Kidney International, Vol. 66 (2004), pp.

24112415

Mycophenolate therapy of SLE membranous nephropathy

Mycophenolate therapy of SLE membranous nephropathy. Background. The immunosuppressant mycophenolic acid (MMF) has been used successfully to manage proliferative forms of systemic lupus erythematosus (SLE) glomerulonephritis (GN) World Health Organization (WHO) Classes III and IV. Less is known about MMF treatment of membranous SLE GN (WHO Class V, SLE MN). Methods. We report our experience with MMF therapy in 13 consecutive SLE MN patients participating in a prospective study of risk factors for SLE are. Results. Baseline characteristics were: mean age 33 14 SD years, female/male ratio 11/2, Caucasians 7, African Americans 5, Oriental 1, serum creatinine 1.02 0.41, and mean 24-hour urine protein (P)/creatinine (C), ratio 5.1 4.1. Initial therapy was prednisone mean dose 31 17 mg/day, and MMF mean dose 1173 746 mg/day. Therapy also featured interventions to achieve renoprotection and proteinuria reduction. At 6 months of therapy, complete or partial remission was achieved in 10 of 13 patients. At most recent follow-up visit (mean follow-up 16 8 months), 9 of 13 patients were in complete remission, and in 11 of 13 patients, urine P/C ratio was <0.8. During follow-up, serum creatinine either stabilized or was improved. The only serious complication during 208 patient months of follow-up was histoplasma pneumonia in 1 patient. Conclusion. These promising results suggest that moderate dose MMF in combination with renoprotective/antiproteinuria therapy warrants further study in the management of SLE MN.

The role of mycophenolic acid (MMF) as an effective immunosuppressant was established in randomized clinical trials comparing MMF to azathioprine to prevent kidney transplant rejection [13]. There is a growing body of evidence that MMF is also effective in systemic lupus erythematosus glomerulonephritis (SLE GN). However, almost all of those studies treated proliferative

Key words: mycophenolate therapy, systemic lupus erythematosus, SLE nephropathy. Received for publication January 2, 2004 and in revised form April 7, 2004, and June 4, 2004 Accepted for publication June 30, 2004
C

2004 by the International Society of Nephrology

forms of SLE GN [47] [abstract; Ginzler, Arth Rheum 48(Suppl):S647, 2003]. The largest previously reported experience involving MMF therapy in SLE MN is the 10 patients in the Ginzler study who completed the 6 months of protocol MMF therapy [abstract; Ginzler, Arth Rheum 48(Suppl):S647]. Our work complements that of Ginzler, who studied the effects of higher dose MMF (3000 mg/ day). We studied lower dose MMF (mean about 1200 mg/day) with emphasis on concurrent renoprotective/antiproteinuric therapies. It is generally agreed that SLE MN is less aggressive than the proliferative forms of SLE GN, but there is not general agreement regarding its management. Some recommend no therapy of SLE MN except for that needed to control nonrenal SLE manifestations [810]. The rationale is that SLE MN is generally indolent and can undergo spontaneous remission, similar to that of idiopathic membranous nephropathy (MN) [11, 12]. Arguing against nontreatment of SLE MN are the long-term follow-up studies showing that by 7 to 10 years of sustained proteinuria, about 25% of SLE MN patients progress to endstage renal disease (ESRD) [13, 14]. The mechanisms of SLE MN progression to ESRD may involve the nephrotoxicity of proteinuria [15, 16], or transformation to a proliferative form of SLE GN [17]. A further risk of untreated SLE MN is that chronic heavy proteinuria leads to hyperlipidemia and atherosclerosis, and to a hypercoagulable state and thromboses [16]. Currently, most authors favor treatment of SLE MN [13, 1719]. Glucocorticoids (steroids) were the drugs rst used to treat SLE MN [9, 11, 19, 20]. However, only about 35% of these steroid-treated SLE MN patients experienced remission [12, 1719] [abstract; Radhakrishnan J et al, J Am Soc Nephrol 4:284], a frequency similar to that observed in untreated idiopathic MN [21]. This suggests that steroid therapy is of limited effectiveness in inducing and sustaining remission of proteinuria in SLE MN. Better results in the therapy of SLE MN have been obtained by combining steroids with immunosuppressive drugs, such as alkylating agents, azathioprine, or cyclosporine [13, 14, 18]. MMF may have advantages

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Spetie et al: Mycophenolate therapy of SLE membranous nephropathy

over these drugs with regard to safety and efcacy. Specically, MMF has a better side effects prole than alkylating agents, better immunosuppressive effects than azathioprine without increasing the toxicity, and is free of the nephrotoxicity associated with cyclosporine therapy. Indeed, the results of our study, although uncontrolled, suggest that moderate-dose MMF therapy when combined with steroids and antiproteinuria/renoprotective therapies is safe and effective in inducing and sustaining remission of proteinuria in SLE MN.

METHODS The study patients are the rst 13 patients with biopsyproven SLE MN [22] enrolled in the Ohio SLE Study (OSS), which is the clinical component of the National Institutes of Health Program Project titled Genetic and Clinical Risk Factors for Human SLE nephritis. The OSS is a prospective longitudinal study of SLE patients with 4 or more American College of Rheumatology criteria for SLE [23] and recurrently active SLE (2 or more SLE relapses requiring an increase in therapy in the previous 3 years) or persistently active disease (4 months of active SLE despite therapy consisting of at least 20 mg prednisone daily). The goal of the OSS is to identify risk factors for SLE are. None had received ACE inhibitor (ACEI), angiotensin receptor blocker (ARB), or immunosuppressive therapy prior to the onset of their nephropathy. MMF was begun usually at 500 mg twice daily and then increased to 750 or 1000 mg twice daily by 2 to 4 weeks, if tolerated. These doses were patterned after our original report of MMF use in SLE nephritis [4]. The prednisone dose was chosen to control extrarenal SLE manifestations. Renoprotective/antiproteinuria therapies used are those previously described [15, 16]. In brief, the blood pressure goal was a sitting systolic blood pressure in the 120 mm Hg or less, if tolerated. All patients received either an ACEI, an ARB, or both, after the onset of their nephropathy. Statin therapy was begun if the lowdensity lipoprotein (LDL) cholesterol was >100 mg/dL. Furosemide was used as needed for edema control, blood pressure control, or both. Diuretic therapy was generally reduced as nephrotic proteinuria subsided. Dietary therapy consisted of counseling to achieve a daily protein intake of approximately 0.8 g/kg ideal body weight + 1 g of dietary protein for each gram of proteinuria/24 hr, Na intake of <120 mEq/day, and avoidance of excessive uid intake (>2.0 L/day) [16]. Two patients received chronic warfarin therapy because of previous venous thrombosis. Data analysis Mean values are shown SD. The statistical tests used are shown in relationship to the data. The denitions

used in our analysis include: nephrotic-range proteinuria, urine protein (P)/creatinine (C) ratio 3.0; complete remission, urine P/C ratio <0.5 (upper limits of normal for urine P/C ratio = 0.25 in the study laboratory, The Ohio State University Clinical Laboratories) partial remission, 50% or greater reduction of nephrotic-range proteinuria and to a urine P/C ratio <3.0. The minimal duration of remission was the 2-month period between consecutive follow-ups. In almost all instances, the urine P/C ratios were calculated from measurements made on samples submitted as 24-hour collections. This should be more accurate than spot urine P/C ratio to estimate 24-hour proteinuria rate, and adjusts for differences in body size among study participants [16].

RESULTS Table 1 shows the individual patient baseline characteristics. Our cohort is typical of SLE MN patients previously described [24]. Their age tended to be less than 35 years, 10/13 had nephrotic-range proteinuria, 11/13 were female, and elevated serum creatinine level occurred in a minority of the patients. Mean study follow-up was 16 8 months. Table 2 shows details of individual therapy. All patients remain on MMF except patient 3. She participated in the Ginzler study, where she received MMF 3000 mg daily for 6 months, at which time it was stopped. The current median MMF therapy is 1500 mg/day. Initial prednisone therapy was 60 mg daily in patients 5 and 11 to treat associated SLE enteritis. In most patients the prednisone dose was tapered at the rate of 10 mg each 2 to 4 weeks. During follow-up, patients 1, 2, 3, and 5 each experienced a minor extrarenal are that required a temporary increase in prednisone therapy. Patient 2 also experienced a moderate renal are (increase in urine P/C ratio from <0.5 to 1.8), which has resolved with increased therapy. With respect to renoprotective/antiproteinuric therapies, Table 3 shows that the blood pressure goal was achieved in 10/13 patients. Each received an ACEI, ARB, or both. Statins were used in 10/13 patients. All received low-dose aspirin therapy. Most patients were compliant with the goals of avoiding a high salt, protein, and uid intake [25], as shown in Table 2. Figure 1 shows the changes in proteinuria in each of the study patients since the start of MMF therapy. All but patient 8 showed reductions in proteinuria. By 6 months of therapy, 10 of 13 experienced complete (N = 8) or partial (N = 2) remission. By the most recent follow-up, 11 of 13 have achieved complete (N = 9) or partial remission (N = 2) (Table 3). Patient 8 has not shown improvement in proteinuria; however, she has been inconsistently compliant with her treatment regimen. The others have been consistently compliant.

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Table 1. Baseline characteristics of the study patients Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 Mean SD

Age years 43 23 23 22 26 28 49 24 21 60 51 37 20 33 14

Sex M F F F F F F F F F F F M

Racea C C A A A C C A C C O C A

BMIb 22.5 23.0 42.6 50.2 30.4 33.9 42.0 27.4 37.3 27.8 16.1 25.8 23.8 31.0 9.72

S cr c mg/dL 1.1 2.0 0.7 1.1 1.6 1.2 1.1 0.8 0.77 0.6 0.67 0.68 1.0 1.02 0.41

Urine

P/Cd

C3/C4e mg/dL 79/18 40/6 189/44 67/11 67/17 73/15 81/13 58/14 76/6 142/20 44/3 53/7 69/8 80 41/14 10

a DS-DNAf + + + + + + +

UAg >20/>5/5 8/4/0 1/0/0 >20/>5/6 1/0/0 20/5/2 1/0/0 2/0/1 4/0/0 1/0/3 2/0/0 0/0/0 0/0/0

WHO Class V V V V V V V V V+III V V V V

4.5 7.4 4.0 9.6 16.5 3.4 1.0 4.4 4.3 1.7 2.0 4.2 4.0 5.1 4.1

C, Caucasian; A, African American; O, Oriental. Body mass index (weight, kg/height, m2 ). c Serum creatinine. d Urine protein/creatinine ratio based on 24-hour urine collection. e Complement level C3, normal 80 mg/dL; C4, normal 12 mg/dL. f Antidouble-stranded DNA antibody; +, present; , absent. g Red cells per high-power eld/acanthocytes per high-power eld/cellular casts (WBC or RBC casts per slide).

Table 2. Therapy of the study patients MMFa Patient Initial mg/day Current Prednisone mg/day Initial Current 10 15 5 10 25 0 10 20 15 6 15 15 10 12 7 Other Rxb As, R, S A,As,B,D A,As,D,S D,R,W A,As,C,D,R,S A,As,D,S A,As,D,S A,As A,As,S,W A,As,S, A,As,S A,As,S A,As,S Blood pressurec Systolic 126 10 118 13 133 17 119 20 133 17 106 23 116 10 132 22 125 4 129 8.5 113 1.4 112 118 5 122 8 24-hour urined

Diastolic Na mEq/day Urea g/day Volume mL/day 82 6 78 8 81 12 72 11 95 11 72 9 81 3 81 8 83 4 74 4 77 1 68 71 6 78 7 127 43 154 58 130 53 145 136 79 171 49 170 34 388 86 113 36 122 33 154 102 23 159 75 9.7 1.5 8.3 2.5 5.4 2.5 3.0 6.5 4.2 6.8 1.2 13.8 3.0 12.3 8.5 7.1 1.2 6.6 1.5 11.4 7.0 1.2 8.2 3 1883 405 972 318 1181 306 1036 1021 728 1904 444 2126 392 2014 386 1471 272 1936 32 2480 825 272 1571 551

1 250 1500 40 2 1000 2000 20 3 3000 0 10 4 2000 2000 20 5 1000 1000 60 6 1000 1500 40 7 1000 1000 20 8 1000 1500 15 9 1000 500 40 10 500 500 10 11 1000 1000 60 12 2000 2000 40 13 500 2000 30 Mean SD 1173 746 1269 665 31 17
a b

Initial, MMF dose 2 months after start of MMF; current, MMF dose at manuscript submission. Other therapy during follow-up: A, ACE inhibitor; As, aspirin 81 mg daily; D, diuretic; C, dihydropyridine calcium channel blocker; D, diuretic; R, angiotensin receptor blocker; S, statin; W, warfarin. c Mean of the blood pressure measured at each 2-month visit. d Mean of the values measured generally each 2 months during follow-up; patient 4 submitted one 24-hour urine collection; patient 8 consistently submitted urine collections that were less than 24-hour collection (e.g., 8- to 12-hour collections). Her values are not shown.

In no instance was it necessary to decrease MMF because of leukopenia, thrombocytopenia, or anemia. Patient 10 had mild diarrhea on MMF 750 mg twice daily. The diarrhea cleared by decreasing MMF to 500 mg twice daily. The only serious complication was that patient 9 developed histoplasmosis pneumonia, requiring intubation and ventilatory support. She may have been exposed to histoplasmosis on her college campus where she encountered an excavation site daily and Canadian goose droppings. She recovered completely, but remains on long-term itraconazole therapy.

DISCUSSION The present study shows that therapy with MMF, prednisone, and renoprotective/antiproteinuria agents was associated with relatively rapid and marked proteinuria reduction in 11/13 of our study cohort. Although spontaneous remission of nephrotic-range proteinuria is seen in SLE MN, it occurs in a minority of patients, and generally occurs over years of follow-up [11, 12], not within months of the onset of therapy, as observed in our cohort. Thus, we suggest that the relatively prompt improvement uniformly seen in our patients was the result of their therapy, not spontaneous remission.

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Spetie et al: Mycophenolate therapy of SLE membranous nephropathy Table 3. Current clinical status of each study patienta Blood pressure Follow-up #of months 30 28 20 18 18 18 14 12 12 6 4 6 24 16.15 8.22

Patient 1 2 3 4 5 6 7 8 9 10 11 12 13 Mean SD
a

Systolic 124 122 138 108 136 100 130 146 128 126 112 112 118 123 13

Diastolic 82 82 84 70 92 60 82 94 86 72 78 68 62 78 1

S Cr 0.9 0.9 0.8 0.7 1.6 0.8 1.0 1.1 0.8 0.8 0.7 0.6 1.02 0.90 0.25

Urine P/C 0.088 0.426 0.668 0.068 3.585 0.200 0.426 5.150 0.638 0.188 0.307 0.381 0.162 0.95 1.56

C3 64 90 144 171 73 85 126 30 108 124 70 93 96 98 37

C4 13 12 27 26 16 20 20 8 20 19 9 11 14 17 6

a DS-DNA + +

UA 0/0/0 2/1/0 1/0/0 3/2/0 0/0/0 3/0/0 0/0/0 2/1/1 3/1/1 0/0/0 >20/0/0 0/0/0 2/1/0

Duration of MMF treatment and months of follow-up are the same for all patients except patient #3. She received MMF therapy for only 6 months (see Results).

Urine protein/creatinine ratio

15

African American (N = 5) % in Remission Caucasian (N = 7)

100 Complete or partial Complete 50

10

Oriental (N = 1)

0 0 10 20 Follow-up study, months 30

0 0 10 Follow-up study, months 20

Fig. 1. Sequential changes in urine protein/creatinine ratio in the study cohort during study follow-up.

Fig. 2. Kaplan-Meier estimates of the probability of a complete remission or the composite of a complete or partial remission during follow-up in the study.

The extent to which our cohorts improvement is attributable to MMF, the other therapies they received, or the combination, is not clear. However, it seems unlikely that prednisone alone played a major role in the rapid proteinuria reduction. As discussed earlier in the paper, steroids alone are relatively ineffective in inducing and sustaining remission of SLE MN nephrotic syndrome [11, 12]. Our patients antiproteinuria therapies likely contributed to proteinuria reduction; however, it seems unlikely that these therapies alone were responsible for the observed marked proteinuria reductions. Consistent with this interpretation are the previous studies of antiproteinuria therapy, showing that generally, proteinuria reductions of about 50% can be expected [16]. Also relevant is the placebo-controlled trial of ACEI therapy in IgA nephritis, an immune complex disease similar to SLE GN [26]. In the Praga study, ACEI therapy was effective in reducing proteinuria, but it did so slowly and only partially over about 2 years of follow-up.

In light of the above, it seems likely that steroid and antiproteinuria therapy together cannot totally account for the improvement in our patients. Therefore, we postulate that MMF therapy, through its immunosuppressive and renoprotective effects [15], played a major role in achieving the marked proteinuria reductions. The median MMF dose in our cohort (1500 mg/day) is less than the MMF goal dose in the Ginzler study (3000 mg/day) [abstract; Ginzler, Arth Rheum 48(Suppl):S647,]. Nevertheless, most of our patients have achieved suppression of proteinuria, as well as SLE immunologic and inammatory phenomena based on the serial changes in C3, C4, antidouble-stranded DNA antibodies, and urine sediment. Also, our patients complete or partial remission rate at 6 months of therapy (10 of 13) compares favorably with that of the Ginzler study (7 of 10 patients). Miller et al [27] reported reduction in proteinuria in only 50% of their patients with idiopathic MN, treated with MMF for at least 6 months. Also, Kapitsinou et al

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[28] recently reported results less successful than ours with the use of MMF in patients with SLE nephropathy. Their results, which show less favorable response to MMF, might be explained by their patients having previously failed other immunosuppressive therapies. Thus, prior therapy should be taken into account in the design of future trials of MMF therapy in SLE MN. With regard to the duration of MMF therapy, our expectation is that treatment with MMF would not be indenite, but rather follow our SLE nephritis protocol, which is to maintain therapy for 12 months beyond the induction of complete remission, then taper the therapy. CONCLUSION The results of the Ginzler study and ours suggest that MMF is effective therapy in SLE MN. Our study suggests further that when MMF is combined with renoprotective/antiproteinuria therapies, moderate dose MMF therapy is sufcient. A large-scale trial of MMF therapy in SLE MN to test this hypothesis is warranted. ACKNOWLEDGMENTS
Collaborating investigators: The authors gratefully acknowledge the collaboration of Amy Aziz, M.D., Naseer Chaudry, M.D., Joseph Flood, M.D., Linda Gray, M.D., Kevin Hackshaw, M.D., Shereen Hashmi, M.D., Anwarul Kabir, M.D., Seth Kantor, M.D., Catherine Lee, M.D., Michael Mishkind, M.D., Robert Rice, Ph.D., Kevin Schlessel, M.D., Marvin Thomas, M.D., Ronald Whisler, M.D. This work was supported by NIH grants PO1 DK 55546 and MO1 RR00034. Reprint requests to Lee A. Hebert, M.D., The Ohio State University Medical Center, 1654 Upham Dr., Room N210, Columbus, OH 43210 1250. E-mail: hebert.1@osu.edu

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