Endstage renal failure in primary antiphospholipid syndrome—case report and review of literature

N. A. Dayal and D. A. Isenberg1

Charing Cross Hospital, Rheumatology, London and
1 University College London, Rheumatology, London, UK

SIR, We report the case of a 53-yr-old lady of Greek-Cypriot origin who presented in 1987 with recurrent migraine-like headaches, which were treated with simple analgesia, and a history of four miscarriages. In addition she complained of Raynaud-like phenomena and some recurrent mouth ulcers. She had no arthralgia or other mucocutaneous symptoms. Except for one of the patient's siblings, who had two miscarriages, there was no family history of systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS).

General examination revealed an overweight female who was hypertensive (162/95). Livido reticularis was present on her arms. There was no malar rash or synovitis. Fundoscopy revealed grade II hypertensive retinopathy. Urine analysis revealed protein and blood; urine microscopy confirmed haematuria. Investigation of the hypertension including CT scan of the adrenals was normal.

Initial investigations showed the haemoglobin to be 11.9 g/dl with a normal white cell count, platelets were 200x109/l and erythrocyte sedimentation rate (ESR) 80 mm/h. Urea was 9.2 mmol/l and creatinine was 171 mmol/l; urine dipstick showed proteinuria (+++); [51Cr]EDTA (ethylenediaminetetraacetic acid) clearance was measured at 69 ml/min; and 24-h protein was 0.22 g.

Antinuclear antibody (ANA) was weakly positive (1:20), and her DNA Crithidia test was negative. Testing for extractable nuclear antigens (ENA) revealed a weakly positive anti-Ro antibody, but anti-La antibodies were negative.

Further investigation revealed an abnormal clotting screen with a prolonged activated partial thromboplastin time (APTT). Lupus anticoagulant was detected. The anticardiolipin antibodies were markedly elevated [IgG 30.0 GPL U/ml (normally <9.0); IgM 22.6 GPL U/ml (normally <11.0)]. Although nifedipine was started at 10 mg and increased to 20 mg b.d., the blood pressure remained elevated.

In 1991 her renal function deteriorated with the 51[Cr]EDTA clearance reduced to 53 ml/min. She also remained hypertensive and was started on enalapril at 2.5 mg daily. Renal biopsy showed cortical scarring and glomerosclerosis associated with small vessel pathology and microthrombi.

Four years later, repeat renal biopsy showed features that were persistent, with small vessel disease as well as microthrombi present. There were no features consistent with an immune complex glomerulonephritis. The blood pressure remained chronically elevated and was resistant to treatment with atenolol, nifedipine and alpha-blockers. Frusemide was added and enalapril was increased to 5.0 mg to control the blood pressure, after which the proteinuria disappeared. The renal function continued to deteriorate (by 1997 the 51[Cr]EDTA had fallen to 25 ml/min).

In 1999 she experienced two episodes of absences with associated memory loss and confusion. Magnetic resonance imaging (MRI) revealed changes consistent with ischaemic damage with areas of established infarction. At this stage anticoagulation was started with warfarin.

Later that year her renal function deteriorated further (urea 15 mmol/l and creatinine 220 mmol/l, 51[Cr]EDTA was 15 ml/min). Antiphospholipid antibody levels remained elevated (IgG 68.9, IgM 38.9). [51Cr]EDTA clearance was further reduced to 17 ml/min and dialysis was commenced.

In this patient's initial presentation, severe hypertension was prominent with almost normal renal function. The hypertension became progressively worse and has needed aggressive and multiple antihypertensive medications.

Antiphospholipid syndrome is characterized by recurrent clinical events of thrombosis or fetal loss and an antiphospholipid antibody such as the lupus anticoagulant or anticardiolipin antibody [1]. Renal involvement in primary APS (PAPS) can be acute or may present with insidious and progressive decline in renal function and hypertension.

The renal morphology in patients with PAPS is variable, ranging from mild mesangial hypercellularity to severe endocapillary damage, thrombotic microangiopathy and lesions similar to the haemolytic uraemic syndrome. Various other histopathological features have also been described in other studies, including intrarenal vascular lesions occurring in the absence of glomerulonephritis [2, 3]. They may give rise to severe or malignant hypertension. These lesions are seen in primary and secondary APS. Thrombosis of the renal artery trunk is rare. Patients with circulating lupus anticoagulant may also be at an increased risk of renal vein thrombosis [4], although this is more usually attributed to a coexisting nephrotic syndrome. In this patient the renal biopsies showed cortical scarring and glomerosclerosis associated with small vessel pathology and microthrombi.

In our previous study of 20 patients with PAPS alone compared with 25 patients with SLE and PAPS and 275 patients with SLE alone, endstage renal failure was not observed [5]. This case illustrates that it may rarely occur in an insidious and progressive fashion. Chronic renal impairment and associated reduced glomerular filtration rate (GFR) is a common finding in most studies. The incidence ranges from 56% [6] to 100%[7]

Reviewing the literature, endstage renal failure (ESRF) is a rare complication of PAPS. Only three studies [3, 5, 8] have been published in which ESRF occurred in PAPS patients (see Table 1Go). In one retrospective study of 78 patients only one patient developed ESRF [5], but this patient had associated SLE, which may have contributed to the ESRF. Erkan et al. [8] in a prospective study of 39 patients also described only one patient with ESRF. The commonest histological finding in these patients was microangiopathic haemolytic anaemia. In the third study [3] there were two cases of ESRF, the causes of which were not known.


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TABLE 1. Summary of findings from the literature review

 
Our patient's initial presentation was sustained hypertension, which over the past 12 yr has been difficult to treat and has needed multiple antihypertensives. Chronic sustained hypertension was present in between 83.3 and 100% of patients with PAPS in a number of previous studies [3, 5, 6].

Nephrotic syndrome, which is a common finding in APS associated with SLE, is unusual in patients with PAPS. Our patient's maximum protein excretion was 0.22 g/24 h. The incidence of proteinuria in biopsy-proven PAPS-associated renal involvement is variable. Three studies [57] all had a single case of nephrotic syndrome and two other studies [3, 6] had four and two cases, respectively.

Unusually, our patient developed haematuria approximately 5 yr after initial diagnosis. It is not a common feature of renal disease in patients with PAPS. In previously published data [37] the incidence of haematuria was low and in some series was not reported as a feature.

In summary, renal impairment and the ensuing hypertension is a well-documented complication of PAPS. The hypertension can be difficult to treat, as the exact nature of the renal pathology is uncertain. Good control of systemic hypertension and adequate anticoagulation (if evidence of microthrombi is present) may prevent progression to ESRF, although this is rarely reported in PAPS.

Notes

Correspondence to: N. A. Dayal. E-mail: dayalnimesh{at}hotmail.com Back

References

  1. Anderson RA, Khamasta MA, Ordis-Ros J et al. The primary antiphospholipid syndrome: Major clinical and serological features. Medicine (Baltimore) 1989;68:366–74.[ISI][Medline]
  2. Jouquan J, Pennec Y, Mottier D et al. Accelerated hypertension associated with lupus anticoagulant and false positive VDRL in systemic lupus erythematosus. Arthritis Rheum 1986;29:147.[ISI][Medline]
  3. Amigo MC, Garcia-Torres R, Robles M, Bochiccho T, Reyes PAI. Renal involvement in primary antiphospholipid syndrome. J Rheumatol 1992;19:1181–5.[ISI][Medline]
  4. Mintz G, Acevedo-Vazquez E, Guittierrez-Espinoza G, Avelar-Garnica F. Renal vein thrombosis and inferior vena cava thrombosis in systemic lupus erythematosus. Arthritis Rheum 1984;27:539–44.[ISI][Medline]
  5. Moss KE, Isenberg DA. Comparison of renal disease severity and outcome in patients with primary antiphospholipid syndrome, antiphospholipid syndrome secondary to systemic lupus erythematosus (SLE) and SLE alone. Rheumatology 2001;40:863–7.[Abstract/Free Full Text]
  6. Vlachoyiannopolous PG, Kenellopolous, Tektonidou M and Moutsopoulos. Renal involvement in antiphospholipid syndrome. Nephrol Dial Transplant 2001;16(Suppl. 6):60–2.[Free Full Text]
  7. Griffiths MH, Papadaki L, Nield GH. The renal pathology of primary antiphospholipid syndrome: a distinctive form of endothelial injury. Q J Med 2000;93:457–67.
  8. Erkan D, Yazici Y, Sobel R, Locksin MD. Primary antiphospholipid syndrome: functional outcome after 10 years. J Rheumatol 2000;27:2817–21.[ISI][Medline]
  9. Nochy D, Daugas E, Droz D et al. The intrarenal vascular lesions associated with primary antiphospholipid syndrome. J Am Soc Nephrol 1999;10:507–18.[Abstract/Free Full Text]
Accepted 5 February 2003





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