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NDT Advance Access originally published online on August 25, 2006
Nephrology Dialysis Transplantation 2006 21(11):3311-3315; doi:10.1093/ndt/gfl478
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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

Inappropriate secretion of ADH and central diabetes insipidus are related to antiphospholipid antibodies in SLE—case report and review of the literature*

Gankam Kengne Fabrice and Decaux Guy

Université Libre de Bruxelles, Hôpital Erasme, Service de Médecine Interne Générale, 808, route de Lennik, 1070 Brussels, Belgium

Correspondence and offprint request to: Gankam K. Fabrice, Université Libre de Bruxelles, Hôpital Erasme, Service de Médecine Interne, 808 route de Lennik, 1070 Brussels, Belgium. Email: fgankamk{at}ulb.ac.be

Keywords: antiphospholipid; central diabetes insipidus; hyponatraemia; SLE



   Introduction
Top
 Introduction
Case 1
 Case 2
 Discussion
 Acknowledgements
 References
 
A syndrome of inappropriate secretion of antidiuretic hormone (ADH) (SIADH) and central diabetes insipidus (CDI) has been described as occurring in various central nervous system conditions. Antiphospholipid antibodies (APL) have been implicated in many neurological symptoms in patients with systemic lupus erythematosus (SLE). The presence of APL and their eventual role in the development of SIADH or CDI in SLE has never been studied.

We describe two cases of SIADH occurring in the setting of SLE with APL. We retrospectively reviewed the literature on SLE associated with SIADH or CDI using a computer-assisted search from 1967 to 2005 in French, Spanish and English in the Medline Database using the keywords SIADH, CDI, APL and hyponatraemia. We found 11 cases of SIADH and five cases of CDI associated with SLE and one case of pure antiphospholipid syndrome associated with SIADH. The clinical and radiological data on all those reported patients were analysed. Laboratory data were also extracted from all the reports, and a positive status of APL was recorded if a patient had one of the following diagnostic criteria at the time SIADH (or CDI) appeared: false positive Veneral Disease Research Laboratory (VDRL), lupus anticoagulant (LA) or presence of anticardiolipin antibodies (ACA). We compared the prevalence of APL in the classic SLE population and in our collection of reported SLE patients with ADH disorders. We found that ADH disorders (SIADH and CDI) in SLE patients were significantly associated with the presence of APL. We also found that most patients had no radiological evidence of thrombotic brain disease (evaluated by CT scan or MRI), and only one patient had focal neurological impairment. We suggest that there is a causal relationship between APL and the development of SIADH or CDI in patients with SLE, mostly not mediated by a thrombotic mechanism.



   Case 1
Top
 Introduction
 Case 1
Case 2
 Discussion
 Acknowledgements
 References
 
A 51-year-old woman presented at the emergency department because of recurrence of arthralgias, abdominal pain and purple cutaneous lesions. She had been hospitalized several times before for recurrent flare-ups of SLE that was diagnosed ~10 years earlier (arthralgias, photosensitivity, pericarditis, lymphopenia, ANA and anti dsDNA). She previously had had several episodes of mild hyponatraemia (serum Na value between 119 and 132 mmol/l) treated by water restriction and urea. She was currently on methylprednisolone, 8 mg daily. Her physical examination showed malar rash, ulcerative lesions of the fingers and numerous petechias in both hands and feet. Laboratory analysis yielded the following data: Na 122 mmol/l, Cl 89 mmol/l, K 3.9 mmol/l, TCO2 25 mmol/l, urea 38 mg/dl, creatinine 0.7 mg/dl, uric acid 3.7 mg/dl, amylase 615 U/l (normal 0–125 U/l), lipase 444 U/l (normal 0–75 U/l). Other laboratory tests were within normal limits. Urinalysis showed Na at 95 mmol/l and an osmolality of 851 mmol/kg. Her antibody profile was as follows: antinuclear antibodies (ANA) positive at 1/5000, dsDNA titre 200 (normal <30), positive extractable nuclear antigen (ENA), positive SSA, normal complement levels and positive direct Coombs’ test with normal haptoglobin and a normal Lactase Dehydrogenase (LDH) value. The anticardiolipin IgG titre was 37 U (normal <12 U), and she had a negative lupus anticoagulant test. She had a normal cranial MRI. Her serum Na was still low (124 mmol/l) 3 weeks after normalization of her serum amylase and lipase levels. APL titres were above 20 units 1 month after the first measurement. We diagnosed SIADH and considered her pancreatitis to be secondary to SLE.

Our patient was taking no medication that might be causing SIADH. Pancreatitis as the cause of SIADH was unlikely, since 3 weeks after complete recovery of pancreatitis her serum Na was still low; furthermore, she did not have pancreatitis during her other hospitalizations for hyponatraemia. Idiopathic SIADH was not likely in this woman; SLE was the most likely cause of her SIADH. She was successfully treated with vasopressin receptor antagonists (conivaptan) over 6 months, with no recurrence of hyponatraemia after cessation of the drug. A year later, her serum Na was normal and her APL titre was under 10 on two measurements.



   Case 2
Top
 Introduction
 Case 1
 Case 2
Discussion
 Acknowledgements
 References
 
A 31-year-old woman presented at our emergency department for seizures. One month earlier she had been diagnosed to have SLE in our internal medicine out-patient clinic (arthralgias, pleural effusions, malar rash, photosensitivity and ANA with dsDNA), and she was on methylprednisolone 32 mg and hydroxychloroquine 200 mg daily. Her past medical history was unremarkable. Her physical examination showed postical confusion, lethargy and joint pain. Chest X-ray and lumbar puncture were normal. Routine laboratory analyses showed the following: Na 128 mmol/l, Cl 86 mmol/l, K 3.3 mmol/l, TCO2 20 mmol/l, urea 46 mg/dl, creatinine 1.0 mg/dl, serum osmolality 279 mmol/kg, Hb 10.4 g/l, WBC 11300/µl, with 8000 neutrophils, and normal blood glucose, lipids and thyroid function. Urinalysis showed urine Na at 129 mmol/l and an osmolality of 549 mmol/kg. She had a positive ANA at 1/10000 with a dsDNA titre of 42 and the presence of anti SSA and SSB. Her APL value was 37 U (normal <12 U) and lupus anticoagulant was absent. She had decreased C3 and C4—C3: 0.28 g/l (normal 72–156 g/l); C4: 0.06 g/l (normal 10–46 g/l). A cranial MRI showed non-specific multiple small non-thrombotic lesions (not taking contrast after gadolinium enhancement) in the basal ganglia and in parietal white matter, compatible with neurolupus. Her lupus flare-up was controlled with a IV bolus of cyclophosphamide (cyc), 1000 mg, followed by 500 mg twice monthly. She was also placed on valproic acid and water restriction. Her serum Na gradually returned to normal after 2 weeks and hyponatraemia did not recur. Her APL value 6 weeks after the admission was 20 U (normal <12 U).

The most likely cause of SIADH in this patient was SLE, since valproic acid was added to her therapeutic regimen after the episode of hyponatraemia.



   Discussion
Top
 Introduction
 Case 1
 Case 2
 Discussion
Acknowledgements
 References
 
There are several reports of SIADH occurring in the setting of SLE [1–11] and few of CDI complicating SLE [12–15]. Table 1 summarizes the data of 12 published cases of SIADH and SLE and Table 2 summarizes relevant laboratory data in published cases of SIADH and CDI in SLE.


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  		Table 1. Review of published cases of SIADH and SLE

 

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  		Table 2. Immunologic parameters in patient with SIADH/CDI and SLE

 
Scolari et al. [4] reported a patient who had a ‘lupus-like’ syndrome at the time hyponatraemia occurred, and in whom overt manifestations of SLE occurred only 2 years after the emergence of hyponatraemia and APL. The authors were the first to postulate that SIADH could be due to APL. They hypothesized that a thrombotic mechanism was implicated in the pathogenesis of SIADH, although that patient's cranial CT scan and MRI were both negative. Leventhal et al. [7] later suggested that SIADH arises because of increased lupus activity, since they found a correlation between hyponatraemia and high lupus activity measured by high dsDNA titres and elevated erythrocyte sedimentation rate values; and Mirsattari et al. [5] suggested that U1RNP could be involved in the pathogenesis of SIADH associated with SLE, since they found a correlation between high U1RNP titres and hyponatraemia. Of the articles we reviewed, no others reported the presence of U1RNP. Garrido et al. [16] was the first to report a case of primary APL associated with SIADH without distant SLE.

As can be seen in Table 2, almost all reported cases had biologically active lupus and a SLEDAI [17] >6. The intensification of immunosuppression administered for lupus control leads to the normalization of serum Na in most patients with SIADH. The CDI in two patients [12,13] was transitory, disappearing after treatment with CYC—this is rather remarkable, since CDI in adults is usually irreversible. The prevalence of antiphospholipid antibodies (APA) in SLE varies from 17 to 39% in well-designed studies; however, the largest and latest studies report a prevalence of around 26% [18]. At the prevalence of 26%, SIADH and CDI were significantly associated with APL in SLE (P = 0.0013). At a prevalence of 39% the association was still significant for both ADH disorders (P = 0.028).

A study of 39 patients [19] found higher ADH levels and altered water-load tests in SLE patients compared with controls, however, all of the patients were normonatraemic.

In the present study, we analysed 19 patients with SIADH and CDI (18 cases tabulated in Table 2 and one case of pure APL with SIADH)—15 of whom had either a brain CT scan or MRI, and none showed thrombotic brain disease at the time hyponatraemia was detected. The negative brain imaging in 15 patients is not consistent with an APL-induced microthrombosis as the putative mechanism in ADH disturbances; moreover, while hyponatraemia or CDI appeared, almost none of the studied patients had focal neurological symptoms, which suggests the absence of significant brain thrombotic pathology. The duality of ADH secretion disorders (both SIADH and CDI) is more consistent with subtle underlying immunological mechanisms than with vascular lesions. Together, those clues suggest that, in most reviewed cases, ADH disturbances were more likely caused by a non-thrombotic mechanism. Interestingly, SIADH in SLE with APL is transient; chorea associated with APL has been described to follow the same pattern.

So far, many experimental studies have found that APL play an important role in the physiology of CNS neurons: they have been shown to act on GABA and glutamate receptors [20–22], that are directly implicated in neuroendocrine cell physiology [23].

Our review found a statistical relationship between APL and ADH complications in a series of reported cases. APL in the reviewed cases might actually have a higher presence than reported—the usual kits do not detect all isotypes, and their presence in the sera of patients with SLE is fluctuant. The compared populations were different, and this may have confounded our results. The low prevalence of SIADH and CDI in SLE, however, makes adequate estimation of the real differences in prevalence very difficult. Reporting bias, unavailable data and variations in the prevalence of APL in SLE (including those arising out of ethnic differences) may also influence the significance of our statistics. Moreover, SIADH or CDI in those patients could be due to SLE alone or other antibodies peculiar to SLE (e.g. ANA). In these cases, however, SIADH and CDI should be more commonly reported in patients with SLE; furthermore, in published data, associations with other antibodies (SSA, SSB or U1RNP) are weaker than the association with APL.

The possible role of APL in CDI as well as in SIADH, two divergent physiological situations, might seem strange; nevertheless, the fact is that there are several types of APL, and it is well-known that each type could react with different epitopes present in the cell membrane. They could recognize and react with different regions of the receptors of gamma aminobutyric acid (GABA) or N-methyl-D-aspartate receptor (NMDA) on different neurons in the central nervous system (CNS) and produce different effects on the regulation of ADH synthesis, transport and release, resulting in various secretory patterns of hypothalamic endocrine neurons.

Better designed case studies and experiments are needed to pinpoint the possible role of APL in the disregulation of hypothalamic supraoptic and paraventricular neurons.



   Acknowledgements
Top
 Introduction
 Case 1
 Case 2
 Discussion
 Acknowledgements
References
 
The author thank Dr Frederic Vandergheynst, Dr Xavier Vandermergel, Dr Veronique De Brouckère and Dr Mohamed Fares for their contribution to the care provided to our two patients.

Conflict of interest statement. None declared.



   Notes
 
* Part of this work was presented as abstract at the 14th congress of the Belgian Society of Internal Medicine (December 2005) Back



   References
Top
 Introduction
 Case 1
 Case 2
 Discussion
 Acknowledgements
 References
 

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Received for publication: 6. 3.06
Accepted in revised form: 7. 6.06


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