Decrease in serum antiphospholipid antibody levels upon development of nephrotic syndrome in patients with systemic lupus erythematosus: Relationship to urinary loss of IgG and other factors

doi:10.1016/0002-9343(92)90264-C

The American Journal of Medicine

Volume 92, Issue 4, April 1992, Pages 357-362

https://doi.org/10.1016/0002-9343(92)90264-C Get rights and content

Abstract

purpose: Having observed a decrease in antiphospholipid antibodies (aPL) upon the development of nephrotic syndrome, as well as a negative association between nephrotic syndrome and secondary antiphospholipid syndrome, in patients with systemic lupus erythematosus (SLE), we sought to determine if this could be due to urinary loss of aPL and/or other factors.

subjects and methods: IgG and IgM aPL as well as other autoantibodies were studied by enzyme-linked immunosorbent assay with cardiolipin as antigen in serum and urine from six patients with SLE who had elevated serum aPL levels and developed nephrotic syndrome (cases). For controls, we studied: (1) three SLE patients with nephrotic syndrome but low aPL levels; (2) three patients with non-SLE nephrotic syndrome; (3) three SLE patients with high-titer aPL but no proteinuria; and (4) 10 healthy volunteers.

results: We found urinary IgG, but no IgM, aPL in all cases and in one control from Group 2. Serum IgG aPL had gradually decreased after the development of nephrotic syndrome and had become normal. IgM aPL had also decreased in the four patients who had elevated levels, having reached normal levels at the time of the study in two. There was an apparent correlation between serum and urine IgG aPL levels but not between urinary IgG aPL and total proteinuria. By Farr's method, we found no urinary anti-DNA despite high serum titers in three cases. The two cases and one of the controls in Group 1 who had serum antibodies to extractable antigens also had these antibodies in the urine.

conclusion: Urinary loss of IgG aPL during nephrotic syndrome does not completely explain the reduction in serum aPL, since IgM also decreases. There could also be decreased synthesis and/or increased catabolism of immunoglobulins.

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Seronegative antiphospholipid syndrome: Myth or reality?
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Le syndrome des antiphospholipides (SAPL) est une maladie systémique auto-immune caractérisée par l’association de manifestations thrombotiques et/ou de complications obstétricales à la présence persistante à 12 semaines d’anticorps antiphospholipides (aPL) : anticoagulant circulant de type lupique ou « lupus anticoagulant » (LA) et/ou anticorps anticardiolipine (ACL) et/ou anticorps anti-β2 glycoprotéine I (aβ2GPI). La découverte de patients avec un tableau clinique très évocateur de SAPL en l’absence des critères biologiques conventionnels a conduit au concept de SAPL « séronégatif ». Durant ces dernières années, de nouvelles cibles antigéniques et de nouvelles approches méthodologiques ont été utilisées afin d’identifier plus clairement ce syndrome chez des patients présentant des thromboses ou des complications obstétricales en l’absence d’aPL conventionnels. Bien que le SAPL « séronégatif » fait encore l’objet de controverse, il existe une reconnaissance croissante de l’existence de ce sous-groupe. Cependant, l’utilité clinique des aPL non conventionnels nécessite d’être confirmée par des efforts de standardisation de ces nouveaux outils biologiques et par des études longitudinales impliquant de larges cohortes de patients.
The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombosis and/or obstetrical manifestations and the persistent presence, at least 12 weeks apart, of antiphospholipid antibodies (aPL) such as lupus anticoagulant (LA) and/or anticardiolipin antibodies (ACL) and/or anti-β2 glycoprotein I antibodies (aβ2GPI). The finding of patients with clinical profile highly suggestive of APS but who are negative for conventional biological criteria has led to the concept of seronegative APS. In the last few years, new antigen targets and methodological approaches have been employed to more clearly identify this syndrome in patients with thrombosis or obstetrical complications without conventional aPL. Although seronegative APS is still controversial, there is increasing recognition of the existence of this subgroup. However, clinical relevance of non conventional aPL need to be confirmed by efforts toward standardizing new biological tools and longitudinal studies involving large cohort of patients.
Controversies concerning the antiphospholipid syndrome in obstetrics
2017, Reumatologia Clinica
El síndrome de anticuerpos antifosfolipídicos es una enfermedad autoinmune no inflamatoria, caracterizada por eventos trombóticos recurrentes y/o complicaciones obstétricas, asociados a la presencia de anticuerpos antifosfolipídicos circulantes: anticuerpos anticardiolipina, anti-β₂ glucoproteína-i y/o anticoagulante lúpico.
Los anticuerpos antifosfolipídicos son un grupo heterogéneo de autoanticuerpos asociados con morbilidad obstétrica, como pérdida gestacional recurrente, muerte fetal, parto pretérmino asociado a insuficiencia placentaria como enfermedad hipertensiva del embarazo y/o restricción del crecimiento intrauterino. Los procesos fisiopatológicos relacionados con la morbilidad obstétrica no se han comprendido del todo, involucrándose múltiples eventos inmunológicos, entre ellos los inflamatorios, la activación del complemento, el desbalance de los factores angiogénicos y, en alguna proporción de los casos, se ha demostrado trombosis e infarto. Debido a la controversia en los criterios clínicos y de laboratorio, así como a la repercusión en la mejora de los resultados perinatales en pacientes que inician tratamiento, decidimos llevar a cabo esta revisión sobre los conceptos de síndrome de anticuerpos antifosfolipídico relacionado con complicaciones obstétricas y síndrome de anticuerpos antifosfolipídico seronegativo, así como su manejo en obstetricia.
Antiphospholipid antibody syndrome is a non-inflammatory autoimmune disease characterized by recurrent thrombotic events and/or obstetric complications associated with the presence of circulating antiphospholipid antibodies (anticardiolipin antibodies, anti-β₂ glycoprotein-i antibodies, and/or lupus anticoagulant.
Antiphospholipid antibodies are a heterogeneous group of autoantibodies associated with recurrent miscarriage, stillbirth, fetal growth restriction and premature birth. The diversity of the features of the proposed placental antiphospholipid antibodies fingerprint suggests that several disease processes may occur in the placentae of women with antiphospholipid antibody syndrome in the form of immune responses: inflammatory events, complement activation, angiogenic imbalance and, less commonly, thrombosis and infarction. Because of the disparity between clinical and laboratory criteria, and the impact on perinatal outcome in patients starting treatment, we reviewed the aspects of antiphospholipid antibody syndrome related to obstetric complications and seronegative antiphospholipid antibody syndrome, and their treatment in obstetrics.
Does seronegative antiphospholipid syndrome really exist?
2012, Autoimmunity Reviews
Citation Excerpt :
A variety of other proteins have been implicated as targets for aPL, including prothrombin, protein C, protein S and placental anticoagulant protein. A decrease in aPL levels has been observed after the development of nephrotic syndrome, that has been attributed to urinary loss of IgG aPL, a decrease in their synthesis, and/or increase in their catabolism [29]. The aPL titles may markedly decrease during treatment with corticosteroids (i.e., for the treatment of inflammatory manifestations of associated systemic lupus erythematosus), although the correlation between prednisone treatment and aPL titles has not been definitively documented [30].
The diagnosis of seronegative (SN-) antiphospholipid syndrome (APS) has been suggested for patients with clinical manifestations indicative of APS but with persistently negative results in the commonly used assays to detect anti-cardiolipin (aCL) antibodies, anti-β2 Glycoprotein I antibodies (aβ2GPI), and lupus anticoagulant (LA). To date the best management of these patients is still unclear.
New emerging anti-phospholipid (aPL) assays could improve our ability in diagnosing APS. However, the availability of aPL assays in routine laboratory practice is limited. In fact, even aβ2GPI is routinely tested in only a small number of laboratories, and other aPL, such as anti-prothrombin or anti-annexin antibodies, in only a few research laboratories.
On the other hand transient or false negative aPL assay and other genetic or acquired pro-thrombotic conditions can further complicate this issue.
This paper is focused on the arguments for and against the diagnosis of SN-APS and is aimed to help the clinician when approaching a patient with clinical manifestations consistent with APS diagnosis but with negative aPL using the commonly available tests.
The clinical presentation of systemic lupus erythematosus
2004, Systemic Lupus Erythematosus, Fourth Edition
Anticardiolipin and anti-β<inf>2</inf>-glycoprotein-I antibodies in hypertensive disorders of pregnancy
2002, Archives of Medical Research
This study was undertaken in order to determine the frequency of anticardiolipin (aCL) and anti-β₂-glycoprotein-I antibodies (anti-β₂GP-I) in patients with hypertensive disorders of pregnancy.
We studied aCL (IgG and IgM) and IgG anti-β₂GP-I by ELISA in the serum and IgG aCL and anti-β₂GP-I in the urine of 125 women with hypertensive disorders of pregnancy (cases) (75 had preeclampsia, 25 had eclampsia, and 25 had chronic hypertension). One hundred and twenty seven normal women were used as controls. Antibody positivity was defined as above the 90^th percentile of the controls.
We found no differences in frequency of serum anti-β₂GP-I or serum and urinary aCL between cases and controls. In contrast, we found that frequency of IgG anti-β₂GP-I was higher in the urine of cases (26.1%) compared to controls (9.4%, p = 0.001). Strength of association was stronger for urinary anti-β₂-glycoprotein-I in women with preeclampsia (odds ratio [OR] = 4.3, 95% confidence limit [CI 95%] = 1.95–9.62, p <0.0001). Cases and the subgroup of preeclamptic patients also had higher titers of urinary IgG anti-β₂GP-I than control women (p <0.0001).
Our work suggests that urine testing is necessary in order to ascertain whether antibodies to β₂GP-I are associated with preeclampsia.
The anti-phospholipid antibody syndrome: Clinical and serological aspects
2000, Bailliere's Best Practice and Research in Clinical Rheumatology
The association of thromboses and/or cytopenias with anti-phospholipid antibodies (aPL), the anti-phospholipid syndrome (APS), is well recognized. The syndrome may be primary or occur within systemic lupus erythematosus (SLE). The notion of the syndrome occurring within SLE is important since patients found to have aPL may be at risk for developing APS manifestations, those who develop some manifestations may be at risk for developing others and, finally, SLE patients with this syndrome may need special treatment. There are subtle differences between the primary and the secondary forms, mostly due to the frequently higher and more persistent autoantibody levels in the primary and the influence of lupus in the secondary. These syndromes may be related to various antigen/antibody systems in which phospholipids participate either directly or through their effect on the proteins that bind them. Similar clinical manifestations also occur in patients who have serum antibodies to such proteins (e.g. β₂-glycoprotein-I) in the absence of phospholipid. Some of these antibodies may even be more important pathogenically than the antibodies against cardiolipin that were originally described. Testing for the latter is, however, still the first choice when suspecting an anti-phospholipid syndrome. If this is negative in this situation, a search for the other autoantibodies is indicated.

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^☆: This work was supported with grants from the Consejo Nacional de Ciencia y Tecnología, Mexico, and the “German Portilla” Fund for Investigations in Systemic Lupus Erythematosus, Mexico City, Mexico.

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Decrease in serum antiphospholipid antibody levels upon development of nephrotic syndrome in patients with systemic lupus erythematosus: Relationship to urinary loss of IgG and other factors☆

Abstract

Ann Biochem

Kidney Int

Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus

The 1982 revised criteria for the classification of systemic lupus erythematosus

Arthritis Rheum

Most commonly discontinuous buffer system for SDS electrophoresis

Nature

Measurement of anticardiolipin antibodies by an enzyme-linked immunosorbent assay (ELISA)

Anticardiolipin antibodies

Occurrence of both hemolytic anemia and thrombocytopenic purpura (Evans' syndrome) in systemic lupus erythematosus