Rheumatology 2001; 40: 863-867
© 2001 British Society for Rheumatology
Original Papers |
Comparison of renal disease severity and outcome in patients with primary antiphospholipid syndrome, antiphospholipid syndrome secondary to systemic lupus erythematosus (SLE) and SLE alone
Centre for Rheumatology, Department of Medicine, University College Hospital, London W1P 9PG, UK
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Abstract |
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Objective. To ascertain the clinical presentation, histopathology and outcome of renal involvement in patients with primary antiphospholipid syndrome (PAPS), antiphospholipid syndrome secondary to systemic lupus erythematosus (SAPS) and systemic lupus erythematosus alone.
Method. A retrospective analysis was undertaken of 20 patients with PAPS, 25 patients with SAPS and 275 patients with systemic lupus erythematosus to ascertain the frequency and pattern of renal involvement.
Results. Renal involvement was found most frequently in patients with SAPS, in whom it occurred in 68% of patients. Renal disease was equally common in patients with PAPS and systemic lupus erythematosus alone where it was seen in 30% of patients. Patients with systemic lupus erythematosus most frequently presented with nephrotic syndrome due to glomerulonephritis, whereas those with PAPS and SAPS were more likely to present with hypertension and reduced glomerular filtration rate. No patients with PAPS developed end-stage renal failure compared with 5.9% of patients with SAPS and 16.9% of patients with systemic lupus erythematosus alone; 23.5% of patients with SAPS died compared with 15.7% of patients with systemic lupus erythematosus alone and no patients with PAPS.
Conclusion. Renal involvement is a major feature of both PAPS and SAPS, where renal thrombosis frequently leads to reduced glomerular filtration rate and hypertension. One-third of patients with systemic lupus erythematosus alone develop glomerulonephritis leading to renal disease which most commonly presents with nephrotic syndrome. Patients with PAPS were less likely to develop end-stage renal failure or die during the follow-up period.
KEY WORDS: Systemic lupus erythematosus, Antiphospholipid syndrome, Renal disease.
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Introduction |
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The incidence of renal involvement in systemic lupus erythematosus (SLE) varies widely between different series, ranging from 29 to 53% [1, 2]. This is partly due to differing definitions of abnormal renal function, but is also dependent on how extensively the patient is investigated. Renal disease appears to be less common in primary antiphospholipid syndrome (PAPS) than in SLE, but may occur in around 25% of patients [3]. However, most studies are of small numbers of patients with a short length of follow-up, and there may be many more patients with unrecognized subclinical renal involvement.
Renal damage in SLE is primarily due to immune complex-mediated glomerulonephritis. However, in PAPS, vascular thrombosis can affect any part of the kidney, leading to diverse effects, depending on the size, type and site of the vessel involved. Patients with SLE and secondary antiphospholipid syndrome (SAPS) can develop kidney damage due to a combination of both processes [4]. The differing pathological lesions may lead to different patterns of presentation of renal disease in each of the three groups and this may in turn influence the severity of renal disease and the outcome.
At the Centre for Rheumatology, University College London (UCL) we have undertaken a retrospective analysis of all patients under follow-up with a diagnosis of PAPS, SAPS or SLE without APS followed for a period of up to 22 yr. We have studied the frequency and severity of renal involvement in each of the three groups, as well as the clinical presentation, pathology and outcome.
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Patients and methods |
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A retrospective analysis was performed of all patients registered at the Centre for Rheumatology (UCL) with a diagnosis of PAPS, SLE with SAPS and SLE alone. The information was obtained from our database and from patients’ case notes. All patients with SLE registered between 1 January 1978 (when the lupus database was established) and 1 July 2000 were included. Patients with PAPS have been identified in the last 10 yr. Patients with SLE fulfilled the 1982 American College of Rheumatology's (ACR) revised criteria for the classification of SLE [5]. Patients with drug-induced or discoid lupus were excluded. All patients with PAPS or SAPS had a persistently positive test (two measurements 6 weeks apart) for either immunoglobulin G (IgG) anticardiolipin antibodies (with or without IgM anticardiolipin antibodies) or lupus anticoagulant, together with at least one thrombotic event or a history of three or more miscarriages. Disease duration was defined as the time interval from diagnosis of SLE or APS (in cases of SAPS the time of diagnosis of SLE was used) to 1 July 2000. Patient years of follow-up were defined as the time from registration at the Centre for Rheumatology (UCL) to 1 July 2000. Renal disease duration was defined as the time interval between the first documentation of renal involvement to the end of the follow-up period.
Renal disease was defined as varying combinations of the following: urine protein >0.5 g/24 h, creatinine clearance <60 ml/min [measured by ethylene diamine tetraacetic acid (EDTA) creatinine clearance test], oedema requiring diuretic therapy, diastolic blood pressure >90 mmHg and serum creatinine >124 mmol/l [6]. Hypertension alone was not assumed to be due to renal damage. Clinical presentation at the time of first documented renal involvement was categorized as follows: nephrotic syndrome (protein >3.5 g/24 h); nephritic syndrome (haematuria/red cell casts/hypertension); hypertension with reduced glomerular filtration rate (GFR) <60 ml/min. We ascertained the severity and type of renal involvement from renal biopsy results wherever possible. Renal outcome was assessed by analysing the proportion of patients who developed end-stage renal failure (ESRF) requiring dialysis or renal transplantation. Mortality in each of the groups was also analysed. Details of deaths were obtained by discussion with the lead physician caring for the patient at the time of death, from death certification, case notes and post-mortem records.
2 was used to analyse dichotomous variables. Student's t-test was used to analyse continuous variables.
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Results |
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There were 20 patients with PAPS (5% male), 25 patients with SLE and SAPS (no males) and 275 patients with SLE alone (8.4% males). Thirty-seven patients with SLE alone died and four patients with SLE and SAPS died during the follow-up period. Thirty-one (11.3%) patients with SLE alone were lost to follow-up. However, as part of an on-going study at this centre, information has been obtained about the current status of 20 of these patients. Therefore, only 11 cases (4%) are unaccounted for. One (4%) patient with SAPS and renal disease and no patients with PAPS were lost to follow-up. The patient characteristics are presented in Table 1
. Patients with SLE alone and those with SLE and SAPS did not differ with regard to age at diagnosis or disease duration. However, patients with PAPS were diagnosed at a significantly older age and had a significantly shorter disease duration than the other two groups. Renal disease was most frequently seen in those with SAPS, affecting 17 of 25 (68%) in this group. Renal disease was less common in the other two groups, where it affected six (30%) patients with PAPS and 83 (30.2%) patients with SLE. We found no significant difference in frequency of renal disease between males and females in any of the three groups. Patients with PAPS developed renal disease at a significantly older age (39 yr compared with 29.6 yr for patients with SAPS and 29.7 yr for patients with SLE). Renal disease duration was longest in patients with SLE (8.5 yr), followed by SAPS (8.3 yr), and was shortest in patients with PAPS (4 yr). Hypertension was found in >75% of patients in each of the three groups.
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Table 2
shows the details of clinical and pathological findings of patients with renal disease and their outcome. Nephrotic syndrome was the most frequent clinical presentation of renal disease in patients with SLE, accounting for 53 (63.9%) cases. Hypertension and reduced GFR were more common presentations in patients with PAPS and SAPS, accounting for five (83.3%) and eight cases (47.1%), respectively. Only 4.8% of cases of SLE renal disease presented with hypertension and reduced GFR. Eighty-six patients underwent a biopsy out of a total of 106 patients with renal disease. Glomerulonephritis was the histological finding in 98.6% of biopsies of patients with SLE, in 81.8% of those with SAPS, but in none of those with PAPS. WHO grade IV lupus glomerulonephritis was the most common lesion seen in patients with SLE, in whom it was found in 51.4% of cases who underwent a renal biopsy; 27.3% of patients with SAPS who underwent a biopsy had thrombotic renal disease. One patient with SAPS developed both glomerulonephritis and thrombotic renal disease and another patient, who did not undergo a renal biopsy, developed bilateral renal vein thrombosis. All the renal lesions in patients with PAPS were due to thrombosis, two patients developed glomerular capillary thrombosis and the other patient developed thrombotic microangiopathy.
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More patients with SLE alone developed ESRF (16.9%) than in the other groups (5.9% of patients with SAPS and none of those with PAPS), although this did not reach statistical significance; 42.8% of those patients with SLE-related ESRF have undergone renal transplantation. In four of the six patients who underwent renal transplantation, the transplanted kidney has failed. The mean survival of the transplant was 5 yr (range 4–6 yr). In patients with SLE renal disease, 15.7% died, compared with 23.5% of patients with SAPS and none of the patients with PAPS.
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Discussion |
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Renal disease was found in 33.3% of the total cohort of patients with SLE (including those with and without SAPS). This compares with other studies which have found renal disease in 29–53% of patients with SLE [1, 2]. Renal manifestations of APS were barely mentioned in the early studies of this syndrome. However, more recently, the importance of renal involvement in PAPS [7, 8] and SAPS [9] has been recognized. Our study found a particularly high frequency of renal disease in patients with SAPS (68%). Bhandari et al. [10] found anticardiolipin antibodies to be a strong predictor of intraglomerular thrombi in SLE patients with renal involvement and found that this conferred a worse long-term renal outcome. The frequency of renal disease in patients with PAPS (30%) is comparable with that found in a previous study of 20 PAPS patients which found renal involvement in 25% of patients [3].
Our study shows that nephrotic syndrome is the most likely presentation of renal disease in patients with SLE alone. However, patients with PAPS or SAPS are less likely to present with nephrotic syndrome, as shown in previous studies [3, 11], as they most commonly present with hypertension and reduced GFR which can be of insidious onset. The duration of renal disease varied between the three groups and was shortest in patients with PAPS (4.0 yr) and longest in patients with SLE alone (8.5 yr). The short duration of renal disease in patients with PAPS may explain why no patient in this group has yet developed ESRF. A further study with longer follow-up is needed to clarify this issue. Our findings contrast with those of Amigo et al. [3] who found that two of five cases of PAPS with renal involvement developed ESRF requiring dialysis. However, they do not state the duration of renal disease. In a recent study at this centre, renal disease was the primary cause of death in 15.4% of patients with SLE (± SAPS) who died. However, 45.2% of patients who died had renal involvement, compared with 30.2% of patients who survived [12].
We found a relatively low frequency of APS in our cohort of SLE patients (8.3%) compared with other studies. It is unlikely that patients with SAPS have been missed, as our patients are regularly asked specifically about symptoms of APS and are tested annually for the presence of antiphospholipid (APL) antibodies. The frequency of APL antibodies (lupus anticoagulant, anticardiolipin IgG or anticardiolipin IgM) in the SLE cohort without evidence of the clinical APS syndrome was 28.6%.
It was not possible to analyse patient characteristics at the onset of SLE to look for predictors of poor outcome in renal disease due to the retrospective nature of this study, as some of the early data were incomplete. We also recognize that the numbers of patients with SAPS and PAPS were relatively small and ideally we would have liked to have biopsy data on all our patients with presumed renal disease. However, some patients refused to have a biopsy and in other cases our colleagues in the Department of Nephrology were disinclined to biopsy on the grounds that it was unlikely to affect the management of the patient. We have, however, provided all the biopsy data available to us.
Renal disease is a major feature of both PAPS and SAPS, occurring in 30 and 68%, respectively. Renal involvement was found in 30.2% of patients with SLE in the absence of APS. Grade IV glomerulonephritis was the predominant lesion in patients with SLE, whereas patients with PAPS developed small vessel thrombosis. Patients with SAPS developed both glomerulonephritis and thrombosis. The differing pathology in each of the three groups was reflected in the clinical presentation of renal disease. Patients with SLE alone were most likely to present with nephrotic syndrome, whereas patients with PAPS or SAPS presented most frequently with hypertension and reduced GFR. Patients with PAPS and renal involvement seemed to fare better as none developed ESRF and there were no deaths in this group.
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Acknowledgments |
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We gratefully acknowledge the invaluable support of Professor Guy Neild and his colleagues in managing the renal disease in these patients.
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Notes |
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Correspondence to: K. Moss, Centre for Rheumatology, 4th Floor, Arthur Stanley House, 40–50 Tottenham Street, London W1P 9PG, UK
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