Dextran sulphate cellulose columns for the treatment of nephrotic syndrome due to inactive lupus nephritis
Shoichiro Daimon1,
Tsutomu Saga1,
Miho Nakayama1,
Yumi Nomura2,
Hajime Chikaki2,
Kazushi Dan2 and
Ichiro Koni3
1 Department of Internal Medicine,
2 Division of Blood Purification, Maizuru Kyosai Hospital, Maizuru and
3 The Second Department of Internal Medicine, School of Medicine, Kanazawa University, Kanazawa, Japan
Correspondence and offprint requests to:
Dr Shoichiro Daimon, Department of Internal Medicine, Maizuru Kyosai Hospital, Hama 1035, Maizuru 625-8585, Kyoto, Japan.
Keywords: dextran sulphate cellulose column; nephrotic syndrome; systemic lupus erythematosus
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Introduction
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The kidney is one of the major target organs of systemic lupus erythematosus (SLE). Although in recent years, the advent of immunosuppressive therapy has contributed to the prevention of renal functional deterioration in patients with SLE [13], diffuse proliferative lupus nephritis (DPLN), a frequent form of lupus nephritis, has a poor prognosis and a refractory nephrotic state frequently develops. In recent years, low-density lipoprotein apheresis (LDL-A) using dextran sulphate cellulose columns (DSCC) has been reported to be an effective tool for the treatment of some types of steroid-resistant nephrotic syndrome due to focal glomerular sclerosis, minimal change nephrotic syndrome or membranous nephropathy [4,5]. Because of its negatively charged characteristics, DSCC also has a high affinity to anti-DNA antibodies, and adsorption of anti-DNA antibodies (DNA-A) using DSCC has been adopted for the treatment of active lupus nephritis [6]. The difference between DSCC for LDL-A and that for DNA-A is the pore size on the dextran sulphate cellulose beads packed in DSCC, which are smaller for DNA-A [7].
We report a case of nephrotic syndrome due to DPLN which emerged after disease activity was suppressed by intensive therapies in which, despite the lack of any apparent effect of immunosuppressive therapy, it was possible to mitigate the nephrotic state during DNA-A and LDL-A using DSCC.
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Case report
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A 23-year-old woman who had been diagnosed as having SLE and had consulted another hospital for 3 years was transferred to our hospital on 21 February 1997 because of rapid deterioration of renal function and oliguria. On admission to our hospital, physical examination disclosed anasarca, temperature of 36.8°C and blood pressure of 160/100 mmHg, and auscultation of the chest revealed moist rales. Laboratory investigations revealed serum creatinine 5.3 mg/dl, urea nitrogen 124.4 mg/dl, total protein 4.1 g/dl, albumin 1.6 g/dl, sodium 139.0 mEq/l, potassium 4.0 mEq/l, CRP 0.4 mg/dl, white blood cell count 13500/mm3 with 10.0% lymphocytes, haemoglobin 7.7 g/dl, platelet count 11.7x104/mm3, IgG 521 mg/dl, IgA 53 mg/dl, IgM 124 mg/dl, ASO 80 IU/ml and rheumatoid factor was
25 IU/ml (normal range 10002060 for IgG, 115440 for IgA, 74330 for IgM,
240 for ASO and
25 for rheumatoid factor). C3, C4 and CH50 levels were 20 mg/dl, 4 mg/dl and 19.5 U/ml, respectively (normal range 50109 mg/dl for C3, 1147 for C4 and 3045 for CH50). Circulating immune complexes (C1q) were 1.9 µg/ml (normal range
2.9). Anti-DNA antibodies and anti-double-stranded (ds) DNA antibodies were
100 IU/ml and 244.9 IU/ml (normal range
7 for anti-DNA antibodies, <20 for anti-dsDNA antibodies). Anti-cardiolipin antibodies (IgM) and (IgG) were 2.9 and 0.5 (normal range <1.0 for IgM and <1.0 for IgG). Anti-glomerular basement membrane antibodies and anti-neutrophil cytoplasmic antibodies were not detected. On the fifth hospital day, renal biopsy was performed. Four of 22 glomeruli were sclerosed, and other glomeruli showed moderate to severe mesangial proliferation with hypercelluarity. Capillary walls were greatly thickened and showed a wire loop appearance. Fibrous or fibrocellular crescents were seen in 11 glomeruli. DPLN (WHO Class IVc) was diagnosed.
From the day she was transferred to our hospital haemodialysis was initiated. As shown in Figure 1
, after treatment with methylprednisolone pulse therapy (MPSL), plasmapheresis and DNA-A, serological activity was markedly suppressed and renal function recovered from the anuric state. Finally, it was possible to discontinue haemodialysis after a total of 27 sessions over a 85-day period. Although subsequently, renal function was maintained and serological activity suppressed, a nephrotic state (urinary protein 3.66.0 g/day) emerged and anasarca and hypoproteinaemia worsened. From the 126th hospital day, we performed LDL-A using DSCC (Suflux: Kanegafuchi Chemical, Osaka, Japan as the plasma separator and Liposorba 15 LA: Kanegafuchi Chemical, Osaka, Japan as the LDL absorber). Between 2000 and 3000 ml of plasma were treated in each LDL-A and a total of 12 sessions of LDL-A were performed. After the initiation of LDL-A, urinary protein excretion decreased gradually and reached a non-nephrotic level (23 g/day). We discontinued LDL-A, after which urinary protein again increased rapidly. From the 229th hospital day, DNA-A using DSCC (Suflux as the plasma separator and Selesorb: Kanegafuchi Chemical, Osaka, Japan as the anti-DNA antibody absorber) was initiated. As shown in Figure 1
, urinary protein excretion again decreased gradually and during this therapy, immunosuppressive therapy was switched from mizoribine to cyclosporin A (CsA). As shown in Table 1
, after the discontinuation of DNA-A, urinary protein again increased, but remained below the nephrotic range. Subsequently, the patient has been treated at our hospital as a stable out-patient.

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Fig. 1. Clinical course of the patient. Abbreviations: PE, plasmapheresis; MPSL, methylprednisolone pulse therapy; CYC, cyclophosphamide; MZ, mizoribine, CSA; cyclosporin A, PSL; prednisolone, DNA-A; absorption of anti-DNA antibodies, LDL-A; low- density lipoprotein apheresis, TCH; total cholesterol, Cr; creatinine, HD; hemodialysis, anti-DNA ab; anti-DNA antibodies. TCH during DNA-A or LDL-A was measured before each therapy session.
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Discussion
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Lupus nephritis is a frequent severe complication of SLE. Although in recent years, the prognosis of lupus nephritis has improved with immunosuppressive therapy [2,3], DPLN has a poor prognosis. Although plasmapheresis was reported to be an effective tool for the treatment of severe lupus nephritis [8], a large-scale, prospective randomized trial demonstrated no improvement in the clinical outcome of lupus nephritis by the addition of plasmapheresis [9]. In recent years, DNA-A has been reported to be a potentially effective technique to suppress the disease activity of SLE without severe complications [6], but despite the effect of DNA-A on removing anti-DNA antibodies, the long-term prognosis has not yet been reported to improve.
In the present case, we could achieve improvement of renal function by suppressing disease activity with intensive treatment, which included MPSL, plasmapheresis and DNA-A, allowing haemodialysis to be discontinued 3 months later. Although 1028% of patients with lupus nephritis who require haemodialysis recover renal function [10], and in some cases spontaneous remission occurs [11], renal functional improvement may be attributable to these therapies in this case. Despite the suppression of disease activity serologically and histologically by the therapies mentioned above, the nephrotic state persisted and required other treatment. In DPLN, the nephrotic state presents frequently and hyperlipidaemia develops as a consequence. In addition to nephrotoxicity [12], high levels of LDL have undesirable effects on blood rheology [13] and viscosity [14], and LDL-A is currently performed not only to prevent the progression of coronary atherosclerosis in patients with primary hyperlipidaemia [15], but also to improve the peripheral circulation by ameliorating blood rheology and viscosity in patients with arteriosclerotic obstruction [16]. Furthermore, LDL-A has been reported to be an effective tool for the treatment of some kinds of steroid-resistant nephrotic syndrome due to focal glomerular sclerosis, minimal-change nephrotic syndrome or membranous nephropathy [4,5].
Dextran sulphate, which has negatively charged characteristics, has a high affinity for anti-DNA antibodies, anticardiolipin antibodies and LDL. In DSCC, a large number of dextran sulphate cellulose beads are packed, and DSCC for DNA-A has a smaller size of pores on beads than those in DSCC for LDL-A. Because of the difference in molecular size between LDL and anti-DNA antibodies, DNA-A has more than two-fold selectivity for adsorbing anti-DNA antibodies over LDL in comparison with LDL-A [7], but from the standpoint of LDL adsorption, DNA-A and LDL-A may have almost the same potential. In the present case, we performed DNA-A and LDL-A, which resulted in comparable effects on the reduction in total cholesterol levels (LDL-A: from 214304 mg/dl to 94124 mg/dl, DNA-A: from 290386 mg/dl to 107135 mg/dl) and urinary protein excretion. Dextran sulphate resembles heparan sulphate as a polyanion, and heparan sulphate has a pivotal role in the charge-dependent permeability of the glomerular basement membrane [17]. Although the mechanisms of DSCC in the reduction of proteinuria in patients with lupus nephritis are not clear, it is possible that antibody binding to dextran sulphate in DSCC prevents antibody binding to heparan sulphate in the glomerular basement membrane, which contributes to the reduction of proteinuria [18]. In this case, however, reduction of proteinuria was recognized when anti-DNA antibody titres were already decreased, so it is possible that unknown factors, other than anti-DNA antibodies which bind to dextran sulphate, contributed to the reduction of proteinuria.
CsA is reported to have an anti-proteinuric effect in glomerular diseases by its haemodynamic and immunological effects and by direct action on the permselectivity of the glomerular basement membrane [19]. There are also many reports on the efficacy of CsA in patients with nephrotic syndrome due to lupus nephritis [20], and severe hypercholesteroaemia is an inhibiting factor for CsA in the treatment of nephrotic syndrome [21]. In the present case, administration of CsA was initiated during lipid-lowering therapy by DSCC and administration of pravastatin, and despite the discontinuation of the therapy with DSCC, urinary protein excretion was maintained within the non-nephrotic range. Although CsA seems to exert an anti-proteinuric effect, it is possible that this effect could not be obtained without lipid-lowering therapy with DSCC. Although the impact of the nephrotic state on the prognosis of patients with lupus nephritis is not clear [22], and it is difficult to distinguish the efficacy of one therapy from another because of the simultaneous administration of multiple therapies in this case, the outcome in this patient would probably have been much poorer if DSCC had not been administered.
Further investigation is necessary to elucidate the mechanisms of DSCC on urinary protein excretion, and the high cost of this therapy is a practical problem. Nevertheless, therapy with DSCC may be an effective tool, not only in cases with active SLE, but also in those with inactive SLE with a refractory nephrotic state.
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Received for publication: 8. 2.99
Accepted in revised form: 23. 6.99