|Year : 2019 | Volume
| Issue : 4 | Page : 953-959
|A “double-seropositive” Vasculitis for antiglomerular basement membrane antibodies and antineutrophil cytoplasmic antibody, and multiple myeloma, all three with simultaneous diagnosis of renal involvement, common pathophysiology, or pure coincidence? first case in the World
Mariam Chettati, Adil Adnouni, Nadia Bouchemla, Sara Anibar, Wafaa Fadili, Inass Laouad
Department of Nephrology-Hemodialysis and Kidney Ttransplantation, University Hospital Mohammed VI, Marrakech, Morocco
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|Date of Submission||01-Aug-2018|
|Date of Acceptance||16-Sep-2018|
|Date of Web Publication||27-Aug-2019|
| Abstract|| |
The combination of Goodpasture’s disease and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is not exceptional. However, to the best of our knowledge, their association with multiple myeloma (MM) with kidney involvemen thas not been described. We report probably the first case of double-seropositive vasculitis for antiglomerular basement membrane (GBM) antibodies and ANCA associated with MM with renal involvement. A 60- year-old-female presented with severe acute kidney injury. Three months earlier, she had a history of bone pain. Blood workup found a creatinine of 1100 μmol/L and a C-reactive protein of 60 mg/L. Anti-GBM antibodies returned positive at 400 U/mL and pANCA positive at 380 U/mL. Plasma protein immunofixation found a monoclonal immunoglobulin G (IgG) KAPPA peak; the myelogram found a 10% plasmocytosis. On the day 4 of hospitalization, the patient presented with alveolar hemorrhage. The renal biopsy showed diffuse crescentic glomerulo-nephritis with linear glomerular deposits of IgG, with kappa light chain cast nephropathy. The association between vasculitis and malignant blood disease is very rare; the pathophysiology of this association remains unclear. It would seem interesting to look for possible ANCA or anti- GBM activity carried by the monoclonal immunoglobulin.
|How to cite this article:|
Chettati M, Adnouni A, Bouchemla N, Anibar S, Fadili W, Laouad I. A “double-seropositive” Vasculitis for antiglomerular basement membrane antibodies and antineutrophil cytoplasmic antibody, and multiple myeloma, all three with simultaneous diagnosis of renal involvement, common pathophysiology, or pure coincidence? first case in the World. Saudi J Kidney Dis Transpl 2019;30:953-9
|How to cite this URL:|
Chettati M, Adnouni A, Bouchemla N, Anibar S, Fadili W, Laouad I. A “double-seropositive” Vasculitis for antiglomerular basement membrane antibodies and antineutrophil cytoplasmic antibody, and multiple myeloma, all three with simultaneous diagnosis of renal involvement, common pathophysiology, or pure coincidence? first case in the World. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2021 Sep 22];30:953-9. Available from: https://www.sjkdt.org/text.asp?2019/30/4/953/265473
| Introduction|| |
Goodpasture’s (GP) disease, or antiglomerular basement membrane (GBM) antibodies associated disease, is an autoimmune disease characterized by necrotizing glomerulonephritis, associated with intra-alveolar hemorrhage and the presence of immunoglobulin G (IgG) deposits along glomerular and alveolar basement membranes. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a group of systemic vasculitides that affects the small arteries, capillaries, and venules in the Chapel Hill classification. Renal involvement is characterized by fibrinoid and focal necrosis of the glomerular capillaries, associated with extracapillary proliferation of variable importance. Unlike other small vessel vasculitis, there is no or little glomerular immune deposition, and renal involvement is pauci-immune crescentic glomerulonephritis. The association of these two entities is not exceptional, its prevalence varies from 7% to 41% depending on the series, and it is more common in the elderly., It is recognized that the two antibody populations associated with these diseases are antigenically distinct and that this phenomenon is not due to cross-reactivity, although the mechanisms of association are not fully understood. The anti-GBM disease and ANCA-associated vasculitis represent an extreme nephrological emergency. Multiple myeloma (MM) is a hematological malignancy characterized by the proliferation of a plasmo-cyte clone invading the bone marrow. Several types of renal manifestations associated with myeloma have been described; these involve different physiopathological mechanisms, and the most important is related to the deposition of monoclonal Ig or its fractions in the kidney. We report, to the best of our knowledge, the first case in the world that illustrates the association of a double-seropositive vasculitis for anti-GBM and ANCA, and MM with renal involvement diagnosed simultaneously.
| Case Report|| |
A 60-year-old Moroccan female presented with severe acute kidney injury (AKI), with creatinine of 1100 μmol/L. Three months before, she had a history of bone pain, associated with an alteration of the general state (loss of weight, anorexia, and deep asthenia). On admission, the physical examination revealed asthenia, a blood pressure to 150/80 mm Hg, a heart rate to 70 beats/min, edema of the lower limbs, afebrile, and crepitations in the lower zones of both lungs. The rest of the clinical examination is normal. Urine output was less than 100 mL/24 h, and urinalysis demonstrated 1+ protein and 2+ blood.
Initial laboratory findings and emergency treatment
Blood workup found a creatinine of 1100 μmol/L, a urea of 49 mmol/L, potassium 7.2 mmol/L, sodium 124 mmol/L, bicarbonate 13 mmol/L, hemoglobin 8.3 g/dL without schizo-cytosis, hypercalcemia of 2.7 mmol/L, and inflammatory syndrome marked by C-reactive protein of 60 mg/L. The C3, C4 and CH50 fractions of the serum complement were normal. The serologies of hepatitis B, and C, HIV, and syphilis were negative. The abdo-minopelvic ultrasonography revealed kidneys of normal size.
In the presence of anuric AKI with hyper- kalemia and acidosis and fluid overload, the patient was immediately started on dialysis, and in front of the clinical picture suggesting a crescentic glomerulonephritis, treatment with methylprednisolone at 15 mg/kg per day for three days was started.
Further examinations and evolution
Immunoassay: Anti-GBM antibodies returned positive at 400 U/mL (N <20) and p-ANCA positive at 380 U/mL (N <20) with antimyelo-proxidase specificity (MPO). Plasma protein electrophoresis revealed a hypergammaglobu-linemia, immunofixation found a monoclonal IgG KAPPA peak, and the search for cryo-globulinemia was negative.
A thoracic–abdominal–pelvic computed tomography (CT) revealed a diffuse interstitial lung disease, and pleuritis, and microlytic lesions in lumbar vertebrae, and in both iliac wings [Figure 1].
|Figure 1: Cross-section of a thoracic abdominal computed tomography, showing microlytic lesions at a lumbar vertebra.|
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The myelogram found a 10% plasmocytosis, with deep cytonuclear atypia [Figure 2].
|Figure 2: Myelogram showing plasmocytosis with deep cytonucleate atypia.|
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On day 4 of hospitalization, the patient presents an acute dyspnea with orthopnea, and hemoptysis, with a hemorrhaging, hemoglobin 5 g/dL; a new chest CT performed shows parenchymatous condensations with bilateral crazy paving appearance in favor of an alveolar hemorrhage [Figure 3], the bron-chioloalveolar lavage was not done, and the management consisted of a blood transfusion in dialysis with continued corticosteroid treatment.
|Figure 3: Coronal section of a lung computed tomography scan without injection of iodinated contrast showing parenchymal condensations with bilateral crazy paving appearance.|
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Light microscopy: 40 glomeruli, one is normal, two show an appearance of glomerulo-sclerosis, 37 glomeruli show complete encircling cellular crescents, the interstitium show inflammatory cell infiltrate (lymphocytes and abundant plasmocytes) with the presence of fractured casts with syncytial giant-cell reaction, interstitial fibrosis is around 20% [Figure 4] and [Figure 5].
|Figure 4: (a) Renal parenchyma showing four glomeruli with complete encircling cellular crescents; the interstitium show inflammatory cell infiltrate (lymphocyte and abundant plasmocyte) with the presence of fractured casts with syncytial giant-cell reaction. Light microscopy, Hematoxylin staining <40, (b) Distal atrophic renal tubules containing fractured casts with a vacuolated appearance, predominantly plasmacytic interstitial infiltrate: light microscopy, Hexamoxylin staining x40.|
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|Figure 5: (a) Glomeruli with complete encircling cellular crescents, interstitium show inflammatory cell infiltrate, presence of fractured casts, jones coloration x40, (b) Distal atrophic renal tubules with fractured casts, interstitial fibrosis: light microscopy, Trichrome Masson coloration x40.|
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Immunofluorescence revealed linear IgG staining at the glomeruli and a pronounced monoclonal cast staining for KAPPA light chain [Figure 6].
|Figure 6: (a) Linear IGG deposits at glomeruli: immunofluorescence, (b) deposits of Kappa light chains in the distal renal tubes: immunofluorescence.|
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Final diagnosis and treatment
The diagnosis is the combination of double-seropositive vasculitis for ANCA and anti-GBM antibodies with light chain cast nephro-pathy.
Treatment of vasculitis: Intravenous methyl-prednisolone 15 mg/kg/day for three days and subsequently treated with oral prednisone 1 mg/kg/day with tapering doses, cyclophospha-mide administered intravenously at 10 mg/kg according to the CYCLOPS protocol, and 14 daily sessions of plasma exchange with albumin (40 mL/kg/day). The anti-GBM control rate was 21 U/mL.
Treatment of myeloma: Hematologists recommended standard chemotherapy according to the VCD protocol (thalidomide, cyclophos- phamide, and dexamethasone).
Respiratory: disappearance of dyspnea and rarefaction of alveolar hemorrhage.
Renal: there was no recovery of renal function; the patient remained dependent on dialysis three months after the beginning of treatment and progressed to end-stage renal disease requiring a renal replacement therapy.
Immunological control: anti-GBM antibodies: 21 U/mL, anti-MPO antibodies: 40 U/mL.
Myeloma: the patient continues her follow-up in hematology for the maintenance treatment of the myeloma.
| Discussion|| |
To the best of our knowledge, the present case is probably the first case of double-seropositive vasculitis for anti-GBM and ANCA associated with MM with renal evolvement. The diagnosis of double-seropositive vasculitis was based on pulmonary-renal syndrome associating severe AKI and alveolar hemorrhage, serological findings (anti-GBM and anti-MPO were positive), and histopatho-logical findings that revealed crescentic glomerulonephritis with linear staining of IgG in glomeruli by immunofluorescence analysis of the kidney biopsy. The myeloma was confirmed by the results of serum immunofixation combined with myelogram results in addition to lytic bone images, as well as the presence of KAPPA light chain cast nephropathy.
The copresentation of anti-GBM antibodies and ANCA is a phenomenon that is not uncommon since the early 2000s; its prevalence varies from 7% to 41% depending on series., In the largest series which included 646 patients from four centers in three European countries, 5.7% of patients were double-positive and 70% of them were positive for anti-MPO. In a Dutch study, the authors reported that 43% of patients who were positive for anti-GBM were also positive for anti-MPO. In the Levy study, 5% of patients who were positive for ANCA were also positive for anti-GBM, and 32% of patients who were positive for anti-MBG sera were also positive for ANCA. The patho- physiology of this association is not fully understood. Several experimental studies suggest that anti-MPO antibodies are detectable prior to the development of anti-GBM anti-bodies., An interesting clinical study by Olson et al, using stored sera from the US Department of Defense, suggested that the majority of patients with anti-GBM disease had detectable ANCA before the development of anti-GBM antibodies, which in turn predated the development of clinical disease, suggesting that ANCA may act as trigger for anti-GBM disease. It appears that ANCA-induced glomerular inflammation is capable of altering the quaternary structure of GBM and revealing antigenic targets, thus inducing the formation of anti-GBM antibodies. Whether additional environmental or genetic factors predispose to forming both antibodies is unclear. The genetic associations of both anti- GBM antibodies associated disease and ANCA associated vasculitis are increasingly well-described.,, Several studies have reported the outcomes of these patients who are double positive, although with conflicting findings, some have observed better outcomes compared with those with single-positive anti-GBM disease,, while others have suggested that patients who are double positive have comparable or worse outcomes.,, A French-Belgian study of 19 patients concluded that double-positive vasculitis shares clinical features with ANCA-associated vasculitis, including a potential risk of recurrence requiring long-term follow-up. However, renal damage is particularly severe and rarely reversible, the early morbidity and mortality is typical of anti-GBM disease.
Renal impairment is a common complication of MM, occurring in 50% of patients during follow-up; it has an important impact on the outcome of the disease. AKI secondary to MM is most often related to the deposit of monoclonal light chain in distal renal tubules which specifically characterizes the light chain cast nephropathy. Treatment of light chain cast nephropathy is based on urgent symptomatic measures (alkalization, rehydration, treatment of hypercalcemia, and discontinuation of nephrotoxic drugs), combined with chemotherapy to rapidly reduce the production of monoclonal IG.
Copresentation with both double-seropositive vasculitis and malignant blood diseases is very rare. In a review that was published in 2013, the authors had studied the association between malignancy and ANCA-associated vasculitis and found that neoplasias are in the majority of cases secondary to the pro-carcinogenic effects of the therapies used, in some rare situations a subclinical neoplasia could be a “trigger” at the occurrence of vasculitis. Thus, vasculitis associated with neoplasia has been described with solid cancers but also with hematologic malignancy such as lymphoma or myeloma. The prevalence of this association is around 0.4%–4.2%. Very recently, Philipponnet et al reported a series of 16 cases of ANCA-associated vasculitis combined with hemato-logic malignancies including a single case of MM; in this study, the authors suggested that it would be interesting to search, if there is an ANCA activity carried by the monoclonal IG. Liu et al also report a case of MM with renal involvement that presented with ANCA-associated vasculitis after three years of follow-up, and suggest, based on the findings of Nocente et al, that the monoclonal IG may have autoantibody activity, causing fragmentation of neutrophils and release of antigens responsible for the appearance of p-ANCA. Nouvier reports the only published case of MM, which is complicated by GP syndrome, and concludes that monoclonal IG may be one of the triggering factors of GP syndrome.
The physiopathological mechanisms of co-presentation with both double-seropositive vasculitis and MM remain uncertain. Some studies suggest the hypothesis of an inflammatory stimulation, even of an immune imbalance linked to one of the pathologies which could be at the origin of the second one. Thus, to establish an intrinsic pathophysiological link between vasculitis and MM, more in-depth studies are needed. However, it would seem interesting to look for possible ANCA or anti-GBM activity carried by the monoclonal IG.
| Conclusion|| |
We report probably the first case of double-seropositive vasculitis for anti-GBM antibodies and ANCA associated with multiple myeloma. Double-seropositive vasculitis is not an exceptional situation; its prevalence varies from 7% to 41% depending on the series.
The association between vasculitis and malignant blood disease is very rare; the monoclonal IG could have an antineutrophil antibody activity, causing their fragmentation and the release of antigens responsible for the appearance of ANCA, and be one of the triggering factors from the Goodpasture’s syndrome. It would seem interesting to look for possible ANCA or anti-GBM activity carried by the monoclonal IG.
Pending the confirmation of these theories, the pathophysiology of this association remains unclear; however, this association must be known because of the pejorative outcomes on renal and patient’s survival. It requires treatment for multiple myeloma but also vasculitis while preventing the risk of infection.
Conflict of interest: None declared.
| References|| |
Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised international Chapel Hill consensus conference nomenclature of vasculitides. Arthritis Rheum 2013;65:1-1.
Pedchenko V, Bondar O, Fogo AB, et al. Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. N Engl J Med 2010;363:343-54.
Short AK, Esnault VL, Lockwood CM. Anti-neutrophil cytoplasm antibodies and anti-glomerular basement membrane antibodies: Two coexisting distinct autoreactivities detectable in patients with rapidly progressive glomerulonephritis. Am J Kidney Dis 1995;26: 439-45.
McAdoo SP, Tanna A, Hrušková Z, et al. Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients. Kidney Int 2017;92:693-702.
Rutgers A, Slot M, van Paassen P, et al. Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase- ANCAs in crescentic glomerulonephritis. Am J Kidney Dis 2005;46:253-62.
Levy JB, Hammad T, Coulthart A, Dougan T, Pusey CD. Clinical features and outcome of patients with both ANCA and anti-GBM antibodies. Kidney Int 2004;66:1535-40.
Yang G, Tang Z, Chen Y, et al. Antineutrophil cytoplasmic antibodies (ANCA) in Chinese patients with anti-GBM crescentic glomerulo-nephritis. Clin Nephrol 2005;63:423-8.
Jennette JC. Rapidly progressive crescentic glomerulonephritis. Kidney Int 2003;63:1164- 77.
Olson SW, Arbogast CB, Baker TP, et al. Asymptomatic autoantibodies associate with future anti-glomerular basement membrane disease. J Am Soc Nephrol 2011;22:1946-52.
Rahmattulla C, Mooyaart AL, van Hooven D, et al. Genetic variants in ANCA-associated vasculitis: A meta-analysis. Ann Rheum Dis 2016;75:1687-92.
Zhou XJ, Lv JC, Zhao MH, Zhang H. Advances in the genetics of anti-glomerular basement membrane disease. Am J Nephrol 2010;32:482-90.
Persson U, Hertz JM, Carlsson M, et al. Patients with Goodpasture’s disease have two normal COL4A3 alleles encoding the NC1 domain of the type IV collagen alpha 3 chain. Nephrol Dial Transplant 2004;19:2030-5.
Bosch X, Mirapeix E, Font J, et al. Prognostic implication of anti-neutrophil cytoplasmic autoantibodies with myeloperoxidase specificity in anti-glomerular basement membrane disease. Clin Nephrol 1991;36:107-13.
Segelmark M, Hellmark T, Wieslander J. The prognostic significance in Goodpasture’s disease of specificity, titre and affinity of anti- glomerular-basement-membrane antibodies. Nephron Clin Pract 2003;94:c59-68.
Lindic J, Vizjak A, Ferluga D, et al. Clinical outcome of patients with coexistent antineu-trophil cytoplasmic antibodies and antibodies against glomerular basement membrane. Ther Apher Dial 2009;13:278-81.
Clerte M, Levi C, Touzot M, et al. “Double-positive” vasculitis: A’ rare and particularly severe form of systemic vasculitis. Nephrol Ther 2014;10:343.
Mahr A, Heijl C, Le Guenno G, Faurschou M. ANCA-associated vasculitis and malignancy: Current evidence for cause and consequence relationships. Best Pract Res Clin Rheumatol 2013;27:45-56.
Philipponnet C, Garrouste C, Le Guenno G, et al. ANCA vasculitis associated with hemato-logic malignancies: A retrospective study of 16 cases. Rev Rheum 2017;84:307-13.
Liu H, Xiong J, Zhang J, et al. Possible intrinsic association of anti-neutrophil cytoplasmic antibody-associated vasculitis coexisting with multiple myeloma. Oncol Lett 2016;12:2084-6.
Nocente R, Cammarota G, Gentiloni Silveri N, et al. A case of Sweet’s syndrome associated with monoclonal immunoglobulin of IgG-Lambada type and p-ANCA positivity. Panminerva Med 2002;44:149-50.
Nouvier M. Trolliet P, Teuma C, et al. A monoclonal immunoglobulin may hide another: First case of multiple myeloma associated with Goodpasture’s syndrome. Nephrol Ther 2014;10:353-4.
Department of Nephrology-Hemodialysis and Kidney Transplantation, University Hospital Mohammed VI, Marrakech
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
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