to recognize syphilis as an underlying cause of MGN because appropriate antibiotic treatment can yield complete remission of the kidney disease.4, 13, 14, 15, 16
In our patient, there were several confounding factors that favored early lupus-associated MGN. These factors include female sex, young age, African American ethnicity, few mesangial immune-complex deposits and endothelial tubuloreticular inclusions on ultrastructural examination of the biopsy specimen, and predominance of IgG1 and IgG3 subtypes on DIF, a pattern more common in lupus nephritis. Endothelial tubuloreticular inclusions are interlacing branching tubular structures found in glomerular endothelial cells believed to represent an effect of interferon, therefore also called “interferon footprints.” Although they are seen in association with such viral infections as human immunodeficiency virus (HIV), hepatitis B, and hepatitis C, they are characteristically described in association with lupus nephritis. Absence of interstitial inflammation, “full-house” pattern, and C1q staining on DIF do not preclude the diagnosis of early membranous lupus nephritis. Serological test results for SLE were negative, but they can be negative in patients with early lupus nephritis, especially membranous lupus nephritis. Clinically, there were no stigmata of SLE. However, MGN can be the first manifestation of SLE, preceding other physical symptoms and signs by months or years.17
It is interesting to note that in our patient, the proteinuria seemed to have essentially abated before specific treatment for syphilis with intramuscular penicillin. Fluoroquinolones administered early in the course for presumptive urinary tract infection are unlikely to have an effect against syphilis.18, 19, 20 A more likely possibility seems to be that empirical treatment with corticosteroids and mycophenolate mofetil may have caused remission in proteinuria before penicillin treatment.21
The patient in this case clearly showed a hypercoagulable state, manifested by findings of sagittal sinus thrombosis and pulmonary thromboembolism. Thrombophilia is a well-described complication of nephrotic syndrome.22 Our patient was positive for IgG anticardiolipin antibodies, which often are found in association with syphilis infection, but, in general, are not believed to be thrombogenic.23 Antibodies against β2 glycoprotein I, the main antigenic target in the antiphospholipid syndrome, were not found.
Our case serves as a reminder that MGN is a heterogeneous immunologic disease with diverse potential causes. Clinical, morphological, and immunostaining results (including IgG subtypes) should be evaluated in detail, and if any of these parameters do not fit with idiopathic MGN or the more commonly seen causes, such as lupus nephritis, hepatitis B infection, nonsteroidal anti-inflammatory drugs, or malignancy (in elderly patients), an effort to look for the uncommon causes should be made because both treatment and outcome can change. MGN can be associated with both congenital and acquired (secondary phase) syphilis. Regardless of the clinical course and histopathologic pattern, serological test results usually are strongly positive.4 There is a good chance of clinical remission in these patients. Also, misdiagnosis of autoimmune disease can trigger immunosuppressive therapy, which can be detrimental if infection is the underlying cause.
Acknowledgements
Support: None.
Financial Disclosure: None.
References
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- Glomerular and serum IgG subclasses in diffuse proliferative lupus nephritis, membranous lupus nephritis, and idiopathic membranous nephropathy. Intern Med. 2002;41:936–942
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Originally published online as doi:10.1053/j.ajkd.2009.06.015 on July 31, 2009.
PII: S0272-6386(09)00878-6
doi:10.1053/j.ajkd.2009.06.015
© 2010 National Kidney Foundation, Inc. All rights reserved.
Volume 55, Issue 2 , Pages 386-390, February 2010
