Renal manifestations of the antiphospholipid syndrome

The antiphospholipid syndrome is characterized by recurrent arterial and venous thromboses and pregnancy morbidity in association with antiphospholipid antibodies. Recurrent thrombotic events are associated with significant morbidity and mortality. Renal involvement encompasses the whole renal vasculature and may lead to proteinuria, renal impairment, hypertension, and end-stage renal failure. Renal involvement is especially difficult to distinguish from glomerulonephritis when the antiphospholipid syndrome develops in patients with systemic lupus erythematosus. This article reviews the diagnosis and treatment of the major features of this syndrome, with particular reference to the kidney.     

The family history of patients with primary or secondary antiphospholipid syndrome (APS)

OBJECTIVE: To evaluate familial history for evidence of antiphospholipid syndrome (APS) and autoimmune disease in rheumatology department patients with primary or secondary APS. METHODS: We retrospectively studied patients with APS and systemic lupus erythematosus (SLE) managed at the Rheumatology Department of the Bichat University Hospital, Paris, between 1987 and 1996. Data were collected by chart review and by a 1997 standardized telephone interview. RESULTS: We identified 108 patients with APS managed during the ten-year study period. According to classical classification criteria, 39 patients had primary antiphospholipid syndrome (PAPS) and 69 secondary antiphospholipid syndrome (SAPS). Family history data were obtained for 29 (74%) and 55 (80%) PAPS and SAPS patients. respectively (78% of the 108 patients). Twelve PAPS (41% and 19 SAPS (35%) patients had one or more relatives with evidence of at least one clinical feature of APS such as thrombosis or recurrent fetal loss; of these patients, seven in the PAPS (24%) and 11 in the SAPS (20%) group had two or more relatives with evidence of a clinical feature of APS. Three PAPS (10%) and 14 SAPS (25%) patients had one or more family members with an autoimmune disease. CONCLUSION: A positive family history for autoimmune disease and/or antiphospholipid syndrome is common in patients with PAPS or SAPS. This finding supports a genetic contribution to APS. The percentage of a positive family history for autoimmune disease tend to be higher in patients with SAPS than in those with PAPS.     

Primary antiphospholipid syndrome as the forerunner of systemic lupus erythematosus

The objective of this study was to analyse whether primary antiphospholipid syndrome (PAPS) may precede and modify the characteristics of systemic lupus erythematosus (SLE). Out of the total 362 SLE patients in our service, 223 patients had antiphospholipid antibodies (aPL), of whom 110 met the criteria of antiphospholipid syndrome. In 26 cases (7.2%) PAPS appeared 5.5 years before the onset of lupus (PAPS+SLE Group). Their clinical findings were compared to lupus patients without (SLE only Group, n = 26) and with secondary APS (SLE+SAPS Group, n = 26). The prevalence of deep venous thrombosis, stroke/TIA, recurrent fetal loss, coronary heart disease and myocardial infarction was significantly higher in PAPS+SLE Group as compared to SLE only Group. The difference in prevalence of fetal loss (P = 0.014) between PAPS+SLE and SLE+SAPS Groups was also recorded. On comparison to PAPS+SLE Group, patients without APS (SLE only Group) were younger at onset of lupus, with more frequent flares and a higher prevalence of WHO type III/IV nephritis (P = 0.007), requiring higher doses of cyclophosphamide and corticosteroids. Lupus started in the form of PAPS in 7.2% of our SLE patients, who presented with more thrombotic and less inflammatory complications than in SLE patients without a prior or with a following secondary APS. Considering the long latency between the two diseases, PAPS may be a forerunner of lupus, but it may also coexist with SLE as an independent autoimmune disorder.     

Clinical spectrum of males with primary antiphospholipid syndrome and systemic lupus erythematosus: a comparative study of 73 patients

The objective of this study was to compare the clinical findings, laboratory data, functional outcome and chronic damage in male patients with primary antiphospholipid syndrome (PAPS) and systemic lupus erythematosus (SLE). We studied 29 male patients with PAPS and 44 with SLE. Clinical findings, laboratory data, lupus damage index (SLICC/ACR DI), and functional outcome in PAPS, were analysed in each group. The mean age at diagnosis was 29.8 +/- 10.4 years in patients with PAPS and 26 +/- 10.1 years in SLE patients. The duration of disease was 4.5 +/- 2.6 versus 5.2 +/- 3.8 years in patients with PAPS and SLE, respectively (P = NS). In patients with PAPS the most frequent clinical manifestations were venous thrombosis, thrombocytopenia, and pulmonary thromboembolism. Patients with SLE had joint, skin and renal involvement more frequently than those with PAPS (P = 0.0001). All PAPS patients had anticardiolipin antibodies (aCL), and 14 patients (48%) had lupus anticoagulant (LA). All SLE patients had antinuclear antibodies (ANAs). Anti-dsDNA antibodies were positive in 39% of SLE patients. Five patients died: one with 'catastrophic' APS and four with SLE. SLICC/ACR-DI score in SLE patients was 1.9 (SD = 1). In PAPS patients poor functional outcome was due to myocardial infarction, pulmonary thromboembolism, stroke and mesenteric thrombosis. Lupus nephritis was the principal organ damage in SLE. In conclusion, in male patients with PAPS and SLE, the clinical manifestations were significantly different. Arterial thrombosis was the major cause of functional impairment and permanent organ damage in PAPS. Renal involvement was the major cause of chronic damage in SLE.     

Classification of an intermediate group of patients with antiphospholipid syndrome and lupus-like disease: primary or secondary antiphospholipid syndrome?

OBJECTIVE: (1) To classify an intermediate group of patients (IntAPS) with antiphospholipid syndrome (APS) and lupus-like disease either as primary (PAPS) or secondary APS (SAPS) and to discuss 2 different classifications. (2) To compare patients of a division of rheumatology with either PAPS or SAPS. METHODS: Patients with APS and patients with systemic lupus erythematosus (SLE) followed at the Department of Rheumatology, University Hospital Bichat, Paris, from 1987 to 1996 were analyzed. A chart review and a standardized telephone interview in 1997 completed the data of this study. RESULTS: (1) We found a total of 108 patients with APS: 22 with PAPS, 69 with SAPS, and 17 with IntAPS. The group of IntAPS did not differ from PAPS in any clinical or laboratory signs with the exception of antibodies to dsDNA and to extractable nuclear antigen (ENA). Between IntAPS and SAPS, there were several significant differences in clinical signs of SLE (malar rash, discoid rash, arthralgia) and in laboratory values (leukocytopenia). (2) Comparison of PAPS and SAPS showed statistically significant differences for positive Coombs' test, leukocytopenia, lymphocytopenia, antinuclear antibodies, antibodies to dsDNA and to ENA, and hypocomplementemia. CONCLUSION: The mainstay of the diagnosis of APS is the clinical event of thrombosis or miscarriage in the presence of antiphospholipid antibodies. Less important are laboratory values, which may help to differentiate PAPS from SAPS in order to initiate adequate therapy (e.g., anticoagulation in the first and additional corticosteroids in the second). Patients with IntAPS are more likely to be integrated into the group of PAPS than in the group of SAPS; therefore, special exclusion criteria for PAPS are not appropriate.     

Renal involvement in primary antiphospholipid syndrome.

Our objective was to define the renal involvement in primary antiphospholipid syndrome (APS). We studied 20 patients with primary APS. Fourteen were women, mean age 34.4 years. None met ARA criteria for systemic lupus erythematosus. All patients underwent complete renal function studies. The presence of hypertension was also investigated. Renal disease was found in 5 patients, and was characterized by proteinuria, hypertension and renal failure. Kidney biopsy was performed in these 5 patients, showing thromboses of the microvasculature, mesangiolysis, mesangial interposition, electron lucent subendothelial material and ischemic obsolescence of glomeruli. Arterioles showed luminal narrowing due to medial hypertrophy, mucoid thickening of the intima, thrombosis and fibrosis. We found renal disease in 25% of our patients with primary APS. Biopsy findings were consistent with a thrombotic microangiopathy involving both arterioles and glomerular capillaries.     

Hypertension as the presenting feature of the antiphospholipid syndrome

The antiphospholipid or Hughes syndrome is the association between antiphospholipid antibodies (aPL), venous and arterial thromboses and pregnancy morbidity. Antiphospholipid syndrome (APS) commonly coexists with autoimmune diseases usually systemic lupus erythematosus (SLE), when it is known as secondary APS. When present in isolation it is known as primary APS (PAPS). Although the kidney may be affected in APS, its involvement is perhaps not as well described as that of other organs. Thrombotic microangiopathy (TMA) affecting the kidney has been reported as a manifestation in both primary and secondary APS. This report describes hypertension related to underlying renal TMA as a presenting symptom of APS.     

Emerging minimal-change nephrotic syndrome in a patient with chronic mesangial proliferative lupus nephritis

A 41-year-old Japanese woman with a 25-year history of systemic lupus erythematosus was admitted because of abrupt onset of nephrotic syndrome and acute renal failure. Renal biopsy specimen showed only mild mesangial proliferative glomerulonephritis associated with mesangial deposition of immunoglobulins/complements. No significant immune deposits were found in the glomerular capillary walls, but mild foot process effacement was observed on electron microscopy. Further, two-month corticosteroid therapy improved her massive proteinuria and renal dysfunction, indicating that this patient showed minimal-change nephropathy superimposed on mesangial proliferative lupus nephritis.     

Primary antiphospholipid syndrome associated with malignant hypertension

The antiphospholipid syndrome is defined by the presence of antiphospholipid antibodies and recurrent thrombosis, affecting the venous system more frequently than the arterial one. Renal involvement is only observed in approximately 20-25% of cases, main renal artery thrombosis has been exceptionally described. We report a 39-year-old woman with previous history of recurrent thrombosis diagnosed as primary antiphospholipid syndrome, who presented malignant hypertension in the context of a renal artery thrombosis. She had a high IgG anticardiolipin antibody titre and positive lupus anticoagulant. An isotopic renogram demonstrated asymmetrical activity (60% right vs 40% left kidney). Renal arteriography demonstrated preoclusive thrombosis in the left renal artery. Blood pressure was well controlled by the use of ACE-inhibitor and alpha blockers.     

Antinucleosome antibodies may help predict development of systemic lupus erythematosus in patients with primary antiphospholipid syndrome

Patients with primary antiphospholipid syndrome (PAPS) may evolve to systemic lupus erythematosus (SLE), even many years later. This makes differentiation between primary and secondary antiphospholipid syndrome a difficult task. Studies in murine models of lupus have shown that the development of antinucleosome (anti-NCS) antibodies may occur from the early stages of life. We therefore hypothesize that anti-NCS antibodies could help predict development of SLE in patients with PAPS. We studied anti-NCS antibodies in 18 PAPS patients (15 female, three male), followed for a mean of 11 years to evaluate the potential development of SLE. When PAPS was diagnosed, nine patients were positive for anti-NCS antibodies. Six of them developed clinical manifestations of SLE. In contrast, none of the patients who were negative to anti-NCS antibodies developed it. These findings suggest that anti-NCS antibodies could help predict which patients with PAPS may eventually develop SLE.     

Vascular endothelial growth factor plasma levels in patients with systemic lupus erythematosus and primary antiphospholipid syndrome

The objective of this study was to assess the possible role of vascular endothelial growth factor (VEGF) in the pathogenesis of systemic lupus erythematosus (SLE) and primary antiphospholipid syndrome (PAPS). We studied 28 patients with SLE, 10 patients with PAPS, and 24 healthy controls. VEGF plasma levels were measured by ELISA. Immunolocalization of VEGF was done in renal tissue from SLE patients and cadaveric controls. Our results showed that VEGF plasma levels were increased in SLE patients compared with PAPS and controls. The correlation between clinical manifestations and VEGF levels revealed that SLE patients with renal failure had significantly increased plasma VEGF levels (134.1 + 91.0 pg/ml) compared with SLE patients with normal renal function (42.9 + 19.0 pg/ml), PAPS patients (41.9 + 26.6 pg/ml), and controls (36.2 + 27.0 pg/ml; P < 0.01). Immunostaining showed a strong expression of VEGF in SLE renal tissue samples. Our preliminary results indicate that VEGF is increased in plasma from patients with lupus nephritis and a moderate degree of renal failure and is overexpressed in renal tissue from these patients.     

Nierenmanifestationen bei rheumatischen Erkrankungen

Inflammatory rheumatic diseases other than systemic vasculitides and systemic lupus erythematosus are frequently associated with renal abnormalities, which are clinically less apparent due to their subtle course and impairment of renal function that is often only moderate. These diseases encompass vascular, glomerular, and tubulointerstitial changes. Necrotizing glomerulonephritis in the course of rheumatoid vasculitis influences the prognosis of rheumatoid arthritis. Renal involvement due to AA amyloidosis following long-standing inflammatory joint disease can lead within years to end-stage renal disease, and scleroderma renal crisis in the course of systemic sclerosis can evolve within only days to this outcome. The differential diagnosis of renal abnormalities in a rheumatic patient should include drug-induced renal impairment as well as infection.     

Distribution of two common idiotypes of anticardiolipin antibodies in sera of patients with primary antiphospholipid syndrome, systemic lupus erythematosus and monoclonal gammopathies.

The frequency of two common idiotypes of anticardiolipin antibodies (aCL) was determined in sera from three groups of subjects, patients with systemic lupus erythematosus (SLE), with primary antiphospholipid syndrome (PAPS) and with monoclonal gammopathies (MG), as compared to normal population. The idiotype 1.10, which was derived from a patient with active SLE and antiphospholipid syndrome, was found more frequently among patients with PAPS (10.5%, 10.5% and 22.2% in MG, SLE and PAPS, respectively) than the idiotype H3, which was derived from a human hybridoma monoclonal aCL generated from a healthy subject immunized with tetanus and diphtheria. The latter idiotype was detected in 8.7%, 6.5% and 11.7% of patients with MG, SLE and PAPS, respectively. Incidental findings in this study include a high prevalence of aCL among patients with MG (23%) and a high prevalence of anti-dsDNA antibodies, detected only by a sensitive enzyme-linked immunosorbent assay, among patients with PAPS. Our results indicate that idiotypic diversity exists among aCL derived from different sources. Some of these cross-reactive idiotypes may be more pathogenic than others.     

40-year-old man with primary antiphospholipid syndrome

We report the case o a 40-year-old male patient with "primary antiphospholipid syndrome" who developed ischemic cerebral infarctions and renal microangiopathy with infarction. A review of the literature on renal involvement in the primary antiphospholipid syndrome disclosed the differences from the antiphospholipid syndrome in the systemic lupus erythematosus. We describe the evolution of the patient at eight years, and we emphasize the importance of the treatment with warfarin. Also, we review the pathophysiology of severe secondary arterial hypertension.     

Primary antiphospholipid nephropathy beginning during pregnancy

We describe a 29-year-old pregnant woman at 16 weeks gestation and antiphospholipid antibodies who developed nephrotic syndrome with massive hematuria. Renal biopsy evidenced chronic glomerular lesions of ischemic nature without proliferative changes and immune deposits suggestive of lupus nephritis. Anticoagulation was initiated, along supportive measures, and the patient recovered completely. This case demonstrates that chronic renal lesions of antiphospholipid syndrome may present with marked clinical manifestation including hypertension, massive proteinuria and hematuria, resembling the course of acute thrombotic microangiopathy and/or lupus nephritis.     

Pauci-immune glomerulonephritis associated with primary antiphospholipid syndrome

The antiphospholipid syndrome (APS) is characterized by thrombotic events associated with the presence of antiphospholipid antibodies. Renal involvement is a frequent feature in patients with APS. APS presenting with proteinuria showed that the renal involvement in this syndrome could also be a different form of glomerulonephritis. We describe a rare case report of pauci-immune vasculitis associated with primary APS in the absence of other underlying autoimmune disorders.     

Is HLA class II susceptibility to primary antiphospholipid syndrome different from susceptibility to secondary antiphospholipid syndrome?

To assess whether the major histocompatibility complex (MHC) profile of patients presenting with primary antiphospholipid syndrome (PAPS) is different from that of patients with secondary antiphospholipid syndrome (SAPS), we studied 123 patients, 34 of whom presented PAPS and 35 SAPS due to systemic lupus erythematosus (SLE), 54 SLE patients without antiphospholipid syndrome (APS), and 166 controls. HLA-DRB1 and DQB1 alleles were typed using amplified DNA hybridized with sequence-specific primers. Compared to controls, PAPS patients exhibited a nonsignificantly increased frequency of DR53-associated alleles, and SAPS patients presented an increased frequency of HLA-DRB1*03 alleles (corrected P = 0.05). In addition, HLA-DRB1*03 alleles were over-represented in SAPS patients presenting anticardiolipin antibody (aCL) (Pc = 0.02), in SLE patients as a whole (Pc < 0.0001), and in SLE patients without APS (Pc = 0.02). The frequency of aCL among SLE patients presenting or not HLA-DRB1*03 alleles was closely similar. A trend to an increase in the frequency of the DQB1*0604 allele (14.3 versus 4.2%, P = 0.03) and of the DQB1*0302 allele (31.4 versus 12.7%, P = 0.01) was observed in SAPS. Taken together, these results indicate that the association of SAPS with HLA-DRB1*03 is due to the association with SLE and is not due to aCL, and suggest that the HLA class II profile of PAPS is different from that of SAPS.     

Leg ulcers in the primary antiphospholipid syndrome. Report of a case with a peculiar proliferative small vessel vasculopathy

Leg ulcers are associated with antiphospholipid antibodies in patients with systemic lupus erythematosus. They may also occur in patients with primary antiphospholipid syndrome(PAPS). Histopathologic findings at the edges of the ulcers may give insight into their pathogenesis. In a patient with PAPS and a leg ulcer, a biopsy of the ulcer's edge revealed a peculiar small vessel nodular proliferation in the upper and lower dermis. There was mild mixed inflammatory infiltrate in the surrounding connective tissue, a few vessels with fibrin thrombi, and some with fibrin deposition within their walls. A review of the literature revealed similar findings in other skin ulcers associated with lupus anticoagulants. This suggests peculiar pathogenetic mechanisms that may be akin to those responsible for antiphospholipid arterial vasculopathy.     

The impact of gender on clinical manifestations of primary antiphospholipid syndrome

The objective of the study was to determine the clinical differences at diagnosis and during follow-up between male and female patients with primary antiphospholipid syndrome (PAPS). We analysed 68 patients, 30 males and 38 females diagnosed and followed between 1990 and 2003. Patients with antiphospholipid syndrome associated with systemic lupus erythematosus at onset and during follow-up were excluded. The mean age at diagnosis was 31.4 +/- 11 years in males and 35.7 +/- 11 years in females (NS). The follow-up after diagnosis was 8.7 +/- 3.1 years in males and 9.2 +/- 2.9 years in females (NS). We did not find significant differences between the two groups with respect to venous and arterial thrombosis. However, in female patients, stroke was more prevalent than in male patients (12/38 versus 3/30, P = 0.03). In contrast, we found a significant prevalence of severe gastrointestinal complications in male compared to female patients (7/30 versus 1/38, P = 0.009). One male patient died due to catastrophic antiphospholipid syndrome. This study suggests that clinical course in patients with PAPS may be different with significant prevalence of central nervous system involvement in females and gastrointestinal involvement in males. Factors such as accelerated atherosclerosis, hormones, related to gender could be the explanation of these findings.     

Nierenmanifestationen bei rheumatischen Erkrankungen

Inflammatory rheumatic diseases other than systemic vasculitides and systemic lupus erythematosus are frequently associated with renal abnormalities, which are clinically less apparent due to the subtle course and the often only moderate impairment of renal function. These abnormalities include vascular, glomerular and tubulointerstitial changes. Renal manifestations in the course of rheumatoid arthritis influence the prognosis of the disease. Renal involvement due to AA amyloidosis following long-standing inflammatory joint disease can lead slowly, over years, to end-stage renal disease. A scleroderma renal crisis in the course of systemic sclerosis can potentially result in end-stage renal disease within days. The differential diagnosis of renal abnormalities in a rheumatic patient should include drug induced renal impairment as well as infection.