NDT Advance Access originally published online on April 27, 2006
Nephrology Dialysis Transplantation 2006 21(8):2328-2330; doi:10.1093/ndt/gfl220
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Teaching Point
(Section Editor: A. Meyrier)
A Friday afternoon case of apparent anti-glomerular basement nephritis
1 Department of Internal Medicine III, 2 Institute of Clinical Chemistry and Laboratory Diagnostics, University of Jena and 3 Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany
Correspondence and offprint requests to: Gunter Wolf, MD, Klinik für Innere Medizin III, University Hospital Jena, Erlanger Allee 101, D-07747 Jena Germany. Email: gunter.wolf{at}med.uni-jena.de
Keywords: anti-GBM antibodies; acute renal failure; goodpasture syndrome; interstitial nephritis
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Introduction |
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The role of anti-GBM antibodies in the pathogenesis of Goodpasture's syndrome is well-known. Anti-GBM nephritis is a rapidly progressive disease and an early aggressive immunosuppressive treatment including plasmapheresis is necessary, as in advanced stages, a recovery of renal function rarely occurs. In addition, pulmonary haemorrhage is a life-threatening complication of Goodpasture's syndrome, requiring consequent removal of auto-antibodies against the
3 chain of type IV collagen. A high sensitivity, but also specificity of the diagnostic tests detecting circulating anti-GBM antibodies is therefore essential. |
Case |
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A 63-year-old man was first admitted to the hospital with sudden fever >39°C lasting for 5 days, accompanied by breath-dependent right-sided abdominal pain and melena. Furthermore, the patient had recently noticed a declining volume of urine. The patient had suffered from ankylosing spondylitis since 1998. No other accompanying diseases were known. The patient was transferred to our clinic, with the working diagnosis of acute renal failure on a Friday morning.
There was no arthritis and haemoptysis. The patient admitted contact with mice in the past, as he was an avid gardener. He reported the intake of two tablets of a combination of acetyl salicylic acid and acetaminophen in the last days and of circa 40 tablets of diclofenac in the previous 3 months for back pain. He had taken no other medication. On admission, the patient appeared sickly, with fever of 38.0°C and pain in the right epigastric region on palpation. Blood pressure was 120/80 mmHg. The patient remained anuric (<80 ml/day) despite volume infusion (1.5 l of 0.9% NaCl). There were no skin signs of vasculitis and the neurological examination was within normal limits. Initial serum laboratory investigations revealed serum creatinine of 647 µmol/l (normal range 72–124 µmol/l) and urea of 26.2 mmol/l (normal range 1.7–8.3 mmol/l), which corresponds to a calculated clearance of 13.5 ml/min (Cockcroft–Gault formula). Inflammatory markers were increased with a C-reactive protein of 365.4 mg/l (normal range 0–5mg/l) and a ferritin as acute phase protein of 3107 µg/l (normal range 30–300 µg/l). A modest elevation of liver enzymes was also observed. A urinary sediment showed <5% dysmorphic erythrocytes, a few hyaline casts, but proteinuria was <300 mg/l. Electrocardiogram, X-ray of the chest and a gastroscopy, performed due to melena, were normal. The ultrasound revealed enlarged kidneys up to 14 x 7 cm, suggesting acute renal failure and not chronic renal disease.
An acute Hantavirus infection was excluded. The titres of different auto-antibodies were negative (ANA, ds-DNA, c-ANCA, p-ANCA), but an enzyme-linked immunosorbent assay (ELISA) (quantitative anti-GBM from Imtec, Berlin, Germany) for anti-GBM antibodies was positive, with high titres (>200 U/ml). Although anti-GBM disease was unlikely because of the clinical presentation (no active urinary sediment, no proteinuria), the high anti-GBM titre, received on Friday afternoon in the presence of deteriorating renal function, prompted us to consider rapid-progressive glomerulonephritis. Treatment with methylprednisolone pulse therapy (1 g/day) and plasmapheresis was promptly initiated. Due to the anuria and uraemia, this regimen was supported by an intermittent haemodialysis therapy (a total of three dialysis sessions). A renal biopsy was performed the following Monday. By light microscopy, a diffuse, moderate, acute and potentially reversible tubular damage, in combination with a focal mild-to-moderate interstitial nephritis, was seen (data not shown). However, glomeruli were normal and revealed no signs of rapid progressive glomerulonephritis (Figure 1). The indirect immunofluorescence for IgG was also negative (Figure 2). Immunohistochemistry for IgA, IgG, IgM, C1q, C3, fibrine and C4d were negative. Plasmapheresis was stopped and prednisolone was tapered. The serum was tested for the presence of anti-GBM antibodies again and remained positive with the ELISA kit from Imtec. However, using monkey renal slides as target, no binding to glomerular basement membranes was not seen by indirect immunofluorescence. Furthermore, an anti-GBM ELISA from another manufacturer (Orgentec Diagnostika, Mainz, Germany) and a western blot test (Prof. Selig, Karlsruhe, Germany) did not reveal anti-GBM antibodies. Further analysis of the serum revealed antibodies against bovine albumin and after questioning the patient, an allergy to milk was revealed. The blocking reagent of the ELISA kit from Imtec contained bovine serum albumin, suggesting the reason for the false-positive result. The likely diagnosis in this case was analgesic and volume depletion-induced acute renal failure complicated by urinary infection, but not anti-GBM disease. After 4 months, renal function was completely recovered, and proteinuria was 204 mg/24 h. No immunosuppressive treatment was given.
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Discussion |
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The differential diagnosis of acute renal failure is complex and must be made swiftly to improve the outcome. In particular, rapid-progressive glomerulonephritis as a syndrome of underlying disease must be detected early, to enable prompt initiation of immunosuppressive therapy to maintain healthy renal function. In our case, an expensive therapeutical cascade with potential side-effects was started because of a false-positive anti-GBM test.
The target antigen that reacts with anti-GBM auto-antibodies is the 3(IV) collagen chain [1]. Historically, various methods have been used to detect circulating anti-GBM antibodies. The molecular identification of the antigen has facilitated the development of ELISA with the recombinant 3(IV) collagen chain as a target. A recent study compared different anti-GBM tests and found that the sensitivity of all tests was very high, but the specificity varied considerably [2]. In another report, anti-GBM antibodies were found in the serum of a patient with diabetic nephropathy [3]. Thus, false-positive results exist.
Our case adds an important new insight into a potentially false diagnosis of anti-GBM nephritis, by demonstrating that antibodies react against the blocking reagent bovine albumin. Dairy milk allergy is a complex disorder with a considerable heterogeneity amongst allergic individuals where IgE-mediated reactions are common in infancy, but IgG-dependent reactions are dominant in adults [4]. Although the exact role of different dairy milk proteins in the pathogenesis of allergy is still controversial, a recent study using mass spectroscopy showed that 45% of the individuals with a dairy milk allergy have antibodies against bovine serum albumin [5]. It is likely that due to the allergy to dairy milk, our patient, developed antibodies against bovine albumin that cross-reacted with the blocking substance of the anti-GBM ELISA.
The chance of a non-specific positive result increases with the number of individual parameters and often a ‘battery’ of screening laboratory tests is ordered by the inexperienced physician. The wide use of laboratory tests does not relieve the physician from the responsibility of careful clinical examination of the patient. In this regard, the clinical presentation of the patient, without active sediment and proteinuria, made the diagnosis of acute glomerulonephritis unlikely.
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Teaching points |
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- False-positive tests for anti-GBM antibodies are possible, the gold standard for diagnosis being the renal biopsy.
- Do not be misled by a positive laboratory value if other clinical presentations do not suggest rapid-progressive glomerulonephritis.
- Be cautious with patients with known milk allergy who have high titres of anti-GBM antibodies—the cow may turn into Goodpasture's syndrome.
Conflict of interest statement. None declared.
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References |
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TopIntroductionCaseDiscussionTeaching pointsReferences |
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- Turner AN, Mason PJ, Brown R, et al. Molecular cloning of the human Goodpasture antigen demonstrates it to be the 3 chain of type IV collagen. J Clin Invest 1992; 89: 592–601
- Sinico RA, Radice A, Corace C, Sabadini E, Bollini B. Anti-glomerular basement membrane antibodies in the diagnosis of Goodpasture syndrome: comparison of different assays. Nephrol Dial Transplant 2006; 21: 397–401
- DeAngelo AJ, Lancaster-Weiss KJ, Eliason S, Troyer D, Wortham WG. Diabetic nephropathy with interstitial nephritis presenting with a false-positive anti-GBM-antibody. Clin Nephrol 2002; 57: 381–385
- Crittenden RG, Benneett LE. Cow's milk allergy: a complex disorder. J Am Coll Nutr 2005; 24 [Suppl 6]: 582S–591S
- Natale M, Bisson C, Monti G, et al. Cow's milk allergens identification by two-dimensional immunoblotting and mass spectrometry. Mol Nutr Food Res 2004; 48: 363–369
Accepted in revised form: 27. 3.06
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