Evidence for a beneficial effect of plasma exchange in severe active lupus nephritis

0955-3886/89 $3.00+0.00 Copyright 0 1989 Pergamon Press plc

Transfus. Sci. 1989; 10:69-75 Printed in Great Britain. All rights reserved

Evidence for a Beneficial Effect of Plasma Exchange in Severe Active Lupus Nephritis Randolph D. Christen Gerald Keusch Jiirg Gmiir Hans Ruedi Burger Ulrich Binswanger Paul Frick n We examined the impact of plasma exchange (PE) on the long-term course of active lupus nephritis in 7 female patients (age 2148 yr, mean 32). Before starting PE all patients had renal failure (serum creatinine 347 f 194urnol/L) proteinuria (6.2 f 3.4 g/24 h) and hematuria. Renal biopsies performed before PE in 5 cases showed a membranoproliferative glomerulonephritis in 3 cases, a moderate focal and segmental glomerulonephritis in one case, and a diffuse proliferative glomerulonephritis in one case. All specimens showed active lesions. PE was carried out with the Haemonetic Model 50 blood cell separator. The volume of plasma removed (2.3-4 L per run) was replaced by human plasma-protein fraction (PPL, SRK-Human). 7-135 runs (mean 36) were performed over a period of 13-1619 days (mean 359). At the time of PE all patients received prednisone in combination with azathioprine or cyclophosphamid. The course of renal failure was analyzed by plotting the reciprocal values of the serum creatinine vs time. The mean period of analysis before and after initiation of PE was 15.8 and 30.3 months, respectively. Before PE renal function was deteriorating rapidly in all 7 patients. After From the Medical Clinic and Department

PE renal function improved in 3 patients, stabilized in 1 patient and deteriorated at a slower rate compared to the pre-treatment period in 2 patients. No beneficial effect of PE on renal function was observed in 1 patient. We conclude that PE combined with immunosuppressive drugs may have a favorable impact on the long time-course of lupus nephritis. n

INTRODUCTION

Lupus Nephritis can usually be controlled with a combination of steroids and immunosuppressive drugs. 1-3The role of plasma exchange (PE)in the treatment of lupus nephritis has not been firmly established. No large randomized trials have been published to date comparing plasma exchange (PE) and immunosuppression with immunosuppression alone. Uncontrolled studies have shown a variable effect of PE in lupus nephritis.“a We report on the long time follow-up of 7 female patients with severe active lupus nephritis who received PE therapy. In order to assess the effect of PE on the long time-course of lupus nephritis, we compared the rates of renal function loss before and after PE. A significant decrease in the rate of renal function loss and an improvement of all immunological findings was noted.

of Pathology,

University Hospital of Ziirich, Switzerland. Received and Accepted 12/88.

69

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Transfus. Sci.

PATIENTS

Vol. 10, NO. 1

AND METHODS

7 female patients (age 21-48 yr, mean 32 + 12) who fulfilled the criteria of the American Rheumatism Association for the diagnosis of lupus erythematosus entered the study. Extrarenal manifestations were present in all 7 patients at various time before starting PE, including arthritis in 5 patients (Nos 1, 2, 4, 5, 7), skin rush in 2 patients (Nos 1 & 4), alopecia in 2 patients (Nos 6 & 7), pericarditis in 1 patient (No. 3), pleural effusion in 1 patient (No. 2) and CNS manifestations in3 patients (Nos. 1,5, 7). Renal findings of the 7 patients are summarized in Table 1. Before starting PE all patients had clinical evidence of severe active lupus nephritis with rapidly deteriorating renal function: The mean serum creatinine at the beginning of pre-PE follow up was 118.7 It 68.1 umol/ L and increased to 347 f 194pmol/L immediately before starting the PE course (pre-PE follow up 15.8 f 12.2 months). Except two (patient Nos 6 & 7) all patients had proteinuria in the nephrotic range. Hematuria (47 + 31 red blood cells per high power field) was present in all patients at onset of PE. Immunological parameters were consistent with disease activity; (normal range): C3 complement 0.45 + 0.15 g/L (l&1.9), C,complement0.12 + O.O7g/L (0.14-0.3), antibodies to DNA 73.4 f 43 (O-20) u/L, circulating immune complexes Raji cell test 454 f 280pg/mL (<25), C,dbinding test 14 + 19% (O-2). Renal biopsy was performed before PE in 5 patients and showed a membranopro-

Table 1.

liferative glomerulonephritis in 3 cases (patient Nos 1, 2 & 5), a moderate focal and segmental proliferative glomerulonephritis in one case (patient No. 4) and a diffuse proliferative glomerulonephritis in one case (patient No. 3). All specimen showed active lesions. Before starting PE all patients received prednisone, 10-50 mg/day for 3 days to 260 weeks. 4 patients (Nos 1,4,5 & 7) received high dose intravenous methylprednisone pulse therapy (0.5-l g given 3 to 6 times) during the last 8 days prior to PE-therapy. In 6 patients prednisone was combined with an immunosuppressive drug as follows: 4 patients (Nos 4,5, 6 & 7) received azathioprine 25-100 mg/day and 2 patients (Nos 1 and 2) cyclophosphamide 50-100 mg/day. During and after PE prednisone therapy was continued (5-60 mg) in all patients in combination with azathioprine or cyclophosphamide. In one patient (No. 3) azathioprine was started at onset of PE. PE was performed using the Haemonetics Model 50 Blood Cell Separator. Volume of plasma removed (2.3-4L per run) was replaced by human protein fraction (PPL, SRK-Human). 7-135 runs (36 + 45) were performed over a period of 13-1619 days (359 f 583). During the first 1-2 weeks of the PE-course, runs were performed 3-4 times a week, then, with decreasing frequency, depending on the clinical situation, twice a week or weekly. The 3 patients (Nos 1, 2 & 3) with improving renal function during the PE-course were exchanged during 2-5 weeks. Patient No. 4 with unchanged renal function after

Renal Findings in 7 Female Patients Prior to Plasma Exchange

Patient No.

Serum-Creatinine (bmol/L)

Proteinuria (ti24 hl

Biopsy (WHO classification)

130 154 fiti

12.3 9 4.5 7.0

III IV

:

350 468

3.0 3.9

No BiopsyIvperformed

7

673

3

No Biopsy performed

Mean f SD

347 + 194

6.24? 3.39

1

2 3 4

Iv Iv

PE and Active Lupus Nephritis

starting PE, had a PE-course of 50 weeks. The remaining 3 patients (Nos 5, 6 & 7) who eventually progressed to endstage renal failure (ESRF) were treated with PE during the whole period of renal function deterioration, till ESRF was reached, that is 17, 58 and 1 month respectively. Renal function, proteinuria, hematuria and the immunological parameters (CB, Cd, anti-DNA antibody titers, circuwere lating immuno-complexes) documented l-48 months (mean 15.8 + 12.3) before PE-therapy and l-88 months (30.3 + 31.4) after beginning PE-therapy. For evaluation of proteinuria, hematuria and the immunological findings, the values at onset of PE were compared with the corresponding value of least disease activity during the post-PE follow-up period. The changes of renal function before and after starting PE were analyzed by plotting the reciprocal values of the serum creatinine vs time, as was originally proposed by Rutherford et ~1.~ The slope of linear regression analysis, correlation coefficient and standard error of estimate were calculated before and after starting PE. The significance of each regression analysis was tested by an analysis of variance procedure.‘O The difference of the two slopes for each patient was analyzed by paired Student t-test.” To test the null hypothesis-that the average slopes before PE and after PR were equal-the difference in average slopes was tested by paired sample t-test. The differences in laboratory values (proteinuria, hematuria, Cs, Cq, anti-DNA antibodies circulating immunocomplexes) before and after PE were tested by paired sample t-test. In addition nonparametric rank sum testing was performed, when outliners were present or variances were unequal. For regression analysis and testing on Olivetti M-24 personal computer and Statgraph software were used. RESULTS The 7 patients were followed-up for a mean of 24.4 months (range 148 months) before PE and for a mean of 30.3

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months (range l-88) during and after PE. Extrarenal manifestations improved during PE-therapy in all patients, except patient Nos 1 and 7. Patient No. 7 had persisting arthralgias and a thalamic lesion, probably due to vasculitic changes, which developed during the PE-course. Moreover this patient showed no renal response to PE. Another patient (No. 1) had a grand ma1 seizure during her 5-week course of PE. Follow-up of renal function pre-PE, post-PE and the duration of the period of PE are shown in Fig. 1 (patient Nos 1,2 & 3), and Fig. 2 (patient Nos, 4, 5, 6 & 7). After starting PE renal function improved in 3 patients (Nos 1, 2 & 3) and continued to improve even after completion of the PE course. At the end of follow-up serum creatinine ranged from 121 to 147 in this group (patient Nos 1,2 & 3). In one patient (No. 4) renal function remained unchanged since the beginning creatinine PE-therapy (serum of 190 umol/L). The remaining 3 patients (Nos 5, 6 & 7) had progressive renal function deterioration during the period of PE-therapy and eventually progressed to ESRF. In 2 patients (Nos 5 & 6) the rate of renal function loss was decreased during the PE course as compared to the pre-PE rate of renal function loss. The delay in onset of ESRF by PE was estimated by extrapolating regression lines relating L/creatinine with time before and after PE, ESRF was assumed to be present at the serum creatinine level of 900umoVL. In patient Nos 5 and 6 calculated delay in onset of ESRF by PE was 16 and 49 months respectively. In patient No. 7 PE was not found to decrease the rate of renal function loss. The testing of pre-PE regression (reciprocal serum creatinine level vs time) was significant for all 7 patients. The post-PE regression were not significant for patients Nos 1, 2 & 4. Post-PE regressions were less significant because renal function tended to be more stable during this period as compared to the pre-PE period. Thus the correlation coeficient relating time and L/serum creatinine is weaker in the post-PE regression

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Tran.$zs. Sci.

Vol. 10, No. 1

Follow

up pre-PE

Begin

PE

Follow up post-PE (months 1

( months 1

Figure 1. Long time-course of renal function (serum creatinine, pmol/L) before and after starting plasma exchange (PE) in patient Nos 1,2 and 3. Each horizontal bar indicates the duration of the period of PE.

TOO-

Follow

up pre-PE

(months

Begin PE

1

Follow

up post-PE

( months 1

Figure 2. Long time-course of renal function (serum creatinine, umol/L) before and after starting

plasma exchange (PE)in patient Nos 4,5,6 and 7. Each horizontal bar indicates the duration of the period of PE.

and the corresponding regression analysis less significant. After PE all patients had a reduced L./serum creatinine-slope, reaching statistical significance in patients Nos 1, 3,

5 & 6 (Fig. 3). The mean L/creatinineslope for all 7 patients was -9.06 f 10.9 (L/creatinine per month) pre-PE and -0.79 + 3.27 post-PE, respectively. This difference in mean slope pre-PE vs post-

PE

The following complications were observed during PE: Herpes zoster (patient No. 31, herpes labialis (patient No. 6), gastroenteritis (patient Nos 5 a 6) and thrombocytopenia (patient No. 7). The later complication was found to be mainly due to systemic lupus erythematodes as bone marrow smears showed an active megakaryopoiesis and platelet associated antibodies were found.

3l*

2-

and Active Lupus Nephritis 73

l-

0,

. .

. .

DISCUSSION

-6t

I

Pre-PE

Port-

PE

Figure 3. Progression of renal function deterioration before and after starting plasma exchange. Slope of regression of reciprocal serum creatinine level (l@ol/L) vs time (l/creatinine per month) is represented pre-PE and post-PE for each patient. Number indicates individual patients. *Indicates significant differences by Student’s t-test.

PE is significant by nonparametric rank sum test :P < 0.01, one tailed MannWhitney Test). After starting PE proteinuria was significantly reduced in all 7 patients from 6.2 + 3.4 g/24 h pre-PE to 2.9 & 3.7 post-PE (P
Efforts to determine the relative efficacy of various therapeutic approaches including PE to lupus nephritis have been hampered by the highly variable nature of this disease and the small number of patients involved in many contemporary studies. Prednisone and azathioprine or cyclophosphamide have been evaluated in the treatment of lupus nephritis.13 Renal function was better preserved with low dose prednisone plus intravenous cyclophosphamide as compared to high dose prednisone alone.2 PE is used in combination with immunosuppressive drugs in the treatment of lupus nephritis. PE alone has not been recommended in this disease because antibody depression by PE alone was followed by overshoot synthesis in animals.12 The beneficial effect of PE and immunosuppressive drugs has been described in several uncontrolled studies.“B A diminution of histologic activity with resolution of crescentic lesions after a course of PE and immunosuppressive drugs was observed in 7 of 8 patients.6 In contrast to these results of uncontrolled studies a randomized trial of PE in mild systemic lupus erythemato-

Table 2. Immunological Parameters Pre- and Post-PE Pre-PE

Post-PE

Significance

Cj-complement (1.0-l .9 g/L) C,-complement (0.14-0.3 g/L) Antibodies to DNA (O-20 IU/L)

0.5 + 0.2 0.12 It 0.07 74_+43

0.8 + 0.3 0.25 + 0.10 22+ 18

P
Circulating Immunocomplexes Raji cell test (25 @mL) C,, Binding test (O-2%)

454 + 280 14f 19

59+42 If0

P < 0.0005

P< 0.05

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sus has shown the same degree of clinical improvement in both PE and control groups.13 Monthly PE for SLE with diffuse proliferative glomerulonephritis and stable renal function has been shown in a randomized trial of 12 patients to reduce disease activity, number of admissions to hospital and dosage of steroid and immunosuppressive therapy.14 The two later randomized studies focus on patients with mildly active disease. As far as we know, no randomized trial has evaluated the role of PE in severe lupus nephritis with rapidly deteriorating renal function. This study differs from many previous publications on the treatment of lupus nephritis in patient selection. All our patients had lupus nephritis with rapidly deteriorating renal function, whereas several other studies focus on patients with a more stable course of lupus nephritis. 415~12~13 We observed a beneficial effect of PE and immunosuppressive drugs on the long time-course of lupus nephritis. The rate of renal function loss was significantly reduced after starting PE. Moreover proteinuria, hematuria and the immunological parameters (C,, C4, anti-DNA antibodies, CIC) improved significantly after PE. We found no correlation relating serological findings with either the initial rate of renal function loss or the response to treatment. This is in contradiction with other studies.5J”17 During PE a few patients developed minor infections. No life-threatening complications of PE were observed. Thus PE is a safe procedure. We conclude that PE has a beneficial effect on the long time-course of lupus nephritis with rapidly deteriorating renal function. Even if renal function continues to deteriorate, the onset of ESRF may be delayed by PE. As long as no large scale randomized clinical trials are carried out, the value of PE in the treatment of severe active lupus nephritis will continue to depend on uncontrolled studies like ours.

REFERENCES 1. Felson DR, Anderson J: Evidence for the superiority of immunosuppressive drugs and prednisone over prednisone alone in lupus nephritis: results of a pooled analysis. N Engl I Med 1984; 311:1528-1533. 2. Austin HA, Klippel JH, Balow JE, Le Riche NGH, Steinberg AD, Plotz PH, Decker JL: Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl I Med 1986; 314:614619. 3. Balow JE, Austin HA, Muenz LR, Joayce KM, Antonovych TT, Klippel JH, Steinberg AD, Plotz PH, Decker JL: Effect of treatment on the evolution of renal abnormalities in lupus nephritis. N Engl I Med 1984; 311:491-495. 4. Verrier JJ, Cumming RH, Bucknall RC, Asplin CM: Plasmapheresis in the management of actute lupus erythematosus. Lancet 1976; 1:709-711. 5. Verrier JJ, Cumming RH, Bacon PA, Evers J, Fraser D, Bothamley J, Tribe CR, Davis CR, Davis P, Hughes GRV: Evidence for a therapeutic effect of plasmapheresis in patients with systemic lupus erythemasus. Q 1 Med 1979; XLVIII: 555-576. 6. Leaker BR, Becker GJ, Dowling JP, Sincaid-Smith PS: Rapid improvement in severe lupus glomerular lesions following intensive plasma exchange associated with immunosuppression. Clin Nephrol 1986; 25:2-S-244. 7. Lockwood CM, Worlledge S, Path FRC, Nicholas A, Cotton C, Peters DK: Reversal of impaired splenic function in patients with nephritis or vasculitis (or both] by plasma exchange. N Engl I Med 1979; 300:524-530. 8. Lewis EJ: Plasmapheresis for the treatment of severe lupus nephritis; tmcontrolled observations. Am / Kidney Dis 1982; II: 182-187. 9. Rutherford WE, Blondin J, Miller JP, Greenwalt AS, Vavra JD: Chronic progressive renal disease: rate of change of serum creatinine concentration. Kidney Znt 1977; II:62-70. 10. Zar JR: Simple linear regression, in Zar JR (ed): Biostatistical Analysis, Vol. 16. 1974, pp. 198-227. 11. Zar JR: Comparing simple linear regression equations, in Zar JR (ed): Biostatistical Analysis vol. 17. 1974, pp. 228-235. 12. Balow JE: Role of immunosuppressive agents in plasmapheresis. Plasma Thex Transfus Technol 19833 4~189.

PE and Active Lupus Nephritis

13. Wei N, Huston DP, Lawley TJ, Steinberg AD, Klippel JH, Hall RP, Balow JE, Decker JL: Randomised trial of plasma exchange in mild systemic lupus erythematosus. Lancet 1983; I: 17-21. 14. Clark WF, Lindsay RM, Cattran DC, Chodirker WB, Barnes CC, Linton AL: Monthly plasmapheresis for systemic lupus erythematosus with diffuse proliferative glomerulonephritis; a pilot study. CMA 11981; 125:171-174. 15. Levinsky RJ, Cameron JS, Soothill JF: Serum immune complexes and disease

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activity in lupus nephritis. Luncet 1977; 1564. 16. Cairns SA, London A, Mallick NP: The value of three immune-complex assays in the management of SLE. Clin Exp Zmmunol 1980; 273:40. 17. Hurd ER, Jasin HE, Gilliam JN: Correlation of disease activity and C,,-binding immune complexes with the neutrophil inclusions which form in the presence of SLE sera. Clin Exp Zmmunol 1980; 40:283.